Acamprosate is used as an adjunct to comprehensive management programs and psychosocial support to help alcoholics maintain abstinence following ethanol withdrawal. Acamprosate is structurally related to endogenous homotaurine, a structural analogue of gamma-aminobutyric acid (GABA) and the amino acid taurine. In a review of 16 placebo-controlled clinical trials, all but 5 showed a clinically significant difference between acamprosate and placebo regarding the proportion of patients remaining abstinent at the end of the study. Combination therapy with acamprosate and other agents is promising but limited data exists. One study involving combined acamprosate and disulfiram showed that addition of disulfiram improves the efficacy of acamprosate to prevent relapse and maintain abstinence; this conclusion should be approached cautiously given that patients receiving disulfiram were not randomized. Another study combining acamprosate and naltrexone demonstrated that the proportion of patients completely abstinent after the 12-week treatment period was twice that of placebo. The proportion of patients receiving acamprosate and naltrexone alone was also superior to placebo. Currently in progress, the COMBINE study is testing combined acamprosate and naltrexone with behavioral interventions in alcohol dependence. As single therapy, acamprosate offers a better safety profile in comparison to disulfiram or naltrexone. The FDA approved acamprosate in July 2004.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
-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.
During clinical trials with acamprosate at doses of 1332-1998 mg/day, the following centrally-mediated effects occurred in at least 3% of patients receiving acamprosate and more frequently than in patients receiving placebo: anxiety (5-8% vs 6%), depression (4-8% vs 5%), dizziness (3-4% vs 3%), insomnia (6-9% vs 7%), and paresthesias (2-3% vs 2%). Other CNS effects reported in at least 1% of patients during clinical trial evaluation included drowsiness, amnesia, abnormal thinking, tremor, and headache. Infrequent effects (0.1-1%) included seizures, confusion, vertigo, withdrawal syndrome, apathy, suicidal ideation (including suicide attempt and intentional overdose), intentional injury, neuropathic pain, hostility, agitation, neurosis, abnormal dreams, hallucinations, hyperesthesia, and migraine. Rare effects (< 0.1%) included alcohol craving, psychosis, hyperkinesis, twitching, depersonalization, hypersalivation, paranoia, torticollis, encephalopathy, and mania.
During clinical trials with acamprosate at doses of 1332-1998 mg/day, the following gastrointestinal (GI) effects occurred in at least 3% of patients receiving acamprosate and more frequently than in patients receiving placebo: anorexia (2-5% vs 3%), diarrhea (10-17% vs 10%), flatulence (1-4% vs 2%), and nausea (3-4% vs 3%). Other GI effects reported in at least 1% of patients during clinical trial evaluation include abdominal pain, vomiting, dyspepsia, constipation, appetite stimulation, and weight gain. Infrequent effects (0.1-1%) include elevated hepatic enzymes, gastroenteritis, gastritis, dysphagia, eructation, GI bleeding, pancreatitis, rectal hemorrhage, liver cirrhosis, esophagitis, hematemesis, hepatitis, and weight loss. Rare effects (< 0.1%) include melena, peptic ulcer, cholecystitis, colitis, duodenal ulcer, oral ulceration, and hepatic carcinoma.
During clinical trial evaluation of acamprosate, impotence (erectile dysfunction) and libido decrease were reported in at least 1% of patients receiving acamprosate. GU effects reported in 0.1-1% of patients included metrorrhagia, increased urinary frequency, sexual dysfunction (unspecified), libido increase, urinary incontinence, and vaginitis. Rare effects (< 0.1%) included kidney calculus (nephrolithiasis), ejaculation dysfunction, hematuria, menorrhagia, nocturia, polyuria, and urinary urgency. Acute renal failure (unspecified) has been reported in at least 3 patients during non-US post-marketing evaluation of acamprosate. Although serious, no causal relationship has been found and the event was reported as temporarily associated with acamprosate.
During clinical trials with acamprosate at doses of 1332-1998 mg/day, the following dermatologic effects occurred in at least 3% of patients receiving acamprosate and more frequently than in patients receiving placebo: pruritus (3-4% vs 3%) and hyperhidrosis (2-3% vs 2%). Rash (unspecified) was reported in at least 1% of patients during clinical trial evaluation. Infrequent effects (0.1-1%) included acne vulgaris, atopic dermatitis, alopecia, maculopapular rash, xerosis, urticaria, exfoliative dermatitis, vesiculobullous rash, varicose vein, and phlebitis. Psoriasis and photosensitivity were reported rarely (< 0.1%).
During clinical trial evaluation of acamprosate, the following cardiovascular events were reported in at least 1% of patients receiving acamprosate: palpitations, syncope, peripheral vasodilation, hypertension, and chest pain (unspecified). Cardiac effects reported in 0.1-1% of patients included hypotension, sinus tachycardia, hemorrhage, angina, myocardial infarction, and orthostatic hypotension. Rare effects (< 0.1%) included heart failure, mesenteric arterial occlusion, cardiomyopathy, thrombophlebitis, and shock.
During clinical trial evaluation of acamprosate, goiter and hypothyroidism were reported rarely (< 0.1%).
During clinical trial evaluation of acamprosate, the following hematologic and lymphatic system effects were reported in 0.1-1% of patients: anemia, ecchymosis, eosinophilia, lymphocytosis, and thrombocytopenia. Rare effects (< 0.1%) included leukopenia, lymphadenopathy, and monocytosis.
During clinical trial evaluation of acamprosate, peripheral edema was reported in at least 1% of patients receiving acamprosate. Metabolic and nutritional effects reported in 0.1-1% of patients included hyperglycemia, gout, thirst, hyperuricemia, diabetes mellitus, avitaminosis, and hyperbilirubinemia. Rare effects (< 0.1%) included increased alkaline phosphatase, increased creatinine, hyponatremia, and increased lactic dehydrogenase.
During clinical trial evaluation of acamprosate, the following musculoskeletal effects were reported in at least 1% of patients receiving acamprosate: myalgia and arthralgia. Cardiac effects reported in 0.1-1% of patients included muscle cramps (legs). Rare effects (< 0.1%) included rheumatoid arthritis and myopathy.
During clinical trial evaluation of acamprosate, the following respiratory effects were reported in at least 1% of patients receiving acamprosate: rhinitis, increased cough, dyspnea, pharyngitis, and bronchitis. Respiratory effects reported in 0.1-1% of patients included asthma (bronchospasm), epistaxis, and pneumonia. Rare effects (< 0.1%) included laryngismus and pulmonary embolism.
During clinical trial evaluation of acamprosate, the following special senses effects were reported in at least 1% of patients receiving acamprosate: abnormal vision (visual impairment) and dysgeusia. Adverse effects reported in 0.1-1% of patients included tinnitus, amblyopia and hearing loss (deafness). Rare effects (< 0.1%) included ophthalmitis, diplopia, and photophobia.
During clinical trials with acamprosate at doses of 1332-1998 mg/day, the following general effects occurred in at least 3% of patients receiving acamprosate and more frequently than in patients receiving placebo: accidental injury including bone fractures (3-4% vs 3%), asthenia (5-7% vs 5%), and pain (2-4% vs 3%). Other general effects reported in at least 1% of patients during clinical trial evaluation included back pain, infection, influenza, and chills. Infrequent effects (0.1-1%) included fever, malaise, allergic reaction, abscess, neck pain, urinary tract infection, and hernia. Rare effects (< 0.1%) included ascites, facial edema, enlarged abdomen, and sudden death.
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.
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.
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).
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.
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.
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.
Safety and efficacy of acamprosate have not been established in neonates, infants, children and adolescents less than 18 years of age.
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.
For the maintenance treatment of alcohol dependence:
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.
-for use in combination with naltrexone*:
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.
Maximum Dosage Limits:
Maximum dosage limit information is not available.
Maximum dosage limit information is not available.
Safety and efficacy have not been established.
Safety and efficacy have not been established.
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Patients with Renal Impairment Dosing
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.
Bupropion; Naltrexone: (Minor) The administration of naltrexone with acamprosate results in an increase in acamprosate exposure (AUC) by 25% and in peak concentration (Cmax) by 33%. However, acamprosate dosage adjustments are not required.
Naltrexone: (Minor) The administration of naltrexone with acamprosate results in an increase in acamprosate exposure (AUC) by 25% and in peak concentration (Cmax) by 33%. However, acamprosate dosage adjustments are not required.
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.
Acamprosate is administered orally. Protein binding of acamprosate is negligible and the volume of distribution is approximately 72 to 109 L (approximately 1 L/kg). Acamprosate does not undergo hepatic metabolism but is excreted as unchanged drug via the kidneys. The terminal half-life is approximately 20 to 33 hours. A linear relationship exists between creatinine clearance, total apparent plasma clearance and acamprosate half-life.
Affected Cytochrome P450 (CYP450) isoenzymes and drug transporters: None
Acamprosate had no inducing potential on CYP1A2 and CYP3A4, and acamprosate does not inhibit in vivo metabolism mediated by CYP1A2, 2C9, 2C19, 2D6, 2E1, or 3A4. The pharmacokinetic parameters of acamprosate were unaffected when administered with alcohol, disulfiram or diazepam. While co-administration of acamprosate calcium delayed-release tablets with naltrexone led to a 33% increase in the Cmax and a 25% increase acamprosate exposure (AUC), no adjustment of acamprosate dosage is recommended.
The absolute bioavailability of acamprosate is approximately 11% after oral administration. When taken with food, acamprosate peak concentration (Cmax) and exposure (AUC) are reduced by approximately 42% and 23%, respectively. However, no dosage adjustment is necessary and the drug may be given with meals.
The pharmacokinetic profile of acamprosate is not altered in patients with mild to moderate hepatic disease (Child-Pugh A and B) or in alcohol-dependent patients. No adjustment of dosage is needed in such patients.
The pharmacokinetic profile of acamprosate is altered by renal impairment. Peak plasma concentrations (Cmax) were 2- and 4-fold greater in patients with moderate and severe renal impairment, respectively, compared to healthy volunteers. The elimination half-life was 1.8- and 2.6-times that of healthy volunteers in patients with moderate and severe renal impairment, respectively. A dosage reduction is required in patients with moderate renal impairment (CrCl 30 to 50 mL/minute). Patients with severe renal impairment (CrCl less than 30 mL/minute) should not use acamprosate.
The pharmacokinetics of acamprosate have not been evaluated in pediatric patients.
The pharmacokinetics of acamprosate have not been evaluated in elderly patients.