Drug Interactions
Interactions with herbal products have not been established.
The concomitant intake of alcohol and CAMPRAL does not affect the pharmacokinetics of either alcohol or CAMPRAL.
Administration of CAMPRAL with food diminishes its bioavailability compared with administration of the drug in the fasting state. Although dosing may be done without regard to a meal, dosing with meals was employed during clinical trials and is suggested as an aid to compliance in those patients who regularly eat three meals daily.
The pharmacokinetics of acamprosate calcium 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. However, co-administration of CAMPRAL with naltrexone led to a 33% increase in the Cmax and a 25% increase in the AUC of acamprosate calcium. No adjustment of dosage is recommended in such patients.
An open-label study in patients receiving febarbamate, difebarbamate, phenobarbital, meprobamate, or oxazepam, showed that acamprosate calcium could be initiated safely during the acute detoxification phase with these medications.
Other concomitant therapies: In clinical trials, CAMPRAL has been safely administered in combination with antidepressants, anxiolytics, hypnotics and sedatives, and non-opioid analgesics.
In clinical studies, CAMPRAL had no detrimental effects on standard laboratory tests, including tests that evaluated hepatic and renal function.
Acamprosate calcium had no inducing potential on the cytochrome CYP1A2 and 3A4 systems, and in vitro enzyme inhibition studies suggest that acamprosate calcium does not inhibit in vivo metabolism mediated by cytochrome CYP1A2, 2C9, 2C19, 2D6, 2E1, or 3A4.
Information for the Patient
Campral
Dosage and Administration
Placebo controlled studies demonstrated the efficacy of CAMPRAL as an adjunct to counselling. Treatment with CAMPRAL should be part of a comprehensive management program that includes counselling.
Renal impairment (see Recommended Dose and Dosage Adjustment).
In some patients, daily dose could be lowered temporarily for tolerability reasons.
The recommended treatment duration is 1 year.
The recommended dose of CAMPRAL is two 333 mg tablets taken three times daily. Treatment with CAMPRAL should be initiated as soon as possible after detoxification and should be maintained if the patient relapses. Re-detoxification may be required according to clinical judgement.
No dose adjustment is recommended in patients with mild renal impairment (creatinine clearance of 80-50 mL/min). For patients with moderate renal impairment (creatinine clearance of 30-50 mL/min), a dose of one 333 mg tablet taken three times daily is recommended. Patients with severe renal impairment (creatinine clearance of ≤30 mL/min) should not be given CAMPRAL (see Contraindications).
CAMPRAL tablets are enteric coated and should be swallowed whole, not split or crushed or chewed. Although dosing may be done without regard to a meal, dosing with meals was employed during clinical trials and is suggested as an aid to compliance in those patients who regularly eat three meals daily.
Double doses of CAMPRAL tablets should not be taken. If a dose is missed or the patient does not remember whether the dose was taken, he/she should be instructed to take the next dose at the scheduled time.
Adverse Reactions
It is estimated that more than 1.6 million alcohol-dependent patients have been treated with CAMPRAL since market introduction. Although no causal relationship to CAMPRAL has been found, the following serious adverse events have been reported to be temporally associated with CAMPRAL treatment in at least 3 patients and are not described elsewhere in the monograph: acute kidney failure.
Overall, there was no evidence of any negative effect of acamprosate calcium on hematologic or clinical chemistry parameters during the course of clinical trials in alcohol-dependent patients of up to one year in duration.
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.
For studies where adverse events were reported either by worksheet or spontaneously, among the 1749 alcohol dependent patients who received CAMPRAL 1998/2000 mg/day in placebo-controlled trials, 8% discontinued treatment due to an adverse event, as compared to 6% of 1962 patients receiving placebo. Among patients receiving CAMPRAL 1998/2000 mg/day in studies collecting spontaneous adverse events, only diarrhea was associated with the discontinuation of more than 1% of patients. Diarrhea occurred at a higher rate among patients taking CAMPRAL (2%) versus patients taking placebo (<1%).
Frequent: abnormal vision, taste perversion; Infrequent: tinnitus, amblyopia, deafness; Rare: ophthalmitis, diplopia, photophobia.
Frequent: peripheral edema, weight gain; Infrequent: weight loss, hyperglycemia, AST increased, ALT increased, gout, thirst, hyperuricemia, diabetes mellitus, avitaminosis, bilirubinemia; Rare: alkaline phosphatase increased, creatinine increased, hyponatremia, lactic dehydrogenase increased.
Frequent: rash; Infrequent: acne, eczema, alopecia, maculopapular rash, dry skin, urticaria, exfoliative dermatitis, vesiculobullous rash; Rare: psoriasis.
Frequent: myalgia, arthralgia; Infrequent: leg cramps; Rare: rheumatoid arthritis, myopathy.
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.
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.
Rare: goiter, hypothyroidism.
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.
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.
Adverse events associated with CAMPRAL tend to be mild and transient in nature. They are predominantly gastrointestinal or dermatological in nature.
Diarrhoea, and less frequently, vomiting and abdominal pain are the gastrointestinal adverse reaction. Pruritus is the predominant dermatological adverse reaction. An occasional maculopapular rash and rare cases of bullous skin reactions have been reported.
Frequent: rhinitis, cough increased, dyspnea, pharyngitis, bronchitis; Infrequent: asthma, epistaxis, pneumonia; Rare: laryngismus, pulmonary embolus.
Infrequent: anemia, ecchymosis, eosinophilia, lymphocytosis, thrombocytopenia; Rare: leukopenia, lymphadenopathy, monocytosis.
Indications and Clinical Use
The safety and efficacy of CAMPRAL have not been established in the pediatric population.
Forty-one of the 4234 patients in double-blind, placebo-controlled, clinical trials of CAMPRAL were 65 years of age or older. There were too few patients in this age group to evaluate any differences in safety or efficacy in geriatric patients compared to younger patients. 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. (See Warnings and Precautions, Special Populations, Geriatrics (>65 years of age).)
CAMPRAL (acamprosate calcium) is indicated for the maintenance of abstinence from alcohol in patients with alcohol dependence who are abstinent at treatment initiation. Treatment with CAMPRAL should be part of a comprehensive management program that includes counselling.
The efficacy of CAMPRAL in promoting abstinence has not been demonstrated in subjects who have not undergone detoxification and not achieved alcohol abstinence prior to beginning CAMPRAL treatment. The efficacy of CAMPRAL in promoting abstinence from alcohol in polysubstance abusers has not been adequately assessed.
Overdosage
For management of a suspected drug overdose, CPhA recommends that you contact your regional Poison Control Centre. See the eCPS Directories section for a list of Poison Control Centres.
In all reported cases of acute overdosage with CAMPRAL (total reported doses of up to 56 g of acamprosate calcium), the main symptom was diarrhea. No case of hypercalcaemia has ever been reported. A risk of hypercalcemia may be considered in chronic overdosage. Treatment of overdose should be symptomatic and supportive.
Dosage Forms, Composition and Packaging
Each delayed-release, enteric-coated, white, round-shaped tablet with “333” on one side, contains: acamprosate calcium 333 mg. Nonmedicinal ingredients: anionic copolymer of methacrylic acid and acrylic acid ethyl ester, colloidal anhydrous silica, crospovidone, magnesium silicate, magnesium stearate, microcrystalline cellulose, propylene glycol, sodium starch glycolate and talc. Boxes of 84 (12×7 blisters).
Warnings and Precautions
The safety and efficacy of CAMPRAL have not been established in the pediatric population, therefore, acamprosate is not recommended for use in patients under 18 years of age.
No dose adjustment is recommended in patients with mild renal impairment (creatinine clearance of 80-50 mL/min). Treatment with CAMPRAL in patients with moderate renal impairment (creatinine clearance of 30-50 mL/min) requires a reduction of the dose (see Dosage and Administration). Patients with severe renal impairment (creatinine clearance of ≤30 mL/min) should not be given CAMPRAL (see Contraindications).
The safety and efficacy of acamprosate have not been established in patients older than 65 years of age. CAMPRAL is excreted unchanged in the urine, and the elderly are more likely to have decreased renal function. Therefore, care should be taken in dose selection. (See Dosage and Administration.)
CAMPRAL did not produce any evidence of withdrawal symptoms in patients in clinical trials at therapeutic doses. Post marketing data, retrospectively collected, provided no evidence of drug abuse or dependence.
CAMPRAL treatment should only be initiated after detoxification or weaning therapy, once the patient is abstinent from alcohol.
CAMPRAL does not constitute treatment for the withdrawal period.
CAMPRAL does not prevent the harmful effects of continuous alcohol abuse.
Although in controlled studies CAMPRAL has not been shown to impair psychomotor coordination, any psychoactive drug may impair judgment, thinking, or motor skills. Patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that CAMPRAL therapy does not affect their ability to engage in such activities.
The safety of this product for use in human pregnancy has not been established. Acamprosate may be used during pregnancy only after a careful benefit/risk assessment, when the patient cannot abstain from drinking alcohol without being treated with acamprosate and when there is consequently a risk of foetotoxicity or teratogenicity due to alcohol.
Acamprosate calcium has been shown to be teratogenic in rats when given in doses that are approximately equal to the human dose (on a mg/m2 basis) and in Burgundy Tawny rabbits when given in doses that were approximately 3 times the human dose (on a mg/m2 basis). No developmental effects were observed in New Zealand white rabbits at doses up to approximately 8 times the human dose (on a mg/m2 basis).
The findings in animals should be considered in relation to known adverse developmental effects of ethyl alcohol, which include the characteristics of foetal alcohol syndrome (craniofacial dysmorphism, intrauterine and postnatal growth retardation, retarded psychomotor and intellectual development) and milder forms of neurological and behavioural disorders in humans).
In animal studies, acamprosate calcium was excreted in the milk of lactating rats dosed orally with acamprosate calcium. It is not known whether acamprosate calcium is excreted in human milk, therefore, CAMPRAL is contraindicated for use in nursing mothers (see Contraindications).
No dose adjustment is needed in patients with mild to moderate liver impairment (Child-Pugh A and B). No pharmacokinetic study has been done in the severely liver impaired patients (Child-Pugh C), however, physicians should carefully consider the potential risks and benefits of using acamprosate, when the patient cannot abstain from drinking alcohol without being treated with acamprosate.
Suicidality: In controlled clinical trials of acamprosate, adverse events of a suicidal nature (suicidal ideation, suicide attempts, completed suicides) were infrequent overall, but were more common in acamprosate-treated patients than in patients treated with placebo (1.4% vs. 0.5% in studies of 6 months or less; 2.4% vs. 0.8% in year-long studies). Completed suicides occurred in 3 of 2272 (0.13%) patients in the pooled acamprosate group from all controlled studies and 2 of 1962 patients (0.10%) in the placebo group. Adverse events coded as "depression" were reported at similar rates in acamprosate-treated and placebo-treated patients. Because the interrelationship between alcohol dependence, depression and suicidality is well-recognized and complex, rigorous clinical monitoring is recommended in alcohol-dependent patients, including those treated with acamprosate.
Storage and Stability
Keep in a safe place out of the reach of children.
Action and Clinical Pharmacology
Acamprosate calcium 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.
No pharmacokinetic study has been done in the severely liver impaired patients (Child-Pugh C), however, physician should carefully consider the potential risks and benefits of using acamprosate, when the patient cannot abstain from drinking alcohol without being treated with acamprosate.
The pharmacokinetics of CAMPRAL have not been evaluated in a geriatric population. However, since renal function diminishes in elderly patients and acamprosate is excreted unchanged in urine, its plasma concentrations are likely to be higher in the elderly population compared with younger adults.
The volume of distribution for acamprosate calcium following intravenous administration of acamprosate is estimated to be 72-109 liters (approximately 1 L/kg), and the volume of distribution at steady-state is estimated to be 24 liters. The binding of acamprosate to plasma proteins is negligible.
Pharmacokinetic studies of acamprosate were based on acetylhomotaurine determination in urine and plasma.
Cross-study comparison of CAMPRAL at doses of 2×333 mg TID indicated similar pharmacokinetics between alcohol-dependent subjects and healthy subjects.
The absolute bioavailability of CAMPRAL after oral administration is about 11%. Steady-state plasma concentrations of acamprosate calcium are reached within 5 days of dosing. Steady-state peak plasma concentrations after CAMPRAL doses of 2×333 mg tablets TID average 350 ng/mL and occur at 3-8 hours post-dose. Coadministration of CAMPRAL with food decreases bioavailability by 20% compared with its administration in the fasting state. This decrease is not clinically significant and no adjustment of dose is necessary.
Acamprosate calcium is a synthetic compound which dissociates into two molecules of acetylhomotaurine and one calcium ion. Acetylhomotaurine has a chemical structure similar to that of the endogenous amino acid homotaurine, which is a structural analogue of the amino acid neurotransmitter γ-aminobutyric acid and the amino acid neuromodulator taurine. Acetylation of its amine function facilitates passage of acetylhomotaurine through the blood brain barrier. Acamprosate calcium modulates glutamatergic and GABAergic neurotransmission and modifies neuronal excitability.
The mechanism of action of acamprosate calcium in maintenance of alcohol abstinence is not completely understood. In animal studies, acamprosate calcium acts centrally and appears to restore the normal balance between neuronal excitation and inhibition that becomes altered as a result of chronic alcohol exposure.
No specific study of CAMPRAL pharmacokinetics in various racial groups has been performed.
After oral dosing of 2×333 mg of CAMPRAL, the terminal half-life of acamprosate was about 20-33 hours. Following oral administration of 14C-acamprosate calcium, urinary excretion accounted for 11% of the administered dose, i.e. 100% of the absorbed drug, while fecal excretion accounted for the remainder.
Peak plasma concentrations of acamprosate after administration of a single dose of 2×333 mg CAMPRAL tablets to patients with moderate or severe renal impairment were about 2-fold and 4-fold higher, respectively, compared to healthy subjects. Similarly, elimination half-life of acamprosate 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 calcium.
No dose adjustment is recommended in patients with mild renal impairment (creatinine clearance of 80-50 mL/min).
A dose of 1×333 mg TID is recommended in patients with moderate renal impairment (creatinine clearance of 30-50 mL/min, see Warnings and Precautions, Renal).
Patients with severe renal impairment (creatinine clearance ≤30 mL/min) must not be given CAMPRAL (see Contraindications).
CAMPRAL does not exhibit any significant pharmacokinetic differences between male and female subjects.
Acamprosate calcium does not undergo metabolism following oral and intravenous administration.
Acamprosate calcium has negligible CNS activity outside of its effects on alcohol dependence, exhibiting no anticonvulsant, antidepressant, or anxiolytic activity in animals or effects on psychometric tests in healthy volunteers.
The administration of CAMPRAL is not associated with the development of tolerance or dependence in animal studies, nor would it be expected to precipitate withdrawal symptoms in patients physically dependent on opioids, by virtue of its mechanism of action.
CAMPRAL is not alcohol aversive therapy and does not cause a disulfiram-like reaction as a result of ethanol ingestion.
The pharmacokinetics of CAMPRAL have not been evaluated in a pediatric population.
Contraindications
Patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. For a complete listing, see Dosage Forms, Composition and Packaging.
Patients with severe renal impairment (creatinine clearance ≤30 mL/min).
In nursing women.
