Campral information, interactions and side effects, Campral (acamprosate calcium) is supplied in an enteric-coated tablet for oral administration. Acamprosate calcium is a synthetic compound with 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. Its chemical name is calcium acetylaminopropane sulfonate. Its chemical formula is C10H20N2O8S2Ca and molecular weight is 400.48. Its structural formula is:
Acamprosate calcium is a white, odorless or nearly odorless powder. It is freely soluble in water, and practically insoluble in absolute ethanol and dichloromethane.
Each Campral tablet contains acamprosate calcium 333 mg, equivalent to 300 mg of acamprosate. Inactive ingredients in Campral tablets include: crospovidone, microcrystalline cellulose, magnesium silicate, sodium starch glycolate, colloidal anhydrous silica, magnesium stearate, talc, propylene glycol and Eudragit® L 30 D or equivalent. Sulfites were used in the synthesis of the drug substance and traces of residual sulfites may be present in the drug product.
Campral® 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 psychosocial support.
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.
DOSAGE AND ADMINISTRATION
The recommended dose of Campral is two 333 mg tablets (each dose should total 666 mg) taken three times daily. A 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 Campral 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. Campral should be used as part of a comprehensive psychosocial treatment program.
Dosage in Renal Impairment
For patients with moderate renal impairment (creatinine clearance of 30-50 mL/min), a starting dose of one 333 mg tablet taken three times daily is recommended. Campral is contraindicated in patients with severe renal impairment (creatinine clearance of ≤ 30 mL/min) [see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, Use In Specific Populations, and CLINICAL PHARMACOLOGY].
Dosage Forms And Strengths
Campral 333 mg tablets are enteric-coated, white, round, biconvex tablets, identified with “333” debossed on one side.
Opaque HDPE bottles of 180 NDC #0456-3330-01
Storage and Handling
Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F).
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a 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 Campral described elsewhere in labeling include suicidality and depression and acute kidney failure [see WARNINGS AND PRECAUTIONS].
The adverse event data described below reflect the safety experience in over 7000 patients exposed to Campral for up to one year, including over 2000 Campral-exposed patients who participated in placebo-controlled trials.
Adverse Events Leading to Discontinuation
In placebo-controlled trials of 6 months or less, 8% of Campral-treated patients discontinued treatment due to an adverse event, as compared to 6% of patients treated with placebo. In studies longer than 6 months, the discontinuation rate due to adverse events was 7% in both the placebo-treated and the Campral-treated patients. Only diarrhea was associated with the discontinuation of more than 1% of patients (2% of Campral-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 Campral-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 a checklist in other studies. The overall profile of adverse events was similar using either method. Table 1 shows those events that occurred in any Campral treatment group at a 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, a 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 a Rate of at Least 3% and Greater than Placebo in any Campral Treatment Group in Controlled Clinical Trials with Spontaneously Reported Adverse Events.
|Number of Patients (%) with Events
|Campral 1332 mg/day
||Campral 1998 mg/day1
|Number of patients in Treatment Group
|Number (%) of patients with an AE
|Body as a Whole
| Accidental Injury*†
||17 ( 4%)
||44 ( 3%)
||70 ( 3%)
||52 ( 3%)
||29 ( 7%)
||79 ( 5%)
||114 ( 6%)
||93 ( 5%)
||6 ( 2%)
||56 ( 4%)
||65 ( 3%)
||55 ( 3%)
||20 ( 5%)
||35 ( 2%)
||57 ( 3%)
||44 ( 3%)
||4 ( 1%)
||55 ( 4%)
||63 ( 3%)
||28 ( 2%)
||11 ( 3%)
||69 ( 4%)
||87 ( 4%)
||58 ( 3%)
||32 ( 8%)
||80 ( 5%)
||118 ( 6%)
||98 ( 6%)
||33 ( 8%)
||63 ( 4%)
||102 ( 5%)
||87 ( 5%)
||15 ( 4%)
||49 ( 3%)
||67 ( 3%)
||44 ( 3%)
| Dry mouth
||13 ( 3%)
||23 ( 1%)
||36 ( 2%)
||28 ( 2%)
||34 ( 9%)
||94 ( 6%)
||137 ( 7%)
||121 ( 7%)
||11 ( 3%)
||29 ( 2%)
||40 ( 2%)
||34 ( 2%)
|Skin and Appendages
||26 ( 7%)
||187 ( 9%)
||12 ( 3%)
||68 ( 4%)
||82 ( 4%)
||58 ( 3%)
||11 ( 3%)
||27 ( 2%)
||40 ( 2%)
||39 ( 2%)
|†*includes events coded as “fracture” by sponsor;
††**includes events coded as “nervousness” by sponsor
1 includes 258 patients treated with acamprosate calcium 2000 mg/day, using a different dosage strength and regimen.
2 includes all patients in the first two columns as well as 83 patients treated with acamprosate calcium 3000 mg/day, using a different dosage strength and regimen.
In clinical trials, the safety profile in subjects treated with Campral 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 Campral 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 Campral
Following is a list of terms that reflect treatment-emergent adverse events reported by patients treated with Campral in 20 clinical trials (4461 patients treated with Campral, 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 a 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 a 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.
The following adverse reactions have been identified during post approval use of Campral. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Serious Adverse Events Observed During the Non-US Postmarketing Evaluation of Campral (acamprosate calcium)
The serious adverse event of acute kidney failure has been reported to be temporally associated with Campral treatment in at least 3 patients and is not described elsewhere in the labeling.
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].
Treatment with Campral in patients with moderate renal impairment (creatinine clearance of 30-50 mL/min) requires a dose reduction [see DOSAGE AND ADMINISTRATION]. Campral is contraindicated in patients with severe renal impairment (creatinine clearance of ≤ 30 mL/min) [see DOSAGE AND ADMINISTRATION, CONTRAINDICATIONS, Use in Specific Populations, and CLINICAL PHARMACOLOGY].
Suicidality and Depression
In controlled clinical trials of Campral, adverse events of a suicidal nature (suicidal ideation, suicide attempts, completed suicides) were infrequent overall, but were more common in Campral-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 Campral-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 Campral, should be monitored for the development of symptoms of depression or suicidal thinking. Families and caregivers of patients being treated with Campral should be alerted to the need to monitor patients for the emergence of symptoms of depression or suicidality, and to report such symptoms to the patient’s health care provider.
Use of Campral does not eliminate or diminish withdrawal symptoms.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Dietary administration of acamprosate calcium for 2 years to Sprague-Dawley rats at doses of 25, 100 and 400 mg/kg/day (up to 3 times the maximum recommended human daily (MRHD) oral dose on an AUC basis) and CD-1 mice at doses of 400, 1200 and 3600 mg/kg/day (up to 25 times the MRHD on an AUC basis) showed no evidence of increased tumor incidence.
Acamprosate calcium was negative in all genetic toxicology studies conducted. Acamprosate calcium demonstrated no evidence of genotoxicity in an in vitro bacterial reverse point mutation assay (Ames assay) or an in vitro mammalian cell gene mutation test using Chinese Hamster Lung V79 cells. No clastogenicity was observed in an in vitro chromosomal aberration assay in human lymphocytes and no chromosomal damage detected in an in vivo mouse micronucleus assay.
Acamprosate calcium had no effect on fertility after treatment for 70 days prior to mating in male rats and for 14 days prior to mating, throughout mating, gestation and lactation in female rats at doses up to 1000 mg/kg/day (approximately 4 times the MRHD oral dose on a mg/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 5 times the MRHD oral dose on a mg/m² basis) had no effect on fertility.
Use In Specific Populations
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 a mg/m² basis) and in rabbits when given in doses that are approximately 3 times the human dose (on a mg/m² basis). Acamprosate calcium produced a 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 a 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 a 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 3 times the MRHD oral dose on a mg/m² basis). No developmental effects were observed in New Zealand white rabbits at oral doses up to 1000 mg/kg/day (approximately 8 times the MRHD oral 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 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. Campral should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nonteratogenic effects: A 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 2 times the MRHD oral dose on a mg/m² basis). No effects were observed at a dose of 320 mg/kg/day (approximately one-half the MRHD dose on a mg/m² basis).
Labor and Delivery
The potential for Campral to affect the duration of labor and delivery is unknown.
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 Campral is administered to a nursing woman.
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, 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, ADVERSE REACTIONS, and DOSAGE AND ADMINISTRATION].
Campral is contraindicated in patients with severe renal impairment (creatinine clearance of ≤ 30 mL/min) [see DOSAGE AND ADMINISTRATION, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and CLINICAL PHARMACOLOGY].
In all reported cases of acute overdosage with Campral (total reported doses of up to 56 grams of acamprosate calcium), the only symptom that could be reasonably associated with Campral was diarrhea. Hypercalcemia has not been reported in cases of acute overdose. A risk of hypercalcemia should be considered in chronic overdosage only. Treatment of overdose should be symptomatic and supportive.
Hypersensitivity to Acamprosate Calcium
Campral is contraindicated in patients who previously have exhibited hypersensitivity to acamprosate calcium or any of its components.
Severe Renal Impairment
Campral is contraindicated in patients with severe renal impairment (creatinine clearance of ≤ 30 mL/min) [see DOSAGE AND ADMINISTRATION), WARNINGS AND PRECAUTIONS, Use in Specific Populations, and CLINICAL PHARMACOLOGY].