Acamprosate Calcium
A white powder. Freely soluble in water; practically insoluble in alcohol and in dichloromethane. A 5% solution in water has a pH of 5.5 to 7.0.
Adverse Effects
The main adverse effect of acamprosate is dosage-related diarrhoea; nausea, vomiting, and abdominal pain occur less frequently. Other adverse effects have included pruritus, and occasionally a maculopapular rash; bullous skin reactions have occurred rarely. Depression and fluctuations in libido have also been reported.
Effects on the skin.
A case of erythema multiforme in a woman with cirrhosis of the liver has been attributed to use of acamprosate although both the diagnosis and any association with acamprosate have been seriously challenged.
Precautions
Acamprosate is contra-indicated in patients with severe hepatic impairment. For precautions regarding the use of acamprosate in patients with renal impairment, see under Uses and Administration.
Renal impairment.
It is considered likely that accumulation of acamprosate would occur with prolonged use of therapeutic doses in patients with renal impairment. It has been reported that the mean maximum concentration of acamprosate after a single 666-mg dose was 813 nanograms/mL in 12 patients with moderate or severe renal impairment compared with 198 nanograms/mL in 6 healthy subjects; values for the plasma elimination half-life were 47 and 18 hours, respectively.
Pharmacokinetics
Absorption of acamprosate from the gastrointestinal tract is slow but sustained and is subject to considerable interindividual variation. Steady-state concentrations are achieved after dosage for 7 days. Bioavailability is reduced if given with food. Acamprosate is not protein bound and although it is hydrophilic it is reported to cross the blood-brain barrier. Acamprosate does not appear to be metabolised and is excreted unchanged in the urine. The elimination half-life after oral doses has been reported to be about 33 hours.
Uses and Administration
Acamprosate has a chemical structure similar to that of gamma-aminobutyric acid (GABA). It is given by mouth as the calcium salt to prevent relapse in alcoholics who have been weaned off alcohol. The usual dose is 666 mg of acamprosate calcium given three times daily. UK licensed product information also recommends that patients weighing less than 60 kg should be given a dose of 666 mg at breakfast followed by 333 mg at midday and 333 mg at night. For doses in patients with renal impairment. Treatment should be started as soon as possible after alcohol withdrawal and maintained, even if the patient relapses, for the recommended period of 1 year.
Administration in renal impairment.
Licensed product information in the UK does not recommend the use of acamprosate in patients with renal impairment.
In the USA the use of acamprosate is contra-indicated in those with severe renal impairment (creatinine clearance less than 30 mL/min). However, in those with moderate impairment (creatinine clearance 30 to 50 mL/min), a dose of 333 mg three times daily may be given.
Alcohol dependence.
Acamprosate is considered to be of use as an adjunct to psychotherapy in maintaining abstinence after alcohol withdrawal in patients with alcohol dependence. Reviews of placebo-controlled studies conclude that acamprosate helps to prevent relapse and increase the number of drink-free days during a 1-year course of treatment and possibly for up to one year thereafter. Efficacy appears to be dose related but its effects in promoting abstinence may wane during treatment. Use with disulfiram or naltrexone may improve results but a large multicentre study in the USA found that adding acamprosate to naltrexone or behavioural therapy did not produce any additional benefit, and that the drug was ineffective when used alone. Several mechanisms have been proposed to account for acamprosate's action including inhibition of neuronal hyperexcitability by antagonising excitatory amino acids such as glutamate.
Acamprosate calcium
DRUG DESCRIPTION
CAMPRALยฎ (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 ?-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. 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 Eudragitยฎ 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.
INDICATIONS
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. Although dosing may be done without regard to meals, 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. A lower dose may be effective in some patients.
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. Patients with severe renal impairment (creatinine clearance of ? 30 mL/min) should not be given CAMPRAL.
SIDE EFFECTS
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, non-serious 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.
Table1. 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
Body System/ Preferred Term CAMPRAL
1332 mg/day CAMPRAL
1998 mg/day1 CAMPRAL
Pooled2 Placebo
Number of patients in Treatment Group 397 1539 2019 1706
Number (%) ofpatients with an AE 248 (62%) 910 (59%) 1231 (61%) 955 (56%)
Body as a Whole 121 (30%) 513 (33%) 685 (34%) 517 (30%)
Accidental Injury* 17 ( 4%) 44 ( 3%) 70 ( 3%) 52 ( 3%)
Asthenia 29 ( 7%) 79 ( 5%) 114 ( 6%) 93 ( 5%)
Pain 6 ( 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 4 ( 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%)
Anxiety** 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%)
vPruritus 12 ( 3%) 68 ( 4%) 82 ( 4%) 58 ( 3%)
Sweating 11 ( 3%) 27 ( 2%) 40 ( 2%) 39 ( 2%)
*includes events coded as"fracture" by sponsor;**includes events codedas "nervousness"by sponsor
1includes 258 patients treated with acamprosate calcium 2000 mg/day, using a different dosage strength and regimen.
2includes all patients in thefirst two columns aswell as 83 patientstreated withacamprosate calcium 3000 mg/day, using a different dosage strength and regimen.
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, tachy-cardia, 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, ambly-opia, 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.
Serious Adverse Events Observed During the Non-US Postmarketing Evaluation of CAMPRAL (acamprosate calcium)
Although no causal relationship to CAMPRAL has been found, 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.
Drug Abuse And Dependence
Controlled Substance Class
Acamprosate calcium is not a controlled substance.
Physical and Psychological Dependence
CAMPRAL 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 CAMPRAL abuse or dependence.
DRUG INTERACTIONS
The concomitant intake of alcohol and CAMPRAL does not affect the pharmacokinetics of either alcohol or acamprosate.
Pharmacokinetic studies indicate that administration of disulfiram or diazepam does not affect the pharmacokinetics of acamprosate. Co-administration of naltrexone with CAMPRAL produced a 25% increase in AUC and a 33% increase in the Cmax of acamprosate. No adjustment of dosage is recommended in such patients.
The pharmacokinetics of naltrexone and its major metabolite 6-beta-naltrexol were unaffected following co-administration with CAMPRAL.
Other concomitant therapies: In clinical trials, the safety profile in subjects treated with CAMPRAL concomitantly with anxiolytics, hypnotics and sedatives (including benzodi-azepines), 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.
SIDE EFFECTS
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, non-serious 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.
Table1. 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
Body System/ Preferred Term CAMPRAL
1332 mg/day CAMPRAL
1998 mg/day1 CAMPRAL
Pooled2 Placebo
Number of patients in Treatment Group 397 1539 2019 1706
Number (%) ofpatients with an AE 248 (62%) 910 (59%) 1231 (61%) 955 (56%)
Body as a Whole 121 (30%) 513 (33%) 685 (34%) 517 (30%)
Accidental Injury* 17 ( 4%) 44 ( 3%) 70 ( 3%) 52 ( 3%)
Asthenia 29 ( 7%) 79 ( 5%) 114 ( 6%) 93 ( 5%)
Pain 6 ( 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 4 ( 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%)
Anxiety** 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%)
vPruritus 12 ( 3%) 68 ( 4%) 82 ( 4%) 58 ( 3%)
Sweating 11 ( 3%) 27 ( 2%) 40 ( 2%) 39 ( 2%)
*includes events coded as"fracture" by sponsor;**includes events codedas "nervousness"by sponsor
1includes 258 patients treated with acamprosate calcium 2000 mg/day, using a different dosage strength and regimen.
2includes all patients in thefirst two columns aswell as 83 patientstreated withacamprosate calcium 3000 mg/day, using a different dosage strength and regimen.
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, tachy-cardia, 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, ambly-opia, 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.
Serious Adverse Events Observed During the Non-US Postmarketing Evaluation of CAMPRAL (acamprosate calcium)
Although no causal relationship to CAMPRAL has been found, 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.
Drug Abuse And Dependence
Controlled Substance Class
Acamprosate calcium is not a controlled substance.
Physical and Psychological Dependence
CAMPRAL 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 CAMPRAL abuse or dependence.
DRUG INTERACTIONS
The concomitant intake of alcohol and CAMPRAL does not affect the pharmacokinetics of either alcohol or acamprosate.
Pharmacokinetic studies indicate that administration of disulfiram or diazepam does not affect the pharmacokinetics of acamprosate. Co-administration of naltrexone with CAMPRAL produced a 25% increase in AUC and a 33% increase in the Cmax of acamprosate. No adjustment of dosage is recommended in such patients.
The pharmacokinetics of naltrexone and its major metabolite 6-beta-naltrexol were unaffected following co-administration with CAMPRAL.
Other concomitant therapies: In clinical trials, the safety profile in subjects treated with CAMPRAL concomitantly with anxiolytics, hypnotics and sedatives (including benzodi-azepines), 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.
OVERDOSE
The expected symptoms with overdosage are those of excessive beta-adrenergic receptor stimulation and/or occurrence or exaggeration of any of the symptoms listed under ADVERSE REACTIONS, e.g., seizures, angina, hypertension or hypotension, tachycardia with rates up to 200 beats/min., arrhythmias, nervousness, headache, tremor, dry mouth, palpitation, nausea, dizziness, fatigue, malaise, and sleeplessness. Hypokalemia also may occur. As with all sympathomimetic medications, cardiac arrest and even death may be associated with the abuse of Xopenex Inhalation Solution. Treatment consists of discontinuation of Xopenex Inhalation Solution together with appropriate symptomatic therapy. The judicious use of a cardioselective beta-receptor blocker may beconsidered, bearing in mind that such medication can produce bronchospasm. There is insufficient evidence to determine if dialysis is beneficial for overdosage of Xopenex Inhalation Solution.
The intravenous median lethal dose of levalbuterol HCl in mice is approximately 66 mg/kg (approximately 70 times the maximum recommended daily inhalation dose of levalbuterol HCl for adults and children on a mg/m2 basis). The inhalation median lethal dose has not been determined in animals.
CONTRAINDICATIONS
Xopenex (levalbuterol HCl) Inhalation Solution is contraindicated in patients with a history of hypersensitivity to levalbuterol HCl or racemic albuterol.
CLINICAL PHARMACOLOGY
Pharmacodynamics
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.
Pharmacodynamic studies have shown that acamprosate calcium reduces alcohol intake in alcohol-dependent animals in a 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.
CAMPRAL is not known to cause alcohol aversion and does not cause a disulfiram-like reaction as a result of ethanol ingestion.
Pharmacokinetics
Absorption
The absolute bioavailability of CAMPRAL after oral administration is about 11%. Steady-state plasma concentrations of acamprosate are reached within 5 days of dosing. Steady-state peak plasma concentrations after CAMPRAL doses of 2 x 333 mg tablets three times daily average 350 ng/mL and occur at 3-8 hours post-dose. Coadministration of CAMPRAL 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 1 L/kg). Plasma protein binding of acamprosate is negligible.
Metabolism
Acamprosate does not undergo metabolism.
Elimination
After oral dosing of 2 x 333 mg of CAMPRAL, the terminal half-life ranges from approximately 20 - 33 hours. Following oral administration of CAMPRAL, the major route of excretion is via the kidneys as acamprosate.
Special Populations
Gender: CAMPRAL does not exhibit any significant pharmacokinetic differences between male and female subjects.
Age: 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, acamprosate plasma concentrations are likely to be higher in the elderly population compared to younger adults.
Pediatrics: The pharmacokinetics of CAMPRAL have not been evaluated in a pediatric population.
Renal Impairment: Peak plasma concentrations after administration of a single dose of 2 x 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 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. A dose of 1 x 333 mg CAMPRAL, three times daily, is recommended in patients with moderate renal impairment (creatinine clearance of 30-50 mL/min, see also PRECAUTIONS).
Patients with severe renal impairment (creatinine clearance ? 30 mL/min) should not be given CAMPRAL (see also CONTRAINDICATIONS).
Hepatic Impairment: Acamprosate is not metabolized by the liver and the pharmacokinetics of CAMPRAL 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.
Alcohol-dependent subjects: A cross-study comparison of CAMPRAL at doses of 2 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 CAMPRAL 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 CAMPRAL. However, co-administration of CAMPRAL with naltrexone led to a 33% increase in the Cmax and a 25% increase in the AUC of acamprosate. No adjustment of dosage is recommended in such patients.
Clinical Studies
The efficacy of CAMPRAL in the maintenance of abstinence was supported by three clinical studies involving a total of 998 patients who were administered at least one dose of CAMPRAL or placebo as an adjunct to psychosocial therapy. Each study was a 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. CAMPRAL proved superior to placebo in maintaining abstinence, as indicated by a greater percentage of subjects being assessed as continuously abstinent throughout treatment.
In a fourth study, the efficacy of CAMPRAL was evaluated in alcoholics, including patients with a 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 CAMPRAL over placebo.