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ACAMPROSATE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Acamprosate, a synthetic agent, is a calcium salt of N-acetyl homotaurine, with a chemical structure similar to that of the endogenous amino acid homotaurine. When the salt dissociates in biological fluids, the active moiety is N-acetyl homotaurine, a highly flexible molecule with similarities to many amino acids (ie, glutamate, gamma-aminobutyric acid (GABA) aspartate, glycine, and taurine). It appears to have a role in decreasing alcohol "craving" following the abstinence of alcohol.

Specific Substances

    1) Acamprosate calcium
    2) Acamprosato de calcio
    3) Acamprosatum calcicum
    4) CAS 77337-76-9
    5) Acamprosat
    6) AOTA
    7) CAAOTA
    8) Calcium acetylhomotaurinate
    1.2.1) MOLECULAR FORMULA
    1) C(10)H(20)N(2)O(8)S(2)Ca

Available Forms Sources

    A) FORMS
    1) Acamprosate is available as 333 mg enteric-coated, white, round, biconvex tablets (Prod Info CAMPRAL(R) oral delayed-release tablets, 2012).
    B) USES
    1) Acamprosate, a synthetic agent, is a calcium salt of N-acetyl homotaurine, with a chemical structure similar to that of the endogenous amino acid homotaurine. When the salt dissociates in biological fluids, the active moiety is N-acetyl homotaurine, a highly flexible molecule with similarities to many amino acids (ie, glutamate, gamma-aminobutyric acid (GABA) aspartate, glycine, and taurine). It appears to have a role in decreasing alcohol "craving" following the abstinence of alcohol (Prod Info CAMPRAL(R) oral delayed-release tablets, 2012; Littleton & Zieglgansberger, 2003; Schuckit, 1996).
    2) Acamprosate has been approved by the US FDA for the maintenance of abstinence from alcohol in individuals with alcohol dependence who have stopped drinking (Prod Info CAMPRAL(R) oral delayed-release tablets, 2012; FDA, 2004). It is intended for use as part of a comprehensive alcohol treatment program (Prod Info CAMPRAL(R) oral delayed-release tablets, 2012).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Acamprosate has been approved for the maintenance of abstinence from alcohol in individuals with alcohol dependence who have stopped drinking.
    B) PHARMACOLOGY: Acamprosate calcium helps maintain abstinence to alcohol through a mechanism that may involve an interaction with glutamate and GABA neurotransmitter systems centrally. It possesses dose-dependent reduction of alcohol intake specific for the type of alcohol and the mechanisms of dependence, without exhibiting anticonvulsant, antidepressant, or anxiolytic properties.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) The most commonly occurring adverse effects following therapeutic administration of acamprosate include: diarrhea, nausea, vomiting, anxiety, headache, depression, asthenia, dizziness, dry mouth, pain and insomnia. Other reported adverse effects include: pruritus, rash, sweating, vasodilation, syncope, hypertension, hypotension, palpitations, dizziness, headache, confusion, somnolence, extrapyramidal symptoms, fluctuations in libido (decreased or increased), amnesia, and abnormal thinking. Therapy with acamprosate does not eliminate or diminish alcohol withdrawal symptoms.
    E) WITH POISONING/EXPOSURE
    1) In limited cases of overdose, doses of up to 56 grams (normal dose approximately 2 g/day) were generally well tolerated, and the only associated symptom was diarrhea.
    2) At the time of this review, hypercalcemia has not been reported following overdose, however, hypercalcemia may occur in chronic overdosage.
    0.2.20) REPRODUCTIVE
    A) Acamprosate has been rated FDA pregnancy category C. Acamprosate has been found to be teratogenic in rats at doses approximately equivalent to a human dose (on a mg/m(2) basis) and in rabbits at doses approximately 3 times the human dose.

Laboratory Monitoring

    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs in symptomatic patients.
    C) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    D) Obtain a calcium concentration following chronic overdosage or as indicated.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Manage mild hypotension with IV fluids.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Treat severe hypotension with IV 0.9% NaCl at 10 to 20 mL/kg. Add dopamine or norepinephrine if unresponsive to fluids. Correct any significant fluid and/or electrolyte abnormalities in patients with severe diarrhea and/or vomiting.
    C) DECONTAMINATION
    1) PREHOSPITAL: Severe toxicity after an acute ingestion is unlikely. Prehospital gastrointestinal decontamination is generally unnecessary.
    2) HOSPITAL: Severe toxicity after an acute ingestion is unlikely. Consider activated charcoal after very large ingestions or those involving more toxic co-ingestants, Consider activated charcoal if the overdose is recent, the patient is not vomiting, and is able to maintain airway.
    D) AIRWAY MANAGEMENT
    1) Airway management is very unlikely to be necessary unless other toxic agents have been administered concurrently. Ensure adequate ventilation and perform endotracheal intubation early in patients with significant hemodynamic instability.
    E) ANTIDOTE
    1) None.
    F) ENHANCED ELIMINATION
    1) Hemodialysis is expected to be effective in removing acamprosate due to its small volume of distribution and low protein binding. Because acamprosate appears to cause minimal toxicity after overdose, hemodialysis is unlikely to be necessary.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    2) OBSERVATION CRITERIA: Patients with a deliberate overdose, and those who are symptomatic should be observed with frequent monitoring of vital signs. Patients that remain asymptomatic can be discharged.
    3) ADMISSION CRITERIA: Patients should be admitted for severe vomiting, profuse diarrhea, severe abdominal pain, dehydration, and electrolyte abnormalities.
    4) CONSULT CRITERIA: Consult a local poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    H) PITFALLS
    1) When managing a suspected acamprosate overdose, the possibility of multidrug involvement should be considered.
    I) PHARMACOKINETICS
    1) Steady state peak concentrations of 350 ng/mL were achieved 3 to 8 hours after acamprosate doses (666 mg tablets 3 times daily). Protein binding is negligible. Vd: approximately 1 L/kg. Acamprosate does not undergo metabolism. The kidney is the major route of excretion. Elimination half-life: approximately 20 to 33 hours; +/- 4.3 hours.
    J) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that cause hypotension (eg, vasodilators, beta blockers, calcium channel blockers).

Range Of Toxicity

    A) TOXICITY: Based on limited overdose data, total doses of up to 56 grams have been well tolerated. Diarrhea was the only adverse effect associated with acute overdose. THERAPEUTIC DOSES: Adults: Two 333-mg tablets (for a total of 666 mg) taken3 times daily.

Clinical Effects

Summary Of Exposure

    A) USES: Acamprosate has been approved for the maintenance of abstinence from alcohol in individuals with alcohol dependence who have stopped drinking.
    B) PHARMACOLOGY: Acamprosate calcium helps maintain abstinence to alcohol through a mechanism that may involve an interaction with glutamate and GABA neurotransmitter systems centrally. It possesses dose-dependent reduction of alcohol intake specific for the type of alcohol and the mechanisms of dependence, without exhibiting anticonvulsant, antidepressant, or anxiolytic properties.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) The most commonly occurring adverse effects following therapeutic administration of acamprosate include: diarrhea, nausea, vomiting, anxiety, headache, depression, asthenia, dizziness, dry mouth, pain and insomnia. Other reported adverse effects include: pruritus, rash, sweating, vasodilation, syncope, hypertension, hypotension, palpitations, dizziness, headache, confusion, somnolence, extrapyramidal symptoms, fluctuations in libido (decreased or increased), amnesia, and abnormal thinking. Therapy with acamprosate does not eliminate or diminish alcohol withdrawal symptoms.
    E) WITH POISONING/EXPOSURE
    1) In limited cases of overdose, doses of up to 56 grams (normal dose approximately 2 g/day) were generally well tolerated, and the only associated symptom was diarrhea.
    2) At the time of this review, hypercalcemia has not been reported following overdose, however, hypercalcemia may occur in chronic overdosage.

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) PALPITATIONS
    1) WITH THERAPEUTIC USE
    a) During clinical trials, palpitations have been reported in at least 1% of patients (Prod Info CAMPRAL(R) oral delayed-release tablets, 2012).
    B) VASODILATATION
    1) WITH THERAPEUTIC USE
    a) Vasodilation, syncope and hypertension have been reported in at least 1% of patients during clinical trials with acamprosate (Prod Info CAMPRAL(R) oral delayed-release tablets, 2012).
    C) HYPOTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) In patients with alcohol-induced hepatic cirrhosis, transient, significant reductions in diastolic blood pressure were observed at therapeutic dosing. However, no significant changes in heart rate or systolic blood pressure were reported (Anon, 2002).
    b) Hypotension was reported in one patient during therapeutic use for alcohol withdrawal (Staner et al, 2006).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) NEUROLOGICAL FINDING
    1) WITH THERAPEUTIC USE
    a) During clinical trials, anxiety (up to 8%) , depression (up to 8%) and insomnia (up to 9%) have been reported with therapeutic use of acamprosate, but overall rates were similar between the control groups and the placebo-treated group (Prod Info CAMPRAL(R) oral delayed-release tablets, 2012).
    b) Other symptoms reported frequently (occurring in at least 1/100 patients) with acamprosate therapy have included: dizziness, headache, confusion, somnolence, fluctuations in libido (decreased or increased), amnesia, and abnormal thinking (Prod Info CAMPRAL(R) oral delayed-release tablets, 2012; Anon, 2002).
    B) EXTRAPYRAMIDAL DISEASE
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 72-year-old man with alcohol dependency who was receiving lorazepam, thiamine, and acamprosate 999 mg/day for alcohol detoxification, presented 2 days later with a slowed gait with diminished pendular arm movements, excessive saliva pooling in mouth, muscle rigidity of arms without cogwheel rigidity and bradykinesia with slowed speech. He developed acute onset Parkinsonism on day 4. Following the discontinuation of acamprosate, all his symptoms gradually resolved over the next week. It is suggested that acamprosate can decrease dopamine concentrations in the ventral tegmental area mediated by glutamatergic action, resulting in extrapyramidal symptoms (Woo & Rim, 2014)

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) Diarrhea is the most common adverse event reported with therapy. It has occurred in up to 48% of patients and appears to be dose-dependent (Mason, 2001; Pelc et al, 1997). In clinical trials it was associated with the discontinuation of therapy in more than 1% of patients (Prod Info CAMPRAL(R) oral delayed-release tablets, 2012).
    2) WITH POISONING/EXPOSURE
    a) Based on limited reports of acute overdose with doses of up to 56 g acamprosate (usual dose approximately 2 g/day) , the only symptom associated with overdose was diarrhea (Prod Info CAMPRAL(R) oral delayed-release tablets, 2012).
    B) INDIGESTION
    1) WITH THERAPEUTIC USE
    a) Dry mouth, dyspepsia, and flatulence have been reported during therapeutic use for alcohol withdrawal (Staner et al, 2006).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) ACUTE DRUG-INDUCED RENAL FAILURE
    1) WITH THERAPEUTIC USE
    a) In postmarketing experience, acute renal failure has been temporally associated with acamprosate therapy in several patients (Prod Info CAMPRAL(R) oral delayed-release tablets, 2012).
    B) ABNORMAL SEXUAL FUNCTION
    1) WITH THERAPEUTIC USE
    a) Seven patients in one series on acamprosate at therapeutic concentrations experienced increased libido (Pelc et al, 1997).
    b) One patient on acamprosate at therapeutic concentrations reported sexual dysfunction, not further characterized (Laaksonen et al, 2008).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) DERMATOLOGICAL FINDING
    1) WITH THERAPEUTIC USE
    a) Pruritus (up to 4%), rash (at least 1% of patients), and sweating (up to 3%) have occurred during therapeutic use of acamprosate (Prod Info CAMPRAL(R) oral delayed-release tablets, 2012).
    b) Other adverse dermatologic events possibly related to acamprosate therapy may include maculopapular rash and bullous skin reactions (Anon, 2002).
    B) ERYTHEMA MULTIFORME
    1) WITH THERAPEUTIC USE
    a) Erythema multiforme was temporally associated with acamprosate use in a 40-year-old female with a history of cirrhosis and chronic herpes simplex. The patient was also receiving concomitant spironolactone therapy. Symptoms resolved with drug cessation, and spironolactone was restarted uneventfully (Fortier-Beaulieu et al, 1992).

Reproductive

    3.20.1) SUMMARY
    A) Acamprosate has been rated FDA pregnancy category C. Acamprosate has been found to be teratogenic in rats at doses approximately equivalent to a human dose (on a mg/m(2) basis) and in rabbits at doses approximately 3 times the human dose.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) RATS, RABBITS: Fetal malformation in rats (ie, hydronephrosis, malformed iris, retinal dysplasia, retroesophageal subclavian artery) occurred at doses approximately equal to the maximum recommended human dose (on a mg/m(2) basis). In rabbits, an increased incidence of hydronephrosis was noted at doses approximately 3 times the maximum recommended human dose (Prod Info acamprosate calcium oral delayed-release tablets, 2014).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) Acamprosate is rated FDA pregnancy category C (Prod Info acamprosate calcium oral delayed-release tablets, 2014).
    2) Animal findings should be considered in relation to known adverse effects of ethyl alcohol on human development, including fetal alcohol syndrome (ie, craniofacial dysmorphism, intrauterine and postnatal growth retardation, psychomotor and intellectual impairment) and milder forms of behavioral and neurological disorders (Prod Info acamprosate calcium oral delayed-release tablets, 2014).
    B) ANIMAL STUDIES
    1) STILLBORN
    a) MICE: More stillborn fetuses was noted in pregnant mice administered oral acamprosate calcium from gestation day 15 through postnatal day 28 at doses approximately 2 times the maximum recommended human dose (on a mg/m(2) basis). No effects were seen at doses approximately one-half the maximum recommended human dose (Prod Info acamprosate calcium oral delayed-release tablets, 2014).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) At the time of this review, it is not known if acamprosate is excreted in human milk (Prod Info acamprosate calcium oral delayed-release tablets, 2014).
    B) ANIMAL STUDIES
    1) BREAST MILK
    a) RATS: Acamprosate was excreted in the milk of lactating rats following oral doses. The ratio of milk to blood ratio was 1.3 to 1 (Prod Info acamprosate calcium oral delayed-release tablets, 2014).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) RATS: No alterations in fertility where observed in male rats treated pre- and post-mating or in female rats dosed from mating through lactation at doses up to 1000 mg/kg/day (approximately 4 times the maximum recommended human daily oral dose on a mg/m(2) basis) (Prod Info acamprosate calcium oral delayed-release tablets, 2014).

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS77337-76-9 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) Not Listed
    3.21.4) ANIMAL STUDIES
    A) LACK OF EFFECT
    1) No evidence of tumorigenicity was observed in a feeding study using Sprague-Dawley rats receiving 25, 100, or 400 mg/kg/day (0.2, 0.7 or 2.5-fold the maximum recommended human dose based on an AUC comparison) of acamprosate. A complete study in mice is suggested (Prod Info Campral(R), 2004).

Genotoxicity

    A) Acamprosate demonstrated no evidence of genotoxicity in a variety of studies, or evidence of clastogenicity.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs in symptomatic patients.
    C) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    D) Obtain a calcium concentration following chronic overdosage or as indicated.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Following chronic overdosage, hypercalcemia might develop; obtain a calcium concentration as clinically indicated (Prod Info Campral(R), 2004).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients should be admitted for severe vomiting, profuse diarrhea, severe abdominal pain, dehydration, and electrolyte abnormalities.
    6.3.1.2) HOME CRITERIA/ORAL
    A) A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a local poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with a deliberate overdose, and those who are symptomatic should be observed with frequent monitoring of vital signs. Patients that remain asymptomatic can be discharged.

Monitoring

    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs in symptomatic patients.
    C) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    D) Obtain a calcium concentration following chronic overdosage or as indicated.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Severe toxicity after an acute ingestion is unlikely. Prehospital gastrointestinal decontamination is generally unnecessary.
    6.5.2) PREVENTION OF ABSORPTION
    A) SUMMARY
    1) Severe toxicity after an acute ingestion is unlikely. Consider activated charcoal after very large ingestions or those involving more toxic co-ingestants, Consider activated charcoal if the overdose is recent, the patient is not vomiting, and is able to maintain airway.
    B) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) MANAGEMENT OF MILD TO MODERATE TOXICITY
    a) Treatment is symptomatic and supportive. Manage mild hypotension with IV fluids.
    2) MANAGEMENT OF SEVERE TOXICITY
    a) Treatment is symptomatic and supportive. Treat severe hypotension with IV 0.9% NaCl at 10 to 20 mL/kg. Add dopamine or norepinephrine if unresponsive to fluids. Correct any significant fluid and/or electrolyte abnormalities in patients with severe diarrhea and/or vomiting.
    B) MONITORING OF PATIENT
    1) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    2) Monitor vital signs in symptomatic patients.
    3) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    4) Obtain a calcium concentration following chronic overdosage or as indicated.
    C) HYPOTENSIVE EPISODE
    1) SUMMARY
    a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.
    2) DOPAMINE
    a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    3) NOREPINEPHRINE
    a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
    b) DOSE
    1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
    2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
    3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).

Enhanced Elimination

    A) HEMODIALYSIS
    1) Hemodialysis is expected to be effective in removing acamprosate due to its small volume of distribution and low protein binding. However, no cases utilizing hemodialysis in acamprosate toxicity have been reported. Because acamprosate appears to cause minimal toxicity after overdose, hemodialysis is unlikely to be necessary.

Range Of Toxicity

Summary

    A) TOXICITY: Based on limited overdose data, total doses of up to 56 grams have been well tolerated. Diarrhea was the only adverse effect associated with acute overdose. THERAPEUTIC DOSES: Adults: Two 333-mg tablets (for a total of 666 mg) taken3 times daily.

Therapeutic Dose

    7.2.1) ADULT
    A) The recommended dose is two 333 mg tablets (for a total of 666 mg) taken 3 times daily. Doses may be given with meals as an aid to compliance. Lower doses may be effective in some individuals (Prod Info CAMPRAL(R) oral delayed-release tablets, 2012).
    B) Treatment should begin as soon as possible after alcohol abstinence, and should be continued even if the patient relapses. A comprehensive program that includes psychosocial support is also recommended to maintain abstinence from alcohol (Prod Info CAMPRAL(R) oral delayed-release tablets, 2012).
    7.2.2) PEDIATRIC
    A) The safety and efficacy of acamprosate have not been established in pediatric patients (Prod Info CAMPRAL(R) oral delayed-release tablets, 2012).

Maximum Tolerated Exposure

    A) Based on limited acute overdose data, total doses of up to 56 grams (recommended dose is approximately 2 g/day) have been well tolerated. Diarrhea was the only clinical effect that could be associated with acute overdose (Prod Info CAMPRAL(R) oral delayed-release tablets, 2012).

Workplace Standards

    A) ACGIH TLV Values for CAS77337-76-9 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    B) NIOSH REL and IDLH Values for CAS77337-76-9 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    C) Carcinogenicity Ratings for CAS77337-76-9 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    D) OSHA PEL Values for CAS77337-76-9 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

Pharmacology Toxicology

Pharmacologic Mechanism

    A) SUMMARY - The mechanism of action is not fully understood, but chronic alcohol exposure is thought to alter normal balance between neuronal excitation and inhibition. It has been found that chronic alcohol use results in decreased GABAergic transmission and increased glutamate activity (Mason et al, 2002). Based on in vitro and in vivo studies in animals its hypothesized that acamprosate may interact with glutamate and GABA neurotransmitter systems centrally to restore balance (Prod Info Campral(R), 2004; Littleton, 1995).
    B) Acamprosate is a derivative of homotaurine and structural analogue of taurine (an amino acid found in the brain) . Although the exact neuropharmacological effects of acamprosate are not fully understood, it has been suggested that it exerts its main effects on glutamate receptors in the brain, and less likely on GABA receptors as earlier studies suggested (Anton & Swift, 2003; Johnson & Ait-Daoud, 2000). Acamprosate may mimic or modify the levels of taurine, which likely suppresses neuronal hyperexcitation. In Eastern medicine, taurine has been commonly used to treat drug cravings (Littleton, 1995)
    C) By modulating N-methyl-D-aspartate {NMDA} receptor activity in the glutamate system (ie, chronic alcohol use and dependence may be mediated by adaptation in both glutamate receptors and glutamatergic transmission), the effects of "alcohol craving" (which produce a glutamatergic deficiency) can be minimized (Anton & Swift, 2003). It appears that acamprosate may have some role in normalizing that deficiency, thereby reducing the desire to consume alcohol. In humans, the therapeutic potential appears to be the effect of modulating "negative craving" (Mason et al, 2002; Johnson & Ait-Daoud, 2000). Of note, acamprosate did not effect alcohol consumption in animal models (Anton & Swift, 2003).
    D) Acamprosate does not affect food or fluid intake (Johnson & Ait-Daoud, 2000).

Physicochemical

Physical Characteristics

    A) Acamprosate is a white, odorless or nearly odorless powder and is freely soluble in water (Prod Info Campral(R), 2004).

Molecular Weight

    A) 400.48 (Sweetman, 2004)

References

General Bibliography

    1) 40 CFR 372.28: Environmental Protection Agency - Toxic Chemical Release Reporting, Community Right-To-Know, Lower thresholds for chemicals of special concern. National Archives and Records Administration (NARA) and the Government Printing Office (GPO). Washington, DC. Final rules current as of Apr 3, 2006.
    2) 40 CFR 372.65: Environmental Protection Agency - Toxic Chemical Release Reporting, Community Right-To-Know, Chemicals and Chemical Categories to which this part applies. National Archives and Records Association (NARA) and the Government Printing Office (GPO), Washington, DC. Final rules current as of Apr 3, 2006.
    3) 49 CFR 172.101 - App. B: Department of Transportation - Table of Hazardous Materials, Appendix B: List of Marine Pollutants. National Archives and Records Administration (NARA) and the Government Printing Office (GPO), Washington, DC. Final rules current as of Aug 29, 2005.
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