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TETRABENAZINE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Tetrabenazine is a vesicular monamine transporter 2 (VMAT) inhibitor (ie, depletes dopamine, serotonin, norepinephrine, and histamine from nerve terminals) that is used in the treatment of chorea that is associated with Huntington's disease.

Specific Substances

    1) Tetrabenazin
    2) Tetrabenazina
    3) Tetrabenazinum
    4) Ro 1 9569
    5) CAS 58-46-8

Available Forms Sources

    A) FORMS
    1) Tetrabenazine is available in 12.5 mg (white, cylindrical biplanar tablet) and 25 mg (yellowish cylindrical biplanar tablet) tablets in bottles of 112 (Prod Info XENAZINE(R) oral tablets, 2015).
    B) USES
    1) Tetrabenazine, a vesicular monamine transporter 2 (VMAT) inhibitor, is used in the treatment of chorea that is associated with Huntington's disease (Prod Info XENAZINE(R) oral tablets, 2015).

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: Tetrabenazine, a vesicular monamine transporter type 2 (VMAT2) inhibitor, is used in the treatment of chorea that is associated with Huntington's disease.
    B) PHARMACOLOGY: Tetrabenazine is a monoamine depletor whose exact mechanism is unknown. It depletes monoamine such as dopamine, serotonin, norepinephrine, and histamine from nerve terminals. Tetrabenazine reversibly inhibits the human vesicular monoamine transporter type 2 which results in decreased uptake of monoamines into synaptic vesicles and depletion of monoamine stores. In vitro, tetrabenazine exhibits week binding affinity at the dopamine D2 receptor.
    C) TOXICOLOGY: Excessive depletion of monoamines (ie dopamine, serotonin, norepinephrine, histamine) can cause toxic effects.
    D) EPIDEMIOLOGY: Overdose is rare; limited reports of exposure. No fatalities have been reported.
    E) WITH THERAPEUTIC USE
    1) COMMON: Sedation/somnolence, fatigue, insomnia, depression, akathisia, anxiety, and nausea. Other events can include, orthostatic hypotension, dysphagia, extrapyramidal symptoms, headache, balancing difficulty, and vomiting. Tetrabenazine can cause a small increase (about 8 msec) in the corrected QT. RARE: Neuroleptic malignant syndrome and parkinsonism have been rarely reported.
    2) Tetrabenazine therapy may increase the risk of developing depression or suicidal thoughts and/or behaviors. Patients with Huntington's disease may be at an increased risk, especially if receiving other dopamine antagonists.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Effects that have been observed in limited number of exposures include: acute dystonia, oculogyric crisis, nausea and vomiting, sweating, sedation, hypotension, confusion, diarrhea, hallucinations, rubor, and tremor.
    2) SEVERE TOXICITY: Hypotension, syncope, confusion, and hallucinations may develop.
    0.2.3) VITAL SIGNS
    A) WITH THERAPEUTIC USE
    1) Orthostatic hypotension has occurred with therapy. Hyperthermia has been a rare event.
    B) WITH POISONING/EXPOSURE
    1) Based on limited reports, hypotension has developed following overdose.
    0.2.7) NEUROLOGIC
    A) WITH THERAPEUTIC USE
    1) Drowsiness was the most frequently reported symptom associated with tetrabenazine therapy.
    2) Extrapyramidal symptoms (including akathisia and parkinsonism) are relatively common with therapy. As with other drugs that reduce dopaminergic activity, tetrabenazine may be associated with neuroleptic malignant syndrome.
    B) WITH POISONING/EXPOSURE
    1) Based on limited case reports, acute dystonia, oculogyric crisis, drowsiness, sedation, and tremor have been reported following overdose.
    0.2.18) PSYCHIATRIC
    A) WITH THERAPEUTIC USE
    1) Depression and anxiety have been reported with therapy and appear to be dose-related.
    B) WITH POISONING/EXPOSURE
    1) Based on limited data, hallucinations and confusion have been observed in overdose.
    0.2.20) REPRODUCTIVE
    A) Tetrabenazine is classified as FDA pregnancy category C. There are no adequate and well-controlled studies of tetrabenazine use in pregnant women.

Laboratory Monitoring

    A) Drug plasma concentrations are not clinically useful or readily available to guide therapy following exposure.
    B) Monitor vital signs following ingestion. Decreases in blood pressure have been reported.
    C) Monitor fluid and electrolyte status in patients with significant vomiting and/or diarrhea.
    D) Monitor for clinical evidence of neuroleptic malignant syndrome (hyperthermia, autonomic instability, altered mentation, rigidity) following overdose.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Limited case reports of overdose have produced the following symptoms: nausea, vomiting, sweating, sedation, hypotension and confusion. It may be anticipated that symptoms in overdose may be an exacerbation of adverse events.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive; closely monitor neurologic function. Treat significant hypotension with fluids and vasopressors, if necessary.
    C) DECONTAMINATION
    1) PREHOSPITAL: Because of the potential for CNS depression (eg, drowsiness, sedation) with tetrabenazine overdose, emesis is NOT recommended. Activated charcoal may be considered if the ingestion is recent, the patient is alert and the airway can be protected.
    2) HOSPITAL: Activated charcoal may be considered if the ingestion is recent, the patient is alert and the airway can be protected.
    D) AIRWAY MANAGEMENT
    1) Monitor airway status; intubate and ventilate as needed. Drowsiness and sedation are common. Intubation and mechanical ventilation may be necessary if significant CNS depression develops.
    E) ANTIDOTE
    1) None.
    F) ENHANCED ELIMINATION
    1) Enhanced elimination is UNLIKELY to be beneficial due to a relatively high protein binding (range, 82% to 85%).
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: Asymptomatic children (other than mild drowsiness) with a minor (12.5 mg or less) inadvertent ingestion may be monitored at home.
    2) OBSERVATION CRITERIA: All patients with deliberate self-harm ingestions should be evaluated in a healthcare facility and monitored until symptoms resolve. Children with an unintentional ingestion who are symptomatic should be observed in a healthcare facility.
    3) ADMISSION CRITERIA: Patients with a deliberate ingestion that are demonstrating cardiotoxicity, or persistent neurotoxicity should be admitted.
    4) CONSULT CRITERIA: Call a Poison Center for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear.
    H) PITFALLS
    1) When managing a suspected tetrabenazine overdose, the possibility of coingestants should be determined. Extrapyramidal symptoms (including akathisia and parkinsonism), which can occur with therapy, may be related to other causes. Coingestion of other agents that reduce dopaminergic transmission may increase the risk of neuroleptic malignant syndrome.
    I) PHARMACOKINETICS
    1) Peak plasma concentrations of the active metabolites are reached within 90 minutes to 2 hours after ingestion. Approximately, 75% of a dose is absorbed following oral administration. The in vitro protein binding is 82% to 85%, while the in vitro protein binding of the primary metabolites, alpha-HTBZ and beta-HTBZ, are 60% to 68% and 59% to 63%, respectively. Most of the drug is excreted via the kidneys.
    J) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that may reduce dopaminergic activity, neurologic disorders.

Range Of Toxicity

    A) TOXICITY: Limited data. Based on 8 cases of overdose, doses ranging from 100 mg to 1 g produced acute dystonia, drowsiness, oculogyric crisis, hypotension, confusion, diarrhea, hallucinations, rubor, tremor, nausea, vomiting and sweating. Fatalities have not been reported.
    B) THERAPEUTIC DOSE: ADULT: Dosing is individualized, but doses should not exceed 50 mg/day in most individuals. The maximum recommended single dose is 25 mg. PEDIATRIC: The safety and efficacy of tetrabenazine have not been established in children.

Clinical Effects

Summary Of Exposure

    A) USES: Tetrabenazine, a vesicular monamine transporter type 2 (VMAT2) inhibitor, is used in the treatment of chorea that is associated with Huntington's disease.
    B) PHARMACOLOGY: Tetrabenazine is a monoamine depletor whose exact mechanism is unknown. It depletes monoamine such as dopamine, serotonin, norepinephrine, and histamine from nerve terminals. Tetrabenazine reversibly inhibits the human vesicular monoamine transporter type 2 which results in decreased uptake of monoamines into synaptic vesicles and depletion of monoamine stores. In vitro, tetrabenazine exhibits week binding affinity at the dopamine D2 receptor.
    C) TOXICOLOGY: Excessive depletion of monoamines (ie dopamine, serotonin, norepinephrine, histamine) can cause toxic effects.
    D) EPIDEMIOLOGY: Overdose is rare; limited reports of exposure. No fatalities have been reported.
    E) WITH THERAPEUTIC USE
    1) COMMON: Sedation/somnolence, fatigue, insomnia, depression, akathisia, anxiety, and nausea. Other events can include, orthostatic hypotension, dysphagia, extrapyramidal symptoms, headache, balancing difficulty, and vomiting. Tetrabenazine can cause a small increase (about 8 msec) in the corrected QT. RARE: Neuroleptic malignant syndrome and parkinsonism have been rarely reported.
    2) Tetrabenazine therapy may increase the risk of developing depression or suicidal thoughts and/or behaviors. Patients with Huntington's disease may be at an increased risk, especially if receiving other dopamine antagonists.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Effects that have been observed in limited number of exposures include: acute dystonia, oculogyric crisis, nausea and vomiting, sweating, sedation, hypotension, confusion, diarrhea, hallucinations, rubor, and tremor.
    2) SEVERE TOXICITY: Hypotension, syncope, confusion, and hallucinations may develop.

Vital Signs

    3.3.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Orthostatic hypotension has occurred with therapy. Hyperthermia has been a rare event.
    B) WITH POISONING/EXPOSURE
    1) Based on limited reports, hypotension has developed following overdose.
    3.3.3) TEMPERATURE
    A) WITH THERAPEUTIC USE
    1) Hyperthermia has been observed rarely with therapeutic use of tetrabenazine (Stevens et al, 1998; Ossemann et al, 1996; Mateo et al, 1992), and was felt to be likely part of the neuroleptic malignant syndrome in all cases, after potential other causes were ruled out.
    a) CASE REPORT: A 45-year-old man with a history of depression and tardive dyskinesia secondary to neuroleptic drug therapy was started on 75 mg daily of tetrabenazine. Other medications included clomipramine, mianserin and lorazepam. On the day of admission, the patient was confused, agitated and sweating profusely with bizarre dyskinetic movements. Rectal temperature was 41.3 C. Laboratory and diagnostic studies were initially within normal limits except for an elevated WBC. He was treated with cooling measures, dantrolene and bromocriptine therapy; fever resolved within 12 hours. Elevated liver enzymes and creatine kinase (peak 67,000 International Units) were observed on day 4, but resolved without intervention. The patient was discharged on day 10 with pre-existing tardive dyskinesia; tetrabenazine and clomipramine were not restarted (Stevens et al, 1998).
    b) CASE REPORT: A 52-year-old man with Huntington's disease developed hyperthermia (41 degrees C) two weeks after tetrabenazine therapy was increased to 131 mg/day. No other sources for fever were detected. CPK peaked at 42,350 International Units one day following admission and the patient was treated with dantrolene and bromocriptine for suspected NMS. Signs and symptoms quickly improved (Ossemann et al, 1996).
    3.3.4) BLOOD PRESSURE
    A) WITH POISONING/EXPOSURE
    1) Based on limited case reports, hypotension has been reported following overdose (Prod Info XENAZINE(R) oral tablets, 2015).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) PROLONGED QT INTERVAL
    1) WITH THERAPEUTIC USE
    a) Small increases (approximately 8 msec) in corrected QT interval have been reported with tetrabenazine therapy. Concomitant use of other drugs known to prolong the QT interval (eg, antipsychotic drugs, antibiotics, Class 1A and Class III antiarrhythmics) or use in patients with congenital long QT syndrome or a history of cardiac dysrhythmias should be avoided (Prod Info XENAZINE(R) oral tablets, 2015).
    B) ORTHOSTATIC HYPOTENSION
    1) WITH THERAPEUTIC USE
    a) Episodes of orthostatic hypotension have been reported with therapeutic use of tetrabenazine (Prod Info XENAZINE(R) oral tablets, 2015).
    b) INCIDENCE: During a 12-week, double-blind study of patients with chorea associated with Huntington's disease, dizziness was reported in 4% of patients receiving tetrabenazine compared with 0% of patients receiving placebo. Single 25-mg and 50-mg doses of tetrabenazine produced postural dizziness in healthy volunteers, including one with syncope and one with documented orthostasis (Prod Info XENAZINE(R) oral tablets, 2015).
    C) HYPOTENSIVE EPISODE
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 52-year-old man with Huntington's disease inadvertently ingested approximately 500 mg (normal daily dose was 82 mg/daily) of tetrabenazine and developed low blood pressure, falling episodes, nausea, vomiting, diarrhea, hallucinations and worsening confusion. Symptoms improved with temporary drug cessation and the patient was discharged to home on tetrabenazine 100 mg/day (Ossemann et al, 1996).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) DYSPNEA
    1) WITH THERAPEUTIC USE
    a) Shortness of breath was reported in 4% (2/54) of patients receiving tetrabenazine compared with 0% of patients receiving placebo (n=30) during a 12-week, double-blind study of patients with chorea associated with Huntington's disease (Prod Info XENAZINE(R) oral tablets, 2015).
    B) UPPER RESPIRATORY INFECTION
    1) WITH THERAPEUTIC USE
    a) Upper respiratory tract infection was reported in 11% (6 of 54) of patients receiving tetrabenazine compared with 7% (2 of 30) of patients receiving placebo during a 12-week, double-blind study of patients with chorea associated with Huntington's disease (Prod Info XENAZINE(R) oral tablets, 2015).

Neurologic

    3.7.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Drowsiness was the most frequently reported symptom associated with tetrabenazine therapy.
    2) Extrapyramidal symptoms (including akathisia and parkinsonism) are relatively common with therapy. As with other drugs that reduce dopaminergic activity, tetrabenazine may be associated with neuroleptic malignant syndrome.
    B) WITH POISONING/EXPOSURE
    1) Based on limited case reports, acute dystonia, oculogyric crisis, drowsiness, sedation, and tremor have been reported following overdose.
    3.7.2) CLINICAL EFFECTS
    A) DROWSY
    1) WITH THERAPEUTIC USE
    a) Drowsiness was one of the most frequently reported adverse events associated with tetrabenazine therapy (Prod Info XENAZINE(R) oral tablets, 2015; Kenney et al, 2007).
    b) During a 12-week, double-blind study of patients with chorea associated with Huntington's disease, sedation/somnolence was reported in 31% (17 of 54) of patients receiving tetrabenazine compared with 3% (1 of 30) of patients receiving placebo, and resulted in upward titration suspension or dose reduction in 28% (15 of 54) of tetrabenazine-treated patients. All but one patient experienced decreased sedation with dose reduction. During 48-week and 80-week open-label studies, sedation/somnolence was reported in 17% and 57% of tetrabenazine-treated patients, respectively. Symptoms were intolerable in some patients at less-than-efficacious doses (Prod Info XENAZINE(R) oral tablets, 2015).
    c) In a retrospective chart review to evaluate long term tolerability of tetrabenazine in patients (n=448) with involuntary movement disorders treated between 1997 to 2004, drowsiness developed in 25% (112) of patients (Kenney et al, 2007).
    2) WITH POISONING/EXPOSURE
    a) Based on limited case reports, sedation was observed following overdose (the dose ranged from 100 mg to 1 g) (Prod Info XENAZINE(R) oral tablets, 2015).
    b) CASE REPORT - A 27-year-old woman, with a history of physical disability following a head injury and was started on tetrabenazine to treat severe choreoathetosis symptoms, intentionally ingested an estimated 40 25-mg tablets (1 g) of tetrabenazine. Within two hours the patient was drowsy. Vital signs remained stable. Over the next 18 hours, the patient became more drowsy, but was easily arousable. Neurologic improvement was noted at 24 hours, and the patient was fully alert within 48 hours. No permanent sequelae was observed (Kidd & McLellan, 1972).
    B) CENTRAL NERVOUS SYSTEM FINDING
    1) WITH THERAPEUTIC USE
    a) CASE REPORTS - Acute dystonia which included retrocollis and oculogyric crisis occurred in four patients shortly after starting therapy with tetrabenazine. Symptoms were observed after daily doses of 50 to 300 mg, respectively. Episodes resolved with either anticholinergic agents or methylphenidate. The authors suggested that tetrabenazine induced the reactions by its ability to block dopamine transmission (Burke et al, 1985).
    2) WITH POISONING/EXPOSURE
    a) Based on limited case reports, acute dystonia, oculogyric crisis, and tremor were observed following overdose (dose range: 100 mg to 1 g) (Prod Info XENAZINE(R) oral tablets, 2015).
    C) AKATHISIA
    1) WITH THERAPEUTIC USE
    a) Akathisia has been reported frequently with therapeutic use (Prod Info XENAZINE(R) oral tablets, 2015; Kenney et al, 2007).
    b) INCIDENCE: Akathisia was reported in 19% of patients receiving tetrabenazine (n=54) compared with 0% of patients receiving placebo (n=30) during a 12-week, double-blind study of patients with chorea associated with Huntington's disease, and resulted in upward titration suspension or dose reduction in 7 of 54 tetrabenazine-treated patients. Among open-label studies, akathisia was reported in 20% of patients receiving tetrabenazine over 80 weeks and 0% of patients receiving tetrabenazine over 48 weeks (Prod Info XENAZINE(R) oral tablets, 2015).
    c) In a retrospective chart review to evaluate long term tolerability of tetrabenazine in patients (n=448) with involuntary movement disorders treated between 1997 to 2004, akathisia developed in 7.6% (34) of patients (Kenney et al, 2007).
    D) PARKINSONISM
    1) WITH THERAPEUTIC USE
    a) Parkinsonism/bradykinesia was reported in 9% (5 of 54) of patients receiving tetrabenazine compared with 0% of patients receiving placebo (n=30) during a 12-week, double-blind study of patients with chorea associated with Huntington's disease (Prod Info XENAZINE(R) oral tablets, 2015). Symptoms appear to be dose-related. Dose reduction has reduced most CNS effects to a level of tolerability (Jankovic & Orman, 1988a; Asher & Aminoff, 1981a).
    b) Symptoms suggestive of parkinsonism (ie, bradykinesia, hypertonia, and rigidity) were reported in 15% of patients receiving tetrabenazine compared with 0% of patients receiving placebo during a 12-week, double-blind study of patients with chorea associated with Huntington's disease, and resulted in upward titration suspension or dose reduction in 4 of 54 tetrabenazine-treated patients. Among open-label studies, symptoms suggestive of parkinsonism were reported in 10% of patients receiving tetrabenazine over 48 weeks and 3% of patients receiving tetrabenazine over 80 weeks (Prod Info XENAZINE(R) oral tablets, 2015).
    c) Parkinsonism was one of the most frequently reported adverse events, occurring in 11.8% of patients treated with tetrabenazine for involuntary movements which were troubling or disabling despite optimal conventional therapy, according to a retrospective chart review of 518 patients. Patients included in the study had a variety of moderate-to-severe (severity = 2.7 +/- 0.7) hyperkinetic movement disorders, with chorea being the more common (31.3%), followed by dyskinesia (30.1%) and dystonia (27.4%). The mean dose of tetrabenazine was 53 +/- 30.7 mg/day for a mean duration of 29.7 months and a maximum duration of follow-up of 21.6 years (Kenney et al, 2006).
    d) In one large series of patients with movement disorders (n=217), parkinsonian symptoms occurred in 24% of patients. There was no correlation between the type of movement disorder and susceptibility to CNS adverse effects. Rarely exacerbation of head tremor was observed (Jankovic & Orman, 1988a).
    E) INSOMNIA
    1) WITH THERAPEUTIC USE
    a) Insomnia was reported in 22% (12 of 54) of patients receiving tetrabenazine compared with 0% of patients receiving placebo (n=30) during a 12-week, double-blind study of patients with chorea associated with Huntington's disease (Prod Info XENAZINE(R) oral tablets, 2015).
    F) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) Dizziness has been reported with therapeutic use (None Listed, 2006; Prod Info XENAZINE(R) oral tablets, 2015; Kenney et al, 2007).
    b) During a 12-week, double-blind study of patients with chorea associated with Huntington's disease, dizziness was reported in 4% of patients receiving tetrabenazine compared with 0% of patients receiving placebo. Single 25-mg and 50-mg doses of tetrabenazine produced postural dizziness in healthy volunteers, including one with syncope and one with documented orthostasis (Prod Info XENAZINE(R) oral tablets, 2015).
    G) HEADACHE
    1) WITH THERAPEUTIC USE
    a) Headache was reported in 4% (2 of 54) of patients receiving tetrabenazine compared with 3% (1 of 30) of patients receiving placebo during a 12-week, double-blind study of patients with chorea associated with Huntington's disease (Prod Info XENAZINE(R) oral tablets, 2015).
    H) NEUROLEPTIC MALIGNANT SYNDROME
    1) WITH THERAPEUTIC USE
    a) Neuroleptic malignant syndrome (NMS) has been associated with drugs that reduce dopaminergic transmission, including tetrabenazine. Symptoms include hyperpyrexia, muscle rigidity, autonomic instability, and altered mental status, and may also include elevated CPK levels, myoglobinuria, rhabdomyolysis, and acute renal failure. If NMS does occur, all antipsychotic medications and other drugs not essential to concurrent therapy should be discontinued, intensive symptomatic treatment and medical monitoring should be initiated, and treatment of any concomitant serious medical problems should occur. Careful consideration of reintroduction of tetrabenazine after a patient has experienced NMS should be taken; recurrences have been reported (Prod Info XENAZINE(R) oral tablets, 2015).
    b) CASE REPORTS: A 53-year-old woman with chronic generalized chorea (severity score of 75%) developed symptoms consistent with NMS (ie, hyperthermia {axillary temperature 41.0 C}, altered consciousness and severe generalized flexor rigidity) approximately 19 days after starting tetrabenazine 100 mg daily. Laboratory studies, including blood and CSF cultures, were negative with the exception of an elevated CK (peak: 2850 International Units/L). Tetrabenazine was stopped and symptoms improved within 24 hours with the gradual return of chorea symptoms. About one week after stopping therapy, tetrabenazine was gradually restarted and the patient tolerated 75 mg daily with a chorea score of 10% (Mateo et al, 1992).
    c) CASE REPORT - A 52-year-old man with Huntington's disease developed hyperthermia (41.0 C) two weeks after tetrabenazine therapy was increased to 131 mg/day. No other sources for fever were detected. CPK peaked at 42,350 International Units one day following admission and the patient was treated with dantrolene and bromocriptine for suspected NMS. Signs and symptoms quickly improved (Ossemann et al, 1996).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) Nausea occurred in 13% (7/54), and vomiting was reported in 6% (3/54) of patients receiving tetrabenazine compared with 7% (2/30) and 3% (1/30) of patients, respectively receiving placebo during a 12-week, double-blind study of patients with chorea associated with Huntington's disease (Prod Info XENAZINE(R) oral tablets, 2015).
    2) WITH POISONING/EXPOSURE
    a) Based on limited case reports, nausea, vomiting and diarrhea have been reported following overdose (Prod Info XENAZINE(R) oral tablets, 2015; Ossemann et al, 1996).
    B) DYSPHAGIA
    1) WITH THERAPEUTIC USE
    a) Dysphagia (some cases associated with aspiration pneumonia) was reported in 4% of patients receiving tetrabenazine compared with 3% of patients receiving placebo during a 12-week, double-blind study of patients with chorea associated with Huntington's disease (Prod Info XENAZINE(R) oral tablets, 2015).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) DYSURIA
    1) WITH THERAPEUTIC USE
    a) Dysuria was reported in 4% (2/54) of patients receiving tetrabenazine compared with 0% of patients receiving placebo (n=30) during a 12-week, double-blind study of patients with chorea associated with Huntington's disease (Prod Info XENAZINE(R) oral tablets, 2015).
    B) GENITOURINARY SYMPTOMS
    1) WITH THERAPEUTIC USE
    a) Reduced libido and/or impotence have been reported rarely during therapy (less than 1% of patients) (Jankovic, 1982a; Jankovic & Orman, 1988a).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) SWEATING
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 27-year-old woman, with a history of physical disability following a head injury and was started on tetrabenazine to treat severe choreoathetosis symptoms, intentionally ingested an estimated 40 25-mg tablets (1 g) of tetrabenazine. Within 2 hours the patient was drowsy, and profuse sweating was observed approximately 5 hours after exposure. Axillary temperature was 94.4 F. The authors suggested that tetrabenazine may have caused a disruption in central thermoregulation. However, blood levels were not drawn; the patient recovered within 48 hours following close observation (Kidd & McLellan, 1972).
    b) CASE REPORTS: Profuse sweating along with hyperthermia was reported in an adult receiving tetrabenazine 75 mg daily along with clomipramine, mianserin and lorazepam. The patient was treated for suspected neuroleptic malignant syndrome and recovered completely (Stevens et al, 1998).

Reproductive

    3.20.1) SUMMARY
    A) Tetrabenazine is classified as FDA pregnancy category C. There are no adequate and well-controlled studies of tetrabenazine use in pregnant women.
    3.20.3) EFFECTS IN PREGNANCY
    A) LACK OF INFORMATION
    1) There are no adequate and well-controlled studies of tetrabenazine use in pregnant women (Prod Info XENAZINE(R) oral tablets, 2015).
    B) PREGNANCY CATEGORY
    1) Tetrabenazine is classified by the manufacturer as FDA pregnancy category C (Prod Info XENAZINE(R) oral tablets, 2015).
    C) ANIMAL STUDIES
    1) Pregnant animals given tetrabenazine during organogenesis experienced no effects on embryo-fetal development at doses up to 3 times the maximum recommended human dose [MRHD] of 100 mg/day on a mg/m(2) basis and up to 12 times the MRHD on a mg/m(2) basis, respectively (Prod Info XENAZINE(R) oral tablets, 2015).
    2) STILLBIRTHS
    a) When pregnant animals were administered oral tetrabenazine 5, 15 or 30 mg/kg/day during organogenesis through the lactation period, the incidence of stillbirths and offspring postnatal mortality was increased at doses of 15 mg/kg/day and 30 mg/kg/day, while delayed pup maturation was increased at all doses. The stillbirth and postnatal morality no effect dose was 0.5 times the maximum recommended human dose on a mg/m(2) basis (Prod Info XENAZINE(R) oral tablets, 2015).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) It is not known whether tetrabenazine or its metabolites are excreted into human breast milk. The drug or nursing should be discontinued given the importance of the drug to the mother (Prod Info XENAZINE(R) oral tablets, 2015).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Drug plasma concentrations are not clinically useful or readily available to guide therapy following exposure.
    B) Monitor vital signs following ingestion. Decreases in blood pressure have been reported.
    C) Monitor fluid and electrolyte status in patients with significant vomiting and/or diarrhea.
    D) Monitor for clinical evidence of neuroleptic malignant syndrome (hyperthermia, autonomic instability, altered mentation, rigidity) following overdose.

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 with a deliberate ingestion that are demonstrating cardiotoxicity or persistent neurotoxicity should be admitted.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Asymptomatic children (other than mild drowsiness) with a minor (12.5 mg or less) inadvertent ingestion may be monitored at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Call a Poison Center for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) All patients with deliberate self-harm ingestions should be evaluated in a healthcare facility and monitored until symptoms resolve. Children with an unintentional ingestion who are symptomatic should be observed in a healthcare facility.

Monitoring

    A) Drug plasma concentrations are not clinically useful or readily available to guide therapy following exposure.
    B) Monitor vital signs following ingestion. Decreases in blood pressure have been reported.
    C) Monitor fluid and electrolyte status in patients with significant vomiting and/or diarrhea.
    D) Monitor for clinical evidence of neuroleptic malignant syndrome (hyperthermia, autonomic instability, altered mentation, rigidity) following overdose.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) SUMMARY
    1) Because of the potential for CNS depression (drowsiness, sedation) with tetrabenazine overdose, emesis is NOT recommended.
    B) ACTIVATED CHARCOAL
    1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    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).
    6.5.2) PREVENTION OF ABSORPTION
    A) 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. Limited case reports of overdose have produced the following symptoms: nausea, vomiting, sweating, sedation, hypotension and confusion. It may be anticipated that symptoms in overdose may be an exacerbation of adverse events.
    2) MANAGEMENT OF SEVERE TOXICITY
    a) Treatment is symptomatic and supportive; closely monitor neurologic function. Treat significant hypotension with fluids and vasopressors, if necessary.
    B) MONITORING OF PATIENT
    1) Monitor vital signs including blood pressure following exposure.
    2) Monitor CNS function. Drowsiness and sedation are common.
    3) Assess respiratory function and airway status following a significant exposure.
    4) Routine laboratory studies are not indicated. Monitor fluid and electrolyte status as necessary in patients with significant vomiting and/or diarrhea.
    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) SUMMARY
    1) Enhanced elimination is UNLIKELY to be beneficial due to a relatively high protein binding (range, 82% to 85%) (Prod Info XENAZINE(R) oral tablets, 2015).

Range Of Toxicity

Summary

    A) TOXICITY: Limited data. Based on 8 cases of overdose, doses ranging from 100 mg to 1 g produced acute dystonia, drowsiness, oculogyric crisis, hypotension, confusion, diarrhea, hallucinations, rubor, tremor, nausea, vomiting and sweating. Fatalities have not been reported.
    B) THERAPEUTIC DOSE: ADULT: Dosing is individualized, but doses should not exceed 50 mg/day in most individuals. The maximum recommended single dose is 25 mg. PEDIATRIC: The safety and efficacy of tetrabenazine have not been established in children.

Therapeutic Dose

    7.2.1) ADULT
    A) DOSES UP TO 50 MG: INITIAL DOSE: 12.5 mg orally once daily; after 1 week, increase to 25 mg divided into 12.5 mg twice daily doses; titrate slowly at weekly intervals by 12.5 mg daily; if 37.5 to 50 mg is required, divide the dose into 3 doses per day; the maximum recommended single dose is 25 mg (Prod Info XENAZINE(R) oral tablets, 2015).
    B) DOSES OVER 50 MG: Patients should be genotyped for CYP2D6 expression if doses above 50 mg are required (Prod Info XENAZINE(R) oral tablets, 2015).
    7.2.2) PEDIATRIC
    A) The safety and efficacy of tetrabenazine have not been evaluated in children (Prod Info XENAZINE(R) oral tablets, 2015).

Minimum Lethal Exposure

    A) At the time of this review, a minimum lethal dose has not been established.

Maximum Tolerated Exposure

    A) SUMMARY
    1) Based on 8 cases of overdose, doses ranging from 100 mg to 1 g produced acute dystonia, oculogyric crisis, hypotension, confusion, diarrhea, hallucinations, rubor, tremor, nausea, vomiting and sweating (Prod Info XENAZINE(R) oral tablets, 2015).
    B) CASE REPORT: A 52-year-old man with Huntington's disease inadvertently ingested approximately 500 mg (normal daily dose was 82 mg/daily) of tetrabenazine and developed low blood pressure, falling episodes, nausea, vomiting, diarrhea, hallucinations and worsening confusion. Symptoms improved with temporary drug cessation and the patient was discharged to home on tetrabenazine 100 mg/day (Ossemann et al, 1996).
    C) CASE REPORT: A 27-year-old woman, with a history of physical disability following a head injury and was started on tetrabenazine to treat severe choreoathetosis symptoms, intentionally ingested an estimated 40 25-mg tablets (total = 1 g). Within 2 hours the patient was drowsy. Vital signs remained stable. Profuse sweating was observed approximately 5 hours after exposure. Over the next 18 hours, the patient became more drowsy, but was easily arousable. Neurologic improvement was noted at 24 hours, and the patient was fully alert within 48 hours. No permanent sequelae occurred (Kidd & McLellan, 1972).

Serum Plasma Blood Concentrations

    7.5.1) THERAPEUTIC CONCENTRATIONS
    A) THERAPEUTIC CONCENTRATION LEVELS
    1) Peak plasma concentrations of the active metabolites are reached within 90 minutes to 2 hours post-dosing (Prod Info XENAZINE(R) oral tablets, 2015).
    2) Following a single 25-mg dose, the mean Tmax of alpha-HTBZ and beta-HTBZ was approximately 1.75 hours in patients with mild to moderate chronic hepatic impairment (Child-Pugh score 5 to 9) compared to 1 hour in healthy subjects (Prod Info XENAZINE(R) oral tablets, 2015).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Tetrabenazine is a monoamine depletor whose exact mechanism is unknown. It depletes monoamine such as dopamine, serotonin, norepinephrine, and histamine from nerve terminals. Tetrabenazine reversibly inhibits the human vesicular monoamine transporter type 2 which results in decreased uptake of monoamines into synaptic vesicles and depletion of monoamine stores. In vitro, tetrabenazine exhibits week binding affinity at the dopamine D2 receptor (Prod Info XENAZINE(R) oral tablets, 2015).
    B) Tetrabenazine is a benzoquinolizine derivative used for the treatment of dyskinetic disorders (Jankovic & Orman, 1988; Asher & Aminoff, 1981). The drug was initially developed as a neuroleptic agent (Schreiber et al, 1999).
    C) Tetrabenazine depletes cerebral monoamines, and also exhibits dopamine-receptor antagonist activity (Schildkraut et al, 1969; Asher & Aminoff, 1981; Jankovic & Orman, 1988; Schreiber et al, 1999). All major central neurotransmitters (dopamine, norepinephrine, serotonin) are depleted equally by tetrabenazine; there is also a modest reduction in levels of acetylcholine, glutamate and aspartate (Jankovic, 1982). Depletion of brain monoamines occurs via inhibition of vesicular storage; in vitro studies have indicated the ability of tetrabenazine to inhibit the human vesicular monoamine transporter isoform 2 (hVMAT2) (Schreiber et al, 1999).
    D) The mechanism of action of tetrabenazine resembles that of reserpine, although there are some differences. The duration of action of tetrabenazine is shorter, possibly related to reversible monoamine depletion (compared to irreversible depletion with reserpine) (Jankovic, 1982; Jankovic & Orman, 1988). Clinically, tetrabenazine has displayed a more rapid onset of action and appears to be associated with a lower incidence of depression and postural hypotension than reserpine (Jankovic, 1982).

Toxicologic Mechanism

    A) Alterations in CNS function (ie, depression, suicidal thoughts, somnolence, sedation, akathisia) may occur in overdose (Prod Info XENAZINE(R) oral tablets, 2015).

References

General Bibliography

    1) Alaspaa AO, Kuisma MJ, Hoppu K, et al: Out-of-hospital administration of activated charcoal by emergency medical services. Ann Emerg Med 2005; 45:207-12.
    2) Asher SW & Aminoff MJ: Tetrabenazine and movement disorders. Neurology 1981; 31:1051-1054.
    3) Asher SW & Aminoff MJ: Tetrabenazine and movement disorders. Neurology 1981a; 31:1051-1054.
    4) Burke RE, Reches A, Traub MM, et al: Tetrabenazine induces acute dystonic reactions. Ann Neurol 1985; 17(2):200-202.
    5) Chyka PA, Seger D, Krenzelok EP, et al: Position paper: Single-dose activated charcoal. Clin Toxicol (Phila) 2005; 43(2):61-87.
    6) Dagnone D, Matsui D, & Rieder MJ: Assessment of the palatability of vehicles for activated charcoal in pediatric volunteers. Pediatr Emerg Care 2002; 18:19-21.
    7) Elliot CG, Colby TV, & Kelly TM: Charcoal lung. Bronchiolitis obliterans after aspiration of activated charcoal. Chest 1989; 96:672-674.
    8) FDA: Poison treatment drug product for over-the-counter human use; tentative final monograph. FDA: Fed Register 1985; 50:2244-2262.
    9) Frank S, Ondo W, Fahn S, et al: A study of chorea after tetrabenazine withdrawal in patients with Huntington disease. Clin Neuropharmacol 2008; 31(3):127-133.
    10) Golej J, Boigner H, Burda G, et al: Severe respiratory failure following charcoal application in a toddler. Resuscitation 2001; 49:315-318.
    11) Graff GR, Stark J, & Berkenbosch JW: Chronic lung disease after activated charcoal aspiration. Pediatrics 2002; 109:959-961.
    12) Guenther Skokan E, Junkins EP, & Corneli HM: Taste test: children rate flavoring agents used with activated charcoal. Arch Pediatr Adolesc Med 2001; 155:683-686.
    13) Harris CR & Filandrinos D: Accidental administration of activated charcoal into the lung: aspiration by proxy. Ann Emerg Med 1993; 22:1470-1473.
    14) Jankovic J & Orman J: Tetrabenazine therapy of dystonia, chorea, tics, and other dyskinesias. Neurology 1988; 38:391-394.
    15) Jankovic J & Orman J: Tetrabenazine therapy of dystonia, chorea, tics, and other dyskinesias. Neurology 1988a; 38:391-394.
    16) Jankovic J: Treatment of hyperkinetic movement disorders with tetrabenazine: a double-blind crossover study. Ann Neurol 1982; 11:41-47.
    17) Jankovic J: Treatment of hyperkinetic movement disorders with tetrabenazine: a double-blind crossover study. Ann Neurol 1982a; 11:41-47.
    18) Kenney C, Hunter C, & Jankovic J: Long-term tolerability of tetrabenazine in the treatment of hyperkinetic movement disorders. Mov Disord 2007; 22(2):193-197.
    19) Kenney C, Hunter C, Mejia N, et al: Is history of depression a contraindication to treatment with tetrabenazine?. Clin Neuropharmacol 2006; 29(5):259-264.
    20) Kidd DW & McLellan DL: Self-poisoning with tetrabenazine. Br J Clin Pract 1972; 26(4):179-180.
    21) Kleinman ME, Chameides L, Schexnayder SM, et al: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Part 14: pediatric advanced life support. Circulation 2010; 122(18 Suppl.3):S876-S908.
    22) Mateo D, Munoz-Blanco JL, & Gimenez-Roldan S: Neuroleptic malignant syndrome related to tetrabenazine introduction and haloperidol discontinuation in Huntington's disease. Clin Neuropharmacol 1992; 15(1):63-68.
    23) Mikkelsen BO: Tolerance of tetrabenazine during long-term treatment. Acta Neurol Scand 1983; 68(1):57-60.
    24) None Listed: Position paper: cathartics. J Toxicol Clin Toxicol 2004; 42(3):243-253.
    25) None Listed: Tetrabenazine as antichorea therapy in Huntington disease: a randomized controlled trial. Neurology 2006; 66(3):366-372.
    26) Ossemann M, Sindic CJ, & Laterre C: Tetrabenazine as a cause of neuroleptic malignant syndrome. Mov Disord 1996; 11(1):95-.
    27) Peberdy MA , Callaway CW , Neumar RW , et al: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care science. Part 9: post–cardiac arrest care. Circulation 2010; 122(18 Suppl 3):S768-S786.
    28) Pollack MM, Dunbar BS, & Holbrook PR: Aspiration of activated charcoal and gastric contents. Ann Emerg Med 1981; 10:528-529.
    29) Product Information: Nitoman(R), tetrabenazine. Hoffmann-La Roche Limited, Mississauga, Ontario, Canada, 99.
    30) Product Information: XENAZINE(R) oral tablets, tetrabenazine oral tablets. Prestwick Pharmaceuticals,Inc, Washington, DC, 2008.
    31) Product Information: XENAZINE(R) oral tablets, tetrabenazine oral tablets. Lundbeck (per FDA), Deerfield, IL, 2015.
    32) Product Information: dopamine hcl, 5% dextrose IV injection, dopamine hcl, 5% dextrose IV injection. Hospira,Inc, Lake Forest, IL, 2004.
    33) Product Information: norepinephrine bitartrate injection, norepinephrine bitartrate injection. Sicor Pharmaceuticals,Inc, Irvine, CA, 2005.
    34) Rau NR, Nagaraj MV, Prakash PS, et al: Fatal pulmonary aspiration of oral activated charcoal. Br Med J 1988; 297:918-919.
    35) Schildkraut JJ, Schanberg SM, Kopin IJ, et al: Affective disorders and norepinephrine pharmacology. Int Psychiatry Clin 1969; 6(2):83-141.
    36) Schreiber W, Krieg J-C, & Eichhorn T: Reversal of tetrabenazine induced depression by selective noradrenaline (norepinephrine) reuptake inhibition (letter). J Neurol Neurosurg Psychiatr 1999; 67(4):550.
    37) Schreiber W, Krieg J-C, & Eichhorn T: Reversal of tetrabenazine induced depression by selective noradrenaline (norepinephrine) reuptake inhibition (letter). J Neurol Neurosurg Psychiatr 1999a; 67(4):550.
    38) Spiller HA & Rogers GC: Evaluation of administration of activated charcoal in the home. Pediatrics 2002; 108:E100.
    39) Stevens E, Roman A, Houa M, et al: Severe hyperthermia during tetrabenazine therapy for tardive dyskinesia. Intensive Care Med 1998; 24(4):369-371.
    40) Thakore S & Murphy N: The potential role of prehospital administration of activated charcoal. Emerg Med J 2002; 19:63-65.