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PIMOZIDE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Pimozide belongs to the diphenylbutylpiperidine group of neuroleptics. Pimozide is an orally active antipsychotic drug, which shares with other antipsychotics the ability to block dopaminergic receptors on neurons in the central nervous system.

Specific Substances

    1) 2H-Benzimidazol-2-one, 1-(1-(4,4-bis (4-fluorophenyl)butyl)-4-piperidinyl)-1,3-dihydro
    2) Orap
    3) Opiran
    4) R-6238
    5) CAS 2062-78-4

Available Forms Sources

    A) FORMS
    1) Pimozide is available as 1 and 2 mg tablets (Prod Info ORAP(R) oral tablets, 2011).
    B) USES
    1) Pimozide is used for the suppression of motor and phonic tics in adults and children 12 years of age and older with Tourette's disorder who have failed to adequately respond to standard treatment (Prod Info ORAP(R) oral tablets, 2011).

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: Pimozide is used for the suppression of motor and phonic tics in adults and children 12 years of age and older with Tourette's disorder who have failed to adequately respond to standard treatment.
    B) PHARMACOLOGY: The exact mechanism of action has not been established; however, pimozide blocks dopamine receptors in the central nervous system (CNS). The efficacy of pimozide in suppressing the tics of Tourette's syndrome is thought to be due to dopaminergic blockade. Secondary changes in central dopamine function and metabolism, including increased brain turnover of dopamine, may contribute to both the therapeutic and the adverse effects of pimozide.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) Adverse effects following pimozide include hypotension, cardiac dysrhythmias, including QTc prolongation and torsade de pointes, extrapyramidal effects, anorexia, nausea, vomiting, increased salivation, diarrhea, constipation, sedation, facial swelling, seizures, amenorrhea, galactorrhea, xerostomia, dysphoria, lethargy, and depression.
    2) DRUG INTERACTION: CYP 2D6 AND CYP 3A4 INHIBITORS: Pimozide is metabolized by CYP 2D6 and CYP 3A4. The concurrent administration of pimozide and strong CYP 2D6 or CYP 3A4 inhibitors is contraindicated due to the possibility of significantly increased pimozide plasma concentrations resulting in a dangerous risk of pimozide toxicity.
    E) WITH POISONING/EXPOSURE
    1) Overdose data are limited. Overdose effects are anticipated to be an extension of adverse effects following therapeutic doses. Extrapyramidal effects (muscle stiffness, perioral dyskinesia, tremors), hypotension, and cardiac dysrhythmias, including QTc prolongation and torsade de pointes may occur following an overdose. Severe overdoses may result in a comatose state with respiratory depression.
    0.2.20) REPRODUCTIVE
    A) Pimozide is classified as FDA pregnancy category C. When pimozide was given to rats and rabbits during various periods of pregnancy, no increase in teratogenic effects were noted. No studies have been done in humans; however, third-trimester antipsychotic drug exposure has been associated with extrapyramidal and/or withdrawal symptoms in neonates.
    0.2.21) CARCINOGENICITY
    A) Increases in pituitary and mammary tumors have been observed in mice.

Laboratory Monitoring

    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs and mental status.
    C) Obtain an ECG, and institute continuous cardiac monitoring in symptomatic patients.
    D) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.

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 seizures with IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur. Treat severe hypotension with IV fluid. Add dopamine or norepinephrine if unresponsive to fluids. Therapeutic doses of pimozide may cause prolongation of the QT interval. Concomitant use of pimozide and other drugs that prolong the QT interval may increase the risk of torsades de pointes. Treat torsades de pointes with IV magnesium sulfate, and correct electrolyte abnormalities, overdrive pacing may be necessary. Treat ventricular dysrhythmias using ACLS protocols. Manage dystonic reactions with anticholinergic agents.
    C) DECONTAMINATION
    1) PREHOSPITAL: Prehospital gastrointestinal decontamination is generally not recommended because of the potential for CNS depression or persistent seizures and subsequent aspiration.
    2) HOSPITAL: Consider activated charcoal if the overdose is recent, the patient is not vomiting, and is able to maintain airway.
    D) AIRWAY MANAGEMENT
    1) Ensure adequate ventilation and perform endotracheal intubation early in patients with life-threatening cardiac dysrhythmias, CNS or respiratory depression, or persistent seizures.
    E) ANTIDOTE
    1) None
    F) PROLONGED QT INTERVAL
    1) Institute continuous cardiac monitoring and obtain serial ECGs in all symptomatic patients or following significant exposures; prolonged QT interval has developed with therapy and in overdose.
    G) TORSADE DE POINTES
    1) Hemodynamically unstable patients require electrical cardioversion. Treat stable patients with magnesium and/or atrial overdrive pacing. Correct electrolyte abnormalities (ie, hypomagnesemia, hypokalemia, hypocalcemia).
    H) DYSTONIA
    1) Treat adult patients with benztropine or diphenhydramine. Treat children with diphenhydramine.
    I) ENHANCED ELIMINATION
    1) Hemodialysis is UNLIKELY to be of value because of the high degree of protein binding.
    J) PATIENT DISPOSITION
    1) HOME CRITERIA: A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    2) OBSERVATION CRITERIA: Pimozide has a long half-life (55 to 66 hours). Patients with a deliberate overdose, and those who are symptomatic should be observed with frequent monitoring of vital signs, considering the long half-life of pimozide. Patients that remain asymptomatic can be discharged.
    3) ADMISSION CRITERIA: Patients with persistent cardiac dysrhythmias, CNS depression, seizures, and respiratory failure should be admitted to an ICU setting.
    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.
    K) PITFALLS
    1) When managing a suspected pimozide overdose, the possibility of multidrug involvement should be considered.
    L) PHARMACOKINETICS
    1) Tmax: Oral: 6 to 8 hours. Bioavailability, Oral: More than 50%. Protein binding: 99%. Metabolism: Liver: extensive, primarily via CYP3A4. Excretion: Renal excretion is the major route of elimination of pimozide and its metabolites. Elimination half-life: 55 to 66 hours.
    M) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that cause hypotension (eg, vasodilators, beta blockers, calcium channel blockers), extrapyramidal effects (eg, antipsychotics, neuroleptics), or cardiac dysrhythmias.

Range Of Toxicity

    A) TOXICITY: An association with sudden death in schizophrenic patients has been postulated from doses in the 1 mg/kg range. The mechanism may be from prolongation of the QT interval. The manufacturer of pimozide has reported sudden, unexpected deaths and grand mal seizures in some patients taking doses greater than 20 mg/day. However, acute ingestion of 60 mg in a 2.5-year-old child produced only mild effects. Ingestion of 100 mg in a 17-year-old girl also did not produce serious problems. An adult survived an acute pimozide overdose of 800 mg.
    B) THERAPEUTIC DOSES: ADULT: TOURETTE'S SYNDROME: Initial, 1 to 2 mg a day orally in divided doses; may increase dosage gradually every other day; usual maintenance dose is less than 10 mg/day or 0.2 mg/kg/day, whichever is smaller; doses greater than 10 mg/day or 0.2 mg/kg/day are not recommended. PSYCHOSIS: 2 to 20 mg every day have been used. CHILD: TOURETTE'S SYNDROME: Age 12 years and older: Initial, 0.05 mg/kg/day orally preferably taken once at bedtime; the dosage may be increased every third day up to a MAX dose of 0.2 mg/kg/day not to exceed 10 mg/day. Safety and efficacy have not been established for use in children less than 12 years of age.

Clinical Effects

Summary Of Exposure

    A) USES: Pimozide is used for the suppression of motor and phonic tics in adults and children 12 years of age and older with Tourette's disorder who have failed to adequately respond to standard treatment.
    B) PHARMACOLOGY: The exact mechanism of action has not been established; however, pimozide blocks dopamine receptors in the central nervous system (CNS). The efficacy of pimozide in suppressing the tics of Tourette's syndrome is thought to be due to dopaminergic blockade. Secondary changes in central dopamine function and metabolism, including increased brain turnover of dopamine, may contribute to both the therapeutic and the adverse effects of pimozide.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) Adverse effects following pimozide include hypotension, cardiac dysrhythmias, including QTc prolongation and torsade de pointes, extrapyramidal effects, anorexia, nausea, vomiting, increased salivation, diarrhea, constipation, sedation, facial swelling, seizures, amenorrhea, galactorrhea, xerostomia, dysphoria, lethargy, and depression.
    2) DRUG INTERACTION: CYP 2D6 AND CYP 3A4 INHIBITORS: Pimozide is metabolized by CYP 2D6 and CYP 3A4. The concurrent administration of pimozide and strong CYP 2D6 or CYP 3A4 inhibitors is contraindicated due to the possibility of significantly increased pimozide plasma concentrations resulting in a dangerous risk of pimozide toxicity.
    E) WITH POISONING/EXPOSURE
    1) Overdose data are limited. Overdose effects are anticipated to be an extension of adverse effects following therapeutic doses. Extrapyramidal effects (muscle stiffness, perioral dyskinesia, tremors), hypotension, and cardiac dysrhythmias, including QTc prolongation and torsade de pointes may occur following an overdose. Severe overdoses may result in a comatose state with respiratory depression.

Vital Signs

    3.3.3) TEMPERATURE
    A) WITH THERAPEUTIC USE
    1) Severe hyperpyrexia requiring discontinuance of therapy was reported in 1 of 20 patients (Huber et al, 1971).
    3.3.4) BLOOD PRESSURE
    A) WITH THERAPEUTIC USE
    1) HYPOTENSION has been reported (Pinder et al, 1976).
    3.3.5) PULSE
    A) WITH POISONING/EXPOSURE
    1) Tachycardia was reported in an 18-month-old child following an inadvertent pimozide ingestion of up to 6 milligrams (Gair et al, 2004).

Heent

    3.4.2) HEAD
    A) WITH THERAPEUTIC USE
    1) FACIAL EDEMA has been reported (Morris et al, 1979).
    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) PIGMENTATION: A single case of retinal pigmentation was reported in a patient on long-term fluphenazine who also received pimozide and haloperidol (McQueen, 1983). Other authors indicated no changes in ocular pigmentation as noted by slit-lamp examination (Pinder et al, 1976).
    2) BLEPHAREDEMA has been reported (Morris et al, 1970).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) PROLONGED QT INTERVAL
    1) WITH THERAPEUTIC USE
    a) ECG changes, including prolonged QT interval, flattening, notching and inversion of the T wave and the appearance of U waves have been reported with pimozide therapy. Sudden death may occur with pimozide doses greater than 20 mg/day (Prod Info ORAP(R) oral tablets, 2011).
    b) About 25% of patients taking therapeutic dosages of pimozide have prolonged QT intervals similar to those caused by the phenothiazines (Anon, 1985).
    c) Drug interactions with drugs inhibiting metabolism of pimozide and resulting in increased plasma concentrations could result in QT prolongation (Anon, 1999).
    2) WITH POISONING/EXPOSURE
    a) Prolongation of the QTc interval may occur after an overdose (Gair et al, 2004).
    b) CASE REPORT: Krahenbuhl et al (1995) report a case of reversible QTc prolongation with ventricular bigeminy and torsade de pointes in a 53-year-old woman, with a previous diagnosis of schizophrenia, who ingested 800 mg of pimozide in a suicide attempt. Complete recovery ensued following treatment with lidocaine and magnesium (Krahenbuhl et al, 1995).
    c) CASE REPORT: Following an inadvertent pimozide ingestion of up to 6 milligrams in an 18-month-old child, QTc was 420 msec at about 2 hours postingestion and increased to 440 msec at 12 hours postingestion. Over the next 12 hours, QTc decreased to 370 msec without treatment (Gair et al, 2004).
    B) CONDUCTION DISORDER OF THE HEART
    1) WITH THERAPEUTIC USE
    a) An association with sudden death in schizophrenic patients has been postulated from doses in the 1 mg/kg range. The mechanism may be from prolongation of the QT interval (Anon, 1985; Fulop et al, 1987).
    b) The manufacturer of pimozide has reported sudden, unexpected deaths in some patients taking doses greater than 20 mg/day (Prod Info ORAP(R) oral tablets, 2011).
    2) WITH POISONING/EXPOSURE
    a) ECG abnormalities may occur following an overdose (Prod Info ORAP(R) oral tablets, 2011).
    C) HYPOTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) Hypotension has been reported (Prod Info ORAP(R) oral tablets, 2011; Pinder et al, 1976).
    2) WITH POISONING/EXPOSURE
    a) Hypotension may commonly occur following an overdose (Prod Info ORAP(R) oral tablets, 2011).
    b) CASE REPORT: Following an inadvertent ingestion of up to 6 mg of pimozide, an 18-month-old child developed tachycardia and hypotension (blood pressure 75/40 mmHg) at 12 hours post-ingestion (Gair et al, 2004).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) ACUTE RESPIRATORY INSUFFICIENCY
    1) WITH POISONING/EXPOSURE
    a) Severe overdoses may result in a comatose state with respiratory depression (Prod Info ORAP(R) oral tablets, 2011).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) SEIZURE
    1) WITH THERAPEUTIC USE
    a) Pimozide may lower the seizure threshold in both epileptic and non-epileptic patients (Pinder et al, 1976). Grand mal seizures have been reported with pimozide doses greater than 20 mg/day (Prod Info ORAP(R) oral tablets, 2011).
    b) CASE SERIES: In one study, 13.3% (n=30) of patients taking pimozide developed slight tremor and two of these had slight rigidity on doses increasing to 9 mg per day (Morris et al, 1970).
    c) CASE REPORTS: Burkitt & Faulkner (1972) described seizures in three patients with no prior history of seizures and no exposure to epileptogenic drugs. All had been given pimozide and all had the dosage reduced or stopped prior to the seizures. The interval between the dosage change and the onset of seizures was 13 to 31 days. The dose given was not stated (Burkitt & Faulkner, 1972).
    B) EXTRAPYRAMIDAL DISEASE
    1) WITH THERAPEUTIC USE
    a) Extrapyramidal reactions with Parkinson-like symptoms are the most frequent side effects of pimozide. These symptoms are usually mild to moderately severe and reversible. Motor restlessness, dystonia, akathisia, hyperreflexia, opisthotonos, and oculogyric crisis have also been reported. Extrapyramidal reactions are generally dose-related in most patients and have been reversed by dose reduction in the majority (Prod Info ORAP(R) oral tablets, 2011).
    b) Tardive dyskinesia (TD) due to pimozide seems to be rare, occurring in some patients on long-term therapy or after drug therapy has been discontinued. The risk may be greater for elderly patients on high-dose therapy, but may also occur with low doses (Prod Info ORAP(R) oral tablets, 2011).
    c) CASE REPORT: Larkin (1983) reported on a 16-year-old girl treated with 4 mg/day for 1 day, the dose increased to 6 mg/day for 1 day. She developed neck stiffness and oculogyric crisis, which resolved with benztropine 2 mg IM. The dose was reduced to 4 mg/day on day 3 but later in the day she suffered a tonic-clonic seizure. Pimozide was discontinued and no further seizures occurred (Larkin, 1983).
    d) CASE REPORT: Freed (1982) reported a single case of a 50-year-old alcoholic with late onset extrapyramidal side effects thought related to pimozide and alcohol withdrawal or alcohol intake (Freed, 1982).
    e) CASE REPORT: A severe dystonic reaction requiring discontinuance of the drug and treatment with benztropine and diazepam was reported in a patient taking 4 mg/day for approximately 6 weeks (Logan et al, 1982).
    f) CLINICAL TRIAL: Sixteen patients were given doses up to 60 mg/day for 28 days with few side effects. Most notable were mild extrapyramidal effects (tremors and perioral dyskinesias) which responded to antiparkinsonian medication. Side effects were never prominent enough to require discontinuance of therapy (Shopsin & Selzer, 1977).
    2) WITH POISONING/EXPOSURE
    a) Due to pimozide's ability to block dopaminergic receptors in the central nervous system, an overdose is expected to cause extrapyramidal effects (Prod Info ORAP(R) oral tablets, 2011). Gair et al (2004) reported delayed dystonia (12 hours after inadvertent ingestion of up to 6 mg) in an 18-month-old child. The child developed drooling, tongue thrusting and drowsiness which subsided over the next 40 hours with no treatment(Gair et al, 2004).
    C) CENTRAL NERVOUS SYSTEM DEFICIT
    1) WITH POISONING/EXPOSURE
    a) Severe overdoses may result in a comatose state with respiratory depression (Prod Info ORAP(R) oral tablets, 2011). Gair et al (2004) reported a delayed onset of drowsiness in an 18-month-old child following the inadvertent ingestion of up to 6 milligrams of pimozide(Gair et al, 2004).
    b) Shapiro et al (1983) reported sedation, lethargy, depression, and dysphoria as frequent adverse effects of pimozide (Shapiro et al, 1983).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) GASTROENTERITIS
    1) WITH THERAPEUTIC USE
    a) In clinical trials, nausea, vomiting, anorexia, increased salivation, and gastrointestinal distress were observed in patients receiving pimozide (Prod Info ORAP(R) oral tablets, 2011). Diarrhea and constipation were also reported (Pinder et al, 1976).
    b) Significant weight loss occurred more often in the pimozide group than in the placebo group during clinical trials (Huber et al, 1971).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) URINARY INCONTINENCE
    1) WITH THERAPEUTIC USE
    a) Enuresis may be exacerbated.
    b) CASE REPORT: Shapiro (1981) reported on a 9-year-old with Tourette's syndrome treated with pimozide (3 mg HS) and methylphenidate (5 mg BID) for 1 1/2 years. Although the child had a history of night time enuresis prior to using the drug, when given the drug at bedtime control was lost. Methylphenidate was discontinued without effect on enuresis. When pimozide was stopped or when given in the morning, night time enuresis did not occur (Shapiro, 1981).
    B) IMPOTENCE
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 37-year-old man reported impotence when receiving 16 mg/day, the dose which controlled his psychopathology. At 12 mg/day he could not ejaculate. The effect subsided upon withdrawal of the drug and returned when the drug was re-instituted (Ananth, 1982).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) GALACTORRHEA NOT ASSOCIATED WITH CHILDBIRTH
    1) WITH THERAPEUTIC USE
    a) Women taking high doses have developed galactorrhea (Anon, 1985).

Reproductive

    3.20.1) SUMMARY
    A) Pimozide is classified as FDA pregnancy category C. When pimozide was given to rats and rabbits during various periods of pregnancy, no increase in teratogenic effects were noted. No studies have been done in humans; however, third-trimester antipsychotic drug exposure has been associated with extrapyramidal and/or withdrawal symptoms in neonates.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) RATS and RABBITS: Although studies conducted in rats and rabbits have shown that pimozide is not teratogenic, oral doses up to 8 times the maximum human dose resulted in decreased pregnancies and in the retarded development of fetuses. These effects may be caused by implantation inhibition or delay and are similarly observed in rodents administered other antipsychotic drugs. Maternal toxicity, mortality, decreased weight, and embryotoxicity (eg, increased resorptions) were dose-related in the rabbit studies (Prod Info ORAP(R) oral tablets, 2010).
    2) RATS: When pimozide was given to rats during various periods of pregnancy, no increase in fetal abnormalities were noted (Pinder et al, 1976).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) Pimozide is classified as FDA pregnancy category C (Prod Info ORAP(R) oral tablets, 2010).
    B) EXTRAPYRAMIDAL AND/OR WITHDRAWAL SYMPTOMS
    1) Maternal use of antipsychotic drugs during the third trimester of pregnancy has been associated with an increased risk of neonatal extrapyramidal and/or withdrawal symptoms (eg, agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder) following delivery. Severity of these adverse effects have ranged from cases that are self-limiting to cases that required prolonged periods of hospitalization and ICU care (Prod Info ORAP(R) oral tablets, 2010).
    C) ANIMAL STUDIES
    1) Although studies conducted in rats and rabbits have shown that pimozide is not teratogenic, oral doses up to 8 times the maximum human dose resulted in decreased pregnancies and in the retarded development of fetuses. These effects may be caused by implantation inhibition or delay and are similarly observed in rodents administered other antipsychotic drugs. Maternal toxicity, mortality, decreased weight, and embryotoxicity (eg, increased resorptions) were dose-related in the rabbit studies (Prod Info ORAP(R) oral tablets, 2010).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) There are insufficient data to determine if pimozide is excreted in human breast milk (Prod Info ORAP(R) oral tablets, 2010).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) Pimozide administration in female rats resulted in prolonged estrus cycles, an effect also produced by other antipsychotic drugs (Prod Info ORAP(R) oral tablets, 2010).

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) Increases in pituitary and mammary tumors have been observed in mice.
    3.21.4) ANIMAL STUDIES
    A) NEOPLASM
    1) In MICE, pimozide causes a dose-related increase in pituitary and mammary tumors (Prod Info, 1989).

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 and mental status.
    C) Obtain an ECG, and institute continuous cardiac monitoring in symptomatic patients.
    D) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    2) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    4.1.4) OTHER
    A) OTHER
    1) ECG
    a) In cases of overdose, ECG monitoring is recommended since cases of QT prolongation and torsade de pointes have been reported (Anon, 1985; Fulop et al, 1987; Krahenbuhl et al, 1995).

Methods

    A) CHROMATOGRAPHY
    1) A rapid, sensitive (lower limit of detection was 0.3 ng/mL) and selective HPLC-fluorescence method for measuring pimozide in human plasma is available. No interference was found in a patient taking haloperidol, sulpiride, levomepromazine, thiothixene and thioridazine (Miyao, 1983).
    2) Larsson & Forssman (1984) describe a reverse-phase high-performance liquid chromatographic method (lower limit of detection was 1 ng/mL). No interference was found while patients were taking clopenthixol, thioridazine, diazepam, nitrazepam, haloperidol, promethazine, biperiden, furosemide, and digoxin.

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 persistent cardiac dysrhythmias, CNS depression, seizures, and respiratory failure should be admitted to an ICU setting.
    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) Pimozide has a long half-life (55 to 66 hours). Patients should be monitored for at least 4 days following a pimozide overdose (Prod Info ORAP(R) oral tablets, 2011). Patients with a deliberate overdose, and those who are symptomatic should be observed with frequent monitoring of vital signs, considering the long half-life of pimozide. 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 and mental status.
    C) Obtain an ECG, and institute continuous cardiac monitoring in symptomatic patients.
    D) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Prehospital gastrointestinal decontamination is generally not recommended because of the potential for CNS depression or persistent seizures and subsequent aspiration.
    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. Manage mild hypotension with IV fluids.
    2) MANAGEMENT OF SEVERE TOXICITY
    a) Treatment is symptomatic and supportive. Treat seizures with IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur. Treat severe hypotension with IV fluid. Add dopamine or norepinephrine if unresponsive to fluids. Therapeutic doses of pimozide may cause prolongation of the QT interval. Concomitant use of pimozide and other drugs that prolong the QT interval may increase the risk of torsades de pointes. Treat torsades de pointes with IV magnesium sulfate, and correct electrolyte abnormalities, overdrive pacing may be necessary. Treat ventricular dysrhythmias using ACLS protocols. Manage dystonic reactions with anticholinergic agents.
    B) MONITORING OF PATIENT
    1) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    2) Monitor vital signs and mental status.
    3) Obtain an ECG, and institute continuous cardiac monitoring in symptomatic patients.
    4) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    C) SEIZURE
    1) SUMMARY
    a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
    b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
    c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).
    2) DIAZEPAM
    a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .
    3) NO INTRAVENOUS ACCESS
    a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
    b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).
    4) LORAZEPAM
    a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
    b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
    c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2010; Chin et al, 2008).
    5) PHENOBARBITAL
    a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
    b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
    c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
    d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
    e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
    f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).
    6) OTHER AGENTS
    a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):
    1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
    2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
    3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
    4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).
    D) 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).
    E) DRUG-INDUCED DYSTONIA
    1) ADULT
    a) BENZTROPINE: 1 to 4 mg once or twice daily intravenously or intramuscularly; maximum dose: 6 mg/day; 1 to 2 mg of the injection will usually provide quick relief in emergency situations (Prod Info benztropine mesylate IV, IM injection, 2009).
    b) DIPHENHYDRAMINE: 10 to 50 mg intravenously at a rate not exceeding 25 mg/minute or deep intramuscularly; maximum dose: 100 mg/dose; 400 mg/day (Prod Info diphenhydramine hcl injection, 2006).
    2) CHILDREN
    a) DIPHENHYDRAMINE: 5 mg/kg/day or 150 mg/m(2)/day intravenously divided into 4 doses at a rate not to exceed 25 mg/min, or deep intramuscularly; maximum dose: 300 mg/day. Not recommended in premature infants and neonates (Prod Info diphenhydramine hcl injection, 2006).
    F) TORSADES DE POINTES
    1) SUMMARY
    a) Withdraw the causative agent. Hemodynamically unstable patients with Torsades de pointes (TdP) require electrical cardioversion. Emergent treatment with magnesium (first-line agent) or atrial overdrive pacing is indicated. Detect and correct underlying electrolyte abnormalities (ie, hypomagnesemia, hypokalemia, hypocalcemia). Correct hypoxia, if present (Drew et al, 2010; Neumar et al, 2010; Keren et al, 1981; Smith & Gallagher, 1980).
    b) Polymorphic VT associated with acquired long QT syndrome may be treated with IV magnesium. Overdrive pacing or isoproterenol may be successful in terminating TdP, particularly when accompanied by bradycardia or if TdP appears to be precipitated by pauses in rhythm (Neumar et al, 2010). In patients with polymorphic VT with a normal QT interval, magnesium is unlikely to be effective (Link et al, 2015).
    2) MAGNESIUM SULFATE
    a) Magnesium is recommended (first-line agent) for the prevention and treatment of drug-induced torsades de pointes (TdP) even if the serum magnesium concentration is normal. QTc intervals greater than 500 milliseconds after a potential drug overdose may correlate with the development of TdP (Charlton et al, 2010; Drew et al, 2010). ADULT DOSE: No clearly established guidelines exist; an optimal dosing regimen has not been established. Administer 1 to 2 grams diluted in 10 milliliters D5W IV/IO over 15 minutes (Neumar et al, 2010). Followed if needed by a second 2 gram bolus and an infusion of 0.5 to 1 gram (4 to 8 mEq) per hour in patients not responding to the initial bolus or with recurrence of dysrhythmias (American Heart Association, 2005; Perticone et al, 1997). Rate of infusion may be increased if dysrhythmias recur. For persistent refractory dysrhythmias, a continuous infusion of up to 3 to 10 milligrams/minute in adults may be given (Charlton et al, 2010).
    b) PEDIATRIC DOSE: 25 to 50 milligrams/kilogram diluted to 10 milligrams/milliliter for intravenous infusion over 5 to 15 minutes up to 2 g (Charlton et al, 2010).
    c) PRECAUTIONS: Use with caution in patients with renal insufficiency.
    d) MAJOR ADVERSE EFFECTS: High doses may cause hypotension, respiratory depression, and CNS toxicity (Neumar et al, 2010). Toxicity may be observed at magnesium levels of 3.5 to 4.0 mEq/L or greater (Charlton et al, 2010).
    e) MONITORING PARAMETERS: Monitor heart rate and rhythm, blood pressure, respiratory rate, motor strength, deep tendon reflexes, serum magnesium, phosphorus, and calcium concentrations (Prod Info magnesium sulfate heptahydrate IV, IM injection, solution, 2009).
    3) OVERDRIVE PACING
    a) Institute electrical overdrive pacing at a rate of 130 to 150 beats per minute, and decrease as tolerated. Rates of 100 to 120 beats per minute may terminate torsades (American Heart Association, 2005). Pacing can be used to suppress self-limited runs of TdP that may progress to unstable or refractory TdP, or for override refractory, persistent TdP before the potential development of ventricular fibrillation (Charlton et al, 2010). In a case series overdrive pacing was successful in terminating TdP associated with bradycardia and drug-induced QT prolongation (Neumar et al, 2010).
    4) POTASSIUM REPLETION
    a) Potassium supplementation, even if serum potassium is normal, has been recommended by many experts (Charlton et al, 2010; American Heart Association, 2005). Supplementation to supratherapeutic potassium concentrations of 4.5 to 5 mmol/L has been suggested, although there is little evidence to determine the optimal range in dysrhythmia (Drew et al, 2010; Charlton et al, 2010).
    5) ISOPROTERENOL
    a) Isoproterenol has been successful in aborting torsades de pointes that was resistant to magnesium therapy in a patient in whom transvenous overdrive pacing was not an option (Charlton et al, 2010) and has been successfully used to treat torsades de pointes associated with bradycardia and drug induced QT prolongation (Keren et al, 1981; Neumar et al, 2010). Isoproterenol may have a limited role in pharmacologic overdrive pacing in select patients with drug-induced torsades de pointes and acquired long QT syndrome (Charlton et al, 2010; Neumar et al, 2010). Isoproterenol should be avoided in patients with polymorphic VT associated with familial long QT syndrome (Neumar et al, 2010).
    b) DOSE: ADULT: 2 to 10 micrograms/minute via a continuous monitored intravenous infusion; titrate to heart rate and rhythm response (Neumar et al, 2010).
    c) PRECAUTIONS: Correct hypovolemia before using; contraindicated in patients with acute cardiac ischemia (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    1) Contraindicated in patients with preexisting dysrhythmias; tachycardia or heart block due to digitalis toxicity; ventricular dysrhythmias that require inotropic therapy; and angina. Use with caution in patients with coronary insufficiency (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    d) MAJOR ADVERSE EFFECTS: Tachycardia, cardiac dysrhythmias, palpitations, hypotension or hypertension, nervousness, headache, dizziness, and dyspnea (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    e) MONITORING PARAMETERS: Monitor heart rate and rhythm, blood pressure, respirations and central venous pressure to guide volume replacement (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    6) OTHER DRUGS
    a) Mexiletine, verapamil, propranolol, and labetalol have also been used to treat TdP, but results have been inconsistent (Khan & Gowda, 2004).
    7) AVOID
    a) Avoid class Ia antidysrhythmics (eg, quinidine, disopyramide, procainamide, aprindine), class Ic (eg, flecainide, encainide, propafenone) and most class III antidysrhythmics (eg, N-acetylprocainamide, sotalol) since they may further prolong the QT interval and have been associated with TdP.

Enhanced Elimination

    A) HEMODIALYSIS
    1) Hemodialysis is UNLIKELY to be of value because of the high degree of protein binding.

Abstracts

Case Reports

    A) ACUTE EFFECTS
    1) FATALITIES: Three fatalities associated with the use of pimozide were reported during 1973. All three were young, had concurrent drug therapy with phenothiazines or chloral hydrate and may have suffered from respiratory infections (Anon, 1974).

Range Of Toxicity

Summary

    A) TOXICITY: An association with sudden death in schizophrenic patients has been postulated from doses in the 1 mg/kg range. The mechanism may be from prolongation of the QT interval. The manufacturer of pimozide has reported sudden, unexpected deaths and grand mal seizures in some patients taking doses greater than 20 mg/day. However, acute ingestion of 60 mg in a 2.5-year-old child produced only mild effects. Ingestion of 100 mg in a 17-year-old girl also did not produce serious problems. An adult survived an acute pimozide overdose of 800 mg.
    B) THERAPEUTIC DOSES: ADULT: TOURETTE'S SYNDROME: Initial, 1 to 2 mg a day orally in divided doses; may increase dosage gradually every other day; usual maintenance dose is less than 10 mg/day or 0.2 mg/kg/day, whichever is smaller; doses greater than 10 mg/day or 0.2 mg/kg/day are not recommended. PSYCHOSIS: 2 to 20 mg every day have been used. CHILD: TOURETTE'S SYNDROME: Age 12 years and older: Initial, 0.05 mg/kg/day orally preferably taken once at bedtime; the dosage may be increased every third day up to a MAX dose of 0.2 mg/kg/day not to exceed 10 mg/day. Safety and efficacy have not been established for use in children less than 12 years of age.

Therapeutic Dose

    7.2.1) ADULT
    A) DISEASE STATE
    1) TOURETTE SYNDROME: Initial, 1 to 2 mg a day orally in divided doses; may increase dosage gradually every other day. Usual maintenance dose is less than 10 mg/day or 0.2 mg/kg/day, whichever is less. Doses greater than 10 mg/day or 0.2 mg/kg/day are not recommended (Prod Info ORAP(R) oral tablets, 2014).
    2) POOR CYP 2D6 METABOLIZERS: CYP2D6 genotyping should be performed when the pimozide dose is greater than 4 mg/day in adults (Prod Info ORAP(R) oral tablets, 2014).
    3) PSYCHOSIS: 2 to 20 mg every day have been used (Bollini et al, 1994).
    7.2.2) PEDIATRIC
    A) DISEASE STATE
    1) Safety and efficacy have not been established in children less than 12 years of age (Prod Info ORAP(R) oral tablets, 2014).
    2) TOURETTE SYNDROME: Age 12 years and older: Initial, 0.05 mg/kg/day orally preferably taken at bedtime. The dosage may be increased every third day up to a MAX dose of 0.2 mg/kg/day not to exceed 10 mg/day (Prod Info ORAP(R) oral tablets, 2014).
    3) POOR CYP 2D6 METABOLIZERS: CYP2D6 genotyping should be performed when the pimozide dose is greater than 0.05 mg/kg/day in children (Prod Info ORAP(R) oral tablets, 2014).

Minimum Lethal Exposure

    A) An association with sudden death in schizophrenic patients has been postulated from doses in the 1 mg/kg range. The mechanism may be from prolongation of the QT interval (Anon, 1985; Fulop et al, 1987).
    B) The manufacturer of pimozide has reported sudden, unexpected deaths and grand mal seizures in some patients taking doses greater than 20 mg/day (Prod Info ORAP(R) oral tablets, 2011).

Maximum Tolerated Exposure

    A) GENERAL/SUMMARY
    1) DOSES OVER 100 MILLIGRAMS
    a) Following an acute ingestion of 800 mg, a 53-year-old woman experienced QT prolongation with torsade de pointes which reversed following therapy with lidocaine and magnesium (Krahenbuhl et al, 1995).
    2) DOSES OF 60 to 100 MILLIGRAMS
    a) Both adults and children who have ingested the drug in doses of 60 to 100 mg have recovered uneventfully (Pinder et al, 1976).
    b) A 17-year-old girl ingested 100 mg in a suicide attempt. Gastric lavage was done shortly after with no return of pill fragments. No effects were noted and full recovery was reported (Ayd, 1971).
    c) Debray et al (1972) reported only mild effects in a 2 1/2-year-old child who ingested 60 milligrams pimozide (Debray et al, 1972).
    3) THERAPEUTIC DOSES
    a) Side effects occur in about 10% to 15% of patients and are dose-related (Pinder et al, 1976); they occur most frequently when the daily dose exceeds 10 mg per day (Int Drug Ther Newsletter, 1971; McNeil Labs, case files).
    B) INFANT
    1) Following an inadvertent pimozide ingestion of up to 6 mg (0.5 mg/kg) in an 18-month-old child, delayed onset of dystonia, occurring 12 hours post-ingestion was reported. Within 2 hours of the ingestion, hypotension, tachycardia and prolonged QTc (440 milliseconds) were also reported. All signs/symptoms returned to normal within 40 hours post-ingestion (Gair et al, 2004).

Serum Plasma Blood Concentrations

    7.5.1) THERAPEUTIC CONCENTRATIONS
    A) THERAPEUTIC CONCENTRATION LEVELS
    1) ACUTE DOSING: A single oral 3 mg dose produced plasma levels of no higher than 3.3 ng/mL in three patients. At 24 hours following the dose, levels of from 1.7 to 2.6 ng/mL were found demonstrating the relatively long half-life of pimozide (Miyao et al, 1983).
    2) CHRONIC DOSING: Fourteen schizophrenic patients were given oral pimozide (2 to 10 mg/day). Steady state plasma concentrations drawn after two weeks on either oral tablets or liquid were 2.3 ng/mL and 3 ng/mL, respectively (Larsson & Forssman, 1984) .

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) ANIMAL DATA
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 1070 mg/kg (RTECS , 2002)
    2) LD50- (ORAL)MOUSE:
    a) 228 mg/kg (RTECS , 2002)
    3) LD50- (INTRAPERITONEAL)RAT:
    a) 350 mg/kg (RTECS , 2002)
    4) LD50- (ORAL)RAT:
    a) 1100 mg/kg (RTECS , 2002)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) The exact mechanism of action has not been established; however, pimozide blocks dopamine receptors in the central nervous system (CNS). The efficacy of pimozide in suppressing the tics of Tourette's syndrome is thought to be due to dopaminergic blockade. Secondary changes in central dopamine function and metabolism, including increased brain turnover of dopamine, may contribute to both the therapeutic and the adverse effects of pimozide (Prod Info ORAP(R) oral tablets, 2011).

Toxicologic Mechanism

    A) Effects are produced by a striatal dopamine blockade in the brain.

Physicochemical

Physical Characteristics

    A) Pimozide is a colorless tertiary amine (Janssen et al, 1968a).

Molecular Weight

    A) 461.56 (Windholz, 1983)

References

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