AHFS Class:

• Diphenylbutylperidines 28:16.08.30

Generic Name(s):

• Pimozide

Pimozide is a diphenylbutylpiperidine-derivative antipsychotic agent.1,2,3,4,5 The drug is considered a conventional or first-generation antipsychotic agent.213,217

Tourette's Syndrome

Pimozide is used for suppression of motor and vocal tics of Tourette's syndrome (Gilles de la Tourette's syndrome).1,2,48,49,50,51,52,53,54,57,159,172

Pimozide has been used concomitantly with a stimulant in children with tic disorders (e.g., Tourette's syndrome) and comorbid attention deficit hyperactivity disorder (ADHD)† in whom stimulants alone cannot control tics.171

Overview

Tourette's syndrome is a neurologic genetic disorder with a spectrum of neurobehavioral manifestations that may vary with time and fluctuate in severity and frequency of symptoms during the natural course of the disease.172,176 The diagnosis of Tourette's syndrome usually is based on a history and observation of tics often accompanied by behavioral disorders (e.g., ADHD, obsessive-compulsive disorder).172,173 Tics may be sudden, brief, intermittent, involuntary, or semivoluntary movements (motor tics) or sounds (phonic or vocal tics).172 For a diagnosis of Tourette's syndrome, the criteria established by the Tourette Syndrome Classification Study Group may be used.172,190 According to this classification, both multiple motor tics and one or more phonic tics must be present at some time during the disease (although not necessarily concurrently), and such tics must occur many times a day and nearly every day, or intermittently, throughout a period of more than 1 year.172 Motor and phonic tics must be witnessed directly by a reliable examiner some time during the disease or be recorded by video or cinematography.172 In addition, anatomical location, number, frequency, type, complexity, or severity of tics must undergo a change over time.172 Involuntary movements and sounds must not be explained by a medical condition other than Tourette's syndrome.172 Although the onset of the syndrome must occur in patients younger than 21 years of age, in most patients the disease is manifested by 11 years of age, usually beginning in children 2-15 years old.1,172 Generally, tics become more severe when patients reach the age of 10 years, and 50% of patients are free from tics by the time they reach the age of 18 years.172 Severity of tics usually decreases when reaching adulthood.172 These and other diagnostic criteria are designed to assist clinicians in reaching an accurate diagnosis (e.g., differentiating Tourette's syndrome from other tic disorders) and those investigating the genetic factors associated with the syndrome.172

Therapeutic Considerations

Initially, management of Tourette's syndrome should include proper education of patients, family members, and teachers in order to provide a proper environment (at home and in school) for children with the disease.172 Drug therapy usually is considered when symptoms of the disorder begin to interfere with the patient's activities of daily living (e.g., work, school, social activities).172 Because Tourette's syndrome is associated with a wide variety of neurologic and behavioral manifestations, drug therapy should be individualized and the most severe symptoms should be treated first.172,174 The goal in the management of tics is to relieve tic-related discomfort and embarrassment and to achieve a degree of control of tics that allows the patient to function as normally as possible.172 Dopamine receptor blocking agents are considered the most effective drugs for the management of tics,172,173 although only haloperidol and pimozide are approved by the US Food and Drug Administration (FDA) for the treatment of Tourette's syndrome.1,172 Haloperidol generally has been considered the drug of choice for the management of Tourette's syndrome56,57 and pimozide has been an effective alternative in some patients who have had an inadequate response to or did not tolerate haloperidol.48,50,54 Limited data suggest that pimozide may be more effective than haloperidol in reducing tics.171,172,177 Some clinicians, however, prefer other antipsychotic drugs including molindone, phenothiazines (e.g., fluphenazine, thioridazine, trifluoperazine), risperidone, thiothixene, or tiapride (not commercially available in the US).172,173,174,176,182 It is not known whether some other atypical antipsychotics (e.g., clozapine, olanzapine, quetiapine) are effective in the management of tics or other symptoms of Tourette's syndrome; however, limited data indicate that ziprasidone may decrease the severity of tics.172,173,175,183 Tetrabenazine, a drug that interferes with monoamine neurotransmitters and blocks dopamine receptors, has been effective for the management of tics and, unlike conventional antipsychotic agents, tetrabenazine does not appear to cause tardive dyskinesia.172,187 Although several other drugs (e.g., cannabinoids, clonazepam, pergolide, nicotine gum, nicotine transdermal system) have been shown to be effective in the management of tics, these agents have not been evaluated in well-designed, controlled studies.172,173 Focal motor and vocal tics have responded to injections of botulinum toxin in the affected muscles.172,176,184,185,186

Pimozide is considered an orphan drug8,154 and is used for suppression of motor and vocal tics of Tourette's syndrome (Gilles de la Tourette's syndrome) in children1,2,48,49,50,51,52,159 and adults.1,2,48,49,50,52,53,54,57,159 The drug usually should be reserved for the treatment of those patients with Tourette's syndrome who have an inadequate response to, or who do not tolerate, conventional therapy (e.g., haloperidol)1,2,8,48 and whose development and/or daily life function is severely compromised by the presence of motor and vocal tics.1,2 Pimozide usually is not intended as a treatment of first choice for this syndrome, nor is it intended for suppression of tics that are only annoying or cosmetically troublesome.1,2,8

Controlled studies in patients with Tourette's syndrome have shown that pimozide is effective in reducing the number of stimulated and unstimulated motor and vocal tics and the severity of associated symptomatology.2,50,52 Results of several studies suggest that pimozide is at least as effective as haloperidol in the management of Tourette's syndrome2,48,50,54,55,171 and may be associated with fewer and possibly less severe adverse effects, particularly sedation, in some patients.48,50,54,171 The long-term safety of pimozide in the management of this syndrome, however, remains to be determined,9 and additional well-controlled studies comparing pimozide and haloperidol are needed to assess their relative efficacy and safety.48,50,54 Haloperidol generally has been considered the drug of choice for the management of Tourette's syndrome,56,57 and pimozide has been an effective alternative in some patients who have an inadequate response to or do not tolerate haloperidol.48,50,54 Because limited data suggest that pimozide may be more effective than haloperidol in reducing tics48,50,54,153,171,172,177 and pimozide appears to be better tolerated than haloperidol, some clinicians and experts prefer the use of pimozide in patients with Tourette's syndrome.153,159,171,172,177 Limited data suggest that pimozide may be more effective than clonidine54 and that pimozide and penfluridol (not commercially available in the US) may have comparable efficacy in the management of Tourette's syndrome.54,153 Well-controlled clinical studies comparing the efficacy and safety of pimozide and other agents used in the management of Tourette's syndrome are needed.48,50,54

Comorbid Conditions

Patients with Tourette's syndrome often exhibit comorbid conditions (e.g., ADHD, obsessive-compulsive disorder).171,172 Although CNS stimulants, including amphetamines, have been reported to exacerbate motor and vocal tics in patients with Tourette's syndrome, results of several studies indicate that stimulants are effective in the management of ADHD in patients with Tourette's syndrome and the rate of tics is not increased in the majority of patients.171,172,189,191,192 In patients in whom the rate of tics increases, some experts recommend addition of an α-adrenergic agonist (e.g., clonidine, guanfacine), risperidone, pimozide, or haloperidol. Clonidine or guanfacine have been used in the management of ADHD. Although less effective than stimulants, clonidine and guanfacine do not increase the frequency or severity of tics.171,172,173,174,178,188 Tricyclic antidepressants (e.g., imipramine, nortriptyline) also may be used for the treatment of mild cases of ADHD and concomitant tics or Tourette's syndrome in patients who do not respond to or otherwise do not tolerate stimulants, in whom tics are exacerbated by stimulants, or those who develop clinically important depression.172

In addition, there is a high incidence of obsessive-compulsive disorder in patients with Tourette's syndrome.179 Many clinicians recommend that patients with Tourette's syndrome and coexisting obsessive-compulsive disorder receive therapy with a selective serotonin-reuptake inhibitor or a selective serotonin- and norepinephrine-reuptake inhibitor (e.g., citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, venlafaxine) alone or, if needed, in combination with buspirone, clonazepam, lithium, or a dopamine receptor antagonist.172,173 In a limited number of patients, other drugs (e.g., clomipramine, risperidone) also have been effective in the management of this comorbid condition.173,179,180,181

Schizophrenia

Pimozide has been used for the symptomatic management of a variety of psychiatric illnesses†,58,59,60,61,62,63,64,65,66,67,68,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,113,114,115,116,117,118,119,120,121,122,123 principally schizophrenia†,58,59,60,61,62,63,64,65,66,67,68,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91 but other agents generally are preferred.69,70

Pimozide appears to be as effective as phenothiazines4,43,59,60,62,66,71,80,81,87,90 or haloperidol4,77 for the symptomatic management of schizophrenia†. The drug is effective in reducing hallucinations,58,59,74,75,76,77,78,82,84 thought disorders,58,59,74,75,76,77,78,84 change in affect,58,59,75,76,77,78,84 and autism.58,78,82 Pimozide also appears to be effective for the management of social adjustment problems,4,58,64,65,77 emotional withdrawal,58,59,74,75,76,78,84 motor retardation,59,76,77,78,84 apathy,59,84 and conceptual disorganization.75,78,84 Delusions,58,59,74,77,82 bizarre mannerisms,58,75,84 chronic paranoia,58 anxiety,65,66,68,73,75,76,77,78,80,82,84,85,92,94,99 guilt feelings,75,76,78,84 disorientation,75,78,84 and hostility76,84 also may be reduced during therapy with the drug. Pimozide should not be used for the management of schizophrenia in patients whose main manifestations include excitement, agitation, or hyperactivity,3,99 because the efficacy of the drug in these patients has not been established.4

Pimozide also has been used for the symptomatic management of acute schizophrenic episodes†.92,93,94,95,96,97,98,99,100,101,102 Results of initial clinical studies were not encouraging,97,100,101 but subsequent uncontrolled clinical studies suggest that pimozide may be effective in the management of acute schizophrenic episodes when used at dosages substantially higher than those used for the management of schizophrenia.92,93,94,96,98,102 Limited data suggest that high-dose pimozide therapy may be as effective as haloperidol96 or phenothiazines;92,93,98,100 however, the frequency and severity of pimozide-induced extrapyramidal reactions are increased at high dosages.1,2,92,93,96 Pimozide currently is not recommended for the management of acute schizophrenic episodes.3 For further information on the symptomatic management of schizophrenia, see Uses: Psychotic Disorders, in the Phenothiazines General Statement 28:16.08.24.

Mania

Pimozide has been used for the management of manic episodes† (mania) in patients with major affective disorders.116,117,118,119,153 Although limited data suggest that pimozide may be as effective as phenothiazines,117,118 the efficacy of the drug has not been clearly established, and pimozide currently is not recommended for the management of manic episodes.3

Dyskinesias

Pimozide has been used for the management of various dyskinesias†, including chronic progressive hereditary chorea (Huntington's chorea),4,124,125 acute chorea (Sydenham's chorea),126 tardive dyskinesia,4,127,128,129,130,131 and tardive dystonia;132 however, the usefulness of the drug for the management of dyskinesias is questionable because it has both dyskinesia-alleviating and dyskinesia-producing properties.69,133 Because pimozide tends to worsen parkinsonian symptoms, the drug should not be used for the management of levodopa-induced dyskinesias in patients with parkinsonian syndrome.134

Other Uses

Results of uncontrolled clinical studies suggest that pimozide may be useful for the management of phencyclidine-induced psychosis†103 or various personality disorders† (e.g., paranoid, schizoid, compulsive).104,105,111 Pimozide also has reportedly been beneficial in some patients for the management of pathologic jealousy†,109,148,163 erotomania†,157,158 and monosymptomatic hypochondriacal psychosis†,106,107,108,114 including delusions of parasitosis.110,113,115,160

Although pimozide has been used in the treatment of anorexia nervosa†, use of the drug for this purpose does not appear to provide substantial benefit.167

Administration

Pimozide is administered orally.1,2 The drug may usually be administered once daily152,153 but also may be given in divided doses, particularly if once-daily dosing is not well tolerated.152 Some clinicians recommend administration of the drug as a single dose at bedtime to minimize adverse effects.153

Dosage

When pimozide is used for suppression of motor and vocal tics in patients with Tourette's syndrome, the initial dosage of the drug should be low and dosage adjustments should be made gradually.1,2,159 Dosage of pimozide must be carefully adjusted to balance symptomatic relief and the suppression of tics against the adverse effects of the drug.1,2,159 Patients receiving pimozide should have an ECG performed before therapy with the drug is initiated and periodically thereafter, particularly during the period of dosage adjustment.1,2 (See Cautions: Precautions and Contraindications.)

Adult Dosage

For the suppression of motor and vocal tics in adults with Tourette's syndrome, the usual initial dosage of pimozide is 1-2 mg daily.1,2,159,164 The manufacturer and some clinicians state that dosage may be increased every other day according to the patient's tolerance and therapeutic response.1,2,165 Because of pimozide's prolonged elimination half-life, other clinicians suggest that dosage be increased at longer intervals (e.g., every 5-7 days) until signs and symptoms of the disorder decrease by at least 70%, adverse effects occur without symptomatic benefit, or symptomatic benefit and adverse effects occur at the same time.153,164 If adverse effects are minimal and do not interfere with functioning (e.g., dry mouth, slight sedation) but adequate response has not been achieved, dosage should not be increased further until these adverse effects resolve.164 If adverse effects interfere with functioning but are not severe, dosage can be reduced by 1-mg increments at weekly intervals until such effects resolve.164 Dosage should be reduced1,2 by 50% immediately164 or the drug withheld1,2,164 if severe adverse effects occur. (See Cautions: Precautions and Contraindications.) Once serious adverse effects resolve, therapy can be reinstituted with more gradual titration, increasing dosage at intervals ranging from 7-30 days.164 Most patients are adequately treated with dosages less than 0.2 mg/kg daily or 10 mg daily, whichever is less,1,2 and the manufacturer recommends that these dosages not be exceeded.1,2

Pediatric Dosage

For the suppression of motor and vocal tics in children with Tourette's syndrome, the usual initial dosage of pimozide is 0.05 mg/kg daily, preferably at bedtime.1 The dose may be increased every third day to a maximum of 0.2 mg/kg or 10 mg per day.167 Reliable dose-response data for the effects of the drug on tic manifestations in children younger than 12 years of age are not available.1,2

Dosage of pimozide during prolonged maintenance therapy should be kept at the lowest possible effective level.1,2 Once an adequate response has been achieved, periodic attempts (e.g., every 6-12 months)153 should be made to reduce dosage of the drug to determine whether the initial intensity and frequency of tics persist.1,2 When attempting to reduce the dosage of pimozide, consideration should be given to the possibility that observed increases of tic intensity and frequency may represent a transient, withdrawal-related phenomenon rather than a return of the syndrome's symptoms.1,2 Before concluding that an increase in tic manifestations is a function of the underlying disorder rather than a response to drug withdrawal, at least153 1-2 weeks should be allowed to elapse.1,2 If pimozide therapy is to be discontinued, dosage of the drug should be gradually reduced.1,2

Nervous System Effects

The most frequent and potentially severe adverse effects of pimozide involve the CNS.1,2,3,6

Extrapyramidal Reactions

Extrapyramidal reactions occur frequently with pimozide,1,2,3,9,40,50,52,58,59,60,68,71,73,78,81,85,87,88,90,92,93,94,96,97,99,100,102,104,122,145 especially during the first few days of therapy.1,2,52,122 In most patients, these reactions consist of parkinsonian symptoms1,2,4,68,71,78,81,92,94,99,100,102,159 (e.g., tremor,3,58,59,60,68,81,92,93,94,96 rigidity,1,2,3,4,52,58,59,60,68,81,92,93,94,96 akinesia)1,2,52 that are mild to moderate in severity and usually reversible following discontinuance of the drug.1,2 Dystonic reactions1,2,3,71,92 and feelings of motor restlessness1,2,3,60,67,72,75,88,90,96,159 (i.e., akathisia)1,2,3,4,52,58,59,60,68,92,93,94,145,159 occur less frequently.1,2 Generally, the occurrence and severity of most extrapyramidal reactions are dose related because they occur at relatively high dosages and disappear or become less severe following a reduction in dosa 52,58,59 however, severe extrapyramidal reactions have reportedly occurred at relatively low dosages.1,2 Extrapyramidal reactions appear to occur in about 10-15% of patients receiving usual dosages of pimozide.4 Administration of anticholinergic antiparkinsonian agents (e.g., benztropine, trihexyphenidyl) or diphenhydramine may be necessary to control parkinsonian extrapyramidal reactions.1,2,3,4,52,58,59,69,73,87,92,96,99 If persistent extrapyramidal reactions occur, pimozide therapy may have to be discontinued.1,2,102

The most common dystonic reaction is torticollis, which generally is accompanied by orofacial symptoms and, in some instances, oculogyric crisis, as well as spasms of the face, tongue, and jaw.3 Trismus, dysarthria, muscle cramps, and athetoid movements have occurred occasionally.3,71,92,94,96

Akathisia occurs relatively frequently in patients receiving pimozide,1,2,3,4,52,58,59,60,68,92,93,94,145 but usually can be managed by reducing the dosage of pimozide3,4,52,58,59 or by concomitant administration of an anticholinergic antiparkinsonian agent,3,52,58,59 diphenhydramine,69 a benzodiazepine,59,69,153 or propranolol.69,153

Neuroleptic Malignant Syndrome

Neuroleptic malignant syndrome (NMS), a potentially fatal symptom complex, has been reported in patients receiving antipsychotic agents, including pimozide.1,2,146 Clinical manifestations of NMS generally include hyperpyrexia, muscle rigidity, altered mental status (including catatonic signs), and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac arrhythmias).1 Additional signs of NMS may include increased serum creatine kinase (CK, creatine phosphokinase, CPK), myoglobinuria (rhabdomyolysis), and acute renal failure.1

The diagnostic evaluation of patients with NMS is complicated.1 In arriving at a diagnosis, serious medical illnesses (e.g., pneumonia, systemic infection) and untreated or inadequately treated extrapyramidal signs and symptoms must be excluded.1 Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary CNS pathology.1

The management of NMS should include immediate discontinuance of antipsychotic agents and other drugs not considered essential to concurrent therapy, intensive symptomatic treatment and medical monitoring, and treatment of any concomitant serious medical problems for which specific treatments are available.1 If a patient requires antipsychotic therapy following recovery from NMS, the potential reintroduction of drug therapy should be carefully considered.1 In addition, such patients should be carefully monitored since recurrences of NMS have been reported.1 For additional information on NMS, see Neuroleptic Malignant Syndrome under Cautions: Nervous System Effects, in the Phenothiazines General Statement 28:16.08.24.

Hyperpyrexia, not associated with NMS, also has been reported in patients receiving other antipsychotic agents.1

Tardive Dyskinesia

Like other antipsychotic agents, pimozide has been associated with persistent dyskinesias.1,2,3,71,92,94,96 Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements, may occur in some patients during long-term administration of pimozide or possibly following discontinuance of the drug.1,2,3,71 Tardive dyskinesia is characterized by rhythmic involuntary movements of the tongue, face, mouth, or jaw (e.g., protrusion of the tongue, puffing of cheeks, chewing movements, puckering of the mouth), which sometimes may be accompanied by involuntary movements of the extremities and trunk.1,2,3,59,69 The risk of developing tardive dyskinesia appears to be greater in geriatric patients receiving high dosages of the drug, especially females.1,2,3,59 The symptoms are persistent and in some patients appear to be irreversible.1,2,3,59

Although not clearly established,59 the risk of developing the syndrome and the likelihood that it will become irreversible may increase with the duration of therapy and total cumulative dose of antipsychotic agent(s) administered;1,2,59 however, the syndrome may occur, although much less frequently, after relatively short periods of treatment with low dosages.1,2 (See Cautions: Precautions and Contraindications.) For additional information on tardive dyskinesia, see Tardive Dyskinesia under Cautions: Nervous System Effects, in the Phenothiazines General Statement 28:16.08.24.

Other Nervous System Effects

Pimozide is generally considered to be relatively nonsedating compared with other antipsychotic agents,3,4,48,50,51,52,54,55 but sedation,1,2,3,4,48,54,57,159 lethargy,1,2,48,50 and/or drowsiness1,2,3,4 appear to be the most common adverse effects of the drug in patients with Tourette's syndrome.1,2,48,50,51,52,54 Other adverse nervous system effects of pimozide include insomnia,1,2,3,4,52,60,68,75,90,93 dizziness,1,2,3,4,52,59,60,77,96,98 excitement,1,2,3,4 agitation,3,4,43 nervousness,1,2 fainting,1,2 aggressiveness,89 irritability,3,48,52 anxiety,3,4,60,75 tension,3 headache,1,2,3 depression,1,2,3,48,50,52,60,68,76,159 decreased attentiveness,3 confusion,3 nightmares,3 hallucinations,3,4,64 phobia,4,8,147 impaired motivation,48 speech disorder,1,2 handwriting change,1,2 fatigue,3,49,50 weakness,1,2,3 transient affective disturbance,50 and aggravation of psychotic symptomatology.3 Rarely, pimozide has been associated with seizures,1,2,3,140,141,167 including tonic-clonic (grand mal) seizures,1,2,3,140 in patients without a previous history of seizure disorder.140,141

Adverse anticholinergic effects of pimozide include dry mouth,1,2,3,4,9,50,62,78,93,136 blurred vision,1,2,3,50,90,93,96,136 difficulty with accommodation,1,2,3 urinary retention,1,2,3 constipation,1,2,3,4,9,52,92,94,139 and urinary and fecal incontinence.3

Cardiovascular Effects

Various ECG changes, such as prolongation of the QT (including QT_c) interval; flattening, notching, and inversion of the T wave; and appearance of U waves, have occurred in some patients receiving pimozide.1,2,164,165,202 The clinical importance of pimozide-induced ECG changes has not been clearly established, but some clinicians believe that the changes are comparable to those induced by phenothiazines.153 Sudden, unexpected deaths have occurred in some patients receiving high doses of the drug (i.e., exceeding 10 mg; in the range of 1 mg/kg) for conditions other than Tourette's syndrome or in patients receiving concomitant pimozide and clarithromycin.1,168,170 (See Drug Interactions: Drugs That Prolong the QT Interval and see also Drug Interactions: Drugs and Foods Affecting Hepatic Microsomal Enzymes.)1,2,142 A possible mechanism for these deaths is prolongation of the QT interval, predisposing the patients to ventricular arrhythmia.1,2 Patients receiving pimozide should have ECG evaluations before and periodically during therapy with the drug.1,2,202 (See Cautions: Precautions and Contraindications.)

Pimozide rarely may produce hypotension,1,2,3,6 orthostatic hypotension,1,2 hypertension,1,2,3 tachycardia,1,2,3 or palpitations.1,2 In some patients, particularly geriatric or debilitated patients, transient hypotension for several hours after administration of the drug has occurred.3

Endocrine and Metabolic Effects

Amenorrhea,3,4 dysmenorrhea,3 and mild galactorrhea3,4,9 have occurred in some patients receiving pimozide. Like other antipsychotic agents, pimozide increases serum prolactin concentrations.1,2,26,53,92 (See Cautions: Mutagenicity and Carcinogenicity.) Loss of libido,1,2 impotence,1,2,52,60,143 and weight gain1,2,3,52,60,62,90,159 or, more frequently,3 weight loss,1,2,3,4,59,60,64,90 have occurred in patients receiving pimozide.

GI Effects

Adverse GI effects of pimozide include increased salivation,1,2,3 nausea,1,2,3,4,52,60,78 vomiting,1,2,3,90 anorexia,1,2,3,4,75,90 GI distress,1,2,4,90,108 diarrhea,1,2,3,4,59,60 constipation,1,2,3,4,9,52,92,94,139 and abdominal cramps or pain.3 Thirst, altered taste, gingival hyperplasia, and increased appetite also have been reported.1,2

Hematological Effects

In clinical trial and/or postmarketing experience, leukopenia, neutropenia, and agranulocytosis temporally related to antipsychotic agents have been reported.1,220,221 Possible risk factors for leukopenia and neutropenia include preexisting low leukocyte count and a history of drug-induced leukopenia or neutropenia.1 (See Cautions: Precautions and Contraindications.)

Hemolytic anemia also has occurred in pimozide-treated patients, although a causal relationship to the drug has not been established.1,167

Other Adverse Effects

Rash,1,2,3,4 urticaria,3 skin irritation,1,2,3 facial edema (may be severe),3 periorbital edema,1,2,103 sweating,1,2,3,62 cataracts,1,2 visual disturbances or sensitivity to light,1,2 chest pain,1,2 nocturia,1,2 and urinary frequency1,52 have been reported in patients receiving pimozide. Hyponatremia has occurred in patients receiving the drug following marketing approval.1

The possibility that pimozide may cause other adverse effects reported with other antipsychotic agents should be considered.1,2,3 In addition, because clinical experience with pimozide for the management of Tourette's syndrome is limited, uncommon adverse effects may not have been detected to date.1,2

Precautions and Contraindications

Pimozide shares the toxic potentials of other antipsychotic agents (e.g., phenothiazines, butyrophenones), and the usual precautions associated with therapy with these agents should be observed.1,2,3,6 (See Cautions in the Phenothiazines General Statement 28:16.08.24.) Because treatment with pimozide exposes the patient to potentially serious risks, the decision to use the drug for the long-term management of Tourette's syndrome should be carefully considered by the patient (and/or the patient's family or guardians) and the physician.1,2 The use of pimozide for the management of Tourette's syndrome involves different considerations of risks and benefits than the use of other antipsychotic agents for other conditions.1,2 Because the goal of treatment is symptomatic improvement, the patient's view of the need for treatment and assessment of response are critical in evaluating the relative benefits and risks of pimozide therapy.1,2 Patients should be informed that pimozide has an adverse effect profile similar to that of other antipsychotic agents and that adverse effects associated with these agents may occur with pimozide.1,2

Neuroleptic malignant syndrome (NMS), a potentially fatal syndrome requiring immediate discontinuance of the drug and intensive symptomatic treatment, has been reported in patients receiving antipsychotic agents, including pimozide.1,2,146 If a patient requires antipsychotic therapy following recovery from NMS, the potential reintroduction of drug therapy should be carefully considered.1 If antipsychotic therapy is reintroduced, the dosage generally should be increased gradually, and an antipsychotic agent other than the agent believed to have precipitated NMS generally should be chosen.202 In addition, such patients should be carefully monitored since recurrences of NMS have been reported.1 (See Neuroleptic Malignant Syndrome under Cautions: Nervous System Effects.)

Because of the likelihood that a proportion of patients receiving long-term therapy with an antipsychotic agent will develop tardive dyskinesia, patients in whom long-term pimozide therapy is considered should be fully informed, if possible, about the risk of developing this syndrome.1,2 The decision to inform the patient (and/or the patient's family or guardians) should take into account the clinical circumstances and the competency of the patient to understand the information.1,2 Pimozide should be prescribed in a manner that is most likely to minimize the occurrence of this syndrome.1 Chronic antipsychotic treatment generally should be reserved for patients who suffer from a chronic illness that is known to respond to antipsychotic agents, and for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate.1,2,166 In patients who do require chronic treatment, the smallest dosage and the shortest duration of treatment producing a satisfactory clinical response should be sought, and the need for continued treatment should be reassessed periodically.1,2,159,166 The American Psychiatric Association currently recommends that patients receiving first-generation antipsychotic agents be assessed clinically for abnormal involuntary movements every 6 months and that patients considered to be at increased risk for tardive dyskinesia be assessed every 3 months.202 (See Tardive Dyskinesia under Cautions: Nervous System Effects.)

Because sudden, unexpected deaths, which may be related to an effect of pimozide on the heart, have occurred in some patients receiving high doses of the drug (i.e., exceeding 10 mg; in the range of 1 mg/kg) for conditions other than Tourette's syndrome, an ECG should be performed before pimozide therapy is initiated and periodically thereafter, particularly during the period of dosage adjustment.1,2,168,170,202 Some clinicians recommend that a cardiologist be consulted before initiating therapy with the drug in patients with a baseline QT_c interval exceeding 440 ms.164 Patients should be instructed not to exceed the prescribed dosage and should be aware of the need for the initial ECG and follow-up ECGs during pimozide therapy.1,2 Prolongation of the QT_c interval (QT interval corrected for rate) to greater than 470 ms in children or 520 ms in adults, or more than 25% beyond the patient's pretreatment value, or the development of other T-wave abnormalities should be considered a basis for stopping further dosage increases and considering a dosage reduction.1,2,164 Dosage reduction also should be considered if bradycardia (less than 50 bpm) occurs.164 Some clinicians recommend that pimozide be withheld if T-wave inversion, U waves, or cardiac arrhythmia occurs and reinstituted only after ECG findings are normal.164 Because pimozide may cause ECG changes, the drug should be used with caution in patients with cardiovascular disorders.3,164,165 Because hypokalemia has been associated with ventricular arrhythmias, potassium insufficiency secondary to diuretics, diarrhea, or other causes should be corrected before pimozide therapy is initiated, and normal serum potassium concentrations should be maintained during pimozide therapy.1,2

In clinical trial and/or postmarketing experience, leukopenia and neutropenia temporally related to antipsychotic agents have been reported;1,220,221 agranulocytosis also has been reported.1 Because possible risk factors for leukopenia and neutropenia include a preexisting low leukocyte count and a history of drug-induced leukopenia and neutropenia, the manufacturer states that patients with a history of clinically important low leukocyte count or drug-induced leukopenia and/or neutropenia should have their complete blood count monitored frequently during the first few months of therapy.1 Discontinuance of pimozide should be considered at the first sign of a clinically important decline in leukocyte count in the absence of other causative factors.1 Patients with clinically important neutropenia should be carefully monitored for fever or other signs or symptoms of infection and promptly treated if such signs or symptoms occur.1 In patients with severe neutropenia (absolute neutrophil count [ANC] less than 1000/mm³), pimozide should be discontinued and the leukocyte count monitored until recovery occurs.1 (See Cautions: Hematologic Effects.)

The clinical importance is not known, but pimozide has produced a dose-related increase in benign pituitary tumors in female mice.1,2 (See Cautions: Mutagenicity and Carcinogenicity.) The tumorigenic potential of pimozide should be given careful consideration by the patient and physician in the decision to use the drug, especially if the patient is young and long-term therapy is anticipated.1,2

Patients should be warned that pimozide may impair their ability to perform activities requiring mental alertness or physical coordination (e.g., operating machinery, driving a motor vehicle), especially during the first few days of therapy.1,2

Because pimozide produces adverse anticholinergic effects, the drug should be used with caution in individuals whose conditions may be aggravated by anticholinergic activity.1,2

Like other antipsychotic agents, pimozide should be used with caution in patients receiving anticonvulsant agents and in those with EEG abnormalities or a history of seizures because the drug may lower the seizure threshold.1,2 If necessary, adequate anticonvulsant therapy should be maintained during pimozide therapy.1,2

Pimozide should be used with caution in patients with hepatic or renal impairment.1,2

Because pimozide has an antiemetic effect,3,4,25 the drug should be used with caution when suppression of nausea and vomiting might obscure diagnosis of an underlying physical disorder.3

Because increased plasma concentrations of pimozide have occurred following concomitant use of pimozide and sertraline, the manufacturers of pimozide and sertraline state that concomitant use of the drugs is contraindicated.1,200 In addition, increased plasma pimozide concentrations were observed during concurrent use with paroxetine.205,206,210 The manufacturers of paroxetine state that concomitant use of these drugs is contraindicated because of the narrow therapeutic index of pimozide and its known ability to prolong the QT interval.205,206,210 Because of the risk of QT-interval prolongation, concurrent use of either citalopram hydrobromide or escitalopram oxalate with pimozide is contraindicated.1,208,209 Concurrent use of pimozide and fluoxetine also is contraindicated because of the potential for adverse drug interactions or QT_c- interval prolongation.207 In addition, fluvoxamine should not be used concurrently with pimozide.1,211 (See Drug Interactions: Selective Serotonin-reuptake Inhibitors.)

Because pimozide prolongs the QT interval, the drug also is contraindicated in patients with congenital long QT syndrome or a history of cardiac arrhythmias, and in patients receiving other drugs that prolong the QT interval or that inhibit the metabolism of pimozide by inhibiting the cytochrome P-450 (CYP) 3A4 isoenzyme such as macrolide antibiotics (e.g., clarithromycin, erythromycin, azithromycin, dirithromycin, troleandomycin),1,2,168,202 azole antifungal agents (e.g., itraconazole, ketoconazole), protease inhibitors (e.g., boceprevir, indinavir, nelfinavir, ritonavir, saquinavir, telaprevir), nefazodone, or zileuton.1,170 218,219 (See Drug Interactions: Drugs That Prolong the QT Interval and see also Drug Interactions: Drugs and Foods Affecting Hepatic Microsomal Enzymes.)

Pimozide is contraindicated in the treatment of simple tics or tics other than those associated with Tourette's syndrome.1,2 Pimozide should not be used in patients receiving drugs that may cause motor and vocal tics (e.g., pemoline [no longer commercially available in the US], methylphenidate, amphetamines) until such drugs have been withdrawn to determine whether the drugs or Tourette's syndrome is responsible for the tics.1,2

Pimozide is contraindicated in patients with known hypokalemia or hypomagnesemia.1

Pimozide is contraindicated in patients with severe toxic CNS depression or in those who are comatose from any cause;1,2,3 patients with blood dyscrasias, depressive disorders, or parkinsonian syndrome;3 and in patients who are hypersensitive to the drug.1,2 It is not known whether cross-sensitivity exists among antipsychotic agents; however, pimozide should be used with particular caution in patients with known hypersensitivity to other antipsychotic agents.1,2

Pediatric Precautions

The onset of Tourette's syndrome usually occurs between the ages of 2 and 15 years, but data on the use and efficacy of pimozide in children younger than 12 years of age are limited.1,2 Further study is needed to fully evaluate the use and efficacy of the drug for Tourette's syndrome in this age group.1,2 Limited clinical evidence suggests that the safety profile of pimozide in children aged 2-12 years generally is comparable to that observed in older patients.1 Safety and efficacy of pimozide for the management of other conditions in children have not been evaluated, and use of the drug in children for any condition other than Tourette's syndrome is not recommended.1,2

Mutagenicity and Carcinogenicity

No evidence of pimozide-induced mutagenesis was seen in the Ames microbial mutagen test, the micronucleus test in rats, or the dominant lethal assay in mice.1,2

No evidence of carcinogenesis was seen in rats receiving oral pimozide dosages up to 50 times the maximum recommended human dosage for 2 years; however, because of the limited number of rats surviving the study, the meaning of the results is unclear.1,2 Reversible gingival hyperplasia has occurred in dogs receiving oral pimozide dosages greater than 1.5 mg/kg daily (about 5 times the maximum recommended human dosage) for 12 months, and has occurred in at least one patient receiving the drug following marketing approval.1,2 Following oral administration of pimozide 0.62, 5, or 40 mg/kg daily for 18 months in mice, dose-related increases in the incidence of pituitary adenomas and mammary gland adenocarcinomas were observed in females.1,2 Pituitary changes at a dosage of 0.62 mg/kg daily were characterized as hyperplasia, while benign adenomas occurred at the higher dosages.1,2 The mechanism of pimozide-induced pituitary tumors in mice and the clinical importance of this finding are not known;1 however, the tumorigenic potential of pimozide should be given careful consideration by the patient and physician in the decision to use the drug, especially if the patient is young and long-term therapy is anticipated.1,2

Although an increase in mammary neoplasms has been found in rodents following long-term administration of prolactin-stimulating antipsychotic agents, no clinical or epidemiologic studies conducted to date have shown an association between long-term administration of these drugs and mammary tumorigenesis in humans.1,2 Current evidence is considered too limited to be conclusive, and further study is needed to determine the clinical importance in most patients of elevated serum prolactin concentrations associated with antipsychotic agents.1,2 Because in vitro tests indicate that approximately one-third of human breast cancers are prolactin dependent, pimozide should be used with caution in patients with previously detected breast cancer.1,2

Pregnancy, Fertility, and Lactation

Pregnancy

Reproduction studies in rats and rabbits using oral pimozide dosages up to 2.5 mg/kg daily (up to about 8 times the maximum recommended human dosage) have not revealed evidence of fetal malformation; however, in rats receiving oral pimozide dosages of 2.5 mg/kg daily or higher, a decreased pregnancy rate,1,2 increased fetal resorption,2 and retarded development of fetuses1,2 occurred. The observed effects may have resulted from delay or inhibition of implantation.1,2 In rabbits, dose-related maternotoxicity, mortality, decreased weight gain, and embryotoxicity, including increased fetal resorption, occurred.1,2

Neonates exposed to antipsychotic agents during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery.1,222,223,224 There have been reports of agitation, hypertonia, hypotonia, tardive dyskinetic-like symptoms, tremor, somnolence, respiratory distress, and feeding disorder in these neonates.1,222,223,224 The majority of cases were also confounded by other factors, including concomitant use of other drugs known to be associated with withdrawal symptoms, prematurity, congenital malformations, and obstetrical and perinatal complications; however, some cases suggested that neonatal extrapyramidal symptoms and withdrawal may occur with exposure to antipsychotic agents alone.222,224 Some of the cases described time of symptom onset, which ranged from birth to one month after birth.222,223,224 Any neonate exhibiting extrapyramidal or withdrawal symptoms following in utero exposure to antipsychotic agents should be monitored.224 Symptoms were self-limiting in some neonates but varied in severity; some infants required intensive care unit support and prolonged hospitalization.1,222,223,224 For further information on extrapyramidal and withdrawal symptoms in neonates, see Cautions: Pregnancy, Fertility, and Lactation, in the Phenothiazines General Statement 28:16.08.24.

Pimozide should be used during pregnancy only when the potential benefits justify the potential risks to the fetus.1 Women should be advised to notify their clinician if they become pregnant or plan to become pregnant during therapy with the drug.224 In addition, clinicians should advise women of childbearing potential about the benefits and risks of using antipsychotic agents during pregnancy.224 Patients should also be advised not to stop taking their antipsychotic agent if they become pregnant without first consulting with their clinician, since abruptly discontinuing the drugs can cause clinically important complications.224

Fertility

Reproduction studies in animals using oral pimozide were not adequate to fully assess potential effects of the drug on fertility.1 Female rats receiving oral pimozide dosages up to 2.5 mg/kg daily2 had prolonged estrus cycles.1,2

Lactation

It is not known whether pimozide is distributed into milk.1,2 Because of the potential for serious adverse reactions (e.g., tumorigenicity, unknown cardiovascular effects) to pimozide in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.1,2

Selective Serotonin-reuptake Inhibitors

Citalopram

In a controlled study, administration of a single 2-mg dose of pimozide in individuals receiving citalopram (40 mg once daily for 11 days) was associated with mean increases in the QT_c interval of approximately 10 msec compared with pimozide given alone.1,208 Citalopram did not substantially affect the mean AUC or peak plasma concentrations of pimozide.1,208 The mechanism for this potential pharmacodynamic interaction is not known.1,208 Concomitant use of citalopram and pimozide is contraindicated.1,208

Escitalopram

In a controlled study, administration of a single 2-mg dose of pimozide in individuals receiving racemic citalopram (40 mg once daily for 11 days) was associated with mean increases in the QT_c interval of approximately 10 msec compared with pimozide given alone.1,208,209 Racemic citalopram did not substantially affect the mean AUC or peak plasma concentrations of pimozide.1,208,209 Concurrent pimozide and escitalopram administration has not been specifically evaluated to date.209 Concomitant use of escitalopram and pimozide is contraindicated.1,209

Fluoxetine

Clinical studies evaluating pimozide and other antidepressants have demonstrated an increase in adverse drug interactions or QT_c prolongation during combined therapy.207 In addition, rare case reports have suggested possible additive cardiovascular effects of pimozide and fluoxetine, resulting in bradycardia.1,201 Marked changes in mental status (e.g., stupor, inability to think clearly) and hypersalivation also were reported in one woman who received both drugs concurrently.204 Although a specific study evaluating concurrent pimozide and fluoxetine has not been performed to date, concurrent use of these drugs is contraindicated because of the potential for adverse drug interactions or QT_c prolongation.207

Fluvoxamine

Concomitant use of fluvoxamine is contraindicated in patients receiving pimozide, since fluvoxamine may inhibit the metabolism of pimozide and increase the potential for serious adverse cardiac effects.1,211

Paroxetine

In a controlled study, concurrent administration of single 2-mg doses of pimozide in healthy individuals receiving paroxetine (dosage titrated up to 60 mg daily) was associated with mean increases of 151 and 62% in the area under the plasma concentration-time curve (AUC) and peak plasma concentrations of pimozide, respectively, compared with pimozide given alone.205,206,210 The manufacturers of paroxetine state that concomitant use of paroxetine and pimozide is contraindicated because of the narrow therapeutic index of pimozide and its known ability to prolong the QT interval.205,206,210

Sertraline

Administration of a single 2-mg dose of pimozide in individuals receiving sertraline 200 mg daily has resulted in a mean increase of about 40% in pimozide AUC and peak plasma concentrations, but was not associated with changes in ECG parameters.200 The effect on QT interval and pharmacokinetic parameters of pimozide administered in higher doses (i.e., doses exceeding 2 mg) in combination with sertraline is as yet unknown.200 Concomitant use of sertraline and pimozide is contraindicated1,200 because of the low therapeutic index of pimozide and because the reported interaction between the 2 drugs occurred at a low dose of pimozide.200 The mechanism of this interaction is as yet unknown.200

Other CNS Agents

Pimozide may be additive with, or may potentiate the action of, other CNS depressants1,2,4,146 such as opiates1,2,4 or other analgesics,1,2,4 barbiturates1,2,4 or other sedatives,1,2,4 anxiolytics,1,2,4 or alcohol.1,2,4,151 When pimozide is used concomitantly with other CNS depressants, caution should be used to avoid excessive CNS depression.1,2

Drugs That Prolong the QT Interval

Because pimozide prolongs the QT interval, an additive effect on the QT interval might occur if the drug is administered with other agents that may prolong the QT interval such as phenothiazines, tricyclic antidepressants, or antiarrhythmic agents.1,2,202 Therefore, the manufacturer states that pimozide is contraindicated in patients receiving dofetilide, quinidine, sotalol, and other class IA and III antiarrhythmics; chlorpromazine, droperidol, mesoridazine (no longer commercially available in the US), and thioridazine; gatifloxacin, moxifloxacin, and sparfloxacin; halofantrine (licensed in the US but not commercially available); mefloquine; pentamidine; arsenic trioxide; levomethadyl acetate (no longer commercially available in the US); dolasetron mesylate; probucol (no longer commercially available in the US); tacrolimus; ziprasidone; and any other drugs that have demonstrated QT prolongation as one of their pharmacodynamic effects.1,2 (See Cautions: Cardiovascular Effects and see also Cautions: Precautions and Contraindications.)

Drugs and Foods Affecting Hepatic Microsomal Enzymes

Prolongation of QT interval and, rarely, serious cardiovascular effects, including ventricular arrhythmias and death, have been reported in patients receiving drugs that inhibit the cytochrome P-450 (CYP) 3A4 isoenzyme such as macrolide antibiotics (e.g., clarithromycin, erythromycin, azithromycin, dirithromycin, troleandomycin), azole antifungal agents (e.g., itraconazole, ketoconazole), protease inhibitors (e.g., boceprevir, indinavir, nelfinavir, ritonavir, saquinavir, telaprevir), nefazodone, or zileuton concomitantly with pimozide.1,168,170,218,219 Macrolide antibiotics inhibit metabolism of pimozide, which may result in increased plasma concentrations of unchanged drug.168,169 Such alterations in pharmacokinetics of pimozide may be associated with prolongation of the QT and QT_c intervals, and, rarely, associated with ventricular arrhythmias.1,168,169 The manufacturer of pimozide states that concomitant administration of pimozide and macrolide antibiotics, azole antifungal agents, protease inhibitors, nefazodone, or zileuton is contraindicated.1,168,170

Patients receiving pimozide should avoid grapefruit juice because it may inhibit drug metabolism by the CYP3A4 isoenzyme.1,170

Because pimozide also may be metabolized by the CYP1A2 isoenzyme, the manufacturer states the theoretical potential for drug interactions with drugs that inhibit this enzyme system should be considered.1

Acute Toxicity

Pathogenesis

The acute lethal dose of pimozide in humans is not known.152,153 The oral LD₅₀ of pimozide is 228, 5120, 188, and 40 mg/kg in mice, rats, guinea pigs, and dogs, respectively.2,6 The IV and subcutaneous LD₅₀s of pimozide are 11.1 and 40 mg/kg, respectively, for mice, and 5 and 40 mg/kg, respectively, for rats.2

Manifestations

In general, overdosage of pimozide may be expected to produce effects that are extensions of pharmacologic effects and adverse reactions, predominantly ECG abnormalities (including prolongation of the QT interval and torsades de pointes), severe extrapyramidal reactions, hypotension, seizures, and comatose state with respiratory depression.1,2,3,203

A 17-year-old female who reportedly intentionally ingested 100 mg of pimozide and underwent gastric lavage (apparently no drug was recovered) had a complete and uneventful recovery except for slight tremor of the extremities that subsided within a few hours after ingestion.149 A 2½-year-old male who accidentally reportedly ingested 60 mg of pimozide exhibited mild extrapyramidal symptoms that subsequently subsided, and the patient recovered completely.122 Delayed-onset dystonia, hypotension, tachycardia, and drowsiness were reported in an 18-month-old female who ingested up to 6 mg (0.5 mg/kg) of pimozide; manifestations developed more than 12 hours after the accidental ingestion.203 The dystonia subsided over the following 12 hours while the drowsiness and tachycardia persisted for 40 hours.203 The child recovered fully without sequelae.203

Treatment

Treatment of pimozide overdosage generally involves symptomatic and supportive care,1,2,3 with ECG,1,2 blood pressure,1,2,3 and respiratory monitoring.1,2,3 There is no specific antidote for pimozide intoxication.3

Following acute ingestion of the drug, the stomach should be emptied immediately, preferably by gastric lavage.1,2,3,153 If the patient is comatose, having seizures, or lacks the gag reflex, gastric lavage may be performed if an endotracheal tube with cuff inflated is in place to prevent aspiration of gastric contents.150 As in the case of phenothiazine overdosage,161,162 induction of emesis should generally not be attempted because a pimozide-induced dystonic reaction of the head or neck may result in aspiration of gastric contents during emesis;153 however, if the ingestion has only recently occurred (i.e., within an hour or so),153 induction of emesis may be considered.3,153 Following gastric lavage and/or emesis, activated charcoal should be administered.3 A patent airway should be established, using controlled or mechanically assisted respiration as necessary.1,2,3 ECG monitoring should be initiated immediately and continued until ECG parameters are within normal ranges.1,2 For hypotension or circulatory collapse, IV fluids, plasma, albumin, and/or vasopressor agents (e.g., norepinephrine) may be used.1,2,3 Epinephrine should not be used.1,2,3 For severe extrapyramidal reactions, anticholinergic antiparkinsonian agents1,2,3 or diphenhydramine3 should be administered. Because of the long elimination half-life of pimozide, patients should be observed for at least 4 days following acute ingestion of the drug.1,2,203 Clinicians should consider contacting a poison control center for additional information on the management of pimozide overdosage.1,2

Pharmacology

The principal pharmacologic effects of pimozide are similar to those of haloperidol2,4,6 and, to a lesser extent, those of phenothiazines.1,2,4,6,10 In animal studies that are correlated with antipsychotic activity, pimozide is, on a weight basis, almost as potent as haloperidol and more potent than chlorpromazine following oral or subcutaneous administration.2,4,6

Nervous System Effects

In the CNS, pimozide has pharmacologic actions similar to those of haloperidol.2,4,6 The precise mechanism(s) of pimozide in suppressing motor and vocal tics in patients with Tourette's syndrome1,2,10,11 and its antipsychotic action4,15,17,19,20 have not been determined, but it may be related principally to the antidopaminergic effects of the drug.1,2,4,10,11,12,15,17,19,20 Although it has not been clearly established,16 most evidence suggests that pimozide is a selective dopamine-2 (D₂) receptor antagonist.10,21,156 Like butyrophenones (e.g., haloperidol), pimozide appears to predominantly block postsynaptic dopamine receptor sites,2,22,92,146,155 although the drug also may block presynaptic dopamine receptor sites.153,155 Blockade of dopamine receptors by pimozide may be accompanied by a series of secondary alterations in central dopamine metabolism and function that may contribute to the drug's therapeutic and adverse effects.1 Pimozide inhibits electrically induced dopamine release in brain tissue in vitro19 and increases synthesis24 and turnover of brain dopamine.13,24 Unlike most other currently available antipsychotic agents, pimozide appears to have little effect on catecholamines other than dopamine,2,13,24 although turnover of brain norepinephrine may be increased at high doses.3,13 Like other antipsychotic agents, however, pimozide has various effects on CNS receptor systems (e.g., γ-aminobutyric acid [GABA])42 that are not fully characterized.1,42 Pimozide may decrease brain acetylcholine indirectly via its antidopaminergic effects, but such activity is considered relatively weak.4,153 Unlike haloperidol and chlorpromazine, the drug does not provide protection against a lethal dose of norepinephrine in rats.2,6

Pimozide does not affect total sleep time or rapid eye movement (REM) sleep.4 The drug may cause EEG changes, including an increase in α-wave activity.4,75 Although not clearly established, pimozide may also lower the seizure threshold.2,141 The drug does not exhibit anticonvulsant activity in rats.2

Although the exact mechanism(s) of action has not been elucidated, pimozide has an antiemetic effect.3,4,6,25 The antiemetic activity may be mediated via a direct effect of the drug on the medullary chemoreceptor trigger zone (CTZ), apparently by blocking dopamine receptors in the CTZ.25 Pimozide inhibits the central and peripheral effects of apomorphine.2,4,6,18,23,25,38

Like haloperidol and phenothiazines, pimozide inhibits conditioned avoidance behaviors and produces catalepsy and ptosis in animals.4,6 The drug also antagonizes behavioral effects mediated by amphetamines in animals.4,6,42,37 In humans, pimozide antagonizes the euphoric response to amphetamines in amphetamine-dependent individuals,31 but apparently does not antagonize amphetamine-mediated behavioral effects in patients with schizophrenic disorder.32,33,34,35,36 Unlike many other centrally acting agents, pimozide does not appear to exhibit analgesic activity.2 The drug appears to exhibit anxiolytic activity in patients with chronic schizophrenic disorder who exhibit anxiety65,66,68,73,75,76,77,78,80,82,84,85,92,94,99 and in patients with various anxiety states.135,136,137,139

In animals, pimozide does not substantially affect body temperature;2 however, the drug does inhibit apomorphine- and amphetamine-induced fever.2,4,6,23

Pimozide exhibits some anticholinergic activity,1,2,3,4,9,50,62,78,93,136 although it is generally considered to be relatively weak compared with most other antipsychotic agents;4 however, anticholinergic effects (e.g., dry mouth, urinary retention, constipation) may occur during therapy with the drug.1,2,3

Cardiovascular Effects

Pimozide exhibits weak α-adrenergic blocking activity.2,4,6 The drug rarely may produce hypotension,1,2,3,6 orthostatic hypotension,1,2 hypertension,1,2,3 or tachycardia.1,2,3 Pimozide may also produce ECG changes, including prolongation of the QT interval; flattening, notching, and inversion of the T wave; and appearance of U waves.1,2 (See Cautions: Cardiovascular Effects.)

Endocrine Effects

Pimozide induces secretion of prolactin from the anterior pituitary.15,26,27,53 The exact mechanism of increased prolactin secretion has not been determined, but it may be related principally to inhibition of dopamine receptors in the pituitary and hypothalamus.15,27,53,69

Other Effects

In vitro, pimozide exhibits weak antispasmodic effects, resulting from antagonism of various mediator substances (e.g., histamine, bradykinin, angiotensin).6 Pimozide also may inhibit transmembrane influx of extracellular calcium ions via slow calcium channels.18,28,164,165

Pharmacokinetics

Limited information is available on the pharmacokinetics of pimozide.1,2,4,39,40,41

Absorption

Pimozide is slowly1,2,4,39,40 and variably absorbed1,2,4,39 from the GI tract following oral administration. Based on limited data, the drug appears to be at least 40-50% absorbed.1,2,4,39 Pimozide also appears to undergo extensive first-pass metabolism.1,39 It is not known whether food, disease, or concomitant administration of other drugs affects the absorption of pimozide.1

Following oral administration of an individual dose of pimozide, peak plasma concentrations of the drug1,2,4,39,40 and its metabolites39 generally occur within 6-8 hours (range: 4-12 hours).1,2,4,39,40 Following oral administration of a single 6- or 24-mg dose in patients with chronic schizophrenic disorder, peak plasma pimozide concentrations of approximately 4 or 18-19 ng/mL, respectively, were attained.2,40 There are considerable interindividual variations in peak plasma concentrations and areas under the plasma concentration-time curves (AUCs) following single or multiple oral doses of pimozide.1,2,40,41 In a group of patients with chronic schizophrenic disorder receiving 2-10 mg of pimozide daily, steady-state serum concentrations of the drug varied considerably with specific dosages and ranged from undetectable (less than 1 ng/mL) to about 50 ng/mL.41 Because there is little correlation between plasma pimozide concentrations and clinical response, the clinical importance of interindividual variations is unclear.1,15,153 In a group of adults with acute schizophrenic disorder, a correlation between plasma pimozide concentration and dopamine receptor blocking activity, but not between clinical response and dopamine receptor blocking activity, was reported.15

Distribution

Distribution of pimozide into human body tissues and fluids has not been well characterized.152,153 Following subcutaneous administration in animals, pimozide is widely distributed, with highest concentrations attained in the liver,2,4,43,44 lungs,43,44 kidneys,43,44 and heart;43,44 the drug also is distributed into the brain,2,4,42,43,44,45 thymus,43 adrenals,43 thyroid,43 uterus,43 and ovaries,43 and apparently into bile.46 In animals, there is a direct relationship between the administered dose of pimozide and concentrations of the drug attained in the liver and brain.44 Following subcutaneous administration in animals, pimozide is widely distributed throughout the brain,43,45 principally as unchanged drug,42,45 with highest concentrations attained in the pituitary43,45 and caudate nucleus.45 The drug appeared to be selectively retained in the pituitary, caudate nucleus, chemoreceptor trigger zone (CTZ), floor of the third ventricle, lateral hypothalamus, and medulla.45 There was no correlation between concentrations of pimozide in the caudate nucleus and antagonism of effects mediated by amphetamine or apomorphine, but distribution of pimozide into nerve endings in the caudate nucleus was correlated with antagonism of these effects.4,37,42

The extent of pimozide binding to plasma proteins is not known.152

It is not known whether pimozide crosses the placenta or is distributed into milk.1,2

Elimination

Following multiple oral doses in patients with chronic schizophrenic disorder, the elimination half-life of pimozide averaged 55 hours.1,2,40 In one patient who developed a severe dystonic reaction, the elimination half-life of the drug was reportedly 154 hours.47

The exact metabolic fate of pimozide is not clearly established, but the drug appears to undergo extensive first-pass metabolism.1,39 Pimozide is metabolized principally by oxidative N -dealkylation in the liver;1,2,4,46 this metabolism is catalyzed mainly by the cytochrome P-450 (CYP) 3A4 isoenzyme and, to a lesser extent, by cytochrome P-450 (CYP) isoenzyme 1A2.1,168,170 The major metabolites are 4,4- bis (4-fluorophenyl) butyric acid and 1-(4-piperidyl)-2-benzimidazolinone.1,2,4,46 The pharmacologic activity of these metabolites has not been determined;1,2,4 however, results of animal studies suggest that the metabolites of pimozide are inactive.4,37,45

Pimozide and its metabolites are excreted principally in urine1,2,4,39 and, to a lesser extent, in feces.39 About 40% (range: 25-60%) of a single oral dose of the drug is excreted in urine and about 15% (range: 5-20%) in feces within 7 days; most urinary excretion occurs within 3-4 days, and most fecal excretion occurs within 3-6 days.39 Pimozide appears to be excreted in urine almost completely as metabolites,4,39 with probably less than 1% excreted as unchanged drug.39 Fecal excretion has not been well characterized, but pimozide appears to be excreted in feces mainly as unchanged drug and to a small extent as metabolites.39 It is not known whether fecal excretion of the drug and metabolites represents unabsorbed drug or drug excreted via biliary elimination.152,153 In animals, pimozide and its metabolites are excreted in feces following parenteral administration, apparently via biliary elimination.46

It is not known if pimozide and/or its metabolites are removed by hemodialysis or peritoneal dialysis.152

Chemistry and Stability

Chemistry

Pimozide is a diphenylbutylpiperidine-derivative antipsychotic agent.1,2,3,4,5 The drug is structurally similar to butyrophenones (e.g., haloperidol).4,6 Pimozide occurs as a white microcrystalline powder2,6 and has solubilities of less than 0.01 mg/mL in water1,2,5,6 and approximately 7 mg/mL in alcohol at room temperature.152 The drug has a pK_a of 7.32.2,5,6

Stability

Pimozide tablets should be stored in tight, light-resistant containers1,2 at 25°C but may be exposed to temperatures ranging from 15-30°C.1

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

1. Gate Pharmaceuticals. Orap^® (pimozide) tablets prescribing information. Sellersville, PA; 2010 Aug.

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