Adult: For the treatment of chronic schizophrenia and prevention of relapse: Initially, 2 mg once daily, adjusted according to response by increments of 2-4 mg at intervals of not less than 1 week. Usual dose range: 2-20 mg daily. Child: >12 years Same as adult dose. Elderly: Half the usual initial dose.
Oral Tourette's syndrome
Adult: In patients who have failed to respond satisfactorily to standard treatment: Initially, 1-2 mg daily in divided doses, may be increased thereafter every other day. Max: 10 mg daily or 0.2 mg/kg daily. Child: ≥12 years Initially, 0.05 mg/kg once daily at bedtime, may be increased thereafter every 3rd day. Max: 0.2 mg/kg or (not exceeding 10 mg) daily. Elderly: Half the usual initial dose.
Oral Monosymptomatic hypochondria, Paranoid states
Adult: Initially, 4 mg once daily, adjusted according to response by increments of 2-4 mg at intervals of not less than 1 week. Max: 16 mg daily. Child: >12 years Same as adult dose. Elderly: Half the usual initial dose.
Special Patient Group
Pharmacogenomics:
Pimozide is metabolised primarily by CYP3A4 isoenzyme, and to a lesser extent by CYP1A2 and CYP2D6 isoenzymes. Individual variations in pharmacokinetic parameter values and safety with pimozide use are associated with CYP2D6 polymorphisms. Genetic variations resulting in poor CYP2D6 metabolism may have higher concentrations of pimozide than those who are extensive metabolisers. CYP2D6 genotype testing may be performed to determine the safety of pimozide use in both adults and paediatric patients.
CYP2D6 ultrarapid metabolisers
May result in lower pimozide concentrations; however, there is no evidence of reduced effectiveness. No dosage adjustment needed.
CYP2D6 intermediate metabolisers
May increase plasma pimozide concentrations resulting in increased risk of QT prolongation and torsades de pointes.
DPWG guidelines recommends using no more than 80% of the usual Max dose: 16 mg/day (adults); 0.08 mg/kg/day up to Max 3 mg/day (children).
CYP2D6 poor metabolisers
Increased plasma pimozide concentrations resulting in increased risk of QT prolongation and torsades de pointes.
DPWG guidelines recommends using no more than 50% of the usual Max dose: 10 mg/day (adults); 0.05 mg/kg/day up to Max 2 mg/day (children).
For the treatment of Tourette’s syndrome in CYP2D6 poor metabolisers, the FDA recommends Max pimozide doses of 4 mg daily in adults and 0.05 mg/kg daily in children. The interval between dose increases should be at least 14 days in these patients.
Administration
May be taken with or without food.
Contraindications
Prolonged QT interval or family history of congenital long QT syndrome, history of cardiac arrhythmias, severe toxic CNS depression, comatose states, known uncorrected hypokalaemia or hypomagnesaemia; treatment of simple tics or tics other than those associated with Tourette’s syndrome. Concomitant use with QTc-prolonging agents, SSRIs, CYP3A4 and strong CYP2D6 inhibitors; drugs that may cause motor and phonic tics (e.g. pemoline, methylphenidate, amphetamines) until it is determined if these drugs or Tourette disorder are causing tics.
Special Precautions
Patient with CV disease, dementia, history of seizures or other conditions that may lower seizure threshold (e.g. head trauma, brain damage, alcohol withdrawal); thyrotoxicosis, phaeochromocytoma, diabetes, decreased gastrointestinal motility, paralytic ileus, urinary retention, benign prostatic hypertrophy, xerostomia, or visual problems; blood dyscrasia, Parkinson’s disease. Patients subjected to conditions that may elevate core body temperature (e.g. strenuous exercise, heat exposure, dehydration). Avoid abrupt withdrawal. Renal and hepatic impairment. Children and elderly. Pregnancy and lactation. CYP2D6 intermediate and poor metabolisers.
Adverse Reactions
Significant: Extrapyramidal symptoms including acute dystonic reactions, akathisia, pseudoparkinsonism, tardive dyskinesia; venous thromboembolism, grand mal convulsions, anticholinergic effects (e.g. constipation, xerostomia, blurred vision, urinary retention), CNS depression, oesophageal dysmotility or aspiration, hyperprolactinaemia, impaired core body temperature regulation. Eye disorders: Decreased accommodation, visual disturbance. Gastrointestinal disorders: Nausea, vomiting, diarrhoea, salivary hypersecretion, constipation, dry mouth. General disorders and administration site conditions: Hyperhidrosis, extreme exhaustion. Investigations: Weight increased. Metabolism and nutrition disorders: Anorexia, hyperglycaemia, hyponatraemia. Musculoskeletal and connective tissue disorders: Muscle spasm, muscle rigidity. Nervous system disorders: Dizziness, somnolence, headache, tremor, akinesia. Psychiatric disorders: Depression, insomnia, agitation, restlessness. Renal and urinary disorders: Nocturia, urinary frequency. Reproductive system and breast disorders: Erectile dysfunction, galactorrhoea, gynaecomastia, amenorrhoea, decreased libido. Skin and subcutaneous tissue disorders: Sebaceous gland overactivity, rash, pruritus. Potentially Fatal: Neuroleptic malignant syndrome (NMS), altered cardiac conduction (e.g. QT interval prolongation, torsades de pointes, arrhythmias, ventricular tachycardia and fibrillation), blood dyscrasia (e.g. leucopenia, neutropenia, agranulocytosis).
This drug may cause sedation and impaired alertness, if affected, do not drive or operate machinery.
Monitoring Parameters
Perform CYP2D6 genotyping or phenotyping at baseline. Monitor ECG at baseline and periodically thereafter especially during dose adjustments; CBC frequently during the 1st few months in at risk patients and as clinically indicated; cardiac function, electrolytes (e.g. serum K). Perform ocular examination yearly.
Overdosage
Symptoms: Severe extrapyramidal symptoms, hypotension, sedation, cardiac arrhythmias associated with QT-prolongation and ventricular arrhythmias including torsades de pointes, comatose state with respiratory depression. Management: Symptomatic and supportive treatment. Perform gastric lavage. Establish patent airway and if necessary consider mechanically assisted respiration. May administer IV fluids, plasma or concentrated albumin, and vasopressor agents (e.g. norepinephrine, metaraminol, phenylephrine) to counteract hypotension and circulatory collapse. Administer anti-Parkinson agents in cases of severe extrapyramidal symptoms.
Drug Interactions
Increased CNS depression produced by other CNS depressants (e.g. hypnotics, sedatives, strong analgesics). May impair the anti-Parkinson effects of levodopa. Increased risk of extrapyramidal effects with anti-emetics (e.g. metoclopramide). Increased risk of CNS toxicity with sibutramine. Enhanced hypotensive effect with Ca channel blockers. May cause electrolyte imbalance with diuretics (especially those causing hypokalaemia). Potentially Fatal: Increase risk of QT prolongation with CYP3A4 inhibitors, macrolide antibiotics, protease inhibitors, and azole antifungals, strong CYP2D6 inhibitors, SSRIs, TCAs, and antiarrhythmics. Concomitant use of drugs that may cause motor and phonic tics (e.g. pemoline, methylphenidate, amphetamines) may mask or resemble symptoms from that of Tourette’s disorder.
Food Interaction
Grapefruit or grapefruit juice may inhibit the metabolism and increase the plasma concentrations of pimozide. Increased CNS depressant effects of alcohol.
Action
Description: Pimozide, a diphenylbutylpiperidine antipsychotic. It blocks the dopaminergic receptors in the CNS resulting in its characteristic neuroleptic effects. Onset: Within 1 week. Duration: Variable duration. Pharmacokinetics: Absorption: Slowly and variably absorbed from the gastrointestinal tract (≥50%). Time to peak plasma concentration: Approx 6-8 hours (range: 4-12 hours). Distribution: Plasma protein binding: 99%. Metabolism: Extensively metabolised in the liver via N-dealkylation mainly by CYP3A4 isoenzyme, and to a lesser extent by CYP1A2 and CYP2D6 isoenzymes; undergoes significant first-pass effect. Excretion: Via urine and faeces as unchanged drug and metabolites. Elimination half-life: Approx 55 hours.
Chemical Structure
Pimozide Source: National Center for Biotechnology Information. PubChem Database. Pimozide, CID=16362, https://pubchem.ncbi.nlm.nih.gov/compound/Pimozide (accessed on Jan. 22, 2020)
N05AG02 - pimozide ; Belongs to the class of diphenylbutylpiperidine derivatives antipsychotics.
References
Rogers HL et al. CYP2D6 Genotype Information to Guide Pimozide Treatment in Adult and Pediatric Patients: Basis for the U.S. Food and Drug Administration's New Dosing Recommendations. Pharmacogenomics Knowledgebase (PharmGKB). 2012. Accessed 18/11/2019. PMID: 23059146Annotation of DPWG Guideline for Pimozide and CYP2D6. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org. Accessed 18/11/2019.Annotation of FDA Label for Pimozide and CYP2D6. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org/. Accessed 18/11/2019.Anon. CYP2D6 - Pimozide (Pharmacogenomics). Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 18/11/2019.Anon. Pimozide. AHFS Clinical Drug Information [online]. Bethesda, MD. American Society of Health-System Pharmacists, Inc. https://www.ahfscdi.com. Accessed 18/11/2019.Anon. Pimozide. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 18/11/2019.Buckingham R (ed). Pimozide. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 18/11/2019.Joint Formulary Committee. Pimozide. British National Formulary [online]. London. BMJ Group and Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 18/11/2019.Pimozide Tablet (Par Pharmaceutical, Inc.). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/. Accessed 18/11/2019.
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