pimozide (Rx) - Orap

Dosing Forms & Strengths

Tourette Disorder

Initial 1-2 mg PO qD ; increase qOD; not to exceed 10 mg/day

Maintenance: <0.2 mg/kg/day or 10 mg/day, choose lowest dose

Dosing Forms & Strengths

Tourette Disorder

Other Information

No more than 10 mg/d

>10%

Akinesia (40%)

Drowsiness (35%)

EPS (10-15%)

Sedation (70%)

Speech disorder (10-15%)

Visual disturbance (20%)

Dry mouth (25%)

Constipation (20%)

Impotence (10-15%)

1-10%

Appetite increase

Thirst increase

Dizziness

Drug-induced tardive dystonia

Nervousness

Photosensitivity

Taste change

Orthostatic hypotension

Diminished sweating

Nasal congestion

Diarrhea

Urinary retention

Retinitis pigmentosa

Frequency Not Defined

Ineffective thermoregulation

Heatstroke or hypothermia (rare)

Neuroleptic malignant syndrome (rare)

Seizure (rare)

Prolonged QT interval

Torsades de pointes

Obstipation (rare)

Paralytic ileus (rare)

Agranulocytosis (rare)

Disorder of hematopoietic structure (rare)

Leukopenia (rare)

Thrombocytopenia (rare)

Cholestatic jaundice syndrome (rare)

Drug-induced lupus erythematosus, systemic (rare)

Priapism (rare)

Death

Black Box Warnings

Patients with dementia-related psychosis who are treated with antipsychotic drugs are at an increased risk of death as shown in short-term controlled trials. The deaths appeared to be either cardiovascular (eg, heart failure, sudden death) or infectious (eg, pneumonia) in nature.

This drug is not approved for the treatment of patients with dementia-related psychosis.

Contraindications

Documented hypersensitivity

CNS depression (incl coma), neuroleptic malignant syndrome (NMS), poorly controlled seizure disorder

Use as first-line treatment

Tics not associated with Tourette's

Prolongs QT interval: concurrent QT-prolonging drugs or congenital long QT patients

Concomitant CYP3A4 or CYP2D6 inhibitors

Cautions

FDA Warning regarding off-label use for dementia in elderly

Avoid grapefruit juice

Risk of EPS & NMS

Leukopenia/neutropenia and agranulocytosis reported; possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC) and history of drug-induced leukopenia/neutropenia ( if history of clinically significant low WBC or drug-induced leukopenia/neutropenia, monitor complete blood count (CBC) frequently during first few months of therapy; discontinue drug at first sign of a clinically significant decline <1000/mm3 in WBC in absence of other causative factors and continue monitoring WBC until recovery)

Mechanism of Action

Phenylbutylpiperadine; dopamine D2 receptor antagonist

Absorption

Bioavailability: 40-50%

Peak Plasma Time: 6-8 hr

Peak Plasma Concentration: 4-19 ng/mL (dose dependent)

Metabolism

Metabolism: hepatic P450 enzyme CYP3A4 and CYP2D6

Metabolites: inactive

Elimination

Half-Life: 55 hr

Excretion: mainly urine; feces

Dialyzable: unknown

Pharmacogenetics

Poor CYP2D6 metabolizers exhibit higher pimozide concentrations than extensive CYP2D6 metabolizers

Approximately 7-10% of Caucasians and 3-8% of African Americans lack the capacity to metabolize CYP2D6 substrates and are classified as poor metabolizers (PMs)

Serum concentrations observed in poor metabolizers are similar to those seen with strong CYP2D6 inhibitors (eg, paroxetine)

Time to achieve steady state pimozide concentrations is expected to be longer (approximately 2 weeks) in poor metabolizers because of the prolonged half-life

Alternative dosing strategies are recommended in patients who are genetically poor CYP2D6 metabolizers