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SIDE EFFECTS

General

Extrapyramidal Reactions

Neuromuscular (extrapyramidal) reactions during the administration of ORAP® (pimozide) have been reported frequently, often during the first few days of treatment. In most patients, these reactions involved Parkinson-like symptoms which, when first observed, were usually mild to moderately severe and usually reversible.

Other types of neuromuscular reactions (motor restlessness, dystonia, akathisia, hyperreflexia, opisthotonos, oculogyric crises) have been reported far less frequently. Severe extrapyramidal reactions have been reported to occur at relatively low doses. Generally the occurrence and severity of most extrapyramidal symptoms are dose-related since they occur at relatively high doses and have been shown to disappear or become less severe when the dose is reduced. Administration of antiparkinson drugs such as benztropine mesylate or trihexyphenidyl hydrochloride may be required for control of such reactions. It should be noted that persistent extrapyramidal reactions have been reported and that the drug may have to be discontinued in such cases.

Withdrawal Emergent Neurological Signs

Generally, patients receiving short term therapy experience no problems with abrupt discontinuation of antipsychotic drugs.

However, some patients on maintenance treatment experience transient dyskinetic signs after abrupt withdrawal. In certain of these cases the dyskinetic movements are indistinguishable from the syndrome described below under “Tardive Dyskinesia” except for duration. It is not known whether gradual withdrawal of antipsychotic drugs will reduce the rate of occurrence of withdrawal emergent neurological signs, but until further evidence becomes available, it seems reasonable to gradually withdraw use of ORAP.

Tardive Dyskinesia

ORAP may be associated with persistent dyskinesias. Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements, may appear in some patients on long-term therapy or may occur after drug therapy has been discontinued. The risk appears to be greater in elderly patients on high-dose therapy, especially females. The symptoms are persistent and in some patients appear irreversible. The syndrome is characterized by rhythmical involuntary movements of tongue, face, mouth or jaw (e.g., protrusion of tongue, puffing of cheeks, puckering of mouth, chewing movements). Sometimes these may be accompanied by involuntary movements of extremities and the trunk.

There is no known effective treatment for tardive dyskinesia; antiparkinson agents usually do not alleviate the symptoms of this syndrome. It is suggested that all antipsychotic agents be discontinued if these symptoms appear. Should it be necessary to reinstitute treatment, or increase the dosage of the agent, or switch to a different antipsychotic agent, this syndrome may be masked.

It has been reported that fine vermicular movement of the tongue may be an early sign of tardive dyskinesia and if the medication is stopped at that time the syndrome may not develop.

Electrocardiographic Changes

Electrocardiographic changes have been observed in clinical trials of ORAP in Tourette's Disorder and schizophrenia. These have included prolongation of the QT interval, flattening, notching and inversion of the T wave and the appearance of U waves. Sudden, unexpected deaths and grand mal seizure have occurred at doses above 20 mg/day.

Neuroleptic Malignant Syndrome

Neuroleptic malignant syndrome (NMS) has been reported with ORAP. (See WARNINGS for further information concerning NMS.)

Hyperpyrexia

Hyperpyrexia has been reported with other antipsychotic drugs.

Clinical Trials

The following adverse reaction tabulation was derived from 20 patients in a 6-week long placebo-controlled clinical trial of ORAP in Tourette's Disorder.

Body System/ Adverse Reaction Pimozide
(N = 20)
Placebo
(N = 20)
Body as a Whole
  Headache 1 2
Gastrointestinal
  Dry Mouth 5 1
  Diarrhea 1 0
  Nausea 0 2
  Vomiting 0 1
  Constipation 4 2
  Eructations 0 1
  Thirsty 1 0
  Appetite increase 1 0
Endocrine
  Menstrual disorder 0 1
  Breast secretions 0 1
Musculoskeletal
  Muscle cramps 0 1
  Muscle tightness 3 0
  Stooped posture 2 0
CNS
  Drowsiness 7 3
  Sedation 14 5
  Insomnia 2 2
  Dizziness 0 1
  Akathisia 8 0
  Rigidity 2 0
  Speech disorder 2 0
  Handwriting change 1 0
  Akinesia 8 0
Psychiatric
  Depression 2 3
  Excitement 0 1
  Nervous 1 0
  Adverse behavior effect 5 0
Special Senses
  Visual disturbance 4 0
  Taste change 1 0
  Sensitivity of eyes to light 1 0
  Decrease accommodation 4 1
  Spots before eyes 0 1
Urogenital
  Impotence 3 0

The following adverse event tabulation was derived from 36 children (age 2 to 12) in a 24-week open trial of ORAP in Tourette's Disorder.

Body System/ Adverse Reaction Number of Patients Experiencing Each Event (%)
All Events
(N=36)
Drug-Related Events
(N=36)
Body as a Whole
  Asthenia 9 (25.0) 5 (13.8)
  Headache 8 (22.2) 1 (2.7)
Gastrointestinal
  Dysphagia 1 (2.7) 1 (2.7)
  Increased Salivation 5 (13.8) 2 (5.5)
Musculoskeletal
  Myalgia 1 (2.7) 1 (2.7)
Central Nervous System
  Dreaming Abnormal 1 (2.7) 1 (2.7)
  Hyperkinesia 2 (5.5) 1 (2.7)
  Somnolence 10 (27.7) 9 (25.0)
  Torticollis 1 (2.7) 1 (2.7)
  Tremor, Limbs 1 (2.7) 1 (2.7)
Psychiatric
  Adverse Behavior Effect 10 (27.7) 8 (22.2)
  Nervous 3 (8.3) 2 (5.5)
Skin
  Rash 3 (8.3) 1 (2.7)
Special Senses
  Visual Disturbance 2 (5.5) 1 (2.7)
Cardiovascular
  ECG Abnormal 1 (2.7) 1 (2.7)

Because clinical investigational experience with ORAP in Tourette's Disorder is limited, uncommon adverse reactions may not have been detected. The physician should consider that other adverse reactions associated with antipsychotics may occur.

Other Adverse Reactions

In addition to the adverse reactions listed above, those listed below have been reported in U.S. clinical trials of ORAP in conditions other than Tourette's Disorder.

Body as a Whole: Asthenia, chest pain, periorbital edema

Cardiovascular/Respiratory: Postural hypotension, hypotension, hypertension, tachycardia, palpitations

Gastrointestinal: Increased salivation, nausea, vomiting, anorexia, GI distress

Endocrine: Loss of libido

Metabolic/Nutritional: Weight gain, weight loss

Central Nervous System: Dizziness, tremor, parkinsonism, fainting, dyskinesia

Psychiatric: Excitement

Skin: Rash, sweating, skin irritation

Special Senses: Blurred vision, cataracts

Urogenital: Nocturia, urinary frequency

Postmarketing Reports

The following experiences were described in spontaneous postmarketing reports. These reports do not provide sufficient information to establish a clear causal relationship with the use of ORAP.

Gastrointestinal: Gingival hyperplasia in one patient

Hematologic: Hemolytic anemia

Metabolic/Nutritional: Hyponatremia

Other: Seizure

Read the Orap (pimozide) Side Effects Center for a complete guide to possible side effects

DRUG INTERACTIONS

Because ORAP prolongs the QT interval of the electrocardiogram, an additive effect on QT interval would be anticipated if administered with other drugs, such as phenothiazines, tricyclic antidepressants or antiarrhythmic agents, which prolong the QT interval. Accordingly, pimozide should not be given with dofetilide, sotalol, quinidine, other Class Ia and III anti-arrhythmics, mesoridazine, thioridazine, chlorpromazine, droperidol, sparfloxacin, gatifloxacin, moxifloxacin, halofantrine, mefloquine, pentamidine, arsenic trioxide, levomethadyl acetate, dolasetron mesylate, probucol, tacrolimus, ziprasidone, or other drugs that have demonstrated QT prolongation as one of their pharmacodynamic effects. Also, the use of macrolide antibiotics in patients with prolonged QT intervals has been rarely associated with ventricular arrhythmias. Such concomitant administration should not be undertaken (see CONTRAINDICATIONS).

Since ORAP is partly metabolized via CYP 3A4, it should not be administered concomitantly with inhibitors of this metabolic system, such as azole antifungal agents and protease inhibitor drugs (see CONTRAINDICATIONS).

Pimozide and Celexa: In a controlled study, a single dose of pimozide 2 mg coadministered with racemic citalopram 40 mg given once daily for 11 days was associated with a mean increase in QTc values of approximately 10 msec compared to pimozide given alone. Racemic citalopram did not alter the mean AUC or Cmax of pimozide. The mechanism of this pharmacodynamic interaction is not known. Concomitant use of pimozide and Celexa or Lexapro is contraindicated (See CONTRAINDICATIONS).

CYP 2D6 inhibitors: In healthy subjects, co-administration of pimozide 2 mg (single dose) and paroxetine 60 mg resulted in a 151% increase in pimozide AUC and a 62% increase in pimozide Cmax compared to pimozide administered alone. The increase in pimozide AUC and Cmax is related to the CYP 2D6 inhibitory properties of paroxetine. Concomitant use of pimozide and paroxetine or other strong CYP 2D6 inhibitors are contraindicated (see CONTRAINDICATIONS). As CYP 1A2 may also contribute to the metabolism of ORAP, prescribers should be aware of the theoretical potential for drug interactions with inhibitors of this enzymatic system.

ORAP may be capable of potentiating CNS depressants, including analgesics, sedatives, anxiolytics, and alcohol.

Rare case reports have suggested possible additive effects of pimozide and fluoxetine leading to bradycardia.

Concomitant administration of pimozide and sertraline should be contraindicated (See CONTRAINDICATIONS).

Pharmacogenomics

Individuals with genetic variations resulting in poor CYP 2D6 metabolism (approximately 5 to 10% of the population) exhibit higher pimozide concentrations than extensive CYP 2D6 metabolizers. The concentrations observed in poor CYP 2D6 metabolizers are similar to those seen with strong CYP 2D6 inhibitors such as paroxetine. The time to achieve steady state pimozide concentrations is expected to be longer (approximately 2 weeks) in poor CYP 2D6 metabolizers because of the prolonged half-life. Alternative dosing strategies are recommended in patients who are genetically poor CYP 2D6 metabolizers (see DOSAGE AND ADMINISTRATION).

Interaction with Food

Patients should avoid grapefruit juice because it may inhibit the metabolism of pimozide by CYP 3A4.

Read the Orap Drug Interactions Center for a complete guide to possible interactions

Last reviewed on RxList: 10/7/2011
This monograph has been modified to include the generic and brand name in many instances.

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