Pimozide

INDICATIONS AND USAGE Pimozide tablets, USP are indicated for the suppression of motor and phonic tics in patients with Tourette’s Disorder who have failed to respond satisfactorily to standard treatment. Pimozide Tablets, USP are not intended as a treatment of first choice nor is it intended for the treatment of tics that are merely annoying or cosmetically troublesome. Pimozide Tablets, USP should be reserved for use in Tourette’s Disorder patients whose development and/or daily life function is severely compromised by the presence of motor and phonic tics. Evidence supporting approval of pimozide tablets, USP for use in Tourette’s Disorder was obtained in two controlled clinical investigations which enrolled patients between the ages of 8 and 53 years. Most subjects in the two trials were 12 or older.

DOSAGE AND ADMINISTRATION General The suppression of tics by pimozide tablets, USP requires a slow and gradual introduction of the drug. The patient’s dose should be carefully adjusted to a point where the suppression of tics and the relief afforded is balanced against the untoward side effects of the drug. An ECG should be done at baseline and periodically thereafter, especially during the period of dose adjustment (see WARNINGS and PRECAUTIONS - Laboratory Tests). Periodic attempts should be made to reduce the dosage of pimozide tablets, USP to see whether or not tics persist at the level and extent first identified. In attempts to reduce the dosage of pimozide tablets, USP consideration should be given to the possibility that increases of tic intensity and frequency may represent a transient, withdrawal related phenomenon rather than a return of disease symptoms. Specifically, one to two weeks should be allowed to elapse before one concludes that an increase in tic manifestations is a function of the underlying disease syndrome rather than a response to drug withdrawal. A gradual withdrawal is recommended in any case. Children Reliable dose response data for the effects of pimozide tablets, USP on tic manifestation in Tourette’s Disorder patients below the age of twelve are not available. Treatment should be initiated at a dose of 0.05 mg/kg preferably taken once at bedtime. The dose may be increased every third day to a maximum of 0.2 mg/kg not to exceed 10 mg/day. At doses above 0.05 mg/kg/day, CYP 2D6 genotyping should be performed. In poor CYP 2D6 metabolizers, pimozide tablets, USP doses should not exceed 0.05 mg/kg/day, and doses should not be increased earlier than 14 days (see PRECAUTIONS – Pharmacogenomics) . Adults In general, treatment with pimozide tablets, USP should be initiated with a dose of 1 to 2 mg a day in divided doses. The dose may be increased thereafter every other day. Most patients are maintained at less than 0.2 mg/kg/day, or 10 mg/day, whichever is less. Doses greater than 0.2 mg/kg/day or 10 mg/day are not recommended. At doses above 4 mg/day, CYP 2D6 genotyping should be performed. In poor CYP 2D6 metabolizers, pimozide tablets, USP doses should not exceed 4 mg/day, and doses should not be increased earlier than 14 days (see PRECAUTIONS – Pharmacogenomics ).

ADVERSE REACTIONS General Extrapyramidal Reactions: Neuromuscular (extrapyramidal) reactions during the administration of 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 pimozide. Tardive Dyskinesia: Pimozide 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 pimozide 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 pimozide. (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 pimozide 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 pimozide in Tourette’s Disorder. Because clinical investigational experience with pimozide in Tourette’s Disorder is limited, uncommon 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) 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 pimozide 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 pimozide. Gastrointestinal: Gingival hyperplasia in one patient Hematologic: Hemolytic anemia Metabolic/Nutritional: Hyponatremia Other: Seizure