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.

WARNINGS The use of pimozide in the treatment of Tourette’s Disorder involves different risk/benefit considerations than when antipsychotic drugs are used to treat other conditions.

Consequently, a decision to use pimozide should take into consideration the following (see also PRECAUTIONS - Information for Patients ).

Tardive Dyskinesia A syndrome consisting of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs.

Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome.

Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.

Both the risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase.

However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses.

There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn.

Antipsychotic treatment itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying process.

The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.

Given these considerations, antipsychotic drugs should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia.

Chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness, that 1) is known to respond to antipsychotic drugs, and, 2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate.

In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought.

The need for continued treatment should be reassessed periodically.

If signs and symptoms of tardive dyskinesia appear in a patient on antipsychotics, drug discontinuation should be considered.

However, some patients may require treatment despite the presence of the syndrome.

(For further information about the description of tardive dyskinesia and its clinical detection, please refer to ADVERSE REACTIONS and PRECAUTIONS - Information for Patients .) Neuroleptic Malignant Syndrome (NMS) A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with antipsychotic drugs.

Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status (including catatonic signs) and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmias).

Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis) and acute renal failure.

The diagnostic evaluation of patients with this syndrome is complicated.

In arriving at a diagnosis, it is important to identify cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS).

Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever and primary central nervous system (CNS) pathology.

The management of NMS should include 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy, 2) intensive symptomatic treatment and medical monitoring, and 3) treatment of any concomitant serious medical problems for which specific treatments are available.

There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS.

If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered.

The patient should be carefully monitored, since recurrences of NMS have been reported.

Hyperpyrexia, not associated with the above symptom complex, has been reported with other antipsychotic drugs.

Other Sudden, unexpected deaths have occurred in experimental studies of conditions other than Tourette’s Disorder.

These deaths occurred while patients were receiving dosages in the range of 1 mg per kg.

One possible mechanism for such deaths is prolongation of the QT interval predisposing patients to ventricular arrhythmia.

An electrocardiogram should be performed before pimozide treatment is initiated and periodically thereafter, especially during the period of dose adjustment.

Pimozide may have a tumorigenic potential.

Based on studies conducted in mice, it is known that pimozide can produce a dose-related increase in pituitary tumors.

The full significance of this finding is not known, but should be taken into consideration in the physician’s and patient’s decisions to use this drug product.

This finding should be given special consideration when the patient is young and chronic use of pimozide is anticipated (see PRECAUTIONS - Carcinogenesis, Mutagenesis, Impairment of Fertility ).

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