PIMOZIDE Drug Interactions: What You Need to Know

DRUG INTERACTIONS Because pimozide 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 pimozide 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 C max 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 C max compared to pimozide administered alone. The increase in pimozide AUC and C max 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 pimozide, prescribers should be aware of the theoretical potential for drug interactions with inhibitors of this enzymatic system. Pimozide 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.

CONTRAINDICATIONS 1. Pimozide is contraindicated in the treatment of simple tics or tics other than those associated with Tourette’s Disorder. 2. Pimozide should not be used in patients taking drugs that may, themselves, cause motor and phonic tics (e.g., pemoline, methylphenidate and amphetamines) until such patients have been withdrawn from these drugs to determine whether or not the drugs, rather than Tourette’s Disorder, are responsible for the tics. 3. Because pimozide prolongs the QT interval of the electrocardiogram it is contraindicated in patients with congenital long QT syndrome, patients with a history of cardiac arrhythmias, patients taking other drugs which prolong the QT interval of the electrocardiogram or patients with known hypokalemia or hypomagnesemia (see also PRECAUTIONS - DRUG INTERACTIONS ). 4. Pimozide is contraindicated in patients with severe toxic central nervous system depression or comatose states from any cause. 5. Pimozide is contraindicated in patients with hypersensitivity to it. As it is not known whether cross-sensitivity exists among the antipsychotics, pimozide should be used with appropriate caution in patients who have demonstrated hypersensitivity to other antipsychotic drugs. 6. Ventricular arrhythmias have been rarely associated with the use of macrolide antibiotics in patients with prolonged QT intervals, as might be produced by pimozide. Specifically, two sudden deaths have been reported when clarithromycin was added to ongoing pimozide therapy. Furthermore, some evidence suggests that pimozide is metabolized partly by the enzyme system cytochrome P450 3A4 (CYP 3A4). Macrolide antibiotics are inhibitors of CYP 3A4, and thus could potentially impede pimozide metabolism. For these reasons, pimozide is contraindicated in patients receiving the macrolide antibiotics clarithromycin, erythromycin, azithromycin, dirithromycin, and troleandomycin. 7. Concomitant use in patients taking Celexa or Lexapro is contraindicated (see PRECAUTIONS - DRUG INTERACTIONS - Pimozide and Celexa ). 8. Clinical drug interaction studies have demonstrated that pimozide is also metabolized by CYP 2D6. Concomitant use of pimozide with paroxetine and other strong CYP 2D6 inhibitors is contraindicated (See PRECAUTIONS – DRUG INTERACTIONS ). 9. Concomitant use of pimozide in patients taking sertraline is contraindicated (See PRECAUTIONS – DRUG INTERACTIONS ). Because azole antifungal agents are also inhibitors of the CYP 3A4 enzymes and thus may likewise impair pimozide metabolism, pimozide is contraindicated in patients receiving the azole antifungal agents itraconazole and ketoconazole. Similarly, protease inhibitor drugs are also inhibitors of CYP 3A4, and thus pimozide is contraindicated in patients receiving protease inhibitors such as ritonavir, saquinovir, indinavir, and nelfinavir. (See PRECAUTIONS - DRUG INTERACTIONS. ) Nefazodone is a potent inhibitor of CYP 3A4, and its concomitant use with pimozide is also contraindicated. Other drugs that are relatively less potent inhibitors of CYP 3A4 should also be avoided, in view of the risks: e.g., zileuton, fluvoxamine.

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 ).