Orap, Page 1

Orap (pimozide) is indicated for the suppression of motor and phonic tics in patients with Tourette’s Disorder who have failed to respond satisfactorily to standard treatment. ORAP is not intended as a treatment of first choice nor is it intended for the treatment of tics that are merely annoying or cosmetically troublesome.

ORAP- pimozide tablet
Gate Pharmaceuticals

DESCRIPTION

ORAP® (pimozide) is an orally active antipsychotic agent of the diphenyl-butylpiperidine series. The structural formula of pimozide, 1-[1-[4,4-bis(4-fluorophenyl) butyl]-4-piperidinyl]-1,3-dihydro-2H-benzimidazole-2-one is:

Chemical Structure

The solubility of pimozide in water is less than 0.01 mg/mL; it is slightly soluble in most organic solvents.

Each white ORAP tablet contains either 1 mg or 2 mg of pimozide and the following inactive ingredients: calcium stearate, microcrystalline cellulose, lactose anhydrous and corn starch.

CLINICAL PHARMACOLOGY

Pharmacodynamic Actions

ORAP (pimozide) is an orally active antipsychotic drug product which shares with other antipsychotics the ability to blockade dopaminergic receptors on neurons in the central nervous system. Although its exact mode of action has not been established, the ability of pimozide to suppress motor and phonic tics in Tourette’s Disorder is thought to be a function of its dopaminergic blocking activity. However, receptor blockade is often accompanied by a series of secondary alterations in central dopamine metabolism and function which may contribute to both pimozide’s therapeutic and untoward effects. In addition, pimozide, in common with other antipsychotic drugs, has various effects on other central nervous system receptor systems which are not fully characterized.

Metabolism and Pharmacokinetics

More than 50% of a dose of pimozide is absorbed after oral administration. Based on the pharmacokinetic and metabolic profile, pimozide appears to undergo significant first pass metabolism. Peak serum levels occur generally six to eight hours (range 4-12 hours) after dosing.

Pimozide is extensively metabolized, primarily by N-dealkylation in the liver. This metabolism is catalyzed mainly by the cytochrome P450 3A4 (CYP 3A4) enzymatic system and to a lesser extent, by cytochrome P450 1A2 (CYP 1A2). Two major metabolites have been identified, 1-(4-piperidyl)-2-benzimidazolinone and 4,4-bis(4-fluorophenyl) butyric acid. The antipsychotic activity of these metabolites is undetermined. The major route of elimination of pimozide and its metabolites is through the kidney.

The mean serum elimination half-life of pimozide in schizophrenic patients was approximately 55 hours. There was a 13-fold interindividual difference in the area under the serum pimozide level-time curve and an equivalent degree of variation in peak serum levels among patients studied. The significance of this is unclear since there are few correlations between plasma levels and clinical findings.

Effects of food and disease upon the absorption, distribution, metabolism and elimination of pimozide are not known. Effects of concomitant medication on pimozide metabolism are described in the CONTRAINDICATIONS section.

ORAP Indications and Usage

ORAP (pimozide) is indicated for the suppression of motor and phonic tics in patients with Tourette’s Disorder who have failed to respond satisfactorily to standard treatment. ORAP is not intended as a treatment of first choice nor is it intended for the treatment of tics that are merely annoying or cosmetically troublesome. ORAP 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 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.

CONTRAINDICATIONS

  1. ORAP (pimozide) is contraindicated in the treatment of simple tics or tics other than those associated with Tourette’s Disorder.
  2. ORAP 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 ORAP 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. ORAP is contraindicated in patients with severe toxic central nervous system depression or comatose states from any cause.
  5. ORAP 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 ORAP. 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, ORAP 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).

Because azole antifungal agents are also inhibitors of the CYP 3A4 enzymes and thus may likewise impair pimozide metabolism, ORAP is contraindicated in patients receiving the azole antifungal agents itraconazole and ketoconazole.

Similarly, protease inhibitor drugs are also inhibitors of CYP 3A4, and thus ORAP 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 ORAP 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.

Concomitant use of pimozide in patients taking sertraline is contraindicated (See PRECAUTIONS — Drug Interactions).

WARNINGS

The use of ORAP (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 ORAP 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 ORAP treatment is initiated and periodically thereafter, especially during the period of dose adjustment.

ORAP 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).

PRECAUTIONS

Leukopenia, Neutropenia and Agranulocytosis

Class Effect

In clinical trial and/or postmarketing experience, events of leukopenia/neutropenia and agranulocytosis have been reported temporally related to antipsychotic agents.

Possible risk factors for leukopenia/neutropenia include preexisting low white blood cell count (WBC) and history of drug induced leukopenia/neutropenia. Patients with a history of a clinically significant low WBC or drug induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and discontinuation of ORAP should be considered at the first sign of a clinically significant decline in WBC in the absence of other causative factors.

Patients with clinically significant neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count <1000/mm3) should discontinue ORAP and have their WBC followed until recovery.

General

ORAP (pimozide) may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks, such as driving a car or operating machinery, especially during the first few days of therapy.

ORAP produces anticholinergic side effects and should be used with caution in individuals whose conditions may be aggravated by anticholinergic activity.

ORAP should be administered cautiously to patients with impairment of liver or kidney function, because it is metabolized by the liver and excreted by the kidneys.

Antipsychotics should be administered with caution to patients receiving anticonvulsant medication, with a history of seizures, or with EEG abnormalities, because they may lower the convulsive threshold. If indicated, adequate anticonvulsant therapy should be maintained concomitantly.

Information for Patients

Treatment with ORAP exposes the patient to serious risks. A decision to use ORAP chronically in Tourette’s Disorder is one that deserves full consideration by the patient (or patient’s family) as well as by the treating physician. Because the goal of treatment is symptomatic improvement, the patient’s view of the need for treatment and assessment of response are critical in evaluating the impact of therapy and weighing its benefits against the risks. Since the physician is the primary source of information about the use of a drug in any disease, it is recommended that the following information be discussed with patients and/or their families.

ORAP is intended only for use in patients with Tourette’s Disorder whose symptoms are severe and who cannot tolerate, or who do not respond to HALDOL® (haloperidol).

Given the likelihood that a proportion of patients exposed chronically to antipsychotics will develop tardive dyskinesia, it is advised that all patients in whom chronic use is contemplated be given, if possible, full information about this risk. The decision to inform patients and/or their guardians must obviously take into account the clinical circumstances and the competency of the patient to understand the information provided.

There is limited information available on the use of ORAP in children under 12 years of age.

The information available on ORAP from foreign marketing experience and from U.S. clinical trials indicates that ORAP has a side effect profile similar to that of other antipsychotic drugs. Patients should be informed that all types of side effects associated with the use of antipsychotics may be associated with the use of ORAP.

In addition, sudden, unexpected deaths have occurred in patients taking high doses of ORAP for conditions other than Tourette’s Disorder. These deaths may have been the result of an effect of ORAP upon the heart. Therefore, patients should be instructed not to exceed the prescribed dose of ORAP and they should realize the need for the initial ECG and for follow-up ECGs during treatment.

Also, pimozide, at a dose about 15 times that given humans, caused an increase in the number of benign tumors of the pituitary gland in female mice. It is not possible to say how important this is. Similar tumors were not seen in rats given pimozide, nor at lower doses in mice, which is reassuring. However, any such finding must be considered to suggest a possible risk of long term use of the drug.

Because substances in grapefruit juice may inhibit the metabolism of pimozide by CYP 3A4, patients should be advised to avoid grapefruit juice.

Laboratory Tests

An ECG should be done at baseline and periodically thereafter throughout the period of dose adjustment. Any indication of prolongation of QTc interval beyond an absolute limit of 0.47 seconds (children) or 0.52 seconds (adults), or more than 25% above the patient’s original baseline should be considered a basis for stopping further dose increase (see CONTRAINDICATIONS) and considering a lower dose.

Since hypokalemia has been associated with ventricular arrhythmias, potassium insufficiency, secondary to diuretics, diarrhea, or other cause, should be corrected before ORAP therapy is initiated and normal potassium maintained during therapy.

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).

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