Orap

Orap - General Information

A diphenylbutylpiperidine that is effective as an antipsychotic agent and as an alternative to haloperidol for the suppression of vocal and motor tics in patients with Tourette syndrome. Although the precise mechanism of action is unknown, blockade of postsynaptic dopamine receptors has been postulated. (From AMA Drug Evaluations Annual, 1994, p403)

Pharmacology of Orap

Orap 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. 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. Orap also has less potential for inducing sedation and hypotension as it has more specific dopamine receptor blocking activity than other neuroleptic agents (and is therefore a suitable alternative to haloperidol).

Orap for patients

Orap 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.

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.

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.

Interaction with Food

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

Orap 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, or patients taking other drugs which prolong the QT interval of the electrocardiogram.
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 crosssensitivity 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 3A (CYP 3A). macrolide antibiotics are inhibitors of CYP 3A, 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.

Because azole antifungal agents are also inhibitors of the CYP 3A 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 3A, and thus ORAP is contraindicated in patients receiving protease inhibitors such as ritonavir, saquinovir, indinavir, and nelfinavir.

Nefazodone is a potent inhibitor of CYP 3A, 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.

Additional information about Orap

Orap Indication: Used for the suppression of motor and phonic tics in patients with Tourette's Disorder who have failed to respond satisfactorily to standard treatment.
Mechanism Of Action: The ability of pimozide to suppress motor and phonic tics in Tourette's Disorder is thought to be primarily a function of its dopaminergic blocking activity. Orap binds to the dopamine D2 receptor in the CNS. It also appears to block voltage-operated calcium channels and acts as an antagonist at opiate receptors (OP2).
Drug Interactions: Amprenavir Amprenavir increases the effect and toxicity of pimozide
Fosamprenavir Amprenavir increases the effect and toxicity of pimozide
Imatinib Imatinib increases the effect and toxicity of pimozide
Nefazodone increases the effect and toxicity of pimozide
Nelfinavir Nelfinavir increases the effect and toxicity of pimozide
Saquinavir The protease inhibitor increases the effect and toxicity of pimozide
Ritonavir The protease inhibitor increases the effect and toxicity of pimozide
Indinavir The protease inhibitor increases the effect and toxicity of pimozide
Atazanavir The protease inhibitor increases the effect and toxicity of pimozide
Citalopram The SSRI increases the effect and toxicity of pimozide
Escitalopram The SSRI increases the effect and toxicity of pimozide
Sertraline The SSRI increases the effect and toxicity of pimozide
Ziprasidone Increased risk of cardiotoxicity and arrhythmias
Zileuton Increased risk of cardiotoxicity and arrhythmias
Voriconazole Increased risk of cardiotoxicity and arrhythmias
Troleandomycin Increased risk of cardiotoxicity and arrhythmias
Thioridazine Increased risk of cardiotoxicity and arrhythmias
Telithromycin Increased risk of cardiotoxicity and arrhythmias
Posaconazole Contraindicated co-administration
Paroxetine Increased risk of cardiotoxicity/arrhythmias
Mesoridazine Increased risk of cardiotoxicity and arrhythmias
Ketoconazole Increased risk of cardiotoxicity and arrhythmias
Josamycin Increased risk of cardiotoxicity and arrhythmias
Itraconazole Increased risk of cardiotoxicity and arrhythmias
Fluconazole Increased risk of cardiotoxicity and arrhythmias
Erythromycin Increased risk of cardiotoxicity and arrhythmias
Clarithromycin Increased risk of cardiotoxicity and arrhythmias
Aprepitant Increased risk of cardiotoxicity and arrhythmias
Donepezil Possible antagonism of action
Galantamine Possible antagonism of action
Rivastigmine Possible antagonism of action
Food Interactions: Not Available
Generic Name: Pimozide
Synonyms: Pimozidum [INN-Latin]; Primozida [INN-Spanish]
Drug Category: Anti-Dyskinesia Agents; Antipsychotic Agents; Dopamine Antagonists
Drug Type: Small Molecule; Approved

Other Brand Names containing Pimozide: Halomonth; Neoperidole; Opiran; Orap;
Absorption: Greater than 50% absorption after oral administration. Serum peak appears 6-8 hours post ingestion.
Toxicity (Overdose): LD₅₀ = 1100 mg/kg (rat, oral), 228 mg/kg (mouse, oral)
Protein Binding: Not Available
Biotransformation: Notable first-pass metabolism in the liver, primarily by N-dealkylation via the cytochrome P450 isoenzymes CYP3A and CYP1A2 (and possibly CYP2D6). The activity of the two major metabolites has not been determined.
Half Life: 29 ± 10 hours (single-dose study of healthy volunteers).
Dosage Forms of Orap: Tablet Oral
Chemical IUPAC Name: 3-[1-[4,4-bis(4-fluorophenyl)butyl]piperidin-4-yl]-1H-benzimidazol-2-one
Chemical Formula: C28H29F2N3O
Pimozide on Wikipedia: https://en.wikipedia.org/wiki/Pimozide
Organisms Affected: Humans and other mammals