Pimozide

Name: Pimozide

What special precautions should I follow?

Before taking pimozide,

  • tell your doctor and pharmacist if you are allergic to pimozide, other medications for mental illness, or any other medications.
  • tell your doctor if you are taking any of the following medications: certain antibiotics including azithromycin (Zithromax, Z-Pak), clarithromycin (Biaxin), erythromycin (E.E.S., E-Mycin, Erythrocin), and moxifloxacin (Avelox); antifungals such as itraconazole (Sporanox) and ketoconazole (Nizoral); arsenic trioxide (Trisenox); dofetilide (Tikosyn); chlorpromazine; dolasetron (Anzemet); droperidol (Inapsine); HIV protease inhibitors such as indinavir (Crixivan), nelfinavir (Viracept), saquinavir (Invirase), and ritonavir (Norvir, in Kaletra); medications for irregular heartbeat such as amiodarone (Cordarone), disopyramide (Norpace), procainamide, quinidine, and sotalol (Betapace); medications for mental illness and nausea; mefloquine (Lariam); nefazadone; pentamidine (Nebu-Pent); certain selective serotonin reuptake inhibitors (SSRIs) such as citalopram (Celexa), escitalopram (Lexapro), fluoxetine (Prozac, Sarafem), fluvoxamine (Luvox), paroxetine (Paxil, Pexeva), and sertraline (Zoloft); tacrolimus (Prograf); thioridazine; zileuton (Zyflo); and ziprasidone (Geodon). Your doctor may tell you not to take pimozide.
  • tell your doctor if you are taking medications that may cause tics, including amphetamines such as amphetamine (Adderall) and dextroamphetamine (Dexadrine, Dextrostat); pemoline (Cylert) (not available in the US); and methylphenidate (Concerta, Ritalin). Your doctor may tell you to stop taking your medication for a while before you start taking pimozide. This will let your doctor see if your tics were caused by the other medication and can be treated by stopping it.
  • tell your doctor and pharmacist what other prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention any of the following: antidepressants; cimetidine (Tagamet); diuretics ('water pills'); medications for anxiety, pain, and seizures; sedatives; sleeping pills; ticlopidine (Ticlid); and tranquilizers. Many other medications may interact with pimozide, so be sure to tell your doctor about all the medications you are taking, even those not listed here or on the lists above. Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
  • tell your doctor if you have or have ever had long QT syndrome (condition that increases the risk of developing an irregular heartbeat that may cause loss of consciousness or sudden death); an irregular heartbeat; or low levels of potassium or magnesium in your blood. Also tell your doctor if you have severe diarrhea before your treatment or at any time during your treatment. Your doctor may tell you not to take pimozide.
  • tell your doctor if you have or have ever had breast cancer; Parkinson's disease (PD; a disorder of the nervous system that causes difficulties with movement, muscle control, and balance); glaucoma (condition in which increased pressure in the eye can lead to gradual loss of vision); problems with urination; trouble keeping your balance, an abnormal electroencephalogram (EEG; test that records electrical activity in the brain); seizures; or prostate, liver, or kidney disease. Also tell your doctor if you have ever had to stop taking a medication for mental illness due to severe side effects.
  • tell your doctor if you are pregnant, especially if you are in the last few months of your pregnancy, or if you plan to become pregnant or are breast-feeding. If you become pregnant while taking pimozide, call your doctor. Pimozide may cause problems in newborns following delivery if it is taken during the last months of pregnancy.
  • if you are having surgery, including dental surgery, tell the doctor or dentist that you are taking pimozide.
  • you should know that pimozide may make you drowsy and may affect your thinking and movements, especially at the beginning of your treatment. Do not drive a car or operate machinery until you know how this medication affects you.
  • you should know that pimozide may cause dizziness, lightheadedness, and fainting when you get up too quickly from a lying position. To avoid this problem, get out of bed slowly, resting your feet on the floor for a few minutes before standing up.
  • ask your doctor about the safe use of alcohol during your treatment with pimozide. Alcohol can make the side effects of pimozide worse.

Pimozide Side Effects

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have a serious side effect such as:

  • seizure (convulsions);
  • twitching or uncontrollable movements of your eyes, lips, tongue, face, arms, or legs; or
  • very stiff (rigid) muscles, high fever, sweating, confusion, fast or uneven heartbeats, tremors, feeling like you might pass out.

Less serious side effects may include:

  • fever;
  • headache, dizziness, drowsiness;
  • feeling restless;
  • vision problems;
  • constipation; or
  • dry mouth.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

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]-4piperidinyl]-1,3-dihydro-2H-benzimidazole-2-one is:

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.

Interactions for Pimozide

Metabolized by CYP3A41 and, to a lesser extent, by CYP1A2.1 168 170

Drugs and Foods Affecting Hepatic Microsomal Enzymes

Potential pharmacokinetic interaction (decreased metabolism) with inhibitors of CYP3A41 200 or CYP1A2.1

Prolongation of QT interval and, rarely, serious cardiovascular effects, including ventricular arrhythmias and death, reported in patients receiving CYP3A4 inhibitors and pimozide concomitantly;1 168 170 concomitant use contraindicated.1 (See Specific Drugs and Foods under Interactions.)

Drugs That Prolong QT Interval

Potential pharmacologic interaction (additive effect on QT interval prolongation; concomitant use contraindicated) when used with drugs that prolong QTc interval.1 200 207 208 209 (See Contraindications and Cardiovascular Effects under Cautions and also Specific Drugs and Foods under Interactions.)

Specific Drugs and Foods

Drug or Food

Interaction

Comments

Antiarrhythmic agents (e.g., dofetilide, quinidine, sotalol, other class IA and III antiarrhythmics)1

Additive effects on prolongation of QT interval1

Concomitant use contraindicated1

Antidepressants, tricyclics

Additive effects on prolongation of QT interval1

Concomitant use not recommended1

Antidepressants, SSRIs (e.g., citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline)

Decreased pimozide metabolism; increased risk of prolongation of QT interval1 200 201 204 205 206 207 208 209 210 211

Concomitant use contraindicated1 200 205 206 207 208 209 210 211

Antifungals, azole (e.g., itraconazole, ketoconazole, voriconazole)

Decreased pimozide metabolism; increased risk of prolongation of QT interval1

Concomitant use contraindicated1

Aprepitant

Increased plasma pimozide concentrations; potential for serious or life-threatening reaction

Concomitant use contraindicated

Arsenic trioxide

Additive effects on prolongation of QT interval1

Concomitant use contraindicated1

CNS agents (e.g., opiates or other analgesics, barbiturates or other sedatives, anxiolytics, alcohol)

Additive CNS effects or potentiated action of CNS depressant1 2 4 146 151

Use concomitantly with caution to avoid excessive CNS depression1 2

Delavirdine

Potential for serious or life-threatening reactions (e.g., cardiac arrhythmias)

Concomitant use contraindicated

Dolasetron

Additive effects on prolongation of QT interval1

Concomitant use contraindicated1

Droperidol

Additive effects on prolongation of QT interval1

Concomitant use contraindicated1

Fluoroquinolones (e.g., gatifloxacin, moxifloxacin, sparfloxacin)

Additive effects on prolongation of QT interval1

Concomitant use contraindicated1

Grapefruit juice

Decreased pimozide metabolism1

Avoid grapefruit juice during therapy1

Halofantrine (licensed in the US but not commercially available)

Additive effects on prolongation of QT interval1

Concomitant use contraindicated1

HIV protease inhibitors (e.g., amprenavir [no longer commercially available in the US], atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir)

Decreased pimozide metabolism; increased risk of prolongation of QT interval1

Concomitant use contraindicated1

Imatinib

Increased pimozide concentrations

Use with caution because pimozide has a narrow therapeutic window

Levomethadyl acetate (no longer commercially available in the US)

Additive effects on prolongation of QT interval1

Concomitant use contraindicated1

Macrolides (e.g., azithromycin, clarithromycin, dirithromycin, erythromycin, troleandomycin)

Decreased pimozide metabolism; increased risk of prolongation of QT interval and ventricular arrhythmias1

Sudden death reported in at least 2 patients when clarithromycin added to ongoing pimozide therapy1

Concomitant use contraindicated1

Mefloquine

Additive effects on prolongation of QT interval1

Concomitant use contraindicated1

Nefazodone

Decreased pimozide metabolism; increased risk of prolongation of QT interval1

Concomitant use contraindicated1

Pentamidine

Additive effects on prolongation of QT interval1

Concomitant use contraindicated1

Phenothiazines (e.g., chlorpromazine, mesoridazine [no longer commercially available in US], thioridazine1 )

Additive effects on prolongation of QT interval1

Concomitant use contraindicated1

Probucol (no longer commercially available in the US)

Additive effects on prolongation of QT interval1

Concomitant use contraindicated1

Tacrolimus

Additive effects on prolongation of QT interval1

Concomitant use contraindicated1

Zileuton

Decreased pimozide metabolism; increased risk of prolongation of QT interval1

Concomitant use contraindicated1

Ziprasidone

Increased risk of QT interval prolongation1

Concomitant use contraindicated1

Advice to Patients

  • Importance of taking medication exactly as prescribed by the clinician;1 necessity of ECG monitoring before and during therapy.1

  • Importance of avoiding driving, operating machinery, or performing hazardous tasks until gain experience with the drug’s effects.1

  • Importance of clinicians informing patients in whom chronic use is contemplated of risk of tardive dyskinesia, taking into account clinical circumstances and competency of patient to understand information provided.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription or OTC drugs, dietary supplements, and herbal products, as well as any concomitant illnesses (e.g., cardiovascular).1 Importance of avoiding grapefruit juice.1 170

  • Importance of avoiding alcohol during therapy.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 224 Importance of clinicians informing patients about the benefits and risks of taking antipsychotics during pregnancy (see Pregnancy under Cautions).224 Importance of advising patients not to stop taking pimozide if they become pregnant without consulting their clinician; abruptly stopping antipsychotic agents may cause complications.224

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Commonly used brand name(s)

In the U.S.

  • Orap

Available Dosage Forms:

  • Tablet

Therapeutic Class: Antipsychotic

Pharmacologic Class: Dopamine Antagonist

Chemical Class: Diphenylbutylpiperidine

Uses For pimozide

Pimozide is used to treat symptoms of Tourette's syndrome. It is used only for patients with severe symptoms who cannot take or have not been helped by other medicines (e.g., haloperidol).

Pimozide works in the central nervous system to help control the vocal outbursts and uncontrolled, repeated movements of the body (tics) that may interfere with the patient's normal life. It will not completely cure the tics, but will help to reduce their number and severity.

pimozide is available only with your doctor's prescription.

Consumer Information Use and Disclaimer

  • If your symptoms or health problems do not get better or if they become worse, call your doctor.
  • Do not share your drugs with others and do not take anyone else's drugs.
  • Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
  • Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
  • Some drugs may have another patient information leaflet. Check with your pharmacist. If you have any questions about this medicine, please talk with your doctor, nurse, pharmacist, or other health care provider.
  • If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

This information should not be used to decide whether or not to take pimozide or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to pimozide. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.

Review Date: October 4, 2017

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).

Dosage & 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).

How is Pimozide Supplied

Pimozide Tablets USP, 1 mg is white to off white, uncoated round shaped tablets with debossed bisect separating "EP" and "320" on one side and other side has a single bisect. They are available in bottles of 100 (NDC 49884-347-01).

Pimozide Tablets USP, 2 mg is white to off white, uncoated oval shaped tablets with debossed bisect separating "EP" and "321" on one side and other side has a single bisect. They are available in bottles of 100 (NDC 49884-348-01).

Store at 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature].

Pharmacist: Dispense in a tight, light-resistant container as defined in the official compendium with a child-resistant closure as required.


Distributed by:

Par Pharmaceutical Companies, Inc.

Spring Valley, NY 10977 U.S.A.

Made in India by:

Par Formulations Pvt Ltd,

l/58, Pudupakkam, Kelambakkam - 603 103.


I12/14

Mfg.Lic.No.:  TN00002121

OS347-01-74-01

SE7510/00

Pronunciation

(PI moe zide)

Pharmacology

Pimozide, a diphenylbutylperidine conventional antipsychotic, is a potent centrally-acting dopamine-receptor antagonist resulting in its characteristic neuroleptic effects

Absorption

≥50%

Metabolism

Hepatic via N-dealkylation primarily by CYP3A4, but with contributions by CYP1A2 and CYP2D6; significant first-pass effect

Excretion

Urine

Storage

Store at 25°C (77°F); excursion permitted to 15°C to 30°C (59°F to 86°F).

Drug Interactions

Abiraterone Acetate: May increase the serum concentration of CYP2D6 Substrates. Management: Avoid concurrent use of abiraterone with CYP2D6 substrates that have a narrow therapeutic index whenever possible. When concurrent use is not avoidable, monitor patients closely for signs/symptoms of toxicity. Consider therapy modification

AbobotulinumtoxinA: Anticholinergic Agents may enhance the anticholinergic effect of AbobotulinumtoxinA. Monitor therapy

Acetylcholinesterase Inhibitors: Anticholinergic Agents may diminish the therapeutic effect of Acetylcholinesterase Inhibitors. Acetylcholinesterase Inhibitors may diminish the therapeutic effect of Anticholinergic Agents. Monitor therapy

Acetylcholinesterase Inhibitors (Central): May enhance the neurotoxic (central) effect of Antipsychotic Agents. Severe extrapyramidal symptoms have occurred in some patients. Monitor therapy

Aclidinium: May enhance the anticholinergic effect of Anticholinergic Agents. Avoid combination

Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Monitor therapy

Amifampridine: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination

Amisulpride: Antipsychotic Agents may enhance the adverse/toxic effect of Amisulpride. Avoid combination

Amphetamines: Antipsychotic Agents may diminish the stimulatory effect of Amphetamines. Monitor therapy

Analgesics (Opioid): CNS Depressants may enhance the CNS depressant effect of Analgesics (Opioid). Management: Avoid concomitant use of opioid analgesics and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Anticholinergic Agents: May enhance the adverse/toxic effect of other Anticholinergic Agents. Monitor therapy

Antifungal Agents (Azole Derivatives, Systemic): May enhance the arrhythmogenic effect of Pimozide. Antifungal Agents (Azole Derivatives, Systemic) may increase the serum concentration of Pimozide. This increase in serum concentrations may lead to QTc interval prolongation and ventricular arrhythmias. Applicable Isavuconazonium considerations are addressed in separate monographs. Exceptions: Isavuconazonium Sulfate. Avoid combination

Anti-Parkinson Agents (Dopamine Agonist): May diminish the therapeutic effect of Antipsychotic Agents (First Generation [Typical]). Antipsychotic Agents (First Generation [Typical]) may diminish the therapeutic effect of Anti-Parkinson Agents (Dopamine Agonist). Management: Avoid concomitant therapy if possible and monitor for decreased effects of both agents when these combinations cannot be avoided. Atypical antipsychotics such as clozapine and quetiapine may be less likely to reduce the effects of anti-Parkinson agents. Consider therapy modification

Aprepitant: May increase the serum concentration of Pimozide. Avoid combination

Asunaprevir: May increase the serum concentration of CYP2D6 Substrates. Consider therapy modification

Azelastine (Nasal): CNS Depressants may enhance the CNS depressant effect of Azelastine (Nasal). Avoid combination

Bilastine: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Monitor therapy

Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Consider therapy modification

Boceprevir: May increase the serum concentration of Pimozide. Avoid combination

Bosentan: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Buprenorphine: CNS Depressants may enhance the CNS depressant effect of Buprenorphine. Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine patches (Butrans brand) at 5 mcg/hr in adults when used with other CNS depressants. Consider therapy modification

Cannabis: May decrease the serum concentration of CYP1A2 Substrates. Monitor therapy

Cannabis: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Chloral Betaine: May enhance the adverse/toxic effect of Anticholinergic Agents. Monitor therapy

Chlormethiazole: May enhance the CNS depressant effect of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used. Consider therapy modification

Chlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy

Cimetropium: Anticholinergic Agents may enhance the anticholinergic effect of Cimetropium. Avoid combination

CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Monitor therapy

Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Crizotinib: May enhance the QTc-prolonging effect of Pimozide. Crizotinib may increase the serum concentration of Pimozide. Avoid combination

CYP1A2 Inducers (Moderate): May decrease the serum concentration of CYP1A2 Substrates. Monitor therapy

CYP1A2 Inhibitors (Moderate): May decrease the metabolism of CYP1A2 Substrates. Monitor therapy

CYP2D6 Inhibitors (Moderate): May decrease the metabolism of CYP2D6 Substrates. Monitor therapy

CYP2D6 Inhibitors (Strong): May increase the serum concentration of Pimozide. Avoid combination

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Pimozide. Avoid combination

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Pimozide. Avoid combination

CYP3A4 Inhibitors (Weak): May increase the serum concentration of Pimozide. Avoid combination

Cyproterone: May decrease the serum concentration of CYP1A2 Substrates. Monitor therapy

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates. Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Deferasirox: May increase the serum concentration of CYP1A2 Substrates. Monitor therapy

Dimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Doxylamine: May enhance the CNS depressant effect of CNS Depressants. Management: The manufacturer of Diclegis (doxylamine/pyridoxine), intended for use in pregnancy, specifically states that use with other CNS depressants is not recommended. Monitor therapy

Dronabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Eluxadoline: Anticholinergic Agents may enhance the constipating effect of Eluxadoline. Avoid combination

Enzalutamide: May decrease the serum concentration of Pimozide. Avoid combination

Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Consider therapy modification

FLUoxetine: May enhance the QTc-prolonging effect of Pimozide. FLUoxetine may increase the serum concentration of Pimozide. Avoid combination

Fosaprepitant: May increase the serum concentration of Pimozide. The active metabolite aprepitant is likely responsible for this effect. Avoid combination

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Gastrointestinal Agents (Prokinetic): Anticholinergic Agents may diminish the therapeutic effect of Gastrointestinal Agents (Prokinetic). Monitor therapy

Glucagon: Anticholinergic Agents may enhance the adverse/toxic effect of Glucagon. Specifically, the risk of gastrointestinal adverse effects may be increased. Avoid combination

Glycopyrrolate (Oral Inhalation): Anticholinergic Agents may enhance the anticholinergic effect of Glycopyrrolate (Oral Inhalation). Avoid combination

Grapefruit Juice: May increase the serum concentration of Pimozide. Avoid combination

Guanethidine: Antipsychotic Agents may diminish the therapeutic effect of Guanethidine. Monitor therapy

Highest Risk QTc-Prolonging Agents: May enhance the QTc-prolonging effect of other Highest Risk QTc-Prolonging Agents. Avoid combination

HYDROcodone: CNS Depressants may enhance the CNS depressant effect of HYDROcodone. Management: Avoid concomitant use of hydrocodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Hydroxychloroquine: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination

Idelalisib: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Indapamide: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Consider therapy modification

Iohexol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Iohexol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iohexol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic anticonvulsants. Consider therapy modification

Iomeprol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Iomeprol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iomeprol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic anticonvulsants. Consider therapy modification

Iopamidol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Iopamidol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iopamidol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic anticonvulsants. Consider therapy modification

Ipratropium (Oral Inhalation): May enhance the anticholinergic effect of Anticholinergic Agents. Avoid combination

Itopride: Anticholinergic Agents may diminish the therapeutic effect of Itopride. Monitor therapy

Kava Kava: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy

Levosulpiride: Anticholinergic Agents may diminish the therapeutic effect of Levosulpiride. Avoid combination

Lofepramine: May enhance the arrhythmogenic effect of Pimozide. Avoid combination

Macrolide Antibiotics: May enhance the QTc-prolonging effect of Pimozide. Macrolide Antibiotics may decrease the metabolism of Pimozide. This mechanism may not apply to azithromycin. Exceptions: Fidaxomicin; Spiramycin. Avoid combination

Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Methotrimeprazine: May enhance the CNS depressant effect of CNS Depressants. CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Management: Reduce adult dose of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established. Consider therapy modification

Methylphenidate: May enhance the adverse/toxic effect of Antipsychotic Agents. Antipsychotic Agents may enhance the adverse/toxic effect of Methylphenidate. Monitor therapy

Metoclopramide: May enhance the adverse/toxic effect of Antipsychotic Agents. Avoid combination

MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Monitor therapy

MetyroSINE: May enhance the adverse/toxic effect of Antipsychotic Agents. Monitor therapy

MiFEPRIStone: May enhance the QTc-prolonging effect of Pimozide. MiFEPRIStone may increase the serum concentration of Pimozide. Management: Avoid pimozide during and 2 weeks following mifepristone for treatment of hyperglycemia in Cushing's syndrome. The interaction magnitude could be lower with single doses used to terminate pregnancy, but neither effect has been studied clinically. Avoid combination

Minocycline: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Mitotane: May decrease the serum concentration of CYP3A4 Substrates. Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification

Mizolastine: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination

Moderate Risk QTc-Prolonging Agents: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination

Nabilone: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Nefazodone: May increase the serum concentration of Pimozide. Avoid combination

Nitroglycerin: Anticholinergic Agents may decrease the absorption of Nitroglycerin. Specifically, anticholinergic agents may decrease the dissolution of sublingual nitroglycerin tablets, possibly impairing or slowing nitroglycerin absorption. Monitor therapy

Obeticholic Acid: May increase the serum concentration of CYP1A2 Substrates. Monitor therapy

OnabotulinumtoxinA: Anticholinergic Agents may enhance the anticholinergic effect of OnabotulinumtoxinA. Monitor therapy

Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Avoid combination

Oxatomide: May enhance the anticholinergic effect of Anticholinergic Agents. Avoid combination

Oxomemazine: May enhance the CNS depressant effect of CNS Depressants. Avoid combination

OxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Avoid combination

Peginterferon Alfa-2b: May decrease the serum concentration of CYP2D6 Substrates. Peginterferon Alfa-2b may increase the serum concentration of CYP2D6 Substrates. Monitor therapy

Peginterferon Alfa-2b: May increase the serum concentration of CYP1A2 Substrates. Monitor therapy

Perampanel: May enhance the CNS depressant effect of CNS Depressants. Management: Patients taking perampanel with any other drug that has CNS depressant activities should avoid complex and high-risk activities, particularly those such as driving that require alertness and coordination, until they have experience using the combination. Consider therapy modification

Perhexiline: CYP2D6 Substrates may increase the serum concentration of Perhexiline. Perhexiline may increase the serum concentration of CYP2D6 Substrates. Monitor therapy

Piribedil: May diminish the therapeutic effect of Antipsychotic Agents. Antipsychotic Agents may diminish the therapeutic effect of Piribedil. Management: Use of piribedil with antiemetic neuroleptics is contraindicated, and use with antipsychotic neuroleptics, except for clozapine, is not recommended. Avoid combination

Potassium Chloride: Anticholinergic Agents may enhance the ulcerogenic effect of Potassium Chloride. Management: Patients on drugs with substantial anticholinergic effects should avoid using any solid oral dosage form of potassium chloride. Avoid combination

Potassium Citrate: Anticholinergic Agents may enhance the ulcerogenic effect of Potassium Citrate. Avoid combination

Pramlintide: May enhance the anticholinergic effect of Anticholinergic Agents. These effects are specific to the GI tract. Consider therapy modification

Probucol: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination

Promazine: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination

Protease Inhibitors: May increase the serum concentration of Pimozide. Avoid combination

QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying): May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Management: Avoid such combinations when possible. Use should be accompanied by close monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. Consider therapy modification

Quinagolide: Antipsychotic Agents may diminish the therapeutic effect of Quinagolide. Monitor therapy

Ramosetron: Anticholinergic Agents may enhance the constipating effect of Ramosetron. Monitor therapy

RimabotulinumtoxinB: Anticholinergic Agents may enhance the anticholinergic effect of RimabotulinumtoxinB. Monitor therapy

Rolapitant: May increase the serum concentration of Pimozide. Avoid combination

Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Monitor therapy

Saquinavir: Pimozide may enhance the arrhythmogenic effect of Saquinavir. Avoid combination

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Secretin: Anticholinergic Agents may diminish the therapeutic effect of Secretin. Management: Avoid concomitant use of anticholinergic agents and secretin. Discontinue anticholinergic agents at least 5 half-lives prior to administration of secretin. Consider therapy modification

Selective Serotonin Reuptake Inhibitors: May enhance the adverse/toxic effect of Pimozide. Avoid combination

Serotonin Modulators: May enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotic Agents may enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Exceptions: Nicergoline. Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Simeprevir: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Sodium Oxybate: May enhance the CNS depressant effect of CNS Depressants. Management: Consider alternatives to combined use. When combined use is needed, consider minimizing doses of one or more drugs. Use of sodium oxybate with alcohol or sedative hypnotics is contraindicated. Consider therapy modification

St John's Wort: May decrease the serum concentration of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

Stiripentol: May increase the serum concentration of CYP3A4 Substrates. Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Sulpiride: Antipsychotic Agents may enhance the adverse/toxic effect of Sulpiride. Avoid combination

Suvorexant: CNS Depressants may enhance the CNS depressant effect of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Consider therapy modification

Tapentadol: May enhance the CNS depressant effect of CNS Depressants. Management: Avoid concomitant use of tapentadol and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Telaprevir: May increase the serum concentration of Pimozide. Avoid combination

Teneligliptin: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Monitor therapy

Teriflunomide: May decrease the serum concentration of CYP1A2 Substrates. Monitor therapy

Tetrahydrocannabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Avoid combination

Thiazide and Thiazide-Like Diuretics: Anticholinergic Agents may increase the serum concentration of Thiazide and Thiazide-Like Diuretics. Monitor therapy

Tiotropium: Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium. Avoid combination

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Topiramate: Anticholinergic Agents may enhance the adverse/toxic effect of Topiramate. Monitor therapy

Trimeprazine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Umeclidinium: May enhance the anticholinergic effect of Anticholinergic Agents. Avoid combination

Vinflunine: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination

Xipamide: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Monitor therapy

Zileuton: May increase the serum concentration of Pimozide. Avoid combination

Zolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Consider therapy modification

Test Interactions

Increased prolactin (S)

Renal Dose Adjustments

Use with caution.

Precautions

Safety and efficacy have not been established in patients younger than 12 years.

Consult WARNINGS section for additional precautions.

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