Pimozide

Name: Pimozide

Pimozide Genetic Information

CYP2D6 is a protein in your body that is involved in the elimination of pimozide and other drugs from your body. Some patients have less of this protein in their bodies, affecting how much of the drug gets eliminated. Levels of CYP2D6 can vary greatly between individuals, and those having less of this protein are known as "poor metabolizers." 

CYP2D6 testing is done to determine whether you are a poor metabolizer. If you are a poor metabolizer, the levels of pimozide in your blood can become too high. As a result you may be at an increased risk of having more side effects from pimozide. 

Your doctor may adjust your dose of pimozide if you are a poor metabolizer.

Pimozide and Lactation

Tell your doctor if you are breastfeeding or plan to breastfeed.

It is not known if pimozide crosses into human milk. Because many medications can cross into human milk and because of the possibility for serious adverse reactions in nursing infants with use of this medication, a choice should be made whether to stop nursing or stop the use of this medication. Your doctor and you will decide if the benefits outweigh the risk of using pimozide.

What is the most important information I should know about pimozide?

There are many other drugs that can cause serious or life threatening medical problems if you take them together with pimozide, especially if you have a heart rhythm disorder. Tell your doctor about all other medicines you use.

Grapefruit and grapefruit juice may interact with pimozide and lead to potentially dangerous effects. Avoid eating or drinking grapefruit products while taking this medication.

Pimozide may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert.

Drinking alcohol can increase certain side effects of pimozide.

Call your doctor right away if you have uncontrollable movements of your eyes, lips, tongue, face, arms, or legs.

Uses for Pimozide

Tourette’s Syndrome

Suppression of motor and vocal tics of Tourette’s syndrome (Gilles de la Tourette’s syndrome) in adults and children who have failed to respond adequately to, or who do not tolerate, conventional therapy (e.g., haloperidol).1 2 8 48 49 50 51 52 53 54 57 159 172 (See Pediatric Use under Cautions.)

Not intended as a treatment of first choice, nor is it intended for suppression of tics that are only annoying or cosmetically troublesome.1 2 8

Reserve for use in patients whose development and/or daily life function is severely compromised by the presence of motor and vocal tics.1 2

Has been used concomitantly with a stimulant in children with tic disorders (e.g., Tourette’s syndrome) and comorbid attention deficit hyperactivity disorder (ADHD)† in whom stimulants alone cannot control tics.171

Schizophrenia

Has been used for the symptomatic management of a variety of psychiatric illnesses†,58 59 60 61 62 63 64 65 66 67 68 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 principally schizophrenia†,58 59 60 61 62 63 64 65 66 67 68 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 but other agents generally are preferred.69 70

Pimozide Dosage and Administration

General

  • Perform ECG before initiation of therapy and periodically thereafter, particularly during periods of dosage adjustment.1 2 (See Cardiovascular Effects under Cautions.)

Administration

Oral Administration

Administer orally,1 2 usually once daily;152 153 also may administer in divided doses, particularly if once-daily dosing is not well tolerated.1 152

Some clinicians recommend administration as a single dose at bedtime to minimize adverse effects.153

Dosage

Initiate therapy with low dosage and adjust dosage gradually.1 2 159

Pediatric Patients

Tourette’s Syndrome Oral

Children <12 years of age†: Reliable dose-response data for drug effects on tic manifestations not available.1 2

Children ≥12 years of age: Initially, 0.05 mg/kg daily, preferably at bedtime.1 May increase dosage every third day to a maximum of 0.2 mg/kg daily, not to exceed 10 mg daily.1 167

During prolonged maintenance therapy, use lowest possible effective dosage.1 2 Once adequate response is achieved, make periodic attempts (e.g., every 6–12 months) to reduce dosage to determine whether initial intensity and frequency of tics persist.1 2

In attempts to reduce dosage, consider possibility that observed increases of tic intensity and frequency may represent a transient, withdrawal-related phenomenon rather than return of the syndrome’s symptoms.1 2 Allow 1–2 weeks to elapse before concluding that an increase in tic manifestations is a function of the underlying disorder rather than a response to drug withdrawal.1 2

If therapy is to be discontinued, gradually reduce dosage.1 2

Adults

Tourette’s Syndrome Oral

Initially, 1–2 mg daily in divided doses.1 2 159 164 May increase dosage every other day according to patient’s tolerance and therapeutic response.1 2 165 Some clinicians suggest that dosage be increased at longer intervals (e.g., every 5–7 days) until manifestations decrease by ≥70%, adverse effects occur without symptomatic benefit, or symptomatic benefit and adverse effects occur simultaneously.153 164

If minimal adverse effects occur (e.g., not interfering with functioning) before adequate response is achieved, hold further dosage increase until adverse effects resolve.164 If adverse effects interfere with functioning but are not severe, can reduce dosage by 1-mg increments at weekly intervals until such effects resolve.164

If severe adverse effects occur, immediately reduce dosage by 50% or withhold drug.1 2 164 Once serious adverse effects resolve, can reinstitute with more gradual titration, increasing dosage at intervals ranging from 7–30 days.164

Most patients are adequately treated with dosages <0.2 mg/kg daily or 10 mg daily, whichever is less; higher dosages not recommended.1 2

During prolonged maintenance therapy, use lowest possible effective dosage.1 2 Once adequate response is achieved, make periodic attempts (e.g., every 6–12 months) to reduce dosage to determine whether initial intensity and frequency of tics persist.1 2

In attempts to reduce dosage, consider possibility that observed increases of tic intensity and frequency may represent a transient, withdrawal-related phenomenon rather than return of the syndrome’s symptoms.1 2 Allow 1–2 weeks to elapse before concluding that an increase in tic manifestations is a function of the underlying disorder rather than a response to drug withdrawal.1 2

If therapy is to be discontinued, gradually reduce dosage.1 2

Prescribing Limits

Pediatric Patients

Tourette’s Syndrome Oral

Children ≥12 years of age: Maximum 0.2 mg/kg, not exceeding 10 mg daily.1

Adults

Tourette’s Syndrome Oral

Dosages >0.2 mg/kg or 10 mg daily not recommended.1

Before Using pimozide

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For pimozide, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to pimozide or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies performed to date have not demonstrated pediatric-specific problems that would limit the usefulness of pimozide in children 12 years of age and older. However, safety and efficacy have not been established in children younger than 12 years of age.

Geriatric

No information is available on the relationship of age to the effects of pimozide in geriatric patients.

Pregnancy

Pregnancy Category Explanation
All Trimesters C Animal studies have shown an adverse effect and there are no adequate studies in pregnant women OR no animal studies have been conducted and there are no adequate studies in pregnant women.

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking pimozide, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using pimozide with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

  • Alfuzosin
  • Amifampridine
  • Amiodarone
  • Amisulpride
  • Amitriptyline
  • Amprenavir
  • Anagrelide
  • Apomorphine
  • Aprepitant
  • Aripiprazole
  • Aripiprazole Lauroxil
  • Arsenic Trioxide
  • Artemether
  • Asenapine
  • Astemizole
  • Atazanavir
  • Azithromycin
  • Bedaquiline
  • Bepridil
  • Boceprevir
  • Buserelin
  • Chloroquine
  • Chlorpromazine
  • Ciprofloxacin
  • Cisapride
  • Citalopram
  • Clarithromycin
  • Clomipramine
  • Clozapine
  • Cobicistat
  • Crizotinib
  • Cyclobenzaprine
  • Dabrafenib
  • Darunavir
  • Dasatinib
  • Degarelix
  • Delamanid
  • Delavirdine
  • Desipramine
  • Deslorelin
  • Deutetrabenazine
  • Dirithromycin
  • Disopyramide
  • Dofetilide
  • Dolasetron
  • Domperidone
  • Donepezil
  • Doxepin
  • Dronedarone
  • Droperidol
  • Ebastine
  • Efavirenz
  • Eribulin
  • Erythromycin
  • Escitalopram
  • Famotidine
  • Felbamate
  • Fingolimod
  • Flecainide
  • Fluconazole
  • Fluoxetine
  • Formoterol
  • Fosamprenavir
  • Fosaprepitant
  • Foscarnet
  • Fosphenytoin
  • Galantamine
  • Gatifloxacin
  • Gemifloxacin
  • Gonadorelin
  • Goserelin
  • Granisetron
  • Halofantrine
  • Haloperidol
  • Histrelin
  • Hydroquinidine
  • Hydroxychloroquine
  • Hydroxyzine
  • Ibutilide
  • Iloperidone
  • Imipramine
  • Indinavir
  • Itraconazole
  • Ivabradine
  • Ketoconazole
  • Lapatinib
  • Leuprolide
  • Levofloxacin
  • Lumefantrine
  • Mefloquine
  • Mesoridazine
  • Methadone
  • Metoclopramide
  • Metronidazole
  • Miconazole
  • Mifepristone
  • Mizolastine
  • Moxifloxacin
  • Nafarelin
  • Nefazodone
  • Nelfinavir
  • Norfloxacin
  • Octreotide
  • Ofloxacin
  • Olanzapine
  • Ondansetron
  • Paliperidone
  • Panobinostat
  • Paroxetine
  • Pasireotide
  • Pazopanib
  • Pentamidine
  • Perphenazine
  • Pimavanserin
  • Pipamperone
  • Piperaquine
  • Pitolisant
  • Posaconazole
  • Probucol
  • Procainamide
  • Prochlorperazine
  • Promethazine
  • Propafenone
  • Protriptyline
  • Quetiapine
  • Quinidine
  • Quinine
  • Ranolazine
  • Risperidone
  • Ritonavir
  • Saquinavir
  • Sertindole
  • Sertraline
  • Sevoflurane
  • Sodium Phosphate
  • Sodium Phosphate, Dibasic
  • Sodium Phosphate, Monobasic
  • Solifenacin
  • Sorafenib
  • Sotalol
  • Sparfloxacin
  • Sulpiride
  • Sultopride
  • Sunitinib
  • Tacrolimus
  • Tamoxifen
  • Telaprevir
  • Telavancin
  • Telithromycin
  • Terfenadine
  • Tetrabenazine
  • Thioridazine
  • Tipranavir
  • Tizanidine
  • Tolterodine
  • Toremifene
  • Trazodone
  • Trimipramine
  • Triptorelin
  • Troleandomycin
  • Vandetanib
  • Vardenafil
  • Vemurafenib
  • Venlafaxine
  • Vilanterol
  • Vinflunine
  • Voriconazole
  • Vorinostat
  • Ziprasidone
  • Zotepine
  • Zuclopenthixol

Using pimozide with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

  • Alefacept
  • Alfentanil
  • Blinatumomab
  • Bromazepam
  • Buprenorphine
  • Bupropion
  • Butorphanol
  • Ceritinib
  • Conivaptan
  • Dihydrocodeine
  • Doxylamine
  • Eluxadoline
  • Enzalutamide
  • Fentanyl
  • Flibanserin
  • Golimumab
  • Guselkumab
  • Hydromorphone
  • Idelalisib
  • Imatinib
  • Levorphanol
  • Lithium
  • Lumacaftor
  • Meperidine
  • Milnacipran
  • Morphine
  • Morphine Sulfate Liposome
  • Nalbuphine
  • Netupitant
  • Nilotinib
  • Oxycodone
  • Oxymorphone
  • Pentazocine
  • Periciazine
  • Pixantrone
  • Remifentanil
  • Ribociclib
  • Rolapitant
  • Secukinumab
  • Selegiline
  • Sufentanil
  • Tapentadol
  • Tiotropium
  • Tramadol
  • Zileuton

Using pimozide with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

  • Betel Nut

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using pimozide with any of the following is usually not recommended, but may be unavoidable in some cases. If used together, your doctor may change the dose or how often you use pimozide, or give you special instructions about the use of food, alcohol, or tobacco.

  • Grapefruit Juice
  • Tobacco

Other Medical Problems

The presence of other medical problems may affect the use of pimozide. Make sure you tell your doctor if you have any other medical problems, especially:

  • Blood or bone marrow problems (e.g., agranulocytosis) or
  • Breast cancer, history of or
  • Heart disease or
  • Intestinal or bowel problems (e.g., blockage) or
  • Leukopenia or neutropenia (low number of white blood cells) or
  • Narrow angle glaucoma or
  • Pituitary gland problems (e.g., tumors) or
  • Seizures, history of or
  • Urinary tract problems (e.g., blockage or difficult urination)—Use with caution. May make these conditions worse.
  • Central nervous system depression or
  • Heart rhythm problems (e.g., arrhythmia, congenital long QT syndrome), history of or
  • Hypokalemia (low potassium in the blood) or
  • Hypomagnesemia (low magnesium in the blood) or
  • Tics other than those caused by Tourette's syndrome—Should not be used in patients with these conditions.
  • Kidney disease or
  • Liver disease—Higher blood levels of pimozide may occur, increasing the chance of side effects.

What are some things I need to know or do while I take Pimozide?

  • Tell all of your health care providers that you take pimozide. This includes your doctors, nurses, pharmacists, and dentists.
  • Avoid driving and doing other tasks or actions that call for you to be alert until you see how this medicine affects you.
  • Have blood work checked as you have been told by the doctor. Talk with the doctor.
  • You will need an ECG before starting pimozide and during treatment. Talk with your doctor.
  • Low white blood cell counts have happened with drugs like this one. This may lead to a higher chance of getting an infection. Deadly infections have rarely happened. Tell your doctor if you have ever had a low white blood cell count. Call your doctor right away if you have signs of infection like fever, chills, or sore throat. Talk with your doctor.
  • Avoid drinking alcohol while taking this medicine.
  • Talk with your doctor before you use other drugs and natural products that slow your actions.
  • Avoid grapefruit and grapefruit juice.
  • Be careful in hot weather or while being active. Drink lots of fluids to stop fluid loss.
  • If you have been taking pimozide on a regular basis and you stop it all of a sudden, you may have signs of withdrawal. Do not stop taking this medicine all of a sudden without calling your doctor. Tell your doctor if you have any bad effects.
  • An unsafe heartbeat that is not normal (long QT on ECG) has happened with pimozide. Sudden deaths have rarely happened in people taking this medicine. Talk with the doctor.
  • If you are 65 or older, use pimozide with care. You could have more side effects.
  • Tell your doctor if you are pregnant or plan on getting pregnant. You will need to talk about the benefits and risks of using this medicine while you are pregnant.
  • Taking pimozide in the third trimester of pregnancy may lead to muscle movements that cannot be controlled and withdrawal in the newborn. Talk with the doctor.
  • Tell your doctor if you are breast-feeding. You will need to talk about any risks to your baby.

What are some side effects that I need to call my doctor about right away?

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

  • Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
  • Change in eyesight.
  • Trouble controlling body movements, twitching, change in balance, trouble swallowing or speaking.
  • A heartbeat that does not feel normal.
  • Chest pain or pressure or a fast heartbeat.
  • Very bad dizziness or passing out.
  • Very bad headache.
  • Shakiness, trouble moving around, or stiffness.
  • Seizures.
  • Restlessness.
  • Change in how you act.
  • Not able to pass urine.
  • Breast enlargement.
  • Nipple discharge.
  • Change in sex ability.
  • For women, no period.
  • A very bad and sometimes deadly health problem called neuroleptic malignant syndrome (NMS) may happen. Call your doctor right away if you have any fever, muscle cramps or stiffness, dizziness, very bad headache, confusion, change in thinking, fast heartbeat, heartbeat that does not feel normal, or are sweating a lot.
  • Some people who take this medicine may get a very bad muscle problem called tardive dyskinesia. This muscle problem may not go away even if pimozide is stopped. Sometimes, signs may lessen or go away over time after this medicine is stopped. The risk of tardive dyskinesia may be greater in people with diabetes and in older adults, especially older women. The risk is also greater the longer you take pimozide or with higher doses. Muscle problems may also occur after short-term use with low doses. Call your doctor right away if you have trouble controlling body movements or if you have muscle problems with your tongue, face, mouth, or jaw like tongue sticking out, puffing cheeks, mouth puckering, or chewing.

What are some other side effects of Pimozide?

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

  • Feeling sleepy.
  • Feeling tired or weak.
  • Hard stools (constipation).
  • Dry mouth.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

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 Pimozide 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 Pimozide and have their WBC followed until recovery.

GENERAL

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.

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

Pimozide 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 Pimozide tablets, USP exposes the patient to serious risks. A decision to use Pimozide tablets, USP 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.

Pimozide tablets, USP 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 Pimozide tablets, USP in children under 12 years of age.


The information available on Pimozide tablets, USP from foreign marketing experience and from U.S. clinical trials indicates that Pimozide tablets, USP 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 Pimozide tablets, USP.

In addition, sudden, unexpected deaths have occurred in patients taking high doses of Pimozide tablets, USP for conditions other than Tourette’s Disorder. These deaths may have been the result of an effect of Pimozide upon the heart. Therefore, patients should be instructed not to exceed the prescribed dose of Pimozide tablets, USP 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 Pimozide therapy is initiated and normal potassium maintained during therapy.

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 Cmax 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 Cmax compared to Pimozide administered alone. The increase in Pimozide AUC and Cmax 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.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY

Carcinogenicity studies were conducted in mice and rats. In mice, Pimozide causes a dose-related increase in pituitary and mammary tumors.


When mice were treated for up to 18 months with Pimozide, pituitary gland changes developed in females only. These changes were characterized as hyperplasia at doses approximating the human dose and adenoma at doses about fifteen times the maximum recommended human dose on a mg per kg basis. The mechanism for the induction of pituitary tumors in mice is not known.


Mammary gland tumors in female mice were also increased, but these tumors are expected in rodents treated with antipsychotic drugs which elevate prolactin levels. Chronic administration of an antipsychotic also causes elevated prolactin levels in humans. Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin-dependent in vitro, a factor of potential importance if the prescription of these drugs is contemplated in a patient with a previously detected breast cancer. Although disturbances such as galactorrhea, amenorrhea, gynecomastia, and impotence have been reported with antipsychotic drugs, the clinical significance of elevated serum prolactin levels is unknown for most patients. Neither clinical studies nor epidemiologic studies conducted to date have shown an association between chronic administration of these drugs and mammary tumorigenesis. The available evidence, however, is considered too limited to be conclusive at this time.

In a 24-month carcinogenicity study in rats, animals received up to 50 times the maximum recommended human dose. No increased incidence of overall tumors or tumors at any site was observed in either sex. Because of the limited number of animals surviving this study, the meaning of these results is unclear.

Pimozide did not have mutagenic activity in the Ames test with four bacterial test strains, in the mouse dominant lethal test or in the micronucleus test in rats.

Reproduction studies in animals were not adequate to assess all aspects of fertility. Nevertheless, female rats administered Pimozide had prolonged estrus cycles, an effect also produced by other antipsychotic drugs.

PREGNANCY

Teratogenic Effects: Pregnancy Category C. Reproduction studies performed in rats and rabbits at oral doses up to 8 times the maximum human dose did not reveal evidence of teratogenicity. In the rat, however, this multiple of the human dose resulted in decreased pregnancies and in the retarded development of fetuses. These effects are thought to be due to an inhibition or delay in implantation which is also observed in rodents administered other antipsychotic drugs. In the rabbit, maternal toxicity, mortality, decreased weight gain, and embryotoxicity including increased resorptions were dose-related. Because animal reproduction studies are not always predictive of human response, Pimozide should be given to a pregnant woman only if the potential benefits of treatment clearly outweigh the potential risks.
 

Nonteratogenic effects. Neonates exposed to antipsychotic drugs, during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder in these neonates. These complications have varied in severity; while in some cases symptoms have been self-limited, in other cases neonates have required intensive care unit support and prolonged hospitalization.

Pimozide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

LABOR & DELIVERY

This drug has no recognized use in labor or delivery.

NURSING MOTHERS

It is not known whether Pimozide is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for tumorigenicity and unknown cardiovascular effects in the infant, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

PEDIATRIC USE

Although Tourette's Disorder most often has its onset between the ages of 2 and 15 years, information on the use and efficacy of Pimozide in patients less than 12 years of age is limited. A 24-week open label study in 36 children between the ages of 2 and 12 demonstrated that Pimozide has a similar safety profile in this age group as in older patients and there were no safety findings that would preclude its use in this age group.

Because its use and safety have not been evaluated in other childhood disorders, Pimozide is not recommended for use in any condition other than Tourette’s Disorder.

Brand Names U.S.

  • Orap

Dosing Renal Impairment

There are no dosage adjustment provided in manufacturer’s labeling; use with caution.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience fatigue, loss of strength and energy, constipation, or dry mouth. Have patient report immediately to prescriber signs of infection, vision changes, abnormal movements, twitching, change in balance, dysphagia, difficulty speaking, arrhythmia, angina, tachycardia, severe dizziness, passing out, severe headache, tremors, difficulty moving, rigidity, seizures, agitation, behavioral changes, urinary retention, breast enlargement, nipple discharge, sexual dysfunction, amenorrhea, signs of neuroleptic malignant syndrome (fever, muscle cramps or stiffness, dizziness, very bad headache, confusion, change in thinking, fast heartbeat, abnormal heartbeat, or sweating a lot), or signs of tardive dyskinesia (unable to control body movements; tongue, face, mouth, or jaw sticking out; mouth puckering; or puffing cheeks) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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