Orap

Pimozide is also used sometimes to treat schizophrenia (a mental illness that causes disturbed or unusual thinking, loss of interest in life, and strong or inappropriate emotions) and certain behavior, personality, movement, and psychiatric disorders in adults. Talk to your doctor about the possible risks of using this medication for your condition.

This medication may be prescribed for other uses; talk to your doctor or pharmacist for more information.

In case of overdose, call your local poison control center at 1-800-222-1222. If the victim has collapsed or is not breathing, call local emergency services at 911.

Symptoms of overdose may include:

• blank facial expression
• shuffling walk
• unusual, slowed, or uncontrollable movements of any part of the body
• restlessness
• fast heartbeat
• drowsiness
• coma (loss of consciousness for a period of time)
• difficulty breathing

>10%

Akinesia (40%)

Drowsiness (35%)

EPS (10-15%)

Sedation (70%)

Speech disorder (10-15%)

Visual disturbance (20%)

Dry mouth (25%)

Constipation (20%)

Impotence (10-15%)

1-10%

Appetite increase

Thirst increase

Dizziness

Drug-induced tardive dystonia

Nervousness

Photosensitivity

Taste change

Orthostatic hypotension

Diminished sweating

Nasal congestion

Diarrhea

Urinary retention

Retinitis pigmentosa

Frequency Not Defined

Ineffective thermoregulation

Heatstroke or hypothermia (rare)

Neuroleptic malignant syndrome (rare)

Seizure (rare)

Prolonged QT interval

Torsades de pointes

Obstipation (rare)

Paralytic ileus (rare)

Agranulocytosis (rare)

Disorder of hematopoietic structure (rare)

Leukopenia (rare)

Thrombocytopenia (rare)

Cholestatic jaundice syndrome (rare)

Drug-induced lupus erythematosus, systemic (rare)

Priapism (rare)

Death

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.

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

Before using pimozide, tell your doctor if you regularly use other medicines that make you sleepy (such as cold or allergy medicine, sedatives, narcotic pain medicine, sleeping pills, muscle relaxers, and medicine for depression or anxiety). They can add to sleepiness caused by pimozide.

Tell your doctor about all other medicines you use, especially:

• ciprofloxacin (Cipro), norfloxacin (Noroxin), ofloxacin (Floxin);
• a diuretic (water pill);
• fluoxetine (Prozac, Sarafem, Symbyax);
• lidocaine (Xylocaine);
• methoxsalen (Oxsoralen, Uvadex, 8-Mop);
• mexiletine (Mexitil);
• thiabendazole (Mintezol); or
• medicine to treat or prevent seizures.

This list is not complete and other drugs may interact with pimozide. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

General

Neuromuscular (extrapyramidal) reactions during the administration of ORAP® (pimozide) have been reported frequently, often during the first few days of treatment. In most patients, these reactions involved Parkinson-like symptoms which, when first observed, were usually mild to moderately severe and usually reversible.

Other types of neuromuscular reactions (motor restlessness, dystonia, akathisia, hyperreflexia, opisthotonos, oculogyric crises) have been reported far less frequently. Severe extrapyramidal reactions have been reported to occur at relatively low doses. Generally the occurrence and severity of most extrapyramidal symptoms are dose-related since they occur at relatively high doses and have been shown to disappear or become less severe when the dose is reduced. Administration of antiparkinson drugs such as benztropine mesylate or trihexyphenidyl hydrochloride may be required for control of such reactions. It should be noted that persistent extrapyramidal reactions have been reported and that the drug may have to be discontinued in such cases.

Generally, patients receiving short term therapy experience no problems with abrupt discontinuation of antipsychotic drugs.

However, some patients on maintenance treatment experience transient dyskinetic signs after abrupt withdrawal. In certain of these cases the dyskinetic movements are indistinguishable from the syndrome described below under “Tardive Dyskinesia” except for duration. It is not known whether gradual withdrawal of antipsychotic drugs will reduce the rate of occurrence of withdrawal emergent neurological signs, but until further evidence becomes available, it seems reasonable to gradually withdraw use of ORAP.

ORAP may be associated with persistent dyskinesias. Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements, may appear in some patients on long-term therapy or may occur after drug therapy has been discontinued. The risk appears to be greater in elderly patients on high-dose therapy, especially females. The symptoms are persistent and in some patients appear irreversible. The syndrome is characterized by rhythmical involuntary movements of tongue, face, mouth or jaw (e.g., protrusion of tongue, puffing of cheeks, puckering of mouth, chewing movements). Sometimes these may be accompanied by involuntary movements of extremities and the trunk.

There is no known effective treatment for tardive dyskinesia; antiparkinson agents usually do not alleviate the symptoms of this syndrome. It is suggested that all antipsychotic agents be discontinued if these symptoms appear. Should it be necessary to reinstitute treatment, or increase the dosage of the agent, or switch to a different antipsychotic agent, this syndrome may be masked.

It has been reported that fine vermicular movement of the tongue may be an early sign of tardive dyskinesia and if the medication is stopped at that time the syndrome may not develop.

Electrocardiographic changes have been observed in clinical trials of ORAP in Tourette's Disorder and schizophrenia. These have included prolongation of the QT interval, flattening, notching and inversion of the T wave and the appearance of U waves. Sudden, unexpected deaths and grand mal seizure have occurred at doses above 20 mg/day.

Neuroleptic malignant syndrome (NMS) has been reported with ORAP. (See WARNINGS for further information concerning NMS.)

Hyperpyrexia has been reported with other antipsychotic drugs.

Clinical Trials

The following adverse reaction tabulation was derived from 20 patients in a 6-week long placebo-controlled clinical trial of ORAP in Tourette's Disorder.

The following adverse event tabulation was derived from 36 children (age 2 to 12) in a 24-week open trial of ORAP in Tourette's Disorder.

Because clinical investigational experience with ORAP in Tourette's Disorder is limited, uncommon adverse reactions may not have been detected. The physician should consider that other adverse reactions associated with antipsychotics may occur.

Other Adverse Reactions

In addition to the adverse reactions listed above, those listed below have been reported in U.S. clinical trials of ORAP in conditions other than Tourette's Disorder.

Body as a Whole: Asthenia, chest pain, periorbital edema

Cardiovascular/Respiratory: Postural hypotension, hypotension, hypertension, tachycardia, palpitations

Gastrointestinal: Increased salivation, nausea, vomiting, anorexia, GI distress

Endocrine: Loss of libido

Metabolic/Nutritional: Weight gain, weight loss

Central Nervous System: Dizziness, tremor, parkinsonism, fainting, dyskinesia

Psychiatric: Excitement

Skin: Rash, sweating, skin irritation

Special Senses: Blurred vision, cataracts

Urogenital: Nocturia, urinary frequency

Postmarketing Reports

The following experiences were described in spontaneous postmarketing reports. These reports do not provide sufficient information to establish a clear causal relationship with the use of ORAP.

Gastrointestinal: Gingival hyperplasia in one patient

Hematologic: Hemolytic anemia

Metabolic/Nutritional: Hyponatremia

Other: Seizure

In general, the signs and symptoms of overdosage with ORAP (pimozide) would be an exaggeration of known pharmacologic effects and adverse reactions, the most prominent of which would be: 1) electrocardiographic abnormalities, 2) severe extrapyramidal reactions, 3) hypotension, 4) a comatose state with respiratory depression.

In the event of overdosage, gastric lavage, establishment of a patent airway and, if necessary, mechanically-assisted respiration are advised. Electrocardiographic monitoring should commence immediately and continue until the ECG parameters are within the normal range. Hypotension and circulatory collapse may be counteracted by use of intravenous fluids, plasma, or concentrated albumin, and vasopressor agents such as metaraminol, phenylephrine and norepinephrine.

Epinephrine should not be used. In case of severe extrapyramidal reactions, antiparkinson medication should be administered. Because of the long half-life of pimozide, patients who take an overdose should be observed for at least 4 days. As with all drugs, the physician should consider contacting a poison control center for additional information on the treatment of overdose.

Tell your doctor if you are pregnant or plan to become pregnant.

The FDA categorizes medications based on safety for use during pregnancy.  Five categories- A,B,C,D and X, are used to classify the possible risks to an unborn baby when a medication is taken during pregnancy. 

Orap falls into category C. In animal studies, pregnant animals were given this medication and had some babies born with problems. No well-controlled studies have been done in humans, though. Therefore, this medication may be used if the potential benefits to the mother outweigh the potential risks to the unborn child.

• Store Orap at controlled room temperature between 59˚and 86˚F.
• Keep in a tight, light resistant container.
• Keep this and all medications out of the reach of children.

Pimozide is an antipsychotic medication. It works by changing the actions of chemicals in the brain.

Pimozide is used to suppress the motor and phonic tics associated with Tourette's disorder.

Pimozide may also be used for purposes not listed in this medication guide.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Overdose symptoms may include some of the serious side effects listed in this medication guide.

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

Contraindications

• Simple tics or tics other than those associated with Tourette’s syndrome.1

• Concurrent therapy with drugs that cause motor and vocal tics (e.g., amphetamines, methylphenidate, pemoline [no longer commercially available in the US]) until such drugs have been withdrawn to determine whether tics were caused by the drug rather than Tourette’s syndrome.1

• Congenital long QT syndrome, history of cardiac arrhythmias, concomitant therapy with other drugs that prolong QT interval, or known hypokalemia or hypomagnesemia.1 202 (See Cardiovascular Effects under Cautions.)

• Concomitant therapy with drugs that inhibit CYP3A4 or drugs that prolong the QT interval (e.g., azole antifungals, macrolide antibiotics, protease inhibitors, SSRIs [citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline], nefazodone, zileuton).1 200 205 206 207 208 209 210 211 (See Interactions.)

• Severe toxic CNS depression or comatose states from any cause.1

• Hypersensitivity to pimozide;1 use caution in patients who have demonstrated hypersensitivity to other antipsychotic drugs.1

Warnings/Precautions

Warnings

Tardive dyskinesia, a syndrome of potentially irreversible, involuntary, dyskinetic movements, may develop in patients receiving antipsychotic agents, including pimozide.1 2 3 71 92 94 96 Consider discontinuance.1

May occur during long-term administration or following discontinuance.1 2 3 71

Neuroleptic malignant syndrome (NMS), a potentially fatal syndrome requiring immediate discontinuance of the drug and intensive symptomatic treatment, has been reported with antipsychotic agents, including pimozide.1 2 146

Hyperpyrexia not associated with NMS also reported with antipsychotic agents.1

Sudden, unexpected deaths have occurred in some patients receiving high doses (>10 mg; in the range of 1 mg/kg) for conditions other than Tourette’s syndrome or in patients receiving concomitant pimozide and clarithromycin.1 168 170 Possibly due to QT interval prolongation, predisposing patients to ventricular arrhythmia.1 2

Various ECG changes (e.g., QT [including QTc] interval prolongation; flattening, notching, and inversion of the T wave; appearance of U waves) have occurred.1 2 164 165 202

Perform ECG evaluations before and periodically during therapy, especially during periods of dosage adjustment.1 2 202

Some clinicians recommend consultation with a cardiologist before therapy initiation in patients with a baseline QTc interval >440 ms.164

Consider stopping further dosage increases and dosage reduction for QTc interval prolongation >470 ms in children or 520 ms in adults or >25% beyond patient’s pretreatment value, or development of other T-wave abnormalities.1 2 164 Also consider dosage reduction if bradycardia (<50 bpm) occurs.164

Some clinicians recommend withholding drug if T-wave inversion, U waves, or cardiac arrhythmia occurs and reinstituting only after ECG findings are normal.164

Use with caution in patients with cardiovascular disorders.3 164 165

Because hypokalemia has been associated with ventricular arrhythmias, correct potassium insufficiency because of diuretics, diarrhea, or other causes before pimozide initiation; maintain normal serum potassium concentrations during therapy.1 2

Dose-related increase in benign pituitary tumors observed in female mice; clinical importance is not known.1 2 Carefully consider tumorigenic potential in decision to use drug, especially if patient is young and long-term therapy is anticipated.1 2

General Precautions

Possible risk of seizures;1 2 3 140 141 167 may lower seizure threshold.1 Use with caution in patients with history of seizures or EEG abnormalities or in those receiving anticonvulsants.1 Maintain adequate anticonvulsant therapy.1

Possible impairment of ability to perform activities requiring mental alertness or physical coordination (e.g., operating machinery, driving a motor vehicle), especially during first few days of therapy.1

Extrapyramidal symptoms occur frequently;1 2 3 9 40 50 52 58 59 60 68 71 73 78 81 85 87 88 90 92 93 94 96 97 99 100 102 104 122 145 especially during first few days of therapy.1 2 52 122 In most patients, reactions consist of parkinsonian symptoms1 2 4 68 71 78 81 92 94 99 100 102 159 that are mild to moderate in severity and usually reversible following discontinuance.1 2

Causes adverse anticholinergic effects; use with caution in individuals whose condition may be aggravated by such effects.1

Possible transient dyskinetic signs after abrupt withdrawal in some patients receiving maintenance therapy; in some cases, dyskinetic movements are indistinguishable from tardive dyskinesia except for duration.1 2 Not known whether gradual withdrawal will reduce occurrence; pending further evidence, withdraw gradually.1 2

Specific Populations

Category C.1

Risk for extrapyramidal and/or withdrawal symptoms (e.g., agitation, hypertonia, hypotonia, tardive dyskinetic-like symptoms, tremor, somnolence, respiratory distress, feeding disorder) in neonates exposed to antipsychotic agents during the third trimester; monitor neonates exhibiting such symptoms.222 223 224 a Symptoms were self-limiting in some neonates but varied in severity; some infants required intensive support and prolonged hospitalization.222 223 224 a

Not known whether pimozide is distributed into human milk; discontinue nursing or the drug.1

Onset of Tourette’s syndrome usually occurs between ages of 2 and 15 years, but data on use and efficacy in children <12 years of age are limited.1 2 Limited clinical evidence suggests that safety profile in children 2–12 years of age generally is comparable to that in older patients.1

Safety and efficacy for management of other conditions in children not evaluated; use in children for any condition other than Tourette’s syndrome not recommended.1 2

Prevalence of tardive dyskinesia appears to be highest among geriatric patients, particularly geriatric women.1 2 3 59

Transient hypotension for several hours after administration has occurred in some geriatric or debilitated patients.3

Use with caution.1

Use with caution.1

Common Adverse Effects

Extrapyramidal reactions (e.g., pseudoparkinsonism, dystonia, dyskinesia, akathisia), dry mouth, drowsiness, sedation, adverse behavior effect, asthenia, somnolence.1

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

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.

• Store at room temperature.
• Protect from light.
• Store in a dry place. Do not store in a bathroom.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.

Orap® (pimozide) 1 mg tablets are white, oval tablets, debossed “Orap 1”, partially scored on one side and scored on the other. They are available in bottles of 100 (NDC 57844-151-01).

Orap® (pimozide) 2 mg tablets are white, oval tablets, debossed “Orap 2”, partially scored on one side and scored on the other. They are available in bottles of 100 (NDC 57844-198-01).

Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F) [see USP Controlled Room Temperature].

Dispense in a tight, light-resistant container as defined in the official compendium.

Pharmacist: Dispense in child-resistant container.

Manufactured in Croatia by:

PLIVA HRVATSKA d.o.o.

Zagreb, Croatia

Manufactured for:

Teva Select Brands, Horsham, PA 19044

Division of Teva Pharmaceuticals USA

Rev. S 3/2014

Orap® (pimozide) Tablets 1 mg, 100s Label Text

NDC 57844-151-01

Orap® tablets 1 mg

(pimozide)

Rx only

USUAL DOSAGE: For

dosage and other

information for use,

see accompanying

product literature.

TEVA

100 TABLETS

Common side effects of Orap include: akathisia, akinesia, sedation, and visual disturbance. See below for a comprehensive list of adverse effects.

Applies to pimozide: oral tablet

General

The most common side effects include somnolence, hyperhidrosis, nocturia, and dizziness.[Ref]

Nervous system

Very common (10% or more): Somnolence (up to 25%), dizziness (up to 11%)
Common (1% to 10%): Extrapyramidal disorder, akathisia, headache, lethargy, tremor, hyperkinesia, limb tremor, torticollis
Uncommon (0.1% to 1%): Bradykinesia, cogwheel rigidity, dyskinesia, dystonia, dysarthria
Frequency not reported: Neuroleptic malignant syndrome, grand mal convulsion, tardive dyskinesia, electroencephalogram abnormal, motor restlessness, hyperreflexia, opisthotonos, drowsiness, sedation, speech disorder, handwriting change, taste change, akinesia, parkinsonism, fainting
Postmarketing reports: Seizure[Ref]

Extrapyramidal symptoms typically occurred during the first few days of treatment and involved mild to moderate Parkinson-like symptoms. This disorder is usually dose-related, with an increased occurrence and severity of symptoms with high doses; symptoms decreased or disappeared with lower doses. While these symptoms were usually reversible, a few cases of persistent symptoms required discontinuation.

Grand mal seizures occurred at doses greater than 20 mg/day.[Ref]

Psychiatric

Very common (10% or more): Adverse behavior effect (up to 22.2%)
Common (1% to 10%): Depression, agitation, insomnia, abnormal dreams, restlessness, nervous
Frequency not reported: Libido decreased/lost, excitement[Ref]

Other

Sudden, unexpected deaths have occurred at doses greater than 20 mg/day.[Ref]

Very common (10% or more): Asthenia (up to 13.8%)
Common (1% to 10%): Extreme exhaustion
Uncommon (0.1% to 1%): Face edema
Frequency not reported: Neonatal drug withdrawal syndrome, body temperature dysregulation, hypothermia
Postmarketing reports: Sudden, unexplained death, hyperpyrexia, thirst[Ref]

Dermatologic

Very common (10% or more): Hyperhidrosis (up to 13%)
Common (1% to 10%): Sebaceous gland overactivity, rash
Uncommon (less than 1%): Pruritus
Frequency not reported: Urticaria, skin irritation[Ref]

Genitourinary

Very common (10% or more): Nocturia (up to 12%)
Common (1% to 10%): Urinary frequency, erectile dysfunction
Uncommon (0.1% to 1%): Amenorrhea
Frequency not reported: Galactorrhea, menstrual disorder, breast secretions, impotence[Ref]

Gastrointestinal

Common (1% to 10%): Constipation, dry mouth, vomiting, increased salivation/salivary hypersecretion, dysphagia
Frequency not reported: Diarrhea, nausea, gastrointestinal distress
Postmarketing reports: Gingival hyperplasia[Ref]

Gingival hyperplasia occurred in animal models at high doses, but was reversible after discontinuation.[Ref]

Musculoskeletal

Common (1% to 10%): Muscle rigidity, myalgia
Uncommon (0.1% to 1%): Muscle spasms
Frequency not reported: Rigidity, neck rigidity, muscle cramps, muscle tightness, stooped posture[Ref]

Ocular

Common (1% to 10%): Vision blurred, visual disturbance
Uncommon (0.1% to 1%): Oculogyric crisis
Frequency not reported: Sensitivity of eyes to light, decrease accommodation, spots before eyes, periorbital edema, cataracts[Ref]

Metabolic

Hyperglycemia occurred in patients with preexisting diabetes.[Ref]

Common (1% to 10%): Anorexia, weight increased
Frequency not reported: Hyperglycemia, hyponatremia, appetite increase, weight loss[Ref]

Cardiovascular

Electrocardiographic changes include prolongation of the QT interval, flattening/notching/inversion of the T wave, and the appearance of U waves.[Ref]

Common (1% to 10%): ECG abnormal
Frequency not reported: Torsade de Pointes, ventricular tachycardia/tachycardia, ventricular fibrillation, chest pain, postural hypotension/hypotension, hypertension, palpitations
Postmarketing reports: Cardiac arrest, venous thromboembolism, deep vein thrombosis[Ref]

Endocrine

Frequency not reported: Blood prolactin increases, gynecomastia[Ref]

Renal

Frequency not reported: Glycosuria[Ref]

Hematologic

Postmarketing reports: Hemolytic anemia[Ref]

Respiratory

Postmarketing reports: Pulmonary embolism[Ref]

Some side effects of Orap may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.