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Questions & Answers
Side Effects & Adverse Reactions
The use of ORAP (pimozide) in the treatment of Tourette’s Disorder involves different risk/benefit considerations than when antipsychotic drugs are used to treat other conditions. Consequently, a decision to use ORAP should take into consideration the following (see also PRECAUTIONS - Information for Patients).
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cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn.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).
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.
Sudden, unexpected deaths have occurred in experimental studies of conditions other than Tourette’s Disorder. These deaths occurred while patients were receiving dosages in the range of 1 mg per kg. One possible mechanism for such deaths is prolongation of the QT interval predisposing patients to ventricular arrhythmia. An electrocardiogram should be performed before ORAP treatment is initiated and periodically thereafter, especially during the period of dose adjustment.
ORAP may have a tumorigenic potential. Based on studies conducted in mice, it is known that pimozide can produce a dose-related increase in pituitary tumors. The full significance of this finding is not known, but should be taken into consideration in the physician’s and patient’s decisions to use this drug product. This finding should be given special consideration when the patient is young and chronic use of pimozide is anticipated (see PRECAUTIONS - Carcinogenesis, Mutagenesis, Impairment of Fertility).
Legal Issues
There is currently no legal information available for this drug.
FDA Safety Alerts
There are currently no FDA safety alerts available for this drug.
Manufacturer Warnings
There is currently no manufacturer warning information available for this drug.
FDA Labeling Changes
There are currently no FDA labeling changes available for this drug.
Uses
ORAP (pimozide) is indicated for the suppression of motor and phonic tics in patients with Tourette’s Disorder who have failed to respond satisfactorily to standard treatment. ORAP is not intended as a treatment of first choice nor is it intended for the treatment of tics that are merely annoying or cosmetically troublesome. ORAP should be reserved for use in Tourette’s Disorder patients whose development and/or daily life function is severely compromised by the presence of motor and phonic tics.
Evidence supporting approval of pimozide for use in Tourette’s Disorder was obtained in two controlled clinical investigations which enrolled patients between the ages of 8 and 53 years. Most subjects in the two trials were 12 or older.
History
There is currently no drug history available for this drug.
Other Information
ORAP® (pimozide) is an orally active antipsychotic agent of the diphenyl-butylpiperidine series. The structural formula of pimozide, 1-[1-[4,4-bis(4-fluorophenyl)butyl]-4-piperidinyl]-1,3-dihydro-2H-benzimidazole-2-one is:
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.
Sources
Orap Manufacturers
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Teva Select Brands
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Orap | Teva Select Brands
GeneralThe suppression of tics by ORAP 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 ORAP to see whether or not tics persist at the level and extent first identified. In attempts to reduce the dosage of ORAP, 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.
ChildrenReliable dose response data for the effects of ORAP (pimozide) 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, ORAP doses should not exceed 0.05 mg/kg/day, and doses should not be increased earlier than 14 days (see PRECAUTIONS – Pharmacogenomics).
AdultsIn general, treatment with ORAP 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, ORAP doses should not exceed 4 mg/day, and doses should not be increased earlier than 14 days (see PRECAUTIONS – Pharmacogenomics).
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Orap | Dr. Reddy's Laboratories Inc.
2.1 First Treatment CycleThe recommended starting dose for the first treatment cycle, for all patients regardless of baseline hematology laboratory values, is 75 mg/m2 subcutaneously or intravenously, daily for 7 days. Patients should be premedicated for nausea and vomiting.
Complete blood counts, liver chemistries and serum creatinine should be obtained prior to first dose.
2.2 Subsequent Treatment CyclesCycles should be repeated every 4 weeks. The dose may be increased to 100 mg/m2 if no beneficial effect is seen after 2 treatment cycles and if no toxicity other than nausea and vomiting has occurred. It is recommended that patients be treated for a minimum of 4 to 6 cycles. However, complete or partial response may require additional treatment cycles. Treatment may be continued as long as the patient continues to benefit.
2.3 Dosage Adjustment Based on Hematology Laboratory ValuesFor patients with baseline (start oftreatment) WBC ≥3 x109/L,ANC ≥1.5 x109/L and platelets ≥75 x109/L, adjust the dose as follows, based on nadir counts for any given cycle:
Nadir Counts % Dose in the Next Course ANC (x109/L)
<0.5
0.5 –1.5
>1.5 Platelets (x109/L)
<25
25-50
>50 50%
67%
100%For patients whose baseline counts are WBC <3 x109/L, ANC<1.5 x109/L, or platelets <75 x109/L, dose adjustments should be based on nadir counts and bone marrow biopsy cellularity at the time of the nadir as noted below, unless there is clear improvement in differentiation (percentage of mature granulocytes is higher and ANC is higher than at onset of that course) at the time of the next cycle, in which case the dose of the current treatment should be continued.
WBC or PlateletNadir% decrease in countsfrom baseline Bone MarrowBiopsy Cellularity
at Time of Nadir(%) 30-60 15-30 <15 % Dose in the Next Course 50-75 100 50 33 >75 75 50 33If a nadir as defined in the table above has occurred, the next course of treatment should be given 28 days after the start of the preceding course, provided that both the WBC and the platelet counts are >25% above the nadir and rising. If a >25% increase above the nadir is not seen by day 28, counts should be reassessed every 7 days. If a 25% increase is not seen by day 42, then the patient should be treated with 50% of the scheduled dose.
2.4 Dosage Adjustment Based on Serum Electrolytes and Renal ToxicityIf unexplained reductions in serum bicarbonate levels to <20 mEq/L occur, the dosage should be reduced by 50% on the next course. Similarly, if unexplained elevations of BUN or serum creatinine occur, the next cycle should be delayed until values return to normal or baseline and the dose should be reduced by 50% on the next treatment course [see Warnings and Precautions (5.3)].
2.5 Use in Geriatric PatientsAzacitidine and its metabolites are known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function [see Warnings and Precautions (5.3) and Use in Specific Populations (8.5)].
2.6 Preparation of Azacitidine For InjectionAzacitidine for injection is a cytotoxic drug and, as with other potentially toxic compounds, caution should be exercised when handling and preparing azacitidine for injection suspensions [see How Supplied/Storage and Handling (16)].
If reconstituted azacitidine for injection comes into contact with the skin, immediately and thoroughly wash with soap and water. If it comes into contact with mucous membranes, flush thoroughly with water.
The azacitidine for injection vial is single-use and does not contain any preservatives. Unused portions of each vial should be discarded properly [see How Supplied/Storage and Handling (16)]. Do not save any unused portions for later administration.
2.7 Instructions for Subcutaneous AdministrationAzacitidine for injection should be reconstituted aseptically with 4 mL sterile water for injection. The diluent should be injected slowly into the vial. Vigorously shake or roll the vial until a uniform suspension is achieved. The suspension will be cloudy. The resulting suspension will contain azacitidine 25 mg/mL. Do not filter the suspension after reconstitution. Doing so could remove the active substance.
Preparation for Immediate Subcutaneous Administration: Doses greater than 4 mL should be divided equally into 2 syringes. The product may be held at room temperature for up to 1 hour, but must be administered within 1 hour after reconstitution.
Preparation for Delayed Subcutaneous Administration: The reconstituted product may be kept in the vial or drawn into a syringe. Doses greater than 4 mL should be divided equally into 2 syringes. The product must be refrigerated immediately. When azacitidine for injection is reconstituted using water for injection that has not been refrigerated, the reconstituted product may be held under refrigerated conditions (2ºC -8ºC, 36ºF -46ºF) for up to 8 hours. When azacitidine for injection is reconstituted using refrigerated (2ºC -8ºC, 36ºF -46ºF) water for injection, the reconstituted product may be stored under refrigerated conditions (2ºC -8ºC, 36ºF -46ºF) for up to 22 hours. After removal from refrigerated conditions, the suspension may be allowed to equilibrate to room temperature for up to 30 minutes prior to administration.
Subcutaneous Administration
To provide a homogeneous suspension, the contents of the syringe must be re-suspended by inverting the syringe 2-3 times and vigorously rolling the syringe between the palms for 30 seconds immediately prior to administration.
Azacitidine for injection suspension is administered subcutaneously. Doses greater than 4 mL should be divided equally into 2 syringes and injected into 2 separate sites. Rotate sites for each injection (thigh, abdomen, or upper arm). New injections should be given at least one inch from an old site and never into areas where the site is tender, bruised, red, or hard.
Suspension Stability: Azacitidine for injection reconstituted with non-refrigerated water for injection for subcutaneous administration may be stored for up to 1 hour at 25°C (77°F) or for up to 8 hours between 2°C and 8°C (36°F and 46°F); when reconstituted with refrigerated (2ºC -8ºC, 36ºF -46ºF) water for injection, it may be stored for 22 hours between 2°C and 8°C (36°F and 46°F).
2.8 Instructions for Intravenous AdministrationReconstitute the appropriate number of azacitidine for injection vials to achieve the desired dose. Reconstitute each vial with 10 mL sterile water for injection. Vigorously shake or roll the vial until all solids are dissolved. The resulting solution will contain azacitidine 10 mg/mL. The solution should be clear. Parenteral drug product should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
Withdraw the required amount of azacitidine for injection solution to deliver the desired dose and inject into a 50 to 100 mL infusion bag of either 0.9% Sodium Chloride Injection or Lactated Ringer’s Injection.
Intravenous Solution Incompatibility
Azacitidine for injection is incompatible with 5% Dextrose solutions, Hespan, or solutions that contain bicarbonate. These solutions have the potential to increase the rate of degradation of azacitidine for injection and should therefore be avoided.
Intravenous Administration
Azacitidine for injection solution is administered intravenously. Administer the total dose over a period of 10 to 40 minutes. The administration must be completed within 1 hour of reconstitution of the azacitidine for injection vial.
Solution Stability: Azacitidine for injection reconstituted for intravenous administration may be stored at 25°C (77°F), but administration must be completed within 1 hour of reconstitution.
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