How Much Does Pimozide Cost in Mexico vs the USA?

INDICATIONS & USAGE Pimozide tablets are indicated for the suppression of motor and phonic tics in patients with Tourette’s Disorder who have failed to respond satisfactorily to standard treatment. Pimozide tablets are not intended as a treatment of first choice nor is it intended for the treatment of tics that are merely annoying or cosmetically troublesome. Pimozide tablets 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 tablets 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.

DOSAGE & ADMINISTRATION General The suppression of tics by pimozide tablets 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 to see whether or not tics persist at the level and extent first identified. In attempts to reduce the dosage of pimozide tablets 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 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 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 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 doses should not exceed 4 mg/day, and doses should not be increased earlier than 14 days (see PRECAUTIONS – Pharmacogenomics ).

CONTRAINDICATIONS Pimozide is contraindicated in the treatment of simple tics or tics other than those associated with Tourette’s Disorder. Pimozide should not be used in patients taking drugs that may, themselves, cause motor and phonic tics (e.g., pemoline, methylphenidate and amphetamines) until such patients have been withdrawn from these drugs to determine whether or not the drugs, rather than Tourette’s Disorder, are responsible for the tics. Because pimozide prolongs the QT interval of the electrocardiogram it is contraindicated in patients with congenital long QT syndrome, patients with a history of cardiac arrhythmias, patients taking other drugs which prolong the QT interval of the electrocardiogram or patients with known hypokalemia or hypomagnesemia (see also PRECAUTIONS - Drug Interactions ). Pimozide is contraindicated in patients with severe toxic central nervous system depression or comatose states from any cause. Pimozide is contraindicated in patients with hypersensitivity to it. As it is not known whether cross-sensitivity exists among the antipsychotics, pimozide should be used with appropriate caution in patients who have demonstrated hypersensitivity to other antipsychotic drugs. Ventricular arrhythmias have been rarely associated with the use of macrolide antibiotics in patients with prolonged QT intervals, as might be produced by pimozide. Specifically, two sudden deaths have been reported when clarithromycin was added to ongoing pimozide therapy. Furthermore, some evidence suggests that pimozide is metabolized partly by the enzyme system cytochrome P450 3A4 (CYP 3A4). Macrolide antibiotics are inhibitors of CYP 3A4, and thus could potentially impede pimozide metabolism. For these reasons, pimozide is contraindicated in patients receiving the macrolide antibiotics clarithromycin, erythromycin, azithromycin, dirithromycin, and troleandomycin. Concomitant use in patients taking Celexa or Lexapro is contraindicated (see PRECAUTIONS - Drug Interactions - Pimozide and Celexa ). Clinical drug interaction studies have demonstrated that pimozide is also metabolized by CYP 2D6. Concomitant use of pimozide with paroxetine and other strong CYP 2D6 inhibitors is contraindicated (See PRECAUTIONS – Drug Interactions ). Concomitant use of pimozide in patients taking sertraline is contraindicated (See PRECAUTIONS – Drug Interactions ). Because azole antifungal agents are also inhibitors of the CYP 3A4 enzymes and thus may likewise impair pimozide metabolism, pimozide is contraindicated in patients receiving the azole antifungal agents itraconazole and ketoconazole. Similarly, protease inhibitor drugs are also inhibitors of CYP 3A4, and thus pimozide is contraindicated in patients receiving protease inhibitors such as ritonavir, saquinovir, indinavir, and nelfinavir. (See PRECAUTIONS - Drug Interactions. ) Nefazodone is a potent inhibitor of CYP 3A4, and its concomitant use with pimozide is also contraindicated. Other drugs that are relatively less potent inhibitors of CYP 3A4 should also be avoided, in view of the risks: e.g., zileuton, fluvoxamine.

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 ).

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 C max 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 C max compared to pimozide administered alone. The increase in pimozide AUC and C max 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 ).

ADVERSE REACTIONS General Extrapyramidal Reactions: Neuromuscular (extrapyramidal) reactions during the administration of 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 doserelated 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. Withdrawal Emergent Neurological Signs: 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 pimozide. Tardive Dyskinesia: Pimozide 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: Electrocardiographic changes have been observed in clinical trials of pimozide 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: Neuroleptic malignant syndrome (NMS) has been reported with pimozide. (See WARNINGS for further information concerning NMS.) Hyperpyrexia: 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 pimozide in Tourette’s Disorder. Body System/ Adverse Reaction Pimozide (N=20) Placebo (N=20) Body as a Whole Headache 1 2 Gastrointestinal Dry Mouth 5 1 Diarrhea 1 0 Nausea 0 2 Vomiting 0 1 Constipation 4 2 Eructations 0 1 Thirsty 1 0 Appetite increase 1 0 Endocrine Menstrual disorder 0 1 Breast secretions 0 1 Musculoskeletal Muscle cramps 0 1 Muscle tightness 3 0 Stooped posture 2 0 CNS Drowsiness 7 3 Sedation 14 5 Insomnia 2 2 Dizziness 0 1 Akathisia 8 0 Rigidity 2 0 Speech disorder 2 0 Handwriting change 1 0 Akinesia 8 0 Psychiatric Depression 2 3 Excitement 0 1 Nervous 1 0 Adverse behavior effect 5 0 Special Senses Visual disturbance 4 0 Taste change 1 0 Sensitivity of eyes to light 1 0 Decrease accommodation 4 1 Spots before eyes 0 1 Urogenital Impotence 3 0 The following adverse event tabulation was derived from 36 children (age 2 to 12) in a 24-week open trial of pimozide in Tourette’s Disorder. Body System/ Adverse Reaction Number of Patients Experiencing Each Event (%) All Events (N=36) Drug-Related Events (N=36) Body as a Whole Asthenia 9 (25.0) 5 (13.8) Headache 8 (22.2) 1 (2.7) Gastrointestinal Dysphagia 1 (2.7) 1 (2.7) Increased Salivation 5 (13.8) 2 (5.5) Musculoskeletal Myalgia 1 (2.7) 1 (2.7) Central Nervous System Dreaming Abnormal 1 (2.7) 1 (2.7) Hyperkinesia 2 (5.5) 1 (2.7) Somnolence 10 (27.7) 9 (25.0) Torticollis 1 (2.7) 1 (2.7) Tremor, Limbs 1 (2.7) 1 (2.7) Psychiatric Adverse Behavior Effect 10 (27.7) 8 (22.2) Nervous 3 (8.3) 2 (5.5) Skin Rash 3 (8.3) 1 (2.7) Special Senses Visual Disturbance 2 (5.5) 1 (2.7) Cardiovascular ECG Abnormal 1 (2.7) 1 (2.7) Because clinical investigational experience with pimozide 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 pimozide 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 pimozide. Gastrointestinal: Gingival hyperplasia in one patient Hematologic: Hemolytic anemia Metabolic/Nutritional: Hyponatremia Other: Seizure To report SUSPECTED ADVERSE REACTIONS, contact ANI Pharmaceuticals, Inc., at 1-855-204-1431 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

PREGNANCY Teratogenic Effects: 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.