ILOPERIDONE- iloperidone_tablet

The mechanism of action of iloperidone in schizophrenia is unknown. However the efficacy of iloperidone could be mediated through a combination of dopamine type 2 (D 2 2 IIloperidone acts as an antagonist with high (nM) affinity binding to serotonin 5-HT 2A 2 3 alpha1 i 4 6 7 i 1A 1 1 i i 2A i alpha1A alpha1B alpha1D alpha2C i The observed mean elimination half-lives for iloperidone, P88 and P95 in CYP2D6 extensive metabolizers (EM) are 18, 26 and 23 hours, respectively, and in poor metabolizers (PM) are 33, 37 and 31 hours, respectively. Steady-state concentrations are attained within 3 to 4 days of dosing. Iloperidone accumulation is predictable from single-dose pharmacokinetics. The pharmacokinetics of iloperidone is more than dose proportional. Elimination of iloperidone is mainly through hepatic metabolism involving 2 P450 isozymes, CYP2D6 and CYP3A4. Absorption: max max Distribution: Metabolism and Elimination: O Approximately 7%-10% of Caucasians and 3%-8% of black/African Americans lack the capacity to metabolize CYP2D6 substrates and are classified as poor metabolizers (PM), whereas the rest are intermediate, extensive or ultrarapid metabolizers. Co-administration of iloperidone with known strong inhibitors of CYP2D6 like fluoxetine results in a 2. 3-fold increase in iloperidone plasma exposure, and therefore one-half of the iloperidone dose should be administered. Similarly, PMs of CYP2D6 have higher exposure to iloperidone compared with EMs and PMs should have their dose reduced by one-half. Laboratory tests are available to identify CYP2D6 Pms. The bulk of the radioactive materials were recovered in the urine (mean 58. 1% in EM and PM, respectively), with feces accounting for 19. 9% (EM) to 22. 1% (PM) of the dosed radioactivity. Transporter Interaction.

Iloperidone tablets are indicated for the treatment of schizophrenia in adults. When deciding among the alternative treatments available for this condition, the prescriber should consider the finding that iloperidone is associated with prolongation of the QTc interval [see Warnings and Precautions (5. 3) Patients must be titrated to an effective dose of iloperidone tablets. Thus, control of symptoms may be delayed during the first 1 to 2 weeks of treatment compared to some other antipsychotic drugs that do not require a similar titration. Prescribers should be mindful of this delay when selecting an antipsychotic drug for the treatment of schizophrenia [see Dosage and Administration (2. 1) Clinical Studies (14) Iloperidone tablets are an atypical antipsychotic agent indicated for the treatment of schizophrenia in adults. ( 1 14 2 5 14.

The recommended target dosage of iloperidone tablets is 12 to 24 mg/day administered twice daily. This target dosage range is achieved by daily dosage adjustments, alerting patients to symptoms of orthostatic hypotension, starting at a dose of 1 mg twice daily, then moving to 2 mg, 4 mg, 6 mg, 8 mg, 10 mg, and 12 mg twice daily on Days 2, 3, 4, 5, 6, and 7 respectively, to reach the 12 mg/day to 24 mg/day dose range. Iloperidone tablets can be administered without regard to meals. 1 Iloperidone must be titrated slowly from a low starting dose to avoid orthostatic hypotension due to its alpha-adrenergic blocking properties. The recommended starting dose for iloperidone tablets is 1 mg orally twice daily. Dose increases to reach the target range of 6 to 12 mg twice daily (12 to 24 mg/day) may be made with daily dosage adjustments not to exceed 2 mg twice daily (4 mg/day). The maximum recommended dose is 12 mg twice daily (24 mg/day). Iloperidone tablets doses above 24 mg/day have not been systematically evaluated in the clinical trials. Efficacy was demonstrated with iloperidone tablets in a dose range of 6 to 12 mg twice daily. Prescribers should be mindful of the fact that patients need to be titrated to an effective dose of iloperidone. Thus, control of symptoms may be delayed during the first 1 to 2 weeks of treatment compared to some other antipsychotic drugs that do not require similar titration. Prescribers should also be aware that some adverse effects associated with iloperidone use are dose related. [see Adverse Reactions (6. 1) Iloperidone tablets can be administered without regard to meals. Dosage adjustment for patients taking iloperidone concomitantly with potential CYP2D6 inhibitors: [see Drug Interactions (7) Dosage adjustment for patients taking iloperidone concomitantly with potential CYP3A4 inhibitors: [see Drug Interactions (7) Dosage adjustment for patients taking iloperidone who are poor metabolizers of CYP2D6: [see Clinical Pharmacology(12. 3) Hepatic Impairment: [see Use in Specific Populations (8. 6) In a longer-term study, Iloperidone was effective in delaying time to relapse in patients with schizophrenia who were stabilized on Iloperidone up to 24 mg/day [see Clinical Studies ( 14 Although there are no data to specifically address re-initiation of treatment, it is recommended that the initiation titration schedule be followed whenever patients have had an interval off iloperidone of more than 3 days.

Commonly observed adverse reactions (incidence >=5% and 2-fold greater than placebo) were: dizziness, dry mouth, fatigue, nasal congestion, orthostatic hypotension, somnolence, tachycardia, and weight increased. 1 To report SUSPECTED ADVERSE REACTIONS, contact Mylan at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www. gov/medwatch. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trial of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The information below is derived from a clinical trial database for iloperidone consisting of 3229 patients exposed to iloperidone at doses of 10 mg/day or greater, for the treatment of schizophrenia. Of these, 999 received iloperidone for at least 6 months, with 657 exposed to iloperidone for at least 12 months. All of these patients who received iloperidone were participating in multiple-dose clinical trials. The conditions and duration of treatment with iloperidone varied greatly and included (in overlapping categories), open-label and double-blind phases of studies, inpatients and outpatients, fixed-dose and flexible-dose studies, and short-term and longer-term exposure. The information presented in these sections was derived from pooled data from -4 placebo-controlled, 4- or 6-week, fixed- or flexible-dose studies in patients who received iloperidone at daily doses within a range of 10 mg to 24 mg (n=874). Adverse Reactions Occurring at an Incidence of 2% or More among Iloperidone -Treated Patients and More Frequent than Placebo: Table 7:Percentage of Adverse Reactions in Short-Term, Fixed- or Flexible-Dose, Placebo-Controlled Trials in Adult Patients Table includes adverse reactions that were reported in 2% or more of patients in any of the iloperidone tablets dose groups and which occurred at greater incidence than in the placebo group. Figures rounded to the nearest integer Body System or Organ Class Placebo% Iloperidone Tablets 10 to 16 mg/day % Iloperidone Tablets 20 to 24 mg/day % Dictionary-derived Term (N=587) (N=483) (N=391) Body as a Whole Arthralgia 2 3 3 Fatigue 3 4 6 Musculoskeletal Stiffness 1 1 3 Weight Increased 1 1 9 Cardiac Disorders Tachycardia 1 3 12 Eye Disorders Vision Blurred 2 3 1 Gastrointestinal Disorders Nausea 8 7 10 Dry Mouth 1 8 10 Diarrhea 4 5 7 Abdominal Discomfort 1 1 3 Infections Nasopharyngitis 3 4 3 Upper Respiratory Tract Infection 1 2 3 Nervous System Disorders Dizziness 7 10 20 Somnolence 5 9 15 Extrapyramidal Disorder 4 5 4 Tremor 2 3 3 Lethargy 1 3 1 Reproductive System Ejaculation Failure <1 2 2 Respiratory Nasal Congestion 2 5 8 Dyspnea <1 2 2 Skin Rash 2 3 2 Vascular Disorders Orthostatic Hypotension 1 3 5 Hypotension <1 <1 3 Dose-Related Adverse Reactions in Clinical Trials Based on the pooled data from 4 placebo-controlled, 4- or 6-week, fixed- or flexible-dose studies, adverse reactions that occurred with a greater than 2% incidence in the patients treated with iloperidone, and for which the incidence in patients treated with iloperidone 20 to 24 mg/day were twice than the incidence in patients treated with iloperidone 10 to 16 mg/day were: abdominal discomfort, dizziness, hypotension, musculoskeletal stiffness, tachycardia, and weight increased. Common and Drug-Related Adverse Reactions in Clinical Trials: Based on the pooled data from 4 placebo-controlled, 4- or 6-week, fixed- or flexible-dose studies, the following adverse reactions occurred in >=5% incidence in the patients treated with iloperidone and at least twice the placebo rate for at least one dose: dizziness, dry mouth, fatigue, nasal congestion, somnolence, tachycardia, orthostatic hypotension, and weight increased. Dizziness, tachycardia, and weight increased were at least twice as common on 20 to 24 mg/day as on 10 to 16 mg/day. Extrapyramidal Symptoms (EPS) in Clinical Trials Pooled data from the 4 placebo-controlled, 4- or 6-week, fixed- or flexible-dose studies provided information regarding EPS. Adverse event data collected from those trials showed the following rates of EPS-related adverse events as shown in Table 8. Table 8: Percentage of EPS Compared to Placebo Placebo (%) Iloperidone Tablets 10 to 16 mg/day (%) Iloperidone Tablets 20 to 24 mg/day Adverse Event Term (N=587) (N=483) (N=391) All EPS events 11. 1 Akathisia 2. 3 Bradykinesia 0 0. 5 Dyskinesia 1. 0 Dystonia 0. 8 Parkinsonism 0 0. 1 Adverse Reactions Associated with Discontinuation of Treatment in Clinical Trials Based on the pooled data from 4 placebo-controlled, 4- or 6-week, fixed- or flexible-dose studies, there was no difference in the incidence of discontinuation due to adverse events between iloperidone-treated (5%) and placebo-treated (5%) patients. The types of adverse events that led to discontinuation were similar for the iloperidone- and placebo-treated patients. Demographic Differences in Adverse Reactions in Clinical Trials An examination of population subgroups in the 4 placebo-controlled, 4- or 6-week, fixed- or flexible-dose studies did not reveal any evidence of differences in safety on the basis of age, gender or race. Laboratory Test Abnormalities in Clinical Trials There were no differences between iloperidone and placebo in the incidence of discontinuation due to changes in hematology, urinalysis, or serum chemistry. In short-term placebo-controlled trials (4- to 6-weeks), there were 1. 0% (13/1342) iloperidone-treated patients with hematocrit at least one time below the extended normal range during post-randomization treatment, compared to 0. 3% (2/585) on placebo. The extended normal range for lowered hematocrit was defined in each of these trials as the value 15% below the normal range for the centralized laboratory that was used in the trial. Other Reactions During the Pre-marketing Evaluation of Iloperidone The following is a list of MedDRA terms that reflect adverse reactions in patients treated with iloperidone at multiple doses >= 4 mg/day during any phase of a trial with the database of 3,210 iloperidone-treated patients. All reported reactions are included except those already listed in Table 7, or other parts of the Adverse Reactions (6) Warnings and Precautions (5) Reactions are further categorized by MedDRA system organ class and listed in order of decreasing frequency according to the following definitions: frequent adverse events are those occurring in at least 1/100 patients (only those not listed in Table 7 appear in this listing); infrequent adverse reactions are those occurring in 1/100 to 1/1,000 patients; rare events are those occurring in fewer than 1/1,000 patients. Blood and Lymphatic Disorders: Infrequent Rare Cardiac Disorders:Frequent Rare Ear and Labyrinth Disorders:Infrequent Endocrine Disorders: Infrequent Eye Disorders:Frequent Infrequent Gastrointestinal Disorders:Infrequent Rare General Disorders and Administrative Site Conditions:Infrequent Rare Hepatobiliary Disorders:Infrequent Investigations: Frequent Infrequent Metabolism and Nutrition Disorders: Infrequent Musculoskeletal and Connective Tissue Disorders Frequent Rare Nervous System Disorders: Infrequent Rare Psychiatric Disorders:Frequent Infrequent Renal and Urinary Disorders:Frequent Infrequent Rare Reproductive System and Breast Disorders: Frequent Infrequent Rare Respiratory, Thoracic and Mediastinal Disorders: Infrequent Rare The following adverse reactions have been identified during postapproval use of iloperidone: retrograde ejaculation and hypersensitivity reactions (including anaphylaxis; angioedema; throat tightness; oropharyngeal swelling; swelling of the face, lips, mouth, and tongue; urticaria; rash; and pruritus). Because these reactions were reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Iloperidone is contraindicated in individuals with a known hypersensitivity reaction to the product. Anaphylaxis, angioedema, and other hypersensitivity reactions have been reported [see Adverse Reactions (6. 2) Known hypersensitivity to iloperidone or to any components in the formulation.

Pregnancy: May cause extrapyramidal and/or withdrawal symptoms in neonates with third trimester exposure. ( 8 Lactation: Advise not to breast feed ( 8. 2 Pediatric Use: Safety and effectiveness not established in children and adolescents. 3 Hepatic Impairment:Iloperidone is not recommended for patients with severe hepatic impairment. 6 The dose of iloperidone should be reduced in patients who are poor metabolizers of CYP2D6. 3 Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to iloperidone during pregnancy. For more information contact the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or visit http://womensmentalhealth. org/clinical-and-research-programs/pregnancyregistry/ Risk Summary Neonates whose mothers are exposed to antipsychotic drugs, including iloperidone, during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery [see Clinical Considerations]. The limited available data with iloperidone in pregnant women are not sufficient to inform a drug-associated risk for major birth defects and miscarriage. Iloperidone was not teratogenic when administered orally to pregnant rats during organogenesis at doses up to 26 times the maximum recommended human dose of 24 mg/day on mg/m 2 2 The background risk of major birth defects and miscarriage for the indicated population is unknown. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder have been reported in neonates whose mothers were exposed to antipsychotic drugs during the third trimester of pregnancy. These symptoms have varied in severity. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. Data Animal Data In an embryo-fetal development study, pregnant rats were given 4, 16, or 64 mg/kg/day (1. 5, and 26 times the maximum recommended human dose (MRHD) of 24 mg/day on a mg/m 2 In an embryo-fetal development study, pregnant rabbits were given 4, 10, or 25 mg/kg/day (3, 8, and 20 times the MRHD on a mg/m 2 In additional studies in which rats were given iloperidone at doses similar to the above beginning from either pre-conception or from day 17 of gestation and continuing through weaning, adverse reproductive effects included prolonged pregnancy and parturition, increased stillbirth rates, increased incidence of fetal visceral variations, decreased fetal and pup weights, and decreased post-partum pup survival. There were no drug effects on the neurobehavioral or reproductive development of the surviving pups. No-effect doses ranged from 4 to 12 mg/kg except for the increase in stillbirth rates which occurred at the lowest dose tested of 4 mg/kg, which is 1. 6 times the MRHD on a mg/m2 basis. Maternal toxicity was seen at the higher doses in these studies The iloperidone metabolite P95, which is a major circulating metabolite of iloperidone in humans but is not present in significant amounts in rats, was given to pregnant rats during the period of organogenesis at oral doses of 20, 80, or 200 mg/kg/day. No teratogenic effects were seen. Delayed skeletal ossification occurred at all doses. No significant maternal toxicity was produced. Plasma levels of P95 (AUC) at the highest dose tested were 2 times those in humans receiving the MRHD of iloperidone. Risk Summary There is no information regarding the presence of iloperidone or its metabolites in human milk, the effects of iloperidone on a breastfed child, nor the effects of iloperidone on human milk production. Iloperidone is present in rat milk [see Data]. Because of the potential for serious adverse reactions in breastfed infants, advise a woman not to breastfeed during treatment with iloperidone. Data The transfer of radioactivity into the milk of lactating rats was investigated following a single dose of [14C] iloperidone at 5 mg/kg. The concentration of radioactivity in milk at 4 hours post-dose was near 10-fold greater than that in plasma at the same time. However, by 24 hours after dosing, concentrations of radioactivity in milk had fallen to values slightly lower than plasma. The metabolic profile in milk was qualitatively similar to that in plasma. Safety and effectiveness in pediatric and adolescent patients have not been established. Clinical studies of iloperidone in the treatment of schizophrenia did not include sufficient numbers of patients aged 65 years and over to determine whether or not they respond differently than younger adult patients. Of the 3,210 patients treated with iloperidone in premarketing trials, 25 (0. 5%) were >=65 years old and there were no patients >=75 years old. Elderly patients with dementia-related psychosis treated with iloperidone are at an increased risk of death compared to placebo. Iloperidone is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning Warnings and Precautions (5. 2) Because iloperidone is highly metabolized, with less than 1% of the drug excreted unchanged, renal impairment alone is unlikely to have a significant impact on the pharmacokinetics of iloperidone. Renal impairment (creatinine clearance <30 mL/min) had minimal effect on C max 0en dashinfinity No dose adjustment to iloperidone is needed in patients with mild hepatic impairment. Patients with moderate hepatic impairment may require dose reduction. Iloperiodne is not recommended for patients with severe hepatic impairment [see Dosage and Administration(2. 2) In adult subjects with mild hepatic impairment no relevant difference in pharmacokinetics of iloperidone, P88 or P95 (total or unbound) was observed compared to healthy adult controls. In subjects with moderate hepatic impairment a higher (2-fold) and more variable free exposure to the active metabolites P88 was observed compared to healthy controls, whereas exposure to iloperidone and P95 was generally similar (less than 50% change compared to control). Since a study in severe liver impaired subjects has not been conducted, iloperidone is not recommended for patients with severe hepatic impairment. Based on in vitro.

RECENT MAJOR CHANGES
Warnings and Precautions ( 5.3 5.9
DRUG INTERACTIONS
The dose of iloperidone tablets should be reduced in patients co-administered a strong CYP2D6 or CYP3A4 inhibitor. 1 Given the primary CNS effects of iloperidone, caution should be used when it is taken in combination with other centrally acting drugs and alcohol. Due to its -alpha1-adrenergic receptor antagonism, iloperidone has the potential to enhance the effect of certain antihypertensive agents. Iloperidone is not a substrate for CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2E1 enzymes. This suggests that an interaction of iloperidone with inhibitors or inducers of these enzymes, or other factors, like smoking, is unlikely. Both CYP3A4 and CYP2D6 are responsible for iloperidone metabolism. Inhibitors of CYP3A4 (e. , ketoconazole) or CYP2D6 (e. , fluoxetine, paroxetine) can inhibit iloperidone elimination and cause increased blood levels. Ketoconazole: Fluoxetine Paroxetine: Paroxetine and Ketoconazole: In vitro in vitro Dextromethorphan: max Fluoxetine: Midazolam (a sensitive CYP 3A4 substrate): max Iloperidone should not be used with any other drugs that prolong the QT interval [see Warnings and Precautions (5.

OVERDOSAGE
In pre-marketing trials involving over 3,210 patients, accidental or intentional overdose of iloperidone was documented in 8 patients ranging from 48 mg to 576 mg taken at once and 292 mg taken over a 3-day period. No fatalities were reported from these cases. The largest confirmed single ingestion of iloperidone was 576 mg; no adverse physical effects were noted for this patient. The next largest confirmed ingestion of iloperidone was 438 mg over a 4-day period; extrapyramidal symptoms and a QTc interval of 507 msec were reported for this patient with no cardiac sequelae. This patient resumed iloperidone treatment for an additional 11 months. In general, reported signs and symptoms were those resulting from an exaggeration of the known pharmacological effects (e. , drowsiness and sedation, tachycardia and hypotension) of iloperidone. There is no specific antidote for iloperidone. Therefore appropriate supportive measures should be instituted. In case of acute overdose, the physician should establish and maintain an airway and ensure adequate oxygenation and ventilation. Gastric lavage (after intubation, if patient is unconscious) and administration of activated charcoal together with a laxative should be considered. The possibility of obtundation, seizures or dystonic reaction of the head and neck following overdose may create a risk of aspiration with induced emesis. Cardiovascular monitoring should commence immediately and should include continuous ECG monitoring to detect possible arrhythmias. If antiarrhythmic therapy is administered, disopyramide, procainamide and quinidine should not be used, as they have the potential for QT-prolonging effects that might be additive to those of iloperidone. Similarly, it is reasonable to expect that the alpha-blocking properties of bretylium might be additive to those of iloperidone, resulting in problematic hypotension. Hypotension and circulatory collapse should be treated with appropriate measures such as intravenous fluids or sympathomimetic agents (epinephrine and dopamine should not be used, since beta stimulation may worsen hypotension in the setting of iloperidone-induced alpha blockade). In cases of severe extrapyramidal symptoms, anticholinergic medication should be administered. Close medical supervision should continue until the patient recovers.
NONCLINICAL TOXICOLOGY
Carcinogenesis: 2 The carcinogenic potential of the iloperidone metabolite P95, which is a major circulating metabolite of iloperidone in humans but is not present at significant amounts in mice or rats, was assessed in a lifetime carcinogenicity study in Wistar rats at oral doses of 25, 75 and 200 mg/kg/day in males and 50, 150 and 250 (reduced from 400) mg/kg/day in females. Drug-related neoplastic changes occurred in males, in the pituitary gland (pars distalis adenoma) at all doses and in the pancreas (islet cell adenoma) at the high dose. Plasma levels of P95 (AUC) in males at the tested doses (25, 75, and 200 mg/kg/day) were approximately 0.4, 3, and 23 times, respectively, the human exposure to P95 at the MRHD of iloperidone. Mutagenesis: in vivo in vitro The iloperidone metabolite P95 was negative in the Ames test, the V79 chromosome aberration test, and an in vivo Impairment of Fertility: 2
CLINICAL STUDIES
The efficacy of iloperidone in the treatment of schizophrenia was supported by 2 placebo- and active-controlled short-term (4- and 6-week) trials. Both trials enrolled patients who met the DSM-III/IV criteria for schizophrenia. Three instruments were used for assessing psychiatric signs and symptoms in these studies. The Positive and Negative Syndrome Scale (PANSS) and Brief Psychiatric Rating Scale (BPRS) are both multi-item inventories of general psychopathology usually used to evaluate the effects of drug treatment in schizophrenia. The Clinical Global Impression (CGI) assessment reflects the impression of a skilled observer, fully familiar with the manifestation of schizophrenia, about the overall clinical state of the patient. A 6-week, placebo-controlled trial (n = 706) involved 2 flexible dose ranges of iloperidone (12 to 16 mg/day or 20 to 24 mg/day) compared to placebo and an active control (risperidone). For the 12 to 16 mg/day group, the titration schedule of iloperidone was 1 mg twice daily on Days 1 and 2, 2 mg twice daily on Days 3 and 4, 4 mg twice daily on Days 5 and 6, and 6 mg twice daily on Day 7. For the 20 to 24 mg/day group, the titration schedule of iloperidone was 1 mg twice daily on Day 1, 2 mg twice daily on Day 2, 4 mg twice daily on Day 3, 6 mg twice daily on Days 4 and 5, 8 mg twice daily on Day 6, and 10 mg twice daily on Day 7. The primary endpoint was change from baseline on the BPRS total score at the end of treatment (Day 42). Both the 12 to 16 mg/day and the 20 to 24 mg/day dose ranges of iloperidone were superior to placebo on the BPRS total score. The active control antipsychotic drug appeared to be superior to iloperidone in this trial within the first 2 weeks, a finding that may in part be explained by the more rapid titration that was possible for that drug. In patients in this study who remained on treatment for at least 2 weeks, iloperidone appeared to have had comparable efficacy to the active control. A 4-week, placebo-controlled trial (n = 604) involved one fixed dose of iloperidone (24 mg/day) compared to placebo and an active control (ziprasidone). The titration schedule for this study was similar to that for the 6-week study. This study involved titration of iloperidone starting at 1 mg twice daily on Day 1 and increasing to 2, 4, 6, 8, 10 and 12 mg twice daily on Days 2, 3, 4, 5, 6, and 7. The primary endpoint was change from baseline on the PANSS total score at the end of treatment (Day 28). The 24 mg/day iloperidone tablets dose was superior to placebo in the PANSS total score. Iloperidone appeared to have similar efficacy to the active control drug which also needed a slow titration to the target dose. In a longer-term trial, clinically stable adult outpatients (n = 303) meeting DSM-IV criteria for schizophrenia who remained stable following 12 weeks of open-label treatment with flexible doses of Iloperidone (8 mg/day en dash 24 mg/day administered as twice daily doses) were randomized to placebo or to continue on their current Iloperidone dose (8 mg/day en dash 24 mg/day administered as twice daily doses) for observation for possible relapse during the double-blind relapse prevention phase. Stabilization during the open-label phase was defined as being on an established dose of Iloperidone that was unchanged due to efficacy in the 4 weeks prior to randomization, having CGI-Severity score of <= 4 and PANSS total score <= 70, a score of <= 4 on each of the following individual PANSS items (P1-delusions, P2-conceptual disorganization, P3-hallucinatory behavior, P6-suspiciousness/persecution, P7-hostility, or G8-uncooperativeness), and no hospitalization or increase in level of care to treat exacerbations. Relapse or impending relapse during the double-blind relapse prevention phase was defined as any of the following: hospitalization due to worsening of schizophrenia, increase (worsening) of the PANSS total score >= 30%, CGI-Improvement score >= 6, patient had suicidal, homicidal, or aggressive behavior, or need for any other antipsychotic medication. Figure 1: Kaplan Meier Estimation of Percent Relapse/Impending Relapse for iloperidone (Ilo) and placebo (Pbo) Based on the interim analysis, an independent data monitoring committee decided the study should be discontinued early due to evidence of efficacy. Based on results from the interim analysis, which were confirmed by the final analysis dataset, patients treated with Iloperidone experienced a statistically significant longer time to relapse or impending relapse than patients who received placebo. Figure 1 displays the estimated cumulative proportion of patients with relapse or impending relapse based on the final data set.

Mylan Pharmaceuticals Inc.

ILOPERIDONE- iloperidone_tablet Product manual source documgent