ILOPERIDONE

Iloperidone is an atypical antipsychotic belonging to the chemical class of piperidinyl-benzisoxazole derivatives. Its chemical name is 4'-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)piperidino]propoxy]-3'-methoxyacetophenone. Its molecular formula is C 24 H 27 FN 2 O 4 and its molecular weight is 426.48. The structural formula is: Iloperidone is a white to off-white finely crystalline powder. It is practically insoluble in water, very slightly soluble in 0.1 N HCl and freely soluble in chloroform, ethanol, methanol, and acetonitrile. Iloperidone tablets are intended for oral administration only. Each round, uncoated tablet contains 1 mg, 2 mg, 4 mg, 6 mg, 8 mg, 10 mg, or 12 mg of iloperidone. Inactive ingredients are: colloidal silicon dioxide, crospovidone, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, sodium bicarbonate and purified water (removed during processing). The tablets are white to off-white, round, flat with beveled edges uncoated tablet, debossed with "050","051","052","053","054","055",or "056" on one side and plain on other side. 9e1900e4-eae1-4295-826c-d598e3486e5a-01

Iloperidone tablets is indicated for: Treatment of schizophrenia in adults [see Clinical Studies ( 14.1 )]. Iloperidone tablets is an atypical antipsychotic indicated for: Treatment of schizophrenia in adults. ( 1 , 14.1 )

Administer Iloperidone orally twice daily without regard to meals. ( 2.1 ) Titrate the dosage of Iloperidone to avoid orthostatic hypotension. See Full Prescribing Information for titration schedule. ( 2.1 ) Recommended Dosage: Indication Starting Dosage Recommended Dosage Schizophrenia ( 2.1 ) 1 mg twice daily 6 mg to 12 mg twice daily CYP2D6 Poor Metabolizers: See Full Prescribing Information for titration schedule and recommended dosage. ( 2.2 ) 2.1 Recommended Dosage Titrate Iloperidone to avoid orthostatic hypotension [see Warnings and Precautions ( 5.7 )]. Administer Iloperidone orally with or without food. Table 1 includes dosage recommendations for Iloperidone for the treatment of schizophrenia in adults. Indication and Titration schedule Recommended Dosage Population Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Schizophrenia 1mg twice daily 2 mg twice daily 4 mg twice daily 6 mg twice daily 8 mg twice daily 10 mg twice daily 12 mg twice daily 6 mg to 12 mg twice daily 2.2 Dosage Recommendations for Use in Patients Who Are Known CYP2D6 Poor Metabolizers Reduce the dose of Iloperidone by one-half for CYP2D6 poor metabolizers [see Clinical Pharmacology ( 12.3 , 12.5 )]. Table 2 includes dosage recommendations for Iloperidone in adults who are CYP2D6 poor metabolizers. Table 2: Dosage Recommendations for Iloperidone in Adults with Schizophrenia Who are CYP2D6 Poor Metabolizers Indication and Titration schedule Recommended Dosage Population Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Schizophrenia 1mg twice daily 2 mg twice daily 4 mg twice daily 6 mg twice daily Titration complete 3 mg to 6 mg twice daily 2.3 Dosage Recommendations in Patients with Hepatic Impairment No dose adjustment for Iloperidone is needed in patients with mild hepatic impairment. Patients with moderate hepatic impairment may require dose reduction, if clinically indicated. Iloperidone is not recommended for patients with severe hepatic impairment [see Use in Specific Populations ( 8.6 )]. 2.4 Dosage Modifications for Concomitant Use with Strong CYP2D6 Inhibitors and Strong CYP3A4 Inhibitors Coadministration with Strong CYP2D6 Inhibitors Reduce the dose of Iloperidone one-half when administered concomitantly with strong CYP2D6 inhibitors such as fluoxetine or paroxetine. When the CYP2D6 inhibitor is withdrawn from the combination therapy, increase the dose of Iloperidone to where it was before [see Drug Interactions ( 7.1 )]. Coadministration with Strong CYP3A4 Inhibitors Reduce the dose of Iloperidone by one-half when administered concomitantly with strong CYP3A4 inhibitors such as ketoconazole or clarithromycin. When the CYP3A4 inhibitor is withdrawn from the combination therapy, increase the dose of Iloperidone to where it was before [see Drug Interactions ( 7.1 )]. Coadministration with Strong CYP2D6 and Strong CYP3A4 Inhibitors Reduce the dose of Iloperidone by about one-half if administered concomitantly with inhibitors of CYP2D6 and CYP3A4. When both CYP2D6 and CYP3A4 inhibitors are withdrawn from the combination therapy, increase the dose of Iloperidone to where it was before [see Drug Interactions ( 7.1 )]. 2.5 Reinitiation of Treatment in Patients Previously Discontinued Although there are no data to specifically address reinitiation 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.

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. ( 4 , 6.2 )

The following adverse reactions are discussed in more detail in other sections of the labeling: Increased Mortality in Elderly Patients with Dementia-Related Psychosis [see Warnings and Precautions ( 5.1 )] Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients with Dementia-Related Psychosis [see Warnings and Precautions ( 5.2 )] QT Prolongation [see Warnings and Precautions ( 5.3 )] Neuroleptic Malignant Syndrome (NMS) [see Warnings and Precautions ( 5.4 )] Tardive Dyskinesia [see Warnings and Precautions ( 5.5 )] Metabolic Changes [see Warnings and Precautions ( 5.6 )] Orthostatic Hypotension and Syncope [see Warnings and Precautions ( 5.7 )] Falls [see Warnings and Precautions ( 5.8 )] Seizures [see Warnings and Precautions ( 5.9 )] Leukopenia, Neutropenia and Agranulocytosis [see Warnings and Precautions ( 5.10 )] Hyperprolactinemia [see Warnings and Precautions ( 5.11 )] Body Temperature Regulation [see Warnings and Precautions ( 5.12 )] Dysphagia [see Warnings and Precautions ( 5.13 )] Priapism [see Warnings and Precautions ( 5.14 )] Potential for Cognitive and Motor Impairment [see Warnings and Precautions ( 5.15 )] Intraoperative Floppy Iris Syndrome [see Warnings and Precautions ( 5.16 )] Commonly observed adverse reactions (incidence ≥5% and 2-fold greater than placebo) were ( 6.1 ): Schizophrenia: dizziness, dry mouth, fatigue, nasal congestion, orthostatic hypotension, somnolence, tachycardia, and weight increased. 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.fda.gov/medwatch . 6.1 Clinical Studies Experience 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 3,229 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 for the treatment of schizophrenia. 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. Schizophrenia The information presented in this section 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 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 3 enumerates the pooled incidences of adverse reactions that were spontaneously reported in four placebo-controlled, 4- or 6-week, fixed- or flexible-dose studies, listing those reactions that occurred in 2% or more of patients treated with Iloperidone in any of the dose groups, and for which the incidence in Iloperidone- treated patients in any dose group was greater than the incidence in patients treated with placebo. Table 3: Percentage of Adverse Reactions in Short-Term, Fixed- or Flexible-Dose, Placebo- Controlled Schizophrenia 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 Body System or Organ Class Dictionary-derived Term (N=587) (N=483) (N=391) 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 in patients with schizophrenia that occurred with a greater than 2% incidence in the patients treated with Iloperidone, and for which the incidence in patients treated with Iloperidone 20-24 mg/day were twice than the incidence in patients treated with Iloperidone 10-16 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 of patients with schizophrenia, the following adverse reactions occurred in ≥5% incidence in the patients treated with Iloperidone and at least twice the placebo rate for at least 1 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 20-24 mg/day as on 10-16 mg/day. Extrapyramidal Symptoms (EPS) in Clinical Trials Pooled data from the 4 placebo-controlled, 4- or 6-week, fixed- or flexible-dose studies of patients with schizophrenia provided information regarding EPS. Adverse event data collected from those trials showed the following rates of EPS-related adverse events as shown in Table 5. Table 5: Percentage of EPS Compared to Placebo in 4- or 6-week Schizophrenia Trials Placebo (%) Iloperidone Tablets 10 to 16 mg/day (%) Iloperidone Tablets 20 to 24 mg/day (%) Preferred Term (N = 587) (N = 483) (N = 391) All EPS events 11.6 13.5 15.1 Tremor Akathisia 1.9 2.7 2.5 1.7 3.1 2.3 Bradykinesia 0 0.6 0.5 Dyskinesia 1.5 1.7 1.0 Dystonia 0.7 1.0 0.8 Parkinsonism 0 0.2 0.3 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 in patients with schizophrenia, there was no difference in the incidence of discontinuation due to adverse reactions between Iloperidone-treated (5%) and placebo-treated (5%) patients. The types of adverse reactions 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 of patients with schizophrenia did not reveal any evidence of differences in safety on the basis of age, sex 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, or urinalysis. Hematocrit In short-term placebo-controlled trials (4- to 6-weeks) in patients with schizophrenia, 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. Analysis of clinical laboratory data following administration of Iloperidone suggested the mechanism of hemodilution based on consistent decreases in hematocrit, hemoglobin, white blood cells, total protein, and albumin. Decreases in hematocrit and total protein have been observed with other alpha receptor antagonists and are attributed to hemodilution [see Clinical Pharmacology (12.2)]. Other Reactions During the Pre-marketing Evaluation of Iloperidone Patients with Schizophrenia 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 with schizophrenia. All reported reactions are included except those already listed in Table 3, or other parts of the Adverse Reactions (6), those considered in the Warnings and Precautions (5), those reaction terms which were so general as to be uninformative, reactions reported in fewer than 3 patients and which were neither serious nor life-threatening, reactions that are otherwise common as background reactions, and reactions considered unlikely to be drug related. 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 3 appear in this listing); infrequent adverse reactions are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients. Blood and Lymphatic Disorders: Infrequent – anemia, iron deficiency anemia; Rare – leukopenia Cardiac Disorders: Frequent – palpitations; Rare – arrhythmia, atrioventricular block first degree, cardiac failure (including congestive and acute) Ear and Labyrinth Disorders: Infrequent – vertigo, tinnitus Endocrine Disorders: Infrequent – hypothyroidism Eye Disorders: Frequent – conjunctivitis (including allergic); Infrequent – dry eye, blepharitis, eyelid edema, eye swelling, lenticular opacities, cataract, hyperemia (including conjunctival) Gastrointestinal Disorders: Infrequent – gastritis, salivary hypersecretion, fecal incontinence, mouth ulceration; Rare – aphthous stomatitis, duodenal ulcer, hiatus hernia, hyperchlorhydria, lip ulceration, reflux esophagitis, stomatitis General Disorders and Administrative Site Conditions: Infrequent – edema (general, pitting, due to cardiac disease), difficulty in walking, thirst; Rare – hyperthermia Hepatobiliary Disorders: Infrequent – cholelithiasis Investigations: Frequent: weight decreased; Infrequent – hemoglobin decreased, neutrophil count increased, hematocrit decreased Metabolism and Nutrition Disorders: Infrequent – increased appetite, dehydration, hypokalemia, fluid retention Musculoskeletal and Connective Tissue Disorders: Frequent – myalgia, muscle spasms; Rare – torticollis Nervous System Disorders: Infrequent – paresthesia, psychomotor hyperactivity, restlessness, amnesia, nystagmus; Rare – restless legs syndrome Psychiatric Disorders: Frequent – restlessness, aggression, delusion; Infrequent – hostility, libido decreased, paranoia, anorgasmia, confusional state, mania, catatonia, mood swings, panic attack, obsessive-compulsive disorder, bulimia nervosa, delirium, polydipsia psychogenic, impulse-control disorder, major depression Renal and Urinary Disorders: Frequent – urinary incontinence; Infrequent – dysuria, pollakiuria, enuresis, nephrolithiasis; Rare – urinary retention, renal failure acute Reproductive System and Breast Disorders: Frequent – erectile dysfunction; Infrequent – testicular pain, amenorrhea, breast pain; Rare – menstruation irregular, gynecomastia, menorrhagia, metrorrhagia, postmenopausal hemorrhage, prostatitis Respiratory, Thoracic and Mediastinal Disorders: Infrequent – epistaxis, asthma, rhinorrhea, sinus congestion, nasal dryness; Rare – dry throat, sleep apnea syndrome, dyspnea exertional 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of Iloperidone. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency or establish a causal relationship to drug exposure: retrograde ejaculation and hypersensitivity reactions (including anaphylaxis; angioedema; throat tightness; oropharyngeal swelling; swelling of the face, lips, mouth, and tongue; urticaria; rash; and pruritus).

The dose of Iloperidone Tablets should be reduced in patients co-administered a strong CYP2D6 or CYP3A4 inhibitor. ( 2.2 , 7.1 ) 7.1 Clinically Important Drug Interactions with Iloperidone Table 7 presents clinically important drug interactions with Iloperidone. Table 7: Clinically Important Drug Interactions with Iloperidone Strong CYP2D6 Inhibitors Clinical Impact Coadministration of fluoxetine with iloperidone increased exposure (area under curve, [AUC]) of iloperidone and its metabolite P88, by about 2- to 3- fold, and decreased the AUC of its metabolite P95 by one-half [see Clinical Pharmacology ( 12.3 , 12.5 )]. Coadministration of paroxetine with iloperidone resulted in increased mean steady- state peak concentrations of iloperidone and its metabolite P88, by about 1.6- fold, and decreased mean steady-state peak concentrations of its metabolite P95 by one-half [see Clinical Pharmacology ( 12.3 , 12.5 )]. Intervention Reduce the dose of iloperidone by one-half when administered with strong CYP2D6 inhibitors. When a strong CYP2D6 inhibitor is withdrawn from the combination therapy, the iloperidone dose should be returned to the previous level [see Dosage and Administration ( 2.4 )]. Strong CYP3A4 Inhibitors Clinical Impact Co-administration of ketoconazole with iloperidone, increased the AUC of iloperidone and its metabolites P88 and P95 by 57%, 55%, and 35%, respectively [see Clinical Pharmacology ( 12.3 )]. Intervention Reduce the dose of iloperidone by one-half when administered with strong CYP3A4 inhibitors. When the CYP3A4 inhibitor is withdrawn from the combination therapy, the iloperidone dose should be returned to the previous level [see Dosage and Administration ( 2.4 )]. Concomitant use of Strong CYP2D6 and Strong CYP3A4 Inhibitors Clinical Impact Coadministration of iloperidone with paroxetine and ketoconazole resulted in a 1.4- fold increase in steady-state concentrations of iloperidone and its metabolite P88 and a 1.4- fold decrease in the P95 in the presence of paroxetine [see Clinical Pharmacology ( 12.3 )]. Intervention Coadministration of iloperidone with inhibitors of both CYP2D6 and CYP3A4 did not add to the effect of either inhibitor given alone. Reduce the dose of iloperidone by about one-half if administered concomitantly with both a CYP2D6 and CYP3A4 inhibitor same as if it is coadministered with only one inhibitor. When the inhibitors of CYP2D6 and CYP3A4 are withdrawn from the combination therapy, the iloperidone dose should be returned to the previous level [see Dosage and Administration ( 2.4 )]. 7.2 Drugs that Prolong the QT Interval Concomitant use of drugs that prolong the QT interval may add to the QT effects of Iloperidone and increase the risk of cardiac arrhythmia. Avoid the use of Iloperidone in combination with any other drugs that prolong the QT interval [see Warnings and Precautions ( 5.3 )]. 7.3 Drugs that Lower Blood Pressure Concomitant use of Iloperidone with medications that lower blood pressure could potentially cause symptomatic hypotension. Avoid coadministration of Iloperidone with alpha-adrenergic blocking agents and adjust medications that affect blood pressure as needed [see Warnings and Precautions ( 5.7 )].