iloperidone

RECENT MAJOR CHANGES Indications and Usage ( 1 ) 4/2024 Dose and Administration ( 2.1 , 2.2 , 2.3 , 2.4 ) 4/2024 Warnings and Precautions ( 5.6 , 5.7 , 5.11 , 5.15 , 5.16 ) 4/2024 Warnings and Precautions, ( 5.11 ) 1/2025 Warnings and Precautions, Suicide ( 5.14 ) Removed 4/2024

1 INDICATIONS AND USAGE 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 )

2 DOSAGE AND ADMINISTRATION 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.

3 DOSAGE FORMS AND STRENGTHS Iloperidone tablets are available in the following strengths: 1 mg, 2 mg, 4 mg, 6 mg, 8 mg, 10 mg and 12 mg. 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. 1 mg, 2 mg, 4 mg, 6 mg, 8 mg, 10 mg and 12 mg tablets. ( 3 )

4 CONTRAINDICATIONS 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 )

6 ADVERSE REACTIONS 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 a …

7 DRUG INTERACTIONS 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 )].

8 USE IN SPECIFIC POPULATIONS Pregnancy: May cause extrapyramidal and/or withdrawal symptoms in neonates with third trimester exposure. ( 8.1 ) Lactation: Advise not to breast feed ( 8.2 ) Pediatric Use: Safety and effectiveness not established in children and adolescents.( 8.4 ) Hepatic Impairment: Iloperidone is not recommended for patients with severe hepatic impairment. ( 2.3 , 8.6 ) 8.1 Pregnancy 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 basis. However, it prolonged the duration of pregnancy and parturition, increased still births, early intrauterine deaths, increased incidence of developmental delays, and decreased post-partum pup survival. Iloperidone was not teratogenic when administered orally to pregnant rabbits during organogenesis at doses up to 20-times the MRHD on mg/ m 2 basis. However, it increased early intrauterine deaths and decreased fetal viability at term at the highest dose which was also a maternally toxic dose [see Data]. The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. 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 (1.6, 6.5, and 26 times the maximum recommended human dose (MRHD) of 24 mg/day on a mg/m 2 basis) of iloperidone orally during the period of organogenesis. The highest dose caused increased early intrauterine deaths, decreased fetal weight and length, decreased fetal skeletal ossification, and an increased incidence of minor fetal skeletal anomalies and variations; this dose also caused decreased maternal food consumption and weight gain. 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 basis) of iloperidone during the period of organogenesis. The highest dose caused increased early intrauterine deaths and decreased fetal viability at term; this dose also caused maternal toxicity. 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 …

12.1 Mechanism of Action 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 (D2) and serotonin type 2 (5-HT2) antagonism. Iloperidone forms an active metabolite, P88, that has an in vitro receptor binding profile similar to the parent drug.

11 DESCRIPTION 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

10 OVERDOSAGE 10.1 Human Experience In pre-marketing trials involving over 3,522 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.g., drowsiness and sedation, tachycardia and hypotension) of Iloperidone. 10.2 Management of Overdose There is no specific antidote for Iloperidone. Therefore, appropriate supportive measures should be instituted. In case of acute overdose, the healthcare provider 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. Consider contacting the Poison Help Line (1-800-222-1222) or a medical toxicologist for additional overdose management recommendations.

16 HOW SUPPLIED/STORAGE AND HANDLING Iloperidone 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. Tablets are supplied in the following strengths and package configurations: Package Configuration Tablet Strength (mg) NDC Code Bottles of 60 1 mg 0378-0630-91 Bottles of 100 0378-0630-01 Cartons of 100 (10 x 10's) Unit dose blister 0378-0630-88 Bottles of 60 2 mg 0378-0631-91 Bottles of 100 0378-0631-01 Cartons of 100 (10 x 10's) Unit dose blister 0378-0631-88 Bottles of 60 4 mg 0378-0632-91 Bottles of 100 0378-0632-01 Cartons of 100 (10 x 10's) Unit dose blister 0378-0632-88 Bottles of 60 6 mg 0378-0633-91 Bottles of 100 0378-0633-01 Cartons of 100 (10 x 10's) Unit dose blister 0378-0633-88 Bottles of 60 8 mg 0378-0634-91 Bottles of 100 0378-0634-01 Cartons of 100 (10 x 10's) Unit dose blister 0378-0634-88 Bottles of 60 10 mg 0378-0635-91 Bottles of 100 0378-0635-01 Cartons of 100 (10 x 10's) Unit dose blister 0378-0635-88 Bottles of 60 12 mg 0378-0636-91 Bottles of 100 0378-0636-01 Cartons of 100 (10 x 10's) Unit dose blister 0378-0636-88 Storage : Store Iloperidone tablets at controlled room temperature, 25°C (77°F); excursions permitted to 15° to 30 °C (59° to 86°F) [See USP Controlled Room Temperature]. Protect Iloperidone tablets from exposure to light and moisture.