FANAPT- iloperidone_tablet

The mechanism of action of iloperidone in schizophrenia and bipolar I disorder is unknown. However, the efficacy of iloperidone could be mediated through a combination of dopamine type 2 (D 2 2 Iloperidone acts as an antagonist with high (nM) affinity binding to serotonin 5-HT 2A, 2 3 i 4 6 7 i 1A 1 1 i i 2A i alpha1A alpha1B alpha1D alpha2 C i The pharmacokinetics of iloperidone is more than dose proportional. Steady-state concentrations are attained within 3 to 4 days of dosing. Iloperidone accumulation is predictable from single-dose pharmacokinetics. Absorption Iloperidone is well absorbed after administration of the tablet with time to peak plasma concentrations (T max Effect of Food Administration of iloperidone with a standard high-fat meal did not significantly affect the C max max Distribution Iloperidone has an apparent volume of distribution of 1340-2800 L. At therapeutic concentrations, the unbound fraction of iloperidone in plasma is ~3% and of each metabolite (P88 and P95) it is ~8%. Elimination 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. Iloperidone has an apparent clearance (clearance / bioavailability) of 47 to 102 L/h. Metabolism Elimination of iloperidone is mainly through hepatic metabolism. Iloperidone is metabolized primarily by 3 biotransformation pathways: carbonyl reduction, hydroxylation (mediated by CYP2D6) and O-demethylation (mediated by CYP3A4). There are 2 predominant iloperidone metabolites, P95 and P88. The iloperidone metabolite P95 represents 47. 9% of the AUC of iloperidone and its metabolites in plasma at steady-state for extensive metabolizers (EM) and 25% for poor metabolizers (PM). The active metabolite P88 accounts for 19. 0% of total plasma exposure in EM and PM, respectively. 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. Excretion 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. Specific Populations Patients with Renal Impairment Renal impairment (creatinine clearance <30 mL/min) had minimal effect on C max 0en dashinfinity Patients with Hepatic Impairment 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). Studies with severe liver impaired subjects have not been conducted [see Dosage and Administration (2. 3), Use in Specific Populations (8. 6) Effect of Smoking Based on in vitro Drug Interactions Studies CYP2D6 and CYP3A4 Inhibitors The effects of fluoxetine and ketoconazole on the exposures of FANAPT, P88, and P95 are summarized in Figure 1 Figure 1: Effect of CYP3A4 and CYP2D6 Inhibitors on the Pharmacokinetics of FANAPT and its Metabolites Ketoconazole: Fluoxetine: Paroxetine: Paroxetine and Ketoconazole: Dextromethorphan: max Fluoxetine: Midazolam (a sensitive CYP 3A4 substrate): max In Vitro Studies Based on the in vitro data, 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. In vitro in vitro Transporter Interaction: Figure 1 CYP2D6 Poor Metabolizer (PM): Pharmacokinetic data from CYP2D6 poor metabolizers (n=8) treated with iloperidone demonstrated an increase in the AUC of iloperidone and its metabolite P88 by 47% and 85%, respectively and decrease the AUC of metabolite P95 by 85% compared to normal metabolizers (n=18) [see Dosage and Administration (2. 2) Approximately 7% of White populations, 2% of Asian populations, and 2% of African-American populations are poor metabolizers.

FANAPT registered Treatment of schizophrenia in adults [see Clinical Studies (14. 1) Acute treatment of manic or mixed episodes associated with bipolar I disorder in adults [see Clinical Studies (14. 2) FANAPT is an atypical antipsychotic indicated for: Treatment of schizophrenia in adults. 1 Acute treatment of manic or mixed episodes associated with bipolar I disorder in adults.

Administer FANAPT orally twice daily without regard to meals. 1 Titrate the dosage of FANAPT to avoid orthostatic hypotension. See Full Prescribing Information for titration schedule. 1 Recommended Dosage: Indication Starting Dosage Recommended Dosage Schizophrenia 2. 1 1 mg twice daily 6 mg to 12 mg twice daily Bipolar Mania 2. 1 1 mg twice daily 12 mg twice daily CYP2D6 Poor Metabolizers: See Full Prescribing Information for titration schedule and recommended dosage. 2 Titrate FANAPT to avoid orthostatic hypotension [see Warnings and Precautions (5. 7) Administer FANAPT orally with or without food. Table 1 Table 1: Dosage Recommendations for FANAPT in Adults for the Treatment of Schizophrenia or Indication and Population Titration schedule Recommended Dosage Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Schizophrenia 1mg 2 mg 4 mg 6 mg 8 mg 10 mg 12 mg 6 mg to 12 mg Bipolar I Disorder 1 mg 3 mg 6 mg 9 mg 12 mg Titration complete 12 mg Reduce the dose of FANAPT by one-half for CYP2D6 poor metabolizers [see Clinical Pharmacology (12. 5 Table 2 Table 2: Dosage Recommendations for FANAPT in Adults with Schizophrenia or Bipolar I Disorder Indication and Population Titration schedule Recommended Dosage Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Schizophrenia 1mg 2 mg 4 mg 6 mg Titration complete 3 mg to 6 mg Bipolar I Disorder 1 mg 3 mg 6 mg Titration complete 6 mg No dose adjustment for FANAPT is needed in patients with mild hepatic impairment. Patients with moderate hepatic impairment may require dose reduction, if clinically indicated. FANAPT is not recommended for patients with severe hepatic impairment [see Use in Specific Populations (8. 6) Coadministration with Strong CYP2D6 Inhibitors Reduce the dose of FANAPT 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 FANAPT to where it was before [see Drug Interactions (7. 1) Coadministration with Strong CYP3A4 Inhibitors Reduce the dose of FANAPT 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 FANAPT to where it was before [see Drug Interactions (7. 1) Coadministration with Strong CYP2D6 and Strong CYP3A4 Inhibitors Reduce the dose of FANAPT 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 FANAPT to where it was before [see Drug Interactions (7. 1) 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 FANAPT of more than 3 days.

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. Bipolar mania: tachycardia, dizziness, dry mouth, hepatic enzymes increased, nasal congestion, weight increased, hypotension, and somnolence. To report SUSPECTED ADVERSE REACTIONS, contact Vanda Pharmaceuticals Inc. at 1-844-GO-VANDA (1-844-468-2632) 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 FANAPT consisting of 3,229 patients exposed to FANAPT at doses of 10 mg/day or greater, for the treatment of schizophrenia and from a clinical trial database for FANAPT consisting of 312 patients exposed to FANAPT at doses of 24 mg/day, for the treatment of bipolar mania [see Clinical Studies (14. 2) 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 FANAPT at daily doses within a range of 10 to 24 mg (n=874). Adverse Reactions Occurring at an Incidence of 2% or More among FANAPT-Treated Patients and More Frequent than Placebo Table 3 Table 3: Percentage of Adverse Reactions in Short-Term, Fixed- or Flexible-Dose, Placebo- Controlled Schizophrenia Trials in Adult Patients* * Body System or Organ Class Placebo FANAPT 10-16 mg/day FANAPT 20-24 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 Bipolar Mania Table 4 Table 4: Adverse Reactions Occurring in >=2% of Adult Patients Treated with FANAPT and > Placebo in a Short-Term, Fixed-Dose, Placebo-Controlled Bipolar Mania Trial * Tachycardia includes: Nausea includes: Hepatic enzyme increased includes: Weight increased includes: Dizziness includes: Headache includes: Somnolence includes: Urinary urgency and Polyuria includes: Sexual Dysfunction includes: Hypotension includes: Fatigue includes: ** System Organ Class Placebo FANAPT 24 mg/day ** Cardiac disorders Tachycardia * 5 23 Gastrointestinal disorders Dry mouth 2 9 Nausea * 3 4 Investigations Hepatic enzyme increased * 1 8 Weight increased * 1 6 Nervous system disorders Dizziness * 1 12 Headache * 4 5 Somnolence * 3 8 Akathisia 0 4 Renal and urinary disorders Urinary urgency and Polyuria * 0 3 Reproductive system and breast disorders Sexual Dysfunction * 0. 5 4 Respiratory, thoracic, and mediastinal disorders Nasal congestion 1 6 Vascular disorders Hypotension * 3 6 General disorders and administration site conditions Fatigue * 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 FANAPT, and for which the incidence in patients treated with FANAPT 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 FANAPT 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. In a short-term, placebo-controlled trial in patients with bipolar mania the following adverse reactions occurred in >=5% incidence in the patients treated with FANAPT and at least twice the placebo rate: tachycardia, dizziness, dry mouth, hepatic enzymes increased, nasal congestion, weight increased, hypotension, and somnolence. 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 (%) FANAPT 10-16 mg/day (%) FANAPT 20-24 mg/day (%) Preferred Term (N=587) (N=483) (N=391) All EPS events 11. 1 Akathisia 2. 3 Dyskinesia 1. 7 1 Dystonia 0. 8 Bradykinesia 0 0. 5 Parkinsonism 0 0. 3 Table 6 Table 6: Percentage of EPS Compared to Placebo in a 4-week Bipolar Mania Trial * Preferred Term Placebo (%) FANAPT 24 mg/day * N=208 N=206 All EPS events 0 8. 3 Akathisia 0 4. 4 Extrapyramidal Disorder 0 1 Blepharospasm 0 0. 5 Dystonia 0 0. 5 Muscle Spasm 0 0. 5 Restlessness 0 0. 5 Torticollis 0 0. 5 Tremor 0 0. 5 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 FANAPT-treated (5%) and placebo-treated (5%) patients. The types of adverse reactions that led to discontinuation were similar for the FANAPT- and placebo-treated patients. In a 4-week, placebo-controlled study in patients with bipolar mania, the incidence of discontinuation due to adverse reactions was higher in FANAPT-treated (8. 7%) patients than placebo-treated (5. 3%) patients. Adverse reactions that led to discontinuation in more than one FANAPT-treated subject were liver enzyme elevations, nausea and vomiting, dizziness and hypotension. 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 FANAPT and placebo in the incidence of discontinuation due to changes in hematology, or urinalysis. Serum Transaminases In a short-term placebo-controlled trial, asymptomatic alanine aminotransferase (ALT) elevations >=3x ULN occurred in 9. 2% of FANAPT-treated patients with acute mania compared to 1. 5% of placebo treated subjects. AST elevations were less common. Hematocrit In short-term placebo-controlled trials (4- to 6-weeks) in patients with schizophrenia, there were 1. 0% (13/1342) FANAPT-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. In a short-term placebo-controlled trial (4 weeks) in patients with bipolar mania, there were 3. 5% (7/200) FANAPT-treated patients with hematocrit at least one time below the extended normal range (<0. 85xLLN) during post-randomization treatment, compared to 0. 5% (1/196) on placebo. Analysis of clinical laboratory data following administration of FANAPT 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) Serum Urate Levels In a 4-week placebo-controlled trial in patients with bipolar mania, treatment with FANAPT 12 mg twice a day resulted in an increase of serum urate levels of approximately 27. 2 umol/L (0. 457 mg/dL) compared to 0. 1 umol/L (0. 002 mg/dL) in placebo group. Other Reactions During the Pre-marketing Evaluation of FANAPT Patients with Schizophrenia The following is a list of MedDRA terms that reflect adverse reactions in patients treated with FANAPT at multiple doses >= 4 mg/day during any phase of a trial with the database of 3,210 FANAPT-treated patients with schizophrenia. All reported reactions are included except those already listed in Table 3 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 3 Blood and Lymphatic Disorders: Infrequent Rare Cardiac Disorders: Frequent en dash Rare Ear and Labyrinth Disorders: Infrequent en dash Endocrine Disorders: Infrequent Eye Disorders: Frequent en dash Infrequent Gastrointestinal Disorders: Infrequent Rare General Disorders and Administrative Site Conditions: Infrequent Rare Hepatobiliary Disorders: Infrequent en dash Investigations: Frequent: Infrequent Metabolism and Nutrition Disorders: Infrequent Musculoskeletal and Connective Tissue Disorders: Frequent Rare Nervous System Disorders: Infrequent en dash 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 post-approval use of FANAPT. 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).

FANAPT 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 FANAPT or to any components in the formulation.

Pregnancy: May cause extrapyramidal and/or withdrawal symptoms in neonates with third trimester exposure. 1 Lactation: Advise not to breast feed. 2 Pediatric Use: Safety and effectiveness not established in children and adolescents. 4 Hepatic Impairment: FANAPT is not recommended for patients with severe hepatic impairment. 6 Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to FANAPT 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 FANAPT, during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery [see Clinical Considerations 2 2 [see Data] 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/m 2 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 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 of FANAPT have not been established in pediatric patients. Clinical Studies of FANAPT 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 with schizophrenia treated with FANAPT in clinical trials, 25 (0. 5%) were >=65 years old and there were no patients >=75 years old. Of the 206 patients with bipolar mania treated with FANAPT in a clinical trial, 2 (0. 1%) were 65 years old and there were no patients were >65 years old. Elderly patients with dementia-related psychosis treated with FANAPT are at an increased risk of death compared to placebo. FANAPT is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning and Warnings and Precautions (5. 2) No dose adjustment to FANAPT is needed in patients with mild hepatic impairment (Child-Pugh class A). Patients with moderate hepatic impairment (Child-Pugh class B) may require dose reduction. FANAPT is not recommended for patients with severe hepatic impairment (Child-Pugh class C) [see Dosage and Administration (2. 3), Clinical Pharmacology (12.

The dose of FANAPT should be reduced in patients co-administered a strong CYP2D6 or CYP3A4 inhibitor. 1 Table 7 Table 7: Clinically Important Drug Interactions with FANAPT 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. 5) [see Clinical Pharmacology (12. 5) Intervention Reduce the dose of FANAPT 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 FANAPT by one-half when administered with strong CYP3A4 inhibitors. When the CYP3A4 inhibitor is withdrawn from the combination therapy, the FANAPT 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 FANAPT with inhibitors of both CYP2D6 and CYP3A4 did not add to the effect of either inhibitor given alone. Reduce the dose of FANAPT 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 FANAPT dose should be returned to the previous level [see Dosage and Administration (2. 4) Concomitant use of drugs that prolong the QT interval may add to the QT effects of FANAPT and increase the risk of cardiac arrhythmia. Avoid the use of FANAPT in combination with any other drugs that prolong the QT interval [see Warnings and Precautions (5. 3) Concomitant use of FANAPT with medications that lower blood pressure could potentially cause symptomatic hypotension. Avoid coadministration of FANAPT with alpha-adrenergic blocking agents and adjust medications that affect blood pressure as needed [see Warnings and Precautions (5.

OVERDOSAGE
In pre-marketing trials involving over 3,522 patients, accidental or intentional overdose of FANAPT 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 FANAPT was 576 mg; no adverse physical effects were noted for this patient. The next largest confirmed ingestion of FANAPT 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 FANAPT 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 FANAPT. There is no specific antidote for FANAPT. 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 FANAPT. Similarly, it is reasonable to expect that the alpha-blocking properties of bretylium might be additive to those of FANAPT, 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 FANAPT-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.
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 FANAPT in the treatment of schizophrenia was supported by 2 placebo- and active-controlled short-term (4- and 6-week) trials and one long-term placebo-controlled randomized withdrawal trial. All 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 manifestations of schizophrenia, about the overall clinical state of the patient. Study 1, a 6-week, placebo-controlled trial (n=706), involved 2 flexible dose ranges of FANAPT (12 mg to 16 mg/day or 20 mg to 24 mg/day) compared to placebo and an active control (risperidone). For the 12 mg to 16 mg/day group, the titration schedule of FANAPT 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 mg to 24 mg/day group, the titration schedule of FANAPT 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 mg to 16 mg/day and the 20 mg to 24 mg/day dose ranges of FANAPT were superior to placebo on the BPRS total score. The active control antipsychotic drug appeared to be superior to FANAPT 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. Study 2 (NCT00254202), a 4-week, placebo-controlled trial (n=604), involved one fixed-dose of FANAPT (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 FANAPT 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 FANAPT dose was superior to placebo in the PANSS total score. FANAPT 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 (Study 3; NCT01291511), 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 FANAPT (8 mg to 24 mg/day administered as twice daily doses) were randomized to placebo or to continue on their current FANAPT dose (8 mg to 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 FANAPT 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 2: Kaplan Meier Estimation of Percent Relapse/Impending Relapse (Study 3) 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 FANAPT experienced a statistically significant longer time to relapse or impending relapse than patients who received placebo. Figure 2 The efficacy of FANAPT in the acute treatment of manic or mixed episodes associated with bipolar I disorder in adults was supported by one multicenter, randomized, double-blind, placebo-controlled study that enrolled patients who met the DSM-5 criteria for bipolar I disorder, manic or mixed type (Study 1; NCT04819776). Demographic and baseline characteristics were similar for the FANAPT and placebo groups. Median age was 46 (range 18 to 65). 45% were female, 64% were White, and 28% were Black or African-American. Manic symptoms were assessed with the Young Mania Rating Scale (YMRS). The YMRS is an 11-item clinician rated scale traditionally used to assess the degree of manic symptomatology. YMRS total scores may range from 0 to 60 with a higher score reflecting greater severity. A 4-week, placebo-controlled trial (n=392) involved one fixed-dose of FANAPT (24 mg/day) compared to placebo. The primary endpoint was change in YMRS total score from baseline to Day 28. The 24 mg/day dose of FANAPT was superior to placebo on the primary endpoint. Examination of subgroups did not reveal clear evidence of differential responsiveness on the basis of age, sex, or race. The results of the study are shown in Table 8 Figure 3 Table 8: Primary Efficacy Results for Change from Baseline in YMRS Total Score in the Acute Treatment of Manic or Mixed Episodes Associated with Bipolar I Disorder in Adults (Study 1) ITT = intent-to-treat,YMRS = Young Mania Rating Scale, LS mean = Least Squares mean, SD = standard deviation, SE = standard error a * Study Treatment Group Primary Efficacy Endpoint: Change from Baseline to Day 28 in Mean LS Mean Placebo-substracted a 1 FANAPT (24 mg/day) * 29. 25) Placebo 28. 63) Figure 3: Change from Baseline in YMRS Total Score by Study Visit (Study 1) Figure 2 Figure 3.

FANAPT- iloperidone

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