FANAPT

1 INDICATIONS AND USAGE FANAPT ® is indicated for: 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 , 14.1 ) Acute treatment of manic or mixed episodes associated with bipolar I disorder in adults. ( 1 , 14.2 )

2 DOSAGE AND ADMINISTRATION Administer FANAPT orally twice daily without regard to meals. ( 2.1 ) Titrate the dosage of FANAPT 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 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. ( 2.2 ) 2.1 Recommended Dosage Titrate FANAPT to avoid orthostatic hypotension [see Warnings and Precautions (5.7) ] . Administer FANAPT orally with or without food. Table 1 includes dosage recommendations for FANAPT for the treatment of schizophrenia and the acute treatment of manic or mixed episodes associated with bipolar I disorder in adults. Table 1: Dosage Recommendations for FANAPT in Adults for the Treatment of Schizophrenia or Acute Treatment of Manic or Mixed Episodes Associated with 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 Titration Pack A 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 Bipolar I Disorder Manic or Mixed Episodes Titration Pack B 1 mg twice daily 3 mg twice daily 6 mg twice daily 9 mg twice daily 12 mg twice daily Titration complete 12 mg twice daily 2.2 Dosage Recommendations for Use in Patients Who Are Known CYP2D6 Poor Metabolizers Reduce the dose of FANAPT by one-half for CYP2D6 poor metabolizers [see Clinical Pharmacology (12.3 , 12.5 )] . Table 2 includes dosage recommendations for FANAPT in adults who are CYP2D6 poor metabolizers. Table 2: Dosage Recommendations for FANAPT in Adults with Schizophrenia or Bipolar I Disorder Who are CYP2D6 Poor Metabolizers Indication and Population Titration schedule Recommended Dosage Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Schizophrenia Titration Pack A 1mg twice daily 2 mg twice daily 4 mg twice daily 6 mg twice daily Titration complete 3 mg to 6 mg twice daily Bipolar I Disorder Manic or Mixed Episodes Titration Pack C 1 mg twice daily 3 mg twice daily 6 mg twice daily Titration complete 6 mg twice daily 2.3 Dosage Recommendations in Patients with Hepatic Impairment 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) ] . 2.4 Dosage Modifications for Concomitant Use with Strong CYP2D6 Inhibitors and Strong CYP3A4 Inhibitors 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) ] . 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 follo…

5 WARNINGS AND PRECAUTIONS Cerebrovascular Adverse Reactions in Elderly Patients with Dementia- Related Psychosis: Increased incidence of cerebrovascular adverse reactions (e.g., stroke, transient ischemic attack). ( 5.2 ) QT prolongation: Prolongs QT interval and may be associated with arrhythmia and sudden death. Avoid use of FANAPT in combination with other drugs that are known to prolong QTc; use caution and consider dose modification when prescribing FANAPT with other drugs that inhibit FANAPT metabolism. Monitor serum potassium and magnesium in patients at risk for electrolyte disturbances. ( 1 , 5.3 , 7.1 , 7.2 , 12.3 ) Neuroleptic Malignant Syndrome (NMS): Manage with immediate discontinuation of drug and close monitoring. ( 5.4 ) Tardive dyskinesia: Discontinue if clinically appropriate. ( 5.5 ) Metabolic Changes: Monitor for hyperglycemia/diabetes mellitus, dyslipidemia and weight gain. ( 5.6 ) Orthostatic hypotension and Syncope: Monitor heart rate and blood pressure and warn patients with known cardiovascular or cerebrovascular disease, and risk of dehydration or syncope. ( 5.7 ) Seizures: Use cautiously in patients with a history of seizures or with conditions that lower seizure threshold. ( 5.9 ) Leukopenia, Neutropenia, and Agranulocytosis have been reported with antipsychotics. Perform complete blood counts (CBC) in patients with pre-existing low white blood cell count (WBC) or a history of leukopenia/neutropenia. Consider discontinuing FANAPT if clinically significant decline in WBC occurs in the absence of other causative factors. ( 5.10 ) Priapism: Cases have been reported in association with FANAPT treatment. Severe priapism may require surgical intervention. ( 5.14 ) Potential for cognitive and motor impairment: Use caution when operating machinery. ( 5.15 ) Intraoperative Floppy Iris Syndrome (IFIS): IFIS during cataract surgery may require modifications to the surgical technique. ( 5.16 ) 5.1 Increased Mortality in Elderly Patients with Dementia-Related Psychosis Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of 17 dementia-related psychosis placebo-controlled trials (modal duration of 10 weeks) largely in patients taking atypical antipsychotic drugs, revealed a risk of death in the drug-treated patients of between 1.6 to 1.7 times that in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in placebo-treated patients. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. FANAPT is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning , Warnings and Precautions (5.2) ] . 5.2 Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients with Dementia-Related Psychosis In placebo-controlled trials in elderly subjects with dementia, patients randomized to risperidone, aripiprazole, and olanzapine had a higher incidence of stroke and transient ischemic attack, including fatal stroke. FANAPT is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning , Warnings and Precautions (5.1) ] . 5.3 QT Prolongation In an open-label QTc study in patients with schizophrenia or schizoaffective disorder (n=160), FANAPT was associated with QTc prolongation of 9 msec at an iloperidone dose of 12 mg twice daily. The effect of FANAPT on the QT interval was augmented by the presence of CYP450 2D6 or 3A4 metabolic inhibition (paroxetine 20 mg once daily and ketoconazole 200 mg twice daily, respectively). Under conditions of metabolic inhibition for both 2D6 and 3A4, FANAPT 12 mg twice daily was associated with a mean QTcF increase from baseline of about 19 msec. No cases of torsade de pointes or other severe cardiac arrhythm…

4 CONTRAINDICATIONS 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. ( 4 , 6.2 )

7 DRUG INTERACTIONS The dose of FANAPT should be reduced in patients co-administered a strong CYP2D6 or CYP3A4 inhibitor. ( 2.2 , 7.1 ) 7.1 Clinically Important Drug Interactions with FANAPT Table 7 presents clinically important drug interactions with FANAPT. 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 (12.3 , 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 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) ] . 7.2 Drugs that Prolong the QT Interval 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) ] . 7.3 Drugs that Lower Blood Pressure 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 (5.7) ] .

8.1 Pregnancy 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 ] . The limited available data with FANAPT 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 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 basis. Maternal toxicity was seen at the higher doses in these studies. The iloperidone metabolite P95, which is a major circulating met…

12.5 Pharmacogenomics CYP2D6 Poor Metabolizer (PM): The gene encoding CYP2D6 has polymorphisms that impact protein function. CYP2D6 poor metabolizers are individuals with two non-functioning alleles, resulting in no enzyme activity. 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.

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. 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.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 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) ] . Of these, 999 received FANAPT for at least 6 months, with 657 exposed to FANAPT for at least 12 months for the treatment of schizophrenia and 69 received FANAPT for at least 6 months, with 28 exposed to FANAPT for at least 12 months for the treatment of bipolar mania. All of these patients who received FANAPT were participating in multiple-dose clinical trials. The conditions and duration of treatment with FANAPT 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 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 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 FANAPT in any of the dose groups, and for which the incidence in FANAPT- 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 Patie…