BYSANTI

1 INDICATIONS AND USAGE BYSANTI TM is indicated for the: 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) ] . BYSANTI 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 BYSANTI orally twice daily with or without food. ( 2.1 ) Titrate BYSANTI to reduce the risk of orthostatic hypotension. See Full Prescribing Information for titration schedule. ( 2.1 ) After the titration, recommended maintenance dosage for: Schizophrenia is 6 to 12 mg twice daily. ( 2.2 ) Bipolar mania is 12 mg twice daily, ( 2.2 ) CYP2D6 Poor Metabolizers: See Full Prescribing Information for titration schedule and recommended dosage. ( 2.2 ) See Full Prescribing Information for the recommended dosage in patients with hepatic impairment ( 2.3 ) and dosage modifications for drug interactions ( 2.4 ) 2.1 Recommended Dosage Table 1 includes the recommended BYSANTI dosage for the treatment of schizophrenia and the acute treatment of manic or mixed episodes associated with bipolar I disorder in adults. Titrate BYSANTI to reduce the risk of orthostatic hypotension [see Warnings and Precautions (5.7) ] . Administer BYSANTI orally with or without food [see Clinical Pharmacology (12.3) ] . Table 1: BYSANTI Recommended Dosage in Adults with Schizophrenia or Manic or Mixed Episodes Associated with Bipolar I Disorder * Patients with schizophrenia may either (1) follow the recommended titration schedule, OR (2) starting on Day 5, continue 6 mg twice daily BYSANTI dosing. As needed, titrate subsequent doses based on tolerability and response within the recommended maintenance dosing range of 6 mg to 12 mg twice daily. Population Titration Schedule Recommended Maintenance Dosage 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 Manic or Mixed Episodes Associated with Bipolar I Disorder 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 CYP2D6 Poor Metabolizers Consider CYP2D6 genetic testing to determine the patient’s CYP2D6 metabolizer status prior to BYSANTI dosing. Follow the titration schedule outlined in Table 2 for dosage recommendations in CYP2D6 poor metabolizers for the treatment of schizophrenia and the acute treatment of manic or mixed episodes associated with bipolar I disorder in adults [see Clinical Pharmacology (12.3 , 12.5) ] . Table 2: BYSANTI Recommended Dosage in Adults, with Schizophrenia or Manic or Mixed Episodes Associated with Bipolar I Disorder, Who are CYP2D6 Poor Metabolizers * Patients with schizophrenia may either (1) follow the recommended titration schedule, OR (2) starting on Day 3, initiate and continue 3 mg twice daily BYSANTI dosing. As needed, titrate subsequent doses based on tolerability and response within the recommended maintenance dosing range of 3 mg to 6 mg twice daily. Population Titration Schedule Recommended Maintenance Dosage Day 1 Day 2 Day 3 Day 4 Schizophrenia 1mg twice daily 2 mg twice daily 4 mg twice daily* 6 mg twice daily* 3 mg to 6 mg twice daily Manic or Mixed Episodes Associated with Bipolar I Disorder 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 The recommended BYSANTI dosage in patients with mild hepatic impairment (HI) is the same as those with normal hepatic function. Consider a lower maintenance dosage in patients with moderate HI. BYSANTI is not recommended in patients with severe HI [see Use in Specific Populations (8.6) , Clinical Pharmacology (12.3) ] . 2.4 Dosage Modifications for Drug Interactions Concomitant Administration with a Strong CYP2D6 Inhibitor In patients receiving a: Stable dosage of a strong CYP2D6 inhibitor, when initiating BYSANTI, the recommended BYSANTI titration schedule is the same as that in Table 2 . Maintenance BYSANTI dosage, when initiating a strong CYP2D6 inhibitor, reduce the BYSANTI dosage by one-half. When the strong CYP2D6 i …

3 DOSAGE FORMS AND STRENGTHS Tablets: • 1 mg: yellow, oval shaped, debossed with "1" on one side and “ ” logo on other side • 2 mg: pink oblong oval shaped, debossed with "2" on one side and “ ” logo on other side • 4 mg: blue oval shaped, debossed with "4" on one side and “ ” logo on other side • 6 mg: orange oblong oval shaped, debossed with "6" on one side and “ ” logo on other side • 8 mg: white, oval shaped, debossed with "8" on one side and “ ” logo on other side • 10 mg: white, oblong oval shaped, debossed with "10" on one side and “ ” logo on other side • 12 mg: purple, octagon shaped, debossed with "12" on one side and “ ” logo on other side Tablets: 1 mg, 2 mg, 4 mg, 6 mg, 8 mg, 10 mg, and 12 mg. ( 3 ) logo

4 CONTRAINDICATIONS BYSANTI is contraindicated in individuals with a known hypersensitivity reaction to milsaperidone or the inactive ingredients in BYSANTI. Anaphylaxis, angioedema, and other hypersensitivity reactions have been reported [see Adverse Reactions (6.2) ] . Known hypersensitivity to milsaperidone or the inactive ingredients in BYSANTI. ( 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. 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 safety of BYSANTI has been established from adequate and well-controlled studies of iloperidone tablets (referred to hereafter as “iloperidone” (iloperidone and milsaperidone rapidly interconvert in vivo)) in adults with schizophrenia or with mixed or manic episodes associated with bipolar I disorder [see Clinical Studies (14.1 , 14.2) ] . Below is a display of the adverse reactions of iloperidone in these adequate and well-controlled studies. The information below is derived from a clinical trial database for iloperidone that consisted of: 3,229 adult patients exposed to iloperidone at a dosage of 10 mg/day or greater, for the treatment of schizophrenia which included 874 patients with schizophrenia in Studies 1, 2, and 3 [see Clinical Studies (14.1) ] and another schizophrenia study and 312 adult patients exposed to iloperidone at a dosages of 24 mg/day, for the acute treatment of manic or mixed episodes associated with bipolar I disorder (Study 4) [see Clinical Studies (14.2) ] . Of these, 999 patients received iloperidone for at least 6 months, with 657 patients exposed to iloperidone for at least 12 months for the treatment of schizophrenia; and 69 patients received iloperidone for at least 6 months (with 28 patients received iloperidone for at least 12 months) for the treatment of bipolar mania. The conditions and duration of treatment with iloperidone varied and included (in overlapping categories), open-label and double-blind phases of studies, inpatients and outpatients, fixed-dose and flexible-dose studies, and studies with short-term or longer-term exposure. Common Adverse Reactions in Adult Patients with Schizophrenia The information presented below was derived from pooled data from 4 placebo-controlled, 4- or 6-week, fixed- or flexible-dose studies in adult patients with schizophrenia who received iloperidone at daily dosages within a range of 10 to 24 mg (n=874) (Studie …

7 DRUG INTERACTIONS Strong CYP2D6 Inhibitors: Reduce the dosage of BYSANTI when administered with a strong CYP2D6 inhibitor ( 7.1 ) Strong CYP3A4 Inhibitors: Reduce the dosage of BYSANTI when administered with a strong CYP3A4 inhibitor ( 7.1 ) Strong CYP2D6 and Strong CYP3A4 Inhibitors: Reduce the dosage of BYSANTI if administered concomitantly with both a CYP2D6 and a CYP3A4 inhibitor ( 7.1 ). Drugs that Lower Blood Pressure: Avoid concomitant administration of BYSANTI with alpha-adrenergic blocking agents and consider lowering the dosage of other drugs that lower blood pressure ( 7.3 ) 7.1 Effects of Other Drugs on BYSANTI Table 7 presents clinically significant drug interactions where concomitant use of another drug affects BYSANTI. Table 7: Clinically Significant Drug Interactions: Concomitant Use of Other Drugs Affect the Use of BYSANTI Strong CYP2D6 Inhibitors Prevention or Management Reduce the dosage of BYSANTI when administered with a strong CYP2D6 inhibitor [see Dosage and Administration (2.4) ] . When the strong CYP2D6 inhibitor is stopped in BYSANTI-treated patients, gradually increase the BYSANTI dosage to the pre-inhibitor dosage. Mechanism and Clinical Effect(s) Milsaperidone and iloperidone are CYP2D6 substrates (iloperidone and milsaperidone rapidly interconvert in vivo). Strong CYP2D6 inhibitors increased exposure of milsaperidone and iloperidone [see Clinical Pharmacology (12.3, 12.5) ] , which may increase the risk of BYSANTI-associated adverse reactions. Strong CYP3A4 Inhibitors Prevention or Management Reduce the dosage of BYSANTI when administered with a strong CYP3A4 inhibitor [see Dosage and Administration (2.4) ] . When the strong CYP3A4 inhibitor is stopped in BYSANTI-treated patients, gradually increase the BYSANTI dosage to the pre-inhibitor dosage. Mechanism and Clinical Effect(s) Milsaperidone and iloperidone are CYP3A4 substrates. Strong CYP3A4 inhibitors increased the exposure of milsaperidone, iloperidone and P95 [see Clinical Pharmacology (12.3) ] , which may increase the risk of BYSANTI-associated adverse reactions. Strong CYP2D6 and Strong CYP3A4 Inhibitors Prevention or Management Reduce the dosage of BYSANTI if administered concomitantly with both a strong CYP2D6 inhibitor and a strong CYP3A4 inhibitor. Mechanism and Clinical Effect(s) Concomitant administration with a strong CYP2D6 inhibitor and a strong CYP3A4 inhibitor resulted in an increase in steady-state exposure of milsaperidone and iloperidone [see Clinical Pharmacology (12.3) ] , which may increase the risk of BYSANTI-associated adverse reactions. 7.2 Drugs that Prolong the QTc Interval Avoid concomitant use of BYSANTI with other drugs that prolong the QTc interval [see Warnings and Precautions (5.3) ] . Iloperidone causes QTc interval prolongation [see Clinical Pharmacology (12.2) ] . Concomitant use of BYSANTI with other drugs that prolong the QTc interval may result in a greater increase in the QTc interval and adverse reactions associated with QTc interval prolongation, including arrhythmias. 7.3 Drugs that Lower Blood Pressure Concomitant use of BYSANTI with drugs that lower blood pressure could potentially cause symptomatic hypotension. Avoid concomitant administration of BYSANTI with alpha-adrenergic blocking agents and consider lowering the dosage of other drugs that lower blood pressure [see Warnings and Precautions (5.7) ] .

8 USE IN SPECIFIC POPULATIONS Pregnancy: Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk of extrapyramidal and/or withdrawal symptoms following delivery. ( 8.1 ) Lactation: Advise not to breastfeed during BYSANTI treatment and for 6 days after the last dose in CYP2D6 normal metabolizers and 8 days after the last dose in CYP2D6 poor metabolizers. ( 8.2 ) Hepatic Impairment: BYSANTI 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 BYSANTI 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 exposed to antipsychotic drugs, including BYSANTI, during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery (see Clinical Considerations ) . There are no available data with BYSANTI use during pregnancy and available data from pharmacovigilance reports with iloperidone (iloperidone and milsaperidone rapidly interconvert in vivo) use during pregnancy are insufficient to inform a drug-associated risk for major birth defects and miscarriage. There are risks to the mother associated with untreated schizophrenia or bipolar I disorder (see Clinical Considerations ). When iloperidone) was administered orally to pregnant rats during organogenesis at doses up to 26 times the maximum recommended human dose (MRHD) of 24 mg/day on mg/m 2 basis 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. When iloperidone was administered orally to pregnant rabbits during organogenesis at doses up to 20-times the MRHD on mg/m 2 basis 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 safety margins for milsaperidone are expected to be the same as those seen with iloperidone because exposures to iloperidone, milsaperidone, and their major metabolites are similar when either iloperidone tablets or BYSANTI (milsaperidone) tablets are administered in humans. The background risk of major birth defects and miscarriage in patients with schizophrenia or bipolar disorder 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 Disease-Associated Maternal and/or Embryo/Fetal Risk: There is a risk to the mother from untreated schizophrenia or bipolar I disorder, including increased risk of relapse, hospitalization, and suicide. Schizophrenia and bipolar I disorder are associated with increased adverse perinatal outcomes, including preterm birth. It is not known if this is a direct result of the illness or other comorbid factors. 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 high …

12.1 Mechanism of Action The mechanism of action of milsaperidone in the treatment of schizophrenia in adults and the acute treatment of manic or mixed episodes associated with bipolar I disorder in adults is unknown. However, the efficacy of milsaperidone in these conditions could be mediated through a combination of dopamine type 2 (D 2 ) and serotonin type 2 (5-HT 2 ) antagonism. Milsaperidone and iloperidone rapidly interconvert in vivo. Milsaperidone has an in vitro receptor binding profile similar to iloperidone.

11 DESCRIPTION The active ingredient in BYSANTI is milsaperidone, an atypical antipsychotic that is in the piperidinyl-benzisoxazole derivative chemical class. Its chemical name is benzenemethanol, 4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-α- methyl-, (αS)-. Its molecular formula is C 24 H 29 FN 2 O 4 and its molecular weight is 428.50. Milsaperidone is a white to off-white finely crystalline powder. The structural formula of milsaperidone is: Milsaperidone is a white to off-white finely crystalline powder. BYSANTI (milsaperidone) tablets are for oral administration only. Coated tablets contain 1 mg, 2 mg, 4 mg, 6 mg, 8 mg, 10 mg, or 12 mg of milsaperidone. Inactive ingredients are the following: colloidal silicon dioxide, crospovidone, hydroxypropylmethylcellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and water (removed during processing). Chemical Structure

10 OVERDOSAGE 10.1 Human Overdose Experience In pre-marketing trials involving over 3,522 patients, accidental or intentional overdose of iloperidone (iloperidone and milsaperidone rapidly interconvert in vivo) 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. The possibility of obtundation, seizures or dystonic reaction of the head and neck following BYSANTI overdose may create a risk of aspiration with induced emesis. In general, reported signs and symptoms of overdose 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 BYSANTI. In case of acute overdose, the healthcare provider should establish and maintain an airway and ensure adequate oxygenation and ventilation. 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 QTc interval-prolonging effects that might be additive to those of BYSANTI. Alpha-blocking properties of bretylium might be additive to those of BYSANTI, 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 BYSANTI-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 BYSANTI (milsaperidone) tablets are supplied as follows: • 1 mg: yellow, oval shaped, debossed with "1" on one side and “ ” logo on other side • 2 mg: pink oblong oval shaped, debossed with "2" on one side and “ ” logo on other side • 4 mg: blue oval shaped, debossed with "4" on one side and “ ” logo on other side • 6 mg: orange oblong oval shaped, debossed with " 6 " on one side and “ ” logo on other side • 8 mg: white, oval shaped, debossed with "8" on one side and “ ” logo on other side • 10 mg: white, oblong oval shaped, debossed with "10" on one side and “ ” logo on other side • 12 mg: purple, octagon shaped, debossed with "12" on one side and “ ” logo on other side Table 9 displays the package configurations for the single strength packages of BYSANTI (milsaperidone) tablets and Table 10 displays the package configuration for the titration packs. Table 9: Package Configurations for the Single Strength Packages of BYSANTI (milsaperidone) Tablets Package configuration Tablet Strength (mg) NDC Code Bottles of 60 1 mg 43068-701-02 Bottles of 60 2 mg 43068-702-02 Bottles of 60 4 mg 43068-704-02 Bottles of 60 6 mg 43068-706-02 Bottles of 60 8 mg 43068-708-02 Bottles of 60 10 mg 43068-710-02 Bottles of 60 12 mg 43068-712-02 Table 10: Package Configurations for the Titration Packs Package Configuration Indication Tablet Quantity and Strength (mg) NDC Code Titration Pack A For the treatment of schizophrenia Two 1 mg tablets Two 2 mg tablets Two 4 mg tablets Two 6 mg tablets (Total of 8 tablets) 43068-713-04 Titration Pack B For the acute treatment of manic or mixed episodes associated with bipolar I disorder Six 1 mg tablets Two 2 mg tablets Two 6 mg tablets Two 8 mg tablets (Total of 12 tablets) 43068-714-04 Titration Pack C For the acute treatment of manic or mixed episodes associated with bipolar I disorder in: CYP2D6 poor metabolizers concomitant administration with strong CYP2D6 inhibitors and strong CYP3A4 inhibitors Four 1 mg tablets Two 2 mg tablets Two 6 mg tablets (Total of 8 tablets) 43068-715-03 Storage Store the tablets at controlled room temperature, 20°C to 25°C (68°F to 77°F), with excursions permitted between 15° to 30 °C (59°F to 86°F) [See USP Controlled Room Temperature] . Protect the tablets from exposure to light and moisture.