BYSANTI MILSAPERIDONE 8 mg Tablet, 60-count

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 ) QTc Interval Prolongation: may be associated with torsade de pointes and sudden death. Avoid concomitant use of BYSANTI with other drugs that prolong the QTc interval, and in patients with a significant risk of developing torsade de pointes; consider decreasing the BYSANTI dosage when prescribing BYSANTI with other drugs that inhibit milsaperidone metabolism or in CYP2D6 poor metabolizers.

Monitor serum potassium and magnesium at baseline and during treatment in patients at risk for significant electrolyte disturbances ( 5.3 , 7.1 , 7.2 ) Neuroleptic Malignant Syndrome (NMS): If NMS is suspected, immediately discontinue BYSANTI and provide intensive symptomatic treatment 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 in patients who are vulnerable to hypotension, and in those with known cardiovascular or cerebrovascular disease. ( 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: Patients with a pre-existing low white blood cell count (WBC) or absolute neutrophil count or a history of drug induced leukopenia or neutropenia should have frequent monitoring of their complete blood count during the first few months of BYSANTI therapy and should discontinue BYSANTI at the first sign of a decline in WBC in the absence of other causative factors.

Discontinue BYSANTI in patients with absolute ANC <1000/mm3 and follow their WBC until recovery. ( 5.10 ) Priapism: Severe priapism may require surgical intervention. ( 5.14 ) Potential for Cognitive and Motor Impairment: Use caution about driving a motor vehicle or operating hazardous machinery until patients are reasonably certain that therapy with BYSANTI does not adversely affect them.

( 5.15 ) Intraoperative Floppy Iris Syndrome (IFIS): IFIS during cataract surgery may require modifications to the surgical cataract technique. ( 5.16 )

5.1Increased 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 placebo-controlled trials (modal duration of 10 weeks) largely in patients taking atypical antipsychotic drugs for dementia-related psychosis, revealed a risk of death in antipsychotic drug-treated patients was 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the incidence of death in antipsychotic drug-treated patients was about 4.5%, compared to an incidence 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. BYSANTI is not approved for the treatment of patients with dementia-related psychosis [see Indications and Usage (1) ] .

5.2Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients with Dementia-Related Psychosis In placebo-controlled trials in elderly patients with dementia-related psychosis treated with risperidone, aripiprazole, or olanzapine had a higher incidence of stroke and transient ischemic attack, including fatal stroke compared to those treated with placebo. BYSANTI is not approved for the treatment of patients with dementia-related psychosis [see Indications and Usage (1) ] .

5.3QTc Interval Prolongation In a QTc study, the use of iloperidone (iloperidone and milsaperidone rapidly interconvert in vivo) was associated wi…

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 .

6.1Clinical 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 )

7.1Effects 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.

7.2Drugs 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.

7.3Drugs 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) ] .