Milsaperidone

BYSANTI ™ 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 )

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

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 )

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 )

5.1 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 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) ] .

5.2 Cerebrovascular 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) ] . 5.3 QTc Interval Prolongation In a QTc study, the use of iloperidone (iloperidone and milsaperidone rapidly interconvert in vivo) was associated with QTc interval prolongation, especially with concomitant use of a CYP2D6 inhibitor or a CYP3A4 inhibitor. No cases of torsade de pointes or other severe cardiac arrhythmias were observed in the iloperidone studies. Risk Factors for Clinically Significant Risks of QTc Interval Prolongation Certain circumstances may increase the risk of torsade de pointes and/or sudden death in association with the use of drugs that prolong the QTc interval, including ischemic cardiomyopathy; hypokalemia; genetic predisposition, concomitant use of other drugs that prolong the QTc interval or increases the exposure of the drug; and elevated baseline QTc interval. Steps to Prevent or Mitigate Clinically Significant Adverse Reactions or Risks Associated with QTc Interval Prolongation The concomitant use of BYSANTI should be avoided with other drugs that prolong the QTc interval including Class 1A antiarrhythmics (e.g., quinidine, procainamide) or Class III antiarrhythmics (e.g., amiodarone, sotalol), antipsychotic drugs that prolong the QTc interval (e.g., chlorpromazine, thioridazine), antibiotics that prolong the QTc interval (e.g., gatifloxacin, moxifloxacin), or any other class of drugs known to prolong the QTc interval (e.g., pentamidine, levomethadyl acetate, methadone). BYSANTI should also be avoided in other patients with significant risk of developing torsades de pointes including those with congenital long QT syndrome, recent myocardial infarction, ischemic cardiomyopathy, unstable angina, bradyarrhythmias, uncontrolled hypertension, high degree atrioventricular block, severe aortic stenosis, or uncontrolled hypothyroidism. When BYSANTI is used concomitantly with other drugs (e.g., strong CYP2D6 inhibitors, strong CYP3A4 inhibitors, and taking both a CYP2D6 inhibitor and a CYP3A4 inhibitor) [see Drug Interactions (7.1) ] or in patients with decreased activity of CYP2D6 [see Clinical Pharmacology (12.5) ] decrease the BYSANTI dosage [see Dosage and Administration (2.x) ] . Patients being considered for BYSANTI treatment who are at risk for significant electrolyte disturbances should have baseline serum potassium and magnesium measurements with periodic monitoring because hypokalemia (and/or hypomagnesemia) may increase the risk of QTc interval prolongation and arrhythmia. BYSANTI should be discontinued in patients who are found to have persistent QTc measurements >500 msec. If patients taking BYSANTI experience symptoms that could indicate the occurrence of arrhythmias, e.g., dizziness, palpitations, or syncope, the health care provider should initiate further evaluation, including cardiac monitoring.

5.4 Neuroleptic Malignant Syndrome Neuroleptic Malignant Syndrome (NMS), a potentially fatal symptom complex, has been reported in association with administration of antipsychotic drugs, including iloperidone (iloperidone and milsaperidone rapidly interconvert in vivo). Clinical manifestations of NMS include hyperpyrexia, muscle rigidity, altered mental status (including catatonic signs), and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. If NMS is suspected, immediately discontinue BYSANTI and provide intensive symptomatic treatment and monitoring.

5.5 Tardive Dyskinesia Tardive dyskinesia (TD), may develop in patients treated with antipsychotic drugs, including BYSANTI. TD can develop after relatively brief treatment period at low dosages and may also occur after discontinuation of treatment. If antipsychotic drug treatment is discontinued, TD may partially or completely remission. Antipsychotic treatment, however, may suppress or partially suppress the signs and symptoms of TD, possibly masking the underlying process. The effect that symptomatic suppression has upon the long-term course of TD is unknown. […]

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) (Studies 1, 2, and 3, and another study in schizophrenia) [see Clinical Studies (14.1) ] . Table 3 displays adverse reactions that occurred in 2% or more of patients treated with iloperidone in any of the dosing groups, and for which the incidence in iloperidone-treated patients in any dosing group was greater than the incidence in placebo-treated patients in these studies. Adverse reactions that occurred in ≥ 5% in the iloperidone-treated patients and at least twice that in placebo-treated patients included dizziness, dry mouth, fatigue, nasal congestion, somnolence, tachycardia, orthostatic hypotension, and weight increased. Table 3: Percentage of Adverse Reactions in Short-Term, Fixed- or Flexible-Dose, Placebo-Controlled Schizophrenia Trials in Adult Patients * * Includes adverse reactions that were reported in 2% or more of patients in any of the iloperidone dosing group and at greater incidence than in the placebo group. Figures rounded to the nearest integer. a Somnolence includes somnolence and sedation b Tachycardia includes tachycardia and heart rate increased Placebo (N=587) Iloperidone 10-16 mg/day (N=483) Iloperidone 20-24 mg/day (N=391) Dizziness 7% 10% 20% Somnolence a 5% 9% 15% Tachycardia b 1% 3% 12% Dry Mouth 1% 8% 10% Nausea 8% 7% 10% Weight Increased 1% 1% 9% Nasal Congestion 2% 5% 8% Diarrhea 4% 5% 7% Fatigue 3% 4% 6% Orthostatic Hypotension 1% 3% 5% Extrapyramidal Disorder 4% 5% 4% Nasopharyngitis 3% 4% 3% Arthralgia 2% 3% 3% Tremor 2% 3% 3% Upper Respiratory Tract Infection 1% 2% 3% Abdominal Discomfort 1% 1% 3% Hypotension <1% <1% 3% Musculoskeletal Stiffness 1% 1% 3% Ejaculation Failure <1% 2% 2% Dyspnea <1% 2% 2% Rash 2% 3% 2% Lethargy 1% 3% 1% Vision Blurred 2% 3% 1% Common Adverse Reactions in Adult Patients with Bipolar Mania Table 4 displays the adverse reactions that occurred at an incidence of ≥2% in iloperidone-treated patients and greater than in placebo-treated patients in a placebo-controlled, 4-week bipolar mania trial (Study 4) [see Clinical Studies (14.2) ] . In Study 4, the following adverse reactions occurred in ≥5% in the iloperidone- treated patients and at least twice placebo-treated patients: tachycardia, dizziness, dry mouth, hepatic enzymes increased, nasal congestion, weight increased, hypotension, and somnolence. Table 4: Adverse Reactions that Occurred in Adult Patients in a Short-Term, Fixed-Dose, Placebo-Controlled Bipolar Mania Trial (Study 4) * * Adverse reactions occurring at an incidence of ≥2% in iloperidone-treated patients and greater than in placebo-treated patients. Figures rounded to the nearest integer. ** Patients with poor CYP2D6 metabolizer status received 12 mg/day. […]

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) ] .

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 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 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.

8.2 Lactation Risk Summary There are no data on the presence of milsaperidone or its major metabolite, P95, in either human or animal milk, the effects on the breastfed infant, or the effects on milk production. Iloperidone (iloperidone and milsaperidone rapidly interconvert in vivo) is present in rat milk following iloperidone administration (see Data ) . When a drug is present in animal milk, it is likely to be present in human milk. Because of the potential for serious adverse reactions in the breastfed infant, advise patients 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. 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.

8.4 Pediatric Use Safety and effectiveness of BYSANTI have not been established in pediatric patients.

8.5 Geriatric Use Clinical studies of iloperidone (iloperidone and milsaperidone rapidly interconvert in vivo) 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 iloperidone 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 iloperidone in a clinical trial (Study 4), 2 (0.1%) were 65 years old and there were no patients were >75 years old. Elderly patients with dementia-related psychosis treated with BYSANTI are at an increased risk of death compared to placebo. […]

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.