BYSANTI Tablet Ref.[116258] Active ingredients: Milsaperidone

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.

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.

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 inhibitor is stopped in BYSANTI-treated patients, titrate to the recommended dosage as described in Table 1 [see Drug Interactions (7.1)].

Concomitant Administration with a Strong CYP3A4 Inhibitor

In patients receiving a:

• Stable dosage of a strong CYP3A4 inhibitor, when initiating BYSANTI, the recommended BYSANTI titration schedule is the same as that in Table 2.
• Maintenance BYSANTI dosage, when initiating a strong CYP3A4 inhibitor, reduce the BYSANTI dosage by one-half.

When the CYP3A4 inhibitor is stopped in BYSANTI-treated patients, titrate to the recommended dosage as described in Table 1 [see Drug Interactions (7.1)].

Concomitant Administration with a Strong CYP2D6 Inhibitor and a Strong CYP3A4 Inhibitor

In patients receiving a:

• Stable dosage of a strong CYP2D6 inhibitor and a strong CYP3A4 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 and a strong CYP3A4 inhibitor, reduce the BYSANTI dosage by one-half.

When the strong CYP2D6 inhibitor and CYP3A4 inhibitor are both stopped in BYSANTI-treated patients, titrate to the recommended dosage as described in Table 1. [see Drug Interactions (7.1)].

2.5 Recommendations for Missed Dose(s)

If patients miss more than three days of BYSANTI treatment, restart the titration schedule [see Dosage and Administration 2.1)].

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.

Store the tablets at controlled room temperature, 20°C to 25°C (68°F to 77°F), with excursions permitted between 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature]. Protect the tablets from exposure to light and moisture.