Novel Drug Approvals for 2015

1.Name       -  REXULTI

2. Active Ingredient-     Brexpiprazole

3. Indication-      To treat schizophrenia and as add on to an antidepressant to treat                                    major depressive disoder

Date of Approval     July  2015

HIGHLIGHTS OF PRESCRIBING INFORMATION -

These highlights do not include all the information needed to use                               REXULTI® safely and effectively.

See full prescribing information for REXULTI. REXULTI® (brexpiprazole) tablets, for oral use

Initial U.S. Approval: 2015

WARNING:

INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS; and SUICIDAL THOUGHTS AND BEHAVIORS See full prescribing information for complete boxed warning.

 are at increased risk of death. REXULTI is not approved for the treatment of patients with dementia-related psychosis

. • Antidepressants increase the risk of suicidal thoughts and behaviors in patients aged 24 years and younger. Monitor for clinical worsening and emergence of suicidal thoughts and behaviors

. • Safety and effectiveness of REXULTI have not been established in pediatric patients

INDICATIONS AND USAGE-

 REXULTI is an atypical antipsychotic indicated for: • Use as an adjunctive therapy to antidepressants for the treatment of major depressive disorder (MDD)

 • Treatment of schizophrenia

ADVERSE REACTIONS-

 Most common adverse reactions were (6.1): MDD: Weight increased and akathisia (=5% and at least twice the rate for placebo)

Schizophrenia: Weight increased (=4% and at least twice the rate for placebo)

CONTRAINDICATIONS-

 Known hypersensitivity to REXULTI or any of its components

WARNINGS AND PRECAUTIONS-

 • Cerebrovascular Adverse Reactions in Elderly Patients with DementiaRelated Psychosis Increased incidence of cerebrovascular adverse reactions (e.g. stroke, transient ischemic attack) 

Neuroleptic Malignant Syndrome Manage with immediate discontinuation and close monitoring

• Tardive Dyskinesia Discontinue if clinically appropriate

 • Metabolic Changes Monitor for hyperglycemia/diabetes mellitus, dyslipidemia and weight gain

 • Leukopenia, Neutropenia, and Agranulocytosis Perform complete blood counts (CBC) in patients with pre-existing low white blood cell count (WBC) or history of leukopenia or neutropenia. Consider discontinuing REXULTI if a clinically significant decline in WBC occurs in absence of other causative factors

 • 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

DOSAGE AND ADMINISTRATION-

• Administer REXULTI once daily with or without food

Indications-

 Starting Dose Recommended Dose Maximum Dose MDD (2.1) 0.5 mg/day or 1 mg/day 2 mg/day 3 mg/day Schizophrenia (2.2) 1 mg/day 2 to 4 mg/day 4 mg/day

• Moderate to Severe Hepatic Impairment (Child-Pugh score =7): Maximum recommended dosage is 2 mg once daily for patients with MDD and 3 mg once daily for patients with schizophrenia

 • Moderate, Severe or End-Stage Renal Impairment (CLcr<60 mL /minute): Maximum recommended dosage is 2 mg once daily for patients with MDD and 3 mg once daily for patients with schizophrenia (2.4) • Known CYP2D6 Poor Metabolizers: Reduce the usual dosage by half

DOSAGE FORMS AND STRENGTHS-

 Tablets: 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, and 4 mg

PATIENT COUNSELING INFORMATION

Advise the patient or caregiver to read the FDA-approved patient labeling (Medication Guide).

Suicidal Thoughts and Behaviors-

Advise patients and caregivers to look for the emergence of suicidality, especially early during treatment and when the dosage is adjusted up or down and instruct them to report such symptoms to the healthcare provider

 Advise patients that REXULTI can be taken with or without food.

Advise patients regarding importance of following dosage escalation instructions

Neuroleptic Malignant Syndrome (NMS) -

Counsel patients about a potentially fatal adverse reaction - Neuroleptic Malignant Syndrome (NMS) that has been reported in association with administration of antipsychotic drugs.

Advise patients to contact a health care provider or report to the emergency room if they experience signs or symptoms of NMS

Tardive Dyskinesia Counsel patients on the signs and symptoms of tardive dyskinesia and to contact their health care provider if these abnormal movements occur

Metabolic Changes Educate patients about the risk of metabolic changes, how to recognize symptoms of hyperglycemia and diabetes mellitus, and the need for specific monitoring, including blood glucose, lipids, and weight 

Leukopenia, Neutropenia and Agranulocytosis Advise patients with a pre-existing low WBC or a history of drug induced leukopenia/neutropenia that they should have their CBC monitored while taking REXULTI

Orthostatic Hypotension and Syncope- Educate patients about the risk of orthostatic hypotension and syncope especially early in treatment, and also at times of re-initiating treatment or increases in dosage 

Heat Exposure and Dehydration Counsel patients regarding appropriate care in avoiding overheating and dehydration

 Caution patients about performing activities requiring mental alertness, such as operating hazardous machinery or operating a motor vehicle, until they are reasonably certain that REXULTI therapy does not adversely affect their ability to engage in such activities.

Concomitant Medications Advise patients to inform their health care providers of any changes to their current prescription or over-the-counter medications because there is a potential for clinically significant interactions

.Pregnancy-                                                                                                                      Advise patients that third trimester use of REXULTI may cause extrapyramidal and/or withdrawal symptoms in a neonate and to notify their healthcare provider with a known or suspected pregnancy.

Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to REXULTI during pregnancy 

Manufactured by Otsuka Pharmaceutical Co., Ltd., Tokyo, 101-8535 Japan Distributed and Marketed by Otsuka America Pharmaceutical, Inc., Rockville, MD 20850 USA © 2015, Otsuka Pharmaceutical Co., Ltd., Tokyo, 101-8535 Japan Approved July 2015

CLINICAL PHARMACOLOGY

1.Mechanism of Action -                                                                                                  The mechanism of action of brexpiprazole in the treatment of major depressive disorder or schizophrenia is unknown.

2.Pharmacodynamics-                                                                                             Brexpiprazole has affinity (expressed as Ki) for multiple monoaminergic receptors including serotonin 5HT1A (0.12 nM), 5HT2A (0.47 nM), 5HT2B (1.9 nM), 5HT7 (3.7 nM), dopamine D2 (0.30 nM), D3 (1.1 nM), and noradrenergic a1A (3.8 nM), a1B (0.17 nM), a1D (2.6 nM), and a2C (0.59 nM) receptors.

Cardiac Electrophysiology -                                                                                            At a dose 3-times the MRHD for the treatment of schizophrenia and 4-times the MRHD for adjunctive therapy to antidepressants for the treatment of MDD, REXULTI does not prolong the QTc interval to any clinically relevant extent.

3.Pharmacokinetics-                                                                                                  Absorption-                                                                                                                        After single dose administration of REXULTI tablets, the peak plasma brexpiprazole concentrations occurred within 4 hours after administration; and the absolute oral bioavailability was 95%. Brexpiprazole steady-state concentrations were attained within 10-12 days of dosing.

 Distribution-                                                                                                                  The volume of distribution of brexpiprazole following intravenous administration is high (1.56±0.42 L/kg), indicating extravascular distribution.

Elimination-                                                                                                            Metabolism-  Based on in vitro metabolism studies of brexpiprazole using recombinant human cytochrome P450 (CYP1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4), the metabolism of brexpiprazole was shown to be mainly mediated by CYP3A4 and CYP2D6. In vivo brexpirazole is metabolized primarily by CYP3A4 and CYP2D6 enzymes.

Excretion Following a single oral dose of [14C]-labeled brexpiprazole, approximately 25% and 46% of the administered radioactivity was recovered in the urine and feces, respectively. Less than 1% of unchanged brexpiprazole was excreted in the urine and approximately 14% of the oral dose was recovered unchanged in the feces.

USE IN SPECIFIC POPULATIONS

1. Pregnancy Pregnanc- Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to REXULTI during pregnancy.

Risk Summary Adequate and well-controlled studies have not been conducted with REXULTI in pregnant women to inform drug-associated risks.

The background risk of major birth defects and miscarriage for the indicated population(s) is unknown.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

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.

The development and health benefits of breastfeeding should be considered along with the mother’s clinical need for REXULTI and any potential adverse effects on the breastfed infant from REXULTI or from the underlying maternal condition.

2. Pediatric Use-                                                                                                          Safety and effectiveness in pediatric patients have not been established. Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric patients 

3. Geriatric Use-                                                                                                             Clinical studies of the efficacy REXULTI did not include any patients aged 65 or older to determine whether they respond differently from younger patients.

In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, and cardiac function, concomitant diseases, and other drug therapy.

4.Hepatic Impairment-                                                                                                          Reduce the maximum recommended dosage in patients with moderate to severe hepatic impairment (Child-Pugh score =7).

Patients with moderate to severe hepatic impairment (Child-Pugh score =7) generally had higher exposure to brexpiprazole than patients with normal hepatic function

5. Renal Impairment-                                                                                                   Reduce the maximum recommended dosage in patients with moderate, severe, or endstage renal impairment (CLcr<60 mL/minute).

Patients with impaired renal function Reference ID: 3790869 Page 24 of 38 (CLcr<60 mL/minute) had higher exposure to brexpiprazole than patients with normal renal function 

Greater exposure may increase the risk of REXULTI-associated adverse reactions

6.Other Specific Populations No dosage adjustment for REXULTI is required on the basis of a patient’s sex, race, or smoking status [see Clinical Pharmacology (12.3)].

 DRUG ABUSE AND DEPENDENCE

1. Controlled Substance REXULTI is not a controlled substance.

.2. Abuse Animals given access to REXULTI did not self-administer the drug, suggesting that REXULTI does not have rewarding properties.

3. Dependence Humans and animals that received chronic REXULTI administration did not demonstrate any withdrawal signs upon drug discontinuation. This suggests that REXULTI does not produce physical dependence.

10 OVERDOSAGE-

 There is limited clinical trial experience regarding human overdosage with REXULTI. Consult a Certified Poison Control Center (1-800-222-1222 or www.poison.org) for up-to-date guidance and advice regarding a REXULTI overdosage.

Management of overdose should concentrate on supportive therapy, maintaining an adequate airway, oxygenation and ventilation, and management of symptoms. Close medical supervision and monitoring should continue until the patient recovers.

Charcoal Oral activated charcoal and sorbitol (50 g/240 mL), administered one hour after ingesting oral brexpiprazole, decreased brexpiprazole Cmax and area under the curve (AUC) by approximately 5% to 23% and 31% to 39% respectively; however, there is insufficient information available on the therapeutic potential of activated charcoal in treating an overdose with REXULTI.

Hemodialysis-                                                                                                               There is no information on the effect of hemodialysis in treating an overdose with REXULTI; hemodialysis is unlikely to be useful because brexpiprazole is highly bound to plasma proteins.