Rexulti

Name: Rexulti

Manufacturer

  • Otsuka America Pharmaceutical, Inc.

Inform MD

Before taking Rexulti, tell your healthcare provider if you: 

  • have diabetes or high blood sugar or a family history of diabetes or high blood sugar. Your healthcare provider should check your blood sugar before you start Rexulti and during your treatment. 
  • have high levels of cholesterol, triglycerides, LDL-cholesterol, or low levels of HDL cholesterol 
  • have or had seizures (convulsions)
  • have or had abnormal thyroid tests
  • have or had low or high blood pressure
  • have or had heart problems or a stroke
  • have or had low white blood cell count 
  • are pregnant or plan to become pregnant. It is not known if Rexulti may harm your unborn baby.
  • are breastfeeding or plan to breastfeed. It is not known if Rexulti passes into your breast milk. You and your healthcare provider should decide if you will take Rexulti or breastfeed. 

Tell your healthcare provider about all the medicines you take or recently have taken, including prescription medicines, non-prescription medicines, vitamins and herbal supplements. 

  

Rexulti and Lactation

Tell your doctor if you are breastfeeding or plan to breastfeed. 

It is not known if Rexulti crosses into human milk. Because many medications can cross into human milk and because of the possibility for serious adverse reactions in nursing infants with use of this medication, a choice should be made whether to stop nursing or stop the use of this medication. Your doctor and you will decide if the benefits outweigh the risk of using Rexulti.

Rexulti Usage

Take Rexulti exactly as prescribed.

Rexulti comes in tablet form and is taken once a day, with or without food.

If you miss a dose, take the missed dose as soon as you remember. If it is almost time for the next dose, skip the missed dose and take your next dose at the regular time. Do not take two doses of Rexulti at the same time.

What happens if I miss a dose?

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

What should I avoid while taking brexpiprazole?

Brexpiprazole may impair your thinking or reactions. Avoid driving or operating machinery until you know how this medicine will affect you.

Avoid getting up too fast from a sitting or lying position, or you may feel dizzy. Dizziness or severe drowsiness can cause falls, fractures, or other injuries.

Avoid becoming overheated or dehydrated in hot weather. Brexpiprazole can make it harder for your body to control its own temperature. It is easier to become dangerously overheated and dehydrated while you are taking this medicine.

Before Using Rexulti

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of brexpiprazole in children. Safety and efficacy have not been established.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of aripiprazole in elderly patients. This medicine should not be used to treat behavioral problems in elderly patients who have dementia.

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

  • Aprepitant
  • Atazanavir
  • Boceprevir
  • Bupropion
  • Carbamazepine
  • Cinacalcet
  • Clarithromycin
  • Conivaptan
  • Diltiazem
  • Dronedarone
  • Duloxetine
  • Erythromycin
  • Fluconazole
  • Fluoxetine
  • Fosaprepitant
  • Fosphenytoin
  • Imatinib
  • Indinavir
  • Itraconazole
  • Ketoconazole
  • Lopinavir
  • Nefazodone
  • Nelfinavir
  • Paroxetine
  • Phenytoin
  • Posaconazole
  • Quinidine
  • Rifampin
  • Ritonavir
  • Saquinavir
  • St John's Wort
  • Telaprevir
  • Telithromycin
  • Terbinafine
  • Verapamil
  • Voriconazole

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following is usually not recommended, but may be unavoidable in some cases. If used together, your doctor may change the dose or how often you use this medicine, or give you special instructions about the use of food, alcohol, or tobacco.

  • Grapefruit Juice

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

  • Blood vessel disease or
  • Dehydration or
  • Heart attack or stroke, history of or
  • Heart disease or
  • Heart failure, history of or
  • Heart rhythm problems, history of or
  • Hypotension (low blood pressure) or
  • Hypovolemia (decrease in blood volume) or
  • Ischemic heart disease, history of or
  • Trouble swallowing—Use with caution. May cause side effects to become worse.
  • Diabetes, or family history of or
  • Hyperglycemia (high blood sugar)—This medicine may raise your blood sugar levels.
  • Dyslipidemia (high cholesterol or triglyceride levels) or
  • Neuroleptic malignant syndrome (NMS), history of or
  • Seizures, history of—Use with caution. May make these conditions worse.
  • Kidney disease, moderate to severe or
  • Liver disease, moderate to severe—Use with caution. The effects may be increased because of slower removal of the medicine from the body.

Proper Use of Rexulti

Take this medicine exactly as directed by your doctor. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered. To do so may increase the chance of side effects.

This medicine should come with a Medication Guide. Read and follow the instructions carefully. Ask your doctor if you have any questions.

You may take this medicine with or without food.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

  • For oral dosage form (tablets):
    • For depression:
      • Adults—At first, 0.5 or 1 milligram (mg) once a day. Your doctor may increase your dose as needed and tolerated. However, the dose is usually not more than 3 mg per day.
      • Children—Use and dose must be determined by your doctor.
    • For schizophrenia
      • Adults—At first, 1 milligram (mg) once a day on Days 1 to 4. Your doctor may increase your dose to 2 mg on Days 5 to 7, and then to 4 mg on Day 8 as tolerated. However, the dose is usually not more than 4 mg per day.
      • Children—Use and dose must be determined by your doctor.

Missed Dose

If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Uses of Rexulti

  • It is used to treat schizophrenia.
  • It is used to treat low mood (depression).
  • It may be given to you for other reasons. Talk with the doctor.

Rexulti Dosage and Administration

Adjunctive Treatment of Major Depressive Disorder

The recommended starting dosage for Rexulti as adjunctive treatment is 0.5 mg or 1 mg once daily, taken orally with or without food [see Clinical Pharmacology (12.3)].

Titrate to 1 mg once daily, then up to the target dosage of 2 mg once daily. Dosage increases should occur at weekly intervals based on the patient’s clinical response and tolerability. The maximum recommended daily dosage is 3 mg. Periodically reassess to determine the continued need and appropriate dosage for treatment.

Treatment of Schizophrenia

The recommended starting dosage for Rexulti is 1 mg once daily on Days 1 to 4, taken orally with or without food [see Clinical Pharmacology (12.3)].

The recommended target Rexulti dosage is 2 mg to 4 mg once daily. Titrate to 2 mg once daily on Day 5 through Day 7, then to 4 mg on Day 8 based on the patient’s clinical response and tolerability. The maximum recommended daily dosage is 4 mg.

Dosage Adjustments for Hepatic Impairment

For patients with moderate to severe hepatic impairment (Child-Pugh score ≥7), the maximum recommended dosage is 2 mg once daily for patients with MDD, and 3 mg once daily for patients with schizophrenia [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)].

Dosage Adjustments for Renal Impairment

For patients with moderate, severe or end-stage renal impairment (creatinine clearance CLcr<60 mL/minute), the maximum recommended dosage is 2 mg once daily for patients with MDD and 3 mg once daily for patients with schizophrenia [see Use in Specific Populations (8.8), Clinical Pharmacology (12.3)].

Dosage Modifications for CYP2D6 Poor Metabolizers and for Concomitant use with CYP Inhibitors or Inducers

Dosage adjustments are recommended in patients who are known cytochrome P450 (CYP) 2D6 poor metabolizers and in patients taking concomitant CYP3A4 inhibitors or CYP2D6 inhibitors or strong CYP3A4 inducers (see Table 1). If the coadministered drug is discontinued, adjust the Rexulti dosage to its original level. If the coadministered CYP3A4 inducer is discontinued, reduce the Rexulti dosage to the original level over 1 to 2 weeks [see Drug Interactions (7.1), Clinical Pharmacology (12.3)].

Table 1: Dosage Adjustments of Rexulti for CYP2D6 Poor Metabolizers and for Concomitant Use with CYP3A4 and CYP2D6 Inhibitors and/or CYP3A4 Inducers

Factors

Adjusted Rexulti Dosage

CYP2D6 Poor Metabolizers

CYP2D6 poor metabolizers

Administer half of the usual dose

Known CYP2D6 poor metabolizers taking strong/moderate CYP3A4 inhibitors

Administer a quarter of the usual dose

Patients Taking CYP2D6 Inhibitors and/or CYP3A4 Inhibitors

Strong CYP2D6 inhibitors*

Administer half of the usual dose

Strong CYP3A4 inhibitors

Administer half of the usual dose

Strong/moderate CYP2D6 inhibitors with strong/moderate CYP3A4 inhibitors

Administer a quarter of the usual dose

Patients Taking CYP3A4 Inducers

Strong CYP3A4 inducers

Double usual dose over 1 to 2 weeks

*In clinical trials examining the adjunctive use of Rexulti in the treatment of MDD, dosage was not adjusted for strong CYP2D6 inhibitors (e.g., paroxetine, fluoxetine). Thus, CYP considerations are already factored into general dosing recommendations and Rexulti may be administered without dosage adjustment in patients with MDD.

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 Boxed Warning, Warnings and Precautions (5.1)] • Suicidal Thoughts and Behaviors in Adolescents and Young Adults [see Boxed Warning, Warnings and Precautions (5.2)] • Cerebrovascular Adverse Reactions Including Stroke in Elderly Patients with Dementia-Related Psychosis [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)] • Leukopenia, Neutropenia, and Agranulocytosis [see Warnings and Precautions (5.7)] • Orthostatic Hypotension and Syncope [see Warnings and Precautions (5.8)] • Falls [see Warnings and Precautions (5.9)] • Seizures [see Warnings and Precautions (5.10)] • Body Temperature Dysregulation [see Warnings and Precautions (5.11)] • Dysphagia [see Warnings and Precautions (5.12)] • Potential for Cognitive and Motor Impairment [see Warnings and Precautions (5.13)]

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials 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.

Major Depressive Disorder

The safety of Rexulti was evaluated 1,054 patients (18 to 65 years of age) diagnosed with MDD who participated in two 6-week, placebo-controlled, fixed-dose clinical trials in patients with major depressive disorder in which Rexulti was administered at doses of 1 mg to 3 mg daily as adjunctive treatment to continued antidepressant therapy; patients in the placebo group continued to receive antidepressant therapy [see Clinical Studies (14.1)].

Adverse Reactions Reported as Reasons for Discontinuation of Treatment

A total of 3% (17/643) of Rexulti-treated patients and 1% (3/411) of placebo-treated patients discontinued due to adverse reactions.

Common Adverse Reactions

Adverse reactions associated with the adjunctive use of Rexulti (incidence of 2% or greater and adjunctive Rexulti incidence greater than adjunctive placebo) that occurred during acute therapy (up to 6-weeks in patients with MDD) are shown in Table 8.

Table 8: Adverse Reactions in Pooled 6-Week, Placebo-Controlled, Fixed-Dose MDD Trials (Studies 1 and 2)*

Placebo

(N=411)

Rexulti

1 mg/day

(N=226)

2 mg/day

(N=188)

3 mg/day

(N=229)

All

Rexulti

(N=643)

Gastrointestinal Disorders

Constipation

1%

3%

2%

1%

2%

General Disorders and Administration Site Conditions

Fatigue

2%

3%

2%

5%

3%

Infections and Infestations

Nasopharyngitis

2%

7%

1%

3%

4%

Investigations

Weight Increased

2%

7%

8%

6%

7%

Blood Cortisol Decreased

1%

4%

0%

3%

2%

Metabolism and Nutrition

Increased Appetite

2%

3%

3%

2%

3%

Nervous System Disorders

Akathisia

2%

4%

7%

14%

9%

Headache

6%

9%

4%

6%

7%

Somnolence

0.5%

4%

4%

6%

5%

Tremor

2%

4%

2%

5%

4%

Dizziness

1%

1%

5%

2%

3%

Psychiatric Disorders

Anxiety

1%

2%

4%

4%

3%

Restlessness

0%

2%

3%

4%

3%

* Adverse reactions that occurred in ≥2% of Rexulti-treated patients and greater incidence than in placebo-treated patients

Dose-Related Adverse Reactions in the MDD trials

In Studies 1 and 2, among the adverse reactions that occurred at ≥2% incidence in the patients treated with Rexulti +ADT, the incidences of akathisia and restlessness increased with increases in dose.

Schizophrenia

The safety of Rexulti was evaluated in 852 patients (18 to 65 years of age) diagnosed with schizophrenia who participated in two 6-week, placebo-controlled, fixed-dose clinical trials in which Rexulti was administered at daily doses of 1 mg, 2 mg and 4 mg [see Clinical Studies (14.2)].

Common Adverse Reactions

Adverse reactions associated with Rexulti (incidence of 2% or greater and Rexulti incidence greater than placebo) during short-term (up to 6-weeks) trials in patients with schizophrenia are shown in Table 9.

Table 9: Adverse Reactions in Pooled 6-Week, Placebo-Controlled, Fixed-Dose Schizophrenia Trials (Studies 3 and 4)*

Placebo

(N=368)

Rexulti

1 mg/day

(N=120)

2 mg/day

(N=368)

4 mg/day

(N=364)

ALL Rexulti

(N=852)

Gastrointestinal Disorders

  Dyspepsia

2%

6%

2%

3%

3%

  Diarrhea

2%

1%

3%

3%

3%

Investigations

  Weight Increased

2%

3%

4%

4%

4%

  Blood Creatine Phosphokinase Increased

1%

4%

2%

2%

2%

Nervous System Disorders

  Akathisia

5%

4%

5%

7%

6%

  Tremor

1%

2%

2%

3%

3%

  Sedation

1%

2%

2%

3%

2%

* Adverse reactions that occurred in ≥2% of Rexulti-treated patients and greater incidence than in placebo-treated patients

Extrapyramidal Symptoms

Major Depressive Disorder

The incidence of reported EPS-related adverse reactions, excluding akathisia, was 6% for Rexulti+ADT-treated patients versus 3% for placebo+ADT-treated patients. The incidence of akathisia events for Rexulti+ADT-treated patients was 9% versus 2% for placebo+ADT-treated patients.

In the 6-week, placebo-controlled MDD studies, data was objectively collected on the Simpson Angus Rating Scale (SAS) for extrapyramidal symptoms (EPS), the Barnes Akathisia Rating Scale (BARS) for akathisia and the Abnormal Involuntary Movement Score (AIMS) for dyskinesia. The mean change from baseline at last visit for Rexulti+ADT-treated patients for the SAS, BARS and AIMS was comparable to placebo treated patients. The percentage of patients who shifted from normal to abnormal was greater in Rexulti+ADT-treated patients versus placebo+ADT for the BARS (4% versus 0.6%) and the SAS (4% versus 3%).

Schizophrenia

The incidence of reported EPS-related adverse reactions, excluding akathisia, was 5% for Rexulti-treated patients versus 4% for placebo-treated patients. The incidence of akathisia events for Rexulti-treated patients was 6% versus 5% for placebo-treated patients.

In the 6-week, placebo-controlled, fixed-dose schizophrenia studies, data was objectively collected on the Simpson Angus Rating Scale (SAS) for extrapyramidal symptoms (EPS), the Barnes Akathisia Rating Scale (BARS) for akathisia and the Abnormal Involuntary Movement Scale (AIMS) for dyskinesia. The mean change from baseline at last visit for Rexulti-treated patients for the SAS, BARS and AIMS was comparable to placebo-treated patients. The percentage of patients who shifted from normal to abnormal was greater in Rexulti-treated patients versus placebo for the BARS (2% versus 1%) and the SAS (7% versus 5%).

Dystonia

Symptoms of dystonia may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups.

Other Adverse Reactions Observed During the Premarketing Evaluation of Rexulti

Other adverse reactions (≥1% frequency and greater than placebo) within the short-term, placebo-controlled trials in patients with MDD and schizophrenia are shown below. The following listing does not include adverse reactions: 1) already listed in previous tables or elsewhere in the labeling, 2) for which a drug cause was remote, 3) which were so general as to be uninformative, 4) which were not considered to have clinically significant implications, or 5) which occurred at a rate equal to or less than placebo.

Eye Disorders: Vision Blurred

Gastrointestinal Disorders: Nausea, Dry Mouth, Salivary Hypersecretion, Abdominal Pain, Flatulence

Infections and Infestations: Urinary Tract Infection

Investigations: Blood Prolactin Increased

Musculoskeletal and Connective Tissue Disorders: Myalgia

Psychiatric Disorders: Abnormal Dreams, Insomnia

Skin and Subcutaneous Tissue Disorders: Hyperhidrosis

Use in specific populations

Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to Rexulti 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

Adequate and well-controlled studies have not been conducted with Rexulti in pregnant women to inform drug-associated risks. However, neonates whose mothers are exposed to antipsychotic drugs, like Rexulti, during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms. In animal reproduction studies, no teratogenicity was observed with oral administration of brexpiprazole to pregnant rats and rabbits during organogenesis at doses up to 73 and 146 times, respectively, of maximum recommended human dose (MRHD) of 4 mg/day on a mg/m2 basis. However, when pregnant rats were administered brexpiprazole during the period of organogenesis through lactation, the number of perinatal deaths of pups was increased at 73 times the MRHD [see Data]. 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.

Clinical Considerations

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

Pregnant rats were treated with oral doses of 3, 10, and 30 mg/kg/day (7.3, 24, and 73 times the MRHD on a mg/m2 basis) of brexpiprazole during the period of organogenesis. Brexpiprazole was not teratogenic and did not cause adverse developmental effects at doses up to 73 times the MRHD.

Pregnant rabbits were treated with oral doses of 10, 30, and 150 mg/kg/day (49, 146, and 730 times the MRHD) of brexpiprazole during the period of organogenesis. Brexpiprazole was not teratogenic and did not cause adverse developmental effects at doses up to 146 times the MRHD. Findings of decreased body weight, retarded ossification, and increased incidences of visceral and skeletal variations were observed in fetuses at 730 times the MRHD, a dose that induced maternal toxicity.

In a study in which pregnant rats were administered oral doses of 3, 10, and 30 mg/kg/day (7.3, 24, and 73 times the MRHD) during the period of organogenesis and through lactation, the number of live-born pups was decreased and early postnatal deaths increased at a dose 73 times the MRHD. Impaired nursing by dams, and low birth weight and decreased body weight gain in pups were observed at 73 times, but not at 24 times, the MRHD.

Lactation

Risk Summary

Lactation studies have not been conducted to assess the presence of brexpiprazole in human milk, the effects of brexpiprazole on the breastfed infant, or the effects of brexpiprazole on milk production. Brexpiprazole is present in rat milk. 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.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established. Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric patients [see Boxed Warning, Warnings and Precautions (5.2)].

Geriatric Use

Clinical studies of the efficacy of 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.

Based on the results of a safety, tolerability and pharmacokinetics trial, the pharmacokinetics of once daily oral administration of brexpiprazole (up to 3 mg/day for 14 days) as an adjunct therapy in the treatment of elderly subjects (70 to 85 years old, N=11) with MDD were comparable to those observed in adults subjects with MDD.

Antipsychotic drugs increase the risk of death in elderly patients with dementia-related psychosis. Rexulti is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning,Warnings and Precautions (5.1)].

CYP2D6 Poor Metabolizers

Dosage adjustment is recommended in known CYP2D6 poor metabolizers, because these patients have higher brexpiprazole concentrations than normal metabolizers of CYP2D6. Approximately 8% of Caucasians and 3–8% of Black/African Americans cannot metabolize CYP2D6 substrates and are classified as poor metabolizers (PM) [see Dosage and Administration (2.5), Clinical Pharmacology (12.3)].

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 [see Clinical Pharmacology (12.3)]. Greater exposure may increase the risk of Rexulti-associated adverse reactions [see Dosage and Administration (2.3)].

Renal Impairment

Reduce the maximum recommended dosage in patients with moderate, severe, or end-stage renal impairment (CLcr<60 mL/minute). Patients with impaired renal function (CLcr<60 mL/minute) had higher exposure to brexpiprazole than patients with normal renal function [see Clinical Pharmacology (12.3)]. Greater exposure may increase the risk of Rexulti-associated adverse reactions [see Dosage and Administration (2.4)].

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)].

Clinical Studies

Adjunctive Treatment of Major Depressive Disorder

The efficacy of Rexulti in the adjunctive treatment of major depressive disorder (MDD) was evaluated in two 6-week, double-blind, placebo-controlled, fixed-dose trials of adult patients meeting DSM-IV-TR criteria for MDD, with or without symptoms of anxiety, who had an inadequate response to prior antidepressant therapy (1 to 3 courses) in the current episode and who had also demonstrated an inadequate response throughout the 8 weeks of prospective antidepressant treatment (with escitalopram, fluoxetine, paroxetine controlled-release, sertraline, duloxetine delayed release, or venlafaxine extended-release). Inadequate response during the prospective antidepressant treatment phase was defined as having persistent symptoms without substantial improvement throughout the course of treatment.

Patients in Study 228 (hereafter “Study 1”) were randomized to Rexulti 2 mg once a day or placebo. Patients in Study 227 (hereafter “Study 2”) were randomized to Rexulti 1 or 3 mg once a day or placebo. For patients randomized to Rexulti, all patients initiated treatment at 0.5 mg once daily during Week 1. At Week 2, the Rexulti dosage was increased to 1 mg in all treatment groups, and either maintained at 1 mg or increased to 2 mg or 3 mg once daily, based on treatment assignment, from Week 3 onwards. The dosages were then maintained for the 4 remaining weeks.

The primary endpoint was change from baseline to Week 6 in the Montgomery-Asberg Depression Rating Scale (MADRS), a 10-item clinician-related scale used to assess the degree of depressive symptomatology, with 0 representing no symptoms, and 60 representing worst symptoms.

At randomization, the mean MADRS total score was 27. In Studies 1 and 2, Rexulti [+ antidepressant (ADT)] 2 mg/day and 3 mg/day were superior to placebo + ADT in reducing mean MADRS total scores. Results from the primary efficacy parameters for both fixed dose trials are shown below in Table 11. Figure 4 below shows the time course of response based on the primary efficacy measure (MADRS) in Study 1.

Table 11: Summary of Efficacy Results for Studies 1 and 2 for the Adjunctive Treatment of MDD
  Primary Efficacy Measure: MADRS

Study

Treatment Group

N

  Mean Baseline Score (SD)

LS Mean Change from Baseline (SE)

Placebo-subtracted

Differencea (95% CI)

1

Rexulti (2 mg/day) +ADT*

175

26.9 (5.7)

-8.4 (0.6)

-3.2 (-4.9, -1.5)

Placebo +ADT

178

27.3 (5.6)

-5.2 (0.6)

--

2

Rexulti (1 mg/day) +ADT

211

26.5 (5.6)

-7.6 (0.5)

-1.3 (-2.7, 0.1)

Rexulti (3 mg/day) +ADT

213

26.5 (5.3)

-8.3 (0.5)

-2.0 (-3.4, -0.5)

Placebo +ADT

203

26.5 (5.2)

-6.3 (0.5)

--

SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval.

* Dosages statistically significantly superior to placebo.

a Difference (drug minus placebo) in least-squares mean change from baseline.

An examination of population subgroups did not suggest differential response based on age, gender, race or choice of prospective antidepressant.

Figure 4: Change from Baseline in MADRS Total Score by Study Visit (Week) in Patients with MDD in Study 1

Schizophrenia

The efficacy of Rexulti in the treatment of adults with schizophrenia was demonstrated in two 6-week, randomized, double-blind, placebo-controlled, fixed-dose clinical trials in patients who met DSM-IV-TR criteria for schizophrenia.

In both studies, Study 231 (hereafter “Study 3”) and Study 230 (hereafter “Study 4”), patients were randomized to Rexulti 2 or 4 mg once per day or placebo. Patients in the Rexulti groups initiated treatment at 1 mg once daily on Days 1 to 4. The Rexulti dosage was increased to 2 mg on Days 5 to 7. The dosage was then either maintained at 2 mg once daily or increased to 4 mg once daily, depending on treatment assignment, for the 5 remaining weeks.

The primary efficacy endpoint of both trials was the change from baseline to Week 6 in the Positive and Negative Syndrome Scale (PANSS) total score. The PANSS is a 30-item scale that measures positive symptoms of schizophrenia (7 items), negative symptoms of schizophrenia (7 items), and general psychopathology (16 items), each rated on a scale of 1 (absent) to 7 (extreme); the total PANSS scores range from 30 (best) to 210 (worst).

In Study 3, Rexulti at both 2 mg/day and 4 mg/day was superior to placebo on the PANSS total score. In Study 4, Rexulti 4 mg/day was superior to placebo on the PANSS total score (Table 12). Figure 5 shows the time course of response based on the primary efficacy measure (change from baseline in PANSS total score) in Study 3.

Examination of population subgroups based on age, gender and race did not suggest differential responsiveness.

Table 12: Summary of Efficacy Results for Studies in Schizophrenia

  Study

Treatment Group

N

  Primary Efficacy Measure: PANSS

Mean Baseline Score (SD)

LS Mean Change from Baseline (SE)

Placebo-subtracted Differencea (95% CI)

  3

Rexulti (2 mg/day)*

180

95.9 (13.8)

-20.7 (1.5)

-8.7 (-13.1, -4.4)

Rexulti (4 mg/day)*

178

94.7 (12.1)

-19.7 (1.5)

-7.6 (-12.0, -3.1)

Placebo

178

95.7 (11.5)

-12.0 (1.6)

--

  4

Rexulti (2 mg/day)

179

96.3 (12.9)

-16.6 (1.5)

-3.1 (-7.2, 1.1)

Rexulti (4 mg/day)*

181

95.0 (12.4)

-20.0 (1.5)

-6.5 (-10.6, -2.4)

Placebo

180

94.6 (12.8)

-13.5 (1.5)

--

SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval.

* Dosages statistically significantly superior to placebo.

a Difference (drug minus placebo) in least-squares mean change from baseline.

Figure 5: Change from Baseline in PANSS Total Score by Study Visit (Week) in Patients with Schizophrenia in Study 3

The safety and efficacy of Rexulti as maintenance treatment in adults with schizophrenia aged 18 to 65 years were demonstrated in the maintenance phase of a randomized withdrawal trial (Study 331-10-232, hereafter “Study 5”). Patients were stabilized for at least 12 weeks on 1 to 4 mg/day of Rexulti (N=202). They were then randomized in the double-blind treatment phase to either continue Rexulti at their achieved stable dose (N=97), or to switch to placebo (N=105).

The primary endpoint in Study 5 was time from randomization to impending relapse during the double-blind phase, defined as: 1) CGI-Improvement score of ≥5 (minimally worse) and an increase to a score > 4 on PANSS conceptual disorganization, hallucinatory behavior, suspiciousness, or unusual thought content items, with either a ≥2 increase on a specific item or ≥4 point increase on the combined four PANSS items, 2) hospitalization due to worsening of psychotic symptoms, 3) current suicidal behavior, or 4) violent/aggressive behavior.

A pre-specified interim analysis demonstrated a statistically significantly longer time to relapse in patients randomized to the Rexulti group compared to placebo-treated patients. The trial was subsequently terminated early because maintenance of efficacy had been demonstrated. The Kaplan-Meier curves of the cumulative proportion of patients with relapse during the double-blind treatment phase for Rexulti and placebo groups are shown in Figure 6. The key secondary endpoint, the proportion of subjects who met the criteria for impending relapse, was statistically significantly lower in Rexulti-treated patients compared with placebo group.

Figure 6: Kaplan Meier Estimation of Percent Impending Relapse in Study 5

Note: A total of 202 subjects were randomized. Among them, one placebo subject did not take investigational medicinal product and one brexpiprazole subject did not have post-randomization efficacy evaluations. These two subjects were excluded from the efficacy analysis.

Medication guide

Rexulti® (REX-ul-TE)

(brexpiprazole)

Tablets

What is the most important information I should know about Rexulti?

Rexulti may cause serious side effects, including:

• Increased risk of death in elderly people with dementia-related psychosis. Medicines like Rexulti can raise the risk of death in elderly who have lost touch with reality (psychosis) due to confusion and memory loss (dementia). Rexulti is not approved for the treatment of patients with dementia-related psychosis. • Risk of suicidal thoughts or actions. Antidepressant medicines, depression and other serious mental illnesses, may cause suicidal thoughts or actions. Rexulti is not approved for the treatment of people younger than 18 years of age. • Antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, or young adults within the first few months of treatment. • Depression and other serious mental illnesses are the most important causes of suicidal thoughts or actions. Some people may have a particularly high risk of having suicidal thoughts or actions. These include people who have (or have a family history of) bipolar illness (also called manic-depressive illness) or suicidal thoughts or actions. • How can I watch for and try to prevent suicidal thoughts and actions in myself or a family member? • Pay close attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. This is very important when an antidepressant medicine is started or when the dose is changed. • Call the healthcare provider right away to report new or sudden changes in mood, behavior, thoughts, or feelings. • Keep all follow-up visits with the healthcare provider as scheduled. Call the healthcare provider between visits as needed, especially if you have concerns about symptoms.

Call a healthcare provider right away if you or your family member has any of the following symptoms, especially if they are new, worse, or worry you:

• thoughts about suicide or dying • attempts to commit suicide • new or worsening depression • new or worsening anxiety • feeling very agitated or restless • acting on dangerous impulses • panic attacks • trouble sleeping (insomnia) • new or worsening irritability • acting aggressive, being angry, or violent • an extreme increase in activity or talking (mania) • other unusual changes in behavior or mood

What else do I need to know about antidepressant medicines?

• Never stop an antidepressant medicine without first talking to your healthcare provider. Stopping an antidepressant medicine suddenly can cause other symptoms. • Antidepressants are medicines used to treat depression and other illnesses. It is important to discuss all the risks of treating depression and also the risks of not treating it. Patients and their families or other caregivers should discuss all treatment choices with the healthcare provider, not just the use of antidepressants. • Antidepressant medicines have other side effects. Talk to the healthcare provider about the possible side effects of the medicine prescribed for you or your family member. • Antidepressant medicines can interact with other medicines. Know all of the medicines that you or your family member takes. Keep a list of all medicines (including prescription medicines, non-prescription medicines, vitamins and herbal supplements) to show the healthcare provider. Do not start new medicines without first checking with your healthcare provider.

What is Rexulti?

Rexulti is a prescription medicine used to treat:

• Major depressive disorder (MDD): Rexulti is used with antidepressant medicines, when your healthcare provider determines that an antidepressant alone is not enough to treat your depression. • Schizophrenia

It is not known if Rexulti is safe and effective in people under 18 years of age.

Who should not take Rexulti?

Do not take Rexulti if you are allergic to brexpiprazole or any of the ingredients in Rexulti. See the end of this Medication Guide for a complete list of ingredients in Rexulti.

What should I tell my healthcare provider before taking Rexulti?

Before taking Rexulti, tell your healthcare provider if you:

• have diabetes or high blood sugar or a family history of diabetes or high blood sugar. Your healthcare provider should check your blood sugar before you start Rexulti and during your treatment. • have high levels of cholesterol, triglycerides, LDL-cholesterol, or low levels of HDL cholesterol • have or had seizures (convulsions) • have or had low or high blood pressure • have or had heart problems or a stroke • have or had a low white blood cell count • are pregnant or plan to become pregnant. It is not known if Rexulti may harm your unborn baby. Using Rexulti in the last trimester of pregnancy may cause muscle movement problems, medicine withdrawal symptoms, or both of these in your newborn. • If you become pregnant while taking Rexulti, talk to your healthcare provider about registering with the National Pregnancy Registry for Atypical Antipsychotics. You can register by calling 1-866-961-2388 or visit http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/ • are breastfeeding or plan to breastfeed. It is not known if Rexulti passes into your breast milk. You and your healthcare provider should decide if you will take Rexulti or breastfeed.

Tell your healthcare provider about all the medicines you take or recently have taken, including prescription medicines, over-the-counter medicines, vitamins and herbal supplements.
Rexulti and other medicines may affect each other causing possible serious side effects. Rexulti may affect the way other medicines work, and other medicines may affect how Rexulti works.
Your healthcare provider can tell you if it is safe to take Rexulti with your other medicines. Do not start or stop any medicines while taking Rexulti without talking to your healthcare provider first.
Know the medicines you take. Keep a list of your medicines to show your healthcare provider and pharmacist when you get a new medicine.

How should I take Rexulti?

• Take Rexulti exactly as your healthcare provider tells you to take it. Do not change the dose or stop taking Rexulti yourself. • Rexulti can be taken with or without food. • You should not miss a dose of Rexulti. If you miss a dose, take the missed dose as soon as you remember. If you are close to your next dose, just skip the missed dose and take your next dose at your regular time. Donot take 2 doses of Rexulti at the same time. If you are not sure about your dosing, call your healthcare provider. • If you take too much Rexulti, call your healthcare provider or Poison Control Center at 1-800-222-1222 right away, or go to the nearest hospital emergency room.

What should I avoid while taking Rexulti?

• Do not drive a car, operate machinery, or do other dangerous activities until you know how Rexulti affects you. Rexulti may make you feel drowsy. • Avoid getting over-heated or dehydrated while taking Rexulti. • Do not over-exercise. • In hot weather, stay inside in a cool place if possible. • Stay out of the sun. Do not wear too much or heavy clothing. • Drink plenty of water.

What are the possible side effects of Rexulti?

See“What is the most important information I should know about Rexulti?”

Rexulti may cause serious side effects, including:

• Stroke in elderly people (cerebrovascular problems) that can lead to death. • Neuroleptic Malignant Syndrome (NMS): Tell your healthcare provider right away if you have some or all of the following symptoms: high fever, stiff muscles, confusion, sweating, changes in pulse, heart rate, and blood pressure. These may be symptoms of a rare and serious condition that can lead to death. Call your healthcare provider right away if you have any of these symptoms. • Uncontrolled body movements (tardive dyskinesia): Rexulti may cause movements that you cannot control in your face, tongue or other body parts. Tardive dyskinesia may not go away, even if you stop taking Rexulti. Tardive dyskinesia may also start after you stop taking Rexulti. • Problems with your metabolism such as: • high blood sugar (hyperglycemia): Increases in blood sugar can happen in some people who take Rexulti. Extremely high blood sugar can lead to coma or death. If you have diabetes or risk factors for diabetes (such as being overweight or having a family history of diabetes), your healthcare provider should check your blood sugar before you start taking Rexulti and during your treatment.
  Call your healthcare provider if you have any of these symptoms of high blood sugar while taking Rexulti: • feel very thirsty • feel sick to your stomach • need to urinate more than usual • feel very hungry • feel weak or tired • feel confused, or your breath smells fruity • increased fat levels (cholesterol and triglycerides) in your blood. • weight gain: You and your healthcare provider should check your weight regularly.
• Low white blood cell count • Decreased blood pressure (orthostatic hypotension). You may feel lightheaded or faint when you rise too quickly from a sitting or lying position. • Seizures (convulsions) • Problems controlling your body temperature so that you feel too warm. See “What should I avoid while taking Rexulti?” • Difficulty swallowing that can cause food or liquid to get into your lungs. • The most common side effects of Rexulti include weight gain and an inner sense of restlessness such as feeling like you need to move. • These are not all the possible side effects of Rexulti. For more information, ask your healthcare provider or pharmacist. • Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store Rexulti?

Store Rexulti at room temperature, between 68°F to 77°F (20°C to 25°C).

Keep Rexulti and all medicines out of the reach of children.

General information about the safe and effective use of Rexulti.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Rexulti for a condition for which it was not prescribed. Do not give Rexulti to other people, even if they have the same symptoms you have. It may harm them.

This Medication Guide summarizes the most important information about Rexulti. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about Rexulti that is written for healthcare professionals. For more information about Rexulti, go to [www.Rexulti.com] or call 1-800-441-6763.

What are the ingredients in Rexulti?

Active ingredient: brexpiprazole

Inactive ingredients: lactose monohydrate, corn starch, microcrystalline cellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, magnesium stearate, hypromellose, and talc.


Manufactured by Otsuka Pharmaceutical Co., Ltd., Tokyo, 101-8535 Japan

Distributed and Marketed by Otsuka America Pharmaceutical, Inc., Rockville, MD 20850 USA

Marketed by Lundbeck, Deerfield, IL 60015 USA

© 2015, Otsuka Pharmaceutical Co., Ltd., Tokyo, 101-8535 Japan

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Approved: 08/2015

PRINCIPAL DISPLAY PANEL - 0.25 mg Tablet Bottle Label

NDC 59148-035-13

30 Tablets
0.25 mg

Rexulti™
brexpiprazole
tablets

Rx only

Keep out of the reach of children

DISPENSE THE ACCOMPANYING MEDICATION GUIDE TO EACH PATIENT

Manufactured by Otsuka Pharmaceutical Co., Ltd., Tokyo, 101-8535 Japan

Distributed and marketed by Otsuka America Pharmaceutical, Inc., Rockville, MD 20850 USA

Marketed by Lundbeck, Deerfield, IL 60015 USA

PRINCIPAL DISPLAY PANEL - 0.25 mg Tablet Carton Label

NDC 59148-035-13

30 Tablets
0.25 mg

Rexulti™
brexpiprazole
tablets

Rx only

Keep out of the reach of children

DISPENSE THE ACCOMPANYING MEDICATION GUIDE TO EACH PATIENT

Manufactured by Otsuka Pharmaceutical Co., Ltd., Tokyo, 101-8535 Japan

Distributed and marketed by Otsuka America Pharmaceutical, Inc., Rockville, MD 20850 USA

Marketed by Lundbeck, Deerfield, IL 60015 USA

PRINCIPAL DISPLAY PANEL - 0.5 mg Tablet Carton Label

NDC 59148-036-13

30 Tablets

0.5 mg

Rexulti™

brexpiprazole

tablets

Rx only

Keep out of the reach of children

DISPENSE THE ACCOMPANYING MEDICATION GUIDE TO EACH PATIENT

Manufactured by Otsuka Pharmaceutical Co., Ltd., Tokyo, 101-8535 Japan

Distributed and marketed by Otsuka America Pharmaceutical, Inc., Rockville, MD 20850 USA

Marketed by Lundbeck, Deerfield, IL 60015 USA

What happens if I miss a dose?

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

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