What is Rexulti (brexpiprazole)?

Rexulti (brexpiprazole) is an oral atypical antipsychotic used to treat schizophrenia. Atypical antipsychotics differ from typical antipsychotics because they cause a lesser degree of movement (extrapyramidal) side effects and constipation

The exact mechanism of action of Rexulti is not known, but it is believed it affects the way the brain works by interfering with neurotransmitters. The neurotransmitters travel to other nearby nerves where they attach to receptors on the nerves. The attachment of the neurotransmitters either stimulates or inhibits the function of the nearby nerves. 

Rexulti blocks several of the receptors on nerves including:

  • dopamine type 2,
  • serotonin type 2, and
  • alpha 2 adrenergic receptors.

It is believed that many psychotic illnesses are caused by abnormal communication among nerves in the brain and that by altering communication through neurotransmitters, Rexulti can alter the psychotic state. 

Common side effects of Rexulti include:

Serious side effects of Rexulti include:

Drug interactions of Rexulti include other drugs also associated with causing dizziness son standing (orthostatic hypotension). Carbamazepine, rifampin, and St. John's wort may decrease levels of Rexulti in the blood. Itraconazole, clarithromycin, ketoconazole, paroxetine, fluoxetine, and quinidine may increase blood levels and side effects of Rexulti. 

Currently there is no data on the use of Rexulti during pregnancy. Rexulti should only be used during pregnancy if the potential benefit to the mother outweighs the potential for side effects in the unborn baby. Unborn babies exposed to antipsychotics during the third trimester of pregnancy are at risk for extrapyramidal and withdrawal symptoms after birth such as agitation, muscle rigidity or low muscle tone, tremor, somnolence, depressed breathing, and feeding disorder. 

A pregnancy exposure registry has been established to monitor the use of atypical antipsychotics, including Rexulti, during pregnancy. All pregnant women treated with atypical antipsychotics are advised to enroll in this pregnancy registry and report any side effects. 

Rexulti is known to enter human milk but its effects on the breastfeeding infant or milk production is not yet known. Consult your doctor before breastfeeding.

What are the important side effects of Rexulti (brexpiprazole)?

The most common side effects include

Brexpiprazole may increase blood levels of prolactin.

Less common but serious side effects include:

  • Increased risk of stroke and death in elderly patients with dementia-related psychosis.
  • Neuroleptic malignant syndrome (NMS). NMS is a rare but serious side effect associated with the use of antipsychotics. NMS may result in death and must be treated in the hospital. Signs and symptoms of NMS may include
    • high fever,
    • sweating (diaphoresis),
    • severe muscle stiffness or rigidity,
    • confusion,
    • loss of consciousness,
    • high blood pressure,
    • rapid heartbeat, and
    • changes in breathing.

Extrapyramidal side effects (EPS) including:

  • Dystonia: painful spasms of the oral, throat, or neck muscles that may cause problems with speech, swallowing, and stiff neck.
  • Pseudoparkinsonism: drug induced Parkinson's symptoms.
  • Tardive dyskinesia (TD). Tardive dyskinesia usually occurs after long-term use of antipsychotics and usually presents with abnormal uncontrollable movement problems affecting the tongue, lips, jaw, face, and extremities.
  • Metabolic changes including high blood sugar (hyperglycemia), diabetes, increase in blood cholesterol, and weight gain.
  • High blood levels of prolactin. Prolactin is a hormone that allows the production of breast milk. High levels of prolactin may cause menstrual abnormalities, leakage of milk from the breast, development of breasts in males (gynecomastia), and erection problems in men.
  • Brexpiprazole may increase risk of seizures.

Rexulti (brexpiprazole) side effects list for healthcare professionals

The following adverse reactions are discussed in more detail in other sections of the labeling:

  • Increased Mortality in Elderly Patients with Dementia-Related Psychosis
  • Suicidal Thoughts and Behaviors in Adolescents and Young Adults
  • Cerebrovascular Adverse Reactions Including Stroke in Elderly Patients with Dementia-Related Psychosis
  • Neuroleptic Malignant Syndrome (NMS)
  • Tardive Dyskinesia
  • Metabolic Changes
  • Pathological Gambling and Other Compulsive Behaviors
  • Leukopenia, Neutropenia, and Agranulocytosis
  • Orthostatic Hypotension and Syncope
  • Falls
  • Seizures
  • Body Temperature Dysregulation
  • Dysphagia
  • Potential for Cognitive and Motor Impairment

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.

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.

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+ADTtreated 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

What drugs interact with Rexulti (brexpiprazole)?

Drugs Having Clinically Important Interactions With Rexulti

Table 10: Clinically Important Drug Interactions with Rexulti

Strong CYP3A4 Inhibitors
Clinical Impact: Concomitant use of Rexulti with strong CYP3A4 inhibitors increased the exposure of brexpiprazole compared to the use of Rexulti alone
Intervention: With concomitant use of Rexulti with a strong CYP3A4 inhibitor, reduce the Rexulti dosage
Examples: itraconazole, clarithromycin, ketoconazole
Strong CYP2D6 Inhibitors*
Clinical Impact: Concomitant use of Rexulti with strong CYP2D6 inhibitors increased the exposure of brexpiprazole compared to the use of Rexulti alone
Intervention: With concomitant use of Rexulti with a strong CYP2D6 inhibitor, reduce the Rexulti dosage
Examples: paroxetine, fluoxetine, quinidine
Both CYP3A4 Inhibitors and CYP2D6 Inhibitors
Clinical Impact: Concomitant use of Rexulti with 1) a strong CYP3A4 inhibitor and a strong CYP2D6 inhibitor; or 2) a moderate CYP3A4 inhibitor and a strong CYP2D6 inhibitor; or 3) a strong CYP3A4 inhibitor and a moderate CYP2D6 inhibitor; or 4) a moderate CYP3A4 inhibitor and a moderate CYP2D6 inhibitor, increased the exposure of brexpiprazole compared to the use of Rexulti alone
Intervention: With concomitant use of Rexulti with 1) a strong CYP3A4 inhibitor and a strong CYP2D6 inhibitor; or 2) a moderate CYP3A4 inhibitor and a strong CYP2D6 inhibitor; or 3) a strong CYP3A4 inhibitor and a moderate CYP2D6 inhibitor; or 4) a moderate CYP3A4 inhibitor and a moderate CYP2D6 inhibitor, decrease the Rexulti dosage
Examples: 1)    itraconazole + quinidine 2)    fluconazole + paroxetine 3)    itraconazole + duloxetine 4)    fluconazole + duloxetine
Strong CYP3A4 Inducers
Clinical Impact: Concomitant use of Rexulti and a strong CYP3A4 inducer decreased the exposure of brexpiprazole compared to the use of Rexulti alone
Intervention: With concomitant use of Rexulti with a strong CYP3A4 inducer, increase the Rexulti dosage
Examples: rifampin, St. John’s wort
* 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.

Drugs Having No Clinically Important Interactions With Rexulti

Based on pharmacokinetic studies, no dosage adjustment of Rexulti is required when administered concomitantly with CYP2B6 inhibitors (e.g., ticlopidine) or gastric pH modifiers (e.g., omeprazole). Additionally, no dosage adjustment for substrates of CYP2D6 (e.g., dextromethorphan), CYP3A4 (e.g., lovastatin), CYP2B6 (e.g., bupropion), BCRP (e.g., rosuvastatin), or P-gp (e.g., fexofenadine) is required when administered concomitantly with Rexulti.

Drug Abuse And Dependence

Controlled Substance

Rexulti is not a controlled substance.

Abuse

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

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.

Summary

Rexulti (brexpiprazole) is an oral atypical antipsychotic used to treat schizophrenia. Atypical antipsychotics differ from typical antipsychotics because they cause a lesser degree of movement (extrapyramidal) side effects and constipation. Common side effects of Rexulti include drowsiness, weight gain, headache, upper respiratory tract infection, constipation, feeling restless or difficulty sitting still (akathisia), tremors. Currently there is no data on the use of Rexulti during pregnancy. Rexulti is known to enter human milk but its effects on the breastfeeding infant or milk production is not yet known.

Treatment & Diagnosis

Medications & Supplements

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Medically Reviewed on 4/13/2020
References
FDA Prescribing Information
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