Rexulti

Brexpiprazole may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:

• headache
• constipation
• heartburn
• tiredness
• uncontrollable shaking of a part of the body
• dizziness, feeling unsteady, or having trouble keeping your balance

Some side effects can be serious. If you experience any of these symptoms, or those listed in the IMPORTANT WARNINGS and SPECIAL PRECAUTIONS sections, call your doctor immediately:

• rash
• hives
• itching
• swelling of the eyes, face, mouth, lips, tongue, throat, hands, feet, ankles, or lower legs
• difficulty breathing or swallowing
• seizures
• shortness of breath
• sore throat, cough, chills, and other signs of infection
• fever, sweating, confusion, fast or irregular heartbeat, and severe muscle stiffness
• unusual movements of your face or body that you cannot control
• falling
• tightening of the neck muscles
• tightness in the throat

Brexpiprazole may cause other side effects. Call your doctor if you have any unusual problems while taking this medication.

If you experience a serious side effect, you or your doctor may send a report to the Food and Drug Administration's (FDA) MedWatch Adverse Event Reporting program online (http://www.fda.gov/Safety/MedWatch) or by phone (1-800-332-1088).

In case of overdose, call your local poison control center at 1-800-222-1222. If the victim has collapsed or is not breathing, call local emergency services at 911.

• Rexulti^®

Dosage Forms & Strengths

tablet

• 0.25mg
• 0.5mg
• 1mg
• 2mg
• 3mg
• 4mg

Schizophrenia

Indicated for schizophrenia

Recommended starting dose: 1 mg PO qDay on Days 1 through 4

Recommended target dose: 2-4 mg PO qDay; titrate to 2 mg qDay on Days 5 through 7, and then to 4 mg/day on Day 8 based on the patient’s clinical response and tolerability

Not to exceed 4 mg/day

Periodically reassess to determine the continued need and appropriate dose

Depression

Indicated as adjunctive treatment for major depressive disorder

Recommended starting dose: 0.5 mg or 1 mg PO qDay

Recommended target dose: 2 mg PO qDay; at weekly intervals, titrate to 1 mg/day, and then up to 2 mg/day

Titrate according to clinical response and tolerability

Not to exceed 3 mg/day

Periodically reassess to determine the continued need and appropriate dose

Dosage Modifications

Hepatic impairment

• Moderate-to-severe hepatic impairment (Child-Pugh ≥7)
  • MDD: Not to exceed 2 mg/day
  • Schizophrenia: Not to exceed 3 mg/day

Renal impairment

• Moderate, severe, or ESRD (CrCl <60 mL/min)
  • MDD: Not to exceed 2 mg/day
  • Schizophrenia: Not to exceed 3 mg/day

CYP2D6 poor metabolizers

• CYP2D6 poor metabolizers: Administer half of the usual brexpiprazole dose
• Known CYP2D6 poor metabolizers taking strong/moderate CYP3A4 inhibitors: Administer a quarter of the usual brexpiprazole dose

CYP2D6 or CYP3A4 inhibitors

• Strong CYP2D6 inhibitors: Administer half of the usual brexpiprazole dose (see note below for MDD)
• Strong CYP3A4 inhibitors: Administer half of the usual brexpiprazole dose
• Strong/moderate CYP2D6 inhibitors plus strong/moderate CYP3A4 inhibitors: Administer a quarter of the usual brexpiprazole dose
• If the coadministered drug is discontinued, adjust the brexpiprazole dosage to its original level
• NOTE: In MDD clinical trials, brexpiprazole dosage was not adjusted for strong CYP2D6 inhibitors (eg, paroxetine, fluoxetine); thus, CYP considerations are already factored into general dosing recommendations and brexpiprazole may be administered without dosage adjustment in patients with MDD

CYP3A4 inducers

• Strong CYP3A4 inducers: Double usual dose over 1 to 2 weeks
• If the coadministered CYP3A4 inducer is discontinued, reduce the brexpiprazole dosage to the original level over 1-2 weeks

Geriatric Dosage & Uses

Antipsychotic drugs increase the risk of death in elderly patients with dementia-related psychosis

Brexpiprazole is not approved for the treatment of patients with dementia-related psychosis (see Black Box Warnings)

Safety and efficacy not established

Rexulti is part of the drug class:

• Other antipsychotics

Tell your doctor about all the medicines you take including prescription and nonprescription medications, vitamins, and herbal supplements. Especially tell your doctor if you take:

• antidepressants (mood elevators)
• antifungals such as itraconazole (Sporanox) and ketoconazole (Nizoral)
• antihistamines
• bupropion (Wellbutrin)
• carbamazepine (Tegretol)
• clarithromycin (Biaxin)
• fluoxetine (Prozac, Sarafem)
• HIV protease inhibitors such as atazanavir (Reyataz), indinavir (Crixivan), nelfinavir (Viracept), ritonavir (Norvir), and saquinavir (Invirase)
• ipratropium (Atrovent)
• medications for anxiety, high blood pressure, irritable bowel syndrome, mental illness, motion sickness, Parkinson's disease, seizures, ulcers, or urinary problems
• nefazodone (Serzone)
• paroxetine (Paxil, Pexeva)
• quinidine (Cardioquine, Quinact, Duraquin)
• rifampin (Rifadin, Rimactane)
• sedatives
• sleeping pills
• telithromycin (Ketek)
• tranquilizers

This is not a complete list of Rexulti drug interactions. Ask your doctor or pharmacist for more information.

Serious side effects have been reported with Rexulti including the following:

• 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 of this life-threatening nervous system disorder:
  • high fever
  • stiff muscles
  • confusion
  • sweating
  • changes in pulse, heart rate, and blood pressure
• High blood sugar. Increases in blood sugar can happen in some people who take Rexulti.
• Call your healthcare provider if you have any of these symptoms of high blood sugar while taking Rexulti:
  • feel very thirsty
  • need to urinate more than usual
  • feel very hungry
  • feel weak or tired
  • feel sick to your stomach
  • feel confused, or your breath smells fruity
• Increase in weight. Weight gain has been reported in patients taking medicines like Rexulti, so you and your healthcare provider should check your weight regularly. 
• Difficulty swallowing. This may lead to aspiration and choking.
• Tardive dyskinesia. Call your healthcare provider about any movements you cannot control in your face, tongue, or other body parts. These may be signs of a serious condition. Tardive dyskinesia may not go away, even if you stop taking Rexulti. Tardive dyskinesia may also start after you stop taking Rexulti.
• Orthostatic hypotension (decreased blood pressure). Lightheadedness or fainting can occur when rising too quickly from a sitting or lying position.
• Low white blood cell count
• Seizures (convulsions)
• Problems controlling your body temperature so that you feel too warm. Avoid getting over-heated or dehydrated. 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 while taking Rexulti.

• 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 manicdepressive illness) or suicidal thoughts or actions.

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

​Do not drive, operate heavy machinery, or do other dangerous activities until you know how Rexulti affects you. Rexulti may make you drowsy. Do not drink alcohol while taking Rexulti.

Do not take Rexulti if you are allergic to brexpiprazole or any of the ingredients in Rexulti.

Contraindications

• Known hypersensitivity to brexpiprazole or any components in the formulation.1 Rash, facial swelling, urticaria, and anaphylaxis reported.1

Warnings/Precautions

Warnings

Increased risk of death with use of either conventional (first-generation) or atypical (second-generation) antipsychotics in geriatric patients with dementia-related psychosis.1 28 39 73 75

Antipsychotic agents, including brexpiprazole, are not approved for the treatment of dementia-related psychosis.1 39 73 (See Increased Mortality in Geriatric Patients with Dementia-related Psychosis in Boxed Warning, see Cerebrovascular Events in Geriatric Patients with Dementia-related Psychosis under Cautions, and see Dysphagia under Cautions.)

Possible worsening of depression and/or emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior in both adult and pediatric patients with major depressive disorder, whether or not they are taking antidepressants; may persist until clinically important remission occurs.93 94 95 (See Suicidality in Boxed Warning.) However, suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide.92 93 94

Appropriately monitor and closely observe patients receiving antidepressants for any reason, particularly during initiation of therapy (i.e., the first few months) and during periods of dosage adjustments.1 93

Consider changing or discontinuing therapy in patients whose depression is persistently worse or in those with emerging suicidality.1

Other Warnings and Precautions

Increased incidence of adverse cerebrovascular events (cerebrovascular accidents and TIAs), including fatalities, observed in geriatric patients with dementia treated with risperidone, aripiprazole, or olanzapine in placebo-controlled studies.1 The manufacturer states that brexpiprazole is not approved for the treatment of patients with dementia-related psychosis.1 (See Increased Mortality in Geriatric Patients with Dementia-related Psychosis in Boxed Warning.)

Neuroleptic malignant syndrome (NMS), a potentially fatal syndrome characterized by hyperpyrexia, muscle rigidity, altered mental status, and autonomic instability, reported with antipsychotic agents.1

If NMS is suspected, immediately discontinue therapy and provide intensive symptomatic treatment and monitoring.1

Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary dyskinetic movements, reported with use of antipsychotic agents.1

Reserve long-term antipsychotic treatment for patients with chronic illness known to respond to antipsychotic agents, and for whom alternative, effective, but potentially less harmful treatments are not available or appropriate.1 In patients requiring chronic treatment, use lowest dosage and shortest duration of treatment needed to achieve a satisfactory clinical response; periodically reassess need for continued therapy.1

APA recommends assessing patients receiving atypical antipsychotic agents for abnormal involuntary movements every 12 months; for patients at increased risk for tardive dyskinesia, assess every 6 months.28 Consider discontinuance of brexpiprazole if signs and symptoms of tardive dyskinesia appear.1 However, some patients may require treatment despite presence of the syndrome.1

Atypical antipsychotic agents, including brexpiprazole, have caused metabolic changes, including hyperglycemia and diabetes mellitus, dyslipidemia, and weight gain.1 While all atypical antipsychotics produce some metabolic changes, each drug has its own specific risk profile.1 (See Hyperglycemia and Diabetes Mellitus, see Dyslipidemia, and also see Weight Gain under Cautions.)

Hyperglycemia, sometimes severe and associated with ketoacidosis, hyperosmolar coma, or death, reported in patients receiving atypical antipsychotic agents.1 Hyperglycemia reported in patients treated with brexpiprazole.1 In short-term clinical trials, clinically important differences between brexpiprazole and placebo in the proportion of patients experiencing an increase in fasting glucose concentrations from baseline to end point not observed.1 In longer-term clinical studies, 9–10% of patients with normal or borderline fasting glucose concentrations treated with brexpiprazole experienced shifts to high fasting glucose concentrations.1

Periodically monitor patients with an established diagnosis of diabetes mellitus for worsening of glucose control and perform fasting blood glucose testing at baseline and periodically in patients with risk factors for diabetes (e.g., obesity, family history of diabetes).1 If manifestations of hyperglycemia occur in any brexpiprazole-treated patient, perform fasting blood glucose testing.1

Some patients who developed hyperglycemia while receiving an atypical antipsychotic have required continuance of antidiabetic treatment despite discontinuance of the atypical antipsychotic; in other patients, hyperglycemia resolved with discontinuance of the antipsychotic.1

Atypical antipsychotics cause adverse alterations in lipid parameters.1 In short-term clinical studies, a higher incidence of hypertriglyceridemia was reported with brexpiprazole than with placebo while changes in fasting total cholesterol, LDL-cholesterol, and HDL-cholesterol were similar between brexpiprazole-treated patients and those receiving placebo.1 11 In uncontrolled, longer-term depression and schizophrenia studies, shifts to high or very high triglyceride concentrations reported in 13–17 or 0.2–0.4%, respectively, of brexpiprazole-treated patients with normal baseline triglyceride concentrations and shifts from normal to low HDL-cholesterol concentrations reported in 14% of patients in the depression studies.1

Weight gain observed with atypical antipsychotic therapy.1 Brexpiprazole generally appears to be associated with moderate weight gain; mean weight gain of 1–1.6 kg reported during short-term studies.1 Weight gain was ≥7% of baseline body weight in 20–30% of brexpiprazole-treated patients during longer-term studies.1 11 Manufacturer recommends monitoring of weight at baseline and frequently thereafter during therapy.1

Leukopenia and neutropenia reported during therapy with antipsychotic agents.1 78 Agranulocytosis (including fatal cases) reported with other antipsychotic agents.1

Possible risk factors for leukopenia and neutropenia include preexisting low WBC count or ANC or a history of drug-induced leukopenia or neutropenia.1 78 Monitor CBC frequently during the first few months of therapy in patients with such risk factors.1 Discontinue brexpiprazole at the first sign of a decline in WBC count in the absence of other causative factors.1

Carefully monitor patients with neutropenia for signs and symptoms of infection (e.g., fever) and treat promptly if they occur.1 Discontinue brexpiprazole if severe neutropenia (ANC <1000/mm3) occurs; monitor WBC until recovery occurs.1

Risk of orthostatic hypotension and syncope with atypical antipsychotics, particularly during initial dosage titration and when dosage is increased, because of brexpiprazole's α1-adrenergic blocking activity.1

Dizziness (2%), orthostatic hypotension (0.4%), and syncope (0.1%) reported in brexpiprazole-treated patients in short-term schizophrenia studies; dizziness (2%) and orthostatic hypotension (0.1%) reported in brexpiprazole-treated patients in short-term depression trials.1

Monitor orthostatic vital signs in patients susceptible to hypotension (e.g., geriatric patients, patients with dehydration or hypovolemia, patients receiving concomitant antihypertensive therapy), patients with known cardiovascular disease (e.g., history of MI, ischemic heart disease, heart failure, or conduction abnormalities), and patients with cerebrovascular disease.1

Brexpiprazole has not been evaluated in patients with a recent history of MI or unstable cardiovascular disease; such patients were excluded from premarketing clinical trials.1

May cause somnolence, postural hypotension, and motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries.1

In patients with diseases or conditions or receiving other drugs that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic therapy and repeat such testing periodically during long-term therapy.1

Brexpiprazole may cause seizures.1 Higher risk of seizures in patients with a history of seizures or with conditions that lower the seizure threshold; conditions that lower seizure threshold may be more prevalent in older patients.1

Atypical antipsychotic agents may disrupt body's ability to reduce core body temperature.1

Use with caution in patients who may experience conditions that contribute to an elevation in core body temperature (e.g., strenuous exercise, extreme heat, dehydration, concomitant use of agents with anticholinergic activity).1

Esophageal dysmotility and aspiration associated with the use of antipsychotic agents.1 Use with caution in patients at risk for aspiration pneumonia.1

Judgment, thinking, or motor skills may be impaired.1 Somnolence (including sedation and hypersomnia) reported in 4–5% of brexpiprazole-treated patients in short-term depression and schizophrenia trials.1 (See Advice to Patients.)

Specific Populations

No adequate and well-controlled studies to date in pregnant women.1 No teratogenicity observed in animal studies, but increased perinatal deaths observed in pups at supratherapeutic dosages.1

Risk for extrapyramidal and/or withdrawal symptoms (e.g., agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, feeding disorder) in neonates exposed to antipsychotic agents during the third trimester; monitor neonates exhibiting such symptoms.1 79 80 81 Symptoms were self-limiting in some neonates but varied in severity; some infants required intensive support and prolonged hospitalization.1 79 80 81

National Pregnancy Registry for Atypical Antipsychotics: 866-961-2388 and .1

Distributes into milk in rats; not known whether distributes into human milk.1 Effects on nursing infants and on milk production also not known.1

Weigh benefits of brexpiprazole therapy to the woman and benefits of breast-feeding against potential risks of infant drug exposure.1

Safety and efficacy not established in pediatric patients.1

FDA warns that a greater risk of suicidal thinking or behavior (suicidality) occurred during the first few months of antidepressant treatment compared with placebo in children and adolescents with major depressive disorder, obsessive-compulsive disorder (OCD), or other psychiatric disorders based on pooled analyses of 24 short-term, placebo-controlled trials of 9 antidepressants (SSRIs and others).1 93 However, a later meta-analysis of 27 placebo-controlled trials of 9 antidepressants (SSRIs and others) in patients <19 years of age with major depressive disorder, OCD, or non-OCD anxiety disorders suggests that the benefits of antidepressant therapy in treating these conditions may outweigh the risks of suicidal behavior or suicidal ideation.95 No suicides occurred in these pediatric trials.1 93 95

Clinical efficacy trials of brexpiprazole did not include any patients ≥65 years of age to determine whether they respond differently than younger adults.1 Pharmacokinetics of the drug in geriatric patients (70–85 years of age) with depression were similar to those observed in younger adults.1 Manufacturer recommends cautious dosage selection in geriatric patients (see Geriatric Patients under Dosage and Administration).1

Geriatric patients with dementia-related psychosis treated with either conventional or atypical antipsychotic agents are at an increased risk of death;1 39 73 75 increased incidence of cerebrovascular events also observed with certain atypical antipsychotic agents.1 Brexpiprazole is not approved for the treatment of patients with dementia-related psychosis.1 (See Boxed Warning and also see Cerebrovascular Events in Geriatric Patients with Dementia-related Psychosis under Cautions.)

In pooled data analyses, a reduced risk of suicidality was observed in adults ≥65 years of age with antidepressant therapy compared with placebo.1 92 93 (See Boxed Warning and also see Worsening of Depression and Suicidality Risk under Cautions.)

Patients with moderate to severe hepatic impairment generally have higher brexpiprazole exposure than patients with normal hepatic function, which may increase the risk of adverse effects.1 10 Manufacturer recommends a reduction in the maximum recommended dosage in patients with moderate or severe hepatic impairment (Child-Pugh score ≥7).1 10 (See Hepatic Impairment under Dosage and Administration and also see Special Populations under Pharmacokinetics.)

Patients with moderate to severe renal impairment or end-stage renal disease generally have higher brexpiprazole exposure than patients with normal renal function, which may increase the risk of adverse effects.1 10 Manufacturer recommends a reduction in the maximum recommended dosage in patients with moderate or severe renal impairment (Clcr <60 mL/minute) or end-stage renal disease.1 (See Renal Impairment under Dosage and Administration and also see Special Populations under Pharmacokinetics.)

Dosage adjustment is recommended in patients known to be poor metabolizers of CYP2D6.1 (See Poor Metabolizers of CYP2D6 under Dosage and Administration and also see Special Populations under Pharmacokinetics.)

Common Adverse Effects

Major depressive disorder (adjunctive therapy with antidepressants): Akathisia,1 2 3 headache, 1 2 3 weight gain,1 2 3 extrapyramidal symptoms (excluding akathisia),1 2 3 somnolence,1 2 3 nasopharyngitis,1 3 tremor,1 3 anxiety,1 2 3 increased appetite,1 dizziness,1 fatigue,1 2 3 restlessness,1 2 3 constipation,1 decreased blood cortisol concentration.1 Akathisia and restlessness were dose related.1

Schizophrenia: Akathisia,1 4 5 extrapyramidal symptoms (excluding akathisia),1 weight gain,1 4 5 diarrhea,1 4 dyspepsia,1 5 tremor,1 increased CK concentrations,1 5 sedation.1 4 5

Principally metabolized by CYP3A4 and CYP2D6.1

In vitro, not a potent inhibitor or inducer of CYP isoenzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A4/5.1 10

In vitro, neither a clinically relevant substrate nor inhibitor of the efflux transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), organic anion transport proteins (OATP) 1B1 and 1B3, organic anion transporter 3 (OAT3), organic cation transporter 2 (OCT2), and multidrug and toxic compound extrusion (MATE) 1 and MATE2K.1 10

Drugs Affecting Hepatic Microsomal Enzymes

CYP3A4 and/or CYP2D6 inhibitors: Potential pharmacokinetic interaction (inhibition of brexpiprazole clearance resulting in increased systemic exposure).1 Reduce usual brexpiprazole dosage by 50% if used concomitantly with a potent inhibitor of CYP3A4 or CYP2D6; may resume previous brexpiprazole dosage upon discontinuance of the CYP3A4 or CYP2D6 inhibitor.1 Dosage adjustment not necessary when potent CYP2D6 inhibitors are used in the adjunctive treatment of major depressive disorder.1 In known poor CYP2D6 metabolizers, reduce usual brexpiprazole dosage by 75% if used concurrently with moderate or potent CYP3A4 inhibitors.1 Also reduce usual brexpiprazole dosage by 75% when given in combination with both moderate or potent CYP2D6 inhibitors and moderate or potent CYP3A4 inhibitors.1 May resume previous brexpiprazole dosage upon discontinuance of the CYP3A4 and/or CYP2D6 inhibitors.1

Potent CYP3A4 inducers: Potential pharmacokinetic interaction (increased brexpiprazole clearance resulting in decreased systemic exposure).1 Double brexpiprazole dosage over 1–2 weeks during concurrent therapy.1 May resume usual brexpiprazole dosage over 1–2 weeks upon discontinuance of the CYP3A4 inducer.1

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP3A4, CYP2B6, or CYP2D6: Dosage adjustment of the CYP substrate not necessary during concurrent use.1 10

Drugs Affecting Gastric pH

Clinically important pharmacokinetic interaction unlikely; dosage adjustment of brexpiprazole not necessary.1 10

Protein-bound Drugs

In vitro studies suggest that protein binding of brexpiprazole not affected by concurrent administration of other highly protein-bound drugs; clinically important drug interactions because of protein displacement unlikely.1 10

Specific Drugs

Rexulti tablets are available in 6 strengths (see Table 2).

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Lifetime carcinogenicity studies were conducted in ICR mice and SD rats. Brexpiprazole was administered orally for two years to male and female mice at doses of 0.75, 2 and 5 mg/kg/day (0.9 to 6.1 times the oral MRHD of 4 mg/day based on mg/m2 body surface area) and to male and female rats at doses of 1, 3, and 10 mg/kg and 3, 10, and 30 mg/kg/day, respectively (2.4 to 24 and 7.3 to 73 times the oral MRHD, males and females). In female mice, the incidence of mammary gland adenocarcinoma was increased at all doses and the incidence of adenosquamous carcinoma was increased at 2.4 and 6.1 times the MRHD. No increase in the incidence of tumors was observed in male mice. In the rat study, brexpiprazole was not carcinogenic in either sex at doses up to 73 times the MRHD.

Proliferative and/or neoplastic changes in the mammary and pituitary glands of rodents have been observed following chronic administration of antipsychotic drugs and are considered to be prolactin mediated. The potential for increasing serum prolactin level of brexpiprazole was shown in both mice and rats. The relevance for human risk of the findings of prolactin-mediated endocrine tumors in rodents is unknown.

Mutagenesis

Brexpiprazole was not mutagenic when tested in the in vitro bacterial reverse mutation assay (Ames test). Brexpiprazole was negative for clastogenic activity in the in vivo micronucleus assay in rats, and was not genotoxic in the in vivo/in vitro unscheduled DNA synthesis assay in rats. In vitro with mammalian cells brexpiprazole was clastogenic but only at doses that induced cytotoxicity. Based on a weight of evidence, brexpiprazole is not considered to present a genotoxic risk to humans.

Impairment of Fertility

Female rats were treated with oral doses of 0.3, 3 or 30 mg/kg/day (0.7, 7.3, and 73 times the oral MRHD on a mg/m2 basis) prior to mating with untreated males and continuing through conception and implantation. Estrus cycle irregularities and decreased fertility were observed at 3 and 30 mg/kg/day. Prolonged duration of pairing and increased preimplantation losses were observed at 30 mg/kg/day.

Male rats were treated with oral doses of 3, 10, or 100 mg/kg/day (7.3, 24 and 240 times the oral MRHD on a mg/m2 basis) for 63 days prior to mating with untreated females and throughout the 14 days of mating. No differences were observed in the duration of mating or fertility indices in males at any dose of brexpiprazole.

NDC 59148-037-13

30 Tablets
1 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

NDC 59148-038-13

30 Tablets
2 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

NDC 59148-039-13

30 Tablets
3 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

Take Rexulti exactly as prescribed by your doctor. Follow all directions on your prescription label. Your doctor may occasionally change your dose. Do not use this medicine in larger or smaller amounts or for longer than recommended.

You may take this medicine with or without food.

Drink plenty of fluids, especially in hot weather and during exercise. You may get dehydrated easily while taking Rexulti.

You should not stop using Rexulti suddenly. Stopping suddenly may make your condition worse.

Rexulti may cause you to have high blood sugar (hyperglycemia). If you are diabetic, check your blood sugar levels on a regular basis while you are taking this medicine.

Store at room temperature away from moisture and heat.

Rexulti 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. Rexulti 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.

Many drugs can interact with brexpiprazole. Not all possible interactions are listed here. Tell your doctor about all your current medicines and any you start or stop using, especially:

• an antibiotic or antifungal medicine;

• an antidepressant;

• antiviral medicine to treat hepatitis C or HIV;

• heart rhythm medicine; or

• seizure medicine.

This list is not complete and many other drugs can interact with brexpiprazole. This includes prescription and over-the-counter medicines, vitamins, and herbal products. Give a list of all your medicines to any healthcare provider who treats you.

More frequent side effects include: anxiety, dizziness, drowsiness, dyspepsia, fatigue, increased creatine phosphokinase, nasopharyngitis, tremor, weight gain, hypersomnia, and sedation. See below for a comprehensive list of adverse effects.