Rexulti

— THERAPEUTIC CATEGORIES —
  • Alzheimer's dementia
  • Mood disorders
  • Psychosis
PAGE CONTENTS
  • Jump to Section
  • Generic Name & Formulations
  • Indications
  • Dosage and Administration
  • Contraindications
  • Boxed Warnings
  • Warnings/Precautions
  • Pharmacokinetics
  • Interactions
  • Adverse Reactions
  • Clinical Trials
  • Note
  • Patient Counseling

    • Rexulti Generic Name & Formulations

    Legal Class

    Rx

    General Description

    Brexpiprazole 0.25mg, 0.5mg, 1mg, 2mg, 3mg, 4mg; tabs.

    Pharmacological Class

    Atypical antipsychotic.

    How Supplied

    Tabs—30

    How Supplied

    • 0.25mg tablets: Light brown, round, “BRX” and “0.25” imprinted on one side.
    • 0.5mg tablets: Light orange, round, “BRX” and “0.5” imprinted on one side.
    • 1mg tablets: Light yellow, round, “BRX” and “1” imprinted on one side.
    • 2mg tablets: Light green, round, “BRX” and “2” imprinted on one side.
    • 3mg tablets: Light purple, round, “BRX” and “3” imprinted on one side.
    • 4mg tablets: White, round, “BRX” and “4” imprinted on one side.

    Storage

    Store tablets at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).

    Manufacturer

    Otsuka America Pharmaceutical, Inc.

    Generic Availability

    NO

    Mechanism of Action

    The mechanism of action of brexpiprazole in the treatment of major depressive disorder or schizophrenia is unknown. However, the efficacy of brexpiprazole may be mediated through a combination of partial agonist activity at serotonin 5-HT1A and dopamine D2 receptors, and antagonist activity at serotonin 5-HT2A receptors.

    Rexulti Indications

    Indications

    Agitation associated with dementia due to Alzheimer disease. 

    Limitations of Use

    Not indicated as an as needed (“prn”) treatment for agitation associated with dementia due to Alzheimer disease.

    Rexulti Dosage and Administration

    Adult

    Initially 0.5mg once daily on Days 1–7; titrate to 1mg once daily on Days 8–14, then to 2mg once daily on Day 15; target dose 2mg/day; max 3mg/day after at least 14 days based on clinical response and tolerability. Moderate to severe hepatic impairment (Child-Pugh ≥7), or renal impairment (CrCl <60mL/min): max 2mg/day. CYP2D6 poor metabolizers: give ½ of usual dose; and if taking with moderate/strong CYP3A4 inhibitors: give ¼ of usual dose. Concomitant strong CYP2D6 or strong CYP3A4 inhibitors: give ½ of usual dose. Concomitant moderate/strong CYP2D6 with moderate/strong CYP3A4 inhibitors: give ¼ of usual dose. Concomitant strong CYP3A4 inducers: double usual dose over 1–2 weeks.

    Children

    Not established.

    Renal impairment

    Creatinine clearance CrCl<60 mL/minute: max recommended dosage is 2mg once daily.

    Hepatic Impairment

    Moderate to severe hepatic impairment (Child-Pugh score ≥7): max recommended dosage is 2mg once daily.

    Other Modifications

    Dosage modifications are recommended in patients who are known cytochrome P450 (CYP) 2D6 poor metabolizers and in patients taking concomitant CYP3A4 inhibitors, CYP2D6 inhibitors, or strong CYP3A4 inducers. 

    • If the concomitant drug is discontinued, adjust the Rexulti dosage to its original level.
    • If the concomitant CYP3A4 inducer is discontinued, reduce the Rexulti dosage to the original level over 1 to 2 weeks.

    CYP2D6 poor metabolizers: Administer half of the recommended dosage.

    Known CYP2D6 poor metabolizers taking strong/moderate CYP3A4 inhibitors: Administer a quarter of the recommended dosage.

    Concomitant strong CYP2D6 inhibitors: Administer half of the recommended dosage.

    Concomitant strong CYP3A4 inhibitors: Administer half of the recommended dosage.

    Concomitant strong/moderate CYP2D6 inhibitors with strong/moderate CYP3A4 inhibitors: Administer a quarter of the recommended dosage.

    Concomitant strong CYP3A4 inducers: Double the recommended dosage over 1 to 2 weeks.

    Administration

    Administer orally, once daily with or without food.

    Rexulti Contraindications

    Not Applicable

    Rexulti Boxed Warnings

    Boxed Warning

    Increased mortality in elderly patients with dementia-related psychosis. Suicidal thoughts and behaviors.

    Rexulti Warnings/Precautions

    Warnings/Precautions

    Elderly with dementia-related psychosis without agitation associated with dementia due to Alzheimer disease (not approved use); increased risk of death or cerebrovascular events (eg, stroke, TIA). Increased risk of suicidal thoughts and behavior in children, adolescents, and young adults; monitor closely for worsening or unusual changes in all patients. Cardio- or cerebrovascular disease. Discontinue immediately if neuroleptic malignant syndrome is suspected; treat appropriately and monitor. Tardive dyskinesia. Pre-existing low WBC or ANC or history of leukopenia/neutropenia; monitor CBCs during 1st few months of treatment; discontinue if WBCs decline. Monitor for hyperglycemia/diabetes, dyslipidemia, weight gain. Risk of hypotension, syncope, or aspiration. Pathological gambling and other compulsive behaviors: consider dose reduction or discontinuation if develops. History of seizures or conditions that lower the seizure threshold. Strenuous exercise. Exposure to extreme heat. Dehydration. Hypovolemia. Perform fall risk assessments when initiating and recurrently on long-term therapy. CYP2D6 poor metabolizers. Renal or moderate to severe hepatic impairment. Write ℞ for smallest practical amount. Neonates: risk of extrapyramidal and/or withdrawal symptoms post-delivery (due to exposure during 3rd-trimester pregnancy). Pregnancy. Nursing mothers.

    Warnings/Precautions

    Increased Mortality, Cerebrovascular Adverse Reactions (Including Stroke) in Elderly Patients with Dementia-Related Psychosis

    • Rexulti is not approved for the treatment of dementia-related psychosis without agitation associated with dementia due to Alzheimer disease.
    • Antipsychotic use for dementia-related psychosis increases the risk of death in elderly patients, based on analyses from 17 placebo-controlled trials.
    • Other antipsychotics (eg, risperidone, aripiprazole, olanzapine) linked to higher incidence of stroke and transient ischemic attack, including fatal stroke.

    Suicidal Thoughts and Behaviors in Children, Adolescents and Young Adults

    • Pooled analyses of placebo-controlled trials (~77,000 adults and 4500 children): Incidence of suicidal thoughts and behaviors in antidepressant-treated patients age 24 years and younger was greater than in placebo-treated patients.
    • Patients on antidepressants should be monitored for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy and during dosage changes.
    • Persistently worse depression, suicidal thoughts or behaviors: Consider changing regimen or possibly discontinuing treatment.

    Neuroleptic Malignant Syndrome (NMS)

    • Antipsychotic medications have been associated with NMS, a potentially fatal symptom complex.
    • Clinical manifestations of NMS: Hyperpyrexia, muscle rigidity, delirium, autonomic instability.
    • Additional signs of NMS: Elevated creatinine phosphokinase, myoglobinuria (rhabdomyolysis), acute renal failure.
    • Discontinue Rexulti immediately if NMS is suspected.
    • Intensive symptomatic treatment and monitoring should be provided to patients who develop NMS.

    Tardive Dyskinesia

    • Patients treated with antipsychotics may develop tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements.
    • Risk highest among elderly, especially elderly women.
    • Tardive dyskinesia may develop after a brief treatment period, even at low doses, and may also occur after discontinuation of treatment.
    • Prescribe Rexulti in a manner that reduces the risk of tardive dyskinesia.
    • Reserve chronic antipsychotic treatment for patients who suffer from chronic illness that is known to respond to antipsychotic drugs; and for whom alternative, effective, but potentially less harmful treatments are not available or appropriate.
    • Use the lowest effective dose and the shortest duration of treatment to produce a satisfactory clinical response.
    • Reassess the need for continued treatment and if signs/symptoms of tardive dyskinesia appear, consider discontinuing treatment with Rexulti.
    • Some patients may require continued treatment despite the presence of tardive dyskinesia.

    Metabolic Changes

    • Hyperglycemia and Diabetes Mellitus
      • There have been reports of hyperglycemia in patients treated with Rexulti.
      • Assess fasting plasma glucose before or soon after initiation of Rexulti and monitor periodically during long term treatment.
    • Dyslipidemia
      • Antipsychotics may cause adverse alterations in lipids.
      • Obtain fasting lipid profile at baseline and monitor periodically during treatment.
    • Weight Gain
      • Antipsychotic use has been associated with weight gain.
      • Monitor weight at baseline and frequently thereafter.

    Pathological Gambling and Other Compulsive Behaviors

    • Postmarketing reports suggest patients can experience intense urges, particularly for gambling, and the inability to control these urges while taking Rexulti.
    • Sexual urges, shopping, and binge eating have also been reported.
    • In some cases, urges stopped when the dose was reduced or the medication was discontinued. 
    • Consider dose reduction or stopping Rexulti if a patient develops behaviors that may result in harm.

    Leukopenia, Neutropenia, and Agranulocytosis

    • Leukopenia and neutropenia have been reported with antipsychotic agents.
    • Risk factors for leukopenia, neutropenia: Pre-existing low white blood cell (WBC) count or absolute neutrophil count (ANC) and history of drug-induced leukopenia or neutropenia; perform CBC in these patients frequently during the first few months of treatment.
    • Consider discontinuing Rexulti at the first sign of a clinically significant decline in WBC in the absence of other causative factors.
    • Monitor patients with clinically significant neutropenia for fever, signs of infection; treat promptly.
    • ANC< 1000/mm3: Discontinue Rexulti.

    Orthostatic Hypotension and Syncope

    • Risk for orthostatic hypotension and syncope is greatest during initial dose administration.
    • Patients vulnerable to hypotension: Orthostatic vital signs should be monitored.
    • Rexulti has not been evaluated in patients with a recent history of myocardial infarction or unstable cardiovascular disease.

    Falls

    • Rexulti may cause somnolence, postural hypotension, and motor and sensory instability.
    • Patients with diseases, conditions or on medications that exacerbate these effects: Complete fall risk assessments when initiating treatment and periodically during long term treatment.

    Seizures

    • Rexulti may cause seizures.
    • The risk is greatest in patients with a history of seizures or with conditions that lower the seizure threshold.

    Potential for Cognitive and Motor Impairment

    • Rexulti may impair judgement, thinking and motor skills.
    • Caution patients not to operate hazardous machinery, including motor vehicles, until they are reasonably certain that therapy does not affect them adversely.

    Body Temperature Dysregulation

    • Atypical antipsychotics may disrupt the body’s ability to reduce core body temperature.
    • Use Rexulti with caution in patients who perform strenuous exercise, are exposed to extreme heat, are dehydrated, or are on anticholinergic medications.

    Dysphagia

    • Esophageal dysmotility and aspiration have been associated with antipsychotic drugs.
    • Use cautiously in patients at risk for aspiration.

    Pregnancy Considerations

    Neonates exposed to antipsychotic drugs during the third trimester are at risk for extrapyramidal and/or withdrawal symptoms following delivery.

    Health care providers are encouraged to register patients in the National Pregnancy Registry for Atypical Antipsychotics at 866-961-2388 or online at https://womensmentalhealth.org/research/pregnancyregistry/.

    Nursing Mother Considerations

    There are no available data on the presence of brexpiprazole in human milk, the effects on the breastfed infant, or the effects on milk production. Consider the mother’s clinical need vs the potential adverse effects for the breastfed infant.

    Pediatric Considerations

    Not applicable.

    Geriatric Considerations

    Clinical studies did not include sufficient numbers of younger patients to determine if patients aged 65 years and older respond differently than younger patients.

    Renal Impairment Considerations

    Patients with renal impairment had higher exposure to brexpiprazole than patients with normal renal function. Max recommended dosage in patients with CrCl<60 mL/minute is lower than those with mild renal impairment and those with normal renal function.

    Hepatic Impairment Considerations

    Patients with moderate to severe hepatic impairment generally had higher exposure to brexpiprazole than patients with normal hepatic function. Max recommended dosage in patients with moderate to severe hepatic impairment (Child-Pugh score ≥7) is lower than those with mild hepatic impairment and those with normal hepatic function.

    Other Considerations for Specific Populations

    CYP2D6 poor metabolizers: Dosage adjustment is recommended because these patients have higher brexpiprazole concentrations than normal metabolizers of CYP2D6.

    Rexulti Pharmacokinetics

    Absorption

    • Peak plasma concentration occurred within 4 hours after administration.

    • Absolute oral bioavailability: 95%.

    • Steady-state concentrations were attained within 10 to 12 days of dosing.

    Distribution

    • Volume of distribution after IV administration: 1.56 ± 0.42 L/kg.

    • Plasma protein bound: >99%.

    Metabolism

    • Mainly mediated by CYP3A4 and CYP2D6. 

    Elimination

    • Fecal (46%), renal (25%). Half-life: 91 hours.

    Rexulti Interactions

    Interactions

    See Adults. May be potentiated by strong CYP3A4 inhibitors (eg, itraconazole, clarithromycin, ketoconazole) or strong CYP2D6 inhibitors (eg, paroxetine, fluoxetine, quinidine). May be antagonized by strong CYP3A4 inducers (eg, rifampin, St. John’s wort). Potentiates antihypertensives. Caution with drugs that interfere with temperature regulation (eg, anticholinergics).

    Rexulti Adverse Reactions

    Adverse Reactions

    Weight gain, akathisia, headache, somnolence, tremor, nasopharyngitis, fatigue, increased appetite, dizziness, anxiety, restlessness.

    Rexulti Clinical Trials

    Clinical Trials

    The approval was based on data from two 12-week, double-blind, placebo-controlled phase 3 studies (Study 331-12-283 and Study 331-14-213) in which patients with dementia due to Alzheimer disease were randomly assigned to receive either brexpiprazole or placebo.

    Study participants were required to have a diagnosis of probable Alzheimer disease (according to NINCDS-ADRDA criteria), have a Mini-Mental State Examination score of at least 5 and less than or equal to 22 and have a total score of at least 4 by the agitation/aggression item of the NPI/NPI-NH, and exhibit sufficient agitation behaviors at time of entry to warrant use of pharmacotherapy, after excluding other factors.

    The primary endpoint for both studies was the change from baseline in the Cohen-Mansfield Agitation Inventory (CMAI) total score at week 12. The CMAI consists of 29 items that assess the frequency and manifestations of agitated behaviors in elderly patients, based on caregiver input. Total scores range from 29 (best) to 203 (worst).

    In Study 331-12-283, results showed that treatment with brexpiprazole 2mg/day significantly improved symptoms of agitation compared with placebo based on the mean change in CMAI total score from baseline to week 12 (placebo-subtracted difference: -3.8 [95% CI, -7.4, -0.2]; P <.05). A statistically significant improvement was also observed with brexpiprazole 2mg/day and 3mg/day compared with placebo in Study 331-14-213 (placebo-subtracted difference: -5.3 [95% CI, -8.8, -1.9]; P <.05).

    Rexulti Note

    Not Applicable

    Rexulti Patient Counseling

    Patient Counseling

    Look for the emergence of suicidality, especially early during treatment; report these symptoms.

    Neuroleptic malignant syndrome has been reported with antipsychotic drugs. Contact a health care provider or report to the emergency room if signs and symptoms of NMS develop.

    Tardive dyskinesia possible with antipsychotic medications; report abnormal movements.

    Risk of metabolic changes, monitoring of blood glucose, lipids, and weight is necessary.

    Compulsive behaviors (shopping, gambling, sexual urges) may develop during treatment.

    Pre-existing low WBC or a history of drug induced leukopenia/ neutropenia: CBC monitoring needed during treatment.

    Risk of orthostatic hypotension and syncope, especially early in treatment, and also at times of re-initiating treatment.

    Do not perform activities requiring mental alertness, such as operating hazardous machinery or operating a motor vehicle, until it has been established that Rexulti does not not impact cognitive and motor performance adversely.

    Avoid overheating and dehydration.

    Changes in prescription medications, OTC/herbal use should be reported because of potential drug interactions.

    Report pregnancy; use of Rexulti during the third trimester may cause extrapyramidal and/or withdrawal symptoms  in the neonate.

    Cost Savings Program

    Rexulti Savings Card

    Rexulti Generic Name & Formulations

    Legal Class

    Rx

    General Description

    Brexpiprazole 0.25mg, 0.5mg, 1mg, 2mg, 3mg, 4mg; tabs.

    Pharmacological Class

    Atypical antipsychotic.

    How Supplied

    Tabs—30

    How Supplied

    • 0.25mg tablets: Light brown, round, “BRX” and “0.25” imprinted on one side.
    • 0.5mg tablets: Light orange, round, “BRX” and “0.5” imprinted on one side.
    • 1mg tablets: Light yellow, round, “BRX” and “1” imprinted on one side.
    • 2mg tablets: Light green, round, “BRX” and “2” imprinted on one side.
    • 3mg tablets: Light purple, round, “BRX” and “3” imprinted on one side.
    • 4mg tablets: White, round, “BRX” and “4” imprinted on one side.

    Storage

    Store tablets at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).

    Manufacturer

    Otsuka America Pharmaceutical, Inc.

    Generic Availability

    NO

    Mechanism of Action

    The mechanism of action of brexpiprazole in the treatment of major depressive disorder or schizophrenia is unknown. However, the efficacy of brexpiprazole may be mediated through a combination of partial agonist activity at serotonin 5-HT1A and dopamine D2 receptors, and antagonist activity at serotonin 5-HT2A receptors.

    Rexulti Indications

    Indications

    Adjunct therapy for major depressive disorder (MDD).

    Rexulti Dosage and Administration

    Adult

    Initially 0.5mg or 1mg once daily; titrate weekly up to target dose of 2mg/day; max 3mg/day. Moderate to severe hepatic impairment (Child-Pugh ≥7), or renal impairment (CrCl <60mL/min): max 2mg/day. CYP2D6 poor metabolizers: give ½ of usual dose; and if taking with moderate/strong CYP3A4 inhibitors: give ¼ of usual dose. Concomitant strong CYP3A4 inhibitors: give ½ of usual dose. Concomitant moderate/strong CYP2D6 with moderate/strong CYP3A4 inhibitors: give ¼ of usual dose. Concomitant strong CYP3A4 inducers: double usual dose over 1–2 weeks.

    Children

    Not established.

    Renal impairment

    Creatinine clearance CrCl<60 mL/minute: max recommended dosage is 2mg once daily.

    Hepatic Impairment

    Moderate to severe hepatic impairment (Child-Pugh score ≥7): max recommended dosage is 2mg once daily.

    Other Modifications

    Dosage modifications are recommended in patients who are known cytochrome P450 (CYP) 2D6 poor metabolizers and in patients taking concomitant CYP3A4 inhibitors, CYP2D6 inhibitors, or strong CYP3A4 inducers. 

    • If the concomitant drug is discontinued, adjust the Rexulti dosage to its original level.
    • If the concomitant CYP3A4 inducer is discontinued, reduce the Rexulti dosage to the original level over 1 to 2 weeks.

    CYP2D6 poor metabolizers: Administer half of the recommended dosage.

    Known CYP2D6 poor metabolizers taking strong/moderate CYP3A4 inhibitors: Administer a quarter of the recommended dosage.

    Concomitant strong CYP2D6 inhibitors: Administer half of the recommended dosage.

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

    Concomitant strong CYP3A4 inhibitors: Administer half of the recommended dosage.

    Concomitant strong/moderate CYP2D6 inhibitors with strong/moderate CYP3A4 inhibitors: Administer a quarter of the recommended dosage.

    Concomitant strong CYP3A4 inducers: Double the recommended dosage over 1 to 2 weeks.

    Administration

    Administer orally, once daily with or without food.

    Rexulti Contraindications

    Not Applicable

    Rexulti Boxed Warnings

    Boxed Warning

    Increased mortality in elderly patients with dementia-related psychosis. Suicidal thoughts and behaviors.

    Rexulti Warnings/Precautions

    Warnings/Precautions

    Elderly with dementia-related psychosis without agitation associated with dementia due to Alzheimer disease (not approved use); increased risk of death or cerebrovascular events (eg, stroke, TIA). Increased risk of suicidal thoughts and behavior in children, adolescents, and young adults; monitor closely for worsening or unusual changes in all patients. Cardio- or cerebrovascular disease. Discontinue immediately if neuroleptic malignant syndrome is suspected; treat appropriately and monitor. Tardive dyskinesia. Pre-existing low WBC or ANC or history of leukopenia/neutropenia; monitor CBCs during 1st few months of treatment; discontinue if WBCs decline. Monitor for hyperglycemia/diabetes, dyslipidemia, weight gain. Risk of hypotension, syncope, or aspiration. Pathological gambling and other compulsive behaviors: consider dose reduction or discontinuation if develops. History of seizures or conditions that lower the seizure threshold. Strenuous exercise. Exposure to extreme heat. Dehydration. Hypovolemia. Perform fall risk assessments when initiating and recurrently on long-term therapy. CYP2D6 poor metabolizers. Renal or moderate to severe hepatic impairment. Write ℞ for smallest practical amount. Neonates: risk of extrapyramidal and/or withdrawal symptoms post-delivery (due to exposure during 3rd-trimester pregnancy). Pregnancy. Nursing mothers.

    Warnings/Precautions

    Increased Mortality, Cerebrovascular Adverse Reactions (Including Stroke) in Elderly Patients with Dementia-Related Psychosis

    • Rexulti is not approved for the treatment of dementia-related psychosis without agitation associated with dementia due to Alzheimer disease.
    • Antipsychotic use for dementia-related psychosis increases the risk of death in elderly patients, based on analyses from 17 placebo-controlled trials.
    • Other antipsychotics (eg, risperidone, aripiprazole, olanzapine) linked to higher incidence of stroke and transient ischemic attack, including fatal stroke.

    Suicidal Thoughts and Behaviors in Children, Adolescents and Young Adults

    • Pooled analyses of placebo-controlled trials (~77,000 adults and 4500 children): Incidence of suicidal thoughts and behaviors in antidepressant-treated patients age 24 years and younger was greater than in placebo-treated patients.
    • Patients on antidepressants should be monitored for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy and during dosage changes.
    • Persistently worse depression, suicidal thoughts or behaviors: Consider changing regimen or possibly discontinuing treatment.

    Neuroleptic Malignant Syndrome (NMS)

    • Antipsychotic medications have been associated with NMS, a potentially fatal symptom complex.
    • Clinical manifestations of NMS: Hyperpyrexia, muscle rigidity, delirium, autonomic instability.
    • Additional signs of NMS: Elevated creatinine phosphokinase, myoglobinuria (rhabdomyolysis), acute renal failure.
    • Discontinue Rexulti immediately if NMS is suspected.
    • Intensive symptomatic treatment and monitoring should be provided to patients who develop NMS.

    Tardive Dyskinesia

    • Patients treated with antipsychotics may develop tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements.
    • Risk highest among elderly, especially elderly women.
    • Tardive dyskinesia may develop after a brief treatment period, even at low doses, and may also occur after discontinuation of treatment.
    • Prescribe Rexulti in a manner that reduces the risk of tardive dyskinesia.
    • Reserve chronic antipsychotic treatment for patients who suffer from chronic illness that is known to respond to antipsychotic drugs; and for whom alternative, effective, but potentially less harmful treatments are not available or appropriate.
    • Use the lowest effective dose and the shortest duration of treatment to produce a satisfactory clinical response.
    • Reassess the need for continued treatment and if signs/symptoms of tardive dyskinesia appear, consider discontinuing treatment with Rexulti.
    • Some patients may require continued treatment despite the presence of tardive dyskinesia.

    Metabolic Changes

    • Hyperglycemia and Diabetes Mellitus
      • There have been reports of hyperglycemia in patients treated with Rexulti.
      • Assess fasting plasma glucose before or soon after initiation of Rexulti and monitor periodically during long term treatment.
    • Dyslipidemia
      • Antipsychotics may cause adverse alterations in lipids.
      • Obtain fasting lipid profile at baseline and monitor periodically during treatment.
    • Weight Gain
      • Antipsychotic use has been associated with weight gain.
      • Monitor weight at baseline and frequently thereafter.

    Pathological Gambling and Other Compulsive Behaviors

    • Postmarketing reports suggest patients can experience intense urges, particularly for gambling, and the inability to control these urges while taking Rexulti.
    • Sexual urges, shopping, and binge eating have also been reported.
    • In some cases, urges stopped when the dose was reduced or the medication was discontinued. 
    • Consider dose reduction or stopping Rexulti if a patient develops behaviors that may result in harm.

    Leukopenia, Neutropenia, and Agranulocytosis

    • Leukopenia and neutropenia have been reported with antipsychotic agents.
    • Risk factors for leukopenia, neutropenia: Pre-existing low white blood cell (WBC) count or absolute neutrophil count (ANC) and history of drug-induced leukopenia or neutropenia; perform CBC in these patients frequently during the first few months of treatment.
    • Consider discontinuing Rexulti at the first sign of a clinically significant decline in WBC in the absence of other causative factors.
    • Monitor patients with clinically significant neutropenia for fever, signs of infection; treat promptly.
    • ANC< 1000/mm3: Discontinue Rexulti.

    Orthostatic Hypotension and Syncope

    • Risk for orthostatic hypotension and syncope is greatest during initial dose administration.
    • Patients vulnerable to hypotension: Orthostatic vital signs should be monitored.
    • Rexulti has not been evaluated in patients with a recent history of myocardial infarction or unstable cardiovascular disease.

    Falls

    • Rexulti may cause somnolence, postural hypotension, and motor and sensory instability.
    • Patients with diseases, conditions or on medications that exacerbate these effects: Complete fall risk assessments when initiating treatment and periodically during long term treatment.

    Seizures

    • Rexulti may cause seizures.
    • The risk is greatest in patients with a history of seizures or with conditions that lower the seizure threshold.

    Potential for Cognitive and Motor Impairment

    • Rexulti may impair judgement, thinking and motor skills.
    • Caution patients not to operate hazardous machinery, including motor vehicles, until they are reasonably certain that therapy does not affect them adversely.

    Body Temperature Dysregulation

    • Atypical antipsychotics may disrupt the body’s ability to reduce core body temperature.
    • Use Rexulti with caution in patients who perform strenuous exercise, are exposed to extreme heat, are dehydrated, or are on anticholinergic medications.

    Dysphagia

    • Esophageal dysmotility and aspiration have been associated with antipsychotic drugs.
    • Use cautiously in patients at risk for aspiration.

    Pregnancy Considerations

    Neonates exposed to antipsychotic drugs during the third trimester are at risk for extrapyramidal and/or withdrawal symptoms following delivery.

    Health care providers are encouraged to register patients in the National Pregnancy Registry for Atypical Antipsychotics at 866-961-2388 or online at https://womensmentalhealth.org/research/pregnancyregistry/.

    Nursing Mother Considerations

    There are no available data on the presence of brexpiprazole in human milk, the effects on the breastfed infant, or the effects on milk production. Consider the mother’s clinical need vs the potential adverse effects for the breastfed infant.

    Pediatric Considerations

    Safety and effectiveness in pediatric patients with MDD; antidepressants increase the risk of suicidal thoughts and behaviors in pediatric patients.

    Geriatric Considerations

    Clinical studies did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger patients. Dosage selection should be cautious, usually starting at the low end of the dosing range.

    Renal Impairment Considerations

    Patients with renal impairment had higher exposure to brexpiprazole than patients with normal renal function. Max recommended dosage in patients with CrCl<60 mL/minute is lower than those with mild renal impairment and those with normal renal function.

    Hepatic Impairment Considerations

    Patients with moderate to severe hepatic impairment generally had higher exposure to brexpiprazole than patients with normal hepatic function. Max recommended dosage in patients with moderate to severe hepatic impairment (Child-Pugh score ≥7) is lower than those with mild hepatic impairment and those with normal hepatic function.

    Other Considerations for Specific Populations

    CYP2D6 poor metabolizers: Dosage adjustment is recommended because these patients have higher brexpiprazole concentrations than normal metabolizers of CYP2D6.

    Rexulti Pharmacokinetics

    Absorption

    • Peak plasma concentration occurred within 4 hours after administration.

    • Absolute oral bioavailability: 95%.

    • Steady-state concentrations were attained within 10 to 12 days of dosing.

    Distribution

    • Volume of distribution after IV administration: 1.56 ± 0.42 L/kg.

    • Plasma protein bound: >99%.

    Metabolism

    • Mainly mediated by CYP3A4 and CYP2D6. 

    Elimination

    • Fecal (46%), renal (25%). Half-life: 91 hours.

    Rexulti Interactions

    Interactions

    See Adults. May be potentiated by strong CYP3A4 inhibitors (eg, itraconazole, clarithromycin, ketoconazole) or strong CYP2D6 inhibitors (eg, paroxetine, fluoxetine, quinidine). May be antagonized by strong CYP3A4 inducers (eg, rifampin, St. John’s wort). Potentiates antihypertensives. Caution with drugs that interfere with temperature regulation (eg, anticholinergics).

    Rexulti Adverse Reactions

    Adverse Reactions

    Weight gain, akathisia, headache, somnolence, tremor, nasopharyngitis, fatigue, increased appetite, dizziness, anxiety, restlessness.

    Rexulti Clinical Trials

    Clinical Trials

    Rexulti was studied in two 6-week, placebo-controlled clinical trials of adults with MDD. Study participants met DSM-IV-TR criteria for MDD and had an inadequate response to prior antidepressant therapy (ADT; 1 to 3 courses) in the current episode and also demonstrated an inadequate response throughout the 8 weeks of prospective antidepressant treatment.

    The primary endpoint for both studies was change in Montgomery-Åsberg Depression Rating Scale (MADRS). Study data showed that Rexulti plus ADT at 2mg and 3mg was superior to placebo. A decrease in baseline MADRS of 8.4 (2mg) and 8.3 (3mg) was seen vs placebo + ADT decreases of 5.2 and 6.3 in the respective studies.

    Rexulti Note

    Not Applicable

    Rexulti Patient Counseling

    Patient Counseling

    Look for the emergence of suicidality, especially early during treatment; report these symptoms.

    Neuroleptic malignant syndrome has been reported with antipsychotic drugs. Contact a health care provider or report to the emergency room if signs and symptoms of NMS develop.

    Tardive dyskinesia possible with antipsychotic medications; report abnormal movements.

    Risk of metabolic changes, monitoring of blood glucose, lipids, and weight is necessary.

    Compulsive behaviors (shopping, gambling, sexual urges) may develop during treatment.

    Pre-existing low WBC or a history of drug induced leukopenia/ neutropenia: CBC monitoring needed during treatment.

    Risk of orthostatic hypotension and syncope, especially early in treatment, and also at times of re-initiating treatment.

    Do not perform activities requiring mental alertness, such as operating hazardous machinery or operating a motor vehicle, until it has been established that Rexulti does not not impact cognitive and motor performance adversely.

    Avoid overheating and dehydration.

    Changes in prescription medications, OTC/herbal use should be reported because of potential drug interactions.

    Report pregnancy; use of Rexulti during the third trimester may cause extrapyramidal and/or withdrawal symptoms  in the neonate.

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    Rexulti Generic Name & Formulations

    Legal Class

    Rx

    General Description

    Brexpiprazole 0.25mg, 0.5mg, 1mg, 2mg, 3mg, 4mg; tabs.

    Pharmacological Class

    Atypical antipsychotic.

    How Supplied

    Tabs—30

    How Supplied

    • 0.25mg tablets: Light brown, round, “BRX” and “0.25” imprinted on one side.
    • 0.5mg tablets: Light orange, round, “BRX” and “0.5” imprinted on one side.
    • 1mg tablets: Light yellow, round, “BRX” and “1” imprinted on one side.
    • 2mg tablets: Light green, round, “BRX” and “2” imprinted on one side.
    • 3mg tablets: Light purple, round, “BRX” and “3” imprinted on one side.
    • 4mg tablets: White, round, “BRX” and “4” imprinted on one side.

    Storage

    Store tablets at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).

    Manufacturer

    Otsuka America Pharmaceutical, Inc.

    Generic Availability

    NO

    Mechanism of Action

    The mechanism of action of brexpiprazole in the treatment of major depressive disorder or schizophrenia is unknown. However, the efficacy of brexpiprazole may be mediated through a combination of partial agonist activity at serotonin 5-HT1A and dopamine D2 receptors, and antagonist activity at serotonin 5-HT2A receptors.

    Rexulti Indications

    Indications

    Schizophrenia.

    Rexulti Dosage and Administration

    Adult

    >17yrs: Initially 1mg once daily on Days 1–4; titrate to 2mg once daily on Day 5–7, then to 4mg once daily on Day 8; target dose 2–4mg/day; max 4mg/day. Moderate to severe hepatic impairment (Child-Pugh ≥7), or renal impairment (CrCl <60mL/min): max 3mg/day. CYP2D6 poor metabolizers: give ½ of usual dose; and if taking with moderate/strong CYP3A4 inhibitors: give ¼ of usual dose. Concomitant strong CYP2D6 or strong CYP3A4 inhibitors: give ½ of usual dose. Concomitant moderate/strong CYP2D6 with moderate/strong CYP3A4 inhibitors: give ¼ of usual dose. Concomitant strong CYP3A4 inducers: double usual dose over 1–2 weeks.

    Children

    <13yrs: not established. 13–17yrs: Initially 0.5mg once daily on Days 1–4; titrate to 1mg once daily on Day 5–7, then to 2mg once daily on Day 8; target dose 2–4mg/day; max 4mg/day. Moderate to severe hepatic impairment (Child-Pugh ≥7), or renal impairment (CrCl <60mL/min): max 3mg/day. CYP2D6 poor metabolizers: give ½ of usual dose; and if taking with moderate/strong CYP3A4 inhibitors: give ¼ of usual dose. Concomitant strong CYP2D6 or strong CYP3A4 inhibitors: give ½ of usual dose. Concomitant moderate/strong CYP2D6 with moderate/strong CYP3A4 inhibitors: give ¼ of usual dose. Concomitant strong CYP3A4 inducers: double usual dose over 1–2 weeks.

    Renal impairment

    Creatinine clearance CrCl<60 mL/minute: max recommended dosage is 3mg once daily.

    Hepatic Impairment

    Moderate to severe hepatic impairment (Child-Pugh score ≥7): max recommended dosage is 3mg once daily.

    Other Modifications

    Dosage modifications are recommended in patients who are known cytochrome P450 (CYP) 2D6 poor metabolizers and in patients taking concomitant CYP3A4 inhibitors, CYP2D6 inhibitors, or strong CYP3A4 inducers. 

    • If the concomitant drug is discontinued, adjust the Rexulti dosage to its original level.
    • If the concomitant CYP3A4 inducer is discontinued, reduce the Rexulti dosage to the original level over 1 to 2 weeks.

    CYP2D6 poor metabolizers: Administer half of the recommended dosage.

    Known CYP2D6 poor metabolizers taking strong/moderate CYP3A4 inhibitors: Administer a quarter of the recommended dosage.

    Concomitant strong CYP2D6 inhibitors: Administer half of the recommended dosage.

    Concomitant strong CYP3A4 inhibitors: Administer half of the recommended dosage.

    Concomitant strong/moderate CYP2D6 inhibitors with strong/moderate CYP3A4 inhibitors: Administer a quarter of the recommended dosage.

    Concomitant strong CYP3A4 inducers: Double the recommended dosage over 1 to 2 weeks.

    Administration

    Administer orally, once daily with or without food.

    Rexulti Contraindications

    Not Applicable

    Rexulti Boxed Warnings

    Boxed Warning

    Increased mortality in elderly patients with dementia-related psychosis. Suicidal thoughts and behaviors.

    Rexulti Warnings/Precautions

    Warnings/Precautions

    Elderly with dementia-related psychosis without agitation associated with dementia due to Alzheimer disease (not approved use); increased risk of death or cerebrovascular events (eg, stroke, TIA). Increased risk of suicidal thoughts and behavior in children, adolescents, and young adults; monitor closely for worsening or unusual changes in all patients. Cardio- or cerebrovascular disease. Discontinue immediately if neuroleptic malignant syndrome is suspected; treat appropriately and monitor. Tardive dyskinesia. Pre-existing low WBC or ANC or history of leukopenia/neutropenia; monitor CBCs during 1st few months of treatment; discontinue if WBCs decline. Monitor for hyperglycemia/diabetes, dyslipidemia, weight gain. Risk of hypotension, syncope, or aspiration. Pathological gambling and other compulsive behaviors: consider dose reduction or discontinuation if develops. History of seizures or conditions that lower the seizure threshold. Strenuous exercise. Exposure to extreme heat. Dehydration. Hypovolemia. Perform fall risk assessments when initiating and recurrently on long-term therapy. CYP2D6 poor metabolizers. Renal or moderate to severe hepatic impairment. Write ℞ for smallest practical amount. Neonates: risk of extrapyramidal and/or withdrawal symptoms post-delivery (due to exposure during 3rd-trimester pregnancy). Pregnancy. Nursing mothers.

    Warnings/Precautions

    Increased Mortality, Cerebrovascular Adverse Reactions (Including Stroke) in Elderly Patients with Dementia-Related Psychosis

    • Rexulti is not approved for the treatment of dementia-related psychosis without agitation associated with dementia due to Alzheimer disease.
    • Antipsychotic use for dementia-related psychosis increases the risk of death in elderly patients, based on analyses from 17 placebo-controlled trials.
    • Other antipsychotics (eg, risperidone, aripiprazole, olanzapine) linked to higher incidence of stroke and transient ischemic attack, including fatal stroke.

    Suicidal Thoughts and Behaviors in Children, Adolescents and Young Adults

    • Pooled analyses of placebo-controlled trials (~77,000 adults and 4500 children): Incidence of suicidal thoughts and behaviors in antidepressant-treated patients age 24 years and younger was greater than in placebo-treated patients.
    • Patients on antidepressants should be monitored for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy and during dosage changes.
    • Persistently worse depression, suicidal thoughts or behaviors: Consider changing regimen or possibly discontinuing treatment.

    Neuroleptic Malignant Syndrome (NMS)

    • Antipsychotic medications have been associated with NMS, a potentially fatal symptom complex.
    • Clinical manifestations of NMS: Hyperpyrexia, muscle rigidity, delirium, autonomic instability.
    • Additional signs of NMS: Elevated creatinine phosphokinase, myoglobinuria (rhabdomyolysis), acute renal failure.
    • Discontinue Rexulti immediately if NMS is suspected.
    • Intensive symptomatic treatment and monitoring should be provided to patients who develop NMS.

    Tardive Dyskinesia

    • Patients treated with antipsychotics may develop tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements.
    • Risk highest among elderly, especially elderly women.
    • Tardive dyskinesia may develop after a brief treatment period, even at low doses, and may also occur after discontinuation of treatment.
    • Prescribe Rexulti in a manner that reduces the risk of tardive dyskinesia.
    • Reserve chronic antipsychotic treatment for patients who suffer from chronic illness that is known to respond to antipsychotic drugs; and for whom alternative, effective, but potentially less harmful treatments are not available or appropriate.
    • Use the lowest effective dose and the shortest duration of treatment to produce a satisfactory clinical response.
    • Reassess the need for continued treatment and if signs/symptoms of tardive dyskinesia appear, consider discontinuing treatment with Rexulti.
    • Some patients may require continued treatment despite the presence of tardive dyskinesia.

    Metabolic Changes

    • Hyperglycemia and Diabetes Mellitus
      • There have been reports of hyperglycemia in patients treated with Rexulti.
      • Assess fasting plasma glucose before or soon after initiation of Rexulti and monitor periodically during long term treatment.
    • Dyslipidemia
      • Antipsychotics may cause adverse alterations in lipids.
      • Obtain fasting lipid profile at baseline and monitor periodically during treatment.
    • Weight Gain
      • Antipsychotic use has been associated with weight gain.
      • Monitor weight at baseline and frequently thereafter.

    Pathological Gambling and Other Compulsive Behaviors

    • Postmarketing reports suggest patients can experience intense urges, particularly for gambling, and the inability to control these urges while taking Rexulti.
    • Sexual urges, shopping, and binge eating have also been reported.
    • In some cases, urges stopped when the dose was reduced or the medication was discontinued. 
    • Consider dose reduction or stopping Rexulti if a patient develops behaviors that may result in harm.

    Leukopenia, Neutropenia, and Agranulocytosis

    • Leukopenia and neutropenia have been reported with antipsychotic agents.
    • Risk factors for leukopenia, neutropenia: Pre-existing low white blood cell (WBC) count or absolute neutrophil count (ANC) and history of drug-induced leukopenia or neutropenia; perform CBC in these patients frequently during the first few months of treatment.
    • Consider discontinuing Rexulti at the first sign of a clinically significant decline in WBC in the absence of other causative factors.
    • Monitor patients with clinically significant neutropenia for fever, signs of infection; treat promptly.
    • ANC< 1000/mm3: Discontinue Rexulti.

    Orthostatic Hypotension and Syncope

    • Risk for orthostatic hypotension and syncope is greatest during initial dose administration.
    • Patients vulnerable to hypotension: Orthostatic vital signs should be monitored.
    • Rexulti has not been evaluated in patients with a recent history of myocardial infarction or unstable cardiovascular disease.

    Falls

    • Rexulti may cause somnolence, postural hypotension, and motor and sensory instability.
    • Patients with diseases, conditions or on medications that exacerbate these effects: Complete fall risk assessments when initiating treatment and periodically during long term treatment.

    Seizures

    • Rexulti may cause seizures.
    • The risk is greatest in patients with a history of seizures or with conditions that lower the seizure threshold.

    Potential for Cognitive and Motor Impairment

    • Rexulti may impair judgement, thinking and motor skills.
    • Caution patients not to operate hazardous machinery, including motor vehicles, until they are reasonably certain that therapy does not affect them adversely.

    Body Temperature Dysregulation

    • Atypical antipsychotics may disrupt the body’s ability to reduce core body temperature.
    • Use Rexulti with caution in patients who perform strenuous exercise, are exposed to extreme heat, are dehydrated, or are on anticholinergic medications.

    Dysphagia

    • Esophageal dysmotility and aspiration have been associated with antipsychotic drugs.
    • Use cautiously in patients at risk for aspiration.

    Pregnancy Considerations

    Neonates exposed to antipsychotic drugs during the third trimester are at risk for extrapyramidal and/or withdrawal symptoms following delivery.

    Health care providers are encouraged to register patients in the National Pregnancy Registry for Atypical Antipsychotics at 866-961-2388 or online at https://womensmentalhealth.org/research/pregnancyregistry/.

    Nursing Mother Considerations

    There are no available data on the presence of brexpiprazole in human milk, the effects on the breastfed infant, or the effects on milk production. Consider the mother’s clinical need vs the potential adverse effects for the breastfed infant.

    Pediatric Considerations

    Use of Rexulti in this population is supported by evidence from adequate and well-controlled studies in adults with schizophrenia, pharmacokinetic data from adults and pediatric patients, and safety data in pediatric patients 13 to 17 years of age.

    Geriatric Considerations

    Clinical studies did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger patients. Dosage selection should be cautious, usually starting at the low end of the dosing range.

    Renal Impairment Considerations

    Patients with renal impairment had higher exposure to brexpiprazole than patients with normal renal function. Max recommended dosage in patients with CrCl<60 mL/minute is lower than those with mild renal impairment and those with normal renal function.

    Hepatic Impairment Considerations

    Patients with moderate to severe hepatic impairment generally had higher exposure to brexpiprazole than patients with normal hepatic function. Max recommended dosage in patients with moderate to severe hepatic impairment (Child-Pugh score ≥7) is lower than those with mild hepatic impairment and those with normal hepatic function.

    Other Considerations for Specific Populations

    CYP2D6 poor metabolizers: Dosage adjustment is recommended because these patients have higher brexpiprazole concentrations than normal metabolizers of CYP2D6.

    Rexulti Pharmacokinetics

    Absorption

    • Peak plasma concentration occurred within 4 hours after administration.

    • Absolute oral bioavailability: 95%.

    • Steady-state concentrations were attained within 10 to 12 days of dosing.

    Distribution

    • Volume of distribution after IV administration: 1.56 ± 0.42 L/kg.

    • Plasma protein bound: >99%.

    Metabolism

    • Mainly mediated by CYP3A4 and CYP2D6. 

    Elimination

    • Fecal (46%), renal (25%). Half-life: 91 hours.

    Rexulti Interactions

    Interactions

    See Adults. May be potentiated by strong CYP3A4 inhibitors (eg, itraconazole, clarithromycin, ketoconazole) or strong CYP2D6 inhibitors (eg, paroxetine, fluoxetine, quinidine). May be antagonized by strong CYP3A4 inducers (eg, rifampin, St. John’s wort). Potentiates antihypertensives. Caution with drugs that interfere with temperature regulation (eg, anticholinergics).

    Rexulti Adverse Reactions

    Adverse Reactions

    Weight gain, akathisia, headache, somnolence, tremor, nasopharyngitis, fatigue, increased appetite, dizziness, anxiety, restlessness.

    Rexulti Clinical Trials

    Clinical Trials

    Rexulti was studied in two 6-week, phase 3 randomized, placebo-controlled trials in adults with schizophrenia comparing fixed doses of Rexulti vs placebo. Study data showed treatment with Rexulti for 6 weeks showed statistically significant efficacy for the primary endpoint of Positive and Negative Syndrome Scale (PANSS). In one trial, the change from baseline in PANSS total score in the Rexulti group was -20.7 (2mg) and -19.7 (4mg) vs -12.0 in the placebo group. In the second trial, the change from baseline in PANSS total score was -20.0 in the Rexulti 4mg group vs -13.5 in the placebo group; the 2mg dose was not superior to placebo in this trial.

    Maintenance treatment for schizophrenia was evaluated in a long-term randomized withdrawal trial in adults aged 18–65 years. After patients were cross-titrated from a prior antipsychotic to Rexulti and underwent a 12-36 week single-blind Rexulti stabilization phase, those who were symptomatically stable on Rexulti for 12 consecutive weeks in the stabilization phase were then randomized in a double-blind treatment phase to either Rexulti (n=97) or placebo (n=105). 

    Relapse during the double-blind phase was established if patients met any of the following criteria: worsening symptoms defined by changes in PANSS or CGI-I scores; hospitalization for worsening psychotic symptoms; suicidal behavior, or violent/aggressive behavior. 

    An interim analysis showed a statistically significant longer time to relapse in patients who took Rexulti vs placebo. This trial was terminated early because maintenance of efficacy was demonstrated. The final analysis showed a statistically significant longer time to relapse (hazard ratio [HR] 0.292; P <.0001) in patients who took Rexulti vs placebo. In addition, the proportion of patients who met the criteria for impending relapse (secondary endpoint), was statistically significantly lower in Rexulti-treated patients vs placebo group.

    Rexulti Note

    Not Applicable

    Rexulti Patient Counseling

    Patient Counseling

    Look for the emergence of suicidality, especially early during treatment; report these symptoms.

    Neuroleptic malignant syndrome has been reported with antipsychotic drugs. Contact a health care provider or report to the emergency room if signs and symptoms of NMS develop.

    Tardive dyskinesia possible with antipsychotic medications; report abnormal movements.

    Risk of metabolic changes, monitoring of blood glucose, lipids, and weight is necessary.

    Compulsive behaviors (shopping, gambling, sexual urges) may develop during treatment.

    Pre-existing low WBC or a history of drug induced leukopenia/ neutropenia: CBC monitoring needed during treatment.

    Risk of orthostatic hypotension and syncope, especially early in treatment, and also at times of re-initiating treatment.

    Do not perform activities requiring mental alertness, such as operating hazardous machinery or operating a motor vehicle, until it has been established that Rexulti does not not impact cognitive and motor performance adversely.

    Avoid overheating and dehydration.

    Changes in prescription medications, OTC/herbal use should be reported because of potential drug interactions.

    Report pregnancy; use of Rexulti during the third trimester may cause extrapyramidal and/or withdrawal symptoms  in the neonate.

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