Rexulti (Tablets) Instructions for Use

Marketing Authorization Holder

H. Lundbeck, A/S (Denmark)

Manufactured By

Otsuka Pharmaceutical, Co. Ltd. (Japan)

Packaging and Quality Control Release

ELAIAPHARM (France)

ATC Code

N05AX16 (Brexpiprazole)

Active Substance

Brexpiprazole (Rec.INN registered by WHO)

Dosage Forms

	Rexulti	Film-coated tablets, 1 mg: 28 pcs.
		Film-coated tablets, 3 mg: 28 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets light yellow in color, round, slightly biconvex, with an embossed inscription on one side “BRX” and “1”, with a bevel on both sides; the tablet core is white in cross-section.

Excipients: lactose monohydrate – 47.4 mg, corn starch – 20 mg, microcrystalline cellulose – 10 mg, low-substituted hydroxypropyl cellulose – 10 mg, hydroxypropyl cellulose – 1 mg, magnesium stearate – 0.6 mg.

Film coating composition Opadry 03A420002 yellow – 3 mg (hypromellose 2910, talc, titanium dioxide (E171), yellow iron oxide (E172)).

7 pcs. – blisters (4) – cardboard packs.
14 pcs. – blisters (2) – cardboard packs with a flap with push-through perforation for first opening control.

Film-coated tablets light purple with a grayish tint, round, slightly biconvex, with an embossed inscription on one side “BRX” and “3”, with a bevel on both sides; the tablet core is white in cross-section.

Excipients: lactose monohydrate – 45.4 mg, corn starch – 20 mg, microcrystalline cellulose – 10 mg, low-substituted hydroxypropyl cellulose – 10 mg, hydroxypropyl cellulose – 1 mg, magnesium stearate – 0.6 mg.

Film coating composition Opadry 03A400000 purple – 3 mg (hypromellose 2910, talc, titanium dioxide (E171), red iron oxide (E172), iron oxide black (E172)).

7 pcs. – blisters (4) – cardboard packs.
14 pcs. – blisters (2) – cardboard packs with a flap with push-through perforation for first opening control.

Clinical-Pharmacological Group

Antipsychotic drug (neuroleptic)

Pharmacotherapeutic Group

Antipsychotic agent (neuroleptic)

Pharmacological Action

Atypical antipsychotic agent. It is believed that the pharmacological effects of brexpiprazole are due to its modulating action on serotonin and dopamine receptors, combining partial agonism to serotonin 5-HT_1A receptors and dopamine D₂ receptors, partial antagonism to serotonin 5-HT_2A receptors and high affinity for all these receptors (Ki: 0.1-0.5 nM).

Brexpiprazole is also an antagonist of α_1B/α_2C-adrenergic receptors with an affinity level in the same subnanomolar range (Ki: 0.2-0.6 nM).

Pharmacokinetics

Brexpiprazole is well absorbed after oral administration. The C_max of brexpiprazole in plasma is reached quickly, within 4 hours after taking a single dose of the drug. The absolute bioavailability of brexpiprazole in the tablet dosage form is 95.1%. C_ss is achieved within a period of 10 to 12 days of oral administration of the drug.

The pharmacokinetics of brexpiprazole are dose-proportional and do not change over time after a single dose (0.2-8 mg) and repeated doses (0.5-4 mg) when used once daily. The V_d of brexpiprazole after IV administration is high (1.56 ± 0.418 L/kg), indicating its extravascular distribution.

Brexpiprazole has a high plasma protein binding capacity (more than 99%), with serum albumin and α1-acid glycoprotein.

Brexpiprazole is metabolized primarily by the CYP3A4 and CYP2D6 isoenzymes to form oxidative metabolites, of which only one metabolite (DM-3411) is found in plasma at concentrations greater than 10%. The steady-state exposure of DM-3411 is 23.1-47.7% of the plasma brexpiprazole exposure (AUC).

After oral administration of a single dose of [¹⁴C]-labeled brexpiprazole, approximately 24.6% and 46% of the radioisotope-labeled substance was excreted in urine and feces, respectively. Less than 1% of brexpiprazole is excreted unchanged in urine and approximately 14% of brexpiprazole is excreted unchanged through the intestine.

The apparent total clearance of brexpiprazole in tablet form after oral administration once daily is 19.8 (±11.4) mL/h/kg. After multiple doses administered once daily, the terminal T_1/2 of brexpiprazole and its main metabolite DM-3411 is 91.4 hours and 85.7 hours, respectively.

Pharmacokinetics in special patient groups

The AUC of brexpiprazole in women was 25% higher than in men.

According to population pharmacokinetic studies in patients with poor metabolism associated with CYP2D6 isoenzyme activity, brexpiprazole exposure is 47% higher than in patients with extensive metabolism.

After oral administration of a single 3 mg dose of brexpiprazole in patients (n=10) with severe renal impairment (CrCl <30 mL/min), the AUC of brexpiprazole increased by 68% compared to healthy volunteers, while C_max did not change. In patients with moderate to severe renal impairment (CrCl <60 mL/min), the maximum dose of brexpiprazole should be reduced to 3 mg once daily.

After oral administration of a single 2 mg dose of brexpiprazole in patients (n=22) with varying degrees of hepatic impairment (Child-Pugh class A, B, C), the AUC of brexpiprazole increased by 24% in mild hepatic impairment, by 60% in moderate hepatic impairment, and did not change in severe hepatic impairment compared to healthy volunteers. In patients with moderate and severe hepatic impairment (Child-Pugh class B, C), the maximum dose of brexpiprazole should be reduced to 3 mg once daily.

Indications

Treatment of schizophrenia.

ICD codes

Dosage Regimen

Administer orally, once daily, with or without food.

For the treatment of schizophrenia in adults, initiate therapy at a starting dose of 1 mg once daily.

Titrate the dose upwards to the recommended target dose of 2 to 4 mg once daily. Increase the dose to 2 mg after one week, based on clinical response and tolerability.

Subsequent dose increases may be considered at weekly intervals.

The maximum recommended daily dose is 4 mg.

For patients with moderate to severe renal impairment (CrCl <60 mL/min) or moderate to severe hepatic impairment (Child-Pugh class B or C), the maximum dose should not exceed 3 mg once daily.

When used concomitantly with a strong CYP3A4 inhibitor (e.g., ketoconazole) or a strong CYP2D6 inhibitor (e.g., quinidine, paroxetine), reduce the brexpiprazole dose to half of the current maintenance dose.

If the concomitant inhibitor is discontinued, increase the brexpiprazole dose to the original level.

When used concomitantly with a strong CYP3A4 inducer (e.g., rifampicin), increase the brexpiprazole daily dose, up to double the original dose over 1-2 weeks. Consider dividing the total daily dose into two administrations.

If the concomitant inducer is discontinued, reduce the brexpiprazole dose to the original level over 1-2 weeks.

For known CYP2D6 poor metabolizers who are also taking a strong or moderate CYP3A4 inhibitor, or for patients taking both a strong/moderate CYP2D6 inhibitor and a strong/moderate CYP3A4 inhibitor, do not initiate therapy. For patients already on therapy, reduce the maintenance dose to 1 mg once daily.

Regularly evaluate the patient for treatment response and tolerability. Adjust the dose based on clinical assessment.

Adverse Reactions

Immune system disorders uncommon – angioedema, urticaria, facial edema.

Psychiatric disorders uncommon – suicide attempts, suicidal thoughts; frequency unknown – pathological gambling, impulsive behavior, compulsive overeating, compulsive shopping, compulsive sexual behavior disorder.

Nervous system disorders common – akathisia, dizziness, tremor, sedative effect; uncommon – parkinsonism; frequency unknown – seizures, neuroleptic malignant syndrome.

Cardiac and vascular disorders uncommon – increased blood pressure, venous thromboembolism (including pulmonary embolism and deep vein thrombosis), orthostatic hypotension; frequency unknown – QT interval prolongation on ECG.

Respiratory, thoracic and mediastinal disorders uncommon – cough.

Gastrointestinal disorders common – diarrhea, nausea, epigastric pain; uncommon – dental caries, flatulence.

Musculoskeletal and connective tissue disorders uncommon – myalgia; frequency unknown – rhabdomyolysis.

Pregnancy, puerperium and perinatal conditions frequency unknown – neonatal withdrawal syndrome.

Investigations very common – increased serum prolactin; common – increased serum CPK; uncommon – increased serum triglycerides and serum hepatic enzyme activity.

General disorders and administration site conditions common – increased body weight, rash, back pain, limb pain.

Contraindications

Hypersensitivity to brexpiprazole; children and adolescents under 18 years of age; use in patients with established poor metabolism associated with CYP2D6 isoenzyme activity who are taking strong/moderate CYP3A4 isoenzyme inhibitors; use in patients taking strong/moderate CYP2D6 isoenzyme inhibitors in combination with strong/moderate CYP3A4 isoenzyme inhibitors.

With caution high risk of suicide; hyperglycemia; risk factors for developing diabetes mellitus; arterial hypotension and conditions predisposing to arterial hypotension (dehydration, hypovolemia, use of antihypertensive drugs) or arterial hypertension (including progressive and severe); history of cerebrovascular and cardiovascular diseases (heart failure, myocardial infarction, myocardial ischemia, cardiac conduction disorders); hereditary QT interval prolongation and concomitant use with drugs that prolong the QT interval; electrolyte disturbances; risk factors for developing venous thromboembolism; moderate and severe renal and hepatic impairment; history of NMS; history of extrapyramidal symptoms; history of seizures and conditions with a lowered seizure threshold; increased risk of aspiration pneumonia (e.g., dysphagia, esophageal dyskinesia); conditions predisposing to increased body temperature (e.g., strenuous exercise, exposure to high temperature, use of anticholinergic drugs); history of impulse control disorder; leukopenia/neutropenia and history of drug-induced leukopenia/neutropenia; concomitant use with strong CYP3A4/CYP2D6 isoenzyme inhibitors; concomitant use with CYP3A4 isoenzyme inducers; concomitant use with drugs for the treatment of CNS diseases that cause similar adverse reactions; breastfeeding period; elderly age (65 years and older).

Use in Pregnancy and Lactation

The use of brexpiprazole is not recommended in pregnant women and in women of childbearing potential not using contraception.

Brexpiprazole should be used with caution during breastfeeding.

Use in Hepatic Impairment

Use with caution in moderate and severe hepatic impairment.

Use in Renal Impairment

Use with caution in moderate and severe renal impairment.

Pediatric Use

Contraindicated for use in children and adolescents under 18 years of age.

Geriatric Use

Use with caution in elderly patients (65 years and older).

Special Precautions

The clinical effect of antipsychotic therapy may occur within a period of several days to several weeks. During this period, patients should be under close observation.

In some cases, early onset of suicidal behavior has been reported after initiation of treatment or when switching to another antipsychotic drug, including Brexpiprazole. High-risk patients taking antipsychotic drugs should be under strict supervision.

Cases of venous thromboembolism have been reported with the use of antipsychotics. Patients receiving antipsychotic therapy often belong to the risk group for developing venous thromboembolism, therefore, before starting and during therapy with brexpiprazole, it is necessary to determine the risk factors for developing venous thromboembolism and take preventive measures.

Adverse reactions associated with orthostatic hypotension may include symptoms such as dizziness, lightheadedness, tachycardia. The risk of these symptoms is highest at the beginning of antipsychotic therapy and during dose escalation. An increased risk of these adverse reactions (e.g., in elderly patients) or the risk of complications of arterial hypotension is observed in patients with dehydration, hypovolemia, in patients receiving antihypertensive therapy, in patients with a history of cardiovascular (e.g., heart failure, myocardial infarction, myocardial ischemia, cardiac conduction disorders) and cerebrovascular diseases, as well as in patients who have not previously received antipsychotic drugs. In these patients, a lower initial dose of the drug and a slower dose titration should be considered, and vital functions should be monitored.

An association has been reported between the use of antipsychotic drugs, including Brexpiprazole, and the development of potentially fatal NMS. If patients develop signs and symptoms characteristic of NMS, or unexplained high fever without other clinical manifestations of NMS, Brexpiprazole should be discontinued immediately.

Extrapyramidal symptoms (including acute dystonia) are specific symptoms for the class of antipsychotics. Brexpiprazole should be used with caution in patients with a history of extrapyramidal symptoms.

Potentially irreversible involuntary dyskinetic movements may develop in patients receiving antipsychotic drugs. Although the highest incidence of this syndrome is observed in the elderly, especially women, at the start of antipsychotic therapy it is impossible to predict which patients will develop it based on prevalence estimates. If a patient receiving Brexpiprazole develops symptoms of tardive dyskinesia, a dose reduction or discontinuation of the drug should be considered. After discontinuation of brexpiprazole, a temporary worsening of symptoms is possible. Symptoms of tardive dyskinesia may also occur for the first time after discontinuation of the antipsychotic.

Results of placebo-controlled studies using some antipsychotic drugs to treat elderly patients with dementia showed an increased incidence of adverse cerebrovascular reactions (acute and transient cerebrovascular accident), including fatal ones, compared with patients taking placebo.

Brexpiprazole is not recommended for the treatment of elderly patients with dementia due to an increased risk of fatal outcome.

Cases of hyperglycemia have been reported, in some cases complicated by ketoacidosis or hyperosmolar coma, sometimes fatal, in patients receiving atypical antipsychotic drugs. Risk factors that predispose to the development of severe complications in patients include obesity and a family history of diabetes. Patients receiving atypical antipsychotic drugs, including Brexpiprazole, should be monitored for symptoms of hyperglycemia (polydipsia, polyuria, polyphagia and weakness). Fasting blood glucose should be determined before or immediately after starting treatment with antipsychotic drugs. During long-term treatment, blood glucose should be regularly monitored to detect worsening of glycemic parameters.

Antipsychotic drugs, including Brexpiprazole, can cause metabolic disorders, which include increased body weight and dyslipidemia. The frequency of cases of increased body weight increased with increasing duration of brexpiprazole therapy. Blood lipid levels should be determined before starting treatment. It is recommended to monitor body weight and lipid levels at the beginning and during treatment.

Brexpiprazole should be used with caution in patients with a history of seizures or with conditions that potentially lower the seizure threshold. Cases of seizures have been reported during the use of brexpiprazole.

Impairment of the body’s ability to reduce core body temperature may be associated with the use of antipsychotic drugs. Adequate monitoring is recommended for patients prescribed Brexpiprazole who may be exposed to factors that contribute to increased body temperature, for example, strenuous exercise, exposure to high temperature, concomitant use of anticholinergic drugs, dehydration.

Esophageal dyskinesia and aspiration may be associated with the use of antipsychotic drugs. Brexpiprazole should be used with caution in patients at risk of aspiration pneumonia.

Impulse control disorders, including pathological gambling, have been reported in patients treated with brexpiprazole. While taking brexpiprazole, patients may experience increased urges, especially for gambling, and an inability to control them. Other pathological urges have also been reported: compulsive sexual behavior disorder, compulsive shopping, compulsive overeating and other types of impulsive and compulsive behavior. Patients with a history of impulse control disorders are at increased risk and require closer monitoring. If a patient develops such urges during treatment with brexpiprazole, the advisability of reducing the dose or discontinuing the drug should be considered.

Cases of leukopenia, neutropenia and agranulocytosis (including fatal cases) have been reported during therapy with antipsychotics. Possible risk factors for the development of leukopenia/neutropenia are low white blood cell count at the start of treatment and a history of drug-induced leukopenia/neutropenia. In patients with the above risk factors, complete blood count parameters should be regularly monitored during the first few months of therapy. Brexpiprazole should be discontinued at the first signs of a decrease in the number of white blood cells in the absence of other factors that may be the cause of this decrease. Patients with neutropenia should be closely monitored for fever or other symptoms of infection, and treatment should be started immediately if such symptoms or signs appear. Brexpiprazole should be discontinued in patients with severe neutropenia (absolute neutrophil count <1000/mm³), and such patients should have regular complete blood counts until recovery.

Brexpiprazole may increase prolactin levels. The increase in prolactin levels associated with the use of brexpiprazole is usually small and may decrease during treatment; however, in some cases, it may persist throughout the treatment period.

Effect on the Ability to Drive Vehicles and Operate Machinery

Brexpiprazole has a minor or moderate influence on the ability to drive and operate machinery due to potential effects on the nervous system, such as the development of sedation and/or dizziness, which are common adverse reactions associated with the use of brexpiprazole.

Drug Interactions

When brexpiprazole is used concomitantly with strong inhibitors of the CYP3A4 isoenzyme (itraconazole, ketoconazole, ritonavir, and clarithromycin), an increase in brexpiprazole exposure (AUC) is possible; therefore, a reduction of the therapeutic dose of brexpiprazole to 1/2 of the maintenance therapeutic dose is recommended.

When brexpiprazole is used concomitantly with strong inducers of the CYP3A4 isoenzyme (e.g., rifampicin), a decrease in C_max and AUC of brexpiprazole is possible; therefore, the daily dose of brexpiprazole may be increased approximately 3-fold. Administration of brexpiprazole once daily during the use of a strong CYP3A4 isoenzyme inducer is accompanied by fluctuations in brexpiprazole concentrations from maximum to minimum values, making dividing the daily therapeutic dose into two doses more preferable.

A single oral dose of brexpiprazole administered simultaneously with quinidine, a strong inhibitor of the CYP2D6 isoenzyme, may lead to an increase in the AUC of brexpiprazole, while C_max remains unchanged. When used concomitantly with strong inhibitors of the CYP2D6 isoenzyme (quinidine, paroxetine, fluoxetine), a reduction of the therapeutic dose of brexpiprazole to 1/2 of the maintenance therapeutic dose is recommended.

In patients with high CYP2D6 isoenzyme activity who are simultaneously receiving inhibitors of the CYP3A4 and CYP2D6 isoenzymes, or in patients with low CYP2D6 isoenzyme activity who are receiving strong inhibitors of the CYP3A4 isoenzyme, an increase in brexpiprazole concentration of approximately 4-5 times is possible. For those patients who are already taking Brexpiprazole, it is recommended to reduce the maintenance dose to the minimum possible (1 mg). It is not recommended to initiate brexpiprazole therapy in patients with established poor metabolism associated with CYP2D6 isoenzyme activity who are taking strong/moderate inhibitors of the CYP3A4 isoenzyme, and in patients taking strong/moderate inhibitors of the CYP2D6 isoenzyme in combination with strong/moderate inhibitors of the CYP3A4 isoenzyme.

Caution should be exercised when co-administering brexpiprazole with medicinal products that prolong the QT interval or disrupt electrolyte balance.

When brexpiprazole is used concomitantly with drugs that increase serum CPK activity, the possible additive effect of brexpiprazole on increasing CPK activity should be considered.

Given the effect of brexpiprazole on the CNS, caution should be exercised when using brexpiprazole together with alcohol or other medicinal products that affect the CNS and are capable of causing the same adverse reactions as Brexpiprazole, such as sedation.

Storage Conditions

Store at 2°C (36°F) to 30°C (86°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.