Ralotex^® (Tablets) Instructions for Use

ATC Code

N05AX12 (Aripiprazole)

Active Substance

Aripiprazole (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Antipsychotic drug (neuroleptic)

Pharmacotherapeutic Group

Antipsychotic agent (neuroleptic)

Pharmacological Action

The therapeutic action of aripiprazole in schizophrenia and bipolar I disorder is presumed to be due to a combination of partial agonist activity at D₂ dopamine and 5-HT_1A serotonin receptors and antagonist activity at 5-HT_2A serotonin receptors. Aripiprazole exhibited antagonism of dopaminergic hyperactivity and agonism of dopaminergic hypoactivity in animal studies.

Aripiprazole has high in vitro affinity for D₂ and D₃ dopamine receptors, 5-HT_1A and 5-HT_2A serotonin receptors, and moderate affinity for D₄ dopamine, 5-HT_2C and 5-HT₇ serotonin, α₁-adrenergic, and H₁ histamine receptors. Aripiprazole also exhibits moderate affinity for serotonin reuptake sites and lacks significant affinity for muscarinic cholinergic receptors. Some of the clinical effects of aripiprazole may be explained by its interaction with other receptor types besides dopamine and serotonin.

Oral administration of aripiprazole in doses from 0.5 to 30 mg once daily to healthy volunteers for 2 weeks resulted in a dose-dependent reduction in the binding of ¹¹C-raclopride, a D₂/D₃ dopamine receptor ligand, to the caudate nucleus and putamen as measured by positron emission tomography.

Pharmacokinetics

Absorption

Aripiprazole is rapidly absorbed after oral administration, with peak plasma concentrations (C_max) reached within 3-5 hours. Aripiprazole undergoes minimal presystemic metabolism. The absolute bioavailability of the aripiprazole tablet is 87%. A high-fat meal does not affect the pharmacokinetics of aripiprazole.

Distribution

Aripiprazole is extensively distributed in tissues, with an apparent volume of distribution (V_d) of 4.9 L/kg, indicating significant extravascular distribution. At therapeutic concentrations, aripiprazole and dehydroaripiprazole are more than 99% bound to plasma proteins, primarily albumin.

Metabolism

Aripiprazole is extensively metabolized in the liver by three pathways: dehydrogenation, hydroxylation, and N-dealkylation. In vitro experiments indicate that dehydrogenation and hydroxylation of aripiprazole are mediated by CYP3A4 and CYP2D6 isoenzymes, and N-dealkylation is catalyzed by CYP3A4. Aripiprazole is the major active moiety in the blood. At steady state, the area under the curve (AUC) of dehydroaripiprazole (the main metabolite) is approximately 40% of the aripiprazole AUC in plasma.

Elimination

The mean elimination half-life (T_1/2) of aripiprazole is approximately 75 hours in patients with extensive CYP2D6 metabolism and approximately 146 hours in patients with poor CYP2D6 metabolism. The total clearance of aripiprazole is 0.7 mL/min/kg, primarily via hepatic elimination.

After a single oral dose of ¹⁴C-labeled aripiprazole, approximately 27% of the radioactivity was recovered in the urine and approximately 60% in the feces. Less than 1% of unchanged aripiprazole is excreted in the urine, and approximately 18% of the administered dose is excreted unchanged in the feces.

Pharmacokinetics in Special Patient Groups

Children. The pharmacokinetics of aripiprazole and dehydroaripiprazole in children aged 10-17 years are similar to those in adults after correcting for body weight differences.

Elderly patients. No differences in the pharmacokinetic parameters of aripiprazole were found between healthy elderly and adult volunteers. A population pharmacokinetic analysis also did not reveal any significant effect of age in patients with schizophrenia.

Sex. No differences in the pharmacokinetic parameters of aripiprazole were found between healthy men and women. A population pharmacokinetic analysis also did not reveal any significant effect of sex in patients with schizophrenia.

Smoking. A population pharmacokinetic analysis showed no clinically significant effects of smoking on the pharmacokinetic parameters of aripiprazole.

Race. A population pharmacokinetic analysis showed no effect of racial differences on the pharmacokinetic parameters of aripiprazole.

Patients with renal impairment. The pharmacokinetic parameters of aripiprazole and dehydroaripiprazole in patients with severe renal disease do not differ from those in healthy volunteers.

Patients with hepatic impairment. In a single-dose study in patients with varying degrees of liver cirrhosis (Child-Pugh class A, B, and C), no significant effect of hepatic impairment on the pharmacokinetics of aripiprazole and dehydroaripiprazole was identified. However, only three patients with Child-Pugh class C cirrhosis participated in the study, making it impossible to draw definitive conclusions regarding their metabolic activity.

Indications

• Schizophrenia: acute episodes and maintenance therapy;
• Bipolar I disorder: manic episodes and maintenance therapy to prevent recurrence in patients with bipolar I disorder who recently experienced a manic or mixed episode;
• Adjunctive therapy to antidepressants for major depressive disorder.

ICD codes

Dosage Regimen

Tablets

Take orally, once daily, regardless of meals.

Schizophrenia

The recommended starting dose is 10-15 mg once daily. The maintenance dose is usually 15 mg/day. Clinical studies have demonstrated the efficacy of the drug in doses ranging from 10 to 30 mg/day.

Manic episodes in bipolar disorder. Monotherapy

The recommended starting dose is 15 mg/day. Dose adjustments, if necessary, should be made at intervals of no less than 24 hours. In clinical studies of manic episodes, the efficacy of the drug was demonstrated at doses of 15-30 mg/day administered for 3-12 weeks. The safety of doses above 30 mg/day was not evaluated in clinical studies.

In patients with bipolar I disorder who experienced a manic or mixed episode and whose symptoms stabilized while taking the drug (15 mg/day or 30 mg/day with a starting dose of 30 mg/day) for 6 weeks, then for 6 months, and further for 17 months, a beneficial effect of such maintenance therapy was established. Patients should be periodically examined to determine the need for continuation of maintenance therapy.

Adjunctive therapy for major depressive disorder

As an adjunct to antidepressant treatment, the recommended starting dose is 5 mg/day. If necessary and well tolerated, the daily dose of the drug can be increased weekly by 5 mg up to a maximum of no more than 15 mg/day.

The duration of aripiprazole therapy for all the above indications has not been established; the patient should be regularly examined for the possibility of discontinuing therapy.

Use in special patient groups

Dose adjustment is not required when prescribing aripiprazole to patients with renal impairment.

Dose adjustment is not required when prescribing aripiprazole to patients with mild to moderate hepatic impairment. In patients with severe hepatic impairment, the 30 mg dose should be used with caution.

Dose adjustment in patients over 65 years of age is not required.

The dosing regimen of aripiprazole is the same for patients of both sexes.

The dosing regimen of aripiprazole is the same for smoking and non-smoking patients.

Dosing regimen for concomitant therapy

When aripiprazole is co-administered with potent CYP3A4 inhibitors (ketoconazole, clarithromycin), the dose of the drug should be reduced by half. Upon discontinuation of the CYP3A4 inhibitors, the dose of the drug should be increased.

When aripiprazole is co-administered with potent CYP2D6 inhibitors (quinidine, fluoxetine, paroxetine), the dose of aripiprazole should be reduced by at least half. Upon discontinuation of the CYP2D6 inhibitors, the dose of aripiprazole should be increased.

The dosing regimen should not be changed if Aripiprazole is prescribed as adjunctive therapy for patients with major depressive disorder.

When aripiprazole is co-administered with potent inhibitors of both CYP2D6 (quinidine, fluoxetine, paroxetine) and CYP3A4 (ketoconazole, clarithromycin), the dose of aripiprazole should be reduced to one-quarter (i.e., to 25% of the usual dose). Upon discontinuation of the CYP2D6 and/or CYP3A4 inhibitors, the dose of aripiprazole should be increased.

When aripiprazole is co-administered with potent, moderate, or weak inhibitors of CYP2D6 and CYP3A4, the dose of aripiprazole may initially be reduced to one-quarter (i.e., to 25% of the usual dose) and then increased to achieve the optimal clinical outcome.

In patients with poor CYP2D6 metabolism, the initial dose of aripiprazole should be reduced by half and then increased to achieve the optimal clinical outcome. When aripiprazole is co-administered with a potent CYP3A4 inhibitor in patients with poor CYP2D6 metabolism, the dose of aripiprazole should be reduced to one-quarter (i.e., to 25% of the usual dose).

When aripiprazole is co-administered with potential CYP3A4 inducers (carbamazepine), the dose of aripiprazole should be doubled. Upon discontinuation of the CYP3A4 inducers, the dose of aripiprazole should be reduced to 10-15 mg.

Adverse Reactions

The most common adverse effects in placebo-controlled clinical studies were akathisia and nausea, each observed in more than 3% of patients taking Aripiprazole.

Adverse reactions (ARs) are classified according to the affected organ system and frequency as follows: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10000 to <1/1000); very rare (<1/10000); frequency not known (cannot be estimated from the available data). Within each frequency group, ARs are presented in order of decreasing severity.

The frequency of ARs in post-marketing studies cannot be determined as reports were spontaneous. Therefore, the frequency of these ARs is stated as “frequency not known”.

Blood and lymphatic system disorders frequency not known – leukopenia, neutropenia, thrombocytopenia.

Immune system disorders: frequency not known – allergic reactions (e.g., anaphylactic reactions, angioedema, including tongue swelling, swollen tongue, facial swelling, itching or urticaria).

Endocrine disorders uncommon – hyperprolactinemia; frequency not known – diabetic hyperosmolar coma, diabetic ketoacidosis, hyperglycemia.

Metabolism and nutrition disorders: common – diabetes mellitus; uncommon – hyperglycemia; frequency not known – hyponatremia, anorexia, weight decreased, weight increased.

Psychiatric disorders common – insomnia, anxiety, agitation; uncommon – depression, increased libido; frequency not known – suicide attempt, suicidal thoughts and completed suicide, pathological gambling, aggression, agitation, nervousness.

Nervous system disorders common – akathisia, extrapyramidal disorder, tremor, headache, sedation, somnolence, dizziness; uncommon – tardive dyskinesia, dystonia.; frequency not known – neuroleptic malignant syndrome (NMS), grand mal convulsion, serotonin syndrome, speech disorder.

Eye disorders common – blurred vision; uncommon – diplopia.

Cardiac disorders uncommon – tachycardia; frequency not known – sudden death, torsade de pointes, QT prolongation, ventricular arrhythmia, cardiac arrest, bradycardia.

Vascular disorders uncommon – orthostatic hypotension; frequency not known – venous thromboembolism (including pulmonary embolism and deep vein thrombosis), increased blood pressure, syncope.

Respiratory, thoracic and mediastinal disorders uncommon – hiccups; frequency not known – aspiration pneumonia, laryngospasm, oropharyngeal dysphagia.

Gastrointestinal disorders common – constipation, dyspepsia, nausea, hypersalivation, vomiting: frequency not known – pancreatitis, dysphagia, diarrhea, abdominal discomfort, stomach discomfort.

Hepatobiliary disorders: frequency not known – hepatic failure, hepatitis, jaundice, increased ALT, increased AST, increased GGT, increased alkaline phosphatase.

Skin and subcutaneous tissue disorders frequency not known – rash, photosensitivity, alopecia, hyperhidrosis.

Musculoskeletal and connective tissue disorders frequency not known – rhabdomyolysis, myalgia, muscle rigidity.

Renal and urinary disorders frequency not known – urinary incontinence, urinary retention.

Pregnancy, puerperium and perinatal conditions frequency not known – neonatal withdrawal syndrome.

Reproductive system and breast disorders frequency not known – priapism.

General disorders and administration site conditions common – fatigue; frequency not known – temperature regulation disorders (e.g., hypothermia, pyrexia), chest pain, peripheral edema.

Investigations frequency not known – increased blood glucose, increased glycated hemoglobin, blood glucose fluctuations, increased creatine phosphokinase.

Contraindications

• Hypersensitivity to aripiprazole and/or to any excipients of the drug;
• Lactase deficiency, lactose intolerance, glucose-galactose malabsorption syndrome (because the drug contains lactose);
• Breastfeeding period;
• Age under 18 years (efficacy and safety have not been established).

With caution

• In patients with cardiovascular diseases (coronary artery disease or history of myocardial infarction, chronic heart failure (CHF) or conduction disorders);
• In patients with cerebrovascular diseases and conditions predisposing to orthostatic hypotension;
• In patients with a history of seizures or with conditions where seizures may occur;
• In patients at increased risk of hyperthermia (e.g., during intense physical exertion, overheating, concomitant use of anticholinergics, dehydration due to the ability of neuroleptics to impair thermoregulation);
• In patients at increased risk of aspiration pneumonia due to the risk of impaired esophageal motor function and aspiration;
• In patients suffering from obesity or with a family history of diabetes mellitus;
• In patients at high risk of suicide (psychotic illnesses, bipolar disorders, major depressive disorder);
• In individuals aged 18-24 years due to the risk of suicidal behavior.

Use in Pregnancy and Lactation

Pregnancy

Adequate and well-controlled studies in pregnant women have not been conducted. It is not known whether the use of aripiprazole by a pregnant woman can have harmful effects on the fetus or cause impairment of reproduction.

It is known that in newborns whose mothers took antipsychotics during the third trimester of pregnancy, there is a risk of developing extrapyramidal disorders and/or withdrawal syndrome in the postpartum period. They exhibited agitation, muscular hypertonia or hypotonia, tremor, drowsiness, respiratory distress syndrome, feeding disorders. These symptoms varied in severity, sometimes resolving without treatment, while in other cases newborns required intensive care and prolonged hospitalization. With the use of aripiprazole, the development of such symptoms in newborns has been reported very rarely.

Patients should be warned that they must immediately inform their doctor if they become pregnant during treatment; they should also inform the doctor about a planned pregnancy.

The use of aripiprazole during pregnancy is only possible if the expected benefit to the mother outweighs the potential risk to the fetus.

Breastfeeding period

Aripiprazole passes into human breast milk. The use of the drug during breastfeeding is not recommended.

Use in Hepatic Impairment

Dose adjustment is not required when prescribing aripiprazole to patients with mild to moderate hepatic impairment. Use with caution in patients with severe hepatic impairment.

Use in Renal Impairment

No dose adjustment is required when prescribing aripiprazole to patients with renal impairment.

Pediatric Use

The use of the drug is contraindicated in children and adolescents under 18 years of age (efficacy and safety have not been established).

Geriatric Use

Dose adjustment in patients over 65 years of age is not required.

Special Precautions

When using antipsychotic drugs (neuroleptics), the therapeutic effect develops over a period of several days to several weeks. During this period, it is necessary to carefully monitor the patient’s condition.

Suicidal Attempts

A tendency to suicidal thoughts and attempts is characteristic of patients with psychosis, bipolar disorder, and major depressive disorder; therefore, drug therapy should be combined with careful medical supervision. Aripiprazole should be prescribed in the minimum quantity sufficient to treat the patient, as this will reduce the risk of overdose.

According to clinical studies, the use of antidepressants increases the risk of suicidal thoughts and attempts in young patients with depression and other mental disorders. In this regard, special caution should be exercised when using antidepressants, including in the form of combination therapy with antidepressants and aripiprazole for the treatment of young patients. In patients over 24 years of age, no increase in the frequency of suicidal thoughts and behavior under the influence of antidepressants was found, and in patients over 65 years of age, a decrease in the frequency of this side effect was noted.

Tardive Dyskinesia

The risk of developing tardive dyskinesia increases with the duration of therapy with neuroleptics; therefore, if symptoms of tardive dyskinesia appear during the use of aripiprazole, the dose of this drug should be reduced or discontinued. After discontinuation of therapy, these symptoms may temporarily worsen or even appear for the first time.

Neuroleptic Malignant Syndrome (NMS)

A life-threatening symptom complex known as neuroleptic malignant syndrome has been described during treatment with neuroleptics, including aripiprazole. This syndrome is manifested by hyperpyrexia, muscle rigidity, mental disorders, and instability of the autonomic nervous system (irregular pulse and blood pressure, tachycardia, sweating, and arrhythmia). In addition, increased plasma CPK activity, myoglobinuria (rhabdomyolysis), and acute renal failure sometimes occur. If symptoms of NMS or unexplained fever occur, all neuroleptics, including Aripiprazole, should be discontinued.

Seizures

Like other neuroleptics, Aripiprazole should be used with caution in patients with a history of seizures or at risk of developing them.

Psychoses Associated with Senile Dementia and Alzheimer’s Disease

According to the results of placebo-controlled studies in elderly patients (56-99 years, mean age 82.4 years) with psychoses due to Alzheimer’s disease, an increased risk of death was noted during therapy with aripiprazole compared to the placebo group.

Mortality in the group of patients receiving aripiprazole treatment compared to the placebo group was 3.5% and 1.7%, respectively. Although the causes of death were varied, most of them were cardiovascular (e.g., heart failure, sudden cardiac death) or infectious (e.g., pneumonia).

Cerebrovascular Adverse Reactions

The same studies reported cerebrovascular adverse reactions (e.g., stroke, transient ischemic attack), including fatal ones, in patients (78-88 years, mean age 84 years). Overall, cerebrovascular adverse reactions were registered in 1.3% of patients receiving aripiprazole treatment compared to 0.6% of patients receiving placebo. This difference was not statistically significant. However, in one of these fixed-dose studies, a pronounced dose-dependent effect on the increase in the frequency of cerebrovascular adverse reactions was noted in patients receiving Aripiprazole. Aripiprazole is not indicated for the treatment of psychosis in the setting of dementia.

Hyperglycemia and Diabetes Mellitus

Hyperglycemia, in some cases severe and accompanied by ketoacidosis or hyperosmolar coma with fatal outcome, has been noted in patients taking atypical neuroleptics. Although the relationship between the use of atypical neuroleptics and hyperglycemic disorders remains unclear, patients diagnosed with diabetes mellitus should regularly monitor blood glucose concentrations when taking atypical neuroleptics. Patients with risk factors for diabetes mellitus (obesity, family history of diabetes) should monitor blood glucose concentrations at the beginning of the course and periodically during the use of atypical neuroleptics. Patients taking atypical neuroleptics require constant monitoring for symptoms of hyperglycemia, including increased thirst, frequent urination, polyphagia, and weakness. Special attention should be paid to patients with diabetes mellitus and risk factors for its development.

Weight Gain

Weight gain is commonly observed in schizophrenia and manic episodes in bipolar disorder and in the presence of comorbidities. The use of neuroleptics leads to weight gain, an unhealthy lifestyle, and can lead to serious complications. According to post-marketing use of aripiprazole, reports of weight gain have been received, usually in patients with severe risk factors such as a history of diabetes mellitus, thyroid disease, or pituitary adenoma. According to clinical studies, the use of aripiprazole does not lead to clinically significant weight gain in adults.

Leukopenia, Neutropenia, Agranulocytosis

It is known that neuroleptics, including Aripiprazole, can cause temporary changes in the blood count – leukopenia, neutropenia, and agranulocytosis. Risk factors for development are a low white blood cell count in the patient before starting treatment, as well as leukopenia and neutropenia caused by other drugs. The blood count should be regularly monitored in such patients, especially in the first months of treatment with aripiprazole. In case of a clinically significant decrease in the concentration of white blood cells of unclear etiology, discontinuation of aripiprazole should be considered.

Patients with clinically significant neutropenia should be carefully monitored for the development of fever or other signs of infection in order to promptly initiate appropriate treatment. In case of severe neutropenia (neutrophil count less than 1000/mm³), treatment with aripiprazole should be interrupted until the blood count normalizes.

Cardiovascular Diseases

Due to the risk of orthostatic hypotension, Aripiprazole should be used with caution in patients with cardiovascular diseases (myocardial infarction, coronary artery disease, heart failure, history of cardiac conduction disorders), cerebrovascular disorders, or conditions predisposing to arterial hypotension (dehydration, hypovolemia, therapy with antihypertensive drugs).

Conduction Disturbance (QT Interval Prolongation)

In clinical studies, the frequency of QT interval prolongation cases in patients using aripiprazole was comparable to the placebo group. Aripiprazole, like other neuroleptics, should be used with caution in patients with congenital long QT syndrome.

Cognitive and Motor Disorders

Like other neuroleptics, Aripiprazole can cause cognitive and motor disorders. In particular, cases of drowsiness and lethargy were noted in clinical studies of aripiprazole. During treatment, patients should refrain from driving vehicles and operating dangerous machinery.

Thermoregulation Impairment

It is known that neuroleptics can cause thermoregulation impairment. This should be taken into account when prescribing aripiprazole to patients who are at increased risk of overheating due to intense physical exertion, high ambient temperature, use of drugs with anticholinergic activity, and dehydration.

Dysphagia

Cases of impaired esophageal peristalsis and, as a consequence, aspiration pneumonia have been noted with the use of neuroleptics. Caution should be exercised when using in patients with risk factors for the development of aspiration pneumonia.

Risk of Venous Thromboembolism

The use of neuroleptics, including aripiprazole, may be associated with the risk of developing venous thromboembolism. In this regard, risk factors for the development of this complication should be identified before prescribing aripiprazole, as well as during treatment with this drug. If necessary, measures to prevent the development of venous thromboembolism should be applied.

Pathological Gambling

According to post-marketing use of aripiprazole, cases of pathological gambling have been noted, regardless of whether patients had previously gambled. Patients with a history of gambling are at increased risk and should be closely monitored.

Patients with Attention Deficit Hyperactivity Disorder (ADHD)

Despite the high frequency of comorbidity of bipolar I disorder and ADHD, data on the safety of simultaneous use of aripiprazole and psychostimulants are limited. Therefore, special caution should be exercised when using them simultaneously.

Effect on the Ability to Drive Vehicles and Operate Machinery

Caution should be exercised when driving vehicles and engaging in potentially hazardous activities that require increased concentration and speed of psychomotor reactions while using aripiprazole.

Overdose

Clinical studies have described accidental and intentional overdoses of aripiprazole with a single dose of up to 1260 mg, which were not fatal.

Symptoms lethargy, increased blood pressure, drowsiness, tachycardia, loss of consciousness. In hospitalized patients, no clinically significant changes in basic physiological parameters, laboratory parameters, or ECG were detected.

Cases of aripiprazole overdose in children (ingestion of up to 195 mg) have been described. Potentially dangerous symptoms: extrapyramidal disorders and transient loss of consciousness.

Treatment monitoring of vital functions, ECG (to detect possible arrhythmia), supportive therapy, ensuring airway patency, oxygenation, effective lung ventilation, activated charcoal, symptomatic treatment, careful medical observation until symptoms disappear.

There are no data on the use of hemodialysis for aripiprazole overdose; the effectiveness of hemodialysis is unlikely because Aripiprazole is not excreted by the kidneys unchanged and is largely bound to plasma proteins.

Drug Interactions

The mechanism of action of aripiprazole is associated with an effect on the central nervous system, which must be taken into account when used simultaneously with other drugs that have a central action.

Having an antagonistic effect on α₁-adrenergic receptors, Aripiprazole may enhance the effect of antihypertensive drugs.

Caution should be exercised when using aripiprazole simultaneously with drugs that cause QT interval prolongation or disrupt electrolyte balance.

Aripiprazole does not affect the pharmacokinetics and pharmacodynamics of warfarin; it does not displace warfarin from plasma protein binding.

The H₂-histamine receptor blocker famotidine, which causes powerful suppression of hydrochloric acid secretion in the stomach, reduces the rate of absorption of aripiprazole; however, this does not affect the clinical effect of aripiprazole.

Various pathways of aripiprazole metabolism are known, including those involving the CYP2D6 and CYP3A4 isoenzymes. In studies in healthy volunteers, potent inhibitors of the CYP2D6 (quinidine) and CYP3A4 (ketoconazole) isoenzymes affected the pharmacokinetics of aripiprazole; therefore, aripiprazole doses should be reduced when used in various combinations with inhibitors of the CYP3A4 and CYP2D6 isoenzymes (see “Dosage Regimen”). When aripiprazole is used simultaneously with weak inhibitors of the CYP3A4 (diltiazem, escitalopram) or CYP2D6 isoenzymes, a slight increase in the plasma concentration of aripiprazole can be expected.

Since the CYP1A isoenzyme is not involved in the metabolism of aripiprazole, smoking does not affect the pharmacokinetics and effect of aripiprazole.

When aripiprazole is taken together with carbamazepine, a potent inducer of the CYP3A4 isoenzyme, the metabolism of aripiprazole is enhanced; therefore, the dose of aripiprazole should be adjusted (see “Dosage Regimen”). A similar effect can be expected from other potent inducers of the CYP3A4 and CYP2D6 isoenzymes.

The isoenzymes CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP2E1 are not involved in the metabolism of aripiprazole in vitro; therefore, its interaction with drugs and other factors (e.g., smoking) capable of inhibiting or activating these enzymes is unlikely.

In clinical studies, Aripiprazole at doses of 10-30 mg/day did not have a significant effect on the metabolism of substrates of the CYP2D6 (dextromethorphan), CYP2C9 (warfarin), CYP2C19 (omeprazole, warfarin), and CYP3A4 (dextromethorphan) isoenzymes. In addition, Aripiprazole and its main metabolite dehydroaripiprazole did not alter metabolism involving the CYP1A2 isoenzyme in vitro. A clinically significant effect of aripiprazole on drugs metabolized by these isoenzymes is unlikely.

With simultaneous use of aripiprazole (10-30 mg/day) and lamotrigine (100-400 mg/day) in patients with bipolar disorder, there were no changes in the pharmacokinetics of lamotrigine; therefore, no dose adjustment is required. Aripiprazole did not affect the pharmacokinetics of escitalopram and venlafaxine in healthy volunteers; therefore, no dose adjustment of these drugs is required when used simultaneously with aripiprazole.

When using aripiprazole simultaneously with fluoxetine (20-40 mg/day), paroxetine (37.5-50 mg/day), or sertraline (2-20 mg/day) in patients with major depressive disorder, no significant changes in the plasma concentrations of the antidepressants were detected.

Consumption of alcohol during treatment with aripiprazole may enhance the sedative effect of the drug; therefore, it should be avoided.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 25°C (77°F).

Shelf Life

Shelf life – 3 years. Do not use after the expiration date printed on the packaging.

Dispensing Status

The drug is dispensed by prescription.

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.