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Indications/Uses
Schizophrenia: Aripiprazole is indicated for the treatment of schizophrenia.
Bipolar I Disorder: Acute Treatment of Manic and Mixed Episodes: Aripiprazole is indicated for acute treatment of manic and mixed episodes associated with bipolar I disorder, both as monotherapy and as an adjunct to lithium and valproate.
Maintenance Treatment of Bipolar I Disorder: Aripiprazole is indicated for the maintenance treatment of bipolar I disorder, both as monotherapy and as an adjunct to either lithium or valproate.
Adjunctive Treatment of Major Depressive Disorder: Aripiprazole is indicated for use as an adjunctive therapy to antidepressants for the treatment of major depressive disorder (MDD).
Irritability Associated with Autistic Disorder: Aripiprazole is indicated for the treatment of irritability associated with autistic disorder.
Tourette's Disorder: Aripiprazole is indicated for the treatment of Tourette's disorder.
Special Considerations in Treating Paediatric Schizophrenia, Bipolar I Disorder, and Irritability Associated with Autistic Disorder: Psychiatric disorder in children and adolescents are often serious mental disorders with variable symptom profiles that are not always congruent with diagnostic criteria. It is recommended that psychotropic medication therapy for paediatric patients only be initiated after a thorough diagnostic test has been conducted and careful consideration given to the risks associated with medication treatment. Medication treatment for paediatric patients with schizophrenia, bipolar I disorder, and irritability associated with autistic disorder is indicated as part of a total treatment program that often consists of psychological, educational, and social interventions.
Bipolar I Disorder: Acute Treatment of Manic and Mixed Episodes: Aripiprazole is indicated for acute treatment of manic and mixed episodes associated with bipolar I disorder, both as monotherapy and as an adjunct to lithium and valproate.
Maintenance Treatment of Bipolar I Disorder: Aripiprazole is indicated for the maintenance treatment of bipolar I disorder, both as monotherapy and as an adjunct to either lithium or valproate.
Adjunctive Treatment of Major Depressive Disorder: Aripiprazole is indicated for use as an adjunctive therapy to antidepressants for the treatment of major depressive disorder (MDD).
Irritability Associated with Autistic Disorder: Aripiprazole is indicated for the treatment of irritability associated with autistic disorder.
Tourette's Disorder: Aripiprazole is indicated for the treatment of Tourette's disorder.
Special Considerations in Treating Paediatric Schizophrenia, Bipolar I Disorder, and Irritability Associated with Autistic Disorder: Psychiatric disorder in children and adolescents are often serious mental disorders with variable symptom profiles that are not always congruent with diagnostic criteria. It is recommended that psychotropic medication therapy for paediatric patients only be initiated after a thorough diagnostic test has been conducted and careful consideration given to the risks associated with medication treatment. Medication treatment for paediatric patients with schizophrenia, bipolar I disorder, and irritability associated with autistic disorder is indicated as part of a total treatment program that often consists of psychological, educational, and social interventions.
Dosage/Direction for Use
Dosage: Adults: Schizophrenia: The recommended starting dose for aripiprazole is 10 or 15 mg/day with a maintenance dose of 15 mg/day administered on a once-a-day schedule without regard to meals.
Aripiprazole is effective in a dose range of 10 to 30 mg/day.
Enhanced efficacy at doses higher than a daily dose of 15 mg has not been demonstrated although individual patients may benefit from a higher dose. The maximum daily dose should not exceed 30 mg.
Manic episodes in Bipolar I Disorder: The recommended starting dose for aripiprazole is 15 mg administered on a once-a-day schedule without regard to meals as monotherapy or combination therapy (see Pharmacology: Pharmacodynamics under Actions). Some patients may benefit from a higher dose. The maximum daily dose should not exceed 30 mg.
Recurrence prevention of manic episodes in Bipolar I Disorder: For preventing recurrence of manic episodes in patients who have been receiving aripiprazole as monotherapy or combination therapy, continue therapy at the same dose.
Adjustments of daily dose, including dose reduction should be considered on the basis of clinical status.
Paediatric population: Schizophrenia in adolescents aged 15 years and older: The recommended dose for aripiprazole is 10 mg/day administered on a once-a-day schedule without regard to meals.
Treatment should be initiated at 2 mg (using an appropriate aripiprazole containing medicinal product) for 2 days, titrated to 5 mg for 2 additional days to reach the recommended daily dose of 10 mg. When appropriate, subsequent dose increases should be administered in 5 mg increments without exceeding the maximum daily dose of 30 mg (see Pharmacology: Pharmacodynamics under Actions).
Aripiprazole is effective in a dose range of 10 to 30 mg/day.
Enhanced efficacy at doses higher than a daily dose of 10 mg has not been demonstrated although individual patients may benefit from a higher dose.
Aripiprazole is not recommended for use in patients with schizophrenia below 15 years of age due to insufficient data on safety and efficacy (see Pharmacology: Pharmacodynamics under Actions and Adverse Reactions).
Manic episodes in Bipolar I Disorder in adolescents aged 13 years and older: The recommended dose for aripiprazole is 10 mg/day administered on a once-a-day schedule without regard to meals.
Treatment should be initiated at 2 mg (using an appropriate aripiprazole containing medicinal product) for 2 days, titrated to 5 mg for 2 additional days to reach the recommended daily dose of 10 mg.
The treatment duration should be the minimum necessary for symptom control and must not exceed 12 weeks. Enhanced efficacy at doses higher than a daily dose of 10 mg has not been demonstrated, and a daily dose of 30 mg is associated with a substantially higher incidence of significant undesirable effects including EPS related events, somnolence, fatigue and weight gain (see Adverse Reactions). Doses higher than 10 mg/day should therefore only be used in exceptional cases and with close clinical monitoring (see Pharmacology: Pharmacodynamics under Actions, Precautions and Adverse Reactions).
Younger patients are at increased risk of experiencing adverse events associated with aripiprazole. Therefore, aripiprazole is not recommended for use in patients below 13 years of age (see Pharmacology: Pharmacodynamics under Actions and Adverse Reactions).
Irritability associated with autistic disorder: The safety and efficacy of aripiprazole in children and adolescents aged below 18 years have not yet been established. Currently available data are described in Pharmacodynamics but no recommendation on a dosage can be made.
Tics associated with Tourette's disorder: The safety and efficacy of aripiprazole in children and adolescents 6 to 18 years of age have not yet been established.
Currently available data are described in Pharmacodynamics under Actions but no recommendation on a posology can be made.
Patients with hepatic impairment: No dose adjustment is required for patients with mild to moderate hepatic impairment. In patients with severe hepatic impairment, the data available are insufficient to establish recommendations. In these patients dosing should be managed cautiously. However, the maximum daily dose of 30 mg should be used with caution in patients with severe hepatic impairment (see Pharmacology: Pharmacokinetics under Actions).
Patients with renal impairment: No dose adjustment is required in patients with renal impairment.
Older patients: The effectiveness of aripiprazole in the treatment of schizophrenia and Bipolar I Disorder in patients aged 65 years and older has not been established. Owing to the greater sensitivity of this population, a lower starting dose should be considered when clinical factors warrant (see Precautions).
Gender: No dose adjustment is required for female patients as compared to male patients (see Pharmacology: Pharmacokinetics under Actions).
Smoking status: According to the metabolic pathway of aripiprazole no dose adjustment is required for smokers (see Interactions).
Dose adjustments due to interactions: When concomitant administration of potent CYP3A4 or CYP2D6 inhibitors with aripiprazole occurs, the aripiprazole dose should be reduced. When the CYP3A4 or CYP2D6 inhibitor is withdrawn from the combination therapy, aripiprazole dose should then be increased (see Interactions).
When concomitant administration of potent CYP3A4 inducers with aripiprazole occurs, the aripiprazole dose should be increased. When the CYP3A4 inducer is withdrawn from the combination therapy, the aripiprazole dose should then be reduced to the recommended dose (see Interactions).
Method of administration: Aripiprazole tablets are for oral use.
Aripiprazole is effective in a dose range of 10 to 30 mg/day.
Enhanced efficacy at doses higher than a daily dose of 15 mg has not been demonstrated although individual patients may benefit from a higher dose. The maximum daily dose should not exceed 30 mg.
Manic episodes in Bipolar I Disorder: The recommended starting dose for aripiprazole is 15 mg administered on a once-a-day schedule without regard to meals as monotherapy or combination therapy (see Pharmacology: Pharmacodynamics under Actions). Some patients may benefit from a higher dose. The maximum daily dose should not exceed 30 mg.
Recurrence prevention of manic episodes in Bipolar I Disorder: For preventing recurrence of manic episodes in patients who have been receiving aripiprazole as monotherapy or combination therapy, continue therapy at the same dose.
Adjustments of daily dose, including dose reduction should be considered on the basis of clinical status.
Paediatric population: Schizophrenia in adolescents aged 15 years and older: The recommended dose for aripiprazole is 10 mg/day administered on a once-a-day schedule without regard to meals.
Treatment should be initiated at 2 mg (using an appropriate aripiprazole containing medicinal product) for 2 days, titrated to 5 mg for 2 additional days to reach the recommended daily dose of 10 mg. When appropriate, subsequent dose increases should be administered in 5 mg increments without exceeding the maximum daily dose of 30 mg (see Pharmacology: Pharmacodynamics under Actions).
Aripiprazole is effective in a dose range of 10 to 30 mg/day.
Enhanced efficacy at doses higher than a daily dose of 10 mg has not been demonstrated although individual patients may benefit from a higher dose.
Aripiprazole is not recommended for use in patients with schizophrenia below 15 years of age due to insufficient data on safety and efficacy (see Pharmacology: Pharmacodynamics under Actions and Adverse Reactions).
Manic episodes in Bipolar I Disorder in adolescents aged 13 years and older: The recommended dose for aripiprazole is 10 mg/day administered on a once-a-day schedule without regard to meals.
Treatment should be initiated at 2 mg (using an appropriate aripiprazole containing medicinal product) for 2 days, titrated to 5 mg for 2 additional days to reach the recommended daily dose of 10 mg.
The treatment duration should be the minimum necessary for symptom control and must not exceed 12 weeks. Enhanced efficacy at doses higher than a daily dose of 10 mg has not been demonstrated, and a daily dose of 30 mg is associated with a substantially higher incidence of significant undesirable effects including EPS related events, somnolence, fatigue and weight gain (see Adverse Reactions). Doses higher than 10 mg/day should therefore only be used in exceptional cases and with close clinical monitoring (see Pharmacology: Pharmacodynamics under Actions, Precautions and Adverse Reactions).
Younger patients are at increased risk of experiencing adverse events associated with aripiprazole. Therefore, aripiprazole is not recommended for use in patients below 13 years of age (see Pharmacology: Pharmacodynamics under Actions and Adverse Reactions).
Irritability associated with autistic disorder: The safety and efficacy of aripiprazole in children and adolescents aged below 18 years have not yet been established. Currently available data are described in Pharmacodynamics but no recommendation on a dosage can be made.
Tics associated with Tourette's disorder: The safety and efficacy of aripiprazole in children and adolescents 6 to 18 years of age have not yet been established.
Currently available data are described in Pharmacodynamics under Actions but no recommendation on a posology can be made.
Patients with hepatic impairment: No dose adjustment is required for patients with mild to moderate hepatic impairment. In patients with severe hepatic impairment, the data available are insufficient to establish recommendations. In these patients dosing should be managed cautiously. However, the maximum daily dose of 30 mg should be used with caution in patients with severe hepatic impairment (see Pharmacology: Pharmacokinetics under Actions).
Patients with renal impairment: No dose adjustment is required in patients with renal impairment.
Older patients: The effectiveness of aripiprazole in the treatment of schizophrenia and Bipolar I Disorder in patients aged 65 years and older has not been established. Owing to the greater sensitivity of this population, a lower starting dose should be considered when clinical factors warrant (see Precautions).
Gender: No dose adjustment is required for female patients as compared to male patients (see Pharmacology: Pharmacokinetics under Actions).
Smoking status: According to the metabolic pathway of aripiprazole no dose adjustment is required for smokers (see Interactions).
Dose adjustments due to interactions: When concomitant administration of potent CYP3A4 or CYP2D6 inhibitors with aripiprazole occurs, the aripiprazole dose should be reduced. When the CYP3A4 or CYP2D6 inhibitor is withdrawn from the combination therapy, aripiprazole dose should then be increased (see Interactions).
When concomitant administration of potent CYP3A4 inducers with aripiprazole occurs, the aripiprazole dose should be increased. When the CYP3A4 inducer is withdrawn from the combination therapy, the aripiprazole dose should then be reduced to the recommended dose (see Interactions).
Method of administration: Aripiprazole tablets are for oral use.
Overdosage
Signs and symptoms: In clinical trials and post-marketing experience, accidental or intentional acute overdose of aripiprazole alone was identified in adult patients with reported estimated doses up to 1,260 mg with no fatalities.
The potentially medically important signs and symptoms observed included lethargy, increased blood pressure, somnolence, tachycardia, nausea, vomiting and diarrhoea. In addition, reports of accidental overdose with aripiprazole alone (up to 195 mg) in children have been received with no fatalities.
The potentially medically serious signs and symptoms reported included somnolence, transient loss of consciousness and extrapyramidal symptoms.
Management of overdose: Management of overdose should concentrate on supportive therapy, maintaining an adequate airway, oxygenation and ventilation, and management of symptoms.
The possibility of multiple medicinal product involvement should be considered. Therefore cardiovascular monitoring should be started immediately and should include continuous electrocardiographic monitoring to detect possible arrhythmias.
Following any confirmed or suspected overdose with aripiprazole, close medical supervision and monitoring should continue until the patient recovers.
Activated charcoal (50 g), administered one hour after aripiprazole, decreased aripiprazole Cmax by about 41 % and AUC by about 51 %, suggesting that charcoal may be effective in the treatment of overdose.
Haemodialysis: Although there is no information on the effect of haemodialysis in treating an overdose with aripiprazole, haemodialysis is unlikely to be useful in overdose management since aripiprazole is highly bound to plasma proteins.
The potentially medically important signs and symptoms observed included lethargy, increased blood pressure, somnolence, tachycardia, nausea, vomiting and diarrhoea. In addition, reports of accidental overdose with aripiprazole alone (up to 195 mg) in children have been received with no fatalities.
The potentially medically serious signs and symptoms reported included somnolence, transient loss of consciousness and extrapyramidal symptoms.
Management of overdose: Management of overdose should concentrate on supportive therapy, maintaining an adequate airway, oxygenation and ventilation, and management of symptoms.
The possibility of multiple medicinal product involvement should be considered. Therefore cardiovascular monitoring should be started immediately and should include continuous electrocardiographic monitoring to detect possible arrhythmias.
Following any confirmed or suspected overdose with aripiprazole, close medical supervision and monitoring should continue until the patient recovers.
Activated charcoal (50 g), administered one hour after aripiprazole, decreased aripiprazole Cmax by about 41 % and AUC by about 51 %, suggesting that charcoal may be effective in the treatment of overdose.
Haemodialysis: Although there is no information on the effect of haemodialysis in treating an overdose with aripiprazole, haemodialysis is unlikely to be useful in overdose management since aripiprazole is highly bound to plasma proteins.
Administration
May be taken with or without food.
Contraindications
Hypersensitivity to the active substance or to any of the excipients.
Special Precautions
During antipsychotic treatment, improvement in the patient's clinical condition may take several days to some weeks. Patients should be closely monitored throughout this period.
Suicidality: The occurrence of suicidal behaviour is inherent in psychotic illnesses and mood disorders and in some cases has been reported early after initiation or switch of antipsychotic treatment, including treatment with aripiprazole (see Adverse Reactions). Close supervision of high-risk patients should accompany antipsychotic therapy.
Cardiovascular disorders: Aripiprazole should be used with caution in patients with known cardiovascular disease (history of myocardial infarction or ischaemic heart disease, heart failure, or conduction abnormalities), cerebrovascular disease, conditions which would predispose patients to hypotension (dehydration, hypovolaemia, and treatment with antihypertensive medicinal products) or hypertension, including accelerated or malignant.
Cases of venous thromboembolism (VTE) have been reported with antipsychotic medicinal products. Since patients treated with antipsychotics often present with acquired risk factors for VTE, all possible risk factors for VTE should be identified before and during treatment with aripiprazole and preventive measures undertaken.
QT-prolongation: As with other antipsychotics, aripiprazole should be used with caution in patients with a family history of QT prolongation (see Adverse Reactions).
Tardive dyskinesia: If signs and symptoms of tardive dyskinesia appear in a patient on aripiprazole, dose reduction or discontinuation should be considered (see Adverse Reactions). These symptoms can temporally deteriorate or can even arise after discontinuation of treatment.
Other extrapyramidal symptoms: If signs and symptoms of other EPS appear in a patient taking aripiprazole, dose reduction and close clinical monitoring should be considered.
Neuroleptic Malignant Syndrome (NMS): NMS is a potentially fatal symptom complex associated with antipsychotic medicinal products. In clinical trials, rare cases of NMS were reported during treatment with aripiprazole. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.
However, elevated creatine phosphokinase and rhabdomyolysis, not necessarily in association with NMS, have also been reported.
If a patient develops signs and symptoms indicative of NMS, or presents with unexplained high fever without additional clinical manifestations of NMS, all antipsychotic medicinal products, including aripiprazole, must be discontinued.
Seizure: Aripiprazole should be used with caution in patients who have a history of seizure disorder or have conditions associated with seizures (see Adverse Reactions).
Elderly patients with dementia-related psychosis: Aripiprazole is not indicated for the treatment of dementia-related psychosis.
Hyperglycaemia and diabetes mellitus: Hyperglycaemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotic medicinal products, including aripiprazole.
Risk factors that may predispose patients to severe complications include obesity and family history of diabetes.
Precise risk estimates for hyperglycaemia-related adverse reactions in patients treated with aripiprazole and with other atypical antipsychotic medicinal products are not available to allow direct comparisons. Patients treated with any antipsychotic agents, including aripiprazole, should be observed for signs and symptoms of hyperglycaemia (such as polydipsia, polyuria, polyphagia and weakness) and patients with diabetes mellitus or with risk factors for diabetes mellitus should be monitored regularly for worsening of glucose control (see Adverse Reactions).
Hypersensitivity: As with other medicinal products, hypersensitivity reactions, characterised by allergic symptoms, may occur with aripiprazole (see Adverse Reactions).
Weight gain: Weight gain is commonly seen in schizophrenic and bipolar mania patients due to co-morbidities, use of antipsychotics known to cause weight gain, poorly managed life-style, and might lead to severe complications. Weight gain has been reported post-marketing among patients prescribed aripiprazole. When seen, it is usually in those with significant risk factors such as history of diabetes, thyroid disorder or pituitary adenoma. Weight gain should be monitored in adolescent patients with bipolar mania. If weight gain is clinically significant, dose reduction should be considered (see Adverse Reactions).
Dysphagia: Oesophageal dysmotility and aspiration have been associated with antipsychotic medicinal product use, including aripiprazole. Aripiprazole and other antipsychotic active substances should be used cautiously in patients at risk for aspiration pneumonia.
Pathological gambling: Post-marketing reports of pathological gambling have been reported among patients prescribed aripiprazole, regardless of whether these patients had a prior history of gambling. Patients with a prior history of pathological gambling may be at increased risk and should be monitored carefully (see Adverse Reactions).
Patients with ADHD comorbidity: Despite the high comorbidity frequency of Bipolar I Disorder and ADHD, very limited safety data are available on concomitant use of aripiprazole and stimulants; therefore, extreme caution should be taken when these medicinal products are co-administered.
Effects on Ability to Drive and Use Machines: As with other antipsychotics, patients should be cautioned about operating hazardous machines, including motor vehicles, until they are reasonably certain that aripriprazole does not affect them adversely.
Some pediatric patients with Bipolar I disorder have an increased incidence of somnolence and fatigue (see Adverse Reactions).
Suicidality: The occurrence of suicidal behaviour is inherent in psychotic illnesses and mood disorders and in some cases has been reported early after initiation or switch of antipsychotic treatment, including treatment with aripiprazole (see Adverse Reactions). Close supervision of high-risk patients should accompany antipsychotic therapy.
Cardiovascular disorders: Aripiprazole should be used with caution in patients with known cardiovascular disease (history of myocardial infarction or ischaemic heart disease, heart failure, or conduction abnormalities), cerebrovascular disease, conditions which would predispose patients to hypotension (dehydration, hypovolaemia, and treatment with antihypertensive medicinal products) or hypertension, including accelerated or malignant.
Cases of venous thromboembolism (VTE) have been reported with antipsychotic medicinal products. Since patients treated with antipsychotics often present with acquired risk factors for VTE, all possible risk factors for VTE should be identified before and during treatment with aripiprazole and preventive measures undertaken.
QT-prolongation: As with other antipsychotics, aripiprazole should be used with caution in patients with a family history of QT prolongation (see Adverse Reactions).
Tardive dyskinesia: If signs and symptoms of tardive dyskinesia appear in a patient on aripiprazole, dose reduction or discontinuation should be considered (see Adverse Reactions). These symptoms can temporally deteriorate or can even arise after discontinuation of treatment.
Other extrapyramidal symptoms: If signs and symptoms of other EPS appear in a patient taking aripiprazole, dose reduction and close clinical monitoring should be considered.
Neuroleptic Malignant Syndrome (NMS): NMS is a potentially fatal symptom complex associated with antipsychotic medicinal products. In clinical trials, rare cases of NMS were reported during treatment with aripiprazole. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.
However, elevated creatine phosphokinase and rhabdomyolysis, not necessarily in association with NMS, have also been reported.
If a patient develops signs and symptoms indicative of NMS, or presents with unexplained high fever without additional clinical manifestations of NMS, all antipsychotic medicinal products, including aripiprazole, must be discontinued.
Seizure: Aripiprazole should be used with caution in patients who have a history of seizure disorder or have conditions associated with seizures (see Adverse Reactions).
Elderly patients with dementia-related psychosis: Aripiprazole is not indicated for the treatment of dementia-related psychosis.
Hyperglycaemia and diabetes mellitus: Hyperglycaemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotic medicinal products, including aripiprazole.
Risk factors that may predispose patients to severe complications include obesity and family history of diabetes.
Precise risk estimates for hyperglycaemia-related adverse reactions in patients treated with aripiprazole and with other atypical antipsychotic medicinal products are not available to allow direct comparisons. Patients treated with any antipsychotic agents, including aripiprazole, should be observed for signs and symptoms of hyperglycaemia (such as polydipsia, polyuria, polyphagia and weakness) and patients with diabetes mellitus or with risk factors for diabetes mellitus should be monitored regularly for worsening of glucose control (see Adverse Reactions).
Hypersensitivity: As with other medicinal products, hypersensitivity reactions, characterised by allergic symptoms, may occur with aripiprazole (see Adverse Reactions).
Weight gain: Weight gain is commonly seen in schizophrenic and bipolar mania patients due to co-morbidities, use of antipsychotics known to cause weight gain, poorly managed life-style, and might lead to severe complications. Weight gain has been reported post-marketing among patients prescribed aripiprazole. When seen, it is usually in those with significant risk factors such as history of diabetes, thyroid disorder or pituitary adenoma. Weight gain should be monitored in adolescent patients with bipolar mania. If weight gain is clinically significant, dose reduction should be considered (see Adverse Reactions).
Dysphagia: Oesophageal dysmotility and aspiration have been associated with antipsychotic medicinal product use, including aripiprazole. Aripiprazole and other antipsychotic active substances should be used cautiously in patients at risk for aspiration pneumonia.
Pathological gambling: Post-marketing reports of pathological gambling have been reported among patients prescribed aripiprazole, regardless of whether these patients had a prior history of gambling. Patients with a prior history of pathological gambling may be at increased risk and should be monitored carefully (see Adverse Reactions).
Patients with ADHD comorbidity: Despite the high comorbidity frequency of Bipolar I Disorder and ADHD, very limited safety data are available on concomitant use of aripiprazole and stimulants; therefore, extreme caution should be taken when these medicinal products are co-administered.
Effects on Ability to Drive and Use Machines: As with other antipsychotics, patients should be cautioned about operating hazardous machines, including motor vehicles, until they are reasonably certain that aripriprazole does not affect them adversely.
Some pediatric patients with Bipolar I disorder have an increased incidence of somnolence and fatigue (see Adverse Reactions).
Use In Pregnancy & Lactation
Pregnancy: There are no adequate and well-controlled trials of aripiprazole in pregnant women.
Congenital anomalies have been reported; however, casual relationship with aripiprazole could not be established.
Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during treatment with aripiprazole.
Due to insufficient safety information in humans and concerns raised by animal reproductive studies, this medicinal product should not be used in pregnancy unless the expected benefit clearly justifies the potential risk to the foetus.
Newborn infants exposed to antipsychotics (including aripiprazole) during the third trimester of pregnancy are at risk of adverse reactions including extrapyramidal and/or withdrawal symptoms that may vary in severity and duration following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, or feeding disorder. Consequently, newborn infants should be monitored carefully.
Breast-feeding: Aripiprazole is excreted in human milk. Patients should be advised not to breast feed if they are taking aripiprazole.
Congenital anomalies have been reported; however, casual relationship with aripiprazole could not be established.
Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during treatment with aripiprazole.
Due to insufficient safety information in humans and concerns raised by animal reproductive studies, this medicinal product should not be used in pregnancy unless the expected benefit clearly justifies the potential risk to the foetus.
Newborn infants exposed to antipsychotics (including aripiprazole) during the third trimester of pregnancy are at risk of adverse reactions including extrapyramidal and/or withdrawal symptoms that may vary in severity and duration following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, or feeding disorder. Consequently, newborn infants should be monitored carefully.
Breast-feeding: Aripiprazole is excreted in human milk. Patients should be advised not to breast feed if they are taking aripiprazole.
Adverse Reactions
Summary of the safety profile: The most commonly reported adverse reactions in placebo-controlled trials are akathisia and nausea each occurring in more than 3% of patients treated with oral aripiprazole.
List of adverse reactions: All ADRs are listed by system organ class and frequency; very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000) and not known (cannot be estimated from the available data).
Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
The frequency of adverse reactions reported during post-marketing use cannot be determined as they are derived from spontaneous reports. Consequently, the frequency of these adverse events is qualified as "not known".
Blood and lymphatic system disorders: Not known: Leukopenia, neutropenia, thrombocytopenia.
Immune system disorders: Not known: Allergic reaction (e.g. anaphylactic reaction, angioedema including swollen tongue, tongue oedema, face oedema, pruritus, or urticaria).
Endocrine disorders: Uncommon: Hyperprolactinaemia.
Not known: Diabetic hyperosmolar coma, diabetic ketoacidosis, hyperglycaemia.
Metabolism and nutrition disorder: Common: Diabetes mellitus.
Uncommon: Hyperglycaemia.
Not known: Hyponatraemia, anorexia, weight decreased, weight gain.
Psychiatric disorders: Common: Insomnia, anxiety, restlessness.
Uncommon: Depression, hypersexuality.
Not known: Suicide attempt, suicidal ideation and completed suicide (see Precautions), pathological gambling, aggression, agitation, nervousness.
Nervous system disorders: Common: Akathisia, extrapyramidal disorder, tremor, headache, sedation, somnolence, dizziness.
Uncommon: Tardive dyskinesia, dystonia.
Not known: Neuroleptic malignant syndrome (NMS), grand mal convulsion, serotonin syndrome, speech disorder.
Eye disorders: Common: Vision blurred.
Uncommon: Diplopia.
Cardiac disorders: Uncommon: Tachycardia.
Not known: Sudden unexplained death, torsades de pointes, QT prolongation, ventricular arrhythmias, cardiac arrest, bradycardia.
Vascular disorders: Uncommon: Orthostatic hypotension.
Not known: Venous thromboembolism (including pulmonary embolism and deep vein thrombosis), hypertension, syncope.
Respiratory, thoracic and mediastinal disorders: Uncommon: Hiccups.
Not known: Aspiration pneumonia, laryngospasm, oropharyngeal spasm.
Gastrointestinal disorders: Common: Constipation, dyspepsia, nausea, salivary hypersecretion, vomiting.
Not known: Pancreatitis, dysphagia, diarrhoea, abdominal discomfort, stomach discomfort.
Hepatobiliary disorders: Not known: Hepatic failure, hepatitis, jaundice, increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), increased gamma glutamyl transferase (GCT), increased alkaline phosphatase.
Skin and subcutaneous tissue disorders: Not known: Rash, photosensitivity reaction, alopecia, hyperhidrosis.
Musculoskeletal and connective tissue disorders: Not known: Rhabdomyolysis, myalgia, stiffness.
Renal and urinary disorders: Not known: Urinary incontinence, urinary retention.
Pregnancy, puerperium and perinatal conditions: Not known: Drug withdrawal syndrome neonatal (see Use in Pregnancy & Lactation).
Reproductive system and breast disorders: Not known: Priapism.
General disorders and administration site conditions: Common: Fatigue.
Not known: Temperature regulation disorder (e.g. hypothermia, pyrexia), chest pain, peripheral oedema.
Investigations: Not known: Blood glucose increased, glycosylated haemoglobin increased, blood glucose fluctuation, increased creatine phosphokinase.
List of adverse reactions: All ADRs are listed by system organ class and frequency; very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000) and not known (cannot be estimated from the available data).
Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
The frequency of adverse reactions reported during post-marketing use cannot be determined as they are derived from spontaneous reports. Consequently, the frequency of these adverse events is qualified as "not known".
Blood and lymphatic system disorders: Not known: Leukopenia, neutropenia, thrombocytopenia.
Immune system disorders: Not known: Allergic reaction (e.g. anaphylactic reaction, angioedema including swollen tongue, tongue oedema, face oedema, pruritus, or urticaria).
Endocrine disorders: Uncommon: Hyperprolactinaemia.
Not known: Diabetic hyperosmolar coma, diabetic ketoacidosis, hyperglycaemia.
Metabolism and nutrition disorder: Common: Diabetes mellitus.
Uncommon: Hyperglycaemia.
Not known: Hyponatraemia, anorexia, weight decreased, weight gain.
Psychiatric disorders: Common: Insomnia, anxiety, restlessness.
Uncommon: Depression, hypersexuality.
Not known: Suicide attempt, suicidal ideation and completed suicide (see Precautions), pathological gambling, aggression, agitation, nervousness.
Nervous system disorders: Common: Akathisia, extrapyramidal disorder, tremor, headache, sedation, somnolence, dizziness.
Uncommon: Tardive dyskinesia, dystonia.
Not known: Neuroleptic malignant syndrome (NMS), grand mal convulsion, serotonin syndrome, speech disorder.
Eye disorders: Common: Vision blurred.
Uncommon: Diplopia.
Cardiac disorders: Uncommon: Tachycardia.
Not known: Sudden unexplained death, torsades de pointes, QT prolongation, ventricular arrhythmias, cardiac arrest, bradycardia.
Vascular disorders: Uncommon: Orthostatic hypotension.
Not known: Venous thromboembolism (including pulmonary embolism and deep vein thrombosis), hypertension, syncope.
Respiratory, thoracic and mediastinal disorders: Uncommon: Hiccups.
Not known: Aspiration pneumonia, laryngospasm, oropharyngeal spasm.
Gastrointestinal disorders: Common: Constipation, dyspepsia, nausea, salivary hypersecretion, vomiting.
Not known: Pancreatitis, dysphagia, diarrhoea, abdominal discomfort, stomach discomfort.
Hepatobiliary disorders: Not known: Hepatic failure, hepatitis, jaundice, increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), increased gamma glutamyl transferase (GCT), increased alkaline phosphatase.
Skin and subcutaneous tissue disorders: Not known: Rash, photosensitivity reaction, alopecia, hyperhidrosis.
Musculoskeletal and connective tissue disorders: Not known: Rhabdomyolysis, myalgia, stiffness.
Renal and urinary disorders: Not known: Urinary incontinence, urinary retention.
Pregnancy, puerperium and perinatal conditions: Not known: Drug withdrawal syndrome neonatal (see Use in Pregnancy & Lactation).
Reproductive system and breast disorders: Not known: Priapism.
General disorders and administration site conditions: Common: Fatigue.
Not known: Temperature regulation disorder (e.g. hypothermia, pyrexia), chest pain, peripheral oedema.
Investigations: Not known: Blood glucose increased, glycosylated haemoglobin increased, blood glucose fluctuation, increased creatine phosphokinase.
Drug Interactions
Due to its α1-adrenergic receptor antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents.
Given the primary CNS effects of aripiprazole, caution should be used when aripiprazole is taken in combination with alcohol or other CNS medicinal products with overlapping adverse reactions such as sedation (see Adverse Reactions).
If aripiprazole is administered concomitantly with medicinal products known to cause QT prolongation or electrolyte imbalance, caution should be used.
Potential for other medicinal products to affect aripiprazole: A gastric acid blocker, the H2 antagonist famotidine, reduces aripiprazole rate of absorption but this effect is deemed not clinically relevant.
Aripiprazole is metabolised by multiple pathways involving the CYP2D6 and CYP3A4 enzymes but not CYP1A enzymes. Thus, no dose adjustment is required for smokers.
Quinidine and other CYP2D6 inhibitors: Aripiprazole dose should be reduced to approximately one-half of its prescribed dose when concomitant administration of aripiprazole with quinidine occurs.
Other potent inhibitors of CYP2D6, such as fluoxetine and paroxetine, may be expected to have similar effects and similar dose reductions should therefore be applied.
Ketoconazole and other CYP3A4 inhibitors: In CYP2D6 poor metabolisers, concomitant use of potent inhibitors of CYP3A4 may result in higher plasma concentrations of aripiprazole compared to that in CYP2D6 extensive metabolisers. When considering concomitant administration of ketoconazole or other potent CYP3A4 inhibitors with aripiprazole, potential benefits should outweigh the potential risks to the patient. When concomitant administration of ketoconazole with aripiprazole occurs, aripiprazole dose should be reduced to approximately one-half of its prescribed dose. Other potent inhibitors of CYP3A4, such as itraconazole and HIV protease inhibitors, may be expected to have similar effects and similar dose reductions should therefore be applied.
Upon discontinuation of the CYP2D6 or CYP3A4 inhibitor, the dose of aripiprazole should be increased to the level prior to the initiation of the concomitant therapy.
When weak inhibitors of CYP3A4 (e.g., diltiazem or escitalopram) or CYP2D6 are used concomitantly with aripiprazole, modest increases in aripiprazole concentrations might be expected.
Carbamazepine and other CYP3A4 inducers: Following concomitant administration of carbamazepine, a potent inducer of CYP3A4, the geometric means of Cmax and AUC for aripiprazole were 68% and 73% lower, respectively, compared to when aripiprazole (30 mg) was administered alone. Similarly, for dehydro-aripiprazole the geometric means of Cmax and AUC after carbamazepine co-administration were 69% and 71 % lower, respectively, than those following treatment with aripiprazole alone. Aripiprazole dose should be doubled when concomitant administration of aripiprazole occurs with carbamazepine.
Other potent inducers of CYP3A4 (such as rifampicin, rifabutin, phenytoin, phenobarbital, primidone, efavirenz, nevirapine and St. John's Wort) may be expected to have similar effects and similar dose increases should therefore be applied. Upon discontinuation of potent CYP3A4 inducers, the dose of aripiprazole should be reduced to the recommended dose.
Valproate and lithium: When either valproate or lithium were administered concomitantly with aripiprazole, there was no clinically significant change in aripiprazole concentrations.
Serotonin syndrome: Cases of serotonin syndrome have been reported in patients taking aripiprazole, and possible signs and symptoms for this condition can occur especially in cases of concomitant use with other serotonergic medicinal products, such as SSRI/SNRI, or with medicinal products that are known to increase aripiprazole concentrations (see Adverse Reactions).
Potential for aripiprazole to affect other medicinal products: Aripiprazole is unlikely to cause clinically important medicinal product interactions medicated by these enzymes.
When aripiprazole was administered concomitantly with either valproate, lithium or lamotrigine, there was no clinically important change in valproate, lithium or lamotrigine concentrations.
Given the primary CNS effects of aripiprazole, caution should be used when aripiprazole is taken in combination with alcohol or other CNS medicinal products with overlapping adverse reactions such as sedation (see Adverse Reactions).
If aripiprazole is administered concomitantly with medicinal products known to cause QT prolongation or electrolyte imbalance, caution should be used.
Potential for other medicinal products to affect aripiprazole: A gastric acid blocker, the H2 antagonist famotidine, reduces aripiprazole rate of absorption but this effect is deemed not clinically relevant.
Aripiprazole is metabolised by multiple pathways involving the CYP2D6 and CYP3A4 enzymes but not CYP1A enzymes. Thus, no dose adjustment is required for smokers.
Quinidine and other CYP2D6 inhibitors: Aripiprazole dose should be reduced to approximately one-half of its prescribed dose when concomitant administration of aripiprazole with quinidine occurs.
Other potent inhibitors of CYP2D6, such as fluoxetine and paroxetine, may be expected to have similar effects and similar dose reductions should therefore be applied.
Ketoconazole and other CYP3A4 inhibitors: In CYP2D6 poor metabolisers, concomitant use of potent inhibitors of CYP3A4 may result in higher plasma concentrations of aripiprazole compared to that in CYP2D6 extensive metabolisers. When considering concomitant administration of ketoconazole or other potent CYP3A4 inhibitors with aripiprazole, potential benefits should outweigh the potential risks to the patient. When concomitant administration of ketoconazole with aripiprazole occurs, aripiprazole dose should be reduced to approximately one-half of its prescribed dose. Other potent inhibitors of CYP3A4, such as itraconazole and HIV protease inhibitors, may be expected to have similar effects and similar dose reductions should therefore be applied.
Upon discontinuation of the CYP2D6 or CYP3A4 inhibitor, the dose of aripiprazole should be increased to the level prior to the initiation of the concomitant therapy.
When weak inhibitors of CYP3A4 (e.g., diltiazem or escitalopram) or CYP2D6 are used concomitantly with aripiprazole, modest increases in aripiprazole concentrations might be expected.
Carbamazepine and other CYP3A4 inducers: Following concomitant administration of carbamazepine, a potent inducer of CYP3A4, the geometric means of Cmax and AUC for aripiprazole were 68% and 73% lower, respectively, compared to when aripiprazole (30 mg) was administered alone. Similarly, for dehydro-aripiprazole the geometric means of Cmax and AUC after carbamazepine co-administration were 69% and 71 % lower, respectively, than those following treatment with aripiprazole alone. Aripiprazole dose should be doubled when concomitant administration of aripiprazole occurs with carbamazepine.
Other potent inducers of CYP3A4 (such as rifampicin, rifabutin, phenytoin, phenobarbital, primidone, efavirenz, nevirapine and St. John's Wort) may be expected to have similar effects and similar dose increases should therefore be applied. Upon discontinuation of potent CYP3A4 inducers, the dose of aripiprazole should be reduced to the recommended dose.
Valproate and lithium: When either valproate or lithium were administered concomitantly with aripiprazole, there was no clinically significant change in aripiprazole concentrations.
Serotonin syndrome: Cases of serotonin syndrome have been reported in patients taking aripiprazole, and possible signs and symptoms for this condition can occur especially in cases of concomitant use with other serotonergic medicinal products, such as SSRI/SNRI, or with medicinal products that are known to increase aripiprazole concentrations (see Adverse Reactions).
Potential for aripiprazole to affect other medicinal products: Aripiprazole is unlikely to cause clinically important medicinal product interactions medicated by these enzymes.
When aripiprazole was administered concomitantly with either valproate, lithium or lamotrigine, there was no clinically important change in valproate, lithium or lamotrigine concentrations.
Caution For Usage
Incompatibilities: Not applicable.
Storage
Store at temperatures not exceeding 30°C.
Action
Pharmacotherapeutic group: Psycholeptics, antipsychotics, other antipsychotics. ATC code: N05AX12.
Pharmacology: Mechanism of action: It has been proposed that aripiprozole's efficacy in schizophrenia and Bipolar I Disorder is mediated through a combination of partial agonism at dopamine D2 and serotonin 5HT1a receptors and antagonism of serotonin 5HT2a receptors.
Aripiprazole exhibited antagonist properties in animal models of dopaminergic hyperactivity and agonist properties in animal models of dopaminergic hypoactivity. Aripiprazole exhibited high binding affinity in vitro for dopamine D2 and D3, serotonin 5HT1a and 5HT2a receptors and moderate affinity for dopamine D4, serotonin 5HT2c and 5HT7, alpha-1 adrenergic and histamine H1 receptors. Aripiprazole also exhibited moderate binding affinity for the serotonin reuptake site and no appreciable affinity for muscarinic receptors. Interaction with receptors other than dopamine and serotonin subtypes may explain some of the other clinical effects of aripiprazole. Aripiprazole doses ranging from 0.5 to 30 mg administered once a day to healthy subjects for 2 weeks produced a dose-dependent reduction in the binding of 11C-raclopride, a D2/D3 receptor ligand, to the coudate and putamen detected by positron emission tomography.
Pharmacokinetics: Absorption: Aripiprazole is well absorbed, with peak plasma concentrations occurring within 3-5 hours after dosing. Aripiprazole undergoes minimal pre-systemic metabolism. The absolute oral bioavailability of the tablet formulation is 87%. There is no effect of a high fat meal on the pharmacokinetics of aripiprazole.
Distribution: Aripiprazole is widely distributed throughout the body with an apparent volume of distribution of 4.9 L/kg, indicating extensive extravascular distribution. At therapeutic concentrations, aripiprazole and dehydro-aripiprazole are greater than 99% bound to serum proteins, binding primarily to albumin.
Biotransformation: Aripiprazole is extensively metabolized by the liver primarily by three biotransformation pathways: dehydrogenation, hydroxylation, and N-dealkylation. Based on in vitro studies, CYP3A4 and CYP2D6 enzymes are responsible for dehydrogenation and hydroxylation of aripiprazole, and N-dealkylation is catalysed by CYP3A4. Aripiprazole is the predominant medicinal product moiety in systemic circulation. At steady state, dehydro-aripiprazole, the active metabolite, represents about 40% of aripiprazole AUC in plasma.
Elimination: The mean elimination half-lives for aripiprazole are approximately 75 hours in extensive metabolisers of CYP2D6 and approximately 146 hours in poor metabolisers of CYP2D6.
The total body clearance of aripiprazole is 0.7 mL/min/kg, which is primarily hepatic.
Following a single oral dose of [14C]-labelled aripiprazole, approximately 27% of the administered radioactivity was recovered in the urine and approximately 60% in the faeces. Less than 1% of unchanged aripiprazole was excreted in the urine and approximately 18% was recovered unchanged in the faeces.
Pharmacokinetics in special patient groups: Paediatric population: The pharmacokinetics of aripiprazole and dehydro-aripiprazole in paediatric patients 10 to 17 years of age were similar 10 those in adults after correcting for the difference in body weights.
Older people: There are no differences in the pharmacokinetics of aripiprazole between healthy older and younger adult subjects, nor is there any detectable effect of age in a population pharmacokinetic analysis in schizophrenic patients.
Gender: There are no differences in the pharmacokinetics of aripiprazole between healthy male and female subjects nor is there any detectable effect of gender in a population pharmacokinetic analysis in schizophrenic patients.
Smoking: Population pharmacokinetic evaluation has revealed no evidence of clinically significant effects from smoking on the pharmacokinetics of aripiprazole.
Race: Population pharmacokinetic evaluation showed no evidence of race-related differences on the pharmacokinetics of aripiprazole.
Renal impairment: The pharmacokinetic characteristics of aripiprazole and dehydro-aripiprazole were found to be similar in patients with severe renal disease compared to young healthy subjects.
Hepatic impairment: A single-dose study in subjects with varying degrees of liver cirrhosis (Child-Pugh Classes A, B, and C) did not reveal a significant effect of hepatic impairment on the pharmacokinetics of aripiprazole and dehydro-aripiprazole, but the study included only 3 patients with Class C liver cirrhosis, which is insufficient to draw conclusions on their metabolic capacity.
Toxicology: Preclinical safety data: Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction and development.
Toxicologically significant effects were observed only at doses or exposures that were sufficiently in excess of the maximum human dose or exposure, indicating that these effects were limited or of no relevance to clinical use. These included: dose-dependent adrenocortical toxicity (lipofuscin pigment accumulation and/or parenchymal cell loss) in rats after 104 weeks at 20 to 60 mg/kg/day (3 to 10 times the mean steady-state AUC at the maximum recommended human dose) and increased adrenocortical carcinomas and combined adrenocortical adenomas/carcinomas in female rats at 60 mg/kg/day (10 times the mean steady-state AUC on the maximum recommended human dose). The highest nontumorigenic exposure in female rats was 7 times the human exposure at the recommended dose.
An additional finding was cholelithiasis as a consequence of precipitation of sulphate conjugates of hydroxy metabolites of aripriprazole in the bile of monkeys after repeated oral dosing at 25 to 125 mg/kg/day (1 to 3 times the mean steady-state AUC at the maximum recommended clinical dose or 16 to 81 times the maximum recommended human dose based on mg/m2).
However, the concentrations of the sulphate conjugates of hydroxy aripiprazole in human bile at the highest dose proposed, 30 mg per day, were no more than 6% of the bile concentrations found in the monkeys in the 39-week study and are well below (6%) their limits of in vitro solubility.
In repeated-dose studies in juvenile rats and dogs, the toxicity profile of aripiprazole was comparable to that observed in adult animals, and there was no evidence of neurotoxicity or adverse effects on development.
Based on results of a full range of standard genotoxicity tests, aripiprazole was considered non-genotoxic.
Aripiprazole did not impair fertility in reproductive toxicity studies. Developmental toxicity, including dose-dependent delayed foetal ossification and possible teratogenic effects, were observed in rats at doses resulting in subtherapeutic exposures (based on AUC) and in rabbits at doses resulting in exposures 3 and 11 times the mean steady-state AUC at the maximum recommended clinical dose. Maternal toxicity occurred at doses similar to those eliciting developmental toxicity.
Pharmacology: Mechanism of action: It has been proposed that aripiprozole's efficacy in schizophrenia and Bipolar I Disorder is mediated through a combination of partial agonism at dopamine D2 and serotonin 5HT1a receptors and antagonism of serotonin 5HT2a receptors.
Aripiprazole exhibited antagonist properties in animal models of dopaminergic hyperactivity and agonist properties in animal models of dopaminergic hypoactivity. Aripiprazole exhibited high binding affinity in vitro for dopamine D2 and D3, serotonin 5HT1a and 5HT2a receptors and moderate affinity for dopamine D4, serotonin 5HT2c and 5HT7, alpha-1 adrenergic and histamine H1 receptors. Aripiprazole also exhibited moderate binding affinity for the serotonin reuptake site and no appreciable affinity for muscarinic receptors. Interaction with receptors other than dopamine and serotonin subtypes may explain some of the other clinical effects of aripiprazole. Aripiprazole doses ranging from 0.5 to 30 mg administered once a day to healthy subjects for 2 weeks produced a dose-dependent reduction in the binding of 11C-raclopride, a D2/D3 receptor ligand, to the coudate and putamen detected by positron emission tomography.
Pharmacokinetics: Absorption: Aripiprazole is well absorbed, with peak plasma concentrations occurring within 3-5 hours after dosing. Aripiprazole undergoes minimal pre-systemic metabolism. The absolute oral bioavailability of the tablet formulation is 87%. There is no effect of a high fat meal on the pharmacokinetics of aripiprazole.
Distribution: Aripiprazole is widely distributed throughout the body with an apparent volume of distribution of 4.9 L/kg, indicating extensive extravascular distribution. At therapeutic concentrations, aripiprazole and dehydro-aripiprazole are greater than 99% bound to serum proteins, binding primarily to albumin.
Biotransformation: Aripiprazole is extensively metabolized by the liver primarily by three biotransformation pathways: dehydrogenation, hydroxylation, and N-dealkylation. Based on in vitro studies, CYP3A4 and CYP2D6 enzymes are responsible for dehydrogenation and hydroxylation of aripiprazole, and N-dealkylation is catalysed by CYP3A4. Aripiprazole is the predominant medicinal product moiety in systemic circulation. At steady state, dehydro-aripiprazole, the active metabolite, represents about 40% of aripiprazole AUC in plasma.
Elimination: The mean elimination half-lives for aripiprazole are approximately 75 hours in extensive metabolisers of CYP2D6 and approximately 146 hours in poor metabolisers of CYP2D6.
The total body clearance of aripiprazole is 0.7 mL/min/kg, which is primarily hepatic.
Following a single oral dose of [14C]-labelled aripiprazole, approximately 27% of the administered radioactivity was recovered in the urine and approximately 60% in the faeces. Less than 1% of unchanged aripiprazole was excreted in the urine and approximately 18% was recovered unchanged in the faeces.
Pharmacokinetics in special patient groups: Paediatric population: The pharmacokinetics of aripiprazole and dehydro-aripiprazole in paediatric patients 10 to 17 years of age were similar 10 those in adults after correcting for the difference in body weights.
Older people: There are no differences in the pharmacokinetics of aripiprazole between healthy older and younger adult subjects, nor is there any detectable effect of age in a population pharmacokinetic analysis in schizophrenic patients.
Gender: There are no differences in the pharmacokinetics of aripiprazole between healthy male and female subjects nor is there any detectable effect of gender in a population pharmacokinetic analysis in schizophrenic patients.
Smoking: Population pharmacokinetic evaluation has revealed no evidence of clinically significant effects from smoking on the pharmacokinetics of aripiprazole.
Race: Population pharmacokinetic evaluation showed no evidence of race-related differences on the pharmacokinetics of aripiprazole.
Renal impairment: The pharmacokinetic characteristics of aripiprazole and dehydro-aripiprazole were found to be similar in patients with severe renal disease compared to young healthy subjects.
Hepatic impairment: A single-dose study in subjects with varying degrees of liver cirrhosis (Child-Pugh Classes A, B, and C) did not reveal a significant effect of hepatic impairment on the pharmacokinetics of aripiprazole and dehydro-aripiprazole, but the study included only 3 patients with Class C liver cirrhosis, which is insufficient to draw conclusions on their metabolic capacity.
Toxicology: Preclinical safety data: Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction and development.
Toxicologically significant effects were observed only at doses or exposures that were sufficiently in excess of the maximum human dose or exposure, indicating that these effects were limited or of no relevance to clinical use. These included: dose-dependent adrenocortical toxicity (lipofuscin pigment accumulation and/or parenchymal cell loss) in rats after 104 weeks at 20 to 60 mg/kg/day (3 to 10 times the mean steady-state AUC at the maximum recommended human dose) and increased adrenocortical carcinomas and combined adrenocortical adenomas/carcinomas in female rats at 60 mg/kg/day (10 times the mean steady-state AUC on the maximum recommended human dose). The highest nontumorigenic exposure in female rats was 7 times the human exposure at the recommended dose.
An additional finding was cholelithiasis as a consequence of precipitation of sulphate conjugates of hydroxy metabolites of aripriprazole in the bile of monkeys after repeated oral dosing at 25 to 125 mg/kg/day (1 to 3 times the mean steady-state AUC at the maximum recommended clinical dose or 16 to 81 times the maximum recommended human dose based on mg/m2).
However, the concentrations of the sulphate conjugates of hydroxy aripiprazole in human bile at the highest dose proposed, 30 mg per day, were no more than 6% of the bile concentrations found in the monkeys in the 39-week study and are well below (6%) their limits of in vitro solubility.
In repeated-dose studies in juvenile rats and dogs, the toxicity profile of aripiprazole was comparable to that observed in adult animals, and there was no evidence of neurotoxicity or adverse effects on development.
Based on results of a full range of standard genotoxicity tests, aripiprazole was considered non-genotoxic.
Aripiprazole did not impair fertility in reproductive toxicity studies. Developmental toxicity, including dose-dependent delayed foetal ossification and possible teratogenic effects, were observed in rats at doses resulting in subtherapeutic exposures (based on AUC) and in rabbits at doses resulting in exposures 3 and 11 times the mean steady-state AUC at the maximum recommended clinical dose. Maternal toxicity occurred at doses similar to those eliciting developmental toxicity.
MedsGo Class
Antipsychotics
Features
Dosage
10mg
Ingredients
- Aripiprazole
Packaging
Tablet 1's
Generic Name
Aripiprazole
Registration Number
DRP-7151
Classification
Prescription Drug (RX)
Product Questions
Questions
