When a pharmaceutical company changes an SPC or PIL, a new version is published on medicines.ie. For each version, we show the dates it was published on medicines.ie and the reasons for change.
4.6 Fertility, pregnancy and lactation
The following text has been added :
Neonates 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, newborns should be monitored carefully.
4.8 Undesirable effects the following has been added :
Pregnancy, puerperium and perinatal conditions:
drug withdrawal syndrome neonatal (see section 4.6)
The following has been added to section 5.1 In a 52-week, placebo-controlled trial, in patients with a current manic or mixed episode of Bipolar I Disorder who achieved sustained remission (Y-MRS and MADRS total scores ≤ 12) on aripiprazole (10 mg/day to 30 mg/day) adjunctive to lithium or valproate for 12 consecutive weeks, adjunctive aripiprazole demonstrated superiority over placebo with a 46% decreased risk (hazard ratio of 0.54) in preventing bipolar recurrence and a 65% decreased risk (hazard ratio of 0.35) in preventing recurrence into mania over adjunctive placebo but failed to demonstrate superiority over placebo in preventing recurrence into depression. Adjunctive aripiprazole demonstrated superiority over placebo on the secondary outcome measure, CGI-BP Severity of Illness score (mania). In this trial, patients were assigned by investigators with either open-label lithium or valproate monotherapy to determine partial non-response. Patients were stabilised for at least 12 consecutive weeks with the combination of aripiprazole and the same mood stabilizer. Stabilized patients were then randomised to continue the same mood stabilizer with double-blind aripiprazole or placebo. Four mood stabilizer subgroups were assessed in the randomised phase: aripiprazole + lithium; aripiprazole + valproate; placebo + lithium; placebo + valproate. The Kaplan-Meier rates for recurrence to any mood episode for the adjunctive treatment arm were 16% in aripiprazole + lithium and 18% in aripiprazole + valproate compared to 45% in placebo + lithium and 19% in placebo + valproate.
In a 52-week, placebo-controlled trial, in patients with a current manic or mixed episode of Bipolar I Disorder who achieved sustained remission (Y-MRS and MADRS total scores ≤ 12) on aripiprazole (10 mg/day to 30 mg/day) adjunctive to lithium or valproate for 12 consecutive weeks, adjunctive aripiprazole demonstrated superiority over placebo with a 46% decreased risk (hazard ratio of 0.54) in preventing bipolar recurrence and a 65% decreased risk (hazard ratio of 0.35) in preventing recurrence into mania over adjunctive placebo but failed to demonstrate superiority over placebo in preventing recurrence into depression. Adjunctive aripiprazole demonstrated superiority over placebo on the secondary outcome measure, CGI-BP Severity of Illness score (mania).
In this trial, patients were assigned by investigators with either open-label lithium or valproate monotherapy to determine partial non-response. Patients were stabilised for at least 12 consecutive weeks with the combination of aripiprazole and the same mood stabilizer.
Stabilized patients were then randomised to continue the same mood stabilizer with double-blind aripiprazole or placebo. Four mood stabilizer subgroups were assessed in the randomised phase: aripiprazole + lithium; aripiprazole + valproate; placebo + lithium; placebo + valproate.
The Kaplan-Meier rates for recurrence to any mood episode for the adjunctive treatment arm were 16% in aripiprazole + lithium and 18% in aripiprazole + valproate compared to 45% in placebo + lithium and 19% in placebo + valproate.
4.8 Undesirable effects- the following text in red has been added Paediatric population: In a short-term, placebo-controlled clinical trial involving 302 adolescents (13-17 years) with schizophrenia, the frequency and type of undesirable effects were similar to those in adults except for the following events that were reported more frequently in adolescents receiving aripiprazole than in adults receiving aripiprazole (and more frequently than placebo): somnolence/sedation and extrapyramidal disorder were reported very commonly (≥ 1/10), and dry mouth, increased appetite and orthostatic hypotension were reported commonly (≥ 1/100 < 1/10). The safety profile in a 26-week open-label extension trial was similar to that observed in the short-term, placebo-controlled trial. In the pooled adolescent schizophrenia population (13-17 years) with exposure up to 2 years, incidence of low serum prolactin levels in females (<3 ng/ml) and males (<2 ng/ml) was 29.5% and 48.3%, respectively.
Paediatric population:
In a short-term, placebo-controlled clinical trial involving 302 adolescents (13-17 years) with schizophrenia, the frequency and type of undesirable effects were similar to those in adults except for the following events that were reported more frequently in adolescents receiving aripiprazole than in adults receiving aripiprazole (and more frequently than placebo): somnolence/sedation and extrapyramidal disorder were reported very commonly (≥ 1/10), and dry mouth, increased appetite and orthostatic hypotension were reported commonly (≥ 1/100 < 1/10).
The safety profile in a 26-week open-label extension trial was similar to that observed in the short-term, placebo-controlled trial.
In the pooled adolescent schizophrenia population (13-17 years) with exposure up to 2 years, incidence of low serum prolactin levels in females (<3 ng/ml) and males (<2 ng/ml) was 29.5% and 48.3%, respectively.
4.2 Posology and method of administration
Posology The recommended initial dose for aripiprazole solution for injection is 9.75 mg (1.3 ml), administered as a single intramuscular injection. The effective dose range of aripiprazole solution for injection is 5.25‑15 mg as a single injection. A lower dose of 5.25 mg (0.7 ml) may be given, on the basis of individual clinical status, which should also include consideration of medicinal products already administered either for maintenance or acute treatment (see section 4.5). A second injection may be administered 2 hours after the first injection, on the basis of individual clinical status and no more than three injections should be given in any 24-hour period. The maximum daily dose of aripiprazole is 30 mg (including all formulations of aripiprazole). If continued treatment is indicated with oral aripiprazole, see the Summary of Product Characteristics for ABILIFY tablets, ABILIFY orodispersible tablets, or ABILIFY oral solution. ABILIFY solution for injection is for intramuscular use. To enhance absorption and minimise variability, injection into the deltoid or deep within the gluteus maximus muscle, avoiding adipose regions, is recommended. ABILIFY solution for injection should not be administered intravenously or subcutaneously. ABILIFY solution for injection is ready to use and intended for short-term use only (see section 5.1). Patient populationChildren and adolescents: there is no experience in children and adolescents under 18 years of age. Patients with hepatic impairment: no dosage 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 section 5.2). Patients with renal impairment: no dosage adjustment is required in patients with renal impairment. Elderly: the effectiveness of ABILIFY solution for injection in patients who are 65 years of age or 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 section 4.4). Gender: no dosage adjustment is required for female patients as compared to male patients (see section 5.2). Smoking status: according to the metabolic pathway of ABILIFY no dosage adjustment is required for smokers (see section 4.5). 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 section 4.5). 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 section 4.5). Method of administration ABILIFY solution for injection is for intramuscular use. To enhance absorption and minimise variability, injection into the deltoid or deep within the gluteus maximus muscle, avoiding adipose regions, is recommended. ABILIFY solution for injection should not be administered intravenously or subcutaneously. ABILIFY solution for injection is ready to use and intended for short-term use only (see section 5.1). 4.4 Special warnings and precautions for use 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 therapy, including treatment with aripiprazole (see section 4.8). Close supervision of high-risk patients should accompany antipsychotic therapy. Results of an epidemiological study foundsuggested that there was no increased risk of suicidality with aripiprazole compared to other antipsychotics among patients with schizophrenia or bipolar disorder. 4.6 PregnancyFertility, pregnancy and lactation There are no adequate and well-controlled trials of aripiprazole in pregnant women. Congenital anomalies have been reported; however, causal relationship with aripiprazole could not be established. Animal studies could not exclude potential developmental toxicity (see section 5.3). 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. Aripiprazole was excreted in the milk of treated rats during lactation. It is not known whether aripiprazole is excreted in human milk. Patients should be advised not to breast feed if they are taking aripiprazole. 4.7 Effects on ability to drive and use machines No studies on the effect on the ability to drive and use machines have been performed. However, asAs with other antipsychotics, patients should be cautioned about operating hazardous machines, including motor vehicles, until they are reasonably certain that aripiprazole does not affect them adversely (see section 4.8). 4.8 Undesirable effects Paediatric patientspopulation: In a short-term placebo-controlled clinical trial involving 302 adolescents (13-17 years) with schizophrenia, the frequency and type of undesirable effects were similar to those in adults except for the following events that were reported more frequently in adolescents receiving oral aripiprazole thatn in adults receiving oral aripiprazole (and more frequently than placebo): somnolence/sedation and extrapyramidal disorder were reported very commonly (≥ 1/10), and dry mouth, increased appetite and orthostatic hypotension were reported commonly (≥ 1/100 < 1/10). The safety profile in a 26-week open-label extension trial was similar to that observed in the short-term, placebo-controlled trial. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Paediatric population: Schizophrenia in adolescents with oral aripiprazole: In in a 6-week placebo-controlled trial involving 302 schizophrenic adolescent patients (13-17 years), presenting with positive or negative symptoms, aripiprazole was associated with statistically significantly greater improvements in psychotic symptoms compared to placebo. In a sub-analysis of the adolescent patients between the ages of 15 to 17 years, representing 74% of the total enrolled population, maintenance of effect was observed over the 26-week open-label extension trial. 5.2 Pharmacokinetic properties Pharmacokinetics in special patient groups Paediatric patientspopulation: The pharmacokinetics of oral aripiprazole and dehydro-aripiprazole in paediatric patients 13 to 17 years of age were similar to those in adults after correcting for the differences in body weights. 5.3 Preclinical safety data Administration of aripiprazole solution for injection was well tolerated and produced no direct target organ toxicity in rats or monkeys after repeated dosing at systemic exposures (AUC) that were 15 and 5 times, respectively, human exposure at the maximum recommended human dose of 30 mg intramuscular. In intravenous reproductive toxicity studies, no new safety concerns were observed at maternal exposures up to 15 (rat) and 29 (rabbit) times human exposure at 30 mg. Non-clinical safety data revealed no special hazard for humans based on conventional oral aripiprazole studies of safety pharmacology, repeat-dose toxicity, genotoxicity, carcinogenic potential, and toxicity to reproduction and development. 10. DATE OF REVISION OF THE TEXT November 2009March 2010 Detailed information on this product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/
The recommended initial dose for aripiprazole solution for injection is 9.75 mg (1.3 ml), administered as a single intramuscular injection. The effective dose range of aripiprazole solution for injection is 5.25‑15 mg as a single injection. A lower dose of 5.25 mg (0.7 ml) may be given, on the basis of individual clinical status, which should also include consideration of medicinal products already administered either for maintenance or acute treatment (see section 4.5). A second injection may be administered 2 hours after the first injection, on the basis of individual clinical status and no more than three injections should be given in any 24-hour period.
The maximum daily dose of aripiprazole is 30 mg (including all formulations of aripiprazole).
If continued treatment is indicated with oral aripiprazole, see the Summary of Product Characteristics for ABILIFY tablets, ABILIFY orodispersible tablets, or ABILIFY oral solution.
ABILIFY solution for injection is for intramuscular use.
To enhance absorption and minimise variability, injection into the deltoid or deep within the gluteus maximus muscle, avoiding adipose regions, is recommended.
ABILIFY solution for injection should not be administered intravenously or subcutaneously. ABILIFY solution for injection is ready to use and intended for short-term use only (see section 5.1). Patient populationChildren and adolescents: there is no experience in children and adolescents under 18 years of age. Patients with hepatic impairment: no dosage 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 section 5.2). Patients with renal impairment: no dosage adjustment is required in patients with renal impairment. Elderly: the effectiveness of ABILIFY solution for injection in patients who are 65 years of age or 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 section 4.4). Gender: no dosage adjustment is required for female patients as compared to male patients (see section 5.2). Smoking status: according to the metabolic pathway of ABILIFY no dosage adjustment is required for smokers (see section 4.5). 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 section 4.5). 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 section 4.5). Method of administration ABILIFY solution for injection is for intramuscular use. To enhance absorption and minimise variability, injection into the deltoid or deep within the gluteus maximus muscle, avoiding adipose regions, is recommended. ABILIFY solution for injection should not be administered intravenously or subcutaneously. ABILIFY solution for injection is ready to use and intended for short-term use only (see section 5.1). 4.4 Special warnings and precautions for use 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 therapy, including treatment with aripiprazole (see section 4.8). Close supervision of high-risk patients should accompany antipsychotic therapy. Results of an epidemiological study foundsuggested that there was no increased risk of suicidality with aripiprazole compared to other antipsychotics among patients with schizophrenia or bipolar disorder. 4.6 PregnancyFertility, pregnancy and lactation There are no adequate and well-controlled trials of aripiprazole in pregnant women. Congenital anomalies have been reported; however, causal relationship with aripiprazole could not be established. Animal studies could not exclude potential developmental toxicity (see section 5.3). 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. Aripiprazole was excreted in the milk of treated rats during lactation. It is not known whether aripiprazole is excreted in human milk. Patients should be advised not to breast feed if they are taking aripiprazole. 4.7 Effects on ability to drive and use machines No studies on the effect on the ability to drive and use machines have been performed. However, asAs with other antipsychotics, patients should be cautioned about operating hazardous machines, including motor vehicles, until they are reasonably certain that aripiprazole does not affect them adversely (see section 4.8). 4.8 Undesirable effects Paediatric patientspopulation: In a short-term placebo-controlled clinical trial involving 302 adolescents (13-17 years) with schizophrenia, the frequency and type of undesirable effects were similar to those in adults except for the following events that were reported more frequently in adolescents receiving oral aripiprazole thatn in adults receiving oral aripiprazole (and more frequently than placebo): somnolence/sedation and extrapyramidal disorder were reported very commonly (≥ 1/10), and dry mouth, increased appetite and orthostatic hypotension were reported commonly (≥ 1/100 < 1/10). The safety profile in a 26-week open-label extension trial was similar to that observed in the short-term, placebo-controlled trial. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Paediatric population: Schizophrenia in adolescents with oral aripiprazole: In in a 6-week placebo-controlled trial involving 302 schizophrenic adolescent patients (13-17 years), presenting with positive or negative symptoms, aripiprazole was associated with statistically significantly greater improvements in psychotic symptoms compared to placebo. In a sub-analysis of the adolescent patients between the ages of 15 to 17 years, representing 74% of the total enrolled population, maintenance of effect was observed over the 26-week open-label extension trial. 5.2 Pharmacokinetic properties Pharmacokinetics in special patient groups Paediatric patientspopulation: The pharmacokinetics of oral aripiprazole and dehydro-aripiprazole in paediatric patients 13 to 17 years of age were similar to those in adults after correcting for the differences in body weights. 5.3 Preclinical safety data Administration of aripiprazole solution for injection was well tolerated and produced no direct target organ toxicity in rats or monkeys after repeated dosing at systemic exposures (AUC) that were 15 and 5 times, respectively, human exposure at the maximum recommended human dose of 30 mg intramuscular. In intravenous reproductive toxicity studies, no new safety concerns were observed at maternal exposures up to 15 (rat) and 29 (rabbit) times human exposure at 30 mg. Non-clinical safety data revealed no special hazard for humans based on conventional oral aripiprazole studies of safety pharmacology, repeat-dose toxicity, genotoxicity, carcinogenic potential, and toxicity to reproduction and development. 10. DATE OF REVISION OF THE TEXT November 2009March 2010 Detailed information on this product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/
Patient populationChildren and adolescents: there is no experience in children and adolescents under 18 years of age.
Patients with hepatic impairment: no dosage 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 section 5.2).
Patients with renal impairment: no dosage adjustment is required in patients with renal impairment.
Elderly: the effectiveness of ABILIFY solution for injection in patients who are 65 years of age or 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 section 4.4).
Gender: no dosage adjustment is required for female patients as compared to male patients (see section 5.2).
Smoking status: according to the metabolic pathway of ABILIFY no dosage adjustment is required for smokers (see section 4.5).
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 section 4.5).
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 section 4.5). Method of administration ABILIFY solution for injection is for intramuscular use. To enhance absorption and minimise variability, injection into the deltoid or deep within the gluteus maximus muscle, avoiding adipose regions, is recommended. ABILIFY solution for injection should not be administered intravenously or subcutaneously. ABILIFY solution for injection is ready to use and intended for short-term use only (see section 5.1). 4.4 Special warnings and precautions for use 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 therapy, including treatment with aripiprazole (see section 4.8). Close supervision of high-risk patients should accompany antipsychotic therapy. Results of an epidemiological study foundsuggested that there was no increased risk of suicidality with aripiprazole compared to other antipsychotics among patients with schizophrenia or bipolar disorder. 4.6 PregnancyFertility, pregnancy and lactation There are no adequate and well-controlled trials of aripiprazole in pregnant women. Congenital anomalies have been reported; however, causal relationship with aripiprazole could not be established. Animal studies could not exclude potential developmental toxicity (see section 5.3). 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. Aripiprazole was excreted in the milk of treated rats during lactation. It is not known whether aripiprazole is excreted in human milk. Patients should be advised not to breast feed if they are taking aripiprazole. 4.7 Effects on ability to drive and use machines No studies on the effect on the ability to drive and use machines have been performed. However, asAs with other antipsychotics, patients should be cautioned about operating hazardous machines, including motor vehicles, until they are reasonably certain that aripiprazole does not affect them adversely (see section 4.8). 4.8 Undesirable effects Paediatric patientspopulation: In a short-term placebo-controlled clinical trial involving 302 adolescents (13-17 years) with schizophrenia, the frequency and type of undesirable effects were similar to those in adults except for the following events that were reported more frequently in adolescents receiving oral aripiprazole thatn in adults receiving oral aripiprazole (and more frequently than placebo): somnolence/sedation and extrapyramidal disorder were reported very commonly (≥ 1/10), and dry mouth, increased appetite and orthostatic hypotension were reported commonly (≥ 1/100 < 1/10). The safety profile in a 26-week open-label extension trial was similar to that observed in the short-term, placebo-controlled trial. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Paediatric population: Schizophrenia in adolescents with oral aripiprazole: In in a 6-week placebo-controlled trial involving 302 schizophrenic adolescent patients (13-17 years), presenting with positive or negative symptoms, aripiprazole was associated with statistically significantly greater improvements in psychotic symptoms compared to placebo. In a sub-analysis of the adolescent patients between the ages of 15 to 17 years, representing 74% of the total enrolled population, maintenance of effect was observed over the 26-week open-label extension trial. 5.2 Pharmacokinetic properties Pharmacokinetics in special patient groups Paediatric patientspopulation: The pharmacokinetics of oral aripiprazole and dehydro-aripiprazole in paediatric patients 13 to 17 years of age were similar to those in adults after correcting for the differences in body weights. 5.3 Preclinical safety data Administration of aripiprazole solution for injection was well tolerated and produced no direct target organ toxicity in rats or monkeys after repeated dosing at systemic exposures (AUC) that were 15 and 5 times, respectively, human exposure at the maximum recommended human dose of 30 mg intramuscular. In intravenous reproductive toxicity studies, no new safety concerns were observed at maternal exposures up to 15 (rat) and 29 (rabbit) times human exposure at 30 mg. Non-clinical safety data revealed no special hazard for humans based on conventional oral aripiprazole studies of safety pharmacology, repeat-dose toxicity, genotoxicity, carcinogenic potential, and toxicity to reproduction and development. 10. DATE OF REVISION OF THE TEXT November 2009March 2010 Detailed information on this product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/
Method of administration ABILIFY solution for injection is for intramuscular use. To enhance absorption and minimise variability, injection into the deltoid or deep within the gluteus maximus muscle, avoiding adipose regions, is recommended. ABILIFY solution for injection should not be administered intravenously or subcutaneously. ABILIFY solution for injection is ready to use and intended for short-term use only (see section 5.1). 4.4 Special warnings and precautions for use 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 therapy, including treatment with aripiprazole (see section 4.8). Close supervision of high-risk patients should accompany antipsychotic therapy. Results of an epidemiological study foundsuggested that there was no increased risk of suicidality with aripiprazole compared to other antipsychotics among patients with schizophrenia or bipolar disorder. 4.6 PregnancyFertility, pregnancy and lactation There are no adequate and well-controlled trials of aripiprazole in pregnant women. Congenital anomalies have been reported; however, causal relationship with aripiprazole could not be established. Animal studies could not exclude potential developmental toxicity (see section 5.3). 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. Aripiprazole was excreted in the milk of treated rats during lactation. It is not known whether aripiprazole is excreted in human milk. Patients should be advised not to breast feed if they are taking aripiprazole. 4.7 Effects on ability to drive and use machines No studies on the effect on the ability to drive and use machines have been performed. However, asAs with other antipsychotics, patients should be cautioned about operating hazardous machines, including motor vehicles, until they are reasonably certain that aripiprazole does not affect them adversely (see section 4.8). 4.8 Undesirable effects Paediatric patientspopulation: In a short-term placebo-controlled clinical trial involving 302 adolescents (13-17 years) with schizophrenia, the frequency and type of undesirable effects were similar to those in adults except for the following events that were reported more frequently in adolescents receiving oral aripiprazole thatn in adults receiving oral aripiprazole (and more frequently than placebo): somnolence/sedation and extrapyramidal disorder were reported very commonly (≥ 1/10), and dry mouth, increased appetite and orthostatic hypotension were reported commonly (≥ 1/100 < 1/10). The safety profile in a 26-week open-label extension trial was similar to that observed in the short-term, placebo-controlled trial. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Paediatric population: Schizophrenia in adolescents with oral aripiprazole: In in a 6-week placebo-controlled trial involving 302 schizophrenic adolescent patients (13-17 years), presenting with positive or negative symptoms, aripiprazole was associated with statistically significantly greater improvements in psychotic symptoms compared to placebo. In a sub-analysis of the adolescent patients between the ages of 15 to 17 years, representing 74% of the total enrolled population, maintenance of effect was observed over the 26-week open-label extension trial. 5.2 Pharmacokinetic properties Pharmacokinetics in special patient groups Paediatric patientspopulation: The pharmacokinetics of oral aripiprazole and dehydro-aripiprazole in paediatric patients 13 to 17 years of age were similar to those in adults after correcting for the differences in body weights. 5.3 Preclinical safety data Administration of aripiprazole solution for injection was well tolerated and produced no direct target organ toxicity in rats or monkeys after repeated dosing at systemic exposures (AUC) that were 15 and 5 times, respectively, human exposure at the maximum recommended human dose of 30 mg intramuscular. In intravenous reproductive toxicity studies, no new safety concerns were observed at maternal exposures up to 15 (rat) and 29 (rabbit) times human exposure at 30 mg. Non-clinical safety data revealed no special hazard for humans based on conventional oral aripiprazole studies of safety pharmacology, repeat-dose toxicity, genotoxicity, carcinogenic potential, and toxicity to reproduction and development. 10. DATE OF REVISION OF THE TEXT November 2009March 2010 Detailed information on this product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/
ABILIFY solution for injection is for intramuscular use. To enhance absorption and minimise variability, injection into the deltoid or deep within the gluteus maximus muscle, avoiding adipose regions, is recommended. ABILIFY solution for injection should not be administered intravenously or subcutaneously. ABILIFY solution for injection is ready to use and intended for short-term use only (see section 5.1). 4.4 Special warnings and precautions for use 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 therapy, including treatment with aripiprazole (see section 4.8). Close supervision of high-risk patients should accompany antipsychotic therapy. Results of an epidemiological study foundsuggested that there was no increased risk of suicidality with aripiprazole compared to other antipsychotics among patients with schizophrenia or bipolar disorder. 4.6 PregnancyFertility, pregnancy and lactation There are no adequate and well-controlled trials of aripiprazole in pregnant women. Congenital anomalies have been reported; however, causal relationship with aripiprazole could not be established. Animal studies could not exclude potential developmental toxicity (see section 5.3). 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. Aripiprazole was excreted in the milk of treated rats during lactation. It is not known whether aripiprazole is excreted in human milk. Patients should be advised not to breast feed if they are taking aripiprazole. 4.7 Effects on ability to drive and use machines No studies on the effect on the ability to drive and use machines have been performed. However, asAs with other antipsychotics, patients should be cautioned about operating hazardous machines, including motor vehicles, until they are reasonably certain that aripiprazole does not affect them adversely (see section 4.8). 4.8 Undesirable effects Paediatric patientspopulation: In a short-term placebo-controlled clinical trial involving 302 adolescents (13-17 years) with schizophrenia, the frequency and type of undesirable effects were similar to those in adults except for the following events that were reported more frequently in adolescents receiving oral aripiprazole thatn in adults receiving oral aripiprazole (and more frequently than placebo): somnolence/sedation and extrapyramidal disorder were reported very commonly (≥ 1/10), and dry mouth, increased appetite and orthostatic hypotension were reported commonly (≥ 1/100 < 1/10). The safety profile in a 26-week open-label extension trial was similar to that observed in the short-term, placebo-controlled trial. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Paediatric population: Schizophrenia in adolescents with oral aripiprazole: In in a 6-week placebo-controlled trial involving 302 schizophrenic adolescent patients (13-17 years), presenting with positive or negative symptoms, aripiprazole was associated with statistically significantly greater improvements in psychotic symptoms compared to placebo. In a sub-analysis of the adolescent patients between the ages of 15 to 17 years, representing 74% of the total enrolled population, maintenance of effect was observed over the 26-week open-label extension trial. 5.2 Pharmacokinetic properties Pharmacokinetics in special patient groups Paediatric patientspopulation: The pharmacokinetics of oral aripiprazole and dehydro-aripiprazole in paediatric patients 13 to 17 years of age were similar to those in adults after correcting for the differences in body weights. 5.3 Preclinical safety data Administration of aripiprazole solution for injection was well tolerated and produced no direct target organ toxicity in rats or monkeys after repeated dosing at systemic exposures (AUC) that were 15 and 5 times, respectively, human exposure at the maximum recommended human dose of 30 mg intramuscular. In intravenous reproductive toxicity studies, no new safety concerns were observed at maternal exposures up to 15 (rat) and 29 (rabbit) times human exposure at 30 mg. Non-clinical safety data revealed no special hazard for humans based on conventional oral aripiprazole studies of safety pharmacology, repeat-dose toxicity, genotoxicity, carcinogenic potential, and toxicity to reproduction and development. 10. DATE OF REVISION OF THE TEXT November 2009March 2010 Detailed information on this product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/
ABILIFY solution for injection should not be administered intravenously or subcutaneously. ABILIFY solution for injection is ready to use and intended for short-term use only (see section 5.1). 4.4 Special warnings and precautions for use 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 therapy, including treatment with aripiprazole (see section 4.8). Close supervision of high-risk patients should accompany antipsychotic therapy. Results of an epidemiological study foundsuggested that there was no increased risk of suicidality with aripiprazole compared to other antipsychotics among patients with schizophrenia or bipolar disorder. 4.6 PregnancyFertility, pregnancy and lactation There are no adequate and well-controlled trials of aripiprazole in pregnant women. Congenital anomalies have been reported; however, causal relationship with aripiprazole could not be established. Animal studies could not exclude potential developmental toxicity (see section 5.3). 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. Aripiprazole was excreted in the milk of treated rats during lactation. It is not known whether aripiprazole is excreted in human milk. Patients should be advised not to breast feed if they are taking aripiprazole. 4.7 Effects on ability to drive and use machines No studies on the effect on the ability to drive and use machines have been performed. However, asAs with other antipsychotics, patients should be cautioned about operating hazardous machines, including motor vehicles, until they are reasonably certain that aripiprazole does not affect them adversely (see section 4.8). 4.8 Undesirable effects Paediatric patientspopulation: In a short-term placebo-controlled clinical trial involving 302 adolescents (13-17 years) with schizophrenia, the frequency and type of undesirable effects were similar to those in adults except for the following events that were reported more frequently in adolescents receiving oral aripiprazole thatn in adults receiving oral aripiprazole (and more frequently than placebo): somnolence/sedation and extrapyramidal disorder were reported very commonly (≥ 1/10), and dry mouth, increased appetite and orthostatic hypotension were reported commonly (≥ 1/100 < 1/10). The safety profile in a 26-week open-label extension trial was similar to that observed in the short-term, placebo-controlled trial. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Paediatric population: Schizophrenia in adolescents with oral aripiprazole: In in a 6-week placebo-controlled trial involving 302 schizophrenic adolescent patients (13-17 years), presenting with positive or negative symptoms, aripiprazole was associated with statistically significantly greater improvements in psychotic symptoms compared to placebo. In a sub-analysis of the adolescent patients between the ages of 15 to 17 years, representing 74% of the total enrolled population, maintenance of effect was observed over the 26-week open-label extension trial. 5.2 Pharmacokinetic properties Pharmacokinetics in special patient groups Paediatric patientspopulation: The pharmacokinetics of oral aripiprazole and dehydro-aripiprazole in paediatric patients 13 to 17 years of age were similar to those in adults after correcting for the differences in body weights. 5.3 Preclinical safety data Administration of aripiprazole solution for injection was well tolerated and produced no direct target organ toxicity in rats or monkeys after repeated dosing at systemic exposures (AUC) that were 15 and 5 times, respectively, human exposure at the maximum recommended human dose of 30 mg intramuscular. In intravenous reproductive toxicity studies, no new safety concerns were observed at maternal exposures up to 15 (rat) and 29 (rabbit) times human exposure at 30 mg. Non-clinical safety data revealed no special hazard for humans based on conventional oral aripiprazole studies of safety pharmacology, repeat-dose toxicity, genotoxicity, carcinogenic potential, and toxicity to reproduction and development. 10. DATE OF REVISION OF THE TEXT November 2009March 2010 Detailed information on this product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/
4.4 Special warnings and precautions for use
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 therapy, including treatment with aripiprazole (see section 4.8). Close supervision of high-risk patients should accompany antipsychotic therapy. Results of an epidemiological study foundsuggested that there was no increased risk of suicidality with aripiprazole compared to other antipsychotics among patients with schizophrenia or bipolar disorder.
4.6 PregnancyFertility, pregnancy and lactation
There are no adequate and well-controlled trials of aripiprazole in pregnant women. Congenital anomalies have been reported; however, causal relationship with aripiprazole could not be established. Animal studies could not exclude potential developmental toxicity (see section 5.3). 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.
Aripiprazole was excreted in the milk of treated rats during lactation. It is not known whether aripiprazole is excreted in human milk. Patients should be advised not to breast feed if they are taking aripiprazole.
4.7 Effects on ability to drive and use machines
No studies on the effect on the ability to drive and use machines have been performed. However, asAs with other antipsychotics, patients should be cautioned about operating hazardous machines, including motor vehicles, until they are reasonably certain that aripiprazole does not affect them adversely (see section 4.8). 4.8 Undesirable effects Paediatric patientspopulation: In a short-term placebo-controlled clinical trial involving 302 adolescents (13-17 years) with schizophrenia, the frequency and type of undesirable effects were similar to those in adults except for the following events that were reported more frequently in adolescents receiving oral aripiprazole thatn in adults receiving oral aripiprazole (and more frequently than placebo): somnolence/sedation and extrapyramidal disorder were reported very commonly (≥ 1/10), and dry mouth, increased appetite and orthostatic hypotension were reported commonly (≥ 1/100 < 1/10). The safety profile in a 26-week open-label extension trial was similar to that observed in the short-term, placebo-controlled trial. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Paediatric population: Schizophrenia in adolescents with oral aripiprazole: In in a 6-week placebo-controlled trial involving 302 schizophrenic adolescent patients (13-17 years), presenting with positive or negative symptoms, aripiprazole was associated with statistically significantly greater improvements in psychotic symptoms compared to placebo. In a sub-analysis of the adolescent patients between the ages of 15 to 17 years, representing 74% of the total enrolled population, maintenance of effect was observed over the 26-week open-label extension trial. 5.2 Pharmacokinetic properties Pharmacokinetics in special patient groups Paediatric patientspopulation: The pharmacokinetics of oral aripiprazole and dehydro-aripiprazole in paediatric patients 13 to 17 years of age were similar to those in adults after correcting for the differences in body weights. 5.3 Preclinical safety data Administration of aripiprazole solution for injection was well tolerated and produced no direct target organ toxicity in rats or monkeys after repeated dosing at systemic exposures (AUC) that were 15 and 5 times, respectively, human exposure at the maximum recommended human dose of 30 mg intramuscular. In intravenous reproductive toxicity studies, no new safety concerns were observed at maternal exposures up to 15 (rat) and 29 (rabbit) times human exposure at 30 mg. Non-clinical safety data revealed no special hazard for humans based on conventional oral aripiprazole studies of safety pharmacology, repeat-dose toxicity, genotoxicity, carcinogenic potential, and toxicity to reproduction and development. 10. DATE OF REVISION OF THE TEXT November 2009March 2010 Detailed information on this product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/
4.8 Undesirable effects
Paediatric patientspopulation:
In a short-term placebo-controlled clinical trial involving 302 adolescents (13-17 years) with schizophrenia, the frequency and type of undesirable effects were similar to those in adults except for the following events that were reported more frequently in adolescents receiving oral aripiprazole thatn in adults receiving oral aripiprazole (and more frequently than placebo): somnolence/sedation and extrapyramidal disorder were reported very commonly (≥ 1/10), and dry mouth, increased appetite and orthostatic hypotension were reported commonly (≥ 1/100 < 1/10).
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Schizophrenia in adolescents with oral aripiprazole:
In in a 6-week placebo-controlled trial involving 302 schizophrenic adolescent patients (13-17 years), presenting with positive or negative symptoms, aripiprazole was associated with statistically significantly greater improvements in psychotic symptoms compared to placebo.
In a sub-analysis of the adolescent patients between the ages of 15 to 17 years, representing 74% of the total enrolled population, maintenance of effect was observed over the 26-week open-label extension trial.
5.2 Pharmacokinetic properties
Pharmacokinetics in special patient groups
The pharmacokinetics of oral aripiprazole and dehydro-aripiprazole in paediatric patients 13 to 17 years of age were similar to those in adults after correcting for the differences in body weights.
5.3 Preclinical safety data
Administration of aripiprazole solution for injection was well tolerated and produced no direct target organ toxicity in rats or monkeys after repeated dosing at systemic exposures (AUC) that were 15 and 5 times, respectively, human exposure at the maximum recommended human dose of 30 mg intramuscular. In intravenous reproductive toxicity studies, no new safety concerns were observed at maternal exposures up to 15 (rat) and 29 (rabbit) times human exposure at 30 mg.
Non-clinical safety data revealed no special hazard for humans based on conventional oral aripiprazole studies of safety pharmacology, repeat-dose toxicity, genotoxicity, carcinogenic potential, and toxicity to reproduction and development.
10. DATE OF REVISION OF THE TEXT
November 2009March 2010
Detailed information on this product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/
The most commonly reported adverse reactions in placebo-controlled trials are nausea, dizziness and somnolence each occurring in more than 3% of patients treated with aripiprazole solution for injection.
Vascular disorders:
syncope, hypertension, venous thromboembolism (including pulmonary embolism and deep vein thrombosis) Section 10 : update the Date of Revision of Text to: November 2009.
Dystonia: Class Effect : Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups.
1. NAME OF THE MEDICINAL PRODUCT
ABILIFY® 7.5 mg/ml solution for injection 4.2 Posology and method of administration 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 section 4.5). 4.4 Special warnings and precautions for use Dysphagia: oesophageal dysmotility and aspiration have been associated with antipsychotic treatment, including ABILIFY. Aripiprazole and other antipsychotic drugs active substances should be used cautiously in patients at risk for aspiration pneumonia. 4.5 Interaction with other medicinal products and other forms of interaction When aripiprazole was administered concomitantly with either valproate or , lithium or lamotrigine, there was no clinically important change in valproate or , lithium or lamotrigine concentrations. 4.7 Effects on ability to drive and use machines No studies on the effect on the ability to drive and use machines have been performed. However, as with other antipsychotics, patients should be cautioned about operating hazardous machines, including motor vehicles, until they are reasonably certain that aripiprazole does not affect them adversely (see section 4.8). . 4.8 Undesirable effects The following undesirable effects adverse events occurred more often (≥ 1/100) than placebo, or were identified as possibly medically relevant adverse reactions (*) in clinical trials with oral formulations of aripiprazole (see section 5.1): Comparisons between aripiprazole and placebo in the proportions of patients experiencing potentially clinically significant changes in routine laboratory and lipid parameters (see section 5.1) revealed no medically important differences. Elevations of CPK (Creatine Phosphokinase), generally transient and asymptomatic, were observed in 3.5% of aripiprazole treated patients as compared to 2.0% of patients who received placebo. Post-Marketing: The following adverse reactions have been reported during post-marketing surveillance. The frequency of these reactions is considered not known (cannot be estimated from the available data). Blood and the lymphatic system disorders: leukopenia, neutropenia, thrombocytopenia Immune system disorders: allergic reaction (e.g. anaphylactic reaction, angioedema including swollen tongue, tongue oedema, face oedema, pruritus, or urticaria) Endocrine disorders: hyperglycaemia, diabetes mellitus, diabetic ketoacidosis, diabetic hyperosmolar coma Metabolism and nutrition disorders: weight gain, weight decreased, anorexia, hyponatremia Psychiatric disorders: agitation, nervousness; suicide attempt, suicidal ideation, and completed suicide (see section 4.4) Nervous system disorders: speech disorder, Neuroleptic Malignant Syndrome (NMS), grand mal convulsion Cardiac disorders: QT prolongation, ventricular arrhythmias, sudden unexplained death, cardiac arrest, torsades de pointes, bradycardia Vascular disorders: syncope, hypertension, thromboembolic reactionsevents Respiratory, thoracic and mediastinal disorders: oropharyngeal spasm, laryngospasm, aspiration pneumonia Gastrointestinal disorders: pancreatitis, dysphagia, abdominal discomfort, stomach discomfort, diarrhoea Hepato-biliary disorders: jaundice, hepatitis, increased Alanine Aminotransferase (ALT), increased Aspartate Aminotransferase (AST), increased Gamma Glutamyl Transferase (GGT), increased alkaline phosphatase Skin and subcutaneous tissue disorders: rash, photosensitivity reaction, alopecia, hyperhidrosis Musculoskeletal and connective tissue disorders: rhabdomyolysis, myalgia, stiffness Renal and urinary disorders: urinary incontinence, urinary retention Reproductive system and breast disorders: priapism General disorders and administration site conditions: temperature regulation disorder (e.g. hypothermia, pyrexia), chest pain, peripheral oedema Investigations: increased Creatine Phosphokinase, blood glucose increased, blood glucose fluctuation, glycosylated haemoglobin increased 4.9 Overdose In clinical trials and post-marketing experience, accidental or intentional acute overdosage 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. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Further information on clinical trials: Weight gain: in clinical trials oral aripiprazole has not been shown to induce clinically relevant weight gain. In a 26‑week, olanzapine-controlled, double-blind, multi-national study of schizophrenia which included 314 patients and where the primary end-point was weight gain, significantly less patients had at least 7% weight gain over baseline (i.e. a gain of at least 5.6 kg for a mean baseline weight of ~80.5 kg) on oral aripiprazole (N= 18, or 13% of evaluable patients), compared to oral olanzapine (N= 45, or 33% of evaluable patients). Lipid parameters: in a pooled analysis on lipid parameters from placebo controlled clinical trials in adults, aripiprazole has not been shown to induce clinically relevant alterations in levels of total cholesterol, triglycerides, HDL and LDL. -Total cholesterol: incidence of changes in levels from normal (<5.18 mmol/l) to high (≥ 6.22 mmol/l) was 2.5% for aripiprazole and 2.8% for placebo and mean change from baseline was -0.15 mmol/l (95% CI: -0.182, -0.115) for aripiprazole and -0.11 mmol/l (95% CI: -0.148, -0.066) for placebo. -Fasting triglycerides: incidence of changes in levels from normal (<1.69 mmol/l) to high (≥ 2.26 mmol/l) was 7.4% for aripiprazole and 7.0% for placebo and mean change from baseline was -0.11 mmol/l (95% CI: -0.182, -0.046) for aripiprazole and -0.07 mmol/l (95% CI: -0.148, 0.007) for placebo. -HDL: incidence of changes in levels from normal (≥ 1.04 mmol/l) to low (<1.04 mmol/l) was 11.4% for aripiprazole and 12.5% for placebo and mean change from baseline was -0.03 mmol/l (95% CI: -0.046, -0.017) for aripiprazole and -0.04 mmol/l (95% CI: -0.056, -0.022) for placebo. -Fasting LDL: incidence of changes in levels from normal (<2.59 mmol/l) to high (≥ 4.14 mmol/l) was 0.6% for aripiprazole and 0.7% for placebo and mean change from baseline was -0.09 mmol/l (95% CI: -0.139, -0.047) for aripiprazole and -0.06 mmol/l (95% CI: -0.116, -0.012) for placebo. 10. DATE OF REVISION OF THE TEXT 0406/2009 Detailed information on this product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/
Dysphagia: oesophageal dysmotility and aspiration have been associated with antipsychotic treatment, including ABILIFY. Aripiprazole and other antipsychotic drugs active substances should be used cautiously in patients at risk for aspiration pneumonia.
4.5 Interaction with other medicinal products and other forms of interaction
When aripiprazole was administered concomitantly with either valproate or , lithium or lamotrigine, there was no clinically important change in valproate or , lithium or lamotrigine concentrations.
No studies on the effect on the ability to drive and use machines have been performed. However, as with other antipsychotics, patients should be cautioned about operating hazardous machines, including motor vehicles, until they are reasonably certain that aripiprazole does not affect them adversely (see section 4.8).
.
The following undesirable effects adverse events occurred more often (≥ 1/100) than placebo, or were identified as possibly medically relevant adverse reactions (*) in clinical trials with oral formulations of aripiprazole (see section 5.1):
Comparisons between aripiprazole and placebo in the proportions of patients experiencing potentially clinically significant changes in routine laboratory and lipid parameters (see section 5.1) revealed no medically important differences. Elevations of CPK (Creatine Phosphokinase), generally transient and asymptomatic, were observed in 3.5% of aripiprazole treated patients as compared to 2.0% of patients who received placebo.
Post-Marketing:
The following adverse reactions have been reported during post-marketing surveillance. The frequency of these reactions is considered not known (cannot be estimated from the available data).
Blood and the lymphatic system disorders:
leukopenia, neutropenia, thrombocytopenia
Immune system disorders:
allergic reaction (e.g. anaphylactic reaction, angioedema including swollen tongue, tongue oedema, face oedema, pruritus, or urticaria)
Endocrine disorders:
hyperglycaemia, diabetes mellitus, diabetic ketoacidosis, diabetic hyperosmolar coma
Metabolism and nutrition disorders:
weight gain, weight decreased, anorexia, hyponatremia
Psychiatric disorders:
agitation, nervousness; suicide attempt, suicidal ideation, and completed suicide (see section 4.4)
Nervous system disorders:
speech disorder, Neuroleptic Malignant Syndrome (NMS), grand mal convulsion
Cardiac disorders:
QT prolongation, ventricular arrhythmias, sudden unexplained death, cardiac arrest, torsades de pointes, bradycardia
syncope, hypertension, thromboembolic reactionsevents
Respiratory, thoracic and mediastinal disorders:
oropharyngeal spasm, laryngospasm, aspiration pneumonia
Gastrointestinal disorders:
pancreatitis, dysphagia, abdominal discomfort, stomach discomfort, diarrhoea
Hepato-biliary disorders:
jaundice, hepatitis, increased Alanine Aminotransferase (ALT), increased Aspartate Aminotransferase (AST), increased Gamma Glutamyl Transferase (GGT), increased alkaline phosphatase
Skin and subcutaneous tissue disorders:
rash, photosensitivity reaction, alopecia, hyperhidrosis
Musculoskeletal and connective tissue disorders:
rhabdomyolysis, myalgia, stiffness
Renal and urinary disorders:
urinary incontinence, urinary retention
Reproductive system and breast disorders:
priapism
General disorders and administration site conditions:
temperature regulation disorder (e.g. hypothermia, pyrexia), chest pain, peripheral oedema
Investigations:
increased Creatine Phosphokinase, blood glucose increased, blood glucose fluctuation, glycosylated haemoglobin increased
4.9 Overdose
In clinical trials and post-marketing experience, accidental or intentional acute overdosage 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. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Further information on clinical trials: Weight gain: in clinical trials oral aripiprazole has not been shown to induce clinically relevant weight gain. In a 26‑week, olanzapine-controlled, double-blind, multi-national study of schizophrenia which included 314 patients and where the primary end-point was weight gain, significantly less patients had at least 7% weight gain over baseline (i.e. a gain of at least 5.6 kg for a mean baseline weight of ~80.5 kg) on oral aripiprazole (N= 18, or 13% of evaluable patients), compared to oral olanzapine (N= 45, or 33% of evaluable patients). Lipid parameters: in a pooled analysis on lipid parameters from placebo controlled clinical trials in adults, aripiprazole has not been shown to induce clinically relevant alterations in levels of total cholesterol, triglycerides, HDL and LDL. -Total cholesterol: incidence of changes in levels from normal (<5.18 mmol/l) to high (≥ 6.22 mmol/l) was 2.5% for aripiprazole and 2.8% for placebo and mean change from baseline was -0.15 mmol/l (95% CI: -0.182, -0.115) for aripiprazole and -0.11 mmol/l (95% CI: -0.148, -0.066) for placebo. -Fasting triglycerides: incidence of changes in levels from normal (<1.69 mmol/l) to high (≥ 2.26 mmol/l) was 7.4% for aripiprazole and 7.0% for placebo and mean change from baseline was -0.11 mmol/l (95% CI: -0.182, -0.046) for aripiprazole and -0.07 mmol/l (95% CI: -0.148, 0.007) for placebo. -HDL: incidence of changes in levels from normal (≥ 1.04 mmol/l) to low (<1.04 mmol/l) was 11.4% for aripiprazole and 12.5% for placebo and mean change from baseline was -0.03 mmol/l (95% CI: -0.046, -0.017) for aripiprazole and -0.04 mmol/l (95% CI: -0.056, -0.022) for placebo. -Fasting LDL: incidence of changes in levels from normal (<2.59 mmol/l) to high (≥ 4.14 mmol/l) was 0.6% for aripiprazole and 0.7% for placebo and mean change from baseline was -0.09 mmol/l (95% CI: -0.139, -0.047) for aripiprazole and -0.06 mmol/l (95% CI: -0.116, -0.012) for placebo. 10. DATE OF REVISION OF THE TEXT 0406/2009 Detailed information on this product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/
Further information on clinical trials:
Weight gain: in clinical trials oral aripiprazole has not been shown to induce clinically relevant weight gain. In a 26‑week, olanzapine-controlled, double-blind, multi-national study of schizophrenia which included 314 patients and where the primary end-point was weight gain, significantly less patients had at least 7% weight gain over baseline (i.e. a gain of at least 5.6 kg for a mean baseline weight of ~80.5 kg) on oral aripiprazole (N= 18, or 13% of evaluable patients), compared to oral olanzapine (N= 45, or 33% of evaluable patients).
Lipid parameters: in a pooled analysis on lipid parameters from placebo controlled clinical trials in adults, aripiprazole has not been shown to induce clinically relevant alterations in levels of total cholesterol, triglycerides, HDL and LDL.
-Total cholesterol: incidence of changes in levels from normal (<5.18 mmol/l) to high (≥ 6.22 mmol/l) was 2.5% for aripiprazole and 2.8% for placebo and mean change from baseline was -0.15 mmol/l
(95% CI: -0.182, -0.115) for aripiprazole and -0.11 mmol/l (95% CI: -0.148, -0.066) for placebo.
-Fasting triglycerides: incidence of changes in levels from normal (<1.69 mmol/l) to high (≥ 2.26 mmol/l) was 7.4% for aripiprazole and 7.0% for placebo and mean change from baseline was -0.11 mmol/l
(95% CI: -0.182, -0.046) for aripiprazole and -0.07 mmol/l (95% CI: -0.148, 0.007) for placebo.
-HDL: incidence of changes in levels from normal (≥ 1.04 mmol/l) to low (<1.04 mmol/l) was 11.4% for aripiprazole and 12.5% for placebo and mean change from baseline was -0.03 mmol/l
(95% CI: -0.046, -0.017) for aripiprazole and -0.04 mmol/l (95% CI: -0.056, -0.022) for placebo.
-Fasting LDL: incidence of changes in levels from normal (<2.59 mmol/l) to high (≥ 4.14 mmol/l) was 0.6% for aripiprazole and 0.7% for placebo and mean change from baseline was -0.09 mmol/l
(95% CI: -0.139, -0.047) for aripiprazole and -0.06 mmol/l (95% CI: -0.116, -0.012) for placebo.
0406/2009
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each ml contains 7.5 mg of aripiprazole.
A Each vial contains 9.75 mg aripiprazole. 4.2 Posology and method of administration For intramuscular use. To enhance absorption and minimise variability, injection into the deltoid or deep within the gluteus maximus muscle, avoiding adipose regions, is recommended. ABILIFY solution for injection should not be administered intravenously or subcutaneously. ABILIFY solution for injection is ready to use and intended for short-term use only (see section 5.1). The recommended initial dose for aripiprazole solution for injection is 9.75 mg (1.3 ml), administered as a single intramuscular injection. The effective dose range of aripiprazole solution for injection is 5.25‑15 mg as a single injection. A lower dose of 5.25 mg (0.7 ml) may be given, on the basis of individual clinical status, which should also include consideration of medicinal products already administered either for maintenance or acute treatment (see section 4.5). A second injection may be administered 2 hours after the first injection, on the basis of individual clinical status and no more than three injections should be given in any 24-hour period. The maximum daily dose of aripiprazole is 30 mg (including all formulations of aripiprazole). If continued treatment is indicated with oral aripiprazole, see the Summary of Product Characteristics for ABILIFY tablets, ABILIFY orodispersible tablets, or ABILIFY oral solution. ABILIFY solution for injection is for intramuscular use. To enhance absorption and minimise variability, injection into the deltoid or deep within the gluteus maximus muscle, avoiding adipose regions, is recommended. ABILIFY solution for injection should not be administered intravenously or subcutaneously. ABILIFY solution for injection is ready to use and intended for short-term use only (see section 5.1). ............................ Smoking status: according to the metabolic pathway of ABILIFY no dosage adjustment is required for smokers (see section 4.5). 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 section 4.5). 4.4 Special warnings and precautions for use .............................................. 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, hypovolemia, and treatment with antihypertensive medicationsmedicinal products) or hypertension, including accelerated or malignant. ....................... Tardive Dyskinesiadyskinesia: in clinical trials of one year or less duration, there were uncommon reports of treatment emergent dyskinesia during treatment with aripiprazole. If signs and symptoms of tardive dyskinesia appear in a patient on ABILIFY, dose reduction or discontinuation should be considered. These symptoms can temporally deteriorate or can even arise after discontinuation of treatment. .................................................... Cerebrovascular adverse eventsreactions: in the same trials, cerebrovascular adverse eventsreactions (e.g. stroke, transient ischaemic attack), including fatalities, were reported in patients (mean age: 84 years; range: 78‑88 years). Overall, 1.3% of aripiprazole-treated patients reported cerebrovascular adverse eventsreactions compared with 0.6% of placebo-treated patients in these trials. This difference was not statistically significant. However, in one of these trials, a fixed-dose trial, there was a significant dose response relationship for cerebrovascular adverse eventsreactions in patients treated with aripiprazole. ABILIFY is not approved indicated for the treatment of dementia-related psychosis. Hyperglycaemia and Diabetes diabetes Mellitusmellitus: hyperglycaemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotic agents, including ABILIFY. Risk factors that may predispose patients to severe complications include obesity and family history of diabetes. In clinical trials with aripiprazole, there were no significant differences in the incidence rates of hyperglycaemia-related adverse eventsreactions (including diabetes) or in abnormal glycaemia laboratory values compared to placebo. Precise risk estimates for hyperglycaemia-related adverse eventsreactions in patients treated with ABILIFY and with other atypical antipsychotic agents are not available to allow direct comparisons. Patients treated with any antipsychotic agents, including ABILIFY, 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. Hypersensitivity: as with other medicinal products hypersensitivity reactions, characterised by allergic symptoms, may occur with aripiprazole (see section 4.8). 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 ABILIFY. When seen, it is usually in those with significant risk factors such as history of diabetes, thyroid disorder or pituitary adenoma. In clinical trials aripiprazole has not been shown to induce clinically relevant weight gain (see section 5.1). Dysphagia: oesophageal dysmotility and aspiration have been associated with antipsychotic drug usetreatment, including ABILIFY. Aripiprazole and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia. Hypersensitivity: as with other medications hypersensitivity reactions, characterised by allergic symptoms, may occur with aripiprazole (see section 4.8). 4.5 Interaction with other medicinal products and other forms of interaction 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 undesirable effects adverse reactions such as sedation (see section 4.8). If aripiprazole is administered concomitantly with medicinesmedicinal products known to cause QT prolongation or electrolyte imbalance, caution should be used. 4.8 Undesirable effects The following undesirable effects adverse reactions occurred more often (≥ 1/100) than placebo, or were identified as possibly medically relevant adverse reactions (*) in clinical trials with aripiprazole solution for injection (see section 5.1): The frequency listed below is defined using the following convention: common (³ 1/100, to < 1/10) and uncommon (³ 1/1,000, to < 1/100). Cardiac disorders Uncommon: tachycardia* Nervous system disorders Common: somnolence, dizziness, headache, akathisia Cardiac disorders Uncommon: tachycardia* Vascular disorders Uncommon: orthostatic hypotension*, increased diastolic blood pressure* Gastrointestinal disorders Common: nausea, vomiting Uncommon: dry mouth* Vascular disorders Uncommon: orthostatic hypotension*, increased diastolic blood pressure* General disorders and administration site conditions Uncommon: fatigue* The following undesirable effects adverse reactionsoccurred more often (≥ 1/100) than placebo, or were identified as possibly medically relevant adverse reactions (*) in clinical trials with oral formulations of aripiprazole (see section 5.1): Psychiatric disorders Common: restlessness, insomnia, anxiety Uncommon: depression* Nervous system disorders Common: extrapyramidal disorder, akathisia, tremor, dizziness, somnolence, sedation, headache Eye disorders Common: blurred vision Cardiac disorders Uncommon: tachycardia* Nervous system disorders Common: extrapyramidal disorder, akathisia, tremor, dizziness, somnolence, sedation, headache Eye disorders Common: blurred vision Vascular disorders Uncommon: orthostatic hypotension* Gastrointestinal disorders Common: dyspepsia, vomiting, nausea, constipation, salivary hypersecretion Vascular disorders Uncommon: orthostatic hypotension* General disorders and administration site conditions Common: fatigue Psychiatric disorders Common: restlessness, insomnia, anxiety Uncommon: depression* ......................... Other findings: Undesirable effectsAdverse reactions known to be associated with antipsychotic therapy and also reported during treatment with aripiprazole include neuroleptic malignant syndrome, tardive dyskinesia, seizure, cerebrovascular adverse eventsreactions and increased mortality in elderly demented patients, hyperglycaemia and diabetes mellitus (see section 4.4). Post-Marketing: The following adverse eventsreactions have been reported during post-marketing surveillance. The frequency of these eventsreactions is considered not known (cannot be estimated from the available data). Blood and the lymphatic system disorders: leukopenia, neutropenia, thrombocytopenia Immune system disorders: allergic reaction (e.g. anaphylactic reaction, angioedema including swollen tongue, tongue oedema, face oedema, pruritus, or urticaria) Endocrine disorders: hyperglycaemia, diabetes mellitus, diabetic ketoacidosis, diabetic hyperosmolar coma Metabolism and nutrition disorders: weight gain, weight decreased, anorexia, hyponatremia Psychiatric disorders: agitation, nervousness; suicide attempt, suicidal ideation, and completed suicide (see section 4.4) Nervous system disorders: speech disorder, Neuroleptic Malignant Syndrome (NMS), grand mal convulsion Cardiac disorders: QT prolongation, ventricular arrhythmias, sudden unexplained death, cardiac arrest, torsades de pointes, bradycardia Vascular disorders: syncope, hypertension, thromboembolic reactions Respiratory, thoracic and mediastinal disorders: oropharyngeal spasm, laryngospasm, aspiration pneumonia Gastrointestinal disorders: pancreatitis, dysphagia, abdominal discomfort, stomach discomfort, diarrhoea Hepatobiliary disorders: jaundice, hepatitis, increased Alanine Aminotransferase (ALT), increased Aspartate Aminotransferase (AST), increased Gamma Glutamyl Transferase (GGT), increased alkaline phosphatase Skin and subcutaneous tissue disorders: rash, photosensitivity reaction, alopecia, hyperhidrosis Musculoskeletal and connective tissue disorders: rhabdomyolysis, myalgia, stiffness Renal and urinary disorders: urinary incontinence, urinary retention Reproductive system and breast disorders: priapism General disorders and administration site conditions: temperature regulation disorder (e.g. hypothermia, pyrexia), chest pain, peripheral oedema Investigations: increased Creatine Phosphokinase, blood glucose increased, blood glucose fluctuation, glycosylated haemoglobin increased Cardiac disorders: QT prolongation, ventricular arrhythmias, sudden unexplained death, cardiac arrest, torsades de pointes, bradycardia Blood and the lymphatic system disorders: leukopenia, neutropenia, thrombocytopenia Nervous system disorders: speech disorder, Neuroleptic Malignant Syndrome (NMS), grand mal convulsion Respiratory, thoracic and mediastinal disorders: oropharyngeal spasm, laryngospasm, aspiration pneumonia Gastrointestinal disorders: pancreatitis, dysphagia, abdominal discomfort, stomach discomfort, diarrhoea Renal and urinary disorders: urinary incontinence, urinary retention Skin and subcutaneous tissue disorders: rash, photosensitivity reaction, alopecia, hyperhidrosis Musculoskeletal and connective tissue disorders: rhabdomyolysis, myalgia, stiffness Endocrine disorders: hyperglycaemia, diabetes mellitus, diabetic ketoacidosis, diabetic hyperosmolar coma Metabolism and nutrition disorders: weight gain, weight decreased, anorexia, hyponatremia Vascular disorders: syncope, hypertension, thromboembolic events General disorders and administration site conditions: temperature regulation disorder (e.g. hypothermia, pyrexia), chest pain, peripheral oedema Immune system disorders: allergic reaction (e.g. anaphylactic reaction, angioedema including swollen tongue, tongue oedema, face oedema, pruritus, or urticaria) Hepatobiliary disorders: jaundice, hepatitis, increased Alanine Aminotransferase (ALT), increased Aspartate Aminotransferase (AST), increased Gamma Glutamyl Transferase (GGT), increased alkaline phosphatase Reproductive system and breast disorders: priapism Psychiatric disorders: agitation, nervousness; suicide attempt, suicidal ideation, and completed suicide (see section 4.4) 5.1 Pharmacodynamic properties Pharmacotherapeutic group: other antipsychotics, ATC code: N05AX12 .................................. 6.3 Shelf life 18 months After opening: uUse product immediately after opening and discard any unused amount. 6.6 Special precautions for disposal and other handling Any unused product or waste material should be disposed of in accordance with local requirements. 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 4 June 2004 Date of latest renewal: 21 April 2009 10. DATE OF REVISION OF THE TEXT August 2008 04/2009 Detailed information on this product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/
For intramuscular use. To enhance absorption and minimise variability, injection into the deltoid or deep within the gluteus maximus muscle, avoiding adipose regions, is recommended. ABILIFY solution for injection should not be administered intravenously or subcutaneously. ABILIFY solution for injection is ready to use and intended for short-term use only (see section 5.1). The recommended initial dose for aripiprazole solution for injection is 9.75 mg (1.3 ml), administered as a single intramuscular injection. The effective dose range of aripiprazole solution for injection is 5.25‑15 mg as a single injection. A lower dose of 5.25 mg (0.7 ml) may be given, on the basis of individual clinical status, which should also include consideration of medicinal products already administered either for maintenance or acute treatment (see section 4.5). A second injection may be administered 2 hours after the first injection, on the basis of individual clinical status and no more than three injections should be given in any 24-hour period. The maximum daily dose of aripiprazole is 30 mg (including all formulations of aripiprazole). If continued treatment is indicated with oral aripiprazole, see the Summary of Product Characteristics for ABILIFY tablets, ABILIFY orodispersible tablets, or ABILIFY oral solution. ABILIFY solution for injection is for intramuscular use. To enhance absorption and minimise variability, injection into the deltoid or deep within the gluteus maximus muscle, avoiding adipose regions, is recommended. ABILIFY solution for injection should not be administered intravenously or subcutaneously. ABILIFY solution for injection is ready to use and intended for short-term use only (see section 5.1). ............................ Smoking status: according to the metabolic pathway of ABILIFY no dosage adjustment is required for smokers (see section 4.5). 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 section 4.5). 4.4 Special warnings and precautions for use .............................................. 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, hypovolemia, and treatment with antihypertensive medicationsmedicinal products) or hypertension, including accelerated or malignant. ....................... Tardive Dyskinesiadyskinesia: in clinical trials of one year or less duration, there were uncommon reports of treatment emergent dyskinesia during treatment with aripiprazole. If signs and symptoms of tardive dyskinesia appear in a patient on ABILIFY, dose reduction or discontinuation should be considered. These symptoms can temporally deteriorate or can even arise after discontinuation of treatment. .................................................... Cerebrovascular adverse eventsreactions: in the same trials, cerebrovascular adverse eventsreactions (e.g. stroke, transient ischaemic attack), including fatalities, were reported in patients (mean age: 84 years; range: 78‑88 years). Overall, 1.3% of aripiprazole-treated patients reported cerebrovascular adverse eventsreactions compared with 0.6% of placebo-treated patients in these trials. This difference was not statistically significant. However, in one of these trials, a fixed-dose trial, there was a significant dose response relationship for cerebrovascular adverse eventsreactions in patients treated with aripiprazole. ABILIFY is not approved indicated for the treatment of dementia-related psychosis. Hyperglycaemia and Diabetes diabetes Mellitusmellitus: hyperglycaemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotic agents, including ABILIFY. Risk factors that may predispose patients to severe complications include obesity and family history of diabetes. In clinical trials with aripiprazole, there were no significant differences in the incidence rates of hyperglycaemia-related adverse eventsreactions (including diabetes) or in abnormal glycaemia laboratory values compared to placebo. Precise risk estimates for hyperglycaemia-related adverse eventsreactions in patients treated with ABILIFY and with other atypical antipsychotic agents are not available to allow direct comparisons. Patients treated with any antipsychotic agents, including ABILIFY, 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. Hypersensitivity: as with other medicinal products hypersensitivity reactions, characterised by allergic symptoms, may occur with aripiprazole (see section 4.8). 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 ABILIFY. When seen, it is usually in those with significant risk factors such as history of diabetes, thyroid disorder or pituitary adenoma. In clinical trials aripiprazole has not been shown to induce clinically relevant weight gain (see section 5.1). Dysphagia: oesophageal dysmotility and aspiration have been associated with antipsychotic drug usetreatment, including ABILIFY. Aripiprazole and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia. Hypersensitivity: as with other medications hypersensitivity reactions, characterised by allergic symptoms, may occur with aripiprazole (see section 4.8). 4.5 Interaction with other medicinal products and other forms of interaction 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 undesirable effects adverse reactions such as sedation (see section 4.8). If aripiprazole is administered concomitantly with medicinesmedicinal products known to cause QT prolongation or electrolyte imbalance, caution should be used. 4.8 Undesirable effects The following undesirable effects adverse reactions occurred more often (≥ 1/100) than placebo, or were identified as possibly medically relevant adverse reactions (*) in clinical trials with aripiprazole solution for injection (see section 5.1): The frequency listed below is defined using the following convention: common (³ 1/100, to < 1/10) and uncommon (³ 1/1,000, to < 1/100). Cardiac disorders Uncommon: tachycardia* Nervous system disorders Common: somnolence, dizziness, headache, akathisia Cardiac disorders Uncommon: tachycardia* Vascular disorders Uncommon: orthostatic hypotension*, increased diastolic blood pressure* Gastrointestinal disorders Common: nausea, vomiting Uncommon: dry mouth* Vascular disorders Uncommon: orthostatic hypotension*, increased diastolic blood pressure* General disorders and administration site conditions Uncommon: fatigue* The following undesirable effects adverse reactionsoccurred more often (≥ 1/100) than placebo, or were identified as possibly medically relevant adverse reactions (*) in clinical trials with oral formulations of aripiprazole (see section 5.1): Psychiatric disorders Common: restlessness, insomnia, anxiety Uncommon: depression* Nervous system disorders Common: extrapyramidal disorder, akathisia, tremor, dizziness, somnolence, sedation, headache Eye disorders Common: blurred vision Cardiac disorders Uncommon: tachycardia* Nervous system disorders Common: extrapyramidal disorder, akathisia, tremor, dizziness, somnolence, sedation, headache Eye disorders Common: blurred vision Vascular disorders Uncommon: orthostatic hypotension* Gastrointestinal disorders Common: dyspepsia, vomiting, nausea, constipation, salivary hypersecretion Vascular disorders Uncommon: orthostatic hypotension* General disorders and administration site conditions Common: fatigue Psychiatric disorders Common: restlessness, insomnia, anxiety Uncommon: depression* ......................... Other findings: Undesirable effectsAdverse reactions known to be associated with antipsychotic therapy and also reported during treatment with aripiprazole include neuroleptic malignant syndrome, tardive dyskinesia, seizure, cerebrovascular adverse eventsreactions and increased mortality in elderly demented patients, hyperglycaemia and diabetes mellitus (see section 4.4). Post-Marketing: The following adverse eventsreactions have been reported during post-marketing surveillance. The frequency of these eventsreactions is considered not known (cannot be estimated from the available data). Blood and the lymphatic system disorders: leukopenia, neutropenia, thrombocytopenia Immune system disorders: allergic reaction (e.g. anaphylactic reaction, angioedema including swollen tongue, tongue oedema, face oedema, pruritus, or urticaria) Endocrine disorders: hyperglycaemia, diabetes mellitus, diabetic ketoacidosis, diabetic hyperosmolar coma Metabolism and nutrition disorders: weight gain, weight decreased, anorexia, hyponatremia Psychiatric disorders: agitation, nervousness; suicide attempt, suicidal ideation, and completed suicide (see section 4.4) Nervous system disorders: speech disorder, Neuroleptic Malignant Syndrome (NMS), grand mal convulsion Cardiac disorders: QT prolongation, ventricular arrhythmias, sudden unexplained death, cardiac arrest, torsades de pointes, bradycardia Vascular disorders: syncope, hypertension, thromboembolic reactions Respiratory, thoracic and mediastinal disorders: oropharyngeal spasm, laryngospasm, aspiration pneumonia Gastrointestinal disorders: pancreatitis, dysphagia, abdominal discomfort, stomach discomfort, diarrhoea Hepatobiliary disorders: jaundice, hepatitis, increased Alanine Aminotransferase (ALT), increased Aspartate Aminotransferase (AST), increased Gamma Glutamyl Transferase (GGT), increased alkaline phosphatase Skin and subcutaneous tissue disorders: rash, photosensitivity reaction, alopecia, hyperhidrosis Musculoskeletal and connective tissue disorders: rhabdomyolysis, myalgia, stiffness Renal and urinary disorders: urinary incontinence, urinary retention Reproductive system and breast disorders: priapism General disorders and administration site conditions: temperature regulation disorder (e.g. hypothermia, pyrexia), chest pain, peripheral oedema Investigations: increased Creatine Phosphokinase, blood glucose increased, blood glucose fluctuation, glycosylated haemoglobin increased Cardiac disorders: QT prolongation, ventricular arrhythmias, sudden unexplained death, cardiac arrest, torsades de pointes, bradycardia Blood and the lymphatic system disorders: leukopenia, neutropenia, thrombocytopenia Nervous system disorders: speech disorder, Neuroleptic Malignant Syndrome (NMS), grand mal convulsion Respiratory, thoracic and mediastinal disorders: oropharyngeal spasm, laryngospasm, aspiration pneumonia Gastrointestinal disorders: pancreatitis, dysphagia, abdominal discomfort, stomach discomfort, diarrhoea Renal and urinary disorders: urinary incontinence, urinary retention Skin and subcutaneous tissue disorders: rash, photosensitivity reaction, alopecia, hyperhidrosis Musculoskeletal and connective tissue disorders: rhabdomyolysis, myalgia, stiffness Endocrine disorders: hyperglycaemia, diabetes mellitus, diabetic ketoacidosis, diabetic hyperosmolar coma Metabolism and nutrition disorders: weight gain, weight decreased, anorexia, hyponatremia Vascular disorders: syncope, hypertension, thromboembolic events General disorders and administration site conditions: temperature regulation disorder (e.g. hypothermia, pyrexia), chest pain, peripheral oedema Immune system disorders: allergic reaction (e.g. anaphylactic reaction, angioedema including swollen tongue, tongue oedema, face oedema, pruritus, or urticaria) Hepatobiliary disorders: jaundice, hepatitis, increased Alanine Aminotransferase (ALT), increased Aspartate Aminotransferase (AST), increased Gamma Glutamyl Transferase (GGT), increased alkaline phosphatase Reproductive system and breast disorders: priapism Psychiatric disorders: agitation, nervousness; suicide attempt, suicidal ideation, and completed suicide (see section 4.4) 5.1 Pharmacodynamic properties Pharmacotherapeutic group: other antipsychotics, ATC code: N05AX12 .................................. 6.3 Shelf life 18 months After opening: uUse product immediately after opening and discard any unused amount. 6.6 Special precautions for disposal and other handling Any unused product or waste material should be disposed of in accordance with local requirements. 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 4 June 2004 Date of latest renewal: 21 April 2009 10. DATE OF REVISION OF THE TEXT August 2008 04/2009 Detailed information on this product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/
To enhance absorption and minimise variability, injection into the deltoid or deep within the gluteus maximus muscle, avoiding adipose regions, is recommended. ABILIFY solution for injection should not be administered intravenously or subcutaneously. ABILIFY solution for injection is ready to use and intended for short-term use only (see section 5.1). The recommended initial dose for aripiprazole solution for injection is 9.75 mg (1.3 ml), administered as a single intramuscular injection. The effective dose range of aripiprazole solution for injection is 5.25‑15 mg as a single injection. A lower dose of 5.25 mg (0.7 ml) may be given, on the basis of individual clinical status, which should also include consideration of medicinal products already administered either for maintenance or acute treatment (see section 4.5). A second injection may be administered 2 hours after the first injection, on the basis of individual clinical status and no more than three injections should be given in any 24-hour period. The maximum daily dose of aripiprazole is 30 mg (including all formulations of aripiprazole). If continued treatment is indicated with oral aripiprazole, see the Summary of Product Characteristics for ABILIFY tablets, ABILIFY orodispersible tablets, or ABILIFY oral solution. ABILIFY solution for injection is for intramuscular use. To enhance absorption and minimise variability, injection into the deltoid or deep within the gluteus maximus muscle, avoiding adipose regions, is recommended. ABILIFY solution for injection should not be administered intravenously or subcutaneously. ABILIFY solution for injection is ready to use and intended for short-term use only (see section 5.1). ............................ Smoking status: according to the metabolic pathway of ABILIFY no dosage adjustment is required for smokers (see section 4.5). 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 section 4.5). 4.4 Special warnings and precautions for use .............................................. 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, hypovolemia, and treatment with antihypertensive medicationsmedicinal products) or hypertension, including accelerated or malignant. ....................... Tardive Dyskinesiadyskinesia: in clinical trials of one year or less duration, there were uncommon reports of treatment emergent dyskinesia during treatment with aripiprazole. If signs and symptoms of tardive dyskinesia appear in a patient on ABILIFY, dose reduction or discontinuation should be considered. These symptoms can temporally deteriorate or can even arise after discontinuation of treatment. .................................................... Cerebrovascular adverse eventsreactions: in the same trials, cerebrovascular adverse eventsreactions (e.g. stroke, transient ischaemic attack), including fatalities, were reported in patients (mean age: 84 years; range: 78‑88 years). Overall, 1.3% of aripiprazole-treated patients reported cerebrovascular adverse eventsreactions compared with 0.6% of placebo-treated patients in these trials. This difference was not statistically significant. However, in one of these trials, a fixed-dose trial, there was a significant dose response relationship for cerebrovascular adverse eventsreactions in patients treated with aripiprazole. ABILIFY is not approved indicated for the treatment of dementia-related psychosis. Hyperglycaemia and Diabetes diabetes Mellitusmellitus: hyperglycaemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotic agents, including ABILIFY. Risk factors that may predispose patients to severe complications include obesity and family history of diabetes. In clinical trials with aripiprazole, there were no significant differences in the incidence rates of hyperglycaemia-related adverse eventsreactions (including diabetes) or in abnormal glycaemia laboratory values compared to placebo. Precise risk estimates for hyperglycaemia-related adverse eventsreactions in patients treated with ABILIFY and with other atypical antipsychotic agents are not available to allow direct comparisons. Patients treated with any antipsychotic agents, including ABILIFY, 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. Hypersensitivity: as with other medicinal products hypersensitivity reactions, characterised by allergic symptoms, may occur with aripiprazole (see section 4.8). 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 ABILIFY. When seen, it is usually in those with significant risk factors such as history of diabetes, thyroid disorder or pituitary adenoma. In clinical trials aripiprazole has not been shown to induce clinically relevant weight gain (see section 5.1). Dysphagia: oesophageal dysmotility and aspiration have been associated with antipsychotic drug usetreatment, including ABILIFY. Aripiprazole and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia. Hypersensitivity: as with other medications hypersensitivity reactions, characterised by allergic symptoms, may occur with aripiprazole (see section 4.8). 4.5 Interaction with other medicinal products and other forms of interaction 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 undesirable effects adverse reactions such as sedation (see section 4.8). If aripiprazole is administered concomitantly with medicinesmedicinal products known to cause QT prolongation or electrolyte imbalance, caution should be used. 4.8 Undesirable effects The following undesirable effects adverse reactions occurred more often (≥ 1/100) than placebo, or were identified as possibly medically relevant adverse reactions (*) in clinical trials with aripiprazole solution for injection (see section 5.1): The frequency listed below is defined using the following convention: common (³ 1/100, to < 1/10) and uncommon (³ 1/1,000, to < 1/100). Cardiac disorders Uncommon: tachycardia* Nervous system disorders Common: somnolence, dizziness, headache, akathisia Cardiac disorders Uncommon: tachycardia* Vascular disorders Uncommon: orthostatic hypotension*, increased diastolic blood pressure* Gastrointestinal disorders Common: nausea, vomiting Uncommon: dry mouth* Vascular disorders Uncommon: orthostatic hypotension*, increased diastolic blood pressure* General disorders and administration site conditions Uncommon: fatigue* The following undesirable effects adverse reactionsoccurred more often (≥ 1/100) than placebo, or were identified as possibly medically relevant adverse reactions (*) in clinical trials with oral formulations of aripiprazole (see section 5.1): Psychiatric disorders Common: restlessness, insomnia, anxiety Uncommon: depression* Nervous system disorders Common: extrapyramidal disorder, akathisia, tremor, dizziness, somnolence, sedation, headache Eye disorders Common: blurred vision Cardiac disorders Uncommon: tachycardia* Nervous system disorders Common: extrapyramidal disorder, akathisia, tremor, dizziness, somnolence, sedation, headache Eye disorders Common: blurred vision Vascular disorders Uncommon: orthostatic hypotension* Gastrointestinal disorders Common: dyspepsia, vomiting, nausea, constipation, salivary hypersecretion Vascular disorders Uncommon: orthostatic hypotension* General disorders and administration site conditions Common: fatigue Psychiatric disorders Common: restlessness, insomnia, anxiety Uncommon: depression* ......................... Other findings: Undesirable effectsAdverse reactions known to be associated with antipsychotic therapy and also reported during treatment with aripiprazole include neuroleptic malignant syndrome, tardive dyskinesia, seizure, cerebrovascular adverse eventsreactions and increased mortality in elderly demented patients, hyperglycaemia and diabetes mellitus (see section 4.4). Post-Marketing: The following adverse eventsreactions have been reported during post-marketing surveillance. The frequency of these eventsreactions is considered not known (cannot be estimated from the available data). Blood and the lymphatic system disorders: leukopenia, neutropenia, thrombocytopenia Immune system disorders: allergic reaction (e.g. anaphylactic reaction, angioedema including swollen tongue, tongue oedema, face oedema, pruritus, or urticaria) Endocrine disorders: hyperglycaemia, diabetes mellitus, diabetic ketoacidosis, diabetic hyperosmolar coma Metabolism and nutrition disorders: weight gain, weight decreased, anorexia, hyponatremia Psychiatric disorders: agitation, nervousness; suicide attempt, suicidal ideation, and completed suicide (see section 4.4) Nervous system disorders: speech disorder, Neuroleptic Malignant Syndrome (NMS), grand mal convulsion Cardiac disorders: QT prolongation, ventricular arrhythmias, sudden unexplained death, cardiac arrest, torsades de pointes, bradycardia Vascular disorders: syncope, hypertension, thromboembolic reactions Respiratory, thoracic and mediastinal disorders: oropharyngeal spasm, laryngospasm, aspiration pneumonia Gastrointestinal disorders: pancreatitis, dysphagia, abdominal discomfort, stomach discomfort, diarrhoea Hepatobiliary disorders: jaundice, hepatitis, increased Alanine Aminotransferase (ALT), increased Aspartate Aminotransferase (AST), increased Gamma Glutamyl Transferase (GGT), increased alkaline phosphatase Skin and subcutaneous tissue disorders: rash, photosensitivity reaction, alopecia, hyperhidrosis Musculoskeletal and connective tissue disorders: rhabdomyolysis, myalgia, stiffness Renal and urinary disorders: urinary incontinence, urinary retention Reproductive system and breast disorders: priapism General disorders and administration site conditions: temperature regulation disorder (e.g. hypothermia, pyrexia), chest pain, peripheral oedema Investigations: increased Creatine Phosphokinase, blood glucose increased, blood glucose fluctuation, glycosylated haemoglobin increased Cardiac disorders: QT prolongation, ventricular arrhythmias, sudden unexplained death, cardiac arrest, torsades de pointes, bradycardia Blood and the lymphatic system disorders: leukopenia, neutropenia, thrombocytopenia Nervous system disorders: speech disorder, Neuroleptic Malignant Syndrome (NMS), grand mal convulsion Respiratory, thoracic and mediastinal disorders: oropharyngeal spasm, laryngospasm, aspiration pneumonia Gastrointestinal disorders: pancreatitis, dysphagia, abdominal discomfort, stomach discomfort, diarrhoea Renal and urinary disorders: urinary incontinence, urinary retention Skin and subcutaneous tissue disorders: rash, photosensitivity reaction, alopecia, hyperhidrosis Musculoskeletal and connective tissue disorders: rhabdomyolysis, myalgia, stiffness Endocrine disorders: hyperglycaemia, diabetes mellitus, diabetic ketoacidosis, diabetic hyperosmolar coma Metabolism and nutrition disorders: weight gain, weight decreased, anorexia, hyponatremia Vascular disorders: syncope, hypertension, thromboembolic events General disorders and administration site conditions: temperature regulation disorder (e.g. hypothermia, pyrexia), chest pain, peripheral oedema Immune system disorders: allergic reaction (e.g. anaphylactic reaction, angioedema including swollen tongue, tongue oedema, face oedema, pruritus, or urticaria) Hepatobiliary disorders: jaundice, hepatitis, increased Alanine Aminotransferase (ALT), increased Aspartate Aminotransferase (AST), increased Gamma Glutamyl Transferase (GGT), increased alkaline phosphatase Reproductive system and breast disorders: priapism Psychiatric disorders: agitation, nervousness; suicide attempt, suicidal ideation, and completed suicide (see section 4.4) 5.1 Pharmacodynamic properties Pharmacotherapeutic group: other antipsychotics, ATC code: N05AX12 .................................. 6.3 Shelf life 18 months After opening: uUse product immediately after opening and discard any unused amount. 6.6 Special precautions for disposal and other handling Any unused product or waste material should be disposed of in accordance with local requirements. 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 4 June 2004 Date of latest renewal: 21 April 2009 10. DATE OF REVISION OF THE TEXT August 2008 04/2009 Detailed information on this product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/
ABILIFY solution for injection should not be administered intravenously or subcutaneously. ABILIFY solution for injection is ready to use and intended for short-term use only (see section 5.1). The recommended initial dose for aripiprazole solution for injection is 9.75 mg (1.3 ml), administered as a single intramuscular injection. The effective dose range of aripiprazole solution for injection is 5.25‑15 mg as a single injection. A lower dose of 5.25 mg (0.7 ml) may be given, on the basis of individual clinical status, which should also include consideration of medicinal products already administered either for maintenance or acute treatment (see section 4.5). A second injection may be administered 2 hours after the first injection, on the basis of individual clinical status and no more than three injections should be given in any 24-hour period. The maximum daily dose of aripiprazole is 30 mg (including all formulations of aripiprazole). If continued treatment is indicated with oral aripiprazole, see the Summary of Product Characteristics for ABILIFY tablets, ABILIFY orodispersible tablets, or ABILIFY oral solution. ABILIFY solution for injection is for intramuscular use. To enhance absorption and minimise variability, injection into the deltoid or deep within the gluteus maximus muscle, avoiding adipose regions, is recommended. ABILIFY solution for injection should not be administered intravenously or subcutaneously. ABILIFY solution for injection is ready to use and intended for short-term use only (see section 5.1). ............................ Smoking status: according to the metabolic pathway of ABILIFY no dosage adjustment is required for smokers (see section 4.5). 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 section 4.5). 4.4 Special warnings and precautions for use .............................................. 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, hypovolemia, and treatment with antihypertensive medicationsmedicinal products) or hypertension, including accelerated or malignant. ....................... Tardive Dyskinesiadyskinesia: in clinical trials of one year or less duration, there were uncommon reports of treatment emergent dyskinesia during treatment with aripiprazole. If signs and symptoms of tardive dyskinesia appear in a patient on ABILIFY, dose reduction or discontinuation should be considered. These symptoms can temporally deteriorate or can even arise after discontinuation of treatment. .................................................... Cerebrovascular adverse eventsreactions: in the same trials, cerebrovascular adverse eventsreactions (e.g. stroke, transient ischaemic attack), including fatalities, were reported in patients (mean age: 84 years; range: 78‑88 years). Overall, 1.3% of aripiprazole-treated patients reported cerebrovascular adverse eventsreactions compared with 0.6% of placebo-treated patients in these trials. This difference was not statistically significant. However, in one of these trials, a fixed-dose trial, there was a significant dose response relationship for cerebrovascular adverse eventsreactions in patients treated with aripiprazole. ABILIFY is not approved indicated for the treatment of dementia-related psychosis. Hyperglycaemia and Diabetes diabetes Mellitusmellitus: hyperglycaemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotic agents, including ABILIFY. Risk factors that may predispose patients to severe complications include obesity and family history of diabetes. In clinical trials with aripiprazole, there were no significant differences in the incidence rates of hyperglycaemia-related adverse eventsreactions (including diabetes) or in abnormal glycaemia laboratory values compared to placebo. Precise risk estimates for hyperglycaemia-related adverse eventsreactions in patients treated with ABILIFY and with other atypical antipsychotic agents are not available to allow direct comparisons. Patients treated with any antipsychotic agents, including ABILIFY, 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. Hypersensitivity: as with other medicinal products hypersensitivity reactions, characterised by allergic symptoms, may occur with aripiprazole (see section 4.8). 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 ABILIFY. When seen, it is usually in those with significant risk factors such as history of diabetes, thyroid disorder or pituitary adenoma. In clinical trials aripiprazole has not been shown to induce clinically relevant weight gain (see section 5.1). Dysphagia: oesophageal dysmotility and aspiration have been associated with antipsychotic drug usetreatment, including ABILIFY. Aripiprazole and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia. Hypersensitivity: as with other medications hypersensitivity reactions, characterised by allergic symptoms, may occur with aripiprazole (see section 4.8). 4.5 Interaction with other medicinal products and other forms of interaction 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 undesirable effects adverse reactions such as sedation (see section 4.8). If aripiprazole is administered concomitantly with medicinesmedicinal products known to cause QT prolongation or electrolyte imbalance, caution should be used. 4.8 Undesirable effects The following undesirable effects adverse reactions occurred more often (≥ 1/100) than placebo, or were identified as possibly medically relevant adverse reactions (*) in clinical trials with aripiprazole solution for injection (see section 5.1): The frequency listed below is defined using the following convention: common (³ 1/100, to < 1/10) and uncommon (³ 1/1,000, to < 1/100). Cardiac disorders Uncommon: tachycardia* Nervous system disorders Common: somnolence, dizziness, headache, akathisia Cardiac disorders Uncommon: tachycardia* Vascular disorders Uncommon: orthostatic hypotension*, increased diastolic blood pressure* Gastrointestinal disorders Common: nausea, vomiting Uncommon: dry mouth* Vascular disorders Uncommon: orthostatic hypotension*, increased diastolic blood pressure* General disorders and administration site conditions Uncommon: fatigue* The following undesirable effects adverse reactionsoccurred more often (≥ 1/100) than placebo, or were identified as possibly medically relevant adverse reactions (*) in clinical trials with oral formulations of aripiprazole (see section 5.1): Psychiatric disorders Common: restlessness, insomnia, anxiety Uncommon: depression* Nervous system disorders Common: extrapyramidal disorder, akathisia, tremor, dizziness, somnolence, sedation, headache Eye disorders Common: blurred vision Cardiac disorders Uncommon: tachycardia* Nervous system disorders Common: extrapyramidal disorder, akathisia, tremor, dizziness, somnolence, sedation, headache Eye disorders Common: blurred vision Vascular disorders Uncommon: orthostatic hypotension* Gastrointestinal disorders Common: dyspepsia, vomiting, nausea, constipation, salivary hypersecretion Vascular disorders Uncommon: orthostatic hypotension* General disorders and administration site conditions Common: fatigue Psychiatric disorders Common: restlessness, insomnia, anxiety Uncommon: depression* ......................... Other findings: Undesirable effectsAdverse reactions known to be associated with antipsychotic therapy and also reported during treatment with aripiprazole include neuroleptic malignant syndrome, tardive dyskinesia, seizure, cerebrovascular adverse eventsreactions and increased mortality in elderly demented patients, hyperglycaemia and diabetes mellitus (see section 4.4). Post-Marketing: The following adverse eventsreactions have been reported during post-marketing surveillance. The frequency of these eventsreactions is considered not known (cannot be estimated from the available data). Blood and the lymphatic system disorders: leukopenia, neutropenia, thrombocytopenia Immune system disorders: allergic reaction (e.g. anaphylactic reaction, angioedema including swollen tongue, tongue oedema, face oedema, pruritus, or urticaria) Endocrine disorders: hyperglycaemia, diabetes mellitus, diabetic ketoacidosis, diabetic hyperosmolar coma Metabolism and nutrition disorders: weight gain, weight decreased, anorexia, hyponatremia Psychiatric disorders: agitation, nervousness; suicide attempt, suicidal ideation, and completed suicide (see section 4.4) Nervous system disorders: speech disorder, Neuroleptic Malignant Syndrome (NMS), grand mal convulsion Cardiac disorders: QT prolongation, ventricular arrhythmias, sudden unexplained death, cardiac arrest, torsades de pointes, bradycardia Vascular disorders: syncope, hypertension, thromboembolic reactions Respiratory, thoracic and mediastinal disorders: oropharyngeal spasm, laryngospasm, aspiration pneumonia Gastrointestinal disorders: pancreatitis, dysphagia, abdominal discomfort, stomach discomfort, diarrhoea Hepatobiliary disorders: jaundice, hepatitis, increased Alanine Aminotransferase (ALT), increased Aspartate Aminotransferase (AST), increased Gamma Glutamyl Transferase (GGT), increased alkaline phosphatase Skin and subcutaneous tissue disorders: rash, photosensitivity reaction, alopecia, hyperhidrosis Musculoskeletal and connective tissue disorders: rhabdomyolysis, myalgia, stiffness Renal and urinary disorders: urinary incontinence, urinary retention Reproductive system and breast disorders: priapism General disorders and administration site conditions: temperature regulation disorder (e.g. hypothermia, pyrexia), chest pain, peripheral oedema Investigations: increased Creatine Phosphokinase, blood glucose increased, blood glucose fluctuation, glycosylated haemoglobin increased Cardiac disorders: QT prolongation, ventricular arrhythmias, sudden unexplained death, cardiac arrest, torsades de pointes, bradycardia Blood and the lymphatic system disorders: leukopenia, neutropenia, thrombocytopenia Nervous system disorders: speech disorder, Neuroleptic Malignant Syndrome (NMS), grand mal convulsion Respiratory, thoracic and mediastinal disorders: oropharyngeal spasm, laryngospasm, aspiration pneumonia Gastrointestinal disorders: pancreatitis, dysphagia, abdominal discomfort, stomach discomfort, diarrhoea Renal and urinary disorders: urinary incontinence, urinary retention Skin and subcutaneous tissue disorders: rash, photosensitivity reaction, alopecia, hyperhidrosis Musculoskeletal and connective tissue disorders: rhabdomyolysis, myalgia, stiffness Endocrine disorders: hyperglycaemia, diabetes mellitus, diabetic ketoacidosis, diabetic hyperosmolar coma Metabolism and nutrition disorders: weight gain, weight decreased, anorexia, hyponatremia Vascular disorders: syncope, hypertension, thromboembolic events General disorders and administration site conditions: temperature regulation disorder (e.g. hypothermia, pyrexia), chest pain, peripheral oedema Immune system disorders: allergic reaction (e.g. anaphylactic reaction, angioedema including swollen tongue, tongue oedema, face oedema, pruritus, or urticaria) Hepatobiliary disorders: jaundice, hepatitis, increased Alanine Aminotransferase (ALT), increased Aspartate Aminotransferase (AST), increased Gamma Glutamyl Transferase (GGT), increased alkaline phosphatase Reproductive system and breast disorders: priapism Psychiatric disorders: agitation, nervousness; suicide attempt, suicidal ideation, and completed suicide (see section 4.4) 5.1 Pharmacodynamic properties Pharmacotherapeutic group: other antipsychotics, ATC code: N05AX12 .................................. 6.3 Shelf life 18 months After opening: uUse product immediately after opening and discard any unused amount. 6.6 Special precautions for disposal and other handling Any unused product or waste material should be disposed of in accordance with local requirements. 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 4 June 2004 Date of latest renewal: 21 April 2009 10. DATE OF REVISION OF THE TEXT August 2008 04/2009 Detailed information on this product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/
The recommended initial dose for aripiprazole solution for injection is 9.75 mg (1.3 ml), administered as a single intramuscular injection. The effective dose range of aripiprazole solution for injection is 5.25‑15 mg as a single injection. A lower dose of 5.25 mg (0.7 ml) may be given, on the basis of individual clinical status, which should also include consideration of medicinal products already administered either for maintenance or acute treatment (see section 4.5). A second injection may be administered 2 hours after the first injection, on the basis of individual clinical status and no more than three injections should be given in any 24-hour period. The maximum daily dose of aripiprazole is 30 mg (including all formulations of aripiprazole). If continued treatment is indicated with oral aripiprazole, see the Summary of Product Characteristics for ABILIFY tablets, ABILIFY orodispersible tablets, or ABILIFY oral solution. ABILIFY solution for injection is for intramuscular use. To enhance absorption and minimise variability, injection into the deltoid or deep within the gluteus maximus muscle, avoiding adipose regions, is recommended. ABILIFY solution for injection should not be administered intravenously or subcutaneously. ABILIFY solution for injection is ready to use and intended for short-term use only (see section 5.1). ............................ Smoking status: according to the metabolic pathway of ABILIFY no dosage adjustment is required for smokers (see section 4.5). 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 section 4.5). 4.4 Special warnings and precautions for use .............................................. 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, hypovolemia, and treatment with antihypertensive medicationsmedicinal products) or hypertension, including accelerated or malignant. ....................... Tardive Dyskinesiadyskinesia: in clinical trials of one year or less duration, there were uncommon reports of treatment emergent dyskinesia during treatment with aripiprazole. If signs and symptoms of tardive dyskinesia appear in a patient on ABILIFY, dose reduction or discontinuation should be considered. These symptoms can temporally deteriorate or can even arise after discontinuation of treatment. .................................................... Cerebrovascular adverse eventsreactions: in the same trials, cerebrovascular adverse eventsreactions (e.g. stroke, transient ischaemic attack), including fatalities, were reported in patients (mean age: 84 years; range: 78‑88 years). Overall, 1.3% of aripiprazole-treated patients reported cerebrovascular adverse eventsreactions compared with 0.6% of placebo-treated patients in these trials. This difference was not statistically significant. However, in one of these trials, a fixed-dose trial, there was a significant dose response relationship for cerebrovascular adverse eventsreactions in patients treated with aripiprazole. ABILIFY is not approved indicated for the treatment of dementia-related psychosis. Hyperglycaemia and Diabetes diabetes Mellitusmellitus: hyperglycaemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotic agents, including ABILIFY. Risk factors that may predispose patients to severe complications include obesity and family history of diabetes. In clinical trials with aripiprazole, there were no significant differences in the incidence rates of hyperglycaemia-related adverse eventsreactions (including diabetes) or in abnormal glycaemia laboratory values compared to placebo. Precise risk estimates for hyperglycaemia-related adverse eventsreactions in patients treated with ABILIFY and with other atypical antipsychotic agents are not available to allow direct comparisons. Patients treated with any antipsychotic agents, including ABILIFY, 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. Hypersensitivity: as with other medicinal products hypersensitivity reactions, characterised by allergic symptoms, may occur with aripiprazole (see section 4.8). 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 ABILIFY. When seen, it is usually in those with significant risk factors such as history of diabetes, thyroid disorder or pituitary adenoma. In clinical trials aripiprazole has not been shown to induce clinically relevant weight gain (see section 5.1). Dysphagia: oesophageal dysmotility and aspiration have been associated with antipsychotic drug usetreatment, including ABILIFY. Aripiprazole and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia. Hypersensitivity: as with other medications hypersensitivity reactions, characterised by allergic symptoms, may occur with aripiprazole (see section 4.8). 4.5 Interaction with other medicinal products and other forms of interaction 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 undesirable effects adverse reactions such as sedation (see section 4.8). If aripiprazole is administered concomitantly with medicinesmedicinal products known to cause QT prolongation or electrolyte imbalance, caution should be used. 4.8 Undesirable effects The following undesirable effects adverse reactions occurred more often (≥ 1/100) than placebo, or were identified as possibly medically relevant adverse reactions (*) in clinical trials with aripiprazole solution for injection (see section 5.1): The frequency listed below is defined using the following convention: common (³ 1/100, to < 1/10) and uncommon (³ 1/1,000, to < 1/100). Cardiac disorders Uncommon: tachycardia* Nervous system disorders Common: somnolence, dizziness, headache, akathisia Cardiac disorders Uncommon: tachycardia* Vascular disorders Uncommon: orthostatic hypotension*, increased diastolic blood pressure* Gastrointestinal disorders Common: nausea, vomiting Uncommon: dry mouth* Vascular disorders Uncommon: orthostatic hypotension*, increased diastolic blood pressure* General disorders and administration site conditions Uncommon: fatigue* The following undesirable effects adverse reactionsoccurred more often (≥ 1/100) than placebo, or were identified as possibly medically relevant adverse reactions (*) in clinical trials with oral formulations of aripiprazole (see section 5.1): Psychiatric disorders Common: restlessness, insomnia, anxiety Uncommon: depression* Nervous system disorders Common: extrapyramidal disorder, akathisia, tremor, dizziness, somnolence, sedation, headache Eye disorders Common: blurred vision Cardiac disorders Uncommon: tachycardia* Nervous system disorders Common: extrapyramidal disorder, akathisia, tremor, dizziness, somnolence, sedation, headache Eye disorders Common: blurred vision Vascular disorders Uncommon: orthostatic hypotension* Gastrointestinal disorders Common: dyspepsia, vomiting, nausea, constipation, salivary hypersecretion Vascular disorders Uncommon: orthostatic hypotension* General disorders and administration site conditions Common: fatigue Psychiatric disorders Common: restlessness, insomnia, anxiety Uncommon: depression* ......................... Other findings: Undesirable effectsAdverse reactions known to be associated with antipsychotic therapy and also reported during treatment with aripiprazole include neuroleptic malignant syndrome, tardive dyskinesia, seizure, cerebrovascular adverse eventsreactions and increased mortality in elderly demented patients, hyperglycaemia and diabetes mellitus (see section 4.4). Post-Marketing: The following adverse eventsreactions have been reported during post-marketing surveillance. The frequency of these eventsreactions is considered not known (cannot be estimated from the available data). Blood and the lymphatic system disorders: leukopenia, neutropenia, thrombocytopenia Immune system disorders: allergic reaction (e.g. anaphylactic reaction, angioedema including swollen tongue, tongue oedema, face oedema, pruritus, or urticaria) Endocrine disorders: hyperglycaemia, diabetes mellitus, diabetic ketoacidosis, diabetic hyperosmolar coma Metabolism and nutrition disorders: weight gain, weight decreased, anorexia, hyponatremia Psychiatric disorders: agitation, nervousness; suicide attempt, suicidal ideation, and completed suicide (see section 4.4) Nervous system disorders: speech disorder, Neuroleptic Malignant Syndrome (NMS), grand mal convulsion Cardiac disorders: QT prolongation, ventricular arrhythmias, sudden unexplained death, cardiac arrest, torsades de pointes, bradycardia Vascular disorders: syncope, hypertension, thromboembolic reactions Respiratory, thoracic and mediastinal disorders: oropharyngeal spasm, laryngospasm, aspiration pneumonia Gastrointestinal disorders: pancreatitis, dysphagia, abdominal discomfort, stomach discomfort, diarrhoea Hepatobiliary disorders: jaundice, hepatitis, increased Alanine Aminotransferase (ALT), increased Aspartate Aminotransferase (AST), increased Gamma Glutamyl Transferase (GGT), increased alkaline phosphatase Skin and subcutaneous tissue disorders: rash, photosensitivity reaction, alopecia, hyperhidrosis Musculoskeletal and connective tissue disorders: rhabdomyolysis, myalgia, stiffness Renal and urinary disorders: urinary incontinence, urinary retention Reproductive system and breast disorders: priapism General disorders and administration site conditions: temperature regulation disorder (e.g. hypothermia, pyrexia), chest pain, peripheral oedema Investigations: increased Creatine Phosphokinase, blood glucose increased, blood glucose fluctuation, glycosylated haemoglobin increased Cardiac disorders: QT prolongation, ventricular arrhythmias, sudden unexplained death, cardiac arrest, torsades de pointes, bradycardia Blood and the lymphatic system disorders: leukopenia, neutropenia, thrombocytopenia Nervous system disorders: speech disorder, Neuroleptic Malignant Syndrome (NMS), grand mal convulsion Respiratory, thoracic and mediastinal disorders: oropharyngeal spasm, laryngospasm, aspiration pneumonia Gastrointestinal disorders: pancreatitis, dysphagia, abdominal discomfort, stomach discomfort, diarrhoea Renal and urinary disorders: urinary incontinence, urinary retention Skin and subcutaneous tissue disorders: rash, photosensitivity reaction, alopecia, hyperhidrosis Musculoskeletal and connective tissue disorders: rhabdomyolysis, myalgia, stiffness Endocrine disorders: hyperglycaemia, diabetes mellitus, diabetic ketoacidosis, diabetic hyperosmolar coma Metabolism and nutrition disorders: weight gain, weight decreased, anorexia, hyponatremia Vascular disorders: syncope, hypertension, thromboembolic events General disorders and administration site conditions: temperature regulation disorder (e.g. hypothermia, pyrexia), chest pain, peripheral oedema Immune system disorders: allergic reaction (e.g. anaphylactic reaction, angioedema including swollen tongue, tongue oedema, face oedema, pruritus, or urticaria) Hepatobiliary disorders: jaundice, hepatitis, increased Alanine Aminotransferase (ALT), increased Aspartate Aminotransferase (AST), increased Gamma Glutamyl Transferase (GGT), increased alkaline phosphatase Reproductive system and breast disorders: priapism Psychiatric disorders: agitation, nervousness; suicide attempt, suicidal ideation, and completed suicide (see section 4.4) 5.1 Pharmacodynamic properties Pharmacotherapeutic group: other antipsychotics, ATC code: N05AX12 .................................. 6.3 Shelf life 18 months After opening: uUse product immediately after opening and discard any unused amount. 6.6 Special precautions for disposal and other handling Any unused product or waste material should be disposed of in accordance with local requirements. 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 4 June 2004 Date of latest renewal: 21 April 2009 10. DATE OF REVISION OF THE TEXT August 2008 04/2009 Detailed information on this product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/
ABILIFY solution for injection is for intramuscular use. To enhance absorption and minimise variability, injection into the deltoid or deep within the gluteus maximus muscle, avoiding adipose regions, is recommended. ABILIFY solution for injection should not be administered intravenously or subcutaneously. ABILIFY solution for injection is ready to use and intended for short-term use only (see section 5.1). ............................ Smoking status: according to the metabolic pathway of ABILIFY no dosage adjustment is required for smokers (see section 4.5). 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 section 4.5). 4.4 Special warnings and precautions for use .............................................. 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, hypovolemia, and treatment with antihypertensive medicationsmedicinal products) or hypertension, including accelerated or malignant. ....................... Tardive Dyskinesiadyskinesia: in clinical trials of one year or less duration, there were uncommon reports of treatment emergent dyskinesia during treatment with aripiprazole. If signs and symptoms of tardive dyskinesia appear in a patient on ABILIFY, dose reduction or discontinuation should be considered. These symptoms can temporally deteriorate or can even arise after discontinuation of treatment. .................................................... Cerebrovascular adverse eventsreactions: in the same trials, cerebrovascular adverse eventsreactions (e.g. stroke, transient ischaemic attack), including fatalities, were reported in patients (mean age: 84 years; range: 78‑88 years). Overall, 1.3% of aripiprazole-treated patients reported cerebrovascular adverse eventsreactions compared with 0.6% of placebo-treated patients in these trials. This difference was not statistically significant. However, in one of these trials, a fixed-dose trial, there was a significant dose response relationship for cerebrovascular adverse eventsreactions in patients treated with aripiprazole. ABILIFY is not approved indicated for the treatment of dementia-related psychosis. Hyperglycaemia and Diabetes diabetes Mellitusmellitus: hyperglycaemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotic agents, including ABILIFY. Risk factors that may predispose patients to severe complications include obesity and family history of diabetes. In clinical trials with aripiprazole, there were no significant differences in the incidence rates of hyperglycaemia-related adverse eventsreactions (including diabetes) or in abnormal glycaemia laboratory values compared to placebo. Precise risk estimates for hyperglycaemia-related adverse eventsreactions in patients treated with ABILIFY and with other atypical antipsychotic agents are not available to allow direct comparisons. Patients treated with any antipsychotic agents, including ABILIFY, 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. Hypersensitivity: as with other medicinal products hypersensitivity reactions, characterised by allergic symptoms, may occur with aripiprazole (see section 4.8). 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 ABILIFY. When seen, it is usually in those with significant risk factors such as history of diabetes, thyroid disorder or pituitary adenoma. In clinical trials aripiprazole has not been shown to induce clinically relevant weight gain (see section 5.1). Dysphagia: oesophageal dysmotility and aspiration have been associated with antipsychotic drug usetreatment, including ABILIFY. Aripiprazole and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia. Hypersensitivity: as with other medications hypersensitivity reactions, characterised by allergic symptoms, may occur with aripiprazole (see section 4.8). 4.5 Interaction with other medicinal products and other forms of interaction 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 undesirable effects adverse reactions such as sedation (see section 4.8). If aripiprazole is administered concomitantly with medicinesmedicinal products known to cause QT prolongation or electrolyte imbalance, caution should be used. 4.8 Undesirable effects The following undesirable effects adverse reactions occurred more often (≥ 1/100) than placebo, or were identified as possibly medically relevant adverse reactions (*) in clinical trials with aripiprazole solution for injection (see section 5.1): The frequency listed below is defined using the following convention: common (³ 1/100, to < 1/10) and uncommon (³ 1/1,000, to < 1/100). Cardiac disorders Uncommon: tachycardia* Nervous system disorders Common: somnolence, dizziness, headache, akathisia Cardiac disorders Uncommon: tachycardia* Vascular disorders Uncommon: orthostatic hypotension*, increased diastolic blood pressure* Gastrointestinal disorders Common: nausea, vomiting Uncommon: dry mouth* Vascular disorders Uncommon: orthostatic hypotension*, increased diastolic blood pressure* General disorders and administration site conditions Uncommon: fatigue* The following undesirable effects adverse reactionsoccurred more often (≥ 1/100) than placebo, or were identified as possibly medically relevant adverse reactions (*) in clinical trials with oral formulations of aripiprazole (see section 5.1): Psychiatric disorders Common: restlessness, insomnia, anxiety Uncommon: depression* Nervous system disorders Common: extrapyramidal disorder, akathisia, tremor, dizziness, somnolence, sedation, headache Eye disorders Common: blurred vision Cardiac disorders Uncommon: tachycardia* Nervous system disorders Common: extrapyramidal disorder, akathisia, tremor, dizziness, somnolence, sedation, headache Eye disorders Common: blurred vision Vascular disorders Uncommon: orthostatic hypotension* Gastrointestinal disorders Common: dyspepsia, vomiting, nausea, constipation, salivary hypersecretion Vascular disorders Uncommon: orthostatic hypotension* General disorders and administration site conditions Common: fatigue Psychiatric disorders Common: restlessness, insomnia, anxiety Uncommon: depression* ......................... Other findings: Undesirable effectsAdverse reactions known to be associated with antipsychotic therapy and also reported during treatment with aripiprazole include neuroleptic malignant syndrome, tardive dyskinesia, seizure, cerebrovascular adverse eventsreactions and increased mortality in elderly demented patients, hyperglycaemia and diabetes mellitus (see section 4.4). Post-Marketing: The following adverse eventsreactions have been reported during post-marketing surveillance. The frequency of these eventsreactions is considered not known (cannot be estimated from the available data). Blood and the lymphatic system disorders: leukopenia, neutropenia, thrombocytopenia Immune system disorders: allergic reaction (e.g. anaphylactic reaction, angioedema including swollen tongue, tongue oedema, face oedema, pruritus, or urticaria) Endocrine disorders: hyperglycaemia, diabetes mellitus, diabetic ketoacidosis, diabetic hyperosmolar coma Metabolism and nutrition disorders: weight gain, weight decreased, anorexia, hyponatremia Psychiatric disorders: agitation, nervousness; suicide attempt, suicidal ideation, and completed suicide (see section 4.4) Nervous system disorders: speech disorder, Neuroleptic Malignant Syndrome (NMS), grand mal convulsion Cardiac disorders: QT prolongation, ventricular arrhythmias, sudden unexplained death, cardiac arrest, torsades de pointes, bradycardia Vascular disorders: syncope, hypertension, thromboembolic reactions Respiratory, thoracic and mediastinal disorders: oropharyngeal spasm, laryngospasm, aspiration pneumonia Gastrointestinal disorders: pancreatitis, dysphagia, abdominal discomfort, stomach discomfort, diarrhoea Hepatobiliary disorders: jaundice, hepatitis, increased Alanine Aminotransferase (ALT), increased Aspartate Aminotransferase (AST), increased Gamma Glutamyl Transferase (GGT), increased alkaline phosphatase Skin and subcutaneous tissue disorders: rash, photosensitivity reaction, alopecia, hyperhidrosis Musculoskeletal and connective tissue disorders: rhabdomyolysis, myalgia, stiffness Renal and urinary disorders: urinary incontinence, urinary retention Reproductive system and breast disorders: priapism General disorders and administration site conditions: temperature regulation disorder (e.g. hypothermia, pyrexia), chest pain, peripheral oedema Investigations: increased Creatine Phosphokinase, blood glucose increased, blood glucose fluctuation, glycosylated haemoglobin increased Cardiac disorders: QT prolongation, ventricular arrhythmias, sudden unexplained death, cardiac arrest, torsades de pointes, bradycardia Blood and the lymphatic system disorders: leukopenia, neutropenia, thrombocytopenia Nervous system disorders: speech disorder, Neuroleptic Malignant Syndrome (NMS), grand mal convulsion Respiratory, thoracic and mediastinal disorders: oropharyngeal spasm, laryngospasm, aspiration pneumonia Gastrointestinal disorders: pancreatitis, dysphagia, abdominal discomfort, stomach discomfort, diarrhoea Renal and urinary disorders: urinary incontinence, urinary retention Skin and subcutaneous tissue disorders: rash, photosensitivity reaction, alopecia, hyperhidrosis Musculoskeletal and connective tissue disorders: rhabdomyolysis, myalgia, stiffness Endocrine disorders: hyperglycaemia, diabetes mellitus, diabetic ketoacidosis, diabetic hyperosmolar coma Metabolism and nutrition disorders: weight gain, weight decreased, anorexia, hyponatremia Vascular disorders: syncope, hypertension, thromboembolic events General disorders and administration site conditions: temperature regulation disorder (e.g. hypothermia, pyrexia), chest pain, peripheral oedema Immune system disorders: allergic reaction (e.g. anaphylactic reaction, angioedema including swollen tongue, tongue oedema, face oedema, pruritus, or urticaria) Hepatobiliary disorders: jaundice, hepatitis, increased Alanine Aminotransferase (ALT), increased Aspartate Aminotransferase (AST), increased Gamma Glutamyl Transferase (GGT), increased alkaline phosphatase Reproductive system and breast disorders: priapism Psychiatric disorders: agitation, nervousness; suicide attempt, suicidal ideation, and completed suicide (see section 4.4) 5.1 Pharmacodynamic properties Pharmacotherapeutic group: other antipsychotics, ATC code: N05AX12 .................................. 6.3 Shelf life 18 months After opening: uUse product immediately after opening and discard any unused amount. 6.6 Special precautions for disposal and other handling Any unused product or waste material should be disposed of in accordance with local requirements. 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 4 June 2004 Date of latest renewal: 21 April 2009 10. DATE OF REVISION OF THE TEXT August 2008 04/2009 Detailed information on this product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/
To enhance absorption and minimise variability, injection into the deltoid or deep within the gluteus maximus muscle, avoiding adipose regions, is recommended. ABILIFY solution for injection should not be administered intravenously or subcutaneously. ABILIFY solution for injection is ready to use and intended for short-term use only (see section 5.1). ............................ Smoking status: according to the metabolic pathway of ABILIFY no dosage adjustment is required for smokers (see section 4.5). 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 section 4.5). 4.4 Special warnings and precautions for use .............................................. 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, hypovolemia, and treatment with antihypertensive medicationsmedicinal products) or hypertension, including accelerated or malignant. ....................... Tardive Dyskinesiadyskinesia: in clinical trials of one year or less duration, there were uncommon reports of treatment emergent dyskinesia during treatment with aripiprazole. If signs and symptoms of tardive dyskinesia appear in a patient on ABILIFY, dose reduction or discontinuation should be considered. These symptoms can temporally deteriorate or can even arise after discontinuation of treatment. .................................................... Cerebrovascular adverse eventsreactions: in the same trials, cerebrovascular adverse eventsreactions (e.g. stroke, transient ischaemic attack), including fatalities, were reported in patients (mean age: 84 years; range: 78‑88 years). Overall, 1.3% of aripiprazole-treated patients reported cerebrovascular adverse eventsreactions compared with 0.6% of placebo-treated patients in these trials. This difference was not statistically significant. However, in one of these trials, a fixed-dose trial, there was a significant dose response relationship for cerebrovascular adverse eventsreactions in patients treated with aripiprazole. ABILIFY is not approved indicated for the treatment of dementia-related psychosis. Hyperglycaemia and Diabetes diabetes Mellitusmellitus: hyperglycaemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotic agents, including ABILIFY. Risk factors that may predispose patients to severe complications include obesity and family history of diabetes. In clinical trials with aripiprazole, there were no significant differences in the incidence rates of hyperglycaemia-related adverse eventsreactions (including diabetes) or in abnormal glycaemia laboratory values compared to placebo. Precise risk estimates for hyperglycaemia-related adverse eventsreactions in patients treated with ABILIFY and with other atypical antipsychotic agents are not available to allow direct comparisons. Patients treated with any antipsychotic agents, including ABILIFY, 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. Hypersensitivity: as with other medicinal products hypersensitivity reactions, characterised by allergic symptoms, may occur with aripiprazole (see section 4.8). 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 ABILIFY. When seen, it is usually in those with significant risk factors such as history of diabetes, thyroid disorder or pituitary adenoma. In clinical trials aripiprazole has not been shown to induce clinically relevant weight gain (see section 5.1). Dysphagia: oesophageal dysmotility and aspiration have been associated with antipsychotic drug usetreatment, including ABILIFY. Aripiprazole and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia. Hypersensitivity: as with other medications hypersensitivity reactions, characterised by allergic symptoms, may occur with aripiprazole (see section 4.8). 4.5 Interaction with other medicinal products and other forms of interaction 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 undesirable effects adverse reactions such as sedation (see section 4.8). If aripiprazole is administered concomitantly with medicinesmedicinal products known to cause QT prolongation or electrolyte imbalance, caution should be used. 4.8 Undesirable effects The following undesirable effects adverse reactions occurred more often (≥ 1/100) than placebo, or were identified as possibly medically relevant adverse reactions (*) in clinical trials with aripiprazole solution for injection (see section 5.1): The frequency listed below is defined using the following convention: common (³ 1/100, to < 1/10) and uncommon (³ 1/1,000, to < 1/100). Cardiac disorders Uncommon: tachycardia* Nervous system disorders Common: somnolence, dizziness, headache, akathisia Cardiac disorders Uncommon: tachycardia* Vascular disorders Uncommon: orthostatic hypotension*, increased diastolic blood pressure* Gastrointestinal disorders Common: nausea, vomiting Uncommon: dry mouth* Vascular disorders Uncommon: orthostatic hypotension*, increased diastolic blood pressure* General disorders and administration site conditions Uncommon: fatigue* The following undesirable effects adverse reactionsoccurred more often (≥ 1/100) than placebo, or were identified as possibly medically relevant adverse reactions (*) in clinical trials with oral formulations of aripiprazole (see section 5.1): Psychiatric disorders Common: restlessness, insomnia, anxiety Uncommon: depression* Nervous system disorders Common: extrapyramidal disorder, akathisia, tremor, dizziness, somnolence, sedation, headache Eye disorders Common: blurred vision Cardiac disorders Uncommon: tachycardia* Nervous system disorders Common: extrapyramidal disorder, akathisia, tremor, dizziness, somnolence, sedation, headache Eye disorders Common: blurred vision Vascular disorders Uncommon: orthostatic hypotension* Gastrointestinal disorders Common: dyspepsia, vomiting, nausea, constipation, salivary hypersecretion Vascular disorders Uncommon: orthostatic hypotension* General disorders and administration site conditions Common: fatigue Psychiatric disorders Common: restlessness, insomnia, anxiety Uncommon: depression* ......................... Other findings: Undesirable effectsAdverse reactions known to be associated with antipsychotic therapy and also reported during treatment with aripiprazole include neuroleptic malignant syndrome, tardive dyskinesia, seizure, cerebrovascular adverse eventsreactions and increased mortality in elderly demented patients, hyperglycaemia and diabetes mellitus (see section 4.4). Post-Marketing: The following adverse eventsreactions have been reported during post-marketing surveillance. The frequency of these eventsreactions is considered not known (cannot be estimated from the available data). Blood and the lymphatic system disorders: leukopenia, neutropenia, thrombocytopenia Immune system disorders: allergic reaction (e.g. anaphylactic reaction, angioedema including swollen tongue, tongue oedema, face oedema, pruritus, or urticaria) Endocrine disorders: hyperglycaemia, diabetes mellitus, diabetic ketoacidosis, diabetic hyperosmolar coma Metabolism and nutrition disorders: weight gain, weight decreased, anorexia, hyponatremia Psychiatric disorders: agitation, nervousness; suicide attempt, suicidal ideation, and completed suicide (see section 4.4) Nervous system disorders: speech disorder, Neuroleptic Malignant Syndrome (NMS), grand mal convulsion Cardiac disorders: QT prolongation, ventricular arrhythmias, sudden unexplained death, cardiac arrest, torsades de pointes, bradycardia Vascular disorders: syncope, hypertension, thromboembolic reactions Respiratory, thoracic and mediastinal disorders: oropharyngeal spasm, laryngospasm, aspiration pneumonia Gastrointestinal disorders: pancreatitis, dysphagia, abdominal discomfort, stomach discomfort, diarrhoea Hepatobiliary disorders: jaundice, hepatitis, increased Alanine Aminotransferase (ALT), increased Aspartate Aminotransferase (AST), increased Gamma Glutamyl Transferase (GGT), increased alkaline phosphatase Skin and subcutaneous tissue disorders: rash, photosensitivity reaction, alopecia, hyperhidrosis Musculoskeletal and connective tissue disorders: rhabdomyolysis, myalgia, stiffness Renal and urinary disorders: urinary incontinence, urinary retention Reproductive system and breast disorders: priapism General disorders and administration site conditions: temperature regulation disorder (e.g. hypothermia, pyrexia), chest pain, peripheral oedema Investigations: increased Creatine Phosphokinase, blood glucose increased, blood glucose fluctuation, glycosylated haemoglobin increased Cardiac disorders: QT prolongation, ventricular arrhythmias, sudden unexplained death, cardiac arrest, torsades de pointes, bradycardia Blood and the lymphatic system disorders: leukopenia, neutropenia, thrombocytopenia Nervous system disorders: speech disorder, Neuroleptic Malignant Syndrome (NMS), grand mal convulsion Respiratory, thoracic and mediastinal disorders: oropharyngeal spasm, laryngospasm, aspiration pneumonia Gastrointestinal disorders: pancreatitis, dysphagia, abdominal discomfort, stomach discomfort, diarrhoea Renal and urinary disorders: urinary incontinence, urinary retention Skin and subcutaneous tissue disorders: rash, photosensitivity reaction, alopecia, hyperhidrosis Musculoskeletal and connective tissue disorders: rhabdomyolysis, myalgia, stiffness Endocrine disorders: hyperglycaemia, diabetes mellitus, diabetic ketoacidosis, diabetic hyperosmolar coma Metabolism and nutrition disorders: weight gain, weight decreased, anorexia, hyponatremia Vascular disorders: syncope, hypertension, thromboembolic events General disorders and administration site conditions: temperature regulation disorder (e.g. hypothermia, pyrexia), chest pain, peripheral oedema Immune system disorders: allergic reaction (e.g. anaphylactic reaction, angioedema including swollen tongue, tongue oedema, face oedema, pruritus, or urticaria) Hepatobiliary disorders: jaundice, hepatitis, increased Alanine Aminotransferase (ALT), increased Aspartate Aminotransferase (AST), increased Gamma Glutamyl Transferase (GGT), increased alkaline phosphatase Reproductive system and breast disorders: priapism Psychiatric disorders: agitation, nervousness; suicide attempt, suicidal ideation, and completed suicide (see section 4.4) 5.1 Pharmacodynamic properties Pharmacotherapeutic group: other antipsychotics, ATC code: N05AX12 .................................. 6.3 Shelf life 18 months After opening: uUse product immediately after opening and discard any unused amount. 6.6 Special precautions for disposal and other handling Any unused product or waste material should be disposed of in accordance with local requirements. 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 4 June 2004 Date of latest renewal: 21 April 2009 10. DATE OF REVISION OF THE TEXT August 2008 04/2009 Detailed information on this product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/
ABILIFY solution for injection should not be administered intravenously or subcutaneously. ABILIFY solution for injection is ready to use and intended for short-term use only (see section 5.1). ............................ Smoking status: according to the metabolic pathway of ABILIFY no dosage adjustment is required for smokers (see section 4.5). 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 section 4.5). 4.4 Special warnings and precautions for use .............................................. 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, hypovolemia, and treatment with antihypertensive medicationsmedicinal products) or hypertension, including accelerated or malignant. ....................... Tardive Dyskinesiadyskinesia: in clinical trials of one year or less duration, there were uncommon reports of treatment emergent dyskinesia during treatment with aripiprazole. If signs and symptoms of tardive dyskinesia appear in a patient on ABILIFY, dose reduction or discontinuation should be considered. These symptoms can temporally deteriorate or can even arise after discontinuation of treatment. .................................................... Cerebrovascular adverse eventsreactions: in the same trials, cerebrovascular adverse eventsreactions (e.g. stroke, transient ischaemic attack), including fatalities, were reported in patients (mean age: 84 years; range: 78‑88 years). Overall, 1.3% of aripiprazole-treated patients reported cerebrovascular adverse eventsreactions compared with 0.6% of placebo-treated patients in these trials. This difference was not statistically significant. However, in one of these trials, a fixed-dose trial, there was a significant dose response relationship for cerebrovascular adverse eventsreactions in patients treated with aripiprazole. ABILIFY is not approved indicated for the treatment of dementia-related psychosis. Hyperglycaemia and Diabetes diabetes Mellitusmellitus: hyperglycaemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotic agents, including ABILIFY. Risk factors that may predispose patients to severe complications include obesity and family history of diabetes. In clinical trials with aripiprazole, there were no significant differences in the incidence rates of hyperglycaemia-related adverse eventsreactions (including diabetes) or in abnormal glycaemia laboratory values compared to placebo. Precise risk estimates for hyperglycaemia-related adverse eventsreactions in patients treated with ABILIFY and with other atypical antipsychotic agents are not available to allow direct comparisons. Patients treated with any antipsychotic agents, including ABILIFY, 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. Hypersensitivity: as with other medicinal products hypersensitivity reactions, characterised by allergic symptoms, may occur with aripiprazole (see section 4.8). 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 ABILIFY. When seen, it is usually in those with significant risk factors such as history of diabetes, thyroid disorder or pituitary adenoma. In clinical trials aripiprazole has not been shown to induce clinically relevant weight gain (see section 5.1). Dysphagia: oesophageal dysmotility and aspiration have been associated with antipsychotic drug usetreatment, including ABILIFY. Aripiprazole and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia. Hypersensitivity: as with other medications hypersensitivity reactions, characterised by allergic symptoms, may occur with aripiprazole (see section 4.8). 4.5 Interaction with other medicinal products and other forms of interaction 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 undesirable effects adverse reactions such as sedation (see section 4.8). If aripiprazole is administered concomitantly with medicinesmedicinal products known to cause QT prolongation or electrolyte imbalance, caution should be used. 4.8 Undesirable effects The following undesirable effects adverse reactions occurred more often (≥ 1/100) than placebo, or were identified as possibly medically relevant adverse reactions (*) in clinical trials with aripiprazole solution for injection (see section 5.1): The frequency listed below is defined using the following convention: common (³ 1/100, to < 1/10) and uncommon (³ 1/1,000, to < 1/100). Cardiac disorders Uncommon: tachycardia* Nervous system disorders Common: somnolence, dizziness, headache, akathisia Cardiac disorders Uncommon: tachycardia* Vascular disorders Uncommon: orthostatic hypotension*, increased diastolic blood pressure* Gastrointestinal disorders Common: nausea, vomiting Uncommon: dry mouth* Vascular disorders Uncommon: orthostatic hypotension*, increased diastolic blood pressure* General disorders and administration site conditions Uncommon: fatigue* The following undesirable effects adverse reactionsoccurred more often (≥ 1/100) than placebo, or were identified as possibly medically relevant adverse reactions (*) in clinical trials with oral formulations of aripiprazole (see section 5.1): Psychiatric disorders Common: restlessness, insomnia, anxiety Uncommon: depression* Nervous system disorders Common: extrapyramidal disorder, akathisia, tremor, dizziness, somnolence, sedation, headache Eye disorders Common: blurred vision Cardiac disorders Uncommon: tachycardia* Nervous system disorders Common: extrapyramidal disorder, akathisia, tremor, dizziness, somnolence, sedation, headache Eye disorders Common: blurred vision Vascular disorders Uncommon: orthostatic hypotension* Gastrointestinal disorders Common: dyspepsia, vomiting, nausea, constipation, salivary hypersecretion Vascular disorders Uncommon: orthostatic hypotension* General disorders and administration site conditions Common: fatigue Psychiatric disorders Common: restlessness, insomnia, anxiety Uncommon: depression* ......................... Other findings: Undesirable effectsAdverse reactions known to be associated with antipsychotic therapy and also reported during treatment with aripiprazole include neuroleptic malignant syndrome, tardive dyskinesia, seizure, cerebrovascular adverse eventsreactions and increased mortality in elderly demented patients, hyperglycaemia and diabetes mellitus (see section 4.4). Post-Marketing: The following adverse eventsreactions have been reported during post-marketing surveillance. The frequency of these eventsreactions is considered not known (cannot be estimated from the available data). Blood and the lymphatic system disorders: leukopenia, neutropenia, thrombocytopenia Immune system disorders: allergic reaction (e.g. anaphylactic reaction, angioedema including swollen tongue, tongue oedema, face oedema, pruritus, or urticaria) Endocrine disorders: hyperglycaemia, diabetes mellitus, diabetic ketoacidosis, diabetic hyperosmolar coma Metabolism and nutrition disorders: weight gain, weight decreased, anorexia, hyponatremia Psychiatric disorders: agitation, nervousness; suicide attempt, suicidal ideation, and completed suicide (see section 4.4) Nervous system disorders: speech disorder, Neuroleptic Malignant Syndrome (NMS), grand mal convulsion Cardiac disorders: QT prolongation, ventricular arrhythmias, sudden unexplained death, cardiac arrest, torsades de pointes, bradycardia Vascular disorders: syncope, hypertension, thromboembolic reactions Respiratory, thoracic and mediastinal disorders: oropharyngeal spasm, laryngospasm, aspiration pneumonia Gastrointestinal disorders: pancreatitis, dysphagia, abdominal discomfort, stomach discomfort, diarrhoea Hepatobiliary disorders: jaundice, hepatitis, increased Alanine Aminotransferase (ALT), increased Aspartate Aminotransferase (AST), increased Gamma Glutamyl Transferase (GGT), increased alkaline phosphatase Skin and subcutaneous tissue disorders: rash, photosensitivity reaction, alopecia, hyperhidrosis Musculoskeletal and connective tissue disorders: rhabdomyolysis, myalgia, stiffness Renal and urinary disorders: urinary incontinence, urinary retention Reproductive system and breast disorders: priapism General disorders and administration site conditions: temperature regulation disorder (e.g. hypothermia, pyrexia), chest pain, peripheral oedema Investigations: increased Creatine Phosphokinase, blood glucose increased, blood glucose fluctuation, glycosylated haemoglobin increased Cardiac disorders: QT prolongation, ventricular arrhythmias, sudden unexplained death, cardiac arrest, torsades de pointes, bradycardia Blood and the lymphatic system disorders: leukopenia, neutropenia, thrombocytopenia Nervous system disorders: speech disorder, Neuroleptic Malignant Syndrome (NMS), grand mal convulsion Respiratory, thoracic and mediastinal disorders: oropharyngeal spasm, laryngospasm, aspiration pneumonia Gastrointestinal disorders: pancreatitis, dysphagia, abdominal discomfort, stomach discomfort, diarrhoea Renal and urinary disorders: urinary incontinence, urinary retention Skin and subcutaneous tissue disorders: rash, photosensitivity reaction, alopecia, hyperhidrosis Musculoskeletal and connective tissue disorders: rhabdomyolysis, myalgia, stiffness Endocrine disorders: hyperglycaemia, diabetes mellitus, diabetic ketoacidosis, diabetic hyperosmolar coma Metabolism and nutrition disorders: weight gain, weight decreased, anorexia, hyponatremia Vascular disorders: syncope, hypertension, thromboembolic events General disorders and administration site conditions: temperature regulation disorder (e.g. hypothermia, pyrexia), chest pain, peripheral oedema Immune system disorders: allergic reaction (e.g. anaphylactic reaction, angioedema including swollen tongue, tongue oedema, face oedema, pruritus, or urticaria) Hepatobiliary disorders: jaundice, hepatitis, increased Alanine Aminotransferase (ALT), increased Aspartate Aminotransferase (AST), increased Gamma Glutamyl Transferase (GGT), increased alkaline phosphatase Reproductive system and breast disorders: priapism Psychiatric disorders: agitation, nervousness; suicide attempt, suicidal ideation, and completed suicide (see section 4.4) 5.1 Pharmacodynamic properties Pharmacotherapeutic group: other antipsychotics, ATC code: N05AX12 .................................. 6.3 Shelf life 18 months After opening: uUse product immediately after opening and discard any unused amount. 6.6 Special precautions for disposal and other handling Any unused product or waste material should be disposed of in accordance with local requirements. 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 4 June 2004 Date of latest renewal: 21 April 2009 10. DATE OF REVISION OF THE TEXT August 2008 04/2009 Detailed information on this product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/
............................ Smoking status: according to the metabolic pathway of ABILIFY no dosage adjustment is required for smokers (see section 4.5). 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 section 4.5). 4.4 Special warnings and precautions for use .............................................. 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, hypovolemia, and treatment with antihypertensive medicationsmedicinal products) or hypertension, including accelerated or malignant. ....................... Tardive Dyskinesiadyskinesia: in clinical trials of one year or less duration, there were uncommon reports of treatment emergent dyskinesia during treatment with aripiprazole. If signs and symptoms of tardive dyskinesia appear in a patient on ABILIFY, dose reduction or discontinuation should be considered. These symptoms can temporally deteriorate or can even arise after discontinuation of treatment. .................................................... Cerebrovascular adverse eventsreactions: in the same trials, cerebrovascular adverse eventsreactions (e.g. stroke, transient ischaemic attack), including fatalities, were reported in patients (mean age: 84 years; range: 78‑88 years). Overall, 1.3% of aripiprazole-treated patients reported cerebrovascular adverse eventsreactions compared with 0.6% of placebo-treated patients in these trials. This difference was not statistically significant. However, in one of these trials, a fixed-dose trial, there was a significant dose response relationship for cerebrovascular adverse eventsreactions in patients treated with aripiprazole. ABILIFY is not approved indicated for the treatment of dementia-related psychosis. Hyperglycaemia and Diabetes diabetes Mellitusmellitus: hyperglycaemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotic agents, including ABILIFY. Risk factors that may predispose patients to severe complications include obesity and family history of diabetes. In clinical trials with aripiprazole, there were no significant differences in the incidence rates of hyperglycaemia-related adverse eventsreactions (including diabetes) or in abnormal glycaemia laboratory values compared to placebo. Precise risk estimates for hyperglycaemia-related adverse eventsreactions in patients treated with ABILIFY and with other atypical antipsychotic agents are not available to allow direct comparisons. Patients treated with any antipsychotic agents, including ABILIFY, 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. Hypersensitivity: as with other medicinal products hypersensitivity reactions, characterised by allergic symptoms, may occur with aripiprazole (see section 4.8). 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 ABILIFY. When seen, it is usually in those with significant risk factors such as history of diabetes, thyroid disorder or pituitary adenoma. In clinical trials aripiprazole has not been shown to induce clinically relevant weight gain (see section 5.1). Dysphagia: oesophageal dysmotility and aspiration have been associated with antipsychotic drug usetreatment, including ABILIFY. Aripiprazole and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia. Hypersensitivity: as with other medications hypersensitivity reactions, characterised by allergic symptoms, may occur with aripiprazole (see section 4.8). 4.5 Interaction with other medicinal products and other forms of interaction 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 undesirable effects adverse reactions such as sedation (see section 4.8). If aripiprazole is administered concomitantly with medicinesmedicinal products known to cause QT prolongation or electrolyte imbalance, caution should be used. 4.8 Undesirable effects The following undesirable effects adverse reactions occurred more often (≥ 1/100) than placebo, or were identified as possibly medically relevant adverse reactions (*) in clinical trials with aripiprazole solution for injection (see section 5.1): The frequency listed below is defined using the following convention: common (³ 1/100, to < 1/10) and uncommon (³ 1/1,000, to < 1/100). Cardiac disorders Uncommon: tachycardia* Nervous system disorders Common: somnolence, dizziness, headache, akathisia Cardiac disorders Uncommon: tachycardia* Vascular disorders Uncommon: orthostatic hypotension*, increased diastolic blood pressure* Gastrointestinal disorders Common: nausea, vomiting Uncommon: dry mouth* Vascular disorders Uncommon: orthostatic hypotension*, increased diastolic blood pressure* General disorders and administration site conditions Uncommon: fatigue* The following undesirable effects adverse reactionsoccurred more often (≥ 1/100) than placebo, or were identified as possibly medically relevant adverse reactions (*) in clinical trials with oral formulations of aripiprazole (see section 5.1): Psychiatric disorders Common: restlessness, insomnia, anxiety Uncommon: depression* Nervous system disorders Common: extrapyramidal disorder, akathisia, tremor, dizziness, somnolence, sedation, headache Eye disorders Common: blurred vision Cardiac disorders Uncommon: tachycardia* Nervous system disorders Common: extrapyramidal disorder, akathisia, tremor, dizziness, somnolence, sedation, headache Eye disorders Common: blurred vision Vascular disorders Uncommon: orthostatic hypotension* Gastrointestinal disorders Common: dyspepsia, vomiting, nausea, constipation, salivary hypersecretion Vascular disorders Uncommon: orthostatic hypotension* General disorders and administration site conditions Common: fatigue Psychiatric disorders Common: restlessness, insomnia, anxiety Uncommon: depression* ......................... Other findings: Undesirable effectsAdverse reactions known to be associated with antipsychotic therapy and also reported during treatment with aripiprazole include neuroleptic malignant syndrome, tardive dyskinesia, seizure, cerebrovascular adverse eventsreactions and increased mortality in elderly demented patients, hyperglycaemia and diabetes mellitus (see section 4.4). Post-Marketing: The following adverse eventsreactions have been reported during post-marketing surveillance. The frequency of these eventsreactions is considered not known (cannot be estimated from the available data). Blood and the lymphatic system disorders: leukopenia, neutropenia, thrombocytopenia Immune system disorders: allergic reaction (e.g. anaphylactic reaction, angioedema including swollen tongue, tongue oedema, face oedema, pruritus, or urticaria) Endocrine disorders: hyperglycaemia, diabetes mellitus, diabetic ketoacidosis, diabetic hyperosmolar coma Metabolism and nutrition disorders: weight gain, weight decreased, anorexia, hyponatremia Psychiatric disorders: agitation, nervousness; suicide attempt, suicidal ideation, and completed suicide (see section 4.4) Nervous system disorders: speech disorder, Neuroleptic Malignant Syndrome (NMS), grand mal convulsion Cardiac disorders: QT prolongation, ventricular arrhythmias, sudden unexplained death, cardiac arrest, torsades de pointes, bradycardia Vascular disorders: syncope, hypertension, thromboembolic reactions Respiratory, thoracic and mediastinal disorders: oropharyngeal spasm, laryngospasm, aspiration pneumonia Gastrointestinal disorders: pancreatitis, dysphagia, abdominal discomfort, stomach discomfort, diarrhoea Hepatobiliary disorders: jaundice, hepatitis, increased Alanine Aminotransferase (ALT), increased Aspartate Aminotransferase (AST), increased Gamma Glutamyl Transferase (GGT), increased alkaline phosphatase Skin and subcutaneous tissue disorders: rash, photosensitivity reaction, alopecia, hyperhidrosis Musculoskeletal and connective tissue disorders: rhabdomyolysis, myalgia, stiffness Renal and urinary disorders: urinary incontinence, urinary retention Reproductive system and breast disorders: priapism General disorders and administration site conditions: temperature regulation disorder (e.g. hypothermia, pyrexia), chest pain, peripheral oedema Investigations: increased Creatine Phosphokinase, blood glucose increased, blood glucose fluctuation, glycosylated haemoglobin increased Cardiac disorders: QT prolongation, ventricular arrhythmias, sudden unexplained death, cardiac arrest, torsades de pointes, bradycardia Blood and the lymphatic system disorders: leukopenia, neutropenia, thrombocytopenia Nervous system disorders: speech disorder, Neuroleptic Malignant Syndrome (NMS), grand mal convulsion Respiratory, thoracic and mediastinal disorders: oropharyngeal spasm, laryngospasm, aspiration pneumonia Gastrointestinal disorders: pancreatitis, dysphagia, abdominal discomfort, stomach discomfort, diarrhoea Renal and urinary disorders: urinary incontinence, urinary retention Skin and subcutaneous tissue disorders: rash, photosensitivity reaction, alopecia, hyperhidrosis Musculoskeletal and connective tissue disorders: rhabdomyolysis, myalgia, stiffness Endocrine disorders: hyperglycaemia, diabetes mellitus, diabetic ketoacidosis, diabetic hyperosmolar coma Metabolism and nutrition disorders: weight gain, weight decreased, anorexia, hyponatremia Vascular disorders: syncope, hypertension, thromboembolic events General disorders and administration site conditions: temperature regulation disorder (e.g. hypothermia, pyrexia), chest pain, peripheral oedema Immune system disorders: allergic reaction (e.g. anaphylactic reaction, angioedema including swollen tongue, tongue oedema, face oedema, pruritus, or urticaria) Hepatobiliary disorders: jaundice, hepatitis, increased Alanine Aminotransferase (ALT), increased Aspartate Aminotransferase (AST), increased Gamma Glutamyl Transferase (GGT), increased alkaline phosphatase Reproductive system and breast disorders: priapism Psychiatric disorders: agitation, nervousness; suicide attempt, suicidal ideation, and completed suicide (see section 4.4) 5.1 Pharmacodynamic properties Pharmacotherapeutic group: other antipsychotics, ATC code: N05AX12 .................................. 6.3 Shelf life 18 months After opening: uUse product immediately after opening and discard any unused amount. 6.6 Special precautions for disposal and other handling Any unused product or waste material should be disposed of in accordance with local requirements. 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 4 June 2004 Date of latest renewal: 21 April 2009 10. DATE OF REVISION OF THE TEXT August 2008 04/2009 Detailed information on this product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/
............................
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 section 4.5). 4.4 Special warnings and precautions for use .............................................. 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, hypovolemia, and treatment with antihypertensive medicationsmedicinal products) or hypertension, including accelerated or malignant. ....................... Tardive Dyskinesiadyskinesia: in clinical trials of one year or less duration, there were uncommon reports of treatment emergent dyskinesia during treatment with aripiprazole. If signs and symptoms of tardive dyskinesia appear in a patient on ABILIFY, dose reduction or discontinuation should be considered. These symptoms can temporally deteriorate or can even arise after discontinuation of treatment. .................................................... Cerebrovascular adverse eventsreactions: in the same trials, cerebrovascular adverse eventsreactions (e.g. stroke, transient ischaemic attack), including fatalities, were reported in patients (mean age: 84 years; range: 78‑88 years). Overall, 1.3% of aripiprazole-treated patients reported cerebrovascular adverse eventsreactions compared with 0.6% of placebo-treated patients in these trials. This difference was not statistically significant. However, in one of these trials, a fixed-dose trial, there was a significant dose response relationship for cerebrovascular adverse eventsreactions in patients treated with aripiprazole. ABILIFY is not approved indicated for the treatment of dementia-related psychosis. Hyperglycaemia and Diabetes diabetes Mellitusmellitus: hyperglycaemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotic agents, including ABILIFY. Risk factors that may predispose patients to severe complications include obesity and family history of diabetes. In clinical trials with aripiprazole, there were no significant differences in the incidence rates of hyperglycaemia-related adverse eventsreactions (including diabetes) or in abnormal glycaemia laboratory values compared to placebo. Precise risk estimates for hyperglycaemia-related adverse eventsreactions in patients treated with ABILIFY and with other atypical antipsychotic agents are not available to allow direct comparisons. Patients treated with any antipsychotic agents, including ABILIFY, 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. Hypersensitivity: as with other medicinal products hypersensitivity reactions, characterised by allergic symptoms, may occur with aripiprazole (see section 4.8). 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 ABILIFY. When seen, it is usually in those with significant risk factors such as history of diabetes, thyroid disorder or pituitary adenoma. In clinical trials aripiprazole has not been shown to induce clinically relevant weight gain (see section 5.1). Dysphagia: oesophageal dysmotility and aspiration have been associated with antipsychotic drug usetreatment, including ABILIFY. Aripiprazole and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia. Hypersensitivity: as with other medications hypersensitivity reactions, characterised by allergic symptoms, may occur with aripiprazole (see section 4.8). 4.5 Interaction with other medicinal products and other forms of interaction 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 undesirable effects adverse reactions such as sedation (see section 4.8). If aripiprazole is administered concomitantly with medicinesmedicinal products known to cause QT prolongation or electrolyte imbalance, caution should be used. 4.8 Undesirable effects The following undesirable effects adverse reactions occurred more often (≥ 1/100) than placebo, or were identified as possibly medically relevant adverse reactions (*) in clinical trials with aripiprazole solution for injection (see section 5.1): The frequency listed below is defined using the following convention: common (³ 1/100, to < 1/10) and uncommon (³ 1/1,000, to < 1/100). Cardiac disorders Uncommon: tachycardia* Nervous system disorders Common: somnolence, dizziness, headache, akathisia Cardiac disorders Uncommon: tachycardia* Vascular disorders Uncommon: orthostatic hypotension*, increased diastolic blood pressure* Gastrointestinal disorders Common: nausea, vomiting Uncommon: dry mouth* Vascular disorders Uncommon: orthostatic hypotension*, increased diastolic blood pressure* General disorders and administration site conditions Uncommon: fatigue* The following undesirable effects adverse reactionsoccurred more often (≥ 1/100) than placebo, or were identified as possibly medically relevant adverse reactions (*) in clinical trials with oral formulations of aripiprazole (see section 5.1): Psychiatric disorders Common: restlessness, insomnia, anxiety Uncommon: depression* Nervous system disorders Common: extrapyramidal disorder, akathisia, tremor, dizziness, somnolence, sedation, headache Eye disorders Common: blurred vision Cardiac disorders Uncommon: tachycardia* Nervous system disorders Common: extrapyramidal disorder, akathisia, tremor, dizziness, somnolence, sedation, headache Eye disorders Common: blurred vision Vascular disorders Uncommon: orthostatic hypotension* Gastrointestinal disorders Common: dyspepsia, vomiting, nausea, constipation, salivary hypersecretion Vascular disorders Uncommon: orthostatic hypotension* General disorders and administration site conditions Common: fatigue Psychiatric disorders Common: restlessness, insomnia, anxiety Uncommon: depression* ......................... Other findings: Undesirable effectsAdverse reactions known to be associated with antipsychotic therapy and also reported during treatment with aripiprazole include neuroleptic malignant syndrome, tardive dyskinesia, seizure, cerebrovascular adverse eventsreactions and increased mortality in elderly demented patients, hyperglycaemia and diabetes mellitus (see section 4.4). Post-Marketing: The following adverse eventsreactions have been reported during post-marketing surveillance. The frequency of these eventsreactions is considered not known (cannot be estimated from the available data). Blood and the lymphatic system disorders: leukopenia, neutropenia, thrombocytopenia Immune system disorders: allergic reaction (e.g. anaphylactic reaction, angioedema including swollen tongue, tongue oedema, face oedema, pruritus, or urticaria) Endocrine disorders: hyperglycaemia, diabetes mellitus, diabetic ketoacidosis, diabetic hyperosmolar coma Metabolism and nutrition disorders: weight gain, weight decreased, anorexia, hyponatremia Psychiatric disorders: agitation, nervousness; suicide attempt, suicidal ideation, and completed suicide (see section 4.4) Nervous system disorders: speech disorder, Neuroleptic Malignant Syndrome (NMS), grand mal convulsion Cardiac disorders: QT prolongation, ventricular arrhythmias, sudden unexplained death, cardiac arrest, torsades de pointes, bradycardia Vascular disorders: syncope, hypertension, thromboembolic reactions Respiratory, thoracic and mediastinal disorders: oropharyngeal spasm, laryngospasm, aspiration pneumonia Gastrointestinal disorders: pancreatitis, dysphagia, abdominal discomfort, stomach discomfort, diarrhoea Hepatobiliary disorders: jaundice, hepatitis, increased Alanine Aminotransferase (ALT), increased Aspartate Aminotransferase (AST), increased Gamma Glutamyl Transferase (GGT), increased alkaline phosphatase Skin and subcutaneous tissue disorders: rash, photosensitivity reaction, alopecia, hyperhidrosis Musculoskeletal and connective tissue disorders: rhabdomyolysis, myalgia, stiffness Renal and urinary disorders: urinary incontinence, urinary retention Reproductive system and breast disorders: priapism General disorders and administration site conditions: temperature regulation disorder (e.g. hypothermia, pyrexia), chest pain, peripheral oedema Investigations: increased Creatine Phosphokinase, blood glucose increased, blood glucose fluctuation, glycosylated haemoglobin increased Cardiac disorders: QT prolongation, ventricular arrhythmias, sudden unexplained death, cardiac arrest, torsades de pointes, bradycardia Blood and the lymphatic system disorders: leukopenia, neutropenia, thrombocytopenia Nervous system disorders: speech disorder, Neuroleptic Malignant Syndrome (NMS), grand mal convulsion Respiratory, thoracic and mediastinal disorders: oropharyngeal spasm, laryngospasm, aspiration pneumonia Gastrointestinal disorders: pancreatitis, dysphagia, abdominal discomfort, stomach discomfort, diarrhoea Renal and urinary disorders: urinary incontinence, urinary retention Skin and subcutaneous tissue disorders: rash, photosensitivity reaction, alopecia, hyperhidrosis Musculoskeletal and connective tissue disorders: rhabdomyolysis, myalgia, stiffness Endocrine disorders: hyperglycaemia, diabetes mellitus, diabetic ketoacidosis, diabetic hyperosmolar coma Metabolism and nutrition disorders: weight gain, weight decreased, anorexia, hyponatremia Vascular disorders: syncope, hypertension, thromboembolic events General disorders and administration site conditions: temperature regulation disorder (e.g. hypothermia, pyrexia), chest pain, peripheral oedema Immune system disorders: allergic reaction (e.g. anaphylactic reaction, angioedema including swollen tongue, tongue oedema, face oedema, pruritus, or urticaria) Hepatobiliary disorders: jaundice, hepatitis, increased Alanine Aminotransferase (ALT), increased Aspartate Aminotransferase (AST), increased Gamma Glutamyl Transferase (GGT), increased alkaline phosphatase Reproductive system and breast disorders: priapism Psychiatric disorders: agitation, nervousness; suicide attempt, suicidal ideation, and completed suicide (see section 4.4) 5.1 Pharmacodynamic properties Pharmacotherapeutic group: other antipsychotics, ATC code: N05AX12 .................................. 6.3 Shelf life 18 months After opening: uUse product immediately after opening and discard any unused amount. 6.6 Special precautions for disposal and other handling Any unused product or waste material should be disposed of in accordance with local requirements. 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 4 June 2004 Date of latest renewal: 21 April 2009 10. DATE OF REVISION OF THE TEXT August 2008 04/2009 Detailed information on this product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/
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 section 4.5). 4.4 Special warnings and precautions for use .............................................. 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, hypovolemia, and treatment with antihypertensive medicationsmedicinal products) or hypertension, including accelerated or malignant. ....................... Tardive Dyskinesiadyskinesia: in clinical trials of one year or less duration, there were uncommon reports of treatment emergent dyskinesia during treatment with aripiprazole. If signs and symptoms of tardive dyskinesia appear in a patient on ABILIFY, dose reduction or discontinuation should be considered. These symptoms can temporally deteriorate or can even arise after discontinuation of treatment. .................................................... Cerebrovascular adverse eventsreactions: in the same trials, cerebrovascular adverse eventsreactions (e.g. stroke, transient ischaemic attack), including fatalities, were reported in patients (mean age: 84 years; range: 78‑88 years). Overall, 1.3% of aripiprazole-treated patients reported cerebrovascular adverse eventsreactions compared with 0.6% of placebo-treated patients in these trials. This difference was not statistically significant. However, in one of these trials, a fixed-dose trial, there was a significant dose response relationship for cerebrovascular adverse eventsreactions in patients treated with aripiprazole. ABILIFY is not approved indicated for the treatment of dementia-related psychosis. Hyperglycaemia and Diabetes diabetes Mellitusmellitus: hyperglycaemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotic agents, including ABILIFY. Risk factors that may predispose patients to severe complications include obesity and family history of diabetes. In clinical trials with aripiprazole, there were no significant differences in the incidence rates of hyperglycaemia-related adverse eventsreactions (including diabetes) or in abnormal glycaemia laboratory values compared to placebo. Precise risk estimates for hyperglycaemia-related adverse eventsreactions in patients treated with ABILIFY and with other atypical antipsychotic agents are not available to allow direct comparisons. Patients treated with any antipsychotic agents, including ABILIFY, 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. Hypersensitivity: as with other medicinal products hypersensitivity reactions, characterised by allergic symptoms, may occur with aripiprazole (see section 4.8). 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 ABILIFY. When seen, it is usually in those with significant risk factors such as history of diabetes, thyroid disorder or pituitary adenoma. In clinical trials aripiprazole has not been shown to induce clinically relevant weight gain (see section 5.1). Dysphagia: oesophageal dysmotility and aspiration have been associated with antipsychotic drug usetreatment, including ABILIFY. Aripiprazole and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia. Hypersensitivity: as with other medications hypersensitivity reactions, characterised by allergic symptoms, may occur with aripiprazole (see section 4.8). 4.5 Interaction with other medicinal products and other forms of interaction 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 undesirable effects adverse reactions such as sedation (see section 4.8). If aripiprazole is administered concomitantly with medicinesmedicinal products known to cause QT prolongation or electrolyte imbalance, caution should be used. 4.8 Undesirable effects The following undesirable effects adverse reactions occurred more often (≥ 1/100) than placebo, or were identified as possibly medically relevant adverse reactions (*) in clinical trials with aripiprazole solution for injection (see section 5.1): The frequency listed below is defined using the following convention: common (³ 1/100, to < 1/10) and uncommon (³ 1/1,000, to < 1/100). Cardiac disorders Uncommon: tachycardia* Nervous system disorders Common: somnolence, dizziness, headache, akathisia Cardiac disorders Uncommon: tachycardia* Vascular disorders Uncommon: orthostatic hypotension*, increased diastolic blood pressure* Gastrointestinal disorders Common: nausea, vomiting Uncommon: dry mouth* Vascular disorders Uncommon: orthostatic hypotension*, increased diastolic blood pressure* General disorders and administration site conditions Uncommon: fatigue* The following undesirable effects adverse reactionsoccurred more often (≥ 1/100) than placebo, or were identified as possibly medically relevant adverse reactions (*) in clinical trials with oral formulations of aripiprazole (see section 5.1): Psychiatric disorders Common: restlessness, insomnia, anxiety Uncommon: depression* Nervous system disorders Common: extrapyramidal disorder, akathisia, tremor, dizziness, somnolence, sedation, headache Eye disorders Common: blurred vision Cardiac disorders Uncommon: tachycardia* Nervous system disorders Common: extrapyramidal disorder, akathisia, tremor, dizziness, somnolence, sedation, headache Eye disorders Common: blurred vision Vascular disorders Uncommon: orthostatic hypotension* Gastrointestinal disorders Common: dyspepsia, vomiting, nausea, constipation, salivary hypersecretion Vascular disorders Uncommon: orthostatic hypotension* General disorders and administration site conditions Common: fatigue Psychiatric disorders Common: restlessness, insomnia, anxiety Uncommon: depression* ......................... Other findings: Undesirable effectsAdverse reactions known to be associated with antipsychotic therapy and also reported during treatment with aripiprazole include neuroleptic malignant syndrome, tardive dyskinesia, seizure, cerebrovascular adverse eventsreactions and increased mortality in elderly demented patients, hyperglycaemia and diabetes mellitus (see section 4.4). Post-Marketing: The following adverse eventsreactions have been reported during post-marketing surveillance. The frequency of these eventsreactions is considered not known (cannot be estimated from the available data). Blood and the lymphatic system disorders: leukopenia, neutropenia, thrombocytopenia Immune system disorders: allergic reaction (e.g. anaphylactic reaction, angioedema including swollen tongue, tongue oedema, face oedema, pruritus, or urticaria) Endocrine disorders: hyperglycaemia, diabetes mellitus, diabetic ketoacidosis, diabetic hyperosmolar coma Metabolism and nutrition disorders: weight gain, weight decreased, anorexia, hyponatremia Psychiatric disorders: agitation, nervousness; suicide attempt, suicidal ideation, and completed suicide (see section 4.4) Nervous system disorders: speech disorder, Neuroleptic Malignant Syndrome (NMS), grand mal convulsion Cardiac disorders: QT prolongation, ventricular arrhythmias, sudden unexplained death, cardiac arrest, torsades de pointes, bradycardia Vascular disorders: syncope, hypertension, thromboembolic reactions Respiratory, thoracic and mediastinal disorders: oropharyngeal spasm, laryngospasm, aspiration pneumonia Gastrointestinal disorders: pancreatitis, dysphagia, abdominal discomfort, stomach discomfort, diarrhoea Hepatobiliary disorders: jaundice, hepatitis, increased Alanine Aminotransferase (ALT), increased Aspartate Aminotransferase (AST), increased Gamma Glutamyl Transferase (GGT), increased alkaline phosphatase Skin and subcutaneous tissue disorders: rash, photosensitivity reaction, alopecia, hyperhidrosis Musculoskeletal and connective tissue disorders: rhabdomyolysis, myalgia, stiffness Renal and urinary disorders: urinary incontinence, urinary retention Reproductive system and breast disorders: priapism General disorders and administration site conditions: temperature regulation disorder (e.g. hypothermia, pyrexia), chest pain, peripheral oedema Investigations: increased Creatine Phosphokinase, blood glucose increased, blood glucose fluctuation, glycosylated haemoglobin increased Cardiac disorders: QT prolongation, ventricular arrhythmias, sudden unexplained death, cardiac arrest, torsades de pointes, bradycardia Blood and the lymphatic system disorders: leukopenia, neutropenia, thrombocytopenia Nervous system disorders: speech disorder, Neuroleptic Malignant Syndrome (NMS), grand mal convulsion Respiratory, thoracic and mediastinal disorders: oropharyngeal spasm, laryngospasm, aspiration pneumonia Gastrointestinal disorders: pancreatitis, dysphagia, abdominal discomfort, stomach discomfort, diarrhoea Renal and urinary disorders: urinary incontinence, urinary retention Skin and subcutaneous tissue disorders: rash, photosensitivity reaction, alopecia, hyperhidrosis Musculoskeletal and connective tissue disorders: rhabdomyolysis, myalgia, stiffness Endocrine disorders: hyperglycaemia, diabetes mellitus, diabetic ketoacidosis, diabetic hyperosmolar coma Metabolism and nutrition disorders: weight gain, weight decreased, anorexia, hyponatremia Vascular disorders: syncope, hypertension, thromboembolic events General disorders and administration site conditions: temperature regulation disorder (e.g. hypothermia, pyrexia), chest pain, peripheral oedema Immune system disorders: allergic reaction (e.g. anaphylactic reaction, angioedema including swollen tongue, tongue oedema, face oedema, pruritus, or urticaria) Hepatobiliary disorders: jaundice, hepatitis, increased Alanine Aminotransferase (ALT), increased Aspartate Aminotransferase (AST), increased Gamma Glutamyl Transferase (GGT), increased alkaline phosphatase Reproductive system and breast disorders: priapism Psychiatric disorders: agitation, nervousness; suicide attempt, suicidal ideation, and completed suicide (see section 4.4) 5.1 Pharmacodynamic properties Pharmacotherapeutic group: other antipsychotics, ATC code: N05AX12 .................................. 6.3 Shelf life 18 months After opening: uUse product immediately after opening and discard any unused amount. 6.6 Special precautions for disposal and other handling Any unused product or waste material should be disposed of in accordance with local requirements. 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 4 June 2004 Date of latest renewal: 21 April 2009 10. DATE OF REVISION OF THE TEXT August 2008 04/2009 Detailed information on this product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/
4.4 Special warnings and precautions for use .............................................. 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, hypovolemia, and treatment with antihypertensive medicationsmedicinal products) or hypertension, including accelerated or malignant. ....................... Tardive Dyskinesiadyskinesia: in clinical trials of one year or less duration, there were uncommon reports of treatment emergent dyskinesia during treatment with aripiprazole. If signs and symptoms of tardive dyskinesia appear in a patient on ABILIFY, dose reduction or discontinuation should be considered. These symptoms can temporally deteriorate or can even arise after discontinuation of treatment. .................................................... Cerebrovascular adverse eventsreactions: in the same trials, cerebrovascular adverse eventsreactions (e.g. stroke, transient ischaemic attack), including fatalities, were reported in patients (mean age: 84 years; range: 78‑88 years). Overall, 1.3% of aripiprazole-treated patients reported cerebrovascular adverse eventsreactions compared with 0.6% of placebo-treated patients in these trials. This difference was not statistically significant. However, in one of these trials, a fixed-dose trial, there was a significant dose response relationship for cerebrovascular adverse eventsreactions in patients treated with aripiprazole. ABILIFY is not approved indicated for the treatment of dementia-related psychosis. Hyperglycaemia and Diabetes diabetes Mellitusmellitus: hyperglycaemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotic agents, including ABILIFY. Risk factors that may predispose patients to severe complications include obesity and family history of diabetes. In clinical trials with aripiprazole, there were no significant differences in the incidence rates of hyperglycaemia-related adverse eventsreactions (including diabetes) or in abnormal glycaemia laboratory values compared to placebo. Precise risk estimates for hyperglycaemia-related adverse eventsreactions in patients treated with ABILIFY and with other atypical antipsychotic agents are not available to allow direct comparisons. Patients treated with any antipsychotic agents, including ABILIFY, 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. Hypersensitivity: as with other medicinal products hypersensitivity reactions, characterised by allergic symptoms, may occur with aripiprazole (see section 4.8). 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 ABILIFY. When seen, it is usually in those with significant risk factors such as history of diabetes, thyroid disorder or pituitary adenoma. In clinical trials aripiprazole has not been shown to induce clinically relevant weight gain (see section 5.1). Dysphagia: oesophageal dysmotility and aspiration have been associated with antipsychotic drug usetreatment, including ABILIFY. Aripiprazole and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia. Hypersensitivity: as with other medications hypersensitivity reactions, characterised by allergic symptoms, may occur with aripiprazole (see section 4.8). 4.5 Interaction with other medicinal products and other forms of interaction 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 undesirable effects adverse reactions such as sedation (see section 4.8). If aripiprazole is administered concomitantly with medicinesmedicinal products known to cause QT prolongation or electrolyte imbalance, caution should be used. 4.8 Undesirable effects The following undesirable effects adverse reactions occurred more often (≥ 1/100) than placebo, or were identified as possibly medically relevant adverse reactions (*) in clinical trials with aripiprazole solution for injection (see section 5.1): The frequency listed below is defined using the following convention: common (³ 1/100, to < 1/10) and uncommon (³ 1/1,000, to < 1/100). Cardiac disorders Uncommon: tachycardia* Nervous system disorders Common: somnolence, dizziness, headache, akathisia Cardiac disorders Uncommon: tachycardia* Vascular disorders Uncommon: orthostatic hypotension*, increased diastolic blood pressure* Gastrointestinal disorders Common: nausea, vomiting Uncommon: dry mouth* Vascular disorders Uncommon: orthostatic hypotension*, increased diastolic blood pressure* General disorders and administration site conditions Uncommon: fatigue* The following undesirable effects adverse reactionsoccurred more often (≥ 1/100) than placebo, or were identified as possibly medically relevant adverse reactions (*) in clinical trials with oral formulations of aripiprazole (see section 5.1): Psychiatric disorders Common: restlessness, insomnia, anxiety Uncommon: depression* Nervous system disorders Common: extrapyramidal disorder, akathisia, tremor, dizziness, somnolence, sedation, headache Eye disorders Common: blurred vision Cardiac disorders Uncommon: tachycardia* Nervous system disorders Common: extrapyramidal disorder, akathisia, tremor, dizziness, somnolence, sedation, headache Eye disorders Common: blurred vision Vascular disorders Uncommon: orthostatic hypotension* Gastrointestinal disorders Common: dyspepsia, vomiting, nausea, constipation, salivary hypersecretion Vascular disorders Uncommon: orthostatic hypotension* General disorders and administration site conditions Common: fatigue Psychiatric disorders Common: restlessness, insomnia, anxiety Uncommon: depression* ......................... Other findings: Undesirable effectsAdverse reactions known to be associated with antipsychotic therapy and also reported during treatment with aripiprazole include neuroleptic malignant syndrome, tardive dyskinesia, seizure, cerebrovascular adverse eventsreactions and increased mortality in elderly demented patients, hyperglycaemia and diabetes mellitus (see section 4.4). Post-Marketing: The following adverse eventsreactions have been reported during post-marketing surveillance. The frequency of these eventsreactions is considered not known (cannot be estimated from the available data). Blood and the lymphatic system disorders: leukopenia, neutropenia, thrombocytopenia Immune system disorders: allergic reaction (e.g. anaphylactic reaction, angioedema including swollen tongue, tongue oedema, face oedema, pruritus, or urticaria) Endocrine disorders: hyperglycaemia, diabetes mellitus, diabetic ketoacidosis, diabetic hyperosmolar coma Metabolism and nutrition disorders: weight gain, weight decreased, anorexia, hyponatremia Psychiatric disorders: agitation, nervousness; suicide attempt, suicidal ideation, and completed suicide (see section 4.4) Nervous system disorders: speech disorder, Neuroleptic Malignant Syndrome (NMS), grand mal convulsion Cardiac disorders: QT prolongation, ventricular arrhythmias, sudden unexplained death, cardiac arrest, torsades de pointes, bradycardia Vascular disorders: syncope, hypertension, thromboembolic reactions Respiratory, thoracic and mediastinal disorders: oropharyngeal spasm, laryngospasm, aspiration pneumonia Gastrointestinal disorders: pancreatitis, dysphagia, abdominal discomfort, stomach discomfort, diarrhoea Hepatobiliary disorders: jaundice, hepatitis, increased Alanine Aminotransferase (ALT), increased Aspartate Aminotransferase (AST), increased Gamma Glutamyl Transferase (GGT), increased alkaline phosphatase Skin and subcutaneous tissue disorders: rash, photosensitivity reaction, alopecia, hyperhidrosis Musculoskeletal and connective tissue disorders: rhabdomyolysis, myalgia, stiffness Renal and urinary disorders: urinary incontinence, urinary retention Reproductive system and breast disorders: priapism General disorders and administration site conditions: temperature regulation disorder (e.g. hypothermia, pyrexia), chest pain, peripheral oedema Investigations: increased Creatine Phosphokinase, blood glucose increased, blood glucose fluctuation, glycosylated haemoglobin increased Cardiac disorders: QT prolongation, ventricular arrhythmias, sudden unexplained death, cardiac arrest, torsades de pointes, bradycardia Blood and the lymphatic system disorders: leukopenia, neutropenia, thrombocytopenia Nervous system disorders: speech disorder, Neuroleptic Malignant Syndrome (NMS), grand mal convulsion Respiratory, thoracic and mediastinal disorders: oropharyngeal spasm, laryngospasm, aspiration pneumonia Gastrointestinal disorders: pancreatitis, dysphagia, abdominal discomfort, stomach discomfort, diarrhoea Renal and urinary disorders: urinary incontinence, urinary retention Skin and subcutaneous tissue disorders: rash, photosensitivity reaction, alopecia, hyperhidrosis Musculoskeletal and connective tissue disorders: rhabdomyolysis, myalgia, stiffness Endocrine disorders: hyperglycaemia, diabetes mellitus, diabetic ketoacidosis, diabetic hyperosmolar coma Metabolism and nutrition disorders: weight gain, weight decreased, anorexia, hyponatremia Vascular disorders: syncope, hypertension, thromboembolic events General disorders and administration site conditions: temperature regulation disorder (e.g. hypothermia, pyrexia), chest pain, peripheral oedema Immune system disorders: allergic reaction (e.g. anaphylactic reaction, angioedema including swollen tongue, tongue oedema, face oedema, pruritus, or urticaria) Hepatobiliary disorders: jaundice, hepatitis, increased Alanine Aminotransferase (ALT), increased Aspartate Aminotransferase (AST), increased Gamma Glutamyl Transferase (GGT), increased alkaline phosphatase Reproductive system and breast disorders: priapism Psychiatric disorders: agitation, nervousness; suicide attempt, suicidal ideation, and completed suicide (see section 4.4) 5.1 Pharmacodynamic properties Pharmacotherapeutic group: other antipsychotics, ATC code: N05AX12 .................................. 6.3 Shelf life 18 months After opening: uUse product immediately after opening and discard any unused amount. 6.6 Special precautions for disposal and other handling Any unused product or waste material should be disposed of in accordance with local requirements. 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 4 June 2004 Date of latest renewal: 21 April 2009 10. DATE OF REVISION OF THE TEXT August 2008 04/2009 Detailed information on this product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/
.............................................. 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, hypovolemia, and treatment with antihypertensive medicationsmedicinal products) or hypertension, including accelerated or malignant. ....................... Tardive Dyskinesiadyskinesia: in clinical trials of one year or less duration, there were uncommon reports of treatment emergent dyskinesia during treatment with aripiprazole. If signs and symptoms of tardive dyskinesia appear in a patient on ABILIFY, dose reduction or discontinuation should be considered. These symptoms can temporally deteriorate or can even arise after discontinuation of treatment. .................................................... Cerebrovascular adverse eventsreactions: in the same trials, cerebrovascular adverse eventsreactions (e.g. stroke, transient ischaemic attack), including fatalities, were reported in patients (mean age: 84 years; range: 78‑88 years). Overall, 1.3% of aripiprazole-treated patients reported cerebrovascular adverse eventsreactions compared with 0.6% of placebo-treated patients in these trials. This difference was not statistically significant. However, in one of these trials, a fixed-dose trial, there was a significant dose response relationship for cerebrovascular adverse eventsreactions in patients treated with aripiprazole. ABILIFY is not approved indicated for the treatment of dementia-related psychosis. Hyperglycaemia and Diabetes diabetes Mellitusmellitus: hyperglycaemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotic agents, including ABILIFY. Risk factors that may predispose patients to severe complications include obesity and family history of diabetes. In clinical trials with aripiprazole, there were no significant differences in the incidence rates of hyperglycaemia-related adverse eventsreactions (including diabetes) or in abnormal glycaemia laboratory values compared to placebo. Precise risk estimates for hyperglycaemia-related adverse eventsreactions in patients treated with ABILIFY and with other atypical antipsychotic agents are not available to allow direct comparisons. Patients treated with any antipsychotic agents, including ABILIFY, 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. Hypersensitivity: as with other medicinal products hypersensitivity reactions, characterised by allergic symptoms, may occur with aripiprazole (see section 4.8). 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 ABILIFY. When seen, it is usually in those with significant risk factors such as history of diabetes, thyroid disorder or pituitary adenoma. In clinical trials aripiprazole has not been shown to induce clinically relevant weight gain (see section 5.1). Dysphagia: oesophageal dysmotility and aspiration have been associated with antipsychotic drug usetreatment, including ABILIFY. Aripiprazole and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia. Hypersensitivity: as with other medications hypersensitivity reactions, characterised by allergic symptoms, may occur with aripiprazole (see section 4.8). 4.5 Interaction with other medicinal products and other forms of interaction 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 undesirable effects adverse reactions such as sedation (see section 4.8). If aripiprazole is administered concomitantly with medicinesmedicinal products known to cause QT prolongation or electrolyte imbalance, caution should be used. 4.8 Undesirable effects The following undesirable effects adverse reactions occurred more often (≥ 1/100) than placebo, or were identified as possibly medically relevant adverse reactions (*) in clinical trials with aripiprazole solution for injection (see section 5.1): The frequency listed below is defined using the following convention: common (³ 1/100, to < 1/10) and uncommon (³ 1/1,000, to < 1/100). Cardiac disorders Uncommon: tachycardia* Nervous system disorders Common: somnolence, dizziness, headache, akathisia Cardiac disorders Uncommon: tachycardia* Vascular disorders Uncommon: orthostatic hypotension*, increased diastolic blood pressure* Gastrointestinal disorders Common: nausea, vomiting Uncommon: dry mouth* Vascular disorders Uncommon: orthostatic hypotension*, increased diastolic blood pressure* General disorders and administration site conditions Uncommon: fatigue* The following undesirable effects adverse reactionsoccurred more often (≥ 1/100) than placebo, or were identified as possibly medically relevant adverse reactions (*) in clinical trials with oral formulations of aripiprazole (see section 5.1): Psychiatric disorders Common: restlessness, insomnia, anxiety Uncommon: depression* Nervous system disorders Common: extrapyramidal disorder, akathisia, tremor, dizziness, somnolence, sedation, headache Eye disorders Common: blurred vision Cardiac disorders Uncommon: tachycardia* Nervous system disorders Common: extrapyramidal disorder, akathisia, tremor, dizziness, somnolence, sedation, headache Eye disorders Common: blurred vision Vascular disorders Uncommon: orthostatic hypotension* Gastrointestinal disorders Common: dyspepsia, vomiting, nausea, constipation, salivary hypersecretion Vascular disorders Uncommon: orthostatic hypotension* General disorders and administration site conditions Common: fatigue Psychiatric disorders Common: restlessness, insomnia, anxiety Uncommon: depression* ......................... Other findings: Undesirable effectsAdverse reactions known to be associated with antipsychotic therapy and also reported during treatment with aripiprazole include neuroleptic malignant syndrome, tardive dyskinesia, seizure, cerebrovascular adverse eventsreactions and increased mortality in elderly demented patients, hyperglycaemia and diabetes mellitus (see section 4.4). Post-Marketing: The following adverse eventsreactions have been reported during post-marketing surveillance. The frequency of these eventsreactions is considered not known (cannot be estimated from the available data). Blood and the lymphatic system disorders: leukopenia, neutropenia, thrombocytopenia Immune system disorders: allergic reaction (e.g. anaphylactic reaction, angioedema including swollen tongue, tongue oedema, face oedema, pruritus, or urticaria) Endocrine disorders: hyperglycaemia, diabetes mellitus, diabetic ketoacidosis, diabetic hyperosmolar coma Metabolism and nutrition disorders: weight gain, weight decreased, anorexia, hyponatremia Psychiatric disorders: agitation, nervousness; suicide attempt, suicidal ideation, and completed suicide (see section 4.4) Nervous system disorders: speech disorder, Neuroleptic Malignant Syndrome (NMS), grand mal convulsion Cardiac disorders: QT prolongation, ventricular arrhythmias, sudden unexplained death, cardiac arrest, torsades de pointes, bradycardia Vascular disorders: syncope, hypertension, thromboembolic reactions Respiratory, thoracic and mediastinal disorders: oropharyngeal spasm, laryngospasm, aspiration pneumonia Gastrointestinal disorders: pancreatitis, dysphagia, abdominal discomfort, stomach discomfort, diarrhoea Hepatobiliary disorders: jaundice, hepatitis, increased Alanine Aminotransferase (ALT), increased Aspartate Aminotransferase (AST), increased Gamma Glutamyl Transferase (GGT), increased alkaline phosphatase Skin and subcutaneous tissue disorders: rash, photosensitivity reaction, alopecia, hyperhidrosis Musculoskeletal and connective tissue disorders: rhabdomyolysis, myalgia, stiffness Renal and urinary disorders: urinary incontinence, urinary retention Reproductive system and breast disorders: priapism General disorders and administration site conditions: temperature regulation disorder (e.g. hypothermia, pyrexia), chest pain, peripheral oedema Investigations: increased Creatine Phosphokinase, blood glucose increased, blood glucose fluctuation, glycosylated haemoglobin increased Cardiac disorders: QT prolongation, ventricular arrhythmias, sudden unexplained death, cardiac arrest, torsades de pointes, bradycardia Blood and the lymphatic system disorders: leukopenia, neutropenia, thrombocytopenia Nervous system disorders: speech disorder, Neuroleptic Malignant Syndrome (NMS), grand mal convulsion Respiratory, thoracic and mediastinal disorders: oropharyngeal spasm, laryngospasm, aspiration pneumonia Gastrointestinal disorders: pancreatitis, dysphagia, abdominal discomfort, stomach discomfort, diarrhoea Renal and urinary disorders: urinary incontinence, urinary retention Skin and subcutaneous tissue disorders: rash, photosensitivity reaction, alopecia, hyperhidrosis Musculoskeletal and connective tissue disorders: rhabdomyolysis, myalgia, stiffness Endocrine disorders: hyperglycaemia, diabetes mellitus, diabetic ketoacidosis, diabetic hyperosmolar coma Metabolism and nutrition disorders: weight gain, weight decreased, anorexia, hyponatremia Vascular disorders: syncope, hypertension, thromboembolic events General disorders and administration site conditions: temperature regulation disorder (e.g. hypothermia, pyrexia), chest pain, peripheral oedema Immune system disorders: allergic reaction (e.g. anaphylactic reaction, angioedema including swollen tongue, tongue oedema, face oedema, pruritus, or urticaria) Hepatobiliary disorders: jaundice, hepatitis, increased Alanine Aminotransferase (ALT), increased Aspartate Aminotransferase (AST), increased Gamma Glutamyl Transferase (GGT), increased alkaline phosphatase Reproductive system and breast disorders: priapism Psychiatric disorders: agitation, nervousness; suicide attempt, suicidal ideation, and completed suicide (see section 4.4) 5.1 Pharmacodynamic properties Pharmacotherapeutic group: other antipsychotics, ATC code: N05AX12 .................................. 6.3 Shelf life 18 months After opening: uUse product immediately after opening and discard any unused amount. 6.6 Special precautions for disposal and other handling Any unused product or waste material should be disposed of in accordance with local requirements. 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 4 June 2004 Date of latest renewal: 21 April 2009 10. DATE OF REVISION OF THE TEXT August 2008 04/2009 Detailed information on this product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/
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, hypovolemia, and treatment with antihypertensive medicationsmedicinal products) or hypertension, including accelerated or malignant.
.......................
Tardive Dyskinesiadyskinesia: in clinical trials of one year or less duration, there were uncommon reports of treatment emergent dyskinesia during treatment with aripiprazole. If signs and symptoms of tardive dyskinesia appear in a patient on ABILIFY, dose reduction or discontinuation should be considered. These symptoms can temporally deteriorate or can even arise after discontinuation of treatment.
....................................................
Cerebrovascular adverse eventsreactions: in the same trials, cerebrovascular adverse eventsreactions (e.g. stroke, transient ischaemic attack), including fatalities, were reported in patients (mean age: 84 years; range: 78‑88 years). Overall, 1.3% of aripiprazole-treated patients reported cerebrovascular adverse eventsreactions compared with 0.6% of placebo-treated patients in these trials. This difference was not statistically significant. However, in one of these trials, a fixed-dose trial, there was a significant dose response relationship for cerebrovascular adverse eventsreactions in patients treated with aripiprazole.
ABILIFY is not approved indicated for the treatment of dementia-related psychosis.
Hyperglycaemia and Diabetes diabetes Mellitusmellitus: hyperglycaemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotic agents, including ABILIFY. Risk factors that may predispose patients to severe complications include obesity and family history of diabetes. In clinical trials with aripiprazole, there were no significant differences in the incidence rates of hyperglycaemia-related adverse eventsreactions (including diabetes) or in abnormal glycaemia laboratory values compared to placebo. Precise risk estimates for hyperglycaemia-related adverse eventsreactions in patients treated with ABILIFY and with other atypical antipsychotic agents are not available to allow direct comparisons. Patients treated with any antipsychotic agents, including ABILIFY, 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. Hypersensitivity: as with other medicinal products hypersensitivity reactions, characterised by allergic symptoms, may occur with aripiprazole (see section 4.8). 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 ABILIFY. When seen, it is usually in those with significant risk factors such as history of diabetes, thyroid disorder or pituitary adenoma. In clinical trials aripiprazole has not been shown to induce clinically relevant weight gain (see section 5.1). Dysphagia: oesophageal dysmotility and aspiration have been associated with antipsychotic drug usetreatment, including ABILIFY. Aripiprazole and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia. Hypersensitivity: as with other medications hypersensitivity reactions, characterised by allergic symptoms, may occur with aripiprazole (see section 4.8). 4.5 Interaction with other medicinal products and other forms of interaction 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 undesirable effects adverse reactions such as sedation (see section 4.8). If aripiprazole is administered concomitantly with medicinesmedicinal products known to cause QT prolongation or electrolyte imbalance, caution should be used. 4.8 Undesirable effects The following undesirable effects adverse reactions occurred more often (≥ 1/100) than placebo, or were identified as possibly medically relevant adverse reactions (*) in clinical trials with aripiprazole solution for injection (see section 5.1): The frequency listed below is defined using the following convention: common (³ 1/100, to < 1/10) and uncommon (³ 1/1,000, to < 1/100). Cardiac disorders Uncommon: tachycardia* Nervous system disorders Common: somnolence, dizziness, headache, akathisia Cardiac disorders Uncommon: tachycardia* Vascular disorders Uncommon: orthostatic hypotension*, increased diastolic blood pressure* Gastrointestinal disorders Common: nausea, vomiting Uncommon: dry mouth* Vascular disorders Uncommon: orthostatic hypotension*, increased diastolic blood pressure* General disorders and administration site conditions Uncommon: fatigue* The following undesirable effects adverse reactionsoccurred more often (≥ 1/100) than placebo, or were identified as possibly medically relevant adverse reactions (*) in clinical trials with oral formulations of aripiprazole (see section 5.1): Psychiatric disorders Common: restlessness, insomnia, anxiety Uncommon: depression* Nervous system disorders Common: extrapyramidal disorder, akathisia, tremor, dizziness, somnolence, sedation, headache Eye disorders Common: blurred vision Cardiac disorders Uncommon: tachycardia* Nervous system disorders Common: extrapyramidal disorder, akathisia, tremor, dizziness, somnolence, sedation, headache Eye disorders Common: blurred vision Vascular disorders Uncommon: orthostatic hypotension* Gastrointestinal disorders Common: dyspepsia, vomiting, nausea, constipation, salivary hypersecretion Vascular disorders Uncommon: orthostatic hypotension* General disorders and administration site conditions Common: fatigue Psychiatric disorders Common: restlessness, insomnia, anxiety Uncommon: depression* ......................... Other findings: Undesirable effectsAdverse reactions known to be associated with antipsychotic therapy and also reported during treatment with aripiprazole include neuroleptic malignant syndrome, tardive dyskinesia, seizure, cerebrovascular adverse eventsreactions and increased mortality in elderly demented patients, hyperglycaemia and diabetes mellitus (see section 4.4). Post-Marketing: The following adverse eventsreactions have been reported during post-marketing surveillance. The frequency of these eventsreactions is considered not known (cannot be estimated from the available data). Blood and the lymphatic system disorders: leukopenia, neutropenia, thrombocytopenia Immune system disorders: allergic reaction (e.g. anaphylactic reaction, angioedema including swollen tongue, tongue oedema, face oedema, pruritus, or urticaria) Endocrine disorders: hyperglycaemia, diabetes mellitus, diabetic ketoacidosis, diabetic hyperosmolar coma Metabolism and nutrition disorders: weight gain, weight decreased, anorexia, hyponatremia Psychiatric disorders: agitation, nervousness; suicide attempt, suicidal ideation, and completed suicide (see section 4.4) Nervous system disorders: speech disorder, Neuroleptic Malignant Syndrome (NMS), grand mal convulsion Cardiac disorders: QT prolongation, ventricular arrhythmias, sudden unexplained death, cardiac arrest, torsades de pointes, bradycardia Vascular disorders: syncope, hypertension, thromboembolic reactions Respiratory, thoracic and mediastinal disorders: oropharyngeal spasm, laryngospasm, aspiration pneumonia Gastrointestinal disorders: pancreatitis, dysphagia, abdominal discomfort, stomach discomfort, diarrhoea Hepatobiliary disorders: jaundice, hepatitis, increased Alanine Aminotransferase (ALT), increased Aspartate Aminotransferase (AST), increased Gamma Glutamyl Transferase (GGT), increased alkaline phosphatase Skin and subcutaneous tissue disorders: rash, photosensitivity reaction, alopecia, hyperhidrosis Musculoskeletal and connective tissue disorders: rhabdomyolysis, myalgia, stiffness Renal and urinary disorders: urinary incontinence, urinary retention Reproductive system and breast disorders: priapism General disorders and administration site conditions: temperature regulation disorder (e.g. hypothermia, pyrexia), chest pain, peripheral oedema Investigations: increased Creatine Phosphokinase, blood glucose increased, blood glucose fluctuation, glycosylated haemoglobin increased Cardiac disorders: QT prolongation, ventricular arrhythmias, sudden unexplained death, cardiac arrest, torsades de pointes, bradycardia Blood and the lymphatic system disorders: leukopenia, neutropenia, thrombocytopenia Nervous system disorders: speech disorder, Neuroleptic Malignant Syndrome (NMS), grand mal convulsion Respiratory, thoracic and mediastinal disorders: oropharyngeal spasm, laryngospasm, aspiration pneumonia Gastrointestinal disorders: pancreatitis, dysphagia, abdominal discomfort, stomach discomfort, diarrhoea Renal and urinary disorders: urinary incontinence, urinary retention Skin and subcutaneous tissue disorders: rash, photosensitivity reaction, alopecia, hyperhidrosis Musculoskeletal and connective tissue disorders: rhabdomyolysis, myalgia, stiffness Endocrine disorders: hyperglycaemia, diabetes mellitus, diabetic ketoacidosis, diabetic hyperosmolar coma Metabolism and nutrition disorders: weight gain, weight decreased, anorexia, hyponatremia Vascular disorders: syncope, hypertension, thromboembolic events General disorders and administration site conditions: temperature regulation disorder (e.g. hypothermia, pyrexia), chest pain, peripheral oedema Immune system disorders: allergic reaction (e.g. anaphylactic reaction, angioedema including swollen tongue, tongue oedema, face oedema, pruritus, or urticaria) Hepatobiliary disorders: jaundice, hepatitis, increased Alanine Aminotransferase (ALT), increased Aspartate Aminotransferase (AST), increased Gamma Glutamyl Transferase (GGT), increased alkaline phosphatase Reproductive system and breast disorders: priapism Psychiatric disorders: agitation, nervousness; suicide attempt, suicidal ideation, and completed suicide (see section 4.4) 5.1 Pharmacodynamic properties Pharmacotherapeutic group: other antipsychotics, ATC code: N05AX12 .................................. 6.3 Shelf life 18 months After opening: uUse product immediately after opening and discard any unused amount. 6.6 Special precautions for disposal and other handling Any unused product or waste material should be disposed of in accordance with local requirements. 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 4 June 2004 Date of latest renewal: 21 April 2009 10. DATE OF REVISION OF THE TEXT August 2008 04/2009 Detailed information on this product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/
Hypersensitivity: as with other medicinal products hypersensitivity reactions, characterised by allergic symptoms, may occur with aripiprazole (see section 4.8). 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 ABILIFY. When seen, it is usually in those with significant risk factors such as history of diabetes, thyroid disorder or pituitary adenoma. In clinical trials aripiprazole has not been shown to induce clinically relevant weight gain (see section 5.1). Dysphagia: oesophageal dysmotility and aspiration have been associated with antipsychotic drug usetreatment, including ABILIFY. Aripiprazole and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia. Hypersensitivity: as with other medications hypersensitivity reactions, characterised by allergic symptoms, may occur with aripiprazole (see section 4.8). 4.5 Interaction with other medicinal products and other forms of interaction 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 undesirable effects adverse reactions such as sedation (see section 4.8). If aripiprazole is administered concomitantly with medicinesmedicinal products known to cause QT prolongation or electrolyte imbalance, caution should be used. 4.8 Undesirable effects The following undesirable effects adverse reactions occurred more often (≥ 1/100) than placebo, or were identified as possibly medically relevant adverse reactions (*) in clinical trials with aripiprazole solution for injection (see section 5.1): The frequency listed below is defined using the following convention: common (³ 1/100, to < 1/10) and uncommon (³ 1/1,000, to < 1/100). Cardiac disorders Uncommon: tachycardia* Nervous system disorders Common: somnolence, dizziness, headache, akathisia Cardiac disorders Uncommon: tachycardia* Vascular disorders Uncommon: orthostatic hypotension*, increased diastolic blood pressure* Gastrointestinal disorders Common: nausea, vomiting Uncommon: dry mouth* Vascular disorders Uncommon: orthostatic hypotension*, increased diastolic blood pressure* General disorders and administration site conditions Uncommon: fatigue* The following undesirable effects adverse reactionsoccurred more often (≥ 1/100) than placebo, or were identified as possibly medically relevant adverse reactions (*) in clinical trials with oral formulations of aripiprazole (see section 5.1): Psychiatric disorders Common: restlessness, insomnia, anxiety Uncommon: depression* Nervous system disorders Common: extrapyramidal disorder, akathisia, tremor, dizziness, somnolence, sedation, headache Eye disorders Common: blurred vision Cardiac disorders Uncommon: tachycardia* Nervous system disorders Common: extrapyramidal disorder, akathisia, tremor, dizziness, somnolence, sedation, headache Eye disorders Common: blurred vision Vascular disorders Uncommon: orthostatic hypotension* Gastrointestinal disorders Common: dyspepsia, vomiting, nausea, constipation, salivary hypersecretion Vascular disorders Uncommon: orthostatic hypotension* General disorders and administration site conditions Common: fatigue Psychiatric disorders Common: restlessness, insomnia, anxiety Uncommon: depression* ......................... Other findings: Undesirable effectsAdverse reactions known to be associated with antipsychotic therapy and also reported during treatment with aripiprazole include neuroleptic malignant syndrome, tardive dyskinesia, seizure, cerebrovascular adverse eventsreactions and increased mortality in elderly demented patients, hyperglycaemia and diabetes mellitus (see section 4.4). Post-Marketing: The following adverse eventsreactions have been reported during post-marketing surveillance. The frequency of these eventsreactions is considered not known (cannot be estimated from the available data). Blood and the lymphatic system disorders: leukopenia, neutropenia, thrombocytopenia Immune system disorders: allergic reaction (e.g. anaphylactic reaction, angioedema including swollen tongue, tongue oedema, face oedema, pruritus, or urticaria) Endocrine disorders: hyperglycaemia, diabetes mellitus, diabetic ketoacidosis, diabetic hyperosmolar coma Metabolism and nutrition disorders: weight gain, weight decreased, anorexia, hyponatremia Psychiatric disorders: agitation, nervousness; suicide attempt, suicidal ideation, and completed suicide (see section 4.4) Nervous system disorders: speech disorder, Neuroleptic Malignant Syndrome (NMS), grand mal convulsion Cardiac disorders: QT prolongation, ventricular arrhythmias, sudden unexplained death, cardiac arrest, torsades de pointes, bradycardia Vascular disorders: syncope, hypertension, thromboembolic reactions Respiratory, thoracic and mediastinal disorders: oropharyngeal spasm, laryngospasm, aspiration pneumonia Gastrointestinal disorders: pancreatitis, dysphagia, abdominal discomfort, stomach discomfort, diarrhoea Hepatobiliary disorders: jaundice, hepatitis, increased Alanine Aminotransferase (ALT), increased Aspartate Aminotransferase (AST), increased Gamma Glutamyl Transferase (GGT), increased alkaline phosphatase Skin and subcutaneous tissue disorders: rash, photosensitivity reaction, alopecia, hyperhidrosis Musculoskeletal and connective tissue disorders: rhabdomyolysis, myalgia, stiffness Renal and urinary disorders: urinary incontinence, urinary retention Reproductive system and breast disorders: priapism General disorders and administration site conditions: temperature regulation disorder (e.g. hypothermia, pyrexia), chest pain, peripheral oedema Investigations: increased Creatine Phosphokinase, blood glucose increased, blood glucose fluctuation, glycosylated haemoglobin increased Cardiac disorders: QT prolongation, ventricular arrhythmias, sudden unexplained death, cardiac arrest, torsades de pointes, bradycardia Blood and the lymphatic system disorders: leukopenia, neutropenia, thrombocytopenia Nervous system disorders: speech disorder, Neuroleptic Malignant Syndrome (NMS), grand mal convulsion Respiratory, thoracic and mediastinal disorders: oropharyngeal spasm, laryngospasm, aspiration pneumonia Gastrointestinal disorders: pancreatitis, dysphagia, abdominal discomfort, stomach discomfort, diarrhoea Renal and urinary disorders: urinary incontinence, urinary retention Skin and subcutaneous tissue disorders: rash, photosensitivity reaction, alopecia, hyperhidrosis Musculoskeletal and connective tissue disorders: rhabdomyolysis, myalgia, stiffness Endocrine disorders: hyperglycaemia, diabetes mellitus, diabetic ketoacidosis, diabetic hyperosmolar coma Metabolism and nutrition disorders: weight gain, weight decreased, anorexia, hyponatremia Vascular disorders: syncope, hypertension, thromboembolic events General disorders and administration site conditions: temperature regulation disorder (e.g. hypothermia, pyrexia), chest pain, peripheral oedema Immune system disorders: allergic reaction (e.g. anaphylactic reaction, angioedema including swollen tongue, tongue oedema, face oedema, pruritus, or urticaria) Hepatobiliary disorders: jaundice, hepatitis, increased Alanine Aminotransferase (ALT), increased Aspartate Aminotransferase (AST), increased Gamma Glutamyl Transferase (GGT), increased alkaline phosphatase Reproductive system and breast disorders: priapism Psychiatric disorders: agitation, nervousness; suicide attempt, suicidal ideation, and completed suicide (see section 4.4) 5.1 Pharmacodynamic properties Pharmacotherapeutic group: other antipsychotics, ATC code: N05AX12 .................................. 6.3 Shelf life 18 months After opening: uUse product immediately after opening and discard any unused amount. 6.6 Special precautions for disposal and other handling Any unused product or waste material should be disposed of in accordance with local requirements. 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 4 June 2004 Date of latest renewal: 21 April 2009 10. DATE OF REVISION OF THE TEXT August 2008 04/2009 Detailed information on this product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/
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 ABILIFY. When seen, it is usually in those with significant risk factors such as history of diabetes, thyroid disorder or pituitary adenoma. In clinical trials aripiprazole has not been shown to induce clinically relevant weight gain (see section 5.1).
Dysphagia: oesophageal dysmotility and aspiration have been associated with antipsychotic drug usetreatment, including ABILIFY. Aripiprazole and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia.
Hypersensitivity: as with other medications hypersensitivity reactions, characterised by allergic symptoms, may occur with aripiprazole (see section 4.8). 4.5 Interaction with other medicinal products and other forms of interaction 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 undesirable effects adverse reactions such as sedation (see section 4.8). If aripiprazole is administered concomitantly with medicinesmedicinal products known to cause QT prolongation or electrolyte imbalance, caution should be used. 4.8 Undesirable effects The following undesirable effects adverse reactions occurred more often (≥ 1/100) than placebo, or were identified as possibly medically relevant adverse reactions (*) in clinical trials with aripiprazole solution for injection (see section 5.1): The frequency listed below is defined using the following convention: common (³ 1/100, to < 1/10) and uncommon (³ 1/1,000, to < 1/100). Cardiac disorders Uncommon: tachycardia* Nervous system disorders Common: somnolence, dizziness, headache, akathisia Cardiac disorders Uncommon: tachycardia* Vascular disorders Uncommon: orthostatic hypotension*, increased diastolic blood pressure* Gastrointestinal disorders Common: nausea, vomiting Uncommon: dry mouth* Vascular disorders Uncommon: orthostatic hypotension*, increased diastolic blood pressure* General disorders and administration site conditions Uncommon: fatigue* The following undesirable effects adverse reactionsoccurred more often (≥ 1/100) than placebo, or were identified as possibly medically relevant adverse reactions (*) in clinical trials with oral formulations of aripiprazole (see section 5.1): Psychiatric disorders Common: restlessness, insomnia, anxiety Uncommon: depression* Nervous system disorders Common: extrapyramidal disorder, akathisia, tremor, dizziness, somnolence, sedation, headache Eye disorders Common: blurred vision Cardiac disorders Uncommon: tachycardia* Nervous system disorders Common: extrapyramidal disorder, akathisia, tremor, dizziness, somnolence, sedation, headache Eye disorders Common: blurred vision Vascular disorders Uncommon: orthostatic hypotension* Gastrointestinal disorders Common: dyspepsia, vomiting, nausea, constipation, salivary hypersecretion Vascular disorders Uncommon: orthostatic hypotension* General disorders and administration site conditions Common: fatigue Psychiatric disorders Common: restlessness, insomnia, anxiety Uncommon: depression* ......................... Other findings: Undesirable effectsAdverse reactions known to be associated with antipsychotic therapy and also reported during treatment with aripiprazole include neuroleptic malignant syndrome, tardive dyskinesia, seizure, cerebrovascular adverse eventsreactions and increased mortality in elderly demented patients, hyperglycaemia and diabetes mellitus (see section 4.4). Post-Marketing: The following adverse eventsreactions have been reported during post-marketing surveillance. The frequency of these eventsreactions is considered not known (cannot be estimated from the available data). Blood and the lymphatic system disorders: leukopenia, neutropenia, thrombocytopenia Immune system disorders: allergic reaction (e.g. anaphylactic reaction, angioedema including swollen tongue, tongue oedema, face oedema, pruritus, or urticaria) Endocrine disorders: hyperglycaemia, diabetes mellitus, diabetic ketoacidosis, diabetic hyperosmolar coma Metabolism and nutrition disorders: weight gain, weight decreased, anorexia, hyponatremia Psychiatric disorders: agitation, nervousness; suicide attempt, suicidal ideation, and completed suicide (see section 4.4) Nervous system disorders: speech disorder, Neuroleptic Malignant Syndrome (NMS), grand mal convulsion Cardiac disorders: QT prolongation, ventricular arrhythmias, sudden unexplained death, cardiac arrest, torsades de pointes, bradycardia Vascular disorders: syncope, hypertension, thromboembolic reactions Respiratory, thoracic and mediastinal disorders: oropharyngeal spasm, laryngospasm, aspiration pneumonia Gastrointestinal disorders: pancreatitis, dysphagia, abdominal discomfort, stomach discomfort, diarrhoea Hepatobiliary disorders: jaundice, hepatitis, increased Alanine Aminotransferase (ALT), increased Aspartate Aminotransferase (AST), increased Gamma Glutamyl Transferase (GGT), increased alkaline phosphatase Skin and subcutaneous tissue disorders: rash, photosensitivity reaction, alopecia, hyperhidrosis Musculoskeletal and connective tissue disorders: rhabdomyolysis, myalgia, stiffness Renal and urinary disorders: urinary incontinence, urinary retention Reproductive system and breast disorders: priapism General disorders and administration site conditions: temperature regulation disorder (e.g. hypothermia, pyrexia), chest pain, peripheral oedema Investigations: increased Creatine Phosphokinase, blood glucose increased, blood glucose fluctuation, glycosylated haemoglobin increased Cardiac disorders: QT prolongation, ventricular arrhythmias, sudden unexplained death, cardiac arrest, torsades de pointes, bradycardia Blood and the lymphatic system disorders: leukopenia, neutropenia, thrombocytopenia Nervous system disorders: speech disorder, Neuroleptic Malignant Syndrome (NMS), grand mal convulsion Respiratory, thoracic and mediastinal disorders: oropharyngeal spasm, laryngospasm, aspiration pneumonia Gastrointestinal disorders: pancreatitis, dysphagia, abdominal discomfort, stomach discomfort, diarrhoea Renal and urinary disorders: urinary incontinence, urinary retention Skin and subcutaneous tissue disorders: rash, photosensitivity reaction, alopecia, hyperhidrosis Musculoskeletal and connective tissue disorders: rhabdomyolysis, myalgia, stiffness Endocrine disorders: hyperglycaemia, diabetes mellitus, diabetic ketoacidosis, diabetic hyperosmolar coma Metabolism and nutrition disorders: weight gain, weight decreased, anorexia, hyponatremia Vascular disorders: syncope, hypertension, thromboembolic events General disorders and administration site conditions: temperature regulation disorder (e.g. hypothermia, pyrexia), chest pain, peripheral oedema Immune system disorders: allergic reaction (e.g. anaphylactic reaction, angioedema including swollen tongue, tongue oedema, face oedema, pruritus, or urticaria) Hepatobiliary disorders: jaundice, hepatitis, increased Alanine Aminotransferase (ALT), increased Aspartate Aminotransferase (AST), increased Gamma Glutamyl Transferase (GGT), increased alkaline phosphatase Reproductive system and breast disorders: priapism Psychiatric disorders: agitation, nervousness; suicide attempt, suicidal ideation, and completed suicide (see section 4.4) 5.1 Pharmacodynamic properties Pharmacotherapeutic group: other antipsychotics, ATC code: N05AX12 .................................. 6.3 Shelf life 18 months After opening: uUse product immediately after opening and discard any unused amount. 6.6 Special precautions for disposal and other handling Any unused product or waste material should be disposed of in accordance with local requirements. 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 4 June 2004 Date of latest renewal: 21 April 2009 10. DATE OF REVISION OF THE TEXT August 2008 04/2009 Detailed information on this product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/
4.5 Interaction with other medicinal products and other forms of interaction 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 undesirable effects adverse reactions such as sedation (see section 4.8). If aripiprazole is administered concomitantly with medicinesmedicinal products known to cause QT prolongation or electrolyte imbalance, caution should be used. 4.8 Undesirable effects The following undesirable effects adverse reactions occurred more often (≥ 1/100) than placebo, or were identified as possibly medically relevant adverse reactions (*) in clinical trials with aripiprazole solution for injection (see section 5.1): The frequency listed below is defined using the following convention: common (³ 1/100, to < 1/10) and uncommon (³ 1/1,000, to < 1/100). Cardiac disorders Uncommon: tachycardia* Nervous system disorders Common: somnolence, dizziness, headache, akathisia Cardiac disorders Uncommon: tachycardia* Vascular disorders Uncommon: orthostatic hypotension*, increased diastolic blood pressure* Gastrointestinal disorders Common: nausea, vomiting Uncommon: dry mouth* Vascular disorders Uncommon: orthostatic hypotension*, increased diastolic blood pressure* General disorders and administration site conditions Uncommon: fatigue* The following undesirable effects adverse reactionsoccurred more often (≥ 1/100) than placebo, or were identified as possibly medically relevant adverse reactions (*) in clinical trials with oral formulations of aripiprazole (see section 5.1): Psychiatric disorders Common: restlessness, insomnia, anxiety Uncommon: depression* Nervous system disorders Common: extrapyramidal disorder, akathisia, tremor, dizziness, somnolence, sedation, headache Eye disorders Common: blurred vision Cardiac disorders Uncommon: tachycardia* Nervous system disorders Common: extrapyramidal disorder, akathisia, tremor, dizziness, somnolence, sedation, headache Eye disorders Common: blurred vision Vascular disorders Uncommon: orthostatic hypotension* Gastrointestinal disorders Common: dyspepsia, vomiting, nausea, constipation, salivary hypersecretion Vascular disorders Uncommon: orthostatic hypotension* General disorders and administration site conditions Common: fatigue Psychiatric disorders Common: restlessness, insomnia, anxiety Uncommon: depression* ......................... Other findings: Undesirable effectsAdverse reactions known to be associated with antipsychotic therapy and also reported during treatment with aripiprazole include neuroleptic malignant syndrome, tardive dyskinesia, seizure, cerebrovascular adverse eventsreactions and increased mortality in elderly demented patients, hyperglycaemia and diabetes mellitus (see section 4.4). Post-Marketing: The following adverse eventsreactions have been reported during post-marketing surveillance. The frequency of these eventsreactions is considered not known (cannot be estimated from the available data). Blood and the lymphatic system disorders: leukopenia, neutropenia, thrombocytopenia Immune system disorders: allergic reaction (e.g. anaphylactic reaction, angioedema including swollen tongue, tongue oedema, face oedema, pruritus, or urticaria) Endocrine disorders: hyperglycaemia, diabetes mellitus, diabetic ketoacidosis, diabetic hyperosmolar coma Metabolism and nutrition disorders: weight gain, weight decreased, anorexia, hyponatremia Psychiatric disorders: agitation, nervousness; suicide attempt, suicidal ideation, and completed suicide (see section 4.4) Nervous system disorders: speech disorder, Neuroleptic Malignant Syndrome (NMS), grand mal convulsion Cardiac disorders: QT prolongation, ventricular arrhythmias, sudden unexplained death, cardiac arrest, torsades de pointes, bradycardia Vascular disorders: syncope, hypertension, thromboembolic reactions Respiratory, thoracic and mediastinal disorders: oropharyngeal spasm, laryngospasm, aspiration pneumonia Gastrointestinal disorders: pancreatitis, dysphagia, abdominal discomfort, stomach discomfort, diarrhoea Hepatobiliary disorders: jaundice, hepatitis, increased Alanine Aminotransferase (ALT), increased Aspartate Aminotransferase (AST), increased Gamma Glutamyl Transferase (GGT), increased alkaline phosphatase Skin and subcutaneous tissue disorders: rash, photosensitivity reaction, alopecia, hyperhidrosis Musculoskeletal and connective tissue disorders: rhabdomyolysis, myalgia, stiffness Renal and urinary disorders: urinary incontinence, urinary retention Reproductive system and breast disorders: priapism General disorders and administration site conditions: temperature regulation disorder (e.g. hypothermia, pyrexia), chest pain, peripheral oedema Investigations: increased Creatine Phosphokinase, blood glucose increased, blood glucose fluctuation, glycosylated haemoglobin increased Cardiac disorders: QT prolongation, ventricular arrhythmias, sudden unexplained death, cardiac arrest, torsades de pointes, bradycardia Blood and the lymphatic system disorders: leukopenia, neutropenia, thrombocytopenia Nervous system disorders: speech disorder, Neuroleptic Malignant Syndrome (NMS), grand mal convulsion Respiratory, thoracic and mediastinal disorders: oropharyngeal spasm, laryngospasm, aspiration pneumonia Gastrointestinal disorders: pancreatitis, dysphagia, abdominal discomfort, stomach discomfort, diarrhoea Renal and urinary disorders: urinary incontinence, urinary retention Skin and subcutaneous tissue disorders: rash, photosensitivity reaction, alopecia, hyperhidrosis Musculoskeletal and connective tissue disorders: rhabdomyolysis, myalgia, stiffness Endocrine disorders: hyperglycaemia, diabetes mellitus, diabetic ketoacidosis, diabetic hyperosmolar coma Metabolism and nutrition disorders: weight gain, weight decreased, anorexia, hyponatremia Vascular disorders: syncope, hypertension, thromboembolic events General disorders and administration site conditions: temperature regulation disorder (e.g. hypothermia, pyrexia), chest pain, peripheral oedema Immune system disorders: allergic reaction (e.g. anaphylactic reaction, angioedema including swollen tongue, tongue oedema, face oedema, pruritus, or urticaria) Hepatobiliary disorders: jaundice, hepatitis, increased Alanine Aminotransferase (ALT), increased Aspartate Aminotransferase (AST), increased Gamma Glutamyl Transferase (GGT), increased alkaline phosphatase Reproductive system and breast disorders: priapism Psychiatric disorders: agitation, nervousness; suicide attempt, suicidal ideation, and completed suicide (see section 4.4) 5.1 Pharmacodynamic properties Pharmacotherapeutic group: other antipsychotics, ATC code: N05AX12 .................................. 6.3 Shelf life 18 months After opening: uUse product immediately after opening and discard any unused amount. 6.6 Special precautions for disposal and other handling Any unused product or waste material should be disposed of in accordance with local requirements. 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 4 June 2004 Date of latest renewal: 21 April 2009 10. DATE OF REVISION OF THE TEXT August 2008 04/2009 Detailed information on this product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/
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 undesirable effects adverse reactions such as sedation (see section 4.8). If aripiprazole is administered concomitantly with medicinesmedicinal products known to cause QT prolongation or electrolyte imbalance, caution should be used. 4.8 Undesirable effects The following undesirable effects adverse reactions occurred more often (≥ 1/100) than placebo, or were identified as possibly medically relevant adverse reactions (*) in clinical trials with aripiprazole solution for injection (see section 5.1): The frequency listed below is defined using the following convention: common (³ 1/100, to < 1/10) and uncommon (³ 1/1,000, to < 1/100). Cardiac disorders Uncommon: tachycardia* Nervous system disorders Common: somnolence, dizziness, headache, akathisia Cardiac disorders Uncommon: tachycardia* Vascular disorders Uncommon: orthostatic hypotension*, increased diastolic blood pressure* Gastrointestinal disorders Common: nausea, vomiting Uncommon: dry mouth* Vascular disorders Uncommon: orthostatic hypotension*, increased diastolic blood pressure* General disorders and administration site conditions Uncommon: fatigue* The following undesirable effects adverse reactionsoccurred more often (≥ 1/100) than placebo, or were identified as possibly medically relevant adverse reactions (*) in clinical trials with oral formulations of aripiprazole (see section 5.1): Psychiatric disorders Common: restlessness, insomnia, anxiety Uncommon: depression* Nervous system disorders Common: extrapyramidal disorder, akathisia, tremor, dizziness, somnolence, sedation, headache Eye disorders Common: blurred vision Cardiac disorders Uncommon: tachycardia* Nervous system disorders Common: extrapyramidal disorder, akathisia, tremor, dizziness, somnolence, sedation, headache Eye disorders Common: blurred vision Vascular disorders Uncommon: orthostatic hypotension* Gastrointestinal disorders Common: dyspepsia, vomiting, nausea, constipation, salivary hypersecretion Vascular disorders Uncommon: orthostatic hypotension* General disorders and administration site conditions Common: fatigue Psychiatric disorders Common: restlessness, insomnia, anxiety Uncommon: depression* ......................... Other findings: Undesirable effectsAdverse reactions known to be associated with antipsychotic therapy and also reported during treatment with aripiprazole include neuroleptic malignant syndrome, tardive dyskinesia, seizure, cerebrovascular adverse eventsreactions and increased mortality in elderly demented patients, hyperglycaemia and diabetes mellitus (see section 4.4). Post-Marketing: The following adverse eventsreactions have been reported during post-marketing surveillance. The frequency of these eventsreactions is considered not known (cannot be estimated from the available data). Blood and the lymphatic system disorders: leukopenia, neutropenia, thrombocytopenia Immune system disorders: allergic reaction (e.g. anaphylactic reaction, angioedema including swollen tongue, tongue oedema, face oedema, pruritus, or urticaria) Endocrine disorders: hyperglycaemia, diabetes mellitus, diabetic ketoacidosis, diabetic hyperosmolar coma Metabolism and nutrition disorders: weight gain, weight decreased, anorexia, hyponatremia Psychiatric disorders: agitation, nervousness; suicide attempt, suicidal ideation, and completed suicide (see section 4.4) Nervous system disorders: speech disorder, Neuroleptic Malignant Syndrome (NMS), grand mal convulsion Cardiac disorders: QT prolongation, ventricular arrhythmias, sudden unexplained death, cardiac arrest, torsades de pointes, bradycardia Vascular disorders: syncope, hypertension, thromboembolic reactions Respiratory, thoracic and mediastinal disorders: oropharyngeal spasm, laryngospasm, aspiration pneumonia Gastrointestinal disorders: pancreatitis, dysphagia, abdominal discomfort, stomach discomfort, diarrhoea Hepatobiliary disorders: jaundice, hepatitis, increased Alanine Aminotransferase (ALT), increased Aspartate Aminotransferase (AST), increased Gamma Glutamyl Transferase (GGT), increased alkaline phosphatase Skin and subcutaneous tissue disorders: rash, photosensitivity reaction, alopecia, hyperhidrosis Musculoskeletal and connective tissue disorders: rhabdomyolysis, myalgia, stiffness Renal and urinary disorders: urinary incontinence, urinary retention Reproductive system and breast disorders: priapism General disorders and administration site conditions: temperature regulation disorder (e.g. hypothermia, pyrexia), chest pain, peripheral oedema Investigations: increased Creatine Phosphokinase, blood glucose increased, blood glucose fluctuation, glycosylated haemoglobin increased Cardiac disorders: QT prolongation, ventricular arrhythmias, sudden unexplained death, cardiac arrest, torsades de pointes, bradycardia Blood and the lymphatic system disorders: leukopenia, neutropenia, thrombocytopenia Nervous system disorders: speech disorder, Neuroleptic Malignant Syndrome (NMS), grand mal convulsion Respiratory, thoracic and mediastinal disorders: oropharyngeal spasm, laryngospasm, aspiration pneumonia Gastrointestinal disorders: pancreatitis, dysphagia, abdominal discomfort, stomach discomfort, diarrhoea Renal and urinary disorders: urinary incontinence, urinary retention Skin and subcutaneous tissue disorders: rash, photosensitivity reaction, alopecia, hyperhidrosis Musculoskeletal and connective tissue disorders: rhabdomyolysis, myalgia, stiffness Endocrine disorders: hyperglycaemia, diabetes mellitus, diabetic ketoacidosis, diabetic hyperosmolar coma Metabolism and nutrition disorders: weight gain, weight decreased, anorexia, hyponatremia Vascular disorders: syncope, hypertension, thromboembolic events General disorders and administration site conditions: temperature regulation disorder (e.g. hypothermia, pyrexia), chest pain, peripheral oedema Immune system disorders: allergic reaction (e.g. anaphylactic reaction, angioedema including swollen tongue, tongue oedema, face oedema, pruritus, or urticaria) Hepatobiliary disorders: jaundice, hepatitis, increased Alanine Aminotransferase (ALT), increased Aspartate Aminotransferase (AST), increased Gamma Glutamyl Transferase (GGT), increased alkaline phosphatase Reproductive system and breast disorders: priapism Psychiatric disorders: agitation, nervousness; suicide attempt, suicidal ideation, and completed suicide (see section 4.4) 5.1 Pharmacodynamic properties Pharmacotherapeutic group: other antipsychotics, ATC code: N05AX12 .................................. 6.3 Shelf life 18 months After opening: uUse product immediately after opening and discard any unused amount. 6.6 Special precautions for disposal and other handling Any unused product or waste material should be disposed of in accordance with local requirements. 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 4 June 2004 Date of latest renewal: 21 April 2009 10. DATE OF REVISION OF THE TEXT August 2008 04/2009 Detailed information on this product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/
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 undesirable effects adverse reactions such as sedation (see section 4.8).
If aripiprazole is administered concomitantly with medicinesmedicinal products known to cause QT prolongation or electrolyte imbalance, caution should be used.
The following undesirable effects adverse reactions occurred more often (≥ 1/100) than placebo, or were identified as possibly medically relevant adverse reactions (*) in clinical trials with aripiprazole solution for injection (see section 5.1):
The frequency listed below is defined using the following convention: common (³ 1/100, to < 1/10) and uncommon (³ 1/1,000, to < 1/100). Cardiac disorders Uncommon: tachycardia* Nervous system disorders Common: somnolence, dizziness, headache, akathisia Cardiac disorders Uncommon: tachycardia* Vascular disorders Uncommon: orthostatic hypotension*, increased diastolic blood pressure* Gastrointestinal disorders Common: nausea, vomiting Uncommon: dry mouth* Vascular disorders Uncommon: orthostatic hypotension*, increased diastolic blood pressure* General disorders and administration site conditions Uncommon: fatigue* The following undesirable effects adverse reactionsoccurred more often (≥ 1/100) than placebo, or were identified as possibly medically relevant adverse reactions (*) in clinical trials with oral formulations of aripiprazole (see section 5.1): Psychiatric disorders Common: restlessness, insomnia, anxiety Uncommon: depression* Nervous system disorders Common: extrapyramidal disorder, akathisia, tremor, dizziness, somnolence, sedation, headache Eye disorders Common: blurred vision Cardiac disorders Uncommon: tachycardia* Nervous system disorders Common: extrapyramidal disorder, akathisia, tremor, dizziness, somnolence, sedation, headache Eye disorders Common: blurred vision Vascular disorders Uncommon: orthostatic hypotension* Gastrointestinal disorders Common: dyspepsia, vomiting, nausea, constipation, salivary hypersecretion Vascular disorders Uncommon: orthostatic hypotension* General disorders and administration site conditions Common: fatigue Psychiatric disorders Common: restlessness, insomnia, anxiety Uncommon: depression* ......................... Other findings: Undesirable effectsAdverse reactions known to be associated with antipsychotic therapy and also reported during treatment with aripiprazole include neuroleptic malignant syndrome, tardive dyskinesia, seizure, cerebrovascular adverse eventsreactions and increased mortality in elderly demented patients, hyperglycaemia and diabetes mellitus (see section 4.4). Post-Marketing: The following adverse eventsreactions have been reported during post-marketing surveillance. The frequency of these eventsreactions is considered not known (cannot be estimated from the available data). Blood and the lymphatic system disorders: leukopenia, neutropenia, thrombocytopenia Immune system disorders: allergic reaction (e.g. anaphylactic reaction, angioedema including swollen tongue, tongue oedema, face oedema, pruritus, or urticaria) Endocrine disorders: hyperglycaemia, diabetes mellitus, diabetic ketoacidosis, diabetic hyperosmolar coma Metabolism and nutrition disorders: weight gain, weight decreased, anorexia, hyponatremia Psychiatric disorders: agitation, nervousness; suicide attempt, suicidal ideation, and completed suicide (see section 4.4) Nervous system disorders: speech disorder, Neuroleptic Malignant Syndrome (NMS), grand mal convulsion Cardiac disorders: QT prolongation, ventricular arrhythmias, sudden unexplained death, cardiac arrest, torsades de pointes, bradycardia Vascular disorders: syncope, hypertension, thromboembolic reactions Respiratory, thoracic and mediastinal disorders: oropharyngeal spasm, laryngospasm, aspiration pneumonia Gastrointestinal disorders: pancreatitis, dysphagia, abdominal discomfort, stomach discomfort, diarrhoea Hepatobiliary disorders: jaundice, hepatitis, increased Alanine Aminotransferase (ALT), increased Aspartate Aminotransferase (AST), increased Gamma Glutamyl Transferase (GGT), increased alkaline phosphatase Skin and subcutaneous tissue disorders: rash, photosensitivity reaction, alopecia, hyperhidrosis Musculoskeletal and connective tissue disorders: rhabdomyolysis, myalgia, stiffness Renal and urinary disorders: urinary incontinence, urinary retention Reproductive system and breast disorders: priapism General disorders and administration site conditions: temperature regulation disorder (e.g. hypothermia, pyrexia), chest pain, peripheral oedema Investigations: increased Creatine Phosphokinase, blood glucose increased, blood glucose fluctuation, glycosylated haemoglobin increased Cardiac disorders: QT prolongation, ventricular arrhythmias, sudden unexplained death, cardiac arrest, torsades de pointes, bradycardia Blood and the lymphatic system disorders: leukopenia, neutropenia, thrombocytopenia Nervous system disorders: speech disorder, Neuroleptic Malignant Syndrome (NMS), grand mal convulsion Respiratory, thoracic and mediastinal disorders: oropharyngeal spasm, laryngospasm, aspiration pneumonia Gastrointestinal disorders: pancreatitis, dysphagia, abdominal discomfort, stomach discomfort, diarrhoea Renal and urinary disorders: urinary incontinence, urinary retention Skin and subcutaneous tissue disorders: rash, photosensitivity reaction, alopecia, hyperhidrosis Musculoskeletal and connective tissue disorders: rhabdomyolysis, myalgia, stiffness Endocrine disorders: hyperglycaemia, diabetes mellitus, diabetic ketoacidosis, diabetic hyperosmolar coma Metabolism and nutrition disorders: weight gain, weight decreased, anorexia, hyponatremia Vascular disorders: syncope, hypertension, thromboembolic events General disorders and administration site conditions: temperature regulation disorder (e.g. hypothermia, pyrexia), chest pain, peripheral oedema Immune system disorders: allergic reaction (e.g. anaphylactic reaction, angioedema including swollen tongue, tongue oedema, face oedema, pruritus, or urticaria) Hepatobiliary disorders: jaundice, hepatitis, increased Alanine Aminotransferase (ALT), increased Aspartate Aminotransferase (AST), increased Gamma Glutamyl Transferase (GGT), increased alkaline phosphatase Reproductive system and breast disorders: priapism Psychiatric disorders: agitation, nervousness; suicide attempt, suicidal ideation, and completed suicide (see section 4.4) 5.1 Pharmacodynamic properties Pharmacotherapeutic group: other antipsychotics, ATC code: N05AX12 .................................. 6.3 Shelf life 18 months After opening: uUse product immediately after opening and discard any unused amount. 6.6 Special precautions for disposal and other handling Any unused product or waste material should be disposed of in accordance with local requirements. 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 4 June 2004 Date of latest renewal: 21 April 2009 10. DATE OF REVISION OF THE TEXT August 2008 04/2009 Detailed information on this product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/
Cardiac disorders Uncommon: tachycardia*
Uncommon: tachycardia*
Nervous system disorders
Common: somnolence, dizziness, headache, akathisia
Vascular disorders
Uncommon: orthostatic hypotension*, increased diastolic blood pressure*
Gastrointestinal disorders
Common: nausea, vomiting Uncommon: dry mouth*
Uncommon: dry mouth*
General disorders and administration site conditions
Uncommon: fatigue*
The following undesirable effects adverse reactionsoccurred more often (≥ 1/100) than placebo, or were identified as possibly medically relevant adverse reactions (*) in clinical trials with oral formulations of aripiprazole (see section 5.1):
Psychiatric disorders Common: restlessness, insomnia, anxiety Uncommon: depression*
Common: restlessness, insomnia, anxiety Uncommon: depression*
Uncommon: depression*
Nervous system disorders Common: extrapyramidal disorder, akathisia, tremor, dizziness, somnolence, sedation, headache
Common: extrapyramidal disorder, akathisia, tremor, dizziness, somnolence, sedation, headache
Eye disorders Common: blurred vision
Common: blurred vision
Cardiac disorders
Vascular disorders Uncommon: orthostatic hypotension*
Uncommon: orthostatic hypotension*
Common: dyspepsia, vomiting, nausea, constipation, salivary hypersecretion
Common: fatigue
.........................
Other findings:
Undesirable effectsAdverse reactions known to be associated with antipsychotic therapy and also reported during treatment with aripiprazole include neuroleptic malignant syndrome, tardive dyskinesia, seizure, cerebrovascular adverse eventsreactions and increased mortality in elderly demented patients, hyperglycaemia and diabetes mellitus (see section 4.4). Post-Marketing: The following adverse eventsreactions have been reported during post-marketing surveillance. The frequency of these eventsreactions is considered not known (cannot be estimated from the available data). Blood and the lymphatic system disorders: leukopenia, neutropenia, thrombocytopenia Immune system disorders: allergic reaction (e.g. anaphylactic reaction, angioedema including swollen tongue, tongue oedema, face oedema, pruritus, or urticaria) Endocrine disorders: hyperglycaemia, diabetes mellitus, diabetic ketoacidosis, diabetic hyperosmolar coma Metabolism and nutrition disorders: weight gain, weight decreased, anorexia, hyponatremia Psychiatric disorders: agitation, nervousness; suicide attempt, suicidal ideation, and completed suicide (see section 4.4) Nervous system disorders: speech disorder, Neuroleptic Malignant Syndrome (NMS), grand mal convulsion Cardiac disorders: QT prolongation, ventricular arrhythmias, sudden unexplained death, cardiac arrest, torsades de pointes, bradycardia Vascular disorders: syncope, hypertension, thromboembolic reactions Respiratory, thoracic and mediastinal disorders: oropharyngeal spasm, laryngospasm, aspiration pneumonia Gastrointestinal disorders: pancreatitis, dysphagia, abdominal discomfort, stomach discomfort, diarrhoea Hepatobiliary disorders: jaundice, hepatitis, increased Alanine Aminotransferase (ALT), increased Aspartate Aminotransferase (AST), increased Gamma Glutamyl Transferase (GGT), increased alkaline phosphatase Skin and subcutaneous tissue disorders: rash, photosensitivity reaction, alopecia, hyperhidrosis Musculoskeletal and connective tissue disorders: rhabdomyolysis, myalgia, stiffness Renal and urinary disorders: urinary incontinence, urinary retention Reproductive system and breast disorders: priapism General disorders and administration site conditions: temperature regulation disorder (e.g. hypothermia, pyrexia), chest pain, peripheral oedema Investigations: increased Creatine Phosphokinase, blood glucose increased, blood glucose fluctuation, glycosylated haemoglobin increased Cardiac disorders: QT prolongation, ventricular arrhythmias, sudden unexplained death, cardiac arrest, torsades de pointes, bradycardia Blood and the lymphatic system disorders: leukopenia, neutropenia, thrombocytopenia Nervous system disorders: speech disorder, Neuroleptic Malignant Syndrome (NMS), grand mal convulsion Respiratory, thoracic and mediastinal disorders: oropharyngeal spasm, laryngospasm, aspiration pneumonia Gastrointestinal disorders: pancreatitis, dysphagia, abdominal discomfort, stomach discomfort, diarrhoea Renal and urinary disorders: urinary incontinence, urinary retention Skin and subcutaneous tissue disorders: rash, photosensitivity reaction, alopecia, hyperhidrosis Musculoskeletal and connective tissue disorders: rhabdomyolysis, myalgia, stiffness Endocrine disorders: hyperglycaemia, diabetes mellitus, diabetic ketoacidosis, diabetic hyperosmolar coma Metabolism and nutrition disorders: weight gain, weight decreased, anorexia, hyponatremia Vascular disorders: syncope, hypertension, thromboembolic events General disorders and administration site conditions: temperature regulation disorder (e.g. hypothermia, pyrexia), chest pain, peripheral oedema Immune system disorders: allergic reaction (e.g. anaphylactic reaction, angioedema including swollen tongue, tongue oedema, face oedema, pruritus, or urticaria) Hepatobiliary disorders: jaundice, hepatitis, increased Alanine Aminotransferase (ALT), increased Aspartate Aminotransferase (AST), increased Gamma Glutamyl Transferase (GGT), increased alkaline phosphatase Reproductive system and breast disorders: priapism Psychiatric disorders: agitation, nervousness; suicide attempt, suicidal ideation, and completed suicide (see section 4.4) 5.1 Pharmacodynamic properties Pharmacotherapeutic group: other antipsychotics, ATC code: N05AX12 .................................. 6.3 Shelf life 18 months After opening: uUse product immediately after opening and discard any unused amount. 6.6 Special precautions for disposal and other handling Any unused product or waste material should be disposed of in accordance with local requirements. 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 4 June 2004 Date of latest renewal: 21 April 2009 10. DATE OF REVISION OF THE TEXT August 2008 04/2009 Detailed information on this product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/
The following adverse eventsreactions have been reported during post-marketing surveillance. The frequency of these eventsreactions is considered not known (cannot be estimated from the available data).
syncope, hypertension, thromboembolic reactions
Hepatobiliary disorders:
chest pain, peripheral oedema
syncope, hypertension, thromboembolic events
5.1 Pharmacodynamic properties Pharmacotherapeutic group: other antipsychotics, ATC code: N05AX12 .................................. 6.3 Shelf life 18 months After opening: uUse product immediately after opening and discard any unused amount. 6.6 Special precautions for disposal and other handling Any unused product or waste material should be disposed of in accordance with local requirements. 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 4 June 2004 Date of latest renewal: 21 April 2009 10. DATE OF REVISION OF THE TEXT August 2008 04/2009 Detailed information on this product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/
Pharmacotherapeutic group: other antipsychotics, ATC code: N05AX12 .................................. 6.3 Shelf life 18 months After opening: uUse product immediately after opening and discard any unused amount. 6.6 Special precautions for disposal and other handling Any unused product or waste material should be disposed of in accordance with local requirements. 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 4 June 2004 Date of latest renewal: 21 April 2009 10. DATE OF REVISION OF THE TEXT August 2008 04/2009 Detailed information on this product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/
..................................
6.3 Shelf life
18 months After opening: uUse product immediately after opening and discard any unused amount. 6.6 Special precautions for disposal and other handling Any unused product or waste material should be disposed of in accordance with local requirements. 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 4 June 2004 Date of latest renewal: 21 April 2009 10. DATE OF REVISION OF THE TEXT August 2008 04/2009 Detailed information on this product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/
After opening: uUse product immediately after opening and discard any unused amount. 6.6 Special precautions for disposal and other handling Any unused product or waste material should be disposed of in accordance with local requirements. 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 4 June 2004 Date of latest renewal: 21 April 2009 10. DATE OF REVISION OF THE TEXT August 2008 04/2009 Detailed information on this product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/
6.6 Special precautions for disposal and other handling
Any unused product or waste material should be disposed of in accordance with local requirements. 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 4 June 2004 Date of latest renewal: 21 April 2009 10. DATE OF REVISION OF THE TEXT August 2008 04/2009 Detailed information on this product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 4 June 2004 Date of latest renewal: 21 April 2009 10. DATE OF REVISION OF THE TEXT August 2008 04/2009 Detailed information on this product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorisation: 4 June 2004 Date of latest renewal: 21 April 2009 10. DATE OF REVISION OF THE TEXT August 2008 04/2009 Detailed information on this product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/
Date of latest renewal: 21 April 2009 10. DATE OF REVISION OF THE TEXT August 2008 04/2009 Detailed information on this product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/
10. DATE OF REVISION OF THE TEXT August 2008 04/2009 Detailed information on this product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/
August 2008 04/2009 Detailed information on this product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/
Addition of: 'Results of an epidemiological study found that there was no increased risk of suicidality with aripiprazole compared to other antipsychotics among patients with bipolar disorder.'
Changed from February 2008 to August 2008
4.1 Therapeutic indications
ABILIFY solution for injection is indicated for the rapid control of agitation and disturbed behaviours in patients with schizophrenia or in patients with manic episodes in Bipolar I Disorder, when oral therapy is not appropriate.
The following undesirable effects occurred more often (¡Ã 1/100) than placebo, or were identified as possibly medically relevant adverse reactions (*) in clinical trials with aripiprazole solution for injection (see section 5.1):
The frequency listed below is defined using the following convention: common (©ø 1/100, < 1/10) and uncommon (©ø 1/1,000, < 1/100).
Common: nausea, vomiting
The following undesirable effects occurred more often (¡Ã 1/100) than placebo, or were identified as possibly medically relevant adverse reactions (*) in clinical trials with oral formulations of aripiprazole (see section 5.1):
Eye disorders
Common: fatigue[K1]
Psychiatric disorders
Common: restlessness, insomnia, anxiety
Extrapyramidal symptoms (EPS): Schizophrenia - in a long term 52-week controlled trial, aripiprazole-treated patients had an overall-lower incidence (25.8%) of EPS including parkinsonism, akathisia, dystonia and dyskinesia compared with those treated with haloperidol (57.3%). In a long term 26-week placebo-controlled trial, the incidence of EPS was 19% for aripiprazole-treated patients and 13.1% for placebo-treated patients. In another long-term 26-week controlled trial, the incidence of EPS was 14.8% for aripiprazole-treated patients and 15.1% for olanzapine-treated patients. Manic episodes in Bipolar I Disorder - in a 12-week controlled trial, the incidence of EPS was 23.5% for aripiprazole-treated patients and 53.3% for haloperidol-treated patients. In another 12-week trial, the incidence of EPS was 26.6% for patients treated with aripiprazole and 17.6% for those treated with lithium. In the long term 26-week maintenance phase of a placebo-controlled trial, the incidence of EPS was 18.2% for aripiprazole-treated patients and 15.7% for placebo-treated patients.
In placebo-controlled trials, the incidence of akathisia in bipolar patients was 12.1% with aripiprazole and 3.2% with placebo. In schizophrenia patients the incidence of akathisia was 6.2% with aripiprazole and 3.0% with placebo.
Comparisons between aripiprazole and placebo in the proportions of patients experiencing potentially clinically significant changes in routine laboratory parameters revealed no medically important differences. Elevations of CPK (Creatine Phosphokinase), generally transient and asymptomatic, were observed in 3.5% of aripiprazole treated patients as compared to 2.0% of patients who received placebo.
Undesirable effects known to be associated with antipsychotic therapy and also reported during treatment with aripiprazole include neuroleptic malignant syndrome, tardive dyskinesia, seizure, cerebrovascular adverse events and increased mortality in elderly demented patients, hyperglycaemia and diabetes mellitus (see section 4.4).
The following adverse events have been reported during post-marketing surveillance. The frequency of these events is considered not known (cannot be estimated from the available data).
leucopenia, neutropenia, thrombocytopenia
pancreatitis, dysphagia, abdominal discomfort, stomach discomfort, diarrhoea[K2]
temperature regulation disorder (e.g. hypothermia, pyrexia),
agitation, nervousness; suicide attempt, suicidal ideation, and completed suicide (see section 4.4[K3] )
[K1]Asthenia deleted
[K2]Inc salivation removed
[K3] Suicide section enters table
Anxiety here for oral, not IM
Pharmacotherapeutic group: antipsychotics, ATC code: N05AX12
It has been proposed that aripiprazole¡¯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 caudate and putamen detected by positron emission tomography.
Agitation in schizophrenia and Bipolar I Disorder with aripiprazole solution for injection:
In two short- term (24-hour) placebo-controlled trials involving 554 schizophrenic patients presenting with agitation and disturbed behaviours, aripiprazole solution for injection was associated with statistically significant greater improvements in agitation/behavioural symptoms compared to placebo and was similar to haloperidol. In one short-term (24-hour) placebo-controlled trial involving 291 patients with bipolar disorder presenting with agitation and disturbed behaviours, aripiprazole solution for injection was associated with statistically significant greater improvements in agitation/behavioural symptoms compared to placebo and was similar to the reference arm lorazepam. The observed mean improvement from baseline on the PANSS Excitement Component score at the primary 2-hour endpoint was 5.8 for placebo, 9.6 for lorazepam, and 8.7 for aripiprazole. In subpopulation analyses on patients with mixed episodes or on patients with severe agitation, a similar pattern of efficacy to the overall population was observed but statistical significance could not be established due to a reduced sample size.
Schizophrenia with oral aripiprazole:
In three short-term (4 to 6 weeks) placebo-controlled trials involving 1,228 schizophrenic patients, presenting with positive or negative symptoms, oral aripiprazole was associated with statistically significantly greater improvements in psychotic symptoms compared to placebo.
ABILIFY is effective in maintaining the clinical improvement during continuation therapy in patients who have shown an initial treatment response. In a haloperidol-controlled trial, the proportion of responder patients maintaining response to medicinal product at 52‑weeks was similar in both groups (oral aripiprazole 77% and haloperidol 73%). The overall completion rate was significantly higher for patients on oral aripiprazole (43%) than for oral haloperidol (30%). Actual scores in rating scales used as secondary endpoints, including PANSS and the Montgomery-Asberg Depression Rating Scale showed a significant improvement over haloperidol.
In a 26‑week, placebo-controlled trial in stabilised patients with chronic schizophrenia, oral aripiprazole had significantly greater reduction in relapse rate, 34% in oral aripiprazole group and 57% in placebo.
Manic episodes in Bipolar I Disorder with oral aripiprazole:
In two 3-week, flexible-dose, placebo-controlled monotherapy trials involving patients with a manic or mixed episode of Bipolar I Disorder, aripiprazole demonstrated superior efficacy to placebo in reduction of manic symptoms over 3 weeks. These trials included patients with or without psychotic features and with or without a rapid-cycling course.
In one 3-week, fixed-dose, placebo-controlled monotherapy trial involving patients with a manic or mixed episode of Bipolar I Disorder, aripiprazole failed to demonstrate superior efficacy to placebo.
In two 12-week, placebo- and active-controlled monotherapy trials in patients with a manic or mixed episode of Bipolar I Disorder, with or without psychotic features, aripiprazole demonstrated superior efficacy to placebo at week 3 and a maintenance of effect comparable to lithium or haloperidol at week 12. Aripiprazole also demonstrated a comparable proportion of patients in symptomatic remission from mania as lithium or haloperidol at week 12.
In a 6-week, placebo-controlled trial involving patients with a manic or mixed episode of Bipolar I Disorder, with or without psychotic features, who were partially non-responsive to lithium or valproate monotherapy for 2 weeks at therapeutic serum levels, the addition of aripiprazole as adjunctive therapy resulted in superior efficacy in reduction of manic symptoms than lithium or valproate monotherapy.
Non-clinical safety data revealed no special hazard for humans based on conventional oral aripiprazole studies of safety pharmacology, repeat-dose toxicity, genotoxicity, carcinogenic potential, and toxicity to reproduction.
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 at 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 aripiprazole 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.
06/2008