Azolar

Posology

Adults

Schizophrenia: the recommended starting dose for Azolar is 10 or 15 mg/day with a maintenance dose of 15 mg/day administered on a once-a-day schedule without regard to meals. Azolar is effective in a dose range of 10 to 30 mg/day. Enhanced efficacy at doses higher than a daily dose of 15 mg has not been demonstrated although individual patients may benefit from a higher dose. The maximum daily dose should not exceed 30 mg.

Manic episodes in Bipolar I Disorder: the recommended starting dose for Azolar is 15 mg administered on a once-a-day schedule without regard to meals as monotherapy or combination therapy. Some patients may benefit from a higher dose. The maximum daily dose should not exceed 30 mg.

Recurrence prevention of manic episodes in Bipolar I Disorder: for preventing recurrence of manic episodes in patients, who have been receiving aripiprazole as monotherapy or combination therapy, continue therapy at the same dose. Adjustments of daily dosage, including dose reduction should be considered on the basis of clinical status.

Paediatric population

Schizophrenia in adolescents aged 15 years and older: the recommended dose for Azolar is 10 mg/day administered on a once-a-day schedule without regard to meals. Treatment should be initiated at 2 mg (using Azolar oral solution 1 mg/ml) for 2 days, titrated to 5 mg for 2 additional days to reach the recommended daily dose of 10 mg. When appropriate, subsequent dose increases should be administered in 5 mg increments without exceeding the maximum daily dose of 30 mg. Azolar is effective in a dose range of 10 to 30 mg/day. Enhanced efficacy at doses higher than a daily dose of 10 mg has not been demonstrated although individual patients may benefit from a higher dose.

Azolar is not recommended for use in patients with schizophrenia below 15 years of age due to insufficient data on safety and efficacy.

Manic episodes in Bipolar I Disorder in adolescents aged 13 years and older: the recommended dose for Azolar is 10 mg/day administered on a once-a-day schedule without regard to meals. Treatment should be initiated at 2 mg (using Azolar oral solution 1 mg/ml) for 2 days, titrated to 5 mg for 2 additional days to reach the recommended daily dose of 10 mg. The treatment duration should be the minimum necessary for symptom control and must not exceed 12 weeks. Enhanced efficacy at doses higher than a daily dose of 10 mg has not been demonstrated, and a daily dose of 30 mg is associated with a substantially higher incidence of significant adverse reactions including EPS related events, somnolence, fatigue and weight gain. Doses higher than 10 mg/day should therefore only be used in exceptional cases and with close clinical monitoring. Younger patients are at increased risk of experiencing adverse events associated with aripiprazole. Therefore, Azolar is not recommended for use in patients below 13 years of age.

Irritability associated with autistic disorder: the safety and efficacy of Azolar in children and adolescents aged below 18 years have not yet been established.

Tics associated with Tourette's disorder: the safety and efficacy of Azolar in children and adolescents 6 to 18 years of age have not yet been established.

Special populations

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.

Renal impairment

No dosage adjustment is required in patients with renal impairment.

Elderly

The safety and efficacy of Azolar in the treatment of schizophrenia or manic episodes in Bipolar I Disorder in patients aged 65 years and older has not been established. Owing to the greater sensitivity of this population, a lower starting dose should be considered when clinical factors warrant.

Gender

No dosage adjustment is required for female patients as compared to male patients.

Smoking status

According to the metabolic pathway of aripiprazole no dosage adjustment is required for smokers.

Dose adjustments due to interactions

When concomitant administration of strong 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.

When concomitant administration of strong 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.

Method of administration

Azolar is for oral use.

The orodispersible tablet should be placed in the mouth on the tongue, where it will rapidly disperse in saliva. It can be taken with or without liquid. Removal of the intact orodispersible tablet from the mouth is difficult. Since the orodispersible tablet is fragile, it should be taken immediately on opening the blister. Alternatively, disperse the tablet in water and drink the resulting suspension.

Orodispersible tablets or oral solution may be used as an alternative to Azolar tablets for patients who have difficulty swallowing Azolar tablets.

Posology

For patients who have never taken aripiprazole, tolerability with oral aripiprazole must occur prior to initiating treatment with Azolar.

The recommended starting and maintenance dose of Azolar is 400 mg.

Titration of the dose of this medicinal product is not required. It should be administered once monthly as a single injection (no sooner than 26 days after the previous injection).

After the first injection, treatment with 10 mg to 20 mg oral aripiprazole should be continued for 14 consecutive days to maintain therapeutic aripiprazole concentrations during initiation of therapy.

If there are adverse reactions with the 400 mg dosage, reduction of the dose to 300 mg once monthly should be considered.

Missed doses

Special populations

Elderly

The safety and efficacy of Azolar in the treatment of schizophrenia in patients 65 years of age or older has not been established.

Renal impairment

No dosage adjustment is required for patients with renal impairment.

Hepatic impairment

No dosage adjustment is required for patients with mild or 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. Oral formulation should be preferred.

Known CYP2D6 poor metabolisers

In patients who are known to be CYP2D6 poor metabolisers, the starting and maintenance dose should be 300 mg. When used concomitantly with strong CYP3A4 inhibitors the dose should be reduced to 200 mg.

Dose adjustments due to interactions

Dosage adjustments should be made in patients taking concomitant strong CYP3A4 inhibitors or strong CYP2D6 inhibitors for more than 14 days. If the CYP3A4 inhibitor or CYP2D6 inhibitor is withdrawn, the dosage may need to be increased to the previous dose. In case of adverse reactions despite dose adjustments of Azolar, the necessity of concomitant use of CYP2D6 or CYP3A4 inhibitor should be reassessed.

Concomitant use of CYP3A4 inducers with Azolar should be avoided for more than 14 days because the blood levels of aripiprazole are decreased and may be below the effective levels.

Dose adjustments of Azolar in patients who are taking concomitant strong CYP2D6 inhibitors, strong CYP3A4 inhibitors, and/or CYP3A4 inducers for more than 14 days

* 200 mg and 160 mg can be achieved via adjustment of the injection volume only by using Azolar powder and solvent for prolonged-release suspension for injection.

Paediatric population

The safety and efficacy of Azolar in children and adolescents aged 0-17 years have not been established. No data are available.

Method of administration

Azolar is only intended for intramuscular use and should not be administered intravenously or subcutaneously. It should only be administered by a healthcare professional.

Azolar powder and solvent for prolonged-release suspension for injection

The suspension should be injected immediately after reconstitution but can be stored below 25 °C for up to 4 hours in the vial.

Azolar powder and solvent for prolonged-release suspension for injection in pre-filled syringe

The suspension should be injected immediately after reconstitution but can be stored below 25 °C for up to 2 hours in the syringe.

The suspension should be injected slowly as a single injection (doses must not be divided) into the gluteal or deltoid muscle. Care should be taken to avoid inadvertent injection into a blood vessel.

Gluteal muscle administration

The recommended needle for gluteal administration is a 38 mm (1.5 inch), 22 gauge hypodermic safety needle; for obese patients (Body mass index > 28 kg/m²), a 51 mm (2 inch), 21 gauge hypodermic safety needle should be used. Gluteal injections should be alternated between the two gluteal muscles.

Deltoid muscle administration

The recommended needle for deltoid administration is a 25 mm (1 inch), 23 gauge hypodermic safety needle; for obese patients, a 38 mm (1.5 inch), 22 gauge hypodermic safety needle should be used.

Deltoid injections should be alternated between the two deltoid muscles.

The powder and solvent vials and the pre-filled syringe are for single-use only.

Full instructions for use and handling of Azolar are provided in the package leaflet (information intended for healthcare professionals).

Posology

For patients who have never taken aripiprazole, tolerability with oral aripiprazole must occur prior to initiating treatment with Abilify Maintena.

The recommended starting and maintenance dose of Abilify Maintena is 400 mg.

Titration of the dose of this medicinal product is not required. It should be administered once monthly as a single injection (no sooner than 26 days after the previous injection).

After the first injection, treatment with 10 mg to 20 mg oral aripiprazole should be continued for 14 consecutive days to maintain therapeutic aripiprazole concentrations during initiation of therapy.

If there are adverse reactions with the 400 mg dosage, reduction of the dose to 300 mg once monthly should be considered.

Missed doses

Special populations

Elderly

The safety and efficacy of Abilify Maintena in the treatment of schizophrenia in patients 65 years of age or older has not been established.

Renal impairment

No dosage adjustment is required for patients with renal impairment.

Hepatic impairment

No dosage adjustment is required for patients with mild or 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. Oral formulation should be preferred.

Known CYP2D6 poor metabolisers

In patients who are known to be CYP2D6 poor metabolisers, the starting and maintenance dose should be 300 mg. When used concomitantly with strong CYP3A4 inhibitors the dose should be reduced to 200 mg.

Dose adjustments due to interactions

Dosage adjustments should be made in patients taking concomitant strong CYP3A4 inhibitors or strong CYP2D6 inhibitors for more than 14 days. If the CYP3A4 inhibitor or CYP2D6 inhibitor is withdrawn, the dosage may need to be increased to the previous dose. In case of adverse reactions despite dose adjustments of Abilify Maintena, the necessity of concomitant use of CYP2D6 or CYP3A4 inhibitor should be reassessed.

Concomitant use of CYP3A4 inducers with Abilify Maintena should be avoided for more than 14 days because the blood levels of aripiprazole are decreased and may be below the effective levels.

Dose adjustments of Abilify Maintena in patients who are taking concomitant strong CYP2D6 inhibitors, strong CYP3A4 inhibitors, and/or CYP3A4 inducers for more than 14 days

* 200 mg and 160 mg can be achieved via adjustment of the injection volume only by using Abilify Maintena powder and solvent for prolonged-release suspension for injection.

Paediatric population

The safety and efficacy of Abilify Maintena in children and adolescents aged 0-17 years have not been established. No data are available.

Method of administration

Abilify Maintena is only intended for intramuscular use and should not be administered intravenously or subcutaneously. It should only be administered by a healthcare professional.

Abilify Maintena powder and solvent for prolonged-release suspension for injection

The suspension should be injected immediately after reconstitution but can be stored below 25 °C for up to 4 hours in the vial.

Abilify Maintena powder and solvent for prolonged-release suspension for injection in pre-filled syringe

The suspension should be injected immediately after reconstitution but can be stored below 25 °C for up to 2 hours in the syringe.

The suspension should be injected slowly as a single injection (doses must not be divided) into the gluteal or deltoid muscle. Care should be taken to avoid inadvertent injection into a blood vessel.

Gluteal muscle administration

The recommended needle for gluteal administration is a 38 mm (1.5 inch), 22 gauge hypodermic safety needle; for obese patients (Body mass index > 28 kg/m²), a 51 mm (2 inch), 21 gauge hypodermic safety needle should be used. Gluteal injections should be alternated between the two gluteal muscles.

Deltoid muscle administration

The recommended needle for deltoid administration is a 25 mm (1 inch), 23 gauge hypodermic safety needle; for obese patients, a 38 mm (1.5 inch), 22 gauge hypodermic safety needle should be used.

Deltoid injections should be alternated between the two deltoid muscles.

The powder and solvent vials and the pre-filled syringe are for single-use only.

Full instructions for use and handling of Abilify Maintena are provided in the package leaflet (information intended for healthcare professionals).

Posology

Adults

Schizophrenia: the recommended starting dose for ABILIFY is 10 or 15 mg/day with a maintenance dose of 15 mg/day administered on a once-a-day schedule without regard to meals. ABILIFY is effective in a dose range of 10 to 30 mg/day. Enhanced efficacy at doses higher than a daily dose of 15 mg has not been demonstrated although individual patients may benefit from a higher dose. The maximum daily dose should not exceed 30 mg.

Manic episodes in Bipolar I Disorder: the recommended starting dose for ABILIFY is 15 mg administered on a once-a-day schedule without regard to meals as monotherapy or combination therapy. Some patients may benefit from a higher dose. The maximum daily dose should not exceed 30 mg.

Recurrence prevention of manic episodes in Bipolar I Disorder: for preventing recurrence of manic episodes in patients, who have been receiving aripiprazole as monotherapy or combination therapy, continue therapy at the same dose. Adjustments of daily dosage, including dose reduction should be considered on the basis of clinical status.

Paediatric population

Schizophrenia in adolescents aged 15 years and older: the recommended dose for ABILIFY is 10 mg/day administered on a once-a-day schedule without regard to meals. Treatment should be initiated at 2 mg (using ABILIFY oral solution 1 mg/ml) for 2 days, titrated to 5 mg for 2 additional days to reach the recommended daily dose of 10 mg. When appropriate, subsequent dose increases should be administered in 5 mg increments without exceeding the maximum daily dose of 30 mg. ABILIFY is effective in a dose range of 10 to 30 mg/day. Enhanced efficacy at doses higher than a daily dose of 10 mg has not been demonstrated although individual patients may benefit from a higher dose.

ABILIFY is not recommended for use in patients with schizophrenia below 15 years of age due to insufficient data on safety and efficacy.

Manic episodes in Bipolar I Disorder in adolescents aged 13 years and older: the recommended dose for ABILIFY is 10 mg/day administered on a once-a-day schedule without regard to meals. Treatment should be initiated at 2 mg (using ABILIFY oral solution 1 mg/ml) for 2 days, titrated to 5 mg for 2 additional days to reach the recommended daily dose of 10 mg. The treatment duration should be the minimum necessary for symptom control and must not exceed 12 weeks. Enhanced efficacy at doses higher than a daily dose of 10 mg has not been demonstrated, and a daily dose of 30 mg is associated with a substantially higher incidence of significant adverse reactions including EPS related events, somnolence, fatigue and weight gain. Doses higher than 10 mg/day should therefore only be used in exceptional cases and with close clinical monitoring. Younger patients are at increased risk of experiencing adverse events associated with aripiprazole. Therefore, ABILIFY is not recommended for use in patients below 13 years of age.

Irritability associated with autistic disorder: the safety and efficacy of ABILIFY in children and adolescents aged below 18 years have not yet been established.

Tics associated with Tourette's disorder: the safety and efficacy of ABILIFY in children and adolescents 6 to 18 years of age have not yet been established.

Special populations

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.

Renal impairment

No dosage adjustment is required in patients with renal impairment.

Elderly

The safety and efficacy of ABILIFY in the treatment of schizophrenia or manic episodes in Bipolar I Disorder in patients aged 65 years and older has not been established. Owing to the greater sensitivity of this population, a lower starting dose should be considered when clinical factors warrant.

Gender

No dosage adjustment is required for female patients as compared to male patients.

Smoking status

According to the metabolic pathway of aripiprazole no dosage adjustment is required for smokers.

Dose adjustments due to interactions

When concomitant administration of strong 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.

When concomitant administration of strong 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.

Method of administration

ABILIFY is for oral use.

The orodispersible tablet should be placed in the mouth on the tongue, where it will rapidly disperse in saliva. It can be taken with or without liquid. Removal of the intact orodispersible tablet from the mouth is difficult. Since the orodispersible tablet is fragile, it should be taken immediately on opening the blister. Alternatively, disperse the tablet in water and drink the resulting suspension.

Orodispersible tablets or oral solution may be used as an alternative to ABILIFY tablets for patients who have difficulty swallowing ABILIFY tablets.

Posology

Adults

Schizophrenia: the recommended starting dose for Azolar Milpharm is 10 or 15 mg/day with a maintenance dose of 15 mg/day administered on a once-a-day schedule without regard to meals.

Azolar Milpharm is effective in a dose range of 10 to 30 mg/day. Enhanced efficacy at doses higher than a daily dose of 15 mg has not been demonstrated although individual patients may benefit from a higher dose. The maximum daily dose should not exceed 30 mg.

Paediatric population

Other pharmaceutical formulations containing Azolar are available and may be more suitable to perform any initial titration in paediatric population.

Schizophrenia in adolescents aged 15 years and older: the recommended dose for Azolar is 10 mg/day administered on a once-a-day schedule without regard to meals.

Tics associated with Tourette's disorder: the safety and efficacy of Azolar in children and adolescents 6 to 18 years of age have not yet been established.

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.

Patients with renal impairment:

No dosage adjustment is required in patients with renal impairment.

Older people:

The effectiveness of Azolar in the treatment of schizophrenia in patients aged 65 years and older has not been established. Owing to the greater sensitivity of this population, a lower starting dose should be considered when clinical factors warrant.

Gender:

No dosage adjustment is required for female patients as compared to male patients.

Smoking status:

According to the metabolic pathway of Azolar Milpharm no dosage adjustment is required for smokers.

Dose adjustments due to interactions:

When concomitant administration of potent CYP3A4 or CYP2D6 inhibitors with Azolar occurs, the Azolar dose should be reduced. When the CYP3A4 or CYP2D6 inhibitor is withdrawn from the combination therapy, Azolar dose should then be increased.

When concomitant administration of potent CYP3A4 inducers with Azolar occurs, the Azolar dose should be increased. When the CYP3A4 inducer is withdrawn from the combination therapy, the Azolar dose should then be reduced to the recommended dose.

Method of administration

Azolar Milpharm tablets are for oral use.

Posology

Adults

Schizophrenia: the recommended starting dose for Azolar is 10 or 15 mg/day with a maintenance dose of 15 mg/day administered on a once-a-day schedule without regard to meals.

Azolar is effective in a dose range of 10 to 30 mg/day. Enhanced efficacy at doses higher than a daily dose of 15 mg has not been demonstrated although individual patients may benefit from a higher dose. The maximum daily dose should not exceed 30 mg.

Manic episodes in Bipolar I Disorder: the recommended starting dose for Azolar is 15 mg administered on a once-a-day schedule without regard to meals as monotherapy or combination therapy. Some patients may benefit from a higher dose. The maximum daily dose should not exceed 30 mg.

Recurrence prevention of manic episodes in Bipolar I Disorder: for preventing recurrence of manic episodes in patients, who have been receiving aripiprazole as monotherapy or combination therapy, continue therapy at the same dose. Adjustments of daily dosage, including dose reduction should be considered on the basis of clinical status.

Paediatric population

Schizophrenia in adolescents aged 15 years and older: the recommended dose for Azolar is 10 mg/day administered on a once-a-day schedule without regard to meals. Treatment should be initiated at 2 mg (using aripiprazole oral solution 1 mg/ml) for 2 days, titrated to 5 mg for 2 additional days to reach the recommended daily dose of 10 mg. When appropriate, subsequent dose increases should be administered in 5 mg increments without exceeding the maximum daily dose of 30 mg.

Azolar is effective in a dose range of 10 to 30 mg/day. Enhanced efficacy at doses higher than a daily dose of 10 mg has not been demonstrated although individual patients may benefit from a higher dose.

Azolar is not recommended for use in patients with schizophrenia below 15 years of age due to insufficient data on safety and efficacy.

Manic episodes in Bipolar I Disorder in adolescents aged 13 years and older: the recommended dose for Azolar is 10 mg/day administered on a once-a-day schedule without regard to meals. Treatment should be initiated at 2 mg (using aripiprazole oral solution 1 mg/ml) for 2 days, titrated to 5 mg for 2 additional days to reach the recommended daily dose of 10 mg.

The treatment duration should be the minimum necessary for symptom control and must not exceed 12 weeks. Enhanced efficacy at doses higher than a daily dose of 10 mg has not been demonstrated, and a daily dose of 30 mg is associated with a substantially higher incidence of significant adverse reactions including EPS related events, somnolence, fatigue and weight gain. Doses higher than 10 mg/day should therefore only be used in exceptional cases and with close clinical monitoring.

Younger patients are at increased risk of experiencing adverse events associated with aripiprazole. Therefore, Azolar is not recommended for use in patients below 13 years of age.

Irritability associated with autistic disorder: the safety and efficacy of Azolar in children and adolescents aged below 18 years have not yet been established.

Tics associated with Tourette's disorder: the safety and efficacy of Azolar in children and adolescents 6 to 18 years of age have not yet been established.

Special population

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.

Renal impairment

No dosage adjustment is required in patients with renal impairment.

Elderly

The safety and efficacy of Azolar in the treatment of schizophrenia or manic episodes inBipolar I Disorder in patients aged 65 years and older has not been established. Owing to the greater sensitivity of this population, a lower starting dose should be considered when clinical factors warrant.

Gender

No dosage adjustment is required for female patients as compared to male patients.

Smoking status

According to the metabolic pathway of aripiprazole no dosage adjustment is required for smokers.

Dose adjustments due to interactions

When concomitant administration of strong 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.

When concomitant administration of strong 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.

Method of administration

Azolar is for oral use.

During antipsychotic treatment, improvement in the patient's clinical condition may take several days to some weeks. Patients should be closely monitored throughout this period.

Suicidality

The occurrence of suicidal behaviour is inherent in psychotic illnesses and mood disorders and in some cases has been reported early after initiation or switch of antipsychotic treatment, including treatment with aripiprazole. Close supervision of high-risk patients should accompany antipsychotic treatment.

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 medicinal products) or hypertension, including accelerated or malignant. Cases of venous thromboembolism (VTE) have been reported with antipsychotic medicinal products. Since patients treated with antipsychotics often present with acquired risk factors for VTE, all possible risk factors for VTE should be identified before and during treatment with aripiprazole and preventive measures undertaken.

QT prolongation

In clinical trials of aripiprazole, the incidence of QT prolongation was comparable to placebo. Aripiprazole should be used with caution in patients with a family history of QT prolongation.

Tardive dyskinesia

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 aripiprazole, dose reduction or discontinuation should be considered. These symptoms can temporally deteriorate or can even arise after discontinuation of treatment.

Other extrapyramidal symptoms

In paediatric clinical trials of aripiprazole akathisia and Parkinsonism were observed. If signs and symptoms of other EPS appear in a patient taking aripiprazole, dose reduction and close clinical monitoring should be considered.

Neuroleptic Malignant Syndrome (NMS)

NMS is a potentially fatal symptom complex associated with antipsychotics. In clinical trials, rare cases of NMS were reported during treatment with aripiprazole. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. However, elevated creatine phosphokinase and rhabdomyolysis, not necessarily in association with NMS, have also been reported. If a patient develops signs and symptoms indicative of NMS, or presents with unexplained high fever without additional clinical manifestations of NMS, all antipsychotics, including aripiprazole, must be discontinued.

Seizure

In clinical trials, uncommon cases of seizure were reported during treatment with aripiprazole. Therefore, aripiprazole should be used with caution in patients who have a history of seizure disorder or have conditions associated with seizures.

Elderly patients with dementia-related psychosis

Increased mortality

In three placebo-controlled trials (n = 938; mean age: 82.4 years; range: 56-99 years) of aripiprazole in elderly patients with psychosis associated with Alzheimer's disease, patients treated with aripiprazole were at increased risk of death compared to placebo. The rate of death in aripiprazole-treated patients was 3.5 % compared to 1.7 % in the placebo group. Although the causes of deaths were varied, most of the deaths appeared to be either cardiovascular (e.g. heart failure, sudden death) or infectious (e.g. pneumonia) in nature.

Cerebrovascular adverse reactions

In the same trials, cerebrovascular adverse reactions (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 reactions 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 reactions in patients treated with aripiprazole.

Aripiprazole is not indicated for the treatment of patients with dementia-related psychosis.

Hyperglycaemia and diabetes mellitus

Hyperglycaemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics, including aripiprazole. 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 reactions (including diabetes) or in abnormal glycaemia laboratory values compared to placebo. Precise risk estimates for hyperglycaemia-related adverse reactions in patients treated with aripiprazole and with other atypical antipsychotics are not available to allow direct comparisons. Patients treated with any antipsychotics, including aripiprazole, should be observed for signs and symptoms of hyperglycaemia (such as polydipsia, polyuria, polyphagia and weakness) and patients with diabetes mellitus or with risk factors for diabetes mellitus should be monitored regularly for worsening of glucose control.

Hypersensitivity

Hypersensitivity reactions, characterised by allergic symptoms, may occur with aripiprazole.

Weight gain

Weight gain is commonly seen in schizophrenic and bipolar mania patients due to co-morbidities, use of antipsychotics known to cause weight gain, poorly managed life-style, and might lead to severe complications. Weight gain has been reported post-marketing among patients prescribed aripiprazole. When seen, it is usually in those with significant risk factors such as history of diabetes, thyroid disorder or pituitary adenoma. In clinical trials aripiprazole has not been shown to induce clinically relevant weight gain in adults. In clinical trials of adolescent patients with bipolar mania, aripiprazole has been shown to be associated with weight gain after 4 weeks of treatment. Weight gain should be monitored in adolescent patients with bipolar mania. If weight gain is clinically significant, dose reduction should be considered.

Dysphagia

Oesophageal dysmotility and aspiration have been associated with the use of antipsychotics, including aripiprazole. Aripiprazole should be used cautiously in patients at risk for aspiration pneumonia.

Pathological gambling and other impulse control disorders

Patients can experience increased urges, particularly for gambling, and the inability to control these urges while taking aripiprazole. Other urges, reported, include: increased sexual urges, compulsive shopping, binge or compulsive eating, and other impulsive and compulsive behaviours. It is important for prescribers to ask patients or their caregivers specifically about the development of new or increased gambling urges, sexual urges, compulsive shopping, binge or compulsive eating, or other urges while being treated with aripiprazole. It should be noted that impulse-control symptoms can be associated with the underlying disorder; however, in some cases, urges were reported to have stopped when the dose was reduced or the medication was discontinued. Impulse control disorders may result in harm to the patient and others if not recognised. Consider dose reduction or stopping the medication if a patient develops such urges while taking aripiprazole.

Phenylketonurics

Azolar orodispersible tablets contain aspartame, a source of phenylalanine which may be harmful for people with phenylketonuria.

Lactose

Azolar orodispersible tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Patients with ADHD comorbidity

Despite the high comorbidity frequency of Bipolar I Disorder and ADHD, very limited safety data are available on concomitant use of aripiprazole and stimulants; therefore, extreme caution should be taken when these medicinal products are co-administered.

During antipsychotic treatment, improvement in the patient's clinical condition may take several days to some weeks. Patients should be closely monitored throughout this period.

Use in patients who are in an acutely agitated or severely psychotic state

Azolar should not be used to manage acutely agitated or severely psychotic states when immediate symptom control is warranted.

Suicidality

The occurrence of suicidal behaviour is inherent in psychotic illnesses, and in some cases has been reported early after initiation or switch of antipsychotic treatment, including treatment with aripiprazole. Close supervision of high risk patients should accompany antipsychotic treatment.

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 medicinal products) or hypertension, including accelerated or malignant. Cases of venous thromboembolism (VTE) have been reported with antipsychotic medicinal products. Since patients treated with antipsychotics often present with acquired risk factors for VTE, all possible risk factors for VTE should be identified before and during treatment with aripiprazole and preventive measures undertaken.

QT prolongation

In clinical trials of treatment with oral aripiprazole, the incidence of QT prolongation was comparable to placebo. Aripiprazole should be used with caution in patients with a family history of QT prolongation.

Tardive dyskinesia

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 aripiprazole, dose reduction or discontinuation should be considered. These symptoms can temporally deteriorate or can even arise after discontinuation of treatment.

Neuroleptic Malignant Syndrome (NMS)

NMS is a potentially fatal symptom complex associated with antipsychotics. In clinical trials, rare cases of NMS were reported during treatment with aripiprazole. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. However, elevated creatine phosphokinase and rhabdomyolysis, not necessarily in association with NMS, have also been reported. If a patient develops signs and symptoms indicative of NMS, or presents with unexplained high fever without additional clinical manifestations of NMS, all antipsychotics, including aripiprazole, must be discontinued.

Seizure

In clinical trials, uncommon cases of seizure were reported during treatment with aripiprazole. Therefore, aripiprazole should be used with caution in patients who have a history of seizure disorder or have conditions associated with seizures.

Elderly patients with dementia-related psychosis

Increased mortality

In three placebo-controlled trials of oral aripiprazole in elderly patients with psychosis associated with Alzheimer's disease (n = 938; mean age: 82.4 years; range: 56-99 years), patients treated with aripiprazole were at an increased risk of death compared to placebo. The rate of death in oral aripiprazole-treated patients was 3.5 % compared to 1.7 % in placebo. Although the causes of deaths were varied, most of the deaths appeared to be either cardiovascular (e.g. heart failure, sudden death) or infectious (e.g. pneumonia) in nature.

Cerebrovascular adverse reactions

In the same trials with oral aripiprazole, cerebrovascular adverse reactions (e.g. stroke, transient ischaemic attack), including fatalities, were reported in patients (mean age: 84 years; range: 78-88 years). Overall, 1.3 % of oral aripiprazole-treated patients reported cerebrovascular adverse reactions 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 reactions in patients treated with aripiprazole.

Aripiprazole is not indicated for the treatment of patients with dementia-related psychosis.

Hyperglycaemia and diabetes mellitus

Hyperglycaemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics, including aripiprazole. 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 reactions (including diabetes) or in abnormal glycaemia laboratory values compared to placebo. Precise risk estimates for hyperglycaemia-related adverse reactions in patients treated with aripiprazole and with other atypical antipsychotics are not available to allow direct comparisons. Patients treated with any antipsychotics, including aripiprazole, should be observed for signs and symptoms of hyperglycaemia (such as polydipsia, polyuria, polyphagia and weakness) and patients with diabetes mellitus or with risk factors for diabetes mellitus should be monitored regularly for worsening of glucose control.

Hypersensitivity

Hypersensitivity reactions, characterised by allergic symptoms, may occur with aripiprazole.

Weight gain

Weight gain is commonly seen in schizophrenic patients due to use of antipsychotics known to cause weight gain, co-morbidities, poorly managed life-style and might lead to severe complications. Weight gain has been reported post-marketing among patients prescribed oral aripiprazole. 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.

Dysphagia

Oesophageal dysmotility and aspiration have been associated with the use of antipsychotics, including aripiprazole. Aripiprazole should be used cautiously in patients at risk for aspiration pneumonia.

Pathological gambling and other impulse control disorders

Patients can experience increased urges, particularly for gambling, and the inability to control these urges while taking aripiprazole. Other urges, reported, include: increased sexual urges, compulsive shopping, binge or compulsive eating, and other impulsive and compulsive behaviours. It is important for prescribers to ask patients or their caregivers specifically about the development of new or increased gambling urges, sexual urges, compulsive shopping, binge or compulsive eating, or other urges while being treated with aripiprazole. It should be noted that impulse-control symptoms can be associated with the underlying disorder; however, in some cases, urges were reported to have stopped when the dose was reduced or the medication was discontinued. Impulse control disorders may result in harm to the patient and others if not recognised. Consider dose reduction or stopping the medication if a patient develops such urges while taking aripiprazole.

During antipsychotic treatment, improvement in the patient's clinical condition may take several days to some weeks. Patients should be closely monitored throughout this period.

Use in patients who are in an acutely agitated or severely psychotic state

Abilify Maintena should not be used to manage acutely agitated or severely psychotic states when immediate symptom control is warranted.

Suicidality

The occurrence of suicidal behaviour is inherent in psychotic illnesses, and in some cases has been reported early after initiation or switch of antipsychotic treatment, including treatment with aripiprazole. Close supervision of high risk patients should accompany antipsychotic treatment.

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 medicinal products) or hypertension, including accelerated or malignant. Cases of venous thromboembolism (VTE) have been reported with antipsychotic medicinal products. Since patients treated with antipsychotics often present with acquired risk factors for VTE, all possible risk factors for VTE should be identified before and during treatment with aripiprazole and preventive measures undertaken.

QT prolongation

In clinical trials of treatment with oral aripiprazole, the incidence of QT prolongation was comparable to placebo. Aripiprazole should be used with caution in patients with a family history of QT prolongation.

Tardive dyskinesia

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 aripiprazole, dose reduction or discontinuation should be considered. These symptoms can temporally deteriorate or can even arise after discontinuation of treatment.

Neuroleptic Malignant Syndrome (NMS)

NMS is a potentially fatal symptom complex associated with antipsychotics. In clinical trials, rare cases of NMS were reported during treatment with aripiprazole. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. However, elevated creatine phosphokinase and rhabdomyolysis, not necessarily in association with NMS, have also been reported. If a patient develops signs and symptoms indicative of NMS, or presents with unexplained high fever without additional clinical manifestations of NMS, all antipsychotics, including aripiprazole, must be discontinued.

Seizure

In clinical trials, uncommon cases of seizure were reported during treatment with aripiprazole. Therefore, aripiprazole should be used with caution in patients who have a history of seizure disorder or have conditions associated with seizures.

Elderly patients with dementia-related psychosis

Increased mortality

In three placebo-controlled trials of oral aripiprazole in elderly patients with psychosis associated with Alzheimer's disease (n = 938; mean age: 82.4 years; range: 56-99 years), patients treated with aripiprazole were at an increased risk of death compared to placebo. The rate of death in oral aripiprazole-treated patients was 3.5 % compared to 1.7 % in placebo. Although the causes of deaths were varied, most of the deaths appeared to be either cardiovascular (e.g. heart failure, sudden death) or infectious (e.g. pneumonia) in nature.

Cerebrovascular adverse reactions

In the same trials with oral aripiprazole, cerebrovascular adverse reactions (e.g. stroke, transient ischaemic attack), including fatalities, were reported in patients (mean age: 84 years; range: 78-88 years). Overall, 1.3 % of oral aripiprazole-treated patients reported cerebrovascular adverse reactions 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 reactions in patients treated with aripiprazole.

Aripiprazole is not indicated for the treatment of patients with dementia-related psychosis.

Hyperglycaemia and diabetes mellitus

Hyperglycaemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics, including aripiprazole. 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 reactions (including diabetes) or in abnormal glycaemia laboratory values compared to placebo. Precise risk estimates for hyperglycaemia-related adverse reactions in patients treated with aripiprazole and with other atypical antipsychotics are not available to allow direct comparisons. Patients treated with any antipsychotics, including aripiprazole, should be observed for signs and symptoms of hyperglycaemia (such as polydipsia, polyuria, polyphagia and weakness) and patients with diabetes mellitus or with risk factors for diabetes mellitus should be monitored regularly for worsening of glucose control.

Hypersensitivity

Hypersensitivity reactions, characterised by allergic symptoms, may occur with aripiprazole.

Weight gain

Weight gain is commonly seen in schizophrenic patients due to use of antipsychotics known to cause weight gain, co-morbidities, poorly managed life-style and might lead to severe complications. Weight gain has been reported post-marketing among patients prescribed oral aripiprazole. 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.

Dysphagia

Oesophageal dysmotility and aspiration have been associated with the use of antipsychotics, including aripiprazole. Aripiprazole should be used cautiously in patients at risk for aspiration pneumonia.

Pathological gambling and other impulse control disorders

Patients can experience increased urges, particularly for gambling, and the inability to control these urges while taking aripiprazole. Other urges, reported, include: increased sexual urges, compulsive shopping, binge or compulsive eating, and other impulsive and compulsive behaviours. It is important for prescribers to ask patients or their caregivers specifically about the development of new or increased gambling urges, sexual urges, compulsive shopping, binge or compulsive eating, or other urges while being treated with aripiprazole. It should be noted that impulse-control symptoms can be associated with the underlying disorder; however, in some cases, urges were reported to have stopped when the dose was reduced or the medication was discontinued. Impulse control disorders may result in harm to the patient and others if not recognised. Consider dose reduction or stopping the medication if a patient develops such urges while taking aripiprazole.

During antipsychotic treatment, improvement in the patient's clinical condition may take several days to some weeks. Patients should be closely monitored throughout this period.

Suicidality

The occurrence of suicidal behaviour is inherent in psychotic illnesses and mood disorders and in some cases has been reported early after initiation or switch of antipsychotic treatment, including treatment with aripiprazole. Close supervision of high-risk patients should accompany antipsychotic treatment.

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 medicinal products) or hypertension, including accelerated or malignant. Cases of venous thromboembolism (VTE) have been reported with antipsychotic medicinal products. Since patients treated with antipsychotics often present with acquired risk factors for VTE, all possible risk factors for VTE should be identified before and during treatment with aripiprazole and preventive measures undertaken.

QT prolongation

In clinical trials of aripiprazole, the incidence of QT prolongation was comparable to placebo. Aripiprazole should be used with caution in patients with a family history of QT prolongation.

Tardive dyskinesia

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 aripiprazole, dose reduction or discontinuation should be considered. These symptoms can temporally deteriorate or can even arise after discontinuation of treatment.

Other extrapyramidal symptoms

In paediatric clinical trials of aripiprazole akathisia and Parkinsonism were observed. If signs and symptoms of other EPS appear in a patient taking aripiprazole, dose reduction and close clinical monitoring should be considered.

Neuroleptic Malignant Syndrome (NMS)

NMS is a potentially fatal symptom complex associated with antipsychotics. In clinical trials, rare cases of NMS were reported during treatment with aripiprazole. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. However, elevated creatine phosphokinase and rhabdomyolysis, not necessarily in association with NMS, have also been reported. If a patient develops signs and symptoms indicative of NMS, or presents with unexplained high fever without additional clinical manifestations of NMS, all antipsychotics, including aripiprazole, must be discontinued.

Seizure

In clinical trials, uncommon cases of seizure were reported during treatment with aripiprazole. Therefore, aripiprazole should be used with caution in patients who have a history of seizure disorder or have conditions associated with seizures.

Elderly patients with dementia-related psychosis

Increased mortality

In three placebo-controlled trials (n = 938; mean age: 82.4 years; range: 56-99 years) of aripiprazole in elderly patients with psychosis associated with Alzheimer's disease, patients treated with aripiprazole were at increased risk of death compared to placebo. The rate of death in aripiprazole-treated patients was 3.5 % compared to 1.7 % in the placebo group. Although the causes of deaths were varied, most of the deaths appeared to be either cardiovascular (e.g. heart failure, sudden death) or infectious (e.g. pneumonia) in nature.

Cerebrovascular adverse reactions

In the same trials, cerebrovascular adverse reactions (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 reactions 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 reactions in patients treated with aripiprazole.

Aripiprazole is not indicated for the treatment of patients with dementia-related psychosis.

Hyperglycaemia and diabetes mellitus

Hyperglycaemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics, including aripiprazole. 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 reactions (including diabetes) or in abnormal glycaemia laboratory values compared to placebo. Precise risk estimates for hyperglycaemia-related adverse reactions in patients treated with aripiprazole and with other atypical antipsychotics are not available to allow direct comparisons. Patients treated with any antipsychotics, including aripiprazole, should be observed for signs and symptoms of hyperglycaemia (such as polydipsia, polyuria, polyphagia and weakness) and patients with diabetes mellitus or with risk factors for diabetes mellitus should be monitored regularly for worsening of glucose control.

Hypersensitivity

Hypersensitivity reactions, characterised by allergic symptoms, may occur with aripiprazole.

Weight gain

Weight gain is commonly seen in schizophrenic and bipolar mania patients due to co-morbidities, use of antipsychotics known to cause weight gain, poorly managed life-style, and might lead to severe complications. Weight gain has been reported post-marketing among patients prescribed aripiprazole. When seen, it is usually in those with significant risk factors such as history of diabetes, thyroid disorder or pituitary adenoma. In clinical trials aripiprazole has not been shown to induce clinically relevant weight gain in adults. In clinical trials of adolescent patients with bipolar mania, aripiprazole has been shown to be associated with weight gain after 4 weeks of treatment. Weight gain should be monitored in adolescent patients with bipolar mania. If weight gain is clinically significant, dose reduction should be considered.

Dysphagia

Oesophageal dysmotility and aspiration have been associated with the use of antipsychotics, including aripiprazole. Aripiprazole should be used cautiously in patients at risk for aspiration pneumonia.

Pathological gambling and other impulse control disorders

Patients can experience increased urges, particularly for gambling, and the inability to control these urges while taking aripiprazole. Other urges, reported, include: increased sexual urges, compulsive shopping, binge or compulsive eating, and other impulsive and compulsive behaviours. It is important for prescribers to ask patients or their caregivers specifically about the development of new or increased gambling urges, sexual urges, compulsive shopping, binge or compulsive eating, or other urges while being treated with aripiprazole. It should be noted that impulse-control symptoms can be associated with the underlying disorder; however, in some cases, urges were reported to have stopped when the dose was reduced or the medication was discontinued. Impulse control disorders may result in harm to the patient and others if not recognised. Consider dose reduction or stopping the medication if a patient develops such urges while taking aripiprazole.

Phenylketonurics

ABILIFY orodispersible tablets contain aspartame, a source of phenylalanine which may be harmful for people with phenylketonuria.

Lactose

ABILIFY orodispersible tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Patients with ADHD comorbidity

Despite the high comorbidity frequency of Bipolar I Disorder and ADHD, very limited safety data are available on concomitant use of aripiprazole and stimulants; therefore, extreme caution should be taken when these medicinal products are co-administered.

During antipsychotic treatment, improvement in the patient's clinical condition may take several days to some weeks. Patients should be closely monitored throughout this period.

Suicidality:

The occurrence of suicidal behaviour is inherent in psychotic illnesses and mood disorders and in some cases has been reported early after initiation or switch of antipsychotic therapy, including treatment with Azolar. Close supervision of high-risk patients should accompany antipsychotic therapy. Results of an epidemiological study suggested that there was no increased risk of suicidality with Azolar compared to other antipsychotics among adult patients with schizophrenia or bipolar disorder. There are insufficient paediatric data to evaluate this risk in younger patients (below 18 years of age), but there is evidence that the risk of suicide persists beyond the first 4 weeks of treatment for atypical antipsychotics, including Azolar.

Cardiovascular disorders:

Azolar 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 medicinal products) or hypertension, including accelerated or malignant.

Cases of venous thromboembolism (VTE) have been reported with antipsychotic drugs. Since patients treated with antipsychotics often present with acquired risk factors for VTE, all possible risk factors for VTE should be identified before and during treatment with Azolar and preventive measures undertaken.

Conduction abnormalities:

In clinical trials of Azolar, the incidence of QT prolongation was comparable to placebo. As with other antipsychotics, Azolar should be used with caution in patients with a family history of QT prolongation.

Tardive dyskinesia:

In clinical trials of one year or less duration, there were uncommon reports of treatment emergent dyskinesia during treatment with Azolar. If signs and symptoms of tardive dyskinesia appear in a patient on Azolar, dose reduction or discontinuation should be considered.These symptoms can temporally deteriorate or can even arise after discontinuation of treatment.

Other extrapyramidal symptoms:

In paediatric clinical trials of Azolar akathisia and parkinsonism were observed. If signs and symptoms of other EPS appear in a patient taking Azolar, dose reduction and close clinical monitoring should be considered.

Neuroleptic Malignant Syndrome (NMS):

NMS is a potentially fatal symptom complex associated with antipsychotic medicinal products. In clinical trials, rare cases of NMS were reported during treatment with Azolar. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. However, elevated creatine phosphokinase and rhabdomyolysis, not necessarily in association with NMS, have also been reported. If a patient develops signs and symptoms indicative of NMS, or presents with unexplained high fever without additional clinical manifestations of NMS, all antipsychotic medicinal products, including Azolar, must be discontinued.

Seizure:

In clinical trials, uncommon cases of seizure were reported during treatment with Azolar.

Therefore, Azolar should be used with caution in patients who have a history of seizure disorder or have conditions associated with seizures.

Elderly patients with dementia-related psychosis:

Increased mortality:

In three placebo-controlled trials (n= 938; mean age: 82.4 years; range: 56-99 years) of Azolar in elderly patients with psychosis associated with Alzheimer's disease, patients treated with Azolar were at increased risk of death compared to placebo. The rate of death in Azolar-treated patients was 3.5% compared to 1.7% in the placebo group. Although the causes of deaths were varied, most of the deaths appeared to be either cardiovascular (e.g. heart failure, sudden death) or infectious (e.g. pneumonia) in nature.

Cerebrovascular adverse reactions:

In the same trials, cerebrovascular adverse reactions (e.g. stroke, transient ischaemic attack), including fatalities, were reported in patients (mean age: 84 years; range: 78-88 years). Overall, 1.3% of Azolar-treated patients reported cerebrovascular adverse reactions 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 reactions in patients treated with Azolar.

Azolar Milpharm is not indicated for the treatment of dementia-related psychosis.

Hyperglycaemia and diabetes mellitus:

Hyperglycaemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotic agents, including Azolar. Risk factors that may predispose patients to severe complications include obesity and family history of diabetes. In clinical trials with Azolar, there were no significant differences in the incidence rates of hyperglycaemia-related adverse reactions (including diabetes) or in abnormal glycaemia laboratory values compared to placebo. Precise risk estimates for hyperglycaemia-related adverse reactions in patients treated with Azolar and with other atypical antipsychotic agents are not available to allow direct comparisons. Patients treated with any antipsychotic agents, including Azolar, 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 Azolar.

Weight gain:

Weight gain is commonly seen in schizophrenic and bipolar mania patients due to comorbidities, 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 Azolar. When seen, it is usually in those with significant risk factors such as history of diabetes, thyroid disorder or pituitary adenoma. In clinical trials Azolar has not been shown to induce clinically relevant weight gain in adults. In clinical trials of adolescent patients with bipolar mania, Azolar has been shown to be associated with weight gain after 4 weeks of treatment. Weight gain should be monitored in adolescent patients with bipolar mania. If weight gain is clinically significant, dose reduction should be considered.

Dysphagia:

Oesophageal dysmotility and aspiration have been associated with antipsychotic treatment, including Azolar. Azolar and other antipsychotic active substances should be used cautiously in patients at risk for aspiration pneumonia.

Pathological gambling:

Post-marketing reports of pathological gambling have been reported among patients prescribed Azolar, regardless of whether these patients had a prior history of gambling. Patients with a prior history of pathological gambling may be at increased risk and should be monitored carefully.

Lactose:

Azolar Milpharm tablets contain lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Patients with ADHD comorbidity: despite the high comorbidity frequency of Bipolar I Disorder and ADHD, very limited safety data are available on concomitant use of Azolar and stimulants; therefore, extreme caution should be taken when these drugs are co-administered.

During antipsychotic treatment, improvement in the patient's clinical condition may take several days to some weeks. Patients should be closely monitored throughout this period.

Suicidality

The occurrence of suicidal behaviour is inherent in psychotic illnesses and mood disorders and in some cases has been reported early after initiation or switch of antipsychotic treatment, including treatment with aripiprazole. Close supervision of high-risk patients should accompany antipsychotic treatment.

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 medicinal products) or hypertension, including accelerated or malignant.

Cases of venous thromboembolism (VTE) have been reported with antipsychotic medicinal products. Since patients treated with antipsychotics often present with acquired risk factors for VTE, all possible risk factors for VTE should be identified before and during treatment with aripiprazole and preventive measures undertaken.

QT prolongation

In clinical trials of aripiprazole, the incidence of QT prolongation was comparable to placebo. A, aripiprazole should be used with caution in patients with a family history of QT prolongation.

Tardive dyskinesia

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 aripiprazole, dose reduction or discontinuation should be considered. These symptoms can temporally deteriorate or can even arise after discontinuation of treatment.

Other extrapyramidal symptoms

In paediatric clinical trials of aripiprazole akathisia and Parkinsonism were observed. If signs and symptoms of other EPS appear in a patient taking aripiprazole, dose reduction and close clinical monitoring should be considered.

Neuroleptic Malignant Syndrome (NMS)

NMS is a potentially fatal symptom complex associated with antipsychotics. In clinical trials, rare cases of NMS were reported during treatment with aripiprazole. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. However, elevated creatine phosphokinase and rhabdomyolysis, not necessarily in association with NMS, have also been reported. If a patient develops signs and symptoms indicative of NMS, or presents with unexplained high fever without additional clinical manifestations of NMS, all antipsychotics, including aripiprazole, must be discontinued.

Seizure

In clinical trials, uncommon cases of seizure were reported during treatment with aripiprazole. Therefore, aripiprazole should be used with caution in patients who have a history of seizure disorder or have conditions associated with seizures.

Elderly patients with dementia-related psychosis

Increased mortality

In three placebo-controlled trials (n = 938; mean age: 82.4 years; range: 56-99 years) of aripiprazole in elderly patients with psychosis associated with Alzheimer's disease, patients treated with aripiprazole were at increased risk of death compared to placebo. The rate of death in aripiprazole-treated patients was 3.5 % compared to 1.7 % in the placebo group. Although the causes of deaths were varied, most of the deaths appeared to be either cardiovascular (e.g. heart failure, sudden death) or infectious (e.g. pneumonia) in nature.

Cerebrovascular adverse reactions

In the same trials, cerebrovascular adverse reactions (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 reactions 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 reactions in patients treated with aripiprazole.

Aripiprazole is not indicated for the treatment of patients with dementia-related psychosis.

Hyperglycaemia and diabetes mellitus

Hyperglycaemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics, including aripiprazole. 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 reactions (including diabetes) or in abnormal glycaemia laboratory values compared to placebo. Precise risk estimates for hyperglycaemia-related adverse reactions in patients treated with aripiprazole and with other atypical antipsychotics are not available to allow direct comparisons. Patients treated with any antipsychotics, including aripiprazole, should be observed for signs and symptoms of hyperglycaemia (such as polydipsia, polyuria, polyphagia and weakness) and patients with diabetes mellitus or with risk factors for diabetes mellitus should be monitored regularly for worsening of glucose control.

Hypersensitivity

Hypersensitivity reactions, characterised by allergic symptoms, may occur with aripiprazole.

Weight gain

Weight gain is commonly seen in schizophrenic and bipolar mania patients due to co-morbidities, use of antipsychotics known to cause weight gain, poorly managed life-style, and might lead to severe complications. Weight gain has been reported post-marketing among patients prescribed aripiprazole. When seen, it is usually in those with significant risk factors such as history of diabetes, thyroid disorder or pituitary adenoma. In clinical trials aripiprazole has not been shown to induce clinically relevant weight gain in adults. In clinical trials of adolescent patients with bipolar mania, aripiprazole has been shown to be associated with weight gain after 4 weeks of treatment. Weight gain should be monitored in adolescent patients with bipolar mania. If weight gain is clinically significant, dose reduction should be considered.

Dysphagia

Oesophageal dysmotility and aspiration have been associated with the use of antipsychotics, including aripiprazole. Aripiprazole should be used cautiously in patients at risk for aspiration pneumonia.

Pathological gambling and other impulse control disorders

Patients can experience increased urges, particularly for gambling, and the inability to control these urges while taking aripiprazole. Other urges, reported, include: increased sexual urges, compulsive shopping, binge or compulsive eating, and other impulsive and compulsive behaviours. It is important for prescribers to ask patients or their caregivers specifically about the development of new or increased gambling urges, sexual urges, compulsive shopping, binge or compulsive eating, or other urges while being treated with aripiprazole. It should be noted that impulse-control symptoms can be associated with the underlying disorder; however, in some cases, urges were reported to have stopped when the dose was reduced or the medication was discontinued. Impulse control disorders may result in harm to the patient and others if not recognised. Consider dose reduction or stopping the medication if a patient develops such urges while taking aripiprazole.

Lactose

Azolar contains lactose. Patients with rare hereditary problems of galactose intolerance, the lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Patients with ADHD comorbidity

Despite the high comorbidity frequency of Bipolar I Disorder and ADHD, very limited safety data are available on concomitant use of aripiprazole and stimulants; therefore, extreme caution should be taken when these medicinal products are co-administered.

Summary of the safety profile

The most commonly reported adverse reactions in placebo-controlled trials are akathisia and nausea each occurring in more than 3% of patients treated with oral Azolar.

Tabulated list of adverse reactions

The following adverse reactions occurred more often (> 1/100) than placebo, or were identified as possibly medically relevant adverse reactions (*).

The frequency listed below is defined using the following convention: common (> 1/100 to < 1/10) and uncommon (> 1/1,000 to < 1/100).

Description of selected adverse reactions

Extrapyramidal symptoms (EPS)

Schizophrenia - in a long term 52-week controlled trial, Azolar-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 Azolar-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 Azolar-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 Azolar-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 Azolar 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 Azolar-treated patients and 15.7% for placebo-treated patients.

Akathisia

In placebo-controlled trials, the incidence of akathisia in bipolar patients was 12.1% with Azolar and 3.2% with placebo. In schizophrenia patients the incidence of akathisia was 6.2% with Azolar and 3.0% with placebo.

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.

Comparisons between Azolar and placebo in the proportions of patients experiencing potentially clinically significant changes in routine laboratory and lipid parameters revealed no medically important differences. Elevations of CPK (Creatine Phosphokinase), generally transient and asymptomatic, were observed in 3.5% of Azolar treated patients as compared to 2.0% of patients who received placebo.

Other findings

Adverse reactions known to be associated with antipsychotic therapy and also reported during treatment with Azolar include neuroleptic malignant syndrome, tardive dyskinesia, seizure, cerebrovascular adverse reactions and increased mortality in elderly demented patients, hyperglycaemia and diabetes mellitus.

Paediatric population

Schizophrenia in adolescents aged 15 years and older

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 reactions that were reported more frequently in adolescents receiving Azolar than in adults receiving Azolar (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.In the adolescent (13-17 years) schizophrenia population with Azolar exposure of 5 to 30 mg up to 72 months, incidence of low serum prolactin levels in females (<3 ng/ml) and males (<2 ng/ml) was 25.6% and 45.0%, respectively.

Manic episodes in Bipolar I Disorder in adolescents aged 13 years and older

The frequency and type of undesirable effects in adolescents with Bipolar I Disorder were similar to those in adults except for the following reactions: very commonly (> 1/10) somnolence (23.0%), extrapyramidal disorder (18.4%), akathisia (16.0%), and fatigue (11.8%); and commonly (> 1/100, < 1/10) abdominal pain upper, heart rate increased, weight increased, increased appetite, muscle twitching, and dyskinesia.

The following undesirable effects had a possible dose response relationship; extrapyramidal disorder (incidences were 10 mg, 9.1%, 30 mg, 28.8%, placebo, 1.7%,); and akathisia (incidences were 10 mg, 12.1%, 30 mg, 20.3%, placebo, 1.7%).

Mean changes in body weight in adolescents with Bipolar I Disorder at 12 and 30 weeks for Azolar were 2.4 kg and 5.8 kg, and for placebo 0.2 kg and 2.3 kg, respectively.

In the paediatric population somnolence and fatigue were observed more frequently in patients with bipolar disorder compared to patients with schizophrenia.

In the paediatric bipolar population (10-17 years) with exposure up to 30 weeks, incidence of low serum prolactin levels in females (<3 ng/ml) and males (<2 ng/ml) was 28.0% and 53.3%, respectively.

Hyperprolactinaemia

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).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme at: www.mhra.gov.uk/yellowcard

Summary of the safety profile

The most commonly reported adverse reactions in placebo-controlled trials are akathisia and nausea each occurring in more than 3% of patients treated with oral aripiprazole.

Tabulated list of adverse reactions

The incidences of the Adverse Drug Reactions (ADRs) associated with aripiprazole therapy are tabulated below. The table is based on adverse events reported during clinical trials and/or post-marketing use.

All ADRs are listed by system organ class and frequency; very common (> 1/10), common (> 1/100 to < 1/10), uncommon (> 1/1,000 to < 1/100), rare (> 1/10,000 to < 1/1,000), very rare (< 1/10,000) and not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

The frequency of adverse reactions reported during post-marketing use cannot be determined as they are derived from spontaneous reports. Consequently, the frequency of these adverse events is qualified as “not known”

Description of selected adverse reactions

Adults

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.

Akathisia

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.

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 medicinal products. An elevated risk of acute dystonia is observed in males and younger age groups.

Prolactin

In clinical trials for the approved indications and post-marketing, both increase and decrease in serum prolactin as compared to baseline was observed with aripiprazole (section 5.1).

Laboratory parameters

Comparisons between aripiprazole and placebo in the proportions of patients experiencing potentially clinically significant changes in routine laboratory and lipid 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.

Paediatric population

Schizophrenia in adolescents aged 15 years and older

In a short-term placebo-controlled clinical trial involving 302 adolescents (13-17 years) with schizophrenia, the frequency and type of adverse reactions were similar to those in adults except for the following reactions 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.

The safety profile of a long-term, double-blind placebo controlled trial was also similar except for the following reactions that were reported more frequently than paediatric patients taking placebo: weight decreased, blood insulin increased, arrhythmia, and leukopenia were reported commonly (> 1/100, < 1/10).

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. In the adolescent (13-17 years) schizophrenia population with aripiprazole exposure of 5 to 30 mg up to 72 months, incidence of low serum prolactin levels in females (<3 ng/ml) and males (< 2 ng/ml) was 25.6 % and 45.0 %, respectively.

In two long term trials with adolescent (13-17 years) schizophrenia and bipolar patients treated with aripiprazole, incidence of low serum prolactin levels in females (<3 ng/ml) and males (<2 ng/ml) was 37.0 % and 59.4 %, respectively.

Manic episodes in Bipolar I Disorder in adolescents aged 13 years and older

The frequency and type of adverse reactions in adolescents with Bipolar I Disorder were similar to those in adults except for the following reactions: very commonly (> 1/10) somnolence (23.0 %), extrapyramidal disorder (18.4 %), akathisia (16.0 %), and fatigue (11.8 %); and commonly (> 1/100, < 1/10) abdominal pain upper, heart rate increased, weight increased, increased appetite, muscle twitching, and dyskinesia.

The following adverse reactions had a possible dose response relationship; extrapyramidal disorder (incidences were 10 mg, 9.1 %, 30 mg, 28.8 %, placebo, 1.7 %,); and akathisia (incidences were 10 mg, 12.1 %, 30 mg, 20.3 %, placebo, 1.7 %).

Mean changes in body weight in adolescents with Bipolar I Disorder at 12 and 30 weeks for aripiprazole were 2.4 kg and 5.8 kg, and for placebo 0.2 kg and 2.3 kg, respectively.

In the paediatric population somnolence and fatigue were observed more frequently in patients with bipolar disorder compared to patients with schizophrenia.

In the paediatric bipolar population (10-17 years) with exposure up to 30 weeks, incidence of low serum prolactin levels in females (< 3 ng/ml) and males (< 2 ng/ml) was 28.0 % and 53.3 %, respectively.

Pathological gambling and other impulse control disorders

Pathological gambling, hypersexuality, compulsive shopping and binge or compulsive eating can occur in patients treated with aripiprazole.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

Pharmacotherapeutic group: other antipsychotics, ATC code: N05AX12

Mechanism of action

It has been proposed that Azolar's efficacy in schizophrenia is mediated through a combination of partial agonism at dopamine D2 and serotonin 5HT1a receptors and antagonism of serotonin 5HT2a receptors. Azolar exhibited antagonist properties in animal models of dopaminergic hyperactivity and agonist properties in animal models of dopaminergic hypoactivity. Azolar 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. Azolar 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 Azolar.

Azolar 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.

Clinical efficacy and safety

Schizophrenia

In three short-term (4 to 6 weeks) placebo-controlled trials involving 1,228 schizophrenic adult patients, presenting with positive or negative symptoms, Azolar was associated with statistically significantly greater improvements in psychotic symptoms compared to placebo.

Azolar is effective in maintaining the clinical improvement during continuation therapy in adult 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 (Azolar 77% and haloperidol 73%). The overall completion rate was significantly higher for patients on Azolar (43%) than for 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 adult stabilised patients with chronic schizophrenia, Azolar had significantly greater reduction in relapse rate, 34% in Azolar group and 57% in placebo.

Weight gain

In clinical trials Azolar 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 adult 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 Azolar (n= 18, or 13% of evaluable patients), compared to olanzapine (n= 45, or 33% of evaluable patients).

Lipid parameters

In a pooled analysis on lipid parameters from placebo controlled clinical trials in adults, Azolar 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 Azolar and 2.8% for placebo and mean change from baseline was -0.15 mmol/l (95% CI: -0.182, -0.115) for Azolar 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 Azolar and 7.0% for placebo and mean change from baseline was -0.11 mmol/l (95% CI: -0.182, -0.046) for Azolar 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 Azolar and 12.5% for placebo and mean change from baseline was -0.03 mmol/l (95% CI: -.046, -0.017) for Azolar 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 Azolar and 0.7% for placebo and mean change from baseline was -0.09 mmol/l (95% CI: -0.139, -0.047) for Azolar and -0.06 mmol/l (95% CI: -0.116, -0.012) for placebo.

Paediatric population

Schizophrenia in adolescents

In a 6-week placebo-controlled trial involving 302 schizophrenic adolescent patients (13-17 years), presenting with positive or negative symptoms, Azolar 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.

The most common treatment-emergent adverse events among patients receiving 30 mg were extrapyramidal disorder (28.3%), somnolence (27.3%), headache (23.2%), and nausea (14.1%). Mean weight gain in the 30 weeks treatment-interval was 2.9 kg as compared to 0.98 kg in patients treated with placebo.

Irritability associated with autistic disorder in paediatric patients

Azolar was studied in patients aged 6 to 17 years in two 8-week, placebo-controlled trials [one flexible-dose (2-15 mg/day) and one fixed-dose (5, 10, or 15 mg/day)] and in one 52-week open-label trial. Dosing in these trials was initiated at 2 mg/day, increased to 5 mg/day after one week, and increased by 5 mg/day in weekly increments to the target dose. Over 75% of patients were less than 13 years of age. Azolar demonstrated statistically superior efficacy compared to placebo on the Aberrant behaviour Checklist Irritability subscale. However, the clinical relevance of this finding has not been established. The safety profile included weight gain and changes in prolactin levels. The duration of the long-term safety study was limited to 52 weeks. In the pooled trials, the incidence of low serum prolactin levels in females (<3 ng/ml) and males (<2 ng/ml) in Azolar-treated patients was 27/46 (58.7%) and 258/298 (86.6%), respectively. In the placebo-controlled trials, the mean weight gain was 0.4 kg for placebo and 1.6 kg for Azolar.

Azolar was also studied in a placebo-controlled, long-term maintenance trial. After a 13-26 week stabilisation on Azolar (2-15 mg/day) patients with a stable response were either maintained on Azolar or substituted to placebo for further 16 weeks. Kaplan-Meier relapse rates at week 16 were 35% for Azolar and 52% for placebo; the hazard ratio for relapse within 16 weeks (Azolar/placebo) was 0.57 (non-statistically significant difference). The mean weight gain over the stabilisation phase (up to 26 weeks) on Azolar was 3.2 kg, and a further mean increase of 2.2 kg for Azolar as compared to 0.6 kg for placebo was observed in the second phase (16 weeks) of the trial. Extrapyramidal symptoms were mainly reported during the stabilisation phase in 17% of patients, with tremor accounting for 6.5%.

Tics associated with Tourette's disorder in paediatric patients

The efficacy of Azolar was studied in paediatric subjects with Tourette's disorder (Azolar:

n = 99, placebo: n = 44) in a randomised, double-blind, placebo controlled, 8 week study using a fixed dose weight-based treatment group design over the dose range of 5 mg/day to 20 mg/day and a starting dose of 2 mg.).

Pharmacotherapeutic group: Psycholeptics, other antipsychotics, ATC code: N05AX12

Mechanism of action

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 5HT_1a receptors and antagonism of serotonin 5HT_2a 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 5HT_1a and 5HT_2a receptors and moderate affinity for dopamine D₄, serotonin 5HT_2c 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.

Clinical efficacy and safety

Adults

Schizophrenia

In three short-term (4 to 6 weeks) placebo-controlled trials involving 1,228 schizophrenic adult patients, presenting with positive or negative symptoms, aripiprazole was associated with statistically significantly greater improvements in psychotic symptoms compared to placebo.

Aripiprazole is effective in maintaining the clinical improvement during continuation therapy in adult 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 (aripiprazole 77 % and haloperidol 73 %). The overall completion rate was significantly higher for patients on aripiprazole (43 %) than for 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 adult stabilised patients with chronic schizophrenia, aripiprazole had significantly greater reduction in relapse rate, 34 % in aripiprazole group and 57 % in placebo.

Weight gain

In clinical trials 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 adult 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 aripiprazole (n = 18, or 13 % of evaluable patients), compared to 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.

Prolactin

Prolactin levels were evaluated in all trials of all doses of aripiprazole (n = 28,242). The incidence of hyperprolactinaemia or increased serum prolactin in patients treated with aripiprazole (0.3 %) was similar to that of placebo (0.2 %). For patients receiving aripiprazole, the median time to onset was 42 days and median duration was 34 days.

The incidence of hypoprolactinaemia or decreased serum prolactin in patients treated with aripiprazole was 0.4 %, compared with 0.02 % for patients treated with placebo. For patients receiving aripiprazole, the median time to onset was 30 days and median duration was 194 days.

Manic episodes in Bipolar I Disorder

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.

In a 26-week, placebo-controlled trial, followed by a 74-week extension, in manic patients who achieved remission on aripiprazole during a stabilization phase prior to randomisation, aripiprazole demonstrated superiority over placebo in preventing bipolar recurrence, primarily in preventing recurrence into mania but failed to demonstrate superiority over placebo in preventing recurrence into depression.

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.

Paediatric population

Schizophrenia in adolescents

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.

In a 60- to 89-week, randomised, double-blind, placebo-controlled trial in adolescent subjects (n = 146; ages 13-17 years) with schizophrenia, there was a statistically significant difference in the rate of relapse of psychotic symptoms between the aripiprazole (19.39%) and placebo (37.50%) groups. The point estimate of the hazard ratio (HR) was 0.461 (95% confidence interval, 0.242-0.879) in the full population. In subgroup analyses the point estimate of the HR was 0.495 for subjects 13 to 14 years of age compared to 0.454 for subjects 15 to 17 years of age. However, the estimation of the HR for the younger (13-14 years) group was not precise, reflecting the smaller number of subjects in that group (aripiprazole, n = 29; placebo, n = 12), and the confidence interval for this estimation (ranging from 0.151 to 1.628) did not allow conclusions to be drawn on the presence of a treatment effect. In contrast the 95% confidence interval for the HR in the older subgroup (aripiprazole, n = 69; placebo, n = 36) was 0.242 to 0.879 and hence a treatment effect could be concluded in the older patients.

Manic episodes in Bipolar I Disorder in children and adolescents

Aripiprazole was studied in a 30-week placebo-controlled trial involving 296 children and adolescents (10-17 years), who met DSM-IV criteria for Bipolar I Disorder with manic or mixed episodes with or without psychotic features and had a Y-MRS score > 20 at baseline. Among the patients included in the primary efficacy analysis, 139 patients had a current co-morbid diagnosis of ADHD.

Aripiprazole was superior to placebo in change from baseline at week 4 and at week 12 on the Y-MRS total score. In a post-hoc analysis, the improvement over placebo was more pronounced in the patients with associated co-morbidity of ADHD compared to the group without ADHD, where there was no difference from placebo. Recurrence prevention was not established.

The most common treatment-emergent adverse events among patients receiving 30 mg were extrapyramidal disorder (28.3 %), somnolence (27.3 %), headache (23.2 %), and nausea (14.1 %). Mean weight gain in the 30 weeks treatment-interval was 2.9 kg as compared to 0.98 kg in patients treated with placebo.

Irritability associated with autistic disorder in paediatric patients

Aripiprazole was studied in patients aged 6 to 17 years in two 8-week, placebo-controlled trials [one flexible-dose (2-15 mg/day) and one fixed-dose (5, 10, or 15 mg/day)] and in one 52-week open-label trial. Dosing in these trials was initiated at 2 mg/day, increased to 5 mg/day after one week, and increased by 5 mg/day in weekly increments to the target dose. Over 75 % of patients were less than 13 years of age. Aripiprazole demonstrated statistically superior efficacy compared to placebo on the Aberrant Behaviour Checklist Irritability subscale. However, the clinical relevance of this finding has not been established. The safety profile included weight gain and changes in prolactin levels. The duration of the long-term safety study was limited to 52 weeks. In the pooled trials, the incidence of low serum prolactin levels in females (< 3 ng/ml) and males (< 2 ng/ml) in aripiprazole-treated patients was 27/46 (58.7 %) and 258/298 (86.6 %), respectively. In the placebo-controlled trials, the mean weight gain was 0.4 kg for placebo and 1.6 kg for aripiprazole.

Aripiprazole was also studied in a placebo-controlled, long-term maintenance trial. After a 13-26 week stabilisation on aripiprazole (2-15 mg/day) patients with a stable response were either maintained on aripiprazole or substituted to placebo for further 16 weeks. Kaplan-Meier relapse rates at week 16 were 35 % for aripiprazole and 52 % for placebo; the hazard ratio for relapse within 16 weeks (aripiprazole/placebo) was 0.57 (non-statistically significant difference). The mean weight gain over the stabilisation phase (up to 26 weeks) on aripiprazole was 3.2 kg, and a further mean increase of 2.2 kg for aripiprazole as compared to 0.6 kg for placebo was observed in the second phase (16 weeks) of the trial. Extrapyramidal symptoms were mainly reported during the stabilisation phase in 17 % of patients, with tremor accounting for 6.5 %.

Tics associated with Tourette's disorder in paediatric patients

The efficacy of aripiprazole was studied in paediatric subjects with Tourette's disorder (aripiprazole: n = 99, placebo: n = 44) in a randomised, double-blind, placebo controlled, 8 week study using a fixed dose weight-based treatment group design over the dose range of 5 mg/day to 20 mg/day and a starting dose of 2 mg. Patients were 7 - 17 years of age and presented an average score of 30 on Total Tic Score on the Yale Global Tic Severity Scale (TTS-YGTSS) at baseline. Aripiprazole showed an improvement on TTS-YGTSS change from baseline to week 8 of 13.35,for the low dose group (5 mg or 10 mg) and 16.94 for the high dose group (10 mg or 20 mg) as compared with an improvement of 7.09 in the placebo group.

The efficacy of aripiprazole in paediatric subjects with Tourette's syndrome (aripiprazole: n = 32, placebo: n = 29) was also evaluated over a flexible dose range of 2 mg/day to 20 mg/day and a starting dose of 2 mg, in a 10 week, randomised, double blind, placebo-controlled study conducted in South-Korea. Patients were 6 - 18 years and presented an average score of 29 on TTS-YGTSS at baseline. Aripiprazole group showed an improvement of 14.97 on TTS-YGTSS change from baseline to week 10 as compared with an improvement of 9.62 in the placebo group.

In both of these short term trials, the clinical relevance of the efficacy findings has not been established, considering the magnitude of treatment effect compared to the large placebo effect and the unclear effects regarding psycho-social functioning. No long term data are available with regard to the efficacy and the safety of aripiprazole in this fluctuating disorder.

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Any unused product or waste material should be disposed of in accordance with local requirements.

Any unused medicinal product or waste material must be disposed of in accordance with local requirements.