Abilify Maintena · 4.4 Special warnings and precautions for use · 1

HOS-096724 · has-adverse-reaction-information · PDF-Seite 9

Summary of the safety profile The most frequently observed adverse drug reactions (ADRs) reported in ≥ 5 % of patients in two double-blind, long-term trials of Abilify Maintena 400 mg/300 mg were weight increased (9.0 %), akathisia (7.9 %), insomnia (5.8 %) and injection site pain (5.1 %). Tabulated list of adverse reactions The incidences of the ADRs associated with aripiprazole therapy are tabulated below. The table is based on adverse reactions 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 ADRs listed under the frequency “not known” were reported during post-marketing use. 9  Common Uncommon Not known Blood and Neutropenia Leukopenia lymphatic Anaemia system Thrombocytopenia disorders Neutrophil count decreased White blood cell count decreased Immune Hypersensitivity Allergic reaction (e.g. system anaphylactic reaction, disorders angioedema including swollen tongue, tongue oedema, face oedema, pruritus, or urticaria) Endocrine Blood prolactin Diabetic hyperosmolar disorders decreased coma Hyperprolactinaemia Diabetic ketoacidosis Metabolism Weight increased Hyperglycaemia Anorexia and nutrition Diabetes mellitus Hypercholesterolaemia Hyponatraemia disorders Weight decreased

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HOS-096730 · has-adverse-reaction-information · PDF-Seite 31

Summary of the safety profile The safety profile of Abilify Maintena 960 mg and Abilify Maintena 720 mg for the treatment of schizophrenia in adults is based on adequate and well-controlled studies of Abilify Maintena 400 mg and Abilify Maintena 300 mg. In general, the observed adverse drug reactions (ADRs) in Abilify Maintena 960 mg/720 mg clinical trials were similar to the ADRs observed in the Abilify Maintena 400 mg/300 mg clinical trials. The most frequently observed ADRs reported in ≥ 5 % of patients in two double-blind, long-term trial of Abilify Maintena 400 mg/300 mg were weight increased (9.0%), akathisia (7.9%) and insomnia (5.8%). In the Abilify Maintena 960 mg/720 mg clinical trials, weight increased (22.7%), injection site pain (18.2%) akathisia (9.8 %), anxiety (8.3 %), headache (7.6 %), insomnia (7.6 %), and constipation (6.1 %) were the most frequently observed ADRs. Tabulated list of adverse reactions The incidences of the ADRs associated with Abilify Maintena 400 mg/300 mg and 960 mg/720 mg are tabulated below. The table is based on adverse reactions 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 ADRs listed under the frequency “not known” were reported during post-marketing use. System organ class Common Uncommon Not known Blood and Neutropenia Leukopenia lymphatic system Anaemia disorders Thrombocytopenia Neutrophil count decreased White blood cell count decreased Immune system Hypersensitivity Allergic reaction (e.g. disorders anaphylactic reaction, angioedema including

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HOS-096726 · has-contraindication-information · PDF-Seite 26

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

HOS-096720 · has-contraindication-information · PDF-Seite 5

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

HOS-096725 · has-indication-information · PDF-Seite 24

Abilify Maintena is indicated for maintenance treatment of schizophrenia in adult patients stabilised with aripiprazole.

HOS-096719 · has-indication-information · PDF-Seite 2

Abilify Maintena is indicated for maintenance treatment of schizophrenia in adult patients stabilised with oral aripiprazole.

HOS-096728 · has-interaction-information · PDF-Seite 29

No interaction studies have been performed with Abilify Maintena. The information below is obtained from studies with oral aripiprazole. The 2-month dosing interval and long half-life of aripiprazole after dosing with Abilify Maintena 960 mg or 720 mg should also be considered when assessing the drug- drug interaction potential. Due to its α1-adrenergic receptor antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive medicinal products. Given the primary central nervous system (CNS) effects of aripiprazole, caution should be used when aripiprazole is administered in combination with alcohol or other CNS medicinal products with overlapping adverse reactions such as sedation (see section 4.8). If aripiprazole is administered concomitantly with medicinal products known to cause QT prolongation or electrolyte imbalance, caution should be used. Potential for other medicinal products to affect aripiprazole Quinidine and other strong CYP2D6 inhibitors In a clinical trial of oral aripiprazole in healthy subjects, a strong inhibitor of CYP2D6 (quinidine) increased aripiprazole AUC by 107 %, while Cmax was unchanged. The AUC and Cmax of dehydro- aripiprazole, the active metabolite, decreased by 32 % and 47 %, respectively. Other strong inhibitors of CYP2D6, such as fluoxetine and paroxetine, may be expected to have similar effects and similar dose reduction should, therefore, be applied (see section 4.2). Ketoconazole and other strong CYP3A4 inhibitors In a clinical trial of oral aripiprazole in healthy subjects, a strong inhibitor of CYP3A4 (ketoconazole) increased aripiprazole AUC and Cmax by 63 % and 37 %, respectively. The AUC and Cmax of dehydro- aripiprazole increased by 77 % and 43 %, respectively. In CYP2D6 poor metabolisers, concomitant use of strong inhibitors of CYP3A4 may result in higher plasma concentrations of aripiprazole compared to that in CYP2D6 extensive metabolisers (see section 4.2). When considering concomitant administration of ketoconazole or other strong CYP3A4 inhibitors with aripiprazole, potential benefits should outweigh the potential risks to the patient. Other strong inhibitors of CYP3A4, such as itraconazole and HIV protease inhibitors may be expected to have similar effects and similar dose reductions should, therefore, be applied (see section 4.2). Upon discontinuation of the CYP2D6 or CYP3A4 inhibitor, the dose of aripiprazole should be increased to the dose prior to the initiation of the

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HOS-096722 · has-interaction-information · PDF-Seite 7

No interaction studies have been performed with Abilify Maintena. The information below is obtained from studies with oral aripiprazole. Due to its α1-adrenergic receptor antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive medicinal products. Given the primary central nervous system (CNS) effects of aripiprazole, caution should be used when aripiprazole is administered in combination with alcohol or other CNS medicinal products with overlapping adverse reactions such as sedation (see section 4.8). If aripiprazole is administered concomitantly with medicinal products known to cause QT prolongation or electrolyte imbalance, caution should be used. Potential for other medicinal products to affect aripiprazole 7 Quinidine and other strong CYP2D6 inhibitors In a clinical trial of oral aripiprazole in healthy subjects, a strong inhibitor of CYP2D6 (quinidine) increased aripiprazole AUC by 107 %, while Cmax was unchanged. The AUC and Cmax of dehydro- aripiprazole, the active metabolite, decreased by 32 % and 47 %, respectively. Other strong inhibitors of CYP2D6, such as fluoxetine and paroxetine, may be expected to have similar effects and similar dose reduction should, therefore, be applied (see section 4.2). Ketoconazole and other strong CYP3A4 inhibitors In a clinical trial of oral aripiprazole in healthy subjects, a strong inhibitor of CYP3A4 (ketoconazole) increased aripiprazole AUC and Cmax by 63 % and 37 %, respectively. The AUC and Cmax of dehydro- aripiprazole increased by 77 % and 43 %, respectively. In CYP2D6 poor metabolisers, concomitant use of strong inhibitors of CYP3A4 may result in higher plasma concentrations of aripiprazole compared to that in CYP2D6 extensive metabolisers (see section 4.2). When considering concomitant administration of ketoconazole or other strong CYP3A4 inhibitors with aripiprazole, potential benefits should outweigh the potential risks to the patient. Other strong inhibitors of CYP3A4, such as itraconazole and HIV protease inhibitors may be expected to have similar effects and similar dose reductions should, therefore, be applied (see section 4.2). Upon discontinuation of the CYP2D6 or CYP3A4 inhibitor, the dose of aripiprazole should be increased to the dose prior to the initiation of the concomitant therapy. When weak inhibitors of CYP3A4 (e.g. diltiazem) or CYP2D6 (e.g. escitalopram) are used concomitantly with aripiprazol

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HOS-096723 · has-pregnancy-information · PDF-Seite 8

Women of childbearing potential Plasma exposure to aripiprazole after a single dose of Abilify Maintena is expected to remain for up to 34 weeks (see section 5.2). This should be taken into account when initiating treatment in women of childbearing potential, considering a possible future pregnancy or breast-feeding. Abilify Maintena should only be used in women planning to become pregnant if clearly necessary. Pregnancy There are no adequate and well-controlled trials of aripiprazole in pregnant women. Congenital anomalies have been reported; however, causal relationship with aripiprazole could not be established. Animal studies could not exclude potential developmental toxicity (see section 5.3). Patients must be 8 advised to notify their physician if they become pregnant or intend to become pregnant during treatment with aripiprazole.. Prescribers need to be aware of the long-acting properties of Abilify Maintena. Aripiprazole has been detected in plasma in adult patients up to 34 weeks after a single-dose administration of the prolonged- release suspension. New-born infants exposed to antipsychotics (including aripiprazole) during the third trimester of pregnancy are at risk of adverse reactions including extrapyramidal and/or withdrawal symptoms that may vary in severity and duration following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, or feeding disorder. Consequently, new-born infants should be monitored carefully (see section 4.8). Maternal exposure to Abilify Maintena before and during pregnancy may lead to adverse reactions in the newborn child. Abilify Maintena should not be used during pregnancy unless clearly necessary. Breast-feeding Aripiprazole/metabolites are excreted in the breast milk to such an extent that effects on the breast-fed infant are likely if Abilify Maintena is administered to breast-feeding women. Since a single dose of Abilify Maintena is expected to remain for up to 34 weeks in plasma (see section 5.2), breast-fed infants may be at risk even from Abilify Maintena administration long before breast-feeding. Patients currently under treatment or who have been treated in the past 34 weeks with Abilify Maintena should not breast feed. Fertility Aripiprazole did not impair fertility based on data from reproductive toxicity studies with aripiprazole.

HOS-096729 · has-pregnancy-information · PDF-Seite 30

Women of childbearing potential Plasma exposure to aripiprazole after a single dose of Abilify Maintena is expected to remain for up to 34 weeks (see section 5.2). This should be taken into account when initiating treatment in women of childbearing potential, considering a possible future pregnancy or breast-feeding. Abilify Maintena should only be used in women planning to become pregnant if clearly necessary. Pregnancy There are no adequate and well-controlled trials of aripiprazole in pregnant women. Congenital anomalies have been reported; however, causal relationship with aripiprazole could not be established. Animal studies could not exclude potential developmental toxicity (see section 5.3). Patients must be advised to notify their physician if they become pregnant or intend to become pregnant during treatment with aripiprazole. Prescribers need to be aware of the long-acting properties of Abilify Maintena. Aripiprazole has been detected in plasma in adult patients up to 34 weeks after a single-dose administration of the prolonged- release suspension. New-born infants exposed to antipsychotics (including aripiprazole) during the third trimester of pregnancy are at risk of adverse reactions including extrapyramidal and/or withdrawal symptoms that may vary in severity and duration following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, or feeding disorder. Consequently, new-born infants should be monitored carefully (see section 4.8). Maternal exposure to Abilify Maintena before and during pregnancy may lead to adverse reactions in the newborn child. Abilify Maintena should not be used during pregnancy unless clearly necessary. Breast-feeding Aripiprazole/metabolites are excreted in the breast milk to such an extent that effects on the breast-fed infant are likely if Abilify Maintena is administered to breast-feeding women. Since a single dose of Abilify Maintena is expected to remain for up to 34 weeks in plasma (see section 5.2), breast-fed infants may be at risk even from Abilify Maintena administration long before breast-feeding. Patients currently under treatment or who have been treated in the past 34 weeks with Abilify Maintena should not breast feed. 30 Fertility Aripiprazole did not impair fertility based on data from reproductive toxicity studies with aripiprazole.

HOS-096721 · has-warning-information · PDF-Seite 5

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 400 mg/300 mg 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 (see section 4.8). 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 (see section 4.8). 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 (see section 4.8). 5 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 (see section 4.8). 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 rigidit

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HOS-096727 · has-warning-information · PDF-Seite 26

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. 26 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 (see section 4.8). 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 (see section 4.8). 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 (see section 4.8). 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 (see section 4.8). 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 m

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