Leitlinien & Arzneimittelsicherheit

HOS-096758 · has-adverse-reaction-information · PDF-Seite 8

Summary of the safety profile The most frequently reported adverse drug reactions (ADRs) with cariprazine in the dose range (1.5-6 mg) were akathisia (19%) and parkinsonism (17.5%). Most events were mild to moderate in severity. Tabulated list of adverse reactions ADRs based upon pooled data from cariprazine schizophrenia studies are shown by system organ class and by preferred term in Table 1. Adverse reactions are ranked by MedDRA system organ class and by frequency, the most frequent first, using the following convention: 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), not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Table 1 Adverse drug reactions occurring in patients with schizophrenia MedDRA Very common Common Uncommon Rare Frequency System (≥1/10) (≥1/100 to (≥1/1 000 to (≥1/10 000 to not known Organ Class <1/10) <1/100) <1/1 000) Blood and Anaemia Neutropenia lymphatic Eosinophilia system disorders Immune Hypersensitivi system ty disorders Endocrine Blood thyroid Hypothyroidis disorders stimulating m hormone decreased Metabolism Dyslipidaemia Blood sodium and Weight abnormal nutrition increased Diabetes 8 disorders Decreased mellitus appetite Blood glucose Increased increased appetite Psychiatric Sleep Suicidal disorders disorders1 behaviour Anxiety Delirium Depression

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HOS-096764 · has-adverse-reaction-information · PDF-Seite 26

Summary of the safety profile The most frequently reported adverse drug reactions (ADRs) with cariprazine in the dose range (1.5-6 mg) were akathisia (19%) and parkinsonism (17.5%). Most events were mild to moderate in severity. Tabulated list of adverse reactions ADRs based upon pooled data from cariprazine schizophrenia studies are shown by system organ class and by preferred term in Table 1. Adverse reactions are ranked by MedDRA system organ class and by frequency, the most frequent first, using the following convention: 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), not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Table 1 Adverse drug reactions occurring in patients with schizophrenia MedDRA Very common Common Uncommon Rare Frequency System (≥1/10) (≥1/100 to (≥1/1 000 to (≥1/10 000 to not known Organ Class <1/10) <1/100) <1/1 000) Blood and Anaemia Neutropenia lymphatic Eosinophilia system disorders Immune Hypersensitivi system ty disorders Endocrine Blood thyroid Hypothyroidis disorders stimulating m hormone decreased Metabolism Dyslipidaemia Blood sodium and Weight abnormal nutrition increased Diabetes disorders Decreased mellitus appetite Blood glucose Increased increased appetite Psychiatric Sleep Suicidal disorders disorders1 behaviour Anxiety Delirium Depression Libido

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HOS-096760 · has-contraindication-information · PDF-Seite 22

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Concomitant administration of strong CYP3A4 inhibitors (see section 4.5). Concomitant administration of strong or moderate CYP3A4 inducers (see section 4.5).

HOS-096754 · has-contraindication-information · PDF-Seite 4

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Concomitant administration of strong CYP3A4 inhibitors (see section 4.5). Concomitant administration of strong or moderate CYP3A4 inducers (see section 4.5).

HOS-096753 · has-indication-information · PDF-Seite 3

Reagila is indicated for the treatment of schizophrenia in adult patients.

HOS-096759 · has-indication-information · PDF-Seite 21

Reagila is indicated for the treatment of schizophrenia in adult patients.

HOS-096762 · has-interaction-information · PDF-Seite 24

Potential for other medicinal products to affect cariprazine Metabolism of cariprazine and its major active metabolites, desmethyl cariprazine (DCAR) and didesmethyl cariprazine (DDCAR), is mediated mainly by CYP3A4 with a minor contribution of CYP2D6. CYP3A4 inhibitors Ketoconazole, a strong CYP3A4 inhibitor, caused two-fold increase in plasma exposure for total cariprazine (sum of cariprazine and its active metabolites) during short-term (4 days) co-administration, either if unbound or unbound+bound moieties considered. Due to the long half-life of the active moieties of cariprazine a further increase in plasma exposure of total cariprazine can be expected during longer co-administration. Therefore, co-administration of cariprazine with strong CYP3A4 inhibitors (e.g., boceprevir, clarithromycin, cobicistat, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole) is contraindicated (see section 4.3). Erythromycin (500 mg twice daily), a moderate CYP3A4 inhibitor, caused on average a 1.4-fold (range 1.03-2.32-fold) increase in plasma exposure of total cariprazine after 3 weeks of co- administration. Therefore, during a period of co-administration of cariprazine with a moderate CYP3A4 inhibitor (e.g., erythromycin, fluconazole, diltiazem, verapamil), monitoring of the individual response and tolerability is recommended and, if needed, the cariprazine dose should be (temporarily) reduced to account for the potential increase in exposure. Because of the long half-life of cariprazine and its active metabolites, starting or stopping a treatment with a moderate CYP 3A4 inhibitor or changing the dose will not be fully reflected in plasma drug levels until after several weeks. Patients should be monitored for adverse reactions and treatment response for several weeks after initiating or stopping an interacting drug or after each cariprazine dose change. Consumption of grapefruit juice should be avoided. CYP3A4 inducers Co-administration of cariprazine with strong and moderate inducers of CYP3A4 may result in a significant decrease in total cariprazine exposure, therefore the co-administration of cariprazine and strong or moderate CYP3A4 inducers (e.g., carbamazepine, phenobarbital, phenytoin, rifampicin, St. John’s wort (Hypericum perforatum), bosentan, efavirenz, etravirine, modafinil, nafcillin) is 24 contraindicated (see

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HOS-096756 · has-interaction-information · PDF-Seite 6

Potential for other medicinal products to affect cariprazine Metabolism of cariprazine and its major active metabolites, desmethyl cariprazine (DCAR) and didesmethyl cariprazine (DDCAR), is mediated mainly by CYP3A4 with a minor contribution of CYP2D6. CYP3A4 inhibitors Ketoconazole, a strong CYP3A4 inhibitor, caused two-fold increase in plasma exposure for total cariprazine (sum of cariprazine and its active metabolites) during short-term (4 days) co-administration, either if unbound or unbound+bound moieties considered. Due to the long half-life of the active moieties of cariprazine a further increase in plasma exposure of total cariprazine can be expected during longer co-administration. Therefore, co-administration of cariprazine with strong CYP3A4 inhibitors (e.g., boceprevir, clarithromycin, cobicistat, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole) is contraindicated (see section 4.3). Erythromycin (500 mg twice daily), a moderate CYP3A4 inhibitor, caused on average a 1.4-fold (range 1.03-2.32-fold) increase in plasma exposure of total cariprazine after 3 weeks of co- administration. Therefore, during a period of co-administration of cariprazine with a moderate CYP3A4 inhibitor (e.g., erythromycin, fluconazole, diltiazem, verapamil), monitoring of the individual response and tolerability is recommended and, if needed, the cariprazine dose should be (temporarily) reduced to account for the potential increase in exposure. Because of the long half-life of cariprazine and its active metabolites, starting or stopping a treatment with a moderate CYP 3A4 inhibitor or changing the dose will not be fully reflected in plasma drug levels until after several 6 weeks. Patients should be monitored for adverse reactions and treatment response for several weeks after initiating or stopping an interacting drug or after each cariprazine dose change. Consumption of grapefruit juice should be avoided. CYP3A4 inducers Co-administration of cariprazine with strong and moderate inducers of CYP3A4 may result in a significant decrease in total cariprazine exposure, therefore the co-administration of cariprazine and strong or moderate CYP3A4 inducers (e.g., carbamazepine, phenobarbital, phenytoin, rifampicin, St. John’s wort (Hypericum perforatum), bosentan, efavirenz, etravirine, modafinil, nafcillin) is contraindicated (see

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HOS-096757 · has-pregnancy-information · PDF-Seite 7

Women of childbearing potential/Contraception Women of childbearing potential must be advised to avoid pregnancy while on Reagila. Female patients of child-bearing potential must use highly effective contraceptive methods during treatment and for at least 10 weeks following the last dose of Reagila. Pregnancy There are no or limited amount of data from the use of cariprazine in pregnant women. Studies in animals have shown reproductive toxicity including developmental malformations in rats (see section 5.3). Reagila is not recommended during pregnancy and in women of childbearing potential not using effective contraception. After discontinuation of cariprazine treatment contraception should be used for at least 10 weeks due to the slow elimination of active moieties. Neonates exposed to antipsychotics (including cariprazine) 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. These complications have varied in severity; while in some cases symptoms have been self-limited, in other cases, neonates have required intensive care unit support and prolonged hospitalization. Consequently, newborns should be 7 monitored carefully. Breast-feeding It is unknown whether cariprazine or its major active metabolites are excreted in human milk. Cariprazine and its metabolites are excreted in milk of rats during lactation (see section 5.3). A risk to the newborns/infants cannot be excluded. Breast-feeding should be discontinued during treatment with cariprazine. Fertility The effect of cariprazine on human fertility has not been evaluated. In rat studies lower female fertility and conception indices were observed (see section 5.3).

HOS-096763 · has-pregnancy-information · PDF-Seite 25

Women of childbearing potential/Contraception Women of childbearing potential must be advised to avoid pregnancy while on Reagila. Female patients of child-bearing potential must use highly effective contraceptive methods during treatment and for at least 10 weeks following the last dose of Reagila. Pregnancy There are no or limited amount of data from the use of cariprazine in pregnant women. Studies in animals have shown reproductive toxicity including developmental malformations in rats (see section 5.3). Reagila is not recommended during pregnancy and in women of childbearing potential not using effective contraception. After discontinuation of cariprazine treatment contraception should be used for at least 10 weeks due to the slow elimination of active moieties. Neonates exposed to antipsychotics (including cariprazine) 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. These complications have varied in severity; while in some cases symptoms have been self-limited, in other cases, neonates have required intensive care unit support and prolonged hospitalization. Consequently, newborns should be monitored carefully. Breast-feeding It is unknown whether cariprazine or its major active metabolites are excreted in human milk. Cariprazine and its metabolites are excreted in milk of rats during lactation (see section 5.3). A risk to the newborns/infants cannot be excluded. Breast-feeding should be discontinued during treatment with cariprazine. Fertility 25 The effect of cariprazine on human fertility has not been evaluated. In rat studies lower female fertility and conception indices were observed (see section 5.3).

HOS-096761 · has-warning-information · PDF-Seite 22

Suicidal ideation and behaviour The possibility of suicidality (suicidal ideation, suicide attempt and completed suicide) is inherent in psychotic illnesses and, generally, it is reported early after initiation or switch of antipsychotic therapy. Close supervision of high-risk patients should accompany antipsychotic therapy. Akathisia, restlessness Akathisia and restlessness are frequently occurring adverse reactions of antipsychotics. Akathisia is a movement disorder characterized by a feeling of inner restlessness and a compelling need to be in constant motion, as well as by actions such as rocking while standing or sitting, lifting the feet as if marching on the spot, and crossing and uncrossing the legs while sitting. As cariprazine causes akathisia and restlessness, it should be used cautiously in patients who are prone to or already exhibit symptoms of akathisia. Akathisia develops early in treatment. Therefore, close monitoring in the first phase of treatment is important. Prevention includes slow up-titration; treatment measures include slight down-titration of cariprazine or anti-extrapyramidal symptoms (EPS) medicinal product The dose can be modified based on individual response and tolerability (see section 4.8). Tardive dyskinesia Tardive dyskinesia is a syndrome consisting of potentially irreversible, rhythmical, involuntary movements, predominantly of the tongue and/or face that can develop in patients treated with antipsychotics. If signs and symptoms of tardive dyskinesia appear in a patient treated with cariprazine, discontinuation should be considered. Parkinson's disease If prescribed to patients with Parkinson's disease, antipsychotic medicinal products may exacerbate the underlying disease and worsen symptoms of Parkinson’s disease. Physicians should, therefore, weigh the risks versus the benefits when prescribing cariprazine to patients with Parkinson's disease. Ocular symptoms/cataract In the preclinical studies of cariprazine lens opacity/cataract was detected in dogs (see sections 4.8 and 22 5.3). However, a causal relationship between lenticular changes / cataracts observed in human studies and cariprazine use has not been established. Nevertheless, patients who would develop symptoms potentially related to cataract should be advised to ophthalmologic examination and re-evaluated for treatment continuation. Neuroleptic malignant syndrome (NMS) A potentially fatal sym

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HOS-096755 · has-warning-information · PDF-Seite 4

Suicidal ideation and behaviour The possibility of suicidality (suicidal ideation, suicide attempt and completed suicide) is inherent in psychotic illnesses and, generally, it is reported early after initiation or switch of antipsychotic therapy. Close supervision of high-risk patients should accompany antipsychotic therapy. Akathisia, restlessness Akathisia and restlessness are frequently occurring adverse reactions of antipsychotics. Akathisia is a movement disorder characterized by a feeling of inner restlessness and a compelling need to be in constant motion, as well as by actions such as rocking while standing or sitting, lifting the feet as if marching on the spot, and crossing and uncrossing the legs while sitting. As cariprazine causes akathisia and restlessness, it should be used cautiously in patients who are prone to or already exhibit symptoms of akathisia. Akathisia develops early in treatment. Therefore, close monitoring in the first phase of treatment is important. Prevention includes slow up-titration; treatment measures include slight down-titration of cariprazine or anti-extrapyramidal symptoms (EPS) medicinal product The dose can be modified based on individual response and tolerability (see section 4.8). Tardive dyskinesia Tardive dyskinesia is a syndrome consisting of potentially irreversible, rhythmical, involuntary movements, predominantly of the tongue and/or face that can develop in patients treated with antipsychotics. If signs and symptoms of tardive dyskinesia appear in a patient treated with 4 cariprazine, discontinuation should be considered. Parkinson's disease If prescribed to patients with Parkinson's disease, antipsychotic medicinal products may exacerbate the underlying disease and worsen symptoms of Parkinson’s disease. Physicians should, therefore, weigh the risks versus the benefits when prescribing cariprazine to patients with Parkinson's disease. Ocular symptoms/cataract In the preclinical studies of cariprazine lens opacity/cataract was detected in dogs (see sections 4.8 and 5.3). However, a causal relationship between lenticular changes / cataracts observed in human studies and cariprazine use has not been established. Nevertheless, patients who would develop symptoms potentially related to cataract should be advised to ophthalmologic examination and re-evaluated for treatment continuation. Neuroleptic malignant syndrome (NMS) A potentially fatal sy

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