Sycrest

HOS-154879 · has-adverse-reaction-information · PDF-Seite 6

Summary of safety profile The most frequently reported adverse drug reactions (ADRs) associated with the use of asenapine in clinical trials were somnolence and anxiety. Serious hypersensitivity reactions have been reported. Other serious ADRs are discussed in more detail in section 4.4. Tabulated list of adverse reactions The incidences of the ADRs associated with asenapine 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) and not known (cannot be estimated from the available data). Within each frequency grouping, ADRs are presented in order of decreasing seriousness. System organ Very Common Uncommon Rare Not class common known Blood and Neutropenia lymphatic disorders Immune system Allergic disorders reactions Metabolism Weight Hyperglycaemi and nutrition increased a disorders Increased appetite Psychiatric Anxiety disorders 6 System organ Very Common Uncommon Rare Not class common known Nervous Somnolenc Dystonia Syncope Neuroleptic system e Akathisia Seizure malignant disorders Dyskinesia Extrapyramidal syndrome Parkinsonism disorder Sedation Dysarthria Dizziness Restless legs Dysgeusia syndrome Eye disorders Accommodatio n disorder Cardiac Sinus disorders

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HOS-154885 · has-adverse-reaction-information · PDF-Seite 19

Summary of safety profile The most frequently reported adverse drug reactions (ADRs) associated with the use of asenapine in clinical trials were somnolence and anxiety. Serious hypersensitivity reactions have been reported. Other serious ADRs are discussed in more detail in section 4.4. Tabulated list of adverse reactions The incidences of the ADRs associated with asenapine 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) and not known (cannot be estimated from the available data). Within each frequency grouping, ADRs are presented in order of decreasing seriousness. System organ Very Common Uncommon Rare Not class common known Blood and Neutropenia lymphatic disorders Immune system Allergic disorders reactions Metabolism Weight Hyperglycaemi and nutrition increased a disorders Increased appetite Psychiatric Anxiety disorders 19 System organ Very Common Uncommon Rare Not class common known Nervous Somnolenc Dystonia Syncope Neuroleptic system e Akathisia Seizure malignant disorders Dyskinesia Extrapyramidal syndrome Parkinsonism disorder Sedation Dysarthria Dizziness Restless legs Dysgeusia syndrome Eye disorders Accommodatio n disorder Cardiac Sinus disorders

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HOS-154875 · has-contraindication-information · PDF-Seite 3

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

HOS-154881 · has-contraindication-information · PDF-Seite 16

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

HOS-154874 · has-indication-information · PDF-Seite 2

Sycrest is indicated for the treatment of moderate to severe manic episodes associated with bipolar I disorder in adults.

HOS-154880 · has-indication-information · PDF-Seite 15

Sycrest is indicated for the treatment of moderate to severe manic episodes associated with bipolar I disorder in adults.

HOS-154877 · has-interaction-information · PDF-Seite 5

Given the primary effects of asenapine on the central nervous system (CNS) (see section 4.8), caution should be used when it is taken in combination with other centrally acting medicinal products. Patients should be advised to avoid alcohol while taking Sycrest. Potential for other medicinal products to affect Sycrest Asenapine is cleared primarily through direct glucuronidation by UGT1A4 and oxidative metabolism by cytochrome P450 isoenzymes (predominantly CYP1A2). The potential effects of inhibitors and an inducer of several of these enzyme pathways on asenapine pharmacokinetics were studied, specifically fluvoxamine (CYP1A2 inhibitor), paroxetine (CYP2D6 inhibitor), imipramine (CYP1A2/2C19/3A4 inhibitor), cimetidine (CYP3A4/2D6/1A2 inhibitor), carbamazepine (CYP3A4/1A2 inducer) and valproate (UGT inhibitor). Except for fluvoxamine, none of the interacting medicinal products resulted in clinically relevant alterations in asenapine pharmacokinetics. During combined administration with a single dose of asenapine 5 mg, fluvoxamine 25 mg twice daily resulted in a 29 % increase in asenapine AUC. The full therapeutic dose of fluvoxamine would be expected to produce a greater increase in asenapine plasma concentrations. Therefore, co-administration of asenapine and fluvoxamine should be approached with caution. Potential for Sycrest to affect other medicinal products Because of its α1-adrenergic antagonism with potential for inducing orthostatic hypotension (see section 4.4), Sycrest may enhance the effects of certain antihypertensive agents. Asenapine may antagonise the effect of levodopa and dopamine agonists. If this combination is deemed necessary, the lowest effective dose of each treatment should be prescribed. In vitro studies indicate that asenapine weakly inhibits CYP2D6. Clinical drug interaction studies investigating the effects of CYP2D6 inhibition by asenapine showed the following results: − Following co-administration of dextromethorphan and asenapine in healthy subjects, the ratio of dextrorphan/dextromethorphan (DX/DM) as a marker of CYP2D6 activity was measured. Indicative of CYP2D6 inhibition, treatment with asenapine 5 mg twice daily resulted in a fractional decrease in DX/DM ratio to 0.43. In the same study, treatment with paroxetine 20 mg daily decreased the DX/DM ratio to 0.032. − In a separate study, co-administration of a single 75 mg dose of imipramine with a single 5 mg dose of asenapine did

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HOS-154883 · has-interaction-information · PDF-Seite 18

Given the primary effects of asenapine on the central nervous system (CNS) (see section 4.8), caution should be used when it is taken in combination with other centrally acting medicinal products. Patients should be advised to avoid alcohol while taking Sycrest. Potential for other medicinal products to affect Sycrest Asenapine is cleared primarily through direct glucuronidation by UGT1A4 and oxidative metabolism by cytochrome P450 isoenzymes (predominantly CYP1A2). The potential effects of inhibitors and an inducer of several of these enzyme pathways on asenapine pharmacokinetics were studied, specifically fluvoxamine (CYP1A2 inhibitor), paroxetine (CYP2D6 inhibitor), imipramine (CYP1A2/2C19/3A4 inhibitor), cimetidine (CYP3A4/2D6/1A2 inhibitor), carbamazepine (CYP3A4/1A2 inducer) and valproate (UGT inhibitor). Except for fluvoxamine, none of the interacting medicinal products resulted in clinically relevant alterations in asenapine pharmacokinetics. During combined administration with a single dose of asenapine 5 mg, fluvoxamine 25 mg twice daily resulted in a 29 % increase in asenapine AUC. The full therapeutic dose of fluvoxamine would be expected to produce a greater increase in asenapine plasma concentrations. Therefore, co-administration of asenapine and fluvoxamine should be approached with caution. Potential for Sycrest to affect other medicinal products Because of its α1-adrenergic antagonism with potential for inducing orthostatic hypotension (see section 4.4), Sycrest may enhance the effects of certain antihypertensive agents. Asenapine may antagonise the effect of levodopa and dopamine agonists. If this combination is deemed necessary, the lowest effective dose of each treatment should be prescribed. In vitro studies indicate that asenapine weakly inhibits CYP2D6. Clinical drug interaction studies investigating the effects of CYP2D6 inhibition by asenapine showed the following results: − Following co-administration of dextromethorphan and asenapine in healthy subjects, the ratio of dextrorphan/dextromethorphan (DX/DM) as a marker of CYP2D6 activity was measured. Indicative of CYP2D6 inhibition, treatment with asenapine 5 mg twice daily resulted in a fractional decrease in DX/DM ratio to 0.43. In the same study, treatment with paroxetine 20 mg daily decreased the DX/DM ratio to 0.032. − In a separate study, co-administration of a single 75 mg dose of imipramine with a single 5 mg dose of asenapine did

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HOS-154878 · has-pregnancy-information · PDF-Seite 5

Pregnancy There are no adequate data from the use of Sycrest in pregnant women. Asenapine was not teratogenic in animal studies. Maternal and embryo toxic effects were found in animal studies (see section 5.3). 5 Newborn infants exposed to antipsychotics (including Sycrest) 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 in newborn infants. Consequently, newborn infants should be monitored carefully. Sycrest should not be used during pregnancy unless the clinical condition of the woman requires treatment with asenapine and only if the potential benefit outweighs the potential risk to the foetus. Breast-feeding Asenapine was excreted in milk of rats during lactation. It is not known whether asenapine or its metabolites are excreted in human milk. Breast-feeding should be discontinued during treatment with Sycrest. Fertility No impairment of fertility has been observed in nonclinical studies (see section 5.3).

HOS-154884 · has-pregnancy-information · PDF-Seite 18

Pregnancy There are no adequate data from the use of Sycrest in pregnant women. Asenapine was not teratogenic in animal studies. Maternal and embryo toxic effects were found in animal studies (see section 5.3). 18 Newborn infants exposed to antipsychotics (including Sycrest) 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 in newborn infants. Consequently, newborn infants should be monitored carefully. Sycrest should not be used during pregnancy unless the clinical condition of the woman requires treatment with asenapine and only if the potential benefit outweighs the potential risk to the foetus. Breast-feeding Asenapine was excreted in milk of rats during lactation. It is not known whether asenapine or its metabolites are excreted in human milk. Breast-feeding should be discontinued during treatment with Sycrest. Fertility No impairment of fertility has been observed in nonclinical studies (see section 5.3).

HOS-154882 · has-warning-information · PDF-Seite 16

Elderly patients with dementia-related psychosis Elderly patients with dementia-related psychosis treated with antipsychotic substances are at an increased risk of death. Sycrest is not approved for the treatment of patients with dementia-related psychosis and is not recommended for use in this particular group of patients. Neuroleptic malignant syndrome Neuroleptic malignant syndrome (NMS), characterised by hyperthermia, muscle rigidity, autonomic instability, altered consciousness and elevated serum creatine phosphokinase levels, has been reported to occur with antipsychotics, including asenapine. Additional clinical signs may include myoglobinuria (rhabdomyolysis) and acute renal failure. If a patient develops signs and symptoms indicative of NMS Sycrest must be discontinued. Seizures In clinical trials, cases of seizure were occasionally reported during treatment with asenapine. Therefore, Sycrest should be used with caution in patients who have a history of seizure disorder or have conditions associated with seizures. Suicide The possibility of a suicide attempt is inherent in psychotic illnesses and bipolar disorder and close supervision of high-risk patients should accompany treatment. Orthostatic hypotension Asenapine may induce orthostatic hypotension and syncope, especially early in treatment, probably reflecting its α1-adrenergic antagonist properties. Elderly patients are particularly at risk for experiencing orthostatic hypotension (see section 4.8). In clinical trials, cases of syncope were occasionally reported during treatment with Sycrest. Sycrest should be used with caution in elderly patients and in patients with known cardiovascular disease (e.g., heart failure, myocardial infarction or 16 ischemia, conduction abnormalities), cerebrovascular disease, or conditions that predispose the patient to hypotension (e.g., dehydration and hypovolemia). Tardive dyskinesia Medicinal products with dopamine receptor antagonistic properties have been associated with the induction of tardive dyskinesia characterised by rhythmical, involuntary movements, predominantly of the tongue and/or face. In clinical trials, cases of tardive dyskinesia were occasionally reported during treatment with asenapine. The onset of extrapyramidal symptoms is a risk factor for tardive dyskinesia. If signs and symptoms of tardive dyskinesia appear in a patient on Sycrest, discontinuation of treatment should be con

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HOS-154876 · has-warning-information · PDF-Seite 3

Elderly patients with dementia-related psychosis Elderly patients with dementia-related psychosis treated with antipsychotic substances are at an increased risk of death. Sycrest is not approved for the treatment of patients with dementia-related psychosis and is not recommended for use in this particular group of patients. Neuroleptic malignant syndrome Neuroleptic malignant syndrome (NMS), characterised by hyperthermia, muscle rigidity, autonomic instability, altered consciousness and elevated serum creatine phosphokinase levels, has been reported to occur with antipsychotics, including asenapine. Additional clinical signs may include myoglobinuria (rhabdomyolysis) and acute renal failure. If a patient develops signs and symptoms indicative of NMS Sycrest must be discontinued. Seizures In clinical trials, cases of seizure were occasionally reported during treatment with asenapine. Therefore, Sycrest should be used with caution in patients who have a history of seizure disorder or have conditions associated with seizures. Suicide The possibility of a suicide attempt is inherent in psychotic illnesses and bipolar disorder and close supervision of high-risk patients should accompany treatment. Orthostatic hypotension Asenapine may induce orthostatic hypotension and syncope, especially early in treatment, probably reflecting its α1-adrenergic antagonist properties. Elderly patients are particularly at risk for experiencing orthostatic hypotension (see section 4.8). In clinical trials, cases of syncope were occasionally reported during treatment with Sycrest. Sycrest should be used with caution in elderly patients and in patients with known cardiovascular disease (e.g., heart failure, myocardial infarction or 3 ischemia, conduction abnormalities), cerebrovascular disease, or conditions that predispose the patient to hypotension (e.g., dehydration and hypovolemia). Tardive dyskinesia Medicinal products with dopamine receptor antagonistic properties have been associated with the induction of tardive dyskinesia characterised by rhythmical, involuntary movements, predominantly of the tongue and/or face. In clinical trials, cases of tardive dyskinesia were occasionally reported during treatment with asenapine. The onset of extrapyramidal symptoms is a risk factor for tardive dyskinesia. If signs and symptoms of tardive dyskinesia appear in a patient on Sycrest, discontinuation of treatment should be con

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