Noxafil · 4.3 Contraindications · 3

HOS-094070 · has-adverse-reaction-information · PDF-Seite 10

Summary of the safety profile Safety data derive from clinical trials in adults with the oral suspension, intravenous, and tablet formulations, and in paediatric participants with the intravenous, tablet, and powder for suspension formulations. The most frequently reported serious related adverse reactions included nausea, vomiting, diarrhoea, pyrexia, and increased bilirubin. Tabulated list of adverse reactions Within the organ system classes, adverse reactions are listed under headings of frequency using the following categories: 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). Table 2. Adverse reactions* System organ class Adverse reactions Frequency Blood and lymphatic neutropenia Common system disorders thrombocytopenia, leukopenia, anaemia, eosinophilia, Uncommon lymphadenopathy, splenic infarction haemolytic uraemic syndrome, thrombotic Rare thrombocytopenic purpura, pancytopenia, coagulopathy, haemorrhage Immune system allergic reaction Uncommon disorders hypersensitivity reaction Rare Endocrine disorders adrenal insufficiency, blood gonadotropin decreased, Rare pseudoaldosteronism 10 System organ class Adverse reactions Frequency Metabolism and electrolyte imbalance, anorexia, decreased appetite, Common nutrition disorders hypokalaemia, hypomagnesaemia hyperglycaemia, hypoglycaemia Uncommon Psychiatric disorders abnormal dreams, confusional state, sleep disorder Uncommon psychotic disorder, depression Rare Nervous system paraesthesia, dizziness, somnolence, headache, dysgeusia Common disorders convulsions, neuropathy, hypoaesthesia, tremor, aphasia, Uncommon insomnia cerebrovascular accident, encephalopathy, peripheral Rare

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HOS-094076 · has-adverse-reaction-information · PDF-Seite 28

Summary of the safety profile Safety data derive from clinical trials in adults with the oral suspension, intravenous, and tablet formulations, and in paediatric participants with the intravenous, tablet, and powder for suspension formulations. The most frequently reported treatment-related adverse reactions (5%) with posaconazole tablets were nausea and diarrhoea. The most frequently reported adverse reaction leading to discontinuation of posaconazole tablets was nausea. Tabulated list of adverse reactions Within the organ system classes, adverse reactions are listed under headings of frequency using the following categories: 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). Table 2. Adverse reactions* System organ class Adverse reactions Frequency Blood and lymphatic neutropenia Common system disorders thrombocytopenia, leukopenia, anaemia, eosinophilia, Uncommon lymphadenopathy, splenic infarction haemolytic uraemic syndrome, thrombotic Rare thrombocytopenic purpura, pancytopenia, coagulopathy, haemorrhage Immune system allergic reaction Uncommon disorders hypersensitivity reaction Rare Endocrine disorders adrenal insufficiency, blood gonadotropin decreased, Rare pseudoaldosteronism Metabolism and electrolyte imbalance, anorexia, decreased appetite, Common nutrition disorders hypokalaemia, hypomagnesaemia hyperglycaemia, hypoglycaemia Uncommon Psychiatric disorders abnormal dreams, confusional state, sleep disorder Uncommon psychotic disorder, depression Rare Nervous system paraesthesia, dizziness, somnolence, headache, dysgeusia Common disorders convulsions, neuropathy, hypoaesthesia, tremor, aphasia, Uncommon insomnia cerebrovascular accident, encephalopathy, peripheral Rare

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HOS-094088 · has-adverse-reaction-information · PDF-Seite 74

Summary of the safety profile Safety data derive from clinical trials in adults with the oral suspension, intravenous, and tablet formulations, and in paediatric participants with the intravenous, tablet, and powder for suspension formulations. The most frequently reported adverse reactions during treatment were alanine aminotransferase increased (2.6 %), aspartate aminotransferase increased (3.5 %) and rash (2.6 %). Tabulated list of adverse reactions Within the organ system classes, adverse reactions are listed under headings of frequency using the following categories: 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). Table 2. Adverse reactions* System organ class Adverse reactions Frequency Blood and lymphatic neutropenia Common system disorders thrombocytopenia, leukopenia, anaemia, eosinophilia, Uncommon lymphadenopathy, splenic infarction haemolytic uraemic syndrome, thrombotic Rare thrombocytopenic purpura, pancytopenia, coagulopathy, haemorrhage Immune system allergic reaction Uncommon disorders hypersensitivity reaction Rare Endocrine disorders adrenal insufficiency, blood gonadotropin decreased, Rare pseudoaldosteronism 74 System organ class Adverse reactions Frequency Metabolism and electrolyte imbalance, anorexia, decreased appetite, Common nutrition disorders hypokalaemia, hypomagnesaemia hyperglycaemia, hypoglycaemia Uncommon Psychiatric disorders abnormal dreams, confusional state, sleep disorder Uncommon psychotic disorder, depression Rare Nervous system paraesthesia, dizziness, somnolence, headache, dysgeusia Common disorders convulsions, neuropathy, hypoaesthesia, tremor, aphasia, Uncommon insomnia cerebrovascular accide

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HOS-094082 · has-adverse-reaction-information · PDF-Seite 50

Summary of the safety profile Safety data derive from clinical trials in adults with the oral suspension, intravenous, and tablet formulations, and in paediatric participants with the intravenous, tablet, and powder for suspension formulations. The most frequently reported adverse reactions for patients treated with posaconazole concentrate for solution for infusion were diarrhoea (9%), nausea (8%), rash (6%), hypokalaemia (5%), and vomiting (5%). The most frequently reported adverse reaction (> 25 %) with an onset during the posaconazole intravenous phase of dosing with 300 mg once daily was diarrhoea (32 %). The most frequently reported adverse reactions leading to discontinuation of posaconazole concentrate for solution for infusion 300 mg once daily were rash (2%), pulmonary mycosis (2%) and AML (1 %). In initial studies of healthy volunteers, administration of a single dose of posaconazole infused over 30 minutes via a peripheral venous catheter was associated with a 12 % incidence of infusion site reactions (4 % incidence of thrombophlebitis). Multiple doses of posaconazole administered via a peripheral venous catheter were associated with thrombophlebitis (60 % incidence). Therefore, in subsequent studies posaconazole was administered via central venous catheter. If a central venous catheter was not readily available, patients could receive a single infusion over 30 minutes via a peripheral venous catheter. Peripheral infusion time longer than 30 minutes, leads to a higher incidence of infusion site reactions and thrombophlebitis. 50 Tabulated list of adverse reactions Within the organ system classes, adverse reactions are listed under headings of frequency using the following categories: 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). Table 2. Adverse reactions* System organ class Adverse reactions Frequency Blood and lymphatic neutropenia Common system disorders thrombocytopenia, leukopenia, anaemia, eosinophilia, Uncommon lymphadenopathy, splenic infarction haemolytic uraemic syndrome, thrombotic Rare thrombocytopenic purpura, pancytopenia, coagulo

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HOS-094078 · has-contraindication-information · PDF-Seite 44

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Co-administration with ergot alkaloids (see section 4.5). Co-administration with the CYP3A4 substrates terfenadine, astemizole, cisapride, pimozide, halofantrine or quinidine since this may result in increased plasma concentrations of these medicinal products, leading to QTc prolongation and rare occurrences of torsade de pointes (see sections 4.4 and 4.5). 44 Co-administration with the HMG-CoA reductase inhibitors simvastatin, lovastatin and atorvastatin (see section 4.5). Co-administration during the initiation and dose-titration phase of venetoclax in Chronic Lymphocytic Leukaemia (CLL) patients (see sections 4.4 and 4.5).

HOS-094066 · has-contraindication-information · PDF-Seite 4

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Co-administration with ergot alkaloids (see section 4.5). Co-administration with the CYP3A4 substrates terfenadine, astemizole, cisapride, pimozide, halofantrine or quinidine since this may result in increased plasma concentrations of these medicinal products, leading to QTc prolongation and rare occurrences of torsade de pointes (see sections 4.4 and 4.5). Co-administration with the HMG-CoA reductase inhibitors simvastatin, lovastatin and atorvastatin (see section 4.5). Co-administration during the initiation and dose-titration phase of venetoclax in Chronic Lymphocytic Leukaemia (CLL) patients (see sections 4.4 and 4.5).

HOS-094084 · has-contraindication-information · PDF-Seite 68

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Co-administration with ergot alkaloids (see section 4.5). Co-administration with the CYP3A4 substrates terfenadine, astemizole, cisapride, pimozide, halofantrine or quinidine since this may result in increased plasma concentrations of these medicinal products, leading to QTc prolongation and rare occurrences of torsade de pointes (see sections 4.4 and 4.5). Co-administration with the HMG-CoA reductase inhibitors simvastatin, lovastatin and atorvastatin (see section 4.5). Co-administration during the initiation and dose-titration phase of venetoclax in Chronic Lymphocytic Leukaemia (CLL) patients (see sections 4.4 and 4.5).

HOS-094072 · has-contraindication-information · PDF-Seite 22

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Co-administration with ergot alkaloids (see section 4.5). Co-administration with the CYP3A4 substrates terfenadine, astemizole, cisapride, pimozide, halofantrine or quinidine since this may result in increased plasma concentrations of these medicinal products, leading to QTc prolongation and rare occurrences of torsade de pointes (see sections 4.4 and 4.5). Co-administration with the HMG-CoA reductase inhibitors simvastatin, lovastatin and atorvastatin (see section 4.5). Co-administration during the initiation and dose-titration phase of venetoclax in Chronic Lymphocytic Leukaemia (CLL) patients (see sections 4.4 and 4.5).

HOS-094065 · has-indication-information · PDF-Seite 2

Noxafil oral suspension is indicated for use in the treatment of the following fungal infections in adults (see section 5.1): - Invasive aspergillosis in patients with disease that is refractory to amphotericin B or itraconazole or in patients who are intolerant of these medicinal products; - Fusariosis in patients with disease that is refractory to amphotericin B or in patients who are intolerant of amphotericin B; - Chromoblastomycosis and mycetoma in patients with disease that is refractory to itraconazole or in patients who are intolerant of itraconazole; - Coccidioidomycosis in patients with disease that is refractory to amphotericin B, itraconazole or fluconazole or in patients who are intolerant of these medicinal products; - Oropharyngeal candidiasis: as first-line therapy in patients who have severe disease or are immunocompromised, in whom response to topical therapy is expected to be poor. Refractoriness is defined as progression of infection or failure to improve after a minimum of 7 days of prior therapeutic doses of effective antifungal therapy. Noxafil oral suspension is also indicated for prophylaxis of invasive fungal infections in the following patients: - Patients receiving remission-induction chemotherapy for acute myelogenous leukaemia (AML) or myelodysplastic syndromes (MDS) expected to result in prolonged neutropenia and who are at high-risk of developing invasive fungal infections; - Hematopoietic stem cell transplant (HSCT) recipients who are undergoing high-dose immunosuppressive therapy for graft versus host disease and who are at high-risk of developing invasive fungal infections. Please refer to the Summary of Product Characteristics of Noxafil concentrate for solution for infusion and the gastro-resistant tablets for use in primary treatment of invasive aspergillosis. 2

HOS-094077 · has-indication-information · PDF-Seite 42

Noxafil concentrate for solution for infusion is indicated for use in the treatment of the following invasive fungal infections in adults and paediatric patients from 2 years of age (see sections 4.2 and 5.1): - Invasive aspergillosis; - Fusariosis in patients with disease that is refractory to amphotericin B or in patients who are intolerant of amphotericin B; - Chromoblastomycosis and mycetoma in patients with disease that is refractory to itraconazole or in patients who are intolerant of itraconazole; - Coccidioidomycosis in patients with disease that is refractory to amphotericin B, itraconazole or fluconazole or in patients who are intolerant of these medicinal products. Refractoriness is defined as progression of infection or failure to improve after a minimum of 7 days of prior therapeutic doses of effective antifungal therapy. Noxafil concentrate for solution for infusion is also indicated for prophylaxis of invasive fungal infections in adults and paediatric patients from 2 years of age (see section 5.1): - Patients receiving remission-induction chemotherapy for acute myelogenous leukaemia (AML) or myelodysplastic syndromes (MDS) expected to result in prolonged neutropenia and who are at high-risk of developing invasive fungal infections; - Hematopoietic stem cell transplant (HSCT) recipients who are undergoing high-dose immunosuppressive therapy for graft versus host disease (GVHD) and who are at high-risk of developing invasive fungal infections. Please refer to the Summary of Product Characteristics of Noxafil oral suspension for use in adults with oropharyngeal candidiasis. 42

HOS-094071 · has-indication-information · PDF-Seite 20

Noxafil gastro-resistant tablets are indicated for use in the treatment of the following invasive fungal infections in adults and paediatric patients from 2 years of age weighing more than 40 kg (see sections 4.2 and 5.1): - Invasive aspergillosis; - Fusariosis in patients with disease that is refractory to amphotericin B or in patients who are intolerant of amphotericin B; - Chromoblastomycosis and mycetoma in patients with disease that is refractory to itraconazole or in patients who are intolerant of itraconazole; - Coccidioidomycosis in patients with disease that is refractory to amphotericin B, itraconazole or fluconazole or in patients who are intolerant of these medicinal products. Refractoriness is defined as progression of infection or failure to improve after a minimum of 7 days of prior therapeutic doses of effective antifungal therapy. Noxafil gastro-resistant tablets are also indicated for prophylaxis of invasive fungal infections in adults and paediatric patients from 2 years of age weighing more than 40 kg (see section 5.1): - Patients receiving remission-induction chemotherapy for acute myelogenous leukaemia (AML) or myelodysplastic syndromes (MDS) expected to result in prolonged neutropenia and who are at high-risk of developing invasive fungal infections; - Hematopoietic stem cell transplant (HSCT) recipients who are undergoing high-dose immunosuppressive therapy for graft versus host disease and who are at high-risk of developing invasive fungal infections. Please refer to the Summary of Product Characteristics of Noxafil oral suspension for use in oropharyngeal candidiasis.

HOS-094083 · has-indication-information · PDF-Seite 66

Noxafil gastro-resistant powder and solvent for oral suspension is indicated for use in the treatment of the following invasive fungal infections in paediatric patients from 2 years of age (see sections 4.2 and 5.1): - Invasive aspergillosis; - Fusariosis in patients with disease that is refractory to amphotericin B or in patients who are intolerant of amphotericin B; - Chromoblastomycosis and mycetoma in patients with disease that is refractory to itraconazole or in patients who are intolerant of itraconazole; - Coccidioidomycosis in patients with disease that is refractory to amphotericin B, itraconazole or fluconazole or in patients who are intolerant of these medicinal products. Refractoriness is defined as progression of infection or failure to improve after a minimum of 7 days of prior therapeutic doses of effective antifungal therapy. Noxafil gastro-resistant powder and solvent for oral suspension is indicated for prophylaxis of invasive fungal infections in the following paediatric patients from 2 years of age: - Patients receiving remission-induction chemotherapy for acute myelogenous leukaemia (AML) or myelodysplastic syndromes (MDS) expected to result in prolonged neutropenia and who are at high-risk of developing invasive fungal infections; - Haematopoietic stem cell transplant (HSCT) recipients who are undergoing high-dose immunosuppressive therapy for graft versus host disease and who are at high-risk of developing invasive fungal infections. Please refer to the Summary of Product Characteristics of Noxafil oral suspension for use in oropharyngeal candidiasis. 66

HOS-094080 · has-interaction-information · PDF-Seite 46

The following information was derived from data with posaconazole oral suspension or early tablet formulation. All drug interactions with posaconazole oral suspension, except for those that affect the absorption of posaconazole (via gastric pH and motility) are considered relevant to posaconazole concentrate for solution for infusion as well. Effects of other medicinal products on posaconazole Posaconazole is metabolised via UDP glucuronidation (phase 2 enzymes) and is a substrate for p-glycoprotein (P-gp) efflux in vitro. Therefore, inhibitors (e.g. verapamil, ciclosporin, quinidine, 46 clarithromycin, erythromycin, etc.) or inducers (e.g. rifampicin, rifabutin, certain anticonvulsants, etc.) of these clearance pathways may increase or decrease posaconazole plasma concentrations, respectively. Flucloxacillin Flucloxacillin (a CYP450 inducer) may decrease plasma posaconazole concentrations. Concomitant use of posaconazole and flucloxacillin should be avoided unless the benefit to the patient outweighs the risk (see section 4.4). Rifabutin Rifabutin (300 mg once a day) decreased the Cmax (maximum plasma concentration) and AUC (area under the plasma concentration time curve) of posaconazole to 57 % and 51 %, respectively. Concomitant use of posaconazole and rifabutin and similar inducers (e.g. rifampicin) should be avoided unless the benefit to the patient outweighs the risk. See also below regarding the effect of posaconazole on rifabutin plasma levels. Efavirenz Efavirenz (400 mg once a day) decreased the Cmax and AUC of posaconazole by 45 % and 50 %, respectively. Concomitant use of posaconazole and efavirenz should be avoided unless the benefit to the patient outweighs the risk. Fosamprenavir Combining fosamprenavir with posaconazole may lead to decreased posaconazole plasma concentrations. If concomitant administration is required, close monitoring for breakthrough fungal infections is recommended. Repeat dose administration of fosamprenavir (700 mg twice daily x 10 days) decreased the Cmax and AUC of posaconazole oral suspension (200 mg once daily on the 1st day, 200 mg twice daily on the 2nd day, then 400 mg twice daily x 8 Days) by 21 % and 23 %, respectively. The effect of posaconazole on fosamprenavir levels when fosamprenavir is given with ritonavir is unknown. Phenytoin Phenytoin (200 mg once a day) decreased the Cmax and AUC of posaconazole by 41 % and 50 %, respectively. Concomitant use

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HOS-094068 · has-interaction-information · PDF-Seite 6

Effects of other medicinal products on posaconazole Posaconazole is metabolised via UDP glucuronidation (phase 2 enzymes) and is a substrate for p-glycoprotein (P-gp) efflux in vitro. Therefore, inhibitors (e.g. verapamil, ciclosporin, quinidine, clarithromycin, erythromycin, etc.) or inducers (e.g. rifampicin, rifabutin, certain anticonvulsants, etc.) of these clearance pathways may increase or decrease posaconazole plasma concentrations, respectively. Flucloxacillin Flucloxacillin (a CYP450 inducer) may decrease plasma posaconazole concentrations. Concomitant use of posaconazole and flucloxacillin should be avoided unless the benefit to the patient outweighs the risk (see section 4.4). Rifabutin Rifabutin (300 mg once a day) decreased the Cmax (maximum plasma concentration) and AUC (area under the plasma concentration time curve) of posaconazole to 57 % and 51 %, respectively. Concomitant use of posaconazole and rifabutin and similar inducers (e.g. rifampicin) should be avoided unless the benefit to the patient outweighs the risk. See also below regarding the effect of posaconazole on rifabutin plasma levels. Efavirenz Efavirenz (400 mg once a day) decreased the Cmax and AUC of posaconazole by 45 % and 50 %, respectively. Concomitant use of posaconazole and efavirenz should be avoided unless the benefit to the patient outweighs the risk. Fosamprenavir Combining fosamprenavir with posaconazole may lead to decreased posaconazole plasma concentrations. If concomitant administration is required, close monitoring for breakthrough fungal infections is recommended. Repeat dose administration of fosamprenavir (700 mg twice daily x 6 10 days) decreased the Cmax and AUC of posaconazole oral suspension (200 mg once daily on the 1st day, 200 mg twice daily on the 2nd day, then 400 mg twice daily x 8 days) by 21 % and 23 %, respectively. The effect of posaconazole on fosamprenavir levels when fosamprenavir is given with ritonavir is unknown. Phenytoin Phenytoin (200 mg once a day) decreased the Cmax and AUC of posaconazole by 41 % and 50 %, respectively. Concomitant use of posaconazole and phenytoin and similar inducers (e.g. carbamazepine, phenobarbital, primidone) should be avoided unless the benefit to the patient outweighs the risk. H2 receptor antagonists and proton pump inhibitors Posaconazole plasma concentrations (Cmax and AUC) were reduced by 39 % when posaconazole was administered with cimetidine (

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HOS-094074 · has-interaction-information · PDF-Seite 24

Effects of other medicinal products on posaconazole Posaconazole is metabolised via UDP glucuronidation (phase 2 enzymes) and is a substrate for p-glycoprotein (P-gp) efflux in vitro. Therefore, inhibitors (e.g. verapamil, ciclosporin, quinidine, clarithromycin, erythromycin, etc.) or inducers (e.g. rifampicin, rifabutin, certain anticonvulsants, etc.) of these clearance pathways may increase or decrease posaconazole plasma concentrations, respectively. Flucloxacillin Flucloxacillin (a CYP450 inducer) may decrease plasma posaconazole concentrations. Concomitant use of posaconazole and flucloxacillin should be avoided unless the benefit to the patient outweighs the risk (see section 4.4). Rifabutin Rifabutin (300 mg once a day) decreased the Cmax (maximum plasma concentration) and AUC (area under the plasma concentration time curve) of posaconazole to 57 % and 51 %, respectively. Concomitant use of posaconazole and rifabutin and similar inducers (e.g. rifampicin) should be avoided unless the benefit to the patient outweighs the risk. See also below regarding the effect of posaconazole on rifabutin plasma levels. Efavirenz Efavirenz (400 mg once a day) decreased the Cmax and AUC of posaconazole by 45 % and 50 %, respectively. Concomitant use of posaconazole and efavirenz should be avoided unless the benefit to the patient outweighs the risk. Fosamprenavir Combining fosamprenavir with posaconazole may lead to decreased posaconazole plasma concentrations. If concomitant administration is required, close monitoring for breakthrough fungal infections is recommended. Repeat dose administration of fosamprenavir (700 mg twice daily x 10 days) decreased the Cmax and AUC of posaconazole oral suspension (200 mg once daily on the 1st day, 200 mg twice daily on the 2nd day, then 400 mg twice daily x 8 Days) by 21 % and 23 %, respectively. The effect of posaconazole on fosamprenavir levels when fosamprenavir is given with ritonavir is unknown. Phenytoin Phenytoin (200 mg once a day) decreased the Cmax and AUC of posaconazole by 41 % and 50 %, respectively. Concomitant use of posaconazole and phenytoin and similar inducers (e.g. carbamazepine, phenobarbital, primidone) should be avoided unless the benefit to the patient outweighs the risk. H2 receptor antagonists and proton pump inhibitors No clinically relevant effects were observed when posaconazole tablets are concomitantly used with antacids, H2-receptor antagonists and proton pump inhibitors. No dose adjustment

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HOS-094086 · has-interaction-information · PDF-Seite 70

Effects of other medicinal products on posaconazole Posaconazole is metabolised via UDP glucuronidation (phase 2 enzymes) and is a substrate for p-glycoprotein (P-gp) efflux in vitro. Therefore, inhibitors (e.g. verapamil, ciclosporin, quinidine, clarithromycin, erythromycin, etc.) or inducers (e.g. rifampicin, rifabutin, certain anticonvulsants, etc.) of these clearance pathways may increase or decrease posaconazole plasma concentrations, respectively. Flucloxacillin Flucloxacillin (a CYP450 inducer) may decrease plasma posaconazole concentrations. Concomitant use of posaconazole and flucloxacillin should be avoided unless the benefit to the patient outweighs the risk (see section 4.4). Rifabutin Rifabutin (300 mg once a day) decreased the Cmax (maximum plasma concentration) and AUC (area under the plasma concentration time curve) of posaconazole to 57 % and 51 %, respectively. Concomitant use of posaconazole and rifabutin and similar inducers (e.g. rifampicin) should be avoided unless the benefit to the patient outweighs the risk. See also below regarding the effect of posaconazole on rifabutin plasma levels. 70 Efavirenz Efavirenz (400 mg once a day) decreased the Cmax and AUC of posaconazole by 45 % and 50 %, respectively. Concomitant use of posaconazole and efavirenz should be avoided unless the benefit to the patient outweighs the risk. Fosamprenavir Combining fosamprenavir with posaconazole may lead to decreased posaconazole plasma concentrations. If concomitant administration is required, close monitoring for breakthrough fungal infections is recommended. Repeat dose administration of fosamprenavir (700 mg twice daily x 10 days) decreased the Cmax and AUC of posaconazole oral suspension (200 mg once daily on the 1st day, 200 mg twice daily on the 2nd day, then 400 mg twice daily x 8 Days) by 21 % and 23 %, respectively. The effect of posaconazole on fosamprenavir levels when fosamprenavir is given with ritonavir is unknown. Phenytoin Phenytoin (200 mg once a day) decreased the Cmax and AUC of posaconazole by 41 % and 50 %, respectively. Concomitant use of posaconazole and phenytoin and similar inducers (e.g. carbamazepine, phenobarbital, primidone) should be avoided unless the benefit to the patient outweighs the risk. H2 receptor antagonists and proton pump inhibitors No clinically relevant effects were observed when posaconazole tablets are concomitantly used with antacids, H2-receptor

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HOS-094069 · has-pregnancy-information · PDF-Seite 10

Pregnancy There is insufficient information on the use of posaconazole in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Women of childbearing potential have to use effective contraception during treatment. Posaconazole must not be used during pregnancy unless the benefit to the mother clearly outweighs the potential risk to the foetus. Breast-feeding Posaconazole is excreted into the milk of lactating rats (see section 5.3). The excretion of posaconazole in human breast milk has not been investigated. Breast-feeding must be stopped on initiation of treatment with posaconazole. Fertility Posaconazole had no effect on fertility of male rats at doses up to 180 mg/kg (1.7 times the 400-mg twice daily regimen based on steady-state plasma concentrations in healthy volunteers) or female rats at a dose up to 45 mg/kg (2.2 times the 400-mg twice daily regimen). There is no clinical experience assessing the impact of posaconazole on fertility in humans.

HOS-094081 · has-pregnancy-information · PDF-Seite 50

Pregnancy There is insufficient information on the use of posaconazole in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Women of childbearing potential have to use effective contraception during treatment. Posaconazole must not be used during pregnancy unless the benefit to the mother clearly outweighs the potential risk to the foetus. Breast-feeding Posaconazole is excreted into the milk of lactating rats (see section 5.3). The excretion of posaconazole in human breast milk has not been investigated. Breast-feeding must be stopped on initiation of treatment with posaconazole. Fertility Posaconazole had no effect on fertility of male rats at doses up to 180 mg/kg (2.8 times the exposure achieved from a 300 mg intravenous dose in human) or female rats at a dose up to 45 mg/kg (3.4 times the exposure from a 300 mg intravenous dose in patients). There is no clinical experience assessing the impact of posaconazole on fertility in humans.

HOS-094075 · has-pregnancy-information · PDF-Seite 27

Pregnancy There is insufficient information on the use of posaconazole in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Women of childbearing potential have to use effective contraception during treatment. Posaconazole must not be used during pregnancy unless the benefit to the mother clearly outweighs the potential risk to the foetus. Breast-feeding Posaconazole is excreted into the milk of lactating rats (see section 5.3). The excretion of posaconazole in human breast milk has not been investigated. Breast-feeding must be stopped on initiation of treatment with posaconazole. Fertility Posaconazole had no effect on fertility of male rats at doses up to 180 mg/kg (3.4 times the 300-mg tablet based on steady-state plasma concentrations in patients) or female rats at a dose up to 45 mg/kg (2.6 times the 300-mg tablet based on steady-state plasma concentrations in patients). There is no clinical experience assessing the impact of posaconazole on fertility in humans.

HOS-094087 · has-pregnancy-information · PDF-Seite 74

Pregnancy There is insufficient information on the use of posaconazole in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Women of childbearing potential have to use effective contraception during treatment. Posaconazole must not be used during pregnancy unless the benefit to the mother clearly outweighs the potential risk to the foetus. Breast-feeding Posaconazole is excreted into the milk of lactating rats (see section 5.3). The excretion of posaconazole in human breast milk has not been investigated. Breast-feeding must be stopped on initiation of treatment with posaconazole. Fertility Posaconazole had no effect on fertility of male rats at doses up to 180 mg/kg (3.4 times the 300-mg tablet based on steady-state plasma concentrations in patients) or female rats at a dose up to 45 mg/kg (2.6 times the 300-mg tablet based on steady-state plasma concentrations in patients). There is no clinical experience assessing the impact of posaconazole on fertility in humans.

HOS-094085 · has-warning-information · PDF-Seite 68

Hypersensitivity There is no information regarding cross-sensitivity between posaconazole and other azole antifungal agents. Caution should be used when prescribing posaconazole to patients with hypersensitivity to other azoles. 68 Hepatobiliary disorders Hepatic reactions (e.g. mild to moderate elevations in ALT, AST, alkaline phosphatase, total bilirubin and/or clinical hepatitis) have been reported during treatment with posaconazole. Elevated liver function tests were generally reversible on discontinuation of therapy and in some instances these tests normalised without interruption of therapy. Rarely, more severe hepatic reactions with fatal outcomes have been reported (see section 4.8). Monitoring of hepatic function Liver function tests should be evaluated prior to the start of and during the course of posaconazole therapy. Patients who develop abnormal liver function tests during posaconazole therapy must be routinely monitored for the development of more severe hepatic injury. Discontinuation of posaconazole should be considered if clinical signs and symptoms are consistent with development of liver disease. Posaconazole should be used with caution in patients with hepatic impairment due to the possibility of increased plasma levels (see section 5.2). QTc prolongation Some azoles have been associated with prolongation of the QTc interval. Posaconazole must not be administered with medicinal products that are substrates for CYP3A4 and are known to prolong the QTc interval (see sections 4.3 and 4.5). Posaconazole should be administered with caution to patients with pro-arrhythmic conditions such as: • Congenital or acquired QTc prolongation • Cardiomyopathy, especially in the presence of cardiac failure • Sinus bradycardia • Existing symptomatic arrhythmias • Concomitant use with medicinal products known to prolong the QTc interval (other than those mentioned in section 4.3). Electrolyte disturbances, especially those involving potassium, magnesium or calcium levels, should be monitored and corrected as necessary before and during posaconazole therapy. Drug interactions Posaconazole is an inhibitor of CYP3A4 and should only be used under specific circumstances during treatment with other medicinal products that are metabolised by CYP3A4 (see section 4.5). Midazolam and other benzodiazepines Due to the risk of prolonged sedation and possible respiratory depression

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HOS-094079 · has-warning-information · PDF-Seite 45

Hypersensitivity There is no information regarding cross-sensitivity between posaconazole and other azole antifungal agents. Caution should be used when prescribing posaconazole to patients with hypersensitivity to other azoles. Hepatobiliary disorders Hepatic reactions (e.g. mild to moderate elevations in ALT, AST, alkaline phosphatase, total bilirubin and/or clinical hepatitis) have been reported during treatment with posaconazole. Elevated liver function tests were generally reversible on discontinuation of therapy and in some instances these tests normalised without interruption of therapy. Rarely, more severe hepatic reactions with fatal outcomes have been reported (see section 4.8). Monitoring of hepatic function Liver function tests should be evaluated prior to the start of and during the course of posaconazole therapy. Patients who develop abnormal liver function tests during posaconazole therapy must be routinely monitored for the development of more severe hepatic injury. Discontinuation of posaconazole should be considered if clinical signs and symptoms are consistent with development of liver disease. Posaconazole should be used with caution in patients with hepatic impairment due to the possibility of increased plasma levels (see section 5.2). Monitoring of patients with severe renal impairment Due to the variability in exposure, patients with severe renal impairment should be monitored closely for breakthrough fungal infections (see sections 4.2 and 5.2). QTc prolongation Some azoles have been associated with prolongation of the QTc interval. Posaconazole must not be administered with medicinal products that are substrates for CYP3A4 and are known to prolong the QTc interval (see sections 4.3 and 4.5). Posaconazole should be administered with caution to patients with pro-arrhythmic conditions such as: • Congenital or acquired QTc prolongation • Cardiomyopathy, especially in the presence of cardiac failure • Sinus bradycardia • Existing symptomatic arrhythmias • Concomitant use with medicinal products known to prolong the QTc interval (other than those mentioned in section 4.3). Electrolyte disturbances, especially those involving potassium, magnesium or calcium levels, should be monitored and corrected as necessary before and during posaconazole therapy. In patients, mean maximum plasma concentrations (Cmax) after posaconazole concentrate for solution for infusion are 4-fold increased compared to administr

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HOS-094067 · has-warning-information · PDF-Seite 4

Hypersensitivity There is no information regarding cross-sensitivity between posaconazole and other azole antifungal agents. Caution should be used when prescribing posaconazole to patients with hypersensitivity to other azoles. Hepatobiliary disorders Hepatic reactions (e.g. mild to moderate elevations in ALT, AST, alkaline phosphatase, total bilirubin and/or clinical hepatitis) have been reported during treatment with posaconazole. Elevated liver function tests were generally reversible on discontinuation of therapy and in some instances these tests normalised without interruption of therapy. Rarely, more severe hepatic reactions with fatal outcomes have been reported (see section 4.8). Monitoring of hepatic function 4 Liver function tests should be evaluated prior to the start of and during the course of posaconazole therapy. Patients who develop abnormal liver function tests during posaconazole therapy must be routinely monitored for the development of more severe hepatic injury. Discontinuation of posaconazole should be considered if clinical signs and symptoms are consistent with development of liver disease. Posaconazole should be used with caution in patients with hepatic impairment due to the possibility of increased plasma levels (see section 5.2). QTc prolongation Some azoles have been associated with prolongation of the QTc interval. Posaconazole must not be administered with medicinal products that are substrates for CYP3A4 and are known to prolong the QTc interval (see sections 4.3 and 4.5). Posaconazole should be administered with caution to patients with pro-arrhythmic conditions such as: • Congenital or acquired QTc prolongation • Cardiomyopathy, especially in the presence of cardiac failure • Sinus bradycardia • Existing symptomatic arrhythmias • Concomitant use with medicinal products known to prolong the QTc interval (other than those mentioned in section 4.3). Electrolyte disturbances, especially those involving potassium, magnesium or calcium levels, should be monitored and corrected as necessary before and during posaconazole therapy. Drug interactions Posaconazole is an inhibitor of CYP3A4 and should only be used under specific circumstances during treatment with other medicinal products that are metabolised by CYP3A4 (see section 4.5). Midazolam and other benzodiazepines Due to the risk of prolonged sedation and possible respiratory depression co

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HOS-094073 · has-warning-information · PDF-Seite 22

Hypersensitivity There is no information regarding cross-sensitivity between posaconazole and other azole antifungal agents. Caution should be used when prescribing posaconazole to patients with hypersensitivity to other azoles. Hepatobiliary disorders Hepatic reactions (e.g. mild to moderate elevations in ALT, AST, alkaline phosphatase, total bilirubin and/or clinical hepatitis) have been reported during treatment with posaconazole. Elevated liver function tests were generally reversible on discontinuation of therapy and in some instances these tests normalised without interruption of therapy. Rarely, more severe hepatic reactions with fatal outcomes have been reported (see section 4.8). Monitoring of hepatic function Liver function tests should be evaluated prior to the start of and during the course of posaconazole therapy. Patients who develop abnormal liver function tests during posaconazole therapy must be routinely monitored for the development of more severe hepatic injury. Discontinuation of posaconazole should be considered if clinical signs and symptoms are consistent with development of liver disease. Posaconazole should be used with caution in patients with hepatic impairment due to the possibility of increased plasma levels (see section 5.2). 22 QTc prolongation Some azoles have been associated with prolongation of the QTc interval. Posaconazole must not be administered with medicinal products that are substrates for CYP3A4 and are known to prolong the QTc interval (see sections 4.3 and 4.5). Posaconazole should be administered with caution to patients with pro-arrhythmic conditions such as: • Congenital or acquired QTc prolongation • Cardiomyopathy, especially in the presence of cardiac failure • Sinus bradycardia • Existing symptomatic arrhythmias • Concomitant use with medicinal products known to prolong the QTc interval (other than those mentioned in section 4.3). Electrolyte disturbances, especially those involving potassium, magnesium or calcium levels, should be monitored and corrected as necessary before and during posaconazole therapy. Drug interactions Posaconazole is an inhibitor of CYP3A4 and should only be used under specific circumstances during treatment with other medicinal products that are metabolised by CYP3A4 (see section 4.5). Midazolam and other benzodiazepines Due to the risk of prolonged sedation and possible respiratory depression co-

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