Cresemba · 4.1 Therapeutic indications · 2

HOS-096658 · has-adverse-reaction-information · PDF-Seite 36

Summary of the safety profile The most common treatment-related adverse reactions in adults were elevated liver chemistry tests (7.9%), nausea (7.4%), vomiting (5.5%), dyspnoea (3.2%), abdominal pain (2.7%), diarrhoea (2.7%), injection site reaction (2.2%), headache (2.0%), hypokalaemia (1.7%) and rash (1.7%). The adverse reactions which most often led to permanent discontinuation of isavuconazole treatment in adults were confusional state (0.7%), acute renal failure (0.7%), increased blood bilirubin (0.5%), convulsion (0.5%), dyspnoea (0.5%), epilepsy (0.5%), respiratory failure (0.5%) and vomiting (0.5%). Tabulated list of adverse reactions Table 4 presents adverse reactions with isavuconazole in the treatment of invasive fungal infections in adults, by System Organ Class and frequency. The frequency of adverse reactions is defined as follows: very common (≥1/10); common (≥1/100 to <1/10); and uncommon (≥1/1,000 to <1/100); not known (frequency cannot be estimated from available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Table 4 Summary of adverse reactions by MedDRA System Organ Class and frequency System Organ Class Adverse Drug Reactions Blood and lymphatic system disorders Uncommon Neutropenia; Thrombocytopenia^; Pancytopenia; Leukopenia^; Anaemia^ Immune system disorders Uncommon Hypersensitivity^ Not known Anaphylactic reaction* Metabolism and nutrition disorders Common Hypokalaemia; Decreased appetite Uncommon Hypomagnesaemia; Hypoglycaemia; Hypoalbuminaemia; Malnutrition^; Hyponatraemia Psychiatric disorders Common Delirium^# Uncommon Depression; Insomnia^ Nervous system disorders Common Headache; Somnolence Uncommon Convulsion^; Syncope; Dizziness; Paraesthesia^; Encephalopathy; Presyncope; Neuropathy peripheral; Dysgeusia Ear and labyrinth disorders Uncommon Vertigo Cardiac disorders Uncommon Atrial fibrillation; Tachycardia; Bradycardia^; Palpitations; Atrial flutter; Electrocardiogram QT shortened; Supraventricular tachycardia; Ventricular extrasystoles; Supraventricular extrasystoles 36  Vascular disorders Common Thrombophlebitis^ Uncommon Circulatory collapse; H

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HOS-096652 · has-adverse-reaction-information · PDF-Seite 13

Summary of the safety profile The most common treatment-related adverse reactions in adults were elevated liver chemistry tests (7.9%), nausea (7.4%), vomiting (5.5%), dyspnoea (3.2%), abdominal pain (2.7%), diarrhoea (2.7%), injection site reaction (2.2%), headache (2.0%), hypokalaemia (1.7%) and rash (1.7%). The adverse reactions which most often led to permanent discontinuation of isavuconazole treatment in adults were confusional state (0.7%), acute renal failure (0.7%), increased blood bilirubin (0.5%), convulsion (0.5%), dyspnoea (0.5%), epilepsy (0.5%), respiratory failure (0.5%) and vomiting (0.5%). Tabulated list of adverse reactions Table 3 presents adverse reactions with isavuconazole in the treatment of invasive fungal infections in adults, by System Organ Class and frequency. 13 The frequency of adverse reactions is defined as follows: very common (≥1/10); common (≥1/100 to <1/10); and uncommon (≥1/1,000 to <1/100); not known (frequency cannot be estimated from available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Table 3 Summary of adverse reactions by MedDRA System Organ Class and frequency System Organ Class Adverse Drug Reactions Blood and lymphatic system disorders Uncommon Neutropenia; Thrombocytopenia^; Pancytopenia; Leukopenia^; Anaemia^ Immune system disorders Uncommon Hypersensitivity^ Not known Anaphylactic reaction* Metabolism and nutrition disorders Common Hypokalaemia; Decreased appetite Uncommon Hypomagnesaemia; Hypoglycaemia; Hypoalbuminaemia; Malnutrition^; Hyponatraemia Psychiatric disorders Common Delirium^# Uncommon Depression; Insomnia^ Nervous system disorders Common Headache; Somnolence Uncommon Convulsion^; Syncope; Dizziness; Paraesthesia^; Encephalopathy; Presyncope; Neuropathy peripheral; Dysgeusia Ear and labyrinth disorders Uncommon Vertigo Cardiac disorders Uncommon Atrial fibrillation; Tachycardia; Bradycardia^; Palpitations; Atrial flutter; Electrocardiogram QT shortened; Supraventricular tachycardia; Ventricular extrasystoles; Supraventricular extrasystoles Vascular disorders Common Thrombophlebitis^ Uncommon Circulatory collapse

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HOS-096654 · has-contraindication-information · PDF-Seite 26

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Co-administration with ketoconazole (see section 4.5). Co-administration with high-dose ritonavir (>200 mg every 12 hours) (see section 4.5). Co-administration with strong CYP3A4/5 inducers such as rifampicin, rifabutin, carbamazepine, long- acting barbiturates (e.g. phenobarbital), phenytoin and St. John’s wort or with moderate CYP3A4/5 inducers such as efavirenz, nafcillin and etravirine (see section 4.5). Patients with familial short QT syndrome (see section 4.4).

HOS-096648 · has-contraindication-information · PDF-Seite 3

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Co-administration with ketoconazole (see section 4.5). 3 Co-administration with high-dose ritonavir (>200 mg every 12 hours) (see section 4.5). Co-administration with strong CYP3A4/5 inducers such as rifampicin, rifabutin, carbamazepine, long- acting barbiturates (e.g. phenobarbital), phenytoin and St. John’s wort or with moderate CYP3A4/5 inducers such as efavirenz, nafcillin and etravirine (see section 4.5). Patients with familial short QT syndrome (see section 4.4).

HOS-096647 · has-indication-information · PDF-Seite 2

CRESEMBA is indicated in patients from 1 year of age and older for the treatment of • invasive aspergillosis • mucormycosis in patients for whom amphotericin B is inappropriate (see sections 4.4 and 5.1) Consideration should be given to official guidance on the appropriate use of antifungal agents.

HOS-096653 · has-indication-information · PDF-Seite 24

CRESEMBA hard capsules are indicated in adults and in paediatric patients from 6 years of age for the treatment of • invasive aspergillosis • mucormycosis in patients for whom amphotericin B is inappropriate (see sections 4.4 and 5.1) Consideration should be given to official guidance on the appropriate use of antifungal agents. CRESEMBA 40 mg hard capsules are intended to be used for paediatric patients.

HOS-096650 · has-interaction-information · PDF-Seite 6

Potential of medicinal products to affect the pharmacokinetics of isavuconazole Isavuconazole is a substrate of CYP3A4 and CYP3A5 (see section 5.2). Co-administration of medicinal products which are inhibitors of CYP3A4 and/or CYP3A5 may increase the plasma concentrations of isavuconazole. Co-administration of medicinal products which are inducers of CYP3A4 and/or CYP3A5 may decrease the plasma concentrations of isavuconazole. Medicinal products that inhibit CYP3A4/5 Co-administration of isavuconazole with the strong CYP3A4/5 inhibitor ketoconazole is contraindicated, since this medicinal product can significantly increase plasma concentrations of isavuconazole (see sections 4.3 and 4.5). For the strong CYP3A4 inhibitor lopinavir/ritonavir, a two-fold increase in isavuconazole exposure was observed. For other strong CYP3A4 inhibitors, such as clarithromycin, indinavir and saquinavir, a less pronounced effect can be expected, based on their relative potency. No dose adjustment of isavuconazole is necessary when co-administered with strong CYP3A4/5 inhibitors, however caution is advised as adverse drug reactions may increase (see section 4.4). No dose adjustment is warranted for moderate to mild CYP3A4/5 inhibitors. Medicinal products that induce CYP3A4/5 Co-administration of isavuconazole with potent CYP3A4/5 inducers such as rifampicin, rifabutin, carbamazepine, long-acting barbiturates (e.g., phenobarbital), phenytoin and St. John’s wort, or with moderate CYP3A4/5 inducers such as efavirenz, nafcillin and etravirine, is contraindicated, since these medicinal products can significantly decrease plasma concentrations of isavuconazole (see section 4.3). Co-administration with mild CYP3A4/5 inducers such as aprepitant, prednisone and pioglitazone, may result in mild to moderate decreases of isavuconazole plasma levels; co-administration with mild CYP3A4/5 inducers should be avoided unless the potential benefit is considered to outweigh the risk (see section 4.4). Co-administration with high-dose ritonavir (>200 mg twice daily) is contraindicated, as at high doses ritonavir may induce CYP3A4/5 and decrease isavuconazole plasma concentrations (see section 4.3). Potential for isavuconazole to affect exposures of other medicines Medicinal products metabolised by CYP3A4/5 Isavuconazole is a moderate inhibitor of CYP3A4/5; co-administration of isavuconazole with medicinal products which are substrates of CYP3A4/5 may result in increased plasma concentra

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HOS-096656 · has-interaction-information · PDF-Seite 28

Potential of medicinal products to affect the pharmacokinetics of isavuconazole Isavuconazole is a substrate of CYP3A4 and CYP3A5 (see section 5.2). Co-administration of medicinal products which are inhibitors of CYP3A4 and/or CYP3A5 may increase the plasma concentrations of isavuconazole. Co-administration of medicinal products which are inducers of CYP3A4 and/or CYP3A5 may decrease the plasma concentrations of isavuconazole. Medicinal products that inhibit CYP3A4/5 Co-administration of isavuconazole with the strong CYP3A4/5 inhibitor ketoconazole is contraindicated, since this medicinal product can significantly increase plasma concentrations of isavuconazole (see sections 4.3 and 4.5). For the strong CYP3A4 inhibitor lopinavir/ritonavir, a two-fold increase in isavuconazole exposure was observed. For other strong CYP3A4 inhibitors, such as clarithromycin, indinavir and saquinavir, a less pronounced effect can be expected, based on their relative potency. No dose adjustment of isavuconazole is necessary when co-administered with strong CYP3A4/5 inhibitors, however caution is advised as adverse drug reactions may increase (see section 4.4). No dose adjustment is warranted for moderate to mild CYP3A4/5 inhibitors. 28 Medicinal products that induce CYP3A4/5 Co-administration of isavuconazole with potent CYP3A4/5 inducers such as rifampicin, rifabutin, carbamazepine, long-acting barbiturates (e.g., phenobarbital), phenytoin and St. John’s wort, or with moderate CYP3A4/5 inducers such as efavirenz, nafcillin and etravirine, is contraindicated, since these medicinal products can significantly decrease plasma concentrations of isavuconazole (see section 4.3). Co-administration with mild CYP3A4/5 inducers such as aprepitant, prednisone and pioglitazone, may result in mild to moderate decreases of isavuconazole plasma levels; co-administration with mild CYP3A4/5 inducers should be avoided unless the potential benefit is considered to outweigh the risk (see section 4.4). Co-administration with high-dose ritonavir (>200 mg twice daily) is contraindicated, as at high doses ritonavir may induce CYP3A4/5 and decrease isavuconazole plasma concentrations (see section 4.3). Potential for isavuconazole to affect exposures of other medicines Medicinal products metabolised by CYP3A4/5 Isavuconazole is a moderate inhibitor of CYP3A4/5; co-administration of isavuconazole with medicinal products which are subst

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HOS-096657 · has-pregnancy-information · PDF-Seite 35

Pregnancy There are no data from the use of CRESEMBA in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. CRESEMBA must not be used during pregnancy except in patients with severe or potentially life- threatening fungal infections, in whom isavuconazole may be used if the anticipated benefits outweigh the possible risks to the foetus. Women of child-bearing potential CRESEMBA is not recommended for women of childbearing potential who are not using contraception. Breast-feeding Available pharmacodynamic/toxicological data in animals have shown excretion of isavuconazole/metabolites in milk (see section 5.3). A risk to newborns and infants cannot be excluded. Breast-feeding should be discontinued during treatment with CRESEMBA. Fertility There are no data on the effect of isavuconazole on human fertility. Studies in animals did not show impairment of fertility in male or female rats (see section 5.3). 35

HOS-096651 · has-pregnancy-information · PDF-Seite 13

Pregnancy There are no data from the use of CRESEMBA in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. CRESEMBA must not be used during pregnancy except in patients with severe or potentially life- threatening fungal infections, in whom isavuconazole may be used if the anticipated benefits outweigh the possible risks to the foetus. Women of child-bearing potential CRESEMBA is not recommended for women of childbearing potential who are not using contraception. Breast-feeding Available pharmacodynamic/toxicological data in animals have shown excretion of isavuconazole/metabolites in milk (see section 5.3). A risk to newborns and infants cannot be excluded. Breast-feeding should be discontinued during treatment with CRESEMBA. Fertility There are no data on the effect of isavuconazole on human fertility. Studies in animals did not show impairment of fertility in male or female rats (see section 5.3).

HOS-096649 · has-warning-information · PDF-Seite 4

Hypersensitivity Hypersensitivity to isavuconazole may result in adverse reactions that include: anaphylactic reaction, hypotension, respiratory failure, dyspnoea, drug eruption, pruritus, and rash (see section 4.8). In case of anaphylactic reaction, isavuconazole should be discontinued immediately and appropriate medical treatment should be initiated. Caution should be used in prescribing isavuconazole to patients with hypersensitivity to other azole antifungal agents. Infusion-related reactions During intravenous administration of isavuconazole, infusion-related reactions including hypotension, dyspnoea, dizziness, paraesthesia, nausea, and headache were reported (see section 4.8). The infusion should be stopped if these reactions occur. Severe cutaneous adverse reactions Severe cutaneous adverse reactions, such as Stevens-Johnson syndrome, have been reported during treatment with azole antifungal agents. If a patient develops a severe cutaneous adverse reaction, CRESEMBA should be discontinued. Cardiovascular QT shortening Isavuconazole is contraindicated in patients with familial short QT syndrome (see section 4.3). In a QT study in healthy human subjects, isavuconazole shortened the QTc interval in a concentration-related manner. For the 200 mg dosing regimen, the least squares mean (LSM) difference from placebo was 13.1 ms at 2 hours post dose [90% CI: 17.1, 9.1 ms]. Increasing the dose to 600 mg resulted in an LSM difference from placebo of 24.6 ms at 2 hours post dose [90% CI: 28.7, 20.4 ms]. Caution is warranted when prescribing isavuconazole to patients taking other medicinal products known to decrease the QT interval, such as rufinamide. Elevated liver transaminases or hepatitis Elevated liver transaminases have been reported in clinical studies (see section 4.8). The elevations in liver transaminases rarely required discontinuation of isavuconazole. Monitoring of hepatic enzymes should be considered, as clinically indicated. Hepatitis has been reported with azole antifungal agents including isavuconazole. Severe hepatic impairment Isavuconazole has not been studied in patients with severe hepatic impairment (Child-Pugh Class C). Use in these patients is not recommended unless the potential benefit is considered to outweigh the 4 risks. These patients should be carefully monitored for potential drug toxicity (see sections 4.2, 4.8 and 5.2). Concomitant use with other medicinal pro

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HOS-096655 · has-warning-information · PDF-Seite 26

Hypersensitivity Hypersensitivity to isavuconazole may result in adverse reactions that include: anaphylactic reaction, hypotension, respiratory failure, dyspnoea, drug eruption, pruritus, and rash (see section 4.8). In case of anaphylactic reaction, isavuconazole should be discontinued immediately and appropriate medical treatment should be initiated. Caution should be used in prescribing isavuconazole to patients with hypersensitivity to other azole antifungal agents. Severe cutaneous adverse reactions Severe cutaneous adverse reactions, such as Stevens-Johnson syndrome, have been reported during treatment with azole antifungal agents. If a patient develops a severe cutaneous adverse reaction, CRESEMBA should be discontinued. 26 Cardiovascular QT shortening Isavuconazole is contraindicated in patients with familial short QT syndrome (see section 4.3). In a QT study in healthy human subjects, isavuconazole shortened the QTc interval in a concentration-related manner. For the 200 mg dosing regimen, the least squares mean (LSM) difference from placebo was 13.1 ms at 2 hours post dose [90% CI: 17.1, 9.1 ms]. Increasing the dose to 600 mg resulted in an LSM difference from placebo of 24.6 ms at 2 hours post dose [90% CI: 28.7, 20.4 ms]. Caution is warranted when prescribing isavuconazole to patients taking other medicinal products known to decrease the QT interval, such as rufinamide. Elevated liver transaminases or hepatitis Elevated liver transaminases have been reported in clinical studies (see section 4.8). The elevations in liver transaminases rarely required discontinuation of isavuconazole. Monitoring of hepatic enzymes should be considered, as clinically indicated. Hepatitis has been reported with azole antifungal agents including isavuconazole. Severe hepatic impairment Isavuconazole has not been studied in patients with severe hepatic impairment (Child-Pugh Class C). Use in these patients is not recommended unless the potential benefit is considered to outweigh the risks. These patients should be carefully monitored for potential drug toxicity (see sections 4.2, 4.8 and 5.2). Paediatric patients Isavuconazole has not been studied in paediatric patients with renal or hepatic impairment. Paediatric patients from 6 years to less than 18 years of age and with a bodyweight at least 32 kg may receive CRESEMBA 100 mg capsules. However, the use of CRESEMBA 100 mg capsules has not been stud

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