• Hypersensitivity to the active substance or to any of the excipients listed in the Local Product Document

• Co-administration with ketoconazole, high-dose ritonavir (>200 mg every 12 hours), 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

• Patients with familial short QT syndrome

• Hypersensitivity to isavuconazole may result in adverse reactions that include:
  hypotension, respiratory failure, dyspnoea, drug eruption, pruritus and rash. Prescribe with caution in patients with hypersensitivity to other azole antifungal agents

• Infusion-related reactions including hypotension, dyspnoea, dizziness, paraesthesia, nausea and headache have been reported. The infusion should be stopped if these reactions occur

• 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

• CRESEMBA® is contraindicated in patients with familial short QT syndrome. Caution is warranted when prescribing CRESEMBA® to patients taking medicinal products, such as rufinamide, known to decrease the QT interval

• Elevated liver transaminases have been reported in clinical studies and rarely required discontinuation of CRESEMBA®. Monitoring of hepatic enzymes should be considered, as clinically indicated. Hepatitis has been reported with azole antifungal agents including CRESEMBA®

• CRESEMBA® 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. Patients should be carefully monitored for potential drug toxicity

CYP3A4/5 inhibitors

• Ketoconazole is contraindicated
• A two-fold increase in isavuconazole exposure was observed with the strong CYP3A4 inhibitor lopinavir/ritonavir
• A less pronounced effect can be expected with other strong CYP3A4/5 inhibitors
• No dose adjustment is necessary when co-administered with strong CYP3A4/5 inhibitors; however, caution is advised as adverse drug reactions may increase

CYP3A4/5 inducers

• Co-administration with mild CYP3A4/5 inducers such as aprepitant, prednisone and pioglitazone may result in mild to moderate decreases in isavuconazole plasma levels
• Co-administration with mild CYP3A4/5 inducers should be avoided unless the potential benefit is considered to outweigh the risk

• Isavuconazole can be considered a moderate inhibitor of CYP3A4/5, and systemic exposure to medicinal products metabolised by CYP3A4 may be increased when co-administered with CRESEMBA®
• Concomitant use of CRESEMBA® with CYP3A4 substrates such as the immunosuppressants tacrolimus, sirolimus or ciclosporin may increase systemic exposure to these medicinal products
• Appropriate therapeutic drug monitoring and dose adjustment may be necessary during co-administration

• Isavuconazole is an inducer of CYP2B6
• Systemic exposure to medicinal products metabolised by CYP2B6 may be decreased when co-administered with CRESEMBA®. Therefore, caution is advised when CYP2B6 substrates, especially medicinal products with a narrow therapeutic index such as cyclophosphamide, are co-administered with CRESEMBA®
• The use of the CYP2B6 substrate efavirenz with CRESEMBA® is contraindicated because efavirenz is a moderate inducer of CYP3A4/5

• Isavuconazole may increase the exposure of medicinal products that are P-gp substrates 
• Dose adjustment of medicinal products that are P-gp substrates, especially medicinal products with a narrow therapeutic index such as digoxin, colchicine and dabigatran etexilate, may be needed when concomitantly administered with CRESEMBA®

• There are no data from the use of CRESEMBA® in pregnant women
• Animal studies have shown reproductive toxicity but 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

• CRESEMBA® is not recommended for women of childbearing potential who are not using contraception

• Available pharmacodynamic/toxicological data in animals have shown excretion of isavuconazole/metabolites in milk
• Breast-feeding should be discontinued during treatment with CRESEMBA®
• A risk to newborns and infants cannot be excluded

• There are no data on the effect of CRESEMBA® on human fertility
• Studies in animals did not show impairment of fertility in male or female rats

• 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%)
• Rash (1.7%)

• 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%)
• Vomiting (0.5%)

• CRESEMBA® has a moderate potential to influence the ability to drive and use machines
• Patients should avoid driving or operating machinery if they experience symptoms of confusional state, somnolence, syncope and/or dizziness

• Symptoms reported more frequently at supratherapeutic doses of CRESEMBA® (equivalent to isavuconazole 600 mg/day) evaluated in a QT study than in the therapeutic dose group (equivalent to isavuconazole 200 mg/day dose) included: headache, dizziness, paraesthesia, somnolence, disturbance in attention, dysgeusia, dry mouth, diarrhoea, oral hypoaesthesia, vomiting, hot flush, anxiety, restlessness, palpitations, tachycardia, photophobia and arthralgia
• In the event of an overdose, initiate supportive treatment. Isavuconazole is not removed by haemodialysis and there is no specific antidote for isavuconazole