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​​​​​​​Safety Profile

Contraindications1

  • Hypersensitivity to the active substance or to any of the excipients listed in the Summary of Product Characteristics
  • 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.

Drug Interactions1

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

CYP3A4/5 substrates, including immunosuppresants

  • 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

CYP2B6 sustrates

  • 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

P-gp substrates

  • 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

Fertility, Pregnancy and Lactation1

Pregnancy 

  • 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

Women of childbearing 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
  • Breast-feeding should be discontinued during treatment with CRESEMBA
  • A risk to newborns and infants cannot be excluded

Fertility

  • 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

Adverse reactions​​​​​​​

Summary of the safety profile 

The frequency of adverse reactions is based on data from 403 patients with invasive fungal infections treated with CRESEMBA in phase 3 studies.

The most common treatment-related adverse events 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%)
  • Rash (1.7%)

Adverse reactions that most often led to permanent discontinuation of CRESEMBA 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%)
  • Vomiting (0.5%)

Other adverse reactions include hypersensitivity, syncope, heart rhythm disturbances and circulatory collapse. Please refer to the Summary of Product Characteristics for a full list.

Effects on ability to drive and use machines

  • 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

Overdose

  • 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

References:
  1. ​​​​​​​CRESEMBA GB Summary of Product Characteristics.
PP-CRB-GBR-1216. August 2021

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