CRESEMBA 200 mg powder for concentrate for solution for infusion

Each vial contains 200 mg isavuconazole (as 372.6 mg isavuconazonium sulfate).

For the full list of excipients, see section 6.1.

Powder for concentrate for solution for infusion

White to yellow powder

CRESEMBA is indicated in adults 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.

Posology

Loading dose

The recommended loading dose is one vial after reconstitution and dilution (equivalent to 200 mg of isavuconazole) every 8 hours for the first 48 hours (6 administrations in total).

Maintenance dose

The recommended maintenance dose is one vial after reconstitution and dilution (equivalent to 200 mg of isavuconazole) once daily, starting 12 to 24 hours after the last loading dose.

Duration of therapy should be determined by the clinical response (see section 5.1).

For long-term treatment beyond 6 months, the benefit-risk balance should be carefully considered (see sections 5.1 and 5.3).

Switch to oral isavuconazole

CRESEMBA is also available as hard capsules containing 100 mg isavuconazole, equivalent to 186 mg isavuconazonium sulfate.

On the basis of the high oral bioavailability (98%, see section 5.2), switching between intravenous and oral administration is appropriate when clinically indicated.

Elderly

No dose adjustment is necessary for elderly patients; however the clinical experience in elderly patients is limited.

Renal impairment

No dose adjustment is necessary in patients with renal impairment, including patients with end-stage renal disease (see section 5.2).

Hepatic impairment

No dose adjustment is necessary in patients with mild or moderate hepatic impairment (Child-Pugh Classes A and B) (see sections 4.4 and 5.2).

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. See sections 4.4, 4.8 and 5.2.

Paediatric population

The safety and efficacy of CRESEMBA in children aged below 18 years has not yet been established. No data are available.

Method of administration

Intravenous use.

Precautions to be taken before handling or administering the medicinal product

CRESEMBA must be reconstituted and then further diluted to a concentration corresponding to approximately 0.8 mg/mL isavuconazole prior to administration by intravenous infusion over a minimum of 1 hour to reduce the risk of infusion-related reactions. The infusion must be administered via an infusion set with an in-line filter with a microporous membrane made of polyethersulfone (PES) and with a pore size of 0.2 μm to 1.2 μm. CRESEMBA must only be given as an intravenous infusion.

For detailed instructions on the reconstitution and dilution of CRESEMBA before administration, see section 6.6.

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).

Hypersensitivity

Caution should be used in prescribing isavuconazole to patients with hypersensitivity to other azole antifungal agents. Hypersensitivity to isavuconazole may result in adverse reactions that include: hypotension, respiratory failure, dyspnoea, drug eruption, pruritus, and rash.

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

CRESEMBA 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 CRESEMBA to patients taking other medicinal products known to decrease the QT interval, such as rufinamide.

Elevated liver transaminases

Elevated liver transaminases have been reported in clinical studies (see section 4.8). The elevations in liver transaminases rarely required discontinuation of CRESEMBA. Monitoring of hepatic enzymes should be considered, as clinically indicated.

Severe hepatic impairment

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. These patients should be carefully monitored for potential drug toxicity. See sections 4.2, 4.8 and 5.2.

Concomitant use with other medicinal products

CYP3A4/5 inhibitors

Ketoconazole is contraindicated (see section 4.3). For the strong CYP3A4 inhibitor lopinavir/ritonavir, a two-fold increase in isavuconazole exposure was observed. For other strong CYP3A4/5 inhibitors, a less pronounced effect can be expected. No dose adjustment of CRESEMBA is necessary when co-administered with strong CYP3A4/5 inhibitors, however caution is advised as adverse drug reactions may increase (see section 4.5).

CYP3A4/5 inducers

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 4.5).

CYP3A4/5 substrates including immunosuppressants

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 the systemic exposure to these medicinal products. Appropriate therapeutic drug monitoring and dose adjustment may be necessary during co-administration (see section 4.5).

CYP2B6 substrates

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 (see section 4.3).

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 (see section 4.5).

Limitations of the clinical data

The clinical data for isavuconazole in the treatment of mucormycosis are limitedto one prospective non-controlled clinical study in 37 patients with proven or probable mucormycosis who received isavuconazole for primary treatment, or because other antifungal treatments (predominantly amphotericin B) were inappropriate.

For individual Mucorales species, the clinical efficacy data are very limited, often to one or two patients (see section 5.1). Susceptibility data were available in only a small subset of cases. These data indicate that concentrations of isavuconazole required for inhibition in vitro are very variable between genera/species within the order of Mucorales, and generally higher than concentrations required to inhibit Aspergillus species. It should be noted that there was no dose-finding study in mucormycosis, and patients were administered the same dose of isavuconazole as was used for the treatment of invasive aspergillosis.