4.1. Therapeutic indications

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.

4.2. Posology and method of administration

Posology

Early targeted therapy (pre-emptive or diagnostic-driven therapy) may be instituted pending confirmation of the disease from specific diagnostic tests. However, once these results become available, antifungal therapy should be adjusted accordingly.

Detailed information on dosage recommendations is provided in the following table:

Table 1 Dosage recommendation

Loading dose

(every 8 hours for the first 48 hours) 1

Maintenance dose (once daily) 2

Adults

200 mg isavuconazole (one vial) 3

200 mg isavuconazole (one vial) 3

Paediatric patients aged from 1 year to less than 18 years

Bodyweight ≥ 37 kg

200 mg isavuconazole (one vial) 3

200 mg isavuconazole (one vial) 3

Bodyweight < 37 kg

5.4 mg/kg isavuconazole

5.4 mg/kg isavuconazole

1 Six administrations in total.

2 Maintenance dose: Starting 12 to 24 hours after the last loading dose.

3 After reconstitution and dilution.

The maximum of any individual loading or daily maintenance dose to be administered to any paediatric patient is 200 mg isavuconazole.

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 available as 100 mg and 40 mg hard capsules.

On the basis of the high oral bioavailability (98%, see section 5.2), switching between intravenous and oral administration is appropriate when clinically indicated. For detailed dosing recommendations, please see section 4.2 of the Summary of Product Characteristics for CRESEMBA 40 mg and 100 mg hard capsules.

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 adult patients with renal impairment, including patients with end-stage renal disease (see section 5.2).

No dose recommendation can be made for paediatric patients with renal impairment, as no relevant data are available.

Hepatic impairment

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

Isavuconazole has not been studied in adult 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).

No dose recommendation can be made for paediatric patients with hepatic impairment, as no relevant data are available.

Paediatric population

The safety and efficacy of isavuconazole in paediatric patients aged less than 1 year has not been established.

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 a range of 0.4 to 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. Higher concentrations should be avoided as these may cause local irritation at the site of infusion. 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.

4.3. Contraindications

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).

4.4. Special warnings and precautions for use

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 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 isavuconazole 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 isavuconazole. Concomitant use of isavuconazole 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 isavuconazole. Therefore, caution is advised when CYP2B6 substrates, especially medicinal products with a narrow therapeutic index such as cyclophosphamide, are co-administered with isavuconazole. The use of the CYP2B6 substrate efavirenz with isavuconazole 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 isavuconazole (see section 4.5).

Limitations of the clinical data

The clinical data for isavuconazole in the treatment of mucormycosis are limited to one prospective non-controlled clinical study in 37 adult 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.

4.5. Interaction with other medicinal products and other forms of interaction

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 concentrations of these medicinal products.

Medicinal products metabolised by CYP2B6

Isavuconazole is a mild CYP2B6 inducer; co-administration of isavuconazole may result in decreased plasma concentrations of CYP2B6 substrates.

Medicinal products transported by P-gp in the intestine

Isavuconazole is a mild inhibitor of P-glycoprotein (P-gp); co-administration with isavuconazole may result in increased plasma concentrations of P-gp substrates.

Medicinal products transported by BCRP

Isavuconazole is an inhibitor in vitro of BCRP, and plasma concentrations of substrates of BCRP may therefore be increased. Caution is advised when isavuconazole is given concomitantly with substrates of BCRP.

Medicinal products renally excreted via transport proteins

Isavuconazole is a mild inhibitor of the organic cation transporter 2 (OCT2). Co-administration of isavuconazole with medicinal products which are substrates of OCT2 may result in increased plasma concentrations of these medicinal products.

Uridine diphosphate-glucuronosyltransferases (UGT) substrates

Isavuconazole is a mild inhibitor of UGT. Co-administration of isavuconazole with medicinal products which are substrates of UGT may result in mildly increased plasma concentrations of these medicinal products.

Interaction table

Interactions between isavuconazole and co-administered medicinal products are listed in Table 2 (increase is indicated as “↑”, decrease as “↓”), ordered by therapeutic class. Unless otherwise stated, studies detailed in Table 2 have been performed in adults with the recommended dose of isavuconazole.

Table 2 Interactions

Co-administered medicinal product by therapeutic area

Effects on drug concentrations / Geometric Mean Change (%) in AUC, Cmax

(Mode of action)

Recommendation concerning co-administration

Anticonvulsants

Carbamazepine, phenobarbital and phenytoin

(strong CYP3A4/5 inducers)

Isavuconazole concentrations may decrease (CYP3A induction by carbamazepine, phenytoin and long‑acting barbiturates such as phenobarbital).

The concomitant administration of isavuconazole and carbamazepine, phenytoin and long-acting barbiturates such as phenobarbital is contraindicated.

Antibacterials

Rifampicin

(strong CYP3A4/5 inducer)

Isavuconazole :

AUCtau: ↓ 90%

Cmax: ↓ 75%

(CYP3A4/5 induction)

The concomitant administration of isavuconazole and rifampicin is contraindicated.

Rifabutin

(strong CYP3A4/5 inducer)

Not studied.

Isavuconazole concentrations may significantly decrease.

(CYP3A4/5 induction)

The concomitant administration of isavuconazole and rifabutin is contraindicated.

Nafcillin

(moderate CY3A4/5 inducer)

Not studied.

Isavuconazole concentrations may significantly decrease.

(CYP3A4/5 induction)

The concomitant administration of isavuconazole and nafcillin is contraindicated.

Clarithromycin

(strong CYP3A4/5 inhibitor)

Not studied.

Isavuconazole concentrations may increase.

(CYP3A4/5 inhibition)

No isavuconazole dose adjustment necessary; caution is advised as adverse drug reactions may increase.

Antifungals

Ketoconazole

(strong CYP3A4/5 inhibitor)

Isavuconazole:

AUCtau: ↑ 422%

Cmax: ↑ 9%

(CYP3A4/5 inhibition)

The concomitant administration of isavuconazole and ketoconazole is contraindicated.

Herbal medicines

St John's wort

(strong CYP3A4/5 inducer)

Not studied.

Isavuconazole concentrations may significantly decrease.

(CYP3A4 induction).

The concomitant administration of isavuconazole and St John's wort is contraindicated.

Immunosuppresants

Ciclosporin, sirolimus, tacrolimus

(CYP3A4/5 substrates)

Ciclosporin:

AUCinf: ↑ 29%

Cmax: ↑ 6%

Sirolimus:

AUCinf: ↑ 84%

Cmax: ↑ 65%

Tacrolimus:

AUCinf: ↑ 125%

Cmax: ↑ 42%

(CYP3A4 inhibition)

No isavuconazole dose adjustment necessary.

Ciclosporin, sirolimus, tacrolimus: monitoring of plasma levels and appropriate dose adjustment if required.

Mycophenolate mofetil (MMF)

(UGT substrate)

Mycophenolic acid (MPA, active metabolite):

AUCinf: ↑ 35%

Cmax: ↓ 11%

(UGT inhibition)

No isavuconazole dose adjustment necessary.

MMF: monitoring for MPA-related toxicities is advised.

Prednisone

(CYP3A4 substrate)

Prednisolone (active metabolite):

AUCinf: ↑ 8%

Cmax: ↓ 4%

(CYP3A4 inhibition)

Isavuconazole concentrations may decrease.

(CYP3A4/5 induction)

Co-administration should be avoided unless the potential benefit is considered to outweigh the risk.

Opioids

Short‑acting opiates (alfentanyl, fentanyl)

(CYP3A4/5 substrate)

Not studied.

Short-acting opiate concentrations may increase.

(CYP3A4/5 inhibition).

No isavuconazole dose adjustment necessary.

Short-acting opiates (alfentanyl, fentanyl): careful monitoring for any occurrence of drug toxicity, and dose reduction if required.

Methadone

(CYP3A4/5, 2B6 and 2C9 substrate)

S-methadone (inactive opiate isomer)

AUCinf: ↓ 35%

Cmax: ↑ 1%

40% reduction in terminal half-life

R-methadone (active opiate isomer).

AUCinf: ↓ 10%

Cmax: ↑ 4%

(CYP2B6 induction)

No isavuconazole dose adjustment necessary.

Methadone: no dose adjustment required.

Anti-cancer

Vinca alkaloids (vincristine, vinblastine)

(P-gp substrates)

Not studied.

Vinca alkaloid concentrations may increase.

(P-gp inhibition)

No isavuconazole dose adjustment necessary.

Vinca alkaloids: careful monitoring for any occurrence of drug toxicity, and dose reduction if required.

Cyclophosphamide

(CYP2B6, CYP3A4 substrate)

Not studied.

Active metabolites of cyclophosphamide concentrations may increase or decrease.

(CYP2B6 induction, CYP3A4 inhibition)

No isavuconazole dose adjustment necessary.

Cyclophosphamide: careful monitoring for any occurrence of lack of efficacy or increased toxicity, and dose adjustment if required.

Methotrexate

(BCRP, OAT1, OAT3 substrate)

Methotrexate:

AUCinf: ↓ 3%

Cmax: ↓ 11%

7-hydroxymetabolite:

AUCinf: ↑ 29%

Cmax: ↑ 15%

(Mechanism unknown)

No isavuconazole dose adjustment necessary.

Methotrexate: no dose adjustment required.

Other anticancer agents (daunorubicin, doxorubicin, imatinib, irinotecan, lapatinib, mitoxantrone, topotecan)

(BCRP substrates)

Not studied.

Daunorubicin, doxorubicin, imatinib, irinotecan, lapatinib, mitoxantrone, topotecan concentrations may increase.

(BCRP inhibition)

No isavuconazole dose adjustment necessary.

Daunorubicin, doxorubicin, imatinib, irinotecan, lapatinib, mitoxantrone or topotecan: careful monitoring for any occurrence of drug toxicity, and dose reduction if required.

Antiemetics

Aprepitant

(mild CYP3A4/5 inducer)

Not studied.

Isavuconazole concentrations may decrease.

(CYP3A4/5 induction)

Co-administration should be avoided unless the potential benefit is considered to outweigh the risk.

Antidiabetics

Metformin

(OCT1, OCT2 and MATE1 substrate)

Metformin:

AUCinf: ↑ 52%

Cmax: ↑ 23%

(OCT2 inhibition)

No isavuconazole dose adjustment necessary.

Metformin: dose reduction may be required.

Repaglinide

(CYP2C8 and OATP1B1 substrate)

Repaglinide:

AUCinf: ↓ 8%

Cmax: ↓ 14%

No isavuconazole dose adjustment necessary.

Repaglinide: no dose adjustment required.

Pioglitazone

(mild CYP3A4/5 inducer)

Not studied.

Isavuconazole concentrations may decrease.

(CYP3A4/5 induction)

Co-administration should be avoided unless the potential benefit is considered to outweigh the risk.

Anticoagulants

Dabigatran etexilate

(P-gp substrate)

Not studied.

Dabigatran etexilate concentrations may increase.

(P-gp inhibition).

No isavuconazole dose adjustment necessary.

Dabigatran etexilate has a narrow therapeutic index and should be monitored, and dose reduction if required.

Warfarin

(CYP2C9 substrate)

S-warfarin

AUCinf: ↑ 11%

Cmax: ↓ 12%

R-warfarin

AUCinf: ↑ 20%

Cmax: ↓ 7%

No isavuconazole dose adjustment necessary.

Warfarin: no dose adjustment required.

Antiretroviral agents

Lopinavir 400 mg / Ritonavir 100 mg

(CYP3A4/5 strong inhibitors and substrates)

Lopinavir:

AUCtau: ↓ 27%

Cmax: ↓ 23%

Cmin, ss: ↓ 16%a)

Ritonavir:

AUCtau: ↓ 31%

Cmax: ↓ 33%

(Mechanism unknown)

Isavuconazole:

AUCtau: ↑ 96%

Cmax: ↑ 74%

(CYP3A4/5 inhibition)

No isavuconazole dose adjustment necessary; caution is advised as adverse drug reactions may increase.

Lopinavir/ritonavir: no dose adjustment for lopinavir 400 mg / ritonavir 100 mg every 12 hours required, but careful monitoring for any occurrence of lack of anti-viral efficacy.

Ritonavir

(at doses >200 mg every 12 hours)

(strong CYP3A4/5 inducer)

Not studied.

Ritonavir at high doses may significantly decrease isavuconazole concentrations.

(CYP3A4/5 induction)

The concomitant administration of isavuconazole and high doses of ritonavir (>200 mg every 12 hours) is contraindicated.

Efavirenz

(CYP3A4/5 moderate inducer and CYP2B6 substrate)

Not studied.

Efavirenz concentrations may decrease.

(CYP2B6 induction)

Isavuconazole drug concentrations may significantly decrease.

(CYP3A4/5 induction)

The concomitant administration of isavuconazole and efavirenz is contraindicated.

Etravirine

(moderate CYP3A4/5 inducer)

Not studied.

Isavuconazole concentrations may significantly decrease.

(CYP3A4/5 induction)

The concomitant administration of isavuconazole and etravirine is contraindicated.

Indinavir

(CYP3A4/5 strong inhibitor and substrate)

Indinavir:b)

AUCinf: ↓ 36%

Cmax: ↓ 52%

(Mechanism unknown)

Isavuconazole concentrations may increase.

(CYP3A4/5 inhibition)

No isavuconazole dose adjustment necessary; caution is advised as adverse drug reactions may increase.

Indinavir: careful monitoring for any occurrence of lack of anti-viral efficacy, and dose increase if required.

Saquinavir

(strong CYP3A4 inhibitor)

Not studied.

Saquinavir concentrations may decrease (as observed with lopinavir/ritonavir) or increase.

(CYP3A4 inhibition)

Isavuconazole concentrations may increase.

(CYP3A4/5 inhibition)

No isavuconazole dose adjustment necessary; caution is advised as adverse drug reactions may increase.

Saquinavir: careful monitoring for any occurrence of drug toxicity and /or lack of anti-viral efficacy, and dose adjustment if required

Other protease inhibitors (e.g. fosamprenavir)

(CYP3A4/5 strong or moderate inhibitors and substrates)

Not studied.

Protease inhibitor concentrations may decrease (as observed with lopinavir/ritonavir) or increase.

(CYP3A4 inhibition)

Isavuconazole concentrations may increase.

(CYP3A4/5 inhibition)

No isavuconazole dose adjustment necessary.

Protease inhibitors: careful monitoring for any occurrence of drug toxicity and /or lack of anti-viral efficacy, and dose adjustment if required.

Other NNRTI (e.g. nevirapine)

(CYP3A4/5 and 2B6 inducers and substrates)

Not studied.

NNRTI concentrations may decrease (CYP2B6 induction by isavuconazole) or increase.

(CYP3A4/5 inhibition)

No isavuconazole dose adjustment necessary.

NNRTIs: careful monitoring for any occurrence of drug toxicity and/or lack of anti-viral efficacy, and dose adjustment if required.

Antiacids

Esomeprazole

(CYP2C19 substrate and gastric pH ↑)

Isavuconazole:

AUCtau: ↑ 8%

Cmax: ↑ 5%

No isavuconazole dose adjustment necessary.

Esomeprazole: no dose adjustment required.

Omeprazole

(CYP2C19 substrate and gastric pH ↑)

Omeprazole:

AUCinf: ↓ 11%

Cmax: ↓ 23%

No isavuconazole dose adjustment necessary.

Omeprazole: no dose adjustment required.

Lipid-lowering agents

Atorvastatin and other statins

(CYP3A4 substrates e.g., simvastatin, lovastatin, rosuvastatin)

(CYP3A4/5 and/or BCRP substrates)

Atorvastatin:

AUCinf: ↑ 37%

Cmax: ↑ 3%

Other statins were not studied.

Statins concentrations may increase.

(CYP3A4/5 or BCRP inhibition)

No isavuconazole dose adjustment necessary.

Based on results with atorvastatin, no statin dose adjustment required. Monitoring of adverse reactions typical of statins is advised.

Antiarrhythmics

Digoxin

(P-gp substrate)

Digoxin:

AUCinf: ↑ 25%

Cmax: ↑ 33%

(P-gp inhibition)

No isavuconazole dose adjustment necessary.

Digoxin: serum digoxin concentrations should be monitored and used for titration of the digoxin dose.

Oral contraceptives

Ethinyl oestradiol and norethindrone

(CYP3A4/5 substrates)

Ethinyl oestradiol

AUCinf: ↑ 8%

Cmax: ↑ 14%

Norethindrone

AUCinf: ↑ 16%

Cmax: ↑ 6%

No isavuconazole dose adjustment necessary.

Ethinyl oestradiol and norethindrone: no dose adjustment required.

Antitussives

Dextromethorphan

(CYP2D6 substrate)

Dextromethorphan:

AUCinf: ↑ 18%

Cmax: ↑ 17%

Dextrorphan (active metabolite):

AUCinf: ↑ 4%

Cmax: ↓ 2%

No isavuconazole dose adjustment necessary.

Dextromethorphan: no dose adjustment required.

Benzodiazepines

Midazolam

(CYP3A4/5 substrate)

Oral midazolam:

AUCinf: ↑ 103%

Cmax: ↑ 72%

(CYP3A4 inhibition)

No isavuconazole dose adjustment necessary.

Midazolam: careful monitoring of clinical signs and symptoms recommended, and dose reduction if required.

Antigout agent

Colchicine

(P-gp substrate)

Not studied.

Colchicine concentrations may increase.

(P-gp inhibition)

No isavuconazole dose adjustment necessary.

Colchicine has a narrow therapeutic index and should be monitored, dose reduction if required.

Natural products

Caffeine

(CYP1A2 substrate)

Caffeine:

AUCinf: ↑ 4%

Cmax: ↓ 1%

No isavuconazole dose adjustment necessary.

Caffeine: no dose adjustment required.

Smoking cessation aids

Bupropion

(CYP2B6 substrate)

Bupropion:

AUCinf: ↓ 42%

Cmax: ↓ 31%

(CYP2B6 induction)

No isavuconazole dose adjustment necessary.

Bupropion: dose increase if required.

NNRTI, non-nucleoside reverse-transcriptase inhibitor; P-gp, P-glycoprotein.

a) % decrease of the mean trough level values

b) Indinavir was only studied after a single dose of 400 mg isavuconazole.

AUCinf = area under the plasma concentration-time profiles extrapolated to infinity; AUCtau = area under the plasma concentration-time profiles during the 24 h interval at steady state; Cmax = peak plasma concentration; Cmin,ss = trough levels at steady state.

4.6. Fertility, pregnancy and lactation

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).

4.7. Effects on ability to drive and use machines

Isavuconazole has a moderate potential to influence the ability to drive and use machines. Patients should avoid driving or operating machinery if symptoms of confusional state, somnolence, syncope, and/or dizziness are experienced.

4.8. Undesirable effects

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.

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; Hypotension

Respiratory, thoracic and mediastinal disorders

Common

Dyspnoea^; Acute respiratory failure^

Uncommon

Bronchospasm; Tachypnoea; Haemoptysis; Epistaxis

Gastrointestinal disorders

Common

Vomiting; Diarrhoea; Nausea; Abdominal pain^

Uncommon

Dyspepsia; Constipation; Abdominal distension

Hepatobiliary disorders

Common

Elevated liver chemistry tests^#

Uncommon

Hepatomegaly; Hepatitis

Skin and subcutaneous tissue disorders

Common

Rash^; Pruritus

Uncommon

Petechiae; Alopecia; Drug eruption; Dermatitis^

Musculoskeletal and connective tissue disorders

Uncommon

Back pain

Renal and urinary disorders

Common

Renal failure

General disorders and administration site conditions

Common

Chest pain^; Fatigue; Injection site reaction^

Uncommon

Oedema peripheral^; Malaise; Asthenia

^ Indicates that grouping of appropriate preferred terms into a single medical concept occurred.

*ADR identified post-marketing.

# See section Description of selected adverse reactions below.

Description of selected adverse reactions

Delirium includes reactions of confusional state.

Elevated liver chemistry tests includes events of alanine aminotransferase increased, aspartate aminotransferase increased, blood alkaline phosphatase increased, blood bilirubin increased, blood lactate dehydrogenase increased, gamma-glutamyltransferase increased, hepatic enzyme increased, hepatic function abnormal, hyperbilirubinemia, liver function test abnormal, and transaminases increased.

Laboratory effects

In a double-blind, randomized, active-controlled clinical study of 516 patients with invasive fungal disease caused by Aspergillus species or other filamentous fungi, elevated liver transaminases (alanine aminotransferase or aspartate aminotransferase) > 3 × Upper Limit of Normal (ULN) were reported at the end of study treatment in 4.4% of patients who received isavuconazole. Marked elevations of liver transaminases > 10 × ULN developed in 1.2% of patients on isavuconazole.

Paediatric population

The clinical safety of isavuconazole was assessed in 77 paediatric patients who received at least one dose of intravenous or oral isavuconazole. This included 46 paediatric patients who received isavuconazole as a single dose and who also received other antifungals for prophylaxis, and 31 patients with suspected or confirmed invasive aspergillosis or mucormycosis who received isavuconazole as primary therapy for up to 181 days. Overall, the safety profile of isavuconazole in the paediatric population was similar to that in adults.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Symptoms

Symptoms reported more frequently at supratherapeutic doses of isavuconazole (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.

Management of overdose

Isavuconazole is not removed by haemodialysis. There is no specific antidote for isavuconazole. In the event of an overdose, supportive treatment should be instituted.