Cresemba

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ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS



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1. NAME OF THE MEDICINAL PRODUCT

CRESEMBA 200 mg powder for concentrate for solution for infusion

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

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

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Powder for concentrate for solution for infusion
White to yellow powder

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

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.

4.2 Posology and method of administration

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. 

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.



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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).

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 (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.

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

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



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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 



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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 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



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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 1 
(increase is indicated as “↑”, decrease as “↓”), ordered by therapeutic class. Unless otherwise stated, 
studies detailed in Table 1 have been performed with the recommended dose of isavuconazole. 



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Table 1 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%

No isavuconazole dose 
adjustment necessary. 
Ciclosporin, sirolimus, 
tacrolimus: monitoring of plasma 
levels and appropriate dose
adjustment if required.



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Tacrolimus:
AUCinf: ↑ 125%
Cmax: ↑ 42%

(CYP3A4 inhibition)
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 substrate)

Not studied.
Cyclophosphamide concentrations 
may decrease.

(CYP2B6 induction)

No isavuconazole dose 
adjustment necessary.
Cyclophosphamide: careful 
monitoring for any occurrence of 
lack of efficacy, and dose 
increase if required..

Methotrexate
(BCRP, OAT1, OAT3 
substrate)

Methotrexate:
AUCinf: ↓ 3%
Cmax: ↓ 11%

7-hydroxymetabolite: 

No isavuconazole dose 
adjustment necessary.
Methotrexate: no dose 
adjustment required. 



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AUCinf: ↑ 29%
Cmax: ↑ 15%

(Mechanism unknown)
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.

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%

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.



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(CYP3A4/5 inhibition)
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 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.



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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.

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.

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 Bupropion: No isavuconazole dose 



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(CYP2B6 substrate) AUCinf: ↓ 42%
Cmax: ↓ 31%

(CYP2B6 induction)

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 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%). 



13

The adverse reactions which most often led to permanent discontinuation of isavuconazole treatment 
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 2 presents adverse reactions with isavuconazole in the treatment of invasive fungal infections, 
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). 

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 2 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^
Metabolism and nutrition disorders

Common Hypokalaemia; Decreased appetite
Uncommon Hypomagnesaemia; Hypoglycaemia; Hypoalbuminaemia; Malnutrition^

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^



14

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.

# 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.

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 national reporting system 
listed in Appendix V.

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.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antimycotics for systemic use, triazole derivatives, ATC code: J02AC05

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


15

Mechanism of action

Isavuconazole is the active moiety formed after oral or intravenous administration of isavuconazonium 
sulfate (see section 5.2).

Isavuconazole demonstrates a fungicidal effect by blocking the synthesis of ergosterol, a key 
component of the fungal cell membrane, through the inhibition of cytochrome P-450-dependent 
enzyme lanosterol 14-alpha-demethylase, responsible for the conversion of lanosterol to ergosterol. 
This results in an accumulation of methylated sterol precursors and a depletion of ergosterol within the 
cell membrane, thus weakening the structure and function of the fungal cell membrane. 

Microbiology

In animal models of disseminated and pulmonary aspergillosis, the pharmacodynamic (PD) index 
important in efficacy is exposure divided by minimum inhibitory concentration (MIC) (AUC/MIC). 
No clear correlation between in vitro MIC and clinical response for the different species (Aspergillus
and Mucorales) could be established.

Concentrations of isavuconazole required to inhibit Aspergillus species and genera/species of the order 
Mucorales in vitro have been very variable. Generally, concentrations of isavuconazole required to 
inhibit Mucorales are higher than those required to inhibit the majority of Aspergillus species.

Clinical efficacy has been demonstrated for the following Aspergillus species: Aspergillus fumigatus, 
A. flavus, A. niger, and A. terreus(see further below).

Mechanism(s) of resistance

Reduced susceptibility to triazole antifungal agents has been associated with mutations in the fungal 
cyp51A and cyp51B genes coding for the target protein lanosterol 14-alpha-demethylase involved in 
ergosterol biosynthesis. Fungal strains with reduced in vitro susceptibility to isavuconazole have been 
reported, and cross-resistance with voriconazole and other triazole antifungal agents cannot be 
excluded.

Breakpoints

EUCAST MIC breakpoints are defined for the following species (susceptible S; resistant R): 
 Aspergillus fumigatus: S ≤ 1 mg/L, R > 1 mg/L 
 Aspergillus nidulans: S ≤ 0.25 mg/L, R > 0.25 mg/L
 Aspergillus terreus: S ≤ 1 mg/L, R > 1 mg/L

There are currently insufficient data to set clinical breakpoints for other Aspergillus species.

Clinical efficacy and safety

Treatment of invasive aspergillosis
The safety and efficacy of isavuconazole for the treatment of patients with invasive aspergillosis was 
evaluated in a double-blind, active-controlled clinical study in 516 patients with invasive fungal 
disease caused by Aspergillus species or other filamentous fungi. In the intent-to-treat (ITT) 
population, 258 patients received isavuconazole and 258 patients received voriconazole. 
Isavuconazole was administered intravenously (equivalent to 200 mg isavuconazole) every 8 hours for 
the first 48 hours, followed by once-daily intravenous or oral treatment (equivalent to 200 mg 
isavuconazole). The protocol-defined maximum treatment duration was 84 days. Median treatment 
duration was 45 days.



16

The overall response at end-of-treatment (EOT) in the myITT population (patients with proven and 
probable invasive aspergillosis based on cytology, histology, culture or galactomannan testing) was 
assessed by an independent blinded Data Review Committee. The myITT population comprised 123
patients receiving isavuconazole and 108 patients receiving voriconazole. The overall response in this 
population was n = 43 (35%) for isavuconazole and n = 42 (38.9%) for voriconazole. The adjusted 
treatment difference (voriconazole−isavuconazole) was 4.0% (95% confidence interval: −7.9; 15.9).

The all-cause mortality at Day 42 in this population was 18.7% for isavuconazole and 22.2% for 
voriconazole. The adjusted treatment difference (isavuconazole−voriconazole) was −2.7% (95 % 
confidence interval: −12.9; 7.5).

Treatment of mucormycosis
In an open-label non-controlled study, 37 patients with proven or probable mucormycosis received 
isavuconazole at the same dose regimen as that used to treat invasive aspergillosis. Median treatment 
duration was 84 days for the overall mucormycosis patient population, and 102 days for the 21 
patients not previously treated for mucormycosis. For patients with probable or proven mucormycosis 
as defined by the independent Data Review Committee (DRC), all-cause mortality at Day 84 was 
43.2% (16/37) for the overall patient population, 42.9% (9/21) for mucormycosis patients receiving 
isavuconazole as primary treatment, and 43.8% (7/16) for mucormycosis patients receiving 
isavuconazole who were refractory to, or intolerant of, prior antifungal therapy (mainly amphotericin 
B-based treatments). The DRC-assessed overall success rate at EOT was 11/35 (31.4%), with 5 
patients considered completely cured and 6 patients partially cured. A stable response was observed in 
an additional 10/35 patients (28.6%). In 9 patients with mucormycosis due to Rhizopus spp., 4 patients 
showed a favourable response to isavuconazole. In 5 patients with mucormycosis due to Rhizomucor
spp., no favourable responses were observed. The clinical experience in other species is very limited 
(Lichtheimia spp. n=2, Cunninghamella spp. n=1, Actinomucor elegans n=1).

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with 
CRESEMBA in one or more subsets of the paediatric population in the treatment of invasive 
aspergillosis and the treatment of mucormycosis (see section 4.2 for information on paediatric use).

5.2 Pharmacokinetic properties

Isavuconazonium sulfate is a water-soluble prodrug that can be administered as an intravenous 
infusion or orally as hard capsules. Following administration, isavuconazonium sulfate is rapidly 
hydrolysed by plasma esterases to the active moiety isavuconazole; plasma concentrations of the 
prodrug are very low, and detectable only for a short time after intravenous dosing.

Absorption

Following oral administration of CRESEMBA in healthy subjects, the active moiety isavuconazole is 
absorbed and reaches maximum plasma concentrations (Cmax) approximately 2–3 hours after single 
and multiple dosing (see Table 3). 

Table 3Steady state pharmacokinetic parameters of isavuconazole following oral administration 
of CRESEMBA

Parameter
Statistic

Isavuconazole 200 mg
(n = 37)

Isavuconazole 600 mg
(n = 32)

Cmax (ng/mL)

Mean
SD
CV %

7499
1893.3
25.2

20028
3584.3
17.9

tmax (h)



17

Median
Range

3.0
2.0 – 4.0

4.0
2.0 – 4.0

AUC (h•ng/mL)

Mean
SD
CV %

121402
35768.8

29.5

352805
72018.5

20.4

As shown in table 4 below, the absolute bioavailability of isavuconazole following oral administration 
of a single dose of CRESEMBA is 98%. Based on these findings, intravenous and oral dosing can be 
used interchangeably.

Table 4Pharmacokinetic comparison for oral and intravenous dose (Mean)

ISA 400 mg oral ISA 400 mg i.v.

AUC (h•ng/mL) 189462.8 193906.8

CV % 36.5 37.2

Half-life (h) 110 115

Effect of food on absorption
Oral administration of CRESEMBA equivalent to 400 mg isavuconazole with a high-fat meal reduced 
isavuconazole Cmax by 9% and increased AUC by 9%. CRESEMBA can be taken with or without 
food.

Distribution

Isavuconazole is extensively distributed, with a mean steady state volume of distribution (Vss) of 
approximately 450 L. Isavuconazole is highly bound (> 99%) to human plasma proteins, 
predominantly to albumin.

Biotransformation

In vitro / in vivo studies indicate that CYP3A4, CYP3A5, and subsequently uridine diphosphate-
glucuronosyltransferases (UGT), are involved in the metabolism of isavuconazole. 

Following single doses of [cyano-14C] isavuconazonium and [pyridinylmethyl-14C] isavuconazonium 
sulfate in humans, in addition to the active moiety (isavuconazole) and the inactive cleavage product, a 
number of minor metabolites were identified. Except for the active moiety isavuconazole, no 
individual metabolite was observed with an AUC > 10% of total radio-labelled material.

Elimination

Following oral administration of radio-labelled isavuconazonium sulfate to healthy subjects, a mean of 
46.1% of the radioactive dose was recovered in faeces, and 45.5% was recovered in urine. 

Renal excretion of intact isavuconazole was less than 1% of the dose administered.  

The inactive cleavage product is primarily eliminated by metabolism and subsequent renal excretion 
of the metabolites. 

Linearity/non-linearity

Studies in healthy subjects have demonstrated that the pharmacokinetics of isavuconazole are 
proportional up to 600 mg per day. 

Pharmacokinetics in special populations



18

Paediatric patients
The pharmacokinetics in paediatric patients (< 18 years) have not yet been evaluated. No data are 
available.

Renal impairment
No clinically relevant changes were observed in the total Cmax and AUC of isavuconazole in subjects 
with mild, moderate or severe renal impairment compared to subjects with normal renal function. Of 
the 403 patients who received isavuconazole in the Phase 3 studies, 79 (20%) of patients had an 
estimated glomerular filtration rate (GFR) less than 60 mL/min/1.73 m2. No dose adjustment is 
required in patients with renal impairment, including those patients with end-stage renal disease. 
Isavuconazole is not readily dialysable (see section 4.2).

Hepatic impairment
After a single 100 mg dose of isavuconazole was administered to 32 patients with mild (Child-Pugh 
Class A) hepatic insufficiency and 32 patients with moderate (Child-Pugh Class B) hepatic 
insufficiency (16 intravenous and 16 oral patients per Child-Pugh class), the least square mean 
systemic exposure (AUC) increased 64% in the Child-Pugh Class A group, and 84% in the Child-Pugh 
Class B group, relative to 32 age- and weight-matched healthy subjects with normal hepatic function. 
Mean plasma concentrations (Cmax) were 2% lower in the Child-Pugh Class A group and 30% lower in 
the Child-Pugh Class B group. The population pharmacokinetic evaluation of isavuconazole in healthy 
subjects and patients with mild or moderate hepatic dysfunction demonstrated that the mild and 
moderate hepatic impairment populations had 40% and 48% lower isavuconazole clearance (CL) 
values, respectively, than the healthy population. 

No dose adjustment is required in patients with mild to moderate 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 (see sections 4.2 and 4.4).

5.3 Preclinical safety data

In rats and rabbits, isavuconazole at systemic exposures below the therapeutic level were associated 
with dose-related increases in the incidence of skeletal anomalies (rudimentary supernumerary ribs) in 
offspring. In rats, a dose-related increase in the incidence of zygomatic arch fusion was also noted in 
offspring (see section 4.6).

Administration of isavuconazonium sulfate to rats at a dose of 90 mg/kg/day (2.3-fold the human 
maintenance dose [200 mg] based on mg/m2/day) during pregnancy through the weaning period 
showed an increased perinatal mortality of the pups. In utero exposure to the active moiety 
isavuconazole had no effect on the fertility of the surviving pups.

Intravenous administration of 14C-labelled isavuconazonium sulfate to lactating rats resulted in the 
recovery of radiolabel in the milk. 

Isavuconazole did not affect the fertility of male or female rats treated with oral doses up to 
90 mg/kg/day (2.3-fold the clinical maintenance dose based on mg/m2/day comparisons).

Isavuconazole has no discernible mutagenic or genotoxic potential. Isavuconazole was negative in a 
bacterial reverse mutation assay, was weakly clastogenic at cytotoxic concentrations in the 
L5178Y tk+/- mouse lymphoma chromosome aberration assay, and showed no biologically relevant or 
statistically significant increase in the frequency of micronuclei in an in vivo rat micronucleus test. 

No carcinogenicity studies have been performed.  



19

Isavuconazole inhibited the hERG potassium channel and the L-type calcium channel with an IC50 of 
5.82 µM and 6.57 µM respectively (34- and 38-fold the human non-protein bound Cmax at maximum 
recommended human dose [MRHD], respectively).The in vivo 39-week repeated-dose toxicology 
studies in monkeys did not show QTcF prolongation at doses up to 40 mg/kg/day (2.1-fold the 
recommended clinical maintenance dose, based on mg/m2/day comparisons). 

Environmental risk assessment has shown that CRESEMBA may pose a risk for the aquatic 
environment.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Mannitol (E421)
Sulfuric acid (for pH-adjustment)

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal 
products except those mentioned in section 6.6. 

6.3 Shelf life

4 years

Chemical and physical in-use stability after reconstitution and dilution has been demonstrated for 24
hours at 2 °C to 8 °C, or 6 hours at room temperature.

From a microbiological point of view, the product should be used immediately. If not used 
immediately, in-use storage times and conditions prior to use are the responsibility of the user and 
would normally not be longer than 24 hours at 2 °C to 8 °C, unless reconstitution and dilution has 
taken place in controlled and validated aseptic conditions. 

6.4 Special precautions for storage

Store in a refrigerator (2 °C to 8 °C).
For storage conditions after reconstitution and dilution of the medicinal product, see section 6.3.

6.5 Nature and contents of container

One 10 mL Type I glass vial with rubber stopper and an aluminum cap with plastic seal.

6.6 Special precautions for disposal and other handling

Reconstitution

One vial of the powder for concentrate for solution for infusion should be reconstituted by addition of
5 mL water for injections to the vial. The vial should be shaken to dissolve the powder completely. 
The reconstituted solution should be inspected visually for particulate matter and discoloration. 
Reconstituted concentrate should be clear and free of visible particulate. It must be further diluted 
prior to administration. 

Dilution and administration



20

After reconstitution, the entire content of the reconstituted concentrate should be removed from the 
vial and added to an infusion bag containing at least 250 mL of either sodium chloride 9 mg/mL 
(0.9%) solution for injection or 50 mg/mL (5%) dextrose solution. The infusion solution contains 
approximately 0.8 mg isavuconazole per mL. After the reconstituted concentrate is further diluted, the 
diluted solution may show fine white-to-translucent particulates of isavuconazole, that do not sediment
(but will be removed by in-line filtration). The diluted solution should be mixed gently, or the bag 
should be rolled to minimise the formation of particulates. Unnecessary vibration or vigorous shaking 
of the solution should be avoided. The solution for infusion must be administered via an infusion set 
with an in-line filter (pore size 0.2 μm to 1.2 μm) made of polyether sulfone (PES). 

Isavuconazole should not be infused into the same line or cannula concomitantly with other 
intravenous products. 

Storage conditions after reconstitution and dilution are provided in section 6.3.

If possible, the intravenous administration of isavuconazole should be completed within 6 hours after 
reconstitution and dilution at room temperature. If this is not possible, the infusion solution should be 
immediately refrigerated after dilution, and infusion should be completed within 24 hours. Further 
information regarding the storage conditions after reconstitution and dilution of the medicinal product
is provided in section 6.3.

An existing intravenous line should be flushed with sodium chloride 9 mg/mL (0.9%) solution for 
injection or 50 mg/mL (5%) dextrose solution.

This medicinal product is for single use only. Discard partially-used vials.

This medicinal product may pose a risk to the environment (see section 5.3).

Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements.

7. MARKETING AUTHORISATION HOLDER

Basilea Pharmaceutica Deutschland GmbH
Marie-Curie-Strasse 8
79539 Lörrach
Germany

8. MARKETING AUTHORISATION NUMBER(S) 

EU/1/15/1036/001

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 15 October 2015.
Date of latest renewal:

10. DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu.

http://www.ema.europa.eu/


21

1. NAME OF THE MEDICINAL PRODUCT

CRESEMBA 100 mg hard capsules

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each capsule contains 100 mg isavuconazole (as 186.3 mg isavuconazonium sulfate).

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Hard capsule
Swedish Orange (reddish-brown) capsule body marked with ”100” in black ink and a white cap 
marked with "C" in black ink. Capsules length: 24.2 mm.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

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.

4.2 Posology and method of administration

Posology

Loading dose
The recommended loading dose is two capsules (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 two capsules (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 intravenous infusion
CRESEMBA is also available as powder for concentrate for solution for infusion containing 200 mg 
isavuconazole.

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



22

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).

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 (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

CRESEMBA capsules can be taken with or without food.
CRESEMBA capsules should be swallowed whole. Do not chew, crush, dissolve or open the capsules.

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

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.

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
Isacuvonazole is contraindicated in patients with familial short QT syndrome (see section 4.3).



23

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). 



24

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 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).



25

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 1 
(increase is indicated as “↑”, decrease as “↓”), ordered by therapeutic class. Unless otherwise stated, 
studies detailed in Table 1 have been performed with the recommended dose of isavuconazole. 

Table 1 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 

The concomitant administration of 
isavuconazole and 
carbamazepine, phenytoin and long-



26

long-acting barbiturates such as 
phenobarbital).

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 Prednisolone (active metabolite): Co-administration should be 



27

(CYP3A4 substrate) AUCinf: ↑ 8%
Cmax: ↓ 4%

(CYP3A4 inhibition)

Isavuconazole concentrations may 
decrease.

(CYP3A4/5 induction)

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 substrate)

Not studied.
Cyclophosphamide concentrations 
may decrease.

(CYP2B6 induction)

No isavuconazole dose 
adjustment necessary.
Cyclophosphamide: careful 
monitoring for any occurrence of 
lack of efficacy, and dose 
increase 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.



28

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.

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) 

The concomitant administration 
of isavuconazole and efavirenz is 
contraindicated.



29

Isavuconazole drug concentrations  
may significantly decrease.

(CYP3A4/5 induction)
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 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.

Pioglitazone
(mild CYP3A4/5 inducer)

Not studied.
Isavuconazole concentrations may 

Co-administration should be 
avoided unless the potential 



30

decrease.

(CYP3A4/5 induction)

benefit is considered to outweigh 
the risk.

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.



31

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 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 
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 2 presents adverse reactions with isavuconazole in the treatment of invasive fungal infections, 
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). 



32

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 2 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^
Metabolism and nutrition disorders

Common Hypokalaemia; Decreased appetite
Uncommon Hypomagnesaemia; Hypoglycaemia; Hypoalbuminaemia; Malnutrition^

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
Uncommon Malaise; Asthenia

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

# See section Description of selected adverse reactions below 

Description of selected adverse reactions

Delirium includes reactions of confusional state. 



33

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.

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 national reporting system 
listed in Appendix V.

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.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antimycotics for systemic use, triazole derivatives, ATC code: J02AC05

Mechanism of action

Isavuconazole is the active moiety formed after oral or intravenous administration of isavuconazonium 
sulfate (see section 5.2).

Isavuconazole demonstrates a fungicidal effect by blocking the synthesis of ergosterol, a key 
component of the fungal cell membrane, through the inhibition of cytochrome P-450-dependent 
enzyme lanosterol 14-alpha-demethylase, responsible for the conversion of lanosterol to ergosterol. 
This results in an accumulation of methylated sterol precursors and a depletion of ergosterol within the 
cell membrane, thus weakening the structure and function of the fungal cell membrane. 

Microbiology

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


34

In animal models of disseminated and pulmonary aspergillosis, the pharmacodynamic (PD) index 
important in efficacy is exposure divided by minimum inhibitory concentration (MIC) (AUC/MIC). 
No clear correlation between in vitro MIC and clinical response for the different species (Aspergillus
and Mucorales) could be established.

Concentrations of isavuconazole required to inhibit Aspergillus species and genera/species of the order 
Mucorales in vitro have been very variable. Generally, concentrations of isavuconazole required to 
inhibit Mucorales are higher than those required to inhibit the majority of Aspergillus species.

Clinical efficacy has been demonstrated for the following Aspergillus species: Aspergillus fumigatus, 
A. flavus, A. niger, and A. terreus (see further below).

Mechanism(s) of resistance

Reduced susceptibility to triazole antifungal agents has been associated with mutations in the fungal 
cyp51A and cyp51B genes coding for the target protein lanosterol 14-alpha-demethylase involved in 
ergosterol biosynthesis. Fungal strains with reduced in vitro susceptibility to isavuconazole have been 
reported, and cross-resistance with voriconazole and other triazole antifungal agents cannot be 
excluded.

Breakpoints

EUCAST MIC breakpoints are defined for the following species (susceptible S; resistant R): 
 Aspergillus fumigatus: S ≤ 1 mg/L, R > 1 mg/L 
 Aspergillus nidulans: S ≤ 0.25 mg/L, R > 0.25 mg/L
 Aspergillus terreus: S ≤ 1 mg/L, R > 1 mg/L

There are currently insufficient data to set clinical breakpoints for other Aspergillus species.

Clinical efficacy and safety

Treatment of invasive aspergillosis
The safety and efficacy of isavuconazole for the treatment of patients with invasive aspergillosis was 
evaluated in a double-blind, active-controlled clinical study in 516 patients with invasive fungal 
disease caused by Aspergillus species or other filamentous fungi. In the intent-to-treat (ITT) 
population, 258 patients received isavuconazole and 258 patients received voriconazole. 
Isavuconazole was administered intravenously (equivalent to 200 mg isavuconazole) every 8 hours for 
the first 48 hours, followed by once-daily intravenous or oral treatment (equivalent to 200 mg 
isavuconazole). The protocol-defined maximum treatment duration was 84 days. Median treatment 
duration was 45 days.

The overall response at end-of-treatment (EOT) in the myITT population (patients with proven and 
probable invasive aspergillosis based on cytology, histology, culture or galactomannan testing) was 
assessed by an independent blinded Data Review Committee. The myITT population comprised 123
patients receiving isavuconazole and 108 patients receiving voriconazole. The overall response in this 
population was n = 43 (35%) for isavuconazole and n = 42 (38.9%) for voriconazole. The adjusted 
treatment difference (voriconazole−isavuconazole) was 4.0% (95% confidence interval: −7.9; 15.9).

The all-cause mortality at Day 42 in this population was 18.7% for isavuconazole and 22.2% for 
voriconazole. The adjusted treatment difference (isavuconazole−voriconazole) was −2.7% (95 % 
confidence interval: −12.9; 7.5).

Treatment of mucormycosis
In an open-label non-controlled study, 37 patients with proven or probable mucormycosis received 
isavuconazole at the same dose regimen as that used to treat invasive aspergillosis. Median treatment 
duration was 84 days for the overall mucormycosis patient population, and 102 days for the 21 



35

patients not previously treated for mucormycosis. For patients with probable or proven mucormycosis 
as defined by the independent Data Review Committee (DRC), all-cause mortality at Day 84 was 
43.2% (16/37) for the overall patient population, 42.9% (9/21) for mucormycosis patients receiving 
isavuconazole as primary treatment, and 43.8% (7/16) for mucormycosis patients receiving 
isavuconazole who were refractory to, or intolerant of, prior antifungal therapy (mainly amphotericin 
B-based treatments). The DRC-assessed overall success rate at EOT was 11/35 (31.4%), with 5 
patients considered completely cured and 6 patients partially cured. A stable response was observed in 
an additional 10/35 patients (28.6%). In 9 patients with mucormycosis due to Rhizopus spp., 4 patients 
showed a favourable response to isavuconazole. In 5 patients with mucormycosis due to Rhizomucor
spp., no favourable responses were observed. The clinical experience in other species is very limited 
(Lichtheimia spp. n=2, Cunninghamella spp. n=1, Actinomucor elegans n=1).

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with 
CRESEMBA in one or more subsets of the paediatric population in the treatment of invasive 
aspergillosis and the treatment of mucormycosis (see section 4.2 for information on paediatric use).

5.2 Pharmacokinetic properties

Isavuconazonium sulfate is a water-soluble prodrug that can be administered as an intravenous 
infusion or orally as hard capsules. Following administration, isavuconazonium sulfate is rapidly 
hydrolysed by plasma esterases to the active moiety isavuconazole; plasma concentrations of the 
prodrug are very low, and detectable only for a short time after intravenous dosing.

Absorption

Following oral administration of CRESEMBA in healthy subjects, the active moiety isavuconazole is 
absorbed and reaches maximum plasma concentrations (Cmax) approximately 2–3 hours after single 
and multiple dosing (see Table 3). 

Table 3Steady state pharmacokinetic parameters of isavuconazole following oral administration 
of CRESEMBA

Parameter
Statistic

Isavuconazole 200 mg
(n = 37)

Isavuconazole 600 mg
(n = 32)

Cmax (ng/mL)

Mean
SD
CV %

7499
1893.3
25.2

20028
3584.3
17.9

tmax (h)

Median
Range

3.0
2.0 – 4.0

4.0
2.0 – 4.0

AUC (h•ng/mL)

Mean
SD
CV %

121402
35768.8

29.5

352805
72018.5

20.4

As shown in table 4 below, the absolute bioavailability of isavuconazole following oral administration 
of a single dose of CRESEMBA is 98%. Based on these findings, intravenous and oral dosing can be 
used interchangeably.

Table 4Pharmacokinetic comparison for oral and intravenous dose (Mean)

ISA 400 mg oral ISA 400 mg i.v.

AUC (h•ng/mL) 189462.8 193906.8

CV % 36.5 37.2



36

Half-life (h) 110 115

Effect of food on absorption
Oral administration of CRESEMBA equivalent to 400 mg isavuconazole with a high-fat meal reduced 
isavuconazole Cmax by 9% and increased AUC by 9%. CRESEMBA can be taken with or without 
food.

Distribution

Isavuconazole is extensively distributed, with a mean steady state volume of distribution (Vss) of 
approximately 450 L. Isavuconazole is highly bound (> 99%) to human plasma proteins, 
predominantly to albumin.

Biotransformation

In vitro / in vivo studies indicate that CYP3A4, CYP3A5, and subsequently uridine diphosphate-
glucuronosyltransferases (UGT), are involved in the metabolism of isavuconazole. 

Following single doses of [cyano-14C] isavuconazonium and [pyridinylmethyl-14C] isavuconazonium 
sulfate in humans, in addition to the active moiety (isavuconazole) and the inactive cleavage product, a 
number of minor metabolites were identified. Except for the active moiety isavuconazole, no 
individual metabolite was observed with an AUC > 10% of total radio-labelled material.

Elimination

Following oral administration of radio-labelled isavuconazonium sulfate to healthy subjects, a mean of 
46.1% of the radioactive dose was recovered in faeces, and 45.5% was recovered in urine. 

Renal excretion of intact isavuconazole was less than 1% of the dose administered.  

The inactive cleavage product is primarily eliminated by metabolism and subsequent renal excretion 
of the metabolites. 

Linearity/non-linearity

Studies in healthy subjects have demonstrated that the pharmacokinetics of isavuconazole are 
proportional up to 600 mg per day. 

Pharmacokinetics in special populations

Paediatric patients
The pharmacokinetics in paediatric patients (< 18 years) have not yet been evaluated. No data are 
available.

Renal impairment
No clinically relevant changes were observed in the total Cmax and AUC of isavuconazole in subjects 
with mild, moderate or severe renal impairment compared to subjects with normal renal function. Of 
the 403 patients who received isavuconazole in the Phase 3 studies, 79 (20%) of patients had an 
estimated glomerular filtration rate (GFR) less than 60 mL/min/1.73 m2. No dose adjustment is 
required in patients with renal impairment, including those patients with end-stage renal disease. 
Isavuconazole is not readily dialysable (see section 4.2).

Hepatic impairment
After a single 100 mg dose of isavuconazole was administered to 32 patients with mild (Child-Pugh 
Class A) hepatic insufficiency and 32 patients with moderate (Child-Pugh Class B) hepatic 



37

insufficiency (16 intravenous and 16 oral patients per Child-Pugh class), the least square mean 
systemic exposure (AUC) increased 64% in the Child-Pugh Class A group, and 84% in the Child-Pugh 
Class B group, relative to 32 age- and weight-matched healthy subjects with normal hepatic function. 
Mean plasma concentrations (Cmax) were 2% lower in the Child-Pugh Class A group and 30% lower in 
the Child-Pugh Class B group. The population pharmacokinetic evaluation of isavuconazole in healthy 
subjects and patients with mild or moderate hepatic dysfunction demonstrated that the mild and 
moderate hepatic impairment populations had 40% and 48% lower isavuconazole clearance (CL) 
values, respectively, than the healthy population. 

No dose adjustment is required in patients with mild to moderate 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 (see sections 4.2 and 4.4).

5.3 Preclinical safety data

In rats and rabbits, isavuconazole at systemic exposures below the therapeutic level were associated 
with dose-related increases in the incidence of skeletal anomalies (rudimentary supernumerary ribs) in 
offspring. In rats, a dose-related increase in the incidence of zygomatic arch fusion was also noted in 
offspring (see section 4.6).

Administration of isavuconazonium sulfate to rats at a dose of 90 mg/kg/day (2.3-fold the human 
maintenance dose [200 mg] based on mg/m2/day) during pregnancy through the weaning period 
showed an increased perinatal mortality of the pups. In utero exposure to the active moiety 
isavuconazole had no effect on the fertility of the surviving pups.

Intravenous administration of 14C-labelled isavuconazonium sulfate to lactating rats resulted in the 
recovery of radiolabel in the milk. 

Isavuconazole did not affect the fertility of male or female rats treated with oral doses up to 
90 mg/kg/day (2.3-fold the clinical maintenance dose based on mg/m2/day comparisons).

Isavuconazole has no discernible mutagenic or genotoxic potential. Isavuconazole was negative in a 
bacterial reverse mutation assay, was weakly clastogenic at cytotoxic concentrations in the 
L5178Y tk+/- mouse lymphoma chromosome aberration assay, and showed no biologically relevant or 
statistically significant increase in the frequency of micronuclei in an in vivo rat micronucleus test. 

No carcinogenicity studies have been performed.  

Isavuconazole inhibited the hERG potassium channel and the L-type calcium channel with an IC50 of 
5.82 µM and 6.57 µM respectively (34- and 38-fold the human non-protein bound Cmax at maximum 
recommended human dose [MRHD], respectively).The in vivo 39-week repeated-dose toxicology 
studies in monkeys did not show QTcF prolongation at doses up to 40 mg/kg/day (2.1-fold the 
recommended clinical maintenance dose, based on mg/m2/day comparisons). 

Environmental risk assessment has shown that CRESEMBA may pose a risk for the aquatic 
environment.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Capsule contents
magnesium citrate (anhydrous)



38

microcrystalline cellulose
talc
silica, colloidal anhydrous
stearic acid

Capsule shell
hypromellose 
purified water
red iron oxide (E172) (capsule body only)
titanium dioxide (E171)
gellan gum
potassium acetate
disodium edetate
sodium laurilsulfate

Printing ink
shellac
propylene glycol
potassium hydroxide 
black iron oxide (E172)

6.2 Incompatibilities 

Not applicable.

6.3 Shelf life 

30 months

6.4 Special precautions for storage 

Do not store above 30°C.

Store in the original packaging in order to protect from moisture.

6.5 Nature and contents of container 

14 hard capsules (in two aluminum blisters), with each capsule pocket connected to a pocket with 
desiccant.

6.6 Special precautions for disposal 

This medicinal product may pose a risk to the environment (see section 5.3).

Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements.

7. MARKETING AUTHORISATION HOLDER

Basilea Pharmaceutica Deutschland GmbH
Marie-Curie-Strasse 8
79539 Lörrach
Germany



39

8. MARKETING AUTHORISATION NUMBER(S) 

EU/1/15/1036/002

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 15 October 2015.
Date of latest renewal:

10. DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu.

http://www.ema.europa.eu/


40

ANNEX II

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 
AUTHORISATION

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 
EFFECTIVE USE OF THE MEDICINAL PRODUCT



41

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE

Name and address of the manufacturer(s) responsible for batch release

Almac Pharma Services (Ireland) Limited

Finnabair Industrial Estate

Dundalk

Co. Louth

A91 P9KD

Ireland

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE

Medicinal product subject to medical prescription.

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 
AUTHORISATION 

 Periodic safety update reports (PSURs)

The requirements for submission of PSURs for this medicinal product are set out in the list of 

Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and 

any subsequent updates published on the European medicines web-portal.

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 
EFFECTIVE USE OF THE MEDICINAL PRODUCT

 Risk management plan (RMP)

The marketing authorisation holder (MAH) shall perform the required pharmacovigilance activities 

and interventions detailed in the agreed RMP presented in Module 1.8.2 of the marketing 

authorisation and any agreed subsequent updates of the RMP.

An updated RMP should be submitted:

 At the request of the European Medicines Agency;
 Whenever the risk management system is modified, especially as the result of new 

information being received that may lead to a significant change to the benefit/risk profile or 

as the result of an important (pharmacovigilance or risk minimisation) milestone being 

reached. 



42

ANNEX III

LABELLING AND PACKAGE LEAFLET



43

A. LABELLING



44

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

Carton for vial for 200 mg powder for concentrate for solution for infusion

1. NAME OF THE MEDICINAL PRODUCT

CRESEMBA 200 mg powder for concentrate for solution for infusion 
isavuconazole 

2. STATEMENT OF ACTIVE SUBSTANCE(S)

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

3. LIST OF EXCIPIENTS

Excipients: mannitol (E421) and sulfuric acid

4. PHARMACEUTICAL FORM AND CONTENTS

Powder for concentrate for solution for infusion
1 vial 

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
For intravenous use after reconstitution and dilution
Use an in-line filter for infusion.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

Store in a refrigerator



45

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Basilea Pharmaceutica Deutschland GmbH
Marie-Curie-Strasse 8
79539 Lörrach
Germany

12. MARKETING AUTHORISATION NUMBER(S) 

EU/1/15/1036/001

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Justification for not including Braille accepted.

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC
SN
NN



46

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS

Label on vial for 200 mg powder for concentrate for solution for infusion 

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION

CRESEMBA 200 mg powder for concentrate for solution for infusion
isavuconazole

IV use after reconsitution and dilution

2. METHOD OF ADMINISTRATION

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT

200 mg 

6. OTHER



47

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

Carton for 100 mg hard capsules

1. NAME OF THE MEDICINAL PRODUCT

CRESEMBA 100 mg hard capsules 
isavuconazole 

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each hard capsule contains 100 mg isavuconazole (as 186.3 mg isavuconazonium sulfate)

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

14 hard capsules

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.

Oral use.
The blister card also contains desiccant. Do not swallow the desiccant.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

Do not store above 30°C.

Store in the original package in order to protect from moisture.



48

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Basilea Pharmaceutica Deutschland GmbH
Marie-Curie-Strasse 8
79539 Lörrach
Germany

12. MARKETING AUTHORISATION NUMBER(S) 

EU/1/15/1036/002

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

CRESEMBA 100 mg hard capsules

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC
SN
NN



49

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS

Blister for 100 mg hard capsules 

1. NAME OF THE MEDICINAL PRODUCT

CRESEMBA 100 mg hard capsules
isavuconazole

2. NAME OF THE MARKETING AUTHORISATION HOLDER

Basilea Pharmaceutica Deutschland GmbH

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. OTHER

Do not swallow the desiccant



50

B. PACKAGE LEAFLET



51

Package leaflet: Information for the patient

Cresemba 200 mg powder for concentrate for solution for infusion
isavuconazole

Read all of this leaflet carefully before you start using this medicine because it contains 
important information for you.

- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor, pharmacist or nurse.
- If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible 

side effects not listed in this leaflet. See section 4.

What is in this leaflet

1. What Cresemba is and what it is used for 
2. What you need to know before you use Cresemba
3. How to use Cresemba
4. Possible side effects 
5. How to store Cresemba
6. Contents of the pack and other information

1. What Cresemba is and what it is used for

What Cresemba is
Cresemba is an anti-fungal medicine that contains the active substance isavuconazole. 

How Cresemba works
Isavuconazole works by killing or stopping the growth of the fungus, which causes the infection. 

What Cresemba is used for
Cresemba is used in adults to treat the following fungal infections:
- invasive aspergillosis, caused by a fungus in the ‘Aspergillus’ group; 
- mucormycosis, caused by a fungus beloning to the ‘Mucorales’ group in patients for whom a 

treatment with amphotericin B is not appropriate.

2. What you need to know before you use Cresemba

Do not use Cresemba:
- if you are allergic to isavuconazole or any of the other ingredients of this medicine (listed in 

section 6),
- if you have a heart beat problem called ‘familial short QT syndrome’,
- if you are using any of the following medicines:

- ketoconazole, used for fungal infections,
- high doses of ritonavir (more than 200 mg every 12 hours), used for HIV,
- rifampicin, rifabutin, used for tuberculosis,
- carbamazepine, used for epilepsy,
- barbiturate medicines like phenobarbital, used for epilepsy and sleep disorders,
- phenytoin, used for epilepsy,
- St John’s wort, a herbal medicine used for depression,
- efavirenz, etravirine, used for HIV,
- nafcillin, used for bacterial infections.

Warnings and precautions 
Talk to your doctor, pharmacist or nurse before using Cresemba:



52

- if you have had an allergic reaction to other ‘azole’ anti-fungal treatments in the past, such as 
ketoconazole, fluconazole, itraconazole, voriconazole or posaconazole,

- if you are suffering from severe liver disease. Your doctor should monitor you for possible side 
effects,

Look out for side effects
Stop using Cresemba and tell your doctor straight away if you notice any of the following 
side effects:
- rash, swelling of your lips, mouth, tongue or throat with difficulty breathing - these may be 

signs of an allergic reaction (hypersensitivity). 

Problems while having Cresemba as drip into a vein
Tell your doctor straight away if you notice any of the following side effects:
- low blood pressure, feel short of breath, nausea, dizziness, headache, tingling, – your doctor 

may decide to stop the infusion.

Changes in your liver function
Cresemba can sometimes affect your liver function. Your doctor may carry out blood tests while 
you are taking this medicine. 

Skin problems
Tell your doctor straight away if you get severe blistering of the skin, mouth, eyes or genitals.

Children and adolescents
Cresemba should not be used in children or adolescents younger than 18 years because there is no 
information on use in this age group.

Other medicines and Cresemba
Tell your doctor or pharmacist if you are using, have recently used or might use any other medicines. 
Some medicines may affect the way Cresemba works or Cresemba may affect the way they work, if 
they are taken at the same time.

In particular, do not take this medicine and tell your doctor or pharmacist if you are taking any of the 
following medicines:
- ketoconazole, used for fungal infections,
- high doses of ritonavir (more than 200 mg every 12 hours), used for HIV,
- rifampicin, rifabutin, used for tuberculosis,
- carbamazepine, used for epilepsy,
- barbiturate medicines like phenobarbital, used for epilepsy and sleep disorders,
- phenytoin, used for epilepsy,
- St John’s wort, a herbal medicine used for depression.
- efavirenz, etravirine, used for HIV,
- nafcillin, used for bacterial infections.

Unless your doctor tells you otherwise, do not take this medicine and tell your doctor or pharmacist if 
you are taking any of the following medicines: 
- rufinamide or other medicines which decrease the QT interval on the heart tracing (ECG),
- aprepitant, used to prevent nausea and vomiting by cancer treatment, 
- prednisone, used for rheumatoid arthritis,
- pioglitazone, used for diabetes.

Tell your doctor or pharmacist if you are taking any of the following medicines, as a dose adjustment 
or monitoring may be required to check that the medicines are still having the desired effect: 
- ciclosporin, tacrolimus and sirolimus, used to prevent rejection of a transplant,
- cyclophosphamide, used for cancer,
- digoxin, used to treat heart failure or an uneven heart beat,
- colchicine, used for gout attack,



53

- dabigatran etexilate, used to stop blood clots after hip or knee replacement surgery,
- clarithromycin, used for bacterial infections,
- saquinavir, indinavir, nevirapine, lopinavir/ritonavir combination, used for HIV,
- alfentanil, fentanyl, used against strong pain,
- vincristine, vinblastine, used for cancer,
- mycophenolate mofetil (MMF), used in transplant patients,
- midazolam, used for severe insomnia and stress,
- bupropion, used for depression.
- metformin, used for diabetes,
- daunorubicin, doxorubicin, imatinib, irinotecan, lapatinib, mitoxantrone, topotecan, used for 

different sorts of cancer.

Pregnancy and breast-feeding
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 
your doctor for advice before using this medicine.

Do not take Cresemba if you are pregnant, unless your doctor tells you otherwise. This is because it is 
not known if it may affect or harm your unborn baby. 

Do not breast-feed if you are taking Cresemba. 

Driving and using machines
Cresemba may make you feel confused, tired or sleepy. It can also make you pass out. Therefore, be 
very careful when driving or operating machines.

3. How to use Cresemba

Cresemba will be given to you by a doctor or nurse.

Starting dose for the first two days (48 hours)
The recommended dose is one vial every 8 hours.

Usual dose after the first two days
This is started 12 to 24 hours after your last starting dose. The recommended dose is one vial once a 
day.

You will be given this dose until your doctor tells you otherwise. The duration of treatment with 
Cresemba may be longer than 6 months if your doctor considers this necessary.

The vial will be given as a drip into a vein by your doctor or nurse.

If you use more Cresemba than you should
If you think you have been given too much Cresemba, talk to your doctor or nurse straight away. You 
may have more side effects such as: 
- headache, feeling dizzy, restless or sleepy,
- tingling, reduced sense of touch or sensation in the mouth,
- problems being aware of things, hot flushes, anxiety, joint pain,
- changes in the way things taste, dry mouth, diarrhoea, vomiting,
- feeling your heart beat, faster heart rate, being more sensitive to light.

If you forget to use Cresemba
As you will be given this medicine under close medical supervision, it is unlikely that a dose would be 
missed. However, tell your doctor or nurse if you think that a dose has been forgotten.

If you stop using Cresemba



54

Cresemba treatment will continue for as long as your doctor tells you. This is to make sure that the 
fungal infection has gone.

If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Stop using Cresemba and tell your doctor straight away if you notice any of the following side 
effects:
- rash, swelling of your lips, mouth, tongue or throat with difficulty breathing - these may be signs 

of an allergic reaction (hypersensitivity).

Tell your doctor straight away if you notice any of the following side effects:
- severe blistering of the skin, mouth, eyes or genitals.

Other side effects
Tell your doctor, pharmacist or nurse if you notice any of the following side effects:

Common: may affect up to 1 in 10 people
- low potassium in your blood,
- decreased appetite,
- hallucinations (delirium),
- headache,
- sleepiness,
- inflamed veins that could lead to blood clots,
- shortness of breath or sudden and severe difficulty breathing,
- feeling sick (nausea), being sick (vomiting), diarrhoea, stomach pain,
- changes in blood tests of liver function,
- rash, itching, 
- kidney failure (symptoms could include swelling of legs),
- chest pain, feeling tired or sleepy,
- problems where the injection was given.

Uncommon: may affect up to 1 in 100 people
- reduced white blood cells - can increase your risk of infection and fever,
- reduced blood cells called ‘platelets’ - can increase your risk for bleeding or bruising,
- reduced red blood cells -  can make you feel weak or short of breath or make your skin pale,
- severe reduction in blood cells - can make you feel weak, cause bruising or make infections 

more likely,
- rash, swelling of your lips, mouth, tongue or throat with difficulty breathing (hypersensitivity),
- low blood sugar levels,
- low blood levels of magnesium ,
- low levels in the blood of a protein called ‘albumin’,
- not getting the right goodness from your diet (malnutrition),
- depression, difficulty sleeping,
- seizure, fainting or feeling faint, dizziness,
- sensation of tingling, tickling, or pricking of the skin (paraesthesia),
- altered mental state (encephalopathy), 
- changes in taste (dysgeusia), 
- feeling of ‘spinning’ or being dizzy (vertigo),
- heart beat problems - may be too fast or uneven, or extra heart beats – this may show in your 

heart tracing (electrocardiogram or ECG),
- problems with the blood circulation,
- low blood pressure,



55

- wheezing, very fast breathing, coughing up blood or blood-stained sputum, nose bleeding,
- indigestion,
- constipation,
- feeling bloated (abdominal distension),
- enlarged liver,
- inflammation of the liver,
- problems with the skin, red or purple spots on the skin (petechiae), inflamed skin (dermatitis), 

hair loss, 
- back pain,
- swelling of the extremities,
- feeling weak, very tired, or sleepy or generally out of sorts (malaise).

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 

effects not listed in this leaflet. You can also report side effects directly via the national reporting 

system listed in Appendix V. By reporting side effects you can help provide more information on the 

safety of this medicine.

5. How to store Cresemba

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the label after EXP. The expiry date 
refers to the last day of that month.

Store in in a refrigerator (2°C to 8°C).

Do not throw away any medicines via wastewater. Ask your pharmacist how to throw away medicines 
you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information

What Cresemba contains 
- The active substance is isavuconazole. Each vial contains 372.6 mg isavuconazonium sulfate, 

corresponding to 200 mg isavuconazole.
- The other ingredients (excipients) are mannitol (E421) and sulfuric acid.

What Cresemba looks like and contents of the pack
Cresemba 200 mg is presented in a single use glass vial as a powder for concentrate for solution for 
infusion.

Marketing Authorisation Holder:

Basilea Pharmaceutica Deutschland GmbH
Marie-Curie-Strasse 8
79539 Lörrach
Germany

Manufacturer:

Almac Pharma Services (Ireland) Limited
Finnabair Industrial Estate
Dundalk, Co. Louth

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


56

A91 P9KD
Ireland

For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:

België/Belgique/Belgien
Pfizer SA/NV 
Tel/Tél: +32 (0)2 554 62 11

Lietuva 
Pfizer Luxembourg SARL filialas Lietuvoje
Tel. +3705 2514000

България
Пфайзер Люксембург САРЛ, Клон България
Тел.: +359 2 970 4333

Luxembourg/Luxemburg
Pfizer SA/NV
Tél/Tel: +32 (0)2 554 62 11

Česká republika
Pfizer s.r.o.
Tel: +420-283-004-111

Magyarország
Pfizer Kft.
Tel.: + 36 1 488 37 00

Danmark
Unimedic Pharma AB
Tlf: +46 (0) 10-130 99 50

Malta
Vivian Corporation Ltd.
Tel: +35621 344610

Deutschland
Pfizer Pharma PFE GmbH
Tel: +49 (0)800 8535555

Nederland
Pfizer bv
Tel: +31 (0)10 406 43 01

Eesti
Pfizer Luxembourg SARL Eesti filiaal
Tel: +372 666 7500

Norge
Unimedic Pharma AB
Tlf: +46 (0) 10-130 99 50

Ελλάδα
Pfizer  ΕΛΛΑΣ A.E.
Τηλ: +30 210 67 85 800

Österreich
Pfizer Corporation Austria Ges.m.b.H.
Tel: +43 (0)1 521 15-0

España
Pfizer S.L.
Tel: +34 91 490 99 00

Polska
Pfizer Polska Sp. z o.o.
Tel.: +48 22 335 61 00

France
Pfizer 
Tél: +33 (0)1 58 07 34 40

Portugal
Laboratórios Pfizer, Lda.
Tel: +351 21 423 5500

Hrvatska
Pfizer Croatia d.o.o. 
Tel: +385 1 3908 777

România 
Pfizer România S.R.L.
Tel: +40 (0) 21 20 728 00

Ireland
Pfizer Healthcare Ireland 
Tel: +1800 633 363 (toll free) 
+44 (0)1304 616161

Slovenija
Pfizer Luxembourg SARL
Pfizer, podružnica za svetovanje s področja
farmacevtske dejavnosti, Ljubljana
Tel: + 386 (0) 1 52 11 400

Ísland
Unimedic Pharma AB
Sími: +46 (0) 10-130 99 50

Slovenská republika
Pfizer Luxembourg SARL, organizačná zložka
Tel: +421-2-3355 5500

Italia
Pfizer S.r.l.
Tel: +39 06 33 18 21

Suomi/Finland
Unimedic Pharma AB
Puh/Tel: +46 (0) 10-130 99 50

Κύπρος
Pfizer ΕΛΛΑΣ Α.Ε. (CYPRUS BRANCH)
Τηλ: +357 22 817690

Sverige
Unimedic Pharma AB
Tel: +46 (0) 10-130 99 50

Latvija
Pfizer Luxembourg SARL filiāle Latvijā
Tel: +371 670 35 775

United Kingdom
Pfizer Limited
Tel: +44 (0)1304 616161

This leaflet was last revised in 

Other sources of information



57

Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu. There are also links to other websites about rare diseases and treatments.

---------------------------------------------------------------------------------------------------------------------------
--

The following information is intended for healthcare professionals only:

Cresemba 200 mg powder for concentrate for solution for infusion must be reconstituted and diluted 
prior to infusion.

Reconstitution

One vial of the powder for concentrate for solution for infusion should be reconstituted by addition of 
5 mL water for injection to the vial. The vial should be shaken to dissolve the powder completely. The 
reconstituted solution should be inspected visually for particulate matter and discoloration. 
Reconstituted concentrate should be clear and free of visible particulate. It must be further diluted 
prior to administration. 

Dilution and administration

After reconstitution, the entire content of the reconstituted concentrate should be removed from the
vial and added to an infusion bag containing at least 250 mL of either sodium chloride 9 mg/mL 
(0.9%) solution for injection or 50 mg/mL (5%) dextrose solution. The infusion solution contains 
approximately 1.5 mg/mL isavuconazonium sulfate (corresponding to approximately 0.8 mg 
isavuconazole per mL). After the reconstituted concentrate is further diluted, the diluted solution may 
show fine white-to-translucent particulates of isavuconazole that do not sediment (but will be removed 
by in-line filtration). The diluted solution should be mixed gently, or the bag should be rolled to 
minimise the formation of particulates. Unnecessary vibration or vigorous shaking of the solution 
should be avoided. The solution for infusion must be administered via an infusion set with an in-line 
filter (pore size 0.2 μm to 1.2 μm) made of polyether sulfone (PES). 

Isavuconazole should not be infused into the same line or cannula concomitantly with other 
intravenous products. 

Chemical and physical in-use stability after reconstitution and dilution has been demonstrated for 24 
hours at 2 °C to 8 °C, or 6 hours at room temperature.

From a microbiological point of view, the product should be used immediately. If not used 
immediately, in-use storage times and conditions prior to use are the responsibility of the user and 
would normally not be longer than 24 hours at 2 °C to 8 °C, unless reconstitution and dilution has 
taken place in controlled and validated aseptic conditions. 

If possible, the intravenous administration of isavuconazole should be completed within 6 hours after 
reconstitution and dilution at room temperature. If this is not possible, the infusion solution should be 
immediately refrigerated after dilution, and infusion should be completed within 24 hours. 

An existing intravenous line should be flushed with sodium chloride 9 mg/mL (0.9%) solution for 
injection or 50 mg/mL (5%) dextrose solution.

This medicinal product is for single use only. Discard partially-used vials.

http://www.ema.europa.eu/


58

Package leaflet: Information for the patient

Cresemba 100 mg hard capsules
isavuconazole

Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you.

- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor, pharmacist or nurse.
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours.
- If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible 

side effects not listed in this leaflet. See section 4.

What is in this leaflet

1. What Cresemba is and what it is used for 
2. What you need to know before you take Cresemba
3. How to take Cresemba
4. Possible side effects 
5. How to store Cresemba
6. Contents of the pack and other information

1. What Cresemba is and what it is used for

What Cresemba is
Cresemba is an anti-fungal medicine that contains the active substance isavuconazole. 

How Cresemba works
Isavuconazole works by killing or stopping the growth of the fungus, which causes the infection. 

What Cresemba is used for
Cresemba is used in adults to treat the following fungal infections:
- invasive aspergillosis, caused by a fungus in the ‘Aspergillus’ group; 
- mucormycosis, caused by a fungus beloning to the ‘Mucorales’ group in patients for whom a 

treatment with amphotericin B is not appropriate.

2. What you need to know before you take Cresemba

Do not take Cresemba:
- if you are allergic to isavuconazole or any of the other ingredients of this medicine (listed in 

section 6),
- if you have a heart beat problem called ‘familial short QT syndrome’,
- if you are using any of the following medicines:

- ketoconazole, used for fungal infections,
- high doses of ritonavir (more than 200 mg every 12 hours), used for HIV,
- rifampicin, rifabutin, used for tuberculosis,
- carbamazepine, used for epilepsy,
- barbiturate medicines like phenobarbital, used for epilepsy and sleep disorders,
- phenytoin, used for epilepsy,
- St John’s wort, a herbal medicine used for depression,
- efavirenz, etravirine, used for HIV,
- nafcillin, used for bacterial infections.

Warnings and precautions 



59

Talk to your doctor, pharmacist or nurse before taking Cresemba:
- if you have had an allergic reaction to other ‘azole’ anti-fungal treatments in the past, such as 

ketoconazole, fluconazole, itraconazole, voriconazole or posaconazole,
- if you are suffering from severe liver disease. Your doctor should monitor you for possible side 

effects

Look out for side effects
Stop taking Cresemba and tell your doctor straight away if you notice any of the following 
side effects:
- rash, swelling of your lips, mouth, tongue or throat with difficulty breathing - these may be 

signs of an allergic reaction (hypersensitivity). 

Changes in your liver function
Cresemba can sometimes affect your liver function. Your doctor may carry out blood tests while 
you are taking this medicine. 

Skin problems
Tell your doctor straight away if you get severe blistering of the skin, mouth, eyes or genitals.

Children and adolescents
Cresemba should not be used in children or adolescents younger than 18 years because there is no 
information on use in this age group.

Other medicines and Cresemba
Tell your doctor or pharmacist if you are using, have recently used or might use any other medicines. 
Some medicines may affect the way Cresemba works or Cresemba may affect the way they work, if 
they are taken at the same time.

In particular, do not take this medicine and tell your doctor or pharmacist if you are taking any of the 
following medicines:
- ketoconazole, used for fungal infections,
- high doses of ritonavir (more than 200 mg every 12 hours), used for HIV,
- rifampicin, rifabutin, used for tuberculosis,
- carbamazepine, used for epilepsy,
- barbiturate medicines like phenobarbital, used for epilepsy and sleep disorders,
- phenytoin, used for epilepsy,
- St John’s wort, a herbal medicine used for depression,
- efavirenz, etravirine, used for HIV,
- nafcillin, used for bacterial infections.

Unless your doctor tells you otherwise, do not take this medicine and tell your doctor or pharmacist if 
you are taking any of the following medicines: 
- rufinamide or other medicines which decrease the QT interval on the heart tracing (ECG),
- aprepitant, used to prevent nausea and vomiting by cancer treatment, 
- prednisone, used for rheumatoid arthritis,
- pioglitazone, used for diabetes.

Tell your doctor or pharmacist if you are taking any of the following medicines, as a dose adjustment 
or monitoring may be required to check that the medicines are still having the desired effect: 
- ciclosporin, tacrolimus and sirolimus, used to prevent rejection of a transplant,
- cyclophosphamide, used for cancer,
- digoxin, used to treat heart failure or an uneven heart beat,
- colchicine, used for gout attack,
- dabigatran etexilate, used to stop blood clots after hip or knee replacement surgery,
- clarithromycin, used for bacterial infections,
- saquinavir, indinavir, nevirapine, lopinavir/ritonavir combination, used for HIV,
- alfentanil, fentanyl, used against strong pain,



60

- vincristine, vinblastine, used for cancer,
- mycophenolate mofetil (MMF), used in transplant patients,
- midazolam, used for severe insomnia and stress,
- bupropion, used for depression,
- metformin, used for diabetes,
- daunorubicin, doxorubicin, imatinib, irinotecan, lapatinib, mitoxantrone, topotecan, used for 

different sorts of cancer.

Pregnancy and breast-feeding
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 
your doctor for advice before using this medicine.

Do not take Cresemba if you are pregnant, unless your doctor tells you otherwise. This is because it is 
not known if it may affect or harm your unborn baby. 

Do not breast-feed if you are taking Cresemba. 

Driving and using machines
Cresemba may make you feel confused, tired or sleepy. It can also make you pass out. Therefore, be 
very careful when driving or operating machines.

3. How to take Cresemba

Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor 
or pharmacist if you are not sure.

Starting dose for the first two days (48 hours)
The recommended dose is two capsules every 8 hours.

Usual dose after the first two days
This is started 12 to 24 hours after your last starting dose. The recommended dose is two capsules once 
a day.

You will take this dose until your doctor tells you otherwise. The duration of treatment with Cresemba 
may be longer than 6 months if your doctor considers this necessary.

Capsules can be taken with or without food. Swallow the capsules whole. Do not chew, crush, dissolve 
or open the capsules.

If you take more Cresemba than you should
If you take more Cresemba than you should, talk to a doctor or go to a hospital straight away. Take the 
medicine pack with you so the doctor knows what you have taken. 
You may have more side effects such as: 
- headache, feeling dizzy, restless or sleepy,
- tingling, reduced sense of touch or sensation in the mouth,
- problems being aware of things, hot flushes, anxiety, joint pain,
- changes in the way things taste, dry mouth, diarrhoea, vomiting,
- feeling your heart beat, faster heart rate, being more sensitive to light.

If you forget to take Cresemba
Take the capsules as soon as you remember. However, if it is nearly time for the next dose, skip the 
missed dose. 

Do not take a double dose to make up for a forgotten dose.

If you stop taking Cresemba



61

Do not stop taking Cresemba unless you doctor has told you to do so. It is important to keep taking this 
medicine as long as your doctor tells you. This is to make sure that the fungal infection has gone.

If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Stop taking Cresemba and tell your doctor straight away if you notice any of the following side 
effects:
- rash, swelling of your lips, mouth, tongue or throat with difficulty breathing - these may be signs 

of an allergic reaction (hypersensitivity).

Tell your doctor straight away if you notice any of the following side effects:
- severe blistering of the skin, mouth, eyes or genitals.

Other side effects
Tell your doctor, pharmacist or nurse if you notice any of the following side effects:

Common: may affect up to 1 in 10 people
- low potassium in your blood,
- decreased appetite,
- hallucinations (delirium),
- headache,
- sleepiness,
- inflamed veins that could lead to blood clots,
- shortness of breath or sudden and severe difficulty breathing,
- feeling sick (nausea), being sick (vomiting), diarrhoea, stomach pain,
- changes in blood tests of liver function,
- rash, itching, 
- kidney failure (symptoms could include swelling of legs),
- chest pain, feeling tired or sleepy.

Uncommon: may affect up to 1 in 100 people
- reduced white blood cells - can increase your risk of infection and fever,
- reduced blood cells called ‘platelets’ - can increase your risk for bleeding or bruising,
- reduced red blood cells -  can make you feel weak or short of breath or make your skin pale,
- severe reduction in blood cells - can make you feel weak, cause bruising or make infections 

more likely,
- rash, swelling of your lips, mouth, tongue or throat with difficulty breathing (hypersensitivity),
- low blood sugar levels,
- low blood levels of magnesium ,
- low levels in the blood of a protein called ‘albumin’,
- not getting the right goodness from your diet (malnutrition),
- depression, difficulty sleeping,
- seizure, fainting or feeling faint, dizziness,
- sensation of tingling, tickling, or pricking of the skin (paraesthesia),
- altered mental state (encephalopathy), 
- changes in taste (dysgeusia), 
- feeling of ‘spinning’ or being dizzy (vertigo),
- heart beat problems - may be too fast or uneven, or extra heart beats – this may show in your 

heart tracing (electrocardiogram or ECG),
- problems with the blood circulation,
- low blood pressure,
- wheezing, very fast breathing, coughing up blood or blood-stained sputum, nose bleeding,



62

- indigestion,
- constipation,
- feeling bloated (abdominal distension),
- enlarged liver,
- inflammation of the liver,
- problems with the skin, red or purple spots on the skin (petechiae), inflamed skin (dermatitis), 

hair loss, 
- back pain,
- feeling weak, very tired, or sleepy or generally out of sorts (malaise).

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 

effects not listed in this leaflet. You can also report side effects directly via the national reporting 

system listed in Appendix V. By reporting side effects you can help provide more information on the 

safety of this medicine.

5. How to store Cresemba

Keep this medicine out of the sight and reach of children.

Do not take this medicine after the expiry date which is stated on the label after EXP. The expiry date 
refers to the last day of that month.

Do not store above 30°C.

Store in the original packaging in order to protect from moisture.

Do not throw away any medicines via wastewater. Ask your pharmacist how to throw away medicines 
you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information

What Cresemba contains 
- The active substance is isavuconazole. Each capsule contains 186.3 mg isavuconazonium 

sulfate, corresponding to 100 mg isavuconazole.
- The other ingredients ingredients are:

- Capsule content: magnesium citrate (anhydrous), microcrystalline cellulose, talc, anhydrous 
colloidal silica, stearic acid.

- Capsule shell: hypromellose, water, red iron oxide (E172) (capsule body only), titanium 
dioxide (E171), gellan gum, potassium acetate, disodium edetate, sodium laurilsulfate.

- Printing ink: shellac, propylene glycol, potassium hydroxide, black iron oxide (E172).

What Cresemba looks like and contents of the pack
Cresemba 100 mg hard capsules are capsules with a reddish-brown body marked with “100” in black 
ink and a white cap marked with “C” in black ink.

Cresemba is available in cartons that contain 14 capsules. Each carton contains 2 aluminium blisters 
pack, with 7 capsules each. 

Each capsule pocket is connected to a pocket that contains ‘desiccant’ to protect the capsule from 
moisture. 

Do not puncture the blister containing the desiccant. 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


63

Do not swallow or use the desiccant.

Marketing Authorisation Holder:

Basilea Pharmaceutica Deutschland GmbH
Marie-Curie-Strasse 8
79539 Lörrach
Germany

Manufacturer:

Almac Pharma Services (Ireland) Limited
Finnabair Industrial Estate
Dundalk
Co. Louth
A91 P9KD
Ireland

For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:

België/Belgique/Belgien
Pfizer SA/NV 
Tel/Tél: +32 (0)2 554 62 11

Lietuva
Pfizer Luxembourg SARL filialas Lietuvoje
Tel. +3705 2514000

България
Пфайзер Люксембург САРЛ, Клон България
Тел.: +359 2 970 4333

Luxembourg/Luxemburg
Pfizer SA/NV
Tél/Tel: +32 (0)2 554 62 11

Česká republika
Pfizer s.r.o.
Tel: +420-283-004-111

Magyarország
Pfizer Kft.
Tel.: + 36 1 488 37 00

Danmark
Unimedic Pharma AB
Tlf: +46 (0) 10-130 99 50

Malta
Vivian Corporation Ltd.
Tel: +35621 344610

Deutschland
Pfizer Pharma PFE GmbH
Tel: +49 (0)800 8535555

Nederland
Pfizer bv
Tel: +31 (0)10 406 43 01

Eesti
Pfizer Luxembourg SARL Eesti filiaal
Tel: +372 666 7500

Norge
Unimedic Pharma AB
Tlf: +46 (0) 10-130 99 50

Ελλάδα
Pfizer  ΕΛΛΑΣ A.E.
Τηλ: +30 210 67 85 800

Österreich
Pfizer Corporation Austria Ges.m.b.H.
Tel: +43 (0)1 521 15-0

España
Pfizer S.L.
Tel: +34 91 490 99 00

Polska
Pfizer Polska Sp. z o.o.
Tel.: +48 22 335 61 00

France
Pfizer
Tél: +33 (0)1 58 07 34 40

Portugal
Laboratórios Pfizer, Lda.
Tel: +351 21 423 5500

Hrvatska
Pfizer Croatia d.o.o. 
Tel: +385 1 3908 777

România 
Pfizer România S.R.L.
Tel: +40 (0) 21 20 728 00

Ireland
Pfizer Healthcare Ireland 
Tel: +1800 633 363 (toll free) 
+44 (0)1304 616161

Slovenija
Pfizer Luxembourg SARL
Pfizer, podružnica za svetovanje s področja
farmacevtske dejavnosti, Ljubljana
Tel: + 386 (0) 1 52 11 400



64

Ísland
Unimedic Pharma AB
Sími: +46 (0) 10-130 99 50

Slovenská republika
Pfizer Luxembourg SARL, organizačná zložka
Tel: +421-2-3355 5500

Italia
Pfizer S.r.l.
Tel: +39 06 33 18 21

Suomi/Finland
Unimedic Pharma AB
Puh/Tel: +46 (0) 10-130 99 50

Κύπρος
Pfizer ΕΛΛΑΣ Α.Ε. (CYPRUS BRANCH)
Τηλ: +357 22 817690

Sverige
Unimedic Pharma AB
Tel: +46 (0) 10-130 99 50

Latvija
Pfizer Luxembourg SARL filiāle Latvijā
Tel: +371 670 35 775

United Kingdom
Pfizer Limited
Tel: +44 (0)1304 616161

This leaflet was last revised in

Other sources of information

Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu. There are also links to other websites about rare diseases and treatments.

http://www.ema.europa.eu/

	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETINGAUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE ANDEFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET