Cresemba, isavuconazole

SUMMARY OF PRODUCT CHARACTERISTICS
This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions.
See section 4.8 for how to report adverse reactions.
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
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, equivalent to 186 mg isavuconazonium sulfate.
On the basis of the high oral bioavailability (98%, see section 5.2), switching between intravenous and
oral administration is appropriate when clinically indicated.
Elderly
No dose adjustment is necessary for elderly patients; however the clinical experience in elderly
patients is limited.
Renal impairment
No dose adjustment is necessary in patients with renal impairment, including patients with end-stage
renal disease (see section 5.2).

Hepatic impairment
No dose adjustment is necessary in patients with mild or moderate hepatic impairment (Child-Pugh
Classes A and B) (see sections 4.4 and 5.2).
CRESEMBA has not been studied in patients with severe hepatic impairment (Child-Pugh Class C).
Use in these patients is not recommended unless the potential benefit is considered to outweigh the
risks. See sections 4.4, 4.8 and 5.2.
Paediatric population
The safety and efficacy of CRESEMBA in children aged below 18 years has not yet been established.
No data are available.
Method of administration
Intravenous use.
Precautions to be taken before handling or administering the medicinal product
CRESEMBA must be reconstituted and then further diluted to a concentration corresponding to
approximately 0.8 mg/mL isavuconazole prior to administration by intravenous infusion over a
minimum of 1 hour to reduce the risk of infusion-related reactions. The infusion must be administered
via an infusion set with an in-line filter with a microporous membrane made of polyethersulfone (PES)
and with a pore size of 0.2 μm to 1.2 μm. CRESEMBA must only be given as an intravenous infusion.
For detailed instructions on the reconstitution and dilution of CRESEMBA before administration, see
section 6.6.
4.3
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). 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
During intravenous administration of isavuconazole, infusion-related reactions including hypotension,
dyspnoea, dizziness, paraesthesia, nausea, and headache were reported (see section 4.8). The infusion
should be stopped if these reactions occur.
Severe cutaneous adverse reactions
Severe cutaneous adverse reactions, such as Stevens-Johnson syndrome, have been reported during
treatment with azole antifungal agents. If a patient develops a severe cutaneous adverse reaction,
CRESEMBA should be discontinued.
Cardiovascular
QT shortening
CRESEMBA is contraindicated in patients with familial short QT syndrome (see section 4.3).
In a QT study in healthy human subjects, isavuconazole shortened the QTc interval in a
concentration-related manner. For the 200 mg dosing regimen, the least squares mean (LSM)
difference from placebo was 13.1 ms at 2 hours post dose [90% CI: 17.1, 9.1 ms]. Increasing the dose
to 600 mg resulted in an LSM difference from placebo of 24.6 ms at 2 hours post dose [90% CI: 28.7,
20.4 ms].
Caution is warranted when prescribing CRESEMBA to patients taking other medicinal products
known to decrease the QT interval, such as rufinamide.
Elevated liver transaminases
Elevated liver transaminases have been reported in clinical studies (see section 4.8). The elevations in
liver transaminases rarely required discontinuation of CRESEMBA. Monitoring of hepatic enzymes
should be considered, as clinically indicated.
Severe hepatic impairment
CRESEMBA has not been studied in patients with severe hepatic impairment (Child-Pugh Class C).
Use in these patients is not recommended unless the potential benefit is considered to outweigh the
risks. These patients should be carefully monitored for potential drug toxicity. See sections 4.2, 4.8
and 5.2.
Concomitant use with other medicinal products

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

CYP3A4/5 inducers
Co-administration with mild CYP3A4/5 inducers such as aprepitant, prednisone, and pioglitazone,
may result in mild to moderate decreases of isavuconazole plasma levels; co-administration with mild
CYP3A4/5 inducers should be avoided unless the potential benefit is considered to outweigh the risk
(see section 4.5).

CYP3A4/5 substrates including immunosuppressants

Isavuconazole can be considered a moderate inhibitor of CYP3A4/5, and systemic exposure to
medicinal products metabolised by CYP3A4 may be increased when co-administered with
CRESEMBA. Concomitant use of CRESEMBA with CYP3A4 substrates such as the
immunosuppressants tacrolimus, sirolimus or ciclosporin may increase the systemic exposure to these
medicinal products. Appropriate therapeutic drug monitoring and dose adjustment may be necessary
during co-administration (see section 4.5).
CYP2B6 substrates

Isavuconazole is an inducer of CYP2B6. Systemic exposure to medicinal products metabolised by
CYP2B6 may be decreased when co-administered with CRESEMBA. Therefore, caution is advised
when CYP2B6 substrates, especially medicinal products with a narrow therapeutic index such as
cyclophosphamide, are co-administered with CRESEMBA. The use of the CYP2B6 substrate
efavirenz with CRESEMBA is contraindicated because efavirenz is a moderate inducer of CYP3A4/5
(see section 4.3).

P-gp substrates

Isavuconazole may increase the exposure of medicinal products that are P-gp substrates. Dose
adjustment of medicinal products that are P-gp substrates, especially medicinal products with a narrow
therapeutic index such as digoxin, colchicine and dabigatran etexilate, may be needed when
concomitantly administered with CRESEMBA (see section 4.5).
Limitations of the clinical data
The clinical data for isavuconazole in the treatment of mucormycosis are limitedto one prospective
non-controlled clinical study in 37 patients with proven or probable mucormycosis who received
isavuconazole for primary treatment, or because other antifungal treatments (predominantly
amphotericin B) were inappropriate.
For individual Mucorales species, the clinical efficacy data are very limited, often to one or two
patients (see section 5.1). Susceptibility data were available in only a small subset of cases. These
data indicate that concentrations of isavuconazole required for inhibition in vitro are very variable
between genera/species within the order of Mucorales, and generally higher than concentrations
required to inhibit Aspergillus species. It should be noted that there was no dose-finding study in
mucormycosis, and patients were administered the same dose of isavuconazole as was used for the
treatment of invasive aspergillosis.
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 CRESEMBA 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 CRESEMBA 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 CRESEMBA 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 CRESEMBA to affect exposures of other medicines Medicinal products metabolised by CYP3A4/5 Isavuconazole is a moderate inhibitor of CYP3A4/5; co-administration of CRESEMBA 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 CRESEMBA 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 CRESEMBA 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 CRESEMBA 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
CRESEMBA 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 CRESEMBA 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 CRESEMBA.
Table 1
Co-administered medicinal
Effects on drug concentrations / Recommendation concerning
product by therapeutic area
Geometric Mean Change (%)
co-administration
in AUC, Cmax
(Mode of action)
Anticonvulsants
Carbamazepine, phenobarbital Isavuconazole concentrations may The concomitant administration of
and phenytoin
decrease (CYP3A induction by CRESEMBA and carbamazepine, (strong CYP3A4/5 inducers) carbamazepine, phenytoin and phenytoin and long-acting long-acting barbiturates such as barbiturates such as phenobarbital is phenobarbital). contraindicated. The concomitant administration (strong CYP3A4/5 inducer) of CRESEMBA and rifampicin is contraindicated. (CYP3A4/5 induction) The concomitant administration (strong CYP3A4/5 inducer) Isavuconazole concentrations may of CRESEMBA and rifabutin is significantly decrease. contraindicated. (CYP3A4/5 induction) The concomitant administration (moderate CY3A4/5 inducer) Isavuconazole concentrations may of CRESEMBA and nafcillin is significantly decrease. contraindicated. (CYP3A4/5 induction) No CRESEMBA dose (strong CYP3A4/5 inhibitor) Isavuconazole concentrations may adjustment necessary; caution is increase. advised as adverse drug reactions (CYP3A4/5 inhibition) Antifungals
Ketoconazole
The concomitant administration (strong CYP3A4/5 inhibitor) ketoconazole is contraindicated. (CYP3A4/5 inhibition) Herbal medicines
St John‟s wort
The concomitant administration (strong CYP3A4/5 inducer) Isavuconazole concentrations may of CRESEMBA and St John‟s significantly decrease. wort is contraindicated. (CYP3A4 induction). Immunosuppresants
Ciclosporin, sirolimus,
No CRESEMBA dose adjustment necessary. (CYP3A4/5 substrates) Ciclosporin, sirolimus, tacrolimus: monitoring of plasma levels and appropriate dose adjustment if required. Tacrolimus: AUC : ↑ 125% (CYP3A4 inhibition) Mycophenolate mofetil (MMF) Mycophenolic acid (MPA, active No CRESEMBA dose adjustment necessary. MMF: monitoring for MPA- related toxicities is advised. (UGT inhibition) Prednisolone (active metabolite): Co-administration should be (CYP3A4 substrate) avoided unless the potential benefit is considered to outweigh (CYP3A4 inhibition) Isavuconazole concentrations may decrease. (CYP3A4/5 induction) Opioids
Short-acting opiates
No CRESEMBA dose (alfentanyl, fentanyl) Short-acting opiate concentrations adjustment necessary. (CYP3A4/5 substrate) Short-acting opiates (alfentanyl, fentanyl): careful monitoring for (CYP3A4/5 inhibition). any occurrence of drug toxicity, and dose reduction if required. S-methadone (inactive opiate No CRESEMBA dose (CYP3A4/5, 2B6 and 2C9 adjustment necessary. Methadone: no dose adjustment 40% reduction in terminal half-life R-methadone (active opiate isomer). AUC : ↓ 10% (CYP2B6 induction) Anti-cancer
Vinca alkaloids (vincristine,
No CRESEMBA dose Vinca alkaloid concentrations may adjustment necessary. (P-gp substrates) Vinca alkaloids: careful monitoring for any occurrence of (P-gp inhibition) drug toxicity, and dose reduction if required. Cyclophosphamide No CRESEMBA dose (CYP2B6 substrate) Cyclophosphamide concentrations adjustment necessary. may decrease. Cyclophosphamide: careful monitoring for any occurrence of (CYP2B6 induction) lack of efficacy, and dose increase if required. No CRESEMBA dose (BCRP, OAT1, OAT3 adjustment necessary. Methotrexate: no dose adjustment required. 7-hydroxymetabolite: AUC : ↑ 29% (Mechanism unknown) Other anticancer agents No CRESEMBA dose (daunorubicin, doxorubicin, Daunorubicin, doxorubicin, adjustment necessary. imatinib, irinotecan, lapatinib, imatinib, irinotecan, lapatinib, Daunorubicin, doxorubicin, mitoxantrone, topotecan) mitoxantrone, topotecan imatinib, irinotecan, lapatinib, (BCRP substrates) concentrations may increase. mitoxantrone or topotecan: careful monitoring for any (BCRP inhibition) occurrence of drug toxicity, and dose reduction if required. Antiemetics
Aprepitant
Co-administration should be (mild CYP3A4/5 inducer) Isavuconazole concentrations may avoided unless the potential decrease. benefit is considered to outweigh (CYP3A4/5 induction) Antidiabetics
Metformin
No CRESEMBA dose (OCT1, OCT2 and MATE1 adjustment necessary. Metformin: dose reduction may (OCT2 inhibition) No CRESEMBA dose (CYP2C8 and OATP1B1 adjustment necessary. Repaglinide: no dose adjustment required. Anticoagulants
Dabigatran etexilate
No CRESEMBA dose (P-gp substrate) Dabigatran etexilate concentrations adjustment necessary. may increase. Dabigatran etexilate has a narrow therapeutic index and should be (P-gp inhibition). monitored, and dose reduction if required. No CRESEMBA dose (CYP2C9 substrate) adjustment necessary. Warfarin: no dose adjustment Antiretroviral agents
Lopinavir 400 mg / Ritonavir
No CRESEMBA dose adjustment necessary; caution is (CYP3A4/5 strong inhibitors advised as adverse drug reactions Lopinavir/ritonavir: no dose adjustment for lopinavir 400 mg / ritonavir 100 mg every 12 hours (Mechanism unknown) required, but careful monitoring for any occurrence of lack of anti-viral efficacy. (CYP3A4/5 inhibition) Ritonavir (at doses >200 mg The concomitant administration Ritonavir at high doses may of CRESEMBA and high doses (strong CYP3A4/5 inducer) significantly decrease of ritonavir (>200 mg every 12 isavuconazole concentrations. hours) is contraindicated. (CYP3A4/5 induction) The concomitant administration (CYP3A4/5 moderate inducer Efavirenz concentrations may of CRESEMBA and efavirenz is and CYP2B6 substrate) contraindicated. (CYP2B6 induction) Isavuconazole drug concentrations may significantly decrease. (CYP3A4/5 induction) The concomitant administration (moderate CYP3A4/5 inducer) Isavuconazole concentrations may of CRESEMBA and etravirine is significantly decrease. contraindicated. (CYP3A4/5 induction) No CRESEMBA dose (CYP3A4/5 strong inhibitor adjustment necessary; caution is advised as adverse drug reactions (Mechanism unknown) Indinavir: careful monitoring for any occurrence of lack of anti- Isavuconazole concentrations may viral efficacy, and dose increase increase. (CYP3A4/5 inhibition) No CRESEMBA dose (strong CYP3A4 inhibitor) Saquinavir concentrations may adjustment necessary; caution is decrease (as observed with advised as adverse drug reactions lopinavir/ritonavir) or increase (CYP3A4 inhibition). Saquinavir: careful monitoring for any occurrence of drug Isavuconazole concentrations may toxicity and /or lack of anti-viral efficacy, and dose adjustment if (CYP3A4/5 inhibition). Other protease inhibitors No CRESEMBA dose (e.g., amprenavir, nelfinavir) Protease inhibitor concentrations adjustment necessary. (CYP3A4/5 strong or moderate may decrease (as observed with Protease inhibitors: careful inhibitors and substrates) lopinavir/ritonavir) or increase. monitoring for any occurrence of drug toxicity and /or lack of anti- (CYP3A4 inhibition) viral efficacy, and dose adjustment if required. Isavuconazole concentrations may increase. (CYP3A4/5 inhibition). Other NNRTI (e.g., No CRESEMBA dose delavirdine, and nevaripine) NNRTI concentrations may adjustment necessary. (CYP3A4/5 and 2B6 inducers decrease (CYP2B6 induction by NNRTIs: careful monitoring for isavuconazole) or increase. any occurrence of drug toxicity and/or lack of anti-viral efficacy, (CYP3A4/5 inhibition) and dose adjustment if required. Antiacids
Esomeprazole
No CRESEMBA dose (CYP2C19 substrate and adjustment necessary. Esomeprazole: no dose adjustment required. No CRESEMBA dose (CYP2C19 substrate and adjustment necessary. Omeprazole: no dose adjustment required. Lipid-lowering agents
Atorvastatin and other statins
No CRESEMBA dose (CYP3A4 substrates e.g., adjustment necessary. simvastatin, lovastatin, Based on results with Other statins were not studied. atorvastatin, no statin dose (CYP3A4/5 and/or BCRP Statins concentrations may adjustment required. Monitoring of adverse reactions typical of statins is advised. (CYP3A4/5 or BCRP inhibition) Co-administration should be (mild CYP3A4/5 inducer) Isavuconazole concentrations may avoided unless the potential decrease. benefit is considered to outweigh (CYP3A4/5 induction) Antiarrhythmics
Digoxin
No CRESEMBA dose (P-gp substrate) adjustment necessary. Digoxin: serum digoxin concentrations should be (P-gp inhibition) monitored and used for titration of the digoxin dose. Oral contraceptives
Ethinyl oestradiol and
Ethinyl oestradiol No CRESEMBA dose adjustment necessary. (CYP3A4/5 substrates) Ethinyl oestradiol and norenthrindone: no dose adjustment required. Dextromethorphan: No CRESEMBA dose (CYP2D6 substrate) adjustment necessary. Dextromethorphan: no dose Dextrorphan (active metabolite): adjustment required. No CRESEMBA dose (CYP3A4/5 substrate) adjustment necessary. Midazolam: careful monitoring of clinical signs and symptoms (CYP3A4 inhibition) recommended, and dose reduction if required. Antigout agent
Colchicine
No CRESEMBA dose (P-gp substrate) Colchicine concentrations may adjustment necessary. Colchicine has a narrow therapeutic index and should be (P-gp inhibition) monitored, dose reduction if required. Natural products
Caffeine
No CRESEMBA dose (CYP1A2 substrate) adjustment necessary. Caffeine: no dose adjustment required. Smoking cessation aids
Bupropion
No CRESEMBA dose (CYP2B6 substrate) adjustment necessary. Bupropion: dose increase if (CYP2B6 induction) 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 frequency of adverse reactions shown in Table 2 is based on data from 403 patients with invasive
fungal infections treated with CRESEMBA in phase 3 studies.
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 CRESEMBA 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
Neutropenia; Thrombocytopenia ; Pancytopenia; Leukopenia ; Anaemia Immune system disorders
Hypersensitivity Metabolism and nutrition disorders
Hypokalaemia; Decreased appetite Hypomagnesaemia; Hypoglycaemia; Hypoalbuminaemia; Malnutrition ; Psychiatric disorders
Depression; Insomnia Nervous system disorders
Headache; Somnolence Convulsion ; Syncope; Dizziness ; Paraesthesia ; Encephalopathy; Presyncope; Neuropathy peripheral; Dysgeusia; Ear and labyrinth disorders
Cardiac disorders
Atrial fibrillation; Tachycardia; Bradycardia ; Palpitations Atrial flutter; Electrocardiogram QT shortened; Supraventricular tachycardia; Ventricular extrasystoles ; Supraventricular extrasystoles Vascular disorders
Thrombophlebitis Circulatory collapse; Hypotension Respiratory, thoracic and mediastinal disorders
Dyspnoea; Acute respiratory failure Bronchospasm; Tachypnoea; Haemoptysis; Epistaxis Gastrointestinal disorders
Vomiting; Diarrhoea; Nausea; Abdominal pain ; Dyspepsia; Constipation; Abdominal distension Hepatobiliary disorders
Elevated liver chemistry tests # Skin and subcutaneous tissue disorders
Petechiae; Alopecia; Drug eruption; Dermatitis Musculoskeletal and connective tissue disorders
Renal and urinary disorders
General disorders and administration site conditions
Chest pain ; Fatigue; Injection site reaction 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 CRESEMBA. 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 i
4.9
Overdose

Symptoms
Symptoms reported more frequently at supratherapeutic doses of CRESEMBA (equivalent to
isavuconazole 600 mg/day) evaluated in a QT study than in the therapeutic dose group (equivalent to
isavuconazole 200 mg/day dose) included: headache, dizziness, paraesthesia, somnolence, disturbance
in attention, dysgeusia, dry mouth, diarrhoea, oral hypoaesthesia, vomiting, hot flush, anxiety,
restlessness, palpitations, tachycardia, photophobia and arthralgia
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
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: 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. CRESEMBA 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 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 3 Steady state pharmacokinetic parameters of isavuconazole following oral administration
of CRESEMBA
Parameter
Isavuconazole 200 mg
Isavuconazole 600 mg
Cmax (ng/mL)
Mean
tmax (h)
Median
AUC (h•ng/mL)
Mean

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 4 Pharmacokinetic comparison for oral and intravenous dose (Mean)
ISA 400 mg oral
ISA 400 mg i.v.
AUC (h•ng/mL)
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 CRESEMBA 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.
Cresemba has not been studied in patients with severe hepatic impairment (Child-Pugh Class C). Use
in these patients is not recommended unless the potential benefit is considered to outweigh the risks.
See sections 4.2 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).
6.
PHARMACEUTICAL PARTICULARS
List of excipients

Mannitol
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

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 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 intraveneous 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.
Any unused medicinal product or waste material should be disposed of in accordance with local
requirements.
7.
MARKETING AUTHORISATION HOLDER

Basilea Medical Ltd (c/o Cox Costello & Horne Limited)
Langwood House
63–81 High Street
Rickmansworth
Hertfordshire WD3 1EQ
United Kingdom
8.
MARKETING AUTHORISATION NUMBER(S)

EU/1/15/1036/001
9.
DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
DATE OF REVISION OF THE TEXT
Detailed information on this medicinal product is available on the website of the European Medicines Agency This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions.
See section 4.8 for how to report adverse reactions.
1.
NAME OF THE MEDICINAL PRODUCT

CRESEMBA 100 mg hard capsules
2.
QUALITATIVE AND QUANTITATIVE COMPOSITION
For the full list of excipients, see section 6.1. Each capsule contains 100 mg isavuconazole (as 186.3 mg isavuconazonium sulfate). 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
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, equivalent to 372 mg isavuconazonium sulfate.
On the basis of the high oral bioavailability (98%, see section 5.2), switching between intravenous and
oral administration is appropriate when clinically indicated.
Elderly
No dose adjustment is necessary for elderly patients; however the clinical experience in elderly
patients is limited.
Renal impairment
No dose adjustment is necessary in patients with renal impairment, including patients with end-stage
renal disease (see section 5.2).

Hepatic impairment
No dose adjustment is necessary in patients with mild or moderate hepatic impairment (Child-Pugh
Classes A and B) (see sections 4.4 and 5.2).
CRESEMBA has not been studied in patients with severe hepatic impairment (Child-Pugh Class C).
Use in these patients is not recommended unless the potential benefit is considered to outweigh the
risks. See sections 4.4, 4.8 and 5.2.
Paediatric population
The safety and efficacy of CRESEMBA in children aged below 18 years has not yet been established.
No data are available.
Method of administration
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
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). 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
CRESEMBA is contraindicated in patients with familial short QT syndrome (see section 4.3).
In a QT study in healthy human subjects, isavuconazole shortened the QTc interval in a
concentration-related manner. For the 200 mg dosing regimen, the least squares mean (LSM)
difference from placebo was 13.1 ms at 2 hours post dose [90% CI: 17.1, 9.1 ms]. Increasing the dose
to 600 mg resulted in an LSM difference from placebo of 24.6 ms at 2 hours post dose [90% CI: 28.7,
20.4 ms].
Caution is warranted when prescribing CRESEMBA to patients taking other medicinal products
known to decrease the QT interval, such as rufinamide.
Elevated liver transaminases
Elevated liver transaminases have been reported in clinical studies (see section 4.8). The elevations in
liver transaminases rarely required discontinuation of CRESEMBA. Monitoring of hepatic enzymes
should be considered, as clinically indicated.
Severe hepatic impairment
CRESEMBA has not been studied in patients with severe hepatic impairment (Child-Pugh Class C).
Use in these patients is not recommended unless the potential benefit is considered to outweigh the
risks. These patients should be carefully monitored for potential drug toxicity. See sections 4.2, 4.8
and 5.2.
Concomitant use with other medicinal products

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

CYP3A4/5 inducers
Co-administration with mild CYP3A4/5 inducers such as aprepitant, prednisone, and pioglitazone,
may result in mild to moderate decreases of isavuconazole plasma levels; co-administration with mild
CYP3A4/5 inducers should be avoided unless the potential benefit is considered to outweigh the risk
(see section 4.5).

CYP3A4/5 substrates including immunosuppressants

Isavuconazole can be considered a moderate inhibitor of CYP3A4/5, and systemic exposure to
medicinal products metabolised by CYP3A4 may be increased when co-administered with
CRESEMBA. Concomitant use of CRESEMBA with CYP3A4 substrates such as the
immunosuppressants tacrolimus, sirolimus or ciclosporin may increase the systemic exposure to these
medicinal products. Appropriate therapeutic drug monitoring and dose adjustment may be necessary
during co-administration (see section 4.5).
CYP2B6 substrates

Isavuconazole is an inducer of CYP2B6. Systemic exposure to medicinal products metabolised by
CYP2B6 may be decreased when co-administered with CRESEMBA. Therefore, caution is advised
when CYP2B6 substrates, especially medicinal products with a narrow therapeutic index such as
cyclophosphamide, are co-administered with CRESEMBA. The use of the CYP2B6 substrate
efavirenz with CRESEMBA is contraindicated because efavirenz is a moderate inducer of CYP3A4/5
(see section 4.3).

P-gp substrates

Isavuconazole may increase the exposure of medicinal products that are P-gp substrates. Dose
adjustment of medicinal products that are P-gp substrates, especially medicinal products with a narrow
therapeutic index such as digoxin, colchicine and dabigatran etexilate, may be needed when
concomitantly administered with CRESEMBA (see section 4.5).
Limitations of the clinical data
The clinical data for isavuconazole in the treatment of mucormycosis are limitedto one prospective
non-controlled clinical study in 37 patients with proven or probable mucormycosis who received
isavuconazole for primary treatment, or because other antifungal treatments (predominantly
amphotericin B) were inappropriate.
For individual Mucorales species, the clinical efficacy data are very limited, often to one or two
patients (see section 5.1). Susceptibility data were available in only a small subset of cases. These
data indicate that concentrations of isavuconazole required for inhibition in vitro are very variable
between genera/species within the order of Mucorales, and generally higher than concentrations
required to inhibit Aspergillus species. It should be noted that there was no dose-finding study in
mucormycosis, and patients were administered the same dose of isavuconazole as was used for the
treatment of invasive aspergillosis.
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 CRESEMBA 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 CRESEMBA 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 CRESEMBA 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 CRESEMBA to affect exposures of other medicines Medicinal products metabolised by CYP3A4/5 Isavuconazole is a moderate inhibitor of CYP3A4/5; co-administration of CRESEMBA 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 CRESEMBA 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 CRESEMBA 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 CRESEMBA 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 CRESEMBA 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 CRESEMBA 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 CRESEMBA.
Table 1
Co-administered medicinal
Effects on drug concentrations / Recommendation concerning
product by therapeutic area
Geometric Mean Change (%)
co-administration
in AUC, Cmax
(Mode of action)
Anticonvulsants
Carbamazepine, phenobarbital Isavuconazole concentrations may The concomitant administration of
and phenytoin
decrease (CYP3A induction by CRESEMBA and carbamazepine, (strong CYP3A4/5 inducers) carbamazepine, phenytoin and phenytoin and long-acting long-acting barbiturates such as barbiturates such as phenobarbital is phenobarbital). contraindicated. The concomitant administration (strong CYP3A4/5 inducer) of CRESEMBA and rifampicin is contraindicated. (CYP3A4/5 induction) The concomitant administration (strong CYP3A4/5 inducer) Isavuconazole concentrations may of CRESEMBA and rifabutin is significantly decrease. contraindicated. (CYP3A4/5 induction) The concomitant administration (moderate CY3A4/5 inducer) Isavuconazole concentrations may of CRESEMBA and nafcillin is significantly decrease. contraindicated. (CYP3A4/5 induction) No CRESEMBA dose (strong CYP3A4/5 inhibitor) Isavuconazole concentrations may adjustment necessary; caution is increase. advised as adverse drug reactions (CYP3A4/5 inhibition) Antifungals
Ketoconazole
The concomitant administration (strong CYP3A4/5 inhibitor) ketoconazole is contraindicated. (CYP3A4/5 inhibition) Herbal medicines
St John‟s wort
The concomitant administration (strong CYP3A4/5 inducer) Isavuconazole concentrations may of CRESEMBA and St John‟s significantly decrease. wort is contraindicated. (CYP3A4 induction). Immunosuppresants
Ciclosporin, sirolimus,
No CRESEMBA dose adjustment necessary. (CYP3A4/5 substrates) Ciclosporin, sirolimus, tacrolimus: monitoring of plasma levels and appropriate dose adjustment if required. Tacrolimus: AUC : ↑ 125% (CYP3A4 inhibition) Mycophenolate mofetil (MMF) Mycophenolic acid (MPA, active No CRESEMBA dose adjustment necessary. MMF: monitoring for MPA- related toxicities is advised. (UGT inhibition) Prednisolone (active metabolite): Co-administration should be (CYP3A4 substrate) avoided unless the potential benefit is considered to outweigh (CYP3A4 inhibition) Isavuconazole concentrations may decrease. (CYP3A4/5 induction) Opioids
Short-acting opiates
No CRESEMBA dose (alfentanyl, fentanyl) Short-acting opiate concentrations adjustment necessary. (CYP3A4/5 substrate) Short-acting opiates (alfentanyl, fentanyl): careful monitoring for (CYP3A4/5 inhibition). any occurrence of drug toxicity, and dose reduction if required. S-methadone (inactive opiate No CRESEMBA dose (CYP3A4/5, 2B6 and 2C9 adjustment necessary. Methadone: no dose adjustment 40% reduction in terminal half-life R-methadone (active opiate isomer). AUC : ↓ 10% (CYP2B6 induction) Anti-cancer
Vinca alkaloids (vincristine,
No CRESEMBA dose Vinca alkaloid concentrations may adjustment necessary. (P-gp substrates) Vinca alkaloids: careful monitoring for any occurrence of (P-gp inhibition) drug toxicity, and dose reduction if required. Cyclophosphamide No CRESEMBA dose (CYP2B6 substrate) Cyclophosphamide concentrations adjustment necessary. Cyclophosphamide: careful monitoring for any occurrence of (CYP2B6 induction) lack of efficacy, and dose increase if required. No CRESEMBA dose (BCRP, OAT1, OAT3 adjustment necessary. Methotrexate: no dose adjustment required. 7-hydroxymetabolite: AUC : ↑ 29% (Mechanism unknown) Other anticancer agents No CRESEMBA dose (daunorubicin, doxorubicin, Daunorubicin, doxorubicin, adjustment necessary. imatinib, irinotecan, lapatinib, imatinib, irinotecan, lapatinib, Daunorubicin, doxorubicin, mitoxantrone, topotecan) mitoxantrone, topotecan imatinib, irinotecan, lapatinib, (BCRP substrates) concentrations may increase. mitoxantrone or topotecan: careful monitoring for any (BCRP inhibition) occurrence of drug toxicity, and dose reduction if required. Antiemetics
Aprepitant
Co-administration should be (mild CYP3A4/5 inducer) Isavuconazole concentrations may avoided unless the potential decrease. benefit is considered to outweigh (CYP3A4/5 induction) Antidiabetics
Metformin
No CRESEMBA dose (OCT1, OCT2 and MATE1 adjustment necessary. Metformin: dose reduction may (OCT2 inhibition) No CRESEMBA dose (CYP2C8 and OATP1B1 adjustment necessary. Repaglinide: no dose adjustment required. Anticoagulants
Dabigatran etexilate
No CRESEMBA dose (P-gp substrate) Dabigatran etexilate concentrations adjustment necessary. may increase. Dabigatran etexilate has a narrow therapeutic index and should be (P-gp inhibition). monitored, and dose reduction if required. No CRESEMBA dose (CYP2C9 substrate) adjustment necessary. Warfarin: no dose adjustment Antiretroviral agents
Lopinavir 400 mg / Ritonavir
No CRESEMBA dose adjustment necessary; caution is (CYP3A4/5 strong inhibitors advised as adverse drug reactions Lopinavir/ritonavir: no dose adjustment for lopinavir 400 mg / ritonavir 100 mg every 12 hours (Mechanism unknown) required, but careful monitoring for any occurrence of lack of anti-viral efficacy. (CYP3A4/5 inhibition) Ritonavir (at doses >200 mg The concomitant administration Ritonavir at high doses may of CRESEMBA and high doses (strong CYP3A4/5 inducer) significantly decrease of ritonavir (>200 mg every 12 isavuconazole concentrations. hours) is contraindicated. (CYP3A4/5 induction) The concomitant administration (CYP3A4/5 moderate inducer Efavirenz concentrations may of CRESEMBA and efavirenz is and CYP2B6 substrate) contraindicated. (CYP2B6 induction) Isavuconazole drug concentrations may significantly decrease. (CYP3A4/5 induction) The concomitant administration (moderate CYP3A4/5 inducer) Isavuconazole concentrations may of CRESEMBA and etravirine is significantly decrease. contraindicated. (CYP3A4/5 induction) No CRESEMBA dose (CYP3A4/5 strong inhibitor adjustment necessary; caution is advised as adverse drug reactions (Mechanism unknown) Indinavir: careful monitoring for any occurrence of lack of anti- Isavuconazole concentrations may viral efficacy, and dose increase increase. (CYP3A4/5 inhibition) No CRESEMBA dose (strong CYP3A4 inhibitor) Saquinavir concentrations may adjustment necessary; caution is decrease (as observed with advised as adverse drug reactions lopinavir/ritonavir) or increase (CYP3A4 inhibition). Saquinavir: careful monitoring for any occurrence of drug Isavuconazole concentrations may toxicity and /or lack of anti-viral increase. efficacy, and dose adjustment if (CYP3A4/5 inhibition). Other protease inhibitors No CRESEMBA dose (e.g., amprenavir, nelfinavir) Protease inhibitor concentrations adjustment necessary. (CYP3A4/5 strong or moderate may decrease (as observed with Protease inhibitors: careful inhibitors and substrates) lopinavir/ritonavir) or increase. monitoring for any occurrence of drug toxicity and /or lack of anti- (CYP3A4 inhibition) viral efficacy, and dose adjustment if required. Isavuconazole concentrations may increase. (CYP3A4/5 inhibition). Other NNRTI (e.g., No CRESEMBA dose delavirdine, and nevaripine) NNRTI concentrations may adjustment necessary. (CYP3A4/5 and 2B6 inducers decrease (CYP2B6 induction by NNRTIs: careful monitoring for isavuconazole) or increase. any occurrence of drug toxicity and/or lack of anti-viral efficacy, (CYP3A4/5 inhibition) and dose adjustment if required. Antiacids
Esomeprazole
No CRESEMBA dose (CYP2C19 substrate and adjustment necessary. Esomeprazole: no dose adjustment required. No CRESEMBA dose (CYP2C19 substrate and adjustment necessary. Omeprazole: no dose adjustment required. Lipid-lowering agents
Atorvastatin and other statins
No CRESEMBA dose (CYP3A4 substrates e.g., adjustment necessary. simvastatin, lovastatin, Based on results with Other statins were not studied. atorvastatin, no statin dose (CYP3A4/5 and/or BCRP Statins concentrations may adjustment required. Monitoring of adverse reactions typical of statins is advised. (CYP3A4/5 or BCRP inhibition) Co-administration should be (mild CYP3A4/5 inducer) Isavuconazole concentrations may avoided unless the potential decrease. benefit is considered to outweigh (CYP3A4/5 induction) Antiarrhythmics
Digoxin
No CRESEMBA dose (P-gp substrate) adjustment necessary. Digoxin: serum digoxin concentrations should be (P-gp inhibition) monitored and used for titration of the digoxin dose. Oral contraceptives
Ethinyl oestradiol and
Ethinyl oestradiol No CRESEMBA dose adjustment necessary. (CYP3A4/5 substrates) Ethinyl oestradiol and norenthrindone: no dose adjustment required. Dextromethorphan: No CRESEMBA dose (CYP2D6 substrate) adjustment necessary. Dextromethorphan: no dose Dextrorphan (active metabolite): adjustment required. No CRESEMBA dose (CYP3A4/5 substrate) adjustment necessary. Midazolam: careful monitoring of clinical signs and symptoms (CYP3A4 inhibition) recommended, and dose reduction if required. Antigout agent
Colchicine
No CRESEMBA dose (P-gp substrate) Colchicine concentrations may adjustment necessary. Colchicine has a narrow therapeutic index and should be (P-gp inhibition) monitored, dose reduction if required. Natural products
Caffeine
No CRESEMBA dose (CYP1A2 substrate) adjustment necessary. Caffeine: no dose adjustment required. Smoking cessation aids
Bupropion
No CRESEMBA dose (CYP2B6 substrate) adjustment necessary. Bupropion: dose increase if (CYP2B6 induction) 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 frequency of adverse reactions shown in Table 2 is based on data from 403 patients with invasive
fungal infections treated with CRESEMBA in phase 3 studies.
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 CRESEMBA 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
Neutropenia; Thrombocytopenia ; Pancytopenia; Leukopenia ; Anaemia Immune system disorders
Hypersensitivity Metabolism and nutrition disorders
Hypokalaemia; Decreased appetite Hypomagnesaemia; Hypoglycaemia; Hypoalbuminaemia; Malnutrition ; Psychiatric disorders
Depression; Insomnia Nervous system disorders
Headache; Somnolence Convulsion ; Syncope; Dizziness ; Paraesthesia ; Encephalopathy; Presyncope; Neuropathy peripheral; Dysgeusia; Ear and labyrinth disorders
Cardiac disorders
Atrial fibrillation; Tachycardia; Bradycardia ; Palpitations Atrial flutter; Electrocardiogram QT shortened; Supraventricular tachycardia; Ventricular extrasystoles ; Supraventricular extrasystoles Vascular disorders
Thrombophlebitis Circulatory collapse; Hypotension Respiratory, thoracic and mediastinal disorders
Dyspnoea; Acute respiratory failure Bronchospasm; Tachypnoea; Haemoptysis; Epistaxis Gastrointestinal disorders
Vomiting; Diarrhoea; Nausea; Abdominal pain ; Dyspepsia; Constipation; Abdominal distension Hepatobiliary disorders
Elevated liver chemistry tests # Skin and subcutaneous tissue disorders
Petechiae; Alopecia; Drug eruption; Dermatitis Musculoskeletal and connective tissue disorders
Renal and urinary disorders
General disorders and administration site conditions
Chest pain ; Fatigue 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 CRESEMBA. 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 i
4.9
Overdose

Symptoms
Symptoms reported more frequently at supratherapeutic doses of CRESEMBA (equivalent to
isavuconazole 600 mg/day) evaluated in a QT study than in the therapeutic dose group (equivalent to
isavuconazole 200 mg/day dose) included: headache, dizziness, paraesthesia, somnolence, disturbance
in attention, dysgeusia, dry mouth, diarrhoea, oral hypoaesthesia, vomiting, hot flush, anxiety,
restlessness, palpitations, tachycardia, photophobia and arthralgia
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
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: 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. CRESEMBA 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 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 3 Steady state pharmacokinetic parameters of isavuconazole following oral administration
of CRESEMBA
Parameter
Isavuconazole 200 mg
Isavuconazole 600 mg
Cmax (ng/mL)
Mean
tmax (h)
Median
AUC (h•ng/mL)
Mean

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 4 Pharmacokinetic comparison for oral and intravenous dose (Mean)
ISA 400 mg oral
ISA 400 mg i.v.
AUC (h•ng/mL)
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 CRESEMBA 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.
Cresemba has not been studied in patients with severe hepatic impairment (Child-Pugh Class C). Use
in these patients is not recommended unless the potential benefit is considered to outweigh the risks.
See sections 4.2 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).
6.
PHARMACEUTICAL PARTICULARS
List of excipients
Capsule contents magnesium citrate (anhydrous) microcrystalline cellulose talc silica, colloidal anhydrous 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)
6.2

Not applicable.
6.3
Shelf life

30 months
6.4
Special precautions for storage

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

Any unused medicinal product or waste material should be disposed of in accordance with local
requirements.
7.
MARKETING AUTHORISATION HOLDER

Basilea Medical Ltd (c/o Cox Costello & Horne Limited)
Langwood House
63–81 High Street
Rickmansworth
Hertfordshire WD3 1EQ
United Kingdom
8.
MARKETING AUTHORISATION NUMBER(S)

EU/1/15/1036/002
9.
DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION


10.
DATE OF REVISION OF THE TEXT
Detailed information on this medicinal product is available on the website of the European Medicines
Agency



A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE

Name and address of the manufacturer(s) responsible for batch release
Almac Pharma Services Limited
Seagoe Industrial Estate
Craigavon
Co Armagh
BT63 5UA
United Kingdom
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE

Medicinal product subject to medical prescription.
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING
 Periodic safety update reports
The requirements for submission of periodic safety update reports 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.
The marketing authorisation holder shall submit the first periodic safety update report for this
product within 6 months following authorisation.
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
 Risk Management Plan (RMP)
The 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. ANNEX III
LABELLING AND PACKAGE LEAFLET
A. LABELLING

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
EXPIRY DATE
SPECIAL STORAGE CONDITIONS
Store in a refrigerator 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 Medical Ltd.
(c/o Cox Costello & Horne Limited)
Langwood House
63-81 High Street
Rickmansworth
Hertfordshire WD3 1EQ
United Kingdom
12.
MARKETING AUTHORISATION NUMBER(S)

EU/1/15/1036/001
13.
BATCH NUMBER

Lot
14.
GENERAL CLASSIFICATION FOR SUPPLY
INSTRUCTIONS ON USE
INFORMATION IN BRAILLE
Justification for not including Braille accepted. 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

See leaflet
3.
EXPIRY DATE
BATCH NUMBER
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
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
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
EXPIRY DATE
SPECIAL STORAGE CONDITIONS

Store in the original package in order to protect from moisture.
10.
SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE

NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Basilea Medical Ltd.
(c/o Cox Costello & Horne Limited)
Langwood House
63-81 High Street
Rickmansworth
Hertfordshire WD3 1EQ
United Kingdom
12.
MARKETING AUTHORISATION NUMBER(S)

EU/1/15/1036/002
13.
BATCH NUMBER

Lot


14.
GENERAL CLASSIFICATION FOR SUPPLY
INSTRUCTIONS ON USE
INFORMATION IN BRAILLE
CRESEMBA 100 mg hard capsules 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 Medical Ltd.
3.
EXPIRY DATE
BATCH NUMBER
Do not swallow the desiccant B. PACKAGE LEAFLET
Package leaflet: Information for the patient
Cresemba 200 mg powder for concentrate for solution for infusion
This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. See the end of section 4
for how to report side effects.
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 What you need to know before you use Cresemba How to use Cresemba Possible side effects How to store Cresemba Contents of the pack and other information 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. 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 (400 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:
-
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 (400 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 for after having a transplant, called „immuno-suppressants‟, 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, amprenavir, nelfinavir, indinavir, delavirdine, 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. If this happens,
do not drive or use 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 three times a day (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
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), 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, 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, wheezing, very fast breathing, coughing up blood or blood-stained sputum, nose bleeding, feeling bloated (abdominal distension), problems with the skin, red or purple spots on the skin (petechiae), inflamed skin (dermatitis), hair loss, 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 iy 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 Medical Ltd
(c/o Cox Costello & Horne Limited)
Langwood House
63–81 High Street
Rickmansworth
Hertfordshire WD3 1EQ
United Kingdom
Manufacturer:

Almac Pharma Services Limited
Seagoe Industrial Estate,
Craigavon, County Armagh
BT63 5UA
United Kingdom
This leaflet was last revised in
Other sources of information

Detailed information on this medicine is available on the European Medicines Agency web site:
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
intraveneous 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. Package leaflet: Information for the patient
Cresemba 100 mg hard capsules
This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. See the end of section 4
for how to report side effects.
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 What you need to know before you take Cresemba How to take Cresemba Possible side effects How to store Cresemba Contents of the pack and other information 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. 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 (400 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 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 (400 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 for after having a transplant, called „immuno-suppressants‟, 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, amprenavir, nelfinavir, indinavir, delavirdine, 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. If this happens,
do not drive or use 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 three times a day (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
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), 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, 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, feeling bloated (abdominal distension), problems with the skin, red or purple spots on the skin (petechiae), inflamed skin (dermatitis), hair loss, 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 iy 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.
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.
Do not swallow or use the desiccant.
Marketing Authorisation Holder:

Basilea Medical Ltd
(c/o Cox Costello & Horne Limited)
Langwood House
63–81 High Street
Rickmansworth
Hertfordshire WD3 1EQ
United Kingdom
Manufacturer:

Almac Pharma Services Limited
Seagoe Industrial Estate,
Craigavon, County Armagh
BT63 5UA
United Kingdom
This leaflet was last revised in
Other sources of information

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

Source: http://www.cresemba.co.uk/pdf/CRESEMBA_SmPC.pdf