CRESEMBA 100mg capsules medication leaflet

CRESEMBA 40 mg hard capsules

CRESEMBA 100 mg hard capsules

Each CRESEMBA 40 mg hard capsule contains 40 mg isavuconazole (as 74.5 mg isavuconazoniumsulfate).

Each CRESEMBA 100 mg hard capsule contains 100 mg isavuconazole (as 186.3 mgisavuconazonium sulfate).

For the full list of excipients, see section 6.1.

CRESEMBA 40 mg hard capsule: Swedish Orange (reddish-brown) capsules marked with ”CR40” onthe capsule cap in black ink. Capsules length: 15.9 mm.

CRESEMBA 100 mg 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.

CRESEMBA hard capsules are indicated in adults and in paediatric patients from 6 years of age forthe 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.

CRESEMBA 40 mg hard capsules are intended to be used for paediatric patients.

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

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

Table 1 Recommended dosage for CRESEMBA in adult patients

Loading dose Maintenance dose(three times daily)1 (once daily)2every 8 hours during Days 1 total daily dose during Days 1and 2 and 2

Two 100 mg capsules Six 100 mg capsules Two 100 mg capsules1 Six administrations in total.2 Starting 12 to 24 hours after the last loading dose.

Table 2 Recommended Dosage for CRESEMBA in paediatric patients aged from 6 years to lessthan 18 years

Bodyweight Loading dose Maintenance dose(kg) (three times daily)1 (once daily)2every 8 hours during total daily dose during

Days 1 and 2 Days 1 and 216 kg to < 18 kg Two 40 mg capsules Six 40 mg capsules Two 40 mg capsules18 kg to < 25 kg Three 40 mg capsules Nine 40 mg capsules Three 40 mg capsules25 kg to < 32 kg Four 40 mg capsules Twelve 40 mg capsules Four 40 mg capsules32 kg to < 37 kg One 100 mg capsule Three 100 mg capsules One 100 mg capsuleand and andtwo 40 mg capsules six 40 mg capsules two 40 mg capsules≥ 37 kg Five 40 mg capsules Fifteen 40 mg capsules Five 40 mg capsulesor or ortwo 100 mg capsules six 100 mg capsules two 100 mg capsules1 Six administrations in total.2 Starting 12 to 24 hours after the last loading dose.

The maximum of any individual loading or daily maintenance dose to be administered to any patient is200 mg isavuconazole.

All capsules per dose must be taken at the same time.

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 (seesections 5.1 and 5.3).

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

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

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

No dose adjustment is necessary in adult patients with mild or moderate hepatic impairment (Child-

Pugh Classes A and B) (see sections 4.4 and 5.2).

Isavuconazole has not been studied in adult patients with severe hepatic impairment (Child-Pugh Class

C). Use in these patients is not recommended unless the potential benefit is considered to outweigh therisks (see sections 4.4, pct. 4.8 and 5.2).

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

Paediatric patients from one year to below 6 years of age, or with a bodyweight less than 16 kg, or arenot able to swallow CRESEMBA hard capsules may receive CRESEMBA as intravenous infusion.

The use of CRESEMBA 100 mg capsules has not been studied in paediatric patients (see section 4.4).

The safety and efficacy of CRESEMBA in paediatric patients aged less than 1 year has not beenestablished.

Switch to intravenous infusion

CRESEMBA is also available as powder for concentrate for solution for infusion containing 200 mgisavuconazole.

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

CRESEMBA capsules can be taken with or without food.

CRESEMBA capsules should be swallowed whole. Do not chew, crush, dissolve or open the capsules.

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 CYP3A4/5inducers such as efavirenz, nafcillin and etravirine (see section 4.5).

Patients with familial short QT syndrome (see section 4.4).

Hypersensitivity to isavuconazole may result in adverse reactions that include: anaphylactic reaction,hypotension, respiratory failure, dyspnoea, drug eruption, pruritus, and rash (see section 4.8). In caseof anaphylactic reaction, isavuconazole should be discontinued immediately and appropriate medicaltreatment should be initiated.

Caution should be used in prescribing isavuconazole to patients with hypersensitivity to other azoleantifungal agents.

Severe cutaneous adverse reactions, such as Stevens-Johnson syndrome, have been reported duringtreatment with azole antifungal agents. If a patient develops a severe cutaneous adverse reaction,

CRESEMBA should be discontinued.

QT shortening

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

In a QT study in healthy human subjects, isavuconazole shortened the QTc interval in aconcentration-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 doseto 600 mg resulted in an LSM difference from placebo of 24.6 ms at 2 hours post dose [90% CI: 28.7,20.4 ms].

Caution is warranted when prescribing isavuconazole to patients taking other medicinal productsknown to decrease the QT interval, such as rufinamide.

Elevated liver transaminases or hepatitis

Elevated liver transaminases have been reported in clinical studies (see section 4.8). The elevations inliver transaminases rarely required discontinuation of isavuconazole. Monitoring of hepatic enzymesshould be considered, as clinically indicated. Hepatitis has been reported with azole antifungal agentsincluding isavuconazole.

Isavuconazole has not been studied in patients with severe hepatic impairment (Child-Pugh Class C).

Use in these patients is not recommended unless the potential benefit is considered to outweigh therisks. These patients should be carefully monitored for potential drug toxicity (see sections 4.2, pct. 4.8and 5.2).

Isavuconazole has not been studied in paediatric patients with renal or hepatic impairment.

Paediatric patients from 6 years to less than 18 years of age and with a bodyweight at least 32 kg mayreceive CRESEMBA 100 mg capsules. However, the use of CRESEMBA 100 mg capsules has notbeen studied in paediatric patients.

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, aless pronounced effect can be expected. No dose adjustment of isavuconazole is necessary when co-administered with strong CYP3A4/5 inhibitors, however caution is advised as adverse drug reactionsmay 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 tomedicinal products metabolised by CYP3A4 may be increased when co-administered withisavuconazole. Concomitant use of isavuconazole with CYP3A4 substrates such as theimmunosuppressants tacrolimus, sirolimus or ciclosporin may increase the systemic exposure to thesemedicinal products. Appropriate therapeutic drug monitoring and dose adjustment may be necessaryduring co-administration (see section 4.5).

Isavuconazole is an inducer of CYP2B6. Systemic exposure to medicinal products metabolised by

CYP2B6 may be decreased when co-administered with isavuconazole. Therefore, caution is advisedwhen CYP2B6 substrates, especially medicinal products with a narrow therapeutic index such ascyclophosphamide, are co-administered with isavuconazole. The use of the CYP2B6 substrateefavirenz with isavuconazole is contraindicated because efavirenz is a moderate inducer of CYP3A4/5(see section 4.3).

Isavuconazole may increase the exposure of medicinal products that are P-gp substrates. Doseadjustment of medicinal products that are P-gp substrates, especially medicinal products with a narrowtherapeutic index such as digoxin, colchicine and dabigatran etexilate, may be needed whenconcomitantly administered with isavuconazole (see section 4.5).

Limitations of the clinical data

The clinical data for isavuconazole in the treatment of mucormycosis are limited to one prospectivenon-controlled clinical study in 37 adult patients with proven or probable mucormycosis who receivedisavuconazole for primary treatment, or because other antifungal treatments (predominantlyamphotericin B) were inappropriate.

For individual Mucorales species, the clinical efficacy data are very limited, often to one or twopatients (see section 5.1). Susceptibility data were available in only a small subset of cases. These dataindicate that concentrations of isavuconazole required for inhibition in vitro are very variable betweengenera/species within the order of Mucorales, and generally higher than concentrations required toinhibit 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 ofinvasive aspergillosis.

Potential of medicinal products to affect the pharmacokinetics of isavuconazole

Isavuconazole is a substrate of CYP3A4 and CYP3A5 (see section 5.2). Co-administration ofmedicinal products which are inhibitors of CYP3A4 and/or CYP3A5 may increase the plasmaconcentrations of isavuconazole. Co-administration of medicinal products which are inducers of

CYP3A4 and/or CYP3A5 may decrease the plasma concentrations of isavuconazole.

Medicinal products that inhibit CYP3A4/5

Co-administration of isavuconazole with the strong CYP3A4/5 inhibitor ketoconazole iscontraindicated, since this medicinal product can significantly increase plasma concentrations ofisavuconazole (see sections 4.3 and 4.5).

For the strong CYP3A4 inhibitor lopinavir/ritonavir, a two-fold increase in isavuconazole exposurewas observed. For other strong CYP3A4 inhibitors, such as clarithromycin, indinavir and saquinavir, aless pronounced effect can be expected, based on their relative potency. No dose adjustment ofisavuconazole is necessary when co-administered with strong CYP3A4/5 inhibitors, however cautionis advised as adverse drug reactions may increase (see section 4.4).

No dose adjustment is warranted for moderate to mild CYP3A4/5 inhibitors.

Medicinal products that induce CYP3A4/5

Co-administration of isavuconazole with potent CYP3A4/5 inducers such as rifampicin, rifabutin,carbamazepine, long-acting barbiturates (e.g., phenobarbital), phenytoin and St. John’s wort, or withmoderate CYP3A4/5 inducers such as efavirenz, nafcillin and etravirine, is contraindicated, sincethese medicinal products can significantly decrease plasma concentrations of isavuconazole (seesection 4.3).

Co-administration with mild CYP3A4/5 inducers such as aprepitant, prednisone and pioglitazone, mayresult 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 dosesritonavir may induce CYP3A4/5 and decrease isavuconazole plasma concentrations (see section 4.3).

Potential for isavuconazole to affect exposures of other medicines

Medicinal products metabolised by CYP3A4/5

Isavuconazole is a moderate inhibitor of CYP3A4/5; co-administration of isavuconazole withmedicinal products which are substrates of CYP3A4/5 may result in increased plasma concentrationsof these medicinal products.

Medicinal products metabolised by CYP2B6

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

Medicinal products transported by P-gp in the intestine

Isavuconazole is a mild inhibitor of P-glycoprotein (P-gp); co-administration with isavuconazole mayresult 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 maytherefore be increased. Caution is advised when isavuconazole is given concomitantly with substratesof BCRP.

Medicinal products renally excreted via transport proteins

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

Uridine diphosphate-glucuronosyltransferases (UGT) substrates

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

Interactions between isavuconazole and co-administered medicinal products are listed in Table 3(increase is indicated as “↑”, decrease as “↓”), ordered by therapeutic class. Unless otherwise stated,studies detailed in Table 3 have been performed with the recommended dose of isavuconazole.

Table 3 Interactions

Co-administered medicinal Effects on drug concentrations/Recommendation concerningproduct by therapeutic area Geometric Mean Change (%) co-administrationin AUC, Cmax(Mode of action)

Anticonvulsants

Carbamazepine, phenobarbital Isavuconazole concentrations may The concomitant administration ofand phenytoin decrease (CYP3A induction by isavuconazole and(strong CYP3A4/5 inducers) carbamazepine, phenytoin and carbamazepine, phenytoin and long-long-acting barbiturates such as acting barbiturates such asphenobarbital). phenobarbital is contraindicated.

Antibacterials

Rifampicin Isavuconazole: The concomitant administration(strong CYP3A4/5 inducer) AUCtau: ↓ 90% of isavuconazole and rifampicin

Cmax: ↓ 75% is contraindicated.

(CYP3A4/5 induction)

Rifabutin Not studied. The concomitant administration(strong CYP3A4/5 inducer) Isavuconazole concentrations may of isavuconazole and rifabutinsignificantly decrease. is contraindicated.

(CYP3A4/5 induction)

Nafcillin Not studied. The concomitant administration(moderate CY3A4/5 inducer) Isavuconazole concentrations may of isavuconazole and nafcillin issignificantly decrease. contraindicated.

(CYP3A4/5 induction)

Clarithromycin Not studied. No isavuconazole dose(strong CYP3A4/5 inhibitor) Isavuconazole concentrations may adjustment necessary; caution isincrease. advised as adverse drug reactionsmay increase.

(CYP3A4/5 inhibition)

Antifungals

Ketoconazole Isavuconazole: The concomitant administration(strong CYP3A4/5 inhibitor) AUCtau: ↑ 422% of isavuconazole and

Cmax: ↑ 9% ketoconazole is contraindicated.

(CYP3A4/5 inhibition)

Herbal medicines

St John’s wort Not studied. The concomitant administration(strong CYP3A4/5 inducer) Isavuconazole concentrations may of isavuconazole and St John’ssignificantly decrease. wort is contraindicated.

(CYP3A4 induction).

Immunosuppresants

Ciclosporin, sirolimus, Ciclosporin: No isavuconazole dosetacrolimus AUCinf: ↑ 29% adjustment necessary.(CYP3A4/5 substrates) Cmax: ↑ 6% Ciclosporin, sirolimus,tacrolimus: monitoring of plasma

Sirolimus: levels and appropriate dose

AUCinf: ↑ 84% adjustment if required.

Cmax: ↑ 65%

AUCinf: ↑ 125%

Cmax: ↑ 42%(CYP3A4 inhibition)

Mycophenolate mofetil (MMF) Mycophenolic acid (MPA, active No isavuconazole dose(UGT substrate) metabolite): adjustment necessary.

AUCinf: ↑ 35% MMF: monitoring for MPA-

Cmax: ↓ 11% related toxicities is advised.

(UGT inhibition)

Prednisone Prednisolone (active metabolite): Co-administration should be(CYP3A4 substrate) AUCinf: ↑ 8% avoided unless the potential

Cmax: ↓ 4% benefit is considered to outweighthe risk.

(CYP3A4 inhibition)

Isavuconazole concentrations maydecrease.

(CYP3A4/5 induction)

Opioids

Short-acting opiates Not studied. No isavuconazole dose(alfentanyl, fentanyl) Short-acting opiate concentrations adjustment necessary.(CYP3A4/5 substrate) may increase. Short-acting opiates (alfentanyl,fentanyl): careful monitoring for(CYP3A4/5 inhibition). any occurrence of drug toxicity,and dose reduction if required.

Methadone S-methadone (inactive opiate No isavuconazole dose(CYP3A4/5, 2B6 and 2C9 isomer) adjustment necessary.substrate) AUCinf: ↓ 35% Methadone: no dose adjustment

Cmax: ↑ 1% required.40% reduction in terminal half-life

R-methadone (active opiateisomer).

AUCinf: ↓ 10%

Cmax: ↑ 4%(CYP2B6 induction)

Anti-cancer

Vinca alkaloids (vincristine, Not studied. No isavuconazole dosevinblastine) Vinca alkaloid concentrations may adjustment necessary.(P-gp substrates) increase. Vinca alkaloids: carefulmonitoring for any occurrence of(P-gp inhibition) drug toxicity, and dose reductionif required.

Cyclophosphamide Not studied. No isavuconazole dose(CYP2B6, CYP3A4 substrate) Active metabolites of adjustment necessary.

cyclophosphamide concentrations Cyclophosphamide: carefulmay increase or decrease. monitoring for any occurrence oflack of efficacy or increased(CYP2B6 induction, CYP3A4 toxicity, and dose adjustment ifinhibition) required.

Methotrexate Methotrexate: No isavuconazole dose(BCRP, OAT1, OAT3 AUCinf: ↓ 3% adjustment necessary.substrate) Cmax: ↓ 11%

Methotrexate: no dose7-hydroxymetabolite: adjustment required.

AUCinf: ↑ 29%

Cmax: ↑ 15%(Mechanism unknown)

Other anticancer agents Not studied. No isavuconazole 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, anddose reduction if required.

Antiemetics

Aprepitant Not studied. Co-administration should be(mild CYP3A4/5 inducer) Isavuconazole concentrations may avoided unless the potentialdecrease. benefit is considered to outweighthe risk.

(CYP3A4/5 induction)

Antidiabetics

Metformin Metformin: No isavuconazole dose(OCT1, OCT2 and MATE1 AUCinf: ↑ 52% adjustment necessary.substrate) Cmax: ↑ 23% Metformin: dose reduction maybe required.(OCT2 inhibition)

Repaglinide Repaglinide: No isavuconazole dose(CYP2C8 and OATP1B1 AUCinf: ↓ 8% adjustment necessary.substrate) Cmax: ↓ 14% Repaglinide: no dose adjustmentrequired.

Pioglitazone Not studied. Co-administration should be(mild CYP3A4/5 inducer) Isavuconazole concentrations may avoided unless the potentialdecrease. benefit is considered to outweighthe risk.

(CYP3A4/5 induction)

Anticoagulants

Dabigatran etexilate Not studied. No isavuconazole dose(P-gp substrate) Dabigatran etexilate concentrations adjustment necessary.

may increase. Dabigatran etexilate has a narrowtherapeutic index and should be(P-gp inhibition). monitored, and dose reduction ifrequired.

Warfarin S-warfarin No isavuconazole dose(CYP2C9 substrate) AUCinf: ↑ 11% adjustment necessary.

Cmax: ↓ 12% Warfarin: no dose adjustment

R-warfarin required.

AUCinf: ↑ 20%

Cmax: ↓ 7%

Antiretroviral agents

Lopinavir 400 mg/Ritonavir Lopinavir: No isavuconazole dose100 mg AUCtau: ↓ 27% adjustment necessary; caution is(CYP3A4/5 strong inhibitors Cmax: ↓ 23% advised as adverse drug reactionsand substrates) Cmin, ss: ↓ 16%a) may increase.

AUCtau: ↓ 31% Lopinavir/ritonavir: no dose

Cmax: ↓ 33% adjustment for lopinavir 400 mg /ritonavir 100 mg every 12 hours(Mechanism unknown) required, but careful monitoringfor any occurrence of lack of

Isavuconazole: anti-viral efficacy.

AUCtau: ↑ 96%

Cmax: ↑ 74%(CYP3A4/5 inhibition)

Ritonavir (at doses >200 mg Not studied. The concomitant administrationevery 12 hours) Ritonavir at high doses may of isavuconazole and high doses(strong CYP3A4/5 inducer) significantly decrease of ritonavir (>200 mg every 12isavuconazole concentrations. hours) is contraindicated.

(CYP3A4/5 induction)

Efavirenz Not studied. The concomitant administration(CYP3A4/5 moderate inducer Efavirenz concentrations may of isavuconazole and efavirenz isand CYP2B6 substrate) decrease. contraindicated.

(CYP2B6 induction)

Isavuconazole drug concentrationsmay significantly decrease.

(CYP3A4/5 induction)

Etravirine Not studied. The concomitant administration(moderate CYP3A4/5 inducer) Isavuconazole concentrations may of isavuconazole and etravirinesignificantly decrease. is contraindicated.

(CYP3A4/5 induction)

Indinavir Indinavir:b) No isavuconazole dose(CYP3A4/5 strong inhibitor AUCinf: ↓ 36% adjustment necessary; caution isand substrate) Cmax: ↓ 52% advised as adverse drug reactionsmay increase.(Mechanism unknown) Indinavir: careful monitoring forany occurrence of lack of anti-

Isavuconazole concentrations may viral efficacy, and dose increaseincrease. if required.

(CYP3A4/5 inhibition)

Saquinavir Not studied. No isavuconazole dose(strong CYP3A4 inhibitor) Saquinavir concentrations may adjustment necessary; caution isdecrease (as observed with advised as adverse drug reactionslopinavir/ritonavir) or increase. may increase.

Saquinavir: careful monitoring(CYP3A4 inhibition) for any occurrence of drugtoxicity and /or lack of anti-viral

Isavuconazole concentrations may efficacy, and dose adjustment ifincrease. required(CYP3A4/5 inhibition)

Other protease inhibitors (e.g. Not studied. No isavuconazole dosefosamprenavir) Protease inhibitor concentrations adjustment necessary.(CYP3A4/5 strong or moderate may decrease (as observed with Protease inhibitors: carefulinhibitors and substrates) lopinavir/ritonavir) or increase. monitoring for any occurrence ofdrug toxicity and /or lack of anti-(CYP3A4 inhibition) viral efficacy, and doseadjustment if required.

Isavuconazole concentrations mayincrease.

(CYP3A4/5 inhibition)

Other NNRTI (e.g. nevirapine) Not studied. No isavuconazole dose(CYP3A4/5 and 2B6 inducers NNRTI concentrations may adjustment necessary.and substrates) decrease (CYP2B6 induction by NNRTIs: careful monitoring forisavuconazole) or increase. any occurrence of drug toxicityand/or lack of anti-viral efficacy,(CYP3A4/5 inhibition) and dose adjustment if required.

Antiacids

Esomeprazole Isavuconazole: No isavuconazole dose(CYP2C19 substrate and AUCtau: ↑ 8% adjustment necessary.gastric pH ) Cmax: ↑ 5% Esomeprazole: no doseadjustment required.

Omeprazole Omeprazole: No isavuconazole dose(CYP2C19 substrate and AUCinf: ↓ 11% adjustment necessary.gastric pH ) Cmax: ↓ 23% Omeprazole: no dose adjustmentrequired.

Lipid-lowering agents

Atorvastatin and other statins Atorvastatin : No isavuconazole dose(CYP3A4 substrates e.g., AUCinf: ↑ 37% adjustment necessary.simvastatin, lovastatin, Cmax: ↑ 3% Based on results withrosuvastatin) Other statins were not studied. atorvastatin, no statin dose(CYP3A4/5 and/or BCRP Statins concentrations may adjustment required. Monitoringsubstrates)) increase. of adverse reactions typical ofstatins is advised.(CYP3A4/5 or BCRP inhibition)

Antiarrhythmics

Digoxin Digoxin: No isavuconazole dose(P-gp substrate) AUCinf: ↑ 25% adjustment necessary.

Cmax: ↑ 33% Digoxin: serum digoxinconcentrations should be(P-gp inhibition) monitored and used for titrationof the digoxin dose.

Ethinyl oestradiol and Ethinyl oestradiol No isavuconazole dosenorethindrone AUCinf: ↑ 8% adjustment necessary.(CYP3A4/5 substrates) Cmax: ↑ 14% Ethinyl oestradiol and

Norethindrone norethindrone: no dose

AUCinf: ↑ 16% adjustment required.

Cmax: ↑ 6%

Antitussives

Dextromethorphan Dextromethorphan: No isavuconazole dose(CYP2D6 substrate) AUCinf: ↑ 18% adjustment necessary.

Cmax: ↑ 17% Dextromethorphan: no dose

Dextrorphan (active metabolite): adjustment required.

AUCinf: ↑ 4%

Cmax: ↓ 2%

Benzodiazepines

Midazolam Oral midazolam: No isavuconazole dose(CYP3A4/5 substrate) AUCinf: ↑ 103% adjustment necessary.

Cmax: ↑ 72% Midazolam: careful monitoringof clinical signs and symptoms(CYP3A4 inhibition) recommended, and dosereduction if required.

Antigout agent

Colchicine Not studied. No isavuconazole dose(P-gp substrate) Colchicine concentrations may adjustment necessary.

increase. Colchicine has a narrowtherapeutic index and should be(P-gp inhibition) monitored, dose reduction ifrequired.

Natural products

Caffeine Caffeine: No isavuconazole dose(CYP1A2 substrate) AUCinf: ↑ 4% adjustment necessary.

Cmax: ↓ 1% Caffeine: no dose adjustmentrequired.

Smoking cessation aids

Bupropion Bupropion: No isavuconazole dose(CYP2B6 substrate) AUCinf: ↓ 42% adjustment necessary.

Cmax: ↓ 31% Bupropion: dose increase ifrequired.

(CYP2B6 induction)

NNRTI, non-nucleoside reverse-transcriptase inhibitor; P-gp, P-glycoprotein.a) % decrease of the mean trough level valuesb) 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 theplasma concentration-time profiles during the 24 h interval at steady state; Cmax = peak plasma concentration;

Cmin,ss = trough levels at steady state.

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 isunknown.

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 outweighthe possible risks to the foetus.

CRESEMBA is not recommended for women of childbearing potential who are not usingcontraception.

Available pharmacodynamic/toxicological data in animals have shown excretion ofisavuconazole/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.

There are no data on the effect of isavuconazole on human fertility. Studies in animals did not showimpairment of fertility in male or female rats (see section 5.3).

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

The most common treatment-related adverse reactions in adults were elevated liver chemistry tests(7.9%), nausea (7.4%), vomiting (5.5%), dyspnoea (3.2%), abdominal pain (2.7%), diarrhoea (2.7%),injection site reaction (2.2%), headache (2.0%), hypokalaemia (1.7%) and rash (1.7%).

The adverse reactions which most often led to permanent discontinuation of isavuconazole treatmentin adults were confusional state (0.7%), acute renal failure (0.7%), increased blood bilirubin (0.5%),convulsion (0.5%), dyspnoea (0.5%), epilepsy (0.5%), respiratory failure (0.5%) and vomiting (0.5%).

Table 4 presents adverse reactions with isavuconazole in the treatment of invasive fungal infections inadults, by System Organ Class and frequency.

The frequency of adverse reactions is defined as follows: very common (≥1/10); common (≥1/100 to<1/10); and uncommon (≥1/1,000 to <1/100); not known (frequency cannot be estimated from availabledata).

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

Table 4 Summary of adverse reactions by MedDRA System Organ Class and frequency

System Organ

Class Adverse Drug Reactions

Uncommon Neutropenia; Thrombocytopenia^; Pancytopenia; Leukopenia^; Anaemia^

Uncommon Hypersensitivity^

Not known Anaphylactic reaction*

Common Hypokalaemia; Decreased appetite

Uncommon Hypomagnesaemia; Hypoglycaemia; Hypoalbuminaemia; Malnutrition^

Common Delirium^#

Uncommon Depression; Insomnia^

Common Headache; Somnolence

Uncommon Convulsion^; Syncope; Dizziness; Paraesthesia^;

Encephalopathy; Presyncope; Neuropathy peripheral; Dysgeusia

Ear and labyrinth disorders

Uncommon Vertigo

Uncommon Atrial fibrillation; Tachycardia; Bradycardia^; Palpitations;

Atrial flutter; Electrocardiogram QT shortened; Supraventricular tachycardia;

Ventricular extrasystoles; Supraventricular extrasystoles

Common Thrombophlebitis^

Uncommon Circulatory collapse; Hypotension

Common Dyspnoea^; Acute respiratory failure^

Uncommon Bronchospasm; Tachypnoea; Haemoptysis; Epistaxis

Common Vomiting; Diarrhoea; Nausea; Abdominal pain^

Uncommon Dyspepsia; Constipation; Abdominal distension

Common Elevated liver chemistry tests^#

Uncommon Hepatomegaly; Hepatitis

Common Rash^; Pruritus

Uncommon Petechiae; Alopecia; Drug eruption; Dermatitis^

Uncommon Back pain

Common Renal failure

Common Chest pain^; Fatigue

Uncommon Oedema peripheral^; Malaise; Asthenia^ Indicates that grouping of appropriate preferred terms into a single medical concept occurred.

* ADR identified post-marketing.

# See section Description of selected adverse reactions below.

Delirium includes reactions of confusional state.

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

Laboratory effects

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

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

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Symptoms reported more frequently at supratherapeutic doses of isavuconazole (equivalent toisavuconazole 600 mg/day) evaluated in a QT study than in the therapeutic dose group (equivalent toisavuconazole 200 mg/day dose) included: headache, dizziness, paraesthesia, somnolence, disturbancein attention, dysgeusia, dry mouth, diarrhoea, oral hypoaesthesia, vomiting, hot flush, anxiety,restlessness, palpitations, tachycardia, photophobia and arthralgia.

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

Pharmacotherapeutic group: Antimycotics for systemic use, triazole- and tetrazole derivative, ATCcode: J02AC05.

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

Isavuconazole demonstrates a fungicidal effect by blocking the synthesis of ergosterol, a keycomponent of the fungal cell membrane, through the inhibition of cytochrome P-450-dependentenzyme 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 thecell membrane, thus weakening the structure and function of the fungal cell membrane.

In animal models of disseminated and pulmonary aspergillosis, the pharmacodynamic (PD) indeximportant 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 (Aspergillusand 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 toinhibit 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 fungalcyp51A and cyp51B genes coding for the target protein lanosterol 14-alpha-demethylase involved inergosterol biosynthesis. Fungal strains with reduced in vitro susceptibility to isavuconazole have beenreported, and cross-resistance with voriconazole and other triazole antifungal agents cannot beexcluded.

Table 5 EUCAST Breakpoints

Aspergillus species Minimal Inhibitory Concentration (MIC) breakpoint (mg/L)≤S (Susceptible) >R (Resistant)

Aspergillus flavus 1 2

Aspergillus fumigatus 1 2

Aspergillus nidulans 0.25 0.25

Aspergillus terreus 1 1

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

Treatment of invasive aspergillosis

The safety and efficacy of isavuconazole for the treatment of adult patients with invasive aspergillosiswas evaluated in a double-blind, active-controlled clinical study in 516 patients with invasive fungaldisease caused by Aspergillus species or other filamentous fungi. In the intent-to-treat (ITT)population, 258 patients received isavuconazole and 258 patients received voriconazole.

Isavuconazole was administered intravenously (equivalent to 200 mg isavuconazole) every 8 hours forthe first 48 hours, followed by once-daily intravenous or oral treatment (equivalent to 200 mgisavuconazole). The protocol-defined maximum treatment duration was 84 days. Median treatmentduration was 45 days.

The overall response at end-of-treatment (EOT) in the myITT population (patients with proven andprobable invasive aspergillosis based on cytology, histology, culture or galactomannan testing) wasassessed by an independent blinded Data Review Committee. The myITT population comprised 123patients receiving isavuconazole and 108 patients receiving voriconazole. The overall response in thispopulation was n = 43 (35%) for isavuconazole and n = 42 (38.9%) for voriconazole. The adjustedtreatment 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% forvoriconazole. 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 adult patients with proven or probable mucormycosisreceived isavuconazole at the same dose regimen as that used to treat invasive aspergillosis. Mediantreatment duration was 84 days for the overall mucormycosis patient population, and 102 days for the21 patients not previously treated for mucormycosis. For patients with probable or provenmucormycosis 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 patientsreceiving isavuconazole as primary treatment, and 43.8% (7/16) for mucormycosis patients receivingisavuconazole 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 5patients considered completely cured and 6 patients partially cured. A stable response was observed inan additional 10/35 patients (28.6%). In 9 patients with mucormycosis due to Rhizopus spp., 4 patientsshowed a favourable response to isavuconazole. In 5 patients with mucormycosis due to Rhizomucorspp., 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).

The clinical safety of isavuconazole was assessed in 77 paediatric patients who received at least onedose of intravenous or oral isavuconazole, including 31 paediatric patients who receivedisavuconazole in a clinical study for treating invasive aspergillosis or mucormycosis. Isavuconazolewas safe and well tolerated in the treatment of invasive aspergillosis and mucormycosis at the intendedtreatment durations.

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

Following oral administration of CRESEMBA in healthy adult subjects, the active moietyisavuconazole is absorbed and reaches maximum plasma concentrations (Cmax) approximately 2-3hours after single and multiple dosing (see Table 6).

Table 6 Steady state pharmacokinetic parameters of isavuconazole following oral administrationof CRESEMBA in healthy adults

Parameter Isavuconazole 200 mg Isavuconazole 600 mg

Statistic (n = 37) (n = 32)

Cmax (mg/L)

Mean 7.5 20.0

SD 1.9 3.6

CV % 25.2 17.9tmax (h)

Median 3.0 4.0

Range 2.0 - 4.0 2.0 - 4.0

AUC (h*mg/L)

Mean 121.4 352.8

SD 35.8 72.0

CV % 29.5 20.4

As shown in table 7 below, the absolute bioavailability of isavuconazole following oral administrationof a single dose of CRESEMBA is 98%. Based on these findings, intravenous and oral dosing can beused interchangeably.

Table 7 Pharmacokinetic comparison for oral and intravenous dose (Mean) in adults

Isavuconazole 400 mg oral Isavuconazole 400 mg i.v.

AUC (h*mg/L) 189.5 194.0

CV % 36.5 37.2

Half-life (h) 110 115

Effect of food on absorption

Oral administration of CRESEMBA equivalent to 400 mg isavuconazole with a high-fat meal reducedisavuconazole Cmax by 9% and increased AUC by 9%. CRESEMBA can be taken with or withoutfood.

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

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] isavuconazoniumsulfate in humans, in addition to the active moiety (isavuconazole) and the inactive cleavage product, anumber of minor metabolites were identified. Except for the active moiety isavuconazole, noindividual metabolite was observed with an AUC > 10% of total radio-labelled material.

Following oral administration of radio-labelled isavuconazonium sulfate to healthy subjects, a mean of46.1% 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 excretionof the metabolites.

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

The paediatric dosage regimens were confirmed using a population pharmacokinetic (popPK) modeldeveloped using data from three clinical studies (N = 97); this included two clinical studies (N = 73)conducted in paediatric patients aged 1 to < 18 years, of whom 31 received isavuconazole for treatinginvasive aspergillosis or mucormycosis.

The predicted exposures to isavuconazole for paediatric patients at steady state based on different agegroups, weight, route of administration, and dose are shown in Table 8.

Table 8 Isavuconazole AUC (h*mg/L) values at steady state by age group, weight, route ofadministration, and dose

Age group (years) Route Weight (kg) Dose AUCss (h*mg/L)1 - < 3 Intravenous < 37 5.4 mg/kg 108 (29 - 469)3 - < 6 Intravenous < 37 5.4 mg/kg 123 (27 - 513)6 - < 18 Intravenous < 37 5.4 mg/kg 138 (31 - 602)6 - < 18 Oral 16 - 17 80 mg 116 (31 - 539)6 - < 18 Oral 18 - 24 120 mg 129 (33 - 474)6 - < 18 Oral 25 - 31 160 mg 140 (36 - 442)6 - < 18 Oral 32 - 36 180 mg 137 (27 - 677)6 - < 18 Intravenous ≥ 37 200 mg 113 (27 - 488)and oral≥ 18 Intravenous ≥ 37 200 mg 101 (10 - 343)and oral

The predicted exposures for paediatric patients, regardless of route of administration and age group,were comparable to exposures at steady state (AUCss) from a clinical study conducted in adultpatients with infections caused by Aspergillus species and other filamentous fungi (mean AUCss =101.2 h*mg/L with standard deviation (SD) = 55.9, see Table 8).

The predicted exposures under the paediatric dosing regimen were lower than the exposures of adultswho received multiple daily supratherapeutic doses of 600 mg isavuconazole (Table 6), where therewas a greater occurrence of adverse events (see section 4.9).

No clinically relevant changes were observed in the total Cmax and AUC of isavuconazole in adultsubjects with mild, moderate or severe renal impairment compared to subjects with normal renalfunction. Of the 403 patients who received isavuconazole in the Phase 3 studies, 79 (20%) of patientshad an estimated glomerular filtration rate (GFR) less than 60 mL/min/1.73 m2. No dose adjustment isrequired in patients with renal impairment, including those patients with end-stage renal disease.

Isavuconazole is not readily dialysable (see section 4.2).

No data are available in paediatric patients with renal impairment (see section 4.2).

After a single 100 mg dose of isavuconazole was administered to 32 adult patients with mild (Child-

Pugh Class A) hepatic insufficiency and 32 patients with moderate (Child-Pugh Class B) hepaticinsufficiency (16 intravenous and 16 oral patients per Child-Pugh class), the least square meansystemic 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 inthe Child-Pugh Class B group. The population pharmacokinetic evaluation of isavuconazole in healthysubjects and patients with mild or moderate hepatic dysfunction demonstrated that the mild andmoderate hepatic impairment populations had 40% and 48% lower isavuconazole clearance (CL)values, respectively, than the healthy population.

No dose adjustment is required in adult patients with mild to moderate hepatic impairment.

Isavuconazole has not been studied in adult patients with severe hepatic impairment (Child-Pugh Class

C). Use in these patients is not recommended unless the potential benefit is considered to outweigh therisks (see sections 4.2 and 4.4).

No data are available in paediatric patients with hepatic impairment (see section 4.2).

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

Administration of isavuconazonium sulfate to rats at a dose of 90 mg/kg/day (approximately 1.0-foldthe systemic exposure at the human clinical maintenance dose of 200 mg isavuconazole) duringpregnancy through the weaning period showed an increased perinatal mortality of the pups. In uteroexposure to the active moiety isavuconazole had no effect on the fertility or the normal developmentof the surviving pups.

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

Isavuconazole did not affect the fertility of male or female rats treated with oral doses up to90 mg/kg/day (approximately 1.0-fold the systemic exposure at the human clinical maintenance doseof 200 mg isavuconazole).

Isavuconazole has no discernible mutagenic or genotoxic potential. Isavuconazole was negative in abacterial reverse mutation assay, was weakly clastogenic at cytotoxic concentrations in the

L5178Y tk+/- mouse lymphoma chromosome aberration assay, and showed no biologically relevant orstatistically significant increase in the frequency of micronuclei in an in vivo rat micronucleus test.

Isavuconazole has demonstrated carcinogenic potential in 2-year rodent carcinogenicity studies. Liverand thyroid tumours are likely caused by a rodent-specific mechanism that is not relevant for humans.

Skin fibromas and fibrosarcomas were seen in male rats. The mechanism underlying this effect isunknown. Endometrial adenomas and carcinomas of the uterus were seen in female rats, which islikely due to a hormonal disturbance. There is no safety margin for these effects. The relevance forhumans of the skin and uterine tumours cannot be excluded.

Isavuconazole inhibited the hERG potassium channel and the L-type calcium channel with an IC50 of5.82 µM and 6.57 µM respectively (34- and 38-fold the human non-protein bound Cmax at maximumrecommended human dose [MRHD], respectively). The in vivo 39-week repeated-dose toxicologystudies in monkeys did not show QTcF prolongation at doses up to 40 mg/kg/day (approximately1.0-fold the systemic exposure at the human clinical maintenance dose of 200 mg isavuconazole).

Isavuconazonium sulfate, when administered to juvenile rats, demonstrated a similar toxicologicalprofile to that observed in adult animals. In juvenile rats, treatment-related toxicity considered rodentspecific was observed in the liver and thyroid. These changes are not considered clinically relevant.

Based on the no-observed-adverse-effect level in juvenile rats, the safety margins forisavuconazonium sulfate were approximately 0.2- to 0.5-fold the systemic exposure at the clinicalmaintenance dose for paediatric patients, similar to those observed in adult rats.

Environmental risk assessment has shown that isavuconazole may pose a risk for the aquaticenvironment.

CRESEMBA 40 mg hard capsules:

Capsule contentsmagnesium citrate (anhydrous)microcrystalline cellulose (E460)talc (E553b)silica, colloidal anhydrousstearic acid

Capsule shellhypromellosered iron oxide (E172)titanium dioxide (E171)

Shellac (E904)propylene glycol (E1520)potassium hydroxideblack iron oxide (E172)

CRESEMBA 100 mg hard capsules:

Capsule contentsmagnesium citrate (anhydrous)microcrystalline cellulose (E460)talc (E553b)silica, colloidal anhydrousstearic acid

Capsule shellhypromellosered iron oxide (E172) (capsule body only)titanium dioxide (E171)gellan gumpotassium acetatedisodium edetatesodium laurilsulfate

Shellac (E904)propylene glycol (E1520)potassium hydroxideblack iron oxide (E172)

Not applicable.

30 months.

Do not store above 30°C.

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

CRESEMBA 40 mg hard capsules:

35 hard capsules (in seven aluminum blisters), with each capsule pocket connected to a pocket withdesiccant.

CRESEMBA 100 mg hard capsules:

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

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

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

Basilea Pharmaceutica Deutschland GmbH

Marie-Curie-Strasse 879539 Lörrach

Germany

CRESEMBA 40 mg hard capsules: EU/1/15/1036/003

CRESEMBA 100 mg hard capsules: EU/1/15/1036/002

CRESEMBA 40 mg hard capsules:

Date of first authorisation: 22 August 2024.

Date of latest renewal:

CRESEMBA 100 mg hard capsules:

Date of first authorisation: 15 October 2015.

Date of latest renewal: 13 August 2020.

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.