Interactions : אינטראקציות

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
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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      Interactions

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.
Antibacterials
Rifampicin                   Isavuconazole:                             The concomitant administration (strong CYP3A4/5 inducer)    AUCtau: ↓ 90%                              of CRESEMBA® and rifampicin Cmax: ↓ 75%                                is contraindicated.

(CYP3A4/5 induction)

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Rifabutin                     Not studied.                        The concomitant administration (strong CYP3A4/5 inducer)     Isavuconazole concentrations may    of CRESEMBA® and rifabutin is significantly decrease.             contraindicated.

(CYP3A4/5 induction)
Nafcillin                   Not studied.                     The concomitant administration (moderate CYP3A4/5 inducer) Isavuconazole concentrations may of CRESEMBA® and nafcillin is significantly decrease.          contraindicated.

(CYP3A4/5 induction)
Clarithromycin                Not studied.                        No CRESEMBA® dose (strong CYP3A4/5 inhibitor)   Isavuconazole concentrations may    adjustment necessary; caution is increase.                           advised as adverse drug reactions may increase.
(CYP3A4/5 inhibition)
Antifungals
Ketoconazole                  Isavuconazole:                      The concomitant administration (strong CYP3A4/5 inhibitor)   AUCtau: ↑ 422%                      of CRESEMBA® 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 CRESEMBA® and St. John’s significantly decrease.             wort is contraindicated.

(CYP3A4 induction).
Immunosuppresants
Ciclosporin, sirolimus,       Ciclosporin:                        No CRESEMBA® dose tacrolimus                    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%

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

(CYP3A4 inhibition)
Mycophenolate mofetil (MMF) Mycophenolic acid (MPA, active        No CRESEMBA® 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 outweigh the risk.
(CYP3A4 inhibition)

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Isavuconazole concentrations may decrease.

(CYP3A4/5 induction)
Opioids
Short-acting opiates               Not studied.                          No CRESEMBA® 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 CRESEMBA® 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 opiate isomer).
AUCinf: ↓ 10%
Cmax: ↑ 4%

(CYP2B6 induction)
Anti-cancer
Vinca alkaloids (vincristine,
Not studied.                      No CRESEMBA® dose vinblastine)               Vinca alkaloid concentrations may adjustment necessary.
(P-gp substrates)          increase.                         Vinca alkaloids: careful monitoring for any occurrence of
(P-gp inhibition)                 drug toxicity, and dose reduction if required.
Cyclophosphamide           Not studied.                      No CRESEMBA® dose (CYP2B6, CYP3A4 substrate) Active metabolites of             adjustment necessary.
cyclophosphamide may increase or Cyclophosphamide: careful decrease.                         monitoring for any occurrence of lack of efficacy or increased
(CYP2B6 induction , CYP3A4       toxicity, and dose adjustment if inhibition)                       required.
Methotrexate               Methotrexate:                     No CRESEMBA® dose (BCRP, OAT1, OAT3          AUCinf: ↓ 3%                      adjustment necessary.
substrate)                 Cmax: ↓ 11%                       Methotrexate: no dose adjustment required.
7-hydroxymetabolite:
AUCinf: ↑ 29%
Cmax: ↑ 15%

(Mechanism unknown)
Other anticancer agents            Not studied.                          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)
Cresemba 200 mg IV, LPD, Israel   WC 16 Sep 2024 occurrence of drug toxicity, and dose reduction if required.
Antiemetics
Aprepitant                     Not studied.                        Co-administration should be (mild CYP3A4/5 inducer)        Isavuconazole concentrations may    avoided unless the potential decrease.                           benefit is considered to outweigh the risk.
(CYP3A4/5 induction)
Antidiabetics
Metformin                      Metformin:                          No CRESEMBA® dose (OCT1, OCT2 and MATE1          AUCinf: ↑ 52%                       adjustment necessary.
substrate)                     Cmax: ↑ 23%                         Metformin: dose reduction may be required.
(OCT2 inhibition)
Repaglinide                    Repaglinide:                        No CRESEMBA® dose (CYP2C8 and OATP1B1            AUCinf: ↓ 8%                        adjustment necessary.
substrate)                     Cmax: ↓ 14%                         Repaglinide: no dose adjustment required.
Pioglitazone                   Not studied.                        Co-administration should be (mild CYP3A4/5 inducer)        Isavuconazole concentrations may    avoided unless the potential decrease.                           benefit is considered to outweigh the risk.
(CYP3A4/5 induction)
Anticoagulants
Dabigatran etexilate           Not studied.                        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.
Warfarin                       S-warfarin                          No CRESEMBA® 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 CRESEMBA® dose 100 mg                         AUCtau: ↓ 27%                       adjustment necessary; caution is (CYP3A4/5 strong inhibitors    Cmax: ↓ 23%                         advised as adverse drug reactions and substrates)                Cmin, ss: ↓ 16%a)                   may increase.
Ritonavir:
AUCtau: ↓ 31%                       Lopinavir/ritonavir: no dose
Cmax: ↓ 33%                         adjustment for lopinavir 400 mg / ritonavir 100 mg every 12 hours
(Mechanism unknown)                 required, but careful monitoring for any occurrence of lack of
Isavuconazole:                      anti-viral efficacy.
AUCtau: ↑ 96%
Cmax: ↑ 74%

(CYP3A4/5 inhibition)

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Ritonavir (at doses >200 mg     Not studied.                        The concomitant administration every 12 hours)                 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)
Efavirenz                       Not studied.                        The concomitant administration (CYP3A4/5 moderate inducer      Efavirenz concentrations may        of CRESEMBA® and efavirenz and CYP2B6 substrate)           decrease.                           is contraindicated.

(CYP2B6 induction)

Isavuconazole drug concentrations may significantly decrease.
(CYP3A4/5 induction)
Etravirine                  Not studied.                     The concomitant administration (moderate CYP3A4/5 inducer) Isavuconazole concentrations may of CRESEMBA® and etravirine significantly decrease.          is contraindicated.

(CYP3A4/5 induction)
Indinavir                       Indinavir:b)                     No CRESEMBA® dose (CYP3A4/5 strong inhibitor      AUCinf: ↓ 36%                    adjustment necessary; caution is and substrate)                  Cmax: ↓ 52%                      advised as adverse drug reactions may increase.
(Mechanism unknown)              Indinavir: careful monitoring for any occurrence of lack of anti-
Isavuconazole concentrations may viral efficacy, and dose increase increase.                        if required.

(CYP3A4/5 inhibition)
Saquinavir                      Not studied.                      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  may 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 required
(CYP3A4/5 inhibition)
Other protease inhibitors (e.g. Not studied.                      No isavuconazole dose fosamprenavir)                  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)

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Other NNRTI (e.g.,               Not studied.                       No CRESEMBA® dose delavirdine, and nevirapine)     NNRTI concentrations may           adjustment necessary.
(CYP3A4/5 and 2B6 inducers       decrease (CYP2B6 induction by      NNRTIs: careful monitoring for and substrates)                  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                     Isavuconazole:                     No CRESEMBA® dose (CYP2C19 substrate and           AUCtau: ↑ 8%                       adjustment necessary.
gastric pH ↑)                    Cmax: ↑ 5%                         Esomeprazole: no dose adjustment required.
Omeprazole                       Omeprazole:                        No CRESEMBA® dose (CYP2C19 substrate and           AUCinf: ↓ 11%                      adjustment necessary.
gastric pH ↑)                    Cmax: ↓ 23%                        Omeprazole: no dose adjustment required.
Lipid-lowering agents
Atorvastatin and other statins   Atorvastatin :                     No CRESEMBA® dose (CYP3A4 substrates e.g.,         AUCinf: ↑ 37%                      adjustment necessary.
simvastatin, lovastatin,         Cmax: ↑ 3%                         Based on results with rosuvastatin)                    Other statins were not studied.    atorvastatin, no statin dose (CYP3A4/5 and/or BCRP            Statins concentrations may         adjustment required. Monitoring substrates)                      increase.                          of adverse reactions typical of statins is advised.
(CYP3A4/5 or BCRP inhibition)

Antiarrhythmics
Digoxin                          Digoxin:                           No CRESEMBA® dose (P-gp substrate)                 AUCinf: ↑ 25%                      adjustment necessary.
Cmax: ↑ 33%                        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 norethindrone                    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 CRESEMBA® 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 CRESEMBA® dose (CYP3A4/5 substrate)             AUCinf: ↑ 103%                     adjustment necessary.
Cmax: ↑ 72%                        Midazolam: careful monitoring of clinical signs and symptoms
(CYP3A4 inhibition)
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Antigout agent
Colchicine                       Not studied.                          No CRESEMBA® dose (P-gp substrate)                 Colchicine concentrations may         adjustment necessary.
increase.                             Colchicine has a narrow therapeutic index and should be
(P-gp inhibition)                     monitored, and dose reduction if required.
Natural products
Caffeine                         Caffeine:                             No CRESEMBA® dose (CYP1A2 substrate)               AUCinf: ↑ 4%                          adjustment necessary.
Cmax: ↓ 1%                            Caffeine: no dose adjustment required.
Smoking cessation aids
Bupropion                        Bupropion:                            No CRESEMBA® dose (CYP2B6 substrate)               AUCinf: ↓ 42%                         adjustment necessary.
Cmax: ↓ 31%                           Bupropion: dose increase if required.
(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.