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

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)
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 CY3A4/5 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)

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)                  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)
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 is and CYP2B6 substrate)          decrease.                           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 is significantly decrease.          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
(CYP3A4 inhibition)                anti-viral efficacy, and dose adjustment if required.
Isavuconazole concentrations may increase.

(CYP3A4/5 inhibition)
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)                  recommended, and dose reduction if required.
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, 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.