Interactions : אינטראקציות

4.5   Interaction with other medicinal products and other forms of interaction
Voriconazole is metabolised by, and inhibits the activity of, cytochrome P450 isoenzymes, CYP2C19, CYP2C9, and CYP3A4. Inhibitors or inducers of these isoenzymes may increase or decrease voriconazole plasma concentrations, respectively, and there is potential for voriconazole to increase the plasma concentrations of substances metabolised by these CYP450 isoenzymes, in particular for substances metabolised by CYP3A4 since voriconazole is a strong CYP3A4 inhibitor though the increase in AUC is substrate dependent (see Table below).
Unless otherwise specified, drug interaction studies have been performed in healthy adult male subjects using multiple dosing to steady state with oral voriconazole at 200 mg twice daily (BID).
These results are relevant to other populations and routes of administration.
Voriconazole should be administered with caution in patients with concomitant medication that is known to prolong QTc interval. When there is also a potential for voriconazole to increase the plasma concentrations of substances metabolised by CYP3A4 isoenzymes (certain antihistamines, quinidine, cisapride, pimozide and ivabradine), coadministration is contraindicated (see below and section 4.3).

Interaction table

Interactions between voriconazole and other medicinal products are listed in the table below (once daily as “QD”, twice daily as “BID”, three times daily as “TID” and not determined as “ND”). The direction of the arrow for each pharmacokinetic parameter is based on the 90% confidence interval of the geometric mean ratio being within (↔), below (↓) or above (↑) the 80- 125% range. The asterisk (*) indicates a two-way interaction. AUCτ, AUCt and AUC0-∞ represent area under the curve over a dosing interval, from time zero to the time with detectable measurement and from time zero to infinity, respectively.


The interactions in the table are presented in the following order: contraindications, those requiring dose adjustment and careful clinical and/or biological monitoring, and finally those that have no significant pharmacokinetic interaction but may be of clinical interest in this therapeutic field.



Medicinal product             Interaction                               Recommendations [Mechanism of interaction]    Geometric mean changes (%)                concerning coadministration Astemizole, cisapride,        Although not studied, increased           Contraindicated pimozide, quinidine,          plasma concentrations of these            (see section 4.3) terfenadine and ivabradine    medicinal products can lead to QTc
[CYP3A4 substrates]           prolongation and rare occurrences of torsades de pointes.
Carbamazepine and long-       Although not studied, carbamazepine       Contraindicated acting barbiturates (e.g.,    and long-acting barbiturates are likely   (see section 4.3) phenobarbital,                to significantly decrease plasma mephobarbital)                voriconazole concentrations.
[potent CYP450 inducers]

Efavirenz (a non-nucleoside reverse transcriptase inhibitor)
[CYP450 inducer; CYP3A4 inhibitor and substrate]

Efavirenz 400 mg QD,          Efavirenz Cmax ↑ 38%                      Use of standard doses of coadministered with           Efavirenz AUCτ ↑ 44%                      voriconazole with efavirenz doses of voriconazole                  Voriconazole Cmax ↓ 61%                   400 mg QD or higher is 200 mg BID*                   Voriconazole AUCτ ↓ 77%                   contraindicated (see section 4.3).


Compared to efavirenz 600 mg QD,          Voriconazole may be coadministered Efavirenz Cmax ↔                          with efavirenz if the voriconazole Efavirenz 300 mg QD,          Efavirenz AUCτ ↑ 17%                      maintenance dose is increased to 400 coadministered with                                                     mg BID and the efavirenz dose is voriconazole 400 mg BID*      Compared to voriconazole 200 mg           decreased to 300 mg QD. When BID,                                      voriconazole treatment is stopped, the Voriconazole Cmax ↑ 23%                   initial dose of efavirenz should be Voriconazole AUCτ ↓ 7%                    restored (see section 4.2 and 4.4).

Ergot alkaloids (e.g.,        Although not studied, voriconazole        Contraindicated (see section ergotamine and                is likely to increase the plasma          4.3) dihydroergotamine)            concentrations of ergot alkaloids and
[CYP3A4 substrates]           lead to ergotism.
Lurasidone                    Although not studied, voriconazole is     Contraindicated (see section 4.3) [CYP3A4 substrate]           likely to significantly increase the plasma concentrations of lurasidone.
Naloxegol                     Although not studied, voriconazole is     Contraindicated (see section 4.3) [CYP3A4 substrate]            likely to significantly increase the plasma concentrations of naloxegol.



Medicinal product                Interaction                             Recommendations [Mechanism of interaction]       Geometric mean changes (%)              concerning coadministration Rifabutin
[potent CYP450 inducer]                                                  Contraindicated (see Section 4.3) Voriconazole Cmax ↓ 69%
300 mg QD
Voriconazole AUCτ ↓ 78%


300 mg QD (co-                  Compared to voriconazole 200 mg administered with               BID,
voriconazole 350 mg             Voriconazole Cmax ↓ 4%
BID)*                           Voriconazole AUCτ ↓ 32%



Rifabutin Cmax ↑ 195%
300 mg QD (co-
Rifabutin AUCτ ↑ 331% administered with voriconazole 400 mg             Compared to voriconazole 200 mg
BID)*                            BID,
Voriconazole Cmax ↑ 104%
Voriconazole AUCτ ↑ 87%

Rifampicin (600 mg QD)           Voriconazole Cmax ↓ 93%                 Contraindicated (see section 4.3) [potent CYP450 inducer]          Voriconazole AUCτ ↓ 96%

Ritonavir (protease inhibitor)
[potent CYP450 inducer;
CYP3A4 inhibitor and substrate]                                                               Coadministration of voriconazole and Ritonavir Cmax and AUCτ ↔               high doses of ritonavir (400 mg and High dose (400 mg BID)          Voriconazole Cmax ↓ 66%                 above BID) is contraindicated (see Voriconazole AUCτ ↓ 82%                 section 4.3).

Ritonavir Cmax ↓ 25%                    Coadministration of voriconazole and Low dose (100 mg BID)*          Ritonavir AUCτ ↓13%                     low dose ritonavir (100 mg BID) Voriconazole Cmax ↓ 24%                 should be avoided, unless an Voriconazole AUCτ ↓ 39%                 assessment of the benefit/risk to the patient justifies the use of voriconazole.
St John’s Wort
[CYP450 inducer; P-gp inducer]
300 mg TID (co-                In an independent published study,      Contraindicated (see section 4.3) administered with              Voriconazole AUC0-∞ ↓ 59% voriconazole 400 mg single dose)

Tolvaptan                        Although not studied, voriconazole is   Contraindicated (see section 4.3) [CYP3A substrate                 likely to significantly increase the plasma concentrations of tolvaptan.


Medicinal product             Interaction                             Recommendations [Mechanism of interaction]    Geometric mean changes (%)              concerning coadministration Venetoclax                    Although not studied, voriconazole is   Concomitant administration of [CYP3A substrate]             likely to significantly increase the    voriconazole is contraindicated at plasma concentrations of venetoclax.    initiation and during venetoclax dose titration phase (see section 4.3). Dose reduction of venetoclax is required as instructed in venetoclax prescribing information during steady daily dosing; close monitoring for signs of toxicity is recommended
Fluconazole (200 mg QD)       Voriconazole Cmax ↑ 57%                 The reduced dose and/or frequency of [CYP2C9, CYP2C19 and          Voriconazole AUCτ ↑ 79%                 voriconazole and fluconazole that CYP3A4 inhibitor]             Fluconazole Cmax ND                     would eliminate this effect have not Fluconazole AUCτ ND                     been established. Monitoring for voriconazole-associated adverse reactions is recommended if voriconazole is used sequentially after fluconazole.
Phenytoin
[CYP2C9 substrate and                                                 Concomitant use of voriconazole and potent CYP450 inducer]                                                phenytoin should be avoided unless the benefit outweighs the risk.
300 mg QD                     Voriconazole Cmax ↓ 49%                 Careful monitoring of phenytoin Voriconazole AUCτ ↓ 69%                 plasma levels is recommended.

300 mg QD (coadministered     Phenytoin Cmax ↑ 67%                    Phenytoin may be coadministered with voriconazole 400 mg      Phenytoin AUCτ ↑ 81%                    with voriconazole if the maintenance BID)*                         Compared to voriconazole 200 mg         dose of voriconazole is increased to 5 BID,                                    mg/kg IV BID or from 200 mg to 400 Voriconazole Cmax ↑ 34%                 mg oral BID, (100 mg to 200 mg oral Voriconazole AUCτ ↑ 39%                 BID in patients less than 40 kg) (see section 4.2).


Letermovir                    Voriconazole Cmax ↓ 39%                 If concomitant administration of [CYP2C9 and CYP2C19           Voriconazole AUC0-12 ↓ 44%              voriconazole with letermovir cannot inducer]                      Voriconazole C12 ↓ 51%                  be avoided, monitor for loss of voriconazole effectiveness.
Glasdegib                     Although not studied, voriconazole is   If concomitant use cannot be avoided, [CYP3A4 substrate]            likely to increase the plasma           frequent ECG monitoring is concentrations of glasdegib and         recommended.
increase risk of QTc prolongation.
Tyrosine kinase inhibitors    Although not studied, voriconazole      If concomitant use cannot be avoided, (e.g., axitinib, bosutinib,   may increase plasma concentrations      dose reduction of the tyrosine kinase cabozantinib, ceritinib,      of tyrosine kinase inhibitors           inhibitor is recommended.
cobimetinib, dabrafenib,      metabolized by CYP3A4.
dasatinib, nilotinib,
sunitinib, ibrutinib,
ribociclib) [CYP3A4 substrates]

Medicinal product               Interaction                             Recommendations [Mechanism of interaction]      Geometric mean changes (%)              concerning coadministration Anticoagulants

Warfarin (30 mg single          Maximum increase in prothrombin         Close monitoring of prothrombin dose, co- administered with     time was approximately 2-fold           time or other suitable anticoagulation 300 mg BID voriconazole)                                                tests is recommended, and the dose of [CYP2C9 substrate]                                                      anticoagulants should be adjusted accordingly.
Other oral coumarins
(e.g., phenprocoumon,           Although not studied, voriconazole acenocoumarol)                  may increase the plasma
[CYP2C9 and CYP3A4            concentrations of coumarins that may substrates]                   cause an increase in prothrombin time.

Ivacaftor                       Although not studied, voriconazole is   Dose reduction of ivacaftor is [CYP3A4 substrate]              likely to increase the plasma           recommended.
concentrations of ivacaftor with risk of increased adverse effects.
Benzodiazepines                                                         Dose reduction of benzodiazepines [CYP3A4 substrates]             In an independent published study,      should be considered.
Midazolam (0.05 mg/kg IV,       Midazolam AUC0-∞ ↑ 3.7-fold single dose)
In an independent published study,
Midazolam (7.5 mg oral          Midazolam Cmax ↑ 3.8-fold single dose)                    Midazolam AUC0-∞ ↑ 10.3-fold

Other benzodiazepines (e.g.,    Although not studied, voriconazole is triazolam, alprazolam)          likely to increase the plasma concentrations of other benzodiazepines that are metabolised by CYP3A4 and lead to a prolonged sedative effect.
Immunosuppressants
[CYP3A4 substrates]             In an independent published study,
Sirolimus Cmax ↑ 6.6-fold               Co-administration of voriconazole Sirolimus (2 mg single         Sirolimus AUC0-∞ ↑ 11-fold              and sirolimus is contraindicated (see dose)                                                                  section 4.3).
Although not studied, voriconazole is
Everolimus [also P-gP          likely to significantly increase the    Coadministration of voriconazole and substrate]                     plasma concentrations of everolimus.    everolimus is not recommended because voriconazole is expected to significantly increase everolimus
Ciclosporin (In stable renal   Ciclosporin Cmax ↑ 13%                  concentrations (see section 4.4).
transplant recipients          Ciclosporin AUCτ ↑ 70% receiving chronic ciclosporin therapy)                                                   When initiating voriconazole in patients already on ciclosporin it is recommended that the ciclosporin dose be halved and ciclosporin level carefully monitored. Increased

Medicinal product            Interaction                          Recommendations [Mechanism of interaction]   Geometric mean changes (%)           concerning coadministration ciclosporin levels have been associated with nephrotoxicity.
When voriconazole is discontinued,
ciclosporin levels must be carefully monitored and the dose increased as necessary.
Tacrolimus Cmax ↑ 117%
Tacrolimus (0.1 mg/kg       Tacrolimus AUCt ↑ 221%               When initiating voriconazole in single dose)                                                     patients already on tacrolimus, it is recommended that the tacrolimus dose be reduced to a third of the original dose and tacrolimus level carefully monitored. Increased tacrolimus levels have been associated with nephrotoxicity.
When voriconazole is discontinued,
tacrolimus levels must be carefully monitored and the dose increased as necessary.
Long-Acting Opiates                                               Dose reduction in oxycodone and [CYP3A4 substrates]                                               other long-acting opiates metabolized In an independent published study,   by CYP3A4 (e.g., hydrocodone)
Oxycodone (10 mg single     Oxycodone Cmax ↑ 1.7-fold            should be considered. Frequent dose)                       Oxycodone AUC0-∞ ↑ 3.6-fold          monitoring for opiate-associated adverse reactions may be necessary.

Methadone (32-100 mg QD)                                          Frequent monitoring for adverse [CYP3A4 substrate]           R-methadone (active) Cmax ↑ 31%      reactions and toxicity related to R-methadone (active) AUCτ ↑ 47%      methadone, including QTc
S-methadone Cmax ↑ 65%               prolongation, is recommended. Dose S-methadone AUCτ ↑ 103%              reduction of methadone may be needed.
Non-Steroidal Anti-
Inflammatory Drugs
(NSAIDs)
[CYP2C9 substrates]

Ibuprofen (400 mg single    S-Ibuprofen Cmax ↑ 20%               Frequent monitoring for adverse dose)                       S-Ibuprofen AUC0-∞ ↑ 100%            reactions and toxicity related to NSAIDs is recommended. Dose
Diclofenac (50 mg single    Diclofenac Cmax ↑ 114%               reduction of NSAIDs may be needed.
dose)                       Diclofenac AUC0-∞ ↑ 78%



Medicinal product               Interaction                                Recommendations [Mechanism of interaction]      Geometric mean changes (%)                 concerning coadministration Omeprazole (40 mg QD)*          Omeprazole Cmax ↑ 116%                     No dose adjustment of voriconazole [CYP2C19 inhibitor;             Omeprazole AUCτ ↑ 280%                     is recommended.
CYP2C19 and CYP3A4              Voriconazole Cmax ↑ 15% substrate]                      Voriconazole AUCτ ↑ 41%                    When initiating voriconazole in patients already receiving omeprazole
Other proton pump inhibitors that          doses of 40 mg or above, it is are CYP2C19 substrates may also            recommended that the omeprazole be inhibited by voriconazole and           dose be halved.
may result in increased plasma concentrations of these medicinal products.
Oral Contraceptives*
[CYP3A4 substrate;              Ethinylestradiol Cmax ↑ 36%                Monitoring for adverse reactions CYP2C19 inhibitor]              Ethinylestradiol AUCτ ↑ 61%                related to oral contraceptives, in Norethisterone Cmax ↑ 15%                  addition to those for voriconazole, is Norethisterone/                Norethisterone AUCτ ↑ 53%                  recommended.
ethinylestradiol               Voriconazole Cmax ↑ 14%
(1 mg/0.035 mg QD)             Voriconazole AUCτ ↑ 46%

Short-acting Opiates                                                       Dose reduction of alfentanil, fentanyl [CYP3A4 substrates]                                                        and other short-acting opiates similar in structure to alfentanil and
Alfentanil (20 μg/kg single    In an independent published study,         metabolised by CYP3A4 (e.g., dose, with concomitant         Alfentanil AUC0-∞ ↑ 6-fold                 sufentanil) should be considered.
naloxone)                                                                 Extended and frequent monitoring for respiratory depression and other
Fentanyl (5 μg/kg single       In an independent published study,         opiate associated adverse reactions is dose)                          Fentanyl AUC0-∞ ↑ 1.34-fold                recommended.

Statins (e.g., lovastatin)      Although not studied, voriconazole is      If concomitant administration of [CYP3A4 substrates]             likely to increase the plasma              voriconazole with statins concentrations of statins that are         metabolised by CYP3A4 cannot metabolised by CYP3A4 and could            be avoided, dose reduction of statins lead to rhabdomyolysis.                    should be considered.

Sulphonylureas (e.g.,           Although not studied, voriconazole is      Careful monitoring of blood glucose tolbutamide, glipizide,         likely to increase the plasma              is recommended. Dose reduction of glyburide)                      concentrations of sulphonylureas and       sulfonylureas should be considered.
[CYP2C9 substrates]             cause hypoglycaemia.

Vinca Alkaloids (e.g.,          Although not studied, voriconazole is      Dose reduction of vinca alkaloids vincristine and vinblastine)    likely to increase the plasma              should be considered.
[CYP3A4 substrates]             concentrations of vinca alkaloids and lead to neurotoxicity.

Other HIV Protease              Not studied clinically. In vitro studies   Careful monitoring for any Inhibitors                      show that voriconazole may inhibit         occurrence of drug toxicity and/or (e.g., saquinavir, amprenavir   the metabolism of HIV protease             lack of efficacy, and dose adjustment and nelfinavir)*                inhibitors and the metabolism of           may be needed.
[CYP3A4 substrates and

Medicinal product             Interaction                                Recommendations [Mechanism of interaction]    Geometric mean changes (%)                 concerning coadministration inhibitors]                   voriconazole may also be inhibited by HIV protease inhibitors.
Other Non-Nucleoside          Not studied clinically. In vitro studies   Careful monitoring for any Reverse Transcriptase         show that the metabolism of                occurrence of drug toxicity and/or Inhibitors (NNRTIs) (e.g.,    voriconazole may be inhibited by           lack of efficacy, and dose adjustment delavirdine, nevirapine)*     NNRTIs and voriconazole may                may be needed.
inhibit the metabolism of NNRTIs.
[CYP3A4 substrates,           The findings of the effect of efavirenz inhibitors or CYP450          on voriconazole suggest that the inducers]                     metabolism of voriconazole may be induced by a NNRTI.
Tretinoin [CYP3A4             Although not studied, voriconazole         Dose adjustment of tretinoin is substrate]                    may increase tretinoin concentrations      recommended during treatment with and increase risk of adverse reactions     voriconazole and after its (pseudotumor cerebri,                      discontinuation.
hypercalcaemia).
Cimetidine (400 mg BID)       Voriconazole Cmax ↑ 18%                    No dose adjustment [non-specific CYP450          Voriconazole AUCτ ↑ 23% inhibitor and increases gastric pH]

Digoxin (0.25 mg QD)          Digoxin Cmax ↔                             No dose adjustment [P-gp substrate]              Digoxin AUCτ ↔
Indinavir (800 mg TID)        Indinavir Cmax ↔                           No dose adjustment [CYP3A4 inhibitor and         Indinavir AUCτ ↔ substrate]                    Voriconazole Cmax ↔
Voriconazole AUCτ ↔
Macrolide antibiotics
No dose adjustment
Erythromycin (1 g BID)       Voriconazole Cmax and AUCτ ↔
[CYP3A4 inhibitor]

Azithromycin (500 mg         Voriconazole Cmax and AUCτ ↔
QD)
The effect of voriconazole on either erythromycin or azithromycin is unknown.
Mycophenolic acid             Mycophenolic acid Cmax ↔                   No dose adjustment (1 g single dose)             Mycophenolic acid AUCt ↔
[UDP-glucuronyl transferase substrate]
Corticosteroids               Prednisolone Cmax ↑ 11%                    No dose adjustment Prednisolone AUC0-∞ ↑ 34%
Patients on long-term treatment with
Prednisolone (60 mg single                                               voriconazole and corticosteroids dose)                                                                    (including inhaled corticosteroids [CYP3A4 substrate]                                                       e.g., budesonide and intranasal corticosteroids) should be carefully monitored for adrenal cortex

Medicinal product            Interaction                          Recommendations [Mechanism of interaction]   Geometric mean changes (%)           concerning coadministration dysfunction both during treatment and when voriconazole is discontinued (see section 4.4).
Ranitidine (150 mg BID)      Voriconazole Cmax and AUCτ ↔         No dose adjustment [increases gastric pH]