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


Medicinal product                    Interaction                         Recommendations concerning [Mechanism of interaction]           Geometric mean changes (%)          coadministration Efavirenz (a non-nucleoside reverse transcriptase inhibitor)
[CYP450 inducer; CYP3A4 inhibitor and substrate]
Efavirenz Cmax ↑ 38%                Use of standard doses of
Efavirenz 400 mg QD,                Efavirenz AUCτ ↑ 44%                voriconazole with efavirenz doses of 400 mg QD or higher is coadministered with                 Voriconazole Cmax ↓ 61%             contraindicated (see section voriconazole 200 mg BID*            Voriconazole AUCτ ↓ 77%             4.3).

Compared to efavirenz
Voriconazole may be
600 mg QD,
coadministered with efavirenz if
Efavirenz Cmax ↔                    the voriconazole maintenance
Efavirenz AUCτ ↑ 17%                dose is increased to 400 mg BID and the efavirenz dose is
Efavirenz 300 mg QD,                Compared to voriconazole 200 mg     decreased to 300 mg QD. When coadministered with                 BID,                                voriconazole treatment is voriconazole 400 mg BID*                                                stopped, the initial dose of Voriconazole Cmax ↑ 23%             efavirenz should be restored (see Voriconazole AUCτ ↓ 7%              sections 4.2 and 4.4).
Ergot alkaloids (including but not   Although not studied, voriconazole limited to: ergotamine and           is likely to increase the plasma Contraindicated (see section dihydroergotamine)                   concentrations of ergot alkaloids 4.3)
[CYP3A4 substrates]                  and lead to ergotism.
Lurasidone                           Although not studied,               Contraindicated (see section [CYP3A4 substrate]                                                       4.3) voriconazole is likely to significantly increase the plasma concentrations of lurasidone.
Naloxegol                            Although not studied, voriconazole Contraindicated (see section [CYP3A4 substrate]                   is likely to significantly increase the 4.3) plasma concentrations of naloxegol.


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

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

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

Rifampicin (600 mg QD)          Voriconazole Cmax ↓ 93%                Contraindicated (see section [potent CYP450 inducer]         Voriconazole AUCτ ↓ 96%                4.3) Ritonavir (protease inhibitor)
[potent CYP450 inducer;
CYP3A4 inhibitor and substrate]
Coadministration of
High dose (400 mg BID)            Ritonavir Cmax and AUCτ ↔            voriconazole and high doses of Voriconazole Cmax ↓ 66%              ritonavir (400 mg and above
Voriconazole AUCτ ↓ 82%              BID) is contraindicated (see section 4.3).

Low dose (100 mg BID)*            Ritonavir Cmax ↓ 25%                 Coadministration of Ritonavir AUCτ ↓13%                  voriconazole and low dose
Voriconazole Cmax ↓ 24%              ritonavir (100 mg BID) 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]    In an independent published study,
300 mg TID (coadministered                                             Contraindicated (see section Voriconazole AUC0-∞ ↓ 59% with voriconazole 400 mg single                                        4.3) dose)
Tolvaptan                         Although not studied, voriconazole Contraindicated (see section is likely to significantly increase the 4.3)
[CYP3A substrate] plasma concentrations of tolvaptan.


Medicinal product                 Interaction                               Recommendations concerning [Mechanism of interaction]        Geometric mean changes (%)                 coadministration Venetoclax                        Although not studied, voriconazole        Concomitant administration of is likely to significantly increase the   voriconazole is contraindicated [CYP3A substrate] plasma concentrations of                  at initiation and during venetoclax.                               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 [CYP2C9, CYP2C19 and              Voriconazole AUCτ ↑ 79%                   frequency of voriconazole and CYP3A4 inhibitor]                 Fluconazole Cmax ND                       fluconazole that would eliminate Fluconazole AUCτ ND                       this effect have not been established. Monitoring for voriconazole-associated adverse reactions is recommended if voriconazole is used sequentially after fluconazole.
Phenytoin                                                                   Concomitant use of [CYP2C9 substrate and potent                                                voriconazole and phenytoin CYP450 inducer]                                                             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.

Phenytoin may be
Phenytoin Cmax ↑ 67%                         coadministered with
300 mg QD (coadministered with Phenytoin AUCτ ↑ 81%                         voriconazole if the maintenance voriconazole 400 mg BID)*      Compared to voriconazole 200 mg              dose of voriconazole is BID,                                         increased to 5 mg/kg IV BID or Voriconazole Cmax ↑ 34%                      from 200 mg to 400 mg oral Voriconazole AUCτ ↑ 39%                      BID (100 mg to 200 mg oral BID in patients less than 40 kg)
(see section 4.2).
Letermovir                   Voriconazole Cmax ↓ 39%                        If concomitant administration of [CYP2C9 and CYP2C19 inducer] Voriconazole AUC0-12 ↓ 44% voriconazole with letermovir
Voriconazole C12 ↓ 51%                         cannot be avoided, monitor for loss of voriconazole effectiveness.
Flucloxacillin                    Significantly decreased plasma            If concomitant administration of [CYP450 inducer]                  voriconazole concentrations have          voriconazole with flucloxacillin been reported.                            cannot be avoided, monitor for potential loss of voriconazole effectiveness (e.g., by therapeutic drug monitoring);
increasing the dose of voriconazole may be needed.


Medicinal product                    Interaction                          Recommendations concerning [Mechanism of interaction]           Geometric mean changes (%)            coadministration Glasdegib                            Although not studied, voriconazole   If concomitant use cannot be [CYP3A4 substrate]                   is likely to increase the plasma     avoided, frequent ECG concentrations of glasdegib and      monitoring is recommended.
increase risk of QTc prolongation.
Tyrosine kinase inhibitors           Although not studied, voriconazole   If concomitant use cannot be (including but not limited to:       may increase plasma concentrations   avoided, dose reduction of the axitinib, bosutinib, cabozantinib,   of tyrosine kinase inhibitors        tyrosine kinase inhibitor and ceritinib, cobimetinib,              metabolized by CYP3A4.               close clinical monitoring is dabrafenib, dasatinib, nilotinib,                                         recommended.
sunitinib, ibrutinib, ribociclib)
[CYP3A4 substrates]
Anticoagulants

Warfarin (30 mg single dose,   Maximum increase in prothrombin        Close monitoring of coadministered with 300 mg BID time was approximately 2-fold.         prothrombin time or other voriconazole)                                                         suitable anticoagulation tests is [CYP2C9 substrate]                                                    recommended, and the dose of anticoagulants should be
Other oral coumarins            Although not studied, voriconazole adjusted accordingly.
((including but not limited to: may increase the plasma phenprocoumon, acenocoumarol) concentrations of coumarins that
[CYP2C9 and CYP3A4             may cause an increase in substrates]                     prothrombin time.
Ivacaftor                       Although not studied, voriconazole Dose reduction of ivacaftor is is likely to increase the plasma      recommended.
[CYP3A4 substrate] concentrations of ivacaftor with risk of increased adverse effects.
Benzodiazepines [CYP3A4                                               Dose reduction of substrates]                     In an independent published study, benzodiazepines should be Midazolam (0.05 mg/kg IV Midazolam AUC0-∞ ↑ 3.7-fold              considered.
single dose)
In an independent published study,
Midazolam Cmax ↑ 3.8-fold
Midazolam (7.5 mg oral      Midazolam AUC0-∞ ↑ 10.3-fold single dose)

Although not studied , voriconazole
Other benzodiazepines           is likely to increase the plasma
((including but not limited to: concentrations of other triazolam, alprazolam)          benzodiazepines that are metabolised by CYP3A4 and lead to a prolonged sedative effect.

Medicinal product                  Interaction                               Recommendations concerning [Mechanism of interaction]         Geometric mean changes (%)                coadministration Immunosuppressants
[CYP3A4 substrates]
In an independent published study,        Coadministration of
Sirolimus (2 mg single dose)       Sirolimus Cmax ↑ 6.6-fold                 voriconazole and sirolimus is Sirolimus AUC0-∞ ↑ 11-fold                contraindicated (see section 4.3).

Coadministration of
Everolimus                         Although not studied, voriconazole        voriconazole and everolimus is [also P-gp substrate]              is likely to significantly increase the   not recommended because plasma concentrations of                  voriconazole is expected to everolimus.                               significantly increase everolimus concentrations (see
Ciclosporin (in stable renal       Ciclosporin Cmax ↑ 13%                    section 4.4).
transplant recipients receiving    Ciclosporin AUCτ ↑ 70% 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 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%                    When initiating voriconazole in Tacrolimus (0.1 mg/kg single       Tacrolimus AUCt ↑ 221%                    patients already on tacrolimus, it dose) 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 [CYP3A4 substrates]                                                          and other long-acting opiates metabolized by CYP3A4
Oxycodone (10 mg single dose)      In an independent published study,        (e.g., hydrocodone) should be considered. Frequent monitoring
Oxycodone Cmax ↑ 1.7-fold for opiate-associated adverse
Oxycodone AUC0-∞ ↑ 3.6-fold               reactions may be necessary.


Medicinal product                  Interaction                     Recommendations concerning [Mechanism of interaction]         Geometric mean changes (%)       coadministration Methadone (32-100 mg QD)           R-methadone (active) Cmax ↑ 31% Frequent monitoring for adverse [CYP3A4 substrate]                 R-methadone (active) AUCτ ↑ 47% reactions and toxicity related to S-methadone Cmax ↑ 65%          methadone, including QTc
S-methadone AUCτ ↑ 103%         prolongation, is recommended.
Dose reduction of methadone may be needed.
Non-Steroidal Anti-Inflammatory
Drugs (NSAIDs)
[CYP2C9 substrates]             S-Ibuprofen Cmax ↑ 20%                    Frequent monitoring for adverse S-Ibuprofen AUC0-∞ ↑ 100%                 reactions and toxicity related to Ibuprofen (400 mg single dose)                                            NSAIDs is recommended. Dose reduction of NSAIDs may be
Diclofenac (50 mg single dose)     Diclofenac Cmax ↑ 114%                 needed.
Diclofenac AUC0-∞ ↑ 78%
Omeprazole (40 mg QD) *            Omeprazole Cmax ↑ 116%                 No dose adjustment of [CYP2C19 inhibitor; CYP2C19        Omeprazole AUCτ ↑ 280%                 voriconazole is recommended.
and CYP3A4 substrate]              Voriconazole Cmax ↑ 15%
Voriconazole AUCτ ↑ 41%                When initiating voriconazole in patients already receiving
Other proton pump inhibitors that      omeprazole doses of 40 mg or are CYP2C19 substrates may also        above, it is recommended that be inhibited by voriconazole and       the omeprazole dose be halved.
may result in increased plasma concentrations of these medicinal products.
Oral Contraceptives*               Ethinylestradiol Cmax ↑ 36%            Monitoring for adverse reactions [CYP3A4 substrate; CYP2C19         Ethinylestradiol AUCτ ↑ 61%            related to oral contraceptives, in inhibitor]                         Norethisterone Cmax ↑ 15%              addition to those for Norethisterone/ethinylestradiol    Norethisterone AUCτ ↑ 53%              voriconazole, is recommended.
(1 mg/0.035 mg QD)                 Voriconazole Cmax ↑ 14%
Voriconazole AUCτ ↑ 46%
Short-acting Opiates                                                      Dose reduction of alfentanil, [CYP3A4 substrates]                                                       fentanyl and other short -acting opiates similar in structure to
Alfentanil (20 μg/kg single dose, In an independent published study,      alfentanil and metabolised by with concomitant naloxone)                                                CYP3A4 (sufentanil) should be Alfentanil AUC0-∞ ↑ 6-fold              considered. Extended and
Fentanyl (5 µg/kg single dose)                                            frequent monitoring for respiratory depression and other
In an independent published study,
opiate-associated adverse
Fentanyl AUC0-∞ ↑ 1.34-fold reactions is recommended.
Statins (e.g., lovastatin)          Although not studied , voriconazole   If concomitant administration of [CYP3A4 substrates]                 is 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 lead to rhabdomyolysis.               the statin should be considered.
Sulfonylureas (including but not Although not studied, voriconazole       Careful monitoring of blood limited to: tolbutamide, glipizide, is likely to increase the plasma      glucose is recommended. Dose glyburide)                          concentrations of sulfonylureas and   reduction of sulfonylureas [CYP2C9 substrates]                 cause hypoglycaemia.                  should be considered.


Medicinal product                 Interaction                           Recommendations concerning [Mechanism of interaction]        Geometric mean changes (%)             coadministration Vinca Alkaloids (including but    Although not studied, voriconazole    Dose reduction of vinca not limited to: vincristine and   is likely to increase the plasma      alkaloids should be considered.
vinblastine)                      concentrations of vinca alkaloids
[CYP3A4 substrates]               and lead to neurotoxicity.
Other HIV Protease Inhibitors (   Not studied clinically. In vitro      Careful monitoring for any including but not limited         studies show that voriconazole may    occurrence of drug toxicity to:saquinavir, amprenavir and     inhibit the metabolism of HIV         and/or lack of efficacy, and dose nelfinavir)*                      protease inhibitors and the           adjustment may be needed.
[CYP3A4 substrates and            metabolism of voriconazole may inhibitors]                       also be inhibited by HIV protease inhibitors.
Other Non-Nucleoside Reverse Not studied clinically. In vitro           Careful monitoring for any Transcriptase Inhibitors          studies show that the metabolism of   occurrence of drug toxicity (NNRTIs) (including but not       voriconazole may be inhibited by      and/or lack of efficacy, and dose limited to: delavirdine,          NNRTIs and voriconazole may           adjustment may be needed.
nevirapine)*                      inhibit the metabolism of NNRTIs.
[CYP3A4 substrates, inhibitors or The findings of the effect of
CYP450 inducers]                  efavirenz on voriconazole suggest that the metabolism of voriconazole may be induced by an NNRTI.
Tretinoin                         Although not studied, voriconazole    Dose adjustment of tretinoin is [CYP3A4 substrate]                may increase tretinoin                recommended during treatment concentrations and increase risk of   with voriconazole and after its adverse reactions (pseudotumor        discontinuation.
cerebri, hypercalcaemia).
Cimetidine (400 mg BID)           Voriconazole Cmax ↑ 18%               No dose adjustment [non-specific CYP450 inhibitor Voriconazole AUCτ ↑ 23% 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 substrate] Indinavir AUCτ ↔
Voriconazole Cmax ↔
Voriconazole AUCτ ↔
Macrolide antibiotics
No dose adjustment
Erythromycin (1 g BID)            Voriconazole Cmax and AUCτ ↔
[CYP3A4 inhibitor]

Azithromycin (500 mg QD)          Voriconazole Cmax and AUCτ ↔

The effect of voriconazole on either erythromycin or azithromycin is unknown.
Mycophenolic acid (1 g single     Mycophenolic acid Cmax ↔             No dose adjustment dose)                             Mycophenolic acid AUCt ↔
[UDP-glucuronyl transferase substrate]


Medicinal product                  Interaction                           Recommendations concerning [Mechanism of interaction]         Geometric mean changes (%)            coadministration Corticosteroids                    Prednisolone Cmax ↑ 11%               No dose adjustment Prednisolone AUC0-∞ ↑ 34%
Patients on long-term treatment
Prednisolone (60 mg single dose)                                         with voriconazole and [CYP3A4 substrate]                                                       corticosteroids (including inhaled corticosteroids e.g.,
budesonide and intranasal corticosteroids) should be carefully monitored for adrenal cortex 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]