Nexavar Drug Interactions

CYP3A4 Inducers: CYP1A2 and CYP3A4 activities were not altered after treatment of cultured human hepatocytes with sorafenib, indicating that sorafenib is unlikely to be an inducer of CYP1A2 and CYP3A4. Continuous concomitant administration of sorafenib and rifampicin resulted in an average 37% reduction of sorafenib AUC. Other inducers of CYP3A4 activity (eg, Hypericum perforatum also known as St. John's wort, phenytoin, carbamazepine, phenobarbital and dexamethasone) may also increase metabolism of sorafenib and thus decrease sorafenib concentrations.
CYP3A4 Inhibitors: Ketoconazole, a potent inhibitor of CYP3A4, administered once daily for 7 days to healthy male volunteers did not alter the mean AUC of a single 50-mg dose of sorafenib. Therefore, clinical pharmacokinetic interactions of sorafenib with CYP3A4 inhibitors are unlikely.
CYP2C9 Substrates: The possible effect of sorafenib on warfarin, a CYP2C9 substrate, was assessed in sorafenib-treated patients compared to placebo-treated patients. The concomitant treatment with sorafenib and warfarin did not result in changes in mean PT-INR compared to placebo. However, patients taking warfarin should have their INR checked regularly (see Precautions).
CYP Isoform-Selective Substrates: Concomitant administration of midazolam, dextromethorphan and omeprazole, which are substrates of cytochromes CYP3A4, CYP2D6 and CYP2C19, respectively, following 4 weeks of sorafenib administration did not alter the exposure of these agents. This indicates that sorafenib is neither an inhibitor nor an inducer of these cytochrome P-450 isoenzymes. In a separate clinical study, concomitant administration of sorafenib with paclitaxel resulted in an increase, instead of a decrease, in the exposure of 6-OH paclitaxel, the active metabolite of paclitaxel that is formed by CYP2C8. These data suggest that sorafenib may not be an in vivo inhibitor of CYP2C8. In another clinical study, concomitant administration of sorafenib with cyclophosphamide resulted in a small decrease in cyclophosphamide exposure, but no decrease in the systemic exposure of 4-OH cyclophosphamide, the active metabolite of cyclophosphamide that is formed primarily by CYP2B6. These data suggest that sorafenib may not be an in vivo inhibitor of CYP2B6.
Combination with Other Antineoplastic Agents: In clinical studies, sorafenib has been administered together with a variety of other antineoplastic agents at their commonly used dosing regimens, including gemcitabine, cisplatin, oxaliplatin, paclitaxel, carboplatin, capecitabine, doxorubicin, docetaxel, irinotecan and cyclophosphamide. Sorafenib had no clinically relevant effect on the pharmacokinetics of gemcitabine, cisplatin, carboplatin, oxaliplatin, or cyclophosphamide.
Paclitaxel/Carboplatin: Administration of paclitaxel (225 mg/m²) and carboplatin (AUC=6) with sorafenib (≤400 mg twice daily), administered with a 3-day break in sorafenib dosing around administration of paclitaxel/carboplatin, resulted in no significant effect on the pharmacokinetics of paclitaxel.
Co-administration of paclitaxel (225 mg/m², once every 3 weeks) and carboplatin (AUC=6) with sorafenib (400 mg twice daily, without a break in sorafenib dosing) resulted in a 47% increase in sorafenib exposure, a 29% increase in paclitaxel exposure and a 50% increase in 6-OH paclitaxel exposure. The pharmacokinetics of carboplatin were unaffected.
These data indicate no need for dose adjustments when paclitaxel and carboplatin are co-administered with sorafenib with a 3-day break in sorafenib dosing. The clinical significance of the increases in sorafenib and paclitaxel exposure, upon co-administration of sorafenib without a break in dosing, is unknown.
Capecitabine: Co-administration of capecitabine (750-1050 mg/m² twice daily, days 1-14 every 21 days) and sorafenib (200 or 400 mg twice daily, continuous uninterrupted administration) resulted in no significant change in sorafenib exposure, but a 15-50% increase in capecitabine exposure and a 0-52% increase in 5-FU exposure. The clinical significance of these small to modest increases in capecitabine and 5-FU exposure when co-administered with sorafenib is unknown.
Doxorubicin/Irinotecan: Concomitant treatment with sorafenib resulted in a 21% increase in the AUC of doxorubicin. When administered with irinotecan, whose active metabolite SN-38 is further metabolized by the UGT1A1 pathway, there was a 67-120% increase in the AUC of SN-38 and a 26-42% increase in the AUC of irinotecan. The clinical significance of these findings is unknown (see Precautions).
Docetaxel (75 or 100 mg/m² administered once every 21 days) when co-administered with sorafenib (200 mg twice daily or 400 mg twice daily administered on day 2 through 19 of a 21-day cycle), with a 3-day break in dosing, around administration of docetaxel, resulted in a 36-80% increase in docetaxel AUC and a 16-32% increase in docetaxel C_max. Caution is recommended when sorafenib is co-administered with docetaxel (see Precautions).
Combination with Antibiotics: Co-administration of neomycin, a non-systemic antimicrobial agent used to eradicate gastrointestinal flora, interferes with the enterohepatic recycling of sorafenib (see Pharmacokinetics under Actions), resulting in decreased sorafenib exposure. In healthy volunteers treated with a 5-day regimen of neomycin the average bioavailability of sorafenib decreased by 54%. The clinical significance of these findings is unknown. Effects of other antibiotics have not been studied, but will likely depend on their ability to decrease glucuronidase activity.
Combination with Proton-Pump Inhibitors: Omeprazole: Co-administration of omeprazole has no impact on the pharmacokinetics of sorafenib. No dose adjustment for sorafenib is necessary.