The main drug-drug interactions associated with vemurafenib include

CYP3A4 Inhibitors/ Inducers

CYP3A4 Inhibitors1,2

Base on in vitro data, vemurafenib is a substrate of CYP3A4, and therefore, concomitant administration of strong CYP3A4 inhibitors may alter vemurafenib concentrations. Strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) should be used with caution when coadministered with vemurafenib.

CYP3A Inducers1,2

Base on in vitro data, vemurafenib is a substrate of CYP3A4, and therefore, concomitant administration of strong CYP3A4 inducers may alter vemurafenib concentrations. Strong CYP3A4 inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) should therefore be used with caution when co-administered with vemurafenib.

QT Prolongators

None reported.

Other Drug-Drug Interactions

Effect on Drug Metabolising Enzymes1,2

Based on an in vivo drug-drug interaction study in patients with cancer, vemurafenib is a moderate CYP1A2 inhibitor, a weak CYP2D6 inhibitor and a CYP3A4 inducer:

  • Vemurafenib increased the AUC of dextromethorphan (CYP2D6 substrate) by 47%
  • Vemurafenib decreased decreased the AUC of midazolam (CYP3A4 substrate) by 39%
  • Vemurafenib increased the AUC of S-warfarin CYP2C (substrate) 18%

Concomitant use of vemurafenib with agents with narrow therapeutic windows that are metabolised by CYP1A2, CYP2D6 and CYP3A4 is not recommended as vemurafenib may alter their concentrations. If co-administration cannot be avoided, these agents should be administered with caution and dose reduction of the concomitant CYP1A2 and CYP2D6 substrate drug should be considered. When vemurafenib is administered with warfarin, caution should be exercised, and additional INR monitoring considered.

References

  1. European Medicines Agency. Vemurafenib (ZELBORAF). Summary of Product Characteristics. 2015.
  2. Food and Drug Administration. Vemurafenib (ZELBORAF) Prescribing information. 2015.

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