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The main drug-drug interactions associated with regorafenib include

CYP3A4 Inhibitors/ Inducers

CYP3A4 Inducers

Co-administration of rifampicin increased metabolism of regorafenib, reducing the regorafenib AUC by ~50% and increasing exposure to the active metabolite M-5 by 3- to 4-fold.1,2

CYP3A4 Inhibitors

Co-administration of ketoconazole increased regorafenib exposure by approximately 33%, and decreased exposure to the active metabolites M-2 and M-5 by approximately 90%.1-3

QT Prolongators

Regorafenib and Antineoplastic Agents

Regorafenib increased the AUC of irinotecan and its active metabolite SN-38 by 28% and 44%, respectively, in patients with colorectal cancer; this interaction occurred even with a 4-day interval separating irinotecan and regorafenib dosing.4 (See below: UGT1A1 and UGT1A9 substrates).

Other Drug-drug Interactions

UGT1A9 Inhibitors

Avoid co-administration of a strong UGT1A9 inhibitor with regorafenib as there is currently a lack of data on this interaction.2

UGT1A1 and UGT1A9 Substrates

Regorafenib may increase systemic exposure to UGT1A1 and UGT1A9 substrates. In vitro, regorafenib and its active metabolite M-2 inhibit glucuronidation mediated by UGT1A1 and UGT1A9.2

Breast Cancer Resistance Protein and P-glycoprotein Substrates

Regorafenib may increase the plasma concentrations of concomitant BCRP or P-glycoprotein substrates. Regorafenib, M‑2 and M-5 are in vitro inhibitors of both BCRP and P-glycoprotein.2

BCRP and P-glycoprotein Inducers and Inhibitors

P-glycoprotein may interfere with exposure to M-2 and M-5, which are substrates for both BCRP and P-glycoprotein in vitro, but the clinical relevance of these findings is unknown.2

CYP Isoform-Selective Substrates

At concentrations achieved in vivo, regorafenib is a competitive inhibitor of cytochromes CYP2C8, CYP2C9, and CPYP2B6. However, pharmacokinetic data show no clinically relevant drug interaction when regorafenib is given with substrates of CYP2C8, CYP2C9, CYP3A4, and CYP2C19.2


As regorafenib and its metabolites appear to undergo enterohepatic circulation, co-administration of antibiotics that affect the gastrointestinal flora may interfere with this circulation and decrease regorafenib exposure, potentially decreasing efficacy.2

Bile Salt-Sequestering Agents

Bile salt-sequestering agents (e.g. cholestyramine and Cholestagel) may form insoluble complexes with regorafenib which may reduce absorption (or reabsorption), thus potentially decreasing exposure to, and clinical efficacy of, regorafenib.2


  1. Food and Drug Administration. Regorafenib (STIVARGA) Prescribing information. 2015.
  2. European Medicines Agency. Regorafenib (STIVARGA). Summary of Product Characteristics. 2015.
  3. van Leeuwen RW, van Gelder T, Mathijssen RH, Jansman FG. Drug-drug interactions with tyrosine-kinase inhibitors: a clinical perspective. Lancet Oncol 2014; 15: e315-326.
  4. Schultheis B, Folprecht G, Kuhlmann J et al. Regorafenib in combination with FOLFOX or FOLFIRI as first- or second-line treatment of colorectal cancer: results of a multicenter, phase Ib study. Ann Oncol 2013; 24: 1560-1567.

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