Drug information of Regorafenib


Regorafenib is an orally-administered inhibitor of multiple kinases. It is used for the treatment of metastatic colorectal cancer and advanced gastrointestinal stromal tumours.

Mechanism of effect

Tyrosine kinase inhibitor; shown to inhibit activity of membrane-bound and intracellular kinases involved in normal cellular functions and in pathological processes (eg, oncogenesis, tumor angiogenesis) RET, VEGFR1, VEGFR2, VEGFR3, KIT, PDGFR-alpha, PDGFR-beta, FGFR1, FGFR2, TIE2, DDR2, Trk2A, Eph2A, RAF-1, BRAF, BRAFV600E, SAPK2, PTK5, and Abl


Bioavailability: 69-83% (with low fat meal)

Peak Plasma Time: 4 hr

Peak Plasma Concentration: 2.5 mcg/mL (single dose); 3.9 mcg/mL (steady-state)

AUC: 70.4 mcg•h/mL (single dose); 58.3 mcg•h/mL (steady-state)

Protein Bound: 99.5% (regorafenib); 99.8% (M-2 active metabolite); 99.95% (M-5 active metabolite)

Undergoes enterohepatic circulation with multiple plasma concentration peaks observed during 24-hr interval


Metabolized by CYP3A4 and UGT1A9

Metabolites (active): M-2 (N-oxide) and M-5 (N-oxide and N-desmethyl), both of them having similar in vitro pharmacological activity and steady-state concentrations as regorafenib

Half-life: 28 hr (regorafenib); 25 hr (M-2 active metabolite); 51 hr (M-5 active metabolite)

Excretion: 71% feces; 19% urine (within 12 days of single dose)

Drug indications

Colorectal Cancer , liver cancer

  • It is used to treat colorectal cancer.
  • It is used to treat cancer of the GI (gastrointestinal) tract.
  • It is used to treat liver cancer.



Colorectal Cancer

160 mg (four 40-mg tablets) PO qDay for the first 21 days of each 28-day cycle

Continue treatment until disease progression or unacceptable toxicity

Gastrointestinal Stromal Tumors

160 mg (four 40-mg tablets) PO qDay for the first 21 days of each 28-day cycle

Continue treatment until disease progression or unacceptable toxicity

Hepatocellular Carcinoma

160 mg (four 40-mg tablets) PO qDay for the first 21 days of each 28-day cycle

Continue treatment until disease progression or unacceptable toxicity


Safety and efficacy not established

Side effects

Alopecia , Anemia, , Asthenia/fatigue, Decreased appetite or food intake , Diarrhea, Dysphonia , Fever, Headache , Hemorrhage, HFSR/PPES, Hyperbilirubinemia, Hypertension, Hypocalcemia, Hypokalemia, Hyponatremia , Hypophosphatemia, Hypothyroidism , Increased amylase, Increased AST/ALT, Increased INR , Increased lipase, Infection, Lymphopenia, Mucositis, Muscle spasms , Musculoskeletal stiffness , Nausea, Neutropenia, Pain, Proteinuria, Rash , Thrombocytopenia, Tremor , Vomiting , Weight loss

atazanavir, bosentan, carbamazepine, clarithromycin, conivaptan, dabrafenib, darunavir, delavirdine, dexamethasone, elvitegravir/cobicistat/emtricitabine/tenofovir df, enzalutamide, eslicarbazepine acetate, etravirine, fosamprenavir, fosphenytoin, grapefruit, imatinib, indinavir, isoniazid, ketoconazole, lopinavir, nafcillin, nefazodone, nelfinavir, nevirapine, nicardipine, oxcarbazepine, pentobarbital, phenobarbital, phenytoin, posaconazole, primidone, quinidine, rifabutin, rifampin, rifapentine, ritonavir, saquinavir, st john's wort, tipranavir, voriconazole, apalutamide, efavirenz, idelalisib, itraconazole, ivosidenib, palifermin, talazoparib


Increases risk for hemorrhage; discontinue therapy for severe or life-threatening hemorrhage

Increased risk of infections reported; most common infections include urinary tract infections, nasopharyngitis, mucocutaneous and systemic fungal infections and pneumonia

Increases risk for HFSR/PPES and rash; a higher incidence of HFSR reported in Asian patients; interrupt and then reduce or discontinue regorafenib depending on severity and persistence of dermatologic toxicity

Hypertension may occur, typically during the first treatment cycle; do not initiate therapy unless blood pressure is adequately controlled; monitor blood pressure weekly for first 6 weeks of treatment and then every cycle, or more frequently, as clinically indicated; temporarily or permanently withhold therapy for severe or uncontrolled hypertension

Myocardial ischemia and infarction observed in clinical trials; withhold regorafenib for new or acute cardiac ischemia/infarction and resume only after resolution of acute ischemic events

One case report of reversible posterior leukoencephalopathy syndrome (RPLS) reported (1 of 1100 treated patients); discontinue therapy if RPLS occurs

Discontinue therapy if gastrointestinal perforation or fistula occur

May impair wound healing (class effect of VEGFR inhibitors); discontinue at least 2 weeks before scheduled surgery; discontinue therapy in patients with wound dehiscence

Embryo-fetal toxicity likely if taken while pregnant

Drug interactions overview

  • Strong CYP3A4 inhibitors
    • Coadministration with strong CYP3A4 inhibitors increases regorafenib plasma concentrations, decreased active metabolite (M-2 and M-5) plasma concentrations, and may increase toxicity
    • Avoid concomitant use of regorafenib with strong CYP3A4 inhibitors (eg, clarithromycin, grapefruit juice, itraconazole, ketoconazole, nefazodone, posaconazole, telithromycin, and voriconazole)
  • Breast cancer resistance protein (BCRP) substrates
    • Coadministration with a BCRP substrate increases the BCRP substrate plasma concentrations
    • Closely monitor for signs and symptoms of exposure-related toxicity of the BCRP substrate (eg, methotrexate, fluvastatin, atorvastatin)
  • UGT substrates
    • Regorafenib competitively inhibits UGT1A9 and UGT1A1 substrates

Black Box Warnings


  • Severe and sometimes fatal hepatotoxicity observed in clinical trials
  • Monitor hepatic function prior to and during treatment
  • Interrupt and then reduce or discontinue for hepatotoxicity as manifested by elevated liver function tests or hepatocellular necrosis, depending upon severity and persistence

Points of recommendation

  • Tell all of your health care providers that you take regorafenib. This includes your doctors, nurses, pharmacists, and dentists.
  • Avoid grapefruit and grapefruit juice.
  • High blood pressure has happened with regorafenib. Have your blood pressure checked as you have been told by your doctor.
  • You may have more of a chance of getting an infection. Wash hands often. Stay away from people with infections, colds, or flu. Some infections have been very bad and even deadly.
  • You may bleed more easily. Be careful and avoid injury. Use a soft toothbrush and an electric razor.
  • Very bad and sometimes deadly bleeding problems have happened with regorafenib. Talk with the doctor.
  • A very bad and sometimes deadly brain problem called posterior reversible encephalopathy syndrome (PRES) has happened with regorafenib. Call your doctor right away if you have signs like feeling confused, lowered alertness, change in eyesight, loss of eyesight, seizures, or very bad headache.
  • Very bad and sometimes deadly holes in the GI (gastrointestinal) tract or fistulas have happened with regorafenib. Talk with the doctor.
  • A very bad skin reaction (Stevens-Johnson syndrome/toxic epidermal necrolysis) may happen. It can cause very bad health problems that may not go away, and sometimes death. Get medical help right away if you have signs like red, swollen, blistered, or peeling skin (with or without fever); red or irritated eyes; or sores in your mouth, throat, nose, or eyes.
  • This medicine may affect how wounds heal. If you need to have surgery, you may need to stop regorafenib before surgery. Start taking it again after surgery as you have been told by your doctor. Talk with your doctor.
  • If you have upset stomach, throwing up, diarrhea, or are not hungry, talk with your doctor. There may be ways to lower these side effects.
  • If you are taking warfarin, talk with your doctor. You may need to have your blood work checked more closely while you are taking it with regorafenib.
  • This medicine may affect fertility. Fertility problems may lead to not being able to get pregnant or father a child. Talk with the doctor.
  • If you are a man and have sex with a female who could get pregnant, protect her from pregnancy during care and for 2 months after stopping regorafenib. Use birth control that you can trust.
  • If you are a man and your sex partner gets pregnant while you take regorafenib or within 2 months after your last dose, call your doctor right away.
  • This medicine may cause harm to the unborn baby if you take it while you are pregnant.
  • Use birth control that you can trust during care and for 2 months after care ends.
  • If you get pregnant while taking regorafenib or within 2 months after your last dose, call your doctor right away.
  • Take regorafenib by mouth with water after a low-fat meal. The low-fat meal must be less than 600 calories and less than 30% fat.
  • Take regorafenib at the same time of day.
  • Swallow whole. Do not chew, break, or crush.
  • Take a missed dose as soon as you think about it on the same day you missed the dose.
  • If you do not think about the missed dose until the next day, skip the missed dose and go back to your normal time.
  • Do not take 2 doses on the same day.

Pregnancy level


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