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Drug Formulary information is intended for use by healthcare professionals. It is not intended to be medical advice. Some of the information, including information about funding for cancer drugs, does not apply to all patients. Cancer treatment plans are unique to each patient. If you are a patient, please speak with your healthcare team to understand how this information applies to you.


( RE-goe-RAF-e-nib )
Exceptional Access Program
  • regorafenib - For the treatment of metastatic and/or unresectable gastrointestinal stromal tumors (GIST) in patients who have had disease progression on, or intolerance to,
    imatinib and sunitinib, according to specific criteria
  • regorafenib - For the treatment of hepatocellular carcinoma according to clinical criteria
Other Name(s): Stivarga®
Appearance: tablet
A - Drug Name



B - Mechanism of Action and Pharmacokinetics

Regorafenib is an inhibitor of multiple protein kinases, including those involved in tumor angiogenesis (VEGFR1, ­2, ­3, TIE2), oncogenesis (KIT, RET, RAF­1, BRAF, BRAFV600E), metastasis (VEGFR3, PDGFR, FGFR) and tumour immunity (CSFIR).



Effects with food Exposure to regorafenib and its major metabolites is highest when taken with a low-fat (< 30% fat) meal as compared to either fasting or a high-fat (>50% fat) meal.

PPB 99.5% (similar for regorafenib and its metabolites)
Main enzymes involved CYP3A4, glucuronidation by UGT1A9
Active metabolites M-2 (N-oxide) & M-5 (N-oxide and N-desmethyl)
Inhibitor of UGT1A1 and UGT1A9 (clinical significance unknown), BCRP, Pgp
Half-life 20-30 hours for regorafenib and M-2, 40-100 hours for M-5
Feces 71% of dose
Urine 19% of dose
C - Indications and Status
Health Canada Approvals:

  • Treatment of metastatic colorectal cancer in patients who have been previously treated with fluoropyrimidine-based chemotherapy, oxaliplatin, irinotecan, anti-VEGF therapy, and, if RAS wild type, an anti-EGFR therapy.
  • Treatment of adult patients with metastatic and/or unresectable gastrointestinal stromal tumors (GIST) who have had disease progression on or intolerance to imatinib and sunitinib.
  • Treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. 

D - Adverse Effects

Emetogenic Potential:  

Minimal – No routine prophylaxis; PRN recommended

The following adverse effects are from a phase 3 study for metastatic colorectal cancer, where incidence is higher in the treatment arm than placebo arm.

Cardiovascular Arrhythmia (3%) I  E
Arterial thromboembolism (1%) E
Artery aneurysm (rare) E  D  L
Artery dissection (rare) E  D  L
Cardiotoxicity (1%) E  D
Hypertension (30%) (may be severe) I  E
QT interval prolonged (rare) E
Dermatological Alopecia (8%) D
Hand-foot syndrome (47%) (may be severe) E
Rash (26%) (may be severe, including SJS, TEN, etc) E
Gastrointestinal Anorexia, weight loss (47%) E  D
Diarrhea (43%) E
Gastrointestinal fistula or perforation (1%) E
Mucositis (18%) E
General Delayed wound healing E
Fatigue (64%) E
Fever (28%) E
Pain (59%) E
Hematological Anemia (6%) (severe) E
Disseminated intravascular coagulation (rare) E
Hemorrhage (21%) (GU, GI, respiratory; may be severe) E
INR / prothrombin time abnormal (4%) (severe) E
Thrombocytopenia (3%) (severe) E
Hepatobiliary ↑ Amylase / lipase (46%) E
Cholecystitis (2%) E
↑ LFTs (65%) (may be severe) E
Infection Infection (31%) (may be severe) E
Metabolic / Endocrine Abnormal electrolyte(s) (59%) (Ca, K, Na, PO4; 31% severe) E
Hypothyroidism (4%) D
Musculoskeletal Other (14%) (musculoskeletal stiffness) E
Neoplastic Secondary malignancy (Keratocanthoma/squamous cell carcinoma) (rare) D
Nervous System Dysgeusia (8%) I  E
Headache (10%) E
RPLS / PRES (rare) E
Renal Proteinuria (9%) E
Renal failure (1%) D
Respiratory Dysphonia (30%) E

* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare" may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal reports.

** I = immediate (onset in hours to days)     E = early (days to weeks)
D = delayed (weeks to months)      L = late (months to years)

The most common side effects for regorafenib include ↑ LTFs, fatigue, abnormal electrolyte(s), pain, anorexia, weight loss, hand-foot syndrome, ↑ amylase / lipase, diarrhea, infection and dysphonia.

Onset of hypertension occurred usually during the first cycle. Rare occurrences of hypertensive crisis have been reported.

Severe cases of artery dissection (with or without hypertension) and artery aneurysm (including rupture) have been reported in patients using VEGFR TKIs.

Fatal cases of GI perforation, hepatobiliary disorders, infection and hemorrhage have been observed

Prevention of palmar-plantar erythrodysesthesia (PPE) includes control of calluses and minimizing pressure stress to soles and palms. Management may include the use of keratolytic creams (e.g. urea, salicylic acid, or alpha hydroxyl acid-based creams applied sparingly only on hyperkeratotic areas) and moisturizing creams (applied liberally) for symptomatic relief.   Dose modification or interruption is required in severe, persistent cases (refer to Dosing section).

Rare severe skin reactions have been reported in clinical studies and post-market, including Steven-Johnson syndrome (SJS) and Toxic Epidermal Necrolysis (TEN).

E - Dosing

Hypertension should be controlled before initiating therapy. Regorafenib should be stopped at least 2 weeks before scheduled surgery as it may suppress wound healing.


Q4week cycle -

Oral: 160 mg once daily for 3 weeks followed by 1 week off therapy

until disease progression or unacceptable toxicity

Dosage with Toxicity:

Dose levels:

Dose level

Regorafenib dose


160 mg


120 mg


80 mg

If further dose reduction indicated or > 4 week hold for toxicity


Dosage with toxicity:

(see recommendations for supportive care as well)

Hand-foot syndrome/reaction (PPE)


For 1st occurrence continue therapy with ↓1 dose level.  If not ≤ grade 1 within 7 days, hold drug until ≤ grade 1.  If recurs, hold until ≤ grade 1 and ↓ 1 dose level


Hold for ≥7 days until Grade ≤1,
↓ 1 dose level

2 or 3

Start / increase antihypertensive. If symptomatic, hold until controlled, otherwise continue regorafenib. If cannot control with antihypertensives, ↓ 1 dose level


Hepatotoxicity (AST/ALT)


If bilirubin < 2 x ULN - ↓ 1 dose level;

If bilirubin ≥ 2 x ULN - discontinue


If bilirubin < 2 x ULN, discontinue; if must continue (i.e.  benefit > risk) - hold until AST/ALT ≤ grade 1 or baseline then ↓ 1 dose level; if recurs → discontinue.

If bilirubin ≥ 2 x ULN - discontinue

Pneumonitis Any grade Hold and investigate.  If confirmed, discontinue

Cardiac ischemia


Hold; consider discontinuing

GI perforation or fistula, arterial thromboembolism, RPLS, wound dehiscence, severe hemorrhage, severe dermatologic reaction (SJS/TEN), intolerance of 80mg dose level

Any grade

Other toxicity


Hold until ≤ grade 1 then ↓ 1 dose level


Discontinue; if benefit > risk and regorafenib must be restarted, reduce by 1 dose level

Dosage with Hepatic Impairment:

Starting Dose:
Patients with mild and moderate hepatic impairment experienced a higher incidence of adverse events than patients with normal hepatic function at baseline. Asian patients are more likely to experience hepatotoxicity.

Hepatic impairment

Regorafenib dose

Mild (Child-Pugh A)

No change

Moderate (Child-Pugh B)

No change; monitor closely

Severe (Child-Pugh C)

Avoid use; no data

Dosage with Renal Impairment:

CrCl (ml/min)

Regorafenib dose


No change


No change; monitor closely

< 30 or ESRD

No data

Dosage in the elderly:

No dose adjustments are required. No differences in safety or efficacy were observed between older and younger patients. 

Dosage based on gender:

Female patients have higher overall incidence of adverse effects as compared to males (50% vs 40%).

Dosage based on ethnicity:

Several studies suggest similar exposure in various Asian populations (Chinese, Japanese, Korean) as in Caucasians. A higher incidence of PPE, severe liver function test abnormalities and hepatic dysfunction was observed in clinical trials in Asian (Japanese in particular) patients as compared with Caucasians. Severe liver injury with fatal outcome was reported in 1.5% of Japanese patients as compared with <0.1% in non-Japanese patients.


Regorafenib should not be used in children or adolescents as efficacy and safety in patients aged less than 18 have not been established.  Abnormalities in dentition, epiphyseal hypertrophy, and adverse effects in the reproductive system have been documented in juvenile animal studies.

F - Administration Guidelines
  • Swallow tablets whole with a glass of water, after a low-fat (<30% fat) and low-calorie (~300-550 calories) meal.  Example meal: 2 slices of white toast with 1 tablespoon of low-fat margarine, 1 tablespoon of jelly and 8 ounces of skim milk (~319 calories and 8.2 grams of fat)
  • Take the dose at the same time each day.
  • A missed dose should be taken as soon as remembered on the same day. Otherwise, skip this and take the next dose on the following day.  Do not take two doses on the same day.
  • Store tablets in their original container at 15-30°C.
  • Do not remove desiccant from bottle and keep tightly closed. Protect from moisture.
  • Discard the tablets after the bottle has been opened for 7 weeks.
G - Special Precautions

  • Regorafenib is contraindicated in patients who have a hypersensitivity to this drug or any of its components, to sorafenib, or to any drugs in the same class
  • Do not use with severe hepatic impairment

Other Warnings/Precautions:

  • Blood pressure should be controlled before initiating regorafenib.
  • Stop regorafenib at least 2 weeks before scheduled surgery as it may suppress wound healing.
  • Exercise caution in patients with ischemic heart disease, low baseline heart rate (< 60 bpm), history of syncope or arrhythmia, sick sinus syndrome, SA block, AV block, CHF or on concomitant medications that decrease heart rate.
  • Patients on warfarin should be monitored closely due to increased risk of bleeding.
  • Mild hyperbilirubinemia may occur in patients with Gilbert’s syndrome.

Other Drug Properties:

  • Carcinogenicity: No information available

Pregnancy and Lactation:
  • Excretion into breast milk: Documented in animals
    Breastfeeding is not recommended.
  • Embryotoxicity: Documented in animals
  • Fertility effects: Documented in animals
  • Teratogenicity: Documented in animals
    Adequate contraception should be used by both sexes during treatment, and for at least 8 weeks after the last dose
  • Genotoxicity: Unlikely
  • Clastogenicity: Yes
H - Interactions

Concurrent administration of regorafenib with CYP 2C8, 2C9, 3A4 and 2C19 substrates is unlikely to result in clinically significant drug interactions.

CYP3A4 inhibitors (i.e. ketoconazole, clarithromycin, ritonavir, fruit or juice from grapefruit, Seville oranges or starfruit) ↑ exposure to regorafenib (± 33%) and ↓ exposure to M-2 and M-5 (± 94%) ↓ metabolism of regorafenib Avoid concomitant administration with strong CYP3A4 inhibitors
CYP3A4 inducers (i.e. phenytoin, rifampin, dexamethasone, carbamazepine, phenobarbital, St. John’s Wort, etc) ↓ exposure to regorafenib (50%) and ↑ exposure to M-5 (3-4 fold) ↑ metabolism of regorafenib Avoid concomitant administration with strong CYP3A4 inducers
BCRP substrates (i.e. methotrexate) may ↑ concentration of BCRP substrates Regorafenib is a BCRP inhibitor Caution
P-glycoprotein substrates (i.e. verapamil, digoxin, morphine, ondansetron) may ↑ concentration of Pgp substrates Regorafenib is a Pgp inhibitor Caution
UGT1A1 and 1A9 substrates (e.g. irinotecan) ↑ exposure to substrate and/or its metabolites Regorafenib and M-2 are UGT1A1/9 inhibitors, M-5 is a UGT1A1 inhibitor Caution; monitor closely as clinical significance unknown
Antibiotics Effect unclear ↓ enterohepatic circulation Caution
I - Recommended Clinical Monitoring

Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.

Recommended Clinical Monitoring

Monitor Type Monitor Frequency
Blood pressure Baseline and weekly for the first 6 weeks of therapy, then prior to every cycle or more often if required
Liver function tests (ALT, AST, bilirubin) Baseline and at least every 2 weeks during the first 2 months of therapy then at least monthly and if clinically indicated
Electrolytes, including phosphate, calcium, sodium, potassium Baseline and as clinically indicated
Thyroid function tests Baseline and as clinically indicated

Lipase, amylase

As clinically indicated

Clinical toxicity assessment for rash, fatigue, hand-foot syndrome, cardiovascular or GI effects, bleeding, neurologic or pulmonary symptoms

At each visit

Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version

Suggested Clinical Monitoring

Monitor Type Monitor Frequency


More frequently in patients receiving warfarin
Renal function tests As clinically indicated
J - Supplementary Public Funding

Exceptional Access Program (EAP Website)

  • regorafenib - For the treatment of metastatic and/or unresectable gastrointestinal stromal tumors (GIST) in patients who have had disease progression on, or intolerance to, imatinib and sunitinib, according to specific criteria ()
  • regorafenib - For the treatment of hepatocellular carcinoma according to clinical criteria

K - References

Bruix J, Qin S, Merle P, et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017 Jan 07;389(10064):56-66.

Demetri GD, Reichardt P, Kang YK, et al.  Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an international, multicentre, randomised, placebo-controlled, phase 3 trial.  Lancet. 2013;381(9863):295-302.

Grothey A, Van Cutsem E, Sobrero A, et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet 2013;381:303-12.

Prescribing Information: Stivarga® (regorafenib). Bayer Inc. February 2013.

Product Monograph: Stivarga® (regorafenib). Bayer Inc., Sept. 18, 2017.

Product Monograph Update:  Vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR TKIs).  Health Canada InfoWatch, June 2020.

Strumberg D & Schultheis B. Regorafenib for cancer. Expert Opin Investig Drugs 2012;21(6):879-89.

September 2020 Updated adverse effects (artery aneurysm / dissection) based on Health Canada warning

L - Disclaimer

Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.

The information set out in the drug monographs, regimen monographs, appendices and symptom management information (for health professionals) contained in the Drug Formulary (the "Formulary") is intended for healthcare providers and is to be used for informational purposes only. The information is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects of a particular drug, nor should it be construed to indicate that use of a particular drug is safe, appropriate or effective for a given condition. The information in the Formulary is not intended to constitute or be a substitute for medical advice and should not be relied upon in any such regard. All uses of the Formulary are subject to clinical judgment and actual prescribing patterns may not follow the information provided in the Formulary.

The format and content of the drug monographs, regimen monographs, appendices and symptom management information contained in the Formulary will change as they are reviewed and revised on a periodic basis. The date of last revision will be visible on each page of the monograph and regimen. Since standards of usage are constantly evolving, it is advised that the Formulary not be used as the sole source of information. It is strongly recommended that original references or product monograph be consulted prior to using a chemotherapy regimen for the first time.

Some Formulary documents, such as the medication information sheets, regimen information sheets and symptom management information (for patients), are intended for patients. Patients should always consult with their healthcare provider if they have questions regarding any information set out in the Formulary documents.

While care has been taken in the preparation of the information contained in the Formulary, such information is provided on an “as-is” basis, without any representation, warranty, or condition, whether express, or implied, statutory or otherwise, as to the information’s quality, accuracy, currency, completeness, or reliability.

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