Les renseignements du Formulaire de médicaments s’adressent aux professionnels de la santé. Il ne s’agit pas d’un avis médical. Certains des renseignements, y compris ceux sur le financement des médicaments anticancéreux, ne s’appliquent pas à tous les patients. Les plans de traitement du cancer sont propres à chaque patient. Si vous êtes un patient, veuillez parler avec votre équipe soignante pour comprendre comment ces renseignements s’appliquent à vous.
regorafenib
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).
Bioavailability |
70-83% |
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 |
- Colorectal cancer
- Gastrointestinal stromal tumors (GIST)
- Hepatocellular carcinoma (HCC)
Refer to the product monograph for a full list and details of approved indications.
Emetogenic Potential:
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.
ORGAN SITE | SIDE EFFECT* (%) | ONSET** | |||
---|---|---|---|---|---|
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%) (arterial; 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 | ||||
Posterior reversible encephalopathy syndrome (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 hand-foot syndrome (HFS) 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).
Refer to protocol by which the patient is being treated.
Screen for hepatitis B virus in all cancer patients starting systemic treatment. Refer to the hepatitis B virus screening and management guideline.
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
Dose Level |
Regorafenib Dose |
0 |
160 mg |
-1 |
120 mg |
-2 |
80 mg |
If further dose reduction indicated or > 4 week hold for toxicity |
Discontinue |
Dosage with toxicity:
Toxicity
|
Grade
|
Action
|
Hand-foot syndrome |
2
|
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 |
3
|
Hold for ≥7 days until Grade ≤1, |
|
Hypertension
|
2 or 3
|
Start / increase antihypertensive. If symptomatic, hold until controlled, otherwise continue regorafenib. If cannot control with antihypertensives, ↓ 1 dose level |
4
|
Discontinue
|
|
Hepatotoxicity (AST/ALT) |
2
|
If bilirubin < 2 x ULN - ↓ 1 dose level; If bilirubin ≥ 2 x ULN - discontinue |
3
|
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 |
|
4
|
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
|
Discontinue
|
Other toxicity |
3
|
Hold until ≤ grade 1 then ↓ 1 dose level |
4
|
Discontinue; if benefit > risk and regorafenib must be restarted, reduce by 1 dose level |
Patients with mild and moderate hepatic impairment experienced a higher incidence of adverse events than patients with normal hepatic function at baseline.
Hepatic Impairment |
Regorafenib Dose |
Mild (Child-Pugh A) |
No change; monitor closely |
Moderate (Child-Pugh B) |
No change; monitor closely |
Severe (Child-Pugh C) |
Avoid use; no data |
CrCl (mL/min) |
Regorafenib Dose |
≥ 60 |
No change |
30 - 59 |
No change; monitor closely |
15 - 29 |
No change; monitor closely |
< 15 or ESRD | No data |
Female patients have higher overall incidence of adverse effects as compared to males (50% vs 40%).
Several studies suggest similar exposure in various Asian populations (Chinese, Japanese, Korean) as in Caucasians. A higher incidence of HFS, 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.
- 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.
- 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
- 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:
Unknown
-
Genotoxicity:
Unlikely
-
Clastogenicity:
Yes
-
Embryotoxicity:
Documented in animals
-
Teratogenicity:
Documented in animals
Regorafenib is not recommended for use in pregnancy. Adequate contraception should be used by patients and their partners during treatment, and for at least 8 weeks after the last dose
-
Excretion into breast milk:
Documented in animals
Breastfeeding is not recommended during treatment and for 2 weeks after the last dose.
-
Fertility effects:
Documented in animals
Concurrent administration of regorafenib with CYP 2C8, 2C9, 3A4 and 2C19 substrates is unlikely to result in clinically significant drug interactions.
AGENT | EFFECT | MECHANISM | MANAGEMENT |
---|---|---|---|
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 |
Drugs that result in bradycardia | ↑ risk of bradycardia | Additive | Avoid if possible |
BCRP substrates (i.e. methotrexate, fluvastatin, atorvastatin, rosuvastatin) | ↑ exposure to BCRP substrates | Regorafenib is a BCRP inhibitor | Caution; monitor for substrate toxicity |
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 |
Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.
Refer to the hepatitis B virus screening and management guideline for monitoring during and after treatment.
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 as clinically indicated |
Renal function tests |
Baseline and before each cycle |
Electrolytes (including phosphate, calcium, sodium, potassium), ECG |
Baseline and as clinically indicated (especially in patients at risk of developing QT prolongation) |
Thyroid function tests | Baseline and 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
Monitor Type | Monitor Frequency |
---|---|
INR |
More frequently in patients receiving warfarin |
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 unresectable, advanced hepatocellular carcinoma (HCC) according to clinical criteria
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 and December 2020.
Product Monograph: Stivarga® (regorafenib). Bayer Inc., March 2020.
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.
August 2023 Modified Indications, Adverse effects, Dosage in renal impairment, Pregnancy/breastfeeding, Interactions and Monitoring sections
Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.
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