Severe and sometimes fatal hepatotoxicity has occurred in clinical trials. Monitor hepatic function prior to and during treatment. Interrupt and then reduce or discontinue regorafenib for hepatotoxicity as manifested by elevated liver function tests (LFTs) or hepatocellular necrosis, depending upon severity and persistence.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Stivarga: 40 mg [contains soybean lecithin]
Mechanism of Action
Regorafenib is a multikinase inhibitor; it targets kinases involved with tumor angiogenesis, oncogenesis, and maintenance of the tumor microenvironment which results in inhibition of tumor growth. Specifically, it inhibits VEGF receptors 1-3, KIT, PDGFR-alpha, PDGFR-beta, RET, FGFR1 and 2, TIE2, DDR2, TrkA, Eph2A, RAF-1. BRAF, BRAFV600E, SAPK2, PTK5, and Abl.
A high-fat meal increased the mean AUC of the parent drug by 48% compared to the fasted state and decreased the mean AUC of the M-2 (N-oxide) and M-5 (N-oxide and N-desmethyl) active metabolites by 20% and 51%, respectively. A low-fat meal increased the mean AUC of regorafenib, M-2, and M-5 by 36%, 40% and 23%, respectively (as compared to the fasted state).
Hepatic via CYP3A4 and UGT1A9, primarily to active metabolites M-2 (N-oxide) and M-5 (N-oxide and N-desmethyl)
Feces (71%; 47% as parent compound; 24% as metabolites); Urine (19%)
Time to Peak
Regorafenib: 28 hours (range: 14 to 58 hours); M-2 metabolite: 25 hours (range: 14 to 32 hours); M-5 metabolite: 51 hours (range: 32 to 70 hours)
99.5% (active metabolites M-2 and M-5 are also highly protein bound)
Use: Labeled Indications
Colorectal cancer, metastatic: Treatment of metastatic colorectal cancer in patients previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, anti-VEGF therapy, and anti-EGFR therapy (if RAS wild type)
Gastrointestinal stromal tumors: Treatment of locally-advanced, unresectable, or metastatic gastrointestinal stromal tumor (GIST) in patients previously treated with imatinib and sunitinib
Hepatocellular carcinoma: Treatment of hepatocellular carcinoma in patients previously treated with sorafenib
There are no contraindications listed in the manufacturer's US labeling.
Canadian labeling: Hypersensitivity to regorafenib, any component of the formulation, or sorafenib.
Dosage and Administration
Colorectal cancer, metastatic: Oral: 160 mg once daily for the first 21 days of each 28-day cycle; continue until disease progression or unacceptable toxicity (Grothey 2013)
Reduced initial dosing strategy in metastatic colorectal cancer (off-label): Oral: Initial: 80 mg once daily, escalated weekly (if tolerated) to a goal of 160 mg once daily; administer on days 1 to 21 of a 28-day treatment cycle (Bekaii-Saab 2018)
Gastrointestinal stromal tumor (GIST), locally-advanced, unresectable, or metastatic: Oral: 160 mg once daily for the first 21 days of each 28-day cycle; continue until disease progression or unacceptable toxicity (Demetri 2013)
Hepatocellular carcinoma: Oral: 160 mg once daily for the first 21 days of a 28-day cycle; continue until disease progression or unacceptable toxicity (Bruix 2017)
Missed doses: Do not administer 2 doses on the same day to make up for a missed dose from the previous day.
Refer to adult dosing.
Dosing: Adjustment for Toxicity
If dose reduction is necessary, reduce in 40 mg increments; the lowest recommended dose is 80 mg/day.
Grade 2 hand-foot skin reaction (HFSR; palmar-plantar erythrodysesthesia syndrome [PPES]) of any duration: Reduce dose to 120 mg once daily for first occurrence. If grade 2 HFSR recurs at this dose, further reduce the dose to 80 mg once daily. Interrupt therapy for grade 2 HFSR that is recurrent or fails to improve within 7 days in spite of dosage reduction.
Grade 3 HFSR: Interrupt therapy for a minimum of 7 days. Upon recovery, reduce dose to 120 mg once daily. If grade 2 to 3 toxicity recurs at this dose, further reduce dose to 80 mg once daily upon recovery. Interrupt therapy for grade 2 to 3 HFSR that is recurrent or fails to improve within 7 days in spite of dosage reduction.
Recurrent or persistent HFSR at 80 mg once daily: Discontinue treatment.
Other dermatologic toxicity: Withhold treatment, reduce dose or permanently discontinue treatment depending on the severity and persistence of the dermatologic toxicity. Symptomatic relief may be managed with supportive measures.
Hypertension: Grade 2 (symptomatic): Interrupt therapy.
Infection: Grade 3 or 4 (or worsening infection of any grade): Interrupt therapy; resume regorafenib at the same dose following infection resolution.
Other toxicity: Any grade 3 or 4 adverse reaction (other than hepatotoxicity or infection): Interrupt therapy; upon recovery, reduce dose to 120 mg once daily (except infection). If any grade 3 or 4 adverse reaction occurs (other than hepatotoxicity or infection) while on this reduced dose, may further reduce dose to 80 mg once daily upon recovery. For any grade 4 adverse reaction, only resume therapy if the benefit outweighs the risk. Permanently discontinue therapy if unable to tolerate 80 mg once daily.
Gastrointestinal perforation/fistula: Discontinue permanently.
Hemorrhage (severe or life-threatening): Discontinue permanently.
Reversible posterior leukoencephalopathy syndrome (RPLS): Discontinue.
Wound dehiscence: Discontinue.
Oral: Take at the same time each day. Swallow tablet whole with water after a low-fat meal (containing <600 calories and <30% fat).
Avoid grapefruit juice.
Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Store tablets in the original bottle and protect from moisture (do not remove the desiccant); keep container tightly closed. Discard any unused tablets 7 weeks after opening the bottle.
Alpelisib: BCRP/ABCG2 Inhibitors may increase the serum concentration of Alpelisib. Management: Avoid coadministration of BCRP/ABCG2 inhibitors and alpelisib due to the potential for increased alpelisib concentrations and toxicities. If coadministration cannot be avoided, closely monitor for increased alpelisib adverse reactions. Consider therapy modification
Aprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy
BCRP/ABCG2 Substrates: Regorafenib may increase the serum concentration of BCRP/ABCG2 Substrates. Monitor therapy
Beta-Blockers: Regorafenib may enhance the bradycardic effect of Beta-Blockers. Monitor therapy
Bisphosphonate Derivatives: Angiogenesis Inhibitors (Systemic) may enhance the adverse/toxic effect of Bisphosphonate Derivatives. Specifically, the risk for osteonecrosis of the jaw may be increased. Monitor therapy
Bosentan: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy
Calcium Channel Blockers (Nondihydropyridine): Regorafenib may enhance the bradycardic effect of Calcium Channel Blockers (Nondihydropyridine). Monitor therapy
Cladribine: BCRP/ABCG2 Inhibitors may increase the serum concentration of Cladribine. Management: Avoid concomitant use of BCRP inhibitors during the 4 to 5 day oral cladribine treatment cycles whenever possible. If combined, consider dose reduction of the BCRP inhibitor and separation in the timing of administration. Consider therapy modification
Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy
Conivaptan: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination
CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy
CYP3A4 Inducers (Strong): May decrease the serum concentration of Regorafenib. Avoid combination
CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy
CYP3A4 Inhibitors (Strong): May increase the serum concentration of Regorafenib. Avoid combination
Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification
Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy
Digoxin: Regorafenib may enhance the bradycardic effect of Digoxin. Monitor therapy
Duvelisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy
Erdafitinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy
Erdafitinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy
Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy
Fosnetupitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy
Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination
Grapefruit Juice: May increase the serum concentration of Regorafenib. Avoid combination
Idelalisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination
Irinotecan Products: UGT1A1 Inhibitors may increase serum concentrations of the active metabolite(s) of Irinotecan Products. Specifically, concentrations of SN-38 may be increased. UGT1A1 Inhibitors may increase the serum concentration of Irinotecan Products. Avoid combination
Ivabradine: Regorafenib may enhance the bradycardic effect of Ivabradine. Monitor therapy
Ivosidenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy
Larotrectinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy
Lorlatinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Avoid concurrent use of lorlatinib with any CYP3A4 substrates for which a minimal decrease in serum concentrations of the CYP3A4 substrate could lead to therapeutic failure and serious clinical consequences. Consider therapy modification
Neomycin: May decrease serum concentrations of the active metabolite(s) of Regorafenib. Monitor therapy
Netupitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy
Palbociclib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy
PAZOPanib: BCRP/ABCG2 Inhibitors may increase the serum concentration of PAZOPanib. Avoid combination
Sarilumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy
Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy
Simeprevir: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy
St John's Wort: May decrease the serum concentration of Regorafenib. Avoid combination
Stiripentol: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification
Talazoparib: BCRP/ABCG2 Inhibitors may increase the serum concentration of Talazoparib. Monitor therapy
Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy
Topotecan: BCRP/ABCG2 Inhibitors may increase the serum concentration of Topotecan. Avoid combination
Ubrogepant: BCRP/ABCG2 Inhibitors may increase the serum concentration of Ubrogepant. Management: Use an initial ubrogepant dose of 50 mg and second dose (if needed) of 50 mg when used with a BCRP inhibitor. Consider therapy modification
Warfarin: May enhance the adverse/toxic effect of Regorafenib. Specifically, the risk for bleeding may be increased. Monitor therapy
Cardiovascular: Hypertension (30% to 59%)
Central nervous system: Fatigue (≤64%), pain (55% to 59%), voice disorder (18% to 39%), headache (10% to 16%)
Dermatologic: Palmar-plantar erythrodysesthesia (45% to 67%), skin rash (26% to 30%), alopecia (7% to 24%)
Endocrine & metabolic: Hypophosphatemia (55% to 70%), hypocalcemia (17% to 59%), weight loss (13% to 32%), hypokalemia (21% to 31%), hyponatremia (30%), increased amylase (23% to 26%), hypothyroidism (6% to 18%)
Gastrointestinal: Gastrointestinal pain (60%), diarrhea (41% to 47%), decreased appetite (31% to 47%), increased serum lipase (14% to 46%), stomatitis (13% to 40%; grade ≥3: 1% to 4%), nausea (17% to 20%), vomiting (13% to 17%)
Hematologic & oncologic: Anemia (79%; grade 3: 5%; grade 4: 1%), lymphocytopenia (30% to 68%; grade 3: 8% to 16%; grade 4: 2%), thrombocytopenia (13% to 63%; grade 3: 1% to 5%; grade 4: <1%), increased INR (24% to 44%; grade 3: 4%), hemorrhage (11% to 21%; grade ≥3: 2% to 5%), neutropenia (3% to 16%; grade 3: 1% to 3%; grade 4: 1%)
Hepatic: Increased serum aspartate aminotransferase (58% to 93%), hyperbilirubinemia (33% to 78%), increased serum alanine aminotransferase (45% to 70%)
Infection: Infection (31% to 32%)
Neuromuscular & skeletal: Asthenia (≤64%), muscle spasm (10% to 14%)
Renal: Proteinuria (51% to 84%)
Miscellaneous: Fever (20% to 28%)
1% to 10%:
Dermatologic: Exfoliative dermatitis (1%)
Gastrointestinal: Mucocutaneous candidiasis (≤3%), pancreatitis (2%)
Genitourinary: Urinary tract infection (6%)
Hepatic: Hepatic failure (≤2%)
Infection: Fungal infection (≤3%)
Neuromuscular & skeletal: Tremor (1%)
Respiratory: Nasopharyngitis (4%), pneumonia (3%)
Frequency not defined: Hepatic: Hepatotoxicity
<1%, postmarketing, and/or case reports: Acute myocardial infarction, cardiac failure, erythema multiforme, gastrointestinal fistula, gastrointestinal perforation, hepatic injury, hypersensitivity reaction, hypertensive crisis, ischemic heart disease, nephrotic syndrome, reversible posterior leukoencephalopathy syndrome, Stevens-Johnson syndrome, toxic epidermal necrolysis
Concerns related to adverse effects:
- Cardiovascular events: Myocardial ischemia and infarction were observed at a higher incidence than placebo in a clinical trial. Interrupt therapy in patients who develop new or acute onset ischemia or infarction; resume only if the benefit of therapy outweighs the cardiovascular risk.
- Dermatologic toxicity: Skin reactions occurred commonly, including hand-foot skin reaction (HFSR), also known as palmar-plantar erythrodysesthesia syndrome (PPES), and severe rash requiring dose reduction. Grade 3 or 4 HFSR was observed more frequently in regorafenib-treated patients (compared to placebo), and although rare, erythema multiforme and Stevens Johnson syndrome were also observed more frequently in regorafenib-treated patients. Toxic epidermal necrolysis has also been reported (rare). Onset of HFSR typically occurs in the first cycle of treatment. Therapy interruptions, dosage reductions, and/or discontinuation may be necessary depending on the severity and persistence. Supportive treatment may be of benefit for symptomatic relief. Pooled data from several clinical trials showed a higher incidence of HFSR in Asian patients compared to Caucasians.
In addition to recommended dosage modifications, the following treatments may be used for management of HFSR (McLellan 2015): A manicure/pedicure to remove hyperkeratotic areas/calluses which may predispose to HFSR and mechanical support/correction for abnormal weight bearing prior to treatment are recommended. During treatment, patients should use alcohol-free moisturizers liberally, reduce exposure to hot water (may exacerbate hand-foot symptoms), avoid constrictive footwear and excessive skin friction, and avoid vigorous exercise/activities that may stress hands or feet. Patients should wear thick cotton gloves/socks and wear shoes with padded insoles. Grade 1 HFSR may be relieved with moisturizing creams, cotton gloves and socks (at night) and/or keratolytic creams such as urea (10% to 40%) or salicylic acid (6%) along with a topical analgesic (eg, lidocaine gel) to relieve pain. Apply topical steroid (eg, clobetasol ointment or foam) twice daily to erythematous areas of grade 2 HFSR (in addition to continuing grade 1 management); topical analgesics and then systemic analgesics (if appropriate) may be used for pain control; dose reduction may be necessary. Grade 3 HFSR should be managed by continuing grades 1 and 2 symptomatic management and interrupting treatment for at least 7 days until resolved to grade 1 or lower.
- Gastrointestinal perforation: Gastrointestinal perforation or fistula has occurred in a small number of patients treated with regorafenib; some cases were fatal. Monitor for signs/symptoms of perforation (fever, abdominal pain with constipation, and/or nausea/vomiting); permanently discontinue if perforation or fistula develop.
- Hemorrhage: The incidence of hemorrhage was increased with regorafenib. Hemorrhage of the respiratory, gastrointestinal, or genitourinary tracts was observed in trials; some cases were fatal. Permanently discontinue in patients who experience severe or life-threatening bleeding. In patients receiving concomitant warfarin, monitor INR frequently.
- Hepatotoxicity: [US Boxed Warning]: Severe and sometimes fatal hepatotoxicity has been observed in clinical trials. Monitor hepatic function at baseline and during treatment. Interrupt therapy for hepatotoxicity; dose reductions or discontinuation are necessary depending on the severity and persistence. Hepatic dysfunction, characterized by a hepatocellular injury pattern, typically occurred with the first 2 months of treatment in clinical trials. Closely monitor in patients with mild or moderate impairment for adverse events; use is not recommended in severe impairment. A higher incidence of hepatotoxicity has been observed in Asian patients (particularly Japanese), compared to Caucasians (Li 2015).
- Hypersensitivity: Hypersensitivity reactions have been observed with regorafenib.
- Hypertension: Elevated blood pressure was observed in clinical trials (onset typically in the first cycle of therapy); ensure blood pressure is adequately controlled prior to initiation. Monitor blood pressure weekly for the first 6 weeks and monthly thereafter or as clinically indicated; if hypertension develops, interrupt therapy or permanently discontinue for severe or uncontrolled hypertension. Hypertensive crisis has occurred in some patients. Patients 65 years and older had an increased incidence of grade 3 or higher hypertension (compared to younger patients).
- Infection: An increased rate of infection (including fatal events) was observed in regorafenib-treated patients in clinical trials. The most commonly reported infections were urinary tract infections, nasopharyngitis, mucocutaneous and systemic fungal infections, and pneumonia. Respiratory infections were the most commonly reported fatal infections. Interrupt therapy for grade 3 or 4 infections (or worsening infection of any grade).
- Reversible posterior leukoencephalopathy syndrome (RPLS): RPLS occurred very rarely in regorafenib-treated patients; evaluate promptly if symptoms (eg, seizures, severe headache, visual disturbances, confusion or altered mental function) occur. Discontinue if diagnosis is confirmed.
- Wound healing impairment: Regorafenib inhibits vascular endothelial growth factor, which may lead to impaired wound healing. Discontinue regorafenib at least 2 weeks prior to scheduled surgery; resume regorafenib postsurgery based on clinical judgment of wound healing; discontinue if wound dehiscence occurs.
Concurrent drug therapy issues:
- Drug-drug/drug-food interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.
- Asian patients: A higher incidence of hepatotoxicity and hand-foot skin reactions were observed in Asian patients, particularly in Japanese patients, compared to non-Asian patients (Li 2015).
- Colorectal cancer: Consider a reduced initial dose in patients with metastatic colorectal cancer. In a dose escalation study comparing an initial dose of 80 mg/day (escalated gradually to 160 mg/day on days 1 to 21 every 28 days) to the standard dose (160 mg/day on days 1 to 21 every 28 days), more patients receiving the lower initial dose were able to initiate a third treatment cycle. The lower initial dose demonstrated a favorable toxicity profile as well as improved median overall survival compared to the standard dose (Bekaii-Saab 2018).
Obtain liver function tests at baseline, every 2 weeks during the first 2 months of treatment, then monthly or more frequently if clinically necessary (weekly until improvement if liver function tests are elevated). CBC with differential and platelets and serum electrolytes (baseline and periodic). Monitor INR more frequently if receiving warfarin. Monitor blood pressure weekly for the first 6 weeks of therapy and with every subsequent cycle, or more frequently if indicated. Monitor for hand-foot skin reaction (HFSR)/palmar-plantar erythrodysesthesia syndrome (PPES); it is recommended to monitor for signs of HFSR during the first weeks of treatment, then every 1 to 2 weeks for 2 cycles, then every 4 to 6 weeks thereafter (McLellan 2015). Monitor for signs/symptoms of cardiac ischemia or infarction, bleeding, GI perforation or fistula, infection, and reversible posterior leukoencephalopathy syndrome (severe headaches, seizure, confusion, or change in vision). Monitor for impaired wound healing. Monitor adherence.
Based on animal reproduction studies and on the mechanism of action, regorafenib may cause fetal harm if administered during pregnancy. Women of reproductive potential and men with female partners of reproductive potential should use effective contraception during therapy and for at least 2 months following treatment.
What is this drug used for?
- It is used to treat cancer.
Frequently reported side effects of this drug
- Weight loss
- Mouth irritation
- Change in voice
- Abdominal pain
- Muscle spasm
- Hair loss
Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:
- Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin.
- Posterior reversible encephalopathy syndrome like confusion, not alert, vision changes, seizures, or severe headache
- Bleeding like vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding
- Fluid and electrolyte problems like mood changes, confusion, muscle pain or weakness, abnormal heartbeat, severe dizziness or passing out, fast heartbeat, increased thirst, seizures, loss of strength and energy, lack of appetite, unable to pass urine or change in amount of urine passed, dry mouth, dry eyes, or nausea or vomiting
- Low thyroid level like constipation; difficulty handling heat or cold; memory problems; mood changes; or burning, numbness, or tingling feeling
- Severe headache
- Vision changes
- Redness or irritation of palms or soles of feet
- Severe dizziness
- Passing out
- Chest pain
- Shortness of breath
- Severe loss of strength and energy
- Abdominal edema
- Stevens-Johnson syndrome/toxic epidermal necrolysis like red, swollen, blistered, or peeling skin [with or without fever]; red or irritated eyes; or sores in mouth, throat, nose, or eyes
- Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.
Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.
Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.