This site is intended for UK healthcare professionals
Medscape UK Univadis Logo
Medscape UK Univadis Logo

Regorafenib oral


Oral formulations of regorafenib

Drugs List

  • regorafenib 40mg film coated tablets
  • STIVARGA 40mg film coated tablets
  • Therapeutic Indications


    Hepatocellular carcinoma
    Metastatic colorectal cancer
    Unresectable or metastatic malignant gastrointestinal stromal tumour (GIST)

    Metastatic colorectal cancer (CRC) in patients who have been previously treated with, or are not considered candidates for available therapies.

    Unresectable or metastatic gastrointestinal stromal tumours (GIST) in patients who progressed on or are intolerant to prior treatment with imatinib or sunitinib.

    Hepatocellular carcinoma (HCC) in patients who have been previously treated with sorafenib.


    Whilst the doses stated below are those recommended by the manufacturer, local cancer network protocols for the relevant indication should be consulted.

    Treatment should continue as long as the drug is beneficial or an unacceptable level of toxicity occurs.


    160mg (four 40mg tablets) taken once daily for 3 weeks followed by 1 week off therapy. This 4 week period is considered a treatment cycle.
    The dose should be administered at the same time each day.

    Patients with Hepatic Impairment

    ALT/AST elevations below 5 times the upper limit of normal (ULN) (maximum Grade 2)
    Continue regorafenib treatment. Monitor liver function weekly until transaminases return to below 3 times ULN (Grade 1) or baseline.
    ALT/AST elevations between 5 to 20 times the ULN (Grade 3)
    First occurrence
    Interrupt regorafenib treatment. Monitor transaminases weekly until return to below 3 times ULN (Grade 1) or baseline. Restart if the potential benefit outweighs the risk of hepatotoxicity. If restarting regorafenib treatment, reduce dose by 40mg, and monitor liver function weekly for at least 4 weeks.
    Discontinue treatment with regorafenib permanently.

    ALT/AST elevations above 20 times the ULN (Grade 4)
    Discontinue treatment with regorafenib permanently.

    ALT/AST elevations above 3 times the ULN (Grade 2 or higher) with concurrent bilirubin above 2 times the ULN
    Discontinue treatment with regorafenib permanently. Monitor liver function weekly until resolution or return to baseline.

    Patients with Gilbert's syndrome who develop elevated transaminases should be managed as per the above outlined recommendations for the respective observed elevation of ALT and/or AST.

    Additional Dosage Information

    Dose interruptions and/or dose reductions may be required based on individual safety and tolerability. Dose modifications are to be applied in 40mg steps. The lowest recommended daily dose is 80mg. The maximum daily dose is 160mg.

    Recommended dose modifications and measures for hand-foot skin reactions/palmar-plantar erythrodysesthesia syndrome
    Skin toxicity Grade 1
    Maintain dose level and immediately initiate supportive measures for symptomatic relief.
    Skin toxicity Grade 2
    First occurrence
    Decrease dose by 40mg and immediately institute supportive measures. If no improvement occurs despite dose reduction, interrupt therapy for a minimum of 7 days, until toxicity resolves to Grade 0 or 1.
    No improvement within 7 days or second occurrence
    Interrupt therapy until toxicity resolves to Grade 0 to 1. When restarting treatment, decrease dose by 40mg. Dose re-escalations may be considered.
    Third occurrence
    Interrupt therapy until toxicity resolves to Grade 0 to 1. When restarting treatment, decrease dose by 40mg. Dose re-escalations may be considered.
    Fourth occurrence
    Discontinue treatment with regorafenib permanently.
    Skin toxicity Grade 3
    First occurrence
    Institute supportive measures immediately. Interrupt therapy for a minimum of 7 days until toxicity resolves to Grade 0 to 1. When restarting treatment, decrease dose by 40mg.
    Second occurrence
    Institute supportive measures immediately. Interrupt therapy for a minimum of 7 days until toxicity resolves to Grade 0 to 1. When restarting treatment, decrease dose by 40mg.
    Third occurrence
    Discontinue treatment with regorafenib permanently.


    Children under 18 years
    Severe hepatic impairment

    Precautions and Warnings

    East Asian ancestry
    Females of childbearing potential
    Predisposition to haemorrhage
    Restricted sodium intake
    Tobacco smoking
    Behcet's disease
    Cerebrovascular disorder
    Diabetes mellitus
    Giant cell arteritis
    Gilbert's syndrome
    Haematological disorder
    Hepatic cirrhosis
    History of aneurysm
    History of ischaemic heart disease
    Ischaemic heart disease
    Marfan syndrome
    Moderate hepatic impairment
    New York Heart Association class II failure
    Occlusive peripheral arterial disease
    Takayasu arteritis
    Uncontrolled hypertension
    Vascular Ehlers-Danlos syndrome
    Within 6 months of a myocardial infarction

    Contains more than 1 mmol (23 mg) sodium per dose
    Advise ability to drive/operate machinery may be affected by side effects
    Ensure hypertension is controlled prior to treatment
    Treatment to be prescribed under the supervision of a specialist
    Contains soya or soya derivative
    Consult local policy on the safe use of oral anti-cancer drugs
    Staff: Not to be handled by pregnant staff
    Monitor hepatic function prior to treatment
    Monitor blood counts regularly
    Monitor blood pressure regularly
    Monitor cardiac function in patients with cardiac disease
    Monitor coagulation values
    Monitor for symptoms of gastrointestinal perforation or fistula
    Monitor LFTs every two weeks for 8 weeks, then monthly and as required
    Monitor serum amylase and lipase regularly
    Monitor serum electrolytes
    Monitor thyroid function regularly
    Advise patient to report headaches, seizures, confusion, visual disturbance
    Reduce dose if hypertension cannot be controlled
    Treatment may adversely affect wound healing
    Consider discontinuation if severe haematological events occur
    Discontinue if fistulae develop during treatment
    Discontinue if posterior reversible encephalopathy syndrome (PRES) develops
    Discontinue if severe haemorrhage occurs
    Discontinue permanently if hypertensive crisis occurs
    Discontinue treatment if gastrointestinal perforation occurs
    Interrupt therapy/reduce dose if palmar-plantar erythrodysaesthesia occurs
    Interrupt treatment if cardiac ischaemia and/or infarction develop
    Reduce dose or interrupt treatment if liver function tests worsen
    Temporary interruption of treatment is recommended before major surgery
    Consider interrupting treatment if infection occurs
    Advise patient not to take St John's wort concurrently
    Advise patient grapefruit products may increase plasma level
    May cause impaired fertility
    Female: Contraception required during and for 2 months after treatment
    Male: Contraception required during and for 2 months after treatment
    Advise patient on giving up smoking

    Posterior reversible encephalopathy syndrome (PRES) has been reported in some patients treated with this agent. If patients present with symptoms indicating PRES (such as headache, altered mental state, seizures and visual disturbances) an MRI should be performed. If PRES is diagnosed, treatment should be discontinued and adequate blood pressure and seizure control administration is advisable. The safety of reinstating treatment in patients previously experiencing PRES is unknown.

    Mild, indirect (unconjugated) hyperbilirubinaemia may occur in patients with Gilbert's syndrome.

    Measures for the prevention of palmar-plantar erythrodysesthesia syndrome (PPE) include control of calluses and use of shoe cushions and gloves to prevent pressure stress to soles and palms. Management of PPE may include the use of keratolytic creams and moisturising creams for symptomatic relief. Dose reduction and/or temporary interruption of regorafenib, or in severe or persistent cases, permanent discontinuation of regorafenib should be considered.

    A higher incidence of PPE, hepatic enzyme abnormalities and hepatic dysfunction were observed in Asian patients (particularly Japanese) compared to Caucasian patients. Of the Asian patients participating in the clinical studies, 90% were East Asian.

    Risk factors for aneurysm and artery dissection
    Use of systemic VEGF inhibitors may promote the formation of aneurysms or artery dissections, mainly in relation to aortic aneurysm rupture and aortic dissection. It is therefore important to consider the risk of aneurysm and artery dissection in patients with risk factors such as hypertension, history of aneurysm, smoking, diabetes, coronary, cerebrovascular or peripheral arterial disease, and hyperlipidaemia. Other risk factors include Marfan syndrome, vascular Ehlers-Danlos syndrome, Takayasu arteritis, and the use of fluoroquinolones. In patients receiving VEGF inhibitors, any modifiable risk factors such as smoking and hypertension should be reduced as far as possible.

    Pregnancy and Lactation


    Regorafenib is contraindicated in pregnancy.

    At the time of writing there is limited published information regarding the use of regorafenib during pregnancy. Animal studies have shown reproductive toxicity. The manufacturer states that mechanism of action of regorafenib is suspected to cause foetal harm when administered during pregnancy, and that regorafenib should not be used during pregnancy unless clearly necessary, and after careful consideration of the benefits for the mother and the risk to the foetus.

    It is not known if regorafenib (or its active metabolites) cross the human placenta. The molecular weight and long elimination half life suggest the drug does cross the to the embryo-foetus, however the high plasma protein binding might limit the exposure (Briggs, 2015).

    The use of all medication in pregnancy should be avoided whenever possible; particularly in the first trimester. Non-drug treatments should also be considered. When essential, a medication with the best safety record over time should be chosen, employing the lowest effective dose for the shortest possible time. Polypharmacy should be avoided. Teratogens taken in the pre-embryonic period, often quoted as lasting until 14 to 17 days post-conception, are believed to have an all-or-nothing effect. Where drugs have a short half-life, and when the date of conception is certain, this may allow women to be reassured where drug exposure has occurred within this time frame. Further advice may be available from the UK National Teratology Information Service (NTIS) and through ToxBase, available via password on the internet ( ) or if this is unavailable at the backup site ( ).


    Regorafenib is contraindicated in breastfeeding.

    It is unknown whether regorafenib (or its metabolites) are excreted in human milk, but its molecular weight and long elimination half life would suggest the drug is likely to be excreted into human breast milk. Consequently, a risk to breastfed neonates cannot be excluded. The severe toxicity of the drug in adults suggests that women taking regorafenib should not breastfeed (Briggs, 2015). In rats, regorafenib and its metabolites are excreted in milk.

    The manufacturer suggests that regorafenib could harm infant growth and development.

    Neonates, infants born prematurely, those with low birth weight, those with an unstable gastrointestinal function or who have serious illnesses may require special consideration. For any infant, if a drug is prescribed to the nursing mother, it should be at the lowest practical dose and for the shortest time. When drug administration is unavoidable and breastfeeding is to continue, minimisation of exposure of the infant to the drug may sometimes be achieved by timing the maternal doses to just after a feeding episode. Infants exposed to drugs via breast milk should be monitored for unusual signs or symptoms. Interactions between the drug received by the infant from the mother's milk and medication prescribed for the infant should also be considered, for example, when the drug given to the infant may prevent metabolism of the drug received via breast milk.
    Specialist advice is available from the UK Drugs in Lactation Advisory Service at


    Advise patient if a dose is missed, then it should be taken on the same day as soon as the patient remembers. The patient should not take two doses on the same day to make up for a missed dose. In case of vomiting after regorafenib administration, the patient should not take additional tablets.

    Advise patient to take after a low fat meal (less than 30%).

    Advise patient not to take St Johns wort concurrently.

    Advise patient to avoid grapefruit products. Advise patient to report headaches, seizures, confusion and visual disturbances.

    Advise patient to use contraception during and for 2 months after treatment. Advise patient that their ability to drive and operate machinery may be affected by side effects.

    Side Effects

    Decrease in haemoglobin
    Decreased appetite
    Dry mouth
    Dry skin
    Elevated amylase levels
    Elevated serum lipase
    Elevated TSH
    Erythema multiforme
    Exfoliative rash
    Gastro-intestinal fistulae
    Gastro-intestinal perforation
    Gastroesophageal reflux disease
    Hypersensitivity reactions
    Hypertensive crisis
    Increase of liver transaminases
    Mucosal inflammation
    Musculoskeletal disturbances
    Myocardial infarction
    Myocardial ischaemia
    Nail disorders
    Palmar-plantar erythrodysaesthesia
    Posterior reversible encephalopathy syndrome (PRES)
    Prothrombin time increased
    Serum bilirubin increased
    Severe hepatocellular damage
    Squamous cell carcinoma
    Stevens-Johnson syndrome
    Taste disturbances
    Toxic epidermal necrolysis
    Weight loss


    It is strongly recommended that the UK National Poisons Information Service be consulted on cases of suspected or actual overdose where there is doubt over the degree of risk or about appropriate management.

    The following number will direct the caller to the relevant local centre (0844) 892 0111

    Information may be obtained if you have access to ToxBase the primary clinical toxicology database of the National Poisons Information Service. This is available via password on the internet ( ) or if this is unavailable at the backup site ( ).

    Further Information

    Last Full Review Date: April 2018

    Reference Sources

    Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk, 10th edition (2015) ed. Briggs, G., Freeman, R. Wolters Kluwer Health, Philadelphia.

    MHRA Drug Safety Update July 2020
    Available at:
    Last accessed: 10 November 2020

    NICE Evidence Services Available at: Last accessed: 06 April 2018

    Summary of Product Characteristics: Stivarga 40 mg film-coated tablets. Bayer plc. Revised August 2017.

    Access the full UK drug database with a FREE Medscape UK Account
    It takes just a few minutes, and you’ll get unlimited access to information on over 11,000 UK drugs.
    Register for Free

    Already a member? Log in

    Medscape UK | Univadis prescription drug monographs & interactions are based on FDB Multilex Content

    FDB Logo

    FDB Disclaimer : FDB Multilex is intended for the use of healthcare professionals and is provided on the basis that the healthcare professionals will retain FULL and SOLE responsibility for deciding what treatment to prescribe or dispense for any particular patient or circumstance.