Drugs List

Therapeutic Indications

Uses

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.

Contraindications

Children under 18 years
Breastfeeding
Pregnancy
Severe hepatic impairment

Precautions and Warnings

East Asian ancestry
Females of childbearing potential
Predisposition to haemorrhage
Restricted sodium intake
Tobacco smoking
Angina
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
Hyperlipidaemia
Hypertension
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

Pregnancy

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 ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Lactation

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 https://www.midlandsmedicines.nhs.uk/content.asp?section=6&subsection=17&pageIdx=1

Side Effects

Alopecia
Anaemia
Asthenia
Decrease in haemoglobin
Decreased appetite
Dehydration
Diarrhoea
Dry mouth
Dry skin
Dysphonia
Elevated amylase levels
Elevated serum lipase
Elevated TSH
Erythema multiforme
Exfoliative rash
Fatigue
Gastro-enteritis
Gastro-intestinal fistulae
Gastro-intestinal perforation
Gastroesophageal reflux disease
Haemorrhage
Headache
Hyperbilirubinaemia
Hypersensitivity reactions
Hypertension
Hypertensive crisis
Hyperuricaemia
Hypocalcaemia
Hypokalaemia
Hypomagnesaemia
Hyponatraemia
Hypophosphataemia
Hypothyroidism
Increase of liver transaminases
Infections
Keratoacanthoma
Leucopenia
Lymphopenia
Malaise
Mucosal inflammation
Musculoskeletal disturbances
Myocardial infarction
Myocardial ischaemia
Nail disorders
Nausea
Neutropenia
Pain
Palmar-plantar erythrodysaesthesia
Posterior reversible encephalopathy syndrome (PRES)
Proteinuria
Prothrombin time increased
Pyrexia
Rash
Serum bilirubin increased
Severe hepatocellular damage
Squamous cell carcinoma
Stevens-Johnson syndrome
Stomatitis
Taste disturbances
Thrombocytopenia
Toxic epidermal necrolysis
Tremor
Vomiting
Weight loss

Presentation

Oral formulations of regorafenib

Drugs List

Therapeutic Indications

Uses

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.

Dosage

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.

Adults

Patients with Hepatic Impairment

Additional Dosage Information

Contraindications

Children under 18 years
Breastfeeding
Pregnancy
Severe hepatic impairment

Precautions and Warnings

East Asian ancestry
Females of childbearing potential
Predisposition to haemorrhage
Restricted sodium intake
Tobacco smoking
Angina
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
Hyperlipidaemia
Hypertension
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

Pregnancy

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 ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Lactation

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 https://www.midlandsmedicines.nhs.uk/content.asp?section=6&subsection=17&pageIdx=1

Counselling

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

Alopecia
Anaemia
Asthenia
Decrease in haemoglobin
Decreased appetite
Dehydration
Diarrhoea
Dry mouth
Dry skin
Dysphonia
Elevated amylase levels
Elevated serum lipase
Elevated TSH
Erythema multiforme
Exfoliative rash
Fatigue
Gastro-enteritis
Gastro-intestinal fistulae
Gastro-intestinal perforation
Gastroesophageal reflux disease
Haemorrhage
Headache
Hyperbilirubinaemia
Hypersensitivity reactions
Hypertension
Hypertensive crisis
Hyperuricaemia
Hypocalcaemia
Hypokalaemia
Hypomagnesaemia
Hyponatraemia
Hypophosphataemia
Hypothyroidism
Increase of liver transaminases
Infections
Keratoacanthoma
Leucopenia
Lymphopenia
Malaise
Mucosal inflammation
Musculoskeletal disturbances
Myocardial infarction
Myocardial ischaemia
Nail disorders
Nausea
Neutropenia
Pain
Palmar-plantar erythrodysaesthesia
Posterior reversible encephalopathy syndrome (PRES)
Proteinuria
Prothrombin time increased
Pyrexia
Rash
Serum bilirubin increased
Severe hepatocellular damage
Squamous cell carcinoma
Stevens-Johnson syndrome
Stomatitis
Taste disturbances
Thrombocytopenia
Toxic epidermal necrolysis
Tremor
Vomiting
Weight loss

Overdosage

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 ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

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: https://www.gov.uk/drug-safety-update/systemically-administered-vegf-pathway-inhibitors-risk-of-aneurysm-and-artery-dissection
Last accessed: 10 November 2020

NICE Evidence Services Available at: www.nice.org.uk Last accessed: 06 April 2018

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