Regorafenib

Registered South African indications:

• Metastatic colorectal cancer
• Gastrointestinal stromal tumours

Contraindications

• Hypersensitivity to the active ingredient or any of its excipients

Cautions

• Pregnancy
• Breastfeeding
• Moderate to severe hepatic impairment
• Gilbert's syndrome
• Asian descent (in particular Japanese)
• Patients with conditions predisposing them to bleeding
• Intra-abdominal malignancies
• Unstable angina
• New onset angina (within 3 months)
• Recent myocardial infarction (within 6 months)
• Cardiac failure
• History of ischaemic heart disease
• Hypertension
• History of aneurysm
• Risk factors for aneurysms/arterial dissections
• Major surgical procedures
• Patients under wound care therapy
• Hepatocellular carcinoma patients who discontinued sorafenib therapy (see additional prescribing points)
• Sodium controlled diet
• Soya intolerance

Forms avail. in SA and covered in this monograph: tab

Used for the treatment of

• Metastatic colorectal cancer
  - Previously treated with, or are not considered candidates for, fluoropyrimidine-based chemotherapy, an anti-VEGF therapy, and, if KRAS wild type, an anti-EGFR therapy
• Unresectable or metastatic gastrointestinal stromal tumours
  - Who progressed on or are intolerant to prior treatment with 2 tyrosine kinase inhibitors (imatinib and sunitinib)
• Hepatocellular carcinoma
  - Previously treated with sorafenib

Consult specialist for dosages and regimens

Not established for use in children

Pregnancy

• Caution; positive evidence of risk
• There is no data on the use of regorafenib in pregnant women
• Based on its mechanism of action, regorafenib is suspected to cause foetal harm when administered during pregnancy. Animal studies have shown reproductive toxicity
• Women of childbearing potential must be informed that regorafenib may cause foetal harm
• Women of childbearing potential and men should ensure effective contraception during treatment and up to 8 weeks after completion of therapy
• Regorafenib should not be used during pregnancy unless clearly necessary and after careful consideration of the benefits of the mother and the risk to the foetus

Breastfeeding

• Caution; not recommended
• It is unknown whether regorafenib or its metabolites are excreted in human milk. In rats, regorafenib or its metabolites are excreted in milk
• A risk to the breastfed child cannot be excluded. Regorafenib could harm infant growth and development
• Breastfeeding must be discontinued during treatment with regorafenib

Fertility

• There is no data on the effect of regorafenib on human fertility. Results from animal studies indicate that regorafenib can impair male and female fertility

Renal Impairment

• No dose adjustment recommended

Hepatic Impairment

• Mild (Child-Pugh Class A): No dose adjustment recommended
• Moderate (Child-Pugh Class B): Caution; no dose adjustment recommended
  Since only limited data is available for these patients, no dose recommendation can be provided. Close monitoring of overall safety is recommended in these patients
• Severe (Child-Pugh Class C): Caution; no information available
  Use is not recommended since regorafenib has not been studied in this population

Elderly

• No dose adjustment recommended

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Headache
• Tremor
• Peripheral neuropathy
• Posterior reversible encephalopathy syndrome (PRES)
  - Seizures
  - Headache
  - Altered mental status
  - Visual disturbance
  - Cortical blindness
  - Hypertension
• Fatigue

Cardiovascular Disorders

• Myocardial infarction
• Myocardial ischaemia
• Haemorrhage
• Hypertension
• Hypertensive crisis
• Aneurysms and artery dissections

Respiratory Disorders

• Dysphonia
• Pneumonia

Gastrointestinal Disorders

• Diarrhoea
• Stomatitis
• Nausea and vomiting
• Dry mouth
• Gastro-oesophageal reflux
• Gastroenteritis
• Gastrointestinal perforation
• Gastrointestinal fistula
• Pancreatitis

Hepatobiliary Disorders

• Hyperbilirubinaemia
• Increased transaminases
  - Abnormal alanine aminotransferase
  - Abnormal aspartate aminotransferase
  - Abnormal bilirubin
• Severe hepatic injury

Genitourinary Disorders

• Proteinuria

Endocrine and Metabolic Disorders

• Hypothyroidism
• Decreased appetite
• Hypokalaemia
• Hypophosphataemia
• Hypocalcaemia
• Hyponatraemia
• Hypomagnesaemia
• Hyperuricaemia
• Dehydration
• Weight loss
• Increase in amylase
• Increase in lipase

Musculoskeletal Disorders

• Muscle spasms

Skin and Subcutaneous Tissue Disorders

• Hand-foot skin reaction (palmar-plantar erythrodysesthesia syndrome)
• Rash
• Alopecia
• Dry skin
• Exfoliative rash
• Nail disorder
• Erythema multiforme
• Stevens-Johnson syndrome
• Toxic epidermal necrolysis
• Mucosal inflammation
• Squamous cell carcinoma of the skin

Immune, Blood and Lymphatic System Disorders

• Thrombocytopenia
• Anaemia
• Leucopenia
• Infection
  Urinary tract infections
  - Nasopharyngitis
  - Mucocutaneous and systemic fungal infections
• Decreased haemoglobin
• Keratoacanthoma
• Hypersensitivity reaction
• Abnormal international normalised ratio
• Neutropenia
• Lymphopenia
• Fever

Sensory Disorders

• Taste disorders

Other

• Pain

• Strong CYP3A4 inhibitors
• Clarithromycin
• Itraconazole
• Ketoconazole
• Posaconazole
• Telithromycin
• Voriconazole
• UGT1A9 inhibitors
• Mefenamic acid
• Diflunisal
• Niflumic acid
• CYP3A4 inducers
• Rifampicin
• Phenytoin
• Carbamazepine
• Phenobarbital
• UGT1A1 and UGT1A9 substrates
• Irinotecan
• Breast cancer resistance protein substrates
• Rosuvastatin
• Methotrexate
• Fluvastatin
• Atorvastatin
• P-glycoprotein and breast cancer resistance protein inhibitors
• P-glycoprotein and breast cancer resistance protein inducers
• Bile salt-sequestering agents 
• Cholestyramine
• Cholestagel
• Neomycin
• St John's wort
• Grapefruit juice

• Hepatic function
• Full blood count with differential and platelets
• Electrolytes
• Blood pressure

Specific cases may require

• International normalized ratio

Disease-specific precautions - Hepatocellular carcinoma

• In the pivotal placebo-controlled phase III study, patients received prior therapy with sorafenib
• There is insufficient data on patients who discontinued sorafenib therapy due to sorafenib-related toxicity or only tolerated a low dose (<400mg daily) of sorafenib
• The tolerability of regorafenib in these patients has not been established

Regorafenib is an oral tumour deactivation agent that potently blocks multiple protein kinases, including kinases involved in tumour angiogenesis (VEGFR1, -2, -3, TIE2), oncogenesis (KIT, RET, RAF-1, BRAF, BRAF^V600E), metastasis (VEGFR3, PDGFR, FGFR) and tumour immunity (CSF1R). In particular, regorafenib inhibits mutated KIT, a major oncogenic driver in gastrointestinal stromal tumours, and thereby blocks tumour cell proliferation. 

Tablet 40mg

• Stivarga (Bayer) originator