Regorafenib

Oral
Metastatic colorectal cancer, Unresectable, metastatic malignant gastrointestinal stromal tumours

Patients who develop toxicity during treatment:

Hepatotoxicity:
Grade 3 [(AST/ALT >5-≤20 times upper limit of normal (ULN)]: 1st occurrence: Interrupt therapy until return to <3 times ULN or baseline. If benefit outweighs toxicity risk, resume therapy at a reduced dose of 120 mg once daily. Recurrence: Discontinue permanently.
Grade 4 (AST/ALT >20 times ULN): Discontinue permanently.
Grade 2 or higher (AST/ALT >3 times ULN) and bilirubin >2 times ULN: Discontinue permanently.

Hand-foot skin reaction (HFSR)/palmar-plantar erythrodysesthesia (PPE) syndrome: Grade 2: 1st occurrence: Reduce dose to 120 mg once daily, may further reduce to 80 mg once daily if HFSR recurs at this dose. Recurrent or no improvement w/in 7 days after dose reduction: Interrupt therapy.
Grade 3: 1st occurrence: Interrupt therapy for a min of 7 days. Upon recovery, reduce dose to 120 mg once daily, may further reduce to 80 mg once daily if HFSR recurs at this dose. Recurrent or no improvement w/in 7 days after dose reduction: Interrupt therapy. Recurrent or persistent HFSR at 80 mg once daily: Discontinue treatment.

Other toxicity:
Any grade 3 or 4 adverse reaction (other than hepatotoxicity): Interrupt therapy; upon recovery, reduce dose to 120 mg once daily. If any grade 3 or 4 adverse reaction occurs 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.

HTN: Grade 2 (symptomatic): Interrupt therapy.
Reveresible posterior leukoencephalopathy syndrome; impaired wound healing: Discontinue.
GI perforation/fistula; haemorrhage: Discontinue permanently.

Severe: Not recommended.

Should be taken with food. Take at the same time each day w/ a low-fat meal (<30% fat).

Severe hepatic impairment. Pregnancy and lactation.

Myocardial ischaemia and infarction, HTN, reversible posterior leukoencephalopathy syndrome, hand-foot skin reaction (HFSR) or palmar-plantar erythrodysesthesia (PPE) syndrome, rash, erythema multiforme, Stevens Johnsons syndrome, GI and abdominal pain, fever, electrolyte and metabolic abnormalities, asthenia/fatigue, diarrhoea, decreased appetite, nausea, mucositis, dysphonia, infection, impaired wound healing. Rarely, toxic epidermal necrolysis.
Potentially Fatal: Hepatotoxicity, haemorrhage, GI perforation or fistula.

PO: D

Obtain LFTs (ALT, AST, bilirubin) prior to and during treatment; CBC w/ differential and platelets and serum electrolytes. Monitor BP; hand-foot skin reaction, impaired wound healing; signs/symptoms of cardiac ischaemia or infarction, bleeding, GI perforation or fistula, reversible posterior leukoencephalopathy syndrome.

Symptoms: Dermatological events, dysphonia, diarrhoea, mucosal inflammation, dry mouth, decreased appetite, HTN, fatigue. Management: Supportive treatment. Observe until clinical stabilisation.

Increased exposure w/ strong CYP3A4 inhibitors (e.g. ketoconazole). Decreased exposure w/ strong CYP3A4 inducers (e.g. rifampicin).

Food increases absorption. Altered serum concentration w/ grapefruit or grapefruit juice. Decreased exposure w/ St John’s wort.

Description: Regorafenib, a tyrosine kinase inhibitor, potently blocks multiple protein kinase, including kinases involved in tumour angiogenesis (VEGFR1, -2, -3, TIE2), oncogenesis (KIT, RET, RAF-1, BRAF, BRAF^V600E), and maintenance of the tumour microenvironment (PDGFR, FGFR).
Pharmacokinetics:
Absorption: Increased absorption w/ food. Bioavailability: 69% (tab); 83% (oral soln). Time to peak plasma concentration: Approx 3-4 hr.
Distribution: Plasma protein binding: 99.5%.
Metabolism: Metabolised in the liver; converted primarily to active metabolites M-2 (N-oxide) and M-5 (N-oxide and N-desmethyl) via oxidative metabolism by CYP3A4 enzymes and also via glucuronidation by UGT1A9 enzymes.
Excretion: Via faeces (approx 71%, as unchanged drug and metabolites) and urine (approx 19% as glucuronides). Elimination half-life: 20-30 hr.

Source: National Center for Biotechnology Information. PubChem Database. Regorafenib, CID=11167602, https://pubchem.ncbi.nlm.nih.gov/compound/Regorafenib (accessed on Jan. 22, 2020)

Store at 25°C. Protect from moisture.

Targeted Cancer Therapy

L01EX05 - regorafenib ; Belongs to the class of other protein kinase inhibitors. Used in the treatment of cancer.

Anon. Regorafenib. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 23/09/2015.

Buckingham R (ed). Regorafenib . Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 23/09/2015.

McEvoy GK, Snow EK, Miller J et al (eds). Regorafenib. AHFS Drug Information (AHFS DI) [online]. American Society of Health-System Pharmacists (ASHP). https://www.medicinescomplete.com. Accessed 23/09/2015.

Stivarga Tablet, Film Coated (Bayer HealthCare Pharmaceuticals Inc.). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/. Accessed 23/09/2015.