Regorafenib


Thông tin thuốc gốc
Chỉ định và Liều dùng
Oral
Metastatic colorectal cancer, Unresectable, metastatic malignant gastrointestinal stromal tumours
Adult: In patients who have been previously treated w/ or are not candidates for available therapies: 160 mg once daily for 21 days of each 28-day cycle. Continue treatment until disease progression or if unacceptable toxicity occurs. Missed doses: Do not admin 2 doses on the same day to make up for a missed dose.
Special Patient Group
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.
Hepatic Impairment
Severe: Not recommended.
Cách dùng
Should be taken with food. Take at the same time each day w/ a low-fat meal (<30% fat).
Thận trọng
Severe hepatic impairment. Pregnancy and lactation.
Phản ứng phụ
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.
MonitoringParameters
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.
Quá liều
Symptoms: Dermatological events, dysphonia, diarrhoea, mucosal inflammation, dry mouth, decreased appetite, HTN, fatigue. Management: Supportive treatment. Observe until clinical stabilisation.
Tương tác
Increased exposure w/ strong CYP3A4 inhibitors (e.g. ketoconazole). Decreased exposure w/ strong CYP3A4 inducers (e.g. rifampicin).
Food Interaction
Food increases absorption. Altered serum concentration w/ grapefruit or grapefruit juice. Decreased exposure w/ St John’s wort.
Tác dụng
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, BRAFV600E), 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.
Đặc tính

Chemical Structure Image
Regorafenib

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

Bảo quản
Store at 25°C. Protect from moisture.
Phân loại MIMS
Phân loại ATC
L01XE21 - regorafenib ; Belongs to the class of protein kinase inhibitors, other antineoplastic agents. Used in the treatment of cancer.
References
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.

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