Hepatotoxicity
- Hepatotoxicity that was severe and occasionally deadly was seen in clinical studies.
- Monitor the hepatic function before and during treatment.
- As evidenced by increased liver function tests or hepatic necrosis, interrupt, then decrease or stop the treatment, depending on the severity and duration of the hepatotoxicity.
Allopathy
Prescription Required
DCGI (Drugs Controller General of India)
Schedule H
India, the United States, Switzerland, Canada, countries within the European Union, Australia, Argentina, Japan and South Korea.
Regorafenib is an antineoplastic agent belonging to the pharmacological class of tyrosine kinase inhibitors.
The FDA approved Regorafenib for treating metastatic colorectal cancer, gastrointestinal stromal tumours (GIST), and hepatocellular carcinoma (HCC).
The gastrointestinal system absorbs Regorafenib, and taking it with meals improves absorption. 83% of the oral solution and 69% of the tablets have bioavailability. The drug is mainly excreted in the urine and faeces after being metabolized in the liver by CYP3A4 enzymes.
The most common side effects of Regorafenib include infection, low blood platelets, anaemia, decreased appetite, bleeding, and high blood pressure.
Regorafenib is available in oral tablets.
The molecule is available in India, the United States, Switzerland, Canada, countries within the European Union, Australia, Argentina, Japan and South Korea.
Regorafenib is an antineoplastic agent belonging to the pharmacological class of tyrosine kinase inhibitors.
Regorafenib is an intracellular, multiple membrane-bound kinase involved in normal cellular activities and pathologic processes, including tumour angiogenesis, oncogenesis, and microenvironment maintenance. The activity of RET, VEGFR1, VEGFR2, VEGFR3, KIT, PDGFR-alpha, PDGFR-beta, FGFR1, FGFR2, TIE2, DDR2, TrkA, Eph2A, RAF-1, BRAF, BRAFV600E, SAPK2, PTK5, and Abl was inhibited in vitro biochemical or cellular assays by regorafenib or its primary human active metabolites M-2 and M-5. Regorafenib showed anti-angiogenic efficacy in a rat tumour model; numerous mice xenograft models, including several for human colorectal cancer, also suggested suppression of tumour development and anti-metastatic activity.
Regorafenib reaches peak plasma time at 4 hours after administration.
Regorafenib achieves a peak plasma concentration of 2.5 mcg/mL with a single dose and 3.9 mcg/mL at steady-state.
Regorafenib exhibits an area under the curve (AUC) of 70.4 mcg•h/mL with a single dose and 58.3 mcg•h/mL at steady-state.
Regorafenib is available in oral tablets.
Tablet: To be swallowed whole with water/liquid. Do not chew, crush or break it.
The physician recommends taking this medication orally, with or without food.
- Cancer of the colon and rectum
- Gastrointestinal Stromal Tumors
- Hepatocellular Carcinoma
- Cancer of the colon and rectum: A tumour that develops from both the colon and the rectum, the two parts of the large intestine, is called colorectal cancer (CRC) or bowel cancer. In this type of cancer, the person may have symptoms including fatigue, weight loss, bowel movement changes, and blood in the stool. Along with treatment, regorafenib reduces the probability of getting colon cancer and other malignant growths (polyps). Regorafenib not only stops cancer cells from growing or increasing, but it also eliminates them.
- Gastrointestinal Stromal Tumors: Rare cancers called gastric stromal tumours (GIST) usually develop in the stomach or intestines and are thought to originate in the digestive tract. When used to treat Gastrointestinal Stromal Tumors (GIST), regorafenib effectively targets multiple signalling pathways in tumour growth and angiogenesis. This improves the overall and progression-free survival rates in patients with advanced GIST who have not responded to standard treatment options.
- Hepatocellular Carcinoma: A primary liver cancer that originates in the hepatocytes is called hepatocellular carcinoma (HCC). When all other potential therapies have been examined, regorafenib is an effective alternative for HCC patients. It improves overall survival and progression-free survival in patients with advanced HCC who have previously undergone systemic treatment by blocking several kinase pathways involved in tumour development and angiogenesis.
Regorafenib is indicated in the following health conditions:
- For the treatment and management of patients with metastatic colorectal cancer (CRC) who have had fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, anti-VEGF therapy, and, if the patient has a wild-type RAS for EGFR, anti-EGFR treatment.
- For patients who have received prior treatment with imatinib mesylate and sunitinib for treating locally progressed, incurable, or metastatic gastrointestinal stromal tumours (GISTs).
- For patients with hepatocellular carcinoma (HCC) who have undergone sorafenib therapy in the past.
Orally: Administer Regorafenib orally at the same time daily. Swallow the tablet whole with water, avoiding splitting, chewing, or crushing. Take it after a low-fat meal (<600 calories, <30% fat). If a dose is missed, do not double the next day; resume the regular schedule. Pregnant or breastfeeding individuals should exercise caution. It is crucial to adhere to these instructions for optimal treatment outcomes and to consult healthcare providers for guidance on dosage and administration.
The dosage and duration of treatment should be as per the treating physician's clinical judgment.
Regorafenib is available in oral tablets.
Dose Adjustment in Adult Patients:
Colorectal Cancer
160 mg of colorectal cancer (four 40 mg tablets) On the first 21 days of the 28-day cycle, PO qDay
Continue treatment until the disease worsens or the toxicity becomes unacceptable.
Gastrointestinal Stromal Tumors
160 mg (four 40-mg tablets) PO qDay for the first 21 days of each 28-day cycle
Continue treatment until disease progression or unacceptable toxicity.
Hepatocellular Carcinoma
For the first 21 days of each 28-day cycle, take 160 mg (four 40-mg tablets) PO every day.
Continue therapy until the disease worsens or the toxicity becomes unacceptable.
While undergoing Regorafenib treatment, actively manage side effects by incorporating antioxidant-rich foods like berries and spinach. Enhance digestion with fibre-rich options such as beans, peas, lentils, whole grains, nuts, and seeds. Eliminate smoking and alcohol consumption. Choose a healthier lifestyle by removing fast food, fried items, processed meats, refined carbohydrates, and added sugars from your diet.
The dietary restriction should be individualized as per patient requirements.
- In individuals who have a history of excipient or active drug hypersensitivity (e.g., angioedema, anaphylaxis).
- Pregnancy
- Hemorrhage: If there is significant or potentially fatal bleeding, stop taking regorafenib immediately. Any signs or symptoms of substantial bleeding require immediate medical intervention.
- Dermatological Toxicity: Depending on the extent and duration of dermatologic toxicity, stop taking regorafenib and think about reducing the dosage or stopping the medication altogether.
- Hypertension: If the condition is severe or uncontrolled, you should stop using regorafenib either temporarily or permanently. Blood pressure must be monitored during therapy, and suitable management strategies must be implemented immediately to keep blood pressure levels at ideal ranges.
- Cardiac Ischemia and Infarction Warning: If a new or acute case of heart ischemia or infarction develops, stop taking regorafenib. Continuing therapy should only be done once the acute ischemia episodes have ceased. It is essential to evaluate cardiac health continuously and to seek emergency medical assistance for any symptoms connected to the heart.
- Wound Healing difficulties: To reduce the possibility of wound healing issues, discontinue taking regorafenib before planned procedures. In patients who have a dehiscence of the wound, stop. Close coordination with surgical teams and medical professionals is required for the best perioperative care.
- Toxicity of Embryofetal: Regorafenib may be harmful to fetuses. Use caution. Inform women who may get pregnant of the possible danger to the unborn child. It is recommended to utilize reliable contraception both during and after post-Regorafenib therapy to avoid unwanted births.
- Reversible Posterior Leukoencephalopathy Syndrome (RPLS): Regorafenib should be stopped as soon as symptoms or indicators of the syndrome appear. It is essential to monitor for any neurological symptoms to identify and manage any occurrences of RPLS.
- Gastrointestinal Perforation or Fistula: Stop using Regorafenib if fistulae or gastrointestinal perforations are suspected or confirmed. Treating these potentially dangerous side effects requires prompt action and suitable medical care.
Alcohol Warning
Breast Feeding Warning
Pregnancy Warning
Food Warning
The adverse reactions related to Regorafenib can be categorized as:
- Common Adverse Effects: Nausea, diarrhoea, fatigue, hypertension, and palmar-plantar erythrodysesthesia.
- Less Common Adverse Effects: Gastrointestinal perforations, thrombosis, and reversible posterior leukoencephalopathy syndrome.
- Rare Adverse Effects: Hepatotoxicity, renal failure, osteonecrosis of the jaw, and impaired wound healing.
Reports from postmarketing
Syndrome Nephrotic
Heart attack
Arterial dissections, ruptures, and aneurysms (including aortic)
The clinically relevant drug interactions of Regorafenib are briefly summarized here.
- Drug-Drug Interactions: Regorafenib may interact with strong CYP3A4 inducers (carbamazepine, rifampicin, phenytoin, phenobarbitone) as well as potent CYP3A4 inhibitors (clarithromycin, diltiazem, erythromycin, itraconazole, ketoconazole, ritonavir).
- Interactions between Drugs and Food: Food enhances absorption. Changed blood concentration when exposed to grapefruit or grapefruit juice. Reduced contact with St John's wort. Refrain from smoking and drinking alcohol.
- Interactions with Dug-Diseases: Before commencing therapy, let the physician know if one has kidney or liver illness, cardiac issues, GI perforation, or lung toxicity.
The common side effects of Regorafenib include nausea, diarrhoea, loss of appetite, skin rash, hoarseness, tiredness, chest pain, low blood platelets, anaemia (low red blood cell count), fever, decreased appetite, mucosal inflammation, stomatitis (mouth inflammation), elevated liver enzymes, weight loss, voice changes, presence of bilirubin in urine, dizziness, weakness, and increased susceptibility to infections.
- Pregnancy
Pregnancy Category D (FDA): Use in cases where no safer medication is available and life is in danger. Positive evidence of prenatal risk in humans.
Pregnant women who take certain medications may experience fetal damage due to the mechanism of action and animal research.
Pregnancy-related statistics on usage are not yet available.
Inform expectant mothers about the possible risk to the fetus.
Animal data
When regorafenib was administered to rats and rabbits at exposures lower than those of humans at the approved dose, the animals developed teratogenic and embryo-lethal side effects, including an increased risk of skeletal, genitourinary, and cardiovascular abnormalities.
Contraception
Women: Use effective contraception during therapy and for two months after the last dosage.
Men: Recommend effective contraception to male patients who have female partners who may become pregnant both during therapy and for two months after the last dosage.
Infertility
Information on the impact on human fertility is limited.
Studies on animals have shown that regorafenib can reduce both male and female fertility.
- Nursing Mothers
The effects of regorafenib on a breastfed newborn, the production of milk, or the presence of regorafenib or its metabolites in human milk are not well-documented. Regorafenib and its byproducts are eliminated from rats' milk.
Do not breastfeed during treatment or for two weeks following the last dosage due to the possibility of major adverse events in breastfed newborns from regorafenib.
- Pediatric Use
As per FDA, the safety and effectiveness have not been established in pediatric patients.
Dose Adjustment in Kidney Impairment Patients:
Mild-to-severe: No dose modification is required.
Dialysis patients: Not being studied.
Dose Adjustment in Hepatic Impairment Patients:
Moderate (total bilirubin >1.5 to ≤3x ULN and any AST) or mild (total bilirubin ≤ULN and AST>ULN, or total bilirubin >ULN to ≤1.5x ULN): No dose change is required.
Severe (total bilirubin >3 times ULN): Not advised; unstudied.
The physician should be vigilant about the knowledge pertaining to identifying and treating overdosage of Regorafenib.
Signs and Symptoms
Overconsumption of Regorafenib could lead to dermatological events, dysphonia, diarrhoea, mucosal inflammation, dry mouth, decreased appetite, HTN, and fatigue.
Management
There is no known antidote for regorafenib overdose. If an overdose is suspected, discontinue regorafenib, start supportive treatment, and patiently await clinical stabilization. Hemodialysis may not significantly contribute to drug removal due to extensive protein binding. It is advised to closely monitor the hepatic and renal functions, electrolytes, heart function, and vital signs. The management of Regorafenib overdose requires frequent monitoring and the use of suitable supportive interventions.
Pharmacodynamics
Electrophysiology of the Cardiac
This open-label, single-arm trial examined the impact of several doses of STIVARGA (160 mg once daily for 21 days) on the QTc interval in 25 patients with advanced solid tumours. The investigation found no significant variations in the mean QTc interval (i.e., > 20 msec).
Pharmacokinetics
- Absorption: When taken with meals, regorafenib is more readily absorbed through the gastrointestinal tract. For tablets, the bioavailability is 69%, while for an oral solution, it is 83%.
- Distribution: 99.5% of regorafenib is bound to bloodstream proteins, demonstrating strong plasma protein binding.
- Metabolism: Regorafenib is primarily metabolized in the liver, producing the active metabolites M-2 (N-oxide) and M-5 (N-oxide and N-desmethyl). CYP3A4 enzymes mediate oxidative metabolism in this pathway, while UGT1A9 enzymes mediate glucuronidation.
- Excretion: The drug is eliminated by urine (about 19% as glucuronides) and faeces (71% as unchanged drug and metabolites), with an elimination half-life of 20 to 30 hours.
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- Hofheinz RD, Arnold D, Kubicka S, Prasnikar N, Vogel A. Improving patient outcomes with regorafenib for metastatic colorectal cancer - patient selection, dosing, patient education, prophylaxis, and management of adverse events. Oncol Res Treat. 2015;38(6):300-8. doi: 10.1159/000382067. Epub 2015 May 12. PMID: 26045027.
- Zanwar S, Ostwal V, Gupta S, Sirohi B, Toshniwal A, Shetty N, Banavali S. Toxicity and early outcomes of regorafenib in multiply pre-treated metastatic colorectal adenocarcinoma-experience from a tertiary cancer centre in India. Ann Transl Med. 2016 Feb;4(4):74. doi: 10.3978/j.issn.2305-5839.2016.02.05. PMID: 27004221; PMCID: PMC4779767.
- Petrioli R, Chirra M, Messuti L, Fiaschi AI, Savelli V, Martellucci I, Francini E. Efficacy and Safety of Regorafenib With 2/1 Schedule for Patients ≥ 75 Years With Metastatic Colorectal Cancer (mCRC) After Failure of 2 Lines of Chemotherapy. Clin Colorectal Cancer. 2018 Dec;17(4):307-312. doi: 10.1016/j.clcc.2018.02.005. Epub 2018 Feb 21. PMID: 29548772.
- https://www.ncbi.nlm.nih.gov/books/NBK548608/
- US Food and Drug Administration (FDA) [Internet]. Maryland. USA; Package leaflet information for the user; Stivarga (regorafenib).
- https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203085lbl.pdf.
- April Hazard Vallerand, Cynthia A. Sanoski. [link]. Sixteenth Edition. Philadelphia, China: F. A. Davis Company; 2019: Page No 1087-1088
