Regorafenib is a medication used in the treatment of certain types of cancer. It belongs to a class of drugs called multikinase inhibitors. The brand name for regorafenib is Stivarga.

Regorafenib is primarily prescribed for the treatment of metastatic colorectal cancer (CRC) that has progressed after other treatments have been ineffective. It is also used to treat advanced gastrointestinal stromal tumors (GIST) in patients who are no longer responding to other medications. Additionally, regorafenib may be considered for the treatment of hepatocellular carcinoma (HCC), a type of liver cancer, in patients who have previously received sorafenib.

As a multikinase inhibitor, regorafenib works by targeting and inhibiting various protein kinases, which are enzymes involved in cell signaling pathways. By blocking these kinases, regorafenib helps to disrupt the growth and survival of cancer cells.

Regorafenib is used to treat the following conditions:

• Metastatic Colorectal cancer:  

  • It is used in the treatment of metastatic colorectal cancer in patients previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, anti-VEGF therapy, and anti-EGFR therapy (if RAS wild type)

• Gastrointestinal stromal tumors:  

  • It is used in the treatment of locally-advanced, unresectable, or metastatic gastrointestinal stromal tumor (GIST) in patients previously treated with imatinib and sunitinib

• Hepatocellular carcinoma:  

  • It is used in the treatment of hepatocellular carcinoma in patients previously treated with sorafenib

Stivarga (Regorafenib) Dose in Adults

Stivarga (Regorafenib) Dosage in the treatment of metastatic colorectal cancer:

• In the treatment of metastatic colorectal cancer, the recommended dose of regorafenib is usually 160 mg taken orally once daily.
• This is done for the first 21 days of a 28-day treatment cycle.
• The medication is continued until there is disease progression or if the patient experiences unacceptable side effects.

Off-label dosing strategy in the treatment of metastatic colorectal cancer:

• There is an off-label alternative dosing strategy for regorafenib in metastatic colorectal cancer. It involves starting with a reduced initial dose of 80 mg taken orally once daily.
• The dosage can then be escalated weekly if it is well-tolerated, with the goal of reaching the standard dose of 160 mg once daily.
• This alternative dosing strategy, as suggested by Bekaii-Saab in 2018, follows the same 21-day treatment cycle, where the medication is administered on days 1 to 21 of the 28-day cycle.

Dose in the treatment of locally advanced, unresectable or metastatic gastrointestinal stromal tumor (GIST):

• In the treatment of locally advanced, unresectable, or metastatic gastrointestinal stromal tumor (GIST), the recommended dose of regorafenib is 160 mg taken orally once a day.
• This dosage is administered for the first 21 days of each 28-day treatment cycle.
• The treatment should be continued until there is disease progression or if the patient experiences unacceptable side effects.

Dose in the treatment of Hepatocellular carcinoma:

• In the treatment of hepatocellular carcinoma, the recommended dose of regorafenib is 160 mg taken orally once a day for the first 21 days of a 28-day treatment cycle.
• The treatment should be continued until there is disease progression or if the patient experiences unacceptable side effects.
• Missed doses:
  • If a patient misses a dose, it is advised not to administer two doses on the same day to make up for the missed dose from the previous day.
  • Instead, the patient should take the next dose at the scheduled time.

Stivarga (Regorafenib) Dose in Children

Not indicated for use in children.

Stivarga (Regorafenib) Pregnancy Risk Category: D

• In animal studies, regorafenib has shown teratogenic effects (causing birth defects) at doses lower than the equivalent human dose.
• Considering these findings and the mechanism of action, regorafenib has the potential to cause harm to the fetus if administered during pregnancy.
• Therefore, it is important for both male and female patients to use effective contraception methods while undergoing regorafenib therapy.
• Additionally, contraception should be continued for at least 2 months after completing the treatment to minimize the risk of potential harm to the fetus.
• It is essential to discuss contraceptive options and considerations with a healthcare provider before starting regorafenib treatment, especially if there is a possibility of pregnancy.

Use Regorafenib while breastfeeding

• The presence of regorafenib in breast milk is currently unknown.
• Since there is a potential risk of serious adverse reactions in the breastfed infant, the manufacturer does not recommend breastfeeding during regorafenib treatment and for two weeks after the last dose.

Stivarga (Regorafenib) dose in Renal disease:

• For patients with a creatinine clearance (CrCl) of 15 mL/minute or higher, no dosage adjustment is necessary when using regorafenib. The standard recommended dosage can be used in these cases.
• For patients with end-stage renal disease (ESRD) who are on dialysis, there are no specific dosage adjustments provided in the manufacturer's labeling as regorafenib has not been extensively studied in this population. It is recommended to follow the standard dosage guidelines in the absence of specific recommendations.

Stivarga (Regorafenib) dose in Liver disease:

• For patients with preexisting mild or moderate liver impairment, no dosage adjustment is necessary when using regorafenib. However, close monitoring for adverse effects is recommended in these cases.
• For patients with preexisting severe liver impairment, regorafenib use is not recommended, as it has not been studied extensively in this population.

In the event of hepatotoxicity (liver toxicity) occurring during treatment, the following guidelines should be followed:

• If there is a grade 3 elevation of AST and/or ALT (liver enzymes), the dose should be withheld until recovery. If the potential benefits of continuing treatment outweigh the risk of toxicity, therapy can be resumed at a reduced dose of 120 mg once daily.
• If AST or ALT levels exceed 20 times the upper limit of normal (ULN), regorafenib should be permanently discontinued.
• If AST or ALT levels exceed 3 times the ULN and bilirubin (a marker of liver function) exceeds 2 times the ULN, regorafenib should be permanently discontinued.
• If AST or ALT levels continue to increase to more than 5 times the ULN, even with the reduced dose of 120 mg, regorafenib should be permanently discontinued.

Common Side Effects of Regorafenib (Sitvarga) Include:

• Cardiovascular:
  • Hypertension
• Central Nervous System:
  • Fatigue
  • Pain
  • Voice Disorder
  • Headache
• Dermatologic:
  • Palmar-Plantar Erythrodysesthesia
  • Skin Rash
  • Alopecia
• Endocrine & Metabolic:
  • Hypophosphatemia
  • Hypocalcemia
  • Weight Loss
  • Hypokalemia
  • Hyponatremia
  • Increased Amylase
  • Hypothyroidism
• Gastrointestinal:
  • Gastrointestinal Pain
  • Diarrhea
  • Decreased Appetite
  • Increased Serum Lipase
  • Stomatitis
  • Nausea
  • Vomiting
• Hematologic & Oncologic:
  • Anemia
  • Lymphocytopenia
  • Thrombocytopenia
  • Increased INR
  • Hemorrhage
  • Neutropenia
• Hepatic:
  • Increased Serum Aspartate Aminotransferase
  • Hyperbilirubinemia
  • Increased Serum Alanine Aminotransferase
• Infection:
  • Infection
• Neuromuscular & Skeletal:
  • Asthenia
  • Muscle Spasm
• Renal:
  • Proteinuria
• Miscellaneous:
  • Fever

Less Common Side Effects of Regorafenib Include:

• Dermatologic:
  • Exfoliative Dermatitis
• Gastrointestinal:
  • Mucocutaneous Candidiasis
  • Pancreatitis
• Genitourinary:
  • Urinary Tract Infection
• Hepatic:
  • Hepatic Failure
• Infection:
  • Fungal Infection
• Neuromuscular & Skeletal:
  • Tremor
• Respiratory:
  • Nasopharyngitis
  • Pneumonia

• Hepatic:
  • Hepatotoxicity

Contraindications to Regorafenib (Sitvarga) Include:

According to the manufacturer's US labeling, there are no specific contraindications listed for regorafenib.

However, in the Canadian labeling, regorafenib is contraindicated in individuals with hypersensitivity to regorafenib itself, any component of the formulation, or sorafenib (another medication).

It's important to note that prescribing information can vary between countries and regions. Therefore, it's always crucial to consult the specific prescribing information and labeling approved in the relevant country or region to obtain accurate and up-to-date information regarding contraindications.

Warnings and Precautions

Cardiovascular events:

• During clinical trials, regorafenib has been associated with a higher incidence of myocardial ischemia (reduced blood flow to the heart) and myocardial infarction (heart attack) compared to placebo.
• In the event that a patient develops new or acute onset ischemia or infarction while on regorafenib therapy, it is recommended to interrupt the treatment.
• The decision to resume therapy should be carefully evaluated, taking into consideration whether the potential benefits of continuing treatment outweigh the cardiovascular risks.

Dermatologic toxicity:

• Dermatologic toxicity is a common side effect of regorafenib treatment and includes skin reactions such as hand-foot skin reaction (HFSR), also known as palmar-plantar erythrodysesthesia syndrome (PPES), as well as severe rash.
• Grade 3 or 4 HFSR, although rare, has been observed more frequently in regorafenib-treated patients compared to those receiving a placebo.
• There have also been reports of erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis, although these are rare occurrences.
• HFSR typically occurs in the first cycle of treatment.
• Management of HFSR may require therapy interruptions, dosage reductions, or discontinuation, depending on the severity and persistence of the symptoms.
• Supportive treatment can provide symptomatic relief. It is worth noting that Asian patients have been shown to have a higher incidence of HFSR compared to Caucasians, based on pooled data from several clinical trials.
• In addition to recommended dosage modifications, the following treatments can be used for managing HFSR:
  • Prior to treatment, it is recommended to undergo a manicure/pedicure to remove hyperkeratotic areas/calluses that may contribute to HFSR and receive mechanical support or correction for abnormal weight bearing.
  • During treatment, patients should apply alcohol-free moisturizers frequently, minimize exposure to hot water (as it can worsen hand-foot symptoms), avoid tight-fitting footwear and excessive skin friction, and refrain from vigorous exercise or activities that put stress on the hands or feet.
  • Wearing thick cotton gloves and socks, as well as shoes with padded insoles, can be beneficial.
  • Grade 1 HFSR can be relieved with moisturizing creams, cotton gloves and socks worn at night, and keratolytic creams containing urea (10% to 40%) or salicylic acid (6%). Topical analgesics like lidocaine gel can be used for pain relief.
  • Grade 2 HFSR can be managed by continuing grade 1 symptomatic management and applying topical steroids (e.g., clobetasol ointment or foam) twice daily to erythematous areas. Topical or systemic analgesics may be used for pain control, and a dose reduction may be necessary.
  • Grade 3 HFSR requires continuation of grade 1 and 2 symptomatic management and interruption of treatment for at least 7 days, or until the symptoms resolve to grade 1 or lower.

Gastrointestinal perforation:

• Regorafenib may cause a hole or abnormal opening in the stomach or intestine, which can be very serious and even deadly.
• Watch out for signs like fever, stomach pain with constipation, and/or feeling sick or vomiting.
• If you have any of these symptoms, stop taking regorafenib right away.

Hemorrhage:

• There is a higher chance of bleeding when taking regorafenib.
• Bleeding in the respiratory (such as coughing up blood), gastrointestinal (such as blood in the stool), or genitourinary (such as blood in the urine) areas has been seen in clinical trials, and some cases have been fatal.
• If you experience severe or life-threatening bleeding, stop taking regorafenib permanently.
• If you are also taking warfarin, your International Normalized Ratio (INR) should be closely monitored.

Hepatotoxicity: [US Boxed Warning]:

• Regorafenib can cause serious liver problems that can be fatal.
• Liver function should be monitored before and during treatment.
• If there are signs of liver problems, treatment may need to be stopped or the dose reduced.
• Liver problems usually occur within the first 2 months of treatment.
• Patients with mild or moderate liver problems should be closely monitored for side effects.
• Regorafenib is not recommended for patients with severe liver problems.
• The risk of liver problems is higher in Asian patients, especially Japanese patients.

Hypersensitivity:

• Regorafenib has been associated with hypersensitivity reactions, although the incidence is not specified in the labelling.

Hypertension:

• Regorafenib can cause high blood pressure, which usually starts during the first cycle of treatment.
• Before starting treatment, the patient's blood pressure should be adequately controlled.
• The patient's blood pressure should be monitored closely during the first six weeks of treatment and then every month or as clinically indicated.
• If the patient develops hypertension, treatment may be stopped temporarily or permanently if the hypertension is severe or uncontrolled.
• Some patients have experienced a hypertensive crisis.
• Patients who are 65 years or older may have a higher risk of experiencing grade 3 or higher hypertension compared to younger patients.

Infection:

• Regorafenib may increase the risk of infection in patients.
• In clinical trials, patients who were treated with regorafenib had a higher rate of infection, including fatal events.
• Common infections reported included urinary tract infections, nasopharyngitis, fungal infections, and pneumonia.
• Respiratory infections were the most common fatal infections reported.
• If a patient develops a grade 3 or 4 infection or their infection worsens, treatment with regorafenib should be interrupted.

Reversible posterior leukoencephalopathy syndrome (RPLS):

• Although very rare, there have been cases of reversible posterior leukoencephalopathy syndrome (RPLS) reported in patients receiving regorafenib.
• If a patient experiences symptoms such as seizures, severe headache, visual disturbances, confusion, or altered mental function, it is important to evaluate them promptly.
• If the diagnosis of RPLS is confirmed, regorafenib treatment should be discontinued.

Wound healing impairment:

• Regorafenib can interfere with the healing of wounds due to its effect on vascular endothelial growth factor.
• To minimize the risk of impaired wound healing, regorafenib should be stopped at least 2 weeks before a scheduled surgery.
• The decision to resume regorafenib after surgery should be based on the clinical judgment of wound healing.
• If wound dehiscence (the reopening of a wound) occurs, regorafenib treatment should be discontinued.
• It is important to discuss any planned surgeries with the healthcare provider to ensure appropriate management of regorafenib therapy.

Regorafenib: Drug Interaction

Drug Interactions: Category C Drugs that need monitoring when given with Regorafenib:

Risk Category D Drugs: Avoid these combinations whenever possible:

Risk Category X: Avoid combination (Combination is contraindicated)

Monitor:

• Obtain liver function tests before starting treatment and every 2 weeks during the first 2 months. After that, monitor monthly or more frequently if needed. If liver function tests are elevated, monitor weekly until they improve.
• Get a complete blood count (CBC) with differential and platelet count, as well as serum electrolyte levels at baseline and periodically.
• If you are taking warfarin, your International Normalized Ratio (INR) should be monitored more frequently.
• Monitor your blood pressure weekly for the first 6 weeks of treatment and with every subsequent treatment cycle. If needed, it may be monitored more often.
• Watch out for signs of hand-foot skin reaction (HFSR) or palmar-plantar erythrodysesthesia syndrome (PPES). Check for signs of HFSR during the first weeks of treatment, then every 1 to 2 weeks for 2 cycles, and then every 4 to 6 weeks afterward.
• Keep an eye out for symptoms of cardiac ischemia or infarction, bleeding, gastrointestinal perforation or fistula, infection, and reversible posterior leukoencephalopathy syndrome. Symptoms may include severe headaches, seizures, confusion, or changes in vision.
• Pay attention to any issues with wound healing.
• Make sure to follow the prescribed dosage and adhere to the treatment regimen.

How to administer Regorafenib (Sitvarga)?

When taking regorafenib orally, here are some instructions to follow:

• Take the medication at the same time each day to maintain a consistent dosage schedule.
• Swallow the tablet whole with water. Do not crush, chew, or break it.
• It is recommended to take regorafenib after a low-fat meal. The meal should contain fewer than 600 calories and less than 30% fat.
• Following these guidelines will help optimize the absorption of the medication.

Mechanism of action of Regorafenib (Stivarga):

Regorafenib is a type of medication known as a multi-kinase inhibitor. It works by targeting specific kinases (enzymes) involved in various processes related to tumor growth and development. By inhibiting these kinases, regorafenib helps to slow down or stop the growth of tumors.

The specific kinases that regorafenib targets include:

• VEGF receptors 1-3: These receptors are involved in the formation of new blood vessels (angiogenesis) that supply nutrients to tumors.
• KIT: This kinase is often mutated in gastrointestinal stromal tumors (GIST) and plays a role in their growth.
• PDGFR-alpha and PDGFR-beta: These receptors are involved in cell growth and division, including in tumor cells.
• RET: This kinase is involved in the development of certain types of thyroid cancer.
• FGFR1 and 2: These receptors are involved in cell growth, division, and blood vessel formation.
• TIE2: This kinase is involved in angiogenesis and blood vessel stability.
• DDR2: This kinase is involved in cancer cell invasion and metastasis.
• TrkA: This kinase is involved in the growth and survival of nerve cells and is implicated in certain types of cancer.
• Eph2A: This kinase is involved in cell signaling and is associated with cancer cell migration and invasion.
• RAF-1 and BRAF: These kinases are involved in the RAF/MEK/ERK pathway, which plays a role in cell growth and division. Mutations in BRAF are found in certain types of cancer.
• SAPK2: This kinase is involved in cell signaling pathways related to cell survival and apoptosis.
• PTK5: This kinase is involved in cell growth and survival.
• Abl: This kinase is involved in cell signaling and plays a role in cancer cell growth and survival.

By inhibiting these kinases, regorafenib helps to disrupt the signals that promote tumor growth and progression. It is used in the treatment of various types of cancers, including colorectal cancer, gastrointestinal stromal tumors, and hepatocellular carcinoma.

Absorption:

• The absorption of regorafenib is affected by food.
• Taking the medication with a high-fat meal increases the amount of the drug in the bloodstream compared to fasting, while a low-fat meal also increases absorption but to a lesser extent.

Protein binding:

• Regorafenib and its active metabolites M-2 and M-5 are highly bound to proteins in the blood, with approximately 99.5% of the drug being bound.

Metabolism:

• Regorafenib is primarily metabolized in the liver by enzymes called CYP3A4 and UGT1A9.
• These enzymes convert regorafenib into its active metabolites, M-2 (N-oxide) and M-5 (N-oxide and N-desmethyl).

Bioavailability:

• The bioavailability of regorafenib is the amount of the drug that reaches the bloodstream after administration.
• For tablets, the bioavailability is approximately 69%, while for the oral solution it is around 83%.

Half-life elimination:

• The half-life elimination is the time it takes for half of the drug or its metabolites to be eliminated from the body.
• For regorafenib, the half-life is about 28 hours, ranging from 14 to 58 hours.
• The M-2 metabolite has a half-life of 25 hours (range: 14 to 32 hours), and the M-5 metabolite has a half-life of 51 hours (range: 32 to 70 hours).

Time to peak:

• The time to reach the maximum concentration of regorafenib in the bloodstream is approximately 4 hours after administration.

Excretion:

• The majority of regorafenib and its metabolites are eliminated from the body through the feces (71%).
• Within the feces, approximately 47% is the parent compound (regorafenib) and 24% is in the form of metabolites.
• Around 19% of the drug and its metabolites are excreted in the urine.

International Brands of Regorafenib (Stivarga):

• Stivarga

Regorafenib Brand Names in Pakistan:

Regorafenib (Stivarga) is not available in Pakistan.