Regorafenib (Stivarga) is an oral medicine that inhibits the growth and spread of tumor 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:

• 160 mg orally once a day is given for the first 21 days of each 28-day cycle
• continue until disease progression or unacceptable toxicity occurs

Reduced dosing strategy in metastatic colorectal cancer as off-label use:

• • The initial dose is 80 mg orally once a day.
  • It is escalated weekly (if tolerated) to a goal of 160 mg once daily
  • Give on days 1 to 21 of a 28-day treatment cycle

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

• 160 mg orally once a day is given for the first 21 days of each 28-day cycle
• continue until disease progression or unacceptable toxicity occurs

Dose in the treatment of Hepatocellular carcinoma:

• 160 mg orally once daily given for the first 21 days of a 28-day cycle
• continue until disease progression or unacceptable toxicity occurs

  • Missed doses:

    • Do not give 2 doses on the same day to make up for a missed dose from the previous day.

Stivarga (Regorafenib) Dose in Childrens

Not indicated for use in children.

Stivarga (Regorafenib) Pregnancy Risk Category: D

• Animal reproduction studies showed that teratogenic effects could be observed with lower doses than the equivalent human dose.
• Regorafenib may cause harm to fetal health if given during pregnancy, based on animal reproduction studies.
• Effective contraception should be used by both male and female patients during treatment and for at most 2 months afterwards.

Use Regorafenib while breastfeeding

• It is unknown if breast milk contains regorafenib.
• The manufacturer does not recommend breastfeeding during treatment or for at least 2 weeks after the last dose.

Stivarga (Regorafenib) dose in Renal disease:

• CrCl ≥15 mL/minute:

  • No dosage adjustment required.

• ESRD on dialysis:

  • There are no dosage adjustments given in the manufacturer's labeling (has not been studied).

Stivarga (Regorafenib) dose in Liver disease:

• Preexisting mild (total bilirubin ≤ ULN and AST > ULN or total bilirubin > ULN to ≤1.5 times ULN) or moderate (total bilirubin >1.5 times to ≤3 times ULN and any AST) impairment:

  • No dosage adjustment required
  • closely monitor for adverse effects.

• Preexisting severe impairment (total bilirubin >3 times ULN):

  • Use is not advised (has not been studied).

• Hepatotoxicity during treatment:

  • Grade 3 AST and/or ALT elevation:

    • Withhold dose till recovery.
    • If the benefit of treatment outweighs toxicity risk, restart therapy at a reduced dose of 120 mg once daily.

  • AST or ALT >20 times ULN:

    • stop permanently.

  • AST or ALT >3 times ULN and bilirubin >2 times ULN:

    • stop permanently.

  • Recurrence of AST or ALT >5 times ULN despite dose reduction to 120 mg:

    • stop permanently.

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:

• There are no contraindications given in the manufacturer's US labeling.
•  Hypersensitivity to regorafenib, any part of the formulation, or sorafenib.

Warnings and Precautions

• Cardiovascular events:

  • Myocardial ischemia and infarction were seen at a higher incidence than placebo in a clinical trial.
  • Withhold therapy in patients who develop new or acute onset ischemia or infarction
  • restart only if the benefit of therapy outweighs the cardiovascular risk.

• Dermatologic toxicity:

  • Skin reactions including hand-foot skin reaction, also known as palmar-plantar erythrodysesthesia syndrome, and severe rash requiring dose reduction may occur.
  • Grade 3 or 4 HFSR was seen more frequently in regorafenib-treated patients (compared to placebo), and although rare, erythema multiforme and Stevens-Johnson syndrome were also seen more frequently in regorafenib-treated patients.
  • Toxic epidermal necrolysis has also been seen(rare).
  • The onset of HFSR typically occurs in the first cycle of treatment.
  • Therapy interruptions, dosage reductions, and/or discontinuation might be necessary depending on the severity and persistence.
  • Supportive treatment might be of benefit for symptomatic relief.
  • Pooled data from several clinical trials show a higher incidence of HFSR in Asian patients compared to Caucasians.

  • In addition to recommended dosage modifications, the following treatments may be used for management of HFSR (McLellan 2015):

    • A manicure/pedicure to remove hyperkeratotic areas/calluses which may cause HFSR and mechanical support/correction for abnormal weight-bearing prior to treatment are recommended.
    • During treatment, patients must use alcohol-free moisturizers liberally, reduce exposure to hot water (may exacerbate hand-foot symptoms)
    • avoid constrictive footwear and excessive skin friction, and avoid vigorous exercise/activities that may stress hands or feet.
    • Patients should also wear thick cotton gloves/socks and wear shoes with padded insoles.
    • Grade 1 HFSR can be relieved with moisturizing creams, cotton gloves, and socks (at night) and/or keratolytic creams such as urea (10% to 40%) or salicylic acid (6%) along with a topical analgesic (eg, lidocaine gel) to relieve pain.
    • Apply topical steroid (eg, clobetasol ointment or foam) twice daily to erythematous areas of grade 2 HFSR (in addition to continuing grade 1 management)
    • topical analgesics and then systemic analgesics (if appropriate) can be used for pain control; dose reduction may be necessary.
    • Grade 3 HFSR must be managed by continuing grades 1 and 2 symptomatic management and interrupting treatment for at least 7 days until resolved to grade 1 or lower.

• Gastrointestinal perforation:

  • Gastrointestinal perforation or fistula has been seen in a small number of patients treated with regorafenib; some cases were fatal.
  • Monitor for signs/symptoms of perforation (fever, abdominal pain with constipation, and/or nausea/vomiting)
  • permanently stop if perforation or fistula develops.

• Hemorrhage:

  • The incidence of hemorrhage is increased with regorafenib.
  • Hemorrhage of the respiratory, gastrointestinal, or genitourinary tracts was seen in trials
  • Permanently stop in patients who experience severe or life-threatening bleeding.
  • In patients receiving concomitant warfarin, monitor INR frequently.

• Hepatotoxicity: [US Boxed Warning]:

  • Severe and sometimes fatal hepatotoxicity has been seen in clinical trials.
  • Monitor hepatic function at baseline and during treatment.
  • Withhold therapy for hepatotoxicity; dose reductions or discontinuation are necessary depending on the severity and persistence.
  • Hepatic dysfunction, characterized by a hepatocellular injury pattern, typically happens with the first 2 months of treatment in clinical trials.
  • Closely monitor in patients with mild or moderate impairment for adverse effects; use is not recommended in severe impairment.
  • A higher incidence of hepatotoxicity has been seen in Asian patients (particularly Japanese), compared to Caucasians.

• Hypersensitivity:

  • Hypersensitivity reactions have been seen with regorafenib.

• Hypertension:

  • Elevated blood pressure was seen in clinical trials (onset typically in the first cycle of therapy)
  • ensure blood pressure is adequately controlled before initiation.
  • Monitor blood pressure weekly for the first 6 weeks and monthly thereafter or as clinically needed
  • if hypertension develops, withhold therapy or permanently discontinue for severe or uncontrolled hypertension.
  • Hypertensive crisis has also occurred in some patients.
  • Patients 65 years and older had an increased incidence of grade 3 or higher hypertension (compared to younger patients).

• Infection:

  • An increased rate of infection (including fatal events) was seen in regorafenib-treated patients in clinical trials.
  • The most commonly reported infections were urinary tract infections, nasopharyngitis, mucocutaneous and systemic fungal infections, and pneumonia.
  • Respiratory infections were the most commonly reported in fatal infections.
  • Withhold therapy for grade 3 or 4 infections (or worsening infection of any grade).

• Reversible posterior leukoencephalopathy syndrome (RPLS):

  • RPLS occurred very rarely in regorafenib-treated patients
  • Monitor promptly if symptoms (eg, seizures, severe headache, visual disturbances, confusion, or altered mental function) occur.
  • Stop if the diagnosis is confirmed.

• Wound healing impairment:

  • Regorafenib inhibits vascular endothelial growth factor, which can lead to impaired wound healing.
  • Stop regorafenib at least 2 weeks before the scheduled surgery
  • restart regorafenib post-surgery based on clinical judgment of wound healing; discontinue if wound dehiscence occurs.

Regorafenib: Drug Interaction

Monitor:

• At baseline, have liver function tests done every two weeks for the first 2 months. Then, monthly or more often if necessary (weekly until improvement is possible if there are high liver function tests).
• Complete blood counts differentials and platelet count
• The baseline serum electrolytes and the periodic thereafter.
• If you are receiving warfarin, it is important to monitor your INR more often.
• For the first six weeks of therapy, blood pressure should be checked weekly. Then, every subsequent cycle. If necessary, more frequent monitoring may be required.
• Monitor for hand-foot skin reactions (HFSR/palmar-plantar epidysesthesia syndrome)
• It is recommended to check for signs of HFSR within the first week of treatment. Then, every 1 to 2 semaines for 2 cycles. Finally, every 4 to 6 weeks thereafter.
• Watch out for signs and symptoms such as cardiac ischemia, infarction, bleeding or GI perforation, infection, or reversible posterior Leukoencephalopathy syndrome (severe migraines, seizure or confusion, or changes in vision).
• You should monitor for any signs of impaired wound healing.
• You must ensure that you adhere to the rules.

How to administer Regorafenib (Sitvarga)?

• Use it at the same time each day.
• Swallow the tablet whole with water after a low-fat meal (containing <600 calories and <30% fat).

Mechanism of action of Regorafenib (Stivarga):

• Regorafenib works by inhibiting multiple kinases
• It targets the kinases that are involved in tumor angiogenesis and oncogenesis as well as maintenance of the tumor microenvironment, which in turn results in inhibiting tumor growth.
• It inhibits VEGF receptors 1-3 and KIT, PDGFR–alpha, PDGFR–beta, RET. BRAF, BRAF. SAPK2, PTK5, Abl.

Absorption:

• A high-fat meal increased the mean AUC of the parent drug
• A low-fat meal increased the mean AUC of regorafenib, M-2, and M-5 by 36%, 40% and 23%, respectively

Protein binding:

• 99.5% (active metabolites M-2 and M-5 are also highly protein-bound)

Metabolism:

• Mainly Hepatic via CYP3A4 and UGT1A9, primarily to active metabolites M-2 (N-oxide) and M-5 (N-oxide and N-desmethyl)

Bioavailability:

• Tablets: 69%
• Oral solution: 83%

Half-life elimination:

• Regorafenib: 28 hours (range: 14 to 58 hours)
• M-2 metabolite: 25 hours (range: 14 to 32 hours)
• M-5 metabolite: 51 hours (range: 32 to 70 hours)

Time to peak:

• 4 hours

Excretion:

• Via Feces (71%; 47% as parent compound; 24% as metabolites) & Urine (19%) 

International Brands of Regorafenib (Stivarga):

• Stivarga

Regorafenib Brand Names in Pakistan:

Regorafenib (Stivarga) is not available in Pakistan.