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Regorafenib

FDA Drug Information • Also known as: Stivarga

Brand Names
Stivarga
Dosage Form
TABLET, FILM COATED
Product Type
DRUG FOR FURTHER PROCESSING

⚠ Boxed Warning (Black Box)

WARNING: HEPATOTOXICITY

  • Severe and sometimes fatal hepatotoxicity has occurred in clinical trials [see Warnings and Precautions ( 5.1 )] .
  • Monitor hepatic function prior to and during treatment [see Warnings and Precautions ( 5.1 )].
  • Interrupt and then reduce or discontinue STIVARGA for hepatotoxicity as manifested by elevated liver function tests or hepatocellular necrosis, depending upon severity and persistence [see Dosage and Administration ( 2.2 )] . WARNING: HEPATOTOXICITY See full prescribing information for complete boxed warning.
  • Severe and sometimes fatal hepatotoxicity has occurred in clinical trials. ( 5.1 )
  • Monitor hepatic function prior to and during treatment. ( 5.1 )
  • Interrupt and then reduce or discontinue STIVARGA for hepatotoxicity as manifested by elevated liver function tests or hepatocellular necrosis, depending upon severity and persistence. ( 2.2 )

    • Description

    11 DESCRIPTION STIVARGA (regorafenib) is a multikinase inhibitor with the chemical name 4-[4-({[4-chloro-3-(trifluoromethyl) phenyl] carbamoyl} amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide monohydrate. Regorafenib has the following structural formula: Regorafenib is a monohydrate and it has a molecular formula C 21 H 15 ClF 4 N 4 O 3

  • H 2 O and a molecular weight of 500.83. Regorafenib is practically insoluble in water, slightly soluble in acetonitrile, methanol, ethanol, and ethyl acetate and sparingly soluble in acetone. STIVARGA tablets for oral administration are formulated as light pink, oval-shaped tablets debossed with "BAYER" on one side and "40" on the other. Each tablet contains 40 mg of regorafenib in the anhydrous state, which corresponds to 41.49 mg of regorafenib monohydrate, and the following inactive ingredients: cellulose microcrystalline, croscarmellose sodium, magnesium stearate, povidone, and colloidal silicon dioxide. The film-coating contains the following inactive ingredients: ferric oxide red, ferric oxide yellow, lecithin (soy), polyethylene glycol 3350, polyvinyl alcohol, talc, and titanium dioxide. Description: Chemical Structure

    • What Is Regorafenib Used For?

    1 INDICATIONS AND USAGE STIVARGA is a kinase inhibitor indicated for the treatment of adult patients with:

  • Metastatic colorectal cancer (CRC) who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if RAS wild-type, an anti-EGFR therapy. ( 1.1 )
  • Locally advanced, unresectable or metastatic gastrointestinal stromal tumor (GIST) who have been previously treated with imatinib mesylate and sunitinib malate. ( 1.2 )
  • Hepatocellular carcinoma (HCC) who have been previously treated with sorafenib ( 1.3 ) 1.1 Colorectal Cancer STIVARGA is indicated for the treatment of adult patients with metastatic colorectal cancer (CRC) who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if RAS wild-type, an anti-EGFR therapy. 1.2 Gastrointestinal Stromal Tumors STIVARGA is indicated for the treatment of adult patients with locally advanced, unresectable or metastatic gastrointestinal stromal tumor (GIST) who have been previously treated with imatinib mesylate and sunitinib malate. 1.3 Hepatocellular Carcinoma STIVARGA is indicated for the treatment of adult patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib.

    • Dosage and Administration

    2 DOSAGE AND ADMINISTRATION

  • Recommended dose: 160 mg orally, once daily for the first 21 days of each 28-day cycle. ( 2.1 )
  • Take STIVARGA after a low-fat meal. ( 2.1 , 12.3 ) 2.1 Recommended Dose The recommended dose is 160 mg STIVARGA (four 40 mg tablets) taken orally once daily for the first 21 days of each 28-day cycle. Continue treatment until disease progression or unacceptable toxicity. Take STIVARGA at the same time each day. Swallow tablet whole with water after a low-fat meal that contains less than 600 calories and less than 30% fat [see Clinical Pharmacology ( 12.3 )] . Do not take two doses of STIVARGA on the same day to make up for a missed dose from the previous day. 2.2 Dose Modifications If dose modifications are required, reduce the dose in 40 mg (one tablet) increments; the lowest recommended daily dose of STIVARGA is 80 mg daily. Interrupt STIVARGA for the following:
  • Grade 2 hand-foot skin reaction (HFSR) [palmar-plantar erythrodysesthesia syndrome (PPES)] that is recurrent or does not improve within 7 days despite dose reduction; interrupt therapy for a minimum of 7 days for Grade 3 HFSR
  • Symptomatic Grade 2 hypertension
  • Any Grade 3 or 4 adverse reaction
  • Worsening infection of any grade Reduce the dose of STIVARGA to 120 mg:
  • For the first occurrence of Grade 2 HFSR of any duration
  • After recovery of any Grade 3 or 4 adverse reaction except infection
  • For Grade 3 aspartate aminotransferase (AST)/alanine aminotransferase (ALT) elevation, only resume if the potential benefit outweighs the risk of hepatotoxicity Reduce the dose of STIVARGA to 80 mg:
  • For re-occurrence of Grade 2 HFSR at the 120 mg dose
  • After recovery of any Grade 3 or 4 adverse reaction at the 120 mg dose (except hepatotoxicity or infection) Discontinue STIVARGA permanently for the following:
  • Failure to tolerate 80 mg dose
  • Any occurrence of AST or ALT more than 20 times the upper limit of normal (ULN)
  • Any occurrence of AST or ALT more than 3 times ULN with concurrent bilirubin more than 2 times ULN
  • Re-occurrence of AST or ALT more than 5 times ULN despite dose reduction to 120 mg
  • For any Grade 4 adverse reaction; only resume if the potential benefit outweighs the risks

    • Side Effects (Adverse Reactions)

    6 ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the labeling:

  • Hepatotoxicity [see Warnings and Precautions ( 5.1 )]
  • Infections [see Warnings and Precautions ( 5.2 )]
  • Hemorrhage [see Warnings and Precautions ( 5.3 )]
  • Gastrointestinal Perforation or Fistula [see Warnings and Precautions ( 5.4 )]
  • Dermatological Toxicity [see Warnings and Precautions ( 5.5 )]
  • Hypertension [see Warnings and Precautions ( 5.6 )]
  • Cardiac Ischemia and Infarction [see Warnings and Precautions ( 5.7 )]
  • Reversible Posterior Leukoencephalopathy Syndrome (RPLS) [see Warnings and Precautions ( 5.8 )] The most common adverse reactions (≥20%) are pain (including gastrointestinal and abdominal pain), HFSR, asthenia/fatigue, diarrhea, decreased appetite/food intake, hypertension, infection, dysphonia, hyperbilirubinemia, fever, mucositis, weight loss, rash, and nausea. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Bayer HealthCare Pharmaceuticals Inc. at 1-888-842-2937 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rate observed in practice. The data described in the WARNINGS AND PRECAUTIONS section reflect exposure to STIVARGA in more than 4800 patients who were enrolled in four randomized, placebo-controlled trials (n=1142), an expanded access program (CONSIGN, n=2864), or single arm clinical trials (single agent or in combination with other agents). There were 4518 patients who received STIVARGA as a single agent; the distribution of underlying malignancies was 80% CRC, 4% GIST, 10% HCC, 6% other solid tumors; and 74% were White, 11% Asian, and 15% race not known. Among these 4518 patients, 83% received STIVARGA for at least 21 days and 20% received STIVARGA for 6 months or longer. In randomized placebo-controlled trials (CORRECT, GRID, RESORCE and CONCUR), the most frequently observed adverse drug reactions (≥20%) in patients receiving STIVARGA are pain (including gastrointestinal and abdominal pain), HFSR, asthenia/fatigue, diarrhea, decreased appetite/food intake, hypertension, infection, dysphonia, hyperbilirubinemia, fever, mucositis, weight loss, rash, and nausea. Colorectal Cancer The safety data described below, except where noted, are derived from a randomized (2:1), double-blind, placebo-controlled trial (CORRECT) in which 500 patients (median age 61 years; 61% men) with previously-treated metastatic colorectal cancer (CRC) received STIVARGA as a single agent at the dose of 160 mg daily for the first 3 weeks of each 4 week treatment cycle and 253 patients (median age 61 years; 60% men) received placebo. The median duration of therapy was 1.7 months (range 2 days, 10.8 months) for patients receiving STIVARGA. Due to adverse reactions, 61% of the patients receiving STIVARGA required a dose interruption and 38% of the patients had their dose reduced. Adverse reactions that resulted in treatment discontinuation occurred in 8.2% of STIVARGA-treated patients compared to 1.2% of patients who received placebo. Hand-foot skin reaction (HFSR) and rash were the most common reasons for permanent discontinuation of STIVARGA. Table 1 provides the incidence of adverse reactions (≥10%) in patients in CORRECT. Table 1: Adverse drug reactions reported in ≥10% of patients treated with STIVARGA in CORRECT and reported more commonly than in patients receiving placebo a Adverse Reactions STIVARGA (N=500) Placebo (N=253) Grade Grade All % ≥ 3 % All % ≥ 3 % General disorders and administration site conditions Asthenia/fatigue Pain Fever 64 59 28 15 9 2 46 48 15 9 7 0 Metabolism and nutrition disorders Decreased appetite and food intake 47 5 28 4 Skin and subcutaneous tissue disorders HFSR/PPES Rash b 45 26 17 6 7 4 0 <1 Gastrointestinal disorders...

    • Drug Interactions

    7 DRUG INTERACTIONS

  • Strong CYP3A4 inducers: Avoid strong CYP3A4 inducers. ( 7.1 )
  • Strong CYP3A4 inhibitors: Avoid strong CYP3A4 inhibitors. ( 7.2 )
  • BCRP substrates: Monitor patients closely for symptoms of increased exposure to BCRP substrates. ( 7.3 ) 7.1 Effect of Strong CYP3A4 Inducers on Regorafenib Co-administration of a strong CYP3A4 inducer with STIVARGA decreased the plasma concentrations of regorafenib, increased the plasma concentrations of the active metabolite M-5, and resulted in no change in the plasma concentrations of the active metabolite M-2 [see Clinical Pharmacology ( 12.3 )] , and may lead to decreased efficacy. Avoid concomitant use of STIVARGA with strong CYP3A4 inducers (e.g. rifampin, phenytoin, carbamazepine, phenobarbital, and St. John's Wort). 7.2 Effect of Strong CYP3A4 Inhibitors on Regorafenib Co-administration of a strong CYP3A4 inhibitor with STIVARGA increased the plasma concentrations of regorafenib and decreased the plasma concentrations of the active metabolites M-2 and M-5 [see Clinical Pharmacology ( 12.3 )] , and may lead to increased toxicity. Avoid concomitant use of STIVARGA with strong CYP3A4 inhibitors (e.g. clarithromycin, grapefruit juice, itraconazole, ketoconazole, nefazodone, posaconazole, telithromycin, and voriconazole). 7.3 Effect of Regorafenib on Breast Cancer Resistance Protein (BCRP) Substrates Co-administration of STIVARGA with a BCRP substrate increased the plasma concentrations of the BCRP substrate [see Clinical Pharmacology ( 12.3 )] . Monitor patients closely for signs and symptoms of exposure related toxicity to the BCRP substrate (e.g. methotrexate, fluvastatin, atorvastatin). Consult the concomitant BCRP substrate product information when considering administration of such products together with STIVARGA.

    • Contraindications

    4 CONTRAINDICATIONS None. None.

    Pregnancy and Breastfeeding

    8.1 Pregnancy Risk Summary Based on animal studies and its mechanism of action, STIVARGA can cause fetal harm when administered to a pregnant woman. There are no available data on STIVARGA use in pregnant women. Administration of regorafenib was embryolethal and teratogenic in rats and rabbits at exposures lower than human exposures at the recommended dose, with increased incidences of cardiovascular, genitourinary, and skeletal malformations [see Data ] . Advise pregnant women of the potential hazard to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4 % and 15 to 20%, respectively. Data Animal Data In embryo-fetal development studies, a total loss of pregnancy (100% resorption of litter) was observed in rats at doses as low as 1 mg/kg (approximately 6% of the recommended human dose, based on body surface area) and in rabbits at doses as low as 1.6 mg/kg (approximately 25% of the human exposure at the clinically recommended dose measured by AUC). In a single dose distribution study in pregnant rats, there was increased penetration of regorafenib across the blood-brain barrier in fetuses compared to dams. Daily administration of regorafenib to pregnant rats during organogenesis resulted in fetal findings of delayed ossification at doses > 0.8 mg/kg (approximately 5% of the recommended human dose based on body surface area) and dose-dependent increases in skeletal malformations including cleft palate and enlarged fontanelle at doses ≥ 1 mg/kg (approximately 10% of the clinical exposure based on AUC). At doses ≥ 1.6 mg/kg (approximately 11% of the recommended human dose based on body surface area), there were dose-dependent increases in the incidence of cardiovascular malformations, external abnormalities, diaphragmatic hernia, and dilation of the renal...

    Overdosage

    10 OVERDOSAGE The highest dose of STIVARGA studied clinically is 220 mg per day. The most frequently observed adverse drug reactions at this dose were dermatological events, dysphonia, diarrhea, mucosal inflammation, dry mouth, decreased appetite, hypertension, and fatigue. There is no known antidote for STIVARGA overdose. In the event of suspected overdose, interrupt STIVARGA, institute supportive care, and observe until clinical stabilization.

    How Supplied

    16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied STIVARGA (regorafenib) is supplied as 40 mg tablets that are light pink, oval-shaped, film-coated tablets, debossed with 'BAYER' on one side and '40' on the other side in the following:

  • Packages containing three bottles, with each bottle containing 28 tablets, for a total of 84 tablets per package (NDC 50419-171-03).
  • Packages containing four bottles, with each bottle containing 21 tablets, for a total of 84 tablets per package (NDC 50419-171-06). Storage and Handling Store STIVARGA at 25°C (77°F); excursions are permitted from 15 to 30°C (59 to 86°F) [see USP Controlled Room Temperature]. Store tablets in the original bottle and do not remove the desiccant. Keep the bottle tightly closed after first opening. Discard any unused tablets 7 weeks after opening the bottle. Dispose of unused tablets in accordance with local requirements.

    • About This Information

    This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

    What are side effects?

    Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

    What are drug interactions?

    Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.