`
` Hemorrhage: Permanently discontinue STIVARGA for severe or life-
`
`
`
`
`
`
`
` threatening hemorrhage. (5.3)
`
`
` Gastrointestinal perforation or fistula: Discontinue STIVARGA. (5.4)
`
`
`
`
`
`
`
` Dermatologic toxicity: Withhold and then reduce or discontinue
`
`
`
`
`
`
` STIVARGA depending on severity and persistence of dermatologic
`
`
`
` toxicity. (5.5)
`
`
` Hypertension: Temporarily or permanently withhold STIVARGA for severe
`
`
`
`
`
`
` or uncontrolled hypertension. (5.6)
`
`
` Cardiac ischemia and infarction: Withhold STIVARGA for new or acute
`
`
`
`
`
`
`
`
`
` cardiac ischemia/infarction and resume only after resolution of acute
`
`
`
`
`
` ischemic events. (5.7)
`
`
`
` Reversible posterior leukoencephalopathy syndrome (RPLS): Discontinue
`
`
`
`
`
`
` STIVARGA. (5.8)
`
`
` Wound healing complications: Discontinue STIVARGA before surgery.
`
`
`
`
`
` Discontinue in patients with wound dehiscence. (5.9)
`
`
`
`
` Embryo-fetal toxicity: Can cause fetal harm. Advise women of potential
`
`
`
`
`
`
`
`
`
`
`
` risk to a fetus and to use effective contraception during treatment and for 2
`
`
`
`
`
`
`
` months after the final dose. Advise males to use effective contraception for
`
`
`
`
`
`
`
`
` 2 months after the final dose. (5.10, 8.1, 8.3)
`
`
`
`
`
`
`
`
`
`
`
`
`
` ---------------------------------- ADVERSE REACTIONS -------------------------------
`
`
`
`
`
`
`
`
` HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`
` These highlights do not include all the information needed to use
`
`
`
`
`
`
`
` STIVARGA safely and effectively. See full prescribing information for
`
`
`
`
`
` STIVARGA.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` STIVARGA® (regorafenib) tablets, for oral use
` Initial U.S. Approval: 2012
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` WARNING: HEPATOTOXICITY
`
` See full prescribing information for complete boxed warning.
`
`
`
`
`
` Severe and sometimes fatal hepatotox icity 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
`
`
`
`
`
`
`
`
`
`
`
` hepatotox icity as manifested by elevated liver function tests or
`
`
`
`
`
` hepatocellular necrosis, depending upon severity and persistence.
`
`
`
`
`
`(2.2)
`
`
`
`
`
`
`
`
` ------------------------------ INDICATIONS AND USAGE ----------------------------
`
` STIVARGA is a kinase inhibitor indicated for the treatment of 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)
`
`
` ------------------------- 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)
`
`
`
`
`
`
`
`
`
`
` ------------------------ DOSAGE FORMS AND STRENGTHS ---------------------
`
` Tablets: 40 mg (3)
`
`
`
`
`
`
`
`
`
`
`
`
` --------------------------------- CONTRAINDICATIONS -------------------------------
`
` None.
`
`
`
` -------------------------- WARNINGS AND PRECAUTIONS ------------------------
`
`
`
`
` Hepatotoxicity: Monitor liver function tests. Withhold and then reduce or
`
`
`
`
`
`
`
`
` discontinue STIVARGA based on severity and duration. (5.1)
`
`
`
` Infections: Withhold STIVARGA in patients with worsening or severe
`
`
`
`
`
`
`
`
`
` infections. (5.2)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` FULL PRESCRIBING INFORMATION: CONTENTS*
`
` WARNING: HEPATOTOXICITY
`
`
` 1 INDICATIONS AND USAGE
`
`
`
` 1.1 Colorectal Cancer
`
`
`
` 1.2 Gastrointestinal Stromal Tumors
`
`
` 1.3 Hepatocellular Carcinoma
`
`
` 2 DOSAGE AND ADMINISTRATION
`
`
`
`2.1 Recommended Dose
`
`
` 2.2 Dose Modifications
`
`
` 3 DOSAGE FORMS AND STRENGTHS
`
`
`
`4 CONTRAINDICATIONS
`
` 5 WARNINGS AND PRECAUTIONS
`
`
`
`5.1 Hepatotoxicity
`
`5.2 Infections
`
`5.3 Hemorrhage
`
`
` 5.4 Gastrointestinal Perforation or Fistula
`
` 5.5 Dermatologic Toxicity
`
`
`5.6 Hypertension
`
`
` 5.7 Cardiac Ischemia and Infarction
`
`
` 5.8 Reversible Posterior Leukoencephalopathy Syndrome
`
`
`
`5.9 Wound Healing Complications
`
`
` 5.10 Embryo-Fetal Toxicity
`
` 6 ADVERSE REACTIONS
`
`
` 6.1 Clinical Trials Experience
`
`
`
`6.2 Postmarketing Experience
`
`
`
`
`
`
`
`
`
`
`
`
`
` 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
`
`
`
` ---------------------------------- 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)
`
`
`
`
`
`
`
`
`
`
` -------------------------- USE IN SPECIFIC POPULATIONS ------------------------
` Nursing Mothers: Discontinue drug or nursing, taking into consideration the
`
`
`
`
`
`
` importance of the drug to the mother. (8.3)
`
`
`
`
`
`
`
`
`
`
`
`
` See 17 for PATIENT COUNSELING INFORMATION and FDA-
` approved patient labeling.
`
`
`
`
`
`
`
`
`
`
`
`
` Revised: 6/2018
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 7 DRUG INTERACTIONS
`
`
`
` 7.1 Effect of Strong CYP3A4 Inducers on Regorafenib
`
`
`
`
` 7.2 Effect of Strong CYP3A4 Inhibitors on Regorafenib
`
`
`
` 7.3 Effect of Regorafenib on Breast Cancer Resistance Protein (BCRP)
`
`
`
`
`
`Substrates
`
` 8 USE IN SPECIFIC POPULATIONS
`
`
`
`8.1 Pregnancy
`
`8.2 Lactation
`
` 8.3 Females and Males of Reproductive Potential
`
`
`
` 8.4 Pediatric Use
`
`
` 8.5 Geriatric Use
`
` 8.6 Hepatic Impairment
`
`
` 8.7 Renal Impairment
`
`
`8.8 Race
`
`10 OVERDOSAGE
`
`11 DESCRIPTION
`
` 12 CLINICAL PHARMACOLOGY
`
`
` 12.1 Mechanism of Action
`
`
`
`12.2 Pharmacodynamics
`
`12.3 Pharmacokinetics
`
` 13 NONCLINICAL TOXICOLOGY
`
`
`
` 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`
`
` 13.2 Animal Toxicology and/or Pharmacology
`
`
`
` 14 CLINICAL STUDIES
`
`
` 14.1 Colorectal Cancer
`
`
` 14.2 Gastrointestinal Stromal Tumors
`
`
`
`
`
`
`
`1
`
`
`
`Reference ID: 4278033
`
`
`
`
`
`
`14.3 Hepatocellular Carcinoma (HCC)
`
`
`
`
`
`
` 16 HOW SUPPLIED/STORAGE AND HANDLING
`
` 17 PATIENT COUNSELING INFORMATION
`
`
`
`
` *Sections or subsections omitted from the full prescribing information are not listed.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`2
`
`
`
`Reference ID: 4278033
`
`
`
`
`
`FULL PRESCRIBING INFORMATION
`
`
`
`
`
`
`
` 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)].
`
`
`
`
`
`
`
`
`
` 1 INDICATIONS AND USAGE
`
`
`
` 1.1 Colorectal Cancer
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` STIVARGA is indicated for the treatment of 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 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 patients with hepatocellular carcinoma (HCC) who have been previously
`
` treated with sorafenib.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 2 DOSAGE AND ADMINISTRATION
`
`
`
`
`
` 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
`
`
`
`
`
`
`
`
` 3
`
`
`
`Reference ID: 4278033
`
`
`
`
`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
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 3 DOSAGE FORMS AND STRENGTHS
`
`
`
`
` STIVARGA is a 40 mg, light pink, oval-shaped, film-coated tablet, debossed with ‘BAYER’ on one side and ‘40’ on the
`
`
` other side.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 4 CONTRAINDICATIONS
`
`
`
` None.
`
`
`
` 5 WARNINGS AND PRECAUTIONS
`
`
`
` 5.1 Hepatotoxicity
`
`
`
`
`
`
`
`
`
`
`
` Severe drug-induced liver injury with fatal outcome occurred in STIVARGA-treated patients in clinical trials. In most
`
` cases, liver dysfunction occurred within the first 2 months of therapy and was characterized by a hepatocellular pattern of
`
`
`
`
`
`
`
`
`
`
` injury.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` In the CORRECT study, fatal hepatic failure occurred in 1.6% of patients in the regorafenib arm and in 0.4% of patients
`
` in the placebo arm. In the GRID study, fatal hepatic failure occurred in 0.8% of patients in the regorafenib arm. In the
`
`
`
`
`
`
`
`
`
`
`
`
` RESORCE study, there was no increase in the incidence of fatal hepatic failure as compared to placebo [see Adverse
`
`
`
`
`
`
`
`
`
`
`
`
`
` Reactions (6.1)].
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Obtain liver function tests (ALT, AST, and bilirubin) before initiation of STIVARGA and monitor at least every two
` weeks during the first 2 months of treatment. Thereafter, monitor monthly or more frequently as clinically indicated.
`
`
`
`
`
`
`
`
`
`
`
`
` Monitor liver function tests weekly in patients experiencing elevated liver function tests until improvement to less than 3
`
`
`
`
`
`
`
`
`
` times the ULN or baseline.
`
`
`
`
`
`
`
`
`
`
`
`
` Temporarily hold and then reduce or permanently discontinue STIVARGA depending on the severity and persistence of
` hepatotoxicity as manifested by elevated liver function tests or hepatocellular necrosis [see Dosage and Administration
`
`
`
`
`
`
`
`
` (2.2) and Use in Specific Populations (8.6)].
`
`
`
`
`
`
`
`
` 5.2 Infections
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` STIVARGA caused an increased risk of infections. The overall incidence of infection (Grades 1-5) was higher (32% vs.
` 17%) in 1142 STIVARGA-treated patients as compared to the control arm in randomized placebo-controlled trials.The
`
`
`
`
`
`
`
`
`
` incidence of grade 3 or greater infections in STIVARGA treated patients was 9%. The most common infections were
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` urinary tract infections (5.7%), nasopharyngitis (4.0%), mucocutaneous and systemic fungal infections (3.3%) and
`
`
`
`
`
`
`
`
`
`
`
` pneumonia (2.6%). Fatal outcomes caused by infection occurred more often in patients treated with STIVARGA (1.0%)
`
`
`
`
`
`
`
`
`
` as compared to patients receiving placebo (0.3%); the most common fatal infections were respiratory (0.6% in
`
`
`
`
`
`
`
`
`
`
` STIVARGA-treated patients vs 0.2% in patients receiving placebo).
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Withhold STIVARGA for Grade 3 or 4 infections, or worsening infection of any grade. Resume STIVARGA at the same
`
` dose following resolution of infection [see Dosage and Administration (2.2)].
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 5.3 Hemorrhage
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` STIVARGA caused an increased incidence of hemorrhage. The overall incidence (Grades 1-5) was 18.2% in 1142
`
`
`
` patients treated with STIVARGA and 9.5% in patients receiving placebo in randomized, placebo-controlled trials. The
`
`
`
`
`
` incidence of grade 3 or greater hemorrhage in patients treated with STIVARGA was 3.0%. The incidence of fatal
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 4
`
`
`
`Reference ID: 4278033
`
`
`
`
`
` hemorrhagic events was 0.7%, involving the central nervous system or the respiratory, gastrointestinal, or genitourinary
`
` tracts.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Permanently discontinue STIVARGA in patients with severe or life-threatening hemorrhage. Monitor INR levels more
` frequently in patients receiving warfarin [see Clinical Pharmacology (12.3)].
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 5.4 Gastrointestinal Perforation or Fistula
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Gastrointestinal perforation occurred in 0.6% of 4518 patients treated with STIVARGA across all clinical trials of
`
`
` STIVARGA administered as a single agent; this included eight fatal events.
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`
` Gastrointestinal fistula occurred in 0.8% of patients treated with STIVARGA and 0.2% of patients in placebo arm across
`
` randomized, placebo-controlled trials. Permanently discontinue STIVARGA in patients who develop gastrointestinal
`
`
`
`
`
` perforation or fistula.
`
`
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`
`
` 5.5 Dermatologic Toxicity
`
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`
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`
`
`
` In randomized, placebo-controlled trials, adverse skin reactions occurred in 71.9% of patients in the regorafenib arm and
`
` in 25.5% of patients in the placebo arm, including hand-foot skin reaction (HFSR) also known as palmar-plantar
`
`
`
`
`
`
`
` erythrodysesthesia syndrome (PPES), and severe rash requiring dose modification.
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`
` In the randomized, placebo-controlled trials, the overall incidence of HFSR was higher in 1142 STIVARGA-treated
`
` patients (53%) than in the placebo-treated patients (8%). Most cases of HFSR in STIVARGA-treated patients appeared
`
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`
` during the first cycle of treatment. The incidences of Grade 3 HFSR (16% versus <1%), Grade 3 rash (3% versus <1%),
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`
` serious adverse reactions of erythema multiforme (<0.1% vs. 0%) and Stevens -Johnson Syndrome (<0.1% vs. 0%) were
`
`
`
`
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`
`
`
`
`
`
`
`
` also higher in STIVARGA-treated patients [see Adverse Reactions (6.1)]. Across all trials, a higher incidence of HFSR
`
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`
`
` was observed in Asian patients treated with STIVARGA (all grades: 72%; Grade 3: 18%) [see Use in Specific
`
`
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`
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`
`
`
`
`
`
` Populations (8.8 )].
`
`
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`
`
` Toxic epidermal necrolysis occurred in 0.02% of 4518 STIVARGA-treated patients across all clinical trials of
`
` STIVARGA administered as a single agent.
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`
`
` Withhold STIVARGA, reduce the dose, or permanently discontinue STIVARGA depending on the severity and
`
` persistence of dermatologic toxicity [see Dosage and Administration (2.2)]. Institute supportive measures for
`
`
`
`
`
`
`
`
`
` symptomatic relief.
`
`
`
`
`
` 5.6 Hypertension
`
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`
`
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`
`
`
` In randomized, placebo-controlled trials, hypertensive crisis occurred in 0.2% of patients in the regorafenib arms and in
` none of the patients in the placebo arms. STIVARGA caused an increased incidence of hypertension (30% versus 8% in
`
`
`
`
`
`
`
`
`
`
`
`
` CORRECT, 59% versus 27% in GRID, and 31% versus 6% in RESORCE) [see Adverse Reactions (6.1)]. The onset of
`
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`
`
` hypertension occurred during the first cycle of treatment in most patients who developed hypertension (67% in
`
`
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`
`
`
`
` randomized, placebo-controlled trials).
`
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`
`
` Do not initiate STIVARGA unless blood pressure is adequately controlled. Monitor blood pressure weekly for the first 6
`
`
`
`
` weeks of treatment and then every cycle, or more frequently, as clinically indicated. Temporarily or permanently withhold
`
`
`
`
`
`
` STIVARGA for severe or uncontrolled hypertension [see Dosage and Administration (2.2)].
`
`
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`
` 5.7 Cardiac Ischemia and Infarction
`
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`
`
`
`
` STIVARGA increased the incidence of myocardial ischemia and infarction (0.9% vs 0.2%) in randomized placebo-
`
` controlled trials [see Adverse Reactions (6.1)]. Withhold STIVARGA in patients who develop new or acute onset cardiac
`
`
`
`
`
`
`
`
`
` ischemia or infarction. Resume STIVARGA only after resolution of acute cardiac ischemic events, if the potential
`
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`
`
` benefits outweigh the risks of further cardiac ischemia.
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`
` 5.8 Reversible Posterior Leukoencephalopathy Syndrome
`
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`
`
`
`
` Reversible posterior leukoencephalopathy syndrome (RPLS), a syndrome of subcortical vasogenic edema diagnosed by
` characteristic finding on MRI, occurred in one of 4800 STIVARGA-treated patients across all clinical trials. Perform an
`
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`
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`
`
`
` evaluation for RPLS in any patient presenting with seizures, severe headache, visual disturbances, confusion or altered
`
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`
`
` mental function. Discontinue STIVARGA in patients who develop RPLS.
`
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`
`
` 5
`
`
`
`Reference ID: 4278033
`
`
`
`
` 5.9 Wound Healing Complications
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`
` No formal studies of the effect of regorafenib on wound healing have been conducted. Since vascular endothelial growth
` factor receptor (VEGFR) inhibitors such as STIVARGA can impair wound healing, discontinue treatment with
`
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`
`
` STIVARGA at least 2 weeks prior to scheduled surgery. The decision to resume STIVARGA after surgery should be
`
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`
` based on clinical judgment of adequate wound healing. Discontinue STIVARGA in patients with wound dehiscence.
`
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`
` 5.10 Embryo-Fetal Toxicity
`
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`
`
` 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. Regorafenib was embryolethal and
`
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`
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`
`
`
`
` teratogenic in rats and rabbits at exposures lower than human exposures at the recommended dose, with increased
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`
`
` incidences of cardiovascular, genitourinary, and skeletal malformations. Advise pregnant women of the potential risk to a
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` fetus.
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`
`
` Advise females of reproductive potential to use effective contraception during treatment with STIVARGA and for 2
`
` months after the final dose. Advise males with female partners of reproductive potential to use effective contraception
`
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`
` during treatment with STIVARGA and for 2 months after the final dose [see Use in Specific Populations (8.1), (8.3)].
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`
`
` 6 ADVERSE REACTIONS
`
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`
` The following serious adverse reactions are discussed elsewhere in the labeling:
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`
`
` Hepatotoxicity [see Warnings and Precautions (5.1)]
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`
` Infections [see Warnings and Precautions (5.2)]
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`
` Hemorrhage [see Warnings and Precautions (5.3)]
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`
` Gastrointestinal Perforation or Fistula [see Warnings and Precautions (5.4)]
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`
` Dermatological Toxicity [see Warnings and Precautions (5.5)]
`
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`
`
` Hypertension [see Warnings and Precautions (5.6)]
`
`
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`
` Cardiac Ischemia and Infarction [see Warnings and Precautions (5.7)]
`
`
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`
` Reversible Posterior Leukoencephalopathy Syndrome (RPLS) [see Warnings and Precautions (5.8)]
`
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`
`
` 6.1 Clinical Trials Experience
`
`
`
` Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials
`
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` of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rate observed in
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`
` practice.
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`
`
` 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
`
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`
`
` patients who received STIVARGA as a single agent; the distribution of underlying malignancies was 80% CRC, 4%
`
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`
`
` GIST, 10% HCC, 6% other solid tumors; and 74% were White, 11% Asian, and 15% race not known. Among these 4518
`
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` patients, 83% received STIVARGA for at least 21 days and 20% received STIVARGA for 6 months or longer.
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`
`
` 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,
`
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`
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` fever, mucositis, weight loss, rash, and nausea.
`
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`
`
`
`
`Reference ID: 4278033
`
`
`
` 6
`
`
`
`
` Colorectal Cancer
`
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`
`
` 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
`
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`
`
` week treatment cycle and 253 patients (median age 61 years; 60% men) received placebo. The median duration of therapy
`
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`
`
`
`
`
`
`
`
` was 1.7 months (range 2 days, 10.8 months) for patients receiving STIVARGA. Due to adverse reactions, 61% of the
`
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`
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`
`
` 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.
`
`
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`
`
`
`
` Table 1 provides the incidence of adverse reactions (≥10%) in patients in CORRECT.
`
`
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`
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`
`
`
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`
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`
`
`
`
` Table 1: Adverse drug reactions reported in ≥10%of patients treated with STIVARGA in CORRECT and
` reported more commonly than in patients receiving placeboa
`
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`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Adverse Reactions
`
`
`
`
`
`
`
`
`
`
` General disorders and administration
` site conditions
`
`
` Asthenia/fatigue
`
`
` Pain
` Fever
`
` Metabolism and nutrition disorders
`
`
`
` Decreased appetite and food intake
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` STIVARGA
`
` (N=500)
`
` Grade
`
`
` Placebo
`
` (N=253)
`
` Grade
`
`
` All
`
` %
`
`
` 64
`
` 59
`
` 28
`
`
`
` 47
`
`
`
` 45
`
`
`
` 26
`
`
` ≥ 3
`
` %
`
`
` 15
`
` 9
`
` 2
`
`
`
` 5
`
`
`
` 17
`
`
`
` 6
`
`
` All
`
` %
`
`
` 46
`
` 48
`
` 15
`
`
`
` 28
`
`
`
` 7
`
`
`
` 4
`
` 17
`
`
` ≥ 3
`
` %
`
`
` 9
`
` 7
`
` 0
`
`
`
` 4
`
`
`
` 0
`
`
`
` <1
`
` 2
`
` Skin and subcutaneous tissue disorders
`
`
`
` HFSR/PPES
`
` Rash b
` Gastrointestinal disorders
`
` Diarrhea
` Mucositis
`
`
` Investigations
`
` Weight loss
`
` Infections and infestations
`
`
`
`
`
`
`
`
` 43
`
`
`
` 33
`
`
`
` 32
`
`
`
` 8
`
`
`
` 4
`
`
`
` <1
`
`
`
`
`
` 5
`
`
`
` 10
`
`
`
`
`
` 0
`
`
`
` 0
`
`
` Infection c
`
` Vascular disorders
` Hypertension
`
`
` Hemorrhage c
`
` Respiratory, thoracic and mediastinal
`
`
` disorders
`
` Dysphonia
` Nervous system disorders
`
` <1
` 10
`
`
`
`
` Headache
`
` 7
` 0
`
`
` Adverse reactions graded according to National Cancer Institute Common Toxicity for Adverse Events version 3.0
`
`
`
` (NCI CTCAE v3.0).
`
`
`
`
`
`
`
` The term rash represents reports of events of drug eruption, rash, erythematous rash, generalized rash, macular rash,
`
`
`
` maculo-papular rash, papular rash, and pruritic rash.
`
`
`
`
`
`
` Fatal outcomes observed.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`a
`
`
`
`
` b
`
`
`
` c
`
`
`
`
`
`Reference ID: 4278033
`
`
`
` 31
`
`
` 30
`
` 21
`
`
`
` 30
`
`
`
` 9
`
`
` 8
`
` 2
`
`
`
` 0
`
`
`
` 17
`
`
` 8
`
` 8
`
`
`
` 6
`
`
`
` 6
`
`
` <1
`
` <1
`
`
`
` 0
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 7
`
`
`
`
` Table 2 provides laboratory abnormalities observed in CORRECT.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Table 2: Laboratory test abnormalities reported in CORRECT
`
`
`
`
`
`
`
`
` Blood and lymphatic system
` disorders
`
`
` Anemia
`
` Thrombocytopenia
`
` Neutropenia
`
` Lymphopenia
` Metabolism and nutrition
`
`
`
` disorders
`
` Hypocalcemia
`
` Hypokalemia
` Hyponatremia
`
` Hypophosphatemia
`
` Hepatobiliary disorders
`
` Hyperbilirubinemia
`
` Increased AST
`
` Increased ALT
`
`
`
` Laboratory Parameter
`
`
` STIVARGA
`
` (N=500 a)
`
` Grade b
`
`
`
` Placebo
` (N=253 a)
`
`
` Grade b
`
`
`
`
`
`
`
`
`
` All
`
` %
`
`
`
` 79
`
` 41
`
` 3
`
` 54
`
`
`
` 59
`
` 26
`
` 30
`
` 3
`
`
` %
`
`
`
` 5
`
` 2
`
` 1
`
` 9
`
`
`
` 1
`
` 4
`
` 7
`
` 4
`
`
` %
`
`
` 1
`
`
` <1
`
` 0
`
` 0
`
`
`
` <1
`
` 0
`
` 1
`
`
` All
`
` %
`
`
`
` 66
`
` 17
`
` 0
`
` 35
`
`
`
` 18
`
` 8
`
` 22
`
` 3
`
`
` %
`
`
` 3
`
`
` <1
`
` 0
`
` 4
`
`
` 1
`
`
` <1
`
` 4
`
` 4
`
`
` %
`
`
`
` 0
`
` 0
`
` 0
` <1
`
`
`
`
` 0
`
` 0
`
` 0
`
`
`
`
` 0
`
` 1
`
` 4
` 11
`
`
` 31
`
` 57
`
`
`
`
`
`
`
` 3
`
` 3
`
` 5
`
` 17
`
` 10
`
` 45
`
` 1
`
` 1
`
` 4
`
` 46
`
` 5
`
` 65
`
` <1
`
` 1
`
` 3
`
` 30
`
` 5
`
` 45
`
`
`
`
`
`
`
`
` Renal and urinary disorders
` Proteinuriac
`
`
` 0
`
` 0
`
` 1
` 61
`
`
` 2
`
` 84
`
`
`
`
`
`
`
` Investigations
`
` Increased INRd
`
` N/A
`
` N/A
`
` 2
`
` 17
`
` 4
`
` 24
`
` 2
`
` 2
` Increased Lipase
`
`
` 3
`
` 19
`
` 9
`
` 46
` <1
` <1
` Increased Amylase
`
`
` 2
`
` 17
`
`
` 2
`
` 26
`
`
` a % based on number of patients with post-baseline samples which may be less than 500 (regorafenib) or 253 (placebo).
`
`
`
` b NCI CTCAE v3.0.
`
`
`
`
` c Based on urine protein-creatinine ratio data.
`
`
`
`
` d
` International normalized ratio: No Grade 4 denoted in NCI CTCAE, v3.0.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Gastrointestinal Stromal Tumors
`
`
`
`
`
`
`
`
`
`
`
`
` The safety data described below are derived from a randomized (2:1), double-blind, placebo-controlled trial (GRID) in
`
`
`
` which 132 patients (median age 60 years; 64% men) with previously-treated GIST received STIVARGA as a single agent
`
`
`
`
`
`
`
`
`
` at a dose of 160 mg daily for the first 3 weeks of each 4 week treatment c ycle and 66 patients (median age 61 years; 64%
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` men) received placebo. The median duration of therapy was 5.7 months (range 1 day, 11.7 months) for patients receiving
`
`
`
`
`
`
`
`
`
`
`
`
` STIVARGA. Dose interruptions for adverse events were required in 58% of patients receiving STIVARGA and 50% of
`
`
`
`
`
`
`
`
`
`
`
`
`
` patients had their dose reduced. Adverse reactions that resulted in treatment discontinuation were reported in 2.3% of
`
`
`
`
`
`
`
`
`
`
`
` STIVARGA-treated patients compared to 1.5% of patients who received placebo.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Table 3 provides the incidence of adverse reactions (≥10%) in patients in GRID.
`
`
`
`
`
`
`
`
`
`Reference ID: 4278033
`
`
`
` 8
`
`
`
`
`
`
`
`
`
`
` Table 3: Adverse reactions reported in ≥10%patients treated with STIVARGA in GRID and reported
`
` more commonly than in patients receiving placeboa
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Adverse Reactions
`
`
`
`
`
`
`
`
`
` Skin and subcutaneous tissue disorders
` HFSR/PPE
`
`
` Rash b
` Alopecia
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` STIVARGA
`
` (N=132)
`
`
`
` Grade
`
`
` Placebo
`
` (N=66)
`
`
`
` Grade
`
`
` All
`
` %
`
`
` 67
`
` 30
`
` 24
`
`
`
` 52
`
` 21
`
`
` 59
`
` 11
`
`
` 60
`
` 47
`
` 40
`
` 20
`
` 17
`
`
`
` 39
`
`
` ≥ 3
`
` %
`
`
` 22
`
` 7
`
` 2
`
`
`
` 4
`
` 0
`
`
` 28
`
` 4
`
`
` 8
`
` 8
`
` 2
`
` 2
` <1
`
`
`
`
` 0
`
`
` All
`
` %
`
`
` 12
`
` 3
`
` 2
`
`
`
` 39
`
` 11
`
`
` 27
`
` 3
`
`
` 55
`
` 9
`
` 8
`
` 12
`
` 8
`
`
`
` 9
`
` 5
`
`
` ≥ 3
`
` %
`
`
` 2
`
` 0
`
` 0
`
`
`
` 2
`
` 2
`
`
` 5
`
` 0
`
`
` 14
`
` 0
`
` 2
`
` 2
`
` 0
`
`
`
` 0
`
` 0
`
`
` General disorders and administration
` site conditions
`
`
` Asthenia/Fatigue
`
`
` Fever
` Vascular disorders
`
`
` Hypertension
`
` Hemorrhage
` Gastrointestinal disorders
`
`
` Pain
` Diarrhea
`
`
` Mucositis
`
` Nausea
` Vomiting
`
` Respiratory, thoracic and mediastinal
`
` disorders
`
` Dysphonia
`
` Infections and infestations
`
`
`
`
`
`
`
`
`
`
`
`
`
` Infection c
`
` Metabolism and nutrition disorders
`
`
`
` Decreased appetite and food intake
`
`
`
` Hypothyroidism d
`
` Nervous system disorders
`
` Headache
`
`
` Investigations
`
`
` Weight loss
` Musculoskeletal and connective tissue
`
`
`
` disorders
`
`
` Muscle spasms
`
` 14
` a Adverse reactions graded according to NCI CTCAE v4.0.
`
`
`
`
`
`
` b The term rash represents reports of events of rash, erythematous rash, macular rash, maculo-papular rash, papular rash
`
`
`
`
`
`
`
`
` and pruritic rash.
`
`
` c Fatal outcomes observed.
`
`
`
` d Hypothyroidism incidence based on subset of patients with normal TSH and no thyroid supplementation at baseline.
`
`
`
`
`
`
` 32
`
`
` 31
`
` 18
`
`
`
` 16
`
`
`
` 14
`
`
`
`
`
`
`
`
`
` 5
`
`
` <1
`
` 0
`
`
`
` 0
`
`
`
` 0
`
`
`
` 0
`
`
`
`
` 21
`
` 6
`
`
`
` 9
`
`
`
` 8
`
`
`
` 3
`
`
`
`
` 3
`
` 0
`
`
`
` 0
`
`
`
` 0
`
`
`
` 0
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Table 4 provides laboratory abnormalities observed in GRID.
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4278033
`
`
`
` 9
`
`
`
`
` Table 4: Laboratory test abnormalities reported in G