`
`Approval Package for:
`
`APPLICATION NUMBER:
`
`203085Orig1s007
`
`
`
`
`
`Trade Name:
`
` Stivarga
`
`regorafenib
`
`Bayer HealthCare Pharmaceuticals, Inc.
`
`April 27, 2017
`
`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.
`• Locally advanced, unresectable or metastatic
`gastrointestinal stromal tumor (GIST) who have
`been previously treated with imatinib mesylate and
`sunitinib malate.
`• Hepatocellular carcinoma (HCC) who have been
`previously treated with sorafenib.
`
`Generic or Proper
`Name:
`
`Sponsor:
`
`
`
`
`Approval Date:
`
`
`Indication:
`
`
`
`
`
`
`
`
`CENTER FOR DRUG EVALUATION AND RESEARCH
`203085Orig1s007
`
`CONTENTS
`
`Reviews / Information Included in this NDA Review.
`
`Approval Letter
`Other Action Letters
`Labeling
`REMS
`Summary Review
`Officer/Employee List
`Office Director Memo
`Cross Discipline Team Leader Review
`Medical Review(s)
`Chemistry Review(s)
`Environmental Assessment
`Pharmacology Review(s)
`Statistical Review(s)
`Microbiology / Virology Review(s)
`Clinical Pharmacology/Biopharmaceutics Review(s)
`Other Reviews
`Risk Assessment and Risk Mitigation Review(s)
`Proprietary Name Review(s)
`Administrative/Correspondence Document(s)
`
`X
`
`X
`
`X
`X
`
`
`X
`X
`
`
`X
`
`X
`X
`
`
`X
`
`
`
`
`
`
`
`
`
`
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`203085Orig1s007
`
`
`APPROVAL LETTER
`
`
`
`
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`
`
`
`
`
`NDA 203085/S-007
`
`
`
`
`
`
`Food and Drug Administration
`Silver Spring MD 20993
`
`SUPPLEMENT APPROVAL
`
`
`
`Bayer HealthCare Pharmaceuticals, Inc.
`Attention: Lisa Chao, Ph. D.
`Deputy Director, Global Regulatory Affairs, Specialty Medicine
`100 Bayer Boulevard, P.O. Box 915
`Whippany, NJ 07981-0915
`
`
`Dear Dr. Chao:
`
`Please refer to your Supplemental New Drug Application (sNDA) dated October 30, 2016,
`received October 31, 2016, and your amendments, submitted under section 505(b) of the Federal
`Food, Drug, and Cosmetic Act (FDCA) for Stivarga (regorafenib) tablets, 40 mg.
`
`This Prior Approval supplemental new drug application provides for a new indication for the use
`of Stivarga (regorafenib) for the treatment of patients with hepatocellular carcinoma (HCC) who
`have been previously treated with sorafenib.
`
`APPROVAL & LABELING
`
`We have completed our review of this supplemental application, as amended. It is approved,
`effective on the date of this letter, for use as recommended in the enclosed, agreed-upon labeling
`text.
`
`WAIVER OF HIGHLIGHTS SECTION
`
`We are waiving the requirements of 21 CFR 201.57(d)(8) regarding the length of Highlights of
`prescribing information. This waiver applies to all future supplements containing revised
`labeling unless we notify you otherwise.
`
`CONTENT OF LABELING
`
`As soon as possible, but no later than 14 days from the date of this letter, submit the content of
`labeling [21 CFR 314.50(l)] in structured product labeling (SPL) format using the FDA
`automated drug registration and listing system (eLIST), as described at
`http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm. Content
`of labeling must be identical to the enclosed labeling (text for the package insert, text for the
`patient package insert), with the addition of any labeling changes in pending “Changes Being
`
`Reference ID: 4091525
`
`
`
`NDA 203085/S-007
`Page 2
`
`
`Effected” (CBE) supplements, as well as annual reportable changes not included in the enclosed
`labeling.
`
`Information on submitting SPL files using eList may be found in the guidance for industry titled
`“SPL Standard for Content of Labeling Technical Qs and As at
`http://www.fda.gov/downloads/DrugsGuidanceComplianceRegulatoryInformation/Guidances/U
`CM072392.pdf
`
`The SPL will be accessible from publicly available labeling repositories.
`
`Also within 14 days, amend all pending supplemental applications that include labeling changes
`for this NDA, including CBE supplements for which FDA has not yet issued an action letter,
`with the content of labeling [21 CFR 314.50(l)(1)(i)] in MS Word format, that includes the
`changes approved in this supplemental application, as well as annual reportable changes and
`annotate each change. To facilitate review of your submission, provide a highlighted or marked-
`up copy that shows all changes, as well as a clean Microsoft Word version. The marked-up copy
`should provide appropriate annotations, including supplement number(s) and annual report
`date(s).
`
`REQUIRED PEDIATRIC ASSESSMENTS
`
`Under the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c), all applications for new
`active ingredients, new indications, new dosage forms, new dosing regimens, or new routes of
`administration are required to contain an assessment of the safety and effectiveness of the
`product for the claimed indication(s) in pediatric patients unless this requirement is waived,
`deferred, or inapplicable.
`
`Because this drug product for this indication has an orphan drug designation, you are exempt
`from this requirement.
`
`PROMOTIONAL MATERIALS
`
`You may request advisory comments on proposed introductory advertising and promotional
`labeling. To do so, submit the following, in triplicate, (1) a cover letter requesting advisory
`comments, (2) the proposed materials in draft or mock-up form with annotated references, and
`(3) the package insert(s) to:
`
`
`OPDP Regulatory Project Manager
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Prescription Drug Promotion (OPDP)
`5901-B Ammendale Road
`Beltsville, MD 20705-1266
`
`Reference ID: 4091525
`
`
`
`NDA 203085/S-007
`Page 3
`
`
`
`Alternatively, you may submit a request for advisory comments electronically in eCTD format.
`For more information about submitting promotional materials in eCTD format, see the draft
`Guidance for Industry (available at:
`http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
`CM443702.pdf ).
`
`You must submit final promotional materials and package insert(s), accompanied by a Form
`FDA 2253, at the time of initial dissemination or publication [21 CFR 314.81(b)(3)(i)]. Form
`FDA 2253 is available at
`http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM083570.pdf.
`
`Information and Instructions for completing the form can be found at
`http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM375154.pdf.
`
`For more information about submission of promotional materials to the Office of Prescription
`Drug Promotion (OPDP), see
`http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm090142.htm.
`
`REPORTING REQUIREMENTS
`
`We remind you that you must comply with reporting requirements for an approved NDA
`(21 CFR 314.80 and 314.81).
`
`If you have any questions, call Anuja Patel, Senior Regulatory Health Project Manager, at (301)
`796-9022.
`
`
`
`Sincerely,
`
`{See appended electronic signature page}
`
`Patricia Keegan, M.D.
`Division Director
`Division of Oncology Products 2
`Office of Hematology and Oncology Products
`Center for Drug Evaluation and Research
`
`
`ENCLOSURE:
`Content of Labeling
`
`
`
`Reference ID: 4091525
`
`
`
`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`PATRICIA KEEGAN
`04/27/2017
`
`Reference ID: 4091525
`
`
`
`
` CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`203085Orig1s007
`
`
`LABELING
`
`
`
` 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 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)
`
`
`
`
`
`
`
`
`-------------------------- RECENT MAJOR CHANGES --------------------------
`
`Indications and Usage, Colorectal Cancer (1.1)
`6/2016
`
`Indications and Usage, Hepatocellular Carcinoma (1.3)
`4/2017
`
`
`Dosage and Administration, Dose Modifications (2.2)
`4/2017
`
`
`Warnings and Precautions (5.1-5.8)
`4/2017
`
`
`
`
`--------------------------- 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)
`
`
`
`
`
`
`
`
`
`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
`
`
`
`Reference ID: 4090114
`
`
`
` Infections: Withhold STIVARGA in patients with worsening or severe
`
`
`infections. (5.2)
` 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 -----------------------------
`
`
`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: 4/2017
`
`
`
`6.2 Postmarketing Experience
`
`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
`
`1
`
`
`
`
`
`14 CLINICAL STUDIES
`
`14.1 Colorectal Cancer
`
`14.2 Gastrointestinal Stromal Tumors
`
`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.
`
`
`
`
`Reference ID: 4090114
`
`
`
`
`2
`
`
`
`
`
`
`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
`
`
`
`Reference ID: 4090114
`
`3
`
`
`
`
`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
`
`
`
`Reference ID: 4090114
`
`4
`
`
`
`
`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 as single agent; this included eight fatal events.
`
`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.
`5.5 Dermatologic Toxicity
`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.
`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
`
`during the first cycle of treatment. The incidences of Grade 3 HFSR (16% versus <1%), Grade 3 rash (3% versus <1%),
`serious adverse reactions of erythema multiforme (<0.1% vs. 0%) and Stevens-Johnson Syndrome (<0.1% vs. 0%) were
`
`also higher in STIVARGA-treated patients [see Adverse Reactions (6.1)]. Across all trials, a higher incidence of HFSR
`was observed in Asian patients treated with STIVARGA (all grades: 72%; Grade 3: 18%) [see Use in Specific
`Populations (8.8 )].
`Toxic epidermal necrolysis occurred in 0.02% of 4518 STIVARGA-treated patients across all clinical trials of
`STIVARGA administered as a single agent.
`
`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
`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
`
`hypertension occurred during the first cycle of treatment in most patients who developed hypertension (67% in
`
`randomized, placebo-controlled trials).
`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)].
`
`
`5.7 Cardiac Ischemia and Infarction
`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
`benefits outweigh the risks of further cardiac ischemia.
`5.8 Reversible Posterior Leukoencephalopathy Syndrome
`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
`evaluation for RPLS in any patient presenting with seizures, severe headache, visual disturbances, confusion or altered
`mental function. Discontinue STIVARGA in patients who develop RPLS.
`
`
`
`Reference ID: 4090114
`
`5
`
`
`
`
`5.9 Wound Healing Complications
`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
`STIVARGA at least 2 weeks prior to scheduled surgery. The decision to resume STIVARGA after surgery should be
`
`
`
`based on clinical judgment of adequate wound healing. Discontinue STIVARGA in patients with wound dehiscence.
`
`5.10 Embryo-Fetal Toxicity
`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
`
`teratogenic in rats and rabbits at exposures lower than human exposures at the recommended dose, with increased
`incidences of cardiovascular, genitourinary, and skeletal malformations. Advise pregnant women of the potential risk to a
`fetus.
`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
`during treatment with STIVARGA and for 2 months after the final dose [see Use in Specific Populations (8.1), (8.3)].
`
` 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)]
`
`
`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.
`
`
`
`Reference ID: 4090114
`
`6
`
`
`
`
`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 placeboa
`
`
`Adverse Reactions
`
`STIVARGA
`(N=500)
`Grade
`
`
`All
`%
`
`≥ 3
`%
`
`Placebo
`(N=253)
`Grade
`
`
`All
`%
`
`≥ 3
`%
`
`General disorders and administration
`site conditions
`Asthenia/fatigue
`Pain
`Fever
`Metabolism and nutrition disorders
`
`Decreased appetite and food intake
`
`Skin and subcutaneous tissue disorders
`HFSR/PPES
`Rash b
`
`Gastrointestinal disorders
`Diarrhea
`
`Mucositis
`Investigations
`
`Weight loss
`Infections and infestations
`Infection c
`
`Vascular disorders
`
`Hypertension
`Hemorrhage c
`
`Respiratory, thoracic and mediastinal
`disorders
`
`
`Dysphonia
`Nervous system disorders
`
`0
`7
`<1
`Headache
`10
`
`
` a Adverse reactions graded according to National Cancer Institute Common Toxicity for Adverse Events version 3.0
`
`(NCI CTCAE v3.0).
`b 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.
`c Fatal outcomes observed.
`
`
`64
`
`59
`
`28
`
`
`47
`
`45
`
`26
`
`
`43
`
`33
`
`
`32
`
`31
`
`30
`
`21
`
`
`30
`
`
`15
`
`9
`2
`
`5
`
`17
`
`6
`
`8
`4
`
`<1
`
`9
`
`8
`2
`
`0
`
`46
`
`48
`
`15
`
`
`28
`
`7
`4
`
`17
`
`5
`
`10
`
`
`17
`
`8
`8
`
`6
`
`9
`7
`0
`
`4
`
`0
`<1
`
`2
`0
`
`0
`
`6
`
`<1
`<1
`
`0
`
`
`
`Reference ID: 4090114
`
`7
`
`
`
`
`Table 2 provides laboratory abnormalities observed in CORRECT.
`Table 2: Laboratory test abnormalities reported in CORRECT
`
`
`Laboratory Parameter
`
`
`STIVARGA
`(N=500 a)
`
`Grade b
`
`3
`%
`
`All
`%
`
`4
`%
`
`All
`%
`
`Placebo
`(N=253 a)
`
`
` Grade b
`3
`%
`
`4
`%
`
`
`79
`41
`
`3
`54
`
`
`5
`2
`1
`9
`
`
`1
`<1
`0
`0
`
`
`66
`
`17
`0
`35
`
`
`
`3
`<1
`0
`4
`
`
`0
`0
`0
`<1
`
`
`
`Blood and lymphatic system
`disorders
`
`Anemia
`Thrombocytopenia
`
`Neutropenia
`Lymphopenia
`
`Metabolism and nutrition
`disorders
`
`
`
`
`
`
`
`0
`1
`18
`<1
`1
`59
`Hypocalcemia
`
`
`0
`<1
`8
`0
`4
`26
`Hypokalemia
`
`0
`4
`22
`1
`7
`30
`
`Hyponatremia
`0
`4
`11
`1
`31
`57
`Hypophosphatemia
`
`Hepatobiliary disorders
`
`
`
`
`
`
`3
`5
`17
`3
`10
`45
`Hyperbilirubinemia
`1
`4
`46
`1
`5
`65
`Increased AST
`
`<1
`3
`30
`1
`5
`45
`Increased ALT
`
`Renal and urinary disorders
`
`
`
`
`
`
`Proteinuriac
`
`0
`1
`
` 61
`0
`2
`84
`Investigations
`
`
`
`
`
`
`Increased INRd
`N/A
`2
`
` 17
`N/A
`4
` 24
`
`2
`3
`19
`2
`9
`46
`Increased Lipase
`
`<1
`2
`17
`<1
`2
`26
`Increased Amylase
` 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 cycle and 66 patients (median age 61 years; 64%
`men)