• Dermatological toxicity: Interrupt and then reduce or discontinue Stivarga
`depending on severity and persistence of dermatologic toxicity. (5.3)
`• Hypertension: Temporarily or permanently discontinue Stivarga for severe
`or uncontrolled hypertension. (5.4)
`• Cardiac ischemia and infarction: Withhold Stivarga for new or acute cardiac
`ischemia/infarction and resume only after resolution of acute ischemic events.
`(5.5)
`• Reversible Posterior Leukoencephalopathy Syndrome (RPLS): Discontinue
`Stivarga. (5.6)
`• Gastrointestinal perforation or fistulae: Discontinue Stivarga. (5.7)
`• Wound healing complications: Stop Stivarga before surgery. Discontinue in
`patients with wound dehiscence. (5.8)
`• Embryofetal toxicity: Can cause fetal harm. Advise women of potential risk
`to a fetus. (5.9, 8.1)
`
` ------------------------------ ADVERSE REACTIONS -----------------------------
`The most common adverse reactions (≥30%) are asthenia/fatigue, decreased
`appetite and food intake, hand-foot skin reaction (HFSR) [palmar-plantar
`erythrodysesthesia (PPE)], diarrhea, mucositis, weight loss, infection,
`hypertension, and dysphonia. (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)
`
` ----------------------- 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: 09/2012
`
`
`8 USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`8.3 Nursing Mothers
`8.4 Pediatric Use
`8.5 Geriatric Use
`8.6 Hepatic Impairment
`8.7 Renal Impairment
`8.8 Females and Males of Reproductive Potential
`10 OVERDOSAGE
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.3 Pharmacokinetics
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`13.2 Animal Toxicology and/or Pharmacology
`14 CLINICAL STUDIES
`16 HOW SUPPLIED/STORAGE AND HANDLING
`16.1 How Supplied
`16.2 Storage and Handling
`17 PATIENT COUNSELING INFORMATION
`*Sections or subsections omitted from the full prescribing information are not listed.
`
`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, oral
`Initial U.S. Approval: 2012
`
`
`
`
`
`
`
`
`
`
`
`---------------------- 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 KRAS wild type, an anti-EGFR therapy. (1)
`
`WARNING: HEPATOTOXICITY
`See full prescribing information for complete boxed warning.
`Severe and sometimes fatal hepatotoxicity has been observed in clinical
`trials. Monitor hepatic function prior to and during treatment. 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, 5.1)
`
` ---------------------- DOSAGE AND ADMINISTRATION ----------------------
`• Recommended Dose: 160 mg orally, once daily for the first 21 days of each
`28-day cycle. (2.1)
`• Take Stivarga with food (a low-fat breakfast). (2.1, 12.3)
`
` --------------------- DOSAGE FORMS AND STRENGTHS --------------------
`40 mg film-coated tablets (3)
`
` ------------------------------ CONTRAINDICATIONS -----------------------------
`None.
`
` ----------------------- WARNINGS AND PRECAUTIONS ----------------------
`• Hemorrhage: Permanently discontinue Stivarga for severe or life-threatening
`hemorrhage. (5.2)
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
` INDICATIONS AND USAGE
`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 Hemorrhage
`5.3 Dermatological Toxicity
`5.4 Hypertension
`5.5 Cardiac Ischemia and Infarction
`5.6 Reversible Posterior Leukoencephalopathy Syndrome (RPLS)
`5.7 Gastrointestinal Perforation or Fistula
`5.8 Wound Healing Complications
`5.9 Embryo-Fetal Toxicity
`6 ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`7 DRUG INTERACTIONS
`7.1 Effect of Strong CYP3A4 Inducers on Regorafenib
`7.2 Effect of Strong CYP3A4 Inhibitors on Regorafenib
`
`
` 1
`
`
`
`
`
`
`
`1
`
`

`

`
`
`FULL PRESCRIBING INFORMATION
`
`
`
`
`
`
`
`WARNING: HEPATOTOXICITY
`Severe and sometimes fatal hepatotoxicity has been observed in clinical trials. Monitor hepatic function prior to
`and during treatment. 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), Warnings and Precautions (5.1)].
`
` 1
`
`
` INDICATIONS AND USAGE
`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 KRAS
`wild type, an anti-EGFR therapy.
`
`2 DOSAGE AND ADMINISTRATION
`2.1 Recommended Dose
`The recommended dose is 160 mg regorafenib (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 a low-fat breakfast that contains less than 30% fat
`[see Clinical Pharmacology (12.3)]. Examples of a low-fat breakfast include 2 slices of white toast with 1 tablespoon of
`low-fat margarine and 1 tablespoon of jelly, and 8 ounces of skim milk (319 calories and 8.2 g fat); or 1 cup of cereal, 8
`ounces of skim milk, 1 slice of toast with jam, apple juice, and 1 cup of coffee or tea (520 calories and 2 g fat). 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
`Interrupt Stivarga for the following:
`• NCI CTCAE Version 3.0 (v3.0) Grade 2 hand-foot skin reaction (HFSR) [palmar-plantar erythrodysesthesia (PPE)]
`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 NCI CTCAE v3.0 Grade 3 or 4 adverse reaction
`
`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
`• 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)
`
`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
`
`
`2
`
`

`

`• 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 0.3% of 1100 Stivarga-treated patients across all clinical
`trials. Liver biopsy results, when available, showed hepatocyte necrosis with lymphocyte infiltration. In Study 1, fatal
`hepatic failure occurred in 1.6% of patients in the regorafenib arm and 0.4% of patients in the placebo arm; all the patients
`with hepatic failure had metastatic disease in the liver.
`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)].
`
`5.2 Hemorrhage
`Stivarga caused an increased incidence of hemorrhage. The overall incidence (Grades 1-5) was 21% in Stivarga-treated
`patients compared to 8% in placebo-treated patients in Study 1. Fatal hemorrhage occurred in 4 of 500 (0.8%) of Stivarga-
`treated patients and involved 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)].
`5.3 Dermatological Toxicity
`Stivarga caused an increased incidence of hand-foot skin reaction (HFSR) also known as palmar-plantar
`erythrodysesthesia (PPE) and rash frequently requiring dose modification. The overall incidence of HFSR (45% versus
`7%) and the incidence of Grade 3 HFSR (17% versus 0) were increased in Stivarga-treated patients in Study 1. The
`overall incidence of rash (26% versus 4%) and the incidence of Grade 3 rash (6% versus <1%) were higher in Stivarga-
`treated patients in Study 1 [see Adverse Reactions (6.1)]. The onset of dermatologic toxicity occurred in the first cycle of
`treatment in most patients.
`Temporarily hold and then reduce 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.
`
`5.4 Hypertension
`Stivarga caused an increased incidence of hypertension (30% of Stivarga-treated patients vs. 8% of placebo-treated
`patients in Study 1) [see Adverse Reactions (6.1)]. Hypertensive crisis occurred in 0.18% of 1100 Stivarga-treated patients
`
`
`
`
`
`3
`
`

`

`across all clinical trials. The onset of hypertension occurred during the first cycle of treatment in most patients. Do not
`initiate Stivarga until 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)].
`
`5.5 Cardiac Ischemia and Infarction
`Stivarga increased the incidence of myocardial ischemia and infarction (1.2% for Stivarga-treated patients vs. 0.4% of
`placebo-treated patients) [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.
`5.6 Reversible Posterior Leukoencephalopathy Syndrome (RPLS)
`RPLS (also known as posterior reversible encephalopathy syndrome) occurred in one of 1100 Stivarga-treated patients
`across all clinical trials. Confirm the diagnosis of RPLS with MRI and discontinue Stivarga in patients who develop
`RPLS.
`5.7 Gastrointestinal Perforation or Fistula
`Gastrointestinal perforation or fistula occurred in 0.6% of 1100 patients treated with Stivarga across clinical trials.
`Permanently discontinue Stivarga in patients who develop gastrointestinal perforation or fistula.
`
`5.8 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 regorafenib can impair wound healing, treatment with regorafenib should be
`stopped at least 2 weeks prior to scheduled surgery. The decision to resume regorafenib after surgery should be based on
`clinical judgment of adequate wound healing. Regorafenib should be discontinued in patients with wound dehiscence.
`
`5.9 Embryo-Fetal Toxicity
`Stivarga can cause fetal harm when administered to a pregnant woman. 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. If this drug is used during pregnancy, or if the patient becomes
`pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific
`Populations (8.1)].
`
`6 ADVERSE REACTIONS
`The following serious adverse reactions are discussed elsewhere in the labeling:
`
`• Hepatotoxicity [See Warnings and Precautions (5.1)]
`• Hemorrhage [See Warnings and Precautions (5.2)]
`• Dermatological Toxicity [See Warnings and Precautions (5.3)]
`• Hypertension [See Warnings and Precautions (5.4)]
`• Cardiac Ischemia and Infarction [See Warnings and Precautions (5.5)]
`• Reversible Posterior Leukoencephalopathy Syndrome (RPLS) [See Warnings and Precautions (5.6)]
`• Gastrointestinal Perforation or Fistula [See Warnings and Precautions (5.7)]
`
`
`
`
`
`4
`
`

`

`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 safety data described below, except where noted, are derived from a randomized (2:1), double-blind, placebo-
`controlled trial (Study 1) in which 500 patients (median age 61 years; 61% men) with previously treated metastatic
`colorectal cancer 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 mean duration of therapy was 12
`weeks for patients receiving Stivarga and 8 weeks for patients receiving placebo. Due to adverse reactions, 61% of the
`patients receiving Stivarga required a dose interruption and 38% of the patients had their dose reduced. Drug-related
`adverse reactions that resulted in treatment discontinuation were reported in 8.2% of Stivarga-treated patients compared to
`1.2% of patients who received placebo. Skin toxicity (HFSR/PPE or rash) was the most common cause of permanent drug
`discontinuation.
`The most frequently observed adverse drug reactions (≥30%) in patients receiving Stivarga are asthenia/fatigue, decreased
`appetite and food intake, HFSR/PPE, diarrhea, mucositis, weight loss, infection, hypertension and dysphonia.
`The most serious adverse drug reactions in patients receiving Stivarga are hepatotoxicity, hemorrhage, and gastrointestinal
`perforation.
`Table 1 compares the incidence of adverse reactions (≥10%) in patients receiving Stivarga and reported more commonly
`than in patients receiving placebo (Study 1).
`
`
`
`
`
`5
`
`

`

`Table 1: Adverse drug reactions (≥10%) reported in patients treated with Stivarga and reported more commonly than in
`patients receiving placebo
`
`Adverse Reactions
`
`
`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/PPE
`Rash
`Gastrointestinal disorders
`Diarrhea
`Mucositis
`Investigations
`Weight loss
`Infections and infestations
`Infection
`Vascular disorders
`Hypertension
`Hemorrhage*
`Respiratory, thoracic and
`mediastinal disorders
`Dysphonia
`Nervous system disorders
`Headache
`fatal outcomes observed
`
`*
`
`All
`%
`
`64
`29
`28
`
`47
`
`45
`26
`
`43
`33
`
`32
`
`31
`
`30
`21
`
`30
`
`10
`
`Stivarga
`(n=500)
`Grade
`
`Placebo
`(n=253)
`Grade
`
`≥ 3
`%
`
`15
`3
`2
`
`5
`
`17
`6
`
`8
`4
`
`<1
`
`9
`
`8
`2
`
`0
`
`<1
`
`All
`%
`
`46
`21
`15
`
`28
`
`7
`4
`
`17
`5
`
`10
`
`17
`
`8
`8
`
`6
`
`7
`
`≥ 3
`%
`
`9
`2
`0
`
`4
`
`0
`<1
`
`2
`0
`
`0
`
`6
`
`<1
`<1
`
`0
`
`0
`
`Other clinically important adverse reactions observed more commonly in less than 10% of Stivarga-treated patients and at
`a higher incidence than in placebo-treated patients included the following: alopecia (7.6% vs. 1.6%), taste disorder (7.6%
`vs. 2.4%), musculoskeletal stiffness (6.0% vs. 2.0%), dry mouth (4.8% vs. 2.0%), hypothyroidism (4.2% vs. 0.4%),
`tremor (2.0% vs. 0.0), gastroesophageal reflux (1.4% vs. 0.0), and gastrointestinal fistula (0.8% vs. 0.4%).
`Keratoacanthoma/squamous cell carcinoma of the skin occurred in 0.09% of 1100 Stivarga-treated patients across open-
`label or placebo-controlled clinical trials.
`Laboratory Abnormalities
`Laboratory abnormalities observed in Study 1 are shown in Table 2.
`
`
`
`
`
`6
`
`

`

`Table 2: Laboratory test abnormalities reported in Study 1
`
`Laboratory Parameter
`
`
`Stivarga plus BSC
`(n=500*)
`Grade**
`3
`%
`
`All
`%
`
`Placebo plus BSC
`(n=253*)
`Grade**
`3
`%
`
`4
`%
`
`4
`%
`
`All
`%
`
`
`79
`41
`3
`54
`
`
`5
`2
`1
`9
`
`
`1
`<1
`0
`0
`
`
`66
`17
`0
`34
`
`
`3
`<1
`0
`3
`
`
`0
`0
`0
`0
`
`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
`
`
`
`
`
`
`Proteinuria
`0
`<1
`34
`0
`<1
`60
`Investigations
`
`
`
`
`
`
`N/A
`2
`17
`N/A
`4
`24
`Increased INR ***
`2
`3
`19
`2
`9
`46
`Increased Lipase
`<1
`2
`17
`<1
`2
`26
`Increased Amylase
`* % based on number of patients with post-baseline samples which may be less than 500 (regorafenib) or 253 (placebo)
`** Common Terminology Criteria for Adverse Events (CTCAE), v3.0
`*** International normalized ratio: No Grade 4 denoted in CTCAE, v3.0
`7 DRUG INTERACTIONS
`7.1 Effect of Strong CYP3A4 Inducers on Regorafenib
`Co-administration of a strong CYP3A4 inducer (rifampin) with a single 160 mg dose of Stivarga decreased the mean
`exposure of regorafenib, increased the mean exposure of the active metabolite M-5, and resulted in no change in the mean
`exposure of the active metabolite M-2. Avoid concomitant use of strong CYP3A4 inducers (e.g. rifampin, phenytoin,
`carbamazepine, phenobarbital, and St. John’s Wort) [see Clinical Pharmacology (12.3)].
`7.2 Effect of Strong CYP3A4 Inhibitors on Regorafenib
`Co-administration of a strong CYP3A4 inhibitor (ketoconazole) with a single 160 mg dose of Stivarga increased the mean
`exposure of regorafenib and decreased the mean exposure of the active metabolites M-2 and M-5. Avoid concomitant use
`of strong inhibitors of CYP3A4 activity (e.g. clarithromycin, grapefruit juice, itraconazole, ketoconazole, posaconazole,
`telithromycin, and voriconazole) [see Clinical Pharmacology (12.3)].
`
`
`
`
`
`7
`
`

`

`8 USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`Pregnancy Category D [see Warnings and Precautions (5.9)]
`Risk Summary
`Based on its mechanism of action, Stivarga can cause fetal harm when administered to a pregnant woman. There are no
`adequate and well-controlled studies with Stivarga 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. If this drug is used during pregnancy or if the patient becomes
`pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.
`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. In a repeat dose study with daily administration of regorafenib to pregnant rats
`during organogenesis, findings included delayed ossification in fetuses at doses > 0.8 mg/kg (approximately 5% of the
`recommended human dose based on body surface area) with 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 pelvis.
`
`In pregnant rabbits administered regorafenib daily during organogenesis, there were findings of ventricular septal defects
`evident at the lowest tested dose of 0.4 mg/kg (approximately 7% of the AUC in patients at the recommended dose). At
`doses of ≥ 0.8 mg/kg (approximately 15% of the human exposure at the recommended human dose based on AUC),
`administration of regorafenib resulted in dose-dependent increases in the incidence of additional cardiovascular
`malformations and skeletal anomalies as well as significant adverse effects on the urinary system including missing
`kidney/ureter; small, deformed and malpositioned kidney; and hydronephrosis. The proportion of viable fetuses that were
`male decreased with increasing dose in two rabbit embryo-fetal toxicity studies.
`8.3 Nursing Mothers
`It is unknown whether regorafenib or its metabolites are excreted in human milk. In rats, regorafenib and its metabolites
`are excreted in milk. Because many drugs are excreted in human milk and because of the potential for serious adverse
`reactions in nursing infants from Stivarga, a decision should be made whether to discontinue nursing or discontinue the
`drug, taking into account the importance of the drug to the mother.
`
`8.4 Pediatric Use
`The safety and efficacy of Stivarga in pediatric patients less than18 years of age have not been established.
`In 28-day repeat dose studies in rats there were dose-dependent findings of dentin alteration and angiectasis. These
`findings were observed at regorafenib doses as low as 4 mg/kg (approximately 25% of the AUC in humans at the
`recommended dose). In 13-week repeat dose studies in dogs there were similar findings of dentin alteration at doses as
`low as 20 mg/kg (approximately 43% of the AUC in humans at the recommended dose). Administration of regorafenib in
`these animals also led to persistent growth and thickening of the femoral epiphyseal growth plate.
`
`
`
`
`
`8
`
`

`

`8.5 Geriatric Use
`Of the total number of subjects in clinical studies of Stivarga, 39% were 65 and over, while 8% were 75 and over. No
`overall differences in safety or efficacy were observed between these patients and younger patients.
`8.6 Hepatic Impairment
`No clinically important differences in the mean exposure of regorafenib or the active metabolites M-2 and M-5 were
`observed in patients with hepatocellular carcinoma and mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic
`impairment compared to patients with normal hepatic function [see Clinical Pharmacology (12.3)]. No dose adjustment is
`recommended in patients with mild or moderate hepatic impairment. Closely monitor patients with hepatic impairment for
`adverse reactions [see Warnings and Precautions (5.1)].
`Stivarga is not recommended for use in patients with severe hepatic impairment (Child-Pugh Class C) as it has not been
`studied in this population.
`8.7 Renal Impairment
`No clinically relevant differences in the mean exposure of regorafenib and the active metabolites M-2 and M-5 were
`observed in patients with mild renal impairment (CLcr 60-89 mL/min/1.73m2) compared to patients with normal renal
`function following regorafenib 160 mg daily for 21 days [see Clinical Pharmacology (12.3)]. No dose adjustment is
`recommended for patients with mild renal impairment. Limited pharmacokinetic data are available from patients with
`moderate renal impairment (CLcr 30-59 mL/min/1.73m2). Stivarga has not been studied in patients with severe renal
`impairment or end-stage renal disease.
`8.8 Females and Males of Reproductive Potential
`Contraception
`Use effective contraception during treatment and up to 2 months after completion of therapy.
`Infertility
`There are no data on the effect of Stivarga on human fertility. Results from animal studies indicate that regorafenib can
`impair male and female fertility [see Nonclinical Toxicology (13.1)].
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`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 specific antidote for Stivarga overdose. In the event of suspected overdose, interrupt Stivarga, institute
`supportive care, and observe until clinical stabilization.
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`11 DESCRIPTION
`Stivarga (regorafenib) has 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:
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`Regorafenib is a monohydrate and it has a molecular formula C21H15ClF4N4O3 • H2O 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.
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`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`Regorafenib is a small molecule inhibitor of multiple membrane-bound and intracellular kinases involved in normal
`cellular functions and in pathologic processes such as oncogenesis, tumor angiogenesis, and maintenance of the tumor
`microenvironment. In in vitro biochemical or cellular assays, regorafenib or its major human active metabolites M-2 and
`M-5 inhibited the activity of RET, VEGFR1, VEGFR2, VEGFR3, KIT, PDGFR-alpha, PDGFR-beta, FGFR1, FGFR2,
`TIE2, DDR2, Trk2A, Eph2A, RAF-1, BRAF, BRAFV600E , SAPK2, PTK5, and Abl at concentrations of regorafenib that
`have been achieved clinically. In in vivo models, regorafenib demonstrated anti-angiogenic activity in a rat tumor model,
`and inhibition of tumor growth as well as anti-metastatic activity in several mouse xenograft models including some for
`human colorectal carcinoma.
`12.3 Pharmacokinetics
`Absorption
`Following a single 160 mg dose of Stivarga in patients with advanced solid tumors, regorafenib reaches a geometric mean
`peak plasma level (Cmax) of 2.5 µg/mL at a median time of 4 hours and a geometric mean area under the plasma
`concentration vs. time curve (AUC) of 70.4 µg*h/mL. The AUC of regorafenib at steady-state increases less than dose
`proportionally at doses greater than 60 mg. At steady-state, regorafenib reaches a geometric mean Cmax of 3.9 µg/mL and
`a geometric mean AUC of 58.3 µg*h/mL. The coefficient of variation of AUC and Cmax is between 35% and 44%.
`The mean relative bioavailability of tablets compared to an oral solution is 69% to 83%.
`In a food-effect study, 24 healthy men received a single 160 mg dose of Stivarga on three separate occasions: under a
`fasted state, with a high-fat meal and with a low-fat meal. A high-fat meal (945 calories and 54.6 g fat) increased the mean
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`AUC of regorafenib by 48% and decreased the mean AUC of the M-2 and M-5 metabolites by 20% and 51%,
`respectively, as compared to the fasted state. A low-fat meal (319 calories and 8.2 g fat) increased the mean AUC of
`regorafenib, M-2 and M-5 by 36%, 40% and 23%, respectively as compared to fasted conditions. Stivarga was
`administered with a low-fat meal in Study 1 [see Dosage and Administration (2.1), Clinical Studies (14)].
`Distribution
`Regorafenib undergoes enterohepatic circulation with multiple plasma concentration peaks observed across the 24-hour
`dosing interval. Regorafenib is highly bound (99.5%) to human plasma proteins.
`Metabolism
`Regorafenib is metabolized by CYP3A4 and UGT1A9. The main circulating metabolites of regorafenib measured at
`steady-state in human plasma are M-2 (N-oxide) and M-5 (N-oxide and N-desmethyl), both of them having similar in
`vitro pharmacological activity and steady-state concentrations as regorafenib. M-2 and M-5 are highly protein bound
`(99.8% and 99.95%, respectively).
`Elimination
`Following a single 160 mg oral dose of Stivarga, the geometric mean (range) elimination half-lives for regorafenib and the
`M-2 metabolite in plasma are 28 hours (14 to 58 hours) and 25 hours (14 to 32 hours), respectively. M-5 has a longer
`mean (range) elimination half-life of 51 hours (32 to 70 hours).
`Approximately 71% of a radiolabeled dose was excreted in feces (47% as parent compound, 24% as metabolites) and 19%
`of the dose was excreted in urine (17% as glucuronides) within 12 days after administration of a radiolabeled oral solution
`at a dose of 120 mg.
`Patients with hepatic impairment
`The pharmacokinetics of regorafenib, M-2, and M-5 were evaluated in 14 patients with hepatocellular carcinoma (HCC)
`and mild hepatic impairment (Child-Pugh A); 4 patients with HCC and moderate hepatic impairment (Child-Pugh B); and
`10 patients with solid tumors and normal hepatic function after the administration of a single 100 mg dose of Stivarga. No
`clinically important differences in the mean exposure of regorafenib, M-2, or M-5 were observed in patients with mild or
`moderate hepatic impairment compared to the patients with normal hepatic function. The pharmacokinetics of regorafenib
`has not been studied in patients with severe hepatic impairment (Child-Pugh C).
`Patients with renal impairment
`The pharmacokinetics of regorafenib, M-2, and M-5 were evaluated in 10 patients with mild renal impairment (CLcr 60-
`89 mL/min/1.73m2) and 18 patients with normal renal function following the administration of Stivarga at a dose of 160
`mg daily for 21 days. No differences in the mean steady-state exposure of regorafenib, M-2, or M-5 were observed in
`patients with mild renal impairment compared to patients with normal renal function. Limited pharmacokinetic data are
`available from patients with moderate renal impairment (CLcr 30-59 mL/min/1.73m2). The pharmacokinetics of
`regorafenib has not been studied in patients with severe renal impairment or end-stage renal disease.
`Drug-drug interactions
`In vitro screening on cytochrome P450 enzymes: In vitro studies with human hepatic microsomes or recombinant
`enzymes showed that regorafenib competitively inhibits CYP2C8, CYP2C9, CYP2B6, CYP3A4, and CYP2C19 with R1
`values > 1.1; M-2 inhibits CYP2C9, CYP2C8, CYP3A4, and CYP2D6 with R1 values > 1.1 and M-5 inhibits CYP2C8
`with a R1 value > 1.1. In vitro studies with primary human hepatocytes showed that regorafenib is not expected to induce
`CYP1A2, CYP2B6, CYP2C19, and CYP3A4 enzyme activity.
`In vitro screening on uridine diphosphate glucuronosyltransferases: In vitro studies with human hepatic microsomes
`showed that regorafenib, M