Case 1:16-cv-01221-LPS Document 56-1 Filed 06/13/18 Page 1 of 29 PageID #: 487
`Case 1:16-cv-01221-LPS Document 56-1 Filed 06/13/18 Page 1 of 29 PageID #: 487
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`EXHIBIT A
`EXHIBIT A
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`Case 1:16-cv-01221-LPS Document 56-1 Filed 06/13/18 Page 2 of 29 PageID #: 488
` 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
`
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` 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)
`
`
` 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.
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`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
`
`
`
`
`-------------------------- 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)
`
`
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`
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`
`
`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
`
`
`
`

`

`Case 1:16-cv-01221-LPS Document 56-1 Filed 06/13/18 Page 3 of 29 PageID #: 489
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`
` 
`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
`
`
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`2
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`

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`Case 1:16-cv-01221-LPS Document 56-1 Filed 06/13/18 Page 4 of 29 PageID #: 490
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`
`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
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`

`

`Case 1:16-cv-01221-LPS Document 56-1 Filed 06/13/18 Page 5 of 29 PageID #: 491
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`Reduce the dose of STIVARGA to 80 mg:
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` 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
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`

`

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`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
`
`

`

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`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
`
`

`

`Case 1:16-cv-01221-LPS Document 56-1 Filed 06/13/18 Page 8 of 29 PageID #: 494
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`
`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
`
`

`

`Case 1:16-cv-01221-LPS Document 56-1 Filed 06/13/18 Page 9 of 29 PageID #: 495
`
`
`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) 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: 4090114
`
`8
`
`

`

`Case 1:16-cv-01221-LPS Document 56-1 Filed 06/13/18 Page 10 of 29 PageID #: 496
`
`
`Table 3: Adverse reactions reported in ≥10% patients treated with STIVARGA in GRID and reported
`
`more commonly than in patients receiving placeboa
`
`
`Adverse Reactions
`
`STIVARGA
`(N=132)
`Grade
`
`All
`%
`
`≥ 3
`%
`
`Placebo
`(N=66)
`Grade
`
`
`All
`%
`
`≥ 3
`%
`
`Skin and subcutaneous tissue disorders
`HFSR/PPE
`Rash b
`
`Alopecia
`
`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
`
`14
`Muscle spasms
`
`
` 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.
`
`
`2
`0
`0
`
`
`2
`2
`
`5
`0
`
`14
`
`0
`2
`2
`0
`
`0
`
`0
`
`3
`0
`
`0
`
`0
`
`0
`
`67
`
`30
`
`24
`
`
`
`52
`
`21
`
`
`59
`
`11
`
`
`60
`
`47
`
`40
`
`20
`
`17
`
`
`39
`
`
`
`
` 32
`
`
`31
`
`18
`
`16
`
`
`14
`
`
`22
`
`7
`2
`
`
`4
`0
`
`28
`
`4
`
`8
`8
`2
`2
`<1
`
`0
`
`5
`
`<1
`0
`
`0
`
`0
`
`0
`
`12
`
`3
`2
`
`
`39
`
`11
`
`
`27
`
`3
`
`55
`
`9
`8
`12
`
`8
`
`9
`
`5
`
`
`21
`6
`
`9
`
`8
`
`3
`
`Table 4 provides laboratory abnormalities observed in GRID.
`
`
`
`Reference ID: 4090114
`
`9
`
`

`

`Case 1:16-cv-01221-LPS Document 56-1 Filed 06/13/18 Page 11 of 29 PageID #: 497
`
`
`Table 4: Laboratory test abnormalities reported in GRID
`
`
`Laboratory Parameter
`
`
`STIVARGA
`
`(N=132 a)
`
`
`Grade b
`
`
` 3
` %
`
`
`
` All
`
` %
`
` 4
`
`
` %
`
`
` All
`
` %
`
`Placebo
`
`(N=66 a)
`
`
` Grade b
`
` 3
` %
`
`
` 4
`
`
` %
`
`Blood and lymphatic
`system disorders
`
`Thrombocytopenia
`Neutropenia
`Lymphopenia
`
`Metabolism and nutrition
`disorders
`
`Hypocalcemia
`Hypokalemia
`Hypophosphatemia
`Hepatobiliary disorders
`
`Hyperbilirubinemia
`Increased AST
`Increased ALT
`Renal and urinary
`disorders
`
`Proteinuria c
`Investigations
`0
`0
`5
`1
`0
`Increased Lipase
`14
`
`
` a Percent based on number of patients with post-baseline samples which may be less than 132 (regorafenib) or
`
` 66 (placebo).
`b NCI CTCAE v4.0.
`
`c Based on urine protein-creatinine ratio data.
`
`d No Grade 4 denoted in NCI CTCAE v4.0.
`
`
`
`
`13
`
`16
`
`30
`
`17
`
`21
`
`55
`
`
`33
`
`58
`
`39
`
`
`59
`
`
`1
`2
`8
`
`2
`3
`20
`
`
`3
`3
`4
`
`3
`
`
`
`0
`1
`0
`
`0
`0
`2
`
`1
`1
`1
`
`- d
`
`2
`
`12
`
`24
`
`5
`3
`3
`
`12
`
`47
`
`39
`
`
`53
`
`
`0
`3
`3
`
`0
`0
`2
`
`2
`3
`2
`
`3
`
`2
`0
`0
`
`0
`0
`0
`
`0
`0
`0
`
`- d
`
`
`Hepatocellular Carcinoma
`
`
`
`The safety data described below are derived from a randomized (2:1), double-blind, placebo-controlled trial (RESORCE)
`
`in which patients with previously-treated HCC received either STIVARGA (n=374) 160 mg orally on days 1-21 of each 4
`week treatment cycle or placebo (n=193). The median age was 63 years, 88% were men, 98% had Child-Pugh A cirrhosis,
`66% had an ECOG performance status (PS) of 0 and 34% had PS of 1. The median duration of therapy was 3.5 months
`(range 1 day to 29.4 months) for patients receiving STIVARGA. Of the patients receiving STIVARGA, 33% were
`
`exposed to STIVARGA for greater than or equal to 6 months and 14% were exposed to STIVARGA for greater than or
`equal to 12 months. Dose interruptions for adverse events were required in 58.3% of patients receiving STIVARGA and
`48% of patients had their dose reduced. The most common adverse reactions requiring dose modification (interruption or
`
`dose reduction) were HFSR/PPES (20.6%), blood bilirubin increase (5.9%), fatigue (5.1%) and diarrhea (5.3%). Adverse
`reactions that resulted in treatment discontinuation were reported in 10.4% of STIVARGA-treated patients compared to
`3.6% of patients who received placebo; the most common adverse reactions requiring discontinuation of STIVARGA
`
`were HFSR/PPES (1.9%) and AST increased (1.6%).
`Table 5 provides the incidence of adverse reactions (≥10%) in patients in RESORCE.
`
`
`
`Reference ID: 4090114
`
`10
`
`
`

`

`Case 1:16-cv-01221-LPS Document 56-1 Filed 06/13/18 Page 12 of 29 PageID #: 498
`
`
`Table 5: Adverse reactions reported in ≥10% of patients treated with STIVARGA in RESORCE and
`
`reported more commonly than in patients receiving placeboa
`
`
`Adverse Reactions
`
`STIVARGA
`(N=374)
`Grade
`
`All
`%
`
`51
`
`55
`
`42
`
`20
`
`
`31
`
`18
`
`
`41
`
`17
`
`13
`
`13
`
`
`Skin and subcutaneous tissue
`disorders
`
`HFSR/PPE
`General disorders and
`administration site conditions
`Pain
`Asthenia/Fatigue
`Fever
`Vascular disorders
`
`Hypertension
`Hemorrhage b
`
`Gastrointestinal disorders
`Diarrhea
`Nausea
`Vomiting
`Mucositis
`Respiratory, thoracic and
`mediastinal disorders
`
`Dysphonia
`Infections and infestations
`Infection b
`Metabolism and nutrition
`disorders
`
`Decreased appetite and food
`intake
`Investigations
`Weight loss
`
`Musculoskeletal and
`connective tissue disorders
`
`
`10
`Muscle spasms
`
`
` a Adverse reactions graded according to NCI CTCAE v4.0.
`
`b Fatal outcomes observed.
`
`18
`
`
`
`
` 31
`
`31
`
`
`13
`
`
`
`
`Placebo
`(N=193)
`Grade
`
`
`≥ 3
`%
`
`<1
`
`8
`5
`0
`
`5
`8
`
`0
`0
`<1
`≤1
`
`0
`
`6
`
`2
`
`0
`
`
`0
`
`All
`%
`
`7
`
`44
`
`33
`
`7
`
`6
`16
`
`
`15
`
`13
`
`7
`2
`
`2
`
`
`
` 18
`
`15
`
`
`4
`
`
`2
`
`≥ 3
`%
`
`12
`
`9
`10
`
`0
`
`15
`
`5
`
`3
`<1
`<1
`1
`
`0
`
`8
`
`3
`
`2
`
`
`0
`
`Other clinically significant adverse reactions observed in less than 10% of STIVARGA-treated patients were: alopecia
`(7%), hypothyroidism (6.4%), pancreatitis (1.6%), exfoliative rash (1.3%), tremor (1.3%), erythema multiforme (0.8%),
`
`myocardial ischemia (0.8%), gastrointestinal fistula (0.3%), and myocardial infarction (0.3%).
`
`
`Table 6 provides laboratory abnormalities observed in RESORCE.
`
`
`
`Reference ID: 4090114
`
`11
`
`
`

`

`Case 1:16-cv-01221-LPS Document 56-1 Filed 06/13/18 Page 13 of 29 PageID #: 499
`
`
`Table 6: Laboratory test abnormalities reported in RESORCE
`
`Laboratory Parameter
`
`
`STIVARGA
`
`(N=374 a)
`
`
`Grade b
`
`
` 3
` %
`
`
`
` All
`
` %
`
` 4
`
`
` %
`
`
` All
`
` %
`
`Placebo
`
`(N=193 a)
`
`
` Grade b
`
` 3
` %
`
`
` 4
`
`
` %
`
`
`63
`
`14
`
`68
`
`23
`
`31
`70
`
`
`78
`
`93
`
`70
`
`
`51
`
`
`5
`3
`