•
`
`
`•
`•
`
`
`
`•
`
`•
`
`
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`
`
`NEXAVAR safely and effectively.
`
`See full prescribing information for NEXAVAR.
`
`
`NEXAVAR (sorafenib) tablets, oral
`Initial U.S. Approval: 2005
`--------------------------RECENT MAJOR CHANGES---------------------------
`Contraindications (4)
`10/2010
`
`Warnings and Precautions (5.8, 5.13, 5.14)
`10/2010
`-----------------------------INDICATIONS AND USAGE---------------------------
`NEXAVAR is a kinase inhibitor indicated for the treatment of
`Unresectable hepatocellular carcinoma (1.1)
`•
`
`Advanced renal cell carcinoma (1.2)
`•
`
`-----------------------DOSAGE AND ADMINISTRATION------------------------
`
`
`400 mg (2 tablets) orally twice daily without food. (2)
`•
`
`
`Treatment interruption and/or dose reduction may be needed to
`•
`
`manage suspected adverse drug reactions. Dose may be reduced
`to 400 mg once daily or to 400 mg every other day. (2)
`-----------------------DOSAGE FORMS AND STRENGTHS--------------------
`200 mg Tablets (3)
`-------------------------------CONTRAINDICATIONS-------------------------------
`NEXAVAR is contraindicated in patients with known severe
`•
`hypersensitivity to sorafenib or any other component of
`NEXAVAR. (4)
`NEXAVAR in combination with carboplatin and paclitaxel is
`contraindicated in patients with squamous cell lung cancer. (4)
`-------------------------WARNINGS AND PRECAUTIONS----------------------
`Cardiac ischemia and/or infarction may occur. Consider
`•
`temporary or permanent discontinuation of NEXAVAR. (5.1)
`Bleeding may occur. If bleeding necessitates medical intervention,
`consider discontinuation of NEXAVAR. (5.2)
`Hypertension usually occurred early in the course of treatment
`and was managed with antihypertensive therapy. Monitor blood
`
`
`pressure weekly during the first 6 weeks and periodically
`thereafter and treat, as required. (5.3)
`Hand-foot skin reaction and rash are common. Management may
`include topical therapies for symptomatic relief, temporary
`treatment interruption and/or dose modification, or in severe or
`persistent cases, permanent discontinuation. (5.4)
`
`• Gastrointestinal perforation is an uncommon adverse reaction. In
`
`the event of a gastrointestinal perforation, NEXAVAR therapy
`should be discontinued. (5.5)
`Temporary interruption of NEXAVAR therapy is recommended in
`patients undergoing major surgical procedures. (5.7)
`_______________________________________________________________________________________________________________________________________
`
`
`Caution is recommended when co-administering substances
`
`metabolized/eliminated predominantly by the UGT1A1 pathway
`
`(for example, irinotecan). (5.9, 7.2)
`
`Caution is recommended when co-administering docetaxel. (5.10, 7.3)
`Caution is recommended when co-administering doxorubicin. (5.11,
`7.4)
`Nexavar may cause fetal harm when administered to a pregnant
`woman. Women of childbearing potential should be advised to
`avoid becoming pregnant while on NEXAVAR. (5.14)
`-------------------------------ADVERSE REACTIONS------------------------------
`The most common adverse reactions (≥20%), which were considered
`to be related to NEXAVAR, are fatigue, weight loss,
`rash/desquamation, hand-foot skin reaction, alopecia, diarrhea,
`anorexia, nausea and abdominal pain (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----------------------------­
`
`
`Carboplatin and Paclitaxel: Caution, sorafenib and paclitaxel AUC
`•
`increases when co-administered. (4, 5.8, 7.1)
`UGT1A1 (for example, irinotecan) and UGT1A9 substrates: Caution,
`drug AUC increases when co-administered with NEXAVAR. (5.9, 7.2)
`Docetaxel: Caution, docetaxel AUC increases when co-administered
`with NEXAVAR. (5.10, 7.3)
`Doxorubicin: Caution, doxorubicin AUC increases when co­
`administered with NEXAVAR. (5.11, 7.4)
`Fluorouracil: Caution, fluorouracil AUC changes when co­
`administered with NEXAVAR. (7.5)
`CYP2B6 and CYP2C8 substrates: Caution, systemic exposure is
`expected to increase when co-administered with NEXAVAR. (7.6)
`CYP3A4 inducers: Expected to increase metabolism of sorafenib
`and decrease sorafenib concentrations. (2, 7.7)
`Neomycin: Caution, sorafenib AUC decreases when co­
`administered with oral neomycin. (5.13, 7.12)
`----------------------------USE IN SPECIFIC POPULATIONS-------------------
`Hepatic impairment: No dose adjustment is necessary in HCC
`•
`patients with Child-Pugh A and B hepatic impairment. NEXAVAR
`has not been studied in patients with Child-Pugh C hepatic
`
`impairment. (8.6)
`Renal impairment: NEXAVAR has not been studied in patients
`undergoing dialysis. (8.7)
`See 17 for PATIENT COUNSELING INFORMATION and
`
` FDA-Approved Patient Labeling.
`
`•
`
`•
`
`•
`
`•
`
`•
`
`•
`
`
`
`
`
`•
`
`•
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`Revised: 10/2010
`
`7 DRUG INTERACTIONS
`7.1 Carboplatin and Paclitaxel
`7.2 UGT1A1 and UGT1A9 Substrates
`7.3
` Docetaxel
`7.4
` Doxorubicin
`
`7.5 Fluorouracil
`7.6 CYP2B6 and CYP2C8 Substrates
`7.7
` CYP3A4 Inducers
`7.8 CYP3A4 Inhibitors and CYP Isoform Substrates
`7.9
` P-glycoprotein substrates
`
`7.10 In Vitro Studies: CYP Enzyme Induction
`7.11 Combination with Other Antineoplastic Agents
`7.12 Neomycin
`8 USE IN SPECIFIC POPULATIONS
` Pregnancy
`8.1
`
` Nursing Mothers
`8.3
`8.4
` Pediatric Use
`8.5
` Geriatric Use
`8.6 Patients with Hepatic Impairment
`
`
`8.7 Patients with Renal Impairment
`
`10 OVERDOSAGE
`
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`
`12.1 Mechanism of Action
`
`12.3 Pharmacokinetics
` NONCLINICAL TOXICOLOGY
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`13
`
`
`
`
`
`
`
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`1
`INDICATIONS AND USAGE
`1.1 Hepatocellular Carcinoma
`
`
`1.2 Renal Cell Carcinoma
`
`2 DOSAGE AND ADMINISTRATION
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`5.1 Risk of Cardiac Ischemia and/or Infarction
`5.2 Risk of Hemorrhage
`5.3 Risk of Hypertension
`5.4 Risk of Dermatologic Toxicities
`5.5 Risk of Gastrointestinal Perforation
`5.6
` Warfarin Co-Administration
`5.7
` Wound Healing Complications
`5.8 Use of Nexavar in combination with Carboplatin and
`
`Paclitaxel in Non-small Cell Lung Cancer
`5.9
`Interactions with UGT1A1 Substrates
`5.10 Interaction with Docetaxel
`5.11 Interaction with Doxorubicin
`5.12 Hepatic Impairment
`5.13 Neomycin
`5.14 Use in Pregnancy
`6 ADVERSE REACTIONS
`
`6.1 Adverse Reactions in HCC Study
`6.2 Adverse Reactions in RCC Study 1
`6.3 Additional Data from Multiple Clinical Trials
`
`
`
`
`
`
`
`Ex. 1089-0001
`
`

`
` 14 CLINICAL STUDIES
`
`17.2 Bleeding; Gastrointestinal Perforation
`
`
`17.3 Skin Reactions; Hypertension
`
`
`14.1 Hepatocellular Carcinoma
`17.4 Birth Defects and Fetal Loss
`
`
`14.2 Renal Cell Carcinoma
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`*Sections or subsections omitted from the full prescribing information
`17 PATIENT COUNSELING INFORMATION
`
`are not listed.
`17.1 Cardiac Ischemia; Infarction
`
`
`____________________________________________________________________________________
`
`
`
` FULL PRESCRIBING INFORMATION
`
`1 INDICATIONS AND USAGE
`1.1 Hepatocellular Carcinoma
`NEXAVAR is indicated for the treatment of patients with unresectable hepatocellular carcinoma (HCC).
`
`1.2 Renal Cell Carcinoma
`NEXAVAR is indicated for the treatment of patients with advanced renal cell carcinoma (RCC).
`
`1st occurrence
`
`
`Continue treatment with NEXAVAR and consider
`topical therapy for symptomatic relief
`If no improvement within 7 days, see below
`
`
`
`2 DOSAGE AND ADMINISTRATION
`The recommended daily dose of NEXAVAR is 400 mg (2 x 200 mg tablets) taken twice daily without food (at least
`1 hour before or 2 hours after a meal). Treatment should continue until the patient is no longer clinically benefiting
`from therapy or until unacceptable toxicity occurs.
`Management of suspected adverse drug reactions may require temporary interruption and/or dose reduction of
`NEXAVAR therapy. When dose reduction is necessary, the NEXAVAR dose may be reduced to 400 mg once
`daily. If additional dose reduction is required, NEXAVAR may be reduced to a single 400 mg dose every other day
`[see Warnings and Precautions (5)].
`Suggested dose modifications for skin toxicity are outlined in Table 1.
`Table 1: Suggested Dose Modifications for Skin Toxicity
`
`Suggested Dose Modification
`Skin Toxicity Grade
`Occurrence
`
`
`
`
`Grade 1: Numbness,
`Any occurrence
`Continue treatment with NEXAVAR and consider
`
`dysesthesia, paresthesia,
`topical therapy for symptomatic relief
`
`tingling, painless swelling,
`erythema or discomfort of the
`hands or feet which does not
`
`disrupt the patient’s normal
`
`activities
`
`Grade 2: Painful erythema
`and swelling of the hands or
`feet and/or discomfort
`affecting the patient’s normal
`
`activities
`
`
`
`Grade 3: Moist
`desquamation, ulceration,
`blistering or severe pain of
`
`the hands or feet, or severe
`discomfort that causes the
`patient to be unable to work
`or perform activities of daily
`living
`
`No dose adjustment is required on the basis of patient age, gender, or body weight.
`Concomitant strong CYP3A4 inducers: The use of concomitant strong CYP3A4 inducers may decrease sorafenib
`plasma concentrations and should be avoided (for example, St. John's Wort, dexamethasone, phenytoin,
`
`
`
`3rd occurrence
`
`
`Discontinue NEXAVAR treatment
`
`
`2
`
`No improvement
`within 7 days or 2nd or
`3rd occurrence
`
`
`4th occurrence
`
`1st or 2nd occurrence
`
`
`
`Interrupt NEXAVAR treatment until toxicity resolves
`
`
`to Grade 0–1
`When resuming treatment, decrease NEXAVAR
`dose by one dose level (400 mg daily or 400 mg
`every other day)
`
`Discontinue NEXAVAR treatment
`
` Interrupt NEXAVAR treatment until toxicity resolves
`
` to Grade 0–1
`When resuming treatment, decrease NEXAVAR
`dose by one dose level (400 mg daily or 400 mg
`every other day)
`
`
`
`
`Ex. 1089-0002
`
`

`
`carbamazepine, rifampin, rifabutin, phenobarbital). Although a dose increase has not been studied, if a strong
`CYP3A4 inducer must be co-administered, a NEXAVAR dose increase may be considered. If the dose of
`NEXAVAR is increased, the patient should be monitored carefully for toxicity [see Drug Interactions (7.7)].
`
`
`3 DOSAGE FORMS AND STRENGTHS
`Tablets containing sorafenib tosylate (274 mg) equivalent to 200 mg of sorafenib.
`NEXAVAR tablets are round, biconvex, red film-coated tablets, debossed with the “Bayer cross” on one side and
`“200” on the other side.
`
`4 CONTRAINDICATIONS
`
`
`• NEXAVAR is contraindicated in patients with known severe hypersensitivity to sorafenib or any other
`component of NEXAVAR.
`
`
`• NEXAVAR in combination with carboplatin and paclitaxel is contraindicated in patients with squamous cell
`
`lung cancer [see Warnings and Precautions (5.8)].
`
`5 WARNINGS AND PRECAUTIONS
`5.1 Risk of Cardiac Ischemia and/or Infarction
`In the HCC study, the incidence of cardiac ischemia/infarction was 2.7% in NEXAVAR patients compared with
`1.3% in the placebo group and in RCC Study 1, the incidence of cardiac ischemia/infarction was higher in the
`NEXAVAR group (2.9%) compared with the placebo group (0.4%). Patients with unstable coronary artery disease
`
`or recent myocardial infarction were excluded from this study. Temporary or permanent discontinuation of
`NEXAVAR should be considered in patients who develop cardiac ischemia and/or infarction.
`
`5.2 Risk of Hemorrhage
`An increased risk of bleeding may occur following NEXAVAR administration. In the HCC study, an excess of
`bleeding regardless of causality was not apparent and the rate of bleeding from esophageal varices was 2.4% in
`NEXAVAR patients and 4% in placebo patients. Bleeding with a fatal outcome from any site was reported in 2.4%
`of NEXAVAR patients and 4% in placebo patients. In RCC Study 1, bleeding regardless of causality was reported
`in 15.3% of patients in the NEXAVAR group and 8.2% of patients in the placebo group. The incidence of CTCAE
`Grade 3 and 4 bleeding was 2% and 0%, respectively, in NEXAVAR patients, and 1.3% and 0.2%, respectively, in
`
`placebo patients. There was one fatal hemorrhage in each treatment group in RCC Study 1. If any bleeding
`necessitates medical intervention, permanent discontinuation of NEXAVAR should be considered.
`
`5.3 Risk of Hypertension
`Blood pressure should be monitored weekly during the first 6 weeks of NEXAVAR therapy and thereafter
`monitored and treated, if required, in accordance with standard medical practice. In the HCC study, hypertension
`was reported in approximately 9.4% of NEXAVAR-treated patients and 4.3% of patients in the placebo group. In
`RCC Study 1, hypertension was reported in approximately 16.9% of NEXAVAR-treated patients and 1.8% of
`
`patients in the placebo group. Hypertension was usually mild to moderate, occurred early in the course of
`treatment, and was managed with standard antihypertensive therapy. In cases of severe or persistent
`hypertension, despite institution of antihypertensive therapy, temporary or permanent discontinuation of
`NEXAVAR should be considered. Permanent discontinuation due to hypertension occurred in 1 of 297 NEXAVAR
`patients in the HCC study and 1 of 451 NEXAVAR patients in RCC Study 1.
`
`5.4 Risk of Dermatologic Toxicities
`
`
`Hand-foot skin reaction and rash represent the most common adverse reactions attributed to NEXAVAR. Rash
`and hand-foot skin reaction are usually CTCAE Grade 1 and 2 and generally appear during the first six weeks of
`treatment with NEXAVAR. Management of dermatologic toxicities may include topical therapies for symptomatic
`
`relief, temporary treatment interruption and/or dose modification of NEXAVAR, or in severe or persistent cases,
`permanent discontinuation of NEXAVAR. Permanent discontinuation of therapy due to hand-foot skin reaction
`occurred in 4 of 297 NEXAVAR HCC patients and 3 of 451 NEXAVAR RCC patients.
`
`5.5 Risk of Gastrointestinal Perforation
`Gastrointestinal perforation is an uncommon adverse reaction and has been reported in less than 1% of patients
`taking NEXAVAR. In some cases this was not associated with apparent intra-abdominal tumor. In the event of a
`gastrointestinal perforation, NEXAVAR therapy should be discontinued.
`
`
`3
`
`Ex. 1089-0003
`
`

`
`5.6 Warfarin Co-Administration
`Infrequent bleeding or elevations in the International Normalized Ratio (INR) have been reported in some patients
`taking warfarin while on NEXAVAR therapy. Patients taking concomitant warfarin should be monitored regularly
`for changes in prothrombin time, INR or clinical bleeding episodes.
`
` 5.7 Wound Healing Complications
`
`No formal studies of the effect of NEXAVAR on wound healing have been conducted. Temporary interruption of
`NEXAVAR therapy is recommended in patients undergoing major surgical procedures. There is limited clinical
`experience regarding the timing of reinitiation of NEXAVAR therapy following major surgical intervention.
`Therefore, the decision to resume NEXAVAR therapy following a major surgical intervention should be based on
`clinical judgment of adequate wound healing.
`
`5.8 Use of Nexavar in combination with Carboplatin and Paclitaxel in Non-small Cell Lung
`Cancer
`A randomized controlled trial in chemo-naive patients with Stage IIIB-IV Non-small Cell Lung Cancer, performed
`to compare the safety and efficacy of carboplatin and paclitaxel with or without sorafenib, was stopped early
`
`because overall survival was not improved with the addition of sorafenib. In the analysis of the subset of patients
`with squamous cell carcinoma (prospectively stratified), higher mortality was observed with the addition of
`sorafenib compared to those treated with carboplatin and paclitaxel alone (HR 1.81, 95% CI 1.19-2.74). No
`
`definitive cause was identified for this finding [see Contraindications (4)].
`5.9 Interactions with UGT1A1 Substrates
`Sorafenib can cause increases in plasma concentrations of drugs that are substrates of UGT1A1. Caution is
`
`recommended when administering NEXAVAR with compounds that are metabolized/eliminated predominantly by
`the UGT1A1 pathway (for example, irinotecan) [see Drug Interactions (7.2)].
`
`
`5.10 Interaction with Docetaxel
`Sorafenib can cause increases in plasma concentrations of docetaxel. Caution is recommended when NEXAVAR
`is co-administered with docetaxel [see Drug Interactions (7.3)].
`
`5.11 Interaction with Doxorubicin
`Sorafenib can cause increases in plasma concentrations of doxorubicin. Caution is recommended when
`NEXAVAR is co-administered with doxorubicin [see Drug Interactions (7.4)].
`
`
`5.12 Hepatic Impairment
`Hepatic impairment may reduce plasma concentrations of sorafenib. Comparison of data across studies suggests
`
`that sorafenib levels are lower in HCC patients than in non-HCC patients (without hepatic impairment). The AUC
`of sorafenib is similar between HCC patients with mild (Child-Pugh A) and moderate (Child-Pugh B) hepatic
`impairment. The optimal dose in non-HCC patients with hepatic impairment is not established [see Use in Specific
`
`Populations (8.6) and Clinical Pharmacology (12.3)].
`
`5.13 Neomycin
`
`Co-administration of oral neomycin causes a decrease in sorafenib exposure [see Drug Interactions (7.12)].
`
` 5.14 Use in Pregnancy
`
`There are no adequate and well-controlled studies in pregnant women using NEXAVAR. However, based on its
`mechanism of action and findings in animals, NEXAVAR may cause fetal harm when administered to a pregnant
`woman. Sorafenib caused embryo-fetal toxicities in animals at maternal exposures that were significantly lower
`than the human exposures at the recommended dose of 400 mg twice daily. Women of childbearing potential
`should be advised to avoid becoming pregnant while on NEXAVAR. 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 the
`fetus [see Use in Specific Populations (8.1)].
`
`
`
`6 ADVERSE REACTIONS
`The following risks are discussed in greater detail in the WARNINGS AND PRECAUTIONS section (5):
`
`
`• Cardiac ischemia, infarction [see Warnings and Precautions (5.1)]
`
`• Hemorrhage [see Warnings and Precautions (5.2)]
`
`
`• Hypertension [see Warnings and Precautions (5.3)]
`
`
`4
`
`Ex. 1089-0004
`
`

`
` • Hand-foot skin reaction and rash [see Warnings and Precautions (5.4)]
`
`
` • Gastrointestinal perforation [see Warnings and Precautions (5.5)]
` • Wound healing complications [see Warnings and Precautions (5.7)]
`
`
`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 rates observed in practice.
`
`
`
`The data described in sections 6.1 and 6.2 reflect exposure to NEXAVAR in 748 patients who participated in
`placebo controlled studies in hepatocellular carcinoma (N=297) or advanced renal cell carcinoma (N=451).
`
`
`The most common adverse reactions (≥20%), which were considered to be related to NEXAVAR, in patients with
`HCC or RCC are fatigue, weight loss, rash/desquamation, hand-foot skin reaction, alopecia, diarrhea, anorexia,
`nausea and abdominal pain.
`
` 6.1 Adverse Reactions in HCC Study
`
` Table 2 shows the percentage of HCC patients experiencing adverse reactions that were reported in at least 10%
`
`of patients and at a higher rate in the NEXAVAR arm than the placebo arm. CTCAE Grade 3 adverse reactions
`were reported in 39% of patients receiving NEXAVAR compared to 24% of patients receiving placebo. CTCAE
`
`
`
`
` Grade 4 adverse reactions were reported in 6% of patients receiving NEXAVAR compared to 8% of patients
`receiving placebo.
`Table 2 Adverse Reactions Reported in at Least 10% of Patients and at a Higher Rate in NEXAVAR Arm
`
` than the Placebo Arm – HCC Study
`NEXAVAR
`
`N=297
`
`Placebo
`N=302
`
`
`All
`Grades
`%
`
`96
`
`
`
`Grade
`3
`%
`
`24
`
`
`
`Grade
`4
`%
`
`8
`
`
`
`All
`Grades
`%
`
`98
`
`
`
`Grade Grade
`
`3
`4
`%
`%
`
`
`6
`39
`
`
`
`
`
`
`
`2
`
`0
`
`
`0
`
`0
`
`0
`
`0
`
`0
`
`
`0
`
`<1
`
`0
`
`0
`
`0
`
`
`
`5
`
`46
`
`30
`
`
`19
`
`14
`
`21
`
`10
`
`14
`
`
`55
`
`29
`
`24
`
`15
`
`14
`
`
`
`9
`
`2
`
`
`1
`
`<1
`
`8
`
`0
`
`0
`
`
`10
`
`3
`
`1
`
`2
`
`0
`
`
`
`1
`
`0
`
`
`0
`
`0
`
`0
`
`0
`
`0
`
`
`<1
`
`0
`
`0
`
`0
`
`0
`
`
`
`45
`
`10
`
`
`14
`
`11
`
`3
`
`6
`
`2
`
`
`25
`
`18
`
`20
`
`11
`
`10
`
`
`
`12
`
`1
`
`
`0
`
`<1
`
`<1
`
`0
`
`0
`
`
`2
`
`3
`
`3
`
`2
`
`0
`
`
`
`Adverse Reaction
`NCI- CTCAE v3
`Category/Term
`Any Adverse Reaction
`
`Constitutional
`symptoms
`
`Fatigue
`
`Weight loss
`
`Dermatology/skin
`
`Rash/desquamation
`
`Pruritus
`
`Hand-foot skin reaction
`
`Dry skin
`
`Alopecia
`
`Gastrointestinal
`
`Diarrhea
`
`Anorexia
`
`Nausea
`
`Vomiting
`
`
`Constipation
`
`Hepatobiliary/
`pancreas
`
`1
`2
`8
`1
`2
`11
`Liver dysfunction
`
`
`
`
`
`
`
`Pain
`
`
`
`
`
`
`
`1
`5
`26
`0
`9
`31
`Pain, abdomen
`
`
`
`
`
`
`
`Hypertension was reported in 9% of patients treated with NEXAVAR and 4% of those treated with placebo.
`CTCAE Grade 3 hypertension was reported in 4% of NEXAVAR treated patients and 1% of placebo treated
`
`patients. No patients were reported with CTCAE Grade 4 reactions in either treatment group.
`Hemorrhage/bleeding was reported in 18% of those receiving NEXAVAR and 20% of placebo patients. The rates
`
`of CTCAE Grade 3 and 4 bleeding were also higher in the placebo group (CTCAE Grade 3 – 3% NEXAVAR and
`5% placebo and CTCAE Grade 4 – 2% NEXAVAR and 4% placebo). Bleeding from esophageal varices was
`
`reported in 2.4% in NEXAVAR treated patients and 4% of placebo treated patients.
`
`
`Ex. 1089-0005
`
`

`
`Renal failure was reported in <1% of patients treated with NEXAVAR and 3% of placebo treated patients.
`The rate of adverse reactions (including those associated with progressive disease) resulting in permanent
`discontinuation was similar in both the NEXAVAR and placebo groups (32% of NEXAVAR patients and 35% of
`placebo patients).
`Laboratory Abnormalities
`The following laboratory abnormalities were observed in HCC patients:
`Hypophosphatemia was a common laboratory finding, observed in 35% of NEXAVAR-treated patients compared
`to 11% of placebo patients; CTCAE Grade 3 hypophosphatemia (1–2 mg/dL) occurred in 11% of NEXAVAR-
`treated patients and 2% of patients in the placebo group; there was 1 case of CTCAE Grade 4 hypophosphatemia
`(<1 mg/dL) reported in the placebo group. The etiology of hypophosphatemia associated with NEXAVAR is not
`
`known.
`Elevated lipase was observed in 40% of patients treated with NEXAVAR compared to 37% of patients in the
`placebo group. CTCAE Grade 3 or 4 lipase elevations occurred in 9% of patients in each group. Elevated
`amylase was observed in 34% of patients treated with NEXAVAR compared to 29% of patients in the placebo
`
`group. CTCAE Grade 3 or 4 amylase elevations were reported in 2% of patients in each group. Many of the lipase
`and amylase elevations were transient, and in the majority of cases NEXAVAR treatment was not interrupted.
`Clinical pancreatitis was reported in 1 of 297 NEXAVAR-treated patients (CTCAE Grade 2).
`Elevations in liver function tests were comparable between the 2 arms of the study. Hypoalbuminemia was
`observed in 59% of NEXAVAR-treated patients and 47% of placebo patients; no CTCAE Grade 3 or 4
`hypoalbuminemia was observed in either group.
`INR elevations were observed in 42% of NEXAVAR-treated patients and 34% of placebo patients; CTCAE Grade
`3 INR elevations were reported in 4% of NEXAVAR-treated patients and 2% of placebo patients; there was no
`CTCAE Grade 4 INR elevation in either group.
`
`
`Lymphopenia was observed in 47% of NEXAVAR-treated patients and 42% of placebo patients.
`
`
`
`Thrombocytopenia was observed in 46% of NEXAVAR-treated patients and 41% of placebo patients; CTCAE Grade 3
`
`
`
`
`
`or 4 thrombocytopenia was reported in 4% of NEXAVAR-treated patients and less than 1% of placebo patients.
`
`6.2 Adverse Reactions in RCC Study 1
`Table 3 shows the percentage of RCC patients experiencing adverse reactions that were reported in at least 10%
`of patients and at a higher rate in the NEXAVAR arm than the placebo arm. CTCAE Grade 3 adverse reactions
`were reported in 31% of patients receiving NEXAVAR compared to 22% of patients receiving placebo. CTCAE
`Grade 4 adverse reactions were reported in 7% of patients receiving NEXAVAR compared to 6% of patients
`
`
`
`
`receiving placebo.
`Table 3: Adverse Reactions Reported in at Least 10% of Patients and at a Higher Rate in NEXAVAR Arm
`than the Placebo Arm – RCC Study 1
`
`
`Adverse Reactions
`All
`
`NCI- CTCAE v3 Category/Term Grades
`
`%
`
`95
`
`
`17
`
`
`
`
`Any Adverse Reactions
`
`Cardiovascular, General
`
`
` Hypertension
`
`Constitutional symptoms
`
`Fatigue
`
` Weight loss
`
`Dermatology/skin
`
` Rash/desquamation
`
`
` Hand-foot skin reaction
` Alopecia
`
` Pruritus
`
` Dry skin
`
`Gastrointestinal symptoms
`
`
`NEXAVAR
`N=451
`
`Grade Grade
`3
`4
`%
`%
`
`
`31
`7
`
`
`
`
`3
`<1
`
`
`
`
`37
`
`10
`
`
`40
`
`30
`
`27
`
`19
`
`11
`
`
`
`
`5
`
`<1
`
`
`<1
`
`6
`
`<1
`
`<1
`
`0
`
`
`
`
`<1
`
`0
`
`
`0
`
`0
`
`0
`
`0
`
`0
`
`
`
`Placebo
`N=451
`
`Grade Grade
`3
`4
`%
`%
`
`
`22
`6
`
`
`
`
`<1
`0
`
`
`
`All
`Grades
`%
`
`86
`
`
`2
`
`
`
`28
`
`6
`
`
`16
`
`7
`
`3
`
`6
`
`4
`
`
`
`
`3
`
`0
`
`
`<1
`
`0
`
`0
`
`0
`
`0
`
`
`
`
`
`
`<1
`0
`
`
`0
`
`0
`
`0
`
`0
`
`0
`
`
`
`
`
`6
`
`Ex. 1089-0006
`
`

`
`
`
`
`
`
`
`
`
`
`
`0
` Diarrhea
`<1
`13
`0
`2
`43
`
`
`
`
`
`
`0
` Nausea
`<1
`19
`0
`<1
`23
`
`
`
`
`
`
`
`0
` Anorexia
`1
`13
`0
`<1
`16
`
`
`
`
`
`
`0
` Vomiting
`1
`12
`0
`<1
`16
`
`
`
`
`
`
`
`0
` Constipation
`<1
`11
`0
`<1
`15
`
`
`
`
`
`
`
`Hemorrhage/bleeding
`
`
`
`
`
`
`
`<1
`1
`8
`0
`2
`15
` Hemorrhage – all sites
`
`
`
`
`
`
`Neurology
`
`
`
`
`
`
`
`0
`<1
`6
`0
`<1
`13
` Neuropathy-sensory
`
`
`
`
`
`
`Pain
`
`
`
`
`
`
`
`0
`2
`9
`0
`2
`11
`Pain, abdomen
`
`
`
`
`
`
`0
`<1
`6
`0
`2
`10
` Pain, joint
`
`
`
`
`
`
`
`
`0
`<1
`6
`0
`<1
`10
` Pain, headache
`
`
`
`
`
`
`
`Pulmonary
`
`
`
`
`
`
`<1
`2
`12
`<1
`3
`14
` Dyspnea
`
`
`
`
`
`
`
`The rate of adverse reactions (including those associated with progressive disease) resulting in permanent
`discontinuation was similar in both the NEXAVAR and placebo groups (10% of NEXAVAR patients and 8% of
`placebo patients).
`Laboratory Abnormalities
`
`The following laboratory abnormalities were observed in RCC patients in Study 1:
`Hypophosphatemia was a common laboratory finding, observed in 45% of NEXAVAR-treated patients compared
`to 11% of placebo patients. CTCAE Grade 3 hypophosphatemia (1–2 mg/dL) occurred in 13% of NEXAVAR-
`treated patients and 3% of patients in the placebo group. There were no cases of CTCAE Grade 4
`hypophosphatemia (<1 mg/dL) reported in either NEXAVAR or placebo patients. The etiology of
`hypophosphatemia associated with NEXAVAR is not known.
`Elevated lipase was observed in 41% of patients treated with NEXAVAR compared to 30% of patients in the
`placebo group. CTCAE Grade 3 or 4 lipase elevations occurred in 12% of patients in the NEXAVAR group
`compared to 7% of patients in the placebo group. Elevated amylase was observed in 30% of patients treated with
`NEXAVAR compared to 23% of patients in the placebo group. CTCAE Grade 3 or 4 amylase elevations were
`
`reported in 1% of patients in the NEXAVAR group compared to 3% of patients in the placebo group. Many of the
`lipase and amylase elevations were transient, and in the majority of cases NEXAVAR treatment was not
`interrupted. Clinical pancreatitis was reported in 3 of 451 NEXAVAR-treated patients (one CTCAE Grade 2 and
`two Grade 4) and 1 of 451 patients (CTCAE Grade 2) in the placebo group.
`Lymphopenia was observed in 23% of NEXAVAR-treated patients and 13% of placebo patients. CTCAE Grade 3
`or 4 lymphopenia was reported in 13% of NEXAVAR-treated patients and 7% of placebo patients. Neutropenia
`was observed in 18% of NEXAVAR-treated patients and 10% of placebo patients. CTCAE Grade 3 or 4
`neutropenia was reported in 5% of NEXAVAR-treated patients and 2% of placebo patients.
`
`
`Anemia was observed in 44% of NEXAVAR-treated patients and 49% of placebo patients. CTCAE Grade 3 or 4
`anemia was reported in 2% of NEXAVAR-treated patients and 4% of placebo patients.
`Thrombocytopenia was observed in 12% of NEXAVAR-treated patients and 5% of placebo patients. CTCAE
`Grade 3 or 4 thrombocytopenia was reported in 1% of NEXAVAR-treated patients and 0% of placebo patients.
`
`6.3 Additional Data from Multiple Clinical Trials
`The following additional drug-related adverse reactions and laboratory abnormalities were reported from clinical
`
`trials of NEXAVAR (very common 10% or greater, common 1 to less than 10%, uncommon 0.1% to less than
`1%):
`Cardiovascular: Common: congestive heart failure,*† Uncommon: hypertensive crisis*, myocardial ischemia
`
`
`
`and/or infarction.*
`†In company sponsored clinical trials, congestive heart failure was reported as an adverse event in 1.9% of
`patients treated with sorafenib (N= 2276). In study 11213 (RCC), adverse events consistent with congestive heart
`failure were reported in 1.7% of those treated with sorafenib and in 0.7% of those receiving placebo. In study
`100554 (HCC), these events were reported in 0.99% of those treated with sorafenib and in 1.1% of those
`receiving placebo.
`Dermatologic: Very common: erythema Common: exfoliative dermatitis, acne, flushing Uncommon: folliculitis,
`
`eczema, erythema multiforme, keratoacanthomas/squamous cell cancer of the skin, Stevens - Johnson Syndrome
`
`
`
`
`
`
`
`7
`
`Ex. 1089-0007
`
`

`
`Digestive: Very common: increased lipase, increased amylase Common: mucositis, stomatitis (including dry
`
`mouth and glossodynia), dyspepsia, dysphagia Uncommon: pancreatitis, gastrointestinal reflux, gastritis,
`
`gastrointestinal perforations*, cholecystitis, cholangitis
`Note that elevations in lipase are very common (41%, see below); a diagnosis of pancreatitis should not be made
`solely on the basis of abnormal laboratory values
`General Disorders: Very common: hemorrhage (including gastrointestinal* & respiratory tract* and uncommon
`
`
`cases of cerebral hemorrhage*), asthenia, pain (including mouth, bone, and tumor pain) Common: decreased
`appetite, influenza-like illness, pyrexia Uncommon: infection
`Hematologic: Very common: leukopenia, lymphopenia Common: anemia, neutropenia, thrombocytopenia
`
`
`
`Uncommon: INR abnormal
`Hypersensitivity: Uncommon: hypersensitivity reactions (including skin reactions and urticaria)
`
`
`Metabolic and Nutritional: Very common: hypophosphatemia Common: transient increases in transaminases
`
`
`
`Uncommon: dehydration, hyponatremia, transient increases in alkaline phosphatase, increased bilirubin (including
`jaundice), hypothyroidism, hyperthyroidism
`Musculoskeletal: Common: arthralgia, myalgia
`
`Nervous System and Psychiatric: Common: depression Uncommon: tinnitus, reversible posterior
`
`leukoencephalopathy*
`
`Renal and Genitourinary: Common: renal failure
`Reproductive: Common: erectile dysfunction Uncommon: gynecomastia
`
`Respiratory: Common: hoarseness Uncommon: rhinorrhea, interstitial lung disease-like events (includes reports
`
`
`of pneumonitis, radiation pneumonitis, acute respiratory distress, interstitial pneumonia, pulmonitis and lung
`
`inflammation)
`
`*adverse reactions may have a life-threatening or fatal outcome
`
`In addition, the following medically significant adverse reactions were uncommon during clinical trials of
`NEXAVAR: transient ischemic attack, arrhythmia, thromboembolism. For these adverse reactions, the causal
`relationship to NEXAVAR has not been established.
`
`7 DRUG INTERACTIONS
`7.1 Carboplatin and Paclitaxel
`Concomitant use of carboplatin (AUC=6 mg/ml•min) and paclitaxel (225 mg/m2) once every three weeks with
`NEXAVAR (400 mg twice daily) resulted in a 30% increase in paclitaxel AUC, a 50% increase in sorafenib AUC,
`and no change in carboplatin AUC. Sorafenib in combination with carboplatin and paclitaxel is contraindicated in
`patients with squamous cell lung cancer, due to increased mortality observed with the addition of sorafenib
`
`compared to those treated with carboplatin and paclitaxel alone. No definitive cause was identified for this finding.
`
`[see C