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NEXAVAR (sorafenib) tablets
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
INDICATIONS AND USAGE
NEXAVAR is a kinase inhibitor indicated for the treatment of
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Unresectable hepatocellular carcinoma ( 1.1)
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Advanced renal cell carcinoma ( 1.2)
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Locally recurrent or metastatic, progressive, differentiated thyroid carcinoma refractory to radioactive iodine treatment ( 1.3)
DOSAGE AND ADMINISTRATION
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400 mg (2 tablets) orally twice daily without food. ( 2.1)
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Treatment interruption and/or dose reduction may be needed to manage suspected adverse drug reactions. ( 2.2)
DOSAGE FORMS AND STRENGTHS
200 mg Tablets (3)
CONTRAINDICATIONS
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NEXAVAR is contraindicated in patients with known severe hypersensitivity to sorafenib or any other component of NEXAVAR. ( 4)
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NEXAVAR in combination with carboplatin and paclitaxel is contraindicated in patients with squamous cell lung cancer. ( 4)
WARNINGS AND PRECAUTIONS
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Cardiac Ischemia and/or Infarction: Consider temporary or permanent discontinuation of NEXAVAR. ( 5.1)
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Bleeding: Discontinue NEXAVAR if needed. ( 5.2)
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Hypertension: Monitor blood pressure weekly during the first 6 weeks and periodically thereafter. ( 5.3)
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Dermatologic Toxicities: Interrupt and/or decrease dose. Discontinue for severe or persistent reactions, or if Stevens-Johnson syndrome and toxic epidermal necrolysis is suspected. ( 5.4)
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Gastrointestinal Perforation: Discontinue NEXAVAR. ( 5.5)
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QT Prolongation: Monitor electrocardiograms and electrolytes in patients at increased risk for ventricular arrhythmias. ( 5.9, 12.2)
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Drug-Induced Hepatitis: Monitor liver function tests regularly; discontinue for unexplained transaminase elevations. ( 5.10)
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Embryofetal Toxicity: Advise women of potential risk to fetus and to avoid becoming pregnant. ( 5.11, 8.1)
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Impairment of TSH suppression in DTC: Monitor TSH monthly and adjust thyroid replacement therapy in patients with thyroid cancer. ( 5.12)
ADVERSE REACTIONS
The most common adverse reactions (≥20%) for NEXAVAR are diarrhea, fatigue, infection, alopecia, hand-foot skin reaction, rash, weight loss, decreased appetite, nausea, gastrointestinal and abdominal pains, hypertension, and hemorrhage. (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
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Avoid strong CYP3A4 inducers. ( 7.1)
See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.
Revised: 7/2015
FULL PRESCRIBING INFORMATION: CONTENTS*
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).
1.3 Differentiated Thyroid Carcinoma
NEXAVAR is indicated for the treatment of patients with locally recurrent or metastatic, progressive, differentiated thyroid carcinoma (DTC) that is refractory to radioactive iodine treatment.
2 DOSAGE AND ADMINISTRATION
2.1 Recommended Dose for Hepatocellular Carcinoma, Renal Cell Carcinoma, and Differentiated Thyroid Carcinoma
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.
2.2 Dose Modifications for Suspected Adverse Drug Reactions
Temporary interruption of NEXAVAR is recommended in patients undergoing major surgical procedures [see Warnings and Precautions (5.7)].
Temporary interruption or permanent discontinuation of NEXAVAR may be required for the following:
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Cardiac ischemia or infarction [see Warnings and Precautions (5.1)]
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Hemorrhage requiring medical intervention [see Warnings and Precautions (5.2)]
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Severe or persistent hypertension despite adequate anti-hypertensive therapy [see Warnings and Precautions (5.3)]
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Gastrointestinal perforation [see Warnings and Precautions (5.5)]
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QTc prolongation [see Warnings and Precautions (5.9)]
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Severe drug-induced liver injury [see Warnings and Precautions (5.10)]
Dose modifications for Hepatocellular Carcinoma and Renal Cell Carcinoma
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 dermatologic toxicities are outlined in Table 1.
Dose modifications for Differentiated Thyroid Carcinoma
When dose reduction is necessary for dermatologic toxicities, reduce the NEXAVAR dose as indicated in Table 3 below.
Following improvement of Grade 2 or 3 dermatologic toxicity to Grade 0–1 after at least 28 days of treatment on a reduced dose of NEXAVAR, the dose of NEXAVAR may be increased one dose level from the reduced dose. Approximately 50% of patients requiring a dose reduction for dermatologic toxicity are expected to meet these criteria for resumption of the higher dose and roughly 50% of patients resuming the previous dose are expected to tolerate the higher dose (that is, maintain the higher dose level without recurrent Grade 2 or higher dermatologic toxicity)
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
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NEXAVAR is contraindicated in patients with known severe hypersensitivity to sorafenib or any other component of NEXAVAR.
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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-treated patients compared with 1.3% in the placebo-treated group, in RCC Study 1, the incidence of cardiac ischemia/infarction was higher in the NEXAVAR-treated group (2.9%) compared with the placebo-treated group (0.4%), and in the DTC study, the incidence of cardiac ischemia/infarction was 1.9% in the NEXAVAR-treated group compared with 0% in the placebo-treated group. 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-treated patients and 4% in placebo-treated patients. Bleeding with a fatal outcome from any site was reported in 2.4% of NEXAVAR-treated patients and 4% in placebo-treated patients. In RCC Study 1, bleeding regardless of causality was reported in 15.3% of patients in the NEXAVAR-treated group and 8.2% of patients in the placebo-treated group. The incidence of CTCAE Grade 3 and 4 bleeding was 2% and 0%, respectively, in NEXAVAR-treated patients, and 1.3% and 0.2%, respectively, in placebo-treated patients. There was one fatal hemorrhage in each treatment group in RCC Study 1. In the DTC study, bleeding was reported in 17.4% of NEXAVAR-treated patients and 9.6% of placebo-treated patients; however the incidence of CTCAE Grade 3 bleeding was 1% in NEXAVAR-treated patients and 1.4% in placebo-treated patients. There was no Grade 4 bleeding reported and there was one fatal hemorrhage in a placebo-treated patient. If any bleeding necessitates medical intervention, permanent discontinuation of NEXAVAR should be considered. Due to the potential risk of bleeding, tracheal, bronchial, and esophageal infiltration should be treated with local therapy prior to administering NEXAVAR in patients with DTC.
5.3 Risk of Hypertension
Monitor blood pressure weekly during the first 6 weeks of NEXAVAR. Thereafter, monitor blood pressure and treat hypertension, 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-treated group. In RCC Study 1, hypertension was reported in approximately 16.9% of NEXAVAR-treated patients and 1.8% of patients in the placebo-treated group. In the DTC study, hypertension was reported in 40.6% of NEXAVAR-treated patients and 12.4% of placebo-treated patients. 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, consider temporary or permanent discontinuation of NEXAVAR. Permanent discontinuation due to hypertension occurred in 1 of 297 NEXAVAR-treated patients in the HCC study, 1 of 451 NEXAVAR-treated patients in RCC Study 1, and 1 of 207 NEXAVAR-treated patients in the DTC study.
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 [see Dosage and Administration (2.2)]. Permanent discontinuation of therapy due to hand-foot skin reaction occurred in 4 (1.3%) of 297 NEXAVAR-treated patients with HCC, 3 (0.7%) of 451 NEXAVAR-treated patients with RCC, and 11 (5.3%) of 207 NEXAVAR-treated patients with DTC.
There have been reports of severe dermatologic toxicities, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). These cases may be life-threatening. Discontinue NEXAVAR if SJS or TEN are suspected.
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, discontinue NEXAVAR.
5.6 Warfarin
Infrequent bleeding or elevations in the International Normalized Ratio (INR) have been reported in some patients taking warfarin while on NEXAVAR. Monitor patients taking concomitant warfarin regularly for changes in prothrombin time (PT), 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 is recommended in patients undergoing major surgical procedures. There is limited clinical experience regarding the timing of reinitiation of NEXAVAR following major surgical intervention. Therefore, the decision to resume NEXAVAR following a major surgical intervention should be based on clinical judgment of adequate wound healing.
5.8 Increased Mortality Observed with NEXAVAR Administered in Combination with Carboplatin/Paclitaxel and Gemcitabine/Cisplatin in Squamous Cell Lung Cancer
In a subset analysis of two randomized controlled trials in chemo-naive patients with Stage IIIB-IV non-small cell lung cancer, patients with squamous cell carcinoma experienced higher mortality with the addition of NEXAVAR compared to those treated with carboplatin/paclitaxel alone (HR 1.81, 95% CI 1.19–2.74) and gemcitabine/cisplatin alone (HR 1.22, 95% CI 0.82-1.80). The use of NEXAVAR in combination with carboplatin/paclitaxel is contraindicated in patients with squamous cell lung cancer. NEXAVAR in combination with gemcitabine/cisplatin is not recommended in patients with squamous cell lung cancer. The safety and effectiveness of NEXAVAR has not been established in patients with non-small cell lung cancer.
5.9 Risk of QT Interval Prolongation
NEXAVAR can prolong the QT/QTc interval. QT/QTc interval prolongation increases the risk for ventricular arrhythmias.Avoid NEXAVAR in patients with congenital long QT syndrome. Monitor electrolytes and electrocardiograms in patients with congestive heart failure, bradyarrhythmias, drugs known to prolong the QT interval, including Class Ia and III antiarrhythmics. Correct electrolyte abn |
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