Nexavar - Sorafenib tablet, Film Coated (Sorafenib)

NEXAVAR is a kinase inhibitor indicated for the treatment of

• •Unresectable hepatocellular carcinoma (
  1.1 Hepatocellular Carcinoma

  NEXAVAR^®is indicated for the treatment of patients with unresectable hepatocellular carcinoma (HCC).
  )
• •Advanced renal cell carcinoma (
  1.2 Renal Cell Carcinoma

  NEXAVAR is indicated for the treatment of patients with advanced renal cell carcinoma (RCC).
  )
• •Locally recurrent or metastatic, progressive, differentiated thyroid carcinoma (DTC) refractory to radioactive iodine treatment (
  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.
  )

The recommended dosage is 400 mg orally twice daily without food. (

Tablets:

• •200 mg sorafenib, round, biconvex, red film-coated tablets, debossed with the “Bayer cross” on one side and “200” on the other side.
• •200 mg sorafenib, round, faceted biconvex, red film-coated tablets, debossed with the “Bayer cross” on one side and “200” on the other side.

• •
  Lactation
  : Advise women not to breastfeed. (
  8.2 Lactation

  Risk Summary

  There are no data on the presence of sorafenib or its metabolites in human milk, or its effects on the breast-fed child or on milk production. Sorafenib was present in milk of lactating rats

  (see Data)

  . Because of the potential for serious adverse reactions in a breastfed child from NEXAVAR, advise women not to breastfeed during treatment with NEXAVAR and for 2 weeks after the last dose.

  Data

  Animal Data

  Following administration of radiolabeled sorafenib to lactating Wistar rats, approximately 27% of the radioactivity was secreted into milk. The milk to plasma AUC ratio was approximately 5:1.
  )

• •
  Cardiovascular Events
  : Consider temporary or permanent discontinuation of NEXAVAR. (
  2.2 Dosage Modifications for Adverse Reactions

  Recommended Dosage Modifications

  The recommended dosage modifications for adverse reactions are provided in Tables 1, 2, and 3.

  Table 1: Recommended Dose Reductions for Adverse Reactions

  Dose Reduction	Hepatocellular Carcinoma and Renal Cell Carcinoma	Differentiated Thyroid Carcinoma
  First Dose Reduction	400 mg orally once daily	400 mg orally in the morning and 200 mg orally in the evening about 12 hours apart OR 200 mg orally in the morning and 400 mg orally in the evening about 12 hours apart
  Second Dose Reduction	200 mg orally once daily OR 400 every other day	200 mg orally twice daily
  Third Dose Reduction	None	200 mg orally once daily

  Table 2: Recommended Dosage Modifications of NEXAVAR for Adverse Reactions

  Adverse Reaction	Severity1	NEXAVAR Dosage Modification
  Cardiovascular Events [see Warnings and Precautions ]
  Cardiac Ischemia and/or Infarction	Grade 2 and above	Permanently discontinue.
  Congestive Heart Failure	Grade 3	Interrupt2until Grade 1 or less, resume at reduced dose by 1 dose level.3
  	Grade 4	Permanently discontinue.
  Hemorrhage [see Warnings and Precautions ]	Grade 2 and above requiring medical intervention	Permanently discontinue.
  Hypertension [see Warnings and Precautions ]	Grade 2 (symptomatic/persistent) OR Grade 2 symptomatic increase by greater than 20 mm Hg (diastolic) or greater than 140/90 mm Hg if previously within normal limits OR Grade 3	Interrupt until symptoms resolve and diastolic blood pressure less than 90 mm Hg, then resume at reduced dose by 1 dose level.3 If needed, reduce another dose level.3
  	Grade 4	Permanently discontinue.
  Gastrointestinal Perforation [see Warnings and Precautions ]	Any grade	Permanently discontinue.
  QT Interval Prolongation [see Warnings and Precautions ]	Greater than 500 milliseconds OR Increase from baseline of 60 milliseconds or greater	Interrupt and correct electrolyte abnormalities (magnesium, potassium, calcium). Use medical judgement before restarting.
  Drug-Induced Liver Injury [see Warnings and Precautions ]	Grade 3 ALT or higher in the absence of another cause4 OR AST/ALT greater than 3 × upper limit normal (ULN) with bilirubin greater than 2 × ULN in the absence of another cause4	Permanently discontinue.
  Non-hematological toxicities [see Adverse Reactions ]	Grade 2	Continue treatment at reduced dose by 1 dose level.
  	Grade 3
  	1stoccurrence	Interrupt until Grade 2 or less, then resume at reduced dose by 1 dose level.
  	No improvement within 7 days OR 2ndor 3rdoccurrence	Interrupt until Grade 2 or less, then resume at reduced dose by 2 dose levels.
  	4thoccurrence	Interrupt until Grade 2 or less, then resume at reduced dose by 2 dose levels for HCC and RCC or 3 dose levels for DTC.
  	Grade 4	Permanently discontinue.

  • 1Adverse reactions graded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0 (NCI CTCAE v3.0).
  • 2If no recovery after 30 day interruption, discontinue treatment unless the patient is deriving clinical benefit.
  • 3If more than 2 dose reductions are required, permanently discontinue treatment.
  • 4In addition, any grade increased alkaline phosphatase in the absence of known bone pathology and Grade 2 or worse increased bilirubin; any 1 of the following: INR of 1.5 or greater, ascites and/or encephalopathy in the absence of underlying cirrhosis or other organ failure considered to be due to drug-induced liver injury.

  Table 3: Recommended Dosage Modifications for Dermatologic Toxicities

  Dermatologic Toxicity Grade	Occurrence	NEXAVAR Dosage Modification
  		Hepatocellular and Renal Cell Carcinoma	Differentiated Thyroid Carcinoma
  Grade 2: Painful erythema and swelling of the hands or feet and/or discomfort affecting the patient’s normal activities	1stoccurrence	Continue NEXAVAR and consider topical therapy for symptomatic relief. If no improvement within 7 days, see below.	Decrease NEXAVAR to 600 mg daily. If no improvement within 7 days, see below.
  	No improvement within 7 days at reduced dose OR 2ndand 3rdoccurrence	Interrupt NEXAVAR until resolved or improved to Grade 0 to 1.	Interrupt NEXAVAR until completely resolved or improved to Grade1.
  		When resuming treatment, decrease dose by 1 dose level.	When resuming treatment, decrease dose by 1 dose level for 2ndoccurrence and 2 doses levels for 3rdoccurrence.
  	4thoccurrence	Discontinue NEXAVAR treatment.
  Grade 3: Moist desquamation, ulceration, blistering, or severe pain of the hands or feet, resulting in inability to work or perform activities of daily living	1stoccurrence	Interrupt NEXAVAR until resolved or improved to Grade 0 to 1	Interrupt NEXAVAR until completely resolved or improved to Grade 1.
  		When resuming treatment, decrease dose by 1 dose level.	When resuming treatment, decrease dose by 1 dose level.
  	2ndoccurrence	Interrupt NEXAVAR until resolved or improved to Grade 0 to 1	Interrupt NEXAVAR until completely resolved or improved to Grade 1.
  		When resuming treatment, decrease dose by 1 dose level.	When resuming treatment, decrease dose by 2 dose levels.
  	3rdoccurrence	Discontinue NEXAVAR treatment.

  Following improvement of Grade 2 or 3 dermatologic toxicity to Grade 0 or 1 for at least 28 days on a reduced dose of NEXAVAR, the dose of NEXAVAR may be increased 1 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).
  ,
  5.1 Cardiovascular Events

  In the SHARP (HCC) study, the incidence of cardiac ischemia/infarction was 2.7% in NEXAVAR-treated patients compared with 1.3% in those receiving placebo; in the TARGET (RCC) study, the incidence of cardiac ischemia/infarction was higher in the NEXAVAR-treated group (2.9%) compared with patients receiving placebo (0.4%), and in the DECISION (DTC) study, the incidence of cardiac ischemia/infarction was 1.9% in the NEXAVAR-treated group compared with 0% in patients receiving placebo. Patients with unstable coronary artery disease or recent myocardial infarction were excluded from this study. In multiple clinical trials, congestive heart failure has been reported in 1.9% of NEXAVAR-treated patients (N=2276)

  [see Adverse Reactions ]

  .

  Consider temporary or permanent discontinuation of NEXAVAR in patients who develop cardiovascular events

  [see Dosage and Administration ].
  )
• •
  Hemorrhage:
  Discontinue NEXAVAR if needed. (
  5.2 Hemorrhage

  An increased risk of bleeding may occur following NEXAVAR administration. In the SHARP (HCC) study, the rates of bleeding from esophageal varices (2.4% and 4%) and of bleeding with a fatal outcome from any site (2.4% and 4%) were similar in NEXAVAR-treated patients and those receiving placebo, respectively . In the TARGET (RCC) study, bleeding was reported in 15.3% of patients in the NEXAVAR-treated group and 8.2% of patients receiving placebo. The incidence of Grade 3 and 4 bleeding was 2% and 0%, respectively, in NEXAVAR-treated patients, and 1.3% and 0.2%, respectively, in those receiving placebo. There was one fatal hemorrhage in each treatment group in the TARGET (RCC) study. In the DECISION (DTC) study, bleeding was reported in 17.4% of NEXAVAR-treated patients and 9.6% of those receiving placebo; however, the incidence of Grade 3 bleeding was similar (1% and 1.4%) in NEXAVAR-treated patients and in those receiving placebo.

  If any bleeding necessitates medical intervention, consider permanent discontinuation of NEXAVAR

  [see Dosage and Administration ]

  . Due to the potential risk of bleeding, treat tracheal, bronchial, and esophageal infiltration with local therapy prior to administering NEXAVAR in patients with DTC.
  )
• •
  Hypertension:
  Monitor blood pressure weekly during the first 6 weeks and periodically thereafter. Consider temporary or permanent discontinuation for severe or persistent hypertension despite antihypertensive therapy. (
  5.3 Hypertension

  In the SHARP (HCC) study, hypertension was reported in 9.4% of NEXAVAR-treated patients and 4.3% of patients receiving placebo. In the TARGET (RCC) study, hypertension was reported in 16.9% of NEXAVAR-treated patients and 1.8% of patients receiving placebo. In the DECISION (DTC) study, hypertension was reported in 40.6% of NEXAVAR-treated patients and 12.4% of patients receiving placebo. Hypertension was usually mild to moderate, occurred early in the course of treatment, and was managed with standard antihypertensive therapy. Permanent discontinuation due to hypertension occurred in 1 of 297 NEXAVAR-treated patients in the SHARP (HCC) study, 1 of 451 NEXAVAR-treated patients in the TARGET (RCC) study, and 1 of 207 NEXAVAR-treated patients in the DECISION (DTC) study.

  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 cases of severe or persistent hypertension despite institution of antihypertensive therapy, consider temporary or permanent discontinuation of NEXAVAR

  [see Dosage and Administration ]

  .
  )
• •
  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 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 Grade 1 and 2 and generally appear during the first six weeks of treatment with NEXAVAR. 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.

  Management of dermatologic toxicities may include topical therapies for symptomatic relief, temporary treatment interruption and/or dose reduction of NEXAVAR, or in severe or persistent cases, permanent discontinuation of NEXAVAR

  [see Dosage and Administration ]

  .

  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.
  )
• •
  Gastrointestinal Perforation
  : Discontinue NEXAVAR. (
  5.5 Gastrointestinal Perforation

  Gastrointestinal perforation 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, permanently discontinue NEXAVAR.
  )
• •
  Risk of Impaired Wound Healing
  : Withhold NEXAVAR for at least 10 days prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of NEXAVAR after resolution of wound healing complications has not been established. (
  5.7 Risk of Impaired Wound Healing

  Impaired wound healing can occur in patients who receive drugs that inhibit the VEGF signaling pathway. Therefore, NEXAVAR has the potential to adversely affect wound healing.

  Withhold NEXAVAR for at least 10 days prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of NEXAVAR after resolution of wound healing complications has not been established.
  )
• •
  QT Prolongation
  : Monitor electrocardiograms and electrolytes in patients at increased risk for ventricular arrhythmias. Correct electrolytes. Interrupt if QTc greater than 500 msec or increases greater than 60 msec from baseline. (
  2.2 Dosage Modifications for Adverse Reactions

  Recommended Dosage Modifications

  The recommended dosage modifications for adverse reactions are provided in Tables 1, 2, and 3.

  Table 1: Recommended Dose Reductions for Adverse Reactions

  Dose Reduction	Hepatocellular Carcinoma and Renal Cell Carcinoma	Differentiated Thyroid Carcinoma
  First Dose Reduction	400 mg orally once daily	400 mg orally in the morning and 200 mg orally in the evening about 12 hours apart OR 200 mg orally in the morning and 400 mg orally in the evening about 12 hours apart
  Second Dose Reduction	200 mg orally once daily OR 400 every other day	200 mg orally twice daily
  Third Dose Reduction	None	200 mg orally once daily

  Table 2: Recommended Dosage Modifications of NEXAVAR for Adverse Reactions

  Adverse Reaction	Severity1	NEXAVAR Dosage Modification
  Cardiovascular Events [see Warnings and Precautions ]
  Cardiac Ischemia and/or Infarction	Grade 2 and above	Permanently discontinue.
  Congestive Heart Failure	Grade 3	Interrupt2until Grade 1 or less, resume at reduced dose by 1 dose level.3
  	Grade 4	Permanently discontinue.
  Hemorrhage [see Warnings and Precautions ]	Grade 2 and above requiring medical intervention	Permanently discontinue.
  Hypertension [see Warnings and Precautions ]	Grade 2 (symptomatic/persistent) OR Grade 2 symptomatic increase by greater than 20 mm Hg (diastolic) or greater than 140/90 mm Hg if previously within normal limits OR Grade 3	Interrupt until symptoms resolve and diastolic blood pressure less than 90 mm Hg, then resume at reduced dose by 1 dose level.3 If needed, reduce another dose level.3
  	Grade 4	Permanently discontinue.
  Gastrointestinal Perforation [see Warnings and Precautions ]	Any grade	Permanently discontinue.
  QT Interval Prolongation [see Warnings and Precautions ]	Greater than 500 milliseconds OR Increase from baseline of 60 milliseconds or greater	Interrupt and correct electrolyte abnormalities (magnesium, potassium, calcium). Use medical judgement before restarting.
  Drug-Induced Liver Injury [see Warnings and Precautions ]	Grade 3 ALT or higher in the absence of another cause4 OR AST/ALT greater than 3 × upper limit normal (ULN) with bilirubin greater than 2 × ULN in the absence of another cause4	Permanently discontinue.
  Non-hematological toxicities [see Adverse Reactions ]	Grade 2	Continue treatment at reduced dose by 1 dose level.
  	Grade 3
  	1stoccurrence	Interrupt until Grade 2 or less, then resume at reduced dose by 1 dose level.
  	No improvement within 7 days OR 2ndor 3rdoccurrence	Interrupt until Grade 2 or less, then resume at reduced dose by 2 dose levels.
  	4thoccurrence	Interrupt until Grade 2 or less, then resume at reduced dose by 2 dose levels for HCC and RCC or 3 dose levels for DTC.
  	Grade 4	Permanently discontinue.

  • 1Adverse reactions graded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0 (NCI CTCAE v3.0).
  • 2If no recovery after 30 day interruption, discontinue treatment unless the patient is deriving clinical benefit.
  • 3If more than 2 dose reductions are required, permanently discontinue treatment.
  • 4In addition, any grade increased alkaline phosphatase in the absence of known bone pathology and Grade 2 or worse increased bilirubin; any 1 of the following: INR of 1.5 or greater, ascites and/or encephalopathy in the absence of underlying cirrhosis or other organ failure considered to be due to drug-induced liver injury.

  Table 3: Recommended Dosage Modifications for Dermatologic Toxicities

  Dermatologic Toxicity Grade	Occurrence	NEXAVAR Dosage Modification
  		Hepatocellular and Renal Cell Carcinoma	Differentiated Thyroid Carcinoma
  Grade 2: Painful erythema and swelling of the hands or feet and/or discomfort affecting the patient’s normal activities	1stoccurrence	Continue NEXAVAR and consider topical therapy for symptomatic relief. If no improvement within 7 days, see below.	Decrease NEXAVAR to 600 mg daily. If no improvement within 7 days, see below.
  	No improvement within 7 days at reduced dose OR 2ndand 3rdoccurrence	Interrupt NEXAVAR until resolved or improved to Grade 0 to 1.	Interrupt NEXAVAR until completely resolved or improved to Grade1.
  		When resuming treatment, decrease dose by 1 dose level.	When resuming treatment, decrease dose by 1 dose level for 2ndoccurrence and 2 doses levels for 3rdoccurrence.
  	4thoccurrence	Discontinue NEXAVAR treatment.
  Grade 3: Moist desquamation, ulceration, blistering, or severe pain of the hands or feet, resulting in inability to work or perform activities of daily living	1stoccurrence	Interrupt NEXAVAR until resolved or improved to Grade 0 to 1	Interrupt NEXAVAR until completely resolved or improved to Grade 1.
  		When resuming treatment, decrease dose by 1 dose level.	When resuming treatment, decrease dose by 1 dose level.
  	2ndoccurrence	Interrupt NEXAVAR until resolved or improved to Grade 0 to 1	Interrupt NEXAVAR until completely resolved or improved to Grade 1.
  		When resuming treatment, decrease dose by 1 dose level.	When resuming treatment, decrease dose by 2 dose levels.
  	3rdoccurrence	Discontinue NEXAVAR treatment.

  Following improvement of Grade 2 or 3 dermatologic toxicity to Grade 0 or 1 for at least 28 days on a reduced dose of NEXAVAR, the dose of NEXAVAR may be increased 1 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).
  ,
  5.9 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 abnormalities (magnesium, potassium, calcium). Interrupt NEXAVAR if QTc interval is greater than 500 milliseconds or for an increase from baseline of 60 milliseconds or greater

  [see Clinical Pharmacology ]

  .
  ,
  12.2 Pharmacodynamics

  Cardiac Electrophysiology

  The effect of NEXAVAR 400 mg twice daily on the QTc interval was evaluated in a multi-center, open-label, non-randomized trial in 53 patients with advanced cancer. No large changes in the mean QTc intervals (that is, >20 ms) from baseline were detected in the trial. After one 28-day treatment cycle, the largest mean QTc interval change of 8.5 ms (upper bound of two-sided 90% confidence interval, 13.3 ms) was observed at 6 hours post-dose on day 1 of cycle 2

  [see Warnings and Precautions , Drug Interactions ].
  )
• •
  Drug-Induced Liver Injury
  : Monitor liver function tests regularly; discontinue for unexplained transaminase elevations. (
  5.10 Drug-Induced Liver Injury

  Sorafenib-induced hepatitis is characterized by a hepatocellular pattern of liver damage with significant increases of transaminases which may result in hepatic failure and death. Increases in bilirubin and INR may also occur. The incidence of severe drug-induced liver injury, defined as elevated transaminase levels above 20 times the upper limit of normal or transaminase elevations with significant clinical sequelae (for example, elevated INR, ascites, fatal, or transplantation), was two of 3,357 patients (0.06%) in a global monotherapy database.

  Monitor liver function tests regularly. In case of significantly increased transaminases without alternative explanation, such as viral hepatitis or progressing underlying malignancy, discontinue NEXAVAR

  [see Dosage and Administration ].
  )
• •
  Embryo-Fetal Toxicity
  : NEXAVAR may cause fetal harm. Advise patients of the potential risk to a fetus and to use effective contraception. (
  5.11 Embryo-Fetal Toxicity

  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. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for 6 months following the last dose of NEXAVAR. Advise male patients with female partners of reproductive potential and pregnant partners to use effective contraception during treatment and for 3 months following the last dose of NEXAVAR

  [see Use in Specific Populations ].
  ,
  8.1 Pregnancy

  Risk Summary

  Based on findings from animal studies and its mechanism of action

  [see Clinical Pharmacology ]

  , NEXAVAR may cause fetal harm when administered to a pregnant woman. There are no available data in pregnant women to inform a drug-associated risk. In animal reproduction studies, oral administration of sorafenib to pregnant rats and rabbits during the period of organogenesis resulted in embryo-fetal toxicities at maternal exposures that were significantly lower than human exposures at the recommended dose of 400 mg twice daily

  (see Data).

  Advise pregnant women and females of reproductive potential of the potential risk to a fetus.

  The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

  Data

  Animal Data

  In animal reproduction studies, sorafenib was teratogenic and induced embryo-fetal toxicity (including increased post-implantation loss, resorptions, skeletal retardations, and retarded fetal weight) when administered orally to pregnant rats and rabbits during the period of organogenesis. The effects occurred at doses considerably below the recommended human dose of 400 mg twice daily (approximately 500 mg/m²/day on a body surface area basis). Adverse intrauterine development effects were seen at doses >0.2 .mg/kg/day (1.2 mg/m²/day) in rats and ≥0.3 mg/kg/day (≥3.6 mg/m²/day) in rabbits. These doses result in exposures (AUC) that are approximately 0.008 times the AUC in patients at the recommended dose.
  ,
  8.3 Females and Males of Reproductive Potential

  NEXAVAR may cause fetal harm when administered to a pregnant woman

  [see Use in Specific Populations (8.1)].

  Pregnancy Testing

  Verify the pregnancy status of females of reproductive potential prior to the initiation of NEXAVAR.

  Contraception

  Females

  Advise females of reproductive potential to use effective contraception during treatment and for 6 months following the last dose of NEXAVAR.

  Males

  Based on genotoxicity and findings in animal reproduction studies, advise males with female partners of reproductive potential and pregnant partners to use effective contraception during treatment with NEXAVAR and for 3 months following the last dose of NEXAVAR

  [see Use in Specific Populations , Nonclinical Toxicology ]

  .

  Infertility

  Males

  Based on findings in animal studies, NEXAVAR may impair fertility in males of reproductive potential

  [see Nonclinical Toxicology ]

  .
  )
• •
  Impairment of Thyroid Stimulating Hormone Suppression (TSH) in DTC
  : Monitor TSH monthly and adjust thyroid replacement therapy in patients with thyroid cancer. (
  5.12 Impairment of Thyroid Stimulating Hormone Suppression in Differentiated Thyroid Carcinoma

  NEXAVAR impairs exogenous thyroid suppression. In the DECISION (DTC) study, 99% of patients had a baseline thyroid stimulating hormone (TSH) level less than 0.5 mU/L. Elevation of TSH level above 0.5 mU/L was observed in 41% of NEXAVAR-treated patients as compared with 16% of those receiving placebo patients. For patients with impaired TSH suppression while receiving NEXAVAR, the median maximal TSH was 1.6 mU/L and 25% had TSH levels greater than 4.4 mU/L.

  Monitor TSH levels monthly and adjust thyroid replacement medication as needed in patients with DTC.
  )