NEXAVAR, a multikinase inhibitor targeting several serine/threonine and receptor tyrosine kinases, is the tosylate salt of sorafenib.

Sorafenib tosylate has the chemical name 4-(4-{3-[4-Chloro-3-(trifluoromethyl)phenyl]ureido}phenoxy)-N ²-methylpyridine-2-carboxamide 4-methylbenzenesulfonate and its structural formula is:

Sorafenib tosylate is a white to yellowish or brownish solid with a molecular formula of C₂₁H₁₆ClF₃N₄O₃ x C₇H₈O₃S and a molecular weight of 637.0 g/mole. Sorafenib tosylate is practically insoluble in aqueous media, slightly soluble in ethanol and soluble in PEG 400.

Each red, round NEXAVAR film-coated tablet contains sorafenib tosylate (274 mg) equivalent to 200 mg of sorafenib and the following inactive ingredients:

croscarmellose sodium, microcrystalline cellulose, hypromellose, sodium lauryl sulphate, magnesium stearate, polyethylene glycol, titanium dioxide and ferric oxide red.

Hepatocellular Carcinoma

NEXAVAR is indicated for the treatment of patients with unresectable hepatocellular carcinoma (HCC).

Renal Cell Carcinoma

NEXAVAR is indicated for the treatment of patients with advanced renal cell carcinoma (RCC).

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.].

Suggested dose modifications for skin toxicity are outlined in Table 1.

Table 1: Suggested Dose Modifications for Skin Toxicity

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 (eg, St. John's Wort, dexamethasone, phenytoin, 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].

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.

NEXAVAR tablets are supplied as round, biconvex, red film-coated tablets, debossed with the "Bayer cross" on one side and "200" on the other side, each containing sorafenib tosylate equivalent to 200 mg of sorafenib. Bottles of 120 tablets NDC 0026-8488-58

Storage

Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) (see USP controlled room temperature). Store in a dry place.

Manufactured by: Bayer HealthCare AG, Leverkusen, Germany. Manufactured for: Bayer Pharmaceuticals Corporation, 400 Morgan Lane, West Haven, CT 06516. Onyx Pharmaceuticals, Inc., 2100 Powell Street, Emeryville, CA 94608. Distributed and marketed by: Bayer Pharmaceuticals Corporation, 400 Morgan Lane, West Haven, CT 06516. Marketed by: Onyx Pharmaceuticals, Inc., 2100 Powell Street, Emeryville, CA 94608. FDA Rev date: 11/16/2007

The following risks are discussed in greater detail in the WARNINGS AND PRECAUTIONS section :

• Cardiac ischemia, infarction [See Warnings and PRECAUTIONS]
• Hemorrhage [See Warnings and PRECAUTIONS]
• Hypertension [See Warnings and PRECAUTIONS]
• Hand-foot skin reaction and rash [See Warnings and PRECAUTIONS]
• Gastrointestinal perforation [See Warnings and PRECAUTIONS]
• Wound healing complications [See Warnings and PRECAUTIONS]
• Teratogenicity and embryofetal toxicity [See Warnings and PRECAUTIONS]

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.

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.

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

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. 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.

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

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 451patients (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.

Additional Data from Multiple Clinical Trials

The following additional drug-related adverse reactions and laboratory abnormalities were reported from clinical trials of NEXAVAR as monotherapy (very common 10% or greater, common 1 to less than 10%, uncommon 0.1% to less than 1%):

Cardiovascular: Uncommon: hypertensive crisis*, myocardial ischemia and/or infarction*, congestive heart failure*

Dermatologic: Very common: erythema Common: exfoliative dermatitis, acne, flushing Uncommon: folliculitis, eczema, erythema multiforme, keratoacanthomas/ squamous cell cancer of the skin.

Digestive: Very common: increased lipase, increased amylase Common: mucositis, stomatitis (including dry mouth and glossodynia), dyspepsia, dysphagia Uncommon: pancreatitis, gastrointestinal reflux, gastritis, gastrointestinal perforations*

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

Musculoskeletal: Common: arthralgia, myalgia

Nervous System and Psychiatric: Common:depression Uncommon: tinnitus, reversible posterior leukoencephalopathy*

Reproductive: Common: erectile dysfunction Uncommon: gynecomastia

Respiratory: Common: hoarseness Uncommon: rhinorrhea

*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, acute renal failure. For these adverse reactions, the causal relationship to NEXAVAR has not been established.

UGT1A1 and UGT1A9 Substrates

Caution is recommended when administering NEXAVAR with compounds that are metabolized/eliminated predominantly by the UGT1A1 pathway (e.g. irinotecan). Sorafenib inhibits glucuronidation by the UGT1A1 (K_i value: 1 µM) and UGT1A9 pathways (Ki value: 2 µM). Systemic exposure to substrates of UGT1A1 and UGT1A9 may increase when co-administered with NEXAVAR [see Warnings and PRECAUTIONS].

In clinical studies, when NEXAVAR was administered with irinotecan, whose active metabolite SN-38 is further metabolized by the UGT1A1 pathway, there was a 67-120% increase in the AUC of SN-38 and a 26-42% increase in the AUC of irinotecan. The clinical significance of these findings is unknown.

Docetaxel

Concomitant use of docetaxel (75 or 100 mg/m² administered every 21 days) with NEXAVAR (200 or 400 mg twice daily), administered with a 3-day break in dosing around administration of docetaxel, resulted in a 36-80% increase in docetaxel AUC and a 16-32% increase in docetaxel Cmax. Caution is recommended when NEXAVAR is co-administered with docetaxel [see Warnings and PRECAUTIONS].

Doxorubicin

Concomitant treatment with NEXAVAR resulted in a 21% increase in the AUC of doxorubicin. Caution is recommended when administering doxorubicin with NEXAVAR. The clinical significance of these findings is unknown [see Warnings and PRECAUTIONS].

Fluorouracil

Both increases (21%-47%) and decreases (10%) in the AUC of fluorouracil were observed with concomitant treatment with NEXAVAR. Caution is recommended when NEXAVAR is co-administered with fluorouracil/leucovorin.

CYP2B6 and CYP2C8 Substrates

Sorafenib inhibits CYP2B6 and CYP2C8 in vitro with K_i values of 6 and 1-2 µM, respectively. Systemic exposure to substrates of CYP2B6 and CYP2C8 is expected to increase when co-administered with NEXAVAR. Caution is recommended when administering substrates of CYP2B6 and CYP2C8 with NEXAVAR.

CYP3A4 Inducers

Continuous concomitant administration of NEXAVAR and rifampicin resulted in an average 37% reduction of sorafenib AUC. Other inducers of CYP3A4 activity (e.g. Hypericum perforatum also known as St. John's wort, phenytoin, carbamazepine, phenobarbital, and dexamethasone) may also increase metabolism of sorafenib and thus decrease sorafenib concentrations. [see DOSAGE AND ADMINISTRATION].

CYP3A4 Inhibitors and CYP Isoform Substrates

In vitro data indicate that sorafenib is metabolized by CYP3A4 and UGT1A9 pathways. Ketoconazole (400 mg), a potent inhibitor of CYP3A4, administered once daily for 7 days did not alter the mean AUC of a single oral 50 mg dose of sorafenib in healthy volunteers. Therefore, sorafenib metabolism is unlikely to be altered by CYP3A4 inhibitors. Studies with human liver microsomes demonstrated that sorafenib is a competitive inhibitor of CYP2C19, CYP2D6, and CYP3A4 as indicated by Ki values of 17 µM, 22 µM, and 29 µM, respectively. Administration of NEXAVAR 400 mg twice daily for 28 days did not alter the exposure of concomitantly administered midazolam (CYP3A4 substrate), dextromethorphan (CYP2D6 substrate), and omeprazole (CYP2C19 substrate). This indicates that sorafenib is unlikely to alter the metabolism of substrates of these enzymesin vivo. Studies with human liver microsomes demonstrated that sorafenib is a competitive inhibitor of CYP2C9 with a Ki value of 7-8 µM. The possible effect of sorafenib on the metabolism of the CYP2C9 substrate warfarin was assessed indirectly by measuring PT-INR. The mean changes from baseline in PT-INR were not higher in NEXAVAR patients compared to placebo patients, suggesting that sorafenib did not inhibit warfarin metabolism in vivo [see Warnings and PRECAUTIONS].

In Vitro Studies: CYP Enzyme Induction

CYP1A2 and CYP3A4 activities were not altered after treatment of cultured human hepatocytes with sorafenib, indicating that sorafenib is unlikely to be an inducer of CYP1A2 or CYP3A4.

Combination with Other Antineoplastic Agents

In clinical studies, NEXAVAR has been administered with a variety of other antineoplastic agents at their commonly used dosing regimens, including gemcitabine, oxaliplatin, paclitaxel and carboplatin, doxorubicin, docetaxel, and irinotecan. Sorafenib had no effect on the pharmacokinetics of gemcitabine or oxaliplatin. Concomitant use of paclitaxel (225 mg/m²) and carboplatin (AUC=6) with NEXAVAR (100, 200 or 400 mg twice daily), administered with a 3-day break in dosing around administration of paclitaxel/carboplatin, resulted in no significant effect on the pharmacokinetics of paclitaxel. See DRUG INTERACTIONS for information about interactions with irinotecan, docetaxel, doxorubicin and fluorouracil/leucovorin.

Included as part of the PRECAUTIONS section.

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.

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.

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.

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.

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.

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.

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.

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 (e.g. irinotecan) [see DRUG INTERACTIONS].

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].

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].

Pregnancy

Pregnancy Category D

Sorafenib may cause fetal harm when administered to a pregnant woman. In rats and rabbits, sorafenib has been shown to be teratogenic and to induce embryo-fetal toxicity (including increased post-implantation loss, resorptions, skeletal retardations, and retarded fetal weight). 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 ≥ 1.2 mg/m²/day in rats and 3.6 mg/m²/day in rabbits (approximately 0.008 times the AUC seen in cancer patients at the recommended human dose). A NOAEL (no observed adverse effect level) was not defined for either species, since lower doses were not tested. There are no adequate and well-controlled studies in pregnant women using NEXAVAR. 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.

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 and CLINICAL PHARMACOLOGY]

PATIENT COUNSELING INFORMATION

See FDA-approved Patient Labeling.

Cardiac Ischemia; Infarction

Physicians should also discuss with patients that cardiac ischemia and/or infarction has been reported during NEXAVAR treatment, and that they should immediately report any episodes of chest pain or other symptoms of cardiac ischemia and/or infarction. [See Warnings and PRECAUTIONS]

Bleeding; Gastrointestinal Perforation

Physicians should inform patients that NEXAVAR may increase the risk of bleeding and that they should promptly report any episodes of bleeding.

Patients should be advised that cases of gastrointestinal perforation have been reported in patients taking NEXAVAR. [See Warnings and PRECAUTIONS]

Skin Reactions; Hypertension

Patients should be advised of the possible occurrence of hand-foot skin reaction and rash during NEXAVAR treatment and appropriate countermeasures.

Patients should be informed that hypertension may develop during NEXAVAR treatment, especially during the first six weeks of therapy, and that blood pressure should be monitored regularly during treatment. [See Warnings and PRECAUTIONS]

Birth Defects and Fetal Loss

Physicians should inform female patients that NEXAVAR may cause birth defects or fetal loss and that they should not become pregnant during treatment with NEXAVAR and for at least 2 weeks after stopping treatment. Both male and female patients should be counseled to use effective birth control during treatment with NEXAVAR and for at least 2 weeks after stopping treatment. Female patients should also be advised against breast-feeding while receiving NEXAVAR. [See Warnings and PRECAUTIONS]

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies have not been performed with sorafenib.

Sorafenib was clastogenic when tested in an in vitro mammalian cell assay (Chinese hamster ovary) in the presence of metabolic activation. Sorafenib was not mutagenic in the in vitro Ames bacterial cell assay or clastogenic in an in vivo mouse micronucleus assay. One intermediate in the manufacturing process, which is also present in the final drug substance ( < 0.15%), was positive for mutagenesis in an in vitro bacterial cell assay (Ames test) when tested independently.

No specific studies with sorafenib have been conducted in animals to evaluate the effect on fertility. However, results from the repeat-dose toxicity studies suggest there is a potential for sorafenib to impair reproductive function and fertility. Multiple adverse effects were observed in male and female reproductive organs, with the rat being more susceptible than mice or dogs. Typical changes in rats consisted of testicular atrophy or degeneration, degeneration of epididymis, prostate, and seminal vesicles, central necrosis of the corpora lutea and arrested follicular development. Sorafenib-related effects on the reproductive organs of rats were manifested at daily oral doses ≥ 30 mg/m² (approximately 0.5 times the AUC in cancer patients at the recommended human dose). Dogs showed tubular degeneration in the testes at 600 mg/m²/day (approximately 0.3 times the AUC at the recommended human dose) and oligospermia at 1200 mg/m²/day of sorafenib. Adequate contraception should be used during therapy and for at least 2 weeks after completing therapy.

Use In Specific Populations

Pregnancy

Pregnancy Category D [See Warnings and PRECAUTIONS].

Nursing Mothers

It is not known whether sorafenib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from NEXAVAR, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

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

Pediatric Use

The safety and effectiveness of NEXAVAR in pediatric patients have not been studied.

Repeat dosing of sorafenib to young and growing dogs resulted in irregular thickening of the femoral growth plate at daily sorafenib doses ≥ 600 mg/m² (approximately 0.3 times the AUC at the recommended human dose), hypocellularity of the bone marrow adjoining the growth plate at 200 mg/m²/day (approximately 0.1 times the AUC at the recommended human dose), and alterations of the dentin composition at 600 mg/m²/day. Similar effects were not observed in adult dogs when dosed for 4 weeks or less.

Geriatric Use

In total, 59% of HCC patients treated with NEXAVAR were age 65 years or older, and 19% were 75 and older. In total, 32% of RCC patients treated with NEXAVAR were age 65 years or older, and 4% were 75 and older. No differences in safety or efficacy were observed between older and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Patients with Hepatic Impairment

In vitro and in vivo data indicate that sorafenib is primarily metabolized by the liver. Comparison of data across studies suggests that patients with mild (Child-Pugh A) and moderate (Child-Pugh B) hepatic impairment have sorafenib AUCs that may be 23- 65% lower than subjects with normal hepatic function. Systemic exposure and safety data were comparable in HCC patients with Child-Pugh A and B hepatic impairment. NEXAVAR has not been studied in patients with Child-Pugh C hepatic impairment. [see Warnings and PRECAUTIONS and CLINICAL PHARMACOLOGY].

Patients with Renal Impairment

NEXAVAR has not been studied in patients undergoing dialysis. No dosage adjustment is necessary when administering NEXAVAR to patients with mild, moderate or severe renal impairment not undergoing dialysis [see CLINICAL PHARMACOLOGY].

There is no specific treatment for NEXAVAR overdose. The highest dose of NEXAVAR studied clinically is 800 mg twice daily. The adverse reactions observed at this dose were primarily diarrhea and dermatologic. No information is available on symptoms of acute overdose in animals because of the saturation of absorption in oral acute toxicity studies conducted in animals.

In cases of suspected overdose, NEXAVAR should be withheld and supportive care instituted.

NEXAVAR is contraindicated in patients with known severe hypersensitivity to sorafenib or any other component of NEXAVAR.

Mechanism of Action

Sorafenib is a kinase inhibitor that decreases tumor cell proliferation in vitro. Sorafenib was shown to inhibit multiple intracellular (CRAF, BRAF and mutant BRAF) and cell surface kinases (KIT, FLT-3, RET, VEGFR-1, VEGFR-2, VEGFR-3, and PDGFR-β). Several of these kinases are thought to be involved in tumor cell signaling, angiogenesis, and apoptosis. Sorafenib inhibited tumor growth and angiogenesis of human hepatocellular carcinoma and renal cell carcinoma, and several other human tumor xenografts in immunocompromised mice.

Pharmacokinetics

After administration of NEXAVAR tablets, the mean relative bioavailability is 38-49% when compared to an oral solution. The mean elimination half-life of sorafenib is approximately 25-48 hours. Multiple dosing of NEXAVAR for 7 days resulted in a 2.5- to 7-fold accumulation compared to single dose administration. Steady-state plasma sorafenib concentrations are achieved within 7 days, with a peak-to-trough ratio of mean concentrations of less than 2.

Absorption and Distribution

Following oral administration, sorafenib reaches peak plasma levels in approximately 3 hours. When given with a moderate-fat meal (30% fat; 700 calories), bioavailability was similar to that in the fasted state. With a high-fat meal (50% fat; 900 calories), sorafenib bioavailability was reduced by 29% compared to administration in the fasted state. It is recommended that NEXAVAR be administered without food. [see DOSAGE AND ADMINISTRATION].

Mean Cmax and AUC increased less than proportionally beyond doses of 400 mg administered orally twice daily.

In vitro binding of sorafenib to human plasma proteins is 99.5%.

Metabolism and Elimination

Sorafenib is metabolized primarily in the liver, undergoing oxidative metabolism, mediated by CYP3A4, as well as glucuronidation mediated by UGT1A9.

Sorafenib accounts for approximately 70-85% of the circulating analytes in plasma at steady-state. Eight metabolites of sorafenib have been identified, of which five have been detected in plasma. The main circulating metabolite of sorafenib in plasma, the pyridine N-oxide, shows in vitro potency similar to that of sorafenib. This metabolite comprises approximately 9-16% of circulating analytes at steady-state.

Following oral administration of a 100 mg dose of a solution formulation of sorafenib, 96% of the dose was recovered within 14 days, with 77% of the dose excreted in feces, and 19% of the dose excreted in urine as glucuronidated metabolites. Unchanged sorafenib, accounting for 51% of the dose, was found in feces but not in urine.

Special Populations

Age

Analyses of demographic data suggest that no dose adjustments are necessary for age.

Gender

Analyses of demographic data suggest that no dose adjustments are necessary for gender.

Race

A study of the pharmacokinetics of sorafenib indicated that the mean AUC of sorafenib in Asians (n=78) was 30% lower than in Caucasians (n=40).

Pediatric

There are no pharmacokinetic data in pediatric patients.

Hepatic Impairment

Sorafenib is cleared primarily by the liver.

Comparison of data across studies suggests that in HCC patients with mild (Child-Pugh A) or moderate (Child- Pugh B) hepatic impairment, 400 mg doses of sorafenib appear to be associated with AUC values that were 23 to 65% lower than those of other subjects 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 pharmacokinetics of sorafenib have not been studied in patients with severe (Child-Pugh C) hepatic impairment [see Warnings and PRECAUTIONS and Use in Specific Populations].

Renal Impairment

In a study of drug disposition after a single oral dose of radiolabeled sorafenib to healthy subjects, 19% of the administered dose of sorafenib was excreted in urine.

In a clinical pharmacology study, the pharmacokinetics of sorafenib were evaluated following administration of a single 400 mg dose to subjects with normal renal function, and in subjects with mild (CrCl > 50-80 ml/min), moderate (CrCl 30-50 ml/min), or severe (CrCl < 30 ml/min) renal impairment, not undergoing dialysis. There was no relationship observed between sorafenib exposure and renal function. No dosage adjustment is necessary based on mild, moderate or severe renal impairment not undergoing dialysis [see Use in Specific Populations].

Clinical Studies

The clinical safety and efficacy of NEXAVAR have been studied in patients with hepatocellular carcinoma (HCC) and renal cell carcinoma (RCC).

Hepatocellular Carcinoma

The HCC Study was a Phase 3, international, multicenter, randomized, double blind, placebo-controlled trial in patients with unresectable hepatocellular carcinoma. Overall survival was the primary endpoint. A total of 602 patients were randomized; 299 to NEXAVAR 400 mg twice daily and 303 to matching placebo.

Demographics and baseline disease characteristics were similar between the NEXAVAR and placebo groups with regard to age, gender, race, performance status, etiology (including hepatitis B, hepatitis C and alcoholic liver disease), TNM stage (stage I: < 1% vs. < 1%; stage II: 10.4% vs. 8.3%; stage III: 37.8% vs. 43.6%; stage IV: 50.8% vs. 46.9%), absence of both macroscopic vascular invasion and extrahepatic tumor spread (30.1% vs. 30.0%), and Barcelona Clinic Liver Cancer stage (stage B: 18.1% vs. 16.8%; stage C: 81.6% vs. 83.2%; stage D: < 1% vs. 0%). Liver impairment by Child-Pugh score was comparable between the NEXAVAR and placebo groups (Class A: 95% vs. 98%; B: 5% vs. 2%). Only one patient with Child-Pugh class C was entered. Prior treatments included surgical resection procedures (19.1% vs. 20.5%), locoregional therapies (including radiofrequency ablation, percutaneous ethanol injection and transarterial chemoembolization; 38.8% vs. 40.6%), radiotherapy (4.3% vs. 5.0%) and systemic therapy (3.0% vs. 5.0%).

The trial was stopped for efficacy following a pre-specified second interim analysis for survival showing a statistically significant advantage for NEXAVAR over placebo for overall survival (HR: 0.69, p= 0.00058) (see Table 4 and Figure 1). This advantage was consistent across all subsets analyzed.

Final analysis of time to tumor progression (TTP) based on data from an earlier time point (by independent radiologic review) also was significantly longer in the NEXAVAR arm (HR: 0.58, p=0.000007) (see Table 4).

Table 4: Efficacy Results from HCC Study

Figure 1: Kaplan-Meier Curve of Overall Survival in HCC Study (Intent-to-Treat Population)

Renal Cell Carcinoma

The safety and efficacy of NEXAVAR in the treatment of advanced renal cell carcinoma (RCC) were studied in the following 2 randomized controlled clinical trials.

RCC Study 1 was a Phase 3, international, multicenter, randomized, double blind, placebo-controlled trial in patients with advanced renal cell carcinoma who had received one prior systemic therapy. Primary study endpoints included overall survival and progression-free survival (PFS). Tumor response rate was a secondary endpoint. The PFS analysis included 769 patients stratified by MSKCC (Memorial Sloan Kettering Cancer Center) prognostic risk category (low or intermediate) and country and randomized to NEXAVAR 400 mg twice daily (N=384) or to placebo (N=385).

Table 5 summarizes the demographic and disease characteristics of the study population analyzed. Baseline demographics and disease characteristics were well balanced for both treatment groups. The median time from initial diagnosis of RCC to randomization was 1.6 and 1.9 years for the NEXAVAR and placebo groups, respectively.

Table 5: Demographic and Disease Characteristics - RCC Study 1

Figure 2: Kaplan-Meier Curves for Progression-free Survival - RCC Study 1

NOTE: HR is from Cox regression model with the following covariates: MSKCC prognostic risk category and country. P-value is from two-sided Log-Rank test stratified by MSKCC prognostic risk category and country. The median PFS for patients randomized to NEXAVAR was 167 days compared to 84 days for patients randomized to placebo. The estimated hazard ratio (risk of progression with NEXAVAR compared to placebo) was 0.44 (95% CI: 0.35, 0.55).

A series of patient subsets were examined in exploratory univariate analyses of PFS. The subsets included age above or below 65 years, ECOG PS 0 or 1, MSKCC prognostic risk category, whether the prior therapy was for progressive metastatic disease or for an earlier disease setting, and time from diagnosis of less than or greater than 1.5 years. The effect of NEXAVAR on PFS was consistent across these subsets, including patients with no prior IL-2 or interferon therapy (n=137; 65 patients receiving NEXAVAR and 72 placebo), for whom the median PFS was 172 days on NEXAVAR compared to 85 days on placebo.

Tumor response was determined by independent radiological review according to RECIST criteria. Overall, of 672 patients who were evaluable for response, 7 (2%) NEXAVAR patients and 0 (0%) placebo patients had a confirmed partial response. Thus the gain in PFS in NEXAVAR-treated patients primarily reflects the stable disease population.

At the time of a planned interim survival analysis, based on 220 deaths, overall survival was longer for NEXAVAR than placebo with a hazard ratio (NEXAVAR over placebo) of 0.72. This analysis did not meet the prespecified criteria for statistical significance. Additional analyses are planned as the survival data mature.

RCC Study 2 was a Phase 2 randomized discontinuation trial in patients with metastatic malignancies, including RCC. The primary endpoint was the percentage of randomized patients remaining progression-free at 24 weeks. All patients received NEXAVAR for the first 12 weeks. Radiologic assessment was repeated at week 12. Patients with < 25% change in bi-dimensional tumor measurements from baseline were randomized to NEXAVAR or placebo for a further 12 weeks. Patients who were randomized to placebo were permitted to cross over to open- label NEXAVAR upon progression. Patients with tumor shrinkage ≥ 25% continued NEXAVAR, whereas patients with tumor growth ≥ 25% discontinued treatment.

Two hundred and two patients with advanced RCC were enrolled into RCC Study 2, including patients who had received no prior therapy and patients with tumor histology other than clear cell carcinoma. After the initial 12 weeks of NEXAVAR therapy, 79 RCC patients continued on open-label NEXAVAR, and 65 patients were randomized to NEXAVAR or placebo. After an additional 12 weeks, at week 24, for the 65 randomized patients, the progression-free rate was significantly higher in patients randomized to NEXAVAR (16/32, 50%) than in patients randomized to placebo (6/33, 18%) (p=0.0077). Progression-free survival was significantly longer in the NEXAVAR group (163 days) than in the placebo group (41 days) (p=0.0001, HR=0.29).

NEXAVAR
(NEX-A-VAR)
(sorafenib) Tablets, Oral

Read the Patient Information that comes with NEXAVAR before you start taking it and each time you get a refill. There may be new information. This leaflet does not take the place of talking with your doctor about your medical condition or your treatment.

What is the most important information I should know about NEXAVAR? NEXAVAR may cause birth defects or death of an unborn baby.

• Women should not get pregnant during treatment with NEXAVAR and for at least 2 weeks after stopping treatment.
• Men and women should use effective birth control during treatment with NEXAVAR and for at least 2 weeks after stopping treatment. Talk with your doctor about effective birth control methods.

Call your doctor right away if you become pregnant during treatment with NEXAVAR.

What is NEXAVAR?

NEXAVAR is an anticancer medicine used to treat a certain type of liver or kidney cancer called:

1. Hepatocellular carcinoma (HCC, a type of liver cancer), when it can not be treated with surgery
2. Renal cell carcinoma (RCC, a type of kidney cancer)

NEXAVAR has not been studied in children.

What should I tell my doctor before starting NEXAVAR?

Tell your doctor about all of your health conditions, including if you:

• have any allergies
• have heart problems or chest pain
• have bleeding problems
• have high blood pressure
• have kidney problems in addition to kidney cancer
• have liver problems in addition to liver cancer
• are pregnant or planning to become pregnant. See "What is the most important information I should know about NEXAVAR?"
• are breast-feeding or planning to breast-feed. It is not known if NEXAVAR passes into your breast milk. You and your doctor should decide if you will take NEXAVAR or breast-feed. You should not do both.

Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins and herbal supplements. NEXAVAR and certain other medicines can interact with each other and cause serious side effects. Especially, tell your doctor if you take warfarin (Coumadin®)*.

Know the medicines you take. Keep a list of your medicines and show it to your doctor and pharmacist when you get a new medicine. Do not take other medicines with NEXAVAR until you have talked with your doctor.

How do I take NEXAVAR?

• Take NEXAVAR exactly as prescribed by your doctor.
• The usual dose of NEXAVAR is 2 tablets taken two times a day (for a total of 4 tablets each day). Your doctor may change your dose during treatment or stop treatment for some time if you have side effects.
• Swallow NEXAVAR tablets whole with water.
• Take NEXAVAR without food (at least 1 hour before or 2 hours after a meal)..
• If you miss a dose of NEXAVAR, skip the missed dose, and take your next dose at your regular time. Do not double your dose of NEXAVAR. Call your doctor right away if you take too much NEXAVAR.

What are possible side effects of NEXAVAR?

NEXAVAR may cause serious side effects, including:

• decreased blood flow to the heart and heart attack. Get emergency help right away and call your doctor if you get symptoms such as chest pain, shortness of breath, feel lightheaded or faint, nausea, vomiting, sweating a lot.
• bleeding problems. NEXAVAR may increase your chance of bleeding. Tell your doctor if you have any bleeding while taking NEXAVAR
• high blood pressure. Your blood pressure should be checked every week during the first 6 weeks of starting NEXAVAR. Your blood pressure should be checked regularly and any high blood pressure should be treated while you are receiving NEXAVAR.
• a skin problem called hand-foot skin reaction. This causes redness, pain, swelling, or blisters on the palms of your hands or soles of your feet. If you get this side effect, your doctor may change your dose or stop treatment for some time.
• perforation of the bowel. Tell your doctor right away if you get high fever, nausea, vomiting, severe abdominal pain.
• possible wound healing problems. If you need to have a surgical or dental procedure, tell your doctor that you are taking NEXAVAR. NEXAVAR may need to be stopped until your wound heals after some types of surgery.
• birth defects or death of an unborn baby. See "What is the most important information I should know about NEXAVAR?"

Other side effects with NEXAVAR may include:

• rash, redness, itching or peeling of your skin
• hair thinning or patchy hair loss
• diarrhea (frequent or loose bowel movements)
• nausea or vomiting
• mouth sores
• weakness
• loss of appetite
• numbness, tingling or pain in your hands and feet
• abdominal pain
• tiredness
• weight loss

Tell your doctor if you have any side effects that bother you or that do not go away. These are not all the side effects with NEXAVAR. Ask your doctor or pharmacist for more information.

How should I store NEXAVAR?

• Store NEXAVAR tablets at room temperature between 59° to 86° F (15° to 30° C), in a dry place.
• Keep NEXAVAR and all medicines out of the reach of children.

General information about NEXAVAR

Medicines are sometimes prescribed for purposes other than those listed in the patient information leaflet. Do not use NEXAVAR for a condition for which it is not prescribed. Do not give NEXAVAR to other people even if they have the same symptoms you have. It may harm them.

This patient information leaflet summarizes the most important information about NEXAVAR. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about NEXAVAR that is written for healthcare professionals. You can visit our website at www.NEXAVAR.com, or call 1-866- NEXAVAR (1-866-639-2827).

What are the ingredients in NEXAVAR?

Active Ingredient: sorafenib tosylate

Inactive Ingredients: croscarmellose sodium, microcrystalline cellulose, hypromellose, sodium lauryl sulphate, magnesium stearate, polyethylene glycol, titanium dioxide and ferric oxide red.

Footnote: *Coumadin (warfarin sodium) is a trademark of Bristol-Myers Squibb Company

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

SORAFENIB - ORAL

(sor-AF-e-nib)

COMMON BRAND NAME(S): Nexavar

USES: This medication is used to treat kidney or liver cancer. Sorafenib stops or slows the growth of cancer cells (tumors). It also works by slowing the growth of new blood vessels within the tumor.

HOW TO USE: Read the Patient Information Leaflet provided by your pharmacist before you start using sorafenib and each time you get a refill. If you have any questions, consult your doctor or pharmacist.

Take this medication by mouth on an empty stomach (at least 1 hour before or 2 hours after a meal) as directed by your doctor. Do not chew or crush the tablets. Swallow tablets whole with a full glass of water (8 ounces or 240 milliliters).

Take this medication exactly as prescribed. The dosage is based on your medical condition and response to therapy. You will usually take this medication continuously (without break periods) as directed by your doctor. If you have certain side effects, your doctor may adjust your dose or stop treatment for some time.

Do not increase your dose or take this medication more often without your doctor's approval. Your condition will not improve any faster, and the risk of serious side effects may be increased.

Use this medication regularly in order to get the most benefit from it. To help you remember, use it at the same time(s) each day.

SIDE EFFECTS: Acne, dry skin, nausea, diarrhea, patchy hair loss/thinning, loss of appetite, dry mouth, hoarseness, or tiredness may occur. If these effects persist or worsen, notify your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor immediately if you notice skin problems on the palms of your hands or the soles of your feet (e.g., rash, blisters, redness, swelling, pain). Your doctor might prescribe medication for your skin or change your treatment plan.

Tell your doctor immediately if any of these unlikely but serious side effects occur: bone/muscle pain, depression, stomach/abdominal pain, dark urine, headache, tongue/mouth sores or pain, easy bruising or bleeding, numbness/tingling of the hands/feet, swollen hands/ankles/feet, shortness of breath.

Seek immediate medical attention if these rare but very serious side effects occur: chest/jaw/left arm pain, severe abdominal/stomach pain, bloody vomit, coughing up blood, bloody stools, difficulty speaking, loss of balance, sudden vision changes, seizures, mental/mood changes (e.g., confusion).

This medication can lower the body's ability to fight an infection. Notify your doctor promptly if you develop any signs of an infection such as fever, chills or persistent sore throat.

A very serious allergic reaction to this drug is unlikely, but seek immediate medical attention if it occurs. Symptoms of a serious allergic reaction may include: rash, itching, swelling, severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before taking sorafenib, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: bleeding problems, heart problems (e.g., heart attack, angina), high blood pressure, liver problems.

Do not have immunizations/vaccinations without the consent of your doctor, and avoid contact with people who have recently received oral polio vaccine or flu vaccine inhaled through the nose.

To lower the chance of getting cut, bruised or injured, use caution with sharp objects like safety razors and nail cutters, and avoid activities such as contact sports.

If you need to have a surgical or dental procedure, tell your doctor or dentist that you are using sorafenib.

Wash your hands well to prevent the spread of infections.

This medication is not recommended for use during pregnancy. It may harm an unborn baby. To avoid pregnancy, both males and females using sorafenib must use reliable form(s) of birth control during treatment and for at least 2 weeks after stopping this drug. Consult your doctor for more details.

It is not known whether this drug passes into breast milk. Because of the possible risk to the infant, breast-feeding while using this drug is not recommended. Consult your doctor before breast-feeding.

DRUG INTERACTIONS: Your healthcare professionals (e.g., doctor or pharmacist) may already be aware of any possible drug interactions and may be monitoring you for it. Do not start, stop or change the dosage of any medicine before checking with them first.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: other anti-cancer drugs (e.g., docetaxel, doxorubicin, irinotecan), "blood thinners" (anticoagulants such as warfarin, heparins), drugs affecting liver enzymes that remove sorafenib from your body (such as carbamazepine, dexamethasone, phenobarbital, phenytoin, rifamycins including rifampin/rifabutin, St John's wort).

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US national poison hotline at 1-800-222-1222. Canadian residents should call their local poison control center directly.

NOTES: Do not share this medication with others.

Laboratory and/or medical tests (e.g., blood pressure, phosphate levels, lipase, amylase, complete blood counts, liver function tests) should be performed regularly to monitor your progress or check for side effects. Consult your doctor for more details.

MISSED DOSE: If you miss a dose, take it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

STORAGE: Store at room temperature at 77 degrees F (25 degrees C) away from light and moisture. Brief storage between 59-86 degrees F (15-30 degrees C) is permitted. Do not store in the bathroom. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

MEDICAL ALERT: Your condition can cause complications in a medical emergency. For enrollment information call MedicAlert at 1-800-854-1166 (USA) or 1-800-668-1507 (Canada).

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.