Data from FDA - Curated by EPG Health - Last updated 06 July 2018

Indication(s)

1 INDICATIONS AND USAGE NEXAVAR is a kinase inhibitor indicated for the treatment of •Unresectable hepatocellular carcinoma (1.1) •Advanced renal cell carcinoma (1.2) •Locally recurrent or metastatic, progressive, differentiated thyroid carcinoma refractory to radioactive iodine treatment (1.3) 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.

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Advisory information

contraindications
4 CONTRAINDICATIONS •NEXAVAR is contraindicated in patients with known severe hypersensitivity to sorafenib or any other component of NEXAVAR. •NEXAVAR in combination with carboplatin and paclitaxel is contraindicated in patients with squamous cell lung cancer [see Warnings and Precautions (5.8)]. •NEXAVAR is contraindicated in patients with known severe hypersensitivity to sorafenib or any other component of NEXAVAR. (4) •NEXAVAR in combination with carboplatin and paclitaxel is contraindicated in patients with squamous cell lung cancer. (4)
Adverse reactions
6 ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the labeling: •Cardiac ischemia, infarction [see Warnings and Precautions (5.1)] •Hemorrhage [see Warnings and Precautions (5.2)] •Hypertension [see Warnings and Precautions (5.3)] •Hand-foot skin reaction, rash, Stevens-Johnson syndrome, and toxic epidermal necrolysis [see Warnings and Precautions (5.4)] •Gastrointestinal perforation [see Warnings and Precautions (5.5)] •QT Interval Prolongation [see Warnings and Precautions (5.9) and Clinical Pharmacology (12.2)] •Drug-Induced Hepatitis [see Warnings and Precautions (5.10)] •Impairment of TSH suppression in DTC [see Warnings and Precautions (5.12)] Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described in sections 6.1, 6.2 and 6.3 reflect exposure to NEXAVAR in 955 patients who participated in placebo controlled studies in hepatocellular carcinoma (N=297), advanced renal cell carcinoma (N=451), or differentiated thyroid carcinoma (N = 207). The most common adverse reactions (≥20%), which were considered to be related to NEXAVAR, in patients with HCC, RCC or DTC are diarrhea, fatigue, infection, alopecia, hand-foot skin reaction, rash, weight loss, decreased appetite, nausea, gastrointestinal and abdominal pains, hypertension, and hemorrhage. 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 6.1 Adverse Reactions in HCC Study Table 4 shows the percentage of patients with HCC 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 4: Adverse Reactions Reported in at Least 10% of Patients and at a Higher Rate in NEXAVAR Arm than the Placebo Arm – HCC Study NEXAVAR N=297 Placebo N=302 Adverse Reaction NCI- CTCAE v3 Category/Term All Grades % Grade 3 % Grade 4 % All Grades % Grade 3 % Grade 4 % Any Adverse Reaction 98 39 6 96 24 8 Constitutional symptoms Fatigue 46 9 1 45 12 2 Weight loss 30 2 0 10 1 0 Dermatology/skin Rash/desquamation 19 1 0 14 0 0 Pruritus 14 <1 0 11 <1 0 Hand-foot skin reaction 21 8 0 3 <1 0 Dry skin 10 0 0 6 0 0 Alopecia 14 0 0 2 0 0 Gastrointestinal Diarrhea 55 10 <1 25 2 0 Anorexia 29 3 0 18 3 <1 Nausea 24 1 0 20 3 0 Vomiting 15 2 0 11 2 0 Constipation 14 0 0 10 0 0 Hepatobiliary/pancreas Liver dysfunction 11 2 1 8 2 1 Pain Pain, abdomen 31 9 0 26 5 1 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-treated patients. The rates of CTCAE Grade 3 and 4 bleeding were also higher in the placebo-treated 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-treated groups (32% of NEXAVAR-treated patients and 35% of placebo-treated patients). Laboratory Abnormalities The following laboratory abnormalities were observed in patients with HCC: Hypophosphatemia was a common laboratory finding, observed in 35% of NEXAVAR-treated patients compared to 11% of placebo-treated patients; CTCAE Grade 3 hypophosphatemia (1–2 mg/dL) occurred in 11% of NEXAVAR-treated patients and 2% of patients in the placebo-treated group; there was 1 case of CTCAE Grade 4 hypophosphatemia (<1 mg/dL) reported in the placebo-treated 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-treated 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-treated 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-treated 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-treated patients; CTCAE Grade 3 INR elevations were reported in 4% of NEXAVAR-treated patients and 2% of placebo-treated 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-treated patients. Thrombocytopenia was observed in 46% of NEXAVAR-treated patients and 41% of placebo-treated patients; CTCAE Grade 3 or 4 thrombocytopenia was reported in 4% of NEXAVAR-treated patients and less than 1% of placebo-treated patients. Hypocalcemia was reported in 27% of NEXAVAR-treated patients and 15% of placebo-treated patients. CTCAE Grade 3 hypocalcemia (6–7 mg /dL) occurred in 2% of NEXAVAR-treated patients and 1% of placebo-treated patients. CTCAE Grade 4 hypocalcemia (<6 mg/dL) occurred in 0.4% of NEXAVAR-treated patients and in no placebo-treated patients. Hypokalemia was reported in 9.5% of NEXAVAR- treated patients compared to 5.9% of placebo-treated patients. Most reports of hypokalemia were low grade (CTCAE Grade 1). CTCAE Grade 3 hypokalemia occurred in 0.4% of NEXAVAR-treated patients and 0.7% of placebo-treated patients. There were no reports of Grade 4 hypokalemia. 6.2 Adverse Reactions in RCC Study 1 Table 5 shows the percentage of patients with RCC 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 5: Adverse Reactions Reported in at Least 10% of Patients and at a Higher Rate in NEXAVAR Arm than the Placebo Arm – RCC Study 1 NEXAVAR N=451 Placebo N=451 Adverse Reactions NCI- CTCAE v3 Category/Term All Grades % Grade 3 % Grade 4 % All Grades % Grade 3 % Grade 4 % Any Adverse Reactions 95 31 7 86 22 6 Cardiovascular, General Hypertension 17 3 <1 2 <1 0 Constitutional symptoms Fatigue 37 5 <1 28 3 <1 Weight loss 10 <1 0 6 0 0 Dermatology/skin Rash/desquamation 40 <1 0 16 <1 0 Hand-foot skin reaction 30 6 0 7 0 0 Alopecia 27 <1 0 3 0 0 Pruritus 19 <1 0 6 0 0 Dry skin 11 0 0 4 0 0 Gastrointestinal symptoms Diarrhea 43 2 0 13 <1 0 Nausea 23 <1 0 19 <1 0 Anorexia 16 <1 0 13 1 0 Vomiting 16 <1 0 12 1 0 Constipation 15 <1 0 11 <1 0 Hemorrhage/bleeding Hemorrhage – all sites 15 2 0 8 1 <1 Neurology Neuropathy-sensory 13 <1 0 6 <1 0 Pain Pain, abdomen 11 2 0 9 2 0 Pain, joint 10 2 0 6 <1 0 Pain, headache 10 <1 0 6 <1 0 Pulmonary Dyspnea 14 3 <1 12 2 <1 The rate of adverse reactions (including those associated with progressive disease) resulting in permanent discontinuation was similar in both the NEXAVAR and placebo-treated groups (10% of NEXAVAR-treated patients and 8% of placebo-treated patients). Laboratory Abnormalities The following laboratory abnormalities were observed in patients with RCC in Study 1: Hypophosphatemia was a common laboratory finding, observed in 45% of NEXAVAR-treated patients compared to 11% of placebo-treated patients. CTCAE Grade 3 hypophosphatemia (1–2 mg/dL) occurred in 13% of NEXAVAR-treated patients and 3% of patients in the placebo-treated group. There were no cases of CTCAE Grade 4 hypophosphatemia (<1 mg/dL) reported in either NEXAVAR or placebo-treated 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-treated group. CTCAE Grade 3 or 4 lipase elevations occurred in 12% of patients in the NEXAVAR-treated group compared to 7% of patients in the placebo-treated group. Elevated amylase was observed in 30% of patients treated with NEXAVAR compared to 23% of patients in the placebo-treated group. CTCAE Grade 3 or 4 amylase elevations were reported in 1% of patients in the NEXAVAR-treated group compared to 3% of patients in the placebo-treated group. Many of the lipase and amylase elevations were transient, and in the majority of cases NEXAVAR treatment was not interrupted. Clinical pancreatitis was reported in 3 of 451 NEXAVAR-treated patients (one CTCAE Grade 2 and two Grade 4) and 1 of 451 patients (CTCAE Grade 2) in the placebo-treated group. Lymphopenia was observed in 23% of NEXAVAR-treated patients and 13% of placebo-treated patients. CTCAE Grade 3 or 4 lymphopenia was reported in 13% of NEXAVAR-treated patients and 7% of placebo-treated patients. Neutropenia was observed in 18% of NEXAVAR-treated patients and 10% of placebo-treated patients. CTCAE Grade 3 or 4 neutropenia was reported in 5% of NEXAVAR-treated patients and 2% of placebo-treated patients. Anemia was observed in 44% of NEXAVAR-treated patients and 49% of placebo-treated patients. CTCAE Grade 3 or 4 anemia was reported in 2% of NEXAVAR-treated patients and 4% of placebo-treated patients. Thrombocytopenia was observed in 12% of NEXAVAR-treated patients and 5% of placebo-treated patients. CTCAE Grade 3 or 4 thrombocytopenia was reported in 1% of NEXAVAR-treated patients and in no placebo-treated patients. Hypocalcemia was reported in 12% of NEXAVAR-treated patients and 8% of placebo-treated patients. CTCAE Grade 3 hypocalcemia (6–7 mg/dL) occurred in 1% of NEXAVAR-treated patients and 0.2% of placebo-treated patients, and CTCAE Grade 4 hypocalcemia (<6 mg/dL) occurred in 1% of NEXAVAR-treated patients and 0.5% of placebo-treated patients. Hypokalemia was reported in 5.4% of NEXAVAR-treated patients compared to 0.7% of placebo-treated patients. Most reports of hypokalemia were low grade (CTCAE Grade 1). CTCAE Grade 3 hypokalemia occurred in 1.1% of NEXAVAR-treated patients and 0.2% of placebo-treated patients. There were no reports of Grade 4 hypokalemia. 6.3 Adverse Reactions in DTC Study The safety of NEXAVAR was evaluated in 416 patients with locally recurrent or metastatic, progressive differentiated thyroid carcinoma (DTC) refractory to radioactive iodine (RAI) treatment randomized to receive 400 mg twice daily NEXAVAR (n=207) or matching placebo (n=209) until disease progression or intolerable toxicity in a double-blind trial [see Clinical Studies (14.3)]. The data described below reflect a median exposure to NEXAVAR for 46 weeks (range 0.3 to 135). The population exposed to NEXAVAR was 50% male, and had a median age of 63 years. Dose interruptions for adverse reactions were required in 66% of patients receiving NEXAVAR and 64% of patients had their dose reduced. Drug-related adverse reactions that resulted in treatment discontinuation were reported in 14% of NEXAVAR-treated patients compared to 1.4% of placebo-treated patients. Table 6 shows the percentage of DTC patients experiencing adverse reactions at a higher rate in NEXAVAR-treated patients than placebo-treated patients in the double-blind phase of the DTC study. CTCAE Grade 3 adverse reactions occurred in 53% of NEXAVAR-treated patients compared to 23% of placebo-treated patients. CTCAE Grade 4 adverse reactions occurred in 12% of NEXAVAR-treated patients compared to 7% of placebo-treated patients. Table 6: Per-Patient Incidence of Selected Adverse Reactions Occurring at a Higher Incidence in NEXAVAR-Treated Patients [Between Arm Difference of ≥ 5% (All Grades)1 or ≥ 2% (Grades 3 and 4)] MedDRA Primary System Organ Class & Preferred Term NEXAVAR N = 207 Placebo N = 209 All Grades (%) Grades 3 and 4 (%) All Grades (%) Grades 3 and 4 (%) Gastrointestinal disorders Diarrhea 68 6 15 1 Nausea 21 0 12 0 Abdominal pain2 20 1 7 1 Constipation 16 0 8 0.5 Stomatitis3 24 2 3 0 Vomiting 11 0.5 6 0 Oral pain4 14 0 3 0 General disorders and administration site conditions Fatigue 41 5 20 1 Asthenia 12 0 7 0 Pyrexia 11 1 5 0 Investigations Weight loss 49 6 14 1 Metabolism and nutrition disorders Decreased appetite 30 2 5 0 Musculoskeletal and connective tissue disorders Pain in extremity 15 1 7 0 Muscle spasms 10 0 3 0 Neoplasms benign, malignant and unspecified Squamous cell carcinoma of skin 3 3 0 0 Nervous system disorders Headache 17 0 6 0 Dysgeusia 6 0 0 0 Respiratory, thoracic and mediastinal disorders Dysphonia 13 0.5 3 0 Epistaxis 7 0 1 0 Skin and subcutaneous tissue disorders PPES5 69 19 8 0 Alopecia 67 0 8 0 Rash 35 5 7 0 Pruritus 20 0.5 11 0 Dry skin 13 0.5 5 0 Erythema 10 0 0.5 0 Hyperkeratosis 7 0 0 0 Vascular disorders Hypertension6 41 10 12 2 1 National Cancer Institute Common Terminology Criteria for Adverse Events Version 3.0 2 Includes the following terms: abdominal pain, abdominal discomfort, hepatic pain, esophageal pain, esophageal discomfort, abdominal pain lower, abdominal pain upper, abdominal tenderness, abdominal rigidity 3 Includes the following terms: stomatitis, aphthous stomatitis, mouth ulceration, mucosal inflammation 4 Includes the following terms: oral pain, oropharyngeal discomfort, glossitis, burning mouth syndrome, glossodynia 5 Palmar-plantar erythrodysesthesia syndrome (Hand-foot skin reaction) 6 Includes the following terms: hypertension, blood pressure increased, blood pressure systolic increased Laboratory Abnormalities Elevated TSH levels are discussed elsewhere in the labeling [see Warnings and Precautions (5.12)]. The relative increase for the following laboratory abnormalities observed in NEXAVAR-treated DTC patients as compared to placebo-treated patients is similar to that observed in the RCC and HCC studies: lipase, amylase, hypokalemia, hypophosphatemia, neutropenia, lymphopenia, anemia, and thrombocytopenia [see Adverse Reactions (6.1, 6.2)]. Serum ALT and AST elevations were observed in 59% and 54% of the NEXAVAR-treated patients as compared to 24% and 15% of placebo-treated patients, respectively. High grade (≥ 3) ALT and AST elevations were observed in 4% and 2%, respectively, in the NEXAVAR-treated patients as compared to none of the placebo-treated patients. Hypocalcemia was more frequent and more severe in patients with DTC, especially those with a history of hypoparathyroidism, compared to patients with RCC or HCC. Hypocalcemia was observed in 36% of DTC patients receiving NEXAVAR (with 10% ≥ Grade 3) as compared with 11% of placebo-treated patients (3% ≥ Grade 3). In the DTC study, serum calcium levels were monitored monthly. 6.4 Additional Data from Multiple Clinical Trials The following additional drug-related adverse reactions and laboratory abnormalities were reported from clinical trials of NEXAVAR (very common 10% or greater, common 1 to less than 10%, uncommon 0.1% to less than 1%, rare less than 0.1 %): Cardiovascular: Common: congestive heart failure*†, myocardial ischemia and/or infarction Uncommon: hypertensive crisis* Rare: QT prolongation* Dermatologic: Very common: erythema Common: exfoliative dermatitis, acne, flushing, folliculitis, hyperkeratosis Uncommon: eczema, erythema multiforme Digestive: Very common: increased lipase, increased amylase Common: mucositis, stomatitis (including dry mouth and glossodynia), dyspepsia, dysphagia, gastrointestinal reflux Uncommon: pancreatitis, gastritis, gastrointestinal perforations*, cholecystitis, cholangitis Note that elevations in lipase are very common (41%, see below); a diagnosis of pancreatitis should not be made solely on the basis of abnormal laboratory values General Disorders: Very common: infection, hemorrhage (including gastrointestinal* and respiratory tract* and uncommon cases of cerebral hemorrhage*), asthenia, pain (including mouth, bone, and tumor pain), pyrexia, decreased appetite Common: influenza-like illness Hematologic: Very common: leukopenia, lymphopenia Common: anemia, neutropenia, thrombocytopenia Uncommon: INR abnormal Hepatobiliary disorders: Rare: drug-induced hepatitis (including hepatic failure and death) Hypersensitivity: Uncommon: hypersensitivity reactions (including skin reactions and urticaria), anaphylactic reaction Metabolic and Nutritional: Very common: hypophosphatemia Common: transient increases in transaminases, hypocalcemia, hypokalemia, hyponatremia, hypothyroidism Uncommon: dehydration, transient increases in alkaline phosphatase, increased bilirubin (including jaundice), hyperthyroidism Musculoskeletal: Very common: arthralgia Common: myalgia, muscle spasms Nervous System and Psychiatric: Common: depression, dysgeusia Uncommon: tinnitus, reversible posterior leukoencephalopathy* Renal and Genitourinary: Common: renal failure, proteinuria Rare: nephrotic syndrome Reproductive: Common: erectile dysfunction Uncommon: gynecomastia Respiratory: Common: rhinorrhea Uncommon: interstitial lung disease-like events (includes reports of pneumonitis, radiation pneumonitis, acute respiratory distress, interstitial pneumonia, pulmonitis and lung inflammation) In addition, the following medically significant adverse reactions were uncommon during clinical trials of NEXAVAR: transient ischemic attack, arrhythmia, and thromboembolism. For these adverse reactions, the causal relationship to NEXAVAR has not been established. *adverse reactions may have a life-threatening or fatal outcome. †reported in 1.9% of patients treated with NEXAVAR (N= 2276). 6.5 Postmarketing Experience The following adverse drug reactions have been identified during post-approval use of NEXAVAR. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Dermatologic: Stevens-Johnson syndrome and toxic epidermal necrolysis (TEN) Hypersensitivity: Angioedema Musculoskeletal: Rhabdomyolysis, osteonecrosis of the jaw Respiratory: Interstitial lung disease-like events (which may have a life-threatening or fatal outcome)

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION •400 mg (2 tablets) orally twice daily without food. (2.1) •Treatment interruption and/or dose reduction may be needed to manage suspected adverse drug reactions. (2.2) 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: •Cardiac ischemia or infarction [see Warnings and Precautions (5.1)] •Hemorrhage requiring medical intervention [see Warnings and Precautions (5.2)] •Severe or persistent hypertension despite adequate anti-hypertensive therapy [see Warnings and Precautions (5.3)] •Gastrointestinal perforation [see Warnings and Precautions (5.5)] •QTc prolongation [see Warnings and Precautions (5.9)] •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. Table 1: Suggested Dose Modifications for Dermatologic Toxicities in Patients with Hepatocellular or Renal Cell Carcinoma Dermatologic Toxicity Grade Occurrence Suggested Dose Modification Grade 1: Numbness, dysesthesia, paresthesia, tingling, painless swelling, erythema or discomfort of the hands or feet which does not disrupt the patient’s normal activities Any occurrence Continue treatment with NEXAVAR and consider topical therapy for symptomatic relief Grade 2: Painful erythema and swelling of the hands or feet and/or discomfort affecting the patient’s normal activities 1st occurrence Continue treatment with NEXAVAR and consider topical therapy for symptomatic relief If no improvement within 7 days, see below No improvement within 7 days or 2nd or 3rd occurrence Interrupt NEXAVAR treatment until toxicity resolves to Grade 0–1 When resuming treatment, decrease NEXAVAR dose by one dose level (400 mg daily or 400 mg every other day) 4th occurrence Discontinue NEXAVAR treatment Grade 3: Moist desquamation, ulceration, blistering or severe pain of the hands or feet, or severe discomfort that causes the patient to be unable to work or perform activities of daily living 1st or 2nd occurrence Interrupt NEXAVAR treatment until toxicity resolves to Grade 0–1 When resuming treatment, decrease NEXAVAR dose by one dose level (400 mg daily or 400 mg every other day) 3rd occurrence Discontinue NEXAVAR treatment Dose modifications for Differentiated Thyroid Carcinoma Table 2: Recommended Doses for Patients with Differentiated Thyroid Carcinoma Requiring Dose Reduction Dose Reduction NEXAVAR Dose First Dose Reduction 600 mg daily dose 400 mg and 200 mg 12 hours apart (2 tablets and 1 tablet 12 hours apart – either dose can come first) Second Dose Reduction 400 mg daily dose 200 mg twice daily (1 tablet twice daily) Third Dose Reduction 200 mg daily dose 200 mg once daily (1 tablet once daily) When dose reduction is necessary for dermatologic toxicities, reduce the NEXAVAR dose as indicated in Table 3 below. Table 3: Recommended Dose Modifications for Dermatologic Toxicities for Patients with Differentiated Thyroid Carcinoma Dermatologic Toxicity Grade Occurrence NEXAVAR Dose Modification Grade 1: Numbness, dysesthesia, paresthesia, tingling, painless swelling, erythema or discomfort of the hands or feet which does not disrupt the patient’s normal activities Any occurrence Continue treatment with NEXAVAR Grade 2: Painful erythema and swelling of the hands or feet and/or discomfort affecting the patient’s normal activities 1st occurrence Decrease NEXAVAR dose to 600 mg daily If no improvement within 7 days, see below No improvement within 7 days at reduced dose or 2nd occurrence Interrupt NEXAVAR until resolved or improved to grade 1 If NEXAVAR is resumed, decrease dose (see Table 2) 3rd occurrence Interrupt NEXAVAR until resolved or improved to grade 1 If NEXAVAR is resumed, decrease dose (see Table 2) 4th occurrence Discontinue NEXAVAR permanently 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 1st occurrence Interrupt NEXAVAR until resolved or improved to grade 1 If NEXAVAR is resumed, decrease dose by one dose level (see Table 2) 2nd occurrence Interrupt NEXAVAR until resolved or improved to grade 1 When NEXAVAR is resumed, decrease dose by 2 dose levels (see Table 2) 3rd occurrence Discontinue NEXAVAR permanently 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).
Use in special populations
8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D [see Warnings and Precautions (5.11)]. 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. There are no adequate and well-controlled studies in pregnant women using NEXAVAR. Inform patients of childbearing potential that NEXAVAR can cause birth defects or fetal loss. Instruct both men and women of childbearing potential to use effective birth control during treatment with NEXAVAR and for at least 2 weeks after stopping treatment. Counsel female patients to contact their healthcare provider if they become pregnant while taking NEXAVAR. When administered to rats and rabbits during the period of organogenesis, sorafenib was teratogenic and induced 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 ≥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) approximately 0.008 times the AUC seen in 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. 8.3 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. 8.4 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. 8.5 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. 8.6 Patients with Hepatic Impairment In a trial of HCC patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment, the systemic exposure (AUC) of sorafenib was within the range observed in patients without hepatic impairment. In another trial in subjects without HCC, the mean AUC was similar for subjects with mild (n=15) and moderate (n=14) hepatic impairment compared to subjects (n=15) with normal hepatic function. No dose adjustment is necessary for patients with mild or moderate hepatic impairment. The pharmacokinetics of sorafenib have not been studied in patients with severe (Child-Pugh C) hepatic impairment [see Clinical Pharmacology (12.3)]. 8.7 Patients with Renal Impairment No correlation between sorafenib exposure and renal function was observed following administration of a single oral dose of NEXAVAR 400 mg to subjects with normal renal function and subjects with mild (CLcr 50–80 mL/min), moderate (CLcr 30–<50 mL/min), or severe (CLcr <30 mL/min) renal impairment who are not on dialysis. No dose adjustment is necessary for patients with mild, moderate or severe renal impairment who are not on dialysis. The pharmacokinetics of sorafenib have not been studied in patients who are on dialysis [see Clinical Pharmacology (12.3)].
Pregnancy and lactation
8.3 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.

Interactions

7 DRUG INTERACTIONS •Avoid strong CYP3A4 inducers. (7.1) 7.1 Effect of Strong CYP3A4 Inducers on Sorafenib Rifampin, a strong CYP3A4 inducer, administered at a dose of 600 mg once daily for 5 days with a single oral dose of NEXAVAR 400 mg in healthy volunteers resulted in a 37% decrease in the mean AUC of sorafenib [see Clinical Pharmacology (12.3)]. Avoid concomitant use of strong CYP3A4 inducers (such as, carbamazepine, dexamethasone, phenobarbital, phenytoin, rifampin, rifabutin, St. John’s wort), when possible, because these drugs can decrease the systemic exposure to sorafenib. 7.2 Effect of Strong CYP3A4 Inhibitors on Sorafenib Ketoconazole, a strong inhibitor of CYP3A4 and P-glycoprotein, administered at a dose of 400 mg once daily for 7 days did not alter the mean AUC of a single oral dose of NEXAVAR 50 mg in healthy volunteers. 7.3 Effect of Sorafenib on Other Drugs NEXAVAR 400 mg twice daily for 28 days did not increase the systemic exposure of concomitantly administered midazolam (CYP3A4 substrate), dextromethorphan (CYP2D6 substrate), and omeprazole (CYP2C19 substrate) [see Clinical Pharmacology (12.3)]. 7.4 Neomycin Neomycin administered as an oral dose of 1 g three times daily for 5 days decreased the mean AUC of sorafenib by 54% in healthy volunteers administered a single oral dose of NEXAVAR 400 mg. The effects of other antibiotics on the pharmacokinetics of sorafenib have not been studied [see Clinical Pharmacology (12.3)]. 7.5 Drugs that Increase Gastric pH The aqueous solubility of sorafenib is pH dependent, with higher pH resulting in lower solubility. However, omeprazole, a proton pump inhibitor, administered at a dose of 40 mg once daily for 5 days, did not result in a clinically meaningful change in sorafenib single dose exposure. No dose adjustment for NEXAVAR is necessary.

More information

Category Value
Authorisation number NDA021923
Agency product number 9ZOQ3TZI87
Orphan designation No
Product NDC 50419-488
Date Last Revised 22-12-2017
Type HUMAN PRESCRIPTION DRUG
Marketing authorisation holder Bayer HealthCare Pharmaceuticals Inc.