Nexavar

sorafenib

Dosage Form: tablet, film coated
FULL PRESCRIBING INFORMATION

Indications and Usage for Nexavar

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).

Nexavar Dosage and Administration

The recommended daily dose of Nexavar is 400 mg (2 x 200 mg tablets) taken twice daily without food (at least 1 hour before or 2 hours after a meal). Treatment should continue until the patient is no longer clinically benefiting from therapy or until unacceptable toxicity occurs.

Management of suspected adverse drug reactions may require temporary interruption and/or dose reduction of Nexavar. When dose reduction is necessary, the Nexavar dose may be reduced to 400 mg once daily. If additional dose reduction is required, Nexavar may be reduced to a single 400 mg dose every other day [see Warnings and Precautions (5)].

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

Table 1: Suggested Dose Modifications for Skin Toxicity

Skin 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

No dose adjustment is required on the basis of patient age, gender, or body weight.

Concomitant strong CYP3A4 inducers: Avoid concomitant use of strong CYP3A4 inducers (such as, carbamazepine, dexamethasone, phenobarbital, phenytoin, rifampin, rifabutin, St. John’s wort), when possible, because inducers can decrease the systemic exposure to sorafenib [see Drug Interactions (7.1)].

 

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.

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)].

Warnings and Precautions

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

Monitor blood pressure weekly during the first 6 weeks of Nexavar. Thereafter, monitor blood pressure and treat hypertension, if required, in accordance with standard medical practice. In the HCC study, hypertension was reported in approximately 9.4% of Nexavar-treated patients and 4.3% of patients in the placebo 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, consider temporary or permanent discontinuation of Nexavar. 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 patients with HCC and 3 of 451 Nexavar patients with RCC.

Risk of Gastrointestinal Perforation

Gastrointestinal perforation is an uncommon adverse reaction and has been reported in less than 1% of patients taking Nexavar. In some cases this was not associated with apparent intra-abdominal tumor. In the event of a gastrointestinal perforation, discontinue Nexavar.

Warfarin

Infrequent bleeding or elevations in the International Normalized Ratio (INR) have been reported in some patients taking warfarin while on Nexavar. Monitor patients taking concomitant warfarin regularly for changes in prothrombin time (PT), INR or clinical bleeding episodes.

Wound Healing Complications

No formal studies of the effect of Nexavar on wound healing have been conducted. Temporary interruption of Nexavar is recommended in patients undergoing major surgical procedures. There is limited clinical experience regarding the timing of reinitiation of Nexavar following major surgical intervention. Therefore, the decision to resume Nexavar following a major surgical intervention should be based on clinical judgment of adequate wound healing.

Increased Mortality Observed with Nexavar Administered in Combination with Carboplatin/Paclitaxel and Gemcitabine/Cisplatin in Squamous Cell Lung Cancer

In a subset analysis of two randomized controlled trials in chemo-naive patients with Stage IIIB-IV non-small cell lung cancer, patients with squamous cell carcinoma experienced higher mortality with the addition of sorafenib compared to those treated with carboplatin/paclitaxel alone (HR 1.81, 95% CI 1.19–2.74) and gemcitabine/ cisplatin alone (HR 1.22, 95% CI 0.82-1.80). The use of sorafenib in combination with carboplatin/paclitaxel is contraindicated in patients with squamous cell lung cancer. Sorafenib in combination with gemcitabine/cisplatin is not recommended in patients with squamous cell lung cancer. The safety and effectiveness of Nexavar has not been established in patients with non-small cell lung cancer.

Risk of QT Interval Prolongation

 Nexavar can prolong the QT/QTc interval. QT/QTc interval prolongation increases the risk for ventricular arrhythmias.  Avoid Nexavar in patients with congenital long QT syndrome. Monitor patients with congestive heart failure, bradyarrhythmias, drugs known to prolong the QT interval, including Class Ia and III antiarrhythmics, and electrolyte abnormalities with on-treatment electrocardiograms and electrolytes (magnesium, potassium, calcium) [see Clinical Pharmacology (12.2)].

Risk of Fetal Harm

There are no adequate and well-controlled studies in pregnant women using Nexavar. However, based on its mechanism of action and findings in animals, Nexavar may cause fetal harm when administered to a pregnant woman.  Sorafenib caused embryo-fetal toxicities in animals at maternal exposures that were significantly lower than the human exposures at the recommended dose of 400 mg twice daily. Advise women of childbearing potential to avoid becoming pregnant while on Nexavar because of the potential hazard to the fetus [see Use in Specific Populations (8.1)] .

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 and rash [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)]

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data described in sections 6.1 and 6.2 reflect exposure to Nexavar in 748 patients who participated in placebo controlled studies in hepatocellular carcinoma (N=297) or advanced renal cell carcinoma (N=451).

The most common adverse reactions (≥20%), which were considered to be related to Nexavar, in patients with HCC or RCC are fatigue, weight loss, rash/desquamation, hand-foot skin reaction, alopecia, diarrhea, anorexia, nausea and abdominal pain.

Adverse Reactions in HCC Study

Table 2 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 2 Adverse Reactions Reported in at Least 10% of Patients and at a Higher Rate in Nexavar Arm than the Placebo Arm – HCC Study

	Nexavar			Placebo
	N=297			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 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 patients with HCC:

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 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 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

	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 groups (10% of Nexavar patients and 8% of placebo 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 patients. CTCAE Grade 3 hypophosphatemia (1–2 mg/dL) occurred in 13% of Nexavar-treated patients and 3% of patients in the placebo group. There were no cases of CTCAE Grade 4 hypophosphatemia (<1 mg/dL) reported in either Nexavar or placebo patients. The etiology of hypophosphatemia associated with Nexavar is not known.

Elevated lipase was observed in 41% of patients treated with Nexavar compared to 30% of patients in the placebo group. CTCAE Grade 3 or 4 lipase elevations occurred in 12% of patients in the Nexavar group compared to 7% of patients in the placebo group. Elevated amylase was observed in 30% of patients treated with Nexavar compared to 23% of patients in the placebo group. CTCAE Grade 3 or 4 amylase elevations were reported in 1% of patients in the Nexavar group compared to 3% of patients in the placebo group. Many of the lipase and amylase elevations were transient, and in the majority of cases Nexavar treatment was not interrupted. Clinical pancreatitis was reported in 3 of 451 Nexavar-treated patients (one CTCAE Grade 2 and two Grade 4) and 1 of 451 patients (CTCAE Grade 2) in the placebo group.

Lymphopenia was observed in 23% of Nexavar-treated patients and 13% of placebo patients. CTCAE Grade 3 or 4 lymphopenia was reported in 13% of Nexavar-treated patients and 7% of placebo patients. Neutropenia was observed in 18% of Nexavar-treated patients and 10% of placebo patients. CTCAE Grade 3 or 4 neutropenia was reported in 5% of Nexavar-treated patients and 2% of placebo patients.

Anemia was observed in 44% of Nexavar-treated patients and 49% of placebo patients. CTCAE Grade 3 or 4 anemia was reported in 2% of Nexavar-treated patients and 4% of placebo patients.

Thrombocytopenia was observed in 12% of Nexavar-treated patients and 5% of placebo patients. CTCAE Grade 3 or 4 thrombocytopenia was reported in 1% of Nexavar-treated patients and 0% of placebo patients.

Additional Data from Multiple Clinical Trials

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

Cardiovascular:Common: congestive heart failure*†, myocardial ischemia and/or infarction Uncommon: hypertensive crisis* Rare: QT prolongation*

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*, cholecystitis, cholangitis

Note that elevations in lipase are very common (41%, see below); a diagnosis of pancreatitis should not be made solely on the basis of abnormal laboratory values

General Disorders:Very common: hemorrhage (including gastrointestinal* & respiratory tract* and uncommon cases of cerebral hemorrhage*), asthenia, pain (including mouth, bone, and tumor pain) Common: decreased appetite, influenza-like illness, pyrexia Uncommon: infection

Hematologic:Very common: leukopenia, lymphopenia Common: anemia, neutropenia, thrombocytopenia Uncommon: INR abnormal

Hypersensitivity:Uncommon: hypersensitivity reactions (including skin reactions and urticaria)

Metabolic and Nutritional:Very common: hypophosphatemia Common: transient increases in transaminases Uncommon: dehydration, hyponatremia, transient increases in alkaline phosphatase, increased bilirubin (including jaundice), hypothyroidism, hyperthyroidism

Musculoskeletal:Common: arthralgia, myalgia

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

Renal and Genitourinary: Common: renal failure

Reproductive:Common: erectile dysfunction Uncommon: gynecomastia

Respiratory:Common: hoarseness Uncommon: rhinorrhea, interstitial lung disease-like events (includes reports of pneumonitis, radiation pneumonitis, acute respiratory distress, interstitial pneumonia, pulmonitis and lung inflammation)

In addition, the following medically significant adverse reactions were uncommon during clinical trials of Nexavar: transient ischemic attack, arrhythmia, thromboembolism. For these adverse reactions, the causal relationship to Nexavar has not been established.

*adverse reactions may have a life-threatening or fatal outcome.

†reported in 1.9% of patients treated with sorafenib (N= 2276).

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, anaphylactic reaction

Hepatobiliary disorders: Drug-induced hepatitis, including reports of hepatic failure and death.

Drug Interactions

Drug Metabolism

Effect of Cytochrome P450 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.  Other inducers of CYP3A4 activity (such as, carbamazepine, dexamethasone, phenobarbital, phenytoin, rifabutin, rifampin, St. John's wort) can increase the metabolism of sora