Nexavar Side Effects

Generic Name: sorafenib

Please note - some side effects for Nexavar may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Side Effects of Nexavar - for the Consumer

Nexavar

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Nexavar:

Constipation; diarrhea; dry skin; hair thinning or loss; headache; loss of appetite; mouth, bone, muscle, stomach, or joint pain; nausea; tiredness; vomiting; weakness; weight loss.

Seek medical attention right away if any of these SEVERE side effects occur when using Nexavar:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue; unusual hoarseness); black, tarry stools; chest, jaw, or left arm pain; confusion; coughing or vomiting blood; decreased sexual ability; decreased urination; depression; fainting; fast or irregular heartbeat; fever, chills, or sore throat; mouth sores; numbness of an arm or leg; one-sided weakness; red, swollen, blistered, or peeling skin; redness, pain, swelling, numbness, tingling, ulcers, or blisters on the palms of hands or soles of feet; seizures; severe or persistent dizziness, headache, or light-headedness; severe stomach pain, vomiting, or nausea; shortness of breath; speech changes; sudden increased sweating; sudden weight gain; swelling of the ankles, hands, or feet; symptoms of liver problems (eg, dark urine, loss of appetite, pale stools, unusual tiredness, yellowing of the eyes or skin); unusual bruising or bleeding; unusual tiredness or weakness; vision changes; vomit that looks like coffee grounds.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

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Nexavar Side Effects - for the Professional

Nexavar

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.

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Side Effects by Body System - for Healthcare Professionals

Gastrointestinal

Gastrointestinal (GI) side effects including diarrhea (43%), increased lipase (41%), increased amylase (30%), nausea (23%), anorexia (16%), vomiting (16%), and constipation (15%) have been reported. Common side effects have included mucositis, stomatitis, (including dry mouth and glossodynia), dyspepsia, and dysphagia. Uncommon side effects have included pancreatitis, GI reflux, and gastritis. In addition, GI perforation has been reported in less than 1% of patients receiving sorafenib and not always associated with apparent intra- abdominal tumor.

Dermatologic

Dermatologic side effects including rash/desquamation (40%), Hand-foot skin reaction (30%), alopecia (27%), pruritus (19%), and dry skin (11%) have been reported. Very common side effects have included erythema. Common side effects have included exfoliative dermatitis, acne, and flushing. Scalp dysesthesia and subungual splinter hemorrhages (characterized by straight black or red lines under the nails) have been reported. Uncommon side effects have included folliculitis, eczema, Stevens-Johnson syndrome, and erythema multiforme. Three cases of keratoacanthomas and two cases of sorafenib-induced eruptive melanocytic lesions have been reported. Postmarketing reports of Stevens-Johnson syndrome and toxic epidermal necrolysis have been received.

Endocrine

Endocrine side effects have included hyperthyroidism.

Cardiovascular

Cardiovascular side effects including hypertension (17%), angioedema, and congestive heart failure have been reported. Uncommon side effects have included hypertensive crisis, myocardial ischemia, and/or infarction. Cardiac failure, thromboembolism, and arrhythmia have been reported infrequently.

Hematologic

Hematologic side effects including Hypoalbuminemia (49%), hemorrhage (15%) (i.e., gastrointestinal, respiratory tract and rarely cerebral hemorrhage) have been reported. Common side effects have included anemia and thrombocytopenia. Uncommon side effects have included abnormal international normalized ratio (INR) results. Cases of erythrocytosis have also been reported.

Respiratory

Respiratory side effects including dyspnea (14%) and cough (13%) have been reported. Common side effects have included hoarseness. Uncommon side effects have included rhinorrhea and interstitial lung disease-like events.

Nervous system

Nervous system side effects including sensory neuropathy (13%) and headache (10%) have been reported. Common side effects have included tinnitus. Cerebral hemorrhage, transient ischemic attack, and reversible posterior leukoencephalopathy have also been reported infrequently.

Musculoskeletal

Musculoskeletal side effects including joint pain (10%) have been reported. Common side effects have included arthralgia and myalgia.

Immunologic

Immunologic side effects have very commonly included leukopenia and lymphopenia. Common side effects have included neutropenia.

Hypersensitivity

Hypersensitivity side effects including skin reactions and urticaria have been reported. Postmarketing reports of angioedema and anaphylactic reaction have been received.

Metabolic

Metabolic side effects including weight loss (10%), transient increases in transaminases, and hypophosphatemia have been commonly reported. Uncommon side effects have included dehydration, hyponatremia, transient increases in alkaline phosphatase, increased bilirubin (including jaundice), and hypothyroidism.

Psychiatric

Psychiatric side effects have commonly included depression.

Genitourinary

Genitourinary side effects have commonly included erectile dysfunction. Uncommon side effects have included gynecomastia.

Renal

Renal side effects including acute renal failure have been reported infrequently.

Hepatic

Hepatic side effects including liver dysfunction have been reported in at least 10% of patients. Drug-induced hepatitis, including reports of hepatic failure and death, has been reported during postmarketing surveillance.

Other

Other side effects including fatigue (37%) and abdominal pain (11%) have been reported. Very common side effects have included asthenia and pain (including mouth, bone, and tumor pain). Common side effects have included decreased appetite, influenza-like illness, and pyrexia. Uncommon side effects have included infection.

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