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Nexavar (Sorafenib) - Side Effects and Adverse Reactions

 
 



ADVERSE REACTIONS

The following risks are discussed in greater detail in the WARNINGS AND PRECAUTIONS section (5):

  • 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
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 9839696248
Constitutional symptoms
Fatigue469145122
Weight loss30201010
Dermatology/ Skin
Rash/ desquamation19101400
Pruritus14<1011<10
Hand-foot skin reaction21803<10
Dry skin1000600
Alopecia1400200
Gastrointestinal
Diarrhea5510<12520
Anorexia2930183<1
Nausea24102030
Vomiting15201120
Constipation14001000
Hepatobiliary/ pancreas
Liver dysfunction1121821
Pain
Pain, abdomen31902651

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

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 9531786226
Cardiovascular, General
Hypertension 173<12<10
Constitutional symptoms
Fatigue375<1283<1
Weight loss 10<10600
Dermatology/skin
Rash/desquamation40<1016<10
Hand-foot skin reaction 3060700
Alopecia27<10300
Pruritus 19<10600
Dry skin 1100400
Gastrointestinal symptoms
Diarrhea 432013<10
Nausea 23<1019<10
Anorexia 16<101310
Vomiting16<101210
Constipation 15<1011<10
Hemorrhage/bleeding
Hemorrhage – all sites 152081<1
Neurology
Neuropathy-sensory 13<106<10
Pain
Pain, abdomen 1120920
Pain, joint 10206<10
Pain, headache 10<106<10
Pulmonary
Dyspnea143<1122<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 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 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, Cholecystitis, cholangitis

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

*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.



REPORTS OF SUSPECTED NEXAVAR SIDE EFFECTS / ADVERSE REACTIONS

Below is a sample of reports where side effects / adverse reactions may be related to Nexavar. The information is not vetted and should not be considered as verified clinical evidence.

Possible Nexavar side effects / adverse reactions in 71 year old female

Reported by a physician from Japan on 2011-10-04

Patient: 71 year old female weighing 36.0 kg (79.2 pounds)

Reactions: Malaise, Heat Exhaustion

Adverse event resulted in: hospitalization

Suspect drug(s):
Nexavar



Possible Nexavar side effects / adverse reactions in 65 year old male

Reported by a physician from Japan on 2011-10-04

Patient: 65 year old male

Reactions: Ascites

Suspect drug(s):
Nexavar



Possible Nexavar side effects / adverse reactions in 59 year old male

Reported by a pharmacist from United States on 2011-10-04

Patient: 59 year old male

Reactions: Abdominal Pain, Dyspnoea, Nausea, Fatigue, Renal Impairment, Diarrhoea, Dehydration, Fluid Retention, Blister

Adverse event resulted in: hospitalization

Suspect drug(s):
Nexavar



See index of all Nexavar side effect reports >>

Drug label data at the top of this Page last updated: 2008-10-02

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