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 | 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 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 | 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 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.
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