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Nexavar (Sorafenib) - Side Effects and Adverse Reactions

 
 



ADVERSE REACTIONS

The following serious adverse reactions are discussed elsewhere in the labeling:

  • •Cardiac ischemia, infarction [see Warnings and Precautions ]
  • •Hemorrhage [see Warnings and Precautions]
  • •Hypertension [see Warnings and Precautions ]
  • •Hand-foot skin reaction, rash, Stevens-Johnson syndrome, and toxic epidermal necrolysis [see Warnings and Precautions]
  • •Gastrointestinal perforation [see Warnings and Precautions ]
  • •QT Interval Prolongation [see Warnings and Precautions and Clinical Pharmacology]
  • •Drug-Induced Hepatitis [see Warnings and Precautions ]
  • •Impairment of TSH suppression in DTC [see Warnings and Precautions]
  •  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.

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.

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.

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]. 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]. 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.

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).

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)



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: 2013-11-22

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