ADVERSE REACTIONS
Clinical Trials Experience
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.
Potentially serious adverse reactions with VOTRIENT included hepatotoxicity, QT prolongation and torsades de pointes, hemorrhagic events, arterial thrombotic events, and gastrointestinal perforation and fistula [see Warnings and Precautions (5.1-5.5)].
The safety of VOTRIENT has been evaluated in 977 patients in the monotherapy studies which included 586 patients with RCC. With a median duration of treatment of 7.4 months (range 0.1 to 27.6), the most commonly observed adverse reactions (≥20%) in the 586 patients were diarrhea, hypertension, hair color change, nausea, fatigue, anorexia, and vomiting.
The data described below reflect the safety profile of VOTRIENT in 290 RCC patients who participated in a randomized, double-blind, placebo-controlled study [see Clinical Studies]. The median duration of treatment was 7.4 months (range 0 to 23) for patients who received VOTRIENT and 3.8 months (range 0 to 22) for the placebo arm. Forty-two percent (42%) of patients on VOTRIENT required a dose interruption. Thirty-six percent (36%) of patients on VOTRIENT were dose reduced. Table 1 presents the most common adverse reactions occurring in ≥10% of patients who received VOTRIENT.
Table 1. Adverse Reactions Occurring in ≥10% of Patients who Received VOTRIENT
|
|
VOTRIENT
|
Placebo
|
|
|
(N = 290)
|
(N = 145)
|
|
|
All Gradesa
|
Grade 3
|
Grade 4
|
All Gradesa
|
Grade 3
|
Grade 4
|
|
Adverse Reactions
|
%
|
%
|
%
|
%
|
%
|
%
|
| Diarrhea |
52 |
3 |
<1 |
9 |
<1 |
0 |
| Hypertension |
40 |
4 |
0 |
10 |
<1 |
0 |
| Hair color changes |
38 |
<1 |
0 |
3 |
0 |
0 |
| Nausea |
26 |
<1 |
0 |
9 |
0 |
0 |
| Anorexia |
22 |
2 |
0 |
10 |
<1 |
0 |
| Vomiting |
21 |
2 |
<1 |
8 |
2 |
0 |
| Fatigue |
19 |
2 |
0 |
8 |
1 |
1 |
| Asthenia |
14 |
3 |
0 |
8 |
0 |
0 |
| Abdominal pain |
11 |
2 |
0 |
1 |
0 |
0 |
| Headache |
10 |
0 |
0 |
5 |
0 |
0 |
a National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.
Other adverse reactions observed more commonly in patients treated with VOTRIENT than placebo and that occurred in <10% (any grade) were alopecia (8% versus <1%), chest pain (5% versus 1%), dysgeusia (altered taste) (8% versus <1%), dyspepsia (5% versus <1%), facial edema (1% versus 0%), palmar-plantar erythrodysesthesia (hand-foot syndrome) (6% versus <1%), proteinuria (9% versus 0%), rash (8% versus 3%), skin depigmentation (3% versus 0%), and weight decreased (9% versus 3%).
Table 2 presents the most common laboratory abnormalities occurring in >10% of patients who received VOTRIENT and more commonly (≥5%) in patients who received VOTRIENT versus placebo.
Table 2. Selected Laboratory Abnormalities Occurring in >10% of Patients who Received VOTRIENT and More Commonly (≥5%) in Patients who Received VOTRIENT Versus Placebo
|
|
VOTRIENT
(N = 290)
|
Placebo
(N = 145)
|
|
|
All Grades
a
|
Grade 3
|
Grade 4
|
All Grades
a
|
Grade 3
|
Grade 4
|
|
Parameters
|
%
|
%
|
%
|
%
|
%
|
%
|
|
Hematologic
|
|
|
|
|
|
|
| Leukopenia |
37 |
0 |
0 |
6 |
0 |
0 |
| Neutropenia |
34 |
1 |
<1 |
6 |
0 |
0 |
| Thrombocytopenia |
32 |
<1 |
<1 |
5 |
0 |
<1 |
| Lymphocytopenia |
31 |
4 |
<1 |
24 |
1 |
0 |
|
Chemistry
|
|
|
|
|
|
|
| ALT increased |
53 |
10 |
2 |
22 |
1 |
0 |
| AST increased |
53 |
7 |
<1 |
19 |
<1 |
0 |
| Glucose increased |
41 |
<1 |
0 |
33 |
1 |
0 |
| Total bilirubin increased |
36 |
3 |
<1 |
10 |
1 |
<1 |
| Phosphorus decreased |
34 |
4 |
0 |
11 |
0 |
0 |
| Sodium decreased |
31 |
4 |
1 |
24 |
4 |
0 |
| Magnesium decreased |
26 |
<1 |
1 |
14 |
0 |
0 |
| Glucose decreased |
17 |
0 |
<1 |
3 |
0 |
0 |
a National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.
Hepatic Toxicity: In a controlled clinical study with VOTRIENT for the treatment of RCC, ALT >3 X ULN was reported in 18% and 3% of the VOTRIENT and placebo groups, respectively. ALT >10 X ULN was reported in 4% of patients who received VOTRIENT and in <1% of patients who received placebo. Concurrent elevation in ALT >3 X ULN and bilirubin >2 X ULN in the absence of significant alkaline phosphatase >3 X ULN occurred in 5/290 (2%) of patients on VOTRIENT and 2/145 (1%) on placebo. [See Dosage and Administration and Warnings and Precautions (5.1).]
Hypertension: In a controlled clinical study with VOTRIENT for the treatment of RCC, 115/290 patients (40%) receiving VOTRIENT compared with 15/145 patients (10%) on placebo experienced hypertension. Grade 3 hypertension was reported in 13/290 patients (4%) receiving VOTRIENT compared with 1/145 patients (<1%) on placebo. The majority of cases of hypertension were manageable with anti-hypertensive agents or dose reductions with 2/290 patients (<1%) permanently discontinuing treatment with VOTRIENT because of hypertension. In the overall safety population for RCC (N = 586), one patient had hypertensive crisis on VOTRIENT. [See Warnings and Precautions .]
QT Prolongation and Torsades de Pointes: In a controlled clinical study with VOTRIENT, QT prolongation (≥500 msec) was identified on routine electrocardiogram monitoring in 3/290 (1%) of patients treated with VOTRIENT compared with no patients on placebo. Torsades de pointes was reported in 2/586 (<1%) patients treated with VOTRIENT in the RCC studies. [See Warnings and Precautions .]
Arterial Thrombotic Events: In a controlled clinical study with VOTRIENT, the incidences of arterial thrombotic events such as myocardial infarction/ischemia [5/290 (2%)], cerebral vascular accident [1/290 (<1%)], and transient ischemic attack [4/290 (1%)] were higher in patients treated with VOTRIENT compared to the placebo arm (0/145 for each event). [See Warnings and Precautions .]
Hemorrhagic Events: In a controlled clinical study with VOTRIENT, 37/290 patients (13%) treated with VOTRIENT and 7/145 patients (5%) on placebo experienced at least 1 hemorrhagic event. The most common hemorrhagic events in the patients treated with VOTRIENT were hematuria (4%), epistaxis (2%), hemoptysis (2%), and rectal hemorrhage (1%). Nine (9/37) patients treated with VOTRIENT who had hemorrhagic events experienced serious events including pulmonary, gastrointestinal, and genitourinary hemorrhage. Four (4/290) (1%) patients treated with VOTRIENT died from hemorrhage compared with no (0/145) (0%) patients on placebo. [See Warnings and Precautions .] In the overall safety population in RCC (N = 586), cerebral/intracranial hemorrhage was observed in 2/586 (<1%) patients treated with VOTRIENT.
Hypothyroidism: In a controlled clinical study with VOTRIENT, more patients had a shift from thyroid stimulating hormone (TSH) within the normal range at baseline to above the normal range at any post-baseline visit in VOTRIENT compared with the placebo arm (27% compared with 5%, respectively). Hypothyroidism was reported as an adverse reaction in 19 patients (7%) treated with VOTRIENT and no patients (0%) in the placebo arm. [See Warnings and Precautions .]
Diarrhea: Diarrhea occurred frequently and was predominantly mild to moderate in severity. Patients should be advised how to manage mild diarrhea and to notify their healthcare provider if moderate to severe diarrhea occurs so appropriate management can be implemented to minimize its impact.
Proteinuria: In the controlled clinical study with VOTRIENT, proteinuria has been reported as an adverse reaction in 27 patients (9%) treated with VOTRIENT. In 2 patients, proteinuria led to discontinuation of treatment with VOTRIENT.
Lipase Elevations: In a single-arm clinical study, increases in lipase values were observed for 48/181 patients (27%). Elevations in lipase as an adverse reaction were reported for 10 patients (4%) and were Grade 3 for 6 patients and Grade 4 for 1 patient. In clinical RCC studies of VOTRIENT, clinical pancreatitis was observed in 4/586 patients (<1%).
Cardiac Dysfunction: Pazopanib has been associated with cardiac dysfunction (such as a decrease in ejection fraction and congestive heart failure) in patients with various cancer types, including RCC. In the overall safety population for RCC (N = 586), cardiac dysfunction was observed in 4/586 patients (<1%).
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