VOTRIENT SIDE EFFECTS
- Generic Name: pazopanib tablets
- Brand Name: Votrient
- Drug Class: Antineoplastics, VEGF Inhibitor, Antineoplastic Tyrosine Kinase Inhibitors
SIDE EFFECTS
The following serious adverse reactions are discussed in greater detail in other sections of the labeling:
- Hepatic Toxicity and Hepatic Impairment
- QT Prolongation and Torsades de Pointes
- Cardiac Dysfunction
- Hemorrhagic Events
- Arterial and Venous Thromboembolic Events
- Thrombotic Microangiopathy
- Gastrointestinal Perforation and Fistula
- Interstitial Lung Disease/Pneumonitis
- Reversible Posterior Leukoencephalopathy Syndrome
- Hypertension
- Hypothyroidism
- Proteinuria
- Tumor Lysis Syndrome
- Infection
- Increased Toxicity with Other Cancer Therapy
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 with rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Renal Cell Carcinoma
The safety of VOTRIENT has been evaluated in 977 patients in the monotherapy trials which included 586 patients with RCC at the time of NDA submission. With a median duration of treatment of 7.4 months (range, 0.1 to 27.6), the most commonly observed adverse reactions (greater than or equal to 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 trial.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 of patients on VOTRIENT required a dose interruption. Thirty-six percent of patients on VOTRIENT were dose reduced. Table 1 presents the most common adverse reactions occurring in greater than or equal to 10% of patients who received VOTRIENT.
Table 1: Adverse Reactions Occurring in Greater Than or Equal to 10% of Patients with RCC Who Received VOTRIENT
| Adverse Reactions | VOTRIENT (N = 290) |
Placebo (N = 145) |
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| All Gradesa % | Grade 3 % | Grade 4 % | All Gradesa % | Grade 3 % | Grade 4 % | |
| 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 |
| Abbreviation: RCC, renal cell carcinoma. a National Cancer Institute Common Terminology Criteria for Adverse Events, version 3. |
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Other adverse reactions observed more commonly in patients treated with VOTRIENT than placebo and that occurred in less than 10% (any grade) were alopecia (8% versus less than 1%), chest pain (5% versus 1%), dysgeusia (altered taste) (8% versus less than 1%), dyspepsia (5% versus less than 1%), dysphonia (4% versus less than 1%), facial edema (1% versus 0%), palmar-plantar erythrodysesthesia (hand-foot syndrome) (6% versus less than 1%), proteinuria (9% versus 0%), rash (8% versus 3%), skin depigmentation (3% versus 0%), and weight decreased (9% versus 3%).
Additional adverse reactions from other clinical trials in RCC patients treated with VOTRIENT are listed below:
Musculoskeletal and Connective Tissue Disorders: Arthralgia, muscle spasms.
Table 2 presents the most common laboratory abnormalities occurring in greater than 10% of patients who received VOTRIENT and more commonly (greater than or equal to 5%) in patients who received VOTRIENT versus placebo.
Table 2: Selected Laboratory Abnormalities Occurring in Greater Than 10% of Patients with RCC Who Received VOTRIENT and More Commonly (Greater Than or Equal to 5%) in Patients Who Received VOTRIENT Versus Placebo
| Parameters | VOTRIENT (N = 290) |
Placebo (N = 145) |
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| All Gradesa % | Grade 3 % | Grade 4 % | All Gradesa % | Grade 3 % | Grade 4 % | |
| 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 |
| Abbreviation: ALT, alanine aminotransferase; AST, aspartate aminotransferase; RCC, renal cell carcinoma. a National Cancer Institute Common Terminology Criteria for Adverse Events, version 3. |
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Soft Tissue Sarcoma
The safety of VOTRIENT has been evaluated in 382 patients with advanced soft tissue sarcoma, with a median duration of treatment of 3.6 months (range, 0 to 53). The most commonly observed adverse reactions (greater than or equal to 20%) in the 382 patients were fatigue, diarrhea, nausea, decreased weight, hypertension, decreased appetite, vomiting, tumor pain, hair color changes, musculoskeletal pain, headache, dysgeusia, dyspnea, and skin hypopigmentation.
The data described below reflect the safety profile of VOTRIENT in 240 patients who participated in a randomized, double-blind, placebo-controlled trial.The median duration of treatment was 4.5 months (range, 0 to 24) for patients who received VOTRIENT and 1.9 months (range, 0 to 24) for the placebo arm. Fifty-eight percent of patients on VOTRIENT required a dose interruption. Thirty-eight percent of patients on VOTRIENT had their dose reduced. Seventeen percent of patients who received VOTRIENT discontinued therapy due to adverse reactions. Table 3 presents the most common adverse reactions occurring in greater than or equal to 10% of patients who received VOTRIENT.
Table 3: Adverse Reactions Occurring in Greater Than or Equal to 10% of Patients with STS Who Received VOTRIENT
| Adverse Reactions | VOTRIENT (N = 240) |
Placebo (N = 123) |
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| All Gradesa % | Grade 3 % | Grade 4 % | All Gradesa % | Grade 3 % | Grade 4 % | |
| Fatigue | 65 | 13 | 1 | 48 | 4 | 1 |
| Diarrhea | 59 | 5 | 0 | 15 | 1 | 0 |
| Nausea | 56 | 3 | 0 | 22 | 2 | 0 |
| Weight decreased | 48 | 4 | 0 | 15 | 0 | 0 |
| Hypertension | 42 | 7 | 0 | 6 | 0 | 0 |
| Appetite decreased | 40 | 6 | 0 | 19 | 0 | 0 |
| Hair color changes | 39 | 0 | 0 | 2 | 0 | 0 |
| Vomiting | 33 | 3 | 0 | 11 | 1 | 0 |
| Tumor pain | 29 | 8 | 0 | 21 | 7 | 2 |
| Dysgeusia | 28 | 0 | 0 | 3 | 0 | 0 |
| Headache | 23 | 1 | 0 | 8 | 0 | 0 |
| Musculoskeletal pain | 23 | 2 | 0 | 20 | 2 | 0 |
| Myalgia | 23 | 2 | 0 | 9 | 0 | 0 |
| Gastrointestinal pain | 23 | 3 | 0 | 9 | 4 | 0 |
| Dyspnea | 20 | 5 | < 1 | 17 | 5 | 1 |
| Exfoliative rash | 18 | < 1 | 0 | 9 | 0 | 0 |
| Cough | 17 | < 1 | 0 | 12 | < 1 | 0 |
| Peripheral edema | 14 | 2 | 0 | 9 | 2 | 0 |
| Mucositis | 12 | 2 | 0 | 2 | 0 | 0 |
| Alopecia | 12 | 0 | 0 | 1 | 0 | 0 |
| Dizziness | 11 | 1 | 0 | 4 | 0 | 0 |
| Skin disorderb | 11 | 2 | 0 | 1 | 0 | 0 |
| Skin hypopigmentation | 11 | 0 | 0 | 0 | 0 | 0 |
| Stomatitis | 11 | < 1 | 0 | 3 | 0 | 0 |
| Chest pain | 10 | 2 | 0 | 6 | 0 | 0 |
| Abbreviation: STS, soft tissue sarcoma. a National Cancer Institute Common Terminology Criteria for Adverse Events, version 3. b 27 of the 28 cases of skin disorder were palmar-plantar erythrodysesthesia. |
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Other adverse reactions observed more commonly in patients treated with VOTRIENT that occurred in greater than or equal to 5% of patients and at an incidence of more than 2% difference from placebo included insomnia (9% versus 6%), hypothyroidism (8% versus 0%), dysphonia (8% versus 2%), epistaxis (8% versus 2%), left ventricular dysfunction (8% versus 4%), dyspepsia (7% versus 2%), dry skin (6% versus less than 1%), chills (5% versus 1%), vision blurred (5% versus 2%), and nail disorder (5% versus 0%).
Table 4 presents the most common laboratory abnormalities occurring in greater than 10% of patients who received VOTRIENT and more commonly (greater than or equal to 5%) in patients who received VOTRIENT versus placebo.
Table 4: Selected Laboratory Abnormalities Occurring in Greater Than 10% of Patients with STS Who Received VOTRIENT and More Commonly (≥ 5%) in Patients Who Received VOTRIENT Versus Placebo
| Parameters | VOTRIENT (N = 240) |
Placebo (N = 123) |
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| All Gradesa % | Grade 3 % | Grade 4 % | All Gradesa % | Grade 3 % | Grade 4 % | |
| Hematologic | ||||||
| Leukopenia | 44 | 1 | 0 | 15 | 0 | 0 |
| Lymphocytopeni a | 43 | 10 | 0 | 36 | 9 | 2 |
| Thrombocytopeni a | 36 | 3 | 1 | 6 | 0 | 0 |
| Neutropenia | 33 | 4 | 0 | 7 | 0 | 0 |
| Chemistry | ||||||
| AST increased | 51 | 5 | 3 | 22 | 2 | 0 |
| ALT increased | 46 | 8 | 2 | 18 | 2 | 1 |
| Glucose increased | 45 | < 1 | 0 | 35 | 2 | 0 |
| Albumin decreased | 34 | 1 | 0 | 21 | 0 | 0 |
| Alkaline phosphatase increased | 32 | 3 | 0 | 23 | 1 | 0 |
| Sodium decreased | 31 | 4 | 0 | 20 | 3 | 0 |
| Total bilirubin increased | 29 | 1 | 0 | 7 | 2 | 0 |
| Potassium increased | 16 | 1 | 0 | 11 | 0 | 0 |
| Abbreviation: ALT, alanine aminotransferase; AST, aspartate aminotransferase; STS, soft tissue sarcoma. a National Cancer Institute Common Terminology Criteria for Adverse Events, version 3. |
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Diarrhea
Diarrhea occurred frequently and was predominantly mild-to-moderate in severity in both the RCC and STS clinical trials. 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.
Lipase Elevations
In a single-arm RCC trial, increases in lipase values were observed for 27% (48/181) of patients. Elevations in lipase as an adverse reaction were reported for 4% (10/225) of patients and were Grade 3 for 6 patients and Grade 4 for 1 patient. In the RCC trials of VOTRIENT, clinical pancreatitis was observed in less than 1% (4/586) of patients.
Pneumothorax
Two of 290 patients treated with VOTRIENT and no patient on the placebo arm in the randomized RCC trial developed a pneumothorax. In the randomized trial of VOTRIENT for the treatment of STS, pneumothorax occurred in 3% (8/240) of patients treated with VOTRIENT and in no patients on the placebo arm.
Bradycardia
In the randomized trial of VOTRIENT for the treatment of RCC, bradycardia based on vital signs (less than 60 beats per minute) was observed in 19% (52/280) of patients treated with VOTRIENT and in 11% (16/144) of patients on the placebo arm. Bradycardia was reported as an adverse reaction in 2% (7/290) of patients treated with VOTRIENT compared with less than 1% (1/145) of patients treated with placebo. In the randomized trial of VOTRIENT for the treatment of STS, bradycardia based on vital signs (less than 60 beats per minute) was observed in 19% (45/238) of patients treated with VOTRIENT and in 4% (5/121) of patients on the placebo arm. Bradycardia was reported as an adverse reaction in 2% (4/240) of patients treated with VOTRIENT compared with less than 1% (1/123) of patients treated with placebo.
Adverse Reactions In East Asian Patients
In an analysis of pooled clinical trials (N = 1938) with VOTRIENT, Grade 3 and Grade 4 adverse reactions were observed more frequently in patients of East Asian descent than in patients of non-East Asian descent for neutropenia (12% versus 2%), thrombocytopenia (6% versus less than 1%), and palmar-plantar erythrodysethesia syndrome (6% versus 2%).
Postmarketing Experience
The following adverse reactions have been identified during post-approval use of VOTRIENT. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure.
Blood and Lymphatic System Disorders: Polycythemia
Eye Disorders: Retinal detachment/tear
Gastrointestinal Disorders: Pancreatitis
Metabolic and Nutrition Disorder: Tumor Lysis Syndrome (including fatal cases).
Vascular Disorders: Arterial (including aortic) aneurysms, dissections, and rupture.
SRC: NLM .