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Pazopanib is a brand name for Pazopanib. The medicine, its uses, side effects and dosage are the same regardless of brand.
Used for: 1 INDICATIONS AND USAGE Pazopanib tablets are a kinase inhibitor indicated for the treatment of adults with: advanced renal cell carcinoma (RCC). ( 1.1 ) advanced soft tissue sarcoma (STS) who have received prior chemotherapy. ( 1.2 ) Limitations of Use: The efficacy of pazopanib tablets for the treatment of patients…
Verbatim from this product's FDA label. Tap a section to expand.
2 DOSAGE AND ADMINISTRATION Recommended Dosage: 800 mg orally once daily without food (at least 1 hour before or 2 hours after a meal). 1 ) Moderate Hepatic Impairment: 200 mg orally once daily. 3 )]. 4 )]. Swallow tablets whole. 3 )]. If a dose is missed, it should not be taken if it is <12 hours until the next dose.
2 Dosage Modifications for Adverse Reactions Table 1 summarizes the recommended dose reductions. Table 1. Recommended Dose Reductions of Pazopanib tablets for Adverse Reactions Dose Reduction For Renal Cell Carcinoma For Soft Tissue Sarcoma First 400 mg orally once daily 600 mg orally once daily Second 200 mg orally once daily 400 mg orally once daily Permanently discontinue pazopanib tablets in patients unable to tolerate the second dose reduction.
Table 2 summarizes the recommended dosage modifications for adverse reactions. Table 2. 1 )] Isolated ALT elevations between 3 x ULN and 8 x ULN Continue and monitor liver function weekly until ALT returns to Grade 1 or baseline. Isolated ALT elevations of > 8 x ULN Withhold until improvement to Grade 1 or baseline.
If the potential benefit for resuming treatment with pazopanib tablets is considered to outweigh the risk for hepatotoxicity, then resume at a reduced dose of no more than 400 mg once daily and measure serum liver tests weekly for 8 weeks.
Permanently discontinue if ALT elevations > 3 x ULN recur despite dose reduction(s). ALT elevations > 3 x ULN occur concurrently with bilirubin elevations > 2 x ULN Permanently discontinue and continue to monitor until resolution. Patients with only a mild, indirect (unconjugated) hyperbilirubinemia, known as Gilbert's syndrome, and ALT elevations > 3 x ULN should be managed per the recommendations outlined for isolated ALT elevations.
3 )] Symptomatic or Grade 3 Withhold until improvement to Grade < 3. Resume treatment based on medical judgement. Grade 4 Permanently discontinue. 4 )] Grade 2 Withhold until improvement to Grade ≤ 1. Resume at reduced dose (see Table 1).
Permanently discontinue if Grade 2 recurs after dose interruption and reduction. Grade 3 or 4 Permanently discontinue. 5 )] Any grade Permanently discontinue. 6 )] Grade 3 Withhold pazopanib tablets and resume at same dose if managed with appropriate therapy for at least one week.
Grade 4 Permanently discontinue. 7 ) ] Any grade Permanently discontinue. 8 )] Any grade Permanently discontinue. 8 ) ] Grade 2 or 3 Withhold and resume based on medical judgement. Grade 4 Permanently discontinue. 9 )] Any grade Permanently discontinue.
16 )] The most common adverse reactions in patients with RCC (≥ 20%) are diarrhea, hypertension, hair color changes (depigmentation), nausea, anorexia, and vomiting. 1 ) The most common adverse reactions in patients with STS (≥ 20%) are fatigue, diarrhea, nausea, decreased weight, hypertension, decreased appetite, vomiting, tumor pain, hair color changes, musculoskeletal pain, headache, dysgeusia, dyspnea, and skin hypopigmentation.
1 ) To report SUSPECTED ADVERSE REACTIONS, contact Apotex Corp. gov/medwatch. 1 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.
The data described in the WARNINGS AND PRECAUTIONS section reflect exposure of 977 patients who received pazopanib tablets as a single agent, including 586 pazopanib-treated patients with RCC. 6) in these 977 patients, the most common adverse reactions (≥ 20%) in these 586 patients were diarrhea, hypertension, hair color change, nausea, fatigue, anorexia, and vomiting.
6 months (range, 0 to 53). The most common adverse reactions (≥ 20%) in these 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.
1 ). 4 months (range, 0 to 23) for patients who received pazopanib tablets. Forty-two percent of patients on pazopanib tablets required a dose interruption and 36% required a dose reduction. Table 3 presents adverse reactions in VEG105192.
Table 3. Adverse Reactions (≥ 10%) in Patients with RCC Who Received Pazopanib Tablets in VEG105192 Adverse Reactions Pazopanib Tablets (N = 290) Placebo (N = 145) All Grades a Grade 3 Grade 4 All Grades a 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.
5 WARNINGS AND PRECAUTIONS Hepatic Toxicity: Severe and fatal hepatotoxicity has occurred. Monitor liver tests at baseline, regularly during treatment and as clinically indicated. Withhold pazopanib tablets and resume at reduced dose with continued weekly monitoring for 8 weeks, or permanently discontinue with weekly monitoring until resolution based on severity of hepatotoxicity.
1 ) QT Prolongation and Torsades de Pointes: Monitor patients who are at significant risk of developing QT interval prolongation. Monitor electrocardiograms (ECGs) and electrolytes at baseline and as clinically indicated. Correct hypokalemia, hypomagnesemia, and hypocalcemia prior to initiating pazopanib tablets and during treatment.
2 ) Cardiac Dysfunction: Cardiac dysfunction, including decreased left ventricular ejection fraction (LVEF) and congestive heart failure, have occurred. Monitor blood pressure and manage as appropriate. Monitor for clinical signs or symptoms of congestive heart failure.
Conduct baseline and periodic evaluation of LVEF in patients at risk of cardiac dysfunction. Withhold or permanently discontinue pazopanib tablets based on severity of cardiac dysfunction. 3 ) Hemorrhagic Events: Fatal hemorrhagic events have occurred.
Pazopanib tablets have not been studied in patients who have a history of hemoptysis, cerebral hemorrhage, or clinically significant gastrointestinal hemorrhage in the past 6 months. Withhold pazopanib tablets and resume at reduced dose or permanently discontinue based on severity of hemorrhagic events.
4 ) Arterial Thromboembolic Events: Arterial thromboembolic events have been observed and can be fatal. Pazopanib tablets have not been studied in patients who have had an arterial thromboembolic event within the previous 6 months. Permanently discontinue pazopanib tablets in case of an arterial thromboembolic event.
4 CONTRAINDICATIONS None. None. ( 4 )
Not medical advice. Always read the patient information leaflet and follow your prescriber or pharmacist.
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10 )] Any grade Permanently discontinue. 11 )] Grade 2 or 3 Reduce dose (see Table 1) and initiate or adjust anti-hypertensive therapy. Permanently discontinue if hypertension remains Grade 3 despite dose reduction(s) and adjustment of anti-hypertensive therapy.
Grade 4 or hypertensive crisis Permanently discontinue. 14 )] 24-hour urine protein ≥ 3 grams Confirmed nephrotic syndrome Withhold until improvement to Grade ≤ 1. Resume at a reduced dose (see Table 1). Permanently discontinue if 24-hour urine protein ≥ 3 grams does not improve or recurs despite dose reductions.
Permanently discontinue.
Abbreviations:
ALT, alanine aminotransferase; ULN, upper limit of normal. a National Cancer Institute Common Terminology Criteria for Adverse Events, version 5. 5 to 3 x upper limit of normal (ULN) and any alanine aminotransferase (ALT) value], consider alternatives to pazopanib tablets.
If pazopanib tablets are used in patients with moderate hepatic impairment, reduce the pazopanib tablets dose to 200 mg orally once daily. 7 )). 4 Dosage Modifications for Drug Interactions Strong CYP3A4 Inhibitors Avoid concomitant use of strong CYP3A4 inhibitors by use of an alternate concomitant medication with no or minimal potential to inhibit CYP3A4.
1 )]. Strong CYP3A4 Inducers Avoid concomitant use of strong CYP3A4 inducers by use of an alternate concomitant medication with no or minimal enzyme induction potential. 1 )]. Gastric Acid-Reducing Agents Avoid concomitant use of gastric acid-reducing agents.
If concomitant use of a gastric acid-reducing agent cannot be avoided, consider short-acting antacid in place of proton pump inhibitors (PPIs) and H 2 -receptor antagonists. 3 )].
a National Cancer Institute Common Terminology Criteria for Adverse Events, version 3. Other adverse reactions observed more commonly in patients treated with pazopanib tablets than placebo and that occurred in < 10% (any grade) were alopecia (8% versus < 1%), chest pain (5% versus 1%), dysgeusia (8% versus < 1%), dyspepsia (5% versus < 1%), dysphonia (4% versus < 1%), facial edema (1% versus 0%), palmar-plantar erythrodysesthesia (6% versus < 1%), proteinuria (9% versus 0%), rash (8% versus 3%), skin depigmentation (3% versus 0%), and weight decreased (9% versus 3%).
Table 4 presents the laboratory abnormalities in VEG105192. Table 4. Select Laboratory Abnormalities (> 10%) in Patients with RCC Who Received Pazopanib Tablets with a Difference Between Arms of ≥ 5% Compared to Placebo in VEG105192 Parameters Pazopanib Tablets (N = 290) Placebo (N = 145) All Grades a Grade 3 Grade 4 All Grades a Grade 3 Grade 4 % % % % % % 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 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 Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; RCC, renal cell carcinoma.
a National Cancer Institute Common Terminology Criteria for Adverse Events, version 3. Additional adverse reactions from other clinical trials in patients with RCC who received pazopanib tablets include arthralgia and muscle spasms.
2 )]. 5 months (range, 0 to 24) for patients who received pazopanib tablets. Fifty-eight percent of patients on pazopanib tablets required a dose interruption and 38% required a dose reduction. Seventeen percent of patients who received pazopanib tablets discontinued therapy due to adverse reactions.
Table 5 presents the adverse reactions in VEG110727. Table 5. Adverse Reactions (≥ 10%) in Patients with STS Who Received Pazopanib Tablets in VEG110727 Adverse Reactions Pazopanib Tablets (N = 240) Placebo (N = 123) All Grades a Grade 3 Grade 4 All Grades a 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 disorder b 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. Other adverse reactions observed more commonly in patients treated with pazopanib tablets that occurred in ≥ 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 < 1%), chills (5% versus 1%), vision blurred (5% versus 2%), and nail disorder (5% versus 0%).
Table 6 presents the laboratory abnormalities in VEG110727. Table 6. Select Laboratory Abnormalities (> 10%) in Patients with STS Who Received Pazopanib Tablets with a Difference Between Arms of ≥ 5% Compared to Placebo in VEG110727 Parameters Pazopanib Tablets (N = 240) Placebo (N = 123) All Grades a Grade 3 Grade 4 All Grades a Grade 3 Grade 4 % % % % % % 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 phosphataseincreased 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 Hematologic Leukopenia 44 1 0 15 0 0 Lymphocytopenia 43 10 0 36 9 2 Thrombocytopenia 36 3 1 6 0 0 Neutropenia 33 4 0 7 0 0 Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; STS, soft tissue sarcoma.
a National Cancer Institute Common Terminology Criteria for Adverse Events, version 3 Other Clinically Relevant Adverse Reactions Lipase Elevations In a single-arm RCC trial (VEG102616), elevated lipase was observed for 27% of 181 patients with available laboratory data.
4% (1/225) with Grade 4. In the RCC trials, clinical pancreatitis was observed in < 1% of 586 patients. 3%) treated with pazopanib tablets in the randomized STS trial (VEG110727) developed a pneumothorax. Bradycardia In the randomized RCC trial (VEG105192), bradycardia based on vital signs (< 60 beats per minute) was observed in 19% of 280 patients treated with pazopanib tablets.
Bradycardia was reported as an adverse reaction in 2% of 290 patients. In the randomized STS trial (VEG110727), bradycardia based on vital signs (< 60 beats per minute) was observed in 19% of 238 patients treated with pazopanib tablets.
Bradycardia was reported as an adverse reaction in 2% of 240 patients. Adverse Reactions in East Asian Patients In an analysis of pooled clinical trial data (N = 1,938) with pazopanib tablets, Grade 3 and Grade 4 neutropenia (12% versus 2%), thrombocytopenia (6% versus < 1%) and palmar-plantar erythrodysesthesia (6% versus 2%) were observed more frequently in patients of East Asian descent than in patients of non-East Asian descent.
2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of pazopanib tablets. 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 (including fatal cases)
5 ) Venous Thromboembolic Events: Venous thromboembolic events (VTEs) have been observed, including fatal pulmonary emboli (PE). Monitor for signs and symptoms of VTE and PE. Withhold pazopanib tablets and then resume at same dose or permanently discontinue based on severity of VTE.
6 ) Thrombotic Microangiopathy: Thrombotic microangiopathy (TMA), including thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS), has been observed. Permanently discontinue pazopanib tablets if TMA occurs. 7 ) Gastrointestinal Perforation and Fistula: Fatal perforation events have occurred.
Monitor for signs and symptoms of gastrointestinal perforation or fistula. Withhold pazopanib tablets in case of Grade 2 or 3 gastrointestinal fistula and resume based on medical judgement. Permanently discontinue pazopanib tablets in case of gastrointestinal perforation or Grade 4 gastrointestinal fistula.
8 ) Interstitial Lung Disease/Pneumonitis: Can be fatal. Monitor patients for pulmonary symptoms. Permanently discontinue pazopanib tablets in patients who develop interstitial lung disease (ILD) or pneumonitis. 9 ) Posterior Reversible Encephalopathy Syndrome: Can be fatal.
Permanently discontinue pazopanib tablets in patients who develop posterior reversible encephalopathy syndrome (PRES). 10 ) Hypertension: Hypertension, including hypertensive crisis, has been observed. Do not initiate pazopanib tablets in patients with uncontrolled hypertension.
Optimize blood pressure prior to initiating pazopanib tablets. Monitor blood pressure as clinically indicated and initiate and adjust antihypertensive therapy as appropriate. Withhold and then dose reduce pazopanib tablets or permanently discontinue based on severity of hypertension.
11 ) Risk of lmpaired Wound Healing: Withhold pazopanib tablets for at least 1 week prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of pazopanib tablets after resolution of wound healing complications has not been established.
12 ) Hypothyroidism: Monitor thyroid tests at baseline, during treatment and as clinically indicated and manage hypothyroidism as appropriate. 13 ) Proteinuria: Perform baseline and periodic urinalysis during treatment with follow up measurement of 24-hour urine protein as clinically indicated.
Withhold pazopanib tablets then resume at a reduced dose or permanently discontinue based on severity of proteinuria. Permanently discontinue in patients with nephrotic syndrome. 14 ) Tumor Lysis Syndrome: Cases of tumor lysis syndrome (TLS) (some fatal) have been reported in patients with RCC and STS.
Closely monitor patients at risk and treat as clinically indicated. 15 ) Infection: Serious infections (with or without neutropenia), some with fatal outcome, have been reported. Monitor for signs and symptoms of infection. Institute appropriate anti-infective therapy promptly.
Consider interruption or discontinuation of pazopanib tablets. 16 ) Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to the fetus and patients to use effective contraception.
1 Hepatic Toxicity Hepatotoxicity, manifested as increases in ALT, aspartate aminotransferase (AST) and bilirubin, occurred in patients who received pazopanib tablets. This hepatotoxicity can be severe and fatal. 5 )]. Transaminase elevations occur early in the course of treatment; 92% of all transaminase elevations of any grade occurred in the first 18 weeks.
In the randomized RCC trial (VEG105192), ALT > 3 x ULN occurred in 18% and ALT > 10 x ULN occurred in 4% of the 290 patients who received pazopanib tablets. Concurrent elevation in ALT > 3 x ULN and bilirubin > 2 x ULN in the absence of significant alkaline phosphatase > 3 x ULN occurred in 2%.
In the monotherapy trials, 2 patients died with disease progression and hepatic failure. In the randomized STS trial (VEG110727), ALT > 3 x ULN occurred in 18% and ALT > 8 x ULN occurred in 5% of the 240 patients who received pazopanib tablets.
Concurrent elevation in ALT > 3 x ULN and bilirubin > 2 x ULN in the absence of significant alkaline phosphatase > 3 x ULN occurred in 2%. One patient died of hepatic failure. Monitor liver tests at baseline; at Weeks 3, 5, 7, and 9; at Month 3 and Month 4; and then periodically as clinically indicated.
Increase to weekly monitoring for patients with elevated ALT until ALT returns to Grade 1 or baseline. 2 )]. Gilbert's Syndrome Pazopanib tablets is a uridine diphosphate (UDP)-glucuronosyl transferase 1A1 (UGT1A1) inhibitor. 5 )]. 2 )].
3 )]. Insufficient data are available to assess the risk of concomitant administration of alternative statins and pazopanib tablets. 2 QT Prolongation and Torsades de Pointes In the RCC trials, 558/586 patients were subject to routine electrocardiogram (ECG) monitoring and QT prolongation ≥ 500 msec was identified in 2% of these 558 patients.
In monotherapy trials, torsades de pointes occurred in < 1% of 977 patients who received pazopanib tablets. 4% (1/240) of patients, respectively, who received pazopanib tablets had post-baseline values between 500 to 549 msec. Post-baseline QT data were only collected in the STS trial if ECG abnormalities were reported as an adverse reaction.
5 )]. , calcium, magnesium, potassium) at baseline and as clinically indicated. Correct hypokalemia, hypomagnesemia, and hypocalcemia prior to initiating pazopanib tablets and during treatment. 3 Cardiac Dysfunction Cardiac dysfunction, including decreased left ventricular ejection fraction (LVEF) and congestive heart failure, occurred in patients who received pazopanib tablets.
6% of 586 patients without routine on-study LVEF monitoring. In the randomized RCC trial (VEG105192), myocardial dysfunction was defined as symptoms of cardiac dysfunction or ≥15% absolute decline in LVEF compared with baseline or a decline in LVEF of ≥10% compared with baseline that is also below the lower limit of normal.
In an RCC trial (COMPARZ), myocardial dysfunction occurred in 13% of the 362 patients on pazopanib tablets who had a baseline and post-baseline LVEF measurements. 5% of patients. In the randomized STS trial (VEG110727), myocardial dysfunction occurred in 11% of the 142 patients who had a baseline and a post-baseline LVEF measurements.
One percent (3/240) of patients who received pazopanib tablets had congestive heart failure, which did not resolve in one patient. , those with prior anthracycline therapy) possibly by increasing cardiac afterload. 11 )]. Monitor for clinical signs or symptoms of congestive heart failure.
Conduct baseline and periodic evaluation of LVEF in patients at risk of cardiac dysfunction, including previous anthracycline exposure. 2 )]. 9% of 586 patients, and cerebral/intracranial hemorrhage was observed in < 1% (2/586) of patients treated with pazopanib tablets.
In the randomized RCC trial (VEG105192), 13% of 290 patients treated with pazopanib tablets experienced at least 1 hemorrhagic event. The most common hemorrhagic events were hematuria (4%), epistaxis (2%), hemoptysis (2%), and rectal hemorrhage (1%).
Nine of 37 patients treated with pazopanib tablets who had hemorrhagic events experienced serious events, including pulmonary, gastrointestinal, and genitourinary hemorrhage. One percent of patients treated with pazopanib tablets died from hemorrhage.
In the randomized STS trial (VEG110727), 22% of 240 patients treated with pazopanib tablets experienced at least 1 hemorrhagic event. The most common hemorrhagic events were epistaxis (8%), mouth hemorrhage (3%), and anal hemorrhage (2%).
Grade 4 hemorrhagic events occurred in 1% of patients and included intracranial hemorrhage, subarachnoid hemorrhage, and peritoneal hemorrhage. Pazopanib tablets has not been studied in patients who have a history of hemoptysis, cerebral hemorrhage, or clinically significant gastrointestinal hemorrhage in the past 6 months.
2 )]. 3% of 586 patients. 3% had a cerebrovascular accident, and 1% had an event of transient ischemic attack. 4% had a cerebrovascular accident. Pazopanib tablets has not been studied in patients who have had an arterial thromboembolic event within the previous 6 months.
2 )]. 6 Venous Thromboembolic Events Venous thromboembolic events (VTEs), including venous thrombosis and fatal pulmonary embolus (PE), occurred in patients who received pazopanib tablets. In the randomized RCC trial (VEG105192), VTEs occurred in 1% of 290 patients who received pazopanib tablets.
In the randomized STS trial (VEG110727), VTEs were reported in 5% of 240 patients who received pazopanib tablets. Fatal PE occurred in 1% (2/240). Monitor for signs and symptoms of VTE and PE. 2 )]. 7 Thrombotic Microangiopathy Thrombotic microangiopathy (TMA), including thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS), occurred in clinical trials of pazopanib tablets as monotherapy, in combination with bevacizumab, and in combination with topotecan.
Pazopanib tablets is not indicated for use in combination with other agents. Six of the 7 TMA cases occurred within 90 days of the initiation of pazopanib tablets. Improvement of TMA was observed after treatment was discontinued. Monitor for signs and symptoms of TMA.
Permanently discontinue pazopanib tablets in patients developing TMA. Manage as clinically indicated. 9% of 586 patients and 1% of 382 patients who received pazopanib tablets, respectively. 3% (1/382) of these patients in the STS trials.
Monitor for signs and symptoms of gastrointestinal perforation or fistula. Withhold pazopanib tablets in case of Grade 2 or 3 gastrointestinal fistula and resume based on medical judgement. 2 )]. 9 Interstitial Lung Disease/Pneumonitis Interstitial lung disease (ILD)/pneumonitis, which can be fatal, has been reported with pazopanib tablets across clinical trials.
1% of patients treated with pazopanib tablets. Monitor patients for pulmonary symptoms indicative of ILD/pneumonitis. 2 )]. 10 Posterior Reversible Encephalopathy Syndrome Posterior Reversible Encephalopathy Syndrome (PRES) has been reported in patients who received pazopanib tablets and may be fatal.
PRES is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness, and other visual and neurologic disturbances. Mild to severe hypertension may be present. Confirm diagnosis of PRES by magnetic resonance imaging.
Permanently discontinue pazopanib tablets in patients who develop PRES. 11 Hypertension Hypertension (systolic blood pressure ≥ 150 mmHg or diastolic blood pressure ≥ 100 mmHg) and hypertensive crisis were observed in patients treated with pazopanib tablets.
1 )]. About 40% of cases occurred by Day 9 and about 90% of cases occurred in the first 18 weeks across clinical trials. Approximately 1% of patients required permanent discontinuation of pazopanib tablets because of hypertension. Do not initiate pazopanib tablets in patients with uncontrolled hypertension.
Optimize blood pressure prior to initiating pazopanib tablets. Monitor blood pressure as clinically indicated and initiate and adjust antihypertensive therapy as appropriate. 2 )]. 12 Risk of Impaired Wound Healing Impaired wound healing complications can occur in patients who receive drugs that inhibit the vascular endothelial growth factor (VEGF) signaling pathway.
Therefore, pazopanib tablets has the potential to adversely affect wound healing. Withhold pazopanib tablets at least 1 week prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing.
The safety of resumption of pazopanib tablets after resolution of wound healing complications has not been established. 13 Hypothyroidism Hypothyroidism, confirmed based on a simultaneous rise of TSH and decline of T4, occurred in 7% of 290 patients who received pazopanib tablets in the randomized RCC trial (VEG105192) and in 5% of 240 patients who received pazopanib tablets in the randomized STS trial (VEG110727).
Hypothyroidism occurred in 4% of the 586 patients in the RCC trials and 5% of the 382 patients in the STS trials. Monitor thyroid tests at baseline, during treatment and as clinically indicated and manage hypothyroidism as appropriate.
14 Proteinuria In the randomized RCC trial (VEG105192), proteinuria occurred in 9% of 290 patients who received pazopanib tablets. In 2 patients, proteinuria led to discontinuation of pazopanib tablets. In the randomized STS trial (VEG110727), proteinuria occurred in 1% of 240 patients and nephrotic syndrome occurred in 1 patient.
Treatment was discontinued in the patient with nephrotic syndrome. Perform baseline and periodic urinalysis during treatment with follow up measurement of 24-hour urine protein as clinically indicated. Withhold pazopanib tablets then resume at a reduced dose or permanently discontinue based on severity of proteinuria.
2 )]. 2 )]. Patients may be at risk of TLS if they have rapidly growing tumors, a high tumor burden, renal dysfunction, or dehydration. Closely monitor patients at risk, consider appropriate prophylaxis, and treat as clinically indicated.
16 Infection Serious infections (with or without neutropenia), including some with fatal outcome, have been reported. Monitor patients for signs and symptoms of infection. Institute appropriate anti-infective therapy promptly and consider interruption or discontinuation of pazopanib tablets for serious infections.
17 Increased Toxicity With Other Cancer Therapy Pazopanib tablets is not indicated for use in combination with other agents. Clinical trials of pazopanib tablets in combination with pemetrexed and lapatinib were terminated early due to increased toxicity and mortality.
The fatal toxicities observed included pulmonary hemorrhage, gastrointestinal hemorrhage, and sudden death. A safe and effective combination dose has not been established with these regimens. 18 Increased Toxicity in Developing Organs The safety and effectiveness of pazopanib tablets in pediatric patients have not been established.
Pazopanib tablets are not indicated for use in pediatric patients. 4 )]. 19 Embryo-Fetal Toxicity Based on findings from animal studies and its mechanism of action, pazopanib tablets can cause fetal harm when administered to a pregnant woman.
Administration of pazopanib to pregnant rats and rabbits during the period of organogenesis resulted in maternal toxicity, teratogenicity, and abortion at systemic exposures lower than that observed at the maximum recommended human dose (MRHD) of 800 mg (based on area under the curve [AUC]).
Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with pazopanib tablets and for at least 2 weeks following the final dose. 3 )].