Pazopanib hydrochloride, an inhibitor of multiple receptor tyrosine kinases, is an antineoplastic agent.1, 2
Pazopanib hydrochloride is used for the treatment of advanced renal cell carcinoma in adults.1 Safety and efficacy of pazopanib for the treatment of advanced renal cell carcinoma are based principally on the results of a randomized, double-blind, placebo-controlled, multicenter, phase 3 study (VEG105192), with supportive data from a long-term extension study.1, 2, 3, 19, 20, 21, 22 Guidelines generally recommend pazopanib as a first-line treatment option in patients with clear-cell metastatic renal cell carcinoma who cannot receive or tolerate immune checkpoint inhibitors.50, 54
The current indication for pazopanib hydrochloride in the treatment of advanced renal cell carcinoma is based principally on the results of a randomized, double-blind, placebo-controlled, multicenter, phase 3 study (VEG105192) in 435 patients 18 years of age and older (median age: 59 years) with locally advanced and/or metastatic clear-cell (or predominantly clear-cell) renal cell carcinoma.1, 2, 3 This study initially enrolled patients whose disease had progressed following one prior cytokine-based regimen (i.e., aldesleukin, interferon alfa); the study protocol was subsequently amended (after enrollment of 7 patients) to include patients who had received no prior therapy (treatment-naive patients).2, 3 Because other drugs (e.g., sorafenib, sunitinib) had been approved in the US for treatment of renal cell carcinoma, the US Food and Drug Administration (FDA) expressed concerns about the use of a placebo control, and agreement was not reached on the study design.2 The VEG105192 study, thus, was conducted outside of the US in countries where patients did not have access to established therapies (e.g., aldesleukin, interferon alfa, sorafenib, sunitinib) or where cytokines were not recognized as standard treatment for renal cell carcinoma.2, 3
In this study, 435 patients (233 treatment-naive and 202 cytokine-pretreated patients) were randomized in a 2:1 ratio to receive either pazopanib (800 mg daily) or placebo along with best supportive care.1, 3 Treatment in both groups was continued until disease progression, unacceptable toxicity, death, or discontinuance of therapy for other reasons occurred; upon disease progression, patients previously randomized to receive placebo were permitted to cross over to open-label pazopanib.3 The median duration of treatment was 7.4 or 3.8 months in patients randomized to receive pazopanib or placebo, respectively.2 Enrolled patients had clear cell histology (90%) or predominantly clear cell histology (10%); 88-89% had undergone nephrectomy, and approximately 50% had metastatic disease involving 3 or more organs.1 Radiographic assessment of efficacy was performed every 6 weeks during the first 24 weeks of therapy and then every 8 weeks thereafter.3 The primary measure of efficacy was progression-free survival; the secondary end points included overall survival, overall response rate, and duration of response.1, 3
The median progression-free survival in the overall population was 9.2 months in patients receiving pazopanib compared with 4.2 months in those receiving placebo; the effect size appeared to be larger in the treatment-naive subgroup (11.1 versus 2.8 months) but also was clinically important in the cytokine-pretreated subgroup (7.4 versus 4.2 months).1, 2, 3 Improved progression-free survival was observed in patients receiving pazopanib regardless of Memorial Sloan-Kettering Cancer Center (MSKCC) risk category, gender, age, or ECOG performance status.3 The overall response rate for all patients receiving pazopanib was 30%, and the median duration of response was 58.7 weeks.1, 3 Response rates were similar among treatment-naive (32%) and cytokine-pretreated (29%) subgroups of patients who received pazopanib.3 The median time to response was 11.9 weeks.3 At the time of the final overall survival analysis, median overall survival was 22.9 months in the pazopanib group and 20.5 months in the placebo group (hazard ratio of 0.91; 95% confidence interval: 0.71, 1.16).1, 19 Although 54% of patients in the placebo group crossed over to receive pazopanib;1, 19 median progression-free survival and overall survival were 9.2 and 23.5 months, respectively, in these patients which was consistent with the values observed in pazopanib-treated patients in the VEG105192 trial.20 Use of other subsequent anticancer treatments differed between the treatment arms of the VEG105192 trial as well; 66% of patients in the placebo group received at least 1 systemic anticancer treatment after disease progression, compared to 30% of pazopanib-treated patients.19 Although results of the final overall survival analysis may be confounded by the high rate of crossover from placebo to pazopanib and by receipt of subsequent anticancer treatments, a post-hoc analysis adjusting for treatment crossover suggested a benefit for pazopanib in terms of overall survival.19
An additional randomized, open-label phase 3 trial (COMPARZ) compared pazopanib to sunitinib in 1110 adults with advanced or metastatic clear-cell renal cell carcinoma.21 Patients enrolled in the trial had not received any previous systemic therapy.21 Patients were randomized in a 1:1 ratio (stratified according to Karnofsky performance status score, lactate dehydrogenase level, and history of nephrectomy) to receive pazopanib 800 mg once daily or sunitinib administered in 6-week cycles (sunitinib 50 mg once daily for 4 consecutive weeks followed by a 2-week period without treatment).21 Treatment cycles were repeated until disease progression, unacceptable toxicity, or withdrawal of consent occurred.21 The primary efficacy measure was progression-free survival.21
Treatment with pazopanib was noninferior to treatment with sunitinib in terms of progression-free survival.21 The median progression-free survival was 8.4 months in the pazopanib group and 9.5 months in the sunitinib group.21 Objective response rates were 31 and 25% in the pazopanib and sunitinib groups, respectively.21 In the final overall survival analysis, no substantial difference in median overall survival was observed (28.3 and 29.1 months in patients receiving pazopanib or sunitinib, respectively).22
Prognosis is generally poor in patients with metastatic RCC, including those who have undergone complete tumor resection.51 First-line therapy with vascular endothelial growth factor receptor (VEGFR) inhibitors has been shown to provide benefits in patients with advanced RCC; however, relapsed or refractory RCC eventually develops in most patients.52 Combination regimens (e.g., immune checkpoint inhibitor in combination with a tyrosine kinase inhibitor) have generally become a standard for the treatment of advanced RCC.53 A limited number of randomized controlled trials have compared sunitinib with other treatment options for advanced renal cell carcinoma (e.g., pembrolizumab plus axitinib,26 avelumab plus axitinib,27 atezolizumab plus bevacizumab,28 nivolumab plus ipilimumab,29 nivolumab plus cabozantinib,30 or lenvatinib plus pembrolizumab).31 In clinical trials, combination chemotherapy resulted in longer progression-free survival compared with sunitinib alone in patients with previously untreated advanced renal cell carcinoma.26, 27, 28, 29, 30, 31
Some experts also state that subsequent monotherapy with a tyrosine kinase inhibitor (e.g., sunitinib, pazopanib) may be offered as an alternative to programmed death 1 (PD-1) inhibitor-based combinations in the first-line setting when immune checkpoint therapy is contraindicated or not available or as a second-line option following disease progression during immune checkpoint inhibitor-based therapy.54
Pazopanib hydrochloride is used for the treatment of advanced soft tissue sarcoma in adults who have received prior chemotherapy.1 The drug has been designated an orphan drug by the FDA for the treatment of this cancer.24 Efficacy of pazopanib for the treatment of patients with adipocytic soft tissue sarcoma or GI stomal tumors has not been demonstrated.1 Safety and efficacy of pazopanib for the treatment of advanced soft tissue sarcoma are based principally on the results of a randomized, double-blind, placebo-controlled study (VEG110727).1, 23 Guidelines state that pazopanib is an option for second or subsequent line of therapy in non-adipogenic soft tissue sarcoma.56
The current indication for pazopanib hydrochloride in the treatment of soft tissue sarcoma is based principally on the results of a randomized, double-blind, placebo-controlled trial (PALETTE [VEG110727]).1, 23 In this study, 369 adults with metastatic soft tissue sarcoma who were previously treated with at least 1 anthracycline-containing chemotherapy regimen or were not eligible for anthracycline-based chemotherapy were randomized in a 2:1 ratio (stratified by World Health Organization [WHO] performance status and number of prior therapies) to receive pazopanib 800 mg once daily or placebo.1, 23 Treatment was continued until disease progression, unacceptable toxicity, withdrawal of consent, or death occurred.23 Enrolled patients had leiomyosarcoma (43%), synovial sarcoma (10%), or other soft tissue sarcomas (47%).1 Approximately one-half (56%) of patients had received 2 or more previous lines of systemic therapy.1 The median duration of treatment was 16.4 or 8.1 weeks in patients randomized to receive pazopanib or placebo, respectively.23 The primary measure of efficacy was progression-free survival as assessed by independent radiological review.1
Median progression-free survival was 4.6 months in the pazopanib group and 1.6 months in the placebo group.1, 23 Improved progression-free survival was observed in patients receiving pazopanib regardless of soft tissue sarcoma type.1 Overall response rate was 4 and 0% in the pazopanib and placebo groups, respectively.1 Median duration of response in the pazopanib group was 9 months.1 Median overall survival did not differ significantly between treatment groups in the final analysis (12.6 or 10.7 months in the pazopanib or placebo group, respectively).1, 23
Chemotherapy is standard treatment for soft tissue sarcoma, with single-agent doxorubicin being the treatment of choice.55 Other agents with clinical activity in soft tissue sarcoma include VEGF tyrosine kinase inhibitors such as pazopanib and regorafenib.55
Some experts state that pazopanib is an option for second or subsequent line of therapy in non-adipogenic soft tissue sarcoma.56
Dispensing and Administration Precautions
Pazopanib hydrochloride is administered orally once daily.1 Administer the drug without food (i.e., at least 1 hour before or 2 hours after a meal).1 Pazopanib hydrochloride tablets should be swallowed whole and should not be crushed; crushing the tablets has been shown to increase the rate of absorption and systemic exposure to the drug.1 Store tablets at 20-25°C (excursions permitted between 15-30°C).1
Concomitant use of pazopanib with drugs affecting gastric pH may result in decreased pazopanib exposure and should be avoided.1 If concomitant use with a drug affecting gastric pH cannot be avoided, consider a short-acting antacid rather than a proton-pump inhibitor or histamine H2-receptor antagonist.1 The administration of a short-acting antacid and pazopanib should be separated by several hours.1
Dosage of pazopanib hydrochloride is expressed in terms of pazopanib.1
For the treatment of advanced renal cell carcinoma, the recommended adult dosage of pazopanib is 800 mg once daily.1 Continue therapy for as long as the patient derives clinical benefit from the drug or until unacceptable toxicity occurs.1
For the treatment of advanced soft tissue sarcoma previously treated with chemotherapy, the recommended adult dosage of pazopanib is 800 mg once daily.1 Continue therapy for as long as the patient derives clinical benefit from the drug or until unacceptable toxicity occurs.1
If adverse reactions occur, temporary interruption of therapy, dosage reduction, and/or discontinuance of pazopanib may be necessary.1 If dosage modification is required, reduce the dosage of pazopanib as described in Table 1.1
Dosage Reduction | Renal Cell Carcinoma (Starting dosage = 800 mg once daily) | Soft Tissue Sarcoma (Starting dosage = 800 mg once daily) |
|---|---|---|
First | 400 mg once daily | 600 mg once daily |
Second | 200 mg once daily | 400 mg once daily |
Third | Permanently discontinue drug | Permanently discontinue drug |
If hepatotoxicity occurs, reduce pazopanib dosage, or interrupt or permanently discontinue therapy.1 (See Table 2.)
ALT (SGPT) and/or Bilirubin Concentrations | Recommended Action |
|---|---|
Serum ALT concentration 3-8 times the upper limit of normal (ULN) | Continue pazopanib; monitor liver function weekly until serum ALT concentration returns to grade 1 or baseline |
Serum ALT concentration >8 times the ULN | Interrupt pazopanib therapy until serum ALT concentration returns to grade 1 or baseline; if benefit outweighs risk, reinitiate pazopanib at a reduced dosage of 400 mg or less once daily; following reinitiation, monitor liver function weekly for 8 weeks; if serum ALT concentration rises to >3 times the ULN, discontinue pazopanib permanently |
Serum ALT concentration >3 times the ULN and mild, indirect (unconjugated) hyperbilirubinemia in patients with known Gilbert syndrome | Manage per recommendations for patients with isolated serum ALT elevations |
Serum ALT concentration >3 times the ULN and serum bilirubin concentration >2 times the ULN | Discontinue pazopanib permanently ; monitor liver function until hepatotoxicity resolves |
If symptomatic or grade 3 left ventricular systolic dysfunction occurs, withhold pazopanib until toxicity improves to grade 2 or less; therapy may be resumed based on clinical judgment.1
If grade 4 left ventricular systolic dysfunction occurs, permanently discontinue pazopanib.1
If a grade 2 hemorrhagic event occurs, withhold pazopanib until toxicity improves to grade 1 or less; therapy may then be resumed at a reduced dosage (see Table 1).1
If a grade 3 or 4 hemorrhagic event occurs, permanently discontinue pazopanib.1
If a grade 3 venous thromboembolic event (VTE) occurs, withhold pazopanib; therapy may be resumed at the same dosage after at least 1 week of appropriate therapy for the thromboembolic event.1
If an arterial thromboembolic event or grade 4 VTE occurs, permanently discontinue pazopanib.1
If thrombotic microangiopathy occurs, permanently discontinue pazopanib.1
If GI perforation occurs, permanently discontinue pazopanib.1
If grade 2 or 3 GI fistula occurs, withhold pazopanib; therapy may be resumed based on clinical judgment.1
If grade 4 GI fistula occurs, permanently discontinue pazopanib.1
Interstitial Lung Disease/Pneumonitis
If interstitial lung disease or pneumonitis of any grade occurs, permanently discontinue pazopanib.1
Posterior Reversible Encephalopathy Syndrome
If posterior reversible encephalopathy syndrome of any grade occurs, permanently discontinue pazopanib.1
If grade 2 or 3 hypertension occurs, reduce the dosage of pazopanib (see Table 1) and initiate or adjust antihypertensive therapy.1 If grade 3 hypertension persists despite reducing the dosage of pazopanib and use of antihypertensive therapy, permanently discontinue pazopanib.1
If grade 4 hypertension or hypertensive crisis occurs, permanently discontinue pazopanib.1
If urine protein levels 3 grams or greater per 24 hours occurs, withhold pazopanib until urine protein levels improve to grade 1 or less; therapy may then be resumed at a reduced dosage (see Table 1).1 If urine protein levels over a 24-hour period do not improve or urine protein levels 3 grams or greater per 24 hours recurs despite reducing the dosage of pazopanib, permanently discontinue drug.1
If nephrotic syndrome is confirmed, permanently discontinue pazopanib.1
Concomitant Use with Drugs Affecting Hepatic Microsomal Enzymes
Concomitant use of pazopanib with potent inhibitors of CYP3A4 may result in increased plasma concentrations of pazopanib and should be avoided .1 If concomitant use with a potent CYP3A4 inhibitor cannot be avoided, reduce the dosage of pazopanib to 400 mg daily.1
Concomitant use of pazopanib with potent inducers of CYP3A4 may result in decreased plasma concentrations of pazopanib and should be avoided .1
No dosage adjustment is necessary in patients with mild hepatic impairment (total serum bilirubin concentration not exceeding 1.5 times the ULN with any level of ALT).15 The manufacturer recommends that dosage of pazopanib be reduced to 200 mg once daily in patients with moderate hepatic impairment (total serum bilirubin concentration exceeding 1.5 times, but not more than 3 times, the ULN with any level of ALT).1, 15 Safety of pazopanib has not been established in patients with severe hepatic impairment (total serum bilirubin concentration exceeding 3 times the ULN with any level of ALT); therefore, the manufacturer recommends that the drug not be used in such patients.1
Renal impairment is not expected to influence pazopanib exposure; therefore, the manufacturer states that dosage adjustment is not necessary in patients with renal impairment.1
The manufacturer makes no specific dosage recommendations for geriatric patients.1
A boxed warning about the risk of hepatotoxicity is included in the prescribing information for pazopanib.1 Severe or fatal hepatotoxicity, manifested as increases in serum concentrations of aminotransferases (ALT [SGPT], AST [SGOT]) and bilirubin, has been reported in patients receiving pazopanib.1 Most (92%) cases of aminotransferase elevations (of any grade) occurred during the first 18 weeks of therapy.1 In the randomized, placebo-controlled study (VEG105192) in patients with renal cell carcinoma, increases in ALT concentrations exceeding 3 or 10 times the upper limit of normal (ULN) were reported in approximately 18 or 4%, respectively, of patients receiving pazopanib.1 Concurrent increases in concentrations of ALT (exceeding 3 times the ULN) and bilirubin (exceeding twice the ULN) in the absence of substantial (exceeding 3 times the ULN) increases in alkaline phosphatase concentrations were reported in approximately 2% of patients receiving pazopanib.1 Death (resulting from disease progression and hepatic failure) occurred in 2 patients receiving pazopanib.1 In a randomized, placebo-controlled study (VEG110727) in patients with soft tissue sarcoma, increases in ALT concentrations exceeding 3 or 10 times the ULN were reported in approximately 18 or 5%, respectively, of patients receiving pazopanib.1 Concurrent increases in ALT (exceeding 3 times the ULN) and bilirubin (exceeding twice the ULN) concentrations in the absence of substantial increases in alkaline phosphatase concentrations (exceeding 3 times the ULN) were reported in approximately 2% of patients receiving pazopanib.1 Fatal hepatic failure was reported in one patient.1
Because pazopanib inhibits uridine diphosphate-glucuronosyltransferase (UGT) 1A1 (an enzyme that catalyzes the glucuronidation of bilirubin for elimination), mild elevations in indirect (unconjugated) bilirubin may occur in patients with deficient glucuronidation of bilirubin (i.e., Gilbert syndrome).1, 8
Concomitant use of pazopanib and simvastatin increases the risk of elevations of ALT concentrations.1 In clinical trials evaluating pazopanib monotherapy, increases in ALT concentrations exceeding 3 times the ULN were reported in 14% of patients who were not receiving a HMG-CoA reductase inhibitor (statin) and in 27% of those receiving concomitant simvastatin.1 Data are insufficient to assess the risk of other statins administered concomitantly with pazopanib.1
Perform liver function tests prior to initiation of pazopanib, during weeks 3, 5, 7, and 9 of therapy, at months 3 and 4, and then periodically thereafter as clinically indicated.1 If hepatotoxicity occurs, withhold pazopanib and resume at a reduced dosage with continued weekly liver function monitoring for 8 weeks, or permanently discontinue pazopanib and monitor liver function tests weekly until resolution, depending on the severity of hepatotoxicity.1 If ALT elevations occur in a patient taking concomitant simvastatin, monitor liver function weekly.1
Other Warnings and Precautions
Prolongation of QT Interval and Torsades de Pointes
Prolongation of the QT interval and torsades de pointes have been reported in patients receiving pazopanib.1 In the VEG105192 and VEG110727 studies, prolongation of the QT interval (500-549 msec) was reported in approximately 1 and 0.4%, respectively, of patients receiving pazopanib.1 In an analysis of pooled data from 3 studies involving 55815 patients with renal cell carcinoma, prolongation of the QT interval (500 msec or greater) or torsades de pointes was reported in approximately 2% or less than 1%, respectively, of patients receiving pazopanib.1
Avoid concomitant administration of pazopanib and drugs that prolong the QT interval.1 Monitor patients at significant risk for QT prolongation, including patients with a history of prolongation of the QT interval, patients receiving antiarrhythmic agents or other drugs that cause prolongation of the QT interval, and patients with relevant preexisting cardiac disease.1 Monitor ECG and serum electrolytes (e.g., calcium, magnesium, potassium) prior to initiation of pazopanib and periodically during treatment.1 Correct hypokalemia, hypomagnesemia, and hypocalcemia prior to initiation of pazopanib and as necessary during treatment.1
Cardiac dysfunction, including decreased left ventricular ejection fraction and congestive heart failure, has been reported in patients receiving pazopanib.1 In renal cell carcinoma trials, cardiac dysfunction was observed in 0.6% of patients.1 Among patients who had baseline and post-baseline left ventricular ejection fraction measurement in the COMPARZ trial, cardiac dysfunction occurred in 13% of patients.1 Congestive heart failure has been reported in 0.5% of patients.1 In the VEG110727 study in patients with soft tissue sarcoma, cardiac dysfunction occurred in 11% of patients who had baseline and post-baseline left ventricular ejection fraction measurements; congestive heart failure occurred in 1% of patients.1 Most patients with cardiac dysfunction in the VEG110727 study had concurrent hypertension, which may have exacerbated cardiac dysfunction in patients who had preexisting risk factors for cardiac dysfunction (e.g., those with prior anthracycline therapy).1
Monitor patients receiving pazopanib for signs and symptoms of congestive heart failure.1 Monitor left ventricular ejection fraction in patients at risk of cardiac dysfunction (including those with previous anthracycline exposure) at baseline and periodically during therapy.1 If cardiac dysfunction occurs, withhold or permanently discontinue pazopanib depending on the severity of the cardiac dysfunction.1
Hemorrhage, sometimes severe or fatal, has been reported in patients receiving pazopanib.1 In renal cell carcinoma trials, fatal hemorrhagic events occurred in 0.9% of patients receiving pazopanib, and cerebral/intracranial hemorrhage occurred in <1% of patients receiving pazopanib.1 In the VEG105192 study, hemorrhage was reported in 13% of patients receiving pazopanib.1 The most common hemorrhagic events reported with pazopanib in this study included hematuria, epistaxis, hemoptysis, and rectal hemorrha severe hemorrhagic events included pulmonary, GI, and genitourinary hemorrhage.1 Fatal hemorrhage was reported in approximately 1% of patients receiving pazopanib.1 In the VEG110727 study in patients with soft tissue sarcoma, hemorrhage (most commonly epistaxis and oral or anal hemorrhage) was reported in 22% of patients.1 Grade 4 hemorrhagic events occurred in 1% of patients and included intracranial, subarachnoid, and peritoneal hemorrhage.1
Pazopanib has not been evaluated in patients with a history of hemoptysis or patients with cerebral or clinically important GI hemorrhage within the past 6 months.1 If a hemorrhagic event occurs, withhold pazopanib and resume at a reduced dosage or permanently discontinue drug depending on the severity of the hemorrhagic event.1
Arterial thromboembolic events, sometimes severe or fatal, have been reported in patients receiving pazopanib.1 In renal cell carcinoma trials, fatal arterial embolic events occurred in 0.3% of patients.1 In the VEG105192 study, myocardial infarction/ischemia, cerebrovascular accident, or transient ischemic attack (TIA) was reported in approximately 2, less than 0.3, or 1%, respectively, of patients receiving pazopanib.1 In the VEG110727 study in patients with soft tissue sarcoma, myocardial infarction/ischemia and cerebrovascular accident were reported in 2 and 0.4% of patients receiving pazopanib, respectively.1
Pazopanib has not been evaluated in patients who had experienced an arterial thromboembolic event within the past 6 months.1 If arterial thromboembolism occurs, permanently discontinue pazopanib.1
Venous thromboembolic events (VTE), including venous thrombosis and fatal pulmonary embolism, have been reported in patients receiving pazopanib.1 In the VEG105192 study in patients with renal cell carcinoma, venous thromboembolism occurred in 1% of patients receiving pazopanib; in the VEG110727 study evaluating pazopanib in patients with soft tissue sarcoma, venous thromboembolism and fatal pulmonary embolism occurred in 5 and 1%, respectively, of patients receiving pazopanib.1
Monitor patients receiving pazopanib for signs and symptoms of venous thromboembolism and pulmonary embolism during pazopanib therapy.1 If venous thromboembolism or pulmonary embolism occurs, withhold pazopanib and resume at the same dosage or permanently discontinue drug depending on the severity of the thromboembolic event.1
Thrombotic microangiopathy, including thrombotic thrombocytopenic purpura and hemolytic uremic syndrome, has been reported in patients receiving pazopanib as monotherapy, in combination with bevacizumab†, or in combination with topotecan†.1 Pazopanib is not indicated for use in combination with other agents.1 Thrombotic microangiopathy generally occurs within 90 days of initiation of pazopanib therapy, and improves following discontinuance of the drug.1
Monitor patients receiving pazopanib for signs and symptoms of thrombotic microangiopathy.1 If thrombotic microangiopathy occurs, permanently discontinue pazopanib.1
GI perforation or fistula, sometimes fatal, has been reported in patients receiving pazopanib.1 In renal cell carcinoma trials and soft tissue sarcoma trials, GI perforation or fistula occurred in 0.9 and 1%, respectively, of patients receiving pazopanib.1 Fatal GI perforation occurred in 0.3% of patients in renal cell carcinoma and soft tissue sarcoma trials.1
Monitor patients receiving pazopanib for manifestations of GI perforation or fistula formation.1 If GI fistula occurs, withhold pazopanib and resume based on medical judgment or permanently discontinue pazopanib, depending on the severity of the GI fistula.1 If GI perforation occurs, permanently discontinue pazopanib.1
Interstitial Lung Disease/Pneumonitis
Interstitial lung disease/pneumonitis, which can be fatal, has been reported in patients receiving pazopanib.1 In clinical trials, interstitial lung disease/pneumonitis occurred in 0.1% of patients receiving pazopanib.1
Monitor patients receiving pazopanib for pulmonary symptoms indicative of interstitial lung disease/pneumonitis.1 If interstitial lung disease or pneumonitis occurs, permanently discontinue pazopanib.1
Posterior Reversible Encephalopathy Syndrome
Posterior reversible encephalopathy syndrome, which can be fatal, has been reported in patients receiving pazopanib.1 Symptoms of posterior reversible encephalopathy syndrome may include headache, seizure, lethargy, confusion, blindness, and other visual and neurologic disturbances.1 Mild to severe hypertension may also be present.1
If symptoms of posterior reversible encephalopathy syndrome occur, confirm the diagnosis with MRI.1 If posterior reversible encephalopathy syndrome occurs, permanently discontinue pazopanib.1
Hypertension (systolic blood pressure of 150 mm Hg or greater or diastolic blood pressure of 100 mm Hg or greater) and hypertensive crisis have been reported in patients receiving pazopanib.1 Most (90%) cases occurred during the first 18 weeks of therapy.1 Approximately 1% of patients require permanent discontinuation of pazopanib due to hypertension.1 In the VEG105192 study, hypertension was reported in approximately 40 or 10% of patients receiving pazopanib or placebo, respectively; grade 3 hypertension was reported in approximately 4 or less than 1% of patients receiving pazopanib or placebo, respectively.1 In the VEG110727 study, hypertension was reported in 42 or 6% of patients receiving pazopanib or placebo, respectively; grade 3 hypertension was reported in 7 or 0% of patients receiving pazopanib or placebo, respectively.1 The majority of hypertension cases were managed with antihypertensive therapy or by reduction in pazopanib dosage.1
Blood pressure must be adequately controlled prior to initiation of pazopanib.1 Monitor and treat for hypertension as clinically indicated as clinically indicated.1 If hypertension occurs, withhold pazopanib and resume at a reduced dosage or permanently discontinue pazopanib, depending on the severity of hypertension.1
Because inhibitors of the vascular endothelial growth factor (VEGF) signaling pathway, including pazopanib, may impair wound healing, pazopanib may adversely affect wound healing.1 Discontinue pazopanib at least 7 days prior to scheduled surgery, and withhold for at least 2 weeks following major surgery and until adequate wound healing has occurred.1 The safety of resuming pazopanib therapy after resolution of wound healing complications has not been established.1
Hypothyroidism has been reported in patients receiving pazopanib.1 In the VEG105192 study, hypothyroidism was reported in 7% of patients receiving pazopanib; hypothyroidism was reported in 5% of patients receiving pazopanib.1 In an analysis of pooled data from renal cell carcinoma studies, hypothyroidism was reported in 4% of patients receiving pazopanib; in an analysis of pooled data from soft tissue sarcoma studies, hypothyroidism was reported in 5% of patients receiving pazopanib.1
Assess thyroid function at baseline and during therapy as clinically indicated.1 Manage hypothyroidism as appropriate.1
Proteinuria has been reported in patients receiving pazopanib.1 In the VEG110727 study, proteinuria was reported in 1% of patients receiving pazopanib; nephrotic syndrome was reported in 1 patient.1
Perform urinalysis prior to initiation of pazopanib and periodically during therapy, with follow-up measurement of 24-hour urine protein as clinically indicated.1 If proteinuria occurs, withhold pazopanib and resume at a reduced dosage or permanently discontinue pazopanib, depending on the severity of proteinuria.1 If nephrotic syndrome occurs, permanently discontinue pazopanib.1
Tumor lysis syndrome, sometimes fatal, has been reported in patients receiving pazopanib.1
Monitor patients at risk of tumor lysis syndrome (e.g., those with rapidly growing tumors, high tumor burden, renal dysfunction, dehydration) closely during pazopanib therapy; consider prophylactic therapy, and initiate treatment for tumor lysis syndrome as clinically indicated.1
Serious, sometimes fatal, infections (with or without neutropenia) have been reported in patients receiving pazopanib.1
Monitor for signs and symptoms of infection.1 If serious infections occur, consider interruption or discontinuation of pazopanib.1
Pazopanib is not indicated for use in combination with other agents.1 Clinical trials of pazopanib in combination with pemetrexed or lapatinib were terminated early due to increased toxicity and mortality.1 Fatal toxicities included pulmonary hemorrhage, GI hemorrhage, and sudden death.1
Increased Toxicity in Developing Organs
Pazopanib is not indicated for use in pediatric patients, as safety and efficacy in this patient population have not been established.1 Based on animal studies and its mechanism of action, pazopanib may have severe effects on organ growth and maturation during early postnatal development.1 In studies of juvenile rats less than 21 days old, organ toxicity (i.e., lungs, liver, heart, kidney) and death occurred following administration of pazopanib at doses significantly lower than the clinically recommended dose or doses tolerated in older animals.1
Fetal/Neonatal Morbidity and Mortality
Pazopanib may cause fetal harm; the drug has been shown to cause maternal toxicity, teratogenicity, and abortion in animal studies.1 There are no adequate and well-controlled studies in pregnant women.1 Avoid pregnancy during therapy.1 If used during pregnancy or if the patient becomes pregnant while receiving pazopanib, apprise the patient of the potential fetal hazard.1 Advise females of reproductive potential to use effective contraception during pazopanib therapy and for at least 2 weeks after the final dose.1 Advise males with such female partners to use condoms during pazopanib therapy and for at least 2 weeks after the final dose.1
Based on animal reproduction studies and its mechanism of action, pazopanib may cause fetal harm.1 There are no adequate and well-controlled studies in pregnant women.1 In animal studies, administration of pazopanib during organogenesis resulted in teratogenicity and abortion at systemic exposures lower than those observed at the maximum recommended human dose.1 Avoid pregnancy during therapy.1 If used during pregnancy or if the patient becomes pregnant while receiving pazopanib, apprise the patient of the potential fetal hazard.1
It is not known whether pazopanib or its metabolites are distributed into human milk.1 The effects of pazopanib or its metabolites on a breast-fed infant or milk production are unknown.1 Because of the potential for serious adverse reactions to pazopanib in breast-fed infants, avoid breast-feeding during pazopanib treatment and for 2 weeks after the final dose of pazopanib.1
Females and Males of Reproductive Potential
Prior to initiation of pazopanib therapy, verify pregnancy status of females of reproductive potential.1 Advise females of reproductive potential to use effective contraception during pazopanib treatment and for at least 2 weeks after the last dose of pazopanib.1 Advise males with such female partners to use condoms during pazopanib treatment and for at least 2 weeks after the last dose of pazopanib.1
Based on animal studies, pazopanib may impair fertility in females and males of reproductive potential.1
Safety and efficacy have not been established in pediatric patients younger than 18 years of age.1
Pazopanib may cause serious adverse effects on organ development in pediatric patients, particularly in those less than 2 years of age.1 In animal studies conducted in juvenile rats less than 21 days old, organ toxicity (i.e., lungs, liver, heart, kidney) and death occurred following administration of pazopanib at doses significantly lower than the clinically recommended dose or doses tolerated in older animals.1
In an analysis of pooled clinical trial data from all pazopanib studies, 30% of patients were 65 years of age or older; ALT elevations exceeding 3 times the ULN occurred more frequently in older patients compared to younger adults.1 ALT elevations exceeding 3 times the ULN occurred in 23% of patients 65 years of age or older and in 18% of patients less than 65 years of age.1
In an analysis of pooled data from studies involving 586 patients with renal cell carcinoma, 33% of patients were 65 years of age or older; no overall differences in safety or efficacy were observed between older and younger adults.1
In an analysis of pooled data from studies involving 382 patients with soft tissue sarcoma, 24% of patients were 65 years of age or older.1 Patients 65 years of age or older had a higher incidence of grade 3 or 4 fatigue, hypertension, decreased appetite, ALT elevations, and AST elevations.1 No overall differences in efficacy were observed between patients 65 years of age or older and younger adults.1
An analysis of pharmacokinetic data indicated that pazopanib clearance in patients with mild hepatic impairment (total bilirubin concentration not exceeding the ULN with ALT exceeding the ULN, or total serum bilirubin concentration not exceeding 1.5 times the ULN with any level of ALT) was similar to that in patients with normal hepatic function.18 Therefore, the manufacturer states that no dosage adjustment is necessary in patients with mild hepatic impairment.1
In a pharmacokinetic study, the maximum tolerated dosage of pazopanib in patients with moderate hepatic impairment (total serum bilirubin concentration exceeding 1.5 times, but not more than 3 times, the ULN with any level of ALT) was 200 mg once daily.1 The steady-state peak plasma concentration or median AUC was approximately 43 or 29%, respectively, of the corresponding median values after administration of pazopanib 800 mg once daily in patients with normal hepatic function.1 Pazopanib is not recommended for use in patients with moderate hepatic impairment; if pazopanib is used in such patients, reduce the dosage of pazopanib to 200 mg once daily.1
In a pharmacokinetic study of patients with severe hepatic impairment (total serum bilirubin concentration exceeding 3 times the ULN with any level of ALT) receiving pazopanib 200 mg once daily, the median steady-state peak plasma concentration and median AUC were approximately 18 and 15%, respectively, of the corresponding median values after administration of pazopanib 800 mg once daily in patients with normal hepatic function.1 Avoid the use of pazopanib in patients with severe hepatic impairment.1
In a population pharmacokinetic analysis involving patients with various cancers, creatinine clearance of 30-150 mL/minute did not substantially affect clearance of pazopanib.18 Because renal impairment is unlikely to affect the pharmacokinetics (e.g., exposure) of pazopanib (i.e., less than 4% of a radiolabeled oral dose of pazopanib is recovered in urine), the manufacturer states that no dosage adjustment is necessary in patients with renal impairment.1
Pazopanib has not been studied in patients with severe renal impairment or in patients undergoing peritoneal dialysis or hemodialysis.1
Pazopanib inhibits UGT1A1, an enzyme that catalyzes the glucuronidation of bilirubin for elimination.1 Patients who are homozygous for the UGT1A1*28 allele (characterized by a mutation in the promoter region of the UGT1A1 gene) have reduced expression of UGT1A1, which may manifest as mild hyperbilirubinemia (i.e., Gilbert syndrome).1, 16 Mild elevations of indirect (unconjugated) bilirubin concentrations may occur in patients with Gilbert syndrome receiving pazopanib.1
In a pooled pharmacogenomic analysis of data from 31 clinical studies evaluating pazopanib, ALT elevations exceeding 3 times the upper limit of normal (ULN) occurred in 32% of patients who were HLA-B*57:01 allele carriers and in 19% of noncarriers.1 ALT elevations exceeding 5 times the ULN occurred in 19% of HLA-B*57:01 allele carriers and in 10% of noncarriers.1
Adverse effects reported in 20% or more of patients receiving pazopanib for renal cell carcinoma include diarrhea, hypertension, hair color changes (depigmentation), nausea, anorexia, and vomiting.1
Adverse effects reported in 20% or more of patients receiving pazopanib for soft tissue sarcoma include fatigue, diarrhea, nausea, decreased weight, hypertension, decreased appetite, vomiting, tumor pain, hair color changes, musculoskeletal pain, headache, dysgeusia, dyspnea, and skin hypopigmentation.1
Pazopanib is metabolized principally by cytochrome P-450 (CYP) isoenzyme 3A4 and, to a lesser extent, by CYP isoenzymes 1A2 and 2C8.1 Results of drug interaction studies in cancer patients suggest that pazopanib is a weak inhibitor of CYP isoenzymes 3A4, 2C8, and 2D6 but has no effect on CYP isoenzymes 1A2, 2C9, or 2C19.1 In vitro studies indicate that pazopanib may induce and/or inhibit CYP3A4, and inhibit CYP isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 2E1.1
In vitro studies indicate that pazopanib inhibits uridine diphosphate-glucuronosyltransferase (UGT) 1A1 and organic anion transport protein (OATP) 1B1;1 the drug appears to be a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP).1
Drugs and Foods Affecting Hepatic Microsomal Enzymes
Pharmacokinetic interaction (increased peak plasma concentrations and area under the plasma concentration-time curve [AUC] of pazopanib) observed during concomitant use of oral pazopanib with ketoconazole (a potent inhibitor of CYP3A4 and an inhibitor of P-gp) or during concomitant use of pazopanib oral tablets15 with lapatinib (a substrate and weak inhibitor of CYP3A4, P-gp, and BCRP).1
Avoid concomitant use of pazopanib with potent CYP3A4 inhibitors; if concomitant use cannot be avoided, reduce pazopanib dosage.1 Avoid concomitant use with grapefruit or grapefruit juice.1
Potential pharmacokinetic interaction (decreased plasma concentrations of pazopanib).1
Avoid concomitant use of pazopanib with a potent inducer of CYP3A4; consider selecting an alternative agent with minimal or no enzyme induction potential.1 If long-term use of a potent CYP3A4 inducer is required, do not initiate therapy with pazopanib.1
Drugs Metabolized by Hepatic Microsomal Enzymes
Substrates of CYP isoenzymes 3A4, 2D6, or 2C8
Pharmacokinetic interaction (increased exposure to substrate) observed during concomitant use with midazolam (a CYP3A4 substrate), dextromethorphan (a CYP2D6 substrate), or paclitaxel (a CYP3A4 and CYP2C8 substrate).1 Concomitant use with substrates of CYP isoenzymes 3A4, 2D6, or 2C8 that have a narrow therapeutic index is not recommended.1
Substrates of CYP isoenzymes 1A2, 2C9, or 2C19
No clinically relevant pharmacokinetic interaction with caffeine (a CYP1A2 substrate), warfarin (a CYP2C9 substrate), or omeprazole (a CYP2C19 substrate).1
Drugs Transported by Organic Anion Transport Protein (OATP)
Potential pharmacokinetic interaction (increased plasma concentration of drugs transported by OATP1B1).1
Drugs Metabolized by Uridine Diphosphate-glucuronosyltransferase (UGT)
Potential pharmacokinetic interaction (increased plasma concentration of drugs metabolized by UGT1A1).1
Drugs Affecting Gastric Acidity
Pharmacokinetic interaction (decreased exposure to pazopanib) has been observed during concomitant use with esomeprazole.1
Avoid concomitant use of pazopanib with drugs affecting gastric acidity.1 If concomitant administration of a drug affecting gastric acidity cannot be avoided, consider short-acting antacids rather than a proton-pump inhibitor or histamine H2-receptor antagonist.1 Administration of a short-acting antacid and pazopanib should be separated by several hours.1
Drugs that Prolong the QT Interval
Risk of prolonged QT interval and torsades de pointes.1 Avoid concomitant use of pazopanib and drugs that prolong the QT interval.1
HMG-CoA Reductase Inhibitors (Statins)
Concomitant administration of simvastatin and pazopanib increased the incidence of ALT elevations in clinical trials.1 If a patient develops ALT elevations while receiving concomitant pazopanib and simvastatin, monitor liver function weekly; depending on the severity of hepatotoxicity, withhold pazopanib and resume pazopanib at a reduced dosage or permanently discontinue pazopanib therapy.1
Data are insufficient to assess the risk of other statins administered concomitantly with pazopanib.1
Pazopanib hydrochloride, an inhibitor of multiple receptor tyrosine kinases, is an antineoplastic agent.1, 2, 4 Receptor tyrosine kinases (RTKs) are involved in the initiation of various cascades of intracellular signaling events that lead to cell proliferation and/or influence processes critical to cell survival and tumor progression (e.g., angiogenesis, metastasis, inhibition of apoptosis), based on the respective kinase.10, 12, 13 Pazopanib inhibits signal transduction pathways involving multiple receptor tyrosine kinases, principally vascular endothelial growth factor receptors (i.e., VEGFR-1, VEGFR-2, VEGFR-3), platelet-derived growth factor receptors (i.e., PDGFR-α, PDGFR-β), and stem cell factor receptor (i.e., c-Kit);7, 12, 17, 18 the drug has modest inhibitory effects on fibroblast growth factor receptors (i.e., FGFR1, FGFR3), transmembrane glycoprotein receptor tyrosine kinase (c-Fms), leukocyte-specific protein tyrosine kinase (Lck), and interleukin-2 receptor inducible T-cell kinase (Itk).7, 12 In vitro, pazopanib has been shown to inhibit ligand-induced autophosphorylation of VEGFR-2, PDGFR-β, and c-Kit.1, 7, 12 In vivo, pazopanib inhibited VEGF-induced VEGFR-2 phosphorylation in mouse lungs and in human umbilical vein endothelial cells (HUVEC),4, 10, 12 angiogenesis in a mouse model, and the growth of some human tumor xenografts in mice.1, 12
Pazopanib appears to be as potent as sorafenib and sunitinib against VEGFR (i.e., VEGFR-1, VEGFR-2, VEGFR-3) and less potent than sunitinib against fms-like tyrosine kinase 3 (Flt-3).7, 13 Differences in potencies against non-VEGF receptors may account for variabilities in non-VEGFR-related (“off-target”) adverse effects observed with pazopanib (e.g., hepatotoxicity, lower incidence of palmar-plantar erythrodysesthesia [hand-foot syndrome] and rash compared with sorafenib or sunitinib [based on indirect cross-study comparison], lower incidence of and less severe myelosuppression compared with sunitinib [based on indirect cross-study comparison]).4, 11, 13 The relatively lower incidence of and less severe myelosuppressive effects reported with pazopanib may be explained, in part, by the drug's lower potency against Flt-3 (a regulator of hematopoiesis).7, 11
Pazopanib is incompletely absorbed from the GI tract, with reported bioavailabilities of 14-39%.18 Following oral administration, peak plasma concentrations of pazopanib occurred at a median of 2-4 hours.1 Administration of a single 400-mg crushed tablet increased the peak plasma concentrations and area under the plasma concentration-time curve (AUC) by approximately twofold and 46%, respectively, and decreased the time to peak plasma concentrations by approximately 2 hours, compared with administration of the whole tablet.1 Administration of pazopanib with food (i.e., low-fat or high-fat meal) resulted in an approximately twofold increase in peak plasma concentrations and AUC of the drug.1 Pazopanib is more than 99% bound to plasma proteins; in vitro studies suggest that pazopanib is a substrate of P-glycoprotein (Pgp) and breast cancer resistant protein (BCRP).1 Pazopanib is metabolized by the cytochrome P-450 (CYP) microsomal enzyme system, principally by the isoenzyme 3A4 (CYP3A4) and, to a lesser extent, by CYP1A2 and CYP2C8;1 in plasma, pazopanib metabolites accounted for less than 10% of the administered dose.2, 18 The mean half-life of pazopanib is approximately 31 hours.1 Approximately 82% of a radiolabeled dose of pazopanib is excreted in feces (67% of which is unchanged drug),18 and less than 4% is eliminated in urine.1 Hemodialysis is not expected to enhance elimination of pazopanib because the drug is highly bound to plasma proteins and is not substantially excreted renally.1
Pazopanib inhibits uridine diphosphate-glucuronosyltransferase (UGT) 1A1, an enzyme that catalyzes the glucuronidation of bilirubin for elimination.1 Patients who are homozygous for the UGT1A1*28 allele (characterized by a mutation in the promoter region of the UGT1A1 gene) have reduced expression of UGT1A1, which may manifest as mild hyperbilirubinemia (i.e., Gilbert's syndrome).1, 16 Mild elevations of indirect (unconjugated) bilirubin concentrations may occur in patients with Gilbert's syndrome receiving pazopanib.1 A pooled pharmacogenetic analysis of 236 Caucasian patients that evaluated the polymorphisms of UGT1A1 and its potential association with hyperbilirubinemia during pazopanib treatment found that the (TA)7/(TA)7 genotype (UGT1A1*28/*28, underlying genetic susceptibility to Gilbert's syndrome) was associated with an increase in the risk of hyperbilirubinemia relative to the (TA)6/(TA)6 and (TA)6/(TA)7 genotypes.1
Additional Information
Overview® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets, film-coated | 200 mg (of pazopanib) | Novartis |
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