In clinical trials with VOTRIENT, hepatotoxicity, manifested as increases in serum transaminases (ALT, AST) and bilirubin, was observed [see ADVERSE REACTIONS]. This hepatotoxicity can be severe and fatal. Transaminase elevations occur early in the course of treatment (92.5% of all transaminase elevations of any grade occurred in the first 18 weeks). Across all monotherapy studies with VOTRIENT, ALT > 3 X upper limit of normal (ULN) was reported in 138/977 (14%) and ALT > 8 X ULN was reported in 40/977 (4%) of patients who received VOTRIENT. Concurrent elevations in ALT > 3 X ULN and bilirubin > 2 X ULN regardless of alkaline phosphatase levels were detected in 13/977 (1%) of patients. Four of the 13 patients had no other explanation for these elevations. Two of 977 (0.2%) patients died with disease progression and hepatic failure.
- Monitor serum liver tests before initiation of treatment with VOTRIENT and at least once every 4 weeks for at least the first 4 months of treatment or as clinically indicated. Periodic monitoring should then continue after this time period.
- Patients with isolated ALT elevations between 3 X ULN and 8 X ULN may be continued on VOTRIENT with weekly monitoring of liver function until ALT return to Grade 1 or baseline.
- Patients with isolated ALT elevations of > 8 X ULN should have VOTRIENT interrupted until they return to Grade 1 or baseline. If the potential benefit for reinitiating treatment with VOTRIENT is considered to outweigh the risk for hepatotoxicity, then reintroduce VOTRIENT at a reduced dose of no more than 400 mg once daily and measure serum liver tests weekly for 8 weeks [see DOSAGE AND ADMINISTRATION]. Following reintroduction of VOTRIENT, if ALT elevations > 3 X ULN recur, then VOTRIENT should be permanently discontinued.
- If ALT elevations > 3 X ULN occur concurrently with bilirubin elevations > 2 X ULN, VOTRIENT should be permanently discontinued. Patients should be monitored until resolution. VOTRIENT is a UGT1A1 inhibitor. Mild, indirect (unconjugated) hyperbilirubinemia may occur in patients with Gilbert's syndrome [see CLINICAL PHARMACOLOGY]. Patients with only a mild indirect hyperbilirubinemia, known Gilbert's syndrome, and elevation in ALT > 3 X ULN should be managed as per the recommendations outlined for isolated ALT elevations.
Concomitant use of VOTRIENT and simvastatin increases the risk of ALT elevations and should be undertaken with caution and close monitoring [see DRUG INTERACTIONS]. Insufficient data are available to assess the risk of concomitant administration of alternative statins and VOTRIENT.
In patients with pre-existing moderate hepatic impairment, the starting dose of VOTRIENT should be reduced or alternatives to VOTRIENT should be considered. Treatment with VOTRIENT is not recommended in patients with pre-existing severe hepatic impairment, defined as total bilirubin > 3 X ULN with any level of ALT. [See DOSAGE AND ADMINISTRATION, Use In Specific Populations, and CLINICAL PHARMACOLOGY.]
QT Prolongation and Torsades de Pointes
In clinical RCC studies of VOTRIENT, QT prolongation ( ≥ 500 msec) was identified on routine electrocardiogram monitoring in 11/558 ( < 2%) of patients. Torsades de pointes occurred in 2/977 ( < 1%) of patients who received VOTRIENT in the monotherapy studies.
In the randomized clinical trial, 3 of the 290 patients receiving VOTRIENT had postbaseline values between 500 to 549 msec. None of the 145 patients receiving placebo had postbaseline QTc values ≥ 500 msec.
VOTRIENT should be used with caution in patients with a history of QT interval prolongation, in patients taking antiarrhythmics or other medications that may prolong QT interval, and those with relevant pre-existing cardiac disease. When using VOTRIENT, baseline and periodic monitoring of electrocardiograms and maintenance of electrolytes (e.g., calcium, magnesium, potassium) within the normal range should be performed.
In clinical RCC studies of VOTRIENT, hemorrhagic events have been reported [all Grades (16%) and Grades 3 to 5 (2%)]. Fatal hemorrhage has occurred in 5/586 (0.9%) [see ADVERSE REACTIONS]. VOTRIENT has not been studied in patients who have a history of hemoptysis, cerebral, or clinically significant gastrointestinal hemorrhage in the past 6 months and should not be used in those patients.
Arterial Thrombotic Events
In clinical RCC studies of VOTRIENT, myocardial infarction, angina, ischemic stroke, and transient ischemic attack [all Grades (3%) and Grades 3 to 5 (2%)] were observed. Fatal events have been observed in 2/586 (0.3%). In the randomized study, these events were observed more frequently with VOTRIENT compared to placebo [see ADVERSE REACTIONS]. VOTRIENT should be used with caution in patients who are at increased risk for these events or who have had a history of these events. VOTRIENT has not been studied in patients who have had an event within the previous 6 months and should not be used in those patients.
Gastrointestinal Perforation and Fistula
In clinical RCC studies of VOTRIENT, gastrointestinal perforation or fistula has been reported in 5 patients (0.9%). Fatal perforation events have occurred in 2/586 (0.3%). Monitor for symptoms of gastrointestinal perforation or fistula.
In clinical studies, events of hypertension including hypertensive crisis have occurred. Blood pressure should be well-controlled prior to initiating VOTRIENT. Patients should be monitored for hypertension and treated as needed with anti-hypertensive therapy. Hypertension (systolic blood pressure ≥ 150 or diastolic blood pressure ≥ 100 mm Hg) was observed in 47% of patients with RCC treated with VOTRIENT. Hypertension occurs early in the course of treatment (39% of cases occurred by Day 9 and 88% of cases occurred in the first 18 weeks). [See ADVERSE REACTIONS.] In the case of persistent hypertension despite anti-hypertensive therapy, the dose of VOTRIENT may be reduced [see DOSAGE AND ADMINISTRATION]. VOTRIENT should be discontinued if there is evidence of hypertensive crisis or if hypertension is severe and persistent despite anti-hypertensive therapy and dose reduction of VOTRIENT.
No formal studies on the effect of VOTRIENT on wound healing have been conducted. Since vascular endothelial growth factor receptor (VEGFR) inhibitors such as pazopanib may impair wound healing, treatment with VOTRIENT should be stopped at least 7 days prior to scheduled surgery. The decision to resume VOTRIENT after surgery should be based on clinical judgment of adequate wound healing. VOTRIENT should be discontinued in patients with wound dehiscence.
In clinical RCC studies with VOTRIENT, proteinuria has been reported in 44/586 (8%) [Grade 3, 5/586 ( < 1%) and Grade 4, 1/586 ( < 1%)] [see ADVERSE REACTIONS]. Baseline and periodic urinalysis during treatment is recommended. VOTRIENT should be discontinued if the patient develops Grade 4 proteinuria.
VOTRIENT can cause fetal harm when administered to a pregnant woman. Based on its mechanism of action, VOTRIENT is expected to result in adverse reproductive effects. In pre- clinical studies in rats and rabbits, pazopanib was teratogenic, embryotoxic, fetotoxic, and abortifacient.
There are no adequate and well-controlled studies of VOTRIENT in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while taking VOTRIENT. [See Use In Specific Populations.]
Patient Counseling Information
See Medication Guide. The Medication Guide is contained in a separate leaflet that accompanies the product. However, inform patients of the following:
- Therapy with VOTRIENT may result in hepatobiliary laboratory abnormalities. Monitor serum liver tests (ALT, AST, and bilirubin) prior to initiation of VOTRIENT and at least once every 4 weeks for the first 4 months of treatment or as clinically indicated. Inform patients that they should report any of the following signs and symptoms of liver problems to their healthcare provider right away.
- Gastrointestinal adverse reactions such as diarrhea, nausea, and vomiting have been reported with VOTRIENT. Patients should be advised how to manage diarrhea and to notify their healthcare provider if moderate to severe diarrhea occurs.
- Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant.
- Patients should be advised to inform their healthcare providers of all concomitant medications, vitamins, or dietary and herbal supplements.
- Patients should be advised that depigmentation of the hair or skin may occur during treatment with VOTRIENT.
- Patients should be advised to take VOTRIENT without food (at least 1 hour before or 2 hours after a meal).
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity studies with pazopanib have not been conducted. However, in a 13-week study in mice, proliferative lesions in the liver including eosinophilic foci in 2 females and a single case of adenoma in another female was observed at doses of 1,000 mg/kg/day (approximately 2.5 times the human clinical exposure based on AUC).
Pazopanib did not induce mutations in the microbial mutagenesis (Ames) assay and was not clastogenic in both the in vitro cytogenetic assay using primary human lymphocytes and in the in vivo rat micronucleus assay.
Pazopanib may impair fertility in humans. In female rats, reduced fertility including increased pre-implantation loss and early resorptions were noted at dosages ≥ 30 mg/kg/day (approximately 0.4 times the human clinical exposure based on AUC). Total litter resorption was seen at 300 mg/kg/day (approximately 0.8 times the human clinical exposure based on AUC). Post-implantation loss, embryolethality, and decreased fetal body weight were noted in females administered doses ≥ 10 mg/kg/day (approximately 0.3 times the human clinical exposure based on AUC). Decreased corpora lutea and increased cysts were noted in mice given ≥ 100 mg/kg/day for 13 weeks and ovarian atrophy was noted in rats given ≥ 300 mg/kg/day for 26 weeks (approximately 1.3 and 0.85 times the human clinical exposure based on AUC, respectively). Decreased corpora lutea was also noted in monkeys given 500 mg/kg/day for up to 34 weeks (approximately 0.4 times the human clinical exposure based on AUC).
Pazopanib did not affect mating or fertility in male rats. However, there were reductions in sperm production rates and testicular sperm concentrations at doses ≥ 3 mg/kg/day, epididymal sperm concentrations at doses ≥ 30 mg/kg/day, and sperm motility at ≥ 100 mg/kg/day following 15 weeks of dosing. Following 15 and 26 weeks of dosing, there were decreased testicular and epididymal weights at doses of ≥ 30 mg/kg/day (approximately 0.35 times the human clinical exposure based on AUC); atrophy and degeneration of the testes with aspermia, hypospermia and cribiform change in the epididymis was also observed at this dose in the 6-month toxicity studies in male rats.
Use In Specific Populations
Pregnancy Category D [see WARNINGS AND PRECAUTIONS].
VOTRIENT can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of VOTRIENT in pregnant women.
In pre-clinical studies in rats and rabbits, pazopanib was teratogenic, embryotoxic, fetotoxic, and abortifacient. Administration of pazopanib to pregnant rats during organogenesis at a dose level of ≥ 3 mg/kg/day (approximately 0.1 times the human clinical exposure based on AUC) resulted in teratogenic effects including cardiovascular malformations (retroesophageal subclavian artery, missing innominate artery, changes in the aortic arch) and incomplete or absent ossification. In addition, there was reduced fetal body weight, and pre- and postimplantation embryolethality in rats administered pazopanib at doses ≥ 3 mg/kg/day. In rabbits, maternal toxicity (reduced food consumption, increased post-implantation loss, and abortion) was observed at doses ≥ 30 mg/kg/day (approximately 0.007 times the human clinical exposure). In addition, severe maternal body weight loss and 100% litter loss were observed at doses ≥ 100 mg/kg/day (0.02 times the human clinical exposure), while fetal weight was reduced at doses ≥ 3 mg/kg/day (AUC not calculated).
If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while taking VOTRIENT.
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from VOTRIENT, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
The safety and effectiveness of VOTRIENT in pediatric patients have not been established.
In repeat-dose toxicology studies in rats including 4-week, 13-week, and 26-week administration, toxicities in bone, teeth, and nail beds were observed at doses ≥ 3 mg/kg/day (approximately 0.07 times the human clinical exposure based on AUC). Doses of 300 mg/kg/day (approximately 0.8 times the human clinical exposure based on AUC) were not tolerated in 13- and 26-week studies with rats. Body weight loss and morbidity were observed at these doses. Hypertrophy of epiphyseal growth plates, nail abnormalities (including broken, overgrown, or absent nails) and tooth abnormalities in growing incisor teeth (including excessively long, brittle, broken and missing teeth, and dentine and enamel degeneration and thinning) were observed in rats at ≥ 30 mg/kg/day (approximately 0.35 times the human clinical exposure based on AUC) at 26 weeks, with the onset of tooth and nail bed alterations noted clinically after 4 to 6 weeks.
In clinical trials with VOTRIENT for the treatment of RCC, 196 subjects (33%) were aged ≥ 65 years, and 34 subjects (6%) were aged > 75 years. No overall differences in safety or effectiveness of VOTRIENT were observed between these subjects and younger subjects. However, patients > 60 years of age may be at greater risk for an ALT > 3 X ULN. Other reported clinical experience has not identified differences in responses between elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
In clinical studies for VOTRIENT, patients with total bilirubin ≤ 1.5 X ULN and AST and ALT ≤ 2 X ULN were included [see WARNINGS AND PRECAUTIONS].
An analysis of data from a pharmacokinetic study of pazopanib in patients with varying degrees of hepatic dysfunction suggested that no dose adjustment is required in patients with mild hepatic impairment [either total bilirubin within normal limit (WNL) with ALT > ULN or bilirubin > 1 X to 1.5 X ULN regardless of the ALT value]. The maximum tolerated dose in patients with moderate hepatic impairment (total bilirubin > 1.5 X to 3 X ULN regardless of the ALT value) was 200 mg per day (N = 11). The median steady-state Cmax and AUC(0.24) achieved at this dose was approximately 40% and 29%, respectively of that seen in patients with normal hepatic function at the recommended daily dose of 800 mg. The maximum dose explored in patients with severe hepatic impairment (total bilirubin > 3 X ULN regardless of the ALT value) was 200 mg per day (N = 14). This dose was not well tolerated. Median exposures achieved at this dose were approximately 18% and 15% of those seen in patients with normal liver function at the recommended daily dose of 800 mg. Therefore, VOTRIENT is not recommended in these patients [see CLINICAL PHARMACOLOGY].
Patients with renal cell cancer and mild/moderate renal impairment (creatinine clearance ≥ 30 mL/min) were included in clinical studies for VOTRIENT.
There are no clinical or pharmacokinetic data in patients with severe renal impairment or in patients undergoing peritoneal dialysis or hemodialysis. However, renal impairment is unlikely to significantly affect the pharmacokinetics of pazopanib since < 4% of a radiolabeled oral dose was recovered in the urine. In a population pharmacokinetic analysis using 408 subjects with various cancers, creatinine clearance (30-150 mL/min) did not influence clearance of pazopanib. Therefore, renal impairment is not expected to influence pazopanib exposure, and dose adjustment is not necessary.
Last reviewed on RxList: 4/4/2012
This monograph has been modified to include the generic and brand name in many instances.
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