Votrient Information
Votrient (Pazopanib) Warning: Hepatotoxicity
Severe and fatal hepatotoxicity has been observed in clinical studies. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended.
Votrient (Pazopanib) Indications And Usage
Votrient (Pazopanib) is indicated for the treatment of patients with advanced renal cell carcinoma (RCC).
Votrient (Pazopanib) Dosage And Administration
The recommended dose of Votrient (Pazopanib) is 800 mg orally once daily without food (at least 1 hour before or 2 hours after a meal) . The dose of Votrient (Pazopanib) should not exceed 800 mg.
Do not crush tablets due to the potential for increased rate of absorption which may affect systemic exposure.
If a dose is missed, it should not be taken if it is less than 12 hours until the next dose.
Initial dose reduction should be 400 mg, and additional dose decrease or increase should be in 200 mg steps based on individual tolerability. The dose of Votrient (Pazopanib) should not exceed 800 mg.
Votrient (Pazopanib) Dosage Forms And Strengths
200 mg tablets of Votrient (Pazopanib) — modified capsule-shaped, gray, film-coated with GS JT debossed on one side. Each tablet contains 216.7 mg of pazopanib hydrochloride equivalent to 200 mg of pazopanib.
Votrient (Pazopanib) Contraindications
Votrient (Pazopanib) Warnings And Precautions
In clinical trials with Votrient (Pazopanib) , hepatotoxicity, manifested as increases in serum transaminases (ALT, AST) and bilirubin, was observed . 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 (Pazopanib) , 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 (Pazopanib) . 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.
The safety of Votrient (Pazopanib) in patients with pre-existing severe hepatic impairment, defined as total bilirubin >3 X ULN with any level of ALT, is unknown. Treatment with Votrient (Pazopanib) is not recommended in patients with severe hepatic impairment.
In clinical RCC studies of Votrient (Pazopanib) , QT prolongation (≥500 msec) was identified on routine electrocardiogram monitoring in 11/558 (
In the randomized clinical trial, 3 of the 290 patients receiving Votrient (Pazopanib) had post-baseline values between 500 to 549 msec. None of the 145 patients receiving placebo had post-baseline QTc values ≥500 msec.
Votrient (Pazopanib) 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 (Pazopanib) , baseline and periodic monitoring of electrocardiograms and maintenance of electrolytes (e.g., calcium, magnesium, potassium) within the normal range should be performed.
In clinical studies, events of hypertension including hypertensive crisis have occurred.
[See Adverse Reactions (6.1).]
[see Dosage and Administration (2.2)]
Votrient (Pazopanib) can cause fetal harm when administered to a pregnant woman. Based on its mechanism of action, Votrient (Pazopanib) 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 (Pazopanib) 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 (Pazopanib) .
Votrient (Pazopanib) Drug Interactions
In vitro studies suggested that the oxidative metabolism of pazopanib in human liver microsomes is mediated primarily by CYP3A4, with minor contributions from CYP1A2 and CYP2C8. Therefore, inhibitors and inducers of CYP3A4 may alter the metabolism of pazopanib.
Results from drug-drug interaction studies conducted in cancer patients suggest that pazopanib is a weak inhibitor of CYP3A4, CYP2C8, and CYP2D6 in vivo, but had no effect on CYP1A2, CYP2C9, or CYP2C19
Concomitant use of Votrient (Pazopanib) with agents with narrow therapeutic windows that are metabolized by CYP3A4, CYP2D6, or CYP2C8 is not recommended. Coadministration may result in inhibition of the metabolism of these products and create the potential for serious adverse events.
Votrient (Pazopanib) Use In Specific Populations
Pregnancy Category D .
Votrient (Pazopanib) can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of Votrient (Pazopanib) 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 post-implantation 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 (Pazopanib) .
The safety and effectiveness of Votrient (Pazopanib) 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.
The safety and pharmacokinetics of pazopanib in patients with hepatic impairment have not been fully established. In clinical studies for Votrient (Pazopanib) , patients with total bilirubin ≤1.5 X ULN and AST and ALT ≤2 X ULN were included .
An interim analysis of data from 12 patients with normal hepatic function and 9 with moderate hepatic impairment showed that the maximum tolerated dose in patients with moderate hepatic impairment was 200 mg per day . There are no data on patients with severe hepatic impairment .
Patients with renal cell cancer and mild/moderate renal impairment (creatinine clearance ≥30 mL/min) were included in clinical studies for Votrient (Pazopanib) .
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
Votrient (Pazopanib) Overdosage
Pazopanib doses up to 2,000 mg have been evaluated in clinical trials. Dose-limiting toxicity (Grade 3 fatigue) and Grade 3 hypertension were each observed in 1 of 3 patients dosed at 2,000 mg daily and 1,000 mg daily, respectively.
Treatment of overdose with Votrient (Pazopanib) should consist of general supportive measures. There is no specific antidote for overdosage of Votrient (Pazopanib) .
Hemodialysis is not expected to enhance the elimination of Votrient (Pazopanib) because pazopanib is not significantly renally excreted and is highly bound to plasma proteins.
Votrient (Pazopanib) Description
Votrient (Pazopanib) is a tyrosine kinase inhibitor (TKI). Pazopanib is presented as the hydrochloride salt, with the chemical name 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulfonamide monohydrochloride. It has the molecular formula CHNOS•HCl and a molecular weight of 473.99. Pazopanib hydrochloride has the following chemical structure:
Pazopanib hydrochloride is a white to slightly yellow solid. It is very slightly soluble at pH 1 and practically insoluble above pH 4 in aqueous media.
Tablets of Votrient (Pazopanib) are for oral administration. Each 200 mg tablet of Votrient (Pazopanib) contains 216.7 mg of pazopanib hydrochloride, equivalent to 200 mg of pazopanib free base.
The inactive ingredients of Votrient (Pazopanib) are: Magnesium stearate, microcrystalline cellulose, povidone, sodium starch glycolate. Gray film-coat: Hypromellose, iron oxide black, macrogol/polyethylene glycol 400 (PEG 400), polysorbate 80, titanium dioxide.
Votrient (Pazopanib) Clinical Pharmacology
Increases in blood pressure have been observed and are related to steady-state trough plasma pazopanib concentrations.
The QT prolongation potential of pazopanib was assessed in a randomized, blinded, parallel study (N = 96) using moxifloxacin as a positive control. Pazopanib 800 mg was dosed under fasting conditions on Days 2 to 8 and 1,600 mg was dosed on Day 9 after a mea1 in order to increase exposure to pazopanib and its metabolites. No large changes (i.e., >20 msec) in QTc interval following the treatment of pazopanib were detected in this QT study. The study was not able to exclude small changes (
Absorption:
Administration of a single pazopanib 400 mg crushed tablet increased AUC by 46% and C by approximately 2 fold and decreased t by approximately 2 hours compared to administration of the whole tablet. These results indicate that the bioavailability and the rate of pazopanib oral absorption are increased after administration of the crushed tablet relative to administration of the whole tablet. Therefore, due to this potential for increased exposure, tablets of Votrient (Pazopanib) should not be crushed.
Systemic exposure to pazopanib is increased when administered with food. Administration of pazopanib with a high-fat or low-fat meal results in an approximately 2-fold increase in AUC and C. Therefore, pazopanib should be administered at least 1 hour before or 2 hours after a meal .
Distribution:
Metabolism:
Elimination:
Hepatic Impairment:
Pharmacokinetic data from patients with normal hepatic function (n = 12) and moderate (n = 7) hepatic impairment indicate that pazopanib clearance was decreased by 50% in those with moderate hepatic impairment. The maximum tolerated pazopanib dose in patients with moderate hepatic impairment is 200 mg once daily. There are no data on patients with mild or severe hepatic impairment.
Administration of 1,500 mg lapatinib, a substrate and weak inhibitor of CYP3A4, Pgp, and BCRP, with 800 mg pazopanib resulted in an approximately 50% to 60% increase in mean pazopanib AUC and Ccompared to administration of 800 mg pazopanib alone.
In vitro studies with human liver microsomes showed that pazopanib inhibited the activities of CYP enzymes 1A2, 3A4, 2B6, 2C8, 2C9, 2C19, 2D6, and 2E1. Potential induction of human CYP3A4 was demonstrated in an in vitro human PXR assay. Clinical pharmacology studies, using pazopanib 800 mg once daily, have demonstrated that pazopanib does not have a clinically relevant effect on the pharmacokinetics of caffeine (CYP1A2 probe substrate), warfarin (CYP2C9 probe substrate), or omeprazole (CYP2C19 probe substrate) in cancer patients. Pazopanib resulted in an increase of approximately 30% in the mean AUC and C of midazolam (CYP3A4 probe substrate) and increases of 33% to 64% in the ratio of dextromethorphan to dextrorphan concentrations in the urine after oral administration of dextromethorphan (CYP2D6 probe substrate). Coadministration of pazopanib 800 mg once daily and paclitaxel 80 mg/m (CYP3A4 and CYP2C8 substrate) once weekly resulted in a mean increase of 26% and 31% in paclitaxel AUC and C, respectively.
In vitro studies also showed that pazopanib inhibits UGT1A1 and OATP1B1 with IC50s of 1.2 and 0.79 μM, respectively. Pazopanib may increase concentrations of drugs eliminated by UGT1A1 and OATP1B1.
Votrient (Pazopanib) Clinical Studies
The safety and efficacy of Votrient (Pazopanib) in renal cell carcinoma (RCC) were evaluated in a randomized, double-blind, placebo-controlled, multicenter, Phase 3 study. Patients (N = 435) with locally advanced and/or metastatic RCC who had received either no prior therapy or one prior cytokine-based systemic therapy were randomized (2:1) to receive Votrient (Pazopanib) 800 mg once daily or placebo once daily. The primary objective of the study was to evaluate and compare the 2 treatment arms for progression-free survival (PFS); the secondary endpoints included overall survival (OS), overall response rate (RR), and duration of response.
Of the total of 435 patients enrolled in this study, 233 patients had no prior systemic therapy (treatment-naïve subgroup) and 202 patients received one prior IL-2 or INFα-based therapy (cytokine-pretreated subgroup). The baseline demographic and disease characteristics were balanced between the Votrient (Pazopanib) and placebo arms. The majority of patients were male (71%) with a median age of 59 years. Eighty-six percent of patients were Caucasian, 14% were Asian and less than 1% were other. Forty-two percent were ECOG performance status 0 and 58% were ECOG performance status 1. All patients had clear cell histology (90%) or predominantly clear cell histology (10%). Approximately 50% of all patients had 3 or more organs involved with metastatic disease. The most common metastatic sites at baseline were lung (74%), lymph nodes (56%), bone (27%), and liver (25%).
A similar proportion of patients in each arm were treatment-naïve and cytokine-pretreated (see Table 3). In the cytokine-pretreated subgroup, the majority (75%) had received interferon-based treatment. Similar proportions of patients in each arm had prior nephrectomy (89% and 88% for Votrient (Pazopanib) and placebo, respectively).
The analysis of the primary endpoint PFS was based on disease assessment by independent radiological review in the entire study population. OS data were not mature at the time of the interim survival analysis. Efficacy results are presented in Table 3 and Figure 1.
HR = Hazard Ratio; ITT = Intent to Treat; PFS = Progression-free Survival; CR = Complete Response; PR = Partial Response
Votrient (Pazopanib) How Supplied/storage And Handling
The 200 mg tablets of Votrient (Pazopanib) are modified capsule-shaped, gray, film-coated with GS JT debossed on one side and are available in:
Bottles of 120 tablets: NDC 0173-0804-09
Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature].
Votrient (Pazopanib) 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:
Votrient (Pazopanib)
Votrient (Pazopanib)
Votrient (Pazopanib)
