Pazopanib 200 mg Tablet, 120-count — NDC 60505-4779-7 (Billing 60505-4779-07)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Pazopanib is a multi-tyrosine kinase inhibitor of vascular endothelial growth factor receptor (VEGFR)-1, VEGFR-2, VEGFR-3, platelet-derived growth factor receptor (PDGFR)-ɑ and -β, fibroblast growth factor receptor (FGFR)-1 and -3, cytokine receptor (Kit), interleukin-2 receptor-inducible T-cell kinase (Itk), lymphocyte-specific protein tyrosine kinase (Lck), and transmembrane glycoprotein receptor tyrosine kinase (c­-Fms). In vitro, pazopanib inhibited ligand-induced autophosphorylation of VEGFR-2, Kit, and PDGFR-β receptors.

In vivo, pazopanib inhibited VEGF-induced VEGFR-2 phosphorylation in mouse lungs, angiogenesis in a mouse model, and the growth of some human tumor xenografts in mice.

12.2Pharmacodynamics Increases in blood pressure have been observed and are related to steady-state trough plasma pazopanib concentrations. Cardiac Electrophysiology The QT prolongation potential of pazopanib was assessed in a randomized, blinded, parallel trial (N = 96) using moxifloxacin as a positive control. pazopanib tablets 800 mg orally under fasting conditions was administered on Days 2 to 8 and 1,600 mg was administered on Day 9 after a meal in order to increase exposure to pazopanib and its metabolites. No large changes (i.e.,> 20 msec) in QTc interval following exposure to pazopanib were detected in this QT trial.

The trial was not able to exclude small changes (< 10 msec) in QTc interval, because assay sensitivity below this threshold (< 10 msec) was not established in this trial [see Warnings and Precautions ( 5.2 )].

12.3Pharmacokinetics The recommended dosage of 800 mg once daily results in mean AUC of 1,037 mcg•h/mL and C max of 58.1 mcg/mL. There was no consistent increase in AUC or C max at pazopanib doses above 800 mg. Administration of a single 400-mg crushed tablet increased AUC 0-72h by 46% and C max by approximately 2-fold and decreased T max by approximately 2 hours compared with administration of the whole tablet [see Dosage and Administration ( 2.1 )].

Absorption The median time to achieve peak concentrations was 2 to 4 hours after a dose. Effect of Food Systemic exposure to pazopanib is increased when administered with food. Administration of pazopanib with a high-fat (approximately 50% fat) or low-fat (approximately 5% fat) meal results in an approximately 2-fold increase in AUC and C max .

Distribution Binding of pazopanib to human plasma protein in vivo was > 99% with no concentration dependence over the range of 10 to 100 mcg/mL. In vitro studies suggest that pazopanib is a substrate for P-gp and BCRP. Elimination Pazopanib has a mean half-life of 31 hours after administration of the recommended dose of 800 mg.

Metabolism In vitro studies demonstrated that pazopanib is metabolized by CYP3A4 with a minor contribution from CYP1A2 and CYP2C8. Excretion Elimination is primarily via feces with renal elimination accounting for < 4% of the administered dose. Specific Populations Patients with Hepatic Impairment Table 7 presents a comparison of the median steady-state C max and the median AUC 0-24h values for patients with normal, mild, moderate and severe hepatic impairment.

The median steady-state of pazopanib C max and AUC 0-24h after a once-daily dose of 800 mg in patients with mild impairment were in a similar range as the median steady-state C max and median AUC 0-24h in patients with no hepatic impairment. The maximum tolerated pazopanib dose in patients with moderate hepatic impairment was 200 mg once daily. The median steady-state C max and the median AUC 0-24h were approximately 43% and 29%, respectively, of the corresponding median values after administration of 800 mg once daily in patients with no hepatic impairment.

The median steady-state C max and the median AUC 0-24h were approximately 18% and 15%, respectively, of the corresponding median values after administration of 800 mg once daily in patients with no hepatic impairment. Table 7. Pharmacokinet… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Pazopanib is a multi-tyrosine kinase inhibitor of vascular endothelial growth factor receptor (VEGFR)-1, VEGFR-2, VEGFR-3, platelet-derived growth factor receptor (PDGFR)-ɑ and -β, fibroblast growth factor receptor (FGFR)-1 and -3, cytokine receptor (Kit), interleukin-2 receptor-inducible T-cell kinase (Itk), lymphocyte-specific protein tyrosine kinase (Lck), and transmembrane glycoprotein receptor tyrosine kinase (c­-Fms). In vitro, pazopanib inhibited ligand-induced autophosphorylation of VEGFR-2, Kit, and PDGFR-β receptors.

In vivo, pazopanib inhibited VEGF-induced VEGFR-2 phosphorylation in mouse lungs, angiogenesis in a mouse model, and the growth of some human tumor xenografts in mice.

12.3Pharmacokinetics The recommended dosage of 800 mg once daily results in mean AUC of 1,037 mcg•h/mL and C max of 58.1 mcg/mL. There was no consistent increase in AUC or C max at pazopanib doses above 800 mg. Administration of a single 400-mg crushed tablet increased AUC 0-72h by 46% and C max by approximately 2-fold and decreased T max by approximately 2 hours compared with administration of the whole tablet [see Dosage and Administration ( 2.1 )].

Absorption The median time to achieve peak concentrations was 2 to 4 hours after a dose. Effect of Food Systemic exposure to pazopanib is increased when administered with food. Administration of pazopanib with a high-fat (approximately 50% fat) or low-fat (approximately 5% fat) meal results in an approximately 2-fold increase in AUC and C max .

Distribution Binding of pazopanib to human plasma protein in vivo was > 99% with no concentration dependence over the range of 10 to 100 mcg/mL. In vitro studies suggest that pazopanib is a substrate for P-gp and BCRP. Elimination Pazopanib has a mean half-life of 31 hours after administration of the recommended dose of 800 mg.

Metabolism In vitro studies demonstrated that pazopanib is metabolized by CYP3A4 with a minor contribution from CYP1A2 and CYP2C8. Excretion Elimination is primarily via feces with renal elimination accounting for < 4% of the administered dose. Specific Populations Patients with Hepatic Impairment Table 7 presents a comparison of the median steady-state C max and the median AUC 0-24h values for patients with normal, mild, moderate and severe hepatic impairment.

The median steady-state of pazopanib C max and AUC 0-24h after a once-daily dose of 800 mg in patients with mild impairment were in a similar range as the median steady-state C max and median AUC 0-24h in patients with no hepatic impairment. The maximum tolerated pazopanib dose in patients with moderate hepatic impairment was 200 mg once daily. The median steady-state C max and the median AUC 0-24h were approximately 43% and 29%, respectively, of the corresponding median values after administration of 800 mg once daily in patients with no hepatic impairment.

The median steady-state C max and the median AUC 0-24h were approximately 18% and 15%, respectively, of the corresponding median values after administration of 800 mg once daily in patients with no hepatic impairment. Table 7. Pharmacokinetic Parameters of Pazopanib in Patients with Hepatic Impairment No Hepatic Impairment Mild Hepatic Impairment (total bilirubin ≤ ULN and ALT > ULN or total bilirubin > 1 to 1.5 x ULN and any ALT value) Moderate Hepatic Impairment (total bilirubin > 1.5 to 3 x ULN and any ALT value ) Severe Hepatic Impairment (total bilirubin > 3 x ULN and any ALT value) Dose 800 mg once daily 800 mg once daily 200 mg once daily 200 mg once daily Median steady- state C max (range) mcg/mL 52 (17 to 86) 34 (11 to 104) 22 (4.2 to 33) 9.4 (2.4 to 24) Median AUC 0-24h (range) mcg•h/mL 888 (346 to 1482) 774 (215 to 2034) 257 (66 to 488) 131 (47 to 473) Abbreviations: ALT, alanine aminotransferase; AUC, area under the curve; C max , maximum concentration; ULN, upper limit of normal.

Drug Interactions Studies Clinical Studies Strong CYP3A4 Inhibitor: Coadministration of multiple doses of oral pazopanib tablets 400 mg with multiple doses of oral ketoconazole 400 mg (strong CYP3A4/P-gp inhibitor) resulted in a 1.7-fold increase in the AUC 0-24h and a 1.5-fold increase in the C max of pazopanib [see Dosage and Administration ( 2.4 ), Drug Interactions ( 7.1 )]. Weak CYP3A4 Inhibitor: Coadministration of 1,500 mg lapatinib, a substrate and weak inhibitor of CYP3A4, P-gp, and BCRP, with pazopanib tablets 800 mg resulted in an approximately 50% to 60% increase in mean pazopanib AUC 0-24h and C max .

CYP1A2, CYP2C9 and CYP2C19 Substrates: Clinical studies, using pazopanib tablets 800 mg once daily, have demonstrated that pazopanib does not have a clinically relevant effect on the pharmacokinetics of ca… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics Increases in blood pressure have been observed and are related to steady-state trough plasma pazopanib concentrations. Cardiac Electrophysiology The QT prolongation potential of pazopanib was assessed in a randomized, blinded, parallel trial (N = 96) using moxifloxacin as a positive control. pazopanib tablets 800 mg orally under fasting conditions was administered on Days 2 to 8 and 1,600 mg was administered on Day 9 after a meal in order to increase exposure to pazopanib and its metabolites. No large changes (i.e.,> 20 msec) in QTc interval following exposure to pazopanib were detected in this QT trial.

The trial was not able to exclude small changes (< 10 msec) in QTc interval, because assay sensitivity below this threshold (< 10 msec) was not established in this trial [see Warnings and Precautions ( 5.2 )].

14 CLINICAL STUDIES

14.1Renal Cell Carcinoma The efficacy of pazopanib tablets was evaluated in VEG105192, a randomized, double-blind, placebo-controlled, multicenter trial (NCT00387764). Patients 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 pazopanib tablets 800 mg once daily or placebo once daily. Eligible subjects were stratified according to the following 3 stratification factors: baseline ECOG performance status 0 versus 1; prior nephrectomy yes versus no; and prior systemic therapy for advanced RCC: treatment-naïve versus one prior cytokine-based therapy.

The major efficacy outcome measure was progression-free survival (PFS). Additional outcome measures were overall survival (OS), overall response rate (ORR), and duration of response. Of the total of 435 patients enrolled in this trial, 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 arms receiving pazopanib tablets and placebo. The majority of patients were male (71%) with a median age of 59 years. Eighty-six percent of patients were white, 14% were Asian, and < 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 8). 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 pazopanib tablets and placebo, respectively). The analysis of the primary endpoint PFS was based on disease assessment by independent radiological review in the entire trial population. Efficacy results are presented in Table 8 and Figure 1.

Table 8. Efficacy Results in RCC Patients by Independent Assessment in VEG105192 Endpoint/Trial Population Pazopanib Tablets Placebo HR (95% CI) PFS Overall ITT N=290 N= 145 Median (months) 9.2 4.2 0.46 a (0.34, 0.62) Treatment-naïve subgroup N = 155 (53%) N = 78 (54%) Median (months) 11.1 2.8 0.40 (0.27, 0.60) Cytokine pre-treated subgroup N = 135 (47%) N = 67 (46%) Median (months) 7.4 4.2 0.54 (0.35, 0.84) Response Rate (CR + PR) N=290 N= 145 ­­-- % (95% CI) 30 (25.1, 35.6) 3 (0.5, 6.4) Duration of response Median (weeks) (95% CI) 58.7 (52.1, 68.1) _ b Abbreviations: CI, confidence interval; CR, complete response; HR, hazard ratio; ITT, intent-to-treat; PFS, progression-free survival; PR, partial response; RCC, renal cell carcinoma. a P value < 0.001. b There were only 5 objective responses.

Figure 1. Kaplan-Meier Curve for Progression-free Survival in RCC by Independent Assessment for the Overall Population (Treatment-naïve and Cytokine Pre-treated Populations) in VEG105192 At the protocol-specified final analysis of OS, the median OS was 22.9 months for patients randomized to pazopanib tablets and 20.5 months for the placebo arm [HR= 0.91 (95% CI: 0.71, 1.16)]. The median OS for the placebo arm includes 79 patients (54%) who discontinued placebo treatment because of disease progression and crossed over to treatment with pazopanib tablets.

In the placebo arm, 95 (66%) patients received at least one systemic anticancer treatment after progression compared with 88 (30%) patients randomized to pazopanib tablets.

14.2Soft Tissue Sarcoma The efficacy of pazopanib tablets was evaluated in VEG110727, a randomized, double-blind, placebo-controlled, multicenter trial (NCT00753688). Patients with metastatic… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility The carcinogenic potential of pazopanib was evaluated in CD-1 mice, and Sprague-Dawley rats. Administration of pazopanib to mice for 2 years did not result in increased incidence of neoplasms at doses up to 100 mg/kg/day (approximately 1.4-fold the AUC at the MRHD of 800 mg/day). Administration of pazopanib to rats for 2 years resulted in findings of duodenal adenocarcinoma in males at 30 mg/kg/day (approximately 0.3-fold the AUC at the MRHD of 800 mg/day) and in females at greater than or equal to 10 mg/kg/day (approximately 0.3-fold the AUC at the MRHD of 800 mg/day).

The human relevance of these neoplastic findings is unclear. 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. In an oral female fertility and early embryonic development study, female rats were administered pazopanib at least 15 days prior to mating, and for 6 days after mating.

Pazopanib did affect fertility in female rats. Reduced fertility, including increased pre-implantation loss and early resorptions, were noted at dosages greater than or equal to 30 mg/kg/day (approximately 0.4-fold the AUC at the MRHD of 800 mg/day). Decreased corpora lutea and increased cysts were noted in mice given greater than or equal to 100 mg/kg/day for 13 weeks and ovarian atrophy was noted in rats given greater than or equal to 300 mg/kg/day for 26 weeks (approximately 1.3 and 0.85-fold the AUC at the MRHD of 800 mg/day).

Decreased corpora lutea was also noted in monkeys given 500 mg/kg/day for up to 34 weeks (approximately 0.4-fold the AUC at the MRHD of 800 mg/day). Pazopanib did not affect mating or fertility in male rats. However, there were reductions in sperm production rates and testicular sperm concentrations at doses greater than or equal to 3 mg/kg/day, epididymal sperm concentrations at doses greater than or equal to 30 mg/kg/day, and sperm motility at greater than or equal to 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 greater than or equal to 30 mg/kg/day (approximately 0.35-fold the AUC at the MRHD of 800 mg/day); 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.