PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

PRINCIPAL DISPLAY PANEL

NDC 0078-1077-66

Votrient®

(pazopanib)

Tablets

200 mg

120 Tablets

Rx only

Each tablet contains 216.7 mg of
pazopanib hydrochloride, equivalent
to 200 mg of pazopanib free base.

Dispense with Medication Guide
attached or provided separately.

NOVARTIS

---

DESCRIPTION SECTION

11 DESCRIPTION

Pazopanib is a kinase inhibitor. 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 C21H23N7O2S•HCl and a molecular weight of 473.99 g/mol. 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.

VOTRIENT tablets are for oral use. Each 200-mg tablet of VOTRIENT contains 200 mg of pazopanib equivalent to 216.7 mg of pazopanib hydrochloride. The inactive ingredients of VOTRIENT are:Tablet Core: magnesium stearate, microcrystalline cellulose, povidone, and sodium starch glycolate. Coating: Gray or pink film-coat: hypromellose, iron oxide black, macrogol/polyethylene glycol 400 (PEG 400), polysorbate 80, and titanium dioxide.

CLINICAL PHARMACOLOGY SECTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism 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)-α 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.

12.2 Pharmacodynamics

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. VOTRIENT 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)].

12.3 Pharmacokinetics

The recommended dosage of 800 mg once daily results in mean AUC of 1,037 mcg•h/mL and Cmax of 58.1 mcg/mL. There was no consistent increase in AUC or Cmax at pazopanib doses above 800 mg.

Administration of a single 400-mg crushed tablet increased AUC0-72h by 46% and Cmax by approximately 2-fold and decreased Tmax 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 Cmax.

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 Cmax and the median AUC0-24h values for patients with normal, mild, moderate and severe hepatic impairment.

The median steady-state of pazopanib Cmax and AUC0-24h after a once-daily dose of 800 mg in patients with mild impairment were in a similar range as the median steady-state Cmax and median AUC0-24h 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 Cmax and the median AUC0-24h 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 Cmax and the median AUC0-24h 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

Drug Interactions Studies

Clinical Studies

Strong CYP3A4 Inhibitor: Coadministration of multiple doses of oral VOTRIENT 400 mg with multiple doses of oral ketoconazole 400 mg (strong CYP3A4/P-gp inhibitor) resulted in a 1.7-fold increase in the AUC0-24h and a 1.5-fold increase in the Cmax 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 VOTRIENT 800 mg resulted in an approximately 50% to 60% increase in mean pazopanib AUC0-24h and Cmax.

CYP1A2, CYP2C9 and CYP2C19 Substrates: Clinical studies, using VOTRIENT 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 patients with cancer.

CYP3A4, CYP2D6, and CYP2C8 Substrates: Coadministration of VOTRIENT resulted in an increase of approximately 30% in the mean AUC and Cmax 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 VOTRIENT 800 mg once daily and paclitaxel 80 mg/m2 (CYP3A4 and CYP2C8 substrate) once weekly resulted in a mean increase of 26% and 31% in paclitaxel AUC and Cmax, respectively [see Drug Interactions (7.2)].

Gastric Acid-Reducing Agents: Coadministration of VOTRIENT with esomeprazole, a PPI, decreased the exposure of pazopanib by approximately 40% (AUC and Cmax) [see Dosage and Administration (2.4), Drug Interactions (7.4)].

In Vitro Studies

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 pregnane X receptor (PXR) assay.

In vitro studies also showed that pazopanib inhibits UGT1A1 and organic anion- transporting polypeptide (OATP1B1) with IC50s of 1.2 and 0.79 μM, respectively.

12.5 Pharmacogenomics

Pazopanib can increase serum total bilirubin levels [see Warnings and Precautions (5.1)]. In vitro studies showed that pazopanib inhibits UGT1A1, which glucuronidates bilirubin for elimination. A pooled pharmacogenetic analysis of 236 white patients who received VOTRIENT showed that the (TA)7/(TA)7 genotype (UGT1A1*28/*28) (underlying genetic susceptibility to Gilbert’s syndrome) was associated with a statistically significant increase in the incidence of hyperbilirubinemia relative to the (TA)6/(TA)6 and (TA)6/(TA)7 genotypes.

In a pooled pharmacogenetic analysis of data from 31 clinical studies of pazopanib administered as either monotherapy or in combination with other agents, ALT > 3 × ULN (Grade 2) occurred in 32% (42/133) of HLA-B57:01 allele carriers and in 19% (397/2101) of non-carriers and ALT > 5 × ULN (Grade 3) occurred in 19% (25/133) of HLA-B57:01 allele carriers and in 10% (213/2101) of non-carriers. In this dataset, 6% (133/2234) of the patients carried the HLA-B*57:01 allele [see Warnings and Precautions (5.1)].

---

DOSAGE & ADMINISTRATION SECTION

Highlight: * Recommended Dosage: 800 mg orally once daily without food (at least 1 hour before or 2 hours after a meal). (2.1)

• Moderate Hepatic Impairment: 200 mg orally once daily. (2.2)

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosage

The recommended dosage of VOTRIENT is 800 mg (four 200 mg tablets) orally once daily without food (at least 1 hour before or 2 hours after a meal) until disease progression or unacceptable toxicity [see Clinical Pharmacology (12.3)]. The dosage should be modified for hepatic impairment and in patients taking certain concomitant drugs [see Dosage and Administration (2.3, 2.4)].

Swallow tablets whole. Do not crush tablets due to the potential for increased rate of absorption, which may affect systemic exposure [see Clinical Pharmacology (12.3)].

If a dose is missed, it should not be taken if it is < 12 hours until the next dose.

2.2 Dosage Modifications for Adverse Reactions

Table 1 summarizes the recommended dose reductions.

Table 1. Recommended Dose Reductions of VOTRIENT for Adverse Reactions

Permanently discontinue VOTRIENT in patients unable to tolerate the second dose reduction.

Table 2 summarizes the recommended dosage modifications for adverse reactions.

Table 2. Recommended Dosage Modifications of VOTRIENT for Adverse Reactions

2.3 Dosage Modifications for Hepatic Impairment

Moderate and Severe Hepatic Impairment

In patients with moderate hepatic impairment [total bilirubin > 1.5 to 3 × upper limit of normal (ULN) and any alanine aminotransferase (ALT) value], consider alternatives to VOTRIENT. If VOTRIENT is used in patients with moderate hepatic impairment, reduce the VOTRIENT dose to 200 mg orally once daily.

VOTRIENT is not recommended in patients with severe hepatic impairment (total bilirubin > 3 × ULN and any ALT value) [see Use in Specific Populations (8.7)].

2.4 Dosage Modifications for Drug Interactions

Strong CYP3A4 Inhibitors

Avoid concomitant use of strong CYP3A4 inhibitors by use of an alternate concomitant medication with no or minimal potential to inhibit CYP3A4. If coadministration of a strong CYP3A4 inhibitor is warranted, reduce the dose of VOTRIENT to 400 mg [see Drug Interactions (7.1)].

Strong CYP3A4 Inducers

Avoid concomitant use of strong CYP3A4 inducers by use of an alternate concomitant medication with no or minimal enzyme induction potential. VOTRIENT is not recommended in patients who cannot avoid chronic use of strong CYP3A4 inducers [see Drug Interactions (7.1)].

Gastric Acid-Reducing Agents

Avoid concomitant use of gastric acid-reducing agents. If concomitant use of a gastric acid-reducing agent cannot be avoided, consider short-acting antacid in place of proton pump inhibitors (PPIs) and H2-receptor antagonists. Separate short-acting antacid and VOTRIENT dosing by several hours [see Drug Interactions (7.4), Clinical Pharmacology (12.3)].

DOSAGE FORMS & STRENGTHS SECTION

Highlight: Tablets: 200 mg (3)

3 DOSAGE FORMS AND STRENGTHS

Tablets: 200 mg, modified capsule-shaped, gray or pink, film-coated with ‘GS JT’ debossed on one side.

---

CONTRAINDICATIONS SECTION

Highlight: None. (4)

4 CONTRAINDICATIONS

None.

BOXED WARNING SECTION

WARNING: HEPATOTOXICITY

---

CLINICAL STUDIES SECTION

14 CLINICAL STUDIES

14.1 Renal Cell Carcinoma

The efficacy of VOTRIENT 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 VOTRIENT 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 VOTRIENT 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 VOTRIENT 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

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

14.2 Soft Tissue Sarcoma

The efficacy of VOTRIENT was evaluated in VEG110727, a randomized, double- blind, placebo-controlled, multicenter trial (NCT00753688). Patients with metastatic STS who had received prior chemotherapy, including anthracycline treatment, or were unsuited for such therapy, were randomized (2:1) to receive VOTRIENT 800 mg once daily or placebo. Patients with gastrointestinal stromal tumors (GIST) or adipocytic sarcoma were excluded from the trial. Randomization was stratified by the factors of WHO performance status (WHO PS) 0 or 1 at baseline and the number of lines of prior systemic therapy for advanced disease (0 or 1 versus 2+). The major efficacy outcome measure was PFS assessed by independent radiological review. Additional outcome measures were OS, ORR, and duration of response.

The majority of patients were female (59%) with a median age of 55 years. Seventy-two percent of patients were white, 22% were Asian, and 6% were other. Forty-three percent of patients had leiomyosarcoma, 10% had synovial sarcoma, and 47% had other soft tissue sarcomas. Fifty-six percent of patients had received 2 or more lines of prior systemic therapy and 44% had received 0 or 1 lines of prior systemic therapy.

Efficacy results are presented in Table 9 and Figure 2.

Table 9. Efficacy Results in STS Patients by Independent Assessment in VEG110727

Figure 2. Kaplan-Meier Curve for Progression-free Survival in STS by Independent Assessment for the Overall Population in VEG110727

At the protocol-specified final analysis of OS, the median OS was 12.6 months for patients randomized to VOTRIENT and 10.7 months for the placebo arm [HR = 0.87 (95% CI: 0.67, 1.12)].

---

OVERDOSAGE SECTION

10 OVERDOSAGE

Dose-limiting toxicity (Grade 3 fatigue) and Grade 3 hypertension were each observed in 1 of 3 patients dosed at 2,000 mg daily (2.5 times the recommended dose) and 1,000 mg daily (1.25 times the recommended dose), respectively.

Provide general supportive measures to manage an overdose. Hemodialysis is not expected to enhance the elimination of VOTRIENT because pazopanib is not significantly renally excreted and is highly bound to plasma proteins.

---

INFORMATION FOR PATIENTS SECTION

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

• Hepatic Toxicity: Inform patients that periodic laboratory testing will be performed. Advise patients to report signs and symptoms of liver dysfunction to their healthcare provider right away [see Warnings and Precautions (5.1)].

• QT Prolongation and Torsades de Pointes: Inform patients that ECG monitoring may be performed. Advise patients to inform their physicians of concomitant medications [see Warnings and Precautions (5.2)].

• Interstitial Lung Disease/Pneumonitis: Advise patients to report pulmonary signs or symptoms indicative of interstitial lung disease (ILD) or pneumonitis [see Warnings and Precautions (5.9)].

• Cardiac Dysfunction: Advise patients to report hypertension or signs and symptoms of congestive heart failure [see Warnings and Precautions (5.3)].

• Hemorrhagic Events: Advise patients to report unusual bleeding [see Warnings and Precautions (5.4)].

• Arterial Thromboembolic Events: Advise patients to report signs or symptoms of an arterial thrombosis [see Warnings and Precautions (5.5)].

• Pneumothorax and Venous Thromboembolic Events: Advise patients to report new onset of dyspnea, chest pain, or localized limb edema [see Warnings and Precautions (5.6), Adverse Reactions (6.1)].

• Posterior Reversible Encephalopathy Syndrome: Advise patients to inform their doctor if they have worsening of neurological function consistent with PRES (headache, seizure, lethargy, confusion, blindness, and other visual and neurologic disturbances) [see Warnings and Precautions (5.10)].

• Hypertension: Advise patients to monitor blood pressure early in the course of therapy and frequently thereafter and report increases of blood pressure or symptoms, such as blurred vision, confusion, severe headache, or nausea and vomiting [see Warnings and Precautions (5.11)].

• Gastrointestinal Perforation and Fistula: Advise patients to report signs and symptoms of a GI perforation or fistula [see Warnings and Precautions (5.8)].

• Risk of Impaired Wound Healing: Advise patients that VOTRIENT may impair wound healing. Advise patients to inform their healthcare provider of any scheduled surgical procedure [see Warnings and Precautions (5.12)].

• Hypothyroidism and Proteinuria: Inform patients that thyroid function testing and urinalysis will be performed during treatment [see Warnings and Precautions (5.13, 5.14)].

• Tumor Lysis Syndrome: Advise patients to contact their healthcare provider promptly to report any signs and symptoms of TLS, such as abnormal heart rhythm, seizure, confusion, muscle cramps or spasms, or a decrease in urine output [see Warnings and Precautions (5.15)].

• Infection: Advise patients to promptly report any signs or symptoms of infection [see Warnings and Precautions (5.16)].

• Embryo-Fetal Toxicity: Advise female patients to inform their healthcare provider of a known or suspected pregnancy during treatment with VOTRIENT. Inform female patients of the risk to a fetus and the potential loss of the pregnancy [see Warnings and Precautions (5.19), Use in Specific Populations (8.1)].
  Advise females of reproductive potential to use effective contraception during treatment and for at least 2 weeks after the last dose of VOTRIENT. Advise male patients with female partners of reproductive potential to use condoms during treatment with VOTRIENT and for at least 2 weeks after the last dose [see Warnings and Precautions (5.19), Use in Specific Populations (8.3)].

• Lactation: Advise women not to breastfeed during treatment with VOTRIENT and for 2 weeks after the last dose [see Use in Specific Populations (8.2)].

• Infertility: Advise males and females of reproductive potential that VOTRIENT may impair fertility [see Use in Specific Populations (8.3)].

• Gastrointestinal Adverse Reactions: Advise patients on how to manage nausea, vomiting, and diarrhea and to notify their healthcare provider if moderate-to-severe vomiting or diarrhea occurs or if there is a decrease in oral intake [see Adverse Reactions (6.1)].

• Depigmentation: Advise patients that depigmentation of the hair or skin may occur during treatment with VOTRIENT [see Adverse Reactions (6.1)].

• Drug Interactions: Advise patients to inform their healthcare providers of all concomitant medications, vitamins, or dietary and herbal supplements [see Drug Interactions (7)].

• Dosage and Administration: Advise patients to take VOTRIENT without food (at least 1 hour before or 2 hours after a meal) [see Dosage and Administration (2.1)].

Distributed by:
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936

© Novartis

T2024-07

SPL MEDGUIDE SECTION

T2021-161

---

HOW SUPPLIED SECTION

16 HOW SUPPLIED/STORAGE AND HANDLING

VOTRIENT 200 mg tablets are supplied as modified capsule-shaped, gray or pink, film-coated with ‘GS JT’ debossed on one side and are available in:

• Bottles of 120 tablets: NDC 0078-0670-66 (gray tablets), NDC 0078-1077-66 (pink tablets)

Store at 20°C to 25°C (68°F to 77°F), excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature].

---