VOTRIENT(r) (Pazopanib hydrochloride) Pazopanib is a member of the tyrosine kinase inhibitor family. It is supplied as the hydrochloride salt, with chemical name 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]- 2-methylbenzenesulfonamide monohydrochloride.

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. Molecular formula: C21H23N7O2S *HCl Molecular weight: 473.99 g/mol. CAS number: 635702-64-6

DESCRIPTION

Each film-coated tablet contains pazopanib hydrochloride equivalent to either 200 mg or 400 mg of pazopanib free base. Each film-coated tablet also contains magnesium stearate, cellulose - microcrystalline, povidone, sodium starch glycollate, hypromellose, macrogol 400, titanium dioxide, polysorbate 80, and iron oxide red CI77491 (200 mg tablet only).

PHARMACOLOGY

Mechanism of Action

Pazopanib is an orally administered, potent multi-target tyrosine kinase inhibitor (TKI) of Vascular Endothelial Growth Factor Receptors (VEGFR)-1, -2, and -3, platelet-derived growth factor receptor (PDGFR)-a and -b, and stem cell factor receptor (c-KIT), with IC50 values of 10, 30, 47, 71, 84 and 74 nM, respectively. In preclinical experiments, pazopanib dose-dependently inhibited ligand-induced auto-phosphorylation of VEGF-2, c-Kit and PDGF- receptors in cells. In vivo, pazopanib inhibited VEGF-induced VEGFR-2 phosphorylation in mouse lungs, angiogenesis in various animal models, and the growth of multiple human tumour xenografts in mice.

Pharmacokinetics

Pazopanib is absorbed orally with median time to achieve peak concentrations of 2.0 to 4.0 hours after the dose. Daily dosing results in 1.23- to 4-fold increase in AUC. There was no consistent increase in AUC and Cmax when the pazopanib dose increased above 800 mg. 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 Cmax. Therefore, pazopanib should be administered at least 1 hour before or 2 hours after a meal (see Dosage and Administration). Administration of a single pazopanib 400 mg crushed tablet increased AUC(0-72) by 46% and Cmax by approximately 2 fold and decreased tmax by approximately 1.5 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 should not be crushed (see Dosage and Administration).

Binding of pazopanib to human plasma protein in vivo was greater than 99 % with no concentration dependence over the range of 10-100 g/ml. In vitro studies suggest that pazopanib is a substrate for P-glycoprotein (Pgp) and breast cancer resistant protein (BCRP).

Results from in vitro studies demonstrated that the metabolism of pazopanib is mediated primarily by CYP3A4, with minor contributions from CYP1A2 and CYP2C8.

Pazopanib is eliminated slowly with mean half-life of 30.9 hours after administration of the recommended dose of 800 mg. Elimination is primarily via faeces with renal elimination accounting for < 4 % of the administered dose.

In a population pharmacokinetic analysis using 408 patients with various cancers, creatinine clearance (30-150 ml/min) did not influence clearance of pazopanib. Renal impairment is not expected to influence pazopanib exposure, and dose adjustment is not necessary in patients with creatine clearance >= 30 ml/min.

The median steady-state pazopanib Cmax and AUC(0-24) in patients with mild hepatic impairment (defined as either normal bilirubin and any degree of ALT elevations or as an elevation of bilirubin up to 1.5 x ULN regardless of the ALT value) after a once daily dose of 800 mg/day (30.9 ug/ml, range 12.5-47.3 and 841.8 ug.hr/ml, range 600.4-1078) are similar to the median in patients with no hepatic impairment (49.4 ug/ml, range 17.1-85.7 and 888.2 ug.hr/ml, range 345.5-1482) (see Dosage and Administration). The maximally tolerated pazopanib dose (MTD) in patients with moderate hepatic impairment (defined as an elevation of bilirubin > 1.5 x to 3 x ULN regardless of the ALT values) was 200 mg once daily. The median steady-state values of Cmax (22.4 ug/ml, range 6.4-32.9) and AUC(0-24) (350.0 ug.hr/ml, range 131.8-487.7) after administration of 200 mg pazopanib once daily in patients with moderate hepatic impairment were approximately 45 % and 39 %, respectively, that of the corresponding median values after administration of 800 mg once daily in patients with normal hepatic function (see Dosage and Administration). There are insufficient data in patients with severe hepatic impairment (total bilirubin > 3 x ULN regardless of any level of ALT); therefore, use of pazopanib is not recommended in these patients.

CLINICAL TRIALS

Renal Cell Carcinoma (RCC)

The safety and efficacy of VOTRIENT in renal cell carcinoma (RCC) were evaluated in a randomized, double-blind, placebo-controlled multi-centre study. Patients (N= 435) with locally advanced and/or metastatic RCC were randomized to receive VOTRIENT 800 mg monotherapy once daily or placebo. The primary objective of the study was to evaluate and compare the two treatment arms for progression-free survival (PFS) and the principle secondary endpoint is overall survival (OS). The other objectives were to evaluate the overall response rate and duration of response. From the total of 435 patients in this study, 233 patients were treatment naive and 202 were second line patients who received one prior IL-2 or INF-based therapy. The performance status (ECOG) was similar between the VOTRIENT and placebo groups (ECOG 0: 42 % vs. 41 %, ECOG 1: 58 % vs. 59 %). All patients had clear cell histology or predominantly clear cell histology. Approximately half of all patients had 3 or more organs involved in their disease and most patients had the lung (74 %), and/or lymph nodes (54 %) as a metastatic location for disease at baseline. A similar proportion of patients in each arm were treatment-naive and cytokine-pre-treated (53 % and 47 % in VOTRIENT arm, 54 % and 46 % in placebo arm). In the cytokine-pre-treated subgroup, the majority (75 %) had received interferon based treatment. Similar proportions of patients in each arm had prior nephrectomy (89 % and 88 % in the VOTRIENT and placebo arms, respectively) and/or prior radiotherapy (22 % and 15 % in the VOTRIENT and placebo arms, respectively. The primary analysis of the primary endpoint PFS is based on disease assessment by independent radiological review in the entire study population (first line and second line).

Table 1. Overall Efficacy Results in RCC by Independent Review Committee (IRC) (VEG105192)

CI: confidence interval; HR: hazard ratio; ITT: Intent-to-treat; PFS: progression free survival.

Figure 1 Kaplan-Meier Curve for Progression-Free Survival by Independent Assessment for the Overall Population (Treatment-Naive and Cytokine Pre- Treated Populations)

Figure 2 Kaplan-Meier Curve for Progression-Free Survival by Independent Assessment for the Treatment-Naive Population

Figure 3 Kaplan-Meier Curve for Progression-Free Survival by Independent Assessment for the Cytokine Pre-Treated Population

For patients who responded to treatment, the median time to response was 11.9 weeks and the

The median overall survival (OS) data at the protocol specified final survival analysis were 22.9 months and 20.5 months [HR = 0.91 (95 % CI: 0.71, 1.16; p = 0.224)] for patients randomized to the VOTRIENT and placebo arms, respectively. The OS results are subject to potential bias as 54% of patients in the placebo arm also received VOTRIENT in the extension part of this study following disease progression. Sixty-six percent of placebo patients received post-study therapy compared to 30% of VOTRIENT patients. In the pivotal study, the QoL assessments were based on blinded self-reported global scores from two protocol-specified questionnaires, EORTC QLQ-C30 and EuroQoL EQ-5D. Analysis was based on patients who continued on therapy in both arms, prior to progression. The assessments showed no difference between treatment with VOTRIENT or placebo (p > 0.05), indicating no negative impact of VOTRIENT on global quality of life. In a Phase 2 study of 225 patients with locally recurrent or metastatic clear cell renal cell carcinoma, objective response rate was 35 % and median duration of response was 68 weeks, as per independent review. Median PFS was 11.9 months. The safety, efficacy and quality of life of VOTRIENT versus sunitinib has been evaluated in a randomised, open-label, parallel group Phase III non-inferiority study (VEG108844). In VEG108844, patients (N = 1110) with locally advanced and/or metastatic RCC who had not received prior systemic therapy, were randomized to receive either VOTRIENT 800 mg once daily continuously or sunitinib 50 mg once daily in 6-week cycles of dosing with 4 weeks on treatment followed by 2 weeks without treatment. The primary objective of this study was to evaluate and compare PFS in patients treated with VOTRIENT to those treated with sunitinib. Demographic characteristics were similar between the treatment arms. Disease characteristics at initial diagnosis and at screening were balanced between the treatment arms with the majority of patients having clear cell histology and Stage IV disease. VEG108844 achieved its primary endpoint of PFS and demonstrated that VOTRIENT was non- inferior to sunitinib, as the upper bound of the 95 % CI for the hazard ratio was less than the protocol-specified non-inferiority margin of 1.25. Overall efficacy results are summarised in Table 2.

Table 2. Overall Efficacy Results (VEG108844)

HR = Hazard Ratio; ITT = Intent to Treat; PFS = Progression-free Survival based on independent review committee (IRC) assessment

Soft Tissue Sarcoma (STS)

The safety and efficacy of pazopanib in STS were evaluated in a randomized, double-blind, placebo-controlled multi-centre trial. Patients (N= 369) with advanced STS who had received prior chemotherapy, including anthracycline treatment, or who were intolerant to therapy, were randomized to receive pazopanib 800 mg once daily or placebo. More common tumour types studied were leiomyosarcoma (excluding skin) and synovial sarcoma. Patients with various rare STS types were analysed collectively in an "Other STS" subgroup. STS types ineligible for study included: adipocytic STS; gastrointestinal stromal tumour; rhabdomyosarcoma other than alveolar or pleomorphic; chondrosarcoma; osteosarcoma; Ewings tumour/primitive neuroectodermal tumour; dermofibromatosis sarcoma protuberans; inflammatory myofibroblastic sarcoma; malignant mesothelioma; and mixed mesodermal tumour of the uterus. Patients with WHO performance status >1 (i.e. unable to carry out light work) were excluded from enrolment. Patients with inadequate bone marrow, renal or liver function were excluded. Patients with abnormal cardiac function (LV ejection fraction below institutional lower limit of normal; QTc prolongation >480 msecs; presence within the last 6 months of cardiac angioplasty or stenting, myocardial infarction, unstable angina, coronary artery bypass graft surgery, symptomatic peripheral vascular disease, or NYHA Class III-IV congestive heart failure) and patients with poorly controlled hypertension were excluded. Patients with any history of a cerebrovascular accident, or with a transient ischaemic attack within the last 6 months, or with a pulmonary embolus within the last 6 months, were excluded. Patients with a history of clinically significant gastrointestinal disorders were excluded. Patients with a bleeding diathesis, active bleeding or haemoptysis within the last 6 weeks were also excluded. Prior to randomization, eligible patients were 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 vs. 2+). In each treatment group, there was a slightly greater percentage of patients in the 2+ lines of prior systemic therapy for advanced disease (58 % and 55 % respectively for placebo and pazopanib treatment arms) compared with 0 or 1 lines of prior systemic therapy (42 % and 45 % respectively for placebo and pazopanib treatment arms). There were slightly more patients with a WHO PS of 1 at baseline. The median duration of follow-up of patients (defined as date of randomization to date of last contact or death) was similar for both treatment arms (9.36 months for placebo [range 0.69 to 23.0 months] and 10.04 months for pazopanib [range 0.2 to 24.3 months]. The primary objective of the trial was to evaluate and compare the two treatment arms for progression-free survival (PFS); the secondary endpoints included overall survival (OS), overall response rate and duration of response. The initial analysis of the primary endpoint PFS was based on disease assessment by independent radiological review in the entire ITT study population.

Table 3. Overall efficacy results in STS by independent assessment (VEG110727)

Similar to the assessments by independent radiology review, a clinically meaningful and statistically significant improvement in PFS based on investigator assessments was observed in the pazopanib arm compared with the placebo arm (HR: 0.39; 95 % CI, 0.30 to 0.52, p < 0.001)

Figure 4 Kaplan-Meier Curve for Progression-Free Survival in STS by Independent Assessment for the Overall Population (VEG110727)

The hazard ratio at the pre-specified interim analysis for overall survival in favour of pazopanib was not statistically significant; the median overall survival in the placebo arm was 10.4 months (95 % CI 8.7 to 12.7) and was 11.9 months (95 % CI 10.7 to 15.1) in the pazopanib arm; HR = 0.82 (97.87 % CI: 0.59 to 1.14, p = 0.156). The overall survival in this study is potentially confounded due an imbalance of active treatments after disease progression, with more patients in the placebo arm receiving active therapy. Changes in quality of life were assessed for up to 12 weeks on treatment. Scores for the individual domains of fatigue, diarrhoea, loss of appetite, nausea and vomiting were worse for pazopanib, reflecting the adverse effects profile. However, this was not reflected in global quality of life assessment. Comparison was hindered by the small number of assessments, dropout of subjects due to disease progression (particularly in the placebo arm), and the absence of health outcome assessments after disease progression. In a smaller, uncontrolled Phase 2 study of pazopanib in STS (VEG20002), median progression-free survival was 11.1 weeks in adipocytic STS and 14.0-23.4 weeks in other STS groups, although fewer adipocytic STS subjects were studied (n=19 vs n=37-41 in other groups).

CONTRAINDICATIONS

VOTRIENT is contraindicated in patients with hypersensitivity to the active substance pazopanib hydrochloride or to any of the excipients (see Description).

PRECAUTIONS

Hepatic Effects: Cases of hepatic failure (including fatalities) have been reported during use of VOTRIENT. In clinical trials with VOTRIENT, increase in serum transaminases (ALT, AST) and bilirubin were observed (see Adverse Effects). In the majority of the cases, isolated increases in ALT and AST have been reported, without concomitant elevations of alkaline phosphatase or bilirubin. The vast majority (92.5%) of all transaminase elevations of any grade occurred in the first 18 weeks. Grades are based on the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 3 (NCI CTCAE). Monitor serum liver tests before initiation of treatment with VOTRIENT, and at weeks 3, 5, 7 and 9. Thereafter monitor at month 3 and at month 4, and as clinically indicated. Periodic monitoring should then continue after month 4. The following guidelines are provided for patients with baseline values of total bilirubin <= 1.5 x ULN and AST and ALT <= 2 x ULN.

. 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 return to Grade 1 (NCI CTCAE) or baseline. VOTRIENT is a UGT1A1 inhibitor. Mild, indirect (unconjugated) hyperbilirubinaemia may occur in patients with Gilbert's syndrome. Patients with only a mild indirect hyperbilirubinaemia, known or suspected 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 (see Interactions) and should be undertaken with caution and close monitoring. Beyond recommending that patients with mild hepatic impairment are treated with 800 mg pazopanib once daily and reducing the initial starting dose to 200mg per day for patients with moderate impairment, no further dose modification guidelines based on results of serum liver tests during therapy have been established for patients with pre-existing hepatic impairment. Hypertension: In clinical studies with pazopanib, events of hypertension including hypertensive crisis have occurred. Blood pressure should be well controlled prior to initiating VOTRIENT. Patients should be monitored for hypertension early after starting treatment (no longer than one week after starting VOTRIENT) and frequently thereafter to ensure blood pressure control, and treated promptly with a combination of standard anti-hypertensive therapy and VOTRIENT dose reduction or interruption as clinically warranted (see Dosage and Administration, Adverse Effects). Hypertension (systolic blood pressure >= 150 or diastolic blood pressure >= 100 mm Hg) occurs early in the course of VOTRIENT treatment (approximately 40 of cases occurred by Day 9 and approximately 90 of cases occurred in the first 18 weeks). VOTRIENT should be discontinued if there is evidence of hypertensive crisis or if hypertension is severe and persists despite anti-hypertensive therapy and VOTRIENT dose reduction.

Posterior reversible encephalopathy syndrome (PRES) /Reversible posterior leukoencephalopathy syndrome (RPLS):

PRES/RPLS has been reported in association with VOTRIENT. PRES/RPLS can present with headache, hypertension, seizure, lethargy, confusion, blindness and other visual and neurological disturbances, and can be fatal. Permanently discontinue VOTRIENT in patients developing PRES/RPLS.

Cardiac Dysfunction:

In Clinical trials with VOTRIENT, events of cardiac dysfunction such as congestive heart failure and decreased left ventricular ejection fraction (LVEF) have occurred. Serious treatment-related left ventricular dysfunction was reported in 4 out of 240 patients (1.7%) in the placebo-controlled study VEG110727. In this trial decreases in LVEF in patients who had post-baseline measurement were detected in 11% (16/142) in the VOTRIENT arm compared with 5% (2/40) in the placebo arm. Fourteen of the 16 patients in the VOTRIENT arm

had concurrent hypertension which may have exacerbated cardiac dysfunction in patients at risk (e.g. those with prior anthracycline therapy) by increasing cardiac after-load. Blood pressure should be monitored and managed promptly using a combination of anti- hypertensive therapy and dose modification of VOTRIENT (interruption and re-initiation at a reduced dose based on clinical judgement). Patients should be carefully monitored for clinical signs or symptoms of congestive heart failure. Baseline and periodic evaluation of LVEF is recommended in patients at risk of cardiac dysfunction. QT Prolongation and Torsade de Pointes: In clinical studies with VOTRIENT, events of QT prolongation or Torsade de Pointes have occurred (see Adverse Effects). VOTRIENT should be used with caution in patients with a history of QT interval prolongation, patients taking antiarrythmics or other medications that may potentially prolong QT interval, or those with relevant pre-existing cardiac disease. When using VOTRIENT, baseline and periodic monitoring of electrocardiograms and maintenance of electrolytes (calcium, magnesium, potassium) within normal range is recommended. Arterial Thrombotic Events: In clinical studies with VOTRIENT, myocardial infarctions, angina, ischemic stroke and transient ischemic attack were observed (see Adverse Effects). Fatal events have been observed. VOTRIENT should be used with caution in patients who are at increased risk of thrombotic events or who have had a history of thrombotic events. VOTRIENT has not been studied in patients who have had an event within the previous 6 months. A treatment decision should be made based upon the assessment of individual patient's benefit/risk.

Venous Thromboembolic Events

: In clinical studies with VOTRIENT, venous thromboembolic events including venous thrombosis and fatal pulmonary embolus have occurred. The incidence was higher in the STS population (5%) than in the RCC population (2%).

Thrombotic Microangiopathy: Thrombotic microangiopathy (TMA) has been reported in clinical trials of VOTRIENT as monotherapy, in combination with bevacizumab, and in combination with topotecan (see Adverse Effects). Permanently discontinue VOTRIENT in patients developing TMA. Reversal of effects of TMA has been observed after treatment was discontinued. VOTRIENT is not indicated for use in combination with other agents. Haemorrhagic Events: In clinical studies with VOTRIENT haemorrhagic events have been reported (see Adverse Effects). Fatal haemorrhagic events have occurred. VOTRIENT has not been studied in patients who had a history of haemoptysis, cerebral, or clinically significant gastrointestinal haemorrhage in the past 6 months. VOTRIENT should be used with caution in patients with significant risk of haemorrhage. Gastrointestinal Perforations and Fistula: In clinical studies with VOTRIENT, events of gastrointestinal (GI) perforation or fistula have occurred (see Adverse Effects). Fatal perforation events have occurred. VOTRIENT should be used with caution in patients at risk for GI perforation or fistula.

Wound Healing:

No formal studies on the effect of VOTRIENT on wound healing have been conducted. Since Vascular Endothelial Growth Factor (VEGF) inhibitors 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 judgement of adequate wound healing. VOTRIENT should be discontinued in patients with wound dehiscence.

Hypothyroidism: In clinical studies with VOTRIENT, events of hypothyroidism have occurred (see Adverse Effects). Proactive monitoring of thyroid function tests is recommended. Proteinuria: In clinical studies with VOTRIENT, proteinuria has been reported (see Adverse Effects). Baseline and periodic urinalyses during treatment are recommended and patients should be monitored for worsening proteinuria. VOTRIENT should be discontinued if the patient develops nephrotic syndrome.

Infections:

Cases of serious infections (with or without neutropenia), in some cases with fatal outcomes, have been reported.

Combination with other systemic anti-cancer therapies:

Clinical trials of VOTRIENT in combination with ALIMTA (non-small cell lung cancer (NSCLC)) and TYKERB (cervical cancer) were terminated early due to concerns over increased toxicity and/or mortality, and a safe and effective combination dose have not been established with these regimens. VOTRIENT is not indicated for use in combination with other agents.

Interactions; Concomitant treatment with strong inhibitors of CYP3A4 or P-glycoprotein (P-gp) should be avoided due to risk of increased exposure to pazopanib (see Interactions With Other Medicines). Selection of alternative concomitant medicinal products with no or minimal potential to inhibit CYP3A4, P-gp or BCRP should be considered.

Juvenile Toxicity:

Because the mechanism of action of VOTRIENT can severely affect organ growth and maturation during early post-natal development, VOTRIENT should not be given to human paediatric patients younger than 2 years of age.

In juvenile toxicity studies, when pre-weaning rats were dosed from day 9 post partum through day 14 postpartum , pazopanib caused mortalities and abnormal organ growth/maturation in kidney, lung liver and heart, at a dose approximately 0.1 times the clinical exposure based on AUC in adults. When post weaning rats were dosed from day 21 post partum to day 62 post partum), toxicologic findings were similar to adult rats at comparable exposures with changes in bone, trachea, teeth, adrenal, pancreas, stomach, duodenum, lymph node, male mammary gland and reproductive organs. In rats, weaning occurs at day 21 postpartum which approximately equates to a human paediatric age of 2 years. Human paediatric patients are at increased risk for bone and teeth effects as compared to adults, as these changes, including shortened limbs, were present in juvenile rats at >= 10 mg/kg/day (equal to approximately 0.1- times the clinical exposure based on AUC in adults).

Effects on Fertility

VOTRIENT may impair fertility in human males and females. In female reproductive toxicity studies in rats, reduced female fertility has been observed. Decreased corpora lutea, increased cysts and ovarian atrophy have also been noted in rodents. Pazopanib did not affect mating or fertility in male rats. However, there were reductions in sperm production rates, sperm motility, and epididymal and testicular sperm concentrations observed at >= 100 mg/kg/day (approximately 0.8 times the human clinical exposure based on AUC) following 15 weeks of dosing. Following 26 weeks of dosing, there were decreased testicular and epididymal weights, atrophy and degeneration of the testes with aspermia, hypospermia and cribiform change in the epididymis of male rats given doses >= 30 mg/kg/day (approximately 0.6 times the human clinical exposure based on AUC).

Use in Pregnancy (Category D)

There are no adequate data from the use of pazopanib in pregnant women. Pazopanib has been shown to be embryotoxic and teratogenic when administered to rats and rabbits at exposures below clinical exposure. Effects included cardiovascular malformations, delayed ossification, reduced female fertility, increased pre- and post-implantation loss, early resorptions, embryo lethality, and decreased foetal body weight. The potential risk for humans is unknown. VOTRIENT should not be used during pregnancy unless, in the opinion of the physician, the potential benefits of treatment to the mother outweigh any possible risks to the developing foetus. If VOTRIENT is used during pregnancy, or if the patient becomes pregnant while receiving VOTRIENT, the potential hazard to the foetus should be explained to the patient. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with VOTRIENT.

Use in Lactation

The safe use of VOTRIENT during lactation has not been established. It is not known whether pazopanib is excreted in human milk. Breast feeding should be discontinued during treatment with VOTRIENT.

Ability to Perform Tasks that Require Judgement, Motor or Cognitive Skills

There have been no studies to investigate the effect of VOTRIENT on driving performance or the ability to operate machinery. A detrimental effect on such activities cannot be predicted from the pharmacology of VOTRIENT. The clinical status of the patient and the adverse event profile of VOTRIENT should be borne in mind when considering the patient's ability to perform task that require judgment, motor and cognitive skills.

Pre-clinical Safety Data

The preclinical safety profile of pazopanib was assessed in mice, rats, rabbits and monkeys. In repeat dose studies in rodents, effects in a variety of tissues (bone, teeth, nail beds, reproductive organs, haematological tissues, kidney and pancreas) appear related to the pharmacology of VEGFR inhibition and/or disruption of VEGF signalling pathways with most effects occurring at plasma exposure levels below those observed in the clinic. Higher exposures were not tolerated by rats in studies over 13 weeks duration, with body weight loss and morbidity secondary to pharmacologic effects. In the monkey, exposures equivalent to human exposure based on AUC resulted in diarrhoea, severe weight loss and morbidity associated with gastrointestinal effects secondary to high local mucosal drug exposure. Hepatic effects in animals have included mild elevations of liver enzymes or bilirubin without associated pathology. These enzyme changes were noted as early as 4 days, but were non-progressive in studies of 6 to 12 months duration. Female mice had proliferative hepatic lesions (eosinophilic foci and adenoma) following 13 weeks at exposures 2.5 times human exposure based on AUC.

Genotoxicity

Pazopanib did not cause genetic damage when tested in genotoxicity assays (Ames assay, human peripheral lymphocyte chromosome aberration assay and rat in vivo micronucleus). A synthetic intermediate in manufacture of pazopanib, which is also present in the final drug substance, was not mutagenic but genotoxic in the mouse lymphoma assay and in vivo mouse micronucleus assay and is controlled below a daily intake of 0.1 mg.

Carcinogenicity

Interactions With Other Medicines

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 VOTRIENT.

Concurrent administration of pazopanib (400 mg once daily) with the strong CYP3A4 and P-gp inhibitor, ketoconazole (400 mg once daily) for 5 consecutive days, resulted in a 66 % and 45 % increase in mean pazopanib AUC(0-24) and Cmax, respectively, relative to administration of pazopanib alone (400 mg once daily for 7 days).Pazopanib Cmax and AUC increase in a less than dose proportional fashion with increasing dose over the range of 50 mg to 2000 mg. Therefore, a dose reduction to 400 mg pazopanib once daily in the presence of strong CYP3A4 inhibitors will, in the majority of patients, result in systemic exposure similar to that observed after administration of 800 mg pazopanib once daily alone. Some patients however may have systemic pazopanib exposure greater than what has been observed after administration of 800 mg pazopanib alone. Co-administration of VOTRIENT with other strong inhibitors of the CYP3A4 family (e.g. itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) may increase pazopanib concentrations. Grapefruit juice may also increase plasma concentrations of VOTRIENT. Administration of 1500 mg lapatinib, a substrate and weak inhibitor of CYP3A4, Pgp and BCRP with 800 mg VOTRIENT resulted in an approximately 50 % to 60 % increase in mean pazopanib AUC(0-24) and Cmax compared to administration of 800 mg VOTRIENT alone. Co-administration of VOTRIENT with a CYP3A4, Pgp, and BCRP inhibitor, such as lapatinib, will result in an increase in plasma pazopanib concentrations. Concomitant use of pazopanib with a strong CYP3A4 inhibitor should be avoided. If no medically acceptable alternative to a strong CYP34A inhibitor is available, the dose of pazopanib should be reduced to 400 mg daily during concomitant administration (see Precautions). Further dose reduction may be considered if possible drug-related adverse events are observed. Combination with strong P-gp inhibitors should be avoided, or selection of an alternate concomitant medication with no or minimal potential to inhibit P-gp is recommended.

CYP3A4 inducers such as rifampin may decrease plasma pazopanib concentrations. Selection of an alternate concomitant medication with no or minimal enzyme induction potential is recommended.

In vitro studies with human liver microsomes showed that VOTRIENT inhibited CYP enzymes 1A2, 3A4, 2B6, 2C8, 2C9, 2C19, and 2E1. Potential induction of human CYP3A4 was demonstrated in an in vitro human PXR assay. Clinical pharmacology studies, using VOTRIENT 800 mg once daily, have demonstrated that VOTRIENT 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. 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). Co-administration 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.

In vitro studies also showed that pazopanib is a potent inhibitor of UGT1A1 and OATP1B1 with IC50 of 1.2 and 0.79 M, respectively. Pazopanib may increase concentrations of drugs primarily eliminated through UGT1A1 (e.g. irinotecan) and OATP1B1 (e.g. rosuvastatin).

Concomitant use of pazopanib and simvastatin increases the incidence of ALT elevations. Across monotherapy studies with pazopanib, ALT > 3xULN was reported in 126 / 895 (14 %) of patients who did not use statins, compared with11/41 (27 %) of patients who had concomitant use of simvastatin (p = 0.038). If a patient receiving concomitant simvastatin develops ALT elevations, follow guidelines for pazopanib posology and discontinue simvastatin (see Precautions). Insufficient data are available to assess the risk of concomitant administration of alternative statins and pazopanib.

Administration of VOTRIENT with a high-fat or low-fat meal results in an approximately 2-fold increase in AUC and Cmax. Therefore, VOTRIENT should be administered at least 1 hour before or 2 hours after a meal (see Dosage and Administration).

ADVERSE EFFECTS

Clinical Trial Data

The safety and efficacy of VOTRIENT in renal cell carcinoma (RCC) were evaluated in a randomized, double-blind, placebo-controlled multi-centre study. Patients with locally advanced and/or metastatic RCC were randomized to receive VOTRIENT 800 mg once daily (N=290) or placebo (N=145). The median duration of treatment was 7.4 months for the VOTRIENT arm and 3.8 months for the placebo arm. The safety and efficacy of VOTRIENT in soft tissue sarcoma (STS) were evaluated in a randomized, double-blind, placebo-controlled multi-centre study. Patients (N = 369) with advanced STS who had received prior anthracycline treatment, or were unsuited for such therapy, were randomized to receive VOTRIENT 800 mg once daily (N = 246) or placebo (N = 123). The median duration of treatment was 4.5 months for the pazopanib arm and 1.9 months for the placebo arm. Adverse reactions are listed below by MedDRA body system organ class. The following convention has been utilised for the classification of frequency: Very common 1 in 10 Common 1 in 100 and < 1 in 10 Uncommon 1 in 1,000 and < 1 in 100 Rare >= 1 in 10,000 and < 1 in 1,000 Categories have been assigned based on absolute frequencies in the clinical trial data.

Table 4. Adverse reactions, by organ class and frequency, reported in RCC (VEG105192) and STS (VEG110727) studies

	Frequency Classificat	ion
RCC VEG105192 n=290
Blood and lymphatic system disorders
Neutropenia	Common
Thrombocytopenia	Common

Endocrine disorders
Hypothyroidism *	Common Common

Metabolic disorders
Anorexia	Very common Very	common

STS VEG110727 n=240

Weight decreased	Common	Very common

Nervous System disorders
Dizziness		Very common
Dysgeusia	Common	Very common
Headache	Very common	Very common
Ischaemic stroke *	Uncommon	Uncommon
Transient ischaemic stroke *	Common

Cardiac Disorders
Cardiac dysfunction (such as a decrease in ejection fraction and congestive heart failure) *	Uncommon	Common
Bradycardia +	Common	Common
Myocardial infarction *	Uncommon	Common
Myocardial ischaemia	Common
QT prolongation *	Common	Common
Torsade de pointes *	Uncommon

Vascular disorders
Cerebral haemorrhage *	Uncommon	Uncommon
Epistaxis	Common	Common
Gastrointestinal haemorrhage *	Uncommon	Uncommon
Haematuria	Common	Uncommon
Hypertension *	Very common	Very common
Pulmonary haemorrhage *	Uncommon	Common
Venous thromboembolic events *	Uncommon	Common

Respiratory, thoracic and mediastinal disorders
Cough		Very common
Dysphonia	Common	Common
Dyspnoea		Very common
Pnuemothorax		Common

Gastrointestinal disorders
Abdominal pain	Very common	Very common
Diarrhoea	Very common	Very common
Dyspepsia	Common	Common
Gastrointestinal perforation *	Uncommon
Gastrointestinal fistula *	Uncommon	Uncommon
Lipase elevations ++	Common
Nausea	Very common	Very common
Stomatitis		Very common
Vomiting	Very common	Very common

Hepatobiliary disorders
Alanine amino transferase increased	Very common	Common
Aspartate amino transferase increased	Very common	Common
Hepatic function abnormal	Common
Hyperbilirubinaemia	Common	Uncommon

Skin and subcutaneous tissue disorders
Alopecia	Common	Very common
Dry Skin		Common
Exfoliative rash		Very common
Hair depigmentation	Very common	Very common
Nail disorder		Common
Palmar-plantar erythrodysesthesia syndrome	Common	Very common
Rash	Common	Uncommon
Skin depigmentation	Common	Very common

Musculoskeletal and connective tissue disorders
Musculoskeletal pain		Very common
Myalgia		Very common

Renal urinary disorders
Proteinuria *	Common	Uncommon

General disorders and administration site disorders
Asthenia	Very common	Uncommon
Chest pain *	Common	Very common
Chills		Common
Fatigue	Very common	Very common
Oedema peripheral		Very common
Vision blurred		Common

See Precautions for additional information.

- Adverse event was not considered causally related to pazopanib in the pivotal clinical trial for this indication.

Note: Laboratory findings which met the CTC-AE criteria were recorded as adverse events at the discretion of the Investigator

See below for further information

++ - For RCC, the frequency category is based on data from the supportive single-arm study VEG102616.

Bradycardia: In clinical studies with VOTRIENT, bradycardia has been experienced very commonly based on heart rate measurement. In a randomised, double-blind study in renal cell carcinoma patients (see Clinical Trials), at least one episode of heart rate <60 bpm was experienced in 33/280 patients (11.8%) in the VOTRIENT arm and 11/144 patients (7.6%) in the placebo arm. Bradycardia has also been reported commonly as an adverse event. In the same study, bradycardia or sinus bradycardia were reported as adverse events in 7/290 patients (2.4%) in the VOTRIENT arm, and 1/145 patients (0.7%) in the placebo arm. Most bradycardia with VOTRIENT has been asymptomatic, however syncope due to bradycardia has been reported Table 5 presents the incidence of very common (>10%) treatment-related adverse events in RCC for patients receiving VOTRIENT versus those on placebo

Table 5. Treatment-related Adverse Events Reported for at least 10% of patients who received VOTRIENT or Placebo in RCC (VEG105192)

Adverse Event, n (%)	Number (% of patients)
Adverse Event, n (%)	VOTRIENT (n = 290)			Placebo (n = 145)
	Any Grade	Grade 3	Grade 4	Any Grade	Grade 3	Grade 4
Any	270 (93)	103 (36)	25 (9)	107 (74)	24 (17)	8 (6)
Diarrhoea	152 (52)	11 (4)	2 (<1)	13 (9)	1 (<1)	0
Hair colour changes	109 (38)	1 (<1)	0	4 (3)	0	0
Hypertension	116 (40)	13 (4)	0	15 (10)	1 (<1)	0
Nausea	74 (26)	2 (<1)	0	13 (9)	0	0
Vomiting	62 (21)	7 (2)	1 (<1)	13 (9)	3 (2)	0
Fatigue	57 (20)	7 (2)	0	14 (10)	2 (1)	2 (1)
ALT increased	55 (19)	18 (6)	3 (1)	5 (3)	1 (<1)	0
AST increase	45 (16)	14 (5)	1 (<1)	5 (3)	0	0
Decreased appetite	70 (24)	6 (2)	0	17 (12)	1 (<1)	0
Asthenia	42 (14)	8 (3)	0	13 (9)	0	0
Abdominal pain	32 (11)	7 (2)	0	2 (1)	0	0
Headache	31 (11)	0	0	7 (5)	0	0
Proteinuria	30 (10)	6 (2)	1 (<1)	0	0	0
Weight decrease	30 (10)	2 (<1)	0	5 (3)	1 (<1)	0

Table 6 presents the incidence of very common (>10%) treatment-related adverse events in STS for patients receiving VOTRIENT versus those on placebo.

Table 6. Treatment-related Adverse Events Reported for at least 10% of patients who received VOTRIENT or Placebo in STS (VEG110727)

Adverse Event, n (%)	Number (% of patients)
Adverse Event, n (%)	VOTRIENT (n = 240)			Placebo (n = 123)
	Any Grade	Grade 3	Grade 4	Any Grade	Grade 3	Grade 4
Any AE	219 (91)	84 (35)	17 (7)	78 (63)	6 (5)	3 (2)
Diarrhoea	130 (54)	11 (5)	0	14 (11)	0	0
Fatigue	126 (53)	23 (10)	1 (<1)	33 (27)	2 (2)	0
Nausea	116 (48)	7(3)	0	19 (15)	2 (2)	0
Hypertension	94 (39)	16 (7)	0	5 (4)	0	0
Hair colour changes	93 (39)	0	0	3 (2)	0	0
Decreased appetite	82 (34)	11 (5)	0	10 (8)	0	0
Weight decreased	72 (30)	5 (2)	0	8 (7)	0	0
Dysgeusia	65 (27)	0	0	4 (3)	0	0
Vomiting	61 (25)	7(3)	0	8 (7)	1 (<1)	0
Headache	38 (16)	1 (<1)	0	5 (4)	0	0
Exfoliative rash	35 (15)	2 (<1)	0	9 (7)	0	0
Gastrointestinal pain	34 (14)	3(1)	0	4 (3)	1 (<1)	0
Ear, nose and throat examination abnormal	28 (12)	4 (2)	0	1 (<1)	0	0
Myalgia	27 (11)	2 (<1)	0	3 (2)	0	0
Skin hypopigmentation	27 (11)	0	0	0	0	0
Skin disorder	26 (11)	4 (2)	0	1 (<1)	0	0
Stomatitis	26 (11)	1 (<1)	0	4 (3)	0	0
Alopecia	25 (10)	0	0	1 (<1)	0	0
Musculoskeletal pain	23 (10)	1 (<1)	0	3 (2)	0	0

Table 7 presents laboratory abnormalities occurring in >= 15 % of patients who received VOTRIENT in the pivotal RCC studies. Grades are based on the NCI CTCAE.

Table 7. Selected Laboratory Abnormalities in >= 15 % of Patients who Received VOTRIENT and More Commonly than Placebo Arm (VEG105192)

		VOTRIENT (N = 290)			Placebo (N = 145)
	All Grades	Grade 3	Grade 4	All Grades	Grade 3	Grade 4
Parameters	%	%	%	%	%	%
Haematologic
Leukopenia	37	0	0	6	0	0
Neutropenia	34	1	<1	6	0	0
Thrombocytopenia	32	<1	<1	5	0	<1
Lymphocytopenia	31	4	<1	24	1	0
Chemistry
ALT increased	53	10	2	22	1	0
AST increased	53	7	<1	19	<1	0
Glucose increased	41	<1	0	33	1	0
Total Bilirubin increased	36	3	<1	10	1	<1
Phosphorus decreased	34	4	0	11	0	0
Calcium decreased	33	1	1	26	1	<1
Sodium decreased	31	4	1	24	4	1
Potassium increased	27	4	<1	23	5	0
Creatinine increased	26	0	<1	25	<1	0
Magnesium decreased	26	<1	1	14	0	0
Glucose decreased	17	0	<1	3	0	0

Table 8 presents laboratory abnormalities occurring in >= 15 % of patients who received VOTRIENT in the pivotal STS study. Grades are based on the NCI CTCAE

Table 8. Selected Laboratory Abnormalities in >= 15 % of Patients who Received VOTRIENT and More Common than Placebo Arm (VEG110727)

		Pazopanib (N = 240)			Placebo (N = 123)
	All Grades	Grade 3	Grade 4	All Grades	Grade 3	Grade 4
Parameters	%	%	%	%	%	%
Haematological
Leukopenia	44	1	0	15	0	0
Neutropenia	33	4	0	7	0	0
Thrombocytopenia	36	3	<1	6	0	0
Lymphocytopenia	43	10	0	36	9	2
Anaemia	27	5	2	23	<1	<1
Chemistry
ALKP increased	32	3	0	23	<1	0
ALT increased	46	8	2	18	2	<1
AST increased	51	5	3	22	2	0
Albumin increased	34	<1	0	21	0	0
Glucose increased	45	<1	0	35	2	0
Total Bilirubin increased	29	1	0	7	2	0
Sodium decreased	31	4	0	20	3	0
Potassium increased	16	1	0	11	0	0

Post marketing data

The following adverse reactions have been identified during post-approval use of VOTRIENT. This includes spontaneous case reports as well as serious adverse events from ongoing studies, clinical pharmacology studies and exploratory studies in unapproved indications.

Infections and infestations

Uncommon

Infections (with or without neutropenia)

Blood and lymphatic system disorders

Rare

Thrombotic microangiopathy (including thrombotic thrombocytopenic purpura and haemolytic uraemic syndrome)

Nervous system disorders

Rare

Posterior reversible encephalopathy syndrome

Gastrointestinal disorders

Common

Flatulence

Uncommon

Pancreatitis

Hepatobiliary disorders

Common

Gamma-glutamyl transpeptidase increased

Musculoskeletal and connective tissue disorders

Very common

Arthralgia

DOSAGE AND ADMINISTRATION

The recommended dose of VOTRIENT for the treatment of RCC or STS is 800 mg orally once daily. VOTRIENT should be taken without food (at least one hour before or two hours after a meal) (see Pharmacokinetics). VOTRIENT should be taken whole with water and must not be broken or crushed. If a dose is missed, it should not be taken if it is less than 12 hours until the next dose.

Dose modification, either an increase or decrease in dose, should be in 200 mg increments in a stepwise fashion based on individual tolerability in order to manage adverse reactions. The daily dose of VOTRIENT should not exceed 800 mg.

Populations

VOTRIENT is not recommended for use in children and adolescents below 18 years of age due to insufficient data on safety and efficacy (see Precautions).

No alteration of dosage, dosing frequency or route of administration is required in patients over 65 years.

Renal impairment is not expected to have a clinically relevant effect on VOTRIENT pharmacokinetics given the low renal excretion of pazopanib and metabolites (see Elimination). Renal impairment is not expected to influence pazopanib exposure, and dose adjustment is not necessary in patients with creatine clearance >= 30ml/min. There is no experience of pazopanib in patients with severe renal impairment or in patients undergoing peritoneal dialysis or haemodialysis; therefore, use of pazopanib is not recommended in these patients.

The safety and pharmacokinetics of VOTRIENT in patients with pre-existing hepatic impairment have not been fully established (see Precautions). No dose adjustment is required in patients with mild hepatic impairment as defined by alanine aminotransferase (ALT) and bilirubin (see Precautions). The dose of VOTRIENT should be reduced to 200 mg per day in patients with moderate hepatic impairment). There are insufficient data in patients with severe hepatic impairment (total bilirubin > 3 x ULN regardless of any level of ALT); therefore, use of VOTRIENT is not recommended in these patients.

OVERDOSAGE

VOTRIENT doses up to 2,000 mg have been evaluated in clinical trials. Grade 3 fatigue (dose limiting toxicity) and Grade 3 hypertension were each observed in 1 of 3 patients dosed at 2,000 mg and 1,000 mg daily, respectively.

Symptoms and Signs

Treatment

Further management should be as clinically indicated or as recommended by the national poisons centre, where available. Haemodialysis is not expected to enhance the elimination of VOTRIENT because pazopanib is not significantly renally excreted and is highly bound to plasma proteins.

PRESENTATION AND STORAGE CONDITIONS

The 200 mg tablets are modified capsule-shaped, pink, film-coated with 'GS JT' debossed on one side. The 400 mg tablets are modified capsule-shaped, white, film-coated with 'GS UHL' debossed on one side.

VOTRIENT 200 mg film-coated tablets are supplied in high-density polyethylene (HDPE) bottles with child resistant polypropylene closures containing 30 or 90 tablets. VOTRIENT 400 mg film-coated tablets are supplied in high-density polyethylene (HDPE) bottles with child resistant polypropylene closures containing 30 or 60 tablets. Not all strengths and pack sizes may be distributed in New Zealand.

SPONSOR DETAILS

GlaxoSmithKline NZ Limited Private Bag 106600 Downtown Auckland NEW ZEALAND Phone: (09) 367 2900 Facsimile: (09) 367 2910

MEDICINE CLASSIFICATION

DATE OF PREPARATION

27 June 2013 VOTRIENT(r) is a registered trade mark of the GlaxoSmithKline group of companies. Version 10.0

Endpoints/ Study population	VOTRIENT	Placebo	HR (95% CI)	P value (one-sided)
PFS Overall ITT Treatment-naive Cytokine pre-treated	Median (months)
	N=290 9.2 N=155 11.1 N=135 7.4	N=145 4.2 N=78 2.8 N=67 4.2	0.46 (0.34, 0.62) 0.40 (0.27, 0.60) 0.54 (0.35, 0.84)	<0.0000001 <0.0000001 <0.001
Response rate	% (95% CI)		-	<0.001
Overall	N=290 30 (25.1 ,35.6)	N=145 3 (0.5, 6.4)

Endpoint	VOTRIENT N=557	Sunitinib N=553	HR (95 % CI)
PFS Overall Median (months) (95 % CI)	8.4 (8.3, 10.9)	9.5 (8.3, 11.0)
			1.047 (0.898,1.220)
Overall Survival Median (months) (95 % CI)	28.4 26.2, 35.6)	29.3 (25.3, 32.5)
			0.908 a (0.762, 1.082)

Endpoints / study population	VOTRIENT	Placebo	HR (95% CI)	P value (one-sided)
PFS
Overall ITT	N = 246	N = 123
Median (weeks)	20.0	7.0	0.35 (0.26, 0.48)	< 0.001
Leiomyosarcoma	N = 109	N = 49
Median (weeks)	20.1	8.1	0.37 (0.23, 0.60)	< 0.001
Synovial sarcoma subgroups	N = 25	N = 13
Median (weeks)	17.9	4.1	0.43 (0.19, 0.98)	0.005
'Other STS' subgroups	N = 112	N = 61
Median (weeks)	20.1	4.3	0.39 (0.25, 0.60)	< 0.001
Response Rate (CR+PR)
% (95 % CI)	4 (2.3, 7.9)	0 (0.0, 3.0)
Duration of response
Median (weeks) (95 % CI)	38.9 (16.7, 40.0)
HR = Hazard ratio; ITT = Intent to treat; PFS = Progression-free survival; CR = Complete Response; PR = Partial Response.

NEW ZEALAND DATA SHEET

NAME OF THE MEDICINE