VOTRIENT 200mg tablets medication leaflet

Votrient 200 mg film-coated tablets

Votrient 400 mg film-coated tablets

Votrient 200 mg film-coated tablets

Each film-coated tablet contains 200 mg pazopanib (as hydrochloride).

Votrient 400 mg film-coated tablets

Each film-coated tablet contains 400 mg pazopanib (as hydrochloride).

For the full list of excipients, see section 6.1.

Film-coated tablet.

Votrient 200 mg film-coated tablets

Capsule-shaped, pink, film-coated tablet with GS JT debossed on one side.

Votrient 400 mg film-coated tablets

Capsule-shaped, white, film-coated tablet with GS UHL debossed on one side.

Votrient is indicated in adults for the first-line treatment of advanced renal cell carcinoma (RCC) andfor patients who have received prior cytokine therapy for advanced disease.

Soft-tissue sarcoma (STS)

Votrient is indicated for the treatment of adult patients with selective subtypes of advanced soft-tissuesarcoma (STS) who have received prior chemotherapy for metastatic disease or who have progressedwithin 12 months after (neo) adjuvant therapy.

Efficacy and safety has only been established in certain STS histological tumour subtypes (seesection 5.1).

Votrient treatment should only be initiated by a physician experienced in the administration ofanti-cancer medicinal products.

The recommended dose of pazopanib for the treatment of RCC or STS is 800 mg once daily.

Dose modification (decrease or increase) should be in 200 mg decrements or increments in a stepwisefashion based on individual tolerability in order to manage adverse reactions. The dose of pazopanibshould not exceed 800 mg.

Pazopanib should not be used in children younger than 2 years of age because of safety concerns withregard to organ growth and maturation (see sections 4.4 and 5.3).

The safety and efficacy of pazopanib in children aged 2 to 18 years of age have not yet beenestablished.

Currently available data are described in sections 4.8, 5.1 and 5.2 but no recommendation on a posologycan be made.

There are limited data on the use of pazopanib in patients aged 65 years and older. In the RCC studiesof pazopanib, overall no clinically significant differences in safety of pazopanib were observedbetween subjects aged at least 65 years and younger subjects. Clinical experience has not identifieddifferences in responses between the elderly and younger patients, but greater sensitivity of someelderly patients cannot be ruled out.

Renal impairment is unlikely to have a clinically relevant effect on pazopanib pharmacokinetics giventhe low renal excretion of pazopanib and metabolites (see section 5.2). Therefore, no dose adjustmentis required in patients with creatinine clearance above 30 ml/min. Caution is advised in patients withcreatinine clearance below 30 ml/min as there is no experience of pazopanib in this patient population.

Dosing recommendations in hepatically impaired patients are based on pharmacokinetic studies ofpazopanib in patients with varying degrees of hepatic dysfunction (see section 5.2). All patients shouldhave liver function tests to determine whether they have hepatic impairment before starting and duringpazopanib therapy (see section 4.4). Administration of pazopanib to patients with mild or moderatehepatic impairment should be undertaken with caution and close monitoring of tolerability. 800 mgpazopanib once daily is the recommended dose in patients with mild abnormalities in serum liver tests(defined either as normal bilirubin and any degree of alanine aminotransferase (ALT) elevation or asan elevation of bilirubin (>35% direct) up to 1.5 x upper limit of normal (ULN) regardless of the ALTvalue). A reduced pazopanib dose of 200 mg once daily is recommended in patients with moderatehepatic impairment (defined as an elevation of bilirubin >1.5 to 3 x ULN regardless of the ALT value)(see section 5.2).

Pazopanib is not recommended in patients with severe hepatic impairment (defined as total bilirubin>3 x ULN regardless of the ALT value).

See section 4.4 for liver monitoring and dose modification for patients with drug-inducedhepatotoxicity.

Pazopanib is for oral use. It should be taken without food, at least one hour before or two hours after ameal (see section 5.2). The film-coated tablets should be taken whole with water and not broken orcrushed (see section 5.2).

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Cases of hepatic failure (including fatalities) have been reported during use of pazopanib.

Administration of pazopanib to patients with mild or moderate hepatic impairment should beundertaken with caution and close monitoring. 800 mg pazopanib once daily is the recommended dosein patients with mild abnormalities in serum liver tests (either normal bilirubin and any degree of ALTelevation or elevation of bilirubin up to 1.5 x ULN regardless of the ALT value). A reduced pazopanibdose of 200 mg once daily is recommended in patients with moderate hepatic impairment (elevation ofbilirubin >1.5 to 3 x ULN regardless of the ALT value) (see sections 4.2 and 5.2). Pazopanib is notrecommended in patients with severe hepatic impairment (total bilirubin >3 x ULN regardless of the

ALT value) (see sections 4.2 and 5.2). Exposure at a 200 mg dose is markedly reduced, though highlyvariable, in these patients, with values considered insufficient to obtain a clinically relevant effect.

In clinical studies with pazopanib, increase in serum transaminases (ALT, aspartate aminotransferase[AST]) and bilirubin were observed (see section 4.8). In the majority of the cases, isolated increases in

ALT and AST have been reported, without concomitant elevations of alkaline phosphatase orbilirubin. Patients over 60 years of age may be at greater risk for mild (>3 x ULN) to severe(>8 x ULN) elevation of ALT. Patients who carry the HLA-B*57:01 allele have an increased risk ofpazopanib-associated ALT elevations. Liver function should be monitored in all subjects receivingpazopanib, regardless of genotype or age (see section 5.1).

Serum liver tests should be performed before initiation of treatment with pazopanib, at weeks 3, 5, 7and 9, then at months 3 and 4, with additional tests as clinically indicated. Periodic testing should thencontinue after month 4.

See Table 1 for dose modification guidance for patients with baseline values of total bilirubin1.5 x ULN and AST and ALT 2 x ULN:

Table 1 Dose modifications for drug-induced hepatotoxicity

Liver test values Dose modification

Transaminase elevation Continue on pazopanib with weekly monitoring of liver functionbetween 3 and 8 x ULN until transaminases return to Grade 1 or baseline.

Transaminase elevation of Interrupt pazopanib until transaminases return to Grade 1 or>8 x ULN baseline.

If the potential benefit of reinitiating pazopanib treatment isconsidered to outweigh the risk for hepatotoxicity, thenreintroduce pazopanib at a reduced dose of 400 mg daily andperform serum liver tests weekly for 8 weeks. Followingreintroduction of pazopanib, if transaminase elevations >3 x ULNrecur, then pazopanib should be permanently discontinued.

Transaminase elevations Permanently discontinue pazopanib.

>3 x ULN concurrently with Patients should be monitored until return to Grade 1 or baseline.

bilirubin elevations >2 x ULN Pazopanib is a UGT1A1 inhibitor. Mild, indirect (unconjugated)hyperbilirubinaemia may occur in patients with Gilbert’ssyndrome. 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 recommendationsoutlined for isolated ALT elevations.

Concomitant use of pazopanib and simvastatin increases the risk of ALT elevations (see section 4.5)and should be undertaken with caution and close monitoring.

In clinical studies with pazopanib, events of hypertension including newly diagnosed symptomaticepisodes of elevated blood pressure (hypertensive crisis) have occurred. Blood pressure should be wellcontrolled prior to initiating pazopanib. Patients should be monitored for hypertension early afterstarting treatment (no longer than one week after starting pazopanib) and frequently thereafter toensure blood pressure control. Elevated blood pressure levels (systolic blood pressure ≥150 mm Hg ordiastolic blood pressure ≥100 mm Hg) occurred early in the course of treatment (approximately 40%of cases occurred by day 9 and approximately 90% of cases occurred in the first 18 weeks). Bloodpressure should be monitored and managed promptly using a combination of anti-hypertensive therapyand dose modification of pazopanib (interruption and re-initiation at a reduced dose based on clinicaljudgement) (see sections 4.2 and 4.8). Pazopanib should be discontinued if there is evidence ofhypertensive crisis or if hypertension is severe and persists despite anti-hypertensive therapy andpazopanib dose reduction.

Posterior reversible encephalopathy syndrome (PRES)/Reversible posterior leukoencephalopathysyndrome (RPLS)

PRES/RPLS has been reported in association with pazopanib. PRES/RPLS can present with headache,hypertension, seizure, lethargy, confusion, blindness and other visual and neurological disturbances,and can be fatal. Patients developing PRES/RPLS should permanently discontinue treatment withpazopanib.

ILD, which can be fatal, has been reported in association with pazopanib (see section 4.8). Patientsshould be monitored for pulmonary symptoms indicative of ILD/pneumonitis and pazopanib should bediscontinued in patients developing ILD or pneumonitis.

Cardiac dysfunction/Heart failure

The risks and benefits of pazopanib should be considered before beginning therapy in patients whohave pre-existing cardiac dysfunction. The safety and pharmacokinetics of pazopanib in patients withmoderate to severe heart failure or those with a below normal left ventricular ejection fraction (LVEF)have not been studied.

In clinical studies with pazopanib, events of cardiac dysfunction such as congestive heart failure anddecreased LVEF have occurred (see section 4.8). In a randomised study comparing pazopanib andsunitinib in RCC (VEG108844), subjects had baseline and follow up LVEF measurements.

Myocardial dysfunction occurred in 13% (47/362) of subjects in the pazopanib arm compared to 11%(42/369) of subjects in the sunitinib arm. Congestive heart failure was observed in 0.5% of subjects ineach treatment arm. Congestive heart failure was reported in 3 out of 240 subjects (1%) in the Phase

III VEG110727 STS study. Decreases in LVEF in subjects who had post-baseline and follow-up

LVEF measurement were detected in 11% (15/140) in the pazopanib arm, compared with 3% (1/39) inthe placebo arm.

Thirteen of the 15 subjects in the pazopanib arm of the STS Phase III study had concurrenthypertension which may have exacerbated cardiac dysfunction in patients at risk by increasing cardiacafter-load. 99% of patients (243/246) enrolled in the STS Phase III study, including the 15 subjects,received anthracycline. Prior anthracycline therapy may be a risk factor for cardiac dysfunction.

Outcome

Four of the 15 subjects had full recovery (within 5% of baseline) and 5 had partial recovery (within thenormal range, but >5% below baseline). One subject did not recover and follow-up data were notavailable for the other 5 subjects.

Interruption of pazopanib and/or dose reduction should be combined with treatment of hypertension (ifpresent, refer to hypertension warning section above) in patients with significant reductions in LVEF,as clinically indicated.

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 pazopanib, events of QT prolongation and torsade de pointes have occurred(see section 4.8). Pazopanib should be used with caution in patients with a history of QT intervalprolongation, in patients taking antiarrhythmics or other medicinal products that may prolong QTinterval and in patients with relevant pre-existing cardiac disease. When using pazopanib, baseline andperiodic monitoring of electrocardiograms and maintenance of electrolytes (e.g. calcium, magnesium,potassium) within normal range is recommended.

Arterial thrombotic events

In clinical studies with pazopanib, myocardial infarction, myocardial ischaemia, ischaemic stroke andtransient ischaemic attack were observed (see section 4.8). Fatal events have been observed.

Pazopanib should be used with caution in patients who are at increased risk of thrombotic events orwho have had a history of thrombotic events. Pazopanib has not been studied in patients who have hadan event within the previous 6 months. A treatment decision should be made based on the assessmentof individual patient’s benefit/risk.

In clinical studies with pazopanib, venous thromboembolic events including venous thrombosis andfatal pulmonary embolus have occurred. While observed in both RCC and STS studies, the incidencewas higher in the STS population (5%) than in the RCC population (2%).

TMA has been reported in clinical studies of pazopanib as monotherapy, in combination withbevacizumab, and in combination with topotecan (see section 4.8). Patients developing TMA shouldpermanently discontinue treatment with pazopanib. Reversal of effects of TMA has been observedafter treatment was discontinued. Pazopanib is not indicated for use in combination with other agents.

Haemorrhagic events

In clinical studies with pazopanib haemorrhagic events have been reported (see section 4.8). Fatalhaemorragic events have occurred. Pazopanib has not been studied in patients who had a history ofhaemoptysis, cerebral haemorrhage or clinically significant gastrointestinal (GI) haemorrhage in thepast 6 months. Pazopanib should be used with caution in patients with significant risk of haemorrhage.

The use of VEGF pathway inhibitors in patients with or without hypertension may promote theformation of aneurysms and/or artery dissections. Before initiating pazopanib, this risk should becarefully considered in patients with risk factors such as hypertension or history of aneurysms.

Gastrointestinal (GI) perforations and fistula

In clinical studies with pazopanib, events of GI perforation or fistula have occurred (see section 4.8).

Fatal perforation events have occurred. Pazopanib should be used with caution in patients at risk for

GI perforation or fistula.

Wound healing

No formal studies of the effect of pazopanib on wound healing have been conducted. Since vascularendothelial growth factor (VEGF) inhibitors may impair wound healing, treatment with pazopanibshould be stopped at least 7 days prior to scheduled surgery. The decision to resume pazopanib aftersurgery should be based on clinical judgement of adequate wound healing. Pazopanib should bediscontinued in patients with wound dehiscence.

In clinical studies with pazopanib, events of hypothyroidism have occurred (see section 4.8). Baselinelaboratory measurement of thyroid function is recommended and patients with hypothyroidism shouldbe treated as per standard medical practice prior to the start of pazopanib treatment. All patients shouldbe observed closely for signs and symptoms of thyroid dysfunction on pazopanib treatment.

Laboratory monitoring of thyroid function should be performed periodically and managed as perstandard medical practice.

Proteinuria

In clinical studies with pazopanib, proteinuria has been reported. Baseline and periodic urinanalysisduring treatment is recommended and patients should be monitored for worsening proteinuria.

Pazopanib should be discontinued if the patient develops nephrotic syndrome.

The occurrence of TLS, including fatal TLS, has been associated with the use of pazopanib (seesection 4.8). Patients at increased risk of TLS are those with rapidly growing tumours, a high tumourburden, renal dysfunction, or dehydration. Preventative measures, such as treatment of high uric acidlevels and intravenous hydration, should be considered prior to initiation of Votrient. Patients at riskshould be closely monitored and treated as clinically indicated.

Pneumothorax

In clinical studies with pazopanib in advanced soft tissue sarcoma, events of pneumothorax haveoccurred (see section 4.8). Patients on pazopanib treatment should be observed closely for signs andsymptoms of pneumothorax.

Because the mechanism of action of pazopanib can severely affect organ growth and maturationduring early post-natal development in rodents (see section 5.3), pazopanib should not be given topaediatric patients younger than 2 years of age.

Cases of serious infections (with or without neutropenia), in some cases with fatal outcome, have beenreported.

Combination with other systemic anti-cancer therapies

Clinical studies of pazopanib in combination with a number of other anti-cancer therapies (includingfor example pemetrexed, lapatinib or pembrolizumab) were terminated early due to concerns overincreased toxicity and/or mortality, and a safe and effective combination dose has not been establishedwith these regimens.

Pre-clinical studies in animals have shown reproductive toxicity (see section 5.3). If pazopanib is usedduring pregnancy, or if the patient becomes pregnant whilst receiving pazopanib, the potential hazardto the foetus should be explained to the patient. Women of childbearing potential should be advised toavoid becoming pregnant while receiving treatment with pazopanib (see section 4.6).

Concomitant treatment with strong inhibitors of CYP3A4, P-glycoprotein (P-gp) or breast cancerresistance protein (BCRP) should be avoided due to risk of increased exposure to pazopanib (seesection 4.5). Selection of alternative concomitant medicinal products with no or minimal potential toinhibit CYP3A4, P-gp or BCRP should be considered.

Concomitant treatment with inducers of CYP3A4 should be avoided due to risk of decreased exposureto pazopanib (see section 4.5).

Cases of hyperglycaemia have been observed during concomitant treatment with ketoconazole.

Concomitant administration of pazopanib with uridine diphosphate glucuronosyl transferase 1A1(UGT1A1) substrates (e.g. irinotecan) should be undertaken with caution since pazopanib is aninhibitor of UGT1A1 (see section 4.5).

Grapefruit juice should be avoided during treatment with pazopanib (see section 4.5).

This medicinal product contains less than 1 mmol sodium (23 mg) per film-coated tablet, that is to sayessentially ‘sodium-free’.

Effects of other medicinal products on pazopanib

In vitro studies suggested that the oxidative metabolism of pazopanib in human liver microsomes ismediated primarily by CYP3A4, with minor contributions from CYP1A2 and CYP2C8. Therefore,inhibitors and inducers of CYP3A4 may alter the metabolism of pazopanib.

CYP3A4, P-gp, BCRP inhibitors

Pazopanib is a substrate for CYP3A4, P-gp and BCRP.

Concurrent administration of pazopanib (400 mg once daily) with the strong CYP3A4 and P-gpinhibitor ketoconazole (400 mg once daily) for 5 consecutive days resulted in a 66% and 45% increasein mean pazopanib AUC(0-24) and Cmax, respectively, relative to administration of pazopanib alone(400 mg once daily for 7 days). Pharmacokinetic parameter comparisons of pazopanib Cmax (range ofmeans 27.5 to 58.1 µg/ml) and AUC(0-24) (range of means 48.7 to 1040 µg*h/ml) after administrationof pazopanib 800 mg alone and after administration of pazopanib 400 mg plus ketoconazole 400 mg(mean Cmax 59.2 µg/ml, mean AUC(0-24)1300 µg*h/ml) indicated that, in the presence of a strong

CYP3A4 and P-gp inhibitor a dose reduction to pazopanib 400 mg once daily will, in the majority ofpatients, result in systemic exposure similar to that observed after administration of 800 mg pazopanibonce daily alone. Some patients however may have systemic pazopanib exposure greater than whathas been observed after administration of 800 mg pazopanib alone.

Co-administration of pazopanib 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 contains an inhibitor of

CYP3A4 and may also increase plasma concentrations of pazopanib.

Administration of 1500 mg lapatinib (a substrate for and weak inhibitor of CYP3A4 and P-gp and apotent inhibitor of BCRP) with 800 mg pazopanib resulted in an approximately 50% to 60% increasein mean pazopanib AUC(0-24) and Cmax compared to administration of 800 mg pazopanib alone.

Inhibition of P-gp and/or BCRP by lapatinib likely contributed to the increased exposure to pazopanib.

Co-administration of pazopanib with a CYP3A4, P-gp, and BCRP inhibitor, such as lapatinib, willresult in an increase in plasma pazopanib concentrations. Co-administration with potent P-gp or BCRPinhibitors may also alter the exposure and distribution of pazopanib, including distribution into thecentral nervous systems (CNS).

Concomitant use of pazopanib with a strong CYP3A4 inhibitor should be avoided (see section 4.4). Ifno medically acceptable alternative to a strong CYP34A inhibitor is available, the dose of pazopanibshould be reduced to 400 mg daily during concomitant administration. In such cases there should beclose attention to adverse drug reaction, and further dose reduction may be considered if possibledrug-related adverse events are observed.

Combination with strong P-gp or BCRP inhibitors should be avoided, or selection of an alternateconcomitant medicinal product with no or minimal potential to inhibit P-gp or BCRP is recommended.

CYP3A4, P-gp, BCRP inducers

CYP3A4 inducers such as rifampin may decrease plasma pazopanib concentrations. Co-administrationof pazopanib with potent P-gp or BCRP inducers may alter the exposure and distribution of pazopanib,including distribution into the CNS. Selection of an alternative concomitant medication with no orminimal enzyme or transporter induction potential is recommended.

Effects of pazopanib on other medicinal products

In vitro studies with human liver microsomes showed that pazopanib inhibited CYP enzymes 1A2,3A4, 2B6, 2C8, 2C9, 2C19, and 2E1. Potential induction of human CYP3A4 was demonstrated in anin vitro human PXR assay. Clinical pharmacology studies, using pazopanib 800 mg once daily, havedemonstrated that pazopanib does not have a clinically relevant effect on the pharmacokinetics ofcaffeine (CYP1A2 probe substrate), warfarin (CYP2C9 probe substrate), or omeprazole (CYP2C19probe substrate) in cancer patients. Pazopanib resulted in an increase of approximately 30% in themean AUC and Cmax of midazolam (CYP3A4 probe substrate) and increases of 33% to 64% in theratio of dextrometrophan to dextrophan concentrations in the urine after oral administration ofdextromethorphan (CYP2D6 probe substrate). Co-administration of pazopanib 800 mg once daily andpaclitaxel 80 mg/m2 (CYP3A4 and CYP2C8 substrate) once weekly resulted in a mean increase of26% and 31% in paclitaxel AUC and Cmax, respectively.

Based on in vitro IC50 and in vivo plasma Cmax values, pazopanib metabolites GSK1268992 and

GSK1268997 may contribute to the net inhibitory effect of pazopanib towards BCRP. Furthermore,inhibition of BCRP and P-gp by pazopanib in the gastrointestinal tract cannot be excluded. Careshould be taken when pazopanib is co-administered with other oral BCRP and P-gp substrates.

In vitro, pazopanib inhibited human organic anion transporting polypeptide (OATP1B1). It cannot beexcluded that pazopanib will affect the pharmacokinetics of substrates of OATP1B1 (e.g. statins, see“Effect of concomitant use of pazopanib and simvastatin” below).

Pazopanib is an inhibitor of the uridine diphosphoglucuronosyl-transferase 1A1 (UGT1A1) enzyme invitro. The active metabolite of irinotecan, SN-38, is a substrate for OATP1B1 and UGT1A1.

Co-administration of pazopanib 400 mg once daily with cetuximab 250 mg/m2 and irinotecan150 mg/m2 resulted in an approximately 20% increase in systemic exposure to SN-38. Pazopanib mayhave a greater impact on SN-38 disposition in subjects with the UGT1A1*28 polymorphism relative tosubjects with the wild-type allele. However, the UGT1A1 genotype was not always predictive of theeffect of pazopanib on SN-38 disposition. Care should be taken when pazopanib is co-administeredwith substrates of UGT1A1.

Effect of concomitant use of pazopanib and simvastatin

Concomitant use of pazopanib and simvastatin increases the incidence of ALT elevations. Resultsfrom a meta-analysis using pooled data from clinical studies with pazopanib show that ALT >3x ULNwas reported in 126/895 (14%) of patients who did not use statins, compared with 11/41 (27%) ofpatients who had concomitant use of simvastatin (p = 0.038). If a patient receiving concomitantsimvastatin develops ALT elevations, follow guidelines for pazopanib posology and discontinuesimvastatin (see section 4.4). In addition, concomitant use of pazopanib and other statins should beundertaken with caution as there are insufficient data available to assess their impact on ALT levels. Itcannot be excluded that pazopanib will affect the pharmacokinetics of other statins (e.g. atorvastatin,fluvastatin, pravastatin, rosuvastatin).

Effect of food on pazopanib

Administration of pazopanib with a high-fat or low-fat meal results in an approximately 2-foldincrease in AUC and Cmax. Therefore, pazopanib should be administered at least 1 hour before or2 hours after a meal.

Medicinal products that raise gastric pH

Concomitant administration of pazopanib with esomeprazole decreases the bioavailability ofpazopanib by approximately 40% (AUC and Cmax), and co-administration of pazopanib with medicinesthat increase gastric pH should be avoided. If the concomitant use of a proton-pump inhibitor (PPI) ismedically necessary, it is recommended that the dose of pazopanib be taken without food once daily inthe evening concomitantly with the PPI. If the concomitant administration of an H2-receptorantagonist is medically necessary, pazopanib should be taken without food at least 2 hours before or atleast 10 hours after a dose of an H2-receptor antagonist. Pazopanib should be administered at least1 hour before or 2 hours after administration of short-acting antacids. The recommendations for how

PPIs and H2-receptor antagonists are co-administered are based on physiological considerations.

Pregnancy/ Contraception in males and females

There are no adequate data from the use of pazopanib in pregnant women. Studies in animals haveshown reproductive toxicity (see section 5.3). The potential risk for humans is unknown.

Pazopanib should not be used during pregnancy unless the clinical condition of the woman requirestreatment with pazopanib. If pazopanib is used during pregnancy, or if the patient becomes pregnantwhile receiving pazopanib, the potential hazard to the foetus should be explained to the patient.

Women of childbearing potential should be advised to use adequate contraception during treatmentand for at least 2 weeks after the last dose of pazopanib and to avoid becoming pregnant whilereceiving treatment with pazopanib.

Male patients (including those who have had vasectomies) should use condoms during sexualintercourse while taking pazopanib and for at least 2 weeks after the last dose of pazopanib to avoidpotential exposure to the medicinal product for pregnant partners and female partners of reproductivepotential.

The safe use of pazopanib during breast-feeding has not been established. It is not known whetherpazopanib or its metabolites are excreted in human milk. There are no animal data on the excretion ofpazopanib in animal milk. A risk to the breast-fed child cannot be excluded. Breast-feeding should bediscontinued during treatment with pazopanib.

Animal studies indicate that male and female fertility may be affected by treatment with pazopanib(see section 5.3).

Votrient has no or negligible influence on the ability to drive and use machines. A detrimental effecton such activities cannot be predicted from the pharmacology of pazopanib. The clinical status of thepatient and the adverse event profile of pazopanib should be borne in mind when considering thepatient’s ability to perform tasks that require judgement, motor or cognitive skills. Patients shouldavoid driving or using machines if they feel dizzy, tired or weak.

Pooled data from the pivotal RCC study (VEG105192, n=290), the extension study (VEG107769,n=71), the supportive Phase II study (VEG102616, n=225) and the randomised, open-label, parallelgroup Phase III non-inferiority study (VEG108844, n=557) were evaluated in the overall evaluation ofsafety and tolerability of pazopanib (total n=1149) in subjects with RCC (see section 5.1).

Pooled data from the pivotal STS study (VEG110727, n=369) and the supportive Phase II study(VEG20002, n=142) was evaluated in the overall evaluation of safety and tolerability of pazopanib(total safety population n=382) in subjects with STS (see section 5.1).

The most important serious adverse reactions identified in the RCC or STS studies were transientischaemic attack, ischaemic stroke, myocardial ischaemia, myocardial and cerebral infarction, cardiacdysfunction, gastrointestinal perforation and fistula, QT prolongation, Torsade de Pointes andpulmonary, gastrointestinal and cerebral haemorrhage, all adverse reactions being reported in <1% oftreated patients. Other important serious adverse reactions identified in STS studies included venousthromboembolic events, left ventricular dysfunction and pneumothorax.

Fatal events that were considered possibly related to pazopanib included gastrointestinal haemorrhage,pulmonary haemorrhage/haemoptysis, abnormal hepatic function, intestinal perforation and ischaemicstroke.

The most common adverse reactions (experienced by at least 10% of the patients) of any grade in the

RCC and STS trials included: diarrhoea, hair colour change, skin hypopigmentation, exfoliative rash,hypertension, nausea, headache, fatigue, anorexia, vomiting, dysgeusia, stomatitis, weight decreased,pain, elevated alanine aminotransferase and elevated aspartate aminotransferase.

Adverse drug reactions, all grades, which were reported in RCC and STS subjects or during thepost-marketing period are listed below by MedDRA body system organ class, frequency and grade ofseverity. The following convention has been utilised for the classification of frequency: very common(≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000);very rare (<1/10,000); and not known (cannot be estimated from the available data).

Categories have been assigned based on absolute frequencies in the clinical trial data. Post-marketingdata on safety and tolerability across all pazopanib clinical studies and from spontaneous reports havealso been evaluated. Within each system organ class, adverse reactions with the same frequency arepresented in order of decreasing seriousness.

Table 2 Treatment-related adverse reactions reported in RCC studies (n = 1149) or duringpost-marketing period

System Organ Frequency Adverse reactions All grades Grade 3 Grade 4

Class (all grades) n (%) n (%) n (%)

Common Infections (with or not known not known not

Infections and without neutropenia)† known

Infestations Uncommon Gingival infection 1 (<1%) 0 0

Infectious peritonitis 1 (<1%) 0 0

Neoplasms Uncommon Tumour pain 1 (<1%) 1 (<1%) 0benign, malignantand unspecified(incl cysts andpolyps)

Common Thrombocytopenia 80 (7%) 10 (<1%) 5 (<1%)

Neutropenia 79 (7%) 20 (2%) 4 (<1%)

Leukopenia 63 (5%) 5 (<1%) 0

Uncommon Polycythaemia 6 (0.03%) 1 0

Blood and Rare Thrombotic not known not known notlymphatic system microangiopathy knowndisorders (including thromboticthrombocytopenicpurpura andhaemolytic uraemicsyndrome)†

Endocrine Common Hypothyroidism 83 (7%) 1 (<1%) 0disorders

Very common Decreased appetitee 317 (28%) 14 (1%) 0

Common Hypophosphataemia 21 (2%) 7 (<1%) 0

Metabolism and Dehydration 16 (1%) 5 (<1%) 0nutritiondisorders Uncommon Hypomagnesaemia 10 (<1%) 0 0

Tumour lysis not known not known not

Not knownsyndrome* known

Psychiatric Common Insomnia 30 (3%) 0 0disorders

Very common Dysgeusiac 254 (22%) 1 (<1%) 0

Headache 122 (11%) 11 (<1%) 0

Common Dizziness 55 (5%) 3 (<1%) 1 (<1%)

Lethargy 30 (3%) 3 (<1%) 0

Paraesthesia 20 (2%) 2 (<1%) 0

Peripheral sensory 17 (1%) 0 0neuropathy

Uncommon Hypoaesthesia 8 (<1%) 0 0

Transient ischaemic 7 (<1%) 4 (<1%) 0

Nervous systemattackdisorders

Somnolence 3 (<1%) 1 (<1%) 0

Cerebrovascular 2 (<1%) 1 (<1%) 1 (<1%)accident

Ischaemic stroke 2 (<1%) 0 1 (<1%)

Rare Posterior reversible not known not known notencephalopathy/knownreversible posteriorleukoencephalopathysyndrome†

Common Vision blurred 19 (2%) 1 (<1%) 0

Uncommon Retinal detachment† 1 (<1%) 1 (<1%) 0

Retinal tear† 1 (<1%) 1 (<1%) 0

Eyelash discolouration 4 (<1%) 0 0

Uncommon Bradycardia 6 (<1%) 0 0

Myocardial infarction 5 (<1%) 1 (<1%) 4 (<1%)

Cardiac dysfunctionf 4 (<1%) 1 (<1%) 0

Myocardial ischaemia 3 (<1%) 1 (<1%) 0

Very common Hypertension 473 (41%) 115 (10%) 1 (<1%)

Common Hot flush 16 (1%) 0 0

Venous 13 (1%) 6 (<1%) 7 (<1%)thromboembolicg

Vascular eventdisorders Flushing 12 (1%) 0 0

Uncommon Hypertensive crisis 6 (<1%) 0 2 (<1%)

Haemorrhage 1 (<1%) 0 0

Rare Aneurysms and artery not known not known notdissections† known

Common Epistaxis 50 (4%) 1 (<1%) 0

Dysphonia 48 (4%) 0 0

Dyspnoea 42 (4%) 8 (<1%) 1 (<1%)

Respiratory, Haemoptysis 15 (1%) 1 (<1%) 0thoracic and Uncommon Rhinorrhoea 8 (<1%) 0 0mediastinal Pulmonary 2 (<1%) 0 0disorders haemorrhage

Pneumothorax 1 (<1%) 0 0

Rare Interstitial lung not known not known notdisease/pneumonitis† known

Very common Diarrhoea 614 (53%_) 65 (6%) 2 (<1%)

Nausea 386 (34%) 14 (1%) 0

Vomiting 225 (20%) 18 (2%) 1 (<1%)

Abdominal paina 139 (12%) 15 (1%) 0

Common Stomatitis 96 (8%) 4 (<1%) 0

Dyspepsia 83 (7%) 2 (<1%) 0

Flatulence 43 (4%) 0 0

Abdominal distension 36 (3%) 2 (<1%) 0

Mouth ulceration 28 (2%) 3 (<1%) 0

Dry mouth 27 (2%) 0 0

Uncommon Pancreatitis 8 (<1%) 4 (<1%) 0

Rectal haemorrhage 8 (<1%) 2 (<1%) 0

Haematochezia 6 (<1%) 0 0

Gastrointestinal 4 (<1%) 2 (<1%) 0haemorrhage

Melaena 4 (<1%) 1(<1%) 0

Gastrointestinal Frequent bowel 3 (<1%) 0 0disorders movements

Anal haemorrhage 2 (<1%) 0 0

Large intestine 2 (<1%) 1 (<1%) 0perforation

Mouth haemorrhage 2 (<1%) 0 0

Upper gastrointestinal 2 (<1%) 1 (<1%) 0haemorrhage

Enterocutaneous 1 (<1%) 0 0fistula

Haematemesis 1 (<1%) 0 0

Haemorrhoidal 1 (<1%) 0 0haemorrhage

Ileal perforation 1 (<1%) 0 1 (<1%)

Oesophageal 1 (<1%) 0 0haemorrhage

Retroperitoneal 1 (<1%) 0 0haemorrhage

Common Hyperbilirubinaemia 38 (3%) 2 (<1%) 1 (<1%)

Hepatic function 29 (3%) 13 (1%) 2 (<1%)abnormal

Hepatobiliary Hepatotoxicity 18 (2%) 11(<1%) 2 (<1%)disorders Uncommon Jaundice 3 (<1%) 1 (<1%) 0

Drug induced liver 2 (<1%) 2 (<1%) 0injury

Hepatic failure† 1 (<1%) 0 1 (<1%)

Very common Hair colour change 404 (35%) 1 (<1%) 0

Palmar-plantar 206 (18%) 39 (3%) 0erythrodysaesthesiasyndrome

Alopecia 130 (11%) 0 0

Rash 129 (11%) 7 (<1%) 0

Common Skin 52 (5%) 0 0hypopigmentation

Dry skin 50 (4%) 0 0

Pruritus 29 (3%) 0 0

Erythema 25 (2%) 0 0

Skin depigmentation 20 (2%) 0 0

Hyperhidrosis 17 (1%) 0 0

Skin and

Uncommon Nail disorders 11 (<1%) 0 0subcutaneous

Skin exfoliation 10 (<1%) 0 0disorders

Photosensitivity 7 (<1%) 0 0reaction

Rash erythematous 6 (<1%) 0 0

Skin disorder 5 (<1%) 0 0

Rash macular 4 (<1%) 0 0

Rash pruritic 3 (<1%) 0 0

Rash vesicular 3 (<1%) 0 0

Pruritus generalised 2 (<1%) 1 (<1%) 0

Rash generalised 2 (<1%) 0 0

Rash papular 2 (<1%) 0 0

Plantar erythema 1 (<1%) 0 0

Skin ulcer† not known not known notknown

Common Arthralgia 48 (4%) 8 (<1%) 0

Musculoskeletal

Myalgia 35 (3%) 2 (<1%) 0and connective

Muscle spasms 25 (2%) 0 0tissue disorders

Uncommon Musculoskeletal pain 9 (<1%) 1 (<1%) 0

Very Common Proteinuria 135 (12%) 32 (3%) 0

Renal andurinary disorders Uncommon Haemorrhage urinary 1 (<1%) 0 0tract

Reproductive Uncommon Menorrhagia 3 (<1%) 0 0system and breast Vaginal haemorrhage 3 (<1%) 0 0disorders Metrorrhagia 1 (<1%) 0 0

Very common Fatigue 415 (36%) 65 (6%) 1 (<1%)

Common Mucosal inflammation 86 (7%) 5 (<1%) 0

Asthenia 82 (7%) 20 (2%) 1 (<1%)

General disorders

Oedemab 72 (6%) 1 (<1%) 0andadministration Chest pain 18 (2%) 2 (<1%) 0site conditions Uncommon Chills 4 (<1%) 0 0

Mucous membrane 1 (<1%) 0 0disorder

Very common Alanine 246 (21%) 84 (7%) 14 (1%)aminotransferaseincreased

Aspartate 211 (18%) 51 (4%) 10 (<1%)aminotransferaseincreased

Common Weight decreased 96 (8%) 7 (<1%) 0

Blood bilirubin 61 (5%) 6 (<1%) 1 (<1%)increased

Blood creatinine 55 (5%) 3 (<1%) 0increased

Lipase increased 51 (4%) 21 (2%) 7 (<1%)

White blood cell count 51 (4%) 3 (<1%) 0decreasedd

Blood thyroid 36 (3%) 0 0stimulating hormoneincreased

Amylase increased 35 (3%) 7 (<1%) 0

Gamma- 31 (3%) 9 (<1%) 4 (<1%)glutamyltransferase

Investigationsincreased

Blood pressure 15 (1%) 2 (<1%) 0increased

Blood urea increased 12 (1%) 1 (<1%) 0

Liver function test 12 (1%) 6 (<1%) 1 (<1%)abnormal

Uncommon Hepatic enzyme 11 (<1%) 4 (<1%) 3 (<1%)increased

Blood glucose 7 (<1%) 0 1 (<1%)decreased

Electrocardiogram QT 7 (<1%) 2 (<1%) 0prolonged

Transaminase 7 (<1%) 1 (<1%) 0increased

Thyroid function test 3 (<1%) 0 0abnormal

Blood pressure 2 (<1%) 0 0diastolic increased

Blood pressure 1 (<1%) 0 0systolic increased†Treatment-related adverse reaction reported during post-marketing period (spontaneous case reports and seriousadverse reactions from all pazopanib clinical studies).

*Treatment-related adverse reaction reported only during the post-marketing period. Frequency cannot beestimated from the available data.

The following terms have been combined:a Abdominal pain, abdominal pain upper and abdominal pain lowerb Oedema, oedema peripheral, eye oedema, localised oedema and face oedemac Dysgeusia, ageusia and hypogeusiad White cell count decreased, neutrophil count decreased and leukocyte count decreasede Decreased appetite and anorexiaf Cardiac dysfunction, left ventricular dysfunction, cardiac failure and restrictive cardiomyopathyg Venous thromboembolic event, deep vein thrombosis, pulmonary embolism and thrombosis

Neutropenia, thrombocytopenia and palmar-plantar erythrodysaethesia syndrome were observed morefrequently in patients of East Asian descent.

Table 3 Treatment-related adverse reactions reported in STS studies (n=382) or during post-marketing period

System Organ Frequency Adverse reactions All grades Grade 3 Grade 4

Class (all grades) n (%) n (%) n (%)

Infections and Common Gingival infection 4 (1%) 0 0infestations

Neoplasms Very common Tumour pain 121 (32%) 32 (8%) 0benign, malignantand unspecified(incl cysts andpolyps)

Very common Leukopenia 106 (44%) 3 (1%) 0

Thrombocytopenia 86 (36% 7 (3%) 2 (<1%)

Neutropenia 79 (33%) 10 (4%) 0

Blood and Uncommon Thrombotic 1 (<1%) 1 (<1%) 0lymphatic system microangiopathydisordersf (including thromboticthrombocytopenicpurpura andhaemolytic uraemicsyndrome)

Endocrine Common Hypothyroidism 18 (5%) 0 0disorders

Very common Decreased appetite 108 (28%) 12 (3%) 0

Hypoalbuminemiaf 81 (34%) 2 (<1%) 0

Metabolism and

Common Dehydration 4 (1%) 2 (1%) 0nutrition

Uncommon Hypomagnesaemia 1 (<1%) 0 0disorders

Not known Tumour lysis not known not known notsyndrome* known

Psychiatric Common Insomnia 5 (1%) 1 (<1%) 0disorders

Very common Dysgeusiac 79 (21%) 0 0

Headache 54 (14%) 2 (<1%) 0

Common Peripheral sensory 30 (8%) 1 (<1%) 0

Nervous system neuropathydisorders Dizziness 15 (4%) 0 0

Uncommon Somnolence 3 (<1%) 0 0

Paresthesia 1 (<1%) 0 0

Cerebral infarction 1 (<1%) 0 1 (<1%)

Eye disorders Common Vision blurred 15 (4%) 0 0

Cardiac dysfunctiong 21 (5%) 3 (<1%) 1 (<1%)

Left ventricular 13 (3%) 3 (<1%) 0

Cardiac disorders dysfunction

Bradycardia 4 (1%) 0 0

Uncommon Myocardial infarction 1 (<1%) 0 0

Very common Hypertension 152 (40%) 26 (7%) 0

Common Venous 13 (3%) 4 (1%) 5 (1%)thromboembolic eventd

Vascular Hot flush 12 (3%) 0 0disorders Flushing 4 (1%) 0 0

Uncommon Haemorrhage 2 (<1%) 1 (<1%) 0

Rare Aneurysms and artery not known not known notdissections known

Common Epistaxis 22 (6%) 0 0

Dysphonia 20 (5%) 0 0

Dyspnoea 14 (4%) 3 (<1%) 0

Cough 12 (3%) 0 0

Pneumothorax 7 (2%) 2 (<1%) 1 (<1%)

Respiratory, Hiccups 4 (1%) 0 0thoracic and Pulmonary 4 (1%) 1 (<1%) 0mediastinal haemorrhagedisorders Uncommon Oropharyngeal pain 3 (<1%) 0 0

Bronchial haemorrhage 2 (<1%) 0 0

Rhinorrhoea 1 (<1%) 0 0

Haemoptysis 1 (<1%) 0 0

Rare Interstitial lung not known not known notdisease/pneumonitis† known

Very common Diarrhoea 174 (46%) 17 (4%) 0

Nausea 167 (44%) 8 (2%) 0

Vomiting 96 (25%) 7 (2%) 0

Abdominal paina 55 (14%) 4 (1%) 0

Stomatitis 41 (11%) 1 (<1%) 0

Common Abdominal distension 16 (4%) 2 (1%) 0

Dry mouth 14 (4%) 0 0

Dyspepsia 12 (3%) 0 0

Mouth haemorrhage 5 (1%) 0 0

Flatulence 5 (1%) 0 0

Anal haemorrhage 4 (1%) 0 0

Uncommon Gastrointestinal 2 (<1%) 0 0

Gastrointestinalhaemorrhagedisorders

Rectal haemorrhage 2 (<1%) 0 0

Enterocutaneous fistula 1 (<1%) 1 (<1%) 0

Gastric haemorrhage 1 (<1%) 0 0

Melaena 2 (<1%) 0 0

Oesophageal 1 (<1%) 0 1 (<1%)haemorrhage

Peritonitis 1 (<1%) 0 0

Retroperitoneal 1 (<1%) 0 0haemorrhage

Upper gastrointestinal 1 (<1%) 1 (<1%) 0haemorrhage

Ileal perforation 1 (<1%) 0 1 (<1%)

Uncommon Hepatic function 2 (<1%) 0 1 (<1%)

Hepatobiliary abnormaldisorders Not known Hepatic failure* not known not known notknown

Very common Hair colour change 93 (24%) 0 0

Skin hypopigmentation 80 (21%) 0 0

Exfoliative rash 52 (14%) 2 (<1%) 0

Common Alopecia 30 (8%) 0 0

Skin disorderc 26 (7%) 4 (1%) 0

Dry skin 21 (5%) 0 0

Hyperhydrosis 18 (5%) 0 0

Nail disorder 13 (3%) 0 0

Skin and

Pruritus 11 (3%) 0 0subcutaneous

Erythema 4 (1%) 0 0disorders

Uncommon Skin ulcer 3 (<1%) 1 (<1%) 0

Rash 1 (<1%) 0 0

Rash papular 1 (<1%) 0 0

Photosensitivity 1 (<1%) 0 0reaction

Palmar-plantar 2 (<1%) 0 0erythrodysaesthesiasyndrome

Common Musculoskeletal pain 35 (9%) 2 (<1%) 0

Musculoskeletal

Myalgia 28 (7%) 2 (<1%) 0and connective

Muscle spasms 8 (2%) 0 0tissue disorders

Uncommon Arthralgia 2 (<1%) 0 0

Renal and Uncommon Proteinuria 2 (<1%) 0 0urinary disorders

Reproductive Uncommon Vaginal haemorrhage 3 (<1%) 0 0system and breast Menorrhagia 1 (<1%) 0 0disorder

Very common Fatigue 178 (47%) 34 (9%) 1 (<1%)

General disorders Common Oedemab 18 (5%) 1 (<1%) 0and Chest pain 12 (3%) 4 (1%) 0administration Chills 10 (3%) 0 0site conditions Uncommon Mucosal inflammatione 1 (<1%) 0 0

Asthenia 1 (<1% 0 0

Very common Weight decreased 86 (23%) 5 (1%) 0

Common Ear, nose and throat 29 (8%) 4 (1%) 0examination abnormale

Alanine 8 (2%) 4 (1%) 2 (<1%)aminotransferaseincreased

Blood cholesterol 6 (2%) 0 0abnormal

Aspartate 5 (1%) 2 (<1%) 2 (<1%)aminotransferaseincreased

Gamma 4 (1%) 0 3 (<1%)

Investigationshglutamyltransferaseincreased

Uncommon Blood bilirubin 2 (<1%) 0 0increased

Aspartate 2 (<1%) 0 2 (<1%)aminotransferase

Alanine 1 (<1%) 0 1 (<1%)aminotransferase

Platelet count 1 (<1%) 0 1 (<1%)decreased

Electrocardiogram QT 2 (<1%) 1 (<1%) 0prolonged†Treatment-related adverse reaction reported during post-marketing period (spontaneous case reports and seriousadverse reactions from all pazopanib clinical studies).

*Treatment-related adverse reaction reported only during the post-marketing period. Frequency cannot beestimated from the available data.

The following terms have been combined:a Abdominal pain, abdominal pain upper and gastrointestinal painb Oedema, oedema peripheral and eyelid oedemac The majority of these cases were Palmar-plantar erythrodysaesthesia syndromed Venous thromboembolic events - includes Deep vein thrombosis, Pulmonary embolism and Thrombosis termse The majority of these cases describe mucositisf Frequency is based on laboratory value tables from VEG110727 (N=240). These were reported as adverseevents less frequently by investigators than as indicated by laboratory value tables.g Cardiac dysfunction events - includes Left ventricular dysfunction, Cardiac failure and Restrictivecardiomyopathyh Frequency is based on adverse events reported by investigators. Laboratory abnormalities were reported asadverse events less frequently by investigators than as indicated by laboratory value tables.

Neutropenia, thrombocytopenia and palmar-plantar erythrodysaethesia syndrome were observed morefrequently in patients of East Asian descent.

The safety profile in paediatric patients was similar to that reported with pazopanib in adults in theapproved indications based on data from 44 paediatric patients from Phase I study ADVL0815 and 57paediatric patients from Phase II study PZP034X2203 (see section 5.1).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Pazopanib doses up to 2000 mg have been evaluated in clinical studies. Grade 3 fatigue (dose-limitingtoxicity) and Grade 3 hypertension were each observed in 1 of 3 patients dosed at 2000 mg and1000 mg daily, respectively.

There is no specific antidote for overdose with pazopanib and treatment of overdose should consist ofgeneral supportive measures.

Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitors, other protein kinaseinhibitors, ATC code: L01EX03

Pazopanib is an orally administered, potent multi-target tyrosine kinase inhibitor (TKI) of vascularendothelial growth factor receptors (VEGFR) -1, -2, and -3, platelet-derived growth factor(PDGFR) -α and -β, and stem cell factor receptor (c-KIT), with IC50 values of 10, 30, 47, 71, 84 and74 nM, respectively. In preclinical experiments, pazopanib dose-dependently inhibited ligand-inducedauto-phosphorylation of VEGFR-2, c-Kit and PDGFR- receptors in cells. In vivo, pazopanibinhibited VEGF-induced VEGFR-2 phosphorylation in mouse lungs, angiogenesis in various animalmodels, and the growth of multiple human tumour xenografts in mice.

Pharmacogenomics

In a pharmacogenetic meta-analysis of data from 31 clinical studies of pazopanib administered eitheras monotherapy or in combination with other agents, ALT >5 x ULN (NCI CTC Grade 3) occurred in19% of HLA-B*57:01 allele carriers and in 10% of non-carriers. In this dataset, 133/2235 (6%) of thepatients carried the HLA-B*57:01 allele (see section 4.4).

Clinical studies

The safety and efficacy of pazopanib in RCC were evaluated in a randomised, double-blind,placebo-controlled multicentre study. Patients (N = 435) with locally advanced and/or metastatic RCCwere randomised to receive pazopanib 800 mg once daily or placebo. The primary objective of thestudy was to evaluate and compare the two treatment arms for progression-free survival (PFS) and theprinciple secondary endpoint was overall survival (OS). The other objectives were to evaluate theoverall response rate and duration of response.

From the total of 435 patients in this study, 233 patients were treatment-naïve and 202 weresecond-line patients who had received one prior IL-2 or INF-based therapy. The performance status(ECOG) was similar between the pazopanib and placebo groups (ECOG 0: 42% vs. 41%, ECOG 1:

58% vs. 59%). The majority of patients had either favourable (39%) or intermediate (54%), MSKCC(Memorial Sloan Kettering Cancer Centre)/Motzer prognostic factors. All patients had clear cellhistology or predominantly clear cell histology. Approximately half of all patients had 3 or moreorgans involved in their disease and most patients had the lung (74%), and/or lymph nodes (54%) as ametastatic location for disease at baseline.

A similar proportion of patients in each arm were treatment-naïve and cytokine pre-treated (53% and47% in pazopanib arm, 54% and 46% in placebo arm). In the cytokine pre-treated subgroup, themajority (75%) had received interferon-based treatment.

Similar proportions of patients in each arm had prior nephrectomy (89% and 88% in the pazopaniband placebo arms, respectively) and/or prior radiotherapy (22% and 15% in the pazopanib and placeboarms, respectively.

The primary analysis of the primary endpoint PFS is based on disease assessment by independentradiological review in the entire study population (treatment-naïve and cytokine pre-treated).

Table 4 Overall efficacy results in RCC by independent assessment (VEG105192)

P value

Endpoints/Study population Pazopanib Placebo HR (95% CI) (one-sided)

PFS

Overall* ITT N = 290 N = 145

Median (months) 9.2 4.2 0.46 (0.34, 0.62) <0.0000001

Response rate N = 290 N = 145% (95% CI) 30 (25.1,35.6) 3 (0.5, 6.4) - <0.001

HR = hazard ratio; ITT = intent to treat; PFS = progression-free survival. * - treatment-naïve and cytokinepre-treated populations

Figure 1 Kaplan-Meier curve for progression-free survival by independent assessment for theoverall population (treatment-naïve and cytokine pre-treated populations)(VEG105192)x axis; Months, y axis; Proportion Progression Free, Pazopanib —―— (N = 290) Median 9.2 months; Placebo --

- ----- (N = 145) Median 4.2 months; Hazard Ratio = 0.46, 95% CI (0.34, 0.62), P <0.0000001

Figure 2 Kaplan-Meier curve for progression-free survival by independent assessment for thetreatment-naïve population (VEG105192)x axis; Months, y axis; Proportion Progression Free, Pazopanib —―— (N = 155) Median 11.1 months; Placebo

- ------- (N = 78) Median 2.8 months; Hazard Ratio = 0.40, 95% CI (0.27, 0.60), P <0.0000001

Figure 3 Kaplan-Meier Curve for progression-free survival by independent assessment forthe cytokine pre-treated population (VEG105192)x axis; Months, yaxis; Proportion Progression Free, Pazopanib —―— (N = 135) Median 7.4 months; Placebo -------- (N = 67)

Median 4.2 months; Hazard Ratio = 0.54, 95% CI (0.35, 0.84), P <0.001

For patients who responded to treatment, the median time to response was 11.9 weeks and the medianduration of response was 58.7 weeks as per independent review (VEG105192).

The median overall survival (OS) data at the protocol-specified final survival analysis were22.9 months and 20.5 months [HR = 0.91 (95% CI: 0.71, 1.16; p = 0.224)] for patients randomised tothe pazopanib and placebo arms, respectively. The OS results are subject to potential bias as 54% ofpatients in the placebo arm also received pazopanib in the extension part of this study followingdisease progression. Sixty-six per cent of placebo patients received post-study therapy compared to30% of pazopanib patients.

No statistical differences were observed between treatment groups for Global Quality of Life using

EORTC QLQ-C30 and EuroQoL EQ-5D.

In a Phase II 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 independentreview. Median PFS was 11.9 months.

The safety, efficacy and quality of life of pazopanib versus sunitinib was 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 notreceived prior systemic therapy, were randomised to receive either pazopanib 800 mg once dailycontinuously or sunitinib 50 mg once daily in 6-week cycles of dosing with 4 weeks on treatmentfollowed by 2 weeks without treatment.

The primary objective of this study was to evaluate and compare PFS in patients treated withpazopanib to those treated with sunitinib. Demographic characteristics were similar between thetreatment arms. Disease characteristics at initial diagnosis and at screening were balanced between thetreatment arms with the majority of patients having clear cell histology and Stage IV disease.

VEG108844 achieved its primary endpoint of PFS and demonstrated that pazopanib was non-inferiorto sunitinib, as the upper bound of the 95% CI for the hazard ratio was less than the protocol-specifiednon-inferiority margin of 1.25. Overall efficacy results are summarised in Table 5.

Table 5 Overall efficacy results (VEG108844)

Pazopanib Sunitinib HR

Endpoint N = 557 N = 553 (95% CI)

PFS

Overall

Median (months) 8.4 9.5 1.047(95% CI) (8.3, 10.9) (8.3, 11.0) (0.898, 1.220)

Overall Survival

Median (months) 28.3 29.1 0.915a(95% CI) (26.0, 35.5) (25.4, 33.1) (0.786, 1.065)

HR = hazard ratio; PFS = progression-free survival; a P value = 0.245 (2-sided)

Figure 4 Kaplan-Meier Curve for progression-free survival by independent assessment forthe overall population (VEG108844)

Subgroup analyses of PFS were performed for 20 demographic and prognostic factors. The 95%confidence intervals for all subgroups include a hazard ratio of 1. In the three smallest of these20 subgroups, the point estimate of the hazard ratio exceeded 1.25; i.e. in subjects with no priornephrectomy (n=186, HR=1.403, 95% CI (0.955, 2.061)), baseline LDH >1.5 x ULN (n=68, HR=1.72,95% CI (0.943, 3.139)), and MSKCC: poor risk (n=119, HR=1.472, 95% CI (0.937, 2.313)).

Soft-tissue sarcoma (STS)

The efficacy and safety of pazopanib in STS were evaluated in a pivotal Phase III randomised,double-blind, placebo-controlled multicentre study (VEG110727). A total of 369 patients withadvanced STS were randomised to receive pazopanib 800 mg once daily or placebo. Importantly, onlypatients with selective histological subtypes of STS were allowed to participate to the study, thereforeefficacy and safety of pazopanib can only be considered established for those subgroups of STS andtreatment with pazopanib should be restricted to such STS subtypes.

The following tumour types were eligible:

Fibroblastic (adult fibrosarcoma, myxofibrosarcoma, sclerosing epithelioid fibrosarcoma, malignantsolitary fibrous tumours), so-called fibrohistiocytic (pleomorphic malignant fibrous histiocytoma[MFH], giant cell MFH, inflammatory MFH), leiomyosarcoma, malignant glomus tumours, skeletalmuscles (pleomorphic and alveolar rhabdomyosarcoma), vascular (epithelioid hemangioendothelioma,angiosarcoma), uncertain differentiation (synovial, epithelioid, alveolar soft part, clear cell,desmoplastic small round cell, extra-renal rhabdoid, malignant mesenchymoma, PEComa, intimalsarcoma), malignant peripheral nerve sheath tumours, undifferentiated soft tissue sarcomas nototherwise specified (NOS) and other types of sarcoma (not listed as ineligible).

The following tumour types were not eligible:

Adipocytic sarcoma (all subtypes), all rhabdomyosarcoma that were not alveolar or pleomorphic,chondrosarcoma, osteosarcoma, Ewing tumours/primitive neuroectodermal tumours (PNET), GIST,dermofibromatosis sarcoma protuberans, inflammatory myofibroblastic sarcoma, malignantmesothelioma and mixed mesodermal tumours of the uterus.

Of note, patients with adipocytic sarcoma were excluded from the pivotal Phase III study as in apreliminary Phase II study (VEG20002) activity (PFS at week 12) observed with pazopanib inadipocytic did not meet the prerequisite rate to allow further clinical testing.

Other key eligibility criteria of the VEG110727 study were: histological evidence of high orintermediate grade malignant STS and disease progression within 6 months of therapy for metastaticdisease, or recurrence within 12 months of (neo) -/adjuvant therapy.

Ninety-eight percent (98%) of subjects received prior doxorubicin, 70% prior ifosfamide, and 65% ofsubjects had received at least three or more chemotherapeutic agents prior to study enrolment.

Patients were stratified by the factors of WHO performance status (WHO PS) (0 or 1) at baseline andthe number of lines of prior systemic therapy for advanced disease (0 or 1 vs. 2+). In each treatmentgroup, there was a slightly greater percentage of subjects in the 2+ lines of prior systemic therapy foradvanced disease (58% and 55%, respectively, for placebo and pazopanib treatment arms) comparedwith 0 or 1 lines of prior systemic therapy (42% and 45%, respectively, for placebo and pazopanibtreatment arms). The median duration of follow-up of subjects (defined as date of randomisation todate of last contact or death) was similar for both treatment arms (9.36 months for placebo [range 0.69to 23.0 months] and 10.04 months for pazopanib [range 0.2 to 24.3 months].

The primary objective of the study was progression-free survival (PFS assessed by independentradiological review); the secondary endpoints included overall survival (OS), overall response rate andduration of response.

Table 6 Overall efficacy results in STS by independent assessment (VEG110727)

Endpoints/study Pazopanib Placebo HR (95% CI) P valuepopulation (two-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

OS

Overall ITT N = 246 N = 123

Median (months) 12.6 10.7 0.87 (0.67, 1.12) 0.256

Leiomyosarcoma* N = 109 N = 49

Median (months) 16.7 14.1 0.84 (0.56, 1.26) 0.363

Synovial sarcoma subgroups* N = 25 N = 13

Median (months) 8.7 21.6 1.62 (0.79, 3.33) 0.115“Other STS” subgroups* N = 112 N = 61

Median (months) 10.3 9.5 0.84 (0.59, 1.21) 0.325

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. OS = overall survival

* Overall survival for the respective STS histological subgroups (leiomyosarcoma, synovial sarcoma and“Other” STS) should be interpreted with caution due to the small number of subjects and wide confidenceintervals

A similar improvement in PFS based on investigator assessments was observed in the pazopanib armcompared with the placebo arm (in the overall ITT population HR: 0.39; 95% CI, 0.30 to 0.52,p <0.001).

Figure 5 Kaplan-Meier Curve for Progression-Free Survival in STS by Independent

Assessment for the Overall Population (VEG110727)

No significant difference in OS was observed between the two treatment arms at the final OS analysisperformed after 76% (280/369) of the events had occurred (HR 0.87, 95% CI 0.67, 1.12 p=0.256).

A Phase I study (ADVL0815) of pazopanib was conducted in 44 paediatric patients with variousrecurrent or refractory solid tumours. The primary objective was to investigate the maximum tolerateddose (MTD), the safety profile and the pharmacokinetic properties of pazopanib in children. Themedian duration of exposure in this study was 3 months (1-23 months).

A Phase II study (PZP034X2203) of pazopanib was conducted in 57 paediatric patients with refractorysolid tumours including rhabdomyosarcoma (N=12), non-rhabdomyosarcoma soft tissue sarcoma(N=11), Ewing sarcoma/pPNET (N=10), osteosarcoma (N=10), neuroblastoma (N=8) andhepatoblastoma (N=6). The study was a single-agent, non-controlled, open-label study to determinethe therapeutic activity of pazopanib in children and adolescents aged 1 to <18 years of age. Pazopanibwas administered daily as a tablet at a dose of 450 mg/m2/dose or as an oral suspension at225 mg/m2/dose. The maximum daily dose permitted was 800 mg for the tablet and 400 mg for theoral suspension. The median duration of exposure was 1.8 months (1 day-29 months).

Results of this study did not show any meaningful anti-tumour activity in the respective paediatricpopulation. Pazopanib is therefore not recommended for treatment of these tumours in the paediatricpopulation (see section 4.2 for information on paediatric use).

The European Medicines Agency has waived the obligation to submit the results of studies with

Votrient in all subsets of the paediatric population in treatment of kidney and renal pelvis carcinoma(excluding nephroblastoma, nephroblastomatosis, clear cell sarcoma, mesoblastic nephroma, renalmedullary carcinoma and rhabdoid tumour of the kidney) (see section 4.2 for information onpaediatric use).

Upon oral administration of a single pazopanib 800 mg dose to patients with solid tumours, maximumplasma concentration (Cmax) of approximately 19 ± 13 µg/ml was obtained after median 3.5 hours(range 1.0-11.9 hours) and an AUC0-∞ of approximately 650 ± 500 µg.h/ml was obtained. Daily dosingresults in 1.23- to 4-fold increase in AUC0-T.

There was no consistent increase in AUC or Cmax at pazopanib doses above 800 mg.

Systemic exposure to pazopanib is increased when administered with food. Administration ofpazopanib 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 two hours after food or at least one hourbefore food (see section 4.2).

Administration of a pazopanib 400 mg crushed tablet increased AUC(0-72) by 46% and Cmax byapproximately 2 fold and decreased tmax by approximately 2 hours compared to administration of thewhole tablet. These results indicate that the bioavailability and the rate of pazopanib oral absorptionare increased after administration of the crushed tablet relative to administration of the whole tablet(see section 4.2).

Binding of pazopanib to human plasma protein in vivo was greater than 99% with no concentrationdependence over the range of 10-100 g/ml. In vitro studies suggest that pazopanib is a substrate for

P-gp and BCRP.

Results from in vitro studies demonstrated that metabolism of pazopanib is mediated primarily by

CYP3A4, with minor contributions from CYP1A2 and CYP2C8. The four principle pazopanibmetabolites account for only 6% of the exposure in plasma. One of these metabolites inhibits theproliferation of VEGF-stimulated human umbilical vein endothelial cells with a similar potency to thatof pazopanib, the others are 10- to 20-fold less active. Therefore, activity of pazopanib is mainlydependent on parent pazopanib exposure.

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

Results indicate that less than 4% of an orally administered pazopanib dose is excreted in the urine aspazopanib and metabolites. Results from population pharmacokinetic modelling (data from subjectswith baseline CLCR values ranging from 30.8 ml/min to 150 ml/min) indicated that renal impairmentis unlikely to have clinically relevant effect on pazopanib pharmacokinetics. No dose adjustment isrequired in patients with creatinine clearance above 30 ml/min. Caution is advised in patients withcreatinine clearance below 30 ml/min as there is no experience of pazopanib in this patient population(see section 4.2).

Mild

The median steady-state pazopanib Cmax and AUC(0-24) in patients with mild abnormalities in hepaticparameters (defined as either normal bilirubin and any degree of ALT elevation or as an elevation ofbilirubin up to 1.5 x ULN regardless of the ALT value) after administration of 800 mg once daily aresimilar to the median in patients with normal hepatic function (see Table 7). 800 mg pazopanib oncedaily is the recommended dose in patients with mild abnormalities of serum liver tests (seesection 4.2).

Moderate

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 mgonce daily. The median steady-state Cmax and AUC(0-24) values after administration of 200 mgpazopanib once daily in patients with moderate hepatic impairment were approximately 44% and 39%,of the corresponding median values after administration of 800 mg once daily in patients with normalhepatic function, respectively (see Table 7).

Based on safety and tolerability data, the dose of pazopanib should be reduced to 200 mg once daily insubjects with moderate hepatic impairment (see section 4.2).

Severe

The median steady-state Cmax and AUC(0-24) values after administration of 200 mg pazopanib oncedaily in patients with severe hepatic impairment were approximately 18% and 15%, of thecorresponding median values after administration of 800 mg once daily in patients with normal hepaticfunction. Based on the diminished exposure and limited hepatic reserve pazopanib is notrecommended in patients with severe hepatic impairment (defined as total bilirubin >3 X ULNregardless of any level of ALT) (see section 4.2).

Table 7 Median steady-state pazopanib pharmacokinetics measured in subjects with hepaticimpairment.

Group Investigated Cmax (µg/ml) AUC (0-24) Recommendeddose (µg x hr/ml) dose

Normal hepatic 800 mg OD 52.0 888.2 800 mg ODfunction (17.1-85.7) (345.5-1482)

Mild HI 800 mg OD 33.5 774.2 800 mg OD(11.3-104.2) (214.7-2034.4)

Moderate HI 200 mg OD 22.2 256.8 200 mg OD(4.2-32.9) (65.7-487.7)

Severe HI 200 mg OD 9.4 130.6 Not recommended(2.4-24.3) (46.9-473.2)

OD - once daily

Upon administration of pazopanib 225 mg/m2 (as oral suspension) in paediatric patients, thepharmacokinetic parameters (Cmax, Tmax and AUC) were similar to those previously reported in adultpatients treated with 800 mg pazopanib. Results indicated no marked difference in the clearance ofpazopanib, normalised by body surface area, between children and adults.

The preclinical safety profile of pazopanib was assessed in mice, rats, rabbits and monkeys. In repeatdose 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 inhibitionand/or disruption of VEGF signalling pathways, with most effects occurring at plasma exposure levelsbelow those observed in the clinic. Other observed effects include body weight loss, diarrhoea and/ormorbidity that were either secondary to local gastrointestinal effects caused by high local mucosalmedicinal product exposure (monkeys) or pharmacological effects (rodents). Proliferative hepaticlesions (eosinophilic foci and adenoma) were seen in female mice at exposures 2.5 times humanexposure based on AUC.

In juvenile toxicity studies, when pre-weaning rats were dosed from day 9 post partum through today 14 post partum, 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 adulthumans. When post-weaning rats were dosed from day 21 post partum to day 62 post partum,toxicological findings were similar to adult rats at comparable exposures. Human paediatric patientsare at increased risk for bone and teeth effects as compared to adults, as these changes, includinginhibition of growth (shortened limbs), fragile bones and remodelling of teeth, were present in juvenilerats at ≥10 mg/kg/day (equal to approximately 0.1-0.2 times the clinical exposure based on AUC inadult humans) (see section 4.4).

Reproductive, fertility and teratogenic effects

Pazopanib has been shown to be embryotoxic and teratogenic when administered to rats and rabbits atexposures more than 300-fold lower than the human exposure (based on AUC). Effects includedreduced female fertility, increased pre- and post-implantation loss, early resorptions, embryo lethality,decreased foetal body weight and cardiovascular malformation. Decreased corpora lutea, increasedcysts and ovarian atrophy have also been noted in rodents. In a rat male fertility study, there was noeffect on mating or fertility, but decreased testicular and epididymal weights were noted withreductions in sperm production rates, sperm motility, and epididymal and testicular spermconcentrations observed at exposures 0.3 times human exposure based on AUC.

Pazopanib did not cause genetic damage when tested in genotoxicity assays (Ames assay, humanperipheral lymphocyte chromosome aberration assay and rat in vivo micronucleus). A syntheticintermediate in manufacture of pazopanib, which is also present in the final drug substance in lowamounts, was not mutagenic in the Ames assay but genotoxic in the mouse lymphoma assay and invivo mouse micronucleus assay.

In two-year carcinogenicity studies with pazopanib, there were increased numbers of liver adenomasnoted in mice and duodenal adenocarcinomas noted in rats. Based on the rodent-specific pathogenesisand mechanism for these findings, they are not considered to represent an increased carcinogenic riskfor patients taking pazopanib.

Votrient 200 mg film-coated tablets

Magnesium stearate

Microcrystalline cellulose

Povidone (K30)

Sodium starch glycolate

Hypromellose

Iron oxide red (E172)

Macrogol 400

Polysorbate 80

Titanium dioxide (E171)

Votrient 400 mg film-coated tablets

Magnesium stearate

Microcrystalline cellulose

Povidone (K30)

Sodium starch glycolate

Hypromellose

Macrogol 400

Polysorbate 80

Titanium dioxide (E171)

Not applicable.

3 years.

This medicinal product does not require any special storage conditions.

Votrient 200 mg film-coated tablets

HDPE bottles with polypropylene child resistant closures containing either 30 or 90 tablets.

Votrient 400 mg film-coated tablets

HDPE bottles with polypropylene child resistant closures containing either 30 or 60 tablets.

Not all pack sizes may be marketed.

No special requirements.

Novartis Europharm Limited

Vista Building

Elm Park, Merrion Road

Dublin 4

Ireland

Votrient 200 mg film-coated tablets

EU/1/10/628/001

EU/1/10/628/002

Votrient 400 mg film-coated tablets

EU/1/10/628/003

EU/1/10/628/004

Date of first authorisation: 14 June 2010

Date of latest renewal: 08 January 2018

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.