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NOTE FOR HEALTHCARE PROFESSIONAL This presentation has been provided to you upon request. If presenting this to other healthcare professionals, GSK advises.

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Presentation on theme: "NOTE FOR HEALTHCARE PROFESSIONAL This presentation has been provided to you upon request. If presenting this to other healthcare professionals, GSK advises."— Presentation transcript:

1 NOTE FOR HEALTHCARE PROFESSIONAL This presentation has been provided to you upon request. If presenting this to other healthcare professionals, GSK advises that you use the presentation in full to ensure a fair balance of information, both efficacy and safety. Please delete this slide before presenting. UK/PAZ/0031/13 March 2013

2 GSK has been involved in the preparation of this presentation Prescribing information can be found at the end of the core presentation Votrient in the Treatment of Advanced Renal Cell Carcinoma (RCC): A presentation for use by healthcare professionals ® UK/PAZ/0031/13 February 2013 Study VEG Key considerations before prescribing Guidance on management of side effects associated with Votrient therapy & other TKIs Questions which patients may ask

3 Votrient indication 1 Votrient is indicated in adults for the first-line treatment of advanced renal cell carcinoma (RCC) and for patients who have received prior cytokine therapy for advanced disease. Votrient’s licence is conditional pending further clinical data from GSK, including the outcome of the head-to-head study (COMPARZ) of Votrient versus sunitinib. 1. GlaxoSmithKline. Votrient (pazopanib) Summary of Product Characteristics, January 2013.

4 1 st -line treatment 2 nd -line after cytokines Sunitinib 1 Bevacizumab+IFN 2 Sorafenib 2 Temsirolimus 2 Poor prognosis Good or intermediate prognosis    Not recommended by NICE Recommended by NICE 2 nd -line after anti-VEGF therapies Everolimus 4  Pazopanib 3 Management of advanced RCC in the UK NICE TA 169. March NICE TA 178. August NICE TA 215 Feb NICE TA 219 April 2011.

5 Votrient NICE Technology Appraisal Guidance (TA 215) 1 Votrient is recommended as a first-line treatment option for people with advanced RCC who have not received prior cytokine therapy and have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and under terms of the agreed Patient Access Scheme (PAS) which provides Votrient with a 12.5% discount on the list price, and a possible future rebate linked to the outcome of the head-to-head COMPARZ trial. 1. NICE. Pazopanib for the first-line treatment of advanced renal cell carcinoma. Final appraisal guidance no February 2011.

6 Votrient Scottish Medicines Consortium Advice No. 676/11 1 Votrient is accepted for restricted use within NHS Scotland for the first-line treatment of advanced RCC. This SMC advice takes account of the benefits of a Patient Access Scheme (PAS) that improves the cost-effectiveness of Votrient and is contingent upon the continuing availability of the PAS in NHS Scotland. 1. Scottish Medicines Consortium. Pazopanib 200mg, 400mg film-coated tablets (Votrient). Advice no. 676/11. March 2011.

7 Votrient mode of action - a potent and selective multi-targeted TKI Votrient binds to the cytoplasmic kinase domain of VEGFR-1, -2 and -3; PDGFR-α and –β; and c-Kit; with minimal impact on Flt-3. 1 VEGFR regulates angiogenesis 2 PDGFR regulates angiogenesis and proliferation of some tumour cells 3,4 c-Kit regulates cellular proliferation, survival and metastasis 5 1. Kumar et al. Mol Cancer Ther 2007; 6: 2012– Kerbel. N Engl J Med 2008; 358: 2039– Yu et al. J Biochem Mol Biol 2003; 36: 49– Homsi and Daud. Cancer Control 2007; 14: 285– Demetri. Semin Oncol 2001; 28(5 Suppl 17): 19–26.

8 Phase III Trial of Pazopanib in Locally Advanced and/or Metastatic Renal Cell Carcinoma Cora N. Sternberg, 1 Cezary Szczylik, 2 Eun S. Lee, 3 Pamela Salman, 4 Jozef Mardiak, 5 Ian D. Davis, 6 Lini Pandite, 7 Mei Chen, 8 Lauren McCann, 8 Robert E. Hawkins 9 1 San Camillo and Forlanini Hospitals, Rome, Italy; 2 Military Institute of Medicine, Warsaw, Poland; 3 National Cancer Center, Gyeonggi-do, Korea; 4 Fundación Arturo López Pérez, Santiago, Chile; 5 National Oncological Institute, Klenová, Bratislava, Slovakia; 6 Austin Hospital, Melbourne, Australia; 7 GlaxoSmithKline, Inc., Research Triangle Park, NC, USA; 8 GlaxoSmithKline, Inc., Collegeville, PA, USA; 9 University of Manchester and Christie Hospital NHS Foundation Trust, Manchester, UK Study VEG Presentation at ASCO Stenberg CN, et al. J Clin Oncol 2010; 28(6):

9 Votrient 800mg o.d. (n = 290) Matching Placebo (n = 145) Option to receive Votrient via an open-label study immediately upon disease progression Endpoints: Primary: PFS Secondary: OS, ORR, HRQoL, safety, tolerability Patients with advanced RCC (N = 435) Randomisation 2:1 Stratification: ECOG PS 0 vs. 1 Prior nephrectomy Rx-naive (n = 233) vs. 1 cytokine failure (n = 202) VEG study design Stenberg et al. J Clin Oncol 2010; 28(6):

10 Progression-free survival (overall study population) by independent review Placebo 9.2 Votrient 4.2 Hazard ratio (95% CI) 0.46 (0.34, 0.62) p value (1-sided) < Median PFS (months) Stenberg et al. J Clin Oncol 2010; 28(6): % reduction in risk of progression or death with Votrient treatment compared with placebo Number at risk, n Votrient Placebo Proportion progression-free Time (month) Votrient Placebo

11 Progression-free survival: (treatment-naïve sub- population) by independent review Number at risk, n Votrient Placebo Stenberg et al. J Clin Oncol 2010; 28(6): Placebo 11.1 Votrient 2.8 Hazard ratio (95% CI) 0.40 (0.27, 0.60) p value (1-sided) < Median PFS (months) 60% reduction in risk of progression or death with Votrient treatment compared with placebo Votrient Placebo Time (month) Proportion progression-free

12 1.Votrient (pazopanib) Summary of Product Characteristics, January Sternberg et al. J Clin Oncol 2010; 28: Median progression-free survival (PFS) in pivotal trial (VEG105192) 1,2

13 Sternberg CN, et al. J Clin Oncol 2010; 28: Overall response rate by independent review

14 Overview of adverse events associated with Votrient in advanced RCC 1 The most common adverse events associated with VOTRIENT (all grades incidence >10%) seen in patients treated for advanced RCC are: Diarrhoea Hair colour change Hypertension Nausea Fatigue Anorexia Altered sense of taste Vomiting Elevated liver enzymes (AST and ALT) Most AEs related to Votrient were grades 1 or 2 Low incidence of grade 3 or 4 fatigue, hand-foot syndrome, mucositis/stomatitis and haematological toxicities Serious adverse events have been associated with VOTRIENT, with the most important events each being reported in <1% of treated patients. 1. Votrient (pazopanib) Summary of Product Characteristics, January 2013.

15 Most common AEs regardless of causality (≥10%) 1 a 4% of patients in Votrient arm and 3% of patients in placebo arm had grade 5 AEs; b Included hemorrhage from all sites. Serious adverse reactions (some of which were fatal) have each been reported in <1% of Votrient-treated patients. 1. Sternberg C et al. Presentation at ESMO Abstract No. LBA22. (15 March 2010 cut-off)

16 Selected class effects associated with VEGFR TKI inhibitors 1 * (15 March 2010 cut-off) *AEs with incidence of <10% in the Votrient arm regardless of causality. 1. Sternberg C et al. Presentation at ESMO Abstract No. LBA22.

17 Laboratory abnormalities 1 (15 March 2010 cut-off) 1. Sternberg C et al. Presentation at ESMO Abstract No. LBA22.

18 No clinically important differences between Votrient and placebo in terms of impact on Quality of Life 1 MID=minimal important difference. The difference between Votrient and placebo scores do not exceed MID=5 and are therefore not clinically important according to established MID for the questionnaires Patients with data, n Votrient Placebo –10 –20 Week 48 MID=5 Week 6Week 12Week 18Week 24 Visit Baseline Adjusted means ± SE Votrient Placebo EORTC QLQ C30 Global Health Status/QoL scores 1. Hawkins et al. Eur J Cancer 2009; 7 (Supp)l: 428 (Abstract 7119 and poster presentation).

19 ® Key considerations before prescribing

20 Patient suitability for Votrient Advanced RCC Adults (≥ 18 years) ECOG Performance Status 0 or 1 (NICE guidance) 1 Treatment-naïve or cytokine pre-treated Consider co-morbidities Contraindicated in those with hypersensitivity to active substance/excipients 2 Not recommended in patients with severe hepatic impairment 2 Votrient can be used, although caution is advised, in patients with: 2 mild and moderate hepatic impairment creatinine clearance <30 ml/min history of QT interval prolongation; taking antiarrythmics or other medicines that may prolong QT interval; with relevant pre-existing cardiac disease or cardiac dysfunction at increased risk of arterial thrombotic (myocardial infraction, ischaemic stroke or TIAs) or venous thromboembolic (venous thrombosis or pulmonary embolism) events at risk for GI perforation or fistula at significant risk of haemorrhage Consider profession/job, hobbies and interests 1.NICE. Pazopanib for the first-line treatment of advanced renal cell carcinoma. Final appraisal guidance no February GlaxoSmithKline. Votrient (pazopanib) Summary of Product Characteristics, January 2013.

21 Posology and special warnings (1) 1 Please refer to full SmPC before prescribing Votrient tablets should be taken 800mg daily Whole (not broken or crushed) Without food - at least 1 hour before or 2 hours after a meal Dose modifications Should be in 200mg decrements/increments Drug interactions The concomitant use of strong CYP3A4 inhibitors and inducers, UGT1A1 substrates and medicines that increase gastric pH, should be avoided unless medically necessary. Concomitant use of simvastatin (and potentially other statins) can increase risk of ALT elevations and should be undertaken with caution and close monitoring Renal impairment No dose adjustment is required in patients with creatinine clearance >30 ml/min Caution is advised in patients with creatinine clearance <30 ml/min 1. GlaxoSmithKline. Votrient (pazopanib) Summary of Product Characteristics. January 2013.

22 Posology and special warnings (2) 1 Hepatic impairment & Hepatic effects Cases of hepatic failure have been reported during Votrient use Votrient is not recommended in patients with severe hepatic impairment Use with caution and close monitoring in patients with mild or moderate hepatic impairment Patients with mild hepatic impairment should be treated with 800mg once daily A reduced dose of 200 mg once daily is recommended in moderate hepatic impairment Serum liver tests should be monitored at baseline, at least once every 4 weeks for the first 4 months of treatment, and as clinically indicated with periodic monitoring thereafter. More frequent monitoring, dose interruption, modification or discontinuation may be warranted if liver test abnormalities are detected. Hypertension Blood pressure should be well controlled prior to initiating Votrient Patients should be monitored for hypertension within 1 week of starting treatment and frequently thereafter to ensure blood pressure control Hypertension should be managed using a combination of anti-hypertensive therapy and dose modification of Votrient (interruption and re-initiation at a reduced dose based on clinical judgement) Events of hypertensive crisis have occurred during clinical studies with Votrient (<1% of patients) Votrient should be discontinued if there is evidence of persistently elevated blood pressure (140/90 mmHg) or if arterial hypertension is severe and persists despite antihypertensive therapy and Votrient dose reduction 1. GlaxoSmithKline. Votrient (pazopanib) Summary of Product Characteristics. January 2013.

23 Posology and special warnings (3) 1 PRES / RPLS Posterior reversible encephalopathy syndrome (PRES)/Reversible posterior leukoencephalopathy syndrome (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 pazopanib Cardiac dysfunction/heart failure The safety and pharmacokinetics of Votrient in patients with moderate to severe heart failure or those with a below normal left ventricular ejection fraction (LVEF) has not been studied In clinical trials with pazopanib, events of cardiac dysfunction such as congestive heart failure and decreased left ventricular ejection fraction have occurred. The risks and benefits of Votrient should be considered before beginning therapy in patients who have pre-existing cardiac dysfunction Baseline & periodic evaluation of LVEF is recommended in patients at risk of cardiac dysfunction Patients should be carefully monitored for clinical signs or symptoms of congestive heart failure Interruption of Votrient and/or dose reduction should be combined with treatment of hypertension in patients with significant reductions in LVEF, as clinically indicated Thrombotic microangiopathy (TMA) Thrombotic microangiopathy (TMA) has been reported in clinical trials of pazopanib as monotherapy, in combination with bevacizumab, and in combination with topotecan Patients developing TMA should permanently discontinue pazopanib; reversal of effects of TMA has been observed after pazopanib treatment was discontinued 1. GlaxoSmithKline. Votrient (pazopanib) Summary of Product Characteristics. January 2013.

24 Posology and special warnings (4) 1 Other warnings Events of pneumothorax have occurred in clinical studies with Votrient in advanced soft tissue sarcoma. Patients on Votrient should be observed closely for signs and symptoms of pneumothorax Venous thromboembolic events (VTEs) including venous thrombosis and pulmonary embolus have occurred in clinical studies with Votrient (incidence of 2% in RCC studies and 5% in STS studies) Use with caution in patients who are at increased risk for arterial thrombotic events, those with significant risk of haemorrhage, GI perforation or fistula. Votrient is not recommended in patients with a history of haemoptysis, cerebral or clinically significant GI haemorrhage in the past 6 months. Use with caution in patients with a history of QT interval prolongation, those taking antiarrhythmics or with pre-existing cardiac disease. Baseline and periodic monitoring of electrocardiograms and maintenance of electrolytes within normal range is recommended. Votrient may impair wound healing, and should be stopped at least 7 days prior to scheduled surgery Hypothyroidism has occurred in clinical studies with Votrient. Baseline and periodic monitoring is recommended. Proteinuria has occurred in clinical studies with Votrient. Baseline and periodic urinalysis is recommended, with discontinuation of Votrient if the patient develops grade 4 proteinuria Cases of serious infection (with/without neutropenia) have been reported Combination with other systemic anti-cancer therapies: Safe and effective dose in combination with pemetrexed or lapatinib has not been established 1. GlaxoSmithKline. Votrient (pazopanib) Summary of Product Characteristics. January 2013.

25 Posology and special warnings (5) 1 Instances where Votrient should be permanently discontinued include: In patients with re-occurrence of elevated transaminases (>3 x ULN) following treatment interruption, or with aminotransferases elevations >3 x ULN and bilirubin elevations >2 x ULN, where direct bilirubin fraction >35% In patients with persistently elevated blood pressure or if hypertension is severe and persists despite anti-hypertensive therapy and Votrient dose reduction In patients with wound dehiscence In patients with grade 4 proteinuria In patients developing PRES/RPLS or TMA Serious adverse events have been associated with Votrient, with the most important events each being reported in <1% of treated patients 1. GlaxoSmithKline. Votrient (pazopanib) Summary of Product Characteristics. January 2013.

26 Main drug interactions 1 Primarily metabolised by CYP3A4 Inhibitors or inducers of CYP3A4 may alter the pharmacokinetics of Votrient Avoid co-administration with strong CYP3A4 inhibitors (e.g. ketoconazole, clarithromycin, ritonavir) or consider reduction in Votrient dose Cases of hyperglycaemia have been observed during concomitant treatment with ketoconazole Avoid co-administration with CYP3A4 inducers (e.g. rifampicin) Grapefruit juice contains an inhibitor of CYP3A4 and may increase plasma concentrations of Votrient Concomitant use of Votrient and simvastatin (and potentially other statins) can increase the risk of ALT elevations and should be undertaken with caution and close monitoring. Avoid co-administration with medicines that increase gastric pH (e.g. PPIs and H2 receptor-antagonists) unless medically necessary. 1. GlaxoSmithKline. Votrient (pazopanib) Summary of Product Characteristics. January 2013.

27 Potential drug & food interactions with Votrient (1) 1 1. GlaxoSmithKline. Votrient (pazopanib) Summary of Product Characteristics. January 2013.

28 Potential drug & food interactions with Votrient (2) 1 1. GlaxoSmithKline. Votrient (pazopanib) Summary of Product Characteristics. January *If elevated ALT develops with concomitant use of Votrient and statins, follow liver function management guidelines and discontinue statin

29 Votrient therapy in patients with renal impairment 1 Renal impairment is unlikely to have a clinically relevant effect on Votrient pharmacokinetics given the low renal excretion of Votrient and metabolites (~4%) No dose adjustment is required in patients with creatinine clearance >30 ml/min Caution is advised in patients with creatinine clearance <30 ml/min as no experience of Votrient in this patient population There is no experience of Votrient in patients: with severe renal impairment undergoing peritoneal dialysis or haemodialysis 1. GlaxoSmithKline. Votrient (pazopanib) Summary of Product Characteristics. January 2013.

30 Overview of tests recommended before and during Votrient treatment (as per SPC) 1 * 1. GlaxoSmithKline. Votrient (pazopanib) Summary of Product Characteristics. January * This list is based on the Votrient SPC; it is expected that your normal clinical practice with respect to additional tests (e.g. FBC) still applies

31 Votrient dosing Votrient has a convenient once-daily dosing schedule administered continuously throughout the course of treatment 1 The usual recommended starting dose of Votrient is 800mg once daily 2 Dose can be modified in 200mg steps based on individual tolerability in order to manage adverse reactions 2 The continuous dosing schedule of TKI agents, such as Votrient, may provide sustained anti-tumour activity 3 1.Sternberg et al. J Clin Oncol 2010; 28: GlaxoSmithKline. Votrient (pazopanib) Summary of Product Characteristics, January Liu et al. J Clin Oncol 2008;26(18S):Abstract 3515.

32 Votrient administration Votrient should be taken without food 1 Votrient should be administered at least 1 hour before or 2 hours after a meal Votrient is metabolised primarily by CYP3A4 1 Co-administration with strong CYP3A4 inhibitors or inducers may increase or reduce Votrient plasma concentrations, respectively It is recommended that patients treated with Votrient do not drink grapefruit juice or eat grapefruit products 200 mg400 mg 1. GlaxoSmithKline. Votrient (pazopanib) Summary of Product Characteristics. January 2013.

33 Votrient tablet excipients 1 Tablet core Microcrystalline cellulose Sodium starch glycollate Magnesium stearate Povidone (K30) Coating Polyvinylalcohol Macrogol 400 Titanium oxide Talc Iron oxide red (200mg) 1.GlaxoSmithKline. Votrient (pazopanib) Summary of Product Characteristics, January 2013.

34 Guidance on Management of Side Effects associated with Votrient Therapy and other TKIs

35 Side effect management Regular monitoring, early identification and prompt intervention Thorough baseline assessment LFTs, BP, TFT, ECG, urinalysis, skin, bowels etc Early patient education and provision of information e.g. Booklets explaining possible side effects Diary cards to record tablets taken and side effects experienced Give permission to stop treatment and seek advice Explain when and how to contact physician/nurse Give advice regarding prophylatic/proactive management More frequent clinic visits initially Early assessment of AEs Reinforce education and answer questions

36 Grading of toxicities Common Terminology Criteria for Adverse Events (CTCAE) 1 Grades often used to determine dose adjustments Some toxicities are easy to grade e.g. Diarrhoea Vomiting Laboratory investigations Some toxicities are not easy to grade e.g. Fatigue Pain Taste disturbance 1. NCI CTCAE 2009 version _QuickReference_5x7.pdf

37 Management of hypertension associated with Votrient therapy 1 Hypertension is a class effect of drugs targeting the VEGF pathway 2 Hypertension was experienced by 38% of patients treated with Votrient in the aRCC clinical trials (grade 3/4 events, 6%) 1 Blood pressure (BP) should be well controlled prior to initiating Votrient 1 Monitor BP regularly during Votrient treatment (within 1 week of starting treatment) and frequently thereafter E.g. at clinic visits; ask GP to assist with BP checks between visits; home monitoring Manage BP with anti-hypertensive therapy and dose modification of Votrient (interruption and re-initiation at reduced dose based on clinical judgement) E.g. amlodipine as initial therapy Elevated BP levels (≥150/100 mm Hg) occur early in the course of Votrient treatment 40% of cases occurred by day 9 and 90% in first 18 weeks 1 Discontinue Votrient if BP persistently elevated (140/90 mm Hg) or if arterial hypertension is severe and persists despite anti-hypertensive therapy and dose reduction 1 1.GlaxoSmithKline. Votrient (pazopanib) Summary of Product Characteristics, January Launay-Vacher V, Deray G. Anticancer Drugs 2009; 20: 81–82.

38 PRIOR TO VOTRIENT TREATMENT DURING TREATMENT Continue Votrient treatment & intensify antihypertensive drug therapy* Continue Votrient treatment & initiate antihypertensive drug therapy Monitoring and managing hypertension 1 *Titration of monotherapy and/or combination of different antihypertensive agents. Monitor blood pressure Monitor early (within 1 week) and frequently thereafter If elevated, ensure blood pressure is well controlled Hypertension Persistent Hypertension Interrupt Votrient & re-initiate at reduced dose & continue antihypertensive drug therapy Persistently elevated BP (140/90 mmHg) or severe arterial hypertension Discontinue Votrient treatment & continue antihypertensive drug therapy 1. GlaxoSmithKline. Votrient (pazopanib) Summary of Product Characteristics. January 2013.

39 Management of diarrhoea associated with Votrient therapy Approximately 50% of patients treated with Votrient in the aRCC trials experienced diarrhoea 1 Majority of adverse events were mild-to-moderate (grades 1 and 2) Early identification and intervention is critical for optimal management Establish baseline bowel pattern 2 Educate patients on signs and symptoms, and to report any changes Check frequency, consistency and duration of diarrhoea, and other symptoms (e.g. fever, cramping, dizziness, thirst) to identify those at higher risk of diarrhoea- induced complications 2 Proactive management with anti-diarrhoeal agents (e.g. loperamide) 2 Consider dose reduction if necessary Offer dietary advice e.g. 2 Eat and drink often but in small amounts Avoid alcohol and caffeine Avoid high-fibre, lactose (dairy) containing, spicy and greasy foods Use probiotic foods (e.g. live yoghurt) Marshmallows may help 1.GlaxoSmithKline. Votrient (pazopanib) Summary of Product Characteristics, January Pyle L et al. Cancer Nursing Practice 2008; 7: 42.

40 Recommendations for managing diarrhoea associated with Votrient If a patient experiences grade 1 or 2 diarrhoea with complicating features (such as cramping, severe nausea/vomiting, decreased performance status, fever, sepsis, grade 3 or 4 neutropenia, dehydration) then manage as if a grade 3 or 4 event 1.NCI CTCAE 2009 version QuickReference_5x7.pdf QuickReference_5x7.pdf; 2. GlaxoSmithKline. Votrient (pazopanib) Summary of Product Characteristics, January 2013.

41 Votrient dosing in pre-existing hepatic impairment 1 Dosing recommendations in patients with pre-existing hepatic impairment patients are based on pharmacokinetic studies of Votrient in patients with varying degrees of hepatic dysfunction ALT = alanine aminotransferase; ULN = upper limit of normal 1. GlaxoSmithKline. Votrient (pazopanib) Summary of Product Characteristics. January 2013.

42 Management of liver function in patients receiving Votrient 1 Increase in serum transaminases (ALT, AST) and bilirubin have been observed in Votrient clinical studies 1 In majority of cases, isolated increases in ALT and AST have been reported without concomitant elevations of ALP or bilirubin Ensure patients are aware of this potential side effect Serum liver function monitoring: 1 before initiation of treatment at least once every 4 weeks for the first 4 months of treatment and as clinically indicated periodic monitoring should then continue See next slide for recommendations on treatment interruptions/dose reductions should elevated LFTs be detected Votrient should be discontinued if changes in liver function are severe and patients should not be re-treated 1 Note: Dosing recommendations for Votrient in patients with pre-existing hepatic impairment can be found on an earlier slide 1. GlaxoSmithKline. Votrient (pazopanib) Summary of Product Characteristics. January 2013.

43 PRIOR TO VOTRIENT TREATMENT DURING TREATMENT Monitoring and managing liver function elevations 1 At least every 4 weeks for 4 months and as clinically indicated; periodically thereafter ALT / AST >8X ULN Interrupt until ALT / AST Grade 1 or baseline Reintroduce, if warranted, at lower dose Discontinue if ALT /AST >3X ULN recur Isolated ALT / AST ≤8X ULN ALT / AST >3X ULN AND TBL >2X ULN Direct bilirubin >35% Continue YESNO Discontinue Weekly tests until ALT Grade 1 or baseline Continue treatment Monitor serum liver tests ULN: Upper limit of normal TBL: Total bilirubin level 1. GlaxoSmithKline. Votrient (pazopanib) Summary of Product Characteristics. January 2013.

44 Hepatic Toxicity Definitions 1.General Practice Notebook - a UK medical reference. Available at: (Accessed June 2011)

45 Liver enzyme elevations associated with Votrient are largely reversible following dose modification, interruption or cessation 1,2 Majority of cases have been asymptomatic and occurred within 4 months 1.Goodman VL, Wang Q, Pandite LN, Watkins PB. Abstract and poster presentation at 35th European Society of Medical Oncology Congress, Milan, October Poster 904P. 2.Sternberg CN et al. J Clin Oncol 2010; 28: RCC safety database N=586 ALT elevation ≥3X ULN N=106 (18%) Recovery ≤ Grade 1 N=96 (91%) Dose interruptions followed by re-challenge N=31 (29%) Returned to Grade 0/baseline without interruption N=32 (30%) Outcome data missing N=10 (9%)

46 Adverse events of interest associated with tyrosine kinase inhibitors (TKIs) Despite improved efficacy in the treatment of RCC, TKIs are associated with several side effects that can impact on patients’ quality of life (QoL), including 1,2 Mucositis Fatigue Hand–foot syndrome (HFS) Even non-severe mucositis and fatigue can negatively impact the QoL of patients 2 Recognition and prompt management of adverse events are important to avoid unnecessary dose reductions that may negatively impact treatment efficacy 1 1. Hutson et al. Oncologist 2008;13:1084– Porta and Szczylik. Cancer Treat Rev 2009;35:297–307.

47 Fatigue can have a significant negative effect on everyday activities and QoL of patients Symptoms Altered energy levels Attention deficits Sleep disturbance Reduced endurance Listlessness Sluggishness Dizziness Apathy Exhaustion Anxiety Depression Levels of severity 1 Grade 0 - No symptoms Grade 1 - Mild, relieved by rest Grade 2 - Moderate, impacting activities of daily living Grade 3 - Severe, limiting self-care activities of daily living Grade 4 - Disabling 1.NCI CTCAE 2009 version _QuickReference_5x7.pdf

48 Management of fatigue Fatigue affects % of cancer patients with varying degrees of severity 1 Not always a drug-related side effect Fatigue was reported as an AE in 24% of patients treated with Votrient in the aRCC clinical trials (grade 3/4 events, 3%) 2 Encourage patients to inform HCP as soon as fatigue presents Check for any underlying clinical causes: 3 Anaemia - transfuse if necessary Thyroid function - initiate thyroxine if thyroid underactive Depression - treat if indicated Offer practical advice: 3 Balance exercise and rest Encourage fluid intake and healthy diet Try to maintain a normal sleep pattern Short-term dose reduction may help 1. National Comprehensive Cancer Network. Cancer-Related Fatigue, Version Available at: (Accessed May 2011). 2. GlaxoSmithKline. Votrient (pazopanib) Summary of Product Characteristics, January Pyle L et al. Cancer Nursing Practice 2008; 7:

49 Even low-grade oral mucositis can have a negative effect on everyday activities and QoL of patients Symptoms 1,2 Pain/sensation of burns Feeding difficulties/deterioration in the sense of taste Communication/elocution problems Dehydration/sticky secretions or saliva Halitosis Raw feeling in the throat Swollen tissues in the mouth Super-infection, which can lead to septicaemia (Candida) Levels of severity 1-3 Grade 0 - No symptoms Grade 1 - Sore mouth, no ulcers, mild pain Grade 2 - Sore mouth with ulcers, moderate pain Grade 3 - Severe pain, liquid diet only Grade 4 - Unable to eat or drink 1.Lalla et al. Dent Clin North Am 2008; 52; 61– Naidu et al. Neoplasia 2004; 6: 423– NCI CTCAE 2009 version _QuickReference_5x7.pdf 15_QuickReference_5x7.pdf

50 Management of mucositis/stomatitis 1 Mucositis/stomatitis appears to be an infrequent complication of Votrient treatment in patients with advanced RCC (grade 3/4 events, <1%) 2 Encourage dental check-up prior to commencing treatment Encourage good oral hygiene Use of soft toothbrush and mild toothpaste Use of bicarbonate-based / non-alcohol mouthwashes Early recognition and action is vital Gelclair Oral Gel Bonjela / Orabase for ulcers Lip creams and balms for cheilitis Gargle with soluble paracetamol for pain; Difflam if can tolerate Frozen pineapple chunks can help relieve symptoms Treat oral thrush with anti-fungals Encourage fluid intake Use a straw, cool drinks, avoid alcohol Eat soft food; avoid hot, spicy and acidic foods 1.Pyle L et al. Cancer Nursing Practice 2008; 7: GlaxoSmithKline. Votrient (pazopanib) Summary of Product Characteristics, January 2013.

51 Low-severity hand-foot skin reactions can negatively impact on patients’ daily activities and QoL Grade 2 Grade 3 Grade 1 1. Lacouture et al. Oncologist 2008; 13: 1001– NCI CTCAE 2009 Version 4. CTCAE_4.02_ _QuickReference_5x7.pdf Symptoms 1 Numbness, tingling, burning, redness Erythema Swelling Moist desquamation Ulceration, blistering Severe pain of hands and/or feet Levels of severity 1,2 Grade 1 - minimal skin changes or dermatitis (e.g. erythema) without pain Grade 2 - skin changes (e.g. peeling, blisters, bleeding, oedema) or pain, impacting some activities of daily living (ADL) Grade 3 - ulcerative dermatitis or skin changes with pain, interfering with self-care ADL

52 Management of hand-foot syndrome (HFS) 1 HFS reactions appear to be an infrequent complication of Votrient treatment in patients with advanced RCC (grade 3/4 events, <1%) 2 Prevention is important: 1 Visit a chiropodist/podiatrist before and during treatment if possible Keep skin well moisturised with an emollient Wear cotton socks, trainers Use insoles, pressure-relieving pads/gel inserts Use mild soap, rubber gloves when washing up Avoid activities that put pressure on hands and feet Avoid heat exposure (saunas, sitting in sun or by fire) Treat affected areas promptly: Use of urea-based creams Dose reduction/interruption depending on severity 1. Pyle L et al. Cancer Nursing Practice 2008; 7: GlaxoSmithKline. Votrient (pazopanib) Summary of Product Characteristics, January 2013.

53 Managing other gastrointestinal side effects Nausea & vomiting Nausea and vomiting are common features of TKI therapy 1,2 Reported in 27% and 15% of patients treated with Votrient in aRCC clinical trials, respectively (grade 3/4 events, ≤1%) 2 Advise patients to maintain fluid intake, eat small regular meals, and avoid strong odours 1,3 More severe cases may require anti- emetic therapy (e.g. metoclopramide) 1,3 Consider dose reduction if necessary Other abdominal symptoms Dyspepsia, flatulence, bloating also observed with TKIs 1 Reported in 4%, 3% and 3% of patients treated Votrient in aRCC clinical trials (at any grade) 2 More severe cases may require PPI therapy** 1 Dysgeusia (taste disturbances) Experienced by 16% of patients treated with Votrient in aRCC clinical trials (grade 3/4 events, 0%) 2 Encourage normal food & fluid intake Pineapple chunks may help 1.Schwandt A et al. OncoTargets and Therapy 2009:2 51–61 2. GlaxoSmithKline. Votrient (pazopanib) Summary of Product Characteristics, January Pyle L et al. Cancer Nursing Practice 2008; 7: 42. ** Avoid co-administration with medicines that increase gastric pH unless medically necessary (e.g. PPIs, H2 receptor antagonists and antacids). Please refer to the Summary of Product Characteristics for further information

54 Managing thyroid function Thyroid dysfunction has been observed with TKIs - often under-diagnosed but treatable 1,2 Hypothyroidism appears to be an infrequent side effect of Votrient therapy (reported in 4% patients in aRCC clinical trials) 3 Laboratory measurement of thyroid function should be performed at baseline and periodically (e.g. every 12 weeks) 3 Observe patients for signs and symptoms of thyroid dysfunction 3 (e.g. fatigue, dry skin, shortness of breath, myalgia, feeling cold) Treat patients as needed per standard medical practice (e.g. thyroxine) 3 May require a dose reduction when corrective treatment is not sufficient 1.Schwandt A et al. OncoTargets and Therapy 2009:2 51–61 2. Pyle L et al. Cancer Nursing Practice 2008; 7: GlaxoSmithKline. Votrient (pazopanib) Summary of Product Characteristics, January 2013.

55 Managing proteinuria Proteinuria is known to occur with VEGF inhibitors 1 Reported in 7% of patients treated with Votrient in RCC clinical trials (grade 3/4 events, <1%) 2 Baseline and periodic urinalysis during treatment is recommended 2 Patients should be monitored for worsening proteinuria 2 Votrient should be discontinued if the patient develops grade 4 proteinuria 2 1.Izzedine H et al. Eur J Cancer 2010; 46: GlaxoSmithKline. Votrient (pazopanib) Summary of Product Characteristics, January 2013.

56 Managing hair & skin colour changes Hair and skin colour changes have been observed with TKIs 1,2 Hair colour changes were experienced by 39% of patients receiving Votrient in aRCC trials (grade 3/4 events, <1%) 3 Patients should be warned about the possibility of hair and skin depigmentation May result in greying hair and sallow skin Can be alarming but are harmless effects Hair dyes can be used, provided not too harsh Monitor scalp closely for reactions Reverses after discontinuation of treatment 1.Schwandt A et al. OncoTargets and Therapy 2009:2 51–61 2.Pyle L et al. Cancer Nursing Practice 2008; 7: GlaxoSmithKline. Votrient (pazopanib) Summary of Product Characteristics, January 2013.

57 Managing haematological side effects Haematological toxicities (neutropenia, anaemia, thrombocytopenia) have been observed with TKIs 1,2 Incidence of grade 3/4 haematological toxicities associated with Votrient is low in patients with advanced RCC (0-4%) 2,3 May be attributed to fact that Votrient is not a potent inhibitor of Flt-3 receptor 3 Perform FBC at each clinic visit Observe patients for signs of infection, bleeding and bruising Blood counts usually recover with treatment interruption. Consider dose reduction if toxicity re-appears Since VEGF inhibitors can impair wound healing, suspend Votrient treatment 7 days prior to surgery and re-start when wound judged to be adequately healed 2 1.Schwandt A et al. OncoTargets and Therapy 2009:2 51–61 2. GlaxoSmithKline. Votrient (pazopanib) Summary of Product Characteristics, January Sternberg et al. J Clin Oncol 2010; 28:

58 Managing cardiac toxicities (1) Cardiotoxicity has been observed with TKIs, although the precise mechanism by which this occurs is not fully understood 1 Cardiac disorders such as bradycardia, cardiac dysfunction, QT prolongation, myocardial infarction and myocardial ischaemia occurred infrequently in patients receiving Votrient in RCC trials (grade 3/4 events, <1%) 2,3 Votrient should be used with caution in patients at risk of QT prolongation 1 Baseline and periodic ECG recommended Votrient should be used with caution in patients at risk of arterial thrombotic events (e.g. MI, stroke, TIA) 1 1.Schwandt A et al. OncoTargets and Therapy 2009:2 51–61 2. GlaxoSmithKline. Votrient (pazopanib) Summary of Product Characteristics, January Sternberg et al. J Clin Oncol 2010; 28:

59 Managing cardiac toxicities (2) No reported cases of treatment-related congestive heart failure (CHF) or left ventricular ejection fraction (LVEF) decline in the Phase III advanced RCC study 3 Note: Eligible patients had to have good cardiac function and ECHO/MUGA scans were only performed if clinically indicated The safety and pharmacokinetics of Votrient in patients with moderate to severe heart failure or those with a below normal left ventricular ejection fraction (LVEF) has not been studied 2 The risks and benefits of Votrient should be considered before beginning therapy in patients who have pre-existing cardiac dysfunction 1 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 1 Interruption of Votrient and/or dose reduction should be combined with treatment of hypertension in patients with significant reductions in LVEF, as clinically indicated. 1 1.Schwandt A et al. OncoTargets and Therapy 2009:2 51–61 2. GlaxoSmithKline. Votrient (pazopanib) Summary of Product Characteristics, January Sternberg et al. J Clin Oncol 2010; 28:

60 Votrient summary in advanced RCC Licensed indication Votrient is indicated in adults for the first-line treatment of advanced RCC and for patients who have received prior cytokine therapy for advanced disease Recommended by NICE and SMC as a first-line treatment option for patients with advanced RCC Selective mode of action 1,2 Selectively targets key receptors associated with angiogenesis and tumour cell proliferation Minimal inhibition of other kinases including Flt-3 Significant improvement in PFS vs placebo in: 3 Combined population: 9.2 months vs 4.2 months Treatment-naïve patients: 11.1 months vs 2.8 months Cytokine-pretreated patients: 7.4 months vs 4.2 months Maintains patients’ health-related quality of life, relative to placebo 3 Low incidence of Grade 3 or 4 fatigue, hand- foot syndrome and mucositis/stomatitis 3,4 Convenient once-daily oral dosing 800 mg once daily without food Votrient is available in 200 mg and 400 mg tablets. 200 mg400 mg 1.Karaman MW, et al. Nat Biotechnol 2008;26: 127–132; 2. Kumar R, et al. Br J Cancer 2009; 101: 1717–1723; 3. Sternberg CN, et al. J Clin Oncol 2010; 28: ; 4. Sternberg CN, et al. Oral presentation at ASCO 2009: abstract 5021.

61 Questions Patients May Ask

62 What should I do if I forget to take my tablets? Take your usual number of tablets at your next scheduled time. For example, if you usually take your tablets in the morning but forget, and later in the day you remember that you have missed a dose, do not take your tablets until the following morning. If you have missed a day, do not take a double dose of Votrient to make up for the missed dose.

63 What if I take too much Votrient? If you take too many tablets, contact your doctor, nurse or pharmacist for advice. If possible show them the pack, or the leaflet found inside the pack.

64 Can I crush, split or dissolve the tablets? It is recommended that Votrient tablets are swallowed whole with a drink of water. You should not crush, split, chew or dissolve the tablets as doing so can affect the way the medicine works and may increase the chance of side effects. Talk to your doctor or nurse if swallowing is difficult for you.

65 Can I have an operation while taking Votrient? You should let your doctor know if you are going to have an operation. Your doctor will stop Votrient before your operation as it may affect wound healing. Your treatment will be restarted when the wound has healed adequately.

66 Can I have the flu jab while taking Votrient? Anyone who is more at risk of infection for any reason should have the flu jab. Many cancer treatments can affect the immune system, so you are less able to fight infections. It will generally take you longer to recover from flu if you do get it and you are more likely to develop complications. So it is probably sensible for most people with cancer or having cancer treatment to have it. People who have a severe allergy to eggs (some flu vaccines are prepared on hen’s eggs) or have had a reaction to a flu jab in the past are advised not to have it.

67 What if I need to go to the dentist while taking Votrient? Good mouth care is important during cancer treatment to help keep your mouth healthy. Your cancer doctor may advise you to see your dentist or hygienist a few weeks before you start treatment with Votrient to check whether you have any tooth decay or gum problems so these can be treated beforehand. Votrient can affect wound healing so you should tell your cancer doctor and your dentist if you need to have a tooth taken out. Your doctor will stop Votrient about 7 days before the dental extraction and re-start your treatment once the gum has healed adequately.

68 What sunscreens can I use while taking Votrient? Votrient treatment will not increase the risk of sun damage, however it is important to exercise good practice whilst in the sun by using an appropriate sun screen. The sun protection factor (SPF) of a sunscreen tells you how much of the sun’s harmful UVB rays are filtered out. It is sensible to use a high factor sunscreen (e.g. SPF 30) because this gives you much more protection than a lower one. It is also important to use a sunscreen that protects against both UVA and UVB radiation from the sun. This may be labelled broad spectrum. It is important to apply your sun cream often enough and thickly enough. It is advisable to put it on about 30 minutes before you go out in the sun and reapply it at least every two hours. Wearing loose clothing and spending time in the shade when the sun is strong can also help prevent sunburn.

69 What blood tests will I need to have while taking Votrient? All patients receiving treatment for cancer need to have regular blood tests. The most common tests consist of a full blood count (FBC) to check that the numbers of red cells, white cells and platelets in your blood are within acceptable limits, liver function tests (LFTs) to check how well your liver is working and kidney function tests (U&E). You should also have periodic testing of your thyroid function (known as a TFT) as Votrient can sometimes affect the thyroid gland.

70 Prescribing Information (Please refer to full SmPC before prescribing) Votrient ® ▼(pazopanib) 200mg and 400mg film-coated tablets. Each tablet contains pazopanib hydrochloride, equivalent to 200mg and 400mg of pazopanib, respectively. Indication In adults for first-line treatment of advanced renal cell carcinoma (RCC) and those with prior cytokine therapy. Dosage and administration Only to be initiated by physician experienced in use of anti-cancer agents. 800mg once daily. Take without food (≥1 hour before or ≥2 hours after a meal). Take tablets whole; do not break or crush. Dose modification: In 200mg steps based on individual tolerability to manage ADRs. Not to exceed 800mg. Renal impairment: No dose adjustment required in patients with CrCl >30ml/min. Caution advised in patients with CrCl 8xULN, interrupt pazopanib until they return to ≤Grade 1. If transaminases >3xULN occur following re-introduction, discontinue pazopanib. If transaminases >3xULN occur concurrently with bilirubin >2xULN, perform bilirubin fractionation. If direct (conjugated) bilirubin is >35% of total, discontinue pazopanib. Concomitant use of pazopanib and simvastatin increases risk of ALT elevations: undertake with caution and close monitoring. Hypertension: Events of hypertension, including hypertensive crisis, have occurred in pazopanib studies. Control BP prior to initiating pazopanib. Monitor for hypertension early (≤1 week after starting treatment) and frequently thereafter. Manage elevated BP with anti-hypertensive therapy and pazopanib dose modification. Discontinue pazopanib if BP is persistently elevated (140/90 mmHg) or if arterial hypertension is severe and persists despite anti-hypertensive therapy and dose reduction. Posterior reversible encephalopathy syndrome (PRES) / Reversible posterior leukoencephalopathy syndrome (RPLS): PRES/RPLS has been reported in association with pazopanib. Patients developing PRES/RPLS should permanently discontinue pazopanib. Cardiac dysfunction/heart failure: Consider risks/benefits of pazopanib in patients with pre- existing cardiac dysfunction. Safety and pharmacokinetics of pazopanib not studied in patients with moderate to severe heart failure or those with below normal LVEF. Events of cardiac dysfunction (e.g. CHF and LVEF decline) have occurred in pazopanib trials. Monitor patients for signs and symptoms of CHF. Baseline and periodic LVEF evaluation recommended. QT prolongation and Torsade de Pointes: Use with caution in patients (i) with history of QT interval prolongation, (ii) taking antiarrythmics or other medications that may prolong QT interval or (iii) with relevant pre-existing cardiac disease. Baseline and periodic ECGs, and maintenance of electrolytes within normal range recommended. Arterial thrombotic events: Use with caution in patients at increased risk for these events. Base treatment decision on individual patient’s benefit/risk assessment. Venous thromboembolic events (VTEs): VTEs including venous thrombosis and fatal PE have occurred in pazopanib trials. Thrombotic microangiopathy (TMA): (including thrombotic thrombocytopenic purpura and haemolytic uraemic syndrome) has been reported in clinical trials of pazopanib. Patients developing TMA should permanently discontinue pazopanib. Reversal of effects of TMA has been observed after pazopanib treatment was discontinued. Haemorrhagic events: Not recommended in patients with history of haemoptysis, cerebral, or significant GI haemorrhage in past 6 months. Use with caution in patients with significant risk of haemorrhage. GI perforations and fistula: Use with caution in patients at risk for GI perforation or fistula. Wound healing: Stop treatment ≥7 days prior to surgery. Resume after surgery based on clinical judgement of adequate wound healing. Discontinue pazopanib in patients with wound dehiscence. Hypothyroidism: Baseline measurement of thyroid function recommended prior to start of pazopanib treatment; monitor periodically during treatment. Monitor patients for signs and symptoms of thyroid dysfunction and manage as per standard medical practice. Proteinuria: Baseline and periodic urinalysis recommended. Monitor patients for worsening proteinuria. Discontinue pazopanib if Grade 4 proteinuria develops. Pneumothorax: Observe patients closely for signs and symptoms of pneumothorax. Infections: Cases of serious infection (with/without neutropenia) reported. Interactions Avoid concomitant use with strong inhibitors of CYP3A4, p- glycoprotein (P-gp) or breast cancer resistance protein (BCRP) and CYP3A4 inducers. Hyperglycaemia observed during concomitant administration with ketoconazole. Avoid co- administration with medicines that increase gastric pH (e.g. PPIs and H 2 receptor antagonists) unless medically necessary. Undertake concomitant administration with uridine diphosphate glucuronosyl transferase 1A1 (UGT1A1) substrates and simvastatin (and other statins) with caution. Avoid grapefruit juice during pazopanib treatment. Pregnancy and lactation No adequate data on use in pregnant women. Not to be used unless clearly necessary; appropriate contraception advised. Not known whether pazopanib excreted in human milk; breastfeeding should be discontinued. Animal studies indicate fertility may be affected. Effects on ability to drive and use machines No studies conducted. Avoid driving or using machines if affected. Undesirable effects Most important serious ADRs associated with pazopanib in clinical studies were: TIA, ischaemic stroke, myocardial ischaemia, myocardial and cerebral infarction, cardiac dysfunction, GI perforation and fistula, QT prolongation; pulmonary/GI/cerebral haemorrhage. All events occurred in <1% of patients. Fatal events possibly related to pazopanib included: GI haemorrhage, pulmonary haemorrhage/haemoptysis, abnormal hepatic function, intestinal perforation, ischaemic stroke. Treatment-related events reported with pazopanib in advanced RCC patients with following frequencies: Very common: Decreased appetite; Dysgeusia; Hypertension; Diarrhoea, nausea, vomiting, abdominal pain; Hair colour changes; Fatigue; Increased ALT and AST. Common: Thrombocytopenia, neutropenia, leucopenia; Hypothyroidism; Headache, dizziness, lethargy, paraesthesia; Hot flush; Epistaxis, dysphonia; Dyspepsia, stomatitis, flatulence, abdominal distension; Abnormal hepatic function, hyperbilirubinaemia; Rash, alopecia, PPE, skin hypo/de-pigmentation, erythema, pruritus, dry skin, hyperhidrosis; Myalgia, muscle spasms; Proteinuria; Asthenia, mucosal inflammation, oedema, chest pain; Decreased weight /WBC, Increased creatinine/bilirubin/lipase/BP/TSH/GGT. Uncommon events include: Hypophosphataemia; hypomagnesaemia; Peripheral sensory neuropathy; hypoaesthesia; Eyelash discolouration; CVA, myocardial infarction, bradycardia; Flushing, hypertensive crisis; Mouth ulceration, frequent bowel movements; pancreatitis, peritonitis; Hepatotoxicity, hepatic failure, hepatitis; jaundice; Photosensitivity reaction, skin exfoliation; Menorrhagia, metrorrhagia, Retroperitoneal/urinary tract/vaginal haemorrhage; Mucous membrane disorder; Increased blood urea/amylase, decreased blood glucose, abnormal thyroid function test; Infections (with/without neutropenia). Overdose No specific antidote. Treatment should consist of general supportive measures. Basic NHS Cost 200mg x 30 tablet pack £ mg x 30 tablet pack £ Marketing authorisation (MA) nos. EU/1/10/628/ MA holder Glaxo Group Limited, Berkeley Avenue, Greenford, Middlesex UB6 ONN. Legal category POM. UK/PAZ/0012/13. January Adverse events should be reported. Reporting forms and information can be found at: Adverse events should also be reported to GlaxoSmithKline on Further information is available from Customer Contact Centre, GlaxoSmithKline, Stockley Park West, Uxbridge, Middlesex UB11 1BT; Freephone: Votrient is a trademark of the GlaxoSmithKline group of companies.


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