NOTE FOR HEALTHCARE PROFESSIONAL

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

GSK has been involved in the preparation of this presentation
Votrient in the Treatment of Advanced Renal Cell Carcinoma (RCC): A presentation for use by healthcare professionals Study VEG105192 Key considerations before prescribing Guidance on management of side effects associated with Votrient therapy & other TKIs Questions which patients may ask GSK has been involved in the preparation of this presentation Prescribing information can be found at the end of the core presentation UK/PAZ/0031/13 February 2013

Votrient indication1 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. Votrient has a conditional marketing authorisation A conditional marketing authorisation is granted to a medicinal product with a positive benefit/risk assessment that fulfils an unmet need when the benefit to public health of immediate availability outweighs the risk inherent in the fact that additional data are still required. A conditional marketing authorisation is renewable annually. Clinical conditions include: outcome of ongoing head-to-head study of Votrient vs. sunitinib as first-line treatment in advanced RCC (VEG108844; COMPARZ) pooled analysis of data from studies VEG and VEG (a sub-study of VEG in Asian subjects). 1. GlaxoSmithKline. Votrient (pazopanib) Summary of Product Characteristics, January 2013.

Management of advanced RCC in the UK1-4
Good or intermediate prognosis Poor prognosis    1st-line treatment Sunitinib1 Bevacizumab+IFN2 Pazopanib3  Temsirolimus2  2nd-line after cytokines Sorafenib2 2nd-line after anti-VEGF therapies  Everolimus4 This slides captures the agents that are licensed and have been appraised by NICE for the treatment of advanced RCC and whether they have been recommended or not.  Recommended by NICE  Not recommended by NICE NICE TA 169. March NICE TA 178. August NICE TA 215 Feb NICE TA 219 April 2011.

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. This guidance was issued following a Single Technology Appraisal (STA) for this specific (i.e. first-line) indication. Note: An STA for Votrient in the second-line treatment (i.e. following prior cytokine based therapy) of advanced RCC was also planned. However, following consultation between GSK and the Department of Health, this appraisal was removed from the NICE work programme because, since the introduction of VEGF-targeted agents, the number of patients receiving first-line cytokine-based therapy, and therefore eligible for Votrient in this second-line setting, is very small. 1. NICE. Pazopanib for the first-line treatment of advanced renal cell carcinoma. Final appraisal guidance no February 2011.

Votrient Scottish Medicines Consortium Advice No. 676/111
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. Note: The full indication under review also included patients who had received prior cytokine therapy for advanced disease. The SMC advice restricted its guidance to the first-line treatment of advanced RCC, based on the fact that GSK submitted data primarily for the first-line population, since the number of patients receiving first-line cytokine-based therapy and therefore eligible to receive Votrient second-line is very small. 1. Scottish Medicines Consortium. Pazopanib 200mg, 400mg film-coated tablets (Votrient). Advice no. 676/11. March 2011.

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 angiogenesis2 PDGFR regulates angiogenesis and proliferation of some tumour cells3,4 c-Kit regulates cellular proliferation, survival and metastasis5 Angiogenesis (the formation of new blood vessels) plays a critical role in the growth and spread of many types of tumours.1-4 One of the primary mediators in the regulation of angiogenesis is the signalling cascade involving vascular endothelial growth factor (VEGF).1,4,5 Increasing evidence suggests that platelet-derived growth factor (PDGF) also plays a key role in tumour angiogeneisis.6,7 Votrient is a selective tyrosine kinase inhibitor (TKI) that has a specific kinase affinity profile. Votrient is a potent inhibitor of VEGF receptor 2 (VEGFR-2), the primary mediator of VEGF-induced angiogenesis.1,2,8 It also inhibits VEGFR-1 and VEGFR-3, PDGFR α and β, and c-kit.8-10 Votrient has minimal activity on Flt-39,10, which is critical for the proliferation and differentiation of haematopoietic progenitor cells.11 Hicklin DJ, Ellis LM. Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol 2005; 23: 1011–1027. Folkman J. Angiogenesis. Annu Rev Med 2006; 57: 1–18. Dvorak HF. Vascular permeability factor/vascular endothelial growth factor: a critical cytokine in tumor angiogenesis and a potential target for diagnosis and therapy. J Clin Oncol 2002; 20: 4368–4380. Ferrara N. VEGF as a therapeutic target in cancer. Oncology 2005; 69 (Suppl 3): 11–16. Rini BI, Small EJ. Biology and clinical development of vascular endothelial growth factor-targeted therapy in renal cell carcinoma. J Clin Oncol 2005; 23: 1028–1043. Ostman A. PDGF receptors-mediators of autocrine tumor growth and regulators of tumor vasculature and stroma. Cytokine Growth Factor Rev 2004; 15: 275–286. Betsholtz C. Insight into the physiological functions of PDGF through genetic studies in mice. Cytokine Growth Factor Rev 2004; 15: 215–28. Sonpavde G, Hutson TE, Sternberg CN. Pazopanib, a potent, orally administered small- molecule multitargeted tyrosine kinase inhibitor for renal cell carcinoma. Expert Opin Invest Drugs 2008; 17 (2): Kumar R, Crouthamel MC, Rominger DH, et al. Myelosuppression and kinase selectivity of multikinase angiogenesis inhibitors. Br J Cancer 2009; 101: 1717–1723. Karaman MW, Herrgard S, Treiber DK, et al. A quantitative analysis of kinase inhibitor selectivity. Nat Biotechnol 2008; 26: 127–132. Lyman SD, Jacobsen SE. C-Kit ligand and Flt-3 ligand: stem/progenitor cell factors with overlapping yet distinct activities. Blood 1998; 91 (4): 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.

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. Hawkins9 1San Camillo and Forlanini Hospitals, Rome, Italy; 2Military Institute of Medicine, Warsaw, Poland; 3National Cancer Center, Gyeonggi-do, Korea; 4Fundación Arturo López Pérez, Santiago, Chile; 5National Oncological Institute, Klenová, Bratislava, Slovakia; 6Austin Hospital, Melbourne, Australia; 7GlaxoSmithKline, Inc., Research Triangle Park, NC, USA; 8GlaxoSmithKline, Inc., Collegeville, PA, USA; 9University of Manchester and Christie Hospital NHS Foundation Trust, Manchester, UK This is the pivotal phase III trial supporting the registration of Votrient for the first line treatment of advanced Renal Cell Carcinoma (RCC) and for patients who have received prior cytokine therapy for advanced disease. Study VEG Presentation at ASCO Stenberg CN, et al. J Clin Oncol 2010; 28(6):

VEG105192 study design Patients with advanced RCC (N = 435)
Stratification: ECOG PS 0 vs. 1 Prior nephrectomy Rx-naive (n = 233) vs. 1 cytokine failure (n = 202) Endpoints: Primary: PFS Secondary: OS, ORR, HRQoL, safety, tolerability Randomisation 2:1 Votrient 800mg o.d. (n = 290) Matching Placebo (n = 145) To be eligible patients had to have locally advanced/metastatic RCC, clear cell histology , be treatment-naïve, or have had one prior line of cytokine-based therapy for advanced disease, measurable disease by RECIST, ECOG performance status of 0 or 1, adequate organ function, be aged ≥18 years. Eligible subjects were first stratified according to the following stratification factors: 1) prior systemic therapy: treatment-naïve vs. cytokine-pretreated; 2) baseline ECOG PS 0 vs. 1; and 3) prior nephrectomy status: yes vs. no. Patients were then randomised on a 2:1 basis to either Votrient 800mg orally o.d. or placebo. Those who progressed while on placebo were allowed to crossover to active pazopanib treatment.1,2 Choice of comparator / why placebo controlled? The trial was initially set up to study patients who had failed cytokine treatment. Placebo (with best supportive care) was selected as the choice of comparator because there was no other choice of therapy for those patients at that time. The study protocol was subsequently amended to include treatment-naïve patients based on emerging evidence for the efficacy of VEGF anti-angiogenic agents in the first-line treatment of advanced RCC. Placebo control with best supportive care was retained as the comparator on the following basis: The protocol required that patients were enrolled from regions/countries where sunitinib and sorafenib were either not approved for advanced RCC or were not readily accessible to the patient when they were subsequently approved. Using a placebo control in a randomised double-blind design allowed for better characterisation of the safety and efficacy profiles of Votrient. The exposure of subjects to placebo was minimised by a 2:1 randomisation of Votrient:placebo. Votrient was provided as a treatment option for subjects who progressed on the placebo arm. The ethical aspects for selecting a placebo control had been carefully considered based on the guidelines from regulatory authorities and ICH. Sternberg CN, Szczylik C, Lee ES, et al. Phase III trial of pazopanib in locally advanced and/or metastatic renal cell carcinoma. Oral presentation at American Society of Clinical Oncology Annual Meeting 2009; Abstract no Sternberg CN, Davis ID, Mardiak J, et al. Pazopanib in locally advanced or metastatic renal cell carcinoma: Results of a randomised phase III trial. J Clin Oncol 2010; 28: Option to receive Votrient via an open-label study immediately upon disease progression Stenberg et al. J Clin Oncol 2010; 28(6):

Stenberg et al. J Clin Oncol 2010; 28(6): 1061-1068.
Progression-free survival (overall study population) by independent review 1.0 0.8 0.6 0.4 0.2 0.0 Proportion progression-free Time (month) Votrient Placebo 5 15 20 10 Placebo 9.2 Votrient 4.2 Hazard ratio (95% CI) 0.46 (0.34, 0.62) p value (1-sided) <0.0001 Median PFS (months) 54% reduction in risk of progression or death with Votrient treatment compared with placebo Median progression-free survival (PFS) was statistically significantly prolonged with Votrient compared with placebo in the overall study population (primary end point) (9.2 vs 4.2 months; HR 0.46; p<0.0001), and in the treatment-naïve (11.1 vs 2.8 months; HR 0.40; p<0.0001) and cytokine pre-treated (7.4 vs. 4.2 months; HR 0.54; p<0.001) sub-populations.1,2 Sternberg CN, Szczylik C, Lee ES, et al. Phase III trial of pazopanib in locally advanced and/or metastatic renal cell carcinoma. Oral presentation at American Society of Clinical Oncology Annual Meeting 2009; Abstract no Sternberg CN, Davis ID, Mardiak J, et al. Pazopanib in locally advanced or metastatic renal cell carcinoma: Results of a randomised phase III trial. J Clin Oncol 2010; 28: 6 29 2 76 14 159 38 Number at risk, n Votrient Placebo Stenberg et al. J Clin Oncol 2010; 28(6):

Stenberg et al. J Clin Oncol 2010; 28(6): 1061-1068.
Progression-free survival: (treatment-naïve sub-population) by independent review 1.0 0.8 0.6 0.4 0.2 0.0 5 15 20 10 Votrient Placebo Time (month) Proportion progression-free Placebo 11.1 Votrient 2.8 Hazard ratio (95% CI) 0.40 (0.27, 0.60) p value (1-sided) <0.0001 Median PFS (months) 60% reduction in risk of progression or death with Votrient treatment compared with placebo 1 11 2 39 7 84 22 155 78 Number at risk, n Votrient Placebo Stenberg et al. J Clin Oncol 2010; 28(6):

Median progression-free survival (PFS) in pivotal trial (VEG105192)1,2
Median PFS (months) HR (95% CI) p-value Votrient Placebo Overall study population (n=290) 9.2 (n=145) 4.2 0.46 ( ) p< Treatment-naive sub-population (n=155) 11.1 (n=78) 2.8 0.40 ( ) Cytokine pre-treated (n=135) 7.4 (n=67) 0.54 ( ) p<0.001 Median progression-free survival (PFS) was statistically significantly prolonged with Votrient compared with placebo in the overall study population (primary end point) (9.2 vs 4.2 months; HR 0.46; p<0.0001), and in the treatment-naïve (11.1 vs 2.8 months; HR 0.40; p<0.0001) and cytokine pre-treated (7.4 vs. 4.2 months; HR 0.54; p<0.001) sub-populations.1,2 Sternberg CN, Szczylik C, Lee ES, et al. Phase III trial of pazopanib in locally advanced and/or metastatic renal cell carcinoma. Oral presentation at American Society of Clinical Oncology Annual Meeting 2009; Abstract no Sternberg CN, Davis ID, Mardiak J, et al. Pazopanib in locally advanced or metastatic renal cell carcinoma: Results of a randomised phase III trial. J Clin Oncol 2010; 28: Votrient (pazopanib) Summary of Product Characteristics, January 2013. Sternberg et al. J Clin Oncol 2010; 28:

Overall response rate by independent review
See notes to previous slide. Sternberg CN, et al. J Clin Oncol 2010; 28:

Overview of adverse events associated with Votrient in advanced RCC1
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.

Most common AEs regardless of causality (≥10%)1
(15 March 2010 cut-off) Adverse Event Votrient (n = 290), % Placebo (n = 145), % All Grs Gr 3 Gr 4 Any eventa 93 36 9 74 17 6 Diarrhoea 52 4 < 1 Hypertension 40 10 Hair colour changes 38 3 Nausea 26 Anorexia 24 2 12 Vomiting 21 Fatigue 20 1 Asthenia 14 Haemorrhageb Abdominal pain 11 Headache 5 Proteinuria Weight decreased The table shows most commonly reported on-therapy (treatment-emergent AEs) at the 15 March 2010 cut-off. The most common adverse events (incidence ≥ 20%) seen in Votrient-treated patients were: diarrhoea 52% (G3/4 4%), hypertension 40% (G3/4 4%), hair colour changes 38% (G3/4 <1%), nausea 26% (G3/4 <1%), anorexia 24% (G3/4 2%) and vomiting 21% (grade 3/4 2%). Fatigue and asthenia were reported by 20% and 14% of Votrient-treated patients, respectively.1 Sternberg CN, Hawkins RE, Szczylik C, et al. Randomized, double-blind phase III study of pazopanib in patients with advanced/metastatic renal cell carcinoma (mRCC): final overall survival (OS) results. Abstract and presentation at 35th European Society of Medical Oncology congress, October Abstract no.: LBA22. 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.

1. Sternberg C et al. Presentation at ESMO 2010. Abstract No. LBA22.
Selected class effects associated with VEGFR TKI inhibitors1* (15 March 2010 cut-off) Votrient (n = 290), % Placebo (n = 145), % Adverse event All Grades Grades ≥3 Mucositis/stomatitis 9 <1 Hypothyroidism 7 Hand-foot syndrome 6 Arterial thromboembolic 4 3 Myocardial dysfunction This slide presents selected class effects associated with VEGF inhibitors that were seen in <10% of Votrient-treated patients.1 AEs of mucositis/stomatitis, hypothyroidism and hand-foot syndrome were mostly grades 1 or 2.1 Arterial thromboembolic events occurred in 4% of patients in the Votrient arm compared to none in the placebo arm.1 No signal of myocardial dysfunction was detected (Note: The study only included patients with good cardiac function).1 Sternberg CN, Hawkins RE, Szczylik C, et al. Randomized, double-blind phase III study of pazopanib in patients with advanced/metastatic renal cell carcinoma (mRCC): final overall survival (OS) results. Abstract and presentation at 35th European Society of Medical Oncology congress, October Abstract no.: LBA22. *AEs with incidence of <10% in the Votrient arm regardless of causality. 1. Sternberg C et al. Presentation at ESMO Abstract No. LBA22.

Laboratory abnormalities1 (15 March 2010 cut-off)
Votrient (n = 290), % Placebo (n = 145), % All Grs Gr 3 Gr 4 Chemistry labs ALT 53 11 2 23 1 AST 7 <1 19 Hyperglycemia 43 33 Hyperbilirubinemia 37 3 Hypophosphatemia 36 5 13 Hypocalcemia 35 26 Hyponatremia 4 24 Hypoglycemia 18 Hypokalemia 10 Haematology labs Leukopenia 38 Neutropenia 6 Thrombocytopenia 34 Lymphopenia Anaemia 31 The most common laboratory abnormalities (incidence ≥50%) associated with Votrient were elevated levels of transaminases (ALT 53%, grade 3/4 13%; AST 53%, grade 3/4 8%) but these were mostly reversible.1 Most cases of drug-induced liver enzyme elevations were asymtomatic and occurred within the first 4 months of treatment Grade 3 and 4 haematological toxicities occurred at a low rate (<1% - 5%) in Votrient-treated patients.1 Sternberg CN, Hawkins RE, Szczylik C, et al. Randomized, double-blind phase III study of pazopanib in patients with advanced/metastatic renal cell carcinoma (mRCC): final overall survival (OS) results. Abstract and presentation at 35th European Society of Medical Oncology congress, October Abstract no.: LBA22. 1. Sternberg C et al. Presentation at ESMO Abstract No. LBA22.

No clinically important differences between Votrient and placebo in terms of impact on Quality of Life1 Patients with data, n Votrient Placebo 96 24 20 10 –10 –20 Week 48 MID=5 Week 6 Week 12 Week 18 Week 24 Visit Baseline Adjusted means ± SE Votrient Placebo EORTC QLQ C30 Global Health Status/QoL scores See notes to previous slide. 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 1. Hawkins et al. Eur J Cancer 2009; 7 (Supp)l: 428 (Abstract 7119 and poster presentation).

Key considerations before prescribing

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/excipients2 Not recommended in patients with severe hepatic impairment2 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 Patients suitable for Votrient should: Have advanced RCC1 Be an adult (> 18 years)1 Be treatment-naïve or cytokine pre-treated (Note: NICE guidance only recommends Votrient as a first-line treatment option2, although it is also licensed in patients who have received prior cytokine therapy for advanced disease1). Have an ECOG Performance Status 0 or 1 (Note: NICE guidance recommends Votrient as a first-line treatment option in patients who have ECOG PS 0 or 12, based on the evidence base for Votrient). It is also important to consider any co-morbidities the patient may have: It should be noted that the only contraindication to Votrient is sensitivity to Votrient itself or any of the excipients in the tablet1 Votrient is not recommended in patients with severe hepatic impairment1 Votrient can be used, although caution is advised, in patients with:1 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 It may also be relevant to consider their profession/job, hobbies and interests: E.g. Using computer, gardening, golf, tennis, running, playing musical instrument, sewing, carpentry etc. Votrient (pazopanib) Summary of Product Characteristics, January 2013. 2. NICE. Pazopanib for the first-line treatment of advanced renal cell carcinoma. Technology Appraisal Guidance (TA 215), February 2011. NICE. Pazopanib for the first-line treatment of advanced renal cell carcinoma. Final appraisal guidance no February 2011 GlaxoSmithKline. Votrient (pazopanib) Summary of Product Characteristics, January 2013.

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 This slide summaries the posology and key warnings from the Votrient SmPC. GlaxoSmithKline. Votrient (pazopanib) Summary of Product Characteristics. January 2013.

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 This slide summaries the posology and key warnings from the Votrient SmPC. GlaxoSmithKline. Votrient (pazopanib) Summary of Product Characteristics. January 2013.

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 This slide summaries the posology and key warnings from the Votrient SmPC. GlaxoSmithKline. Votrient (pazopanib) Summary of Product Characteristics. January 2013.

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 This slide summaries the posology and key warnings from the Votrient SmPC. GlaxoSmithKline. Votrient (pazopanib) Summary of Product Characteristics. January 2013.

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 This slide summaries the posology and key warnings from the Votrient SmPC. GlaxoSmithKline. Votrient (pazopanib) Summary of Product Characteristics. January 2013.

Main drug interactions1
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. Votrient is primarily metabolised by CYP3A4 and is also a substrate for CYP3A4, P-glycoprotein (P-gp) and breast cancer resistant protein (BCRP).1 Concomitant treatment with strong inhibitors or inducers of CYP3A4, P-gp or BCRP should therefore be avoided as they may alter the metabolism or distribution of Votrient.1 Selection of alternative concomitant medicinal products with no or minimal potential to inhibit or induce CYP3A4, P-gp or BCRP should be considered.1 Grapefruit juice contains a CYP3A4 inhibitor and therefore should be avoided during Votrient treatment.1 Concomitant use of Votrient and simvastatin (and potentially other statins) has been shown to increases the incidence 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. See table on following slides for further information on potential drug and food interactions with Votrient. Votrient (pazopanib) Summary of Product Characteristics, January 2013. GlaxoSmithKline. Votrient (pazopanib) Summary of Product Characteristics. January 2013.

Potential drug & food interactions with Votrient (1)1
Drug class Examples of agent CYP3A4 inducers Rifampicin class antibiotics Anticonvulsants Antiretrovirals Glucocorticoids (oral) Other Rifampicin, rifabutin Phenytoin, carbamazepine, barbiturates (e.g. phenobarbital) Efavirenz, nevirapine Chronic daily use of: cortisone (>50mg), hydrocortisone (>40mg), prednisone (>10mg), methylprednisolone (>8mg), dexamethasone (>1.5mg) St. John’s Wort (Hypericum perforatum), modafinil CYP3A4 inhibitors Macrolide antibiotics Antifungals Antiretrovirals / proteases inhibitors Calcium channel blockers Antidepressants GI Agents Clarithromycin, erythromycin, telithromycin Itraconazole, ketoconazole, fluconazole, voriconazole, posaconazole Ritonavir, nelfinavir, amprenavir, saquinavir, indinavir, lopinivir, atazanavir Verapamil, diltiazem Fluvoxamine Cimetidine, aprepitant Certain citrus and tropical fruit juices (e.g. grapefruit, lime, Seville orange, star fruit, pomegranate); Amiodarone CYP3A4 substrates Midazolam, cisapride, quinidine, pimozide CYP2C8 substrates Repaglinide, paclitaxel Votrient is a substrate for, inhibitor and/or inducer of several cytochrome P450 (CYP) enzymes and transport proteins. Interactions with other substrates, inhibitors and inducers of these enzymes and proteins are therefore possible.1 Inducers and inhibitors of CYP3A4 Inhibitors Votrient is primarily metabolised by CYP3A4. Concomitant administration with strong CYP3A4 inhibitors (e.g. ketoconazole, clarithromycin, ritonavir) may increase Votrient plasma concentrations and should therefore be avoided.1 CYP3A4 inducers (e.g. rifampicin) may decrease Votrient plasma concentrations and thus concomitant administration of these products with Votrient should be avoided.1 CYP2C8 substrates Co-administration of Votrient with paclitaxel (a CYP2C8 substrate) resulted in a mean increase in systemic exposure of 25%, and a 31% increase in peak plasma concentrations, of paclitaxel.1 P-gp and BCRP Inhibitors and Inducers (see next slide) Votrient is highly protein bound. Co-administration of Votrient with potent inhibitors (e.g. lapatinib) and inducers of the transport proteins, P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), may alter the exposure and distribution of Votrient, including distribution into the CNS, and should therefore be avoided.1 Similarly, it cannot be excluded that Votrient may inhibit P-gp and BCRP in the GI tract. Care should therefore be taken when it is co-administered with other P-gp or BCRP substrates.1 OATP1B1 and UGT1A1 Substrates (see next slide) Votrient has been shown in vitro to inhibit organic anion transporting polypeptide (OATP1B1) and thus it cannot be excluded that Votrient can affect the pharmacokinetics of OATP1B1 substrates (e.g. rosuvastatin).1 Votrient is also an inhibitor of uridine glucuronosyl transferase 1A1 (UGT1A1).3 Co-administration of Votrient with UGT1A1 substrates (e.g. irinotecan) should be undertaken with caution.1 Votrient (pazopanib) Summary of Product Characteristics, January 2013. GlaxoSmithKline. Votrient (pazopanib) Summary of Product Characteristics. January 2013.

Potential drug & food interactions with Votrient (2) 1
Drug class Examples of agent CYP2D6 substrates Dextromethorphan P-gp and BCRP inducers and inhibitors Rifampicin, St. John’s Wort Ketoconazole, itraconazole, quinidine, verapamil, cyclosporin, erythromycin, lapatinib P-gp and BCRP substrates Lapatinib, digoxin, topotecan OAT1B1 substrates Rosuvastatin UGT1A1 substrates Irinotecan, topotecan Statins* Simvastatin, atorvastatin, fluvastatin, pravastatin, rosuvastatin Medicines that increase gastric pH PPIs, H2 receptor-antagonists, antacids Miscellaneous Herbal or dietary supplements St. John’s Wort, ginkgo biloba, kava, grape seed, valerian, ginseng, Echinacea, evening primrose oil Other medications Clinical pharmacology studies have shown that Votrient does not have a clinically relevant effect on the pharmacokinetics of warfarin (a CYP2A9 substrate) or omeprazole (a CYP2C19 substrate).1 Votrient increased the peak plasma concentration and systemic exposure of midazolam (a CYP3A4 substrate) by approximately 30%.1 After oral administration of dextromethorphan (a CYP2D6 substrate) with Votrient, the ratio of dextromethorphan to dextrophan concentrations in the urine increased by 33-64%.1 Herbal supplements Because the composition, pharmacokinetics and metabolism of many herbal supplements are unknown, the concurrent use of all herbal supplements is strongly discouraged during Votrient therapy. In particular, St. John’s Wort should be avoided as it is a known inducer of the CYP3A4 enzyme. Food interactions It is important not to drink grapefruit juice or eat grapefruit products while taking Votrient, as grapefruit juice has inhibitory effects on CYP3A4 and can therefore interfere with the metabolism of Votrient.1 Statins Concomitant use of Votrient and simvastatin has been shown to increases the incidence of ALT elevations and should be undertaken with caution and close monitoring. If a patient receiving concomitant simvastatin develops ALT elevations, guidelines for management of hepatic events associated with Votrient should be followed and simvastatin discontinued. There are insufficient data available to assess the impact on ALT levels of the concomitant use of Votrient with other statins (e.g. atorvastatin, fluvastatin, pravastatin, rosuvastatin). It cannot, however, be excluded that Votrient will affect the pharmacokinetics of other statins, and therefore, concomitant use should be undertaken with caution. Medicines that increase gastric pH Concomitant administration of pazopanib with esomeprazole decreases the bioavailability of pazopanib by approximately 40% (AUC and Cmax), and co-administration of pazopanib with medicines that increase gastric pH should be avoided. If the concomitant use of a proton-pump inhibitor (PPI) is medically necessary, it is recommended that the dose of pazopanib be taken without food once daily in the evening concomitantly with the PPI. If the concomitant administration of an H2-receptor antagonist is medically necessary, pazopanib should be taken without food at least 2 hours before or at least 10 hours after a dose of an H2-receptor antagonist. Pazopanib should be administered at least 1 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. Votrient (pazopanib) Summary of Product Characteristics, January 2013. *If elevated ALT develops with concomitant use of Votrient and statins, follow liver function management guidelines and discontinue statin GlaxoSmithKline. Votrient (pazopanib) Summary of Product Characteristics. January 2013.

Votrient therapy in patients with renal impairment1
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 GlaxoSmithKline. Votrient (pazopanib) Summary of Product Characteristics. January 2013.

Overview of tests recommended before and during Votrient treatment (as per SPC)1*
Frequency Blood pressure (BP) Ensure BP well controlled prior to initiating Votrient. Patients should be monitored within the first week of starting treatment and frequently thereafter, especially during first 18 weeks of treatment Liver function tests (LFTs) Before initiation of treatment At least once every 4 weeks for the first 4 months of treatment, and as clinically indicated Periodic monitoring thereafter Thyroid function tests (TFTs) Baseline and periodic laboratory measurement of thyroid function during treatment Left ventricular ejection fraction (LVEF) Baseline and periodic evaluation of LVEF recommended in patients at risk of cardiac dysfunction ECG Baseline and periodic monitoring during treatment Urinalysis Baseline and periodic urinalysis during treatment Electrolytes (e.g. Mg2+, Ca2+, K+) Ensure maintained within normal range This slide provides an overview of the test required in patients receiving Votrient therapy (as recommended on the SmPC) and the frequency with which these are advised.1 It is difficult to provide a more definitive frequency over and above what is recommended on the SmPC. This list is not exhaustive and it is expected that additional tests, such as a full blood count, would be performed routinely in patients with advanced RCC at each clinic visit. Votrient (pazopanib) Summary of Product Characteristics, January 2013. * 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 GlaxoSmithKline. Votrient (pazopanib) Summary of Product Characteristics. January 2013.

Sternberg et al. J Clin Oncol 2010; 28: 1061-68.
Votrient dosing Votrient has a convenient once-daily dosing schedule administered continuously throughout the course of treatment1 The usual recommended starting dose of Votrient is 800mg once daily2 Dose can be modified in 200mg steps based on individual tolerability in order to manage adverse reactions2 The continuous dosing schedule of TKI agents, such as Votrient, may provide sustained anti-tumour activity3 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.

Votrient administration
Votrient should be taken without food1 Votrient should be administered at least 1 hour before or 2 hours after a meal Votrient is metabolised primarily by CYP3A41 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 Food interactions The pharmacokinetics of Votrient are impacted by food. Peak plasma concentrations and systemic exposure to Votrient are increased approximately two-fold when administered with a high- or low-fat meal.1 Therefore, Votrient should be administered at least 1 hour before or 2 hours after food. Votrient (pazopanib) Summary of Product Characteristics, January 2013. 200 mg 400 mg GlaxoSmithKline. Votrient (pazopanib) Summary of Product Characteristics. January 2013.

Votrient tablet excipients1
Tablet core Microcrystalline cellulose Sodium starch glycollate Magnesium stearate Povidone (K30) Coating Polyvinylalcohol Macrogol 400 Titanium oxide Talc Iron oxide red (200mg) Contraindications Votrient tablets should not be taken by anyone with:1 hypersensitivity to Votrient or other ingredients in the tablets. It should be noted that Votrient tablets do not contain lactose or any nut-based excipients. 1. Votrient (pazopanib) Summary of Product Characteristics, January 2013. GlaxoSmithKline. Votrient (pazopanib) Summary of Product Characteristics, January 2013.

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

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 This section provides practical guidance for oncology nurses on recognising and effectively managing potential side effects associated with Votrient and other tyrosine kinase inhibitors (TKIs). Regular monitoring, early identification and prompt intervention are essential for the optimal management of any therapy-associated side effects. Baseline assessments (i.e. prior to start of therapy) of all variables that may be affected should be taken, in order to help establish the extent of any side effects during treatment.1 Patients can be reticent to report side effects in order to avoid dose reduction or discontinuation, because of their desire for maximum efficacy from treatment. It is important to emphasise that a dose reduction or interruption does not mean that they have failed therapy or that the disease is advancing, but could improve their chances of sustaining long-term treatment.1 Patient education is key to empowering patients to take control of their symptoms. Patients should be provided with up-front advice on preventive measures/self-management strategies that may reduce the likelihood of side effects occurring and/or minimise their impact.1 The more an individual knows about the possible side effects at initiation of treatment, the more likely they are to report them early, act to prevent them, and/or accept the need to alter the treatment regimen.1 Effective verbal communication between patients and healthcare professionals is essential, but this needs to be reinforced by clear, succinct and understandable written information that the patient can take home and absorb.1 Patients can also be encouraged to keep diaries, detailing dosages and symptoms. More frequent clinic visits at the start of treatment provides an opportunity to reinforce education, reassure the patient and answer any questions that may have. The next few slides outline management strategies for specific effects. However, several strategies; dose reductions, treatment delays, patient education, patient empowerment and baseline assessments are common to all.1 Pyle L, Beirne D, Bird J, et al. Managing the side effects of sunitinib: a guide to empowering the patient. Clinical Nursing Practice 2008; 7 (4):

Grading of toxicities Some toxicities are easy to grade e.g.
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 The National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) is widely accepted throughout the oncology community as the standard classification and severity grading scale for adverse events in cancer therapy clinical trials and other oncology settings. An Adverse Event (AE) is any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medical treatment or procedure that may or may not be considered related to the medical treatment or procedure. An AE is a term that is a unique representation of a specific event used for medical documentation and scientific analyses. Each CTCAE v4.0 term is a MedDRA LLT (Lowest Level Term). Grade refers to the severity of the AE. The CTCAE displays Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental activities of daily living (ADL)*. Grade 3 Severe or medically significant but not immediately life-threatening; hospitalisation or prolongation of hospitalisation indicated; disabling; limiting self care ADL**. Grade 4 Life-threatening consequences; urgent intervention indicated. Grade 5 Death related to AE. Activities of Daily Living (ADL) *Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing money, etc. **Self care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden. Ref: 1. NCI CTCAE 2009 version 4.0

Management of hypertension associated with Votrient therapy1
Hypertension is a class effect of drugs targeting the VEGF pathway2 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 Votrient1 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 weeks1 Discontinue Votrient if BP persistently elevated (140/90 mm Hg) or if arterial hypertension is severe and persists despite anti-hypertensive therapy and dose reduction1 Hypertension is acknowledged as a class effect of anti-angiogenic agents that target the VEGF pathway.1 In the clinical trials of Votrient in advanced RCC, 38% of patients (n=586) experienced hypertension (grade 3/4 events, 6%), with events occurring early in the course of treatment (40% of events occurred by day 9 and 90% within the first 18 weeks of treatment).2 The following slide provides an algorithm for the management of hypertension in patients receiving Votrient.1 The occurrence of hypertension may be best monitored by primary care in the community (led by the GP). Therefore, both nurses and patients should remind their GP that they are receiving TKI therapy and hypertension is a common side effect of such treatment. Note: A standard letter is available to make GP aware that patient is on Votrient Launay-Vacher V, Deray G. Hypertension and proteinuria: a class effect of anti-angiogenic therapies. Anticancer Drugs 2009; 20: 81–82. Votrient (pazopanib) Summary of Product Characteristics, January 2013. Kappers MH, van Esch JH, Sleijfer S, et al. Cardiovascular and renal toxicity during angiogenesis inhibition: clinical and mechanistic aspects. Journal of Hypertension 2009; 27: GlaxoSmithKline. Votrient (pazopanib) Summary of Product Characteristics, January 2013. Launay-Vacher V, Deray G. Anticancer Drugs 2009; 20: 81–82.

Monitoring and managing hypertension1
Monitor blood pressure PRIOR TO VOTRIENT TREATMENT If elevated, ensure blood pressure is well controlled DURING TREATMENT Monitor early (within 1 week) and frequently thereafter Continue Votrient treatment & initiate antihypertensive drug therapy Continue Votrient treatment & intensify antihypertensive drug therapy* Hypertension Persistent Hypertension Interrupt Votrient & re-initiate at reduced dose & continue antihypertensive drug therapy This slide provides an algorithm for monitoring BP in patients receiving Votrient. Blood pressure should be measured and, if necessary, well controlled with standard antihypertensive drug therapy, prior to initiating Votrient treatment.1 Similar to other TKIs, antihypertensives from the non-dihydropyridine calcium-channel blocker class should be avoided during treatment with Votrient owing to a potential pharmacokinetic interaction.2 Patients should be monitored within the first week of starting treatment and frequently thereafter, especially during the first 4 months of treatment.1 Between hospital clinic visits, BP monitoring can be performed by the GP or, alternatively, patients may want to purchase a BP monitor for home use, although they should be encouraged to keep accurate records. Manage BP with anti-hypertensive therapy and dose modification of Votrient (interruption and re-initiation at reduced dose based on clinical judgement).1 Discontinuation of Votrient is recommended in patients who experience persistently elevated BP (140/90 mmHg) or if arterial hypertension is severe, despite antihypertensive therapy and Votrient reduction.1 Votrient (pazopanib) Summary of Product Characteristics, January 2013. Kappers MH, van Esch JH, Sleijfer S, et al. Cardiovascular and renal toxicity during angiogenesis inhibition: clinical and mechanistic aspects. Journal of Hypertension 2009; 27: Persistently elevated BP (140/90 mmHg) or severe arterial hypertension *Titration of monotherapy and/or combination of different antihypertensive agents . Discontinue Votrient treatment & continue antihypertensive drug therapy GlaxoSmithKline. Votrient (pazopanib) Summary of Product Characteristics. January 2013.

Management of diarrhoea associated with Votrient therapy
Approximately 50% of patients treated with Votrient in the aRCC trials experienced diarrhoea1 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 complications2 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 Diarrhoea is a well recognised side effect of TKI therapy in advanced RCC1,2 and is the most common adverse event experienced with Votrient, although the majority of events reported as diarrhoea are mild to moderate (grades 1 or 2).3 In the phase III trial, diarrhoea was experienced by 52% of patients receiving Votrient (n=290), although only 4% of patients experienced grade 3 or 4 diarrhoea.4 Early identification and intervention is critical for the optimal management of diarrhoea.5 Decisions on how to manage patients depend to some extent on a patient’s baseline bowel habits which should be established prior to therapy, in order to identify any changes that may occur during treatment, and patients should report any changes in bowel pattern. Nurses should check for other symptoms, such as fever, cramping pain, nausea, vomiting, dizziness and thirst, in order to identify patients at higher risk of diarrhoea-induced complications. Proactive management of diarrhoea with over-the-counter medicines (such as loperamide) can be advised to help control grade 1/2 diarrhoea.6 Further practical advice includes maintaining adequate fluid intake, avoiding alcohol and caffeine, avoiding high-fibre, spicy or greasy foods, and the use of probiotic products, such as live yoghurt. Supportive care for symptoms associated with or affected by diarrhoea may also be required. Application of barrier creams (for example, vaseline) before bowels are opened can provide some relief for the patient.7 Porta C, Paglino C, Imarisio I, Bonomi L. Uncovering Pandora's vase: the growing problem of new toxicities from novel anticancer agents. The case of sorafenib and sunitinib. Clinical and Experimental Medicine 2007; 7: Porta C, Szczylik C. Tolerability of first-line therapy for metastatic renal cell carcinoma. Cancer Treatment Reviews 2009; 35: Votrient (pazopanib) Summary of Product Characteristics, January 2013. Sternberg CN, Davis ID, Mardiak J, et al. Pazopanib in locally advanced or metastatic renal cell carcinoma: Results of a randomised phase III trial. J Clin Oncol 2010; 28: Benson AB, Ajani JA, Catalano RB, et al. Recommended guidelines for the treatment of cancer treatment-induced diarrhea. Journal of Clinical Oncology 2004; 22: Wood LS. Management of vascular endothelial growth factor and multikinase inhibitor side effects. Clinical Journal of Oncology Nursing 2009; 13 Suppl December: Pyle L, Beirne D, Bird J, et al. Managing the side effects of sunitinib: a guide to empowering the patients. Cancer Nursing Practice 2008; 7: GlaxoSmithKline. Votrient (pazopanib) Summary of Product Characteristics, January 2013. Pyle L et al. Cancer Nursing Practice 2008; 7: 42.

Recommendations for managing diarrhoea associated with Votrient
Grade 1 Grade 2 Grade 3 Grade 4 Severity of diarrhoea (NCI CTCAE grade v4)1 Increase of <4 bowel movements/day over baseline; mild increase in ostomy output Increase of 4-6 bowel movements/day over baseline ; moderate increase in ostomy output; Increase of >7 bowel movements/day over baseline; incontinence; hospitalisation indicated; severe increase in ostomy output; limiting self-care activities of daily living Life-threatening consequences ; urgent intervention indicated Votrient dosage2 Dose modification should be in 200mg steps based on individual tolerability in order to manage adverse reactions Treatment Follow local diarrhoea management guidelines For example, administer standard doses of loperamide If diarrhoea unresolved after 48 hours, start second-line agents (e.g. codeine) - see grade 3-4 Initiate loperamide immediately if not already initiated Administer antibiotics as needed (e.g. fluroquinalones), especially if there is fever or grade 3-4 neutropenia or symptoms persist >24 hours Consider electrolyte-restoring therapy Discontinue intervention when diarrhoea-free for 24 hours Supportive care Avoid lactose (dairy) containing products Avoid alcohol, spicy and fried foods Drink 8-10 glasses of clear liquids per day Eat frequent small meals (e.g. rice, pasta, toast) Use IV fluids Consider hospital admission for patients at risk of life-threatening conditions The table above provides some recommendations to manage diarrhoea associated with Votrient. They do not replace sound clinical judgement and local diarrhoea management guidelines should also be followed. Patients should be advised that diarrhoea is a common side effect of Votrient use (experienced by ≥10% patients). Initial patient education should emphasise the importance of maintaining fluid intake and dietary advice (see previous slide). A dose reduction or interruption can be considered if necessary. The dose of Votrient may be modified in 200 mg steps based on individual tolerability in order to manage side effects.1 * NCI CTCAE = National Cancer Institute Common Toxicity Criteria for Adverse Events. Votrient (pazopanib) Summary of Product Characteristics, January 2013. 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 NCI CTCAE 2009 version 4.0 QuickReference_5x7.pdf; 2. GlaxoSmithKline. Votrient (pazopanib) Summary of Product Characteristics, January 2013.

Votrient dosing in pre-existing hepatic impairment1
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 Degree Definition Dose recommendation Mild Normal bilirubin and any degree of ALT elevation or Elevation of bilirubin (>35% direct) up to 1.5 x ULN, regardless of the ALT value Undertake with caution and close monitoring 800mg o.d. Moderate Elevation of bilirubin (>35% direct) >1.5 x to 3 x ULN, regardless of the ALT value 200mg o.d. Severe Elevation of bilirubin (>35% direct) >3 x ULN, regardless of the ALT value Not recommended Definitions of hepatic impairment: Mild hepatic impairment: either normal bilirubin and any degree of alanine aminotransferase (ALT) elevation, or an elevation of bilirubin (>35% direct) up to 1.5 x upper limit of normal (ULN) regardless of the ALT value.1 Moderate hepatic impairment: an elevation of bilirubin (>35% direct) >1.5 x to 3 x ULN, regardless of the ALT value.1 Severe hepatic impairment: an elevation of bilirubin (>35% direct) >3 x ULN, regardless of the ALT value. Votrient (pazopanib) Summary of Product Characteristics, January 2013. General Practice Notebook - a UK medical reference. Available at: (Accessed June 2011) ALT = alanine aminotransferase; ULN = upper limit of normal GlaxoSmithKline. Votrient (pazopanib) Summary of Product Characteristics. January 2013.

Management of liver function in patients receiving Votrient1
Increase in serum transaminases (ALT, AST) and bilirubin have been observed in Votrient clinical studies1 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-treated1 Increases in levels of liver enzymes are recognised as a feature of treatment with TKIs in general, regardless of the target kinase.1,2 In clinical studies with Votrient, increases were seen in serum transaminase enzymes (alanine transaminase [ALT] and aspartate transaminase [AST]) with or without accompanying increases in bilirubin (grade 3/4 ALT and AST elevations reported in 12 and 8% of patients receiving Votrient in the pivotal trial, respectively).3,4 Most cases of drug-induced liver enzyme elevations were asymptomatic and occurred within the first 4 months of treatment.4 Specific guidelines for the management of liver toxicity with pazopanib have been developed and are provided in the Votrient Summary of Product Characteristics (see next slide).3 Loriot Y, Perlemuter G, Malka D, et al. Drug insight: gastrointestinal and hepatic adverse effects of molecular-targeted agents in cancer therapy. Nature Clinical Practice Oncology 2008; 5: Mueller EW, Rockey ML, Rashkin MC. Sunitinib-related fulminant hepatic failure: case report and review of the literature. Pharmacotherapy 2008; 28: Votrient (pazopanib) Summary of Product Characteristics, January 2013. Sternberg CN, Davis ID, Mardiak J, et al. Pazopanib in locally advanced or metastatic renal cell carcinoma: Results of a randomised phase III trial. J Clin Oncol 2010; 28: Note: Dosing recommendations for Votrient in patients with pre-existing hepatic impairment can be found on an earlier slide GlaxoSmithKline. Votrient (pazopanib) Summary of Product Characteristics. January 2013.

Monitoring and managing liver function elevations1
PRIOR TO VOTRIENT TREATMENT Monitor serum liver tests DURING TREATMENT At least every 4 weeks for 4 months and as clinically indicated; periodically thereafter Isolated ALT / AST ≤8X ULN ALT / AST >3X ULN AND TBL >2X ULN ALT / AST >8X ULN Continue treatment Direct bilirubin >35% Interrupt until ALT / AST Grade 1 or baseline The management of liver toxicity will usually be led by a specialist clinician, although the oncology nurse may be involved in co-ordinating liver function tests or liver ultrasound. Liver function tests should be performed before initiation of Votrient treatment, at least once every 4 weeks for the first 4 months of treatment and as clinically indicated, and then periodically thereafter.1 Votrient should be discontinued if changes in liver function are severe and treatment should not be restarted.1 Votrient is not recommended in patients with severe hepatic impairment. Caution and close monitoring is advised in those with mild-to-moderate hepatic impairment (a reduced dose of 200 mg once daily is recommended in moderate impairment)1. Votrient (pazopanib) Summary of Product Characteristics, January 2013. General Practice Notebook - a UK medical reference. Available at: (Accessed June 2011) Weekly tests until ALT Grade 1 or baseline Reintroduce, if warranted, at lower dose YES NO Discontinue Continue Discontinue if ALT /AST >3X ULN recur ULN: Upper limit of normal TBL: Total bilirubin level GlaxoSmithKline. Votrient (pazopanib) Summary of Product Characteristics. January 2013.

Hepatic Toxicity Definitions
Definitions of grade 1 – 4 hepatic toxicities Reference range*1 Grade 1 Grade 2 Grade 3 Grade 4 Aspartate aminotransferase (AST) 8 to 40 IU/L (males) 6 to 34 IU/L (females) >ULN x ULN > x ULN > x ULN > 20.0 x ULN Alanine aminotransferase (ALT) 10 to 50 IU/L Alkaline phosphatase (ALP) 30 to 200 IU/L Gamma glutamyl transpeptidase (GGT) 11 to 50 IU/L (males) 7 to 32 IU/L (females) Bilirubin 3-17 μmol/L >ULN x ULN > x ULN > x ULN > 10.0 x ULN General Practice Notebook - a UK medical reference. Available at: (Accessed June 2011)

Dose interruptions followed Returned to Grade 0/baseline
Liver enzyme elevations associated with Votrient are largely reversible following dose modification, interruption or cessation1,2 Majority of cases have been asymptomatic and occurred within 4 months 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%) Patients with transaminase elevations were identified by querying a safety database of patients receiving Votrient montherapy in RCC studies (n = 586):1 Phase III, VEG105192, n = 290 Phase II, VEG102616, n = 225 Open-label extension study, VEG107769, n = 71 ALT elevations ≥3 times the upper limit of normal were observed in 106 (18%) patients:1 In 96 (91%) of these patients, the elevation resolved to grade ≤1. 31 of these patients (29%) had a dose interruption followed by re-challenge. In 32 patients (30%), raised transaminases returned to baseline/grade 0 without interruption. Outcome data were missing in 10 of 106 patients (9%).1 In the vast majority of patients (91%), transaminase elevations occurred within the first 18 weeks of initiation of Votrient therapy.1 Guidelines on the monitoring and management of liver toxicity are available in the Votrient Summary of Product Characteristics. Goodman VL, Wang Q, Pandite LN, et al. Incidence and management of hepatic toxicity in pazopanib-treated patients. Abstract and poster presentation at 35th European Society of Medical Oncology Congress, Milan, October Poster 904P. Votrient (pazopanib) Summary of Product Characteristics, January 2013. Goodman VL, Wang Q, Pandite LN, Watkins PB. Abstract and poster presentation at 35th European Society of Medical Oncology Congress, Milan, October Poster 904P. Sternberg CN et al. J Clin Oncol 2010; 28:

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), including1,2 Mucositis Fatigue Hand–foot syndrome (HFS) Even non-severe mucositis and fatigue can negatively impact the QoL of patients2 Recognition and prompt management of adverse events are important to avoid unnecessary dose reductions that may negatively impact treatment efficacy1 Despite efficacy in this setting, the toxicities observed with some tyrosine kinase inhibitors remain a challenge for some patients and can affect patients’ daily functioning and/or impact on their quality of life.1-5 Hand-foot syndrome is a frequent and often debilitating condition2 whilst severe oral mucositis/stomatitis can cause profound pain and oral function impairment.6 Fatigue and/or asthenia are also common problems and may be exacerbated by the presence of hypothyroidism or anaemia.7,8 Pyle L, Beirne D, Bird J, et al. Managing the side effects of sunitinib: a guide to empowering the patients. Cancer Nursing Practice 2008; 7: Schwandt A, Wood LS, Rini B, Dreicer R. Management of side effects associated with sunitinib therapy for patients with renal cell carcinoma. OncoTargets and Therapy 2009; 2: Kollmannsberger C, Soulieres D, Wong R, et al. Sunitinib therapy for metastatic renal cell cancer: recommendations for management of side effects. Can Urol Assoc J 2007; 1: s41-54. Hutson TE, Figlin RA, Kuhn JG, Motzer RJ. Targeted therapies for metastatic renal cell carcinoma: an overview of toxicity and dosing strategies. Oncologist 2008; 13: Porta C, Paglino C, Imarisio I, Bonomi L. Uncovering Pandora's vase: the growing problem of new toxicities from novel anticancer agents. The case of sorafenib and sunitinib. Clin Exp Med 2007; 7: Cheng KKF, Leung SF, Liang RHS, et al. Severe oral mucositis associated with cancer therapy: impact on oral functional status and quality of life. Support Care Cancer 2009; published online 15 November 2009. Torino F, Corsello SM, Longo R, Barnabei A, Gasparini G. Hypothyroidism related to tyrosine kinase inhibitors: an emerging toxic effect of targeted therapy. Nat Rev Clin Oncol 2009; 6: Larkin JMG, Pyle LM, Gore ME. Fatigue in renal cell carcinoma: The hidden burden of current targeted therapies. Oncologist 2010; 15: Hutson et al. Oncologist 2008;13:1084–96. Porta and Szczylik. Cancer Treat Rev 2009;35:297–307.

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 severity1 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 Fatigue is common among patients with cancer (estimated to affect at least 70% of patients) and may be partly symptomatic of the disease itself and/or partly drug-induced.1 Fatigue is a multifaceted, subjective symptom and can impair multiple aspects of daily functioning and quality of life. Patients may associate fatigue with an overall lack of energy, cognitive impairment, somnolence, mood disturbance, or muscle weakness.1 In clinical trials, fatigue is commonly graded using the National Cancer Institute Common Toxicity Criteria (NCI-CTC) and ranges from grade 1, whereby fatigue is greater than at baseline but with no impact on daily living, to grade 4, whereby patients are bedbound or experience severe fatigue-related disability.2 Moderate fatigue (NCI-CTC grade 2), which is defined as a reduction in performance status (by one ECOG level) or difficulties in carrying out daily activities 2, can place considerable burden on patients when symptoms persist over time. Indeed, patients report that fatigue is the longest lasting and most intrusive side effect of chemotherapy, persisting longer than pain, nausea, and depression, and having a greater effect on daily life.1 Persistent fatigue can impair multiple aspects of daily functioning and quality of life, including simple day-to-day physical activities, that impact on patients’ ability to care for themselves. Reduced emotional and mental functioning, with feelings of hopelessness, isolation, lack of motivation, sadness, and frustration, and negative effects on social activities are also commonly reported.1 Thus, management of fatigue is recognised as an important component of care for patients with cancer. Larkin JMG, Pyle LM, Gore ME. Fatigue in renal cell carcinoma: The hidden burden of current targeted therapies. Oncologist 2010; 15: NCI CTCAE 2009 version 4.0 NCI CTCAE 2009 version 4.0

Management of fatigue Fatigue affects % of cancer patients with varying degrees of severity1 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 Fatigue is one of the most common symptoms associated with cancer (estimated to affect at least 70% of patients with cancer).1 The causes of fatigue in patients with cancer are multifactorial and interrelated, although the precise underlying pathophysiology of the development of fatigue has yet to be elucidated.1 Fatigue can arise as a result of the cancer itself or as a side effect of cancer treatment.1 Overall, fatigue was reported as an AE in 24% of patients treated with Votrient in the clinical trials in advanced RCC (n=586), with only 3% reporting grade 3 events and no grade 4 events reported.2 Comorbid conditions can also contribute to the development of fatigue and include anaemia, hypothyroidism, depression and sleep disorders.1 Before initiating treatment, all patients should be advised that they may feel tired and should report it at the earliest opportunity.3 Management of fatigue is primarily supportive; however, it is important to identify correctable causes which may also contribute to fatigue, such as anaemia and hypothyroidism. Patients should be assessed for signs and symptoms of clinical depression and appropriate treatment measures should be introduced to optimise emotional and social support with pharmacologic treatment introduced when necessary.3,4 Nurses can offer practical advice on management strategies for minimising the impact of fatigue. These include: Take regular, light exercise Alternate periods of rest and activity Try to maintain a normal sleep pattern, for example, minimise sleep during the day Use relaxation techniques, for example tapes, imagery, breathing, hypnotherapy Pursue hobbies and interests as a means to distract themselves from their feelings of fatigue Ensuring proper nutrition and prevention of malnutrition, anorexia, and dehydration may also help reduce fatigue.3 Despite these interventions, dose reductions or treatment delays may be warranted in some patients to allow them to recover their quality of life and performance status.3,4 Larkin JMG, Pyle LM, Gore ME. Fatigue in renal cell carcinoma: The hidden burden of current targeted therapies. Oncologist 2010; 15: Votrient (pazopanib) Summary of Product Characteristics, January 2013. Pyle L, Beirne D, Bird J, et al. Managing the side effects of sunitinib: a guide to empowering the patients. Cancer Nursing Practice 2008; 7: Schwandt A, Wood LS, Rini B, Dreicer R. Management of side effects associated with sunitinib therapy for patients with renal cell carcinoma. OncoTargets and Therapy 2009; 2: 1. National Comprehensive Cancer Network. Cancer-Related Fatigue, Version Available at: (Accessed May 2011) GlaxoSmithKline. Votrient (pazopanib) Summary of Product Characteristics, January Pyle L et al. Cancer Nursing Practice 2008; 7:

Even low-grade oral mucositis can have a negative effect on everyday activities and QoL of patients
Symptoms1,2 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 severity1-3 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 Oral changes associated with tyrosine kinase inhibitors include mouth sensitivity/tender mouth, and functional and clinical stomatitis.1 Symptoms associated with oral mucositis include ulceration; altered taste; pain/burning sensation in the mouth and/or throat; chewing, swallowing, and speaking difficulties; halitosis; dry mouth; reduction in saliva production etc.2,3 Oral microorganisms (e.g. Candida albicans) may also play a role in aggravating the condition. Cancer therapy-related oral mucositis is frequently described as the most significant, debilitating and distressing complication associated with cancer therapy.3 Mucositis can also occur throughout the digestive tract and patients may complain of gastrointestinal problems such as bloating or abdominal pain, or sores in the anus. Severe oral mucositis has been shown to cause profound pain and oral functional incapability (e.g. ulcers so severe that it renders patients unable to eat or drink) and clinical significant impairment of QoL.2 The exact pathophysiology underling oral mucositis is not fully understood. Evidence is building that the process of oral mucositis involves far more than just the epithelium, but includes multiple cellular processes of the submucosa as well.3 Schwandt A, Wood LS, Rini B, Dreicer R. Management of side effects associated with sunitinib therapy for patients with renal cell carcinoma. OncoTargets and Therapy 2009; 2: 51-61 Cheng KKF, Leung SF, Liang RHS, et al. Severe oral mucositis associated with cancer therapy: impact on oral functional status and quality of life. Support Care Cancer 2009; published online 15 November 2009. Redding SW. Cancer-therapy related oral mucositis. J Dent Educ 2005; 69 (8): Lalla et al. Dent Clin North Am 2008; 52; 61– Naidu et al. Neoplasia 2004; 6: 423– NCI CTCAE 2009 version 4.0

Management of mucositis/stomatitis1
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 The incidence of grade 3/4 mucositis/stomatitis associated with Votrient treatment appears to be low. Overall, only 4% of patients treated with Votrient in the advanced RCC clinical trials (n=586) experienced stomatitis and mouth ulceration, with less than 1% reporting grade 3 events and no grade 4 events reported.1 Oral care changes should include gentle brushing of teeth with toothpaste and mouthwash which are non-alcohol based, such as paediatric toothpaste.2 To relieve the painful symptoms of oral mucositis patients can be advised to gargle with soluble paracetamol.3 Products such as Bonjela or Orobase can help to sooth the pain from ulcers, and lip balms and creams may help to prevent cheilitis. Artificial saliva spray can help to relieve a dry mouth.3 Gelclair is a prescription mouth gel approved for the management and relief of pain caused by mouth sores.3 It works by forming a barrier that protects the nerve endings that cause pain. Antimicrobial agents should be considered for either fungal or bacterial infections (e.g. Canesten for oral thrush).2,3 It is also important to avoid alcohol, tobacco and foods that may cause irritation in the mouth, such as citrus fruit or spicy foods. Patients should be advised to eat soft foods where possible, to eat little and often and keep fluid intake up. Cool drinks sipped with a straw are preferable to hot drinks.3 Votrient (pazopanib) Summary of product characteristics, January 2013. Schwandt A, Wood LS, Rini B, Dreicer R. Management of side effects associated with sunitinib therapy for patients with renal cell carcinoma. OncoTargets and Therapy 2009; 2: Pyle L, Beirne D, Bird J, et al. Managing the side effects of sunitinib: a guide to empowering the patients. Cancer Nursing Practice 2008; 7: Pyle L et al. Cancer Nursing Practice 2008; 7: 2. GlaxoSmithKline. Votrient (pazopanib) Summary of Product Characteristics, January

Lacouture et al. Oncologist 2008; 13: 1001–11.
Low-severity hand-foot skin reactions can negatively impact on patients’ daily activities and QoL Grade 1 Symptoms1 Numbness, tingling, burning, redness Erythema Swelling Moist desquamation Ulceration, blistering Severe pain of hands and/or feet Levels of severity1,2 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 Grade 2 Grade 3 Hand-foot syndrome (HFS), also known as palmar plantar erythrodysaethesia (PPE) is a dermatological condition that has been seen with TKI therapy involving painful blister and callus formation of areas which are subjected to pressure or friction, such as the palms, thumbs and fingers, and soles of feet. 1 Reactions may also occur on other regions of the body that experience friction, such as the armpits. Patients may also experience erythema of the soles of the feet and palms of the hands; parasthesiae, tingling, and burning; tenderness; dry and /or cracked skin; desquamation; oedema; and increased skin sensitivity.1,2 The severity of the painful calluses can interfere with the patient’s ability to maintain their normal schedule of activities and lead to a decline in function and quality of life; in severe cases, patients are unable to bear weight on their feet secondary to pain.1,2 Schwandt A, Wood LS, Rini B, Dreicer R. Management of side effects associated with sunitinib therapy for patients with renal cell carcinoma. OncoTargets and Therapy 2009; 2: Pyle L, Beirne D, Bird J, et al. Managing the side effects of sunitinib: a guide to empowering the patients. Cancer Nursing Practice 2008; 7: Lacouture et al. Oncologist 2008; 13: 1001–11. NCI CTCAE 2009 Version 4. CTCAE_4.02_ _QuickReference_5x7.pdf

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 HFS reactions appear to be an infrequent complication of Votrient treatment. Overall, 7% of patients treated with Votrient in the advanced RCC clinical trials (n=586) experienced stomatitis and mouth ulceration, with 1% reporting grade 3 events and no grade 4 events reported.1 Hand/foot syndrome is preventable if patients are adequately educated, and easily treated if identified early enough. Patients should be encouraged to examine their skin regularly and promptly discuss any changes, however minor, with the nurse or doctor so that therapeutic management can be initiated before dose reduction or therapy discontinuation becomes necessary.2,3 The condition is usually more pronounced in hot climates and on the feet of active people. 3 Patients can be given the following practical advice:3 Visit a chiropodist/podiatrist before and during treatment (a non-blade treatment should be used if possible) Keep skin well moisturised with an emollient cream Use cream containing urea to soften areas of skin with hard calluses to reduce risk of skin cracking Use a sunscreen with a sun protection factor (SPS) of 30 or higher to protect the skin against the sun Keep skin cool when possible, and avoid exposure to heat e.g. hot baths, saunas, sitting in front of a fire Bathe in tepid water containing Epsom salts (magnesium sulphate) Protect the skin against irritants, for example, use gloves when washing up Wear cotton socks and low-heeled, soft, well cushioned shoes if footwear is needed; otherwise keep feet uncovered – bare feet or flip-flops Avoid tight-fitting shoes or jewellery on the hands or feet Use pressure-relieving pads/gel inserts, which can be particularly soothing if kept in the fridge Minimise activities that cause pressure or friction on the hands, such as the use of household tools (e.g. knives, screwdrivers or gardening tools), or on the feet, such as jogging Maintain skin integrity and protect broken areas Leave blistered skin to heal to protect the new skin forming beneath Votrient (pazopanib) Summary of Product Characteristics, January 2013. Pyle L, Beirne D, Bird J, et al. Managing the side effects of sunitinib: a guide to empowering the patients. Cancer Nursing Practice 2008; 7: Schwandt A, Wood LS, Rini B, Dreicer R. Management of side effects associated with sunitinib therapy for patients with renal cell carcinoma. OncoTargets and Therapy 2009; 2: Pyle L et al. Cancer Nursing Practice 2008; 7: GlaxoSmithKline. Votrient (pazopanib) Summary of Product Characteristics, January 2013.

Managing other gastrointestinal side effects
Nausea & vomiting Nausea and vomiting are common features of TKI therapy1,2 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 odours1,3 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 TKIs1 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 Nausea and vomiting are common features of TKI therapies. These symptoms can be distressing and debilitating to patients if prolonged or severe, resulting in dehydration and malnutrition if not treated.1 In the clinical trials, 27 and 15% of patients treated with Votrient for advanced RCC (n=586) were reported to experience any grade of nausea and vomiting, respectively (grade 3 or 4 events were reported in <1% and 1% of patients, respectively).2 Consequently, patient weight and signs of anorexia should be monitored during treatment. To help control these symptoms, patients should be encouraged to eat and drink foods they can tolerate, and to eat small regular servings of food rather than three large meals a day. Patients should be encouraged to avoid exposure to strong odours, and for more severe cases of nausea and vomiting anti-emetics (such as metoclopramide) may be required. Patients may experience taste alterations (dysgeusia) in association with Votrient therapy, which can result in a loss of appetite for which pineapple chunks may be beneficial. Patients have also been reported to experience dyspepsia, flatulence and bloating in association with TKI treatment. In more severe cases, pharmacological intervention with a proton pump inhibitor may be considered.3** ** 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 information2 Morrow GR. Chemotherapy-related nausea and vomiting: etiology and management. CA: A Cancer Journal for Clinicians 1989; 39: Votrient (pazopanib) Summary of Product Characteristics, January 2013. Schwandt A, Wood LS, Rini B, Dreicer R. Management of side effects associated with sunitinib therapy for patients with renal cell carcinoma. OncoTargets and Therapy 2009; 2: ** 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 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.

Managing thyroid function
Thyroid dysfunction has been observed with TKIs - often under-diagnosed but treatable1,2 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 dysfunction3 (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 A number of studies have identified thyroid dysfunction as an effect of sunitinib and sorafenib1,2 - it is a treatable but often under-diagnosed side effect .3 The incidence of hypothyroidism occurring in association with Votrient treatment appears to be low (reported as an AE in 4% patients in the advanced RCC clinical trials, n=586; no grade 3/4 events were observed).3 Baseline laboratory measurement of thyroid function is recommended and patients with hypothyroidism should be treated as per standard medical practice prior to the start of Votrient treatment.4 All patients should be observed closely for signs and symptoms of thyroid dysfunction (e.g. fatigue, oedema, dry skin, shortness of breath and feeling cold) on Votrient treatment.4 Laboratory monitoring of thyroid function should be performed periodically and managed as per standard medical practice.4 If signs of hypothyroidism develop, patients should be treated with thyroxine. Once treated, patients generally take about a month to recover.3 Schwandt A, Wood LS, Rini B, Dreicer R. Management of side effects associated with sunitinib therapy for patients with renal cell carcinoma. OncoTargets and Therapy 2009; 2: Shepard DR, Garcia JA. Toxicity associated with long-term use of targeted therapies in advanced renal cell carcinoma. Expert Rev Anticancer Ther 2009; 9: Pyle L, Beirne D, Bird J, et al. Managing the side effects of sunitinib: a guide to empowering the patients. Cancer Nursing Practice 2008; 7: Votrient (pazopanib) Summary of Product Characteristics, January 2013. Schwandt A et al. OncoTargets and Therapy 2009:2 51– Pyle L et al. Cancer Nursing Practice 2008; 7: GlaxoSmithKline. Votrient (pazopanib) Summary of Product Characteristics, January 2013.

Izzedine H et al. Eur J Cancer 2010; 46: 439-48.
Managing proteinuria Proteinuria is known to occur with VEGF inhibitors1 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 recommended2 Patients should be monitored for worsening proteinuria2 Votrient should be discontinued if the patient develops grade 4 proteinuria2 Proteinuria is known to occur with agents inhibiting the vascular endothelial growth factor and has been observed in advanced RCC patients treated with TKIs.1 Less than 10% of Votrient-treated patients (n=586) were reported to experience any grade of proteinuria (grade 3 or 4 events, <1%) in the clinical trials in advanced RCC.2 Baseline and periodic urinanalysis during Votrient treatment is recommended and patients should be monitored for worsening proteinuria. Votrient should be discontinued if the patient develops Grade 4 proteinuria.2 Izzedine H, Massard C, Spano JP, et al. VEGF signalling inhibition-induced proteinuria: Mechanisms, significance and management. European Journal of Cancer 2010; 46: Votrient (pazopanib) Summary of Product Characteristics, January 2013. Izzedine H et al. Eur J Cancer 2010; 46: 2. GlaxoSmithKline. Votrient (pazopanib) Summary of Product Characteristics, January 2013.

Managing hair & skin colour changes
Hair and skin colour changes have been observed with TKIs1,2 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 Hair and skin discolouration, including greying of the hair and depigmentation of the skin and eyes, can be experienced by patients being treated with TKIs.1 This is thought to be due to inhibition of c-Kit as c-Kit plays an important role in melanocyte / pigmented cell proliferation.2 Hair colour changes (all grades) were reported in 39% of patients treated with Votrient in the RCC clinical trials (grade 3/4 events, <1%).3 It can also affect body hair, eyelashes / eyebrows. There have also been case reports of skin depigmentation (lightening of the skin).2 Patients should be forewarned about the possibility of hair colour changes and reassured that this is a harmless side effect.4 There are few interventions to suggest other than the use of hair dyes, provided they are not too harsh, and that the scalp is carefully monitored for reactions. 4 These changes generally reverse on discontinuation of treatment.5 Lee WJ, Lee JL, Chang SE, et al. Cutaneous adverse effects in patients treated with the multitargeted kinase inhibitors sorafenib and sunitinib. British Journal of Dermatology 2009: 161: Sideras K, Menefee ME, Burton JK, et al. Profound hair and skin hypopigmentation in an African American woman treated with the multi-targeted tyrosine kinase inhibitor pazopanib. J Clin Oncol 2010; 28: Votrient (pazopanib) Summary of Product Characteristics, January 2013. Pyle L, Beirne D, Bird J, et al. Managing the side effects of sunitinib: a guide to empowering the patients. Cancer Nursing Practice 2008; 7: Schwandt A, Wood LS, Rini B, Dreicer R. Management of side effects associated with sunitinib therapy for patients with renal cell carcinoma. OncoTargets and Therapy 2009; 2: Schwandt A et al. OncoTargets and Therapy 2009:2 51–61 Pyle L et al. Cancer Nursing Practice 2008; 7: 42. 3. GlaxoSmithKline. Votrient (pazopanib) Summary of Product Characteristics, January 2013.

Managing haematological side effects
Haematological toxicities (neutropenia, anaemia, thrombocytopenia) have been observed with TKIs1,2 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 receptor3 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 healed2 Myelosuppression has been observed in clinical studies of TKIs and is probably reflective of activity against non-target kinases such as Flt-3.1 Numerous consequences can occur as a result of myelosuppression, the most serious of which include increased risks of infection and bleeding as a result of neutropenia and thrombocytopenia.2 The incidence of grade 3 or 4 haematological toxicities observed in the clinical trials of Votrient in advanced RCC was low (0-4%)3,4, and may be attributed to the fact that Votrient is not a potent inhibitor of Flt-3.4 Complete blood counts should be performed routinely at clinic visits. Blood counts usually recover with drug interruptions. If the same toxicity re-occurs, a dose reduction should be considered.5 Patients receiving angiogenesis inhibitors are at risk of poor surgical wound healing and Votrient should be held in the peri-operative period.5 The half-life of Votrient is 31 hours, thus discontinuation of Votrient for 1 week, or approximately 5 half-lives, prior to major surgical procedures would allow time for adequate drug elimination in order to prevent interference with angiogenesis, haemostasis, and wound healing.3,5 The decision to resume Votrient after surgery should be based on clinical judgement of adequate wound healing. Votrient should be discontinued in patients with wound dehiscence.3 Kumar R, Crouthamel MC, Rominger DH, et al. Myelosuppression and kinase selectivity of multikinase angiogenesis inhibitors. British Journal of Cancer 2009; 101: Carey PJ. Drug-induced myelosuppression: diagnosis and management. Drug Safety 2003; 26: Votrient (pazopanib) Summary of Product Characteristics, January 2013. Sternberg CN, Davis ID, Mardiak J, et al. Pazopanib in locally advanced or metastatic renal cell carcinoma: Results of a randomised phase III trial. J Clin Oncol 2010; 28: Schwandt A, Wood LS, Rini B, Dreicer R. Management of side effects associated with sunitinib therapy for patients with renal cell carcinoma. OncoTargets and Therapy 2009; 2: Schwandt A et al. OncoTargets and Therapy 2009:2 51–61 2. GlaxoSmithKline. Votrient (pazopanib) Summary of Product Characteristics, January 2013. 3. Sternberg et al. J Clin Oncol 2010; 28:

Managing cardiac toxicities (1)
Cardiotoxicity has been observed with TKIs, although the precise mechanism by which this occurs is not fully understood1 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 prolongation1 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 Cardiotoxicity has been observed with the use of TKIs, although the precise mechanism by which this occurs is not fully understood, and can result in serious consequences such as congestive heart failure and left ventricular dysfunction.1 Cardiac disorders such as bradycardia, cardiac dysfunction, QT prolongation, myocardial infarction and myocardial ischaemia have been reported infrequently in the Votrient RCC clinical studies (grade 3 or 4 events, <1%).2-4 There were no reported cases of treatment-related congestive heart failure or left ventricular ejection (LVEF) decline decline in the pivotal phase III trial.3,4 However, it should be noted that that ECHO/MUGA scans were not performed per-protocol to collect LVEF data and only when clinically indicated. Votrient should be used with caution in patients with a history of QT interval prolongation, in patients taking antiarrythmics or other medicinal products that may prolong QT interval and those with relevant pre-existing cardiac disease. When using Votrient, base line and periodic monitoring of electrocardiograms and maintenance of electrolytes (e.g. calcium, magnesium, potassium) within normal range is recommended.2 Votrient should be used with caution in patients who are at increased risk for myocardial infarction, ischaemic stroke, and transient ischaemic attack. A treatment decision should be made based upon the assessment of individual patient's benefit/risk. 2 Porta C, Szczylik C. Tolerability of first-line therapy for metastatic renal cell carcinoma. Cancer Treatment Reviews 2009; 35: Votrient (pazopanib) Summary of Product Characteristics, January 2013. Sternberg CN, Davis ID, Mardiak J, et al. Pazopanib in locally advanced or metastatic renal cell carcinoma: Results of a randomised phase III trial. J Clin Oncol 2010; 28: Sternberg CN, Hawkins RE, Szczylik C, et al. Randomized, double-blind phase III study of pazopanib in patients with advanced/metastatic renal cell carcinoma (mRCC): final overall survival (OS) results. Abstract and presentation at 35th European Society of Medical Oncology congress, October Abstract no.: LBA22. Schwandt A et al. OncoTargets and Therapy 2009:2 51–61 2. GlaxoSmithKline. Votrient (pazopanib) Summary of Product Characteristics, January 2013. 3. Sternberg et al. J Clin Oncol 2010; 28:

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 study3 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 studied2 The risks and benefits of Votrient should be considered before beginning therapy in patients who have pre-existing cardiac dysfunction1 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 dysfunction1 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 Schwandt A et al. OncoTargets and Therapy 2009:2 51–61 2. GlaxoSmithKline. Votrient (pazopanib) Summary of Product Characteristics, January 2013. 3. Sternberg et al. J Clin Oncol 2010; 28:

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 action1,2 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 placebo3 Low incidence of Grade 3 or 4 fatigue, hand- foot syndrome and mucositis/stomatitis3,4 Convenient once-daily oral dosing 800 mg once daily without food Votrient is available in 200 mg and 400 mg tablets. 200 mg 400 mg 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.

Questions Patients May Ask

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.

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.

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.

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.

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.

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.

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.

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.

Prescribing Information (Please refer to full SmPC before prescribing)
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 H2 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 2013. 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 <30ml/min. Hepatic impairment: Severe hepatic impairment - Not recommended. Undertake with caution and close monitoring in mild/moderate impairment. Mild impairment - 800mg once daily; Moderate impairment - 200mg once daily. Elderly: Limited data in patients ≥ 65 yrs. Paediatrics: Not to be used in children <2 yrs. Safety & efficacy not established in children 2-18 yrs; no data available. Contra-indications Hypersensitivity to active substance or excipients. Special Warnings and Precautions Hepatic effects: Hepatic failure reported during pazopanib use; increases in serum transaminases (ALT, AST) and bilirubin also observed. Monitor liver function before initiation of treatment and ≥once every 4 weeks for first 4 months, and periodically thereafter. If transaminases ≤8xULN, continue pazopanib with weekly monitoring until they return to ≤Grade 1. If transaminases >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 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.

NOTE FOR HEALTHCARE PROFESSIONAL

Similar presentations

Presentation on theme: "NOTE FOR HEALTHCARE PROFESSIONAL"— Presentation transcript:

Similar presentations

About project

Feedback

Log in

Auth with social network:

NOTE FOR HEALTHCARE PROFESSIONAL

Similar presentations

Presentation on theme: "NOTE FOR HEALTHCARE PROFESSIONAL"— Presentation transcript:

Similar presentations

About project

Feedback