1 / 70

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.

marcy
Download Presentation

NOTE FOR HEALTHCARE PROFESSIONAL

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. NOTE FOR HEALTHCARE PROFESSIONAL This presentation has been provided to you upon request. If presenting this to other healthcare professionals, GSK advises that you use the presentation in full to ensurea fair balance of information, both efficacy and safety. Please delete this slide before presenting. UK/PAZ/0031/13 March2013

  2. ® 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

  3. 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 outcomeof the head-to-head study (COMPARZ) of Votrient versus sunitinib. 1. GlaxoSmithKline. Votrient (pazopanib) Summary of Product Characteristics, January 2013.

  4. 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-VEGFtherapies Everolimus4  Recommended by NICE  Not recommended by NICE • NICE TA 169. March 2009. 2. NICE TA 178. August 2009.3. NICE TA 215 Feb 2011. 4. NICE TA 219 April 2011.

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

  6. Votrient Scottish Medicines Consortium AdviceNo. 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. 1. Scottish Medicines Consortium. Pazopanib 200mg, 400mg film-coated tablets (Votrient).Advice no. 676/11. March 2011.

  7. Votrient mode of action - a potent and selective multi-targeted TKI • Votrient binds to the cytoplasmic kinase domain of VEGFR-1, -2 and -3; PDGFR-α and –β; and c-Kit; with minimal impact on Flt-3.1 • VEGFR regulates angiogenesis2 • PDGFR regulates angiogenesis and proliferation of some tumour cells3,4 • c-Kit regulates cellular proliferation, survival and metastasis5 1. Kumar et al. Mol Cancer Ther 2007; 6: 2012–21. 2. Kerbel. N Engl J Med 2008; 358: 2039–49. 3. Yu et al. J Biochem Mol Biol 2003; 36: 49–59. 4. Homsi and Daud. Cancer Control 2007; 14: 285–94. 5. Demetri. SeminOncol 2001; 28(5 Suppl 17): 19–26.

  8. Phase III Trial of Pazopanib in Locally Advanced and/or Metastatic Renal Cell Carcinoma Cora N. Sternberg,1 Cezary Szczylik,2 Eun S. Lee,3Pamela Salman,4 Jozef Mardiak,5 Ian D. Davis,6Lini Pandite,7 Mei Chen,8 Lauren McCann,8Robert 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 Study VEG105192. Presentation at ASCO 2009.Stenberg CN, et al. J ClinOncol 2010; 28(6): 1061-1068.

  9. VEG105192 study design Patients with advancedRCC (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) Option to receive Votrient via an open-label study immediately upon disease progression Stenberg et al. J ClinOncol 2010; 28(6): 1061-1068.

  10. Votrient Placebo Progression-free survival (overall study population)by independent review Median PFS (months) 1.0 Votrient 9.2 4.2 Placebo 0.46 (0.34, 0.62) Hazard ratio (95% CI) <0.0001 p value (1-sided) 0.8 54%reduction in risk of progressionor death with Votrient treatment compared with placebo 0.6 Proportion progression-free 0.4 0.2 0.0 0 5 10 15 20 Time (month) Number at risk, n Votrient Placebo 15938 7614 292 6 290145 Stenberg et al. J ClinOncol 2010; 28(6): 1061-1068.

  11. Progression-free survival: (treatment-naïve sub-population) by independent review 1.0 Median PFS (months) Votrient 11.1 2.8 Placebo 0.8 0.40 (0.27, 0.60) Hazard ratio (95% CI) <0.0001 p value (1-sided) 60%reduction in risk of progressionor death with Votrient treatment compared with placebo 0.6 Proportion progression-free 0.4 0.2 Votrient Placebo 0.0 0 5 10 15 20 Time (month) Number at risk, n Votrient Placebo 155 78 84 22 39 7 11 2 1 Stenberg et al. J Clin Oncol 2010; 28(6): 1061-1068.

  12. Median progression-free survival (PFS) in pivotal trial (VEG105192)1,2 • Votrient (pazopanib) Summary of Product Characteristics, January 2013. • Sternberg et al. J ClinOncol 2010; 28: 1061-1068.

  13. Overall response rate by independent review Sternberg CN, et al. J ClinOncol 2010; 28: 1061-1068.

  14. 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.

  15. Most common AEs regardless of causality (≥10%)1 (15 March 2010 cut-off) • 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 2010. Abstract No. LBA22.

  16. Selected class effects associated with VEGFR TKI inhibitors1* (15 March 2010 cut-off) • *AEs with incidence of <10% in the Votrient arm regardless of causality. 1. Sternberg C et al. Presentation at ESMO 2010. Abstract No. LBA22.

  17. Laboratory abnormalities1(15 March 2010 cut-off) 1. Sternberg C et al. Presentation at ESMO 2010. Abstract No. LBA22.

  18. No clinically important differences between Votrient and placebo in terms of impact on Quality of Life1 EORTC QLQ C30 Global Health Status/QoL scores Votrient 20 Placebo 10 MID=5 0 Adjusted means ± SE MID=5 –10 –20 Baseline Week 6 Week 12 Week 18 Week 24 Week 48 Visit Patients with data, nVotrientPlacebo 290145 243110 219 81 191 61 164 49 9624 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).

  19. ® Key considerationsbefore prescribing

  20. Patient suitability for Votrient • Advanced RCC • Adults (≥ 18 years) • ECOG Performance Status 0 or 1 (NICE guidance)1 • Treatment-naïve or cytokine pre-treated • Consider co-morbidities • Contraindicated in those with hypersensitivity to active substance/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 • NICE. Pazopanib for the first-line treatment of advanced renal cell carcinoma. Final appraisal guidance no. 215. February 2011 • GlaxoSmithKline. Votrient (pazopanib) Summary of Product Characteristics, January 2013.

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

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

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

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

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

  26. 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. GlaxoSmithKline. Votrient (pazopanib) Summary of Product Characteristics. January 2013.

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

  28. Potential drug & food interactions with Votrient(2) 1 *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.

  29. 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.

  30. Overview of tests recommended before and during Votrient treatment (as per SPC)1* * 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.

  31. 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 orderto manage adverse reactions2 • The continuous dosing schedule of TKI agents, such as Votrient, may provide sustained anti-tumour activity3 • Sternberg et al. J ClinOncol 2010; 28: 1061-68. • GlaxoSmithKline. Votrient (pazopanib) Summary of Product Characteristics, January 2013 3. Liu et al. J ClinOncol 2008;26(18S):Abstract 3515.

  32. 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 200 mg 400 mg GlaxoSmithKline. Votrient (pazopanib) Summary of Product Characteristics. January 2013.

  33. 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) • GlaxoSmithKline. Votrient (pazopanib) Summary of Product Characteristics, January 2013.

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

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

  36. Grading of toxicities • Common Terminology Criteria for Adverse Events (CTCAE)1 • Grades often used to determine dose adjustments Some toxicities are easyto grade e.g. Diarrhoea Vomiting Laboratory investigations Some toxicities are not easyto grade e.g. Fatigue Pain Taste disturbance 1. NCI CTCAE 2009 version 4.0 http://www.acrin.org/Portals/0/Administration/Regulatory/CTCAE_4.02_2009-09-15_QuickReference_5x7.pdf

  37. 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 • GlaxoSmithKline. Votrient (pazopanib) Summary of Product Characteristics, January 2013. • Launay-Vacher V, Deray G. Anticancer Drugs 2009; 20: 81–82.

  38. 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 Persistently elevated BP (140/90 mmHg) or severe arterial hypertension *Titration of monotherapyand/or combination of different antihypertensive agents . Discontinue Votrient treatment & continue antihypertensive drug therapy GlaxoSmithKline. Votrient (pazopanib) Summary of Product Characteristics. January 2013.

  39. Management of diarrhoea associated with Votrient therapy • Approximately 50% of patients treated with Votrient in the aRCC trials experienced 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 • GlaxoSmithKline. Votrient (pazopanib) Summary of Product Characteristics, January 2013. • Pyle L et al. Cancer Nursing Practice 2008; 7: 42.

  40. Recommendations for managing diarrhoea associated with Votrient If a patient experiences grade 1 or 2 diarrhoea with complicating features (such as cramping, severe nausea/vomiting, decreased performance status, fever, sepsis, grade 3 or 4 neutropenia, dehydration) then manage as if a grade 3 or 4 event • NCI CTCAE 2009 version 4.0 http://www.acrin.org/Portals/0/Administration/Regulatory/CTCAE_4.02_2009-09-15 • QuickReference_5x7.pdf; • 2. GlaxoSmithKline. Votrient (pazopanib) Summary of Product Characteristics, January 2013.

  41. 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 ALT = alanineaminotransferase; ULN = upper limit of normal GlaxoSmithKline. Votrient (pazopanib) Summary of Product Characteristics. January 2013.

  42. Management of liver function in patients receiving Votrient1 • Increase in serum transaminases (ALT, AST) and bilirubinhave been observedin 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 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.

  43. Monitoring and managing liver function elevations1 Monitor serum liver tests PRIOR TO VOTRIENT TREATMENT 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 ANDTBL >2X ULN ALT / AST >8X ULN Continue treatment Direct bilirubin >35% Interrupt until ALT / AST Grade 1 or baseline 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.

  44. Hepatic Toxicity Definitions • General Practice Notebook - a UK medical reference. Available at: http://www.gpnotebook.co.uk/homepage.cfm (Accessed June 2011)

  45. 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%) Outcome data missing N=10 (9%) 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%) • Goodman VL, Wang Q, Pandite LN, Watkins PB. Abstract and poster presentation at 35th European Society of Medical Oncology Congress, Milan, October 2010. Poster 904P. • Sternberg CN et al. J ClinOncol 2010; 28: 1061-1068.

  46. Adverse events of interest associated with tyrosine kinase inhibitors (TKIs) • Despite improved efficacy in the treatment of RCC, TKIs are associated with several side effects that can impact on patients’ quality of life (QoL), 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 • Hutson et al. Oncologist 2008;13:1084–96. • Porta and Szczylik. Cancer Treat Rev 2009;35:297–307.

  47. Symptoms Altered energy levels Attention deficits Sleep disturbance Reduced endurance Listlessness Sluggishness Dizziness Apathy Exhaustion Anxiety Depression Fatigue can have a significant negative effect on everyday activities and QoL of patients • Levels of severity1 • Grade 0 - No symptoms • Grade 1 - Mild, relieved by rest • Grade 2 - Moderate, impacting activitiesof daily living • Grade 3 - Severe, limiting self-care activities of daily living • Grade 4 - Disabling • NCI CTCAE 2009 version 4.0 http://www.acrin.org/Portals/0/Administration/Regulatory/CTCAE_4.02_2009-09-15_QuickReference_5x7.pdf

  48. Management of fatigue • Fatigue affects 70-100% 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 1. National Comprehensive Cancer Network. Cancer-Related Fatigue, Version 1.2009. Available at: http://www.nccn.org/professionals/physician_gls/PDF/fatigue.pdf (Accessed May 2011). 2. GlaxoSmithKline. Votrient (pazopanib) Summary of Product Characteristics, January 2013. 3. Pyle L et al. Cancer Nursing Practice 2008; 7: 42-46.

  49. 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/deteriorationin the sense of taste • Communication/elocution problems • Dehydration/sticky secretionsor saliva • Halitosis • Raw feeling in the throat • Swollen tissues in the mouth • Super-infection, which can leadto 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 • Lalla et al. Dent Clin North Am 2008; 52; 61–77. 2. Naidu et al. Neoplasia 2004; 6: 423–431. 3. NCI CTCAE 2009 version 4.0 http://www.acrin.org/Portals/0/Administration/Regulatory/CTCAE_4.02_2009-09-15_QuickReference_5x7.pdf

  50. Management of mucositis/stomatitis1 • Mucositis/stomatitis appears to be an infrequent complication of Votrient treatmentin 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 Pyle L et al. Cancer Nursing Practice 2008; 7: 42-46. 2. GlaxoSmithKline. Votrient (pazopanib) Summary of Product Characteristics, January 2013 .

More Related