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UK/PAZ/0031/13 March 2013
®
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.
1. GlaxoSmithKline. Votrient (pazopanib) Summary of Product Characteristics, January 2013.
Management of advanced RCC in the UK1-4
Good or intermediate
prognosis
1st-line treatment
Sunitinib1


Bevacizumab+IFN2
Sorafenib2
2nd-line after anti-VEGF
therapies
Everolimus4

Pazopanib3


2nd-line after cytokines

Poor
prognosis
Recommended by NICE
Not recommended by NICE
1. NICE TA 169. March 2009. 2. NICE TA 178. August 2009.
3. NICE TA 215 Feb 2011. 4. NICE TA 219 April 2011.


Temsirolimus2
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.
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.
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
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. 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
Study VEG105192. Presentation at ASCO 2009.
Stenberg CN, et al. J Clin Oncol 2010; 28(6): 1061-1068.
VEG105192 study design
Stratification:
• ECOG PS 0 vs. 1
• Prior nephrectomy
• Rx-naive (n = 233) vs. 1
cytokine failure (n = 202)
Patients with advanced
RCC (N = 435)
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 Clin Oncol 2010; 28(6): 1061-1068.
Progression-free survival (overall study population)
by independent review
Median PFS (months)
Proportion progression-free
1.0
Votrient
Placebo
Hazard ratio (95% CI)
p value (1-sided)
0.8
9.2
4.2
0.46 (0.34, 0.62)
<0.0001
54%
reduction in risk
of progression
or death with
Votrient treatment
compared with
placebo
0.6
0.4
0.2
Votrient
Placebo
0.0
0
5
10
15
20
29
2
6
Time (month)
Number at risk, n
Votrient
Placebo
290
145
159
38
76
14
Stenberg et al. J Clin Oncol 2010; 28(6): 1061-1068.
Progression-free survival: (treatment-naïve subpopulation) by independent review
1.0
Proportion progression-free
Median PFS (months)
Votrient
Placebo
Hazard ratio (95% CI)
p value (1-sided)
0.8
11.1
2.8
0.40 (0.27, 0.60)
<0.0001
0.6
0.4
0.2
Votrient
Placebo
0.0
0
5
10
15
20
11
2
1
Time (month)
Number at risk, n
Votrient
Placebo
60%
reduction in risk
of progression
or death with
Votrient treatment
compared with
placebo
155
78
84
22
39
7
Stenberg et al. J Clin Oncol 2010; 28(6): 1061-1068.
Median progression-free survival (PFS) in pivotal
trial (VEG105192)1,2
Median PFS (months)
Votrient
Placebo
HR (95% CI)
p-value
Overall study
population
(n=290)
9.2
(n=145)
4.2
0.46 (0.34-0.62)
p<0.0000001
Treatment-naive
sub-population
(n=155)
11.1
(n=78)
2.8
0.40 (0.27-0.60)
p<0.0000001
Cytokine pre-treated
sub-population
(n=135)
7.4
(n=67)
4.2
0.54 (0.35-0.84)
p<0.001
1. Votrient (pazopanib) Summary of Product Characteristics, January 2013.
2. Sternberg et al. J Clin Oncol 2010; 28: 1061-1068.
Overall response rate by independent review
Sternberg CN, et al. J Clin Oncol 2010; 28: 1061-1068.
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)
Votrient (n = 290), %
Adverse Event
Placebo (n = 145), %
All Grs
Gr 3
Gr 4
All Grs
Gr 3
Gr 4
Any eventa
93
36
9
74
17
6
Diarrhoea
52
4
<1
9
<1
0
Hypertension
40
4
0
10
<1
0
Hair colour changes
38
<1
0
3
0
0
Nausea
26
<1
0
9
0
0
Anorexia
24
2
0
12
<1
0
Vomiting
21
2
<1
9
2
0
Fatigue
20
2
0
10
1
1
Asthenia
14
3
0
9
0
0
Haemorrhageb
14
1
0
6
<1
0
Abdominal pain
11
2
0
1
0
0
Headache
11
0
0
5
0
0
Proteinuria
Weight decreased
10
2
<1
0
0
0
10
<1
0
3
<1
0
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.
Selected class effects associated with VEGFR TKI
inhibitors1* (15 March 2010 cut-off)
Votrient
(n = 290), %
Placebo
(n = 145), %
All Grades
Grades ≥3
All Grades
Grades ≥3
Mucositis/stomatitis
9
<1
<1
0
Hypothyroidism
7
<1
0
0
Hand-foot syndrome
6
<1
<1
0
Arterial thromboembolic
4
3
0
0
Myocardial dysfunction
<1
<1
<1
<1
Adverse event
*AEs with incidence of <10% in the Votrient arm regardless of causality.
1. Sternberg C et al. Presentation at ESMO 2010. Abstract No. LBA22.
Laboratory abnormalities1 (15 March 2010 cut-off)
Votrient (n = 290), %
Placebo (n = 145), %
All Grs
Gr 3
Gr 4
All Grs
Gr 3
Gr 4
ALT
53
11
2
23
1
0
AST
53
7
<1
19
<1
0
Hyperglycemia
43
<1
0
33
1
0
Hyperbilirubinemia
37
3
<1
11
1
<1
Hypophosphatemia
36
5
0
13
1
0
Hypocalcemia
35
1
1
26
1
<1
Hyponatremia
33
4
1
24
4
0
Hypoglycemia
18
0
<1
3
0
0
Hypokalemia
10
1
<1
2
0
0
Leukopenia
38
<1
0
7
0
0
Neutropenia
36
1
<1
6
0
0
Thrombocytopenia
34
1
<1
5
0
<1
Lymphopenia
34
5
<1
24
1
0
Anaemia
26
2
<1
31
1
<1
Chemistry labs
Haematology labs
1. Sternberg C et al. Presentation at ESMO 2010. Abstract No. LBA22.
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
Adjusted means ± SE
20
Placebo
10
MID=5
0
MID=5
–10
–20
Baseline
Week 6 Week 12 Week 18 Week 24
Week 48
Visit
Patients with data, n
Votrient
290
Placebo
145
243
110
219
81
191
61
164
49
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).
96
24
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
1. NICE. Pazopanib for the first-line treatment of advanced renal cell carcinoma. Final appraisal guidance
no. 215. February 2011
2. 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
1. GlaxoSmithKline. Votrient (pazopanib) Summary of Product Characteristics. January 2013.
Posology and special warnings (2)1
Hepatic impairment & Hepatic effects
Cases of hepatic failure have been reported during Votrient use
Votrient is not recommended in patients with severe hepatic impairment
Use with caution and close monitoring in patients with mild or moderate hepatic impairment
Patients with mild hepatic impairment should be treated with 800mg once daily
A reduced dose of 200 mg once daily is recommended in moderate hepatic impairment
Serum liver tests should be monitored at baseline, at least once every 4 weeks for the first 4
months of treatment, and as clinically indicated with periodic monitoring thereafter.
More frequent monitoring, dose interruption, modification or discontinuation may be
warranted if liver test abnormalities are detected.
Hypertension
Blood pressure should be well controlled prior to initiating Votrient
Patients should be monitored for hypertension within 1 week of starting treatment and
frequently thereafter to ensure blood pressure control
Hypertension should be managed using a combination of anti-hypertensive therapy and dose
modification of Votrient (interruption and re-initiation at a reduced dose based on clinical
judgement)
Events of hypertensive crisis have occurred during clinical studies with Votrient (<1% of
patients)
Votrient should be discontinued if there is evidence of persistently elevated blood pressure
(140/90 mmHg) or if arterial hypertension is severe and persists despite
antihypertensive therapy and Votrient dose reduction
1. GlaxoSmithKline. Votrient (pazopanib) Summary of Product Characteristics. January 2013.
Posology and special warnings (3)1
PRES / RPLS
Posterior reversible encephalopathy syndrome (PRES)/Reversible posterior
leukoencephalopathy syndrome (RPLS) has been reported in association with pazopanib.
PRES/RPLS can present with headache, hypertension, seizure, lethargy, confusion, blindness
and other visual and neurological disturbances, and can be fatal
Patients developing PRES/RPLS should permanently discontinue pazopanib
Cardiac dysfunction/heart failure
The safety and pharmacokinetics of Votrient in patients with moderate to severe heart failure or
those with a below normal left ventricular ejection fraction (LVEF) has not been studied
In clinical trials with pazopanib, events of cardiac dysfunction such as congestive heart failure
and decreased left ventricular ejection fraction have occurred.
The risks and benefits of Votrient should be considered before beginning therapy in patients
who have pre-existing cardiac dysfunction
Baseline & periodic evaluation of LVEF is recommended in patients at risk of cardiac dysfunction
Patients should be carefully monitored for clinical signs or symptoms of congestive heart failure
Interruption of Votrient and/or dose reduction should be combined with treatment of
hypertension in patients with significant reductions in LVEF, as clinically indicated
Thrombotic microangiopathy (TMA)
Thrombotic microangiopathy (TMA) has been reported in clinical trials of pazopanib as
monotherapy, in combination with bevacizumab, and in combination with topotecan
Patients developing TMA should permanently discontinue pazopanib; reversal of effects
of TMA has been observed after pazopanib treatment was discontinued
1. GlaxoSmithKline. Votrient (pazopanib) Summary of Product Characteristics. January 2013.
Posology and special warnings (4)1
Other warnings
Events of pneumothorax have occurred in clinical studies with Votrient in advanced soft
tissue sarcoma. Patients on Votrient should be observed closely for signs and symptoms of
pneumothorax
Venous thromboembolic events (VTEs) including venous thrombosis and pulmonary embolus
have occurred in clinical studies with Votrient (incidence of 2% in RCC studies and 5% in
STS studies)
Use with caution in patients who are at increased risk for arterial thrombotic events, those
with significant risk of haemorrhage, GI perforation or fistula. Votrient is not recommended in
patients with a history of haemoptysis, cerebral or clinically significant GI haemorrhage in the
past 6 months.
Use with caution in patients with a history of QT interval prolongation, those taking
antiarrhythmics or with pre-existing cardiac disease. Baseline and periodic monitoring of
electrocardiograms and maintenance of electrolytes within normal range is recommended.
Votrient may impair wound healing, and should be stopped at least 7 days prior to scheduled
surgery
Hypothyroidism has occurred in clinical studies with Votrient. Baseline and periodic
monitoring is recommended.
Proteinuria has occurred in clinical studies with Votrient. Baseline and periodic urinalysis is
recommended, with discontinuation of Votrient if the patient develops grade 4 proteinuria
Cases of serious infection (with/without neutropenia) have been reported
Combination with other systemic anti-cancer therapies: Safe and effective dose in
combination with pemetrexed or lapatinib has not been established
1. GlaxoSmithKline. Votrient (pazopanib) Summary of Product Characteristics. January 2013.
Posology and special warnings (5)1
Instances where Votrient should be permanently discontinued include:
In patients with re-occurrence of elevated transaminases (>3 x ULN) following treatment
interruption, or with aminotransferases elevations >3 x ULN and bilirubin elevations >2 x
ULN, where direct bilirubin fraction >35%
In patients with persistently elevated blood pressure or if hypertension is severe and persists
despite anti-hypertensive therapy and Votrient dose reduction
In patients with wound dehiscence
In patients with grade 4 proteinuria
In patients developing PRES/RPLS or TMA
Serious adverse events have been associated with Votrient, with the most
important events each being reported in <1% of treated patients
1. GlaxoSmithKline. Votrient (pazopanib) Summary of Product Characteristics. January 2013.
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.
1. 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
Other
Clarithromycin, erythromycin, telithromycin
Itraconazole, ketoconazole, fluconazole, voriconazole, posaconazole
Ritonavir, nelfinavir, amprenavir, saquinavir, indinavir, lopinivir, atazanavir
CYP3A4 substrates
Midazolam, cisapride, quinidine, pimozide
CYP2C8 substrates
Repaglinide, paclitaxel
Verapamil, diltiazem
Fluvoxamine
Cimetidine, aprepitant
Certain citrus and tropical fruit juices (e.g. grapefruit, lime, Seville orange,
star fruit, pomegranate); Amiodarone
1. 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
*If elevated ALT develops with concomitant use of Votrient and statins,
follow liver function management guidelines and discontinue statin
1. 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
1. GlaxoSmithKline. Votrient (pazopanib) Summary of Product Characteristics. January 2013.
Overview of tests recommended before and during
Votrient treatment (as per SPC)1*
Test
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 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
1. GlaxoSmithKline. Votrient (pazopanib) Summary of Product Characteristics. January 2013.
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
1. Sternberg et al. J Clin Oncol 2010; 28: 1061-68.
2. GlaxoSmithKline. Votrient (pazopanib) Summary of Product Characteristics, January 2013
3. 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
200 mg
400 mg
1. 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)
1. 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
Grading of toxicities
Common Terminology Criteria for Adverse Events (CTCAE)1
Grades often used to determine dose adjustments
Some toxicities are easy
to grade e.g.
Diarrhoea
Vomiting
Laboratory investigations
Some toxicities are not easy
to grade e.g.
Fatigue
Pain
Taste disturbance
1. NCI CTCAE 2009 version 4.0 http://www.acrin.org/Portals/0/Administration/Regulatory/CTCAE_4.02_2009-0915_QuickReference_5x7.pdf
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
1. GlaxoSmithKline. Votrient (pazopanib) Summary of Product Characteristics, January 2013.
2. 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
Monitor early (within 1 week)
and frequently thereafter
DURING TREATMENT
Continue Votrient treatment
& initiate antihypertensive
drug therapy
Hypertension
Continue Votrient treatment
& intensify antihypertensive
drug therapy*
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 monotherapy
and/or combination of different
antihypertensive agents
.
Discontinue Votrient treatment & continue
antihypertensive drug therapy
1. 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 diarrhoeainduced 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
1. GlaxoSmithKline. Votrient (pazopanib) Summary of Product Characteristics, January 2013.
2. Pyle L et al. Cancer Nursing Practice 2008; 7: 42.
Recommendations for managing diarrhoea
associated with Votrient
Grade 1
Grade 2
Grade 3
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
Grade 4
Severity of
diarrhoea
(NCI
CTCAE
grade v4)1
Increase of <4 bowel
movements/day over
baseline; mild increase
in ostomy output
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
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)
Life-threatening
consequences ; urgent
intervention indicated
• 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
• Use IV fluids
• Consider hospital admission for patients
at risk of life-threatening conditions
If a patient experiences grade 1 or 2 diarrhoea with complicating features (such as cramping,
severe nausea/vomiting, decreased performance status, fever, sepsis, grade 3 or 4 neutropenia,
dehydration) then manage as if a grade 3 or 4 event
1. NCI CTCAE 2009 version 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.
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
Moderate
Elevation of bilirubin (>35% direct) >1.5 x to 3 x
ULN, regardless of the ALT value
800mg o.d.
Undertake with caution
and close monitoring
200mg o.d.
Severe
Elevation of bilirubin (>35% direct) >3 x ULN,
regardless of the ALT value
Not recommended
ALT = alanine aminotransferase; ULN = upper limit of normal
1. 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
Note: Dosing recommendations for Votrient in patients with pre-existing hepatic impairment
can be found on an earlier slide
1. GlaxoSmithKline. Votrient (pazopanib) Summary of Product Characteristics. January 2013.
Monitoring and managing liver function elevations1
PRIOR TO VOTRIENT
TREATMENT
DURING TREATMENT
Monitor serum liver tests
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
Weekly tests until
ALT Grade 1 or
baseline
YES
NO
Discontinue
Continue
Reintroduce, if
warranted, at lower
dose
Discontinue if ALT
/AST >3X ULN recur
ULN: Upper limit of normal TBL: Total bilirubin level
1. 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 - 2.5 x ULN
>2.5 - 5.0 x ULN
> 5.0 - 20.0 x ULN
> 20.0 x ULN
Alanine
aminotransferase
(ALT)
10 to 50 IU/L
>ULN - 2.5 x ULN
>2.5 - 5.0 x ULN
> 5.0 - 20.0 x ULN
> 20.0 x ULN
Alkaline phosphatase
(ALP)
30 to 200 IU/L
>ULN - 2.5 x ULN
>2.5 - 5.0 x ULN
> 5.0 - 20.0 x ULN
> 20.0 x ULN
Gamma glutamyl
transpeptidase (GGT)
11 to 50 IU/L
(males)
7 to 32 IU/L
(females)
>ULN - 2.5 x ULN
>2.5 - 5.0 x ULN
> 5.0 - 20.0 x ULN
> 20.0 x ULN
Bilirubin
3-17 μmol/L
>ULN - 1.5 x ULN
>1.5 - 3.0 x ULN
> 3.0 - 10.0 x ULN
> 10.0 x ULN
1.General Practice Notebook - a UK medical reference. Available at:
http://www.gpnotebook.co.uk/homepage.cfm (Accessed June 2011)
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%)
1. 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.
2. Sternberg CN et al. J Clin Oncol 2010; 28: 1061-1068.
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
1. Hutson et al. Oncologist 2008;13:1084–96.
2. Porta and Szczylik. Cancer Treat Rev 2009;35:297–307.
Fatigue can have a significant negative effect on
everyday activities and QoL of patients
Levels of severity1
Symptoms
Altered energy levels
Attention deficits
Sleep disturbance
Reduced endurance
Listlessness
Sluggishness
Dizziness
Apathy
Exhaustion
Anxiety
Depression
Grade 0 - No symptoms
Grade 1 - Mild, relieved by
rest
Grade 2 - Moderate,
impacting activities
of daily living
Grade 3 - Severe, limiting
self-care activities of daily
living
Grade 4 - Disabling
1. NCI CTCAE 2009 version 4.0
http://www.acrin.org/Portals/0/Administration/Regulatory/CTCAE_4.02_2009-0915_QuickReference_5x7.pdf
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.
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
1.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_2009-0915_QuickReference_5x7.pdf
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
1.Pyle L et al. Cancer Nursing Practice 2008; 7: 42-46.
2. GlaxoSmithKline. Votrient (pazopanib) Summary of Product Characteristics, January 2013 .
Low-severity hand-foot skin reactions can negatively
impact on patients’ daily activities and QoL
Grade 1
Symptoms1
Levels of severity1,2
Numbness, tingling,
burning, redness
Erythema
Swelling
Moist desquamation
Ulceration, blistering
Severe pain of hands
and/or feet
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
1. Lacouture et al. Oncologist 2008; 13: 1001–11.
2. NCI CTCAE 2009 Version 4. http://www.acrin.org/Portals/0/Administration/Regulatory/
CTCAE_4.02_2009-09-15_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
1. Pyle L et al. Cancer Nursing Practice 2008; 7: 42-46.
2. 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
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)
More severe cases may require antiemetic therapy (e.g. metoclopramide)1,3
Consider dose reduction if necessary
** 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
Experienced by 16% of patients treated with
Votrient in aRCC clinical trials (grade 3/4
events, 0%)2
Encourage normal food & fluid intake
Pineapple chunks may help
1. Schwandt A et al. OncoTargets and Therapy 2009:2 51–61
2. GlaxoSmithKline. Votrient (pazopanib) Summary of Product Characteristics, January 2013.
3. 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
1. Schwandt A et al. OncoTargets and Therapy 2009:2 51–61
2. Pyle L et al. Cancer Nursing Practice 2008; 7: 42.
3. GlaxoSmithKline. Votrient (pazopanib) Summary of Product Characteristics, January 2013.
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
1. Izzedine H et al. Eur J Cancer 2010; 46: 439-48.
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
1. Schwandt A et al. OncoTargets and Therapy 2009:2 51–61
2. 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
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: 1061-68.
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
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: 1061-68.
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
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: 1061-68.
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
Maintains patients’ health-related quality
of life, relative to placebo3
Low incidence of Grade 3 or 4 fatigue, handfoot 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.
Minimal inhibition of other kinases including Flt-3
Significant improvement in PFS vs placebo in:3
200 mg
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
1. Karaman MW, et al. Nat Biotechnol 2008;26: 127–132; 2. Kumar R, et al. Br J Cancer 2009; 101:
1717–1723; 3. Sternberg CN, et al. J Clin Oncol 2010; 28: 1061-1068; 4. Sternberg CN, et al. Oral
presentation at ASCO 2009: abstract 5021.
400 mg
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)
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 preexisting cardiac dysfunction. Safety and pharmacokinetics of pazopanib not studied in patients
with moderate to severe heart failure or those with below normal LVEF. Events of cardiac
dysfunction (e.g. CHF and LVEF decline) have occurred in pazopanib trials. Monitor patients
for signs and symptoms of CHF. Baseline and periodic LVEF evaluation recommended. QT
prolongation and Torsade de Pointes: Use with caution in patients (i) with history of QT
interval prolongation, (ii) taking antiarrythmics or other medications that may prolong QT
interval or (iii) with relevant pre-existing cardiac disease. Baseline and periodic ECGs, and
maintenance of electrolytes within normal range recommended. Arterial thrombotic events:
Use with caution in patients at increased risk for these events. Base treatment decision on
individual patient’s benefit/risk assessment. Venous thromboembolic events (VTEs): VTEs
including venous thrombosis and fatal PE have occurred in pazopanib trials. Thrombotic
microangiopathy (TMA): (including thrombotic thrombocytopenic purpura and haemolytic
uraemic syndrome) has been reported in clinical trials of pazopanib. Patients developing TMA
should permanently discontinue pazopanib. Reversal of effects of TMA has been observed
after pazopanib treatment was discontinued. Haemorrhagic events: Not recommended in
patients with history of haemoptysis, cerebral, or significant GI haemorrhage in past 6 months.
Use with caution in patients with significant risk of haemorrhage. GI perforations and fistula:
Use with caution in patients at risk for GI perforation or fistula. Wound healing: Stop treatment
≥7 days prior to surgery. Resume after surgery based on clinical judgement of adequate
wound healing. Discontinue pazopanib in patients with wound dehiscence. Hypothyroidism:
Baseline measurement of thyroid function recommended prior to start of pazopanib treatment;
monitor periodically during treatment. Monitor patients for signs and symptoms of thyroid
dysfunction and manage as per standard medical practice. Proteinuria: Baseline and periodic
urinalysis recommended. Monitor patients for worsening proteinuria. Discontinue pazopanib if
Grade 4 proteinuria develops. Pneumothorax: Observe patients closely for signs and
symptoms of pneumothorax. Infections: Cases of serious infection (with/without neutropenia)
reported. Interactions Avoid concomitant use with strong inhibitors of CYP3A4, pglycoprotein (P-gp) or breast cancer resistance protein (BCRP) and CYP3A4 inducers.
Hyperglycaemia observed during concomitant administration with ketoconazole. Avoid coadministration 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 £560.50.
400mg x 30 tablet pack £1121.00. Marketing authorisation (MA) nos. EU/1/10/628/001-4.
MA holder Glaxo Group Limited, Berkeley Avenue, Greenford, Middlesex UB6 ONN. Legal
category POM. UK/PAZ/0012/13. January 2013.
Adverse events should be reported. Reporting forms and information can be found at:
http://www.mhra.gov.uk/yellowcard
Adverse events should also be reported to GlaxoSmithKline on 0800 221 441.
Further information is available from Customer Contact Centre, GlaxoSmithKline, Stockley
Park West, Uxbridge, Middlesex UB11 1BT; [email protected]; Freephone: 0800
221 441.
Votrient is a trademark of the GlaxoSmithKline group of companies.