Votrient

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 

 



 

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1. NAME OF THE MEDICINAL PRODUCT 

 

Votrient 200 mg film-coated tablets 

Votrient 400 mg film-coated tablets 

 

 

2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 

Votrient 200 mg film-coated tablets 

 

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

 

Votrient 400 mg film-coated tablets 

 

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

 

For the full list of excipients, see section 6.1. 

 

 

3. PHARMACEUTICAL FORM 
 

Film-coated tablet. 

 

Votrient 200 mg film-coated tablets 

 

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

 

Votrient 400 mg film-coated tablets 

 

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

 

 

4. CLINICAL PARTICULARS 
 

4.1 Therapeutic indications 
 

Renal cell carcinoma (RCC) 

 

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. 

 

Soft-tissue sarcoma (STS) 

 

Votrient is indicated for the treatment of adult patients with selective subtypes of advanced soft-tissue 

sarcoma (STS) who have received prior chemotherapy for metastatic disease or who have progressed 

within 12 months after (neo) adjuvant therapy. 

 

Efficacy and safety has only been established in certain STS histological tumour subtypes (see 

section 5.1). 

 

  



 

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4.2 Posology and method of administration 

 

Votrient treatment should only be initiated by a physician experienced in the administration of 

anti-cancer medicinal products. 

 

Posology 

 

Adults 

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

 

Dose modifications 

Dose modification (decrease or increase) should be in 200 mg decrements or increments in a stepwise 

fashion based on individual tolerability in order to manage adverse reactions. The dose of pazopanib 

should not exceed 800 mg. 

 

Paediatric population 

Pazopanib should not be used in children younger than 2 years of age because of safety concerns with 

regard to organ growth and maturation (see sections 4.4 and 5.3). 

 

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

established. No data are available (see section 5.1). 

 

Elderly 

There are limited data on the use of pazopanib in patients aged 65 years and older. In the RCC studies 

of pazopanib, overall no clinically significant differences in safety of pazopanib were observed 

between subjects aged at least 65 years and younger subjects. Clinical experience has not identified 

differences in responses between the elderly and younger patients, but greater sensitivity of some 

elderly patients cannot be ruled out. 

 

Renal impairment 

Renal impairment is unlikely to have a clinically relevant effect on pazopanib pharmacokinetics given 

the low renal excretion of pazopanib and metabolites (see section 5.2). Therefore, no dose adjustment 

is required in patients with creatinine clearance above 30 ml/min. Caution is advised in patients with 

creatinine clearance below 30 ml/min as there is no experience of pazopanib in this patient population. 

 

Hepatic impairment 

Dosing recommendations in hepatically impaired patients are based on pharmacokinetic studies of 

pazopanib in patients with varying degrees of hepatic dysfunction (see section 5.2). All patients should 

have liver function tests to determine whether they have hepatic impairment before starting and during 

pazopanib therapy (see section 4.4). Administration of pazopanib to patients with mild or moderate 

hepatic impairment should be undertaken with caution and close monitoring of tolerability. 800 mg 

pazopanib once daily is the recommended dose in patients with mild abnormalities in serum liver tests 

(defined either as normal bilirubin and any degree of alanine aminotransferase (ALT) elevation or as 

an elevation of bilirubin (>35% direct) up to 1.5 x upper limit of normal (ULN) regardless of the ALT 

value). A reduced pazopanib dose of 200 mg once daily is recommended in patients with moderate 

hepatic impairment (defined as an elevation of bilirubin >1.5 to 3 x ULN regardless of the ALT value) 

(see section 5.2). 

 

Pazopanib is not recommended in patients with severe hepatic impairment (defined as total bilirubin 

>3 x ULN regardless of the ALT value). 

 

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

hepatotoxicity. 

 



 

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Method of administration 

 

Pazopanib is for oral use. It should be taken without food, at least one hour before or two hours after a 

meal (see section 5.2). The film-coated tablets should be taken whole with water and not broken or 

crushed (see section 5.2). 

 

4.3 Contraindications 
 

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

 

4.4 Special warnings and precautions for use 

 

Hepatic effects 

 

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

Administration of pazopanib to patients with mild or moderate hepatic impairment should be 

undertaken with caution and close monitoring. 800 mg pazopanib once daily is the recommended dose 

in patients with mild abnormalities in serum liver tests (either normal bilirubin and any degree of ALT 

elevation or elevation of bilirubin up to 1.5 x ULN regardless of the ALT value). A reduced pazopanib 

dose of 200 mg once daily is recommended in patients with moderate hepatic impairment (elevation of 

bilirubin >1.5 to 3 x ULN regardless of the ALT value) (see sections 4.2 and 5.2). Pazopanib is not 

recommended in patients with severe hepatic impairment (total bilirubin >3 x ULN regardless of the 

ALT value) (see sections 4.2 and 5.2). Exposure at a 200 mg dose is markedly reduced, though highly 

variable, in these patients, with values considered insufficient to obtain a clinically relevant effect. 

 

In clinical studies with pazopanib, increase in serum transaminases (ALT, aspartate aminotransferase 

[AST]) and bilirubin were observed (see section 4.8). In the majority of the cases, isolated increases in 

ALT and AST have been reported, without concomitant elevations of alkaline phosphatase or 

bilirubin. Patients over 60 years of age may be at greater risk for mild (>3 x ULN) to severe 

(>8 x ULN) elevation of ALT. Patients who carry the HLA-B*57:01 allele have an increased risk of 

pazopanib-associated ALT elevations. Liver function should be monitored in all subjects receiving 

pazopanib, regardless of genotype or age (see section 5.1). 

 

Serum liver tests should be performed before initiation of treatment with pazopanib, at weeks 3, 5, 7 

and 9, then at months 3 and 4, with additional tests as clinically indicated. Periodic testing should then 

continue after month 4. 

 



 

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See Table 1 for dose modification guidance for patients with baseline values of total bilirubin 

1.5 x ULN and AST and ALT 2 x ULN: 

 

Table 1 Dose modifications for drug-induced hepatotoxicity 

 

Liver test values Dose modification 

Transaminase elevation 

between 3 and 8 x ULN 

Continue on pazopanib with weekly monitoring of liver function 

until transaminases return to Grade 1 or baseline. 

Transaminase elevation of 

>8 x ULN 

Interrupt pazopanib until transaminases return to Grade 1 or 

baseline. 

If the potential benefit of reinitiating pazopanib treatment is 

considered to outweigh the risk for hepatotoxicity, then 

reintroduce pazopanib at a reduced dose of 400 mg daily and 

perform serum liver tests weekly for 8 weeks. Following 

reintroduction of pazopanib, if transaminase elevations >3 x ULN 

recur, then pazopanib should be permanently discontinued. 

Transaminase elevations 

>3 x ULN concurrently with 

bilirubin elevations >2 x ULN 

Permanently discontinue pazopanib. 

Patients should be monitored until return to Grade 1 or baseline. 

Pazopanib is a UGT1A1 inhibitor. Mild, indirect (unconjugated) 

hyperbilirubinaemia may occur in patients with Gilbert’s 

syndrome. Patients with only a mild indirect hyperbilirubinaemia, 

known or suspected Gilbert’s syndrome, and elevation in ALT 

>3 x ULN should be managed as per the recommendations 

outlined for isolated ALT elevations. 

 

Concomitant use of pazopanib and simvastatin increases the risk of ALT elevations (see section 4.5) 

and should be undertaken with caution and close monitoring. 

 

Hypertension 

 

In clinical studies with pazopanib, events of hypertension including newly diagnosed symptomatic 

episodes of elevated blood pressure (hypertensive crisis) have occurred. Blood pressure should be well 

controlled prior to initiating pazopanib. Patients should be monitored for hypertension early after 

starting treatment (no longer than one week after starting pazopanib) and frequently thereafter to 

ensure blood pressure control. Elevated blood pressure levels (systolic blood pressure ≥150 mm Hg or 

diastolic blood pressure ≥100 mm Hg) occurred early in the course of treatment (approximately 40% 

of cases occurred by day 9 and approximately 90% of cases occurred in the first 18 weeks). Blood 

pressure should be monitored and managed promptly using a combination of anti-hypertensive therapy 

and dose modification of pazopanib (interruption and re-initiation at a reduced dose based on clinical 

judgement) (see sections 4.2 and 4.8). Pazopanib should be discontinued if there is evidence of 

hypertensive crisis or if hypertension is severe and persists despite anti-hypertensive therapy and 

pazopanib dose reduction. 

 

Posterior reversible encephalopathy syndrome (PRES)/Reversible posterior leukoencephalopathy 

syndrome (RPLS) 

 

PRES/RPLS has been reported in association with pazopanib. PRES/RPLS can present with headache, 

hypertension, seizure, lethargy, confusion, blindness and other visual and neurological disturbances, 

and can be fatal. Patients developing PRES/RPLS should permanently discontinue treatment with 

pazopanib. 

 

Interstitial lung disease (ILD)/Pneumonitis 

 

ILD, which can be fatal, has been reported in association with pazopanib (see section 4.8). Monitor 

patients for pulmonary symptoms indicative of ILD/pneumonitis and discontinue pazopanib in patients 

developing ILD or pneumonitis. 

 



 

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Cardiac dysfunction/Heart failure 

 

The risks and benefits of pazopanib should be considered before beginning therapy in patients who 

have pre-existing cardiac dysfunction. The safety and pharmacokinetics of pazopanib in patients with 

moderate to severe heart failure or those with a below normal left ventricular ejection fraction (LVEF) 

have not been studied. 

 

In clinical studies with pazopanib, events of cardiac dysfunction such as congestive heart failure and 

decreased LVEF have occurred (see section 4.8). In a randomised study comparing pazopanib and 

sunitinib in RCC (VEG108844), subjects had baseline and follow up LVEF measurements. 

Myocardial dysfunction occurred in 13% (47/362) of subjects in the pazopanib arm compared to 11% 

(42/369) of subjects in the sunitinib arm. Congestive heart failure was observed in 0.5% of subjects in 

each treatment arm. Congestive heart failure was reported in 3 out of 240 subjects (1%) in the Phase 

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

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

the placebo arm. 

 

Risk factors 

Thirteen of the 15 subjects in the pazopanib arm of the STS Phase III study had concurrent 

hypertension which may have exacerbated cardiac dysfunction in patients at risk by increasing cardiac 

after-load. 99% of patients (243/246) enrolled in the STS Phase III study, including the 15 subjects, 

received anthracycline. Prior anthracycline therapy may be a risk factor for cardiac dysfunction. 

 

Outcome 

Four of the 15 subjects had full recovery (within 5% of baseline) and 5 had partial recovery (within the 

normal range, but >5% below baseline). One subject did not recover and follow-up data were not 

available for the other 5 subjects. 

 

Management 

Interruption of pazopanib and/or dose reduction should be combined with treatment of hypertension (if 

present, refer to hypertension warning section above) in patients with significant reductions in LVEF, 

as clinically indicated. 

 

Patients should be carefully monitored for clinical signs or symptoms of congestive heart failure. 

Baseline and periodic evaluation of LVEF is recommended in patients at risk of cardiac dysfunction. 

 

QT prolongation and torsade de pointes 

 

In clinical studies with pazopanib, events of QT prolongation and torsade de pointes have occurred 

(see section 4.8). Pazopanib should be used with caution in patients with a history of QT interval 

prolongation, in patients taking antiarrhythmics or other medicinal products that may prolong QT 

interval and in patients with relevant pre-existing cardiac disease. When using pazopanib, baseline and 

periodic monitoring of electrocardiograms and maintenance of electrolytes (e.g. calcium, magnesium, 

potassium) within normal range is recommended. 

 

Arterial thrombotic events 

 

In clinical studies with pazopanib, myocardial infarction, myocardial ischaemia, ischaemic stroke and 

transient ischaemic attack were observed (see section 4.8). Fatal events have been observed. 

Pazopanib should be used with caution in patients who are at increased risk of thrombotic events or 

who have had a history of thrombotic events. Pazopanib has not been studied in patients who have had 

an event within the previous 6 months. A treatment decision should be made based on the assessment 

of individual patient’s benefit/risk. 

 



 

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Venous thromboembolic events 

 

In clinical studies with pazopanib, venous thromboembolic events including venous thrombosis and 

fatal pulmonary embolus have occurred. While observed in both RCC and STS studies, the incidence 

was higher in the STS population (5%) than in the RCC population (2%). 

 

Thrombotic microangiopathy (TMA) 

 

TMA has been reported in clinical studies of pazopanib as monotherapy, in combination with 

bevacizumab, and in combination with topotecan (see section 4.8). Patients developing TMA should 

permanently discontinue treatment with pazopanib. Reversal of effects of TMA has been observed 

after treatment was discontinued. Pazopanib is not indicated for use in combination with other agents. 

 

Haemorrhagic events 

 

In clinical studies with pazopanib haemorrhagic events have been reported (see section 4.8). Fatal 

haemorragic events have occurred. Pazopanib has not been studied in patients who had a history of 

haemoptysis, cerebral haemorrhage or clinically significant gastrointestinal (GI) haemorrhage in the 

past 6 months. Pazopanib should be used with caution in patients with significant risk of haemorrhage. 

 

Aneurysms and artery dissections 

 

The use of VEGF pathway inhibitors in patients with or without hypertension may promote the 

formation of aneurysm and/or artery dissections. Before initiating pazopanib, this risk should be 

carefully considered in patients with risk factors such as hypertension or history of aneurysm. 

 

Gastrointestinal (GI) perforations and fistula 

 

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

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

GI perforation or fistula. 

 

Wound healing 

 

No formal studies of the effect of pazopanib on wound healing have been conducted. Since vascular 

endothelial growth factor (VEGF) inhibitors may impair wound healing, treatment with pazopanib 

should be stopped at least 7 days prior to scheduled surgery. The decision to resume pazopanib after 

surgery should be based on clinical judgement of adequate wound healing. Pazopanib should be 

discontinued in patients with wound dehiscence. 

 

Hypothyroidism 

 

In clinical studies with pazopanib, events of hypothyroidism have occurred (see section 4.8). 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 pazopanib treatment. All patients should 

be observed closely for signs and symptoms of thyroid dysfunction on pazopanib treatment. 

Laboratory monitoring of thyroid function should be performed periodically and managed as per 

standard medical practice. 

 

Proteinuria 

 

In clinical studies with pazopanib, proteinuria has been reported. Baseline and periodic urinanalysis 

during treatment is recommended and patients should be monitored for worsening proteinuria. 

Pazopanib should be discontinued if the patient develops nephrotic syndrome. 

 



 

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Tumour lysis syndrome (TLS) 

 

The occurrence of TLS, including fatal TLS, has been associated with the use of pazopanib (see 

section 4.8). Patients at increased risk of TLS are those with rapidly growing tumours, a high tumour 

burden, renal dysfunction, or dehydration. Preventative measures, such as treatment of high uric acid 

levels and intravenous hydration, should be considered prior to initiation of Votrient. Patients at risk 

should be closely monitored and treated as clinically indicated. 

 

Pneumothorax 

 

In clinical studies with pazopanib in advanced soft tissue sarcoma, events of pneumothorax have 

occurred (see section 4.8). Patients on pazopanib treatment should be observed closely for signs and 

symptoms of pneumothorax. 

 

Paediatric population 

 

Because the mechanism of action of pazopanib can severely affect organ growth and maturation 

during early post-natal development in rodents (see section 5.3), pazopanib should not be given to 

paediatric patients younger than 2 years of age. 

 

Infections 

 

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

reported. 

 

Combination with other systemic anti-cancer therapies 

 

Clinical studies of pazopanib in combination with pemetrexed (non-small cell lung cancer [NSCLC]) 

and lapatinib (cervical cancer) were terminated early due to concerns over increased toxicity and/or 

mortality, and a safe and effective combination dose has not been established with these regimens. 

 

Pregnancy 

 

Pre-clinical studies in animals have shown reproductive toxicity (see section 5.3). If pazopanib is used 

during pregnancy, or if the patient becomes pregnant whilst receiving pazopanib, the potential hazard 

to the foetus should be explained to the patient. Women of childbearing potential should be advised to 

avoid becoming pregnant while receiving treatment with pazopanib (see section 4.6). 

 

Interactions 

 

Concomitant treatment with strong inhibitors of CYP3A4, P-glycoprotein (P-gp) or breast cancer 

resistance protein (BCRP) should be avoided due to risk of increased exposure to pazopanib (see 

section 4.5). Selection of alternative concomitant medicinal products with no or minimal potential to 

inhibit CYP3A4, P-gp or BCRP should be considered. 

 

Concomitant treatment with inducers of CYP3A4 should be avoided due to risk of decreased exposure 

to pazopanib (see section 4.5). 

 

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

 

Concomitant administration of pazopanib with uridine diphosphate glucuronosyl transferase 1A1 

(UGT1A1) substrates (e.g. irinotecan) should be undertaken with caution since pazopanib is an 

inhibitor of UGT1A1 (see section 4.5). 

 

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

 



 

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4.5 Interaction with other medicinal products and other forms of interaction 
 

Effects of other medicinal products on pazopanib 

 

In vitro studies suggested that the oxidative metabolism of pazopanib in human liver microsomes is 

mediated primarily by CYP3A4, with minor contributions from CYP1A2 and CYP2C8. Therefore, 

inhibitors and inducers of CYP3A4 may alter the metabolism of pazopanib. 

 

CYP3A4, P-gp, BCRP inhibitors 

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

 

Concurrent administration of pazopanib (400 mg once daily) with the strong CYP3A4 and P-gp 

inhibitor ketoconazole (400 mg once daily) for 5 consecutive days resulted in a 66% and 45% increase 

in mean pazopanib AUC(0-24) and Cmax, respectively, relative to administration of pazopanib alone 

(400 mg once daily for 7 days). Pharmacokinetic parameter comparisons of pazopanib Cmax (range of 

means 27.5 to 58.1 µg/ml) and AUC(0-24) (range of means 48.7 to 1040 µg*h/ml) after administration 

of pazopanib 800 mg alone and after administration of pazopanib 400 mg plus ketoconazole 400 mg 

(mean Cmax 59.2 µg/ml, mean AUC(0-24)1300 µg*h/ml) indicated that, in the presence of a strong 

CYP3A4 and P-gp inhibitor a dose reduction to pazopanib 400 mg once daily will, in the majority of 

patients, result in systemic exposure similar to that observed after administration of 800 mg pazopanib 

once daily alone. Some patients however may have systemic pazopanib exposure greater than what 

has been observed after administration of 800 mg pazopanib alone. 

 

Co-administration of pazopanib with other strong inhibitors of the CYP3A4 family (e.g. itraconazole, 

clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, 

voriconazole) may increase pazopanib concentrations. Grapefruit juice contains an inhibitor of 

CYP3A4 and may also increase plasma concentrations of pazopanib. 

 

Administration of 1500 mg lapatinib (a substrate for and weak inhibitor of CYP3A4 and P-gp and a 

potent inhibitor of BCRP) with 800 mg pazopanib resulted in an approximately 50% to 60% increase 

in mean pazopanib AUC(0-24) and Cmax compared to administration of 800 mg pazopanib alone. 

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

 

Co-administration of pazopanib with a CYP3A4, P-gp, and BCRP inhibitor, such as lapatinib, will 

result in an increase in plasma pazopanib concentrations. Co-administration with potent P-gp or BCRP 

inhibitors may also alter the exposure and distribution of pazopanib, including distribution into the 

central nervous systems (CNS). 

 

Concomitant use of pazopanib with a strong CYP3A4 inhibitor should be avoided (see section 4.4). If 

no medically acceptable alternative to a strong CYP34A inhibitor is available, the dose of pazopanib 

should be reduced to 400 mg daily during concomitant administration. In such cases there should be 

close attention to adverse drug reaction, and further dose reduction may be considered if possible 

drug-related adverse events are observed. 

 

Combination with strong P-gp or BCRP inhibitors should be avoided, or selection of an alternate 

concomitant medicinal product with no or minimal potential to inhibit P-gp or BCRP is recommended. 

 

CYP3A4, P-gp, BCRP inducers 

CYP3A4 inducers such as rifampin may decrease plasma pazopanib concentrations. Co-administration 

of pazopanib with potent P-gp or BCRP inducers may alter the exposure and distribution of pazopanib, 

including distribution into the CNS. Selection of an alternative concomitant medication with no or 

minimal enzyme or transporter induction potential is recommended. 

 



 

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Effects of pazopanib on other medicinal products 

 

In vitro studies with human liver microsomes showed that pazopanib inhibited CYP enzymes 1A2, 

3A4, 2B6, 2C8, 2C9, 2C19, and 2E1. Potential induction of human CYP3A4 was demonstrated in an 

in vitro human PXR assay. Clinical pharmacology studies, using pazopanib 800 mg once daily, have 

demonstrated that pazopanib does not have a clinically relevant effect on the pharmacokinetics of 

caffeine (CYP1A2 probe substrate), warfarin (CYP2C9 probe substrate), or omeprazole (CYP2C19 

probe substrate) in cancer patients. Pazopanib resulted in an increase of approximately 30% in the 

mean AUC and Cmax of midazolam (CYP3A4 probe substrate) and increases of 33% to 64% in the 

ratio of dextrometrophan to dextrophan concentrations in the urine after oral administration of 

dextromethorphan (CYP2D6 probe substrate). Co-administration of pazopanib 800 mg once daily and 

paclitaxel 80 mg/m2 (CYP3A4 and CYP2C8 substrate) once weekly resulted in a mean increase of 

26% and 31% in paclitaxel AUC and Cmax, respectively. 

 

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

GSK1268997 may contribute to the net inhibitory effect of pazopanib towards BCRP. Furthermore, 

inhibition of BCRP and P-gp by pazopanib in the gastrointestinal tract cannot be excluded. Care 

should be taken when pazopanib is co-administered with other oral BCRP and P-gp substrates. 

 

In vitro, pazopanib inhibited human organic anion transporting polypeptide (OATP1B1). It cannot be 

excluded that pazopanib will affect the pharmacokinetics of substrates of OATP1B1 (e.g. statins, see 

“Effect of concomitant use of pazopanib and simvastatin” below). 

 

Pazopanib is an inhibitor of the uridine diphosphoglucuronosyl-transferase 1A1 (UGT1A1) enzyme in 

vitro. The active metabolite of irinotecan, SN-38, is a substrate for OATP1B1 and UGT1A1. 

Co-administration of pazopanib 400 mg once daily with cetuximab 250 mg/m2 and irinotecan 

150 mg/m2 resulted in an approximately 20% increase in systemic exposure to SN-38. Pazopanib may 

have a greater impact on SN-38 disposition in subjects with the UGT1A1*28 polymorphism relative to 

subjects with the wild-type allele. However, the UGT1A1 genotype was not always predictive of the 

effect of pazopanib on SN-38 disposition. Care should be taken when pazopanib is co-administered 

with substrates of UGT1A1. 

 

Effect of concomitant use of pazopanib and simvastatin 

 

Concomitant use of pazopanib and simvastatin increases the incidence of ALT elevations. Results 

from a meta-analysis using pooled data from clinical studies with pazopanib show that ALT >3x ULN 

was reported in 126/895 (14%) of patients who did not use statins, compared with 11/41 (27%) of 

patients who had concomitant use of simvastatin (p = 0.038). If a patient receiving concomitant 

simvastatin develops ALT elevations, follow guidelines for pazopanib posology and discontinue 

simvastatin (see section 4.4). In addition, concomitant use of pazopanib and other statins should be 

undertaken with caution as there are insufficient data available to assess their impact on ALT levels. It 

cannot be excluded that pazopanib will affect the pharmacokinetics of other statins (e.g. atorvastatin, 

fluvastatin, pravastatin, rosuvastatin). 

 

Effect of food on pazopanib 

 

Administration of pazopanib with a high-fat or low-fat meal results in an approximately 2-fold 

increase in AUC and Cmax. Therefore, pazopanib should be administered at least 1 hour before or 

2 hours after a meal. 

 



 

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Medicinal products that raise 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. 

 

4.6 Fertility, pregnancy and lactation 
 

Pregnancy/ Contraception in males and females 

 

There are no adequate data from the use of pazopanib in pregnant women. Studies in animals have 

shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. 

 

Pazopanib should not be used during pregnancy unless the clinical condition of the woman requires 

treatment with pazopanib. If pazopanib is used during pregnancy, or if the patient becomes pregnant 

while receiving pazopanib, the potential hazard to the foetus should be explained to the patient. 

 

Women of childbearing potential should be advised to use adequate contraception during treatment 

and for at least 2 weeks after the last dose of pazopanib and to avoid becoming pregnant while 

receiving treatment with pazopanib. 

 

Male patients (including those who have had vasectomies) should use condoms during sexual 

intercourse while taking pazopanib and for at least 2 weeks after the last dose of pazopanib to avoid 

potential exposure to the medicinal product for pregnant partners and female partners of reproductive 

potential. 

 

Breast-feeding 

 

The safe use of pazopanib during breast-feeding has not been established. It is not known whether 

pazopanib or its metabolites are excreted in human milk. There are no animal data on the excretion of 

pazopanib in animal milk. A risk to the breast-fed child cannot be excluded. Breast-feeding should be 

discontinued during treatment with pazopanib.  

 

Fertility 

 

Animal studies indicate that male and female fertility may be affected by treatment with pazopanib 

(see section 5.3). 

 

4.7 Effects on ability to drive and use machines 
 

Votrient has no or negligible influence on the ability to drive and use machines. A detrimental effect 

on such activities cannot be predicted from the pharmacology of pazopanib. The clinical status of the 

patient and the adverse event profile of pazopanib should be borne in mind when considering the 

patient’s ability to perform tasks that require judgement, motor or cognitive skills. Patients should 

avoid driving or using machines if they feel dizzy, tired or weak. 

 



 

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4.8 Undesirable effects 

 

Summary of the safety profile 

 

Pooled data from the pivotal RCC study (VEG105192, n=290), the extension study (VEG107769, 

n=71), the supportive Phase II study (VEG102616, n=225) and the randomised, open-label, parallel 

group Phase III non-inferiority study (VEG108844, n=557) were evaluated in the overall evaluation of 

safety and tolerability of pazopanib (total n=1149) in subjects with RCC (see section 5.1). 

 

Pooled data from the pivotal STS study (VEG110727, n=369) and the supportive Phase II study 

(VEG20002, n=142) was evaluated in the overall evaluation of safety and tolerability of pazopanib 

(total safety population n=382) in subjects with STS (see section 5.1). 

 

The most important serious adverse reactions identified in the RCC or STS studies were transient 

ischaemic attack, ischaemic stroke, myocardial ischaemia, myocardial and cerebral infarction, cardiac 

dysfunction, gastrointestinal perforation and fistula, QT prolongation, Torsade de Pointes and 

pulmonary, gastrointestinal and cerebral haemorrhage, all adverse reactions being reported in <1% of 

treated patients. Other important serious adverse reactions identified in STS studies included venous 

thromboembolic events, left ventricular dysfunction and pneumothorax. 

 

Fatal events that were considered possibly related to pazopanib included gastrointestinal haemorrhage, 

pulmonary haemorrhage/haemoptysis, abnormal hepatic function, intestinal perforation and ischaemic 

stroke. 

 

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

RCC and STS trials included: diarrhoea, hair colour change, skin hypopigmentation, exfoliative rash, 

hypertension, nausea, headache, fatigue, anorexia, vomiting, dysgeusia, stomatitis, weight decreased, 

pain, elevated alanine aminotransferase and elevated aspartate aminotransferase. 

 

Adverse drug reactions, all grades, which were reported in RCC and STS subjects or during the 

post-marketing period are listed below by MedDRA body system organ class, frequency and grade of 

severity. The following convention has been utilised for the classification of frequency: very common 

(≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); 

very rare (<1/10,000); and not known (cannot be estimated from the available data). 

 

Categories have been assigned based on absolute frequencies in the clinical trial data. Post-marketing 

data on safety and tolerability across all pazopanib clinical studies and from spontaneous reports have 

also been evaluated. Within each system organ class, adverse reactions with the same frequency are 

presented in order of decreasing seriousness. 

 

  



 

13 

Tabulated list of adverse reactions 

 

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

post-marketing period 

 

System Organ 

Class 

Frequency 

(all grades) 

Adverse reactions All grades 

n (%) 

Grade 3 

n (%) 

Grade 4 

n (%) 

Infections and 

Infestations 

Common Infections (with or 

without neutropenia)† 

not known not known not 

known 

Uncommon Gingival infection 1 (<1%) 0 0 

Infectious peritonitis 1 (<1%) 0 0 

Neoplasms 

benign, malignant 

and unspecified 

(incl cysts and 

polyps) 

Uncommon Tumour pain 1 (<1%) 1 (<1%) 0 

Blood and 

lymphatic system 

disorders 

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

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

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

Uncommon Polycythaemia 6 (0.03%) 1 0 

Rare Thrombotic 

microangiopathy 

(including thrombotic 

thrombocytopenic 

purpura and 

haemolytic uraemic 

syndrome)† 

not known not known not 

known 

Endocrine 

disorders 

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

Metabolism and 

nutrition 

disorders 

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

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

Dehydration 16 (1%) 5 (<1%) 0 

Uncommon Hypomagnesaemia 10 (<1%) 0 0 

Not known 
Tumour lysis 

syndrome* 

not known not known not 

known 

Psychiatric 

disorders 

Common Insomnia 30 (3%) 0 0 



 

14 

Nervous system 

disorders 

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

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

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

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

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

Peripheral sensory 

neuropathy 

17 (1%) 0 0 

Uncommon Hypoaesthesia 8 (<1%) 0 0 

Transient ischaemic 

attack 

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

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

Cerebrovascular 

accident 

2 (<1%) 1 (<1%) 1 (<1%) 

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

Rare Posterior reversible 

encephalopathy / 

reversible posterior 

leukoencephalopathy 

syndrome† 

not known not known not 

known 

Eye disorders 

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

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

Retinal tear† 1 (<1%) 1 (<1%) 0 

Eyelash discolouration 4 (<1%) 0 0 

Cardiac disorders 

Uncommon Bradycardia 6 (<1%) 0 0 

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

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

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

Vascular 

disorders 

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

Common Hot flush 16 (1%) 0 0 

Venous 

thromboembolic 

event g 

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

Flushing 12 (1%) 0 0 

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

Haemorrhage 1 (<1%) 0 0 

Not known Aneurysms and artery 

dissections 

Not known Not known Not 

known 

Respiratory, 

thoracic and 

mediastinal 

disorders 

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

Dysphonia 48 (4%) 0 0 

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

Haemoptysis 15 (1%) 1 (<1%) 0 

Uncommon Rhinorrhoea 8 (<1%) 0 0 

Pulmonary 

haemorrhage 

2 (<1%) 0 0 

Pneumothorax 1 (<1%) 0 0 

Rare Interstitial lung 

disease/pneumonitis† 

not known not known not 

known 



 

15 

Gastrointestinal 

disorders 

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

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

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

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

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

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

Flatulence 43 (4%) 0 0 

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

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

Dry mouth 27 (2%) 0 0 

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

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

Haematochezia 6 (<1%) 0 0 

Gastrointestinal 

haemorrhage 

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

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

Frequent bowel 

movements 

3 (<1%) 0 0 

Anal haemorrhage 2 (<1%) 0 0 

Large intestine 

perforation 

2 (<1%) 1 (<1%) 0 

Mouth haemorrhage 2 (<1%) 0 0 

Upper gastrointestinal 

haemorrhage 

2 (<1%) 1 (<1%) 0 

Enterocutaneous 

fistula 

1 (<1%) 0 0 

Haematemesis 1 (<1%) 0 0 

Haemorrhoidal 

haemorrhage 

1 (<1%) 0 0 

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

Oesophageal 

haemorrhage 

1 (<1%) 0 0 

Retroperitoneal 

haemorrhage 

1 (<1%) 0 0 

Hepatobiliary 

disorders 

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

Hepatic function 

abnormal 

29 (3%) 13 (1%) 2 (<1%) 

Hepatotoxicity 18 (2%) 11(<1%) 2 (<1%) 

Uncommon Jaundice 3 (<1%) 1 (<1%) 0 

Drug induced liver 

injury 

2 (<1%) 2 (<1%) 0 

Hepatic failure 1 (<1%) 0 1 (<1%) 



 

16 

Skin and 

subcutaneous 

disorders 

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

Palmar-plantar 

erythrodysaesthesia 

syndrome 

206 (18%) 39 (3%) 0 

Alopecia 130 (11%) 0 0 

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

Common Skin 

hypopigmentation 

52 (5%) 0 0 

Dry skin 50 (4%) 0 0 

Pruritus 29 (3%) 0 0 

Erythema 25 (2%) 0 0 

Skin depigmentation 20 (2%) 0 0 

Hyperhidrosis 17 (1%) 0 0 

Uncommon Nail disorders 11 (<1%) 0 0 

Skin exfoliation 10 (<1%) 0 0 

Photosensitivity 

reaction 

7 (<1%) 0 0 

Rash erythematous 6 (<1%) 0 0 

Skin disorder 5 (<1%) 0 0 

Rash macular 4 (<1%) 0 0 

Rash pruritic 3 (<1%) 0 0 

Rash vesicular 3 (<1%) 0 0 

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

Rash generalised 2 (<1%) 0 0 

Rash papular 2 (<1%) 0 0 

Plantar erythema 1 (<1%) 0 0 

Musculoskeletal 

and connective 

tissue disorders 

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

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

Muscle spasms 25 (2%) 0 0 

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

Renal and 

urinary disorders 

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

Uncommon Haemorrhage urinary 

tract 

1 (<1%) 0 0 

Reproductive 

system and breast 

disorders 

Uncommon Menorrhagia 3 (<1%) 0 0 

Vaginal haemorrhage 3 (<1%) 0 0 

Metrorrhagia 1 (<1%) 0 0 

General disorders 

and 

administration 

site conditions 

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

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

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

Oedemab 72 (6%) 1 (<1%) 0 

Chest pain 18 (2%) 2 (<1%) 0 

Uncommon Chills 4 (<1%) 0 0 

Mucous membrane 

disorder 

1 (<1%) 0 0 



 

17 

Investigations 

Very common Alanine 

aminotransferase 

increased 

246 (21%) 84 (7%) 14 (1%) 

Aspartate 

aminotransferase 

increased 

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

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

Blood bilirubin 

increased 

61 (5%) 6 (<1%) 1 (<1%) 

Blood creatinine 

increased 

55 (5%) 3 (<1%) 0 

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

White blood cell count 

decreasedd 

51 (4%) 3 (<1%) 0 

Blood thyroid 

stimulating hormone 

increased 

36 (3%) 0 0 

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

Gamma-

glutamyltransferase 

increased 

31 (3%) 9 (<1%) 4 (<1%) 

Blood pressure 

increased 

15 (1%) 2 (<1%) 0 

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

Liver function test 

abnormal 

12 (1%) 6 (<1%) 1 (<1%) 

Uncommon Hepatic enzyme 

increased 

11 (<1%) 4 (<1%) 3 (<1%) 

Blood glucose 

decreased 

7 (<1%) 0 1 (<1%) 

Electrocardiogram QT 

prolonged 

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

Transaminase 

increased 

7 (<1%) 1 (<1%) 0 

Thyroid function test 

abnormal 

3 (<1%) 0 0 

Blood pressure 

diastolic increased 

2 (<1%) 0 0 

Blood pressure 

systolic increased 

1 (<1%) 0 0 

†Treatment-related adverse reaction reported during post-marketing period (spontaneous case reports and serious 

adverse reactions from all pazopanib clinical studies). 

*Treatment-related adverse reaction reported only during the post-marketing period. Frequency cannot be 

estimated from the available data. 

The following terms have been combined: 
a Abdominal pain, abdominal pain upper and abdominal pain lower 
b Oedema, oedema peripheral, eye oedema, localised oedema and face oedema 
c Dysgeusia, ageusia and hypogeusia 
d White cell count decreased, neutrophil count decreased and leukocyte count decreased 
e Decreased appetite and anorexia 
f Cardiac dysfunction, left ventricular dysfunction, cardiac failure and restrictive cardiomyopathy 
g Venous thromboembolic event, deep vein thrombosis, pulmonary embolism and thrombosis 

 

Neutropenia, thrombocytopenia and palmar-plantar erythrodysaethesia syndrome were observed more 

frequently in patients of East Asian descent. 

 



 

18 

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

marketing period 

 

System Organ 

Class 

Frequency 

(all grades) 

Adverse reactions All grades 

n (%) 

Grade 3 

n (%) 

Grade 4 

n (%) 

Infections and 

infestations 

Common Gingival infection 4 (1%) 0 0 

Neoplasms 

benign, malignant 

and unspecified 

(incl cysts and 

polyps) 

Very common Tumour pain 121 (32%) 32 (8%) 0 

Blood and 

lymphatic system 

disordersf 

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

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

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

Uncommon Thrombotic 

microangiopathy 

(including thrombotic 

thrombocytopenic 

purpura and 

haemolytic uraemic 

syndrome) 

1 (<1%) 1 (<1%) 0 

Endocrine 

disorders 

Common Hypothyroidism 18 (5%) 0 0 

Metabolism and 

nutrition 

disorders 

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

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

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

Uncommon Hypomagnesaemia 1 (<1%) 0 0 

Not known Tumour lysis 

syndrome* 

not known not known not 

known 

Psychiatric 

disorders 

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

Nervous system 

disorders 

Very common Dysgeusiac 79 (21%) 0 0 

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

Common Peripheral sensory 

neuropathy 

30 (8%) 1 (<1%) 0 

Dizziness 15 (4%) 0 0 

Uncommon Somnolence 3 (<1%) 0 0 

Paresthesia 1 (<1%) 0 0 

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

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

Cardiac disorders 

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

Left ventricular 

dysfunction 

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

Bradycardia 4 (1%) 0 0 

Uncommon Myocardial infarction 1 (<1%) 0 0 

Vascular 

disorders 

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

Common Venous 

thromboembolic eventd 

13 (3%) 4 (1%) 5 (1%) 

Hot flush 12 (3%) 0 0 

Flushing 4 (1%) 0 0 

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

Not known Aneurysms and artery 

dissections 

Not known Not known Not 

known 



 

19 

Respiratory, 

thoracic and 

mediastinal 

disorders 

Common Epistaxis 22 (6%) 0 0 

Dysphonia 20 (5%) 0 0 

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

Cough 12 (3%) 0 0 

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

Hiccups 4 (1%) 0 0 

Pulmonary 

haemorrhage 

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

Uncommon Oropharyngeal pain 3 (<1%) 0 0 

Bronchial haemorrhage 2 (<1%) 0 0 

Rhinorrhoea 1 (<1%) 0 0 

Haemoptysis 1 (<1%) 0 0 

Rare Interstitial lung 

disease/pneumonitis† 

not known not known not 

known 

Gastrointestinal 

disorders 

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

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

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

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

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

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

Dry mouth 14 (4%) 0 0 

Dyspepsia 12 (3%) 0 0 

Mouth haemorrhage 5 (1%) 0 0 

Flatulence 5 (1%) 0 0 

Anal haemorrhage 4 (1%) 0 0 

Uncommon Gastrointestinal 

haemorrhage 

2 (<1%) 0 0 

Rectal haemorrhage 2 (<1%) 0 0 

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

Gastric haemorrhage 1 (<1%) 0 0 

Melaena 2 (<1%) 0 0 

Oesophageal 

haemorrhage 

1 (<1%) 0 1 (<1%) 

Peritonitis 1 (<1%) 0 0 

Retroperitoneal 

haemorrhage 

1 (<1%) 0 0 

Upper gastrointestinal 

haemorrhage 

1 (<1%) 1 (<1%) 0 

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

Hepatobiliary 

disorders 

Uncommon Hepatic function 

abnormal 

2 (<1%) 0 1 (<1%) 



 

20 

Skin and 

subcutaneous 

disorders 

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

Skin hypopigmentation 80 (21%) 0 0 

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

Common Alopecia 30 (8%) 0 0 

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

Dry skin 21 (5%) 0 0 

Hyperhydrosis 18 (5%) 0 0 

Nail disorder 13 (3%) 0 0 

Pruritus 11 (3%) 0 0 

Erythema 4 (1%) 0 0 

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

Rash 1 (<1%) 0 0 

Rash papular 1 (<1%) 0 0 

Photosensitivity 

reaction 

1 (<1%) 0 0 

Palmar-plantar 

erythrodysaesthesia 

syndrome 

2 (<1%) 0 0 

Musculoskeletal 

and connective 

tissue disorders 

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

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

Muscle spasms 8 (2%) 0 0 

Uncommon Arthralgia 2 (<1%) 0 0 

Renal and 

urinary disorders 

Uncommon Proteinuria 2 (<1%) 0 0 

Reproductive 

system and breast 

disorder 

Uncommon Vaginal haemorrhage 3 (<1%) 0 0 

Menorrhagia 1 (<1%) 0 0 

General disorders 

and 

administration 

site conditions 

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

Common Oedemab 18 (5%) 1 (<1%) 0 

Chest pain 12 (3%) 4 (1%) 0 

Chills 10 (3%) 0 0 

Uncommon Mucosal inflammatione 1 (<1%) 0 0 

Asthenia 1 (<1% 0 0 



 

21 

Investigationsh 

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

Common Ear, nose and throat 

examination abnormale 

29 (8%) 4 (1%) 0 

Alanine 

aminotransferase 

increased 

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

Blood cholesterol 

abnormal 

6 (2%) 0 0 

Aspartate 

aminotransferase 

increased 

5 (1%) 2 (<1%) 2 (<1%) 

Gamma 

glutamyltransferase 

increased 

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

Uncommon Blood bilirubin 

increased 

2 (<1%) 0 0 

Aspartate 

aminotransferase 

2 (<1%) 0 2 (<1%) 

Alanine 

aminotransferase 

1 (<1%) 0 1 (<1%) 

Platelet count 

decreased 

1 (<1%) 0 1 (<1%) 

Electrocardiogram QT 

prolonged 

2 (<1%) 1 (<1%) 0 

†Treatment-related adverse reaction reported during post-marketing period (spontaneous case reports and serious 

adverse reactions from all pazopanib clinical studies). 

*Treatment-related adverse reaction reported only during the post-marketing period. Frequency cannot be 

estimated from the available data. 

The following terms have been combined: 
a Abdominal pain, abdominal pain upper and gastrointestinal pain 
b Oedema, oedema peripheral and eyelid oedema 
c The majority of these cases were Palmar-plantar erythrodysaesthesia syndrome 
d Venous thromboembolic events – includes Deep vein thrombosis, Pulmonary embolism and Thrombosis terms 
e The majority of these cases describe mucositis 
f Frequency is based on laboratory value tables from VEG110727 (N=240). These were reported as adverse 

events less frequently by investigators than as indicated by laboratory value tables. 
g Cardiac dysfunction events – includes Left ventricular dysfunction, Cardiac failure and Restrictive 

cardiomyopathy 
h Frequency is based on adverse events reported by investigators. Laboratory abnormalities were reported as 

adverse events less frequently by investigators than as indicated by laboratory value tables. 

 

Neutropenia, thrombocytopenia and palmar-plantar erythrodysaethesia syndrome were observed more 

frequently in patients of East Asian descent. 

 

Reporting of suspected adverse reactions 

 

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 

allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 

professionals are asked to report any suspected adverse reactions via the national reporting system 

listed in Appendix V. 

 

  

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


 

22 

4.9 Overdose 
 

Pazopanib doses up to 2000 mg have been evaluated in clinical studies. Grade 3 fatigue (dose-limiting 

toxicity) and Grade 3 hypertension were each observed in 1 of 3 patients dosed at 2000 mg and 

1000 mg daily, respectively. 

 

There is no specific antidote for overdose with pazopanib and treatment of overdose should consist of 

general supportive measures. 

 

 

5. PHARMACOLOGICAL PROPERTIES 
 

5.1 Pharmacodynamic properties 
 

Pharmacotherapeutic group: Antineoplastic agents, other antineoplastic agents, protein kinase 

inhibitors, ATC code: L01XE11 

 

Mechanism of action 

 

Pazopanib is an orally administered, potent multi-target tyrosine kinase inhibitor (TKI) of vascular 

endothelial growth factor receptors (VEGFR) -1, -2, and -3, platelet-derived growth factor 

(PDGFR) -α and –β, and stem cell factor receptor (c-KIT), with IC50 values of 10, 30, 47, 71, 84 and 

74 nM, respectively. In preclinical experiments, pazopanib dose-dependently inhibited ligand-induced 

auto-phosphorylation of VEGFR-2, c-Kit and PDGFR- receptors in cells. In vivo, pazopanib 

inhibited VEGF-induced VEGFR-2 phosphorylation in mouse lungs, angiogenesis in various animal 

models, and the growth of multiple human tumour xenografts in mice. 

 

Pharmacogenomics 

 

In a pharmacogenetic meta-analysis of data from 31 clinical studies of pazopanib administered either 

as monotherapy or in combination with other agents, ALT >5 x ULN (NCI CTC Grade 3) occurred in 

19% of HLA-B*57:01 allele carriers and in 10% of non-carriers. In this dataset, 133/2235 (6%) of the 

patients carried the HLA-B*57:01 allele (see section 4.4). 

 

Clinical studies 

 

Renal cell carcinoma (RCC) 

The safety and efficacy of pazopanib in RCC were evaluated in a randomised, double-blind, 

placebo-controlled multicentre study. Patients (N = 435) with locally advanced and/or metastatic RCC 

were randomised to receive pazopanib 800 mg once daily or placebo. The primary objective of the 

study was to evaluate and compare the two treatment arms for progression-free survival (PFS) and the 

principle secondary endpoint was overall survival (OS). The other objectives were to evaluate the 

overall response rate and duration of response. 

 

From the total of 435 patients in this study, 233 patients were treatment-naïve and 202 were 

second-line patients who had received one prior IL-2 or INF-based therapy. The performance status 

(ECOG) was similar between the pazopanib and placebo groups (ECOG 0: 42% vs. 41%, ECOG 1: 

58% vs. 59%). The majority of patients had either favourable (39%) or intermediate (54%), MSKCC 

(Memorial Sloan Kettering Cancer Centre) / Motzer prognostic factors. All patients had clear cell 

histology or predominantly clear cell histology. Approximately half of all patients had 3 or more 

organs involved in their disease and most patients had the lung (74%), and/or lymph nodes (54%) as a 

metastatic location for disease at baseline. 

 

  



 

23 

A similar proportion of patients in each arm were treatment-naïve and cytokine pre-treated (53% and 

47% in pazopanib arm, 54% and 46% in placebo arm). In the cytokine pre-treated subgroup, the 

majority (75%) had received interferon-based treatment. 

 

Similar proportions of patients in each arm had prior nephrectomy (89% and 88% in the pazopanib 

and placebo arms, respectively) and/or prior radiotherapy (22% and 15% in the pazopanib and placebo 

arms, respectively. 

 

The primary analysis of the primary endpoint PFS is based on disease assessment by independent 

radiological review in the entire study population (treatment-naïve and cytokine pre-treated). 

 

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

 

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

P value 

(one-sided) 

PFS     

Overall* ITT N = 290 N = 145   

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

Response rate N = 290 N = 145   

 % (95% CI) 30 (25.1,35.6) 3 (0.5, 6.4) – <0.001 
HR = hazard ratio; ITT = intent to treat; PFS = progression-free survival. * - treatment-naïve and cytokine 

pre-treated populations 

 

Figure 1 Kaplan-Meier curve for progression-free survival by independent assessment for the 

overall population (treatment-naïve and cytokine pre-treated populations) 

(VEG105192) 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 
x axis; Months, y axis; Proportion Progression Free, Pazopanib —―— (N = 290) Median 9.2 months; Placebo --

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

 



 

24 

Figure 2 Kaplan-Meier curve for progression-free survival by independent assessment for the 

treatment-naïve population (VEG105192) 

 

 
 

 

 

 

 

 

 

 

 

 

 

 

 

 
x axis; Months, y axis; Proportion Progression Free, Pazopanib —―— (N = 155) Median 11.1 months; Placebo 

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

 

Figure 3 Kaplan-Meier Curve for progression-free survival by independent assessment for 

the cytokine pre-treated population (VEG105192) 

 

 

 

 

 

 

 

 

 

 

 

 

 

 
 

 

x axis; Months, y 

axis; Proportion Progression Free, Pazopanib —―— (N = 135) Median 7.4 months; Placebo -------- (N = 67) 

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

 

For patients who responded to treatment, the median time to response was 11.9 weeks and the median 

duration of response was 58.7 weeks as per independent review (VEG105192). 

 

The median overall survival (OS) data at the protocol-specified final survival analysis were 

22.9 months and 20.5 months [HR = 0.91 (95% CI: 0.71, 1.16; p = 0.224)] for patients randomised to 

the pazopanib and placebo arms, respectively. The OS results are subject to potential bias as 54% of 

patients in the placebo arm also received pazopanib in the extension part of this study following 

disease progression. Sixty-six per cent of placebo patients received post-study therapy compared to 

30% of pazopanib patients. 

 

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

EORTC QLQ-C30 and EuroQoL EQ-5D. 

 



 

25 

In a Phase II study of 225 patients with locally recurrent or metastatic clear cell renal cell carcinoma, 

objective response rate was 35% and median duration of response was 68 weeks, as per independent 

review. Median PFS was 11.9 months. 

 

The safety, efficacy and quality of life of pazopanib versus sunitinib was evaluated in a randomised, 

open-label, parallel group Phase III non-inferiority study (VEG108844). 

 

In VEG108844, patients (N = 1110) with locally advanced and/or metastatic RCC who had not 

received prior systemic therapy, were randomised to receive either pazopanib 800 mg once daily 

continuously or sunitinib 50 mg once daily in 6-week cycles of dosing with 4 weeks on treatment 

followed by 2 weeks without treatment. 

 

The primary objective of this study was to evaluate and compare PFS in patients treated with 

pazopanib to those treated with sunitinib. Demographic characteristics were similar between the 

treatment arms. Disease characteristics at initial diagnosis and at screening were balanced between the 

treatment arms with the majority of patients having clear cell histology and Stage IV disease. 

 

VEG108844 achieved its primary endpoint of PFS and demonstrated that pazopanib was non-inferior 

to sunitinib, as the upper bound of the 95% CI for the hazard ratio was less than the protocol-specified 

non-inferiority margin of 1.25. Overall efficacy results are summarised in Table 5. 

 

Table 5 Overall efficacy results (VEG108844) 

 

Endpoint 

Pazopanib 

N = 557 

Sunitinib 

N = 553 

HR 

(95% CI) 

PFS    

Overall    

 Median (months) 

 (95% CI) 

8.4 

(8.3, 10.9) 

9.5 

(8.3, 11.0) 

1.047 

(0.898, 1.220) 

Overall Survival 

 Median (months) 

 (95% CI) 

 

28.3 

(26.0, 35.5) 

 

29.1 

(25.4, 33.1) 

 

0.915a 

(0.786, 1.065) 
HR = hazard ratio; PFS = progression-free survival; a P value = 0.245 (2-sided) 

 



 

26 

Figure 4 Kaplan-Meier Curve for progression-free survival by independent assessment for 

the overall population (VEG108844) 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Subgroup analyses of PFS were performed for 20 demographic and prognostic factors. The 95% 

confidence intervals for all subgroups include a hazard ratio of 1. In the three smallest of these 

20 subgroups, the point estimate of the hazard ratio exceeded 1.25; i.e. in subjects with no prior 

nephrectomy (n=186, HR=1.403, 95% CI (0.955, 2.061)), baseline LDH >1.5 x ULN (n=68, HR=1.72, 

95% CI (0.943, 3.139)), and MSKCC: poor risk (n=119, HR=1.472, 95% CI (0.937, 2.313)). 

 

  



 

27 

Soft-tissue sarcoma (STS) 

The efficacy and safety of pazopanib in STS were evaluated in a pivotal Phase III randomised, 

double-blind, placebo-controlled multicentre study (VEG110727). A total of 369 patients with 

advanced STS were randomised to receive pazopanib 800 mg once daily or placebo. Importantly, only 

patients with selective histological subtypes of STS were allowed to participate to the study, therefore 

efficacy and safety of pazopanib can only be considered established for those subgroups of STS and 

treatment with pazopanib should be restricted to such STS subtypes. 

 

The following tumour types were eligible: 

Fibroblastic (adult fibrosarcoma, myxofibrosarcoma, sclerosing epithelioid fibrosarcoma, malignant 

solitary fibrous tumours), so-called fibrohistiocytic (pleomorphic malignant fibrous histiocytoma 

[MFH], giant cell MFH, inflammatory MFH), leiomyosarcoma, malignant glomus tumours, skeletal 

muscles (pleomorphic and alveolar rhabdomyosarcoma), vascular (epithelioid hemangioendothelioma, 

angiosarcoma), uncertain differentiation (synovial, epithelioid, alveolar soft part, clear cell, 

desmoplastic small round cell, extra-renal rhabdoid, malignant mesenchymoma, PEComa, intimal 

sarcoma), malignant peripheral nerve sheath tumours, undifferentiated soft tissue sarcomas not 

otherwise specified (NOS) and other types of sarcoma (not listed as ineligible). 

 

The following tumour types were not eligible: 

Adipocytic sarcoma (all subtypes), all rhabdomyosarcoma that were not alveolar or pleomorphic, 

chondrosarcoma, osteosarcoma, Ewing tumours/primitive neuroectodermal tumours (PNET), GIST, 

dermofibromatosis sarcoma protuberans, inflammatory myofibroblastic sarcoma, malignant 

mesothelioma and mixed mesodermal tumours of the uterus. 

Of note, patients with adipocytic sarcoma were excluded from the pivotal Phase III study as in a 

preliminary Phase II study (VEG20002) activity (PFS at week 12) observed with pazopanib in 

adipocytic did not meet the prerequisite rate to allow further clinical testing. 

 

Other key eligibility criteria of the VEG110727 study were: histological evidence of high or 

intermediate grade malignant STS and disease progression within 6 months of therapy for metastatic 

disease, or recurrence within 12 months of (neo) -/adjuvant therapy. 

 

Ninety-eight percent (98%) of subjects received prior doxorubicin, 70% prior ifosfamide, and 65% of 

subjects had received at least three or more chemotherapeutic agents prior to study enrolment. 

 

Patients were stratified by the factors of WHO performance status (WHO PS) (0 or 1) at baseline and 

the number of lines of prior systemic therapy for advanced disease (0 or 1 vs. 2+). In each treatment 

group, there was a slightly greater percentage of subjects in the 2+ lines of prior systemic therapy for 

advanced disease (58% and 55%, respectively, for placebo and pazopanib treatment arms) compared 

with 0 or 1 lines of prior systemic therapy (42% and 45%, respectively, for placebo and pazopanib 

treatment arms). The median duration of follow-up of subjects (defined as date of randomisation to 

date of last contact or death) was similar for both treatment arms (9.36 months for placebo [range 0.69 

to 23.0 months] and 10.04 months for pazopanib [range 0.2 to 24.3 months]. 

 

The primary objective of the study was progression-free survival (PFS assessed by independent 

radiological review); the secondary endpoints included overall survival (OS), overall response rate and 

duration of response. 

 



 

28 

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

 

Endpoints / study 

population 

Pazopanib Placebo HR (95% CI) P value 

(two-sided) 

PFS     

Overall ITT N = 246 N = 123   

Median (weeks) 20.0 7.0 0.35 (0.26, 0.48) <0.001 

     

Leiomyosarcoma N = 109 N = 49   

Median (weeks) 20.1 8.1 0.37 (0.23, 0.60) <0.001 

     

Synovial sarcoma subgroups N = 25 N = 13   

Median (weeks) 17.9 4.1 0.43 (0.19, 0.98) 0.005 

     

‘Other STS’ subgroups N = 112 N = 61   

Median (weeks) 20.1 4.3 0.39 (0.25, 0.60) <0.001 

     

OS     

Overall ITT N = 246 N = 123   

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

     

Leiomyosarcoma* N = 109 N = 49   

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

     

Synovial sarcoma subgroups* N = 25 N = 13   

Median (months) 8.7 21.6 1.62 (0.79, 3.33) 0.115 

     

“Other STS” subgroups* N = 112 N = 61   

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

     

Response rate (CR+PR)     

% (95% CI) 4 (2.3, 7.9) 0 (0.0, 3.0)   

Duration of response     

Median (weeks) (95% CI) 

 

38.9 (16.7, 40.0) 

 

 

 

 

 

 

 
HR = hazard ratio; ITT = intent to treat; PFS = progression-free survival; CR = complete response; PR = 

partial response. OS = overall survival 

* Overall survival for the respective STS histological subgroups (leiomyosarcoma, synovial sarcoma and 

“Other” STS) should be interpreted with caution due to the small number of subjects and wide confidence 

intervals 

 

A similar improvement in PFS based on investigator assessments was observed in the pazopanib arm 

compared with the placebo arm (in the overall ITT population HR: 0.39; 95% CI, 0.30 to 0.52, 

p <0.001). 

 



 

29 

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

Assessment for the Overall Population (VEG110727) 

 
 

No significant difference in OS was observed between the two treatment arms at the final OS analysis 

performed after 76% (280/369) of the events had occurred (HR 0.87, 95% CI 0.67, 1.12 p=0.256). 

 

Paediatric population 

 

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

Votrient in all subsets of the paediatric population in treatment of kidney and renal pelvis carcinoma 

(excluding nephroblastoma, nephroblastomatosis, clear cell sarcoma, mesoblastic nephroma, renal 

medullary carcinoma and rhabdoid tumour of the kidney) (see section 4.2 for information on 

paediatric use). 

 

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

Votrient in one or more subsets of the paediatric population in the treatment of rhabdomyosarcoma, 

non-rhabdomyosarcoma soft tissue sarcoma and Ewing sarcoma family of tumours (see section 4.2 for 

information on paediatric use). 

 

5.2 Pharmacokinetic properties 
 

Absorption 

 

Upon oral administration of a single pazopanib 800 mg dose to patients with solid tumours, maximum 

plasma concentration (Cmax) of approximately 19 ± 13 µg/ml was obtained after median 3.5 hours 

(range 1.0-11.9 hours) and an AUC0-∞ of approximately 650 ± 500 µg.h/ml was obtained. Daily dosing 

results in 1.23- to 4-fold increase in AUC0-T. 

 

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

 

Systemic exposure to pazopanib is increased when administered with food. Administration of 

pazopanib with a high-fat or low-fat meal results in an approximately 2-fold increase in AUC and 

Cmax. Therefore, pazopanib should be administered at least two hours after food or at least one hour 

before food (see section 4.2). 

 



 

30 

Administration of a pazopanib 400 mg crushed tablet increased AUC(0-72) by 46% and Cmax by 

approximately 2 fold and decreased tmax by approximately 2 hours compared to administration of the 

whole tablet. These results indicate that the bioavailability and the rate of pazopanib oral absorption 

are increased after administration of the crushed tablet relative to administration of the whole tablet 

(see section 4.2). 

 

Distribution 

 

Binding of pazopanib to human plasma protein in vivo was greater than 99% with no concentration 

dependence over the range of 10-100 g/ml. In vitro studies suggest that pazopanib is a substrate for 

P-gp and BCRP. 

 

Biotransformation 

 

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

CYP3A4, with minor contributions from CYP1A2 and CYP2C8. The four principle pazopanib 

metabolites account for only 6% of the exposure in plasma. One of these metabolites inhibits the 

proliferation of VEGF-stimulated human umbilical vein endothelial cells with a similar potency to that 

of pazopanib, the others are 10- to 20-fold less active. Therefore, activity of pazopanib is mainly 

dependent on parent pazopanib exposure. 

 

Elimination 

 

Pazopanib is eliminated slowly with a mean half-life of 30.9 hours after administration of the 

recommended dose of 800 mg. Elimination is primarily via faeces with renal elimination accounting 

for <4% of the administered dose. 

 

Special populations 

 

Renal impairment 

Results indicate that less than 4% of an orally administered pazopanib dose is excreted in the urine as 

pazopanib and metabolites. Results from population pharmacokinetic modelling (data from subjects 

with baseline CLCR values ranging from 30.8 ml/min to 150 ml/min) indicated that renal impairment 

is unlikely to have clinically relevant effect on pazopanib pharmacokinetics. No dose adjustment is 

required in patients with creatinine clearance above 30 ml/min. Caution is advised in patients with 

creatinine clearance below 30 ml/min as there is no experience of pazopanib in this patient population 

(see section 4.2). 

 

Hepatic impairment 

Mild 

The median steady-state pazopanib Cmax and AUC(0-24) in patients with mild abnormalities in hepatic 

parameters (defined as either normal bilirubin and any degree of ALT elevation or as an elevation of 

bilirubin up to 1.5 x ULN regardless of the ALT value) after administration of 800 mg once daily are 

similar to the median in patients with normal hepatic function (see Table 7). 800 mg pazopanib once 

daily is the recommended dose in patients with mild abnormalities of serum liver tests (see 

section 4.2). 

 

Moderate 

The maximally tolerated pazopanib dose (MTD) in patients with moderate hepatic impairment 

(defined as an elevation of bilirubin >1.5 x to 3 x ULN regardless of the ALT values) was 200 mg 

once daily. The median steady-state Cmax and AUC(0-24) values after administration of 200 mg 

pazopanib once daily in patients with moderate hepatic impairment were approximately 44% and 39%, 

of the corresponding median values after administration of 800 mg once daily in patients with normal 

hepatic function, respectively (see Table 7). 

 

Based on safety and tolerability data, the dose of pazopanib should be reduced to 200 mg once daily in 

subjects with moderate hepatic impairment (see section 4.2). 



 

31 

 

Severe 

The median steady-state Cmax and AUC(0-24) values after administration of 200 mg pazopanib once 

daily in patients with severe hepatic impairment were approximately 18% and 15%, of the 

corresponding median values after administration of 800 mg once daily in patients with normal hepatic 

function. Based on the diminished exposure and limited hepatic reserve pazopanib is not 

recommended in patients with severe hepatic impairment (defined as total bilirubin >3 X ULN 

regardless of any level of ALT) (see section 4.2). 

 

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

impairment. 

 

Group Investigated 

dose 

Cmax (µg/ml) AUC (0-24) 

(µg x hr/ml) 

Recommended 

dose 

Normal hepatic 

function 

800 mg OD 52.0 

(17.1-85.7) 

888.2 

(345.5-1482) 

800 mg OD 

Mild HI 800 mg OD 33.5 

(11.3-104.2) 

774.2 

(214.7-2034.4) 

800 mg OD 

Moderate HI 200 mg OD 22.2 

(4.2-32.9) 

256.8 

(65.7-487.7) 

200 mg OD 

Severe HI 200 mg OD 9.4 

(2.4-24.3) 

130.6 

(46.9-473.2) 

Not recommended 

OD – once daily 

 

5.3 Preclinical safety data 
 

The preclinical safety profile of pazopanib was assessed in mice, rats, rabbits and monkeys. In repeat 

dose studies in rodents, effects in a variety of tissues (bone, teeth, nail beds, reproductive organs, 

haematological tissues, kidney and pancreas) appear related to the pharmacology of VEGFR inhibition 

and/or disruption of VEGF signalling pathways, with most effects occurring at plasma exposure levels 

below those observed in the clinic. Other observed effects include body weight loss, diarrhoea and/or 

morbidity that were either secondary to local gastrointestinal effects caused by high local mucosal 

medicinal product exposure (monkeys) or pharmacological effects (rodents). Proliferative hepatic 

lesions (eosinophilic foci and adenoma) were seen in female mice at exposures 2.5 times human 

exposure based on AUC. 

 

In juvenile toxicity studies, when pre-weaning rats were dosed from day 9 post partum through to 

day 14 post partum, pazopanib caused mortalities and abnormal organ growth/maturation in kidney, 

lung, liver and heart, at a dose approximately 0.1 times the clinical exposure based on AUC in adult 

humans. When post-weaning rats were dosed from day 21 post partum to day 62 post partum, 

toxicological findings were similar to adult rats at comparable exposures. Human paediatric patients 

are at increased risk for bone and teeth effects as compared to adults, as these changes, including 

inhibition of growth (shortened limbs), fragile bones and remodelling of teeth, were present in juvenile 

rats at ≥10 mg/kg/day (equal to approximately 0.1-0.2 times the clinical exposure based on AUC in 

adult humans) (see section 4.4). 

 

Reproductive, fertility and teratogenic effects 

 

Pazopanib has been shown to be embryotoxic and teratogenic when administered to rats and rabbits at 

exposures more than 300-fold lower than the human exposure (based on AUC). Effects included 

reduced female fertility, increased pre- and post-implantation loss, early resorptions, embryo lethality, 

decreased foetal body weight and cardiovascular malformation. Decreased corpora lutea, increased 

cysts and ovarian atrophy have also been noted in rodents. In a rat male fertility study, there was no 

effect on mating or fertility, but decreased testicular and epididymal weights were noted with 

reductions in sperm production rates, sperm motility, and epididymal and testicular sperm 

concentrations observed at exposures 0.3 times human exposure based on AUC. 

 



 

32 

Genotoxicity 

 

Pazopanib did not cause genetic damage when tested in genotoxicity assays (Ames assay, human 

peripheral lymphocyte chromosome aberration assay and rat in vivo micronucleus). A synthetic 

intermediate in manufacture of pazopanib, which is also present in the final drug substance in low 

amounts, was not mutagenic in the Ames assay but genotoxic in the mouse lymphoma assay and in 

vivo mouse micronucleus assay. 

 

Carcinogenicity 

 

In two-year carcinogenicity studies with pazopanib, there were increased numbers of liver adenomas 

noted in mice and duodenal adenocarcinomas noted in rats. Based on the rodent-specific pathogenesis 

and mechanism for these findings, they are not considered to represent an increased carcinogenic risk 

for patients taking pazopanib. 

 

 

6. PHARMACEUTICAL PARTICULARS 

 

6.1 List of excipients 
 

Votrient 200 mg film-coated tablets 

 

Tablet core 

Magnesium stearate 

Microcrystalline cellulose 

Povidone (K30) 

Sodium starch glycolate 

 

Tablet coating 

Hypromellose 

Iron oxide red (E172) 

Macrogol 400 

Polysorbate 80 

Titanium dioxide (E171) 

 

Votrient 400 mg film-coated tablets 

 

Tablet core 

Magnesium stearate 

Microcrystalline cellulose 

Povidone (K30) 

Sodium starch glycolate 

 

Tablet coating 

Hypromellose 

Macrogol 400 

Polysorbate 80 

Titanium dioxide (E171) 

 

6.2 Incompatibilities 
 

Not applicable. 

 

6.3 Shelf life 
 

2 years. 

 



 

33 

6.4 Special precautions for storage 
 

This medicinal product does not require any special storage conditions. 

 

6.5 Nature and contents of container 

 

Votrient 200 mg film-coated tablets 

 

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

 

Votrient 400 mg film-coated tablets 

 

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

 

Not all pack sizes may be marketed. 

 

6.6 Special precautions for disposal 
 

No special requirements. 

 

 

7. MARKETING AUTHORISATION HOLDER 
 

Novartis Europharm Limited 

Vista Building 

Elm Park, Merrion Road 

Dublin 4 

Ireland 

 

 

8. MARKETING AUTHORISATION NUMBER(S) 

 

Votrient 200 mg film-coated tablets 

 

EU/1/10/628/001 

EU/1/10/628/002 

 

Votrient 400 mg film-coated tablets 

 

EU/1/10/628/003 

EU/1/10/628/004 

 

 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 

Date of first authorisation: 14 June 2010 

Date of latest renewal: 08 January 2018 

 

 

10. DATE OF REVISION OF THE TEXT 

 

 

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

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

  



 

34 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX II 
 

A. MANUFACTURERS RESPONSIBLE FOR BATCH 

RELEASE 

 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 

AND USE 

 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE 

MARKETING AUTHORISATION 

 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO 

THE SAFE AND EFFECTIVE USE OF THE MEDICINAL 

PRODUCT 

 



 

35 

A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE 

 

Name and address of the manufacturers responsible for batch release 

 

Novartis Pharma GmbH 

Roonstraße 25 

D-90429 Nuremberg 

Germany 
 

Glaxo Wellcome, S.A. 

Avda. Extremadura, 3 

09400 Aranda De Duero, Burgos 

Spain 

 

The printed package leaflet of the medicinal product must state the name and address of the 

manufacturer responsible for the release of the concerned batch. 

 

 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 

 

Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 

Characteristics, section 4.2). 

 

 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 

 

 Periodic safety update reports (PSURs) 
 

The requirements for submission of PSURS for this medicinal product are set out in the list of Union 

reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any 

subsequent updates published on the European medicines web-portal. 

 

 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 

 

 Risk management plan (RMP) 
 

The marketing authorisation holder (MAH) shall perform the required pharmacovigilance 

activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the 

marketing authorisation and any agreed subsequent updates of the RMP. 

 

An updated RMP should be submitted: 

 At the request of the European Medicines Agency; 

 Whenever the risk management system is modified, especially as the result of new information 
being received that may lead to a significant change to the benefit/risk profile or as the result of 

an important (pharmacovigilance or risk minimisation) milestone being reached. 

 

If the submission of a PSUR and the update of a RMP coincide, they can be submitted at the same 

time. 

 

  



 

36 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX III 

 

LABELLING AND PACKAGE LEAFLET 

 

  



 

37 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

A. LABELLING 

 

 

  



 

38 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

OUTER CARTON – 200 mg film-coated tablets 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Votrient 200 mg film-coated tablets 

pazopanib 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

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

 

 

3. LIST OF EXCIPIENTS 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Film-coated tablet 

 

30 film-coated tablets 

90 film-coated tablets 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Read the package leaflet before use. 

Oral use 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

8. EXPIRY DATE 

 

EXP 

 

 

9. SPECIAL STORAGE CONDITIONS 

 

 



 

39 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 

Vista Building 

Elm Park, Merrion Road 

Dublin 4 

Ireland 

 

 

12. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/10/628/001 30 film-coated tablets 

EU/1/10/628/002 90 film-coated tablets 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

votrient 200 mg 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

2D barcode carrying the unique identifier included. 

 

 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

PC 

SN 

NN 
  



 

40 

 

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING 

 

BOTTLE LABEL – 200 mg film-coated tablets 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Votrient 200 mg film-coated tablets 

pazopanib 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

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

 

 

3. LIST OF EXCIPIENTS 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Film-coated tablet 

 

30 film-coated tablets 

90 film-coated tablets 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Read the package leaflet before use. 

Oral use 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

8. EXPIRY DATE 

 

EXP 

 

 

9. SPECIAL STORAGE CONDITIONS 

 

 



 

41 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 

 

 

12. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/10/628/001 30 film-coated tablets 

EU/1/10/628/002 90 film-coated tablets 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

  



 

42 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

OUTER CARTON – 400 mg film-coated tablets 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Votrient 400 mg film-coated tablets 

pazopanib 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

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

 

 

3. LIST OF EXCIPIENTS 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Film-coated tablet 

 

30 film-coated tablets 

60 film-coated tablets 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Read the package leaflet before use. 

Oral use 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

8. EXPIRY DATE 

 

EXP 

 

 

9. SPECIAL STORAGE CONDITIONS 

 

 



 

43 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 

Vista Building 

Elm Park, Merrion Road 

Dublin 4 

Ireland 

 

 

12. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/10/628/003 30 film-coated tablets 

EU/1/10/628/004 60 film-coated tablets 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

votrient 400 mg 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

2D barcode carrying the unique identifier included. 

 

 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

PC 

SN 

NN 
  



 

44 

 

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING 

 

BOTTLE LABEL – 400 mg film-coated tablets 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Votrient 400 mg film-coated tablets 

pazopanib 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

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

 

 

3. LIST OF EXCIPIENTS 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Film-coated tablet 

 

30 film-coated tablets 

60 film-coated tablets 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Read the package leaflet before use. 

Oral use 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

8. EXPIRY DATE 

 

EXP 

 

 

9. SPECIAL STORAGE CONDITIONS 

 

 



 

45 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 

 

 

12. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/10/628/003 30 film-coated tablets 

EU/1/10/628/004 60 film-coated tablets 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

  



 

46 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

B. PACKAGE LEAFLET 



 

47 

Package leaflet: Information for the patient 
 

Votrient 200 mg film-coated tablets 

Votrient 400 mg film-coated tablets 

 

pazopanib 

 

Read all of this leaflet carefully before you start taking this medicine because it contains 

important information for you. 
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor or pharmacist. 
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 

- If you get any side effects, talk to your doctor or pharmacist. This includes any possible side 
effects not listed in this leaflet. See section 4. 

 

 

What is in this leaflet 
 

1. What Votrient is and what it is used for 

2. What you need to know before you take Votrient 

3. How to take Votrient 

4. Possible side effects 

5. How to store Votrient 

6. Contents of the pack and other information 

 

 

1. What Votrient is and what it is used for 

 

Votrient is a type of medicine called a protein kinase inhibitor. It works by preventing the activity of 

proteins that are involved in the growth and spread of cancer cells. 

 

Votrient is used in adults to treat: 

- kidney cancer that is advanced or has spread to other organs. 
- certain forms of soft-tissue sarcoma, which is a type of cancer that affects the supportive tissues 

of the body. It can occur in muscles, blood vessels, fat tissue or other tissues that support, 

surround and protect the organs. 

 

 

2. What you need to know before you take Votrient 

 

Do not take Votrient 

- if you are allergic to pazopanib or any of the other ingredients of this medicine (listed in 

section 6). 

Check with your doctor if you think this applies to you. 

 

  



 

48 

Warnings and precautions 

Talk to your doctor before taking Votrient: 

- if you have heart disease. 

- if you have liver disease. 

- if you have had heart failure or a heart attack. 

- if you have had prior collapse of a lung. 

- if you have had problems with bleeding, blood clots or narrowing of the arteries. 

- if you have had stomach or bowel problems such as perforation (hole) or fistula (abnormal 

passages forming between parts of the intestine). 

- if you have thyroid problems. 

- if you have problems with your kidney function. 

- if you have or have had an aneurysm (enlargement and weakening of a blood vessel wall) or a 

tear in a blood vessel wall. 

Tell your doctor if any of these apply to you. Your doctor will decide whether Votrient is suitable for 

you. You may need extra tests to check that your kidneys, heart and liver are working properly. 

 

High blood pressure and Votrient 

Votrient can raise your blood pressure. Your blood pressure will be checked before you take Votrient 

and while you are taking it. If you have high blood pressure you will be treated with medicines to 

reduce it. 

 

- Tell your doctor if you have high blood pressure. 
 

If you are going to have an operation 

Your doctor will stop Votrient at least 7 days before your operation as it may affect wound healing. 

Your treatment will be restarted when the wound has adequately healed. 

 

Conditions you need to look out for 

Votrient can make some conditions worse or cause serious side effects. You must look out for certain 

symptoms while you are taking Votrient to reduce the risk of any problems. See section 4. 

 

Children and adolescents 

Votrient is not recommended for people aged under 18. It is not yet known how well it works in this 

age group. Moreover it should not be used in children younger than 2 years of age because of safety 

concerns. 

 

Other medicines and Votrient 
Tell your doctor or pharmacist if you are taking, have recently taken, or might take any other 

medicines. This includes herbal medicines and other medicines you’ve bought without a prescription. 

 

Some medicines may affect how Votrient works or make it more likely that you’ll have side effects. 

Votrient can also affect how some other medicines work. These include: 

- clarithromycin, ketoconazole, itraconazole, rifamicin, telithromycin, voriconazzole (used to 

treat infection). 

- atazanavir, indinavir, nelfinavir, ritonavir, saquinavir (used to treat HIV). 

- nefazodone (used to treat depression). 

- simvastatin and possibly other statins (used to treat high cholesterol levels). 

- medicines that reduce stomach acid. The type of medicine that you are taking to reduce your 

stomach acid (e.g. proton pump inhibitor, H2 antagonists or antacids) may affect how Votrient is 

taken. Please consult your doctor or nurse for advice. 

Tell your doctor or pharmacist if you take any of these. 

 

  



 

49 

Votrient with food and drink 

Don’t take Votrient with food, as it affects the way the medicine is absorbed. Take it at least two 

hours after a meal or one hour before a meal (see section 3). 

Do not drink grapefruit juice while you are being treated with Votrient as this may increase the 

chance of side effects. 

 

Pregnancy, breast-feeding and fertility 

Votrient is not recommended if you are pregnant. The effect of Votrient during pregnancy is not 

known. 

- Tell your doctor if you are pregnant or planning to get pregnant. 
- Use a reliable method of contraception while you’re taking Votrient, and at least for 2 weeks 

after, to prevent pregnancy. 

- If you do become pregnant during treatment with Votrient, tell your doctor. 
 

Don’t breast-feed while taking Votrient. It is not known whether the ingredients in Votrient pass 

into breast milk. Talk to your doctor about this. 

 

Male patients (including those who have had vasectomies) who have partners who are either pregnant 

or who could become pregnant (including those who use other methods of contraception) should use 

condoms during sexual intercourse while taking Votrient and for at least 2 weeks after the last dose. 

 

Fertility may be affected by treatment with Votrient. Talk to your doctor about this. 

 

Driving and using machines 
Votrient can have side effects that may affect your ability to drive or use machines. 

- Avoid driving or using machines if you feel dizzy, tired or weak, or if your energy levels are 
low. 

 

 

3. How to take Votrient 

 

Always take this medicine exactly as your doctor has told you. Check with your doctor or 

pharmacist if you are not sure. 

 

How much to take 

The usual dose is two Votrient 400 mg tablets (800 mg pazopanib) taken once a day. This is the 

maximum dose per day. Your doctor may need to reduce your dose if you get side effects. 

 

When to take 

Don’t take Votrient with food. Take it at least two hours after a meal, or one hour before a meal. 

For example, you could take it two hours after breakfast or one hour before lunch. Take Votrient at 

about the same time each day. 

 

Swallow the tablets whole with water, one after the other. Do not break or crush the tablets as this 

affects the way the medicine is absorbed and may increase the chance of side effects. 

 

If you take more Votrient than you should 

If you take too many tablets, contact a doctor or pharmacist for advice. If possible show them the 

pack, or this leaflet. 

 

If you forget to take Votrient 

Do not take a double dose to make up for a forgotten dose. Just take your next dose at the usual time. 

 

Don’t stop Votrient without advice 

Take Votrient for as long as your doctor recommends. Don’t stop unless your doctor advises you to. 

 

 



 

50 

4. Possible side effects 
 

Like all medicines, this medicine can cause side effects, although not everybody gets them. 

 

Possible serious side effects 

 

Swelling of the brain (reversible posterior leukoencephalopathy syndrome) 

Votrient can, on rare occasions, cause swelling of the brain, which may be life threatening. Symptoms 

include: 

- loss of speech 
- change of vision 
- seizure (fits) 
- confusion 
- high blood pressure 
Stop taking Votrient and seek medical help immediately if you get any of these symptoms, or if 

you get headache accompanied with any of these symptoms. 

 

Hypertensive crisis (sudden and severe rise in blood pressure) 

Votrient can on occasion cause a sudden and severe rise in blood pressure. This is known as a 

hypertensive crisis. Your doctor will monitor your blood pressure while you are taking Votrient. Signs 

and symptoms of a hypertensive crisis may include: 

- severe chest pain 

- severe headache 

- blurred vision 

- confusion 

- nausea 

- vomiting 

- severe anxiety 

- shortness of breath 

- seizures (fits) 

- fainting 

Stop taking Votrient and seek medical help immediately if you develop hypertensive crisis. 

 

Heart conditions 
The risks of these problems may be higher for people with an existing heart problem, or who are 

taking other medicines. You will be checked for any heart problems while you are taking Votrient. 

 

Cardiac dysfunction/heart failure, heart attack 

Votrient can affect how well your heart pumps or can increase the likelihood of having a heart attack. 

Signs and symptoms include: 

- irregular or fast heartbeat 

- rapid fluttering of your heart 

- fainting 

- chest pain or pressure 

- pain in your arms, back, neck or jaw 

- shortness of breath 

- leg swelling 

Seek medical help immediately if you get any of these symptoms. 

 

Changes in heart rhythm (QT prolongation) 

Votrient can affect heart rhythm which in some people can develop into a potentially serious heart 

condition known as torsade de pointes. This can result in a very fast heartbeat causing a sudden loss of 

consciousness. 

Tell your doctor if you notice any unusual changes in your heart beat, such as beating too fast or 

too slow. 

 



 

51 

Stroke 
Votrient can increase your likelihood of having a stroke. Signs and symptoms of stroke may include: 

- numbness or weakness on one side of your body 

- difficulty talking 

- headache 

- dizziness 

Seek medical help immediately if you get any of these symptoms. 

 

Bleeding 

Votrient can cause severe bleeding in the digestive system (such as stomach, oesophagus, rectum or 

intestine), or the lungs, kidneys, mouth, vagina and brain, although this is uncommon. Symptoms 

include: 

- passing blood in the stools or passing black stools 
- passing blood in the urine 
- stomach pain 
- coughing or vomiting up blood 
Seek medical help immediately if you get any of these symptoms. 

 

Perforation and fistula 

Votrient can cause a tear (perforation) in your stomach or intestinal wall or the development of an 

abnormal connection between two parts of your digestive tract (a fistula). Signs and symptoms may 

include: 

- severe stomach pain 

- nausea and/or vomiting 

- fever 

- development of a hole (perforation) in the stomach, intestine or bowel from which bloody or 

foul smelling pus is released 

Seek medical help immediately if you get any of these symptoms. 

 

Liver problems 
Votrient can cause problems with your liver which may develop into serious conditions such as liver 

dysfunction and liver failure, which may be fatal. Your doctor will be checking your liver enzymes 

while you are taking Votrient. Signs that your liver may not be working properly may include: 

- yellowing of your skin or the whites of your eyes (jaundice) 

- dark urine 

- tiredness 

- nausea 

- vomiting 

- loss of appetite 

- pain on the right side of your stomach area (abdomen) 

- bruising easily 

Seek medical help immediately if you get any of these symptoms. 

 

Blood clots 
Deep vein thrombosis (DVT) and pulmonary embolism 

Votrient may cause blood clots in your veins, especially in your legs (deep vein thrombosis or DVT), 

which may also travel to your lungs (pulmonary embolism). Signs and symptoms may include: 

- sharp chest pain 

- shortness of breath 

- rapid breathing 

- leg pain 

- swelling of your arms and hands or legs and feet 

 



 

52 

Thrombotic microangiopathy (TMA) 

Votrient may cause blood clots in the small blood vessels in the kidneys and brain accompanied by a 

decrease in red blood cells and cells involved in clotting (thrombotic microangiopathy, TMA). Signs 

and symptoms may include: 

- bruising easily 

- high blood pressure 

- fever 

- confusion 

- drowsiness 

- seizures (fits) 

- decrease in urine output 

Seek medical help immediately if you get any of these symptoms. 

 

Tumour lysis syndrome 
Votrient can cause a fast breakdown of cancer cells resulting in tumour lysis syndrome, which in some 

people may be fatal. Symptoms may include irregular heartbeat, seizures (fits), confusion, muscle 

cramps or spasms, or decrease in urine output. Seek medical help immediately if you get any of these 

symptoms. 

 

Infections 
Infections occurring while you take Votrient may possibly become serious. Symptoms of infections 

may include: 

- fever 

- flu-like symptoms such as cough, tiredness and body aches that do not go away 

- shortness of breath and/or wheezing 

- pain while urinating 

- cuts, scrapes or wounds that are red, warm, swollen or painful 

Seek medical help immediately if you get any of these symptoms. 

 

Lung inflammation 

Votrient can, on rare occasions, cause lung inflammation (interstitial lung disease, pneumonitis), 

which in some people can be fatal. Symptoms include shortness of breath or cough that will not go 

away. You will be checked for any lung problems while you are taking Votrient. 

Seek medical help immediately if you get any of these symptoms. 

 

Thyroid problems 

Votrient can lower the amount of thyroid hormone produced in your body. This can result in weight 

increase and tiredness. You will be checked for thyroid hormone levels while you are taking Votrient. 

Tell your doctor if you notice significant weight gain or tiredness. 

 

Blurry or impaired vision 

Votrient can cause separation or tear of the lining of the back part of the eye (retinal detachment or 

tear). This can result in blurry or impaired vision. 

Tell your doctor if you notice any change in your vision. 

 

  



 

53 

Possible side effects (including possible serious side effects under the relevant frequency 

category). 

 
Very common side effects (may affect more than 1 in 10 people): 

- high blood pressure 
- diarrhoea 
- feeling or being sick (nausea or vomiting) 
- stomach pain 
- loss of appetite 
- weight loss 
- taste disturbance or loss of taste 
- sore mouth 
- headache 
- tumour pain 
- lack of energy, feeling weak or tired 
- changes in hair colour 
- unusual hair loss or thinning 
- loss of skin pigment 
- skin rash, possibly involving peeling of the skin 
- redness and swelling of the palms of the hands or soles of the feet 
Tell your doctor or pharmacist if any of these side effects becomes troublesome. 

 

Very common side effects that may show up in your blood or urine tests: 

- increase in liver enzymes 
- decrease in albumin in the blood 
- protein in the urine 
- decrease in the number of blood platelets (cells that help blood to clot) 
- decrease in the number of white blood cells 
 

Common side effects (may affect up to 1 in 10 people): 

- indigestion, bloating, flatulence 
- nose bleed 
- dry mouth or mouth ulcers 
- infections 
- abnormal drowsiness 
- difficulty sleeping 
- chest pain, shortness of breath, leg pain, and swelling of the legs/feet. These could be signs of a 

blood clot in your body (thromboembolism). If the clot breaks off, it may travel to your lungs 

and this may be life threatening or even fatal. 

- heart becomes less effective at pumping blood around the body (cardiac dysfunction) 
- slow heart beat 
- bleeding in the mouth, rectum or lung 
- dizziness 
- blurred vision 
- hot flushes 
- swelling caused by fluid of face, hands, ankles, feet or eyelids 
- tingling, weakness or numbness of the hands, arms, legs or feet 
- skin disorders, redness, itching, dry skin 
- nail disorders 
- burning, prickling, itching or tingling skin sensation 
- sensation of coldness, with shivering 
- excessive sweating 
- dehydration 
- muscle, joint, tendon or chest pain, muscle spasms 
- hoarseness 
- shortness of breath 
- cough 



 

54 

- coughing up blood 
- hiccups 
- collapsed lung with air trapped in the space between the lung and chest, often causing shortness 

of breath (pneumothorax) 

Tell your doctor or pharmacist if any of these effects become troublesome. 

 

Common side effects that may show up in your blood or urine tests: 

- underactive thyroid gland 
- abnormal liver function 
- increase in bilirubin (a substance produced by the liver) 
- increase in lipase (an enzyme involved in digestion 
- increase in creatinine (a substance produced in muscles) 
- changes in the levels of other different chemicals / enzymes in the blood. Your doctor will 

inform you of the results of the blood tests 

 

Uncommon side effects (may affect up to 1 in 100 people): 

- stroke 
- temporary fall in blood supply to the brain (transient ischaemic attack) 
- interruption of blood supply to part of the heart or heart attack (myocardial infarction) 
- partial interruption of blood supply to part of the heart (myocardial ischaemia) 
- blood clots accompanied by a decrease in red blood cells and cells involved in clotting 

(thrombotic microangiopathy, TMA). These may harm organs such as the brain and kidneys. 

- increase in the number of red blood cells 
- sudden shortness of breath, especially when accompanied with sharp pain in the chest and /or 

rapid breathing (pulmonary embolism) 

- severe bleeding in the digestive system (such as stomach, oesophagus or intestine), or the 
kidneys, vagina and brain 

- heart rhythm disturbance (QT prolongation) 
- hole (perforation) in stomach or intestine 
- abnormal passages forming between parts of the intestine (fistula) 
- heavy or irregular menstrual periods 
- sudden sharp increase in blood pressure (hypertensive crisis) 
- inflammation of the pancreas (pancreatitis) 
- liver inflamed, not working well or damaged 
- yellowing of the skin or whites of the eyes (jaundice) 
- inflammation of the lining of the abdominal cavity (peritonitis) 
- runny nose 
- rashes which may be itchy or inflamed (flat or raised spots or blisters) 
- frequent bowel movements 
- increased sensitivity of the skin to sunlight 
- decreased feeling or sensitivity, especially in the skin 
 

Rare side effects (may affect up to 1 in 1,000 people): 

- inflammation of the lung (pneumonitis) 
 

Not known (frequency cannot be estimated from the available data): 

- an enlargement and weakening of a blood vessel wall or a tear in a blood vessel wall 
(aneurysms and artery dissections) 

- tumour lysis syndrome resulting from a fast breakdown of cancer cells 
 

Reporting of side effects 

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 

not listed in this leaflet. You can also report side effects directly via the national reporting system 

listed in Appendix V. By reporting side effects you can help provide more information on the safety of 

this medicine. 

 

 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


 

55 

5. How to store Votrient 

 

Keep this medicine out of the sight and reach of children. 

 

Do not use this medicine after the expiry date (EXP) which is stated on the bottle and the carton. The 

expiry date refers to the last day of that month. 

 

This medicine does not require any special storage conditions. 

 

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 

throw away medicines you no longer use. These measures will help protect the environment. 

 

 

6. Contents of the pack and other information 

 

What Votrient contains 

- The active substance is pazopanib (as hydrochloride). 
Each Votrient 200 mg film-coated tablet contains 200 mg pazopanib. 

Each Votrient 400 mg film-coated tablet contains 400 mg pazopanib. 

- The other ingredients in the 200 mg and 400 mg tablets are: hypromellose, macrogol 400, 
magnesium stearate, microcrystalline cellulose, polysorbate 80, povidone (K30), sodium starch 

glycolate, titanium dioxide (E171). The 200 mg tablets also contain iron oxide red (E172). 

 

What Votrient looks like and contents of the pack 

Votrient 200 mg film-coated tablets are capsule-shaped, pink with “GS JT” marked on one side. They 

are supplied in bottles of 30 or 90 tablets. 

 

Votrient 400 mg film-coated tablets are capsule-shaped, white with “GS UHL” marked on one side. 

They are supplied in bottles of 30 or 60 tablets. 

 

Not all pack sizes or tablet strengths may be available in your country. 

 

Marketing Authorisation Holder 

Novartis Europharm Limited 

Vista Building 

Elm Park, Merrion Road 

Dublin 4 

Ireland 

 

Manufacturer 
Novartis Pharma GmbH 

Roonstraße 25 

D-90429 Nuremberg 

Germany 

 

Glaxo Wellcome, S.A. 

Avda. Extremadura, 3 

09400 Aranda De Duero, Burgos 

Spain 

 

  



 

56 

For any information about this medicine, please contact the local representative of the Marketing 

Authorisation Holder: 

 

België/Belgique/Belgien 

Novartis Pharma N.V. 

Tél/Tel: +32 2 246 16 11 

 

Lietuva 

SIA Novartis Baltics Lietuvos filialas 

Tel: +370 5 269 16 50 

 

България 

Novartis Bulgaria EOOD 

Тел: +359 2 489 98 28 

 

Luxembourg/Luxemburg 

Novartis Pharma N.V. 

Tél/Tel: +32 2 246 16 11 

 

Česká republika 

Novartis s.r.o. 

Tel: +420 225 775 111 

 

Magyarország 

Novartis Hungária Kft. 

Tel.: +36 1 457 65 00 

Danmark 

Novartis Healthcare A/S 

Tlf: +45 39 16 84 00 

 

Malta 

Novartis Pharma Services Inc. 

Tel: +356 2122 2872 

Deutschland 

Novartis Pharma GmbH 

Tel: +49 911 273 0 

 

Nederland 

Novartis Pharma B.V. 

Tel: +31 88 04 52 555 

Eesti 

SIA Novartis Baltics Eesti filiaal 

Tel: +372 66 30 810 

 

Norge 

Novartis Norge AS 

Tlf: +47 23 05 20 00 

Ελλάδα 

Novartis (Hellas) A.E.B.E. 

Τηλ: +30 210 281 17 12 

 

Österreich 

Novartis Pharma GmbH 

Tel: +43 1 86 6570 

España 

Novartis Farmacéutica, S.A. 

Tel: +34 93 306 42 00 

 

Polska 

Novartis Poland Sp. z o.o. 

Tel.: +48 22 375 4888 

France 

Novartis Pharma S.A.S. 

Tél: +33 1 55 47 66 00 

 

Portugal 

Novartis Farma - Produtos Farmacêuticos, S.A. 

Tel: +351 21 000 8600 

Hrvatska 

Novartis Hrvatska d.o.o. 

Tel. +385 1 6274 220 

 

România 

Novartis Pharma Services Romania SRL 

Tel: +40 21 31299 01 

Ireland 

Novartis Ireland Limited 

Tel: +353 1 260 12 55 

 

Slovenija 

Novartis Pharma Services Inc. 

Tel: +386 1 300 75 50 

Ísland 

Vistor hf. 

Sími: +354 535 7000 

 

Slovenská republika 

Novartis Slovakia s.r.o. 

Tel: +421 2 5542 5439 

 

Italia 

Novartis Farma S.p.A. 

Tel: +39 02 96 54 1 

Suomi/Finland 

Novartis Finland Oy 

Puh/Tel: +358 (0)10 6133 200 

 



 

57 

Κύπρος 

Novartis Pharma Services Inc. 

Τηλ: +357 22 690 690 

 

Sverige 

Novartis Sverige AB 

Tel: +46 8 732 32 00 

 

Latvija 

SIA Novartis Baltics 

Tel: +371 67 887 070 

 

United Kingdom 

Novartis Pharmaceuticals UK Ltd. 

Tel: +44 1276 698370 

 

 

This leaflet was last revised in 

 

Other sources of information 
Detailed information on this medicine is available on the European Medicines Agency web site: 

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

  



 

58 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX IV 

 

SCIENTIFIC CONCLUSIONS AND GROUNDS FOR THE VARIATION TO THE TERMS 

OF THE MARKETING AUTHORISATION(S) 

 



 

59 

Scientific conclusions 

 

Taking into account the PRAC Assessment Report on the PSUR(s) for pazopanib, the scientific 

conclusions of CHMP are as follows: 

 

In view of available data on tumour lysis syndrome from published literature, the Novartis clinical 

database, the Novartis Global Safety Database, and global databases including four noteworthy cases 

with close temporal relationship and six cases where causality with pazopanib could not completely 

be ruled out and in view of a plausible mechanism of action, the PRAC considers a causal 

relationship between pazopanib and Tumour lysis syndrome is at least a reasonable possibility. 

 

The PRAC concluded that the product information of products containing pazopanib should be 

amended accordingly. 

 

The CHMP agrees with the scientific conclusions made by the PRAC. 

 

Grounds for the variation to the terms of the marketing authorisation(s) 

 

On the basis of the scientific conclusions for pazopanib the CHMP is of the opinion that the benefit-

risk balance of the medicinal product(s) containing pazopanib is unchanged subject to the proposed 

changes to the product information. 

 

The CHMP recommends that the terms of the marketing authorisation(s) should be varied. 

 

 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET
	SCIENTIFIC CONCLUSIONS AND GROUNDS FOR THE VARIATION TO THE TERMS OF THE MARKETING AUTHORISATION(S)