Votrient

Votrient^® 200 mg film-coated tablets

Votrient^® 400 mg film-coated tablets

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).

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.

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.

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.

The safety and efficacy of pazopanib in children aged 2 to 18 years of age have not yet been established. No data are available.

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. 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. All patients should have liver function tests to determine whether they have hepatic impairment before starting and during pazopanib therapy. 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).

Pazopanib is not recommended in patients with severe hepatic impairment (defined as total bilirubin >3 x ULN regardless of the ALT value).

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. The film-coated tablets should be taken whole with water and not broken or crushed.

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). Pazopanib is not recommended in patients with severe hepatic impairment (total bilirubin >3 x ULN regardless of the ALT value). 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. 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.

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.

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

Concomitant use of pazopanib and simvastatin increases the risk of ALT elevations 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). 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. Monitor patients for pulmonary symptoms indicative of ILD/pneumonitis and discontinue pazopanib in patients developing ILD or pneumonitis.

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. 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. 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. 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.

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. 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. 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.

Gastrointestinal (GI) perforations and fistula

In clinical studies with pazopanib, events of GI perforation or fistula have occurred. 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. 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.

Pneumothorax

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

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. 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.

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.

Grapefruit juice should be avoided during treatment with pazopanib.

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 C_max, respectively, relative to administration of pazopanib alone (400 mg once daily for 7 days). Pharmacokinetic parameter comparisons of pazopanib C_max (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 C_max 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 C_max 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. 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.

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 C_max 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 C_max, respectively.

Based on in vitro IC₅₀ and in vivo plasma C_max 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. 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 C_max. Therefore, pazopanib should be administered at least 1 hour before or 2 hours after a meal.

Medicinal products that raise gastric pH

Concomitant administration of pazopanib with esomeprazole decreases the bioavailability of pazopanib by approximately 40% (AUC and C_max), 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.

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. 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.

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.

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.

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.

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.

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)â€	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)â€	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
Psychiatric disorders	Common	Insomnia	30 (3%)	0	0
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 syndromeâ€	not known	not known	not known
Eye disorders	Common	Vision blurred	19 (2%)	1 (<1%)	0
	Uncommon	Retinal detachmentâ€	1 (<1%)	1 (<1%)	0
		Retinal tearâ€	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
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/pneumonitisâ€	not known	not known	not known
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%)
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	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. 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-β 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. 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 INFα-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. 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 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. 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) 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)). 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. 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). 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 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. 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. Distribution Binding of pazopanib to human plasma protein in vivo was greater than 99% with no concentration dependence over the range of 10-100 μg/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. 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. 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. 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). 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 Pharmacotherapeutic group Antineoplastic agents, other antineoplastic agents, protein kinase inhibitors, ATC code: L01XE11 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). 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. 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. 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) Incompatibilities Not applicable. Shelf life 2 years. Special precautions for storage This medicinal product does not require any special storage conditions. 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. Special precautions for disposal and other handling No special requirements. Marketing authorisation holder Novartis Europharm Limited Vista Building Elm Park, Merrion Road Dublin 4 Ireland 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 Date of first authorisation/renewal of the authorisation Date of first authorisation: 14 June 2010 Date of latest renewal: 14 June 2013 Date of revision of the text 08 May 2018 Votrient price Average cost of Votrient 200 mg per unit in online pharmacies is from 15.66$ to 46.51$, per pack from 490$ to 5581$. Average cost of Votrient 400 mg per unit in online pharmacies is from 29.5$ to 77.39$, per pack from 905$ to 4402$. References: https://www.drugs.com/mtm/pazopanib.html https://www.rxlist.com/votrient-drug.htm Available in countries Argentina Australia Austria Belgium Bosnia & Herzegowina Bulgaria Canada Chile Colombia Costa Rica Croatia (Hrvatska) Cyprus Czech Republic Denmark El Salvador Estonia Finland France Germany Greece Guatemala Honduras Hong Kong Hungary Iceland Indonesia Ireland Israel Italy Japan Latvia Liechtenstein Lithuania Luxembourg Malaysia Malta Mexico Netherlands New Zealand Norway Philippines Poland Portugal Romania Russia Serbia Singapore Slovakia Slovenia Spain Sweden Switzerland Thailand Turkey United Kingdom USA Vietnam Find in a country: A B C D E F G H I J K L M N O P Q R S T U V Y Z