Sign Out
In clinical studies with pazopanib, increase in serum transaminases (ALT, aspartate aminotransferase [AST]) and bilirubin were observed (see Adverse Reactions). 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 Pharmacology: Pharmacodynamics under Actions).
Serum liver tests should be performed before initiation of treatment with pazopanib and 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 5 for dose modification guidance for patients with baseline values of total bilirubin ≤1.5 x ULN and AST and ALT ≤2 x ULN: (See Table 5.)
Click on icon to see table/diagram/imageConcomitant use of pazopanib and simvastatin increases the risk of ALT elevations (see Interactions) 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 Dosage & Administration and Adverse Reactions). 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 Adverse Reactions). Patients should be monitored for pulmonary symptoms indicative of ILD/pneumonitis and pazopanib should be discontinued 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 (see Adverse Reactions). 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 mentioned previously) 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 Adverse Reactions). 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 Adverse Reactions). 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 (see Adverse Reactions). 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 Adverse Reactions). Fatal haemorrhagic 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 aneurysms and/or artery dissections. Before initiating pazopanib, this risk should be carefully considered in patients with risk factors such as hypertension or history of aneurysms.
Gastrointestinal (GI) perforations and fistula: In clinical studies with pazopanib, events of GI perforation or fistula have occurred (see Adverse Reactions). 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 on 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 Adverse Reactions). 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 urinalysis during treatment is recommended and patients should be monitored for worsening proteinuria. Pazopanib should be discontinued if the patient develops nephrotic syndrome.
Tumour lysis syndrome (TLS): The occurrence of TLS, including fatal TLS, has been associated with the use of pazopanib (see Adverse Reactions). 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 Adverse Reactions). Patients on pazopanib treatment should be observed closely for signs and symptoms of pneumothorax.
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 a number of other anti-cancer therapies (including for example pemetrexed, lapatinib or pembrolizumab) 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.
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 Interactions). 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 Interactions).
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 Interactions).
Grapefruit juice should be avoided during treatment with pazopanib (see Interactions).
Excipients: This medicinal product contains less than 1 mmol sodium (23 mg) per film-coated tablet, that is to say essentially 'sodium-free'.
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.
Use in children: Because the mechanism of action of pazopanib can severely affect organ growth and maturation during early post-natal development in rodents (see Pharmacology: Toxicology: Preclinical safety data under Actions), pazopanib should not be given to paediatric patients younger than 2 years of age.
Use in pregnancy: Pre-clinical studies in animals have shown reproductive toxicity (see Pharmacology: Toxicology: Preclinical safety data under Actions). 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 Use in Pregnancy & Lactation).
