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Votrient is a brand name for Pazopanib. The medicine, its uses, side effects and dosage are the same regardless of brand.
Used for: 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…
Verbatim from this product's EMA label. Tap a section to expand.
Votrient treatment should only be initiated by a physician experienced in the administration of anti-cancer medicinal products. 3 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.
3). The safety and efficacy of pazopanib in children aged 2 to 18 years of age have not yet been established. 2 but no recommendation on a posology can be made. 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.
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.
2). 4). Administration of pazopanib to patients with mild or moderate hepatic impairment should be undertaken with caution and close monitoring of tolerability. 5 x upper limit of normal (ULN) regardless of the ALT value). 2). Pazopanib is not recommended in patients with severe hepatic impairment (defined as total bilirubin >3 x ULN regardless of the ALT value).
4 for liver monitoring and dose modification for patients with drug-induced hepatotoxicity. Method of administration Pazopanib is for oral use. 2). 2). 4
1). 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).
12 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.
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.
5 x ULN regardless of the ALT value). 2). 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. 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. 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. 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.
1.
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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 13 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 Rare 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 14 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 […]
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.
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).
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.
8). 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. 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 […]