Pazotev 200 & 400 200 mg, 400 mg FC TABLETS

PAZOTEV is indicated for the treatment of advanced and/or metastatic renal cell carcinoma (RCC).

Posology: The recommended dose of PAZOTEV is 800 mg orally once daily. Dose modifications: Dose modification should be in 200 mg increments in a stepwise fashion based on individual tolerability in order to manage adverse reactions. The dose of PAZOTEV should not exceed 800 mg. CYP3A4 inhibitor: The concomitant use of strong CYP3A4 inhibitors may increase pazopanib concentrations and should be avoided (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole). If co-administration of a strong CYP3A4 inhibitor is warranted, a dose reduction to 400 mg of PAZOTEV is recommended based on pharmacokinetic studies. This dose is predicted to adjust the pazopanib AUC to the range observed without inhibitors (see section 4.5). However, there are no clinical data with this dose adjustment in patients receiving strong CYP3A4 inhibitors. Special populations: Elderly: No alteration of dosage, dosing frequency or route of administration is required in patients over 65 years. Renal impairment: There is no experience of PAZOTEV in patients with severe renal impairment or in patients undergoing peritoneal dialysis or haemodialysis. 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, Elimination). Hepatic impairment: The safety and pharmacokinetics of PAZOTEV in patients with hepatic impairment have not been fully established (see section 4.4). Paediatric population: The safety and efficacy of PAZOTEV in children have not been established. Method of administration: For oral use. PAZOTEV should be taken without food (at least one hour before or two hours after a meal) (see section 5.2).

• Known hypersensitivity to pazopanib, or any of the excipients of PAZOTEV listed in section 6.1.

Hepatic effects: Cases of hepatic failure (including fatalities) have been reported during use of PAZOTEV. Administration of PAZOTEV 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). PAZOTEV 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. Reports from 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 patients 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. See Table 1 for dose modification guidance for patients with baseline values of total bilirubin u22641,5 x ULN and AST and ALT u2264 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 PAZOTEV with weekly monitoring of liver function until transaminases return to Grade 1 or baseline. Transaminase elevation of >8 x ULN Interrupt PAZOTEV until transaminases return to Grade 1 or baseline. If the potential benefit of re-initiating pazopanib treatment is considered to outweigh the risk for hepatotoxicity, then re-introduce pazopanib at a reduced dose of 400 mg daily and perform serum liver tests weekly for 8 weeks. Following re-introduction of PAZOTEV, if transaminase elevations >3 x ULN recur, then PAZOTEV should be permanently discontinued. Transaminase elevations >3 x ULN concurrently with bilirubin elevations >2 x ULN Permanently discontinue PAZOTEV. Patients should be monitored until return to Grade 1 or baseline. PAZOTEV 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 (e.g., PAZOTEV) and simvastatin increases the risk of ALT elevations (see section 4.5) and should be undertaken with caution and close monitoring. Hypertension: Blood pressure should be well controlled prior to initiating PAZOTEV. Patients should be monitored for hypertension and treated as needed with standard antihypertensive therapy (see section 4.8). Hypertension occurs early in the course of treatment (88 % occurring in first 18 weeks). In the case of persistent hypertension despite antihypertensive therapy, the PAZOTEV dose may be reduced (see section 4.2). PAZOTEV should be discontinued if hypertension is severe and persists despite antihypertensive therapy and PAZOTEV 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 PAZOTEV. Interstitial lung disease (ILD)/Pneumonitis: ILD, which can be fatal, has been reported in association with pazopanib (see section 4.8). Patients should be monitored for pulmonary symptoms indicative of ILD/pneumonitis and PAZOTEV should be discontinued in patients developing ILD or pneumonitis. Cardiac dysfunction/Heart failure: The risks and benefits of PAZOTEV 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. 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 antidysrhythmics or other medicines 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: It has been reported that 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. PAZOTEV 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: It has been reported that 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 PAZOTEV. Reversal of effects of TMA has been observed after treatment was discontinued. PAZOTEV is not indicated for use in combination with other medicines. Haemorrhagic events: Reports from clinical studies with pazopanib, haemorrhagic events have been reported (see section 4.8). 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. PAZOTEV should be used with caution in patients with significant risk of haemorrhage. Aneurysms and artery dissections: The use of vascular endothelial growth factor (VEGF) pathway inhibitors in patients with or without hypertension may promote the formation of aneurysm and/or artery dissections. Before initiating PAZOTEV, this risk should be carefully considered in patients with risk factors such as hypertension or history of aneurysm. Gastrointestinal (GI) perforations and fistula: It has been reported that in clinical studies with pazopanib, events of GI perforation or fistula have occurred (see section 4.8). Fatal perforation events have occurred. PAZOTEV 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 PAZOTEV should be stopped at least 7 days prior to scheduled surgery. The decision to resume PAZOTEV after surgery should be based on clinical judgement of adequate wound healing. PAZOTEV should be discontinued in patients with wound dehiscence. Hypothyroidism: Reports from clinical studies with pazopanib showed 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 PAZOTEV treatment. All patients should be observed closely for signs and symptoms of thyroid dysfunction on PAZOTEV treatment. Laboratory monitoring of thyroid function should be performed periodically and managed as per standard medical practice. Proteinuria: Reports from clinical studies reported proteinuria. Baseline and periodic urine analysis during treatment is recommended and patients should be monitored for worsening proteinuria. PAZOTEV 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 PAZOTEV (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 PAZOTEV. Patients at risk should be closely monitored and treated as clinically indicated. Pneumothorax: Reports from clinical studies with pazopanib in advanced soft tissue sarcoma, have shown events of pneumothorax have occurred (see section 4.8). Patients on PAZOTEV 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: It has been reported from 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.

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 medicines 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 PAZOTEV 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 PAZOTEV (see section 4.5).

Women of childbearing potential/Contraception in males and females: Women of childbearing potential should be advised to use adequate contraception during treatment and for at least 2 weeks after the last dose of PAZOTEV and to avoid becoming pregnant while receiving treatment with PAZOTEV. Male patients (including those who have had vasectomies) should use condoms during sexual intercourse while taking PAZOTEV and for at least 2 weeks after the last dose of PAZOTEV to avoid potential exposure to the medicine for pregnant partners and female partners of reproductive potential. Pregnancy: PAZOTEV should not be used during pregnancy. 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. Breastfeeding: The safe use of PAZOTEV during lactation has not been established. Breastfeeding should be discontinued during treatment with PAZOTEV. Fertility: PAZOTEV may impair fertility in human males and females. In female reproductive toxicity studies in rats, reduced female fertility has been observed.

PAZOTEV 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 PAZOTEV 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.

a. Summary of the safety profile: The safety and efficacy of PAZOTEV in renal cell carcinoma (RCC) were evaluated in a randomised, double-blind, placebo-controlled multi-centre study. Patients with locally advanced and/or metastatic RCC were randomised to receive PAZOTEV 800 mg once daily or placebo. The median duration of treatment was 7,4 months for the PAZOTEV arm and 3,8 months for the placebo arm. Adverse reactions are listed below by MedDRA body system organ class. Categories have been assigned based on absolute frequencies in the clinical trial data. b. Tabulated list of adverse reactions: Table 2: Treatment-related adverse reactions reported in RCC studies or during post-marketing period (MedDRA) System Organ Class Frequency Adverse reactions Infections and infestations Frequent Infections (with or without neutropenia)u2020 Less frequent Gingival infection, infectious peritonitis Neoplasms benign, malignant and unspecified (incl. cysts and polyps) Less frequent Tumour pain Blood and lymphatic system disorders Frequent Thrombocytopenia, neutropenia, leukopenia Less frequent Polycythaemia, thrombotic microangiopathy (including thrombotic thrombocytopenic purpura and haemolytic uraemic syndrome)u2020 Endocrine disorders Frequent Hypothyroidism Metabolism and nutrition disorders Frequent Decreased appetite, hypophosphataemia, dehydration, anorexia Less frequent Hypomagnesaemia, tumour lysis syndrome* Psychiatric disorders Frequent Insomnia Nervous system disorders Frequent Dysgeusia, headache, dizziness, lethargy, paraesthesia, peripheral sensory neuropathy Less frequent Hypoaesthesia, transient ischaemic attack, somnolence, cerebrovascular accident, ischaemic stroke, posterior reversible encephalopathy/reversible posterior leukoencephalopathy syndromeu2020 Eye disorders Frequent Blurred vision Less frequent Retinal detachmentu2020, retinal tearu2020, eyelash discolouration Cardiac disorders Frequent Myocardial ischaemia, QT prolongation Less frequent Bradycardia, myocardial infarction, cardiac dysfunction, Torsades de Pointes Vascular disorders Frequent Hypertension, hot flush, venous thromboembolic event, flushing Less frequent Hypertensive crisis, haemorrhage Frequency unknown Aneurysms and artery dissections Respiratory, thoracic and mediastinal disorders Frequent Epistaxes, dysphonia, dyspnoea, haemoptysis, chest pain Less frequent Rhinorrhoea, pulmonary haemorrhage, pneumothorax, interstitial lung disease/pneumonitisu2020 Gastrointestinal disorders Frequent Diarrhoea, vomiting, nausea, abdominal pain, stomatitis, dyspepsia, flatulence, abdominal distension, mouth ulceration, dry mouth Less frequent Pancreatitis, rectal haemorrhage, haematochezia, gastrointestinal haemorrhage, melaena, frequent bowel movements, anal haemorrhage, large intestine perforation, mouth haemorrhage, upper gastrointestinal haemorrhage, enterocutaneous fistula, haematemesis, haemorrhoidal haemorrhage, ileal perforation, oesophageal haemorrhage, retroperitoneal haemorrhage

PAZOTEV doses up to 2 000 mg have been evaluated in clinical trials without dose-limiting toxicity. Symptoms and signs: There is currently limited experience with overdosage in PAZOTEV. Treatment: Further management should be as clinically indicated or as recommended by the national poisons centre, where available. Haemodialysis is not expected to enhance the elimination of PAZOTEV because pazopanib is not significantly renally excreted and is highly bound to plasma proteins.