Europan 200 Mg Tablets

EUROPAN 200 mg is indicated for the treatment of advanced and/or metastatic renal cell carcinoma (RCC).

Posology
The recommended dose of EUROPAN 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 EUROPAN should not exceed 800 mg.

Method of administration
For oral use. EUROPAN 200 mg should be taken without food (at least one hour before or two hours after a meal) (see section 5.2).

Hypersensitivity to pazopanib and other ingredients listed in section 6.1.

Hepatic Effects
Cases of hepatic failure (including fatalities) have been documented with the use of pazopanib. Pazopanib has not been studied in patients with pre-existing hepatic impairment and therefore should be used with caution in these patients. In studies with pazopanib, increase in serum transaminases (ALT, AST) and bilirubin have been documented (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. Monitor serum liver tests before initiation of treatment with EUROPAN 200 mg and at least once every 4 weeks for the first 4 months of treatment, and as clinically indicated. Periodic monitoring should then continue after this time period.
u2022 Patients with isolated transaminase elevations u2264 8 X ULN may continue on EUROPAN 200 mg with weekly monitoring of liver function until transaminases return to Grade 1 or baseline.
u2022 Patients with transaminases of > 8 X ULN should have EUROPAN 200 mg interrupted until they return to Grade 1 or baseline. If the potential benefit for re-initiating EUROPAN 200 mg treatment is considered to outweigh the risk for hepatotoxicity, then re-introduce EUROPAN 200 mg at a reduced dose and measure serum liver tests weekly for 8 weeks (see section 4.2). If transaminase elevations > 3 X ULN recur, then EUROPAN 200 mg should be discontinued.
u2022 If transaminase elevations > 3 X ULN occur concurrently with bilirubin elevations > 2 X ULN, bilirubin fractionation should be performed. If direct (conjugated) bilirubin is > 35 % of total bilirubin, EUROPAN 200 mg should be discontinued.
Hypertension
Events of hypertension including newly diagnosed symptomatic episodes of elevated blood pressure (hypertensive crisis) have been documented with the use of pazopanib. Blood pressure should be well controlled prior to initiating EUROPAN 200 mg. 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 u2265 150 mm Hg or diastolic blood pressure u2265 100 mm Hg) have been documented 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 EUROPAN 200 mg (interruption and re-initiation at a reduced dose based on clinical judgement). EUROPAN 200 mg should be discontinued if there is evidence of hypertensive crisis or if hypertension is severe and persists despite anti-hypertensive therapy and EUROPAN 200 mg dose reduction (see sections 4.2 and 4.8).
Posterior reversible encephalopathy syndrome (PRES)/ Reversible posterior leukoencephalopathy syndrome (RPLS)
PRES/RPLS have been documented 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. Permanently discontinue EUROPAN 200 mg in patients developing PRES/RPLS.
Interstitial lung disease (ILD)/ Pneumonitis
ILD, which can be fatal, have been documented in association with pazopanib (see section 4.8). Monitor patients for pulmonary symptoms indicative of ILD/pneumonitis and discontinue pazopanib in patients developing ILD or pneumonitis.
Cardiac dysfunction/ Heart failure
The risks and benefits of EUROPAN 200 mg 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. Events of cardiac dysfunction such as congestive heart failure and decreased LVEF have been documented in association with pazopanib (see section 4.8). Concurrent hypertension may have exacerbated cardiac dysfunction in patients at risk by increasing cardiac after-load. Prior anthracycline therapy may be a risk factor for cardiac dysfunction. 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 studies with pazopanib, events of QT prolongation or torsade de pointes have been documented (see section 4.8). EUROPAN 200 mg should be used with caution in patients with a history of QT interval prolongation, patients taking antiarrhythmics or other medications that may potentially prolong QT interval, or those with relevant pre-existing cardiac disease. When using EUROPAN 200 mg, periodic monitoring of electrocardiograms and maintenance of electrolytes (calcium, magnesium, potassium) within normal range is recommended.
Arterial Thrombotic Events
In studies with pazopanib, myocardial infarctions, angina, ischemic stroke and transient ischemic attack have been documented (see section 4.8). EUROPAN 200 mg should be used with caution in patients who are at increased risk for these events. A treatment decision should be made based upon the assessment of individual patientu2019s benefit/risk.
Venous thromboembolic events
In studies with pazopanib, venous thromboembolic events including venous thrombosis and fatal pulmonary embolus have been documented.
Thrombotic microangiopathy (TMA)
In studies with pazopanib, TMA events have been documented (see section 4.8). Patients developing TMA should permanently discontinue treatment with pazopanib. Reversal of effects of TMA has been observed after treatment was discontinued. Pazopanib is not indicated for use in combination with other agents.
Haemorrhagic Events
In studies with pazopanib haemorrhagic events have been documented (see section 4.8). EUROPAN 200 mg is not recommended in patients who had a history of haemoptysis, cerebral, or clinically significant gastrointestinal haemorrhage in the past 6 months. EUROPAN 200 mg 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 pazopanib, this risk should be carefully considered in patients with risk factors such as hypertension or history of aneurysm.
Gastrointestinal Perforations and Fistula
In studies with pazopanib, events of gastrointestinal (GI) perforation or fistula have been documented (see section 4.8). EUROPAN 200 mg 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 VEGF inhibitors may impair wound healing, treatment with EUROPAN 200 mg should be stopped at least 7 days prior to scheduled surgery. The decision to resume EUROPAN 200 mg after surgery should be based on clinical judgement of adequate wound healing. EUROPAN 200 mg should be discontinued in patients with wound dehiscence.
Hypothyroidism
In studies with pazopanib, events of hypothyroidism have been documented (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 EUROPAN 200 mg 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 studies with pazopanib, proteinuria has been documented. Baseline and periodic urine analysis during treatment is recommended and patients should be monitored for worsening proteinuria. EUROPAN 200 mg 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 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 EUROPAN 200 mg. Patients at risk should be closely monitored and treated as clinically indicated.
Infections
Cases of serious infections (with or without neutropenia), in some cases with fatal outcome, have been documented.

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 EUROPAN 200 mg and to avoid becoming pregnant while receiving treatment with EUROPAN 200 mg.
Male patients (including those who have had vasectomies) should use condoms during sexual intercourse while taking EUROPAN 200 mg and for at least 2 weeks after the last dose of EUROPAN 200 mg to avoid potential exposure to the medicinal product for pregnant partners and female partners of reproductive potential.
Pregnancy
There are no adequate data from the use of EUROPAN 200 mg in pregnant women. Studies in animals have shown reproductive toxicity. The potential risk for humans is unknown.
Breastfeeding
The safe use of EUROPAN 200 mg during breastfeeding has not been established. It is not known whether EUROPAN 200 mg or its metabolites are excreted in human milk. There are no animal data on the excretion of EUROPAN 200 mg in animal milk. A risk to the breastfed child cannot be excluded. Breastfeeding should be discontinued during treatment with EUROPAN 200 mg.
Fertility
Animal studies documented that male and female fertility may be affected by treatment with EUROPAN 200 mg.

EUROPAN 200 mg 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 EUROPAN 200 mg should be borne in mind when considering the patientu2019s 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.

Tabulated summary of adverse reactions
Adverse reactions are listed below by MedDRA body system organ class. The following convention has been utilised for the classification of frequency: Frequent, less frequent and frequency unknown
SOC category Frequency Side effect
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 e , Hypophosphataemia, Dehydration, Weight decreased, Anorexia Less frequent Hypomagnesaemia Frequency unknown Tumour lysis syndrome*
Psychiatric disorders Frequent Insomnia
Nervous system disorders Frequent Dysgeusia c , Headache, Dizziness, Lethargy, Paraesthesia, Peripheral sensory neuropathy Less frequent Hypoaesthesia, Transient ischaemic attack, Somnolence, Cerebrovascular accident, Ischaemic stroke, Posterior reversible encephalopathy/ reversible posterior leukoencephalopathy syndrome u2020
Eye disorders Frequent Vision blurred Less frequent Retinal detachment u2020 , Retinal tear u2020 , Eyelash discolouration
Cardiac disorders Frequent QT prolongation Less frequent Bradycardia , Myocardial infarction, Cardiac dysfunction f , Myocardial ischaemia, Torsade de Pointes
Vascular disorders Frequent Hypertension, Hot flush, Venous thromboembolic event g , Flushing Less frequent Hypertensive crisis, Haemorrhage, Cerebral haemorrhage Frequency unknown Aneurysms and artery dissections
Respiratory, thoracic, and mediastinal disorders Frequent Epistaxis, Dysphonia, Dyspnoea, Haemoptysis Respiratory, thoracic, and mediastinal disorders Less frequent Rhinorrhoea, Pulmonary haemorrhage, Pneumothorax, Interstitial lung disease/ pneumonitis u2020
Gastrointestinal disorders Frequent Diarrhoea, Nausea, Vomiting, Abdominal pain a , Stomatitis, Dyspepsia, Flatulence, Abdominal distention, 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
Hepatobiliary disorders Frequent Hyperbilirubinaemia, Hepatic function abnormal, Hepatotoxicity Less frequent Jaundice, Drug induced liver injury, Hepatic failure
Skin and subcutaneous tissue disorders Frequent Hair colour change, Palmar-plantar erythrodysaesthesia syndrome, Alopecia , Rash, Skin hypopigmentation, Dry skin, Pruritus, Erythema, Skin depigmentation, Hyperhidrosis Less frequent Nail disorders, Skin exfoliation, Photosensitivity reaction, Rash erythematous, Skin disorder, Rash macular, Rash pruritic, Rash vesicular, Pruritus generalised, Rash generalised, Rash papular, Plantar erythema
Musculoskeletal and connective tissue disorders Frequent Arthralgia, Myalgia, Muscle spasms Less frequent Musculoskeletal pain
Renal and urinary disorders Frequent Proteinuria Less frequent Haemorrhage urinary tract
Reproductive system and breast disorders Less frequent Menorrhagia, Vaginal haemorrhage, Metrorrhagia
General disorders and administration site conditions Frequent Fatigue, Mucosal inflammation, Asthenia, Oedema b , Chest pain Less frequent Chills, Mucous membrane disorder
Investigations Frequent Alanine aminotransferase increased, Aspartate aminotransferase increased, Blood bilirubin increased, Blood creatinine increased, Lipase increased, White blood cell count decreased d , Blood thyroid stimulating hormone increased, Amylase increase, Gamma-glutamyltransferase increased, Blood pressure increased, Blood urea increased, Liver function test abnormal Less frequent Hepatic enzyme increased

Overdosage
Pazopanib doses up to 2 000 mg have been evaluated in studies without dose limiting toxicity.
Symptoms and Signs
There is currently limited experience with overdosage in pazopanib.
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 pazopanib because pazopanib is not significantly renally excreted and is highly bound to plasma proteins.