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).

For a full list of excipients, see section 6.1.

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.

Votrient is indicated for the first line treatment of advanced Renal Cell Carcinoma (RCC) and for patients who have received prior cytokine therapy for advanced disease.

Votrient treatment should only be initiated by a physician experienced in the administration of anti-cancer agents.

Adults

The recommended dose of pazopanib is 800 mg 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 pazopanib should not exceed 800 mg.

Paediatric population

Pazopanib is not recommended for use in children and adolescents below 18 years of age due to insufficient data on safety and efficacy.

Elderly

There are limited data of 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 older individuals 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 (see section 5.2). 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.

Hepatic impairment

The safety and pharmacokinetics of pazopanib in patients with hepatic impairment have not been fully established (see section 4.4). Dosing recommendations in hepatically impaired patients are based on pharmacokinetic studies of pazopanib in patients with varying degrees of hepatic dysfunction (see section 5.2). Administration of pazopanib to patients with mild or moderate hepatic impairment should be undertaken with caution and close monitoring due to potentially increased exposure to the medicinal product. It is recommended that patients with mild abnormalities in liver parameters (defined as either normal bilirubin and any degree of alanine aminotransferase (ALT) elevation or as an elevation of bilirubin (> 35% direct) up to 1.5 x upper limited of normal (ULN) regardless of the ALT value) are treated initially with 800 mg pazopanib once daily. 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 x to 3 x ULN regardless of the ALT values) (see section 5.2).

Pazopanib is contraindicated in patients with severe hepatic impairment (see section 4.3).

Method of administration

Pazopanib should be taken without food, at least one hour before or two hours after a meal (see section 5.2). Votrient film-coated tablets should be taken whole with water and not broken or crushed (see section 5.2).

Hypersensitivity to the active substance or to any of the excipients.

Severe hepatic impairment.

Hepatic effects

Cases of hepatic failure (including fatalities) have been reported during use of pazopanib. The safety and pharmacokinetics of pazopanib have not been fully established in patients with pre-existing hepatic impairment. Administration of pazopanib to patients with mild or moderate hepatic impairment should be undertaken with caution and close monitoring. It is recommended that patients with mild abnormalities in liver parameter are treated initially with 800 mg pazopanib once daily. A reduced pazopanib dose of 200 mg once daily is recommended in patients with moderate hepatic impairment (see section 4.2). Pazopanib is contraindicated in patients with severe hepatic impairment (see section 4.3).

In clinical studies with pazopanib, increase in serum transaminases (ALT, 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.

Monitor serum liver tests before initiation of treatment with pazopanib 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.

• Patients with isolated transaminase elevations 8 X upper limit of normal (ULN) may be continued on pazopanib with weekly monitoring of liver function until transaminases return to Grade 1 or baseline.

• Patients with transaminases of > 8 X ULN should have pazopanib interrupted until they return to Grade 1 or baseline. If the potential benefit for reinitiating pazopanib treatment is considered to outweigh the risk for hepatotoxicity, then reintroduce pazopanib at a reduced dose and measure serum liver tests weekly for 8 weeks (see section 4.2). Following reintroduction of pazopanib, if transaminase elevations > 3 X ULN recur, then pazopanib should be discontinued.

• 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, pazopanib should be discontinued.

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 and treated as needed with standard anti-hypertensive therapy (see section 4.8). Elevated blood pressure levels (systolic blood pressure 150 or diastolic blood pressure 100 mm Hg) occurred early in the course of treatment (39 % of cases occurred by Day 9 and 88 % of cases occurred in the first 18 weeks). In the case of persistent hypertension despite anti-hypertensive therapy, the pazopanib dose may be reduced (see section 4.2). Pazopanib should be discontinued if there is evidence of persistently elevated values of blood pressure (140/90 mm Hg) or if arterial hypertension is severe and persists despite anti-hypertensive therapy and pazopanib dose reduction.

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 antiarrythmics or other medicinal products that may prolong QT interval and those with relevant pre-existing cardiac disease. When using pazopanib, base line 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, ischemic stroke, and transient ischemic attack were observed (see section 4.8). Pazopanib should be used with caution in patients who are at increased risk for any of these events. A treatment decision should be made based upon the assessment of individual patient's benefit/risk.

Haemorrhagic events

In clinical studies with pazopanib haemorrhagic events have been reported (see section 4.8). Pazopanib is not recommended in patients who had a history of haemoptysis, cerebral, 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 perforations and fistula

In clinical studies with pazopanib, events of GI perforation or fistula have occurred (see section 4.8). 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.

Heart failure

The safety and pharmacokinetics of pazopanib in patients with moderate to severe heart failure has not been studied.

Hypothyroidism

In clinical studies with pazopanib, 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 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 Grade 4 proteinuria.

Pregnancy

Pre-clinical studies in animals have shown reproductive toxicity (see section 5.3). 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 section 4.6).

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 section 4.5). 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 section 4.5).

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 (see section 4.5).

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.

Co-administration of pazopanib with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, 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 1,500 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.

Concurrent administration of a single dose of pazopanib eye drops (at a low dose of 400 µg (80 µl of 5 mg/ml)) with the strong CYP3A4 inhibitor and P-gp inhibitor, ketoconazole, in healthy volunteers resulted in a 2.2- and 1.5-fold increase in mean AUC_(0-t) and C_max values, respectively. Inhibition of P-gp and/or BCRP by ketoconazole likely contributed to the increased exposure to pazopanib. At present no dosing recommendations can be made for either potent specific inhibitors of CYP3A4 or ketoconazole.

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).

Combination with strong CYP3A4, P-gp or BCRP inhibitors should therefore be avoided, or selection of an alternate concomitant medication with no or minimal potential to inhibit CYP3A4, 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 alternate 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 25 % 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. 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.

Pregnancy

There are no adequate data from the use of pazopanib in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown.

Pazopanib should not be used during pregnancy unless the clinical condition of the women 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 and avoid becoming pregnant while receiving treatment with pazopanib.

Breast-feeding

The safe use of pazopanib during lactation has not been established. It is not known whether pazopanib is excreted in human milk. There are no animal data on the excretion of pazopanib in animal milk. A risk to the suckling 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 (see section 5.3).

No studies on the effects on the ability to drive and use machines have been performed. 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.

Pooled data from the pivotal RCC study (VEG105192, n=290), extension study (VEG107769, n=71) and the supportive Phase II study (VEG102616, n=225) was eva luated in the overall eva luation of safety and tolerability of pazopanib (total n=586) in subjects with RCC (see section 5.1).

The most important serious adverse reactions were transient ischaemic attack, ischaemic stroke, myocardial ischaemia, cardiac dysfunction, gastrointestinal perforation and fistula, QT prolongation and pulmonary, gastrointestinal and cerebral haemorrhage, all adverse reactions being reported in < 1 % of treated patients.

Fatal events that were considered possibly related to pazopanib included gastrointestinal haemorrhage, pulmonary haemorrhage/haemoptysis, abnormal hepatic function, intestinal perforation and ischemic stroke.

The most common adverse reactions (experienced by at least 10 % of the patients) of any grade included: diarrhoea, hair colour change, hypertension, nausea, fatigue, anorexia, vomiting, dysgeusia, elevated alanine aminotransferase and elevated aspartate aminotransferase.

Treatment related adverse reactions, all grades, which were reported in RCC patients 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:

Categories have been assigned based on absolute frequencies in the clinical study data. Within each system organ class, adverse reactions with the same frequency are presented in order of decreasing seriousness.

Table 1: Treatment-related adverse reactions reported in RCC studies (n=586)

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