英文药名；VOTRIENT(PAZOPANIB HYDROCHLORIDE) 中文药名：帕唑帕尼片 生产厂家：GlaxoSmithKline 药品介绍 抗肿瘤激酶抑制剂；Votrient(pazopanib)帕唑帕尼片获美国FDA及欧盟批准上市治疗晚期肾细胞癌、软组织肉瘤、晚期卵巢癌的有效药物。 批准日期：2009年10月19日美国FDA；2009年2月18日欧盟EMEA授权孤儿药物。 2010年4月27日美国FDA修改说明书；公司：葛兰素史克GlaxoSmithKline INDICATIONS和USAGE 帕唑帕尼是一种激酶抑制剂适用于为治疗晚期肾细胞癌患者。 剂量和给药方法 800 mg口服每天1次不和食物一起服药(至少在进餐前1小时或后2小时)。 基线中度肝损伤–口服200 mg每天1次。严重肝损伤患者不建议使用。 800mg 口服每天1次无食物 (至少餐前1小时或餐后2小时). 基线中度肝损伤–200mg口服每天1次. Not recommended in患者with严重肝损伤. 剂型和规格 200mg片. 禁忌证 无 警告和注意事项 1）观察到增加血清转氨酶水平和胆红素。曾发生严重致死性肝毒性。开始治疗前和治疗期间定期测定肝化学。 2）曾观察到QT间隔延长和尖端扭转型室速(torsades de pointes)。较高危发生QT间隔延长患者慎用。应考虑监查心电图和电解质。 3) 曾报道致死性出血事件。尚未在既往6个月内有咯血、脑、或有临床意义胃肠道出血史的患者研究VOTRIENT而不应在这些患者中使用。 4) 曾观察到动脉血栓形成事件和可能致死。对这些事件风险增加患者中慎用。 5) 曾发生胃肠道穿孔或瘘管。曾发生致死性穿孔事件。胃肠道穿孔或瘘管风险增加患者中慎用。 6) 曾观察到高血压。开始用VOTRIENT应充分控制血压。需要时监查和治疗高血压。 7) 在进行手术患者中建议中断VOTRIENT治疗。 8) 可能发生甲状腺机能减退。建议监查甲状腺功能。 9）蛋白尿：监查尿蛋白。对4级蛋白尿中断药物。 10) 当妊娠妇女给予VOTRIENT可能危害胎儿。怀孕潜能妇女应忠告对胎儿的潜在危害和服用是避免受孕 不良反应 最常见不良反应(≥20%)是腹泻、高血压、毛发颜色变化(脱色素)、恶心、厌食、和呕吐。 药物相互作用 1） CYP3A4抑制剂：避免使用强抑制剂。VOTRIENT当与强CYP3A4抑制剂使用考虑减低剂量。 2） CYP3A4诱导剂：考率另一种同时药物无或小酶诱导潜能或避免VOTRIENT。 3）CYP底物：不建议VOTRIENT的同时使用治疗窗狭窄被CYP3A4, CYP2D6,或CYP2C8代谢药物。 Votrient 200 mg and 400 mg film coated tablets 1. Name of the medicinal product Votrient® 200 mg and 400 mg film-coated tablets 2. Qualitative and quantitative composition Each film-coated tablet contains 200 mg or 400 mg pazopanib (as hydrochloride). For the full list of excipients, see section 6.1. 3. Pharmaceutical form Film-coated tablet. 200 mg: Capsule-shaped, pink, film-coated tablet with GS JT debossed on one side. 400 mg: Capsule-shaped, white, film-coated tablet with GS UHL debossed on one side. 4. Clinical particulars 4.1 Therapeutic indications 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 advanced Soft Tissue Sarcoma (STS) who have received prior chemotherapy for metastatic disease or who have progressed within 12 months after (neo) adjuvant therapy. Efficacy and safety has only been established in certain STS histological tumour subtypes (see section 5.1). 4.2 Posology and method of administration Votrient treatment should only be initiated by a physician experienced in the administration of anti-cancer agents. Posology Adults The recommended dose of pazopanib for the treatment of RCC or STS 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 should not be used in children younger than 2 years of age because of safety concerns on organ growth and maturation (see section 4.4 and 5.3). The safety and efficacy of pazopanib in children aged 2 to 18 years of age have not yet been established (see section 5.1). No data are available. 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 30ml/min as there is no experience of pazopanib in this patient population. Hepatic impairment 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). All patients should have liver function tests to determine whether they have hepatic impairment before starting and during pazopanib therapy (see section 4.4). Administration of pazopanib to patients with mild or moderate hepatic impairment should be undertaken with caution and close monitoring of tolerability. 800 mg pazopanib once daily is the recommended dose in patients with mild abnormalities in serum liver tests (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 limit of normal (ULN) regardless of the ALT value). 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 to 3 x ULN regardless of the ALT values) (see section 5.2). Pazopanib is not recommended in patients with severe hepatic impairment (defined as total bilirubin > 3 X ULN regardless of any level of ALT). See section 4.4 for liver monitoring and dose modification for patients with drug induced hepatotoxicity. 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). 4.3 Contraindications Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 4.4 Special warnings and precautions for use 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. 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 as an 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 values) (see section 4.2 and 5.2). Pazopanib is not recommended in patients with severe hepatic impairment (total bilirubin > 3 x ULN regardless of any level of ALT) (see section 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. 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. Serum liver tests should be monitored before initiation of treatment with pazopanib and at weeks 3, 5, 7 and 9. Thereafter, monitored at month 3 and at month 4, and as clinically indicated. Periodic monitoring should then continue after month 4. See Table 1 for dose modification guidance for patients with baseline values of total bilirubin ≤ 1.5 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 for reinitiating pazopanib treatment is considered to outweigh the risk for hepatotoxicity, then reintroduce pazopanib at a reduced dose of 400 mg daily and measure 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. 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. Concomitant use of pazopanib and simvastatin increases the risk of ALT elevations (see section 4.5) 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 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 judgment) (see section 4.2 and 4.8). 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. 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 LVEF has not been studied. In clinical trials with pazopanib, events of cardiac dysfunction such as congestive heart failure and decreased left ventricular ejection fraction (LVEF) have occurred (see section 4.8). Congestive heart failure was reported in 2 out of 382 subjects (0.5 %) in the STS population. Decreases in LVEF in subjects who had post-baseline 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 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 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). 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 upon 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 Thrombotic microangiopathy (TMA) has been reported in clinical trials 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 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 section 4.8). Fatal haemorrhagic events have occurred. Pazopanib has not been studied 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). 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 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 nephrotic syndrome. Pneumothorax In clinical studies with pazopanib in advanced soft tissue sarcoma, events of pneumothorax have occurred (see section 4.8). Patients on pazopanib treatment should be observed closely for signs and symptoms of pneumothorax. Paediatric population Because the mechanism of action of pazopanib can severely affect organ growth and maturation during early post natal development in rodents (see section 5.3), pazopanib should not be given to paediatric patients younger than 2 years of age. 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 trials of pazopanib in combination with pemetrexed (non-small cell lung cancer (NSCLC)) and lapatinib (cervical cancer) 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. 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). 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 section 4.5). Grapefruit juice should be avoided during treatment with pazopanib (see section 4.5). 4.5 Interaction with other medicinal products and other forms of interaction 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. Concurrent administration of pazopanib (400 mg once daily) with the strong CYP3A4 and P-gp inhibitor, ketoconazole (400 mg once daily) for 5 consecutive days, resulted in a 66 % and 45 % increase in mean pazopanib AUC(0-24) and Cmax, respectively, relative to administration of pazopanib alone (400 mg once daily for 7 days). Pharmacokinetic parameter comparisons of pazopanib Cmax (range of means 27.5 to 58.1 µg/ml) and AUC(0-24) (range of means 48.7 to 1040 µg*h/ml) after administration of pazopanib 800 mg alone and after administration of pazopanib 400 mg plus ketoconazole 400 mg (mean Cmax 59.2 µg/ml, mean AUC(0-24)1300 µg*h/ml) indicated that, in the presence of a strong CYP3A4 and P-gp inhibitor a dose reduction to pazopanib 400 mg once daily will, in the majority of patients, result in systemic exposure similar to that observed after administration of 800 mg pazopanib once daily alone. Some patients however may have systemic pazopanib exposure greater than what has been observed after administration of 800 mg pazopanib alone. Co-administration of pazopanib with other strong inhibitors of the CYP3A4 family (e.g., 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 Cmax 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. 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). Concomitant use of pazopanib with a strong CYP3A4 inhibitor should be avoided (see section 4.4). If no medically acceptable alternative to a strong CYP34A inhibitor is available, the dose of pazopanib should be reduced to 400 mg daily during concomitant administration. In such cases there should be close attention to adverse drug reaction, and further dose reduction may be considered if possible drug-related adverse events are observed. Combination with strong P-gp or BCRP inhibitors should be avoided, or selection of an alternate concomitant medication with no or minimal potential to inhibit 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 Cmax 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 Cmax, respectively. Based on in vitro IC50 and in vivo plasma Cmax 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. statins, see “Effect of concomitant use of Pazopanib and Simvastatin” below). Pazopanib is an inhibitor of the uridine diphosphoglucuronosyl-transferase 1A1 (UGT1A1) enzyme in vitro. The active metabolite of irinotecan, SN-38, is a substrate for OATP1B1 and UGT1A1. Co-administration of pazopanib 400 mg once daily with cetuximab 250 mg/m2 and irinotecan 150 mg/m2 resulted in an approximately 20 % increase in systemic exposure to SN-38. Pazopanib may have a greater impact on SN-38 disposition in subjects with the UGT1A1*28 polymorphism relative to subjects with the wild-type allele. However, the UGT1A1 genotype was not always predictive of the effect of pazopanib on SN-38 disposition. Care should be taken when pazopanib is co-administered with substrates of UGT1A1. Effect of concomitant use of pazopanib and simvastatin Concomitant use of pazopanib and simvastatin increases the incidence of ALT elevations. Results from a meta-analysis using pooled data from clinical studies with pazopanib show that ALT > 3x ULN was reported in 126/895 (14 %) of patients who did not use statins, compared with11/41 (27 %) of patients who had concomitant use of simvastatin (p = 0.038). If a patient receiving concomitant simvastatin develops ALT elevations, follow guidelines for pazopanib posology and discontinue simvastatin (see section 4.4). In addition, concomitant use of pazopanib and other statins should be undertaken with caution as there are insufficient data available to assess their impact on ALT levels. It cannot be excluded that pazopanib will affect the pharmacokinetics of other statins (e.g., atorvastatin, fluvastatin, pravastatin, 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 Cmax. Therefore, pazopanib should be administered at least 1 hour before or 2 hours after a meal. Medicines that raise gastric pH Concomitant administration of pazopanib with esomeprazole decreases the bioavailability of pazopanib by approximately 40% (AUC and Cmax), and co-administration of pazopanib with medicines that increase gastric pH should be avoided. If the concomitant use of a proton-pump inhibitor (PPI) is medically necessary, it is recommended that the dose of pazopanib be taken without food once daily in the evening concomitantly with the PPI. If the concomitant administration of an H2-receptor antagonist is medically necessary, pazopanib should be taken without food at least 2 hours before or at least 10 hours after a dose of an H2-receptor antagonist. Pazopanib should be administered at least 1 hour before or 2 hours after administration of short-acting antacids. The recommendations for how PPIs and H2-receptor antagonists are co-administered are based on physiological considerations. 4.6 Fertility, pregnancy and lactation 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). 4.7 Effects on ability to drive and use machines 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. 4.8 Undesirable effects Summary of the safety profile Pooled data from the pivotal RCC trial (VEG105192, n=290), extension study (VEG107769, n=71), the supportive Phase II trial (VEG102616, n=225) and the randomised, open-label, parallel group Phase III non-inferiority study (VEG108844, n=557) was evaluated in the overall evaluation of safety and tolerability of pazopanib (total n=1149) in subjects with RCC (see section 5.1). Pooled data from the pivotal STS trial (VEG110727, n=369) and the supportive Phase II trial (VEG20002, n=142) was evaluated in the overall evaluation of safety and tolerability of pazopanib (total safety population n=382) in subjects with STS (see section 5.1). The most important serious adverse reactions identified in the RCC or STS trials were transient ischaemic attack, ischaemic stroke, myocardial ischaemia, myocardial and cerebral infarction, cardiac dysfunction, gastrointestinal perforation and fistula, QT prolongation and pulmonary, gastrointestinal and cerebral haemorrhage, all adverse reactions being reported in < 1 % of treated patients. Other important serious adverse reactions identified in STS trials 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 ischemic 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. Treatment related adverse reactions, all grades, which were reported in RCC and STS subjects or during 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 Not known  (cannot be estimated from the available data) Categories have been assigned based on absolute frequencies in the clinical trial data. Post marketing data on safety and tolerability across all pazopanib clinical trials 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. Tabulated list of adverse reactions Table 2: Treatment-related adverse reactions reported in RCC studies (n = 1149) or during post marketing period System Organ Class Frequency (all grades) Adverse Reactions All Grades n (%) Grade 3 n (%) Grade 4 n (%) Infections and Infestations Uncommon Infections (with or without neutropenia)† not known not known not known Uncommon Gingival infection 1 (< 1 %) 0 0 Uncommon Infectious peritonitis 1 (< 1 %) 0 0 Neoplasms benign, malignant and unspecified (incl cysts and polyps) Common Tumour pain 1 (< 1 %) 1 (< 1 %) 0 Blood and lymphatic system disorders Common Thrombocytopenia 80 (7 %) 10 (< 1 %) 5 (< 1 %) Common Neutropenia 79 (7 %) 20 (2 %) 4 (< 1 %) Common Leukopenia 63 (5 %) 5 (< 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 Common Dehydration 16 (1 %) 5 (< 1 %) 0 Uncommon Hypomagnesaemia 10 (< 1 %) 0 0 Psychiatric disorders Common Insomnia 30 (3 %) 0 0 Nervous system disorders Very common Dysgeusiac 254 (22 %) 1 (< 1 %) 0 Very common Headache 122 (11 %) 11 (< 1 %) 0 Common Dizziness 55 (5 %) 3 (< 1 %) 1 (< 1 %) Common Lethargy 30 (3 %) 3 (< 1 %) 0 Common Paraesthesia 20 (2 %) 2 (< 1 %) 0 Common Peripheral sensory neuropathy 17 (1 %) 0 0 Uncommon Hypoaesthesia 8 (< 1 %) 0 0 Uncommon Transient ischaemic attack 7 (< 1 %) 4 (< 1 %) 0 Uncommon Somnolence 3 (< 1 %) 1 (< 1 %) 0 Uncommon Cerebrovascular accident 2 (< 1 %) 1 (< 1 %) 1 (< 1 %) Uncommon 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 Eyelash discolouration 4 (< 1 %) 0 0 Cardiac disorders Uncommon Bradycardia 6 (< 1 %) 0 0 Uncommon Myocardial infarction 5 (< 1 %) 1 (< 1 %) 4 (< 1 %) Uncommon Cardiac dysfunction f 4 (< 1 %) 1 (< 1 %) 0 Uncommon 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 Common Venous Thromboembolic event g 13 (1 %) 6 (< 1 %) 7 (< 1 %) Common Flushing 12 (1 %) 0 0 Uncommon Hypertensive crisis 6 (< 1 %) 0 2 (< 1 %) Uncommon Haemorrhage 1 (< 1 %) 0 0 Respiratory, thoracic and mediastinal disorders Common Epistaxis 50 (4 %) 1 (< 1 %) 0 Common Dysphonia 48 (4 %) 0 0 Common Dyspnoea 42 (4 %) 8 (< 1 %) 1 (< 1 %) Common Haemoptysis 15 (1 %) 1 (< 1 %) 0 Uncommon Rhinorrhoea 8 (< 1 %) 0 0 Uncommon Pulmonary haemorrhage 2 (< 1 %) 0 0 Uncommon Pneumothorax 1 (< 1 %) 0 0 Gastrointestinal disorders Very common Diarrhoea 614 (53 %_) 65 (6 %) 2 (< 1 %) Very common Nausea 386 (34 %) 14 (1%) 0 Very common Vomiting 225 (20 %) 18 (2 %) 1 (< 1 %) Very common Abdominal paina 139 (12 %) 15 (1 %) 0 Common Stomatitis 96 (8 %) 4 (< 1 %) 0 Common Dyspepsia 83 (7 %) 2 (< 1 %) 0 Common Flatulence 43 (4 %) 0 0 Common Abdominal distension 36 (3 %) 2 (< 1 %) 0 Common Mouth ulceration 28 (2 %) 3 (< 1 %) 0 Common Dry mouth 27 (2 %) 0 0 Uncommon Pancreatitis 8 (< 1 %) 4 (< 1 %) 0 Uncommon Rectal haemorrhage 8 (< 1 %) 2 (< 1 %) 0 Uncommon Haematochezia 6 (< 1 %) 0 0 Uncommon Gastrointestinal haemorrhage 4 (< 1 %) 2 (< 1 %) 0 Uncommon Melaena 4 (< 1 %) 1(< 1 %) 0 Uncommon Frequent bowel movements 3 (< 1 %) 0 0 Uncommon Anal haemorrhage 2 (< 1 %) 0 0 Uncommon Large intestine perforation 2 (< 1 %) 1 (< 1 %) 0 Uncommon Mouth haemorrhage 2 (< 1 %) 0 0 Uncommon Upper gastrointestinal haemorrhage 2 (< 1 %) 1 (< 1 %) 0 Uncommon Enterocutaneous fistula 1 (< 1 %) 0 0 Uncommon Haematemesis 1 (< 1 %) 0 0 Uncommon Haemorrhoidal haemorrhage 1 (< 1 %) 0 0 Uncommon Ileal perforation 1 (< 1 %) 0 1 (< 1 %) Uncommon Oesophageal haemorrhage 1 (< 1 %) 0 0 Uncommon Retroperitoneal haemorrhage 1 (< 1 %) 0 0 Hepatobiliary disorders Common Hyperbilirubinaemia 38 (3 %) 2 (< 1 %) 1 (< 1 %) Common Hepatic function abnormal 29 (3 %) 13 (1 %) 2 (< 1 %) Common Hepatotoxicity 18 (2 %) 11(< 1 %) 2 (< 1 %) Uncommon Jaundice 3 (< 1 %) 1 (< 1 %) 0 Uncommon Drug induced liver injury 2 (< 1 %) 2 (< 1 %) 0 Uncommon Hepatic failure 1 (< 1 %) 0 1 (< 1 %) Skin and subcutaneous disorders Very common Hair colour change 404 (35 %) 1 (< 1 %) 0 Very common Palmar-plantar erythrodysaesthesia syndrome 206 (18 %) 39 (3 %) 0 Very common Alopecia 130 (11 %) 0 0 Very common Rash 129 (11 %) 7 (< 1 %) 0 Common Skin hypopigmentation 52 (5 %) 0 0 Common Dry skin 50 (4 %( 0 0 Common Pruritus 29 (3 %) 0 0 Common Erythema 25 (2 %) 0 0 Common Skin depigmentation 20 (2 %) 0 0 Common Hyperhidrosis 17 (1 %) 0 0 Uncommon Nail disorders 11 (< 1 %) 0 0 Uncommon Skin exfoliation 10 (< 1 %) 0 0 Uncommon Photosensitivity reaction 7 (< 1 %) 0 0 Uncommon Rash erythematous 6 (< 1 %) 0 0 Uncommon Skin disorder 5 (< 1 %) 0 0 Uncommon Rash macular 4 (< 1 %) 0 0 Uncommon Rash pruritic 3 (< 1 %) 0 0 Uncommon Rash vesicular 3 (< 1 %) 0 0 Uncommon Pruritus generalised 2 (< 1 %) 1 (< 1 %) 0 Uncommon Rash generalised 2 (< 1 %) 0 0 Uncommon Rash papular 2 (< 1 %) 0 0 Uncommon Plantar erythema 1 (< 1 %) 0 0 Musculoskeletal and connective tissue disorders Common Arthralgia 48 (4 %) 8 (< 1 %) 0 Common Myalgia 35 (3 %) 2 (< 1 %) 0 Common Muscle spasms 25 (2 %) 0 0 Uncommon Musculoskeletal pain 9 (< 1 %) 1 (< 1 %) 0 Renal and urinary disorders Common Proteinuria 135 (12 %) 32 (3 %) 0 Uncommon Haemorrhage urinary tract 1 (< 1 %) 0 0 Reproductive system and breast disorders Uncommon Menorrhagia 3 (< 1 %) 0 0 Uncommon Vaginal haemorrhage 3 (< 1 %) 0 0 Uncommon Metrorrhagia 1 (< 1 %) 0 0 General disorders and administration site conditions Very common Fatigue 415 (36 %) 65 (6 %) 1 (< 1 %) Common Mucosal inflammation 86 (7 %) 5 (< 1 %) 0 Common Asthenia 82 (7 %) 20 (2 %) 1 (< 1 %) Common Oedemab 72 (6 %) 1 (< 1 %) 0 Common Chest pain 18 (2 %) 2 (< 1 %) 0 Uncommon Chills 4 (< 1 %) 0 0 Uncommon Mucous membrane disorder 1 (< 1 %) 0 0 Investigations Very common Alanine aminotransferase increased 246 (21 %) 84 (7 %) 14 (1 %) Very common Aspartate aminotransferase increased 211 (18 %) 51 (4 %) 10 (< 1 %) Common Weight decreased 96 (8 %) 7 (< 1 %) 0 Common Blood bilirubin increased 61 (5 %) 6 (< 1 %) 1 (< 1 %) Common Blood creatinine increased 55 (5 %) 3 (< 1 %) 0 Common Lipase increased 51 (4 %) 21 (2 %) 7 (< 1 %) Common White blood cell count decreasedd 51 (4 %) 3 (< 1 %) 0 Common Blood thyroid stimulating hormone increased 36 (3 %) 0 0 Common Amylase increased 35 (3 %) 7 (< 1 %) 0 Common Gamma-glutamyltransferase increased 31 (3 %) 9 (< 1 %) 4 (< 1 %) Common Blood pressure increased 15 (1 %) 2 (< 1 %) 0 Common Blood urea increased 12 (1 %) 1 (< 1 %) 0 Common Liver function test abnormal 12 (1 %) 6 (< 1 %) 1 (< 1 %) Uncommon Hepatic enzyme increased 11 (< 1 %) 4 (< 1 %) 3 (< 1 %) Uncommon Blood glucose decreased 7 (< 1 %) 0 1 (< 1 %) Uncommon Electrocardiogram QT prolonged 7 (< 1 %) 2 (< 1 %) 0 Uncommon Transaminase increased 7 (< 1 %) 1 (< 1 %) 0 Uncommon Thyroid function test abnormal 3 (< 1 %) 0 0 Uncommon Blood pressure diastolic increased 2 (< 1 %) 0 0 Uncommon Blood pressure systolic increased 1 (< 1 %) 0 0 †Treatment related adverse reaction reported during post marketing period (spontaneous case reports and serious adverse reactions from all pazopanib clinical trials). The following terms have been combined: a Abdominal pain, abdominal pain upper and abdominal pain lower b Oedema, oedema peripheral, eye oedema, localised oedema and face oedema c Dysgeusia, ageusia and hypogeusia d White cell count decreased, neutrophil count decreased and leukocyte count decreased e Decreased appetite and anorexia f Cardiac dysfunction, left ventricular dysfunction, cardiac failure and restrictive cardiomyopathy g Venous thromboembolic event, deep vein thrombosis, pulmonary embolism and thrombosis Table 3: Treatment-related adverse reactions reported in STS trials (n=382) System Organ Class Frequency (all grades) Adverse Reactions All Grades n (%) Grade 3 n (%) Grade 4 n (%) Infections and infestations Common Gingival infection 4 (1 %) 0 0 Neoplasms benign, malignant and unspecified (incl cysts and polyps) Very common Tumour pain 121 (32 %) 32 (8 %) 0 Blood and lymphatic system disordersf Very common Leukopenia 106 (44 %) 3 (1 %) 0 Very common Thrombocytopenia 86 (36 % 7 (3 %) 2 (< 1 %) Very common Neutropenia 79 (33 %) 10 (4 %) 0 Rare Thrombotic microangiopathy (including thrombotic thrombocytopenic purpura and haemolytic uraemic syndrome) 1 (< 1 %) 1 (< 1 %) 0 Endocrine disorders Common Hypothyroidism 18 (5 %) 0 0 Metabolism and nutrition disorders Very common Decreased appetite 108 (28 %) 12 (3 %) 0 Very common Hyperalbuminemiaf 81 (34 %) 2 (< 1 %) 0 Common Dehydration 4 (1 %) 2 (1 %) 0 Uncommon Hypomagnesaemia 1 (< 1 %) 0 0 Psychiatric disorders Common Insomnia 5 (1 %) 1 (< 1 %) 0 Nervous system disorders Very common Dysgeusiac 79 (21 %) 0 0 Very common Headache 54 (14 %) 2 (< 1 %) 0 Common Peripheral sensory neuropathy 30 (8 %) 1 (< 1 %) 0 Common Dizziness 15 (4 %) 0 0 Uncommon Somnolence 3 (< 1 %) 0 0 Uncommon Paresthesia 1 (< 1 %) 0 0 Uncommon Cerebral infarction 1 (< 1 %) 0 1 (< 1 %) Eye disorders Common Vision blurred 15 (4 %) 0 0 Cardiac disorders Common Cardiac dysfunctiong 21 (5 %) 3 (< 1 %) 1 (< 1 %) Common Left ventricular dysfunction 13 (3 %) 3 (< 1 %) 0 Common Bradycardia 4 (1 %) 0 0 Uncommon Myocardial infarction 1 (< 1 %) 0 0 Vascular disorders Very common Hypertension 152 (40 %) 26 (7 %) 0 Common Venous thromboembolic eventd 13 (3 %) 4 (1 %) 5 (1 %) Common Hot flush 12 (3 %) 0 0 Common Flushing 4 (1 %) 0 0 Uncommon Haemorrhage 2 (< 1 %) 1 (< 1 %) 0 Respiratory, thoracic and mediastinal disorders Common Epistaxis 22 (6 %) 0 0 Common Dysphonia 20 (5 %) 0 0 Common Dyspnoea 14 (4 %) 3 (< 1 %) 0 Common Cough 12 (3 %) 0 0 Common Pneumothorax 7 (2 %) 2 (< 1 %) 1 (< 1 %) Common Hiccups 4 (1 %) 0 0 Common Pulmonary haemorrhage 4 (1 %) 1 (< 1 %) 0 Uncommon Oropharyngeal pain 3 (< 1 %) 0 0 Uncommon Bronchial haemorrhage 2 (< 1 %) 0 0 Uncommon Rhinorrhoea 1 (< 1 %) 0 0 Uncommon Haemoptysis 1 (< 1 %) 0 0 Gastrointestinal disorders Very common Diarrhoea 174 (46 %) 17 (4 %) 0 Very common Nausea 167 (44 %) 8 (2 %) 0 Very common Vomiting 96 (25 %) 7 (2 %) 0 Very common Abdominal paina 55 (14 %) 4 (1 %) 0 Very common Stomatitis 41 (11 %) 1 (< 1 %) 0 Common Abdominal distension 16 (4 %) 2 (1 %) 0 Common Dry mouth 14 (4 %) 0 0 Common Dyspepsia 12 (3 %) 0 0 Common Mouth haemorrhage 5 (1 %) 0 0 Common Flatulence 5 (1 %) 0 0 Common Anal haemorrhage 4 (1 %) 0 0 Uncommon Gastrointestinal haemorrhage 2 (< 1 % 0 0 Uncommon Rectal haemorrhage 2 (< 1 % 0 0 Uncommon Enterocutaneous fistula 1 (< 1 % 1 (< 1 %) 0 Uncommon Gastric haemorrhage 1 (< 1 % 0 0 Uncommon Melaena 2 (< 1 %) 0 0 Uncommon Oesophageal haemorrhage 1 (< 1 % 0 1 (< 1 % Uncommon Peritonitis 1 (< 1 % 0 0 Uncommon Retroperitoneal haemorrhage 1 (< 1 % 0 0 Uncommon Upper gastrointestinal haemorrhage 1 (< 1 % 1 (< 1 % 0 Uncommon Ileal perforation 1 (< 1 % 0 1 (< 1 % Hepatobiliary disorders Uncommon Hepatic function abnormal 2 (< 1 %) 0 1 (< 1 % Skin and subcutaneous disorders Very common Hair colour change 93 (24 %) 0 0 Very common Skin hypopigmentation 80 (21 %) 0 0 Very common Exfoliative rash 52 (14 %) 2 (< 1 %) 0 Common Alopecia 30 (8 %) 0 0 Common Skin disorderc 26 (7 %) 4 (1 %) 0 Common Dry skin 21 (5 %) 0 0 Common Hyperhydrosis 18 (5 %) 0 0 Common Nail disorder 13 (3 %) 0 0 Common Pruritus 11 (3 %) 0 0 Common Erythema 4 (1 %) 0 0 Uncommon Skin ulcer 3 (< 1 %) 1 (< 1 %) 0 Uncommon Rash 1 (< 1 %) 0 0 Uncommon Rash papular 1 (< 1 %) 0 0 Uncommon Photosensitivity reaction 1 (< 1 %) 0 0 Uncommon Palmar-plantar erythrodysaesthesia syndrome 2 (<1 %) 0 0 Musculoskeletal and connective tissue disorders Common Musculoskeletal pain 35 (9 %) 2 (< 1 %) 0 Common Myalgia 28 (7 %) 2 (< 1 %) 0 Common Muscle spasms 8 (2 %) 0 0 Uncommon Arthralgia 2 (< 1 %) 0 0 Renal and urinary disorders Uncommon Proteinuria 2 (<1 %) 0 0 Reproductive system and breast disorder Uncommon Vaginal haemorrhage 3 (< 1 %) 0 0 Uncommon Menorrhagia 1 (< 1 %) 0 0 General disorders and administration site conditions Very common Fatigue 178 (47 %) 34 (9 %) 1 (< 1 %) Common Oedemab 18 (5 %) 1 (< 1 %) 0 Common Chest pain 12 (3 %) 4 (1 %) 0 Common Chills 10 (3 %) 0 0 Uncommon Mucosal inflammatione 1 (<1 %) 0 0 Uncommon Asthenia 1 (< 1 % 0 0 Investigationsh Very common Weight decreased 86 (23 %) 5 (1 %) 0 Common Ear, nose and throat examination abnormale 29 (8 %) 4 (1 %) 0 Common Alanine aminotransferase increased 8 (2 %) 4 (1 %) 2 (< 1 %) Common Blood cholesterol abnormal 6 (2 %) 0 0 Common Aspartate aminotransferase increased 5 (1 %) 2 (< 1 %) 2 (< 1 %) Common Gamma glutamyltransferase increased 4 (1 %) 0 3 (< 1 %) Uncommon Blood bilirubin increased 2 (<1 %) 0 0 Uncommon Aspartate aminotransferase 2 (< 1 %) 0 2 (< 1 %) Uncommon Alanine aminotransferase 1 (< 1 %) 0 1 (< 1 %) Uncommon Platelet count decreased 1 (< 1 %) 0 1 (< 1 %) Uncommon Electrocardiogram QT prolonged 2 (< 1 %) 1 (< 1 %) 0 The following terms have been combined: a Abdominal pain, abdominal pain upper and gastrointestinal pain b Oedema, oedema peripheral and eyelid oedema c The majority of these cases were Palmar-plantar erythrodysaesthesia syndrome d Venous thromboembolic events – includes Deep vein thrombosis, Pulmonary embolism and Thrombosis terms e The majority of these cases describe mucositis f Frequency is based on laboratory value tables from VEG110727 (N=240). These were reported as adverse events less frequently by investigators than as indicated by laboratory value tables. g Cardiac dysfunction events – includes Left ventricular dysfunction, Cardiac failure and Restrictive cardiomyopathy h Frequency is based on adverse events reported by investigators. Laboratory abnormalities were reported as adverse events less frequently by investigators than as indicated by laboratory value tables. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard. 4.9 Overdose Pazopanib doses up to 2,000 mg have been evaluated in clinical studies. Grade 3 fatigue (dose limiting toxicity) and Grade 3 hypertension were each observed in 1 of 3 patients dosed at 2,000 mg and 1,000 mg daily, respectively. There is no specific antidote for overdose with pazopanib and treatment of overdose should consist of general supportive measures. 5. Pharmacological properties 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Antineoplastic agents, other antineoplastic agents, protein- kinase inhibitors, ATC code: L01XE11 Mechanism of action Pazopanib is an orally administered, potent multi-target tyrosine kinase inhibitor (TKI) of Vascular Endothelial Growth Factor Receptors (VEGFR)-1, -2, and -3, platelet-derived growth factor (PDGFR)-α and –β, and stem cell factor receptor (c-KIT), with IC50 values of 10, 30, 47, 71, 84 and 74 nM, respectively. In preclinical experiments, pazopanib dose-dependently inhibited ligand-induced auto-phosphorylation of VEGFR-2, c-Kit and PDGFR-β receptors in cells. In vivo, pazopanib inhibited VEGF-induced VEGFR-2 phosphorylation in mouse lungs, angiogenesis in various animal models, and the growth of multiple human tumour xenografts in mice. Clinical studies Renal Cell Carcinoma (RCC) The safety and efficacy of pazopanib in RCC were evaluated in a randomized, double-blind, placebo-controlled multi-centre study. Patients (N = 435) with locally advanced and/or metastatic RCC were randomized to receive pazopanib 800 mg once daily or placebo. The primary objective of the study was to evaluate and compare the two treatment arms for progression-free survival (PFS) and the principle secondary endpoint is overall survival (OS). The other objectives were to evaluate the overall response rate and duration of response. From the total of 435 patients in this study, 233 patients were treatment naïve and 202 were second line patients who received one prior IL-2 or INFα-based therapy. The performance status (ECOG) was similar between the pazopanib and placebo groups (ECOG 0: 42 % vs. 41 %, ECOG 1: 58 % vs. 59 %). The majority of patients had either favourable (39 %) or intermediate (54 %), MSKCC (Memorial Sloan Kettering Cancer Centre) / Motzer prognostic factors. All patients had clear cell histology or predominantly clear cell histology. Approximately half of all patients had 3 or more organs involved in their disease and most patients had the lung (74 %), and/or lymph nodes (54 %) as a metastatic location for disease at baseline. A similar proportion of patients in each arm were treatment-naïve and cytokine-pre-treated (53 % and 47 % in pazopanib arm, 54 % and 46 % in placebo arm). In the cytokine-pre-treated subgroup, the majority (75 %) had received interferon based treatment. Similar proportions of patients in each arm had prior nephrectomy (89 % and 88 % in the pazopanib and placebo arms, respectively) and/or prior radiotherapy (22 % and 15 % in the pazopanib and placebo arms, respectively. The primary analysis of the primary endpoint PFS is based on disease assessment by independent radiological review in the entire study population (treatment naïve and cytokine pre-treated). Table 4: Overall efficacy results in RCC by independent assessment (VEG105192) Endpoints/Study Population Pazopanib Placebo HR (95% CI) P value (one-sided) PFS Overall* ITT Median (months) N = 290 9.2 N = 145 4.2 0.46 (0.34, 0.62) < 0.0000001 Response rate % (95% CI) N = 290 30 (25.1,35.6) N = 145 3 (0.5, 6.4) –  < 0.001 HR = Hazard ratio; ITT = Intent to treat; PFS = Progression-free survival. * - Treatment-Naïve and Cytokine Pre-treated Populations. Figure 1: Kaplan-Meier curve for progression-free survival by independent assessment for the overall population (treatment-naïve and cytokine pre-treated populations) (VEG105192) x axis; Months, y axis; Proportion Progression Free, Pazopanib —―— (N = 290) Median 9.2 months; Placebo -------- (N = 145) Median 4.2 months; Hazard Ratio = 0.46, 95 % CI (0.34, 0.62), P < 0.0000001 Figure 2: Kaplan-Meier curve for progression-free survival by independent assessment for the treatment-naïve population (VEG105192) x axis; Months, y axis; Proportion Progression Free, Pazopanib —―— (N = 155) Median 11.1 months; Placebo -------- (N = 78) Median 2.8 months; Hazard Ratio = 0.40, 95 % CI (0.27, 0.60), P < 0.0000001 Figure 3: Kaplan-Meier Curve for progression-free survival by independent assessment for the cytokine pre-treated population (VEG105192) x axis; Months, y axis; Proportion Progression Free, Pazopanib —―— (N = 135) Median 7.4 months; Placebo -------- (N = 67) Median 4.2 months; Hazard Ratio = 0.54, 95 % CI (0.35, 0.84), P < 0.001 For patients who responded to treatment, the median time to response was 11.9 weeks and the median duration of response was 58.7 weeks as per independent review (VEG105192). The median overall survival (OS) data at the protocol specified final survival analysis were 22.9 months and 20.5 months [HR = 0.91 (95 % CI: 0.71, 1.16; p = 0.224)] for patients randomized to the pazopanib and placebo arms, respectively. The OS results are subject to potential bias as 54 % of patients in the placebo arm also received pazopanib in the extension part of this study following disease progression. Sixty-six percent of placebo patients received post-study therapy compared to 30 % of pazopanib patients. No statistical differences were observed between treatment groups for Global Quality of Life using EORTC QLQ-C30 and EuroQoL EQ-5D. In a Phase 2 study of 225 patients with locally recurrent or metastatic clear cell renal cell carcinoma, objective response rate was 35 % and median duration of response was 68 weeks, as per independent review. Median PFS was 11.9 months. The safety, efficacy and quality of life of pazopanib versus sunitinib has been evaluated in a randomized, open-label, parallel group Phase III non-inferiority study (VEG108844). In VEG108844, patients (N = 1110) with locally advanced and/or metastatic RCC who had not received prior systemic therapy, were randomized to receive either pazopanib 800 mg once daily continuously or sunitinib 50 mg once daily in 6-week cycles of dosing with 4 weeks on treatment followed by 2 weeks without treatment. The primary objective of this study was to evaluate and compare PFS in patients treated with pazopanib to those treated with sunitinib. Demographic characteristics were similar between the treatment arms. Disease characteristics at initial diagnosis and at screening were balanced between the treatment arms with the majority of patients having clear cell histology and Stage IV disease. VEG108844 achieved its primary endpoint of PFS and demonstrated that pazopanib was non-inferior to sunitinib, as the upper bound of the 95 % CI for the hazard ratio was less than the protocol-specified non-inferiority margin of 1.25. Overall efficacy results are summarised in Table 5. Table 5: Overall efficacy results (VEG108844) Endpoint Pazopanib N = 557 Sunitinib N = 553 HR (95% CI) PFS Overall Median (months) (95 % CI) Overall Survival Median (months) (95 % CI) 8.4 (8.3, 10.9) 28.4 (26.2, 35.6) 9.5 (8.3, 11.0) 29.3 (25.3, 32.5) 1.047 (0.898, 1.220) 0.908a (0.762, 1.082) HR = Hazard Ratio; PFS = Progression-free Survival; a P value = 0.275 (2-sided) Figure 4: Kaplan-Meier Curve for progression-free survival by independent assessment for the overall population (VEG108844) Subgroup analyses of PFS were performed for 20 demographic and prognostic factors. The 95 % confidence intervals for all subgroups include a hazard ratio of 1. In the three smallest of these 20 subgroups, the point estimate of the hazard ratio exceeded 1.25; i.e., in subjects with no prior nephrectomy (n=186, HR=1.403, 95 % CI (0.955, 2.061)), baseline LDH > 1.5 x ULN (n=68, HR=1.72, 95 % CI (0.943, 3.139)), and MSKCC: poor risk (n=119, HR=1.472, 95 % CI (0.937, 2.313)). Soft Tissue Sarcoma (STS) The efficacy and safety of pazopanib in STS were evaluated in a pivotal phase III randomized, double-blind, placebo-controlled multi-centre trial (VEG110727). A total of 369 patients with advanced STS were randomized to receive pazopanib 800 mg once daily or placebo. Importantly, only patients with selective histological subtypes of STS were allowed to participate in the study, therefore efficacy and safety of pazopanib can only be considered established for those subgroups of STS and treatment with pazopanib should be restricted to such STS subtypes. The following tumour types were eligible: Fibroblastic (adult fibrosarcoma, myxofibrosarcoma, sclerosing epithelioid fibrosarcoma, malignant solitary fibrous tumours), so-called fibrohistiocytic (pleomorphic malignant fibrous histiocytoma [MFH], giant cell MFH, inflammatory MFH), leiomyosarcoma, malignant glomus tumours, skeletal muscles (pleomorphic and alveolar rhabdomyosarcoma), vascular (epithelioid hemangioendothelioma, angiosarcoma), uncertain differentiation (synovial, epithelioid, alveolar soft part, clear cell, desmoplastic small round cell, extra-renal rhabdoid, malignant mesenchymoma, PEComa, intimal sarcoma), malignant peripheral nerve sheath tumours, undifferentiated soft tissue sarcomas not otherwise specified (NOS) and other types of sarcoma (not listed as ineligible). The following tumour types were not eligible: Adipocytic sarcoma (all subtypes), all rhabdomyosarcoma that were not alveolar or pleomorphic, chondrosarcoma, osteosarcoma, Ewing tumours/Primitive neuroectodermal tumours (PNET), GIST, dermatofibromatosis sarcoma protuberans, inflammatory myofibroblastic sarcoma, malignant mesothelioma and mixed mesodermal tumours of the uterus. Of note, patients with adipocytic sarcoma were excluded from the pivotal phase III study as in a preliminary phase II study (VEG20002), activity (PFS at week12) observed with pazopanib in adipocytic did not meet the prerequisite rate to allow further clinical testing. Other key eligibility criteria of the VEG110727 study were: histological evidence of high or intermediate grade malignant STS and disease progression within 6 months of therapy for metastatic disease, or recurrence within 12 months of (neo)-/adjuvant therapy. Ninety-eight percent (98 %) of subjects received prior doxorubicin, 70 % prior ifosfamide, and 65 % of subjects had received at least three or more chemotherapeutic agents prior to study enrolment. Patients were stratified by the factors of WHO performance status (WHO PS) (0 or 1) at baseline and the number of lines of prior systemic therapy for advanced disease (0 or 1 vs. 2+). In each treatment group, there was a slightly greater percentage of subjects in the 2+ lines of prior systemic therapy for advanced disease (58 % and 55 % respectively for placebo and pazopanib treatment arms) compared with 0 or 1 lines of prior systemic therapy (42 % and 45 % respectively for placebo and pazopanib treatment arms). The median duration of follow-up of subjects (defined as date of randomization to date of last contact or death) was similar for both treatment arms (9.36 months for placebo [range 0.69 to 23.0 months] and 10.04 months for pazopanib [range 0.2 to 24.3 months]. The primary objective of the trial was progression-free survival (PFS assessed by independent radiological review); the secondary endpoints included overall survival (OS), overall response rate and duration of response. Table 6: Overall efficacy results in STS by independent assessment (VEG110727) Endpoints / study population Pazopanib Placebo HR (95 % CI) P value (two-sided) PFS Overall ITT Median (weeks) Leiomyosarcoma Median (weeks) Synovial sarcoma subgroups Median (weeks) 'Other STS' subgroups Median (weeks) N = 246 20.0 N = 109 20.1 N = 25 17.9 N = 112 20.1 N = 123 7.0 N = 49 8.1 N = 13 4.1 N = 61 4.3 0.35 (0.26, 0.48) 0.37 (0.23, 0.60) 0.43 (0.19, 0.98) 0.39 (0.25, 0.60) < 0.001 < 0.001 0.005 < 0.001 OS Overall ITT Median (months) Leiomyosarcoma* Median (months) Synovial sarcoma subgroups* Median (months) 'Other STS' subgroups* Median (months) N = 246 12.6 N = 109 16.7 N = 25 8.7 N = 112 10.3 N = 123 10.7 N = 49 14.1 N = 13 21.6 N = 61 9.5 0.87 (0.67,1.12) 0.84 (0.56, 1.26 1.62 (0.79, 3.33) 0.84 (0.59, 1.21) 0.256 0.363 0.115 0.325 Response Rate (CR+PR) % (95 % CI) Duration of response Median (weeks) (95 % CI) 4 (2.3, 7.9) 38.9 (16.7, 40.0) 0 (0.0, 3.0)   HR = Hazard ratio; ITT = Intent to treat; PFS = Progression-free survival; CR = Complete Response; PR = Partial Response. OS = Overall survival * Overall survival for the respective STS histological subgroups (leiomyosarcoma, synovial sarcoma and “Other” STS) should be interpreted with caution due to the small number of subjects and wide confidence intervals A similar improvement in PFS based on investigator assessments was observed in the pazopanib arm compared with the placebo arm (in the overall ITT population HR: 0.39; 95 % CI, 0.30 to 0.52, p < 0.001). Figure 5: Kaplan-Meier Curve for Progression-Free Survival in STS by Independent Assessment for the Overall Population (VEG110727) No significant difference in OS was observed between the two treatment arms at the final OS analysis performed after 76% (280/369) of the events had occurred (HR 0.87, 95% CI 0.67, 1.12 p=0.256). Paediatric population The European Medicines Agency has waived the obligation to submit the results of studies with Votrient in all subsets of the paediatric population in treatment of kidney and renal pelvis carcinoma (excluding nephroblastoma, nephroblastomatosis, clear cell sarcoma, mesoblastic nephroma, renal medullary carcinoma and rhabdoid tumour of the kidney). The European Medicines Agency has deferred the obligation to submit the results of studies with Votrient in one or more subsets of the paediatric population in the treatment of rhabdomyosarcoma, non-rhabdomyosarcoma soft tissue sarcoma and Ewing sarcoma family of tumours. See section 4.2 for information on paediatric use. 5.2 Pharmacokinetic properties Absorption Upon oral administration of a single pazopanib 800 mg dose to patients with solid tumours, maximum plasma concentration (Cmax) of approximately 19 ± 13 µg/ml were obtained after median 3.5 hours (range 1.0-11.9 hours) and an AUC0-∞ of approximately 650 ± 500 µg.h/ml was obtained. Daily dosing results in 1.23- to 4-fold increase in AUC0-T. There was no consistent increase in AUC or Cmax at pazopanib doses above 800 mg. Systemic exposure to pazopanib is increased when administered with food. Administration of pazopanib with a high fat or low fat meal results in an approximately 2-fold increase in AUC and Cmax. Therefore, pazopanib should be administered at least two hours after food or at least one hour before food (see section 4.2). Administration of a pazopanib 400 mg crushed tablet increased AUC(0-72) by 46 % and Cmax by approximately 2 fold and decreased tmax by approximately 2 hours compared to administration of the whole tablet. These results indicate that the bioavailability and the rate of pazopanib oral absorption are increased after administration of the crushed tablet relative to administration of the whole tablet (see section 4.2). Distribution Binding of pazopanib to human plasma protein in vivo was greater than 99 % with no concentration dependence over the range of 10-100 μg/ml. In vitro studies suggest that pazopanib is a substrate for P-gp and BCRP. Biotransformation Results from in vitro studies demonstrated that metabolism of pazopanib is mediated primarily by CYP3A4, with minor contributions from CYP1A2 and CYP2C8. The four principle pazopanib metabolites account for only 6 % of the exposure in plasma. One of these metabolites inhibits the proliferation of VEGF-stimulated human umbilical vein endothelial cells with a similar potency to that of pazopanib, the others are 10- to 20-fold less active. Therefore, activity of pazopanib is mainly dependent on parent pazopanib exposure. Elimination Pazopanib is eliminated slowly with a mean half-life of 30.9 hours after administration of the recommended dose of 800 mg. Elimination is primarily via faeces with renal elimination accounting for < 4 % of the administered dose. Special populations Renal impairment: Results indicate that less than 4 % of an orally administered pazopanib dose is excreted in the urine as pazopanib and metabolites. Results from population pharmacokinetic modelling (data from subjects with baseline CLCR values ranging from 30.8 ml/min to 150 ml/min) indicated that renal impairment is unlikely to have clinically relevant effect on pazopanib pharmacokinetics. 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 (see section 4.2). Hepatic impairment: Mild: The median steady-state pazopanib Cmax and AUC(0-24) in patients with mild abnormalities in hepatic parameters (defined as either normal bilirubin and any degree of ALT elevation or as an elevation of bilirubin up to 1.5 x ULN regardless of the ALT value) after administration of 800 mg once daily are similar to the median in patients with normal hepatic function (see Table 7). 800 mg pazopanib once daily is the recommended dose in patients with mild abnormalities of serum liver tests (see section 4.2). Moderate: The maximally tolerated pazopanib dose (MTD) in patients with moderate hepatic impairment (defined as an elevation of bilirubin > 1.5 x to 3 x ULN regardless of the ALT values) was 200 mg once daily. The median steady-state Cmax and AUC(0-24) values after administration of 200 mg pazopanib once daily in patients with moderate hepatic impairment were approximately 44 % and 39 %, of the corresponding median values after administration of 800 mg once daily in patients with normal hepatic function, respectively (see Table 7). Based on safety and tolerability data, the dosage of pazopanib should be reduced to 200 mg once daily in subjects with moderate hepatic impairment (see section 4.2). Severe: The median steady-state Cmax and AUC(0-24) values after administration of 200 mg pazopanib once daily in patients with severe hepatic impairment were approximately 18 % and 15 %, of the corresponding median values after administration of 800 mg once daily in patients with normal hepatic function. Based on the diminished exposure and limited hepatic reserve pazopanib is not recommended in patients with severe hepatic impairment (defined as total bilirubin > 3 X ULN regardless of any level of ALT) (see section 4.2). Table 7; Median steady-state pazopanib pharmacokinetics measured in subjects with hepatic impairment. Group Investigated dose Cmax (µg/ml) AUC (0-24) (µg x hr/ml) Recommended Dose Normal hepatic function 800 mg OD 52.0 (17.1-85.7) 888.2 (345.5-1482) 800 mg OD Mild HI 800 mg OD 33.5 (11.3-104.2) 774.2 (214.7-2034.4) 800 mg OD Moderate HI 200 mg OD 22.2 (4.2-32.9) 256.8 (65.7-487.7) 200 mg OD Severe HI 200 mg OD 9.4 (2.4-24.3) 130.6 (46.9-473.2) Not recommended OD – Once daily 5.3 Preclinical safety data The preclinical safety profile of pazopanib was assessed in mice, rats, rabbits and monkeys. In repeat dose studies in rodents, effects in a variety of tissues (bone, teeth, nail beds, reproductive organs, haematological tissues, kidney and pancreas) appear related to the pharmacology of VEGFR inhibition and/or disruption of VEGF signalling pathways with most effects occurring at plasma exposure levels below those observed in the clinic. Other observed effects include body weight loss, diarrhoea and/or morbidity that were either secondary to local gastrointestinal effects caused by high local mucosal medicinal product exposure (monkeys) or pharmacologic effects (rodents). Proliferative hepatic lesions (eosinophilic foci and adenoma) were seen in female mice at exposures 2.5 times human exposure based on AUC. In juvenile toxicity studies, when pre-weaning rats were dosed from day 9 post partum through day 14 postpartum, pazopanib caused mortalities and abnormal organ growth/maturation in kidney, lung, liver and heart, at a dose approximately 0.1 times the clinical exposure based on AUC in adult humans. When post weaning rats were dosed from day 21 post partum to day 62 post partum, toxicologic findings were similar to adult rats at comparable exposures. Human paediatric patients are at increased risk for bone and teeth effects as compared to adults, as these changes, including inhibition of growth (shortened limbs), fragile bones and remodelling of teeth, were present in juvenile rats at ≥ 10 mg/kg/day (equal to approximately 0.1-0.2 times the clinical exposure based on AUC in adult humans) (see section 4.4). Reproductive, fertility and teratogenic effects Pazopanib has been shown to be embryotoxic and teratogenic when administered to rats and rabbits at exposures more than 300-fold lower than the human exposure (based on AUC). Effects included reduced female fertility, increased pre- and post-implantation loss, early resorptions, embryo lethality, decreased foetal body weight and cardiovascular malformation. Decreased corpora lutea, increased cysts and ovarian atrophy have also been noted in rodents. In a rat male fertility study, there was no effect on mating or fertility, but decreased testicular and epididymal weights were noted with reductions in sperm production rates, sperm motility, and epididymal and testicular sperm concentrations observed at exposures 0.3 times human exposure based on AUC. Genotoxicity Pazopanib did not cause genetic damage when tested in genotoxicity assays (Ames assay, human peripheral lymphocyte chromosome aberration assay and rat in vivo micronucleus). A synthetic intermediate in manufacture of pazopanib, which is also present in the final drug substance in low amounts, was not mutagenic in the Ames assay but genotoxic in the mouse lymphoma assay and in vivo mouse micronucleus assay. Carcinogenicity Carcinogenicity studies with pazopanib have not been performed. 6. Pharmaceutical particulars 6.1 List of excipients Tablet core Magnesium stearate Microcrystalline cellulose Povidone (K30) Sodium starch glycolate (type A) Tablet coating (200mg) Hypromellose Iron oxide red (E172) Macrogol 400 Polysorbate 80 Titanium dioxide (E171) Tablet coating (400mg) Hypromellose Macrogol 400 Polysorbate 80 Titanium dioxide (E171) 6.2 Incompatibilities Not applicable. 6.3 Shelf life 2 years. 6.4 Special precautions for storage This medicinal product does not require any special storage conditions. 6.5 Nature and contents of container HDPE bottles with polypropylene child resistant closures containing either 30, 60 or 90 tablets. Not all pack sizes may be marketed. 6.6 Special precautions for disposal and other handling No special requirements. 7. Marketing authorisation holder Glaxo Group Limited 980 Great West Road Brentford Middlesex TW8 9GS United Kingdom 8. Marketing authorisation number(s) 200 mg (30 tablets)  EU/1/10/628/001 200 mg (90 tablets)  EU/1/10/628/002 400 mg (30 tablets)  EU/1/10/628/003 400 mg (60 tablets)  EU/1/10/628/004 9. Date of first authorisation/renewal of the authorisation Date of first authorisation: 14 June 2010 Date of latest renewal: 22 May 2012 10. Date of revision of the text 18 December 2013 POM Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu. Votrient(pazopanib，帕唑帕尼)获欧盟批准 英国制药巨头葛兰素史克制药公司日前宣布,公司研发的肿瘤药物Votrient(帕唑帕尼)已经获得欧盟批准。该药物主要用于治疗晚期软组织肉瘤病症的特定子类型病,尤其适用于那些此前已经接受化疗治疗或者是接受其他辅助治疗但是一年之内病情加深的患者。 今年四月份,葛兰素史克制药公司已经获得美国食品和药物监管局批准,将该药物用于治疗已经接受化疗治疗的晚期软组织肉瘤患者。葛兰素史克制药公司此前向美国食品和药物监管局提交了关键性的三期临床试验数据,极具说服力,因此获得批准。 葛兰素史克制药公司此前展开的试验名称为PALETTE,接受化学治疗但是病情恶化的晚期软组织肉瘤患者是该试验的主要研究对象,但是胃肠道间质瘤患者和脂肪细胞瘤患者不在此次的研究范围之内。 此次试验结果表明,患者在接受Votrient药物治疗之后,中位无进展生存期达4.6个月,较服用安慰剂小组的1.5个月略胜一筹,但是Votrient药物的整体存活率并不理想,接受Votrient药物治疗之后,患者的中位存活期为11.9个月,而服用安慰剂组的则为10.4个月,相比之下服用安慰剂组并无太大优势。 Votrient药物已经在全球范围内上市,用于治疗晚期肾脏上皮肾细胞癌病症,并且攫取美国肾脏上皮肾细胞癌处方药物市场18%的市场份额。目前,葛兰素史克制药公司也在评估Votrient药物在卵巢癌治疗中的疗效。 ------------------------------------------------------ 注：以下产品不同规格和不同价格，购买以咨询为准！ ------------------------------------------------------ 产地国家: 德国 原产地英文商品名: VOTRIENT 400MG/TAB 30TABS/BOX 原产地英文药品名: PAZOPANIB HYDROCHLORIDE 中文参考商品译名: VOTRIENT 400毫克/片 30片/盒 中文参考药品译名: 盐酸帕唑帕尼 生产厂家中文参考译名: 葛兰素史克 生产厂家英文名: GLAXOSMITHKLINE -------------------------------------------------------- 产地国家: 英国 原产地英文商品名: VOTRIENT 200MG/TAB 30TABS/BOX 原产地英文药品名: PAZOPANIB HYDROCHLORIDE 中文参考商品译名: VOTRIENT 200毫克/片 30片/盒 中文参考药品译名: 盐酸帕唑帕尼 生产厂家中文参考译名: 葛兰素史克 生产厂家英文名: GLAXOSMITHKLINE ---------------------------------------------------------- 产地国家: 香港 原产地英文商品名: VOTRIENT 200MG/TAB 30TABS/BOX 原产地英文药品名: PAZOPANIB HYDROCHLORIDE 中文参考商品译名: VOTRIENT 200毫克/片 30片/盒 中文参考药品译名: 盐酸帕唑帕尼 生产厂家中文参考译名: 葛兰素史克 生产厂家英文名: GLAXOSMITHKLINE ----------------------------------------------------------- 产地国家: 土耳其 原产地英文商品名: VOTRIENT 400MG/TAB 60TABS/BOX 原产地英文药品名: PAZOPANIB HYDROCHLORIDE 中文参考商品译名: VOTRIENT 400毫克/片 60片/盒 中文参考药品译名: 盐酸帕唑帕尼 生产厂家中文参考译名: 葛兰素史克 生产厂家英文名: GLAXOSMITHKLINE ------------------------------------------------------------- 产地国家: 美国 原产地英文商品名: VOTRIENT DS 200MG/TAB 120TABS/BOTTLE 原产地英文药品名: PAZOPANIB HYDROCHLORIDE 中文参考商品译名: VOTRIENT DS 200毫克/片 120片/瓶 中文参考药品译名: 盐酸帕唑帕尼 生产厂家中文参考译名: 葛兰素史克 生产厂家英文名: GLAXOSMITHKLINE