GILOTRIF(afatinib)片获欧盟委员会批准，作为一种单药疗法为口服使用 初次批准：2013 适应证和用途 GILOTRIF是一种激酶抑制剂适用为有转移非小细胞肺癌(NSCLC)患者一线治疗其肿瘤有当用FDA批准的测试检出的表皮生长因子受体(EGFR)外显子19缺失或外显子21(L858R)取代突变。 使用限制：尚未在肿瘤有其他EGFR突变患者中确定GILOTRIF的安全性和疗效。 剂量和给药方法 （1）推荐剂量：40mg口服，每天1次. （2）指导患者在进餐前至少1小时或后2小时服用GILOTRIF. 剂型和规格 片：40mg，30mg，和20mg. 禁忌证 无 警告和注意事项 （1）腹泻：腹泻可能导致脱水和肾衰。对严重和对抗腹泻药物无反应延长腹泻不给GILOTRIF。 （2）大疱和剥脱性皮肤疾病：0.15%患者中生严重大疱，起泡，和去角质病变。对威胁生命的皮肤反应终止药物。对严重和延长皮肤反应不给GILOTRIF。 （3）间质性肺病(ILD)：在1.5%患者发生。对肺症状急性发作或恶化不给GILOTRIF。如被诊断ILD终止 GILOTRIF。 （4）肝毒性：在0.18%患者中发生致命性肝损伤。用定期肝检验监视。对肝检验严重或恶化不给或终止 GILOTRIF。 （5）角膜炎：在0.8%患者中发生。不给GILOTRIF对角膜炎评价。对确证溃疡性角膜炎不给或终止GILOTRIF。 （6）胚胎胎儿毒性：可致胎儿危害。劝告女性对胎儿潜在危害和使用高效避孕。 不良反应 最常见不良反应(≥20%)是腹泻，皮疹/痤疮样皮炎，口腔炎，甲沟炎，干皮肤，食欲减低，瘙痒。 药物相互作用 P-gp抑制剂的共同给药可能增加afatinib暴露。如不能耐受每天减低GILOTRIF 10mg。慢性Pgp诱导剂口服的共同给药可能减低afatinib暴露。当耐受时每天增加GILOTRIF 10mg。 在特殊人群中使用 哺乳母亲：终止药物或哺乳。 1. NAME OF THE MEDICINAL PRODUCT GIOTRIF 20 mg film-coated tablets 2. QUALITATIVE AND QUANTITATIVE COMPOSITION  One film-coated tablet contains 20 mg afatinib (as dimaleate). Excipient with known effect: One film-coated tablet contains 118 mg lactose (as monohydrate). For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Film-coated tablet (tablet). White to yellowish, round, biconvex and bevel-edged film-coated tablet debossed with the code “T20” on one side and the Boehringer Ingelheim company logo on the other. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications  GIOTRIF as monotherapy is indicated for the treatment of Epidermal Growth Factor Receptor (EGFR) TKI-naïve adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with activating EGFR mutation(s) (see section 5.1). 4.2 Posology and method of administration  Treatment with GIOTRIF should be initiated and supervised by a physician experienced in the use of anticancer therapies. EGFR mutation status should be established prior to initiation of GIOTRIF therapy (see section 4.4). Posology The recommended dose is 40 mg once daily. This medicinal product should be taken without food. Food should not be consumed for at least 3 hours before and at least 1 hour after taking this medicinal product (see sections 4.5 and 5.2). GIOTRIF treatment should be continued until disease progression or until no longer tolerated by the patient (see Table 1 below). Dose escalation A dose escalation to a maximum of 50 mg/day may be considered in patients who tolerate a 40 mg/day dose (i.e. absence of diarrhoea, skin rash, stomatitis, and other adverse reactions with CTCAE Grade > 1) in the first 3 weeks. The dose should not be escalated in any patients with a prior dose reduction. The maximum daily dose is 50 mg. Dose adjustment for adverse reactions Symptomatic adverse reactions (e.g. severe/persistent diarrhoea or skin related adverse reactions) may be successfully managed by treatment interruption and dose reductions or treatment discontinuation of GIOTRIF as outlined in Table 1 (see sections 4.4 and 4.8). Table 1: Dose adjustment information for adverse reactions CTCAEa Adverse reactions Recommended dosing Grade 1 or Grade 2 No interruption b No dose adjustment Grade 2 (prolonged c or intolerable) or Grade ≥ 3 Interrupt until Grade 0/1 b Resume with dose reduction by 10 mg decrements d a NCI Common Terminology Criteria for Adverse Events b In case of diarrhoea, anti-diarrhoeal medicinal products (e.g. loperamide) should be taken immediately and continued for persistent diarrhoea until loose bowel movements cease. c > 48 hours of diarrhoea and/or > 7 days of rash d If patient cannot tolerate 20 mg/day, permanent discontinuation of GIOTRIF should be considered Interstitial Lung Disease (ILD) should be considered if a patient develops acute or worsening of respiratory symptoms in which case treatment should be interrupted pending evaluation. If ILD is diagnosed, GIOTRIF should be discontinued and appropriate treatment initiated as necessary (see section 4.4). Missed dose If a dose is missed, it should be taken within the same day as soon as the patient remembers. However, if the next scheduled dose is due within 8 hours then the missed dose must be skipped. Use of P-glycoprotein (P-gp) inhibitors If P-gp inhibitors need to be taken, they should be administered using staggered dosing, i.e. the P-gp inhibitor dose should be taken as far apart in time as possible from the GIOTRIF dose. This means preferably 6 hours (for P-gp inhibitors dosed twice daily) or 12 hours (for P-gp inhibitors dosed once daily) apart from GIOTRIF (see section 4.5). Patients with renal impairment The safety, pharmacokinetics and efficacy of this medicinal product have not been studied in a dedicated trial in patients with renal impairment. Adjustments to the starting dose are not necessary in patients with mild or moderate renal impairment. Treatment in patients with severely impaired renal function (< 30 mL/min creatinine clearance) is not recommended (see section 5.2). Patients with hepatic impairment Exposure to afatinib is not significantly changed in patients with mild (Child Pugh A) or moderate (Child Pugh B) hepatic impairment (see section 5.2). Adjustments to the starting dose are not necessary in patients with mild or moderate hepatic impairment. This medicinal product has not been studied in patients with severe (Child Pugh C) hepatic impairment. Treatment in this population is not recommended (see section 4.4). Paediatric population There is no relevant use of GIOTRIF in the paediatric population in the indication of NSCLC. Therefore, treatment of children or adolescents with this medicinal product is not recommended. Method of administration This medicinal product is for oral use. The tablets should be swallowed whole with water. If swallowing of whole tablets is not possible, these can be dispersed in approximately 100 ml of noncarbonated drinking water. No other liquids should be used. The tablet should be dropped into the water without crushing it, and stirred occasionally for up to 15 min until it is broken up into very small particles. The dispersion should be consumed immediately. The glass should be rinsed with approximately 100 ml of water which should also be consumed. The dispersion can also be administered through a gastric tube. 4.3 Contraindications Hypersensitivity to afatinib or to any of the excipients listed in section 6.1. 4.4 Special warnings and precautions for use Assessment of EGFR mutation status When assessing the EGFR mutation status of a patient, it is important that a well-validated and robust methodology is chosen to avoid false negative or false positive determinations. Diarrhoea Diarrhoea, including severe diarrhoea, has been reported during treatment with GIOTRIF (see section 4.8). Diarrhoea may result in dehydration with or without renal impairment, which in rare cases has resulted in fatal outcomes. Diarrhoea usually occurred within the first 2 weeks of treatment. Grade 3 diarrhoea most frequently occurred within the first 6 weeks of treatment. Proactive management of diarrhoea including adequate hydration combined with anti-diarrhoeal medicinal products especially within the first 6 weeks of the treatment is important and should start at first signs of diarrhoea. Antidiarrhoeal medicinal products (e.g. loperamide) should be used and if necessary their dose should be escalated to the highest recommended approved dose. Anti-diarrhoeal medicinal products should be readily available to the patients so that treatment can be initiated at first signs of diarrhoea and continued until loose bowel movements cease for 12 hours. Patients with severe diarrhoea may require interruption and dose reduction or discontinuation of therapy with GIOTRIF (see section 4.2). Patients who become dehydrated may require administration of intravenous electrolytes and fluids. Skin related adverse events Rash/acne has been reported in patients treated with this medicinal product (see section 4.8). In general, rash manifests as a mild or moderate erythematous and acneiform rash, which may occur or worsen in areas exposed to sun. For patients who are exposed to sun, protective clothing, and use of sun screen is advisable. Early intervention (such as emollients, antibiotics) of dermatologic reactions can facilitate continuous GIOTRIF treatment. Patients with severe skin reactions may also require temporary interruption of therapy, dose reduction (see section 4.2), additional therapeutic intervention, and referral to a specialist with expertise in managing these dermatologic effects. Bullous, blistering and exfoliative skin conditions have been reported including rare cases suggestive of Stevens-Johnson syndrome. Treatment with this medicinal product should be interrupted or discontinued if the patient develops severe bullous, blistering or exfoliating conditions (see section 4.8). Female gender, lower body weight, and underlying renal impairment Higher exposure to afatinib has been observed in female patients, patients with lower body weight and those with underlying renal impairment (see section 5.2). This could result in a higher risk of developing adverse reactions in particular diarrhoea, rash/acne and stomatitis. Closer monitoring is recommended in patients with these risk factors. Interstitial Lung Disease (ILD) There have been reports of ILD or ILD-like adverse reactions (such as lung infiltration, pneumonitis, acute respiratory distress syndrome, allergic alveolitis), including fatalities, in patients receiving GIOTRIF for treatment of NSCLC. ILD-like adverse reactions were reported in 0.7% of more than 3,800 patients treated. CTCAE Grade ≥ 3 ILD-like adverse reactions were reported in 0.5% of patients. Patients with a history of ILD have not been studied. Careful assessment of all patients with an acute onset and/or unexplained worsening of pulmonary symptoms (dyspnoea, cough, fever) should be performed to exclude ILD. Treatment with this medicinal product should be interrupted pending investigation of these symptoms. If ILD is diagnosed, GIOTRIF should be permanently discontinued and appropriate treatment initiated as necessary (see section 4.2). Severe hepatic impairment Hepatic failure, including fatalities, has been reported during treatment with this medicinal product in less than 1% of patients. In these patients, confounding factors have included pre-existing liver disease and/or comorbidities associated with progression of underlying malignancy. Periodic liver function testing is recommended in patients with pre-existing liver disease. Grade 3 alanine aminotransferase (ALT) and aspartate aminotransferase (AST) elevations were observed in 2.4% of patients with normal baseline liver tests treated with 40 mg/day, and were about 3.5 fold higher in patients with abnormal baseline liver tests (see section 4.8). Dose interruption may become necessary in patients who experience worsening of liver function (see section 4.2). In patients who develop severe hepatic impairment while taking GIOTRIF, treatment should be discontinued. Keratitis Symptoms such as acute or worsening eye inflammation, lacrimation, light sensitivity, blurred vision, eye pain and/or red eye should be referred promptly to an ophthalmology specialist. If a diagnosis of ulcerative keratitis is confirmed, treatment should be interrupted or discontinued. If keratitis is diagnosed, the benefits and risks of continuing treatment should be carefully considered. This medicinal product should be used with caution in patients with a history of keratitis, ulcerative keratitis or severe dry eye. Contact lens use is also a risk factor for keratitis and ulceration (see section 4.8). Left ventricular function Left ventricular dysfunction has been associated with HER2 inhibition. Based on the available clinical trial data, there is no suggestion that this medicinal product causes an adverse reaction on cardiac contractility. However, this medicinal product has not been studied in patients with abnormal left ventricular ejection fraction (LVEF) or those with significant cardiac history. In patients with cardiac risk factors and those with conditions that can affect LVEF, cardiac monitoring, including an assessment of LVEF at baseline and during treatment, should be considered. In patients who develop relevant cardiac signs/symptoms during treatment, cardiac monitoring including LVEF assessment should be considered. In patients with an ejection fraction below the institution's lower limit of normal, cardiac consultation as well as treatment interruption or discontinuation should be considered. P-glycoprotein (P-gp) interactions Concomitant treatment with strong inducers of P-gp may decrease exposure to afatinib (see section 4.5). Lactose This medicinal product contains lactose. Patients with rare hereditary conditions of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product. 4.5 Interaction with other medicinal products and other forms of interaction Interactions with drug transport systems Effects of P-gp and breast cancer resistance protein (BCRP) inhibitors on afatinib In vitro studies have demonstrated that afatinib is a substrate of P-gp and BCRP. When the strong P-gp and BCRP inhibitor ritonavir (200 mg twice a day for 3 days) was administered 1 hour before a single dose of 20 mg GIOTRIF, exposure to afatinib increased by 48% (area under the curve (AUC0-∞)) and 39% (maximum plasma concentration (Cmax)). In contrast, when ritonavir was administered simultaneously or 6 hours after 40 mg GIOTRIF, the relative bioavailability of afatinib was 119% (AUC0-∞) and 104% (Cmax) and 111% (AUC0-∞) and 105% (Cmax), respectively. Therefore, it is recommended to administer strong P-gp inhibitors (including but not limited to ritonavir, cyclosporine A, ketoconazole, itraconazole, erythromycin, verapamil, quinidine, tacrolimus, nelfinavir, saquinavir, and amiodarone) using staggered dosing, preferably 6 hours or 12 hours apart from GIOTRIF (see section 4.2). Effects of P-gp inducers on afatinib Pre-treatment with rifampicin (600 mg once daily for 7 days), a potent inducer of P-gp, decreased the plasma exposure to afatinib by 34% (AUC0-∞) and 22% (Cmax) after administration of a single dose of 40 mg GIOTRIF. Strong P-gp inducers (including but not limited to rifampicin, carbamazepine, phenytoin, phenobarbital or St. John's wort (Hypericum perforatum)) may decrease exposure to afatinib (see section 4.4). Effects of afatinib on P-gp substrates Based on in vitro data, afatinib is a moderate inhibitor of P-gp. However, based on clinical data it is considered unlikely that GIOTRIF treatment will result in changes of the plasma concentrations of other P-gp substrates. Interactions with BCRP In vitro studies indicated that afatinib is a substrate and an inhibitor of the transporter BCRP. Afatinib may increase the bioavailability of orally administered BCRP substrates (including but not limited to rosuvastatin and sulfasalazine). Food effect on afatinib Co-administration of a high-fat meal with GIOTRIF resulted in a significant decrease of exposure to afatinib by about 50% in regard to Cmax and 39% in regard to AUC0-∞. This medicinal product should be administered without food (see sections 4.2 and 5.2). 4.6 Pregnancy and lactation Women of childbearing potential As a precautionary measure, women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with GIOTRIF. Adequate contraceptive methods should be used during therapy and for at least 1 month after the last dose. Pregnancy Mechanistically, all EGFR targeting medicinal products have the potential to cause foetal harm. Animal studies with afatinib did not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). Studies in animals have shown no signs of teratogenicity up to and including maternally lethal dose levels. Adverse changes were restricted to toxic dose levels. However, systemic exposures achieved in animals were either in a similar range or below the levels observed in patients (see section 5.3). The time needed for complete elimination of afatinib is unknown. There are no or limited amount of data from the use of this medicinal product in pregnant women. The risk for humans is thus unknown. If used during pregnancy or if the patient becomes pregnant while or after receiving GIOTRIF, she should be informed of the potential hazard to the foetus. Breast-feeding Available pharmacokinetic data in animals have shown excretion of afatinib in milk (see section 5.3). Based on this, it is likely that afatinib is excreted in human milk. A risk to the breast-feeding child cannot be excluded. Mothers should be advised against breast-feeding while receiving this medicinal product. Fertility Fertility studies in humans have not been performed with afatinib. Available non-clinical toxicology data have shown effects on reproductive organs at higher doses. Therefore, an adverse effect of this medicinal product on human fertility cannot be excluded. 4.7 Effects on ability to drive and use machines GIOTRIF has minor influence on the ability to drive and use machines. During treatment, ocular adverse reactions (conjunctivitis, dry eye, keratitis) have been reported in some patients (see section 4.8) which may affect patients ability to drive or use machines. 4.8 Undesirable effects Summary of the safety profile The types of adverse reactions (ADRs) were generally associated with the EGFR inhibitory mode of action of afatinib. The summary of all ADRs is shown in Table 2. The most frequent ADRs were diarrhoea and skin related adverse events (see section 4.4) as well as stomatitis and paronychia (see also Table 3). ILD-like adverse reactions were reported in 0.7% of afatinib treated patients. Overall, dose reduction (see section 4.2) led to a lower frequency of common adverse reactions. In patients treated with once daily GIOTRIF 40 mg, dose reductions due to ADRs occurred in 57% of the patients. Discontinuation due to ADRs diarrhoea and rash/acne was 1.3% and 0%, respectively. Bullous, blistering and exfoliative skin conditions have been reported including rare cases suggestive of Stevens-Johnson syndrome although in these cases there were potential alternative aetiologies (see section 4.4). Tabulated list of adverse reactions Table 2 summarises the frequencies of ADRs pooled from all NSCLC trials with daily GIOTRIF doses of 40 mg (N=497) or 50 mg (N=1638) as monotherapy. The following terms are used to rank the ADRs by 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). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Table 2: Summary of ADRs per frequency category Body System Very common (≥1/10) Common (≥1/100 to <1/10) Uncommon (≥1/1,000 to < 1/100) Infections and infestations Paronychia1 Cystitis   Metabolism and nutrition disorders Decreased appetite Dehydration Hypokalaemia   Nervous system disorders   Dysgeusia   Eye disorders   Conjunctivitis Dry eye Keratitis Respiratory, thoracic and mediastinal disorders Epistaxis Rhinorrhoea Interstitial lung disease Gastrointestinal disorders Diarrhoea Stomatitis2 Dyspepsia Cheilitis   Hepatobiliary disorders   Alanine aminotransferase increased Aspartate aminotransferase increased   Skin and subcutaneous tissue disorders Rash3 Dermatitis acneiform4 Pruritus5 Dry skin6 Palmar-plantar erythrodysaesthesia syndrome   Musculoskeletal and connective tissue disorders   Muscle spasms   Renal and urinary disorders   Renal impairment/Renal failure   General disorders and administration site conditions   Pyrexia   Investigations   Weight decreased 1 Includes Paronychia, Nail infection, Nail bed infection 2 Includes Stomatitis, Aphthous stomatitis, Mucosal inflammation, Mouth ulceration, Oral mucosa erosion, Mucosal erosion, Mucosal ulceration 3 Includes group of rash preferred terms 4 Includes Acne, Acne pustular, Dermatitis acneiform 5 Includes Pruritus, Pruritus generalised 6 Includes Dry skin, Skin chapped Description of selected adverse reactions Very common ADRs in GIOTRIF-treated patients occurring in at least 10% of patients in trial LUX-Lung 3 are summarised by National Cancer Institute-Common Toxicity Criteria (NCI-CTC) Grade in Table 3. Table 3: Very common ADRs in trial LUX-Lung 3 GIOTRIF (40 mg/day) N=229 Pemetrexed/Cisplatin N=111 NCI-CTC Grade Any Grade 3 4 Any Grade 3 4 MedDRA Preferred Term % % % % % % Infections and infestations Paronychia1 57.6 11.4 0 0 0 0 Metabolism and nutrition disorders Decreased appetite 20.5 3.1 0 53.2 2.7 0 Respiratory, thoracic and mediastinal disorders Epistaxis 13.1 0 0 0.9 0.9 0 Gastrointestinal disorders Diarrhoea Stomatitis2 Cheilitis 95.2 69.9  12.2 14.4 8.3  0 0 0.4  0 15.3 13.5  0.9 0 0.9  0 0 0  0 Skin and subcutaneous tissue disorders Rash3 Dermatitis acneiform4 Dry skin5 Pruritus6 70.3  34.9  29.7  19.2  14  2.6  0.4  0.4   0  0  0  0  6.3  0  1.8  0.9  0  0  0  0  0  0  0  0  Investigations Weight decreased 10.5 0 0 9.0 0 0 1 Includes Paronychia, Nail infection, Nail bed infection 2 Includes Stomatitis, Aphthous stomatitis, Mucosal inflammation, Mouth ulceration, Oral mucosa erosion, Mucosal erosion, Mucosal ulceration 3 Includes group of rash preferred terms 4 Includes Acne, Acne pustular, Dermatitis acneiform 5 Includes Dry skin, Skin chapped 6 Includes Pruritus, Pruritus generalised Liver function test abnormalities Liver function test abnormalities (including elevated ALT and AST) were observed in patients receiving GIOTRIF 40 mg. These elevations were mainly transient and did not lead to discontinuation. Grade 2 (> 2.5 to 5.0 times upper limit of normal (ULN)) ALT elevations occurred in < 8% of patients treated with this medicinal product. Grade 3 (> 5.0 to 20.0 times ULN) elevations occurred in <4% of patients treated with GIOTRIF (see section 4.4). 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: United Kingdom Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard Ireland Pharmacovigilance Section Irish Medicines Board Kevin O'Malley House Earlsfort Centre Earlsfort Terrace Dublin 2 Tel: +353 1 6764971 Fax: +353 1 6762517 Website: www.imb.ie e-mail: imbpharmacovigilance@imb.ie Malta ADR Reporting The Medicines Authority Post-Licensing Directorate 203 Level 3, Rue D'Argens GŻR-1368 Gżira Website: www.medicinesauthority.gov.mt e-mail: postlicensing.medicinesauthority@gov.mt 4.9 Overdose Symptoms The highest dose of afatinib studied in a limited number of patients in Phase I clinical trials was 160 mg once daily for 3 days and 100 mg once daily for 2 weeks. The adverse reactions observed at these doses were primarily dermatological (rash/acne) and gastrointestinal events (especially diarrhoea). Overdose in 2 healthy adolescents involving the ingestion of 360 mg each of afatinib (as part of a mixed drug ingestion) was associated with adverse events of nausea, vomiting, asthenia, dizziness, headache, abdominal pain and elevated amylase (< 1.5 times ULN). Both individuals recovered from these adverse events. Treatment There is no specific antidote for overdose with this medicinal product. In cases of suspected overdose, GIOTRIF should be withheld and supportive care initiated. If indicated, elimination of unabsorbed afatinib may be achieved by emesis or gastric lavage. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties  Pharmacotherapeutic group: antineoplastic agents, protein kinase inhibitors, ATC code: L01XE13. Mechanism of action Afatinib is a potent and selective, irreversible ErbB Family Blocker. Afatinib covalently binds to and irreversibly blocks signalling from all homo- and heterodimers formed by the ErbB family members EGFR (ErbB1), HER2 (ErbB2), ErbB3 and ErbB4. Pharmacodynamic effects Aberrant ErbB signalling triggered by receptor mutations, and/or amplification, and/or receptor ligand overexpression contributes to the malignant phenotype. Mutation in EGFR defines a distinct molecular subtype of lung cancer. In non-clinical disease models with ErbB pathway deregulation, afatinib as a single agent effectively blocks ErbB receptor signalling resulting in tumour growth inhibition or tumour regression. NSCLC tumours with common activating EGFR mutations (Del 19, L858R) and several less common EGFR mutations in exon 18 (G719X) and exon 21 (L861Q) are particularly sensitive to afatinib treatment in non-clinical and clinical settings. Afatinib retains significant anti-tumour activity in NSCLC cell lines in vitro and/or tumour models in vivo (xenografts or transgenic models) driven by mutant EGFR isoforms known to be resistant to the reversible EGFR inhibitors erlotinib and gefitinib such as T790M or T854A. Clinically, activity in tumours harbouring the T790M mutation in exon 20 has also been shown. Limited non-clinical and/or clinical activity was observed in NSCLC tumours with insertion mutations in exon 20. Clinical efficacy and safety LUX-Lung 3 In the first-line setting, the efficacy and safety of GIOTRIF in patients with EGFR mutation-positive locally advanced or metastatic NSCLC (stage IIIB or IV) were assessed in a global, randomised, multicenter, open-label trial. Patients were screened for the presence of 29 different EGFR mutations using a polymerase chain reaction (PCR)-based method (TheraScreen®: EGFR29 Mutation Kit, Qiagen Manchester Ltd). Patients were randomised (2:1) to receive GIOTRIF 40 mg once daily or up to 6 cycles of pemetrexed/cisplatin. Among the patients randomised, 65% were female, the median age was 61 years, the baseline ECOG performance status was 0 (39%) or 1 (61%), 26% were Caucasian and 72% were Asian. The primary endpoint was progression free survival (PFS) by independent review. At the time of primary analysis a total of 45 (20%) patients treated with GIOTRIF and 3 (3%) patients treated with chemotherapy were known to be alive and progression-free and are censored in Figure 1 and Table 4. Figure 1: Kaplan-Meier curve for PFS by independent review by treatment group in trial LUX-Lung 3 (Overall Population) Table 4: Efficacy results of GIOTRIF vs. pemetrexed/cisplatin in trial LUX-Lung 3 based on primary analysis (Independent review) GIOTRIF (N=230) Pemetrexed/Cisplatin (N=115) Hazard Ratio (HR)/Odds Ratio (OR) (95%CI) p-value PFS, Overall Trial Population Months (median) 1-year PFS Rate 11.1 46.5% 6.9 22.0% HR 0.58 (0.43-0.78) - 0.0004 - Objective Response Rate (CR+PR) 1 56.1% 22.6% OR 4.66 (2.77-7.83) <0.0001 Overall Survival (OS) Months (median) 2 28.1 28.2 HR 0.91 (0.66-1.25)  0.55 1 CR=complete response; PR=partial response 2 Updated OS analysis as of January 2013 In the pre-defined sub-group of common mutations (Del 19, L858R) for GIOTRIF (N=204) and chemotherapy (N=104) the median PFS was 13.6 months vs. 6.9 months (HR 0.47; 95% CI 0.34-0.65; p<0.0001) and the median OS was 30.3 months vs. 26.2 months (HR 0.82; 95% CI 0.59-1.14; p=0.2244). PFS benefit was accompanied by improvement in disease-related symptoms and delayed time to deterioration (see Table 5). Mean scores over time for overall quality of life, global health status and physical, role, and cognitive functioning were significantly better for GIOTRIF. Table 5: Symptom outcomes for GIOTRIF vs. chemotherapy in trial LUX-Lung 3 (EORTC QLQ-C30 & QLQ-LC13) Cough Dyspnoea Pain % of patients improved a 67% vs. 60%; p=0.2444 64% vs. 50%; p=0.0103 59% vs. 48%; p=0.0513 Delay of time to deterioration (months) a NRb vs. 8.0 HR 0.60; p=0.0072 10.3 vs. 2.9  HR 0.68; p=0.0145 4.2 vs. 3.1  HR 0.83; p=0.1913 a values presented for GIOTRIF vs. chemotherapy b NR= not reached LUX-Lung 2 LUX-Lung 2 was a single arm Phase II trial in 129 EGFR TKI-naïve patients with stage IIIB or IV lung adenocarcinoma with EGFR mutations. Patients were enrolled in the first-line (N=61) or second-line setting (N=68) (i.e. after failure of 1 prior chemotherapy regimen). In 61 patients treated in the first-line setting, confirmed ORR was 65.6% and DCR was 86.9% according to independent review. The median PFS was 12.0 months by independent review. Efficacy was similarly high in the group of patients who had received prior chemotherapy (N=68; ORR 57.4%; median PFS by independent review 8 months). The updated median OS for first- and second‑line was 31.7 months and 23.6 months, respectively. Paediatric population The European Medicines Agency has waived the obligation to submit the results of trials with this medicinal product in all subsets of the paediatric population in NSCLC indications (see section 4.2 for information on paediatric use). 5.2 Pharmacokinetic properties Absorption Following oral administration of GIOTRIF, Cmax of afatinib were observed approximately 2 to 5 hours post dose. Cmax and AUC0-∞ values increased slightly more than proportionally in the dose range from 20 mg to 50 mg GIOTRIF. Systemic exposure to afatinib is decreased by 50% (Cmax) and 39% (AUC0-∞), when administered with a high-fat meal compared to administration in the fasted state. Based on population pharmacokinetic data derived from clinical trials in various tumour types, an average decrease of 26% in AUCτ,ss was observed when food was consumed within 3 hours before or 1 hour after taking GIOTRIF. Therefore, food should not be consumed for at least 3 hours before and at least 1 hour after taking GIOTRIF (see sections 4.2 and 4.5). Distribution In vitro binding of afatinib to human plasma proteins is approximately 95%. Afatinib binds to proteins both non-covalently (traditional protein binding) and covalently. Biotransformation Enzyme-catalyzed metabolic reactions play a negligible role for afatinib in vivo. Covalent adducts to proteins were the major circulating metabolites of afatinib. Elimination In humans, excretion of afatinib is primarily via the faeces. Following administration of an oral solution of 15 mg afatinib, 85.4% of the dose was recovered in the faeces and 4.3% in urine. The parent compound afatinib accounted for 88% of the recovered dose. Afatinib terminal half-life was approximately 37 hours. Steady state plasma concentrations of afatinib were achieved within 8 days of multiple dosing of afatinib resulting in an accumulation of 2.77-fold (AUC0-∞) and 2.11-fold (Cmax). Special populations Renal impairment Less than 5% of a single dose of afatinib is excreted via the kidneys. The safety, pharmacokinetics and efficacy of GIOTRIF have not been studied specifically in patients with renal impairment. Based on population pharmacokinetic data derived from clinical trials in various tumour types, no dose adjustments appear necessary in patients with mild or moderate renal impairment (see “Population pharmacokinetic analysis in special populations” below and section 4.2). Hepatic impairment Afatinib is eliminated mainly by biliary/faecal excretion. Subjects with mild (Child Pugh A) or moderate (Child Pugh B) hepatic impairment had similar exposure in comparison to healthy volunteers following a single dose of 50 mg GIOTRIF. This is consistent with population pharmacokinetic data derived from clinical trials in various tumour types (see “Population pharmacokinetic analysis in special populations” below). No starting dose adjustments appear necessary in patients with mild or moderate hepatic impairment (see section 4.2). The pharmacokinetics of afatinib have not been studied in subjects with severe (Child Pugh C) hepatic dysfunction (see section 4.4). Population pharmacokinetic analysis in special populations A population pharmacokinetic analysis was performed in 927 cancer patients (764 with NSCLC) receiving GIOTRIF monotherapy. No starting dose adjustment was considered necessary for any of the following covariates tested. Age No significant impact of age (range: 28 years - 87 years) on the pharmacokinetics of afatinib could be observed. Body weight Plasma exposure (AUCτ,ss) was increased by 26% for a 42 kg patient (2.5th percentile) and decreased by 22% for a 95 kg patient (97.5th percentile) relative to a patient weighing 62 kg (median body weight of patients in the overall patient population). Gender Female patients had a 15% higher plasma exposure (AUCτ,ss, body weight corrected) than male patients. Race Race had no effect on the pharmacokinetics of afatinib based on a population pharmacokinetic analysis, including patients of Asian, White, and Black racial groups. Data on Black racial groups was limited. Renal impairment Exposure to afatinib moderately increased with lowering of the creatinine clearance (CrCL, calculated according to Cockcroft Gault), i.e. for a patient with a CrCL of 60 mL/min or 30 mL/min exposure (AUCτ,ss) to afatinib increased by 13% and 42%, respectively, and decreased by 6% and 20% for a patient with CrCL of 90 mL/min or 120 mL/min, respectively, compared to a patient with the CrCL of 79 mL/min (median CrCL of patients in the overall patient population analysed). Hepatic impairment Patients with mild and moderate hepatic impairment as identified by abnormal liver tests did not correlate with any significant change in afatinib exposure. There was limited data available for moderate and severe hepatic impairment. Other patient characteristics/intrinsic factors Other patient characteristics/intrinsic factors found with a significant impact on afatinib exposure were: ECOG performance score, lactate dehydrogenase levels, alkaline phosphatase levels and total protein. The individual effect sizes of these covariates were considered not clinically relevant. Smoking history, alcohol consumption (limited data), or presence of liver metastases had no significant impact on the pharmacokinetics of afatinib. Other information on drug-drug interactions Interactions with drug uptake transport systems In vitro data indicated that drug-drug interactions with afatinib due to inhibition of OATB1B1, OATP1B3, OATP2B1, OAT1, OAT3, OCT1, OCT2, and OCT3 transporters are considered unlikely. Interactions with Cytochrome P450 (CYP) enzymes In humans it was found that enzyme-catalyzed metabolic reactions play a negligible role for the metabolism of afatinib. Approximately 2% of the afatinib dose was metabolized by FMO3 and the CYP3A4-dependent N-demethylation was too low to be quantitatively detected. Afatinib is not an inhibitor or an inducer of CYP enzymes. Therefore, this medicinal product is unlikely to interact with other medicines that modulate or are metabolised by CYP enzymes. Effect of UDP-glucuronosyltransferase 1A1 (UGT1A1) inhibition on afatinib In vitro data indicated that drug-drug interactions with afatinib due to inhibition of UGT1A1 are considered unlikely. 5.3 Preclinical safety data Oral administration of single doses to mice and rats indicated a low acute toxic potential of afatinib. In oral repeated-dose studies for up to 26 weeks in rats or 52 weeks in minipigs the main effects were identified in the skin (dermal changes, epithelial atrophy and folliculitis in rats), the gastrointestinal tract (diarrhoea, erosions in the stomach, epithelial atrophy in rats and minipigs) and the kidneys (papillary necrosis in rats). Depending on the finding, these changes occurred at exposures below, in the range of or above clinically relevant levels. Additionally, in various organs pharmacodynamically mediated atrophy of epithelia was observed in both species. Reproduction toxicity Based on the mechanism of action, all EGFR targeting medicinal products including GIOTRIF have the potential to cause foetal harm. The embryo-foetal development studies performed on afatinib revealed no indication of teratogenicity. The respective total systemic exposure (AUC) was either slightly above (2.2 times in rats) or below (0.3 times in rabbits) compared with levels in patients. Radiolabelled afatinib administered orally to rats on Day 11 of lactation was excreted in the breast milk of the dams. A fertility study in male and female rats up to the maximum tolerated dose revealed no significant impact on fertility. The total systemic exposure (AUC0-24) in male and female rats was in the range or less than that observed in patients (1.3 times and 0.51 times, respectively). A study in rats up to the maximum tolerated doses revealed no significant impact on pre-/postnatal development. The highest total systemic exposure (AUC0-24) in female rats was less than that observed in patients (0.23 times). Phototoxicity An in vitro 3T3 test showed that afatinib may have phototoxicity potential. Carcinogenicity Carcinogenicity studies have not been conducted with GIOTRIF. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipient(s) Tablet core Lactose monohydrate Cellulose, microcrystalline (E460) Silica, colloidal anhydrous (E551) Crospovidone type A Magnesium stearate (E470b) Film-coating Hypromellose (E464) Macrogol 400 Titanium dioxide (E171) Talc (E553b) Polysorbate 80 (E433) 6.2 Incompatibilities  Not applicable. 6.3 Shelf life 3 years. 6.4 Special precautions for storage Store in the original package in order to protect from moisture and light. 6.5 Nature and contents of container  PVC/PVDC perforated unit dose blister. Each blister is packed together with a desiccant sachet in a laminated aluminium pouch and contains 7 x 1 film-coated tablets. Pack sizes of 7 x 1, 14 x 1 or 28 x 1 film‑coated tablets. Not all pack sizes may be marketed. 6.6 Special precautions for disposal and other handling  Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 7. MARKETING AUTHORISATION HOLDER  Boehringer Ingelheim International GmbH Binger Strasse 173 D-55216 Ingelheim am Rhein Germany 8. MARKETING AUTHORISATION NUMBER(S)  EU/1/13/879/001 EU/1/13/879/002 EU/1/13/879/003 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 25 September 2013 肺癌新药阿法替尼在欧洲获支持性意见 继获得FDA的批准之后，这一由勃林格殷格翰公司研发的前沿抗肿瘤化合物获得了CHMP的支持性意见 作为最大规模的全球性III期临床试验，LUX-Lung 3研究结果证实，与接受标准化疗相比，阿法替尼能使EGFR突变阳性的肺癌患者受益 德国殷格翰2013年7月31日电 /美通社/ -勃林格殷格翰公司于今日宣布，欧洲药品管理局人用药品委员会（CHMP）已经发表了关于阿法替尼的积极意见，该药已以GIOTRIF®*为商品名递交欧盟审批。 阿法替尼是第一个不可逆性ErbB家族阻滞剂，可抑制表皮生长因子受体（EGFR）酪氨酸激酶，用于初治成年伴有EGFR突变阳性的局部晚期或转移性非小细胞肺癌（NSCLC）患者。 “勃林格殷格翰公司对于CHMP在继FDA批准阿法替尼之后所作出的决定表示欢迎。我们期待能够尽早在欧洲将阿法替尼提供给EGFR突变阳性的肺癌患者，”勃林格殷格翰公司全球医学高级副总裁 Klaus Dugi教授继续说道，“阿法替尼能够不可逆性地阻断EGFR以及ErbB家族的其他相关成员，并已经在临床试验中显示出具有意义的治疗效果。” 在白种人和亚洲非小细胞肺癌（NSCLC）患者中，分别有10-15%和40%患者的肿瘤携带EGFR突变。在临床试验中，阿法替尼已显示出能够显著延迟这种类型肺癌患者的肿瘤进展，同时还能改善肺癌相关性症状以及生活质量。因此，EGFR突变检测是治疗决策过程中的一个关键性步骤，已获得许多国际肿瘤学和病理学学术组织的强烈推荐。这使得医疗专业人员能够作出知情的治疗决策，也使得患者从一开始就获得正确的药物靶向治疗。 靶向治疗提供了一个个体化肺癌治疗方案，患者从中可获得巨大受益，”来自伦敦皇家马斯登NHS信托基金会的医疗肿瘤学顾问医师、LUX-Lung 3试验的临床研究者Sanjay Popat博士如此评论，“今天CHMP针对批准阿法替尼所作出的推荐使我们更加接近为欧洲晚期NSCLC患者提供这一靶向治疗选择的愿景，大规模临床试验已经证实这一靶向治疗相较于标准化疗具有一致性的疗效优势。” CHMP对阿法替尼所作出的支持性意见基于来自关键性LUX-Lung 3试验的数据，这是一个涉及EGFR突变阳性肺癌患者的最大规模的全球性III期临床试验，旨在比较阿法替尼与培美曲塞/顺铂联合化疗的效果。来自LUX-Lung 3研究的数据显示，接受阿法替尼作为一线治疗的患者在肿瘤重新开始生长之前的生存时间达到了一年[中位无进展生存期（PFS）为11.1个月]，而接受培美曲塞/顺铂的患者则稍超过半年（PFS为6.9个月）。值得注意的是，携带两种最常见EGFR突变类型（Del19 或 L858R，占所有EGFR突变类型的90%）的NSCLC患者在接受阿法替尼后的无进展生存期远远超过了一年（PFS为13.6个月），而对照组患者则稍超过半年（PFS为6.9个月）。 临床试验还显示，阿法替尼治疗者的疾病进展延迟与更好地控制生活限制性疾病相关症状有关。通过标准的肺癌问卷评估，更多的接受阿法替尼的患者症状改善，例如呼吸困难（气短）、咳嗽和胸痛。阿法替尼还可延迟这些症状的恶化。 在LUX-Lung 3研究中观察到较低的与治疗相关性不良事件有关的停药发生率（阿法替尼治疗组停药率为8%，化疗组停药率为12%）。在阿法替尼治疗组中，与药物相关的最常见的3级不良事件是腹泻（14%）、皮疹（16%）和甲床炎症（甲沟炎）（11%）。在阿法替尼治疗组中，仅有1%患者由于药物相关性腹泻而停止用药。[2] 在化疗组（培美曲塞/顺铂）中，最常见的与药物有关的3级不良事件是中性粒细胞减少症（15%）、疲劳（13%）和白细胞减少（8%）。 阿法替尼以GILOTRIF™为商品名已在美国获得批准，并已提交亚洲和世界各地的监管机构审核用于治疗EGFR突变阳性的局部晚期和转移性NSCLC。欧盟、亚洲和其他国家的药监当局对该药注册申请的审核正在进行中。 供编辑参考信息 关于阿法替尼 阿法替尼被美国FDA批准用于一线治疗转移性NSCLC患者，这些患者的肿瘤经FDA批准的检测方法检出存在EGFR外显子19缺失或外显子21（L858R）替代突变。 阿法替尼是一种不可逆性ErbB家族抑制剂，能够不可逆性地阻断EGFR (ErbB1)以及ErbB家族的其他相关成员，而这些分子在最常见肿瘤和高死亡率肿瘤的生长和播散过程中发挥关键性作用。与其他化合物可逆性结合受体的不同之处在于，阿法替尼共价、不可逆性结合受体能够持久、选择性、完全地阻断ErbB家族，从而可能产生独特的治疗效果。 阿法替尼目前正处于针对NSCLC和头颈部癌的III期临床试验过程中。 关于肺癌 肺癌是世界上最大的癌症杀手，发病率男性高于女性，每年的新发病例数达到一百六十万。由于肺癌预后较差，每年死于肺癌的人数达到一百三十八万。总体而言，肺癌死亡人数占到所有癌症死亡人数18%。在所有新发癌症中，肺癌约占13% ，而吸烟是肺癌的主要病因。 早期检测肿瘤EGFR突变状况对于改善患者治疗效果至关重要。10%-15%白种人NSCLC患者和 40%亚洲NSCLC患者的肿瘤存在EGFR突变，其中有90%病例具有两种最常见的EGFR突变中的一种（Del19或 L858R）。 ------------------------------------------------------------- 产地国家：德国 原产地英文商品名: Gilotrif 20mg/Tablet 28Tablets/ 原产地英文药品名: afatinib 中文参考商品译名: 妥复克 20mg毫克/片 28片 中文参考药品译名: 阿法替尼 生产厂家中文参考译名: 勃林格殷格翰制药公司 生产厂家英文名: Boehringer Ingelheim Pharmaceuticals Inc. ------------------------------------------------------------- 产地国家：德国 原产地英文商品名: Gilotrif 30mg/Tablet 28Tablets/ 原产地英文药品名: afatinib 中文参考商品译名: 妥复克 30mg毫克/片 28片 中文参考药品译名: 阿法替尼 生产厂家中文参考译名: 勃林格殷格翰制药公司 生产厂家英文名: Boehringer Ingelheim Pharmaceuticals Inc. ------------------------------------------------------------- 产地国家：德国 原产地英文商品名: Gilotrif 40mg/Tablet 28Tablets/ 原产地英文药品名: afatinib 中文参考商品译名: 妥复克 40mg毫克/片 28片 中文参考药品译名: 阿法替尼 生产厂家中文参考译名: 勃林格殷格翰制药公司 生产厂家英文名: Boehringer Ingelheim Pharmaceuticals Inc.