Afatinib(阿法替尼片，GILOTRIF，Giotrif)-药品说明书与价格-中国新特药网第一医药站
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Afatinib(阿法替尼片，GILOTRIF，Giotrif)
Afatinib(阿法替尼片，GILOTRIF，Giotrif)
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英文药名：Gilotrif(afatinib Tablets)
中文药名：阿法替尼片
生产厂家：勃林格殷格翰制药药品介绍：近日，抗癌药物afatinib获欧盟委员会批准，作为一种单药疗法，用于携带激活性EGFR突变的局部晚期或 ...关键字：
英文药名：Gilotrif(afatinib Tablets)
中文药名：阿法替尼片
生产厂家：勃林格殷格翰制药药品介绍：近日，抗癌药物afatinib获欧盟委员会批准，作为一种单药疗法，用于携带激活性EGFR突变的局部晚期或转移性非小细胞肺癌初治成人患者的治疗。在欧洲，afatinib将以品牌名Giotrif上市。Giotrif的获批，是基于关键性LUX-Lung 3临床试验，这是在携带EGFR突变阳性肺癌患者中开展的迄今为止最大规模的的全球性III期试验，研究结果证实了afatinib在携带EGFR突变的IIIb或IV阶段肺腺癌患者中相对于业界最佳化疗药物的优越性。试验中，将afatinib作为一线治疗药物对患者进行了治疗，afatinib患者组疾病无进展生存期为11.1个月，而化疗组PFS为6.9个月。此外，针对携带2种最常见的EGFR突变的NSCLC，afatinib患者组PFS达13.6个月，而对照组仅为6.9个月。Afatinib治疗组疾病进展延迟，患者大都经历了呼吸困难、气短、咳嗽、胸痛等症状的改善，Afatinib也显着延迟了这些症状的恶化。Afatinib是勃林格殷格翰首个肿瘤学药物，是首个不可逆ErbB家族阻断剂，该药积极的临床证据，加上全新的作用模式，使其成为一种杰出的治疗选择，有望为肺癌患者提供其急需的临床需求。Afatinib于日获得了FDA的批准，以商品名Gilotrif上市，作为一种口服的、新的一线治疗药物，用于经由FDA批准的试剂盒证实肿瘤表皮生长因子受体19号外显子缺失或21号外显子突变的转移性非小细胞肺癌患者的治疗。GILOTRIF™ (afatinib)片，为口服使用 美国初次批准：2013 作用机制 Afatinib与EGFR(ErbB1)，HER2 (ErbB2)，和HER4 ErbB4)的激酶结构域共价结合和不可逆地抑制酪氨酸激酶自身磷酸化，导致ErbB信号的下调。 Afatinib显示自身磷酸化的抑制作用和在体外表达野生型EGFR细胞株的增殖或表达选择性EGFR外显子19缺失突变或外显子21 L858R突变，包括在患者中在可到达的afatinib浓度时，至少暂时，某些有一种次发T790M突变。此外，在体外afatinib抑制过表达HER2细胞株的增殖。在植入肿瘤或过表达野生型 EGFR或HER2或在一种EGFR L858R/T790M双突变体模型裸鼠中用afatinib治疗导致肿瘤生长的抑制。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(4) 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。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。
Giotrif 20 mg film-coated tabletsGiotrif 30 mg film-coated tablets Giotrif 40 mg film-coated tablets Giotrif 50 mg film-coated tablets
Giotrif 20 mg film-coated tablets 1. Name of the medicinal productGIOTRIF 20 mg film-coated tablets2. Qualitative and quantitative compositionOne 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 formFilm-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 particulars4.1 Therapeutic indicationsGIOTRIF as monotherapy is indicated for the treatment of Epidermal Growth Factor Receptor (EGFR) TKI-na&ve 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 administrationTreatment 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). PosologyThe 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 escalationA 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 reactionsSymptomatic 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 rashd If patient cannot tolerate 20 mg/day, permanent discontinuation of GIOTRIF should be consideredInterstitial 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 doseIf 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 impairmentThe 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 impairmentExposure 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 populationThere 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 administrationThis 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 ContraindicationsHypersensitivity to afatinib or to any of the excipients listed in section 6.1.4.4 Special warnings and precautions for useAssessment of EGFR mutation statusWhen 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.DiarrhoeaDiarrhoea, 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 eventsRash/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 impairmentHigher 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 impairmentHepatic 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. KeratitisSymptoms 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 functionLeft 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) interactionsConcomitant treatment with strong inducers of P-gp may decrease exposure to afatinib (see section 4.5).LactoseThis 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 interactionInteractions with drug transport systemsEffects of P-gp and breast cancer resistance protein (BCRP) inhibitors on afatinibIn 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 afatinibPre-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 substratesBased 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 afatinibCo-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 Fertility, pregnancy and lactationWomen of childbearing potentialAs 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.PregnancyMechanistically, 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-feedingAvailable 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.FertilityFertility 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 machinesGIOTRIF 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 effectsSummary of the safety profileThe 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 reactionsTable 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
(≥1/100 to &1/10)
(≥1/1,000 to& 1/100)
Infections and infestations
Paronychia1
Metabolism and nutrition disorders
Decreased appetite
Dehydration
Hypokalaemia
Nervous system disorders
Eye disorders
Conjunctivitis
Respiratory, thoracic and mediastinal disorders
Rhinorrhoea
Interstitial lung disease
Gastrointestinal disorders
Stomatitis2
Cheilitis&
Hepatobiliary disorders
Alanine aminotransferase increased
Aspartate aminotransferase increased
Skin and subcutaneous tissue disorders
Dermatitis acneiform4
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
Investigations
Weight decreased
1 Includes Paronychia, Nail infection, Nail bed infection2 Includes Stomatitis, Aphthous stomatitis, Mucosal inflammation, Mouth ulceration, Oral mucosa erosion, Mucosal erosion, Mucosal ulceration 3 Includes group of rash preferred terms4 Includes Acne, Acne pustular, Dermatitis acneiform5 Includes Pruritus, Pruritus generalised6 Includes Dry skin, Skin chappedDescription of selected adverse reactionsVery 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
(40 mg/day)
Pemetrexed/Cisplatin
NCI-CTC Grade
MedDRA Preferred Term
Infections and infestations
Paronychia1
Metabolism and nutrition disorders
Decreased appetite
Respiratory, thoracic and mediastinal disorders
Gastrointestinal disorders
Stomatitis2
Skin and subcutaneous tissue disorders
Dermatitis acneiform4
Investigations
Weight decreased
0 1 Includes Paronychia, Nail infection, Nail bed infection2 Includes Stomatitis, Aphthous stomatitis, Mucosal inflammation, Mouth ulceration, Oral mucosa erosion, Mucosal erosion, Mucosal ulceration 3 Includes group of rash preferred terms4 Includes Acne, Acne pustular, Dermatitis acneiform5 Includes Dry skin, Skin chapped6 Includes Pruritus, Pruritus generalisedLiver 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 reactionsReporting 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 KingdomYellow Card Scheme Website:
IrelandPharmacovigilance SectionIrish Medicines BoardKevin O'Malley HouseEarlsfort CentreEarlsfort TerraceDublin 2Tel: +353 1 6764971Fax: +353 1 6762517Website: e-mail: MaltaADR ReportingThe Medicines Authority Post-Licensing Directorate203 Level 3, Rue D'ArgensGŻR-1368 GżiraWebsite: e-mail: 4.9 OverdoseSymptomsThe 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. TreatmentThere 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 properties5.1 Pharmacodynamic propertiesPharmacotherapeutic group: antineoplastic agents, protein kinase inhibitors, ATC code: L01XE13.Mechanism of actionAfatinib 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 effectsAberrant 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 safetyLUX-Lung 3In 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)
Pemetrexed/Cisplatin
Hazard Ratio (HR)/Odds Ratio (OR) (95%CI)
PFS, Overall Trial Population
Months (median)
1-year PFS Rate
HR 0.58 (0.43-0.78)
Objective Response Rate (CR+PR) 1
(2.77-7.83)
Overall Survival (OS)
Months (median) 2
(0.66-1.25)&
0.55 1 CR= PR=partial response2 Updated OS analysis as of January 2013In 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)
a values presented for GIOTRIF vs. chemotherapyb NR= not reachedLUX-Lung 2LUX-Lung 2 was a single arm Phase II trial in 129 EGFR TKI-na&ve 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 populationThe 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 propertiesAbsorptionFollowing 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).DistributionIn vitro binding of afatinib to human plasma proteins is approximately 95%. Afatinib binds to proteins both non-covalently (traditional protein binding) and covalently.BiotransformationEnzyme-catalyzed metabolic reactions play a negligible role for afatinib in vivo. Covalent adducts to proteins were the major circulating metabolites of afatinib.EliminationIn 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 populationsRenal impairmentLess 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 impairmentAfatinib 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 populationsA 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.AgeNo significant impact of age (range: 28 years - 87 years) on the pharmacokinetics of afatinib could be observed. Body weightPlasma 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). GenderFemale patients had a 15% higher plasma exposure (AUCτ,ss, body weight corrected) than male patients. RaceRace 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 impairmentExposure 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 impairmentPatients 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 factorsOther 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 interactionsInteractions 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) enzymesIn 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 afatinibIn vitro data indicated that drug-drug interactions with afatinib due to inhibition of UGT1A1 are considered unlikely.5.3 Preclinical safety dataOral 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 toxicityBased 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. CarcinogenicityCarcinogenicity studies have not been conducted with GIOTRIF.6. Pharmaceutical particulars6.1 List of excipientsTablet core Lactose monohydrate Cellulose, microcrystalline (E460)Silica, colloidal anhydrous (E551)Crospovidone type AMagnesium stearate (E470b) Film-coating Hypromellose (E464)Macrogol 400 Titanium dioxide (E171)Talc (E553b)Polysorbate 80 (E433)6.2 IncompatibilitiesNot applicable.6.3 Shelf life3 years.6.4 Special precautions for storageStore in the original package in order to protect from moisture and light.6.5 Nature and contents of containerPVC/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 handlingAny unused medicinal product or waste material should be disposed of in accordance with local requirements.7. Marketing authorisation holderBoehringer Ingelheim International GmbHBinger Strasse 173D-55216 Ingelheim am RheinGermany8. Marketing authorisation number(s)EU/1/13/879/001EU/1/13/879/002EU/1/13/879/0039. Date of first authorisation/renewal of the authorisation&Date of first authorisation: 25 September 201310. Date of revision of the text&Detailed information on this medicinal product is available on the website of the European Medicines Agency
阿法替尼首次被证实能为特定肺癌患者提供总体生存获益•基于两项III期临床试验（LUX-Lung 3研究和LUX-Lung 6研究）的事后分析所得出的有关总体生存的结果显示，阿法替尼作为一线治疗可使伴有常见EGFR突变类型的肺癌患者的死亡风险降低19%。•将阿法替尼与化疗作为初始治疗方案的患者相比，阿法替尼可使患者的中位生存时间延长了三个月。•另一项针对肺癌患者接受了数种治疗方案后出现进展后所开展的III期临床试验（LUX-Lung 5研究）的结果显示，患者接受阿法替尼单药治疗出现肿瘤生长后继续联合化疗能够获益。德国殷格翰日电 /美通社/ -- 勃林格殷格翰公司于今日公布了来自一项整合了两项III期临床试验（LUX-Lung 3研究和LUX-Lung 6研究）数据的事后分析的最新总体生存结果。分析结果显示，在伴有常见的EGFR突变类型（Del 19/L858R）的肺癌患者中，与将化疗作为一线治疗方案的患者相比，将阿法替尼作为一线治疗方案可使患者的生存时间更长。在美国临床肿瘤学会（ASCO）第50届年会期间，在6月2日的口头演讲环节（3:00 - 6:00 PM, E大厅 D2; 摘要编号 #8004，计划演讲时间为 4:00 - 4:12 PM）中将会对这些数据展开深入讨论，从而提供上述试验结果对于临床实践和患者医疗护理方面有影响的洞见。与勃林格殷格翰公司抗肿瘤后续产品有关的另外6篇摘要也将在此次ASCO年会上公布或发表，此次会议于5月30日至6月3日在美国芝加哥举办。总体生存结果基于两项针对这一患者人群的规模最大的临床试验的综合性分析的结果显示，在伴有常见的EGFR突变类型的肺癌患者中，与接受标准化疗的患者相比，接受阿法替尼治疗的患者的中位生存时间延长了3个月（27.3个月 vs. 24.3个月），患者的死亡风险也降低了19%。在伴有最常见的EGFR突变类型（EGFR基因外显子19缺失）的患者中，死亡风险的降低幅度达到了41%（详细信息请参见摘要#8004）。此项分析所得出的结论进一步验证了之前已经发表的、有关阿法替尼相较于标准化疗可延缓肿瘤生长（无进展生存）、改善肺癌症状的控制和不良事件的结果。
针对上述总体生存结果，主要研究者、来自中国台湾大学附属医院的James Chih-Hsin Yang教授（M.D., Ph.D.）如此评价道：“这些独立开展的阿法替尼研究首次证实，无论后续治疗是否存在交叉，靶向治疗药物作为一线治疗相较于化疗能够延长EGFR突变（外显子19缺失）阳性的肺癌患者的总体生存时间。上述结果进一步丰富了阿法替尼在其他研究中早已获得证实的治疗受益，后者包括肿瘤缩小、疾病控制时间延长、以及改善限制患者生活的、与疾病相关的症状，例如咳嗽、疼痛和气促。在疾病出现进展之后的治疗另一项针对肺癌患者开展的III期临床试验（LUX-Lung 5）也在此次ASCO年会上公布结果，此项研究也达到了主要终点，表现为阿法替尼单药治疗出现肿瘤生长的患者继续接受阿法替尼加化疗（疾病出现进展后的治疗）能够获得益处。此项III期临床试验是针对接受了包括化疗、厄洛替尼或吉非替尼和阿法替尼单药等数种治疗方案后出现治疗失败的晚期肺癌患者，继续接受阿法替尼加紫杉醇（一种化疗药物）或由研究者选择的单用化疗的效果进行比较。在接受阿法替尼单药治疗后出现疾病进展的患者中，与停用阿法替尼并且仅接受化疗的患者相比，继续阿法替尼治疗、并同时联合化疗的患者的肿瘤生长出现了进一步的延缓（两组患者的肿瘤生长分别延缓了5.6个月和2.8个月），这也相当于将疾病进展风险降低了40%。在接受阿法替尼联合化疗的患者中最常见的不良事件是腹泻（通常与EGFR抑制有关）、脱发和虚弱（通常与化疗有关）。主要研究者、来自德国Essen大学附属医院西德癌症中心的Martin Schuler教授（M.D.）如此评价道：“这些研究结果显示了针对这些难治性患者的新型治疗方法—阿法替尼继续联合化疗治疗，该方案甚至可用于那些之前经历了EGFR TKI治疗失败、肿瘤重新开始生长的患者。”勃林格殷格翰公司的首席医学官 Klaus Dugi教授如此评价道：“肺癌并不仅仅是一种疾病，我们针对阿法替尼应用于伴有不同治疗条件的患者开展了研究、最终将有可能拓展患者的治疗选择范围，我们对此深感自豪。LUX-Lung 3研究和LUX-Lung 6研究的总体生存汇总结果和独立结果、以及之前获得的生活质量结果和患者报告的临床结果数据进一步充实了有关阿法替尼一线治疗伴有EGFR突变的肺癌患者的丰富的数据库。”阿法替尼已经获准的和正处于研发中的适应证阿法替尼（GIOTRIF& / GILOTRIF&）适用于治疗特定类型的EGFR突变阳性的NSCLC患者。在包括欧盟、日本、中国台湾和加拿大在内的市场上，阿法替尼以GIOTRIF&为商品名获得批准，在美国则以GILOTRIF&为商品名获得批准。在其他国家，阿法替尼正处于注册审核过程中。针对该药应用于头颈部鳞癌（HNSCC）的III期临床试验、以及针对该药应用于其他类型的肿瘤的临床试验正在进行之中。
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