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Afatinib(阿法替尼片,GILOTRIF,Giotrif)

2014-07-07 11:44:04  作者:新特药房  来源:互联网  浏览次数:1415  文字大小:【】【】【
简介: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 ...

英文药名:Gilotrif(afatinib film-coated 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2013年7月15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™ (阿法替尼 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

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 tablets
Giotrif 30 mg film-coated tablets
Giotrif 40 mg film-coated tablets
Giotrif 50 mg film-coated tablets


Giotrif 20 mg/30 mg/40 mg/50 mg film-coated tablets
1. Name of the medicinal product
GIOTRIF 20 mg film-coated tablets
GIOTRIF 30 mg film-coated tablets
GIOTRIF 40 mg film-coated tablets
GIOTRIF 50 mg film-coated tablets
2. Qualitative and quantitative composition
GIOTRIF 20 mg film-coated tablets
One film-coated tablet contains 20 mg afatinib (as dimaleate).
Excipient with known effect: One film-coated tablet contains 118 mg lactose (as monohydrate).
GIOTRIF 30 mg film-coated tablets
One film-coated tablet contains 30 mg afatinib (as dimaleate).
Excipient with known effect: One film-coated tablet contains 176 mg lactose (as monohydrate).
GIOTRIF 40 mg film-coated tablets
One film-coated tablet contains 40 mg afatinib (as dimaleate).
Excipient with known effect: One film-coated tablet contains 235 mg lactose (as monohydrate).
GIOTRIF 50 mg film-coated tablets
One film-coated tablet contains 50 mg afatinib (as dimaleate).
Excipient with known effect: One film-coated tablet contains 294 mg lactose (as monohydrate).
For the full list of excipients, see section 6.1.
3. Pharmaceutical form
Film-coated tablet (tablet).
GIOTRIF 20 mg film-coated tablets
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.
GIOTRIF 30 mg film-coated tablets
Dark blue, round, biconvex and bevel-edged film-coated tablet debossed with the code “T30” on one side and the Boehringer Ingelheim company logo on the other.
GIOTRIF 40 mg film-coated tablets
Light blue, round, biconvex and bevel-edged film-coated tablet debossed with the code “T40” on one side and the Boehringer Ingelheim company logo on the other.
GIOTRIF 50 mg film-coated tablets
Dark blue, oval, biconvex film-coated tablet debossed with the code “T50” 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);
• locally advanced or metastatic NSCLC of squamous histology progressing on or after platinum-based chemotherapy (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 starting dose (i.e. absence of diarrhoea, skin rash, stomatitis, and other adverse reactions with CTCAE Grade > 1) in the first cycle of treatment (21 days for EGFR mutation positive NSCLC and 28 days for squamous NSCLC). 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 patients treated with GIOTRIF across all clinical trials (including 0.5% of patients with CTCAE Grade ≥ 3 ILD-like adverse reactions). 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. In the pivotal trials Grade 3 alanine aminotransferase (ALT) and aspartate aminotransferase (AST) elevations were observed in 2.4% (LUX-Lung-3) and 1.6% (LUX-Lung 8) of patients with normal baseline liver tests treated with 40 mg/day. In LUX-Lung-3 Grade 3 ALT/AST elevations were about 3.5 fold higher in patients with abnormal baseline liver tests. There were no Grade 3 ALT/AST elevations in patients with abnormal baseline liver tests in LUX-Lung 8 (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 Fertility, 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).
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 and 4). 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 in the LUX-Lung 3 trial and in 25% of the patients in the LUX-Lung 8 trial. Discontinuation due to ADRs diarrhoea and rash/acne was 1.3% and 0% in LUX-Lung 3 and 3.8% and 2.0% in LUX-Lung 8, respectively.
ILD-like adverse reactions were reported in 0.7% of afatinib treated patients. 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 from all NSCLC trials with daily GIOTRIF doses of 40 mg or 50 mg 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

Nausea

Vomiting

Dyspepsia

Cheilitis

Pancreatitis

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
HPRA Pharmacovigilance
Earlsfort Terrace
IRL - Dublin 2
Tel: +353 1 6764971
Fax: +353 1 6762517
Website: www.hpra.ie
e-mail: medsafety@hpra.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
Description of selected adverse reactions
Very common ADRs in GIOTRIF-treated patients occurring in at least 10% of patients in trial LUX-Lung 8 are summarised by National Cancer Institute-Common Toxicity Criteria (NCI-CTC) Grade in Table 4.
Table 4: Very common ADRs in trial LUX-Lung 8*

GIOTRIF

(40 mg/day)

N=392

erlotinib

N=395

NCI-CTC Grade

Any Grade

3

4

Any Grade

3

4

MedDRA Preferred Term

%

%

%

%

%

%

Infections and infestations

Paronychia1

11.0

0.5

0

5.1

0.3

0

Metabolism and nutrition disorders

Decreased appetite

24.7

3.1

0

26.1

2.0

0

Gastrointestinal disorders

Diarrhoea

Stomatitis2

Nausea

74.7

30.1

20.7

9.9

4.1

1.5

0.8

0

0

41.3

10.6

16.2

3.0

0.5

1.0

0.3

0

0.3

Skin and subcutaneous tissue disorders

Rash3

Dermatitis acneiform4

60.7

14.0

5.4

1.3

0

0

56.7

18.0

8.1

2.5

0

0

* Reporting the frequency of patients with all causality AEs
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
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 ALT elevations occurred in 1% and Grade 3 elevations occurred in 0.8% of patients treated with GIOTRIF (see section 4.4).
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
GIOTRIF in patients with Non-Small Cell Lung Cancer (NSCLC) with EGFR mutations
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, multicentre, 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. 89% of patients had common EGFR mutations (Del 19 or L858R).
The primary endpoint was progression free survival (PFS) by independent review; the secondary endpoints included overall survival and objective response rate. At the time of the analysis, 14 Nov 2013, 176 patients (76.5%) in the afatinib arm and 70 patients (60.9%) in the chemotherapy arm experienced an event contributing to the PFS analysis, i.e. disease progression as determined by central independent review or death. The efficacy results are provided in Figure 1, Tables 5 and 6.
LUX-Lung 6
The efficacy and safety of GIOTRIF in Asian patients with Stage IIIB/IV EGFR mutation-positive locally advanced or metastatic adenocarcinoma of the lung was evaluated in a randomised, multicentre, open-label trial. Similar to LUX-Lung 3, patients with previously untreated NSCLC were screened for EGFR mutations using TheraScreen®: EGFR29 Mutation Kit (Qiagen Manchester Ltd). Among randomized patients, 65% were female, the median age was 58 years and all patients were of Asian ethnicity. Patients with common EGFR mutations accounted for 89% of the study population.
The primary endpoint was PFS as assessed by central independent review; secondary endpoints included OS and ORR.
Both trials demonstrated significant improvement in PFS of EGFR mutation positive patients treated with GIOTRIF compared to chemotherapy. The efficacy results are summarized in Figure 1 (LUX-Lung 3) and Tables 5 and 6 (LUX-Lung 3 and 6). Table 6 shows outcomes in the subgroups of patients with two common EGFR mutations – Del 19 and L858R.
Figure 1: Kaplan-Meier curve for PFS by independent review by treatment group in trial LUX-Lung 3 (Overall Population)


Table 5: Efficacy results of GIOTRIF vs. pemetrexed/cisplatin (LUX-Lung 3) gemcitabine/cisplatin (LUX-Lung 6) (Independent review)

LUX-Lung 3

LUX-Lung 6

GIOTRIF
 

(N=230)

Pemetrexed/ Cisplatin

(N=115)

GIOTRIF
 

(N=242)

Gemcitabine/ Cisplatin

(N=122)

Progression-free survival

Months (median)

11.2

6.9

11.0

5.6

Hazard Ratio (HR)

(95%CI)

0.58

(0.43-0.78)

0.28

(0.20-0.39)

p-value1

0.0002

<0.0001

1-year PFS Rate

48.1%

22.0%

46.7%

2.1%

Objective Response Rate (CR+PR)2

56.5%

22.6%

67.8%

23.0%

Odds Ratio (OR)

(95%CI)

4.80

(2.89-8.08)

7.57

(4.52-12.68)

p-value1

<0.0001

<0.0001

Overall Survival (OS)

Months (median)

28.2

28.2

23.1

23.5

Hazard Ratio (HR)

(95%CI)

0.88

(0.66-1.17)

0.93

(0.72-1.22)

p-value1

0.3850

0.6137

1 p-value for PFS/OS based on stratified log-rank test; p-value for Objective Response Rate based on logistic regression
2 CR=complete response; PR=partial response
Table 6: PFS and OS efficacy results of GIOTRIF vs pemetrexed/cisplatin (LUX-Lung 3) gemcitabine/cisplatin (LUX-Lung 6) in the pre-defined EGFR mutation subgroups Del 19 and L858R (Independent review)

LUX-Lung 3

LUX-Lung 6

Del19

GIOTRIF
 

(N=112)

Pemetrexed/ Cisplatin

(N=57)

GIOTRIF
 

(N=124)

Gemcitabine/ Cisplatin

(N=62)

Progression-free survival

Months (median)

13.8

5.6

13.1

5.6

Hazard Ratio (HR)

(95%CI)

0.26

(0.17-0.42)

0.20

(0.13-0.33)

p-value1

<0.0001

<0.0001

Overall Survival (OS)

Months (median)

33.3

21.1

31.4

18.4

Hazard Ratio (HR)

(95%CI)

0.54

(0.36-0.79)

0.64

(0.44-0.94)

p-value1

0.0015

0.0229

L858R

GIOTRIF
 

(N=91)

Pemetrexed/ Cisplatin

(N=47)

GIOTRIF
 

(N=92)

Gemcitabine/ Cisplatin

(N=46)

Progression-free survival

Months (median)

10.8

8.1

9.6

5.6

Hazard Ratio (HR)

(95%CI)

0.75

(0.48-1.19)

0.31

(0.19-0.52)

p-value1

0.2191

<0.0001

Overall Survival (OS)

Months (median)

27.6

40.3

19.6

24.3

Hazard Ratio (HR)

(95%CI)

1.30

(0.80-2.11)

1.22

(0.81-1.83)

p-value1

0.2919

0.3432

1 p-value for PFS/OS based on stratified log-rank test
In the pre-defined subgroup of common mutations (combined Del 19 and L858R) for GIOTRIF and chemotherapy, the median PFS was 13.6 months vs. 6.9 months (HR 0.48; 95% CI 0.35-0.66; p<0.0001; N=307) in LUX-Lung 3, and 11.0 months vs. 5.6 months (HR 0.24; 95% CI 0.17-0.35; p<0.0001; N=324) in LUX-Lung 6, respectively.
PFS benefit was accompanied by improvement in disease-related symptoms and delayed time to deterioration (see Table 7). Mean scores over time for overall quality of life, global health status and physical, role, cognitive, social and emotional functioning were significantly better for GIOTRIF.
Table 7: Symptom outcomes for GIOTRIF vs. chemotherapy in trials LUX-Lung 3 and LUX-Lung 6 (EORTC QLQ-C30 & QLQ-LC13)

LUX-Lung 3

Cough

Dyspnoea

Pain

% of patients improved a

67% vs. 60%;

p=0.2133

65% vs. 50%;

p=0.0078

60% vs. 48%;

p=0.0427

Delay of median time to deterioration (months) a,b

27.0 vs. 8.0

HR 0.60; p=0.0062

10.4 vs. 2.9

HR 0.68; p=0.0129

4.2 vs. 3.1

HR 0.83; p=0.1882

 

LUX-Lung 6

Cough

Dyspnoea

Pain

% of patients improved a

76% vs. 55%;

p=0.0003

71% vs. 48%;

p<0.0001

65% vs. 47%;

p=0.0017

Delay of median time to deterioration (months) a,b

31.1 vs. 10.3

HR 0.46; p=0.0001

7.7 vs. 1.7

HR 0.53; p<0.0001

6.9 vs. 3.4

HR 0.70; p=0.0220

a values presented for GIOTRIF vs. chemotherapy, p-value based on logistic regression
b p-value for time to deterioration based on stratified log-rank test
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.
GIOTRIF in patients with NSCLC of squamous histology
The efficacy and safety of GIOTRIF as second-line treatment for patients with advanced NSCLC of squamous histology was investigated in a randomized open-label global Phase III trial LUX-Lung 8. Patients who received at least 4 cycles of platinum-based therapy in the first line setting were subsequently randomized 1:1 to daily GIOTRIF 40 mg or erlotinib 150 mg until progression. Randomization was stratified by race (Eastern Asian vs non Eastern Asian). The primary endpoint was PFS; OS was the key secondary endpoint. Other secondary endpoints included ORR, DCR, change in tumour size and HRQOL.
Among 795 patients randomized, the majority were males (84%), white (73%), current or former smokers (95%) with baseline performance status ECOG 1 (67%) and ECOG 0 (33%).
Second-line GIOTRIF significantly improved PFS and OS of patients with squamous NSCLC compared to erlotinib. The efficacy results at the time of the primary analysis of OS including all randomized patients are summarized in Figure 2 and Table 8.
Table 8: Efficacy results for GIOTRIF vs erlotinib in LUX-Lung 8, based on primary analysis of OS, including all randomized patients

GIOTRIF
 

(N=398)

Erlotinib
 

(n=397)

Hazard Ratio/ Odds Ratio

(95%CI)

p-value2

PFS

Months (median)

2.63

1.94

HR 0.81

(0.69, 0.96)

0.0103

OS

Months (median)

Alive at 12 months

Alive at 18 months

7.92

36.4%

22.0%

6.77

28.2%

14.4%

HR 0.81

(0.69, 0.95)

0.0077

Objective Response Rate (CR+PR)1

5.5%

2.8%

OR 2.06

(0.98, 4.32)

0.0551

Duration of response

Months (median)

7.29

3.71

 

1CR=complete response; PR=partial response
2p-value for PFS/OS based on stratified log-rank test; p-value for Objective Response Rate and Disease Control Rate based on logistic regression
The overall survival hazard ratio in patients < 65 years of age was 0.68 (95% CI 0.55, 0.85) and in patients 65 years of age and older it was 0.95 (95% CI 0.76, 1.19).
Figure 2: Kaplan-Meier Curve for OS by treatment group in LUX Lung 8


PFS benefit was accompanied by improvement in disease-related symptoms and delayed time to deterioration (see Table 9).
Table 9: Symptom outcomes for GIOTRIF vs. erlotinib in trial LUX-Lung 8 (EORTC QLQ-C30 & QLQ-LC13)

Cough

Dyspnoea

Pain

% of patients improveda, c

43% vs. 35%;

p=0.0294

51% vs. 44%;

p=0.0605

40% vs. 39%;

p=0.7752

Delay of time to deterioration (months)b, c

4.5 vs. 3.7

HR 0.89; p=0.2562

2.6 vs. 1.9

HR 0.79; p=0.0078

2.5 vs. 2.4

HR 0.99; p=0.8690

a values presented for GIOTRIF vs. erlotinib, p-value based on logistic regression
b p-value for time to deterioration based on stratified log-rank test
c p-values were not adjusted for multiplicity
Efficacy in EGFR-negative tumours has not been established.
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 AUC,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 is eliminated with an effective half-life of approximately 37 hours. Thus, 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). In patients treated with afatinib for more than 6 months a terminal half-life of 344 h was estimated.
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 (AUC,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 (AUC,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 (AUC,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 excipients
Tablet core
Lactose monohydrate
Cellulose, microcrystalline (E460)
Silica, colloidal anhydrous (E551)
Crospovidone type A
Magnesium stearate (E470b)
Film-coating
GIOTRIF 20 mg film-coated tablets
Hypromellose (E464)
Macrogol 400
Titanium dioxide (E171)
Talc (E553b)
Polysorbate 80 (E433)
GIOTRIF 30, 40 and 50 mg film-coated tablets
Hypromellose (E464)
Macrogol 400
Titanium dioxide (E171)
Talc (E553b)
Polysorbate 80 (E433)
Indigo carmine (E132) aluminium hydroxide
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)
GIOTRIF 20 mg film-coated tablets
EU/1/13/879/001
EU/1/13/879/002
EU/1/13/879/003
GIOTRIF 30 mg film-coated tablets
EU/1/13/879/004
EU/1/13/879/005
EU/1/13/879/006
GIOTRIF 40 mg film-coated tablets
EU/1/13/879/007
EU/1/13/879/008
EU/1/13/879/009
GIOTRIF 50 mg film-coated tablets
EU/1/13/879/010
EU/1/13/879/011
EU/1/13/879/012
9. Date of first authorisation/renewal of the authorisation
Date of first authorisation: 25 September 2013
10. Date of revision of the text
03/2016
Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu


欧盟批准口服抗癌药Giotrif(afatinib,阿法替尼)治疗肺鳞状细胞癌
德国制药巨头勃林格殷格翰(Boehringer Ingelheim)抗癌管线近日在欧盟监管方面传来喜讯。欧盟委员会(EC)已批准口服抗癌药Giotrif(afatinib,阿法替尼),用于含铂化疗治疗期间或治疗后病情进展的晚期肺鳞状细胞癌(SqCC)患者的治疗。之前,Giotrif已获批一线治疗EGFR突变阳性非小细胞肺癌(NSCLC)。
肺鳞状细胞癌(SqCC)是非小细胞肺癌(NSCLC)的第二大亚型,约占NSCLC病例的20-30%,预后较差,确诊为晚期SqCC的患者,平均生存期仅为一年左右。近些年,尽管SqCC治疗领域已取得一些进展,但这种疾病在临床治疗上仍然非常具有挑战性。Giotrif将为SqCC群体提供一种重要的、新的口服治疗方案。此次批准,不仅标志着Giotrif成为欧洲专门批准治疗肺鳞状细胞癌的首个口服治疗方案,同时也肯定了Giotrif作为第二代EGFR靶向制剂相对于第一代靶向制剂的积极优势。
头对头LUX-Lung 8研究:Giotrif治疗晚期SqCC疗效显著优于罗氏特罗凯(Tarceva)
欧盟批准Giotrif治疗晚期SqCC,是基于头对头LUX-Lung 8临床研究的积极数据。该研究在一线化疗治疗期间或治疗后病情进展的肺鳞状细胞癌(SqCC)患者中开展,将Giotrif与罗氏靶向抗癌药Tarceva(品牌名:特罗凯,通用名:erlotinib,厄洛替尼)进行了直接比较。
数据显示,与Tarceva相比,Giotrif显著延迟了肺癌的进展(无进展生存期PFS,主要终点),癌症进展风险降低19%;同时,Giotrif也显著延长了总生存期(OS,关键次要终点),死亡风险降低19%。此外,Giotrif还显著提高了疾病控制率(51% vs 40%,p=0.02),Giotrif治疗组患者生活质量和癌症症状控制也得到了改善。
安全性方面,2个治疗组严重不良事件发生率相似,但在特定副作用上具有差异性。与Tarceva治疗组相比,Giotrif治疗组表现出较高的严重腹泻和口腔炎发生率:3级腹泻(10% vs 2%)、3级口腔炎(4% vs 0%)。而Tarceva治疗组在皮疹和痤疮方面表现出较高的发生率:3级皮疹/痤疮(10% vs 6%)。
LUX-Lung临床项目:
LUX-Lung 8研究是Giotrif 大型LUX-Lung项目的一部分,该项目是调查EGFR酪氨酸激酶抑制剂(TKI)的最大临床研究项目,包括8个研究,涉及超过3760例患者。其中包括一线治疗肺癌的2个关键研究(LUX Lung 3,6),同时也包括2个头对头研究(LUX-Lung 7,8),这2个头对头研究将Giotrif与第一代EGFR TKI(阿斯利康易瑞沙和罗氏特罗凯)进行了直接对比。
目前,Giotrif已获全球60多个国家批准,用于EGFR突变阳性非小细胞肺癌(NSCLC)的一线治疗。近日公布的LUX-Lung 7研究数据,证实了Giotrif作为第二代EGFR靶向制剂相对于另一种EGFR靶向制剂——阿斯利康靶向疗法易瑞沙(Iressa,通用名:gefitinib,吉非替尼)的优越性。与Iressa相比,Giotrif使肺癌进展和治疗失败风险降低了27%。
关于Giotrif/Gilotrif(afatinib,阿法替尼):
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,适用于携带常见EGFR突变(del19和L858R)的非小细胞肺癌(NSCLC)患者的治疗。目前,afatinib已获全球60多个国家批准,该药在美国的商品名为Gilotrif,在欧盟的商品名为Giotrif。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。目前,勃林格殷格翰正在III期研究中调查atatinib用于鳞癌头颈部癌及其他类型癌症的治疗。

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