英文药名：Alecensa Hard Capsules(Alectinib)

中文药名：阿雷替尼硬胶囊

生产厂家：罗氏公司
药品介绍
肺癌新药Alecensa(alectinib)获欧盟批准
2017年2月21日，欧盟委员会批准罗氏Alecensa（alectinib）作为一款二线治疗药物用于ALK阳性非小细胞肺癌患者。欧盟委员会的决定基于两项2期研究的结果，研究结果表明，在那些以目前标准治疗药物，即辉瑞旗下克唑替尼治疗后疾病进展的患者中，Alecensa 能使肿瘤缩小程度高达52.2%。
Alecensa单药治疗在这些患者中也能使无进展生存期延长8.9个月，同时，那些疾病已扩散至部分中枢神经系统的患者中，有 64%的人其中枢神经系统肿瘤可以观察到可测量的缩小。
目前Alecensa在美国市场已有销售，该药物于2015年12月在美国获批，当时该药物先是被授予了突破性治疗药物资格，之后两个月，FDA以加速批准程序批准其二线用于非小细胞肺癌。
然而，该药物在欧盟的获批是有条件的，还需要提供Alecensa作为一线治疗药物用于ALK阳性非小细胞肺癌的进一步试验结果。罗氏正在进行的对比Alecensa和克唑替尼的3期ALEX 研究结果有望今年6月份获得。
Horning博士是罗氏首席医疗官兼全球产品开发总监，他表示：每年全球估计有7.5万人被确诊患有ALK 阳性非小细胞肺癌。目前标准治疗药物耐药性的产生凸显了替代治疗药物的需求。今天的批准为欧盟患有这种灾难性疾病的患者提供了一种新的治疗选择。
Alecensa 150mg Hard Capsules
1. Name of the medicinal product
Alecensa 150 mg hard capsules
2. Qualitative and quantitative composition
Each hard capsule contains alectinib hydrochloride equivalent to 150 mg alectinib.
Excipients with known effect
Each hard capsule contains 33.7 mg lactose (as monohydrate) and 6 mg sodium (as sodium laurilsulfate).
For the full list of excipients, see section 6.1.
3. Pharmaceutical form
Hard capsule.
White hard capsule of 19.2 mm length, with “ALE” printed in black ink on the cap and “150 mg” printed in black ink on the body.
4. Clinical particulars
4.1 Therapeutic indications
Alecensa as monotherapy is indicated for the treatment of adult patients with anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC) previously treated with crizotinib.
4.2 Posology and method of administration
Treatment with Alecensa should be initiated and supervised by a physician experienced in the use of anticancer medicinal products.
A validated ALK assay is necessary for the selection of ALK-positive NSCLC patients. ALK-positive NSCLC status should be established prior to initiation of Alecensa therapy.
Posology
The recommended dose of Alecensa is 600 mg (four 150 mg capsules) taken twice daily with food (total daily dose of 1200 mg).
Duration of treatment
Treatment with Alecensa should be continued until disease progression or unacceptable toxicity.
Delayed or missed doses
If a planned dose of Alecensa is missed, patients can make up that dose unless the next dose is due within 6 hours. Patients should not take two doses at the same time to make up for a missed dose. If vomiting occurs after taking a dose of Alecensa, patients should take the next dose at the scheduled time.
Dose adjustments
Management of adverse events may require dose reduction, temporary interruption, or discontinuation of treatment with Alecensa. The dose of Alecensa should be reduced in steps of 150 mg twice daily based on tolerability. Alecensa treatment should be permanently discontinued if patients are unable to tolerate the 300 mg twice daily dose.
Dose modification advice is provided in Tables 1 and 2 below.
Table 1 Dose reduction schedule

Dose reduction schedule	Dose level
Starting dose	600 mg twice daily
First dose reduction	450 mg twice daily
Second dose reduction	300 mg twice daily

Table 2 Dose modification advice for specified Adverse Drug Reactions (see sections 4.4 and 4.8)

CTCAE grade	Alecensa treatment
ILD/pneumonitis of any severity grade	Immediately interrupt and permanently discontinue Alecensa if no other potential causes of ILD/pneumonitis have been identified.
ALT or AST elevation of Grade ≥ 3 (> 5 times ULN) with total bilirubin ≤ 2 times ULN	Temporarily withhold until recovery to baseline or ≤ Grade 1 (≤ 3 times ULN), then resume at reduced dose (see Table 1).
ALT or AST elevation of Grade ≥ 2 (> 3 times ULN) with total bilirubin elevation > 2 times ULN in the absence of cholestasis or haemolysis	Permanently discontinue Alecensa.
Bradycardiaa Grade 2 or Grade 3 (symptomatic, may be severe and medically significant, medical intervention indicated)	Temporarily withhold until recovery to ≤ Grade 1 (asymptomatic) bradycardia or to a heart rate of ≥ 60 bpm. Evaluate concomitant medicinal products known to cause bradycardia, as well as anti-hypertensive medicinal products. If a contributing concomitant medicinal product is identified and discontinued, or its dose is adjusted, resume at previous dose upon recovery to ≤ Grade 1 (asymptomatic) bradycardia or to a heart rate of ≥ 60 bpm. If no contributing concomitant medicinal product is identified, or if contributing concomitant medicinal products are not discontinued or dose modified, resume at reduced dose (see Table 1) upon recovery to ≤ Grade 1 (asymptomatic) bradycardia or to a heart rate of ≥ 60 bpm.
Bradycardiaa Grade 4 (life-threatening consequences, urgent intervention indicated)	Permanently discontinue if no contributing concomitant medicinal product is identified. If a contributing concomitant medicinal product is identified and discontinued, or its dose is adjusted, resume at reduced dose (see Table 1) upon recovery to ≤ Grade 1 (asymptomatic) bradycardia or to a heart rate of ≥ 60 bpm, with frequent monitoring as clinically indicated. Permanently discontinue in case of recurrence.
CPK elevation > 5 times ULN	Temporarily withhold until recovery to baseline or to ≤ 2.5 times ULN, then resume at the same dose.
CPK elevation > 10 times ULN or second occurrence of CPK elevation of > 5 times ULN	Temporarily withhold until recovery to baseline or to ≤ 2.5 times ULN, then resume at reduced dose as per Table 1.

ALT = alanine aminotransferase; AST = aspartate aminotransferase; CPK = creatine phosphokinase; CTCAE = NCI Common Terminology Criteria for Adverse Events; ILD = interstitial lung disease; ULN = upper limit of normal
a Heart rate less than 60 beats per minute (bpm).
Special populations
Hepatic impairment
No dose adjustment is required in patients with mild hepatic impairment. Alecensa has not been studied in patients with moderate to severe hepatic impairment. Therefore, Alecensa is not recommended in patients with moderate to severe hepatic impairment (see section 5.2).
Renal impairment
No dose adjustment is required in patients with mild or moderate renal impairment. Alecensa has not been studied in patients with severe renal impairment. However, since alectinib elimination via the kidney is negligible, no dose adjustment is required in patients with severe renal impairment (see section 5.2).
Elderly (≥ 65 years)
The limited data on the safety and efficacy of Alecensa in patients aged 65 years and older do not suggest that a dose adjustment is required in elderly patients (see section 5.2). There are no available data on patients over 80 years of age.
Paediatric population
The safety and efficacy of Alecensa in children and adolescents below 18 years of age have not been established. No data are available.
Extreme body weight (>130 kg)
Although PK simulations for Alecensa do not indicate a low exposure in patients with extreme body weight (i.e. >130 kg), alectinib is widely distributed and clinical studies for alectinib enrolled patients within a range of body weights of 36.9-123 kg. There are no available data on patients with body weight above 130 kg.
Method of administration
Alecensa is for oral use. The hard capsules should be swallowed whole, and must not be opened or dissolved. They must be taken with food (see section 5.2).
4.3 Contraindications
Hypersensitivity to alectinib or to any of the excipients listed in section 6.1.
4.4 Special warnings and precautions for use
Interstitial lung disease (ILD)/pneumonitis
Cases of ILD/pneumonitis have been reported in clinical trials with Alecensa (see section 4.8). Patients should be monitored for pulmonary symptoms indicative of pneumonitis. Alecensa should be immediately interrupted in patients diagnosed with ILD/pneumonitis and should be permanently discontinued if no other potential causes of ILD/pneumonitis have been identified (see section 4.2).
Hepatotoxicity
Elevations in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) greater than 5 times the ULN as well as bilirubin elevations of more than 3 times the ULN occurred in patients in pivotal phase II clinical trials (NP28761, NP28673) with Alecensa (see section 4.8). The majority (76% of the patients with hepatic aminotransferase elevations and 60% of the patients with bilirubin elevations) of these events occurred during the first 3 months of treatment. In the pivotal phase II clinical trials (NP28761 and NP28673), two patients with Grade 3-4 AST/ALT elevations had documented drug induced liver injury by liver biopsy. Concurrent elevations in ALT or AST greater than or equal 3 times the ULN and total bilirubin greater than or equal 2 times the ULN, with normal alkaline phosphatase, occurred in one patient treated in Alecensa clinical trials.
Liver function, including ALT, AST, and total bilirubin should be monitored at baseline and then every 2 weeks during the first 3 months of treatment. Thereafter, monitoring should be performed periodically, since events may occur later than 3 months, with more frequent testing in patients who develop aminotransferase and bilirubin elevations. Based on the severity of the adverse drug reaction, Alecensa should be withheld and resumed at a reduced dose, or permanently discontinued as described in Table 2 (see section 4.2).
Severe myalgia and creatine phosphokinase (CPK) elevation
Myalgia or musculoskeletal pain occurred in 31% of patients in pivotal phase II trials (NP28761, NP28673) with Alecensa. The incidence of Grade 3 myalgia/musculoskeletal pain was 1.2%. Dose modifications for myalgia/musculoskeletal pain were required in 0.8% of patients.
Elevations of CPK occurred in 46% of 219 patients with CPK laboratory data available in pivotal phase II trials (NP28761, NP28673) with Alecensa. The incidence of Grade 3 elevations of CPK was 5.0%. Median time to Grade 3 CPK elevation was 14 days. Dose modifications for elevation of CPK occurred in 4.0 % of patients (see section 4.8).
Patients should be advised to report any unexplained muscle pain, tenderness, or weakness. CPK levels should be assessed every two weeks for the first month of treatment and as clinically indicated in patients reporting symptoms. Based on the severity of the CPK elevation, Alecensa should be withheld, then resumed or dose reduced (see section 4.2).
Bradycardia
Symptomatic bradycardia can occur with Alecensa (see section 4.8). Heart rate and blood pressure should be monitored as clinically indicated. Dose modification is not required in case of asymptomatic bradycardia (see section 4.2). If patients experience symptomatic bradycardia or life-threatening events, concomitant medicinal products known to cause bradycardia, as well as anti-hypertensive medicinal products should be evaluated and Alecensa treatment should be adjusted as described in Table 2 (see sections 4.2 and 4.5, 'P-gp substrates' and 'BCRP substrates').
Photosensitivity
Photosensitivity to sunlight has been reported with Alecensa administration (see section 4.8). Patients should be advised to avoid prolonged sun exposure while taking Alecensa, and for at least 7 days after discontinuation of treatment. Patients should also be advised to use a broad-spectrum Ultraviolet A (UVA)/ Ultraviolet B (UVB) sun screen and lip balm (SPF ≥50) to help protect against potential sunburn.
Women of child-bearing potential
Alecensa may cause foetal harm when administered to a pregnant woman. Female patients of child-bearing potential receiving Alecensa, must use highly effective contraceptive methods during treatment and for at least 3 months following the last dose of Alecensa (see sections 4.6 and 5.3).
Lactose intolerance
This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, a congenital lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
Sodium content
The recommended daily dose (1200 mg) of Alecensa contains 2.1 mmol (or 48 mg) sodium. To be taken into consideration by patients on a controlled sodium diet.
4.5 Interaction with other medicinal products and other forms of interaction
Effects of other medicinal products on alectinib
Based on in vitro data, CYP3A4 is the primary enzyme mediating the metabolism of both alectinib and its major active metabolite M4, and CYP3A contributes to 40% - 50% of total hepatic metabolism. M4 has shown similar in vitro potency and activity against ALK.
CYP3A inducers
Co-administration of multiple oral doses of 600 mg rifampicin once daily, a strong CYP3A inducer, with a single oral dose of 600 mg alectinib reduced alectinib Cmax, and AUCinf by 51% and 73% respectively and increased M4 Cmax and AUCinf 2.20 and 1.79-fold respectively. The effect on the combined exposure of alectinib and M4 was minor, reducing Cmax and AUCinf by 4% and 18%, respectively. Based on the effects on the combined exposure of alectinib and M4, no dose adjustments are required when Alecensa is co-administered with CYP3A inducers. Appropriate monitoring is recommended for patients taking concomitant strong CYP3A inducers (including, but not limited to, carbamazepine, phenobarbital, phenytoin, rifabutin, rifampicin and St. John's Wort (Hypericum perforatum)).
CYP3A inhibitors
Co-administration of multiple oral doses of 400 mg posaconazole twice daily, a strong CYP3A inhibitor, with a single oral dose of 300 mg alectinib increased alectinib exposure Cmax and AUCinf by 1.18 and 1.75-fold respectively, and reduced M4 Cmax and AUCinf by 71% and 25% respectively.The effect on the combined exposure of alectinib and M4 was minor, reducing Cmax by 7% and increasing AUCinf 1.36-fold. Based on the effects on the combined exposure of alectinib and M4, no dose adjustments are required when Alecensa is co-administered with CYP3A inhibitors. Appropriate monitoring is recommended for patients taking concomitant strong CYP3A inhibitors (including, but not limited to, ritonavir, saquinavir, telithromycin, ketoconazole, itraconazole, voriconazole, posaconazole nefazodone, grapefruit or Seville oranges).
Medicinal products that increase gastric pH
Multiple doses of esomeprazole, a proton pump inhibitor, 40 mg once daily, demonstrated no clinically relevant effect on the combined exposure of alectinib and M4. Therefore, no dose adjustments are required when Alecensa is co-administered with proton pump inhibitors or other medicinal products which raise gastric pH (e.g. H2 receptor antagonists or antacids).
Effect of transporters on alectinib disposition
M4 is a substrate of P-gp. As alectinib inhibits P-gp, it is not expected that co-medication with P-gp inhibitors has a relevant effect on M4 exposure.
Effects of alectinib on other medicinal products
P-gp substrates
In vitro, alectinib and its major active metabolite M4 are inhibitors of the efflux transporter P-glycoprotein (P-gp). Therefore, alectinib and M4 may have the potential to increase plasma concentrations of co-administered substrates of P-gp. When Alecensa is co-administered with P-gp substrates (e.g., digoxin, dabigatran etexilate, topotecan, sirolimus, everolimus, nilotinib and lapatinib), appropriate monitoring is recommended.
BCRP substrates
In vitro, alectinib and M4 are inhibitors of the efflux transporter Breast Cancer Resistance Protein (BCRP). Therefore, alectinib and M4 may have the potential to increase plasma concentrations of co-administered substrates of BCRP. When Alecensa is co-administered with BCRP substrates (e.g., methotrexate, mitoxantrone, topotecan and lapatinib), appropriate monitoring is recommended.
CYP substrates
In vitro, alectinib and M4 show weak time-dependent inhibition of CYP3A4, and alectinib exhibits a weak induction potential of CYP3A4 and CYP2B6 at clinical concentrations.
Multiple doses of 600 mg alectinib had no influence on the exposure of midazolam (2 mg), a sensitive CYP3A substrate. Therefore, no dose adjustment is required for co-administered CYP3A substrates.
A risk for induction of CYP2B6 and PXR regulated enzymes apart from CYP3A4 cannot be completely excluded. The effectiveness of concomitant administration of oral contraceptives may be reduced.
4.6 Fertility, pregnancy and lactation
Women of childbearing potential/contraception
Women of childbearing potential must be advised to avoid pregnancy while on Alecensa. Female patients of child-bearing potential receiving Alecensa must use highly effective contraceptive methods during treatment and for at least 3 months following the last dose of Alecensa.
Pregnancy
There are no or limited amount of data from the use of Alecensa in pregnant women. Based on its mechanism of action, Alecensa may cause foetal harm when administered to a pregnant woman. Studies in animals have shown reproductive toxicity (see section 5.3).
Female patients, who become pregnant while taking Alecensa or during the 3 months following the last dose of Alecensa must contact their doctor and should be advised of the potential harm to the foetus.
Breast-feeding
It is unknown whether alectinib and its metabolites are excreted in human milk. A risk to the newborn/infant cannot be excluded. Mothers should be advised against breast-feeding while receiving Alecensa.
Fertility
No fertility studies in animals have been performed to evaluate the effect of Alecensa. No adverse effects on male and female reproductive organs were observed in general toxicology studies (see section 5.3).
4.7 Effects on ability to drive and use machines
Alecensa has minor influence on the ability to drive and use machines. Caution should be exercised when driving or operating machines as patients may experience symptomatic bradycardia (e.g., syncope, dizziness, hypotension) or vision disorders while taking Alecensa (see section 4.8).
4.8 Undesirable effects
Summary of the safety profile
The safety of Alecensa has been evaluated in 253 patients in pivotal phase II clinical trials (NP28761, NP28673) with ALK-positive non-small cell lung cancer (NSCLC) treated with the recommended dose of 600 mg twice daily. The median duration of exposure to Alecensa was 11 months.
The most common adverse drug reactions (ADRs) (≥ 20%) were constipation (36%), oedema (34%, including oedema peripheral, oedema, generalised oedema, eyelid oedema, periorbital oedema), myalgia (31%, including myalgia and musculoskeletal pain) and nausea (22%).
Tabulated list of adverse drug reactions
Table 3 summarises the ADRs occurring in patients who received Alecensa in pivotal clinical trials and during post-marketing.
The ADRs listed in Table 3 are presented by system organ class and frequency categories, defined using the following convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1000), very rare (<1/10,000). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Table 3 Summary of ADRs occurring in patients treated with Alecensa in pivotal phase II clinical trials (NP28761, NP28673) and during post-marketing

System organ class ADRs (MedDRA)	Alecensa N=253
	All grades (%)	Frequency category (all grades)	Grades 3-4* (%)
Blood and lymphatic system disorders
Anaemia1)	16	Very common	2.0
Eye disorders
Vision disorders2)	12	Very common	0
Cardiac disorders
Bradycardia3)	7.9	Common	0
Respiratory, thoracic and mediastinal disorders
Interstitial lung disease / pneumonitis	0.4	Uncommon	0.4
Gastrointestinal disorders
Diarrhoea	18	Very common	1.2
Vomiting	13	Very common	0.4
Constipation	36	Very common	0
Nausea	22	Very common	0.4
Hepatobiliary disorders
Drug-induced liver injury4)	0.8	Uncommon	0.8
Increased AST	16	Very common	2.8
Increased ALT	14	Very common	3.2
Increased bilirubin5)	17	Very common	3.2
Increased alkaline phosphatase**	7.5	Common	0.4
Skin and subcutaneous tissue disorders
Rash6)	20	Very common	0.4
Photosensitivity	12	Very common	0
Musculoskeletal and connective tissues disorders
Myalgia7)	31	Very common	1.2
Increased blood creatine phosphokinase	13	Very common	3.6
Renal and urinary disorders
Blood creatinine increased	6.7	Common	0.4
General disorders and administration site conditions
Oedema8)	34	Very common	0.8

No Grade 5 events observed
Increased alkaline phosphatase was reported in the post-marketing period. Cases were also reported in pivotal Phase II clinical trials NP28761 and NP28673.
1) includes cases of anaemia and haemoglobin decreased
2) includes cases of blurred vision, visual impairment, vitreous floaters, reduced visual acuity, asthenopia, and diplopia
3) includes cases of bradycardia and sinus bradycardia
4) includes one patient with reported MedDRA term of drug-induced liver injury as well as one patient with reported Grade 4 increased AST and ALT who had documented drug-induced liver injury by liver biopsy
5) includes cases of blood bilirubin increased, hyperbilirubinaemia and bilirubin conjugated increased
6) includes cases of rash, rash maculopapular, dermatitis acneiform, erythema, rash generalised, rash papular, rash pruritic and rash macular
7) includes cases of myalgia and musculoskeletal pain
8) includes cases of oedema peripheral, oedema, generalised oedema, eyelid oedema, periorbital oedema
Description of selected adverse reactions
Interstitial lung disease (ILD) / pneumonitis
Severe ILD/pneumonitis occurred in patients treated with Alecensa. In the pivotal phase II clinical trials (NP28761, NP28673), 1 out of 253 patients treated with Alecensa (0.4%) had a Grade 3 ILD.This event led to withdrawal from Alecensa treatment. There were no fatal cases of ILD. Patients should be monitored for pulmonary symptoms indicative of pneumonitis (see sections 4.2 and 4.4).
Hepatotoxicity
In the pivotal phase II clinical trials (NP28761, NP28673) two patients with Grade 3-4 AST/ALT elevations had documented drug induced liver injury by liver biopsy. One of these cases led to withdrawal from Alecensa treatment. Adverse reactions of increased AST and ALT levels (16% and 14% respectively) were reported in patients treated with Alecensa in pivotal phase II clinical trials (NP28761, NP28673). The majority of these events were of Grade 1 and 2 intensity, and events of Grade ≥ 3 were reported in 2.8% and 3.2% of the patients, respectively. The events generally occurred during the first 3 months of treatment, were usually transient and resolved upon temporary interruption of Alecensa treatment (reported for 1.2% and 3.2% of the patients, respectively) or dose reduction (1.6% and 0.8%, respectively). In 1.2% and 1.6% of the patients, AST and ALT elevations, respectively, led to withdrawal from Alecensa treatment.
Adverse reactions of bilirubin elevations were reported in 17% of the patients treated with Alecensa in pivotal phase II clinical trials (NP28761, NP28673). The majority of the events were of Grade 1 and 2 intensity; Grade 3 events were reported in 3.2% of the patients. The events generally occurred during the first 3 months of treatment, were usually transient and resolved upon temporary interruption of Alecensa treatment (4.7% of the patients) or dose reduction (2.8%). In 4 patients (1.6%), bilirubin elevations led to withdrawal from Alecensa treatment.
Concurrent elevations in ALT or AST greater than or equal to three times the ULN and total bilirubin greater than or equal to two times the ULN, with normal alkaline phosphatase, occurred in one patient (0.2%) treated in Alecensa clinical trials.
Patients should be monitored for liver function including ALT, AST, and total bilirubin as outlined in section 4.4 and managed as recommended in section 4.2.
Bradycardia
Cases of bradycardia (7.9%) of Grade 1 or 2 have been reported in patients treated with Alecensa in pivotal phase II clinical trials (NP28761, NP28673). There were 44 of 221 patients (20%) treated with Alecensa who had post-dose heart rate values below 50 beats per minutes. Patients who develop symptomatic bradycardia should be managed as recommended in sections 4.2 and 4.4. No case of bradycardia led to withdrawal from Alecensa treatment.
Severe myalgia and CPK elevations
Cases of myalgia (31%) including myalgia events (25%) and musculoskeletal pain (7.5%) have been reported in patients treated with Alecensa in pivotal phase II clinical trials (NP28761, NP28673). The majority of events were Grades 1 or 2 and three patients (1.2%) had a Grade 3 event. Dose modifications of Alecensa treatment due to these adverse events were only required for two patients (0.8%); Alecensa treatment was not withdrawn due to these events of myalgia. Elevations of CPK occurred in 46% of 219 patients with CPK laboratory data available in pivotal phase II clinical trials (NP28761, NP28673) with Alecensa. The incidence of Grade 3 elevations of CPK was 5.0%. Median time to Grade 3 CPK elevation was 14 days. Dose modifications for elevation of CPK occurred in 4.0% of patients; withdrawal from Alecensa treatment did not occur due to CPK elevations.
Gastrointestinal effects
Constipation (36%), nausea (22%), diarrhoea (18%) and vomiting (13%) were the most commonly reported gastrointestinal (GI) reactions. Most of these events were of mild or moderate severity; Grade 3 events were reported for diarrhea (1.2%), nausea (0.4%), and vomiting (0.4%). These events did not lead to withdrawal from Alecensa treatment. Median time to onset for constipation, nausea, diarrhea, and/or vomiting events was 18 days. The events declined in frequency after the first month of treatment.
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 (see details below).
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
Website: www.medicinesauthority.gov.mt/adrportal
United Kingdom
Yellow Card Scheme
Website: www.mhra.gov.uk/yellowcard
4.9 Overdose
Patients who experience overdose should be closely supervised and general supportive care instituted. There is no specific antidote for overdose with Alecensa.
5. Pharmacological properties
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: anti-neoplastic agents, protein kinase inhibitor; ATC code: L01XE36.
Mechanism of action
Alectinib is a highly selective and potent ALK and RET tyrosine kinase inhibitor. In preclinical studies, inhibition of ALK tyrosine kinase activity led to blockage of downstream signalling pathways including STAT 3 and PI3K/AKT and induction of tumour cell death (apoptosis).
Alectinib demonstrated in vitro and in vivo activity against mutant forms of the ALK enzyme, including mutations responsible for resistance to crizotinib. The major metabolite of alectinib (M4) has shown similar in vitro potency and activity.
Based on preclinical data, alectinib is not a substrate of p-glycoprotein or BCRP, which are both efflux transporters in the blood brain barrier, and is therefore able to distribute into and be retained within the central nervous system.
Clinical efficacy and safety
ALK positive non-small cell lung cancer
Crizotinib pre-treated patients
The safety and efficacy of Alecensa in ALK-positive NSCLC patients pre-treated with crizotinib were studied in two Phase I/II clinical trials (NP28673 and NP28761).
NP28673
Study NP28673 was a Phase I/II single arm, multicentre study conducted in patients with ALK-positive advanced NSCLC who have previously progressed on crizotinib treatment. In addition to crizotinib, patients may have received previous treatment with chemotherapy. A total of 138 patients were included in the phase II part of the study and received Alecensa orally, at the recommended dose of 600 mg twice daily.
The primary endpoint was to evaluate the efficacy of Alecensa by Objective Response Rate (ORR) as per central Independent Review Committee (IRC) assessment using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 in the overall population (with and without prior exposure of cytotoxic chemotherapy treatments). The co-primary endpoint was to evaluate the ORR as per central IRC assessment using RECIST 1.1 in patients with prior exposure of cytotoxic chemotherapy treatments. A lower confidence limit for the estimated ORR above the pre-specified threshold of 35% would achieve a statistically significant result.
Patient demographics were consistent with that of a NSCLC ALK positive population. The demographic characteristics of the overall study population were 67% Caucasian, 26% Asian, 56% females, and the median age was 52 years. The majority of patients had no history of smoking (70%). The ECOG (Eastern Cooperative Oncology Group) performance status at baseline was 0 or 1 in 90.6% of patients and 2 in 9.4% of patients. At the time of entry in the study, 99% of patients had stage IV disease, 61% had brain metastases and in 96% of patients tumours were classified as adenocarcinoma. Among patients included in the study, 20% of the patients had previously progressed on crizotinib treatment only, and 80% had previously progressed on crizotinib and at least one chemotherapy treatment.
Study NP28761
Study NP28761 was a Phase I/II single arm multicentre study conducted in patients with ALK positive advanced NSCLC who have previously progressed on crizotinib treatment. In addition to crizotinib, patients may have received previous treatment with chemotherapy. A total of 87 patients were included in the phase II part of the study and received Alecensa orally, at the recommended dose of 600 mg twice daily.
The primary endpoint was to evaluate the efficacy of Alecensa by ORR as per central IRC assessment using RECIST version 1.1. A lower confidence limit for the estimated ORR above the pre-specified threshold of 35% would achieve a statistically significant result.
Patient demographics were consistent with that of a NSCLC ALK positive population. The demographic characteristics of the overall study population were 84% Caucasian, 8% Asian, 55% females. The median age was 54 years. The majority of patients had no history of smoking (62%). The ECOG performance status at baseline was 0 or 1 in 89.7% of patients and 2 in 10.3% of patients. At the time of entry in the study, 99% of patients had stage IV disease, 60% had brain metastases and in 94% of patients tumours were classified as adenocarcinoma. Among the patients included in the study, 26% of the patients had previously progressed on crizotinib treatment only, and 74% had previously progressed on crizotinib and at least one chemotherapy treatment.
The main efficacy results from studies NP28673 and NP28761 are summarised in Table 4. A summary of pooled analysis of CNS endpoints is presented in Table 5.
Table 4 Efficacy results from studies NP28673 and NP28761

NP28673 Alectinib 600 mg twice daily	NP28761 Alectinib 600 mg twice daily
Median duration of follow-up (months)	21 (range 1 – 30)	17 (range 1 – 29)
Primary efficacy parameters
ORR (IRC) in RE population Responders N (%) [95% CI]	N=122 a 62 (50.8%) [41.6%, 60.0%]	N = 67 b 35 (52.2%) [39.7%, 64.6%]
ORR (IRC) in patients pre-treated with chemotherapy Responders N (%) [95% CI]	N = 96 43 (44.8%) [34.6%, 55.3%]
Secondary efficacy parameters
DOR (IRC) Number of patients with events N (%) Median (months) [95% CI]	N = 62 36 (58.1%) 15.2 [11.2, 24.9]	N = 35 20 (57.1%) 14.9 [6.9, NE]
PFS (IRC) Number of patients with events N (%) Median duration (months) [95% CI]	N = 138 98 (71.0%) 8.9 [5.6, 12.8]	N = 87 58 (66.7%) 8.2 [6.3, 12.6]

CI = confidence interval; DOR = duration of response; IRC = independent review committee; NE = not estimable; ORR = objective response rate; PFS= progression free survival; RE = response evaluable
a 16 patients did not have measurable disease at baseline according to the IRC and were not included in the IRC response evaluable population.
b 20 patients did not have measurable disease at baseline according to the IRC and were not included in the IRC response evaluable population
ORR results for studies NP28673 and NP28761 were consistent across subgroups of baseline patient characteristics such as age, gender, race, ECOG performance status, Central Nervous System (CNS) metastasis and prior chemotherapy use, especially when considering the small number of patients in some subgroups.
Table 5 Summary of the pooled analysis of CNS endpoints from studies NP28673 and NP28761

CNS Parameters (NP28673 and NP28761)	Alectinib 600 mg twice daily
Patients with measurable CNS lesions at baseline CNS ORR (IRC) Responders (%) [95% CI] Complete response Partial response CNS DOR (IRC) Number of patients with events (%) Median (months) [95%CI]	N = 50 32 (64.0%) [49.2%, 77.1%] 11 (22.0%) 21 (42.0%) N=32 18 (56.3%) 11.1 [7.6, NE]

CI = confidence interval; DOR = duration of response; IRC = independent review committee; ORR = objective response rate; NE = not estimable
Paediatric population
The European Medicines Agency has waived the obligation to submit the results of studies with Alecensa in all subsets of the paediatric population in lung carcinoma (small cell and non-small cell carcinoma) (see section 4.2 for information on paediatric use).
This medicinal product has been authorised under a so-called 'conditional approval' scheme. This means that further evidence on this medicinal product is awaited.
The European Medicines Agency will review new information on this medicinal product at least every year and this SmPC will be updated as necessary.
5.2 Pharmacokinetic properties
The pharmacokinetic parameters for alectinib and its major active metabolite (M4) have been characterised in ALK-positive NSCLC patients and healthy subjects. Based on population pharmacokinetic analysis, the geometric mean (coefficient of variation %) steady-state Cmax, Cmin and AUC0-12hr for alectinib were approximately 665 ng/mL (44.3%), 572 ng/mL (47.8%) and 7430 ng*h/mL (45.7%), respectively. The geometric mean steady-state Cmax, Cmin and AUC0-12hr for M4 were approximately 246 ng/mL (45.4%), 222 ng/mL (46.6%) and 2810 ng*h/mL (45.9%), respectively.
Absorption
Following oral administration of 600 mg twice daily under fed conditions in ALK-positive NSCLC patients, alectinib was absorbed reaching Tmax after approximately 4 to 6 hours.
Alectinib steady-state is reached within 7 days with continuous 600 mg twice daily dosing. The accumulation ratio for the twice-daily 600 mg regimen was approximately 6-fold. Population PK analysis supports dose proportionality for alectinib across the dose range of 300 to 900 mg under fed conditions.
The absolute bioavailability of alectinib capsules was 36.9% (90% CI: 33.9%, 40.3%) under fed conditions in healthy subjects.
Following a single oral administration of 600 mg with a high-fat, high-calorie meal, alectinib and M4 exposure was increased by around 3-fold relative to fasted conditions (see section 4.2).
Distribution
Alectinib and its major metabolite M4 are highly bound to human plasma proteins (>99%), independent of active substance concentration. The mean in vitro human blood-to-plasma concentration ratios of alectinib and M4 are 2.64 and 2.50, respectively, at clinically relevant concentrations.
The geometric mean volume of distribution at steady state (Vss) of alectinib following IV administration was 475 L, indicating extensive distribution into tissues.
Based on in vitro data, alectinib is not a substrate of P-gp. Alectinib and M4 are not substrates of BCRP or organic anion-transporting polypeptide (OATP) 1B1/B3.
Biotransformation
In vitro metabolism studies showed that CYP3A4 is the main CYP isozyme mediating alectinib and its major metabolite M4 metabolism, and is estimated to contribute 40-50% of alectinib metabolism. Results from the human mass balance study demonstrated that alectinib and M4 were the main circulating moieties in plasma with 76% of the total radioactivity in plasma. The geometric mean Metabolite/Parent ratio at steady state is 0.399.
Metabolite M1b was detected as a minor metabolite from in vitro and in human plasma in healthy subjects. Formation of metabolite M1b and its minor isomer M1a is likely to be catalyzed by a combination of CYP isozymes (including isozymes other than CYP3A) and aldehyde dehydrogenase (ALDH) enzymes.
In vitro studies indicate that neither alectinib nor its major active metabolite (M4) inhibits CYP1A2, CYP2B6, CYP2C9, CYP2C19, or CYP2D6 at clinically relevant concentrations. Alectinib did not inhibit OATP1B1/OATP1B3, OAT1, OAT3 or OCT2 at clinically relevant concentrations in vitro.
Elimination
Following administration of a single dose of 14C-labeled alectinib administered orally to healthy subjects the majority of radioactivity was excreted in faeces (mean recovery 97.8%) with minimal excretion in urine (mean recovery 0.46%). In faeces, 84% and 5.8% of the dose was excreted as unchanged alectinib or M4, respectively.
Based on a population PK analysis, the apparent clearance (CL/F) of alectinib was 81.9 L/hour. The geometric mean of the individual elimination half-life estimates for alectinib was 32.5 hours. The corresponding values for M4 were 217 L/hour and 30.7 hours, respectively.
Pharmacokinetics in special populations
Renal impairment
Negligible amounts of alectinib and the active metabolite M4 are excreted unchanged in urine (< 0.2% of the dose). Based on a population pharmacokinetic analysis alectinib and M4 exposures were similar in patients with mild and moderate renal impairment and normal renal function. The pharmacokinetics of alectinib has not been studied in patients with severe renal impairment.
Hepatic impairment
As elimination of alectinib is predominantly through metabolism in the liver, hepatic impairment may increase the plasma concentration of alectinib and/or its major metabolite M4. Based on a population pharmacokinetic analysis, alectinib and M4 exposures were similar in patients with mild hepatic impairment and normal hepatic function.
The pharmacokinetics of alectinib and M4 has not been studied in patients with moderate to severe hepatic impairment.
Effects of age, body weight, race and gender
Age, body weight, race and gender had no clinically meaningful effect on the systemic exposure of alectinib and M4. The range of body weights for patients enrolled in clinical studies is 36.9-123 kg. There are no available data on patients with extreme body weight (>130 kg) (see section 4.2).
5.3 Preclinical safety data
Carcinogenicity
Carcinogenicity studies have not been performed to establish the carcinogenic potential of Alecensa.
Mutagenicity
Alectinib was not mutagenic in vitro in the bacterial reverse mutation (Ames) assay but induced a slight increase in numerical aberrations in the in vitro cytogenetic assay using Chinese Hamster Lung (CHL) cells with metabolic activation, and micronuclei in a rat bone marrow micronucleus test. The mechanism of micronucleus induction was abnormal chromosome segregation (aneugenicity), and not a clastogenic effect on chromosomes.
Impairment of fertility
No fertility studies in animals have been performed to evaluate the effect of Alecensa. No adverse effects on male and female reproductive organs were observed in general toxicology studies. These studies were conducted in rats and monkeys at exposures equal to or greater than 2.6- and 0.5-fold, respectively, of the human exposure, measured by AUC, at the recommended dose of 600 mg twice daily.
Teratogenicity
Alectinib caused embryo-foetal toxicity in pregnant rats and rabbits. In pregnant rats, alectinib caused total embryo-foetal loss (miscarriage) at exposures 4.5-fold of the human AUC exposure and small foetuses with retarded ossification and minor abnormalities of the organs at exposures 2.7-fold of the human AUC exposure. In pregnant rabbits, alectinib caused embryo-foetal loss, small fetuses and increased incidence of skeletal variations at exposures 2.9-fold of the human AUC exposure at the recommended dose.
Other
Alectinib absorbs UV light between 200 and 400 nm and demonstrated a phototoxic potential in an in vitro photosafety test in cultured murine fibroblasts after UVA irradiation.
Target organs in both rat and monkey at clinically relevant exposures in the repeat-dose toxicology studies included, but were not limited to the erythroid system, gastrointestinal tract, and hepatobiliary system.
Abnormal erythrocyte morphology was observed at exposures equal or greater than 10-60% the human exposure by AUC at the recommended dose. Proliferative zone extension in GI mucosa in both species was observed at exposures equal to or greater than 20-120% of the human AUC exposure at the recommended dose. Increased hepatic alkaline phosphatase (ALP) and direct bilirubin as well as vacuolation/degeneration/necrosis of bile duct epithelium and enlargement/focal necrosis of hepatocytes was observed in rats and/or monkeys at exposures equal to or greater than 20-30% of the human exposure by AUC at the recommended dose.
A mild hypotensive effect has been observed in monkeys at around clinically relevant exposures.
6. Pharmaceutical particulars
6.1 List of excipients
Capsule content
Lactose monohydrate
Hydroxypropylcellulose
Sodium laurilsulfate
Magnesium stearate
Carmellose calcium
Capsule shell
Hypromellose
Carrageenan
Potassium chloride
Titanium dioxide (E171)
Maize starch
Carnauba wax
Printing ink
Red iron oxide (E172)
Yellow iron oxide (E172)
Indigo carmine aluminum lake (E132)
Carnauba wax
White shellac
Glyceryl monooleate
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.
6.5 Nature and contents of container
Aluminium/aluminium perforated blisters containing 8 hard capsules.
Pack size: 224 (4 packs of 56) hard capsules.
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
Roche Registration Limited
6 Falcon Way
Shire Park
Welwyn Garden City
AL7 1TW
United Kingdom
8. Marketing authorisation number(s)
EU/1/16/1169/001
9. Date of first authorisation/renewal of the authorisation
Date of first authorisation: 16 February 2017
10. Date of revision of the text
09 June 2017
Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.
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产地国家：德国
原产地英文商品名:
ALECENSA Hard Capsules 150mg/Caps 224Caps/box
原产地英文药品名:
alectinib
中文参考商品译名:
ALECENSA 150毫克/胶囊 224胶囊/盒
中文参考药品译名:
盐酸阿雷替尼
生产厂家中文参考译名:
罗氏
生产厂家英文名:
Roche
-------------------------------------------------
产地国家：英国
原产地英文商品名:
ALECENSA Hard Capsules 150mg/Caps 224Caps/box
原产地英文药品名:
alectinib
中文参考商品译名:
ALECENSA 150毫克/胶囊 224胶囊/盒
中文参考药品译名:
盐酸阿雷替尼
生产厂家中文参考译名:
罗氏
生产厂家英文名:
Roche