ALECENSA 150mg capsules medication leaflet

Alecensa 150 mg hard capsules

Each hard capsule contains alectinib hydrochloride equivalent to 150 mg alectinib.

Each hard capsule contains 33.7 mg lactose (as monohydrate) and 6 mg sodium (as sodiumlaurilsulfate).

For the full list of excipients, see section 6.1.

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.

Adjuvant treatment of resected non-small cell lung cancer (NSCLC)

Alecensa as monotherapy is indicated as adjuvant treatment following complete tumour resection foradult patients with ALK-positive NSCLC at high risk of recurrence (see section 5.1 for selectioncriteria).

Treatment of advanced NSCLC

Alecensa as monotherapy is indicated for the first-line treatment of adult patients with ALK-positiveadvanced NSCLC.

Alecensa as monotherapy is indicated for the treatment of adult patients with ALK-positive advanced

NSCLC previously treated with crizotinib.

Treatment with Alecensa should be initiated and supervised by a physician experienced in the use ofanticancer 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.

The recommended dose of Alecensa is 600 mg (four 150 mg capsules) taken twice daily with food(total daily dose of 1200 mg).

Patients with underlying severe hepatic impairment (Child-Pugh C) should receive a starting dose of450 mg taken twice daily with food (total daily dose of 900 mg).

Adjuvant treatment of resected NSCLC

Treatment with Alecensa should be continued until disease recurrence, unacceptable toxicity or for2 years.

Treatment of advanced NSCLC

Treatment with Alecensa should be continued until disease progression or unacceptable toxicity.

If a planned dose of Alecensa is missed, patients can make up that dose unless the next dose is duewithin 6 hours. Patients should not take two doses at the same time to make up for a missed dose. Ifvomiting occurs after taking a dose of Alecensa, patients should take the next dose at the scheduledtime.

Management of adverse events may require dose reduction, temporary interruption, or discontinuationof treatment with Alecensa. The dose of Alecensa should be reduced in steps of 150 mg twice dailybased on tolerability. Alecensa treatment should be permanently discontinued if patients are unable totolerate 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

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 permanentlydiscontinue Alecensa if no other potential causesof ILD/pneumonitis have been identified.

ALT or AST elevation of > 5 times ULN with Temporarily withhold until recovery to baselinetotal bilirubin  2 times ULN or ≤ 3 times ULN, then resume at reduced dose(see Table 1).

ALT or AST elevation of > 3 times ULN with Permanently discontinue Alecensa.total bilirubin elevation > 2 times ULN in theabsence of cholestasis or haemolysis

Bradycardiaa Grade 2 or Grade 3 (symptomatic, Temporarily withhold until recovery to  Grade 1may be severe and medically significant, (asymptomatic) bradycardia or to a heart rate ofmedical intervention indicated) ≥ 60 bpm. Evaluate concomitant medicinalproducts known to cause bradycardia, as well asanti-hypertensive medicinal products.

CTCAE grade Alecensa treatment

If a contributing concomitant medicinal productis identified and discontinued, or its dose isadjusted, resume at previous dose upon recoveryto  Grade 1 (asymptomatic) bradycardia or to aheart rate of ≥ 60 bpm.

If no contributing concomitant medicinal productis identified, or if contributing concomitantmedicinal products are not discontinued or dosemodified, 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 Permanently discontinue if no contributingconsequences, urgent intervention indicated) concomitant medicinal product is identified.

If a contributing concomitant medicinal productis identified and discontinued, or its dose isadjusted, resume at reduced dose (see Table 1)upon recovery to  Grade 1 (asymptomatic)bradycardia or to a heart rate of ≥ 60 bpm, withfrequent monitoring as clinically indicated.

Permanently discontinue in case of recurrence.

CPK elevation > 5 times ULN Temporarily withhold until recovery to baselineor to ≤ 2.5 times ULN, then resume at the samedose.

CPK elevation > 10 times ULN or second Temporarily withhold until recovery to baselineoccurrence of CPK elevation of > 5 times ULN or to ≤ 2.5 times ULN, then resume at reduceddose as per Table 1.

Haemolytic anaemia with haemoglobin of Temporarily withhold until resolution, then< 10 g/dL (Grade ≥ 2) resume at reduced dose (see Table 1).

ALT = alanine aminotransferase; AST = aspartate aminotransferase; CPK = creatine phosphokinase;

CTCAE = NCI Common Terminology Criteria for Adverse Events; ILD = interstitial lung disease; ULN = upperlimit of normala Heart rate less than 60 beats per minute (bpm).

No starting dose adjustment is required in patients with underlying mild (Child-Pugh A) or moderate(Child-Pugh B) hepatic impairment. Patients with underlying severe hepatic impairment (Child-Pugh

C) should receive a starting dose of 450 mg taken twice daily (total dose of 900 mg) (see section 5.2).

For all patients with hepatic impairment, appropriate monitoring (e.g. markers of liver function) isadvised, see section 4.4.

No dose adjustment is required in patients with mild or moderate renal impairment. Alecensa has notbeen studied in patients with severe renal impairment. However, since alectinib elimination via thekidney is negligible, no dose adjustment is required in patients with severe renal impairment (seesection 5.2).

The limited data on the safety and efficacy of Alecensa in patients aged 65 years and older do notsuggest that a dose adjustment is required in elderly patients (see section 5.2). There are no availabledata on patients over 80 years of age.

The safety and efficacy of Alecensa in children and adolescents below 18 years of age have not beenestablished. No data are available.

Extreme body weight (>130 kg)

Although pharmacokinetic (PK) simulations for Alecensa do not indicate a low exposure in patientswith extreme body weight (i.e. >130 kg), alectinib is widely distributed and clinical studies foralectinib enrolled patients within a range of body weights of 36.9−123 kg. There are no available dataon patients with body weight above 130 kg.

Alecensa is for oral use. The hard capsules should be swallowed whole, and must not be opened ordissolved. They must be taken with food (see section 5.2).

Hypersensitivity to alectinib or to any of the excipients listed in section 6.1.

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 beimmediately interrupted in patients diagnosed with ILD/pneumonitis and should be permanentlydiscontinued if no other potential causes of ILD/pneumonitis have been identified (see section 4.2).

Elevations in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) greater than5 times the upper limit of normal (ULN) as well as bilirubin elevations of more than 3 times the ULNoccurred in patients in pivotal clinical trials with Alecensa (see section 4.8). The majority of theseevents occurred during the first 3 months of treatment. In the pivotal Alecensa clinical trials it wasreported that three patients with Grade 3-4 AST/ALT elevations had drug induced liver injury.

Concurrent elevations in ALT or AST greater than or equal 3 times the ULN and total bilirubin greaterthan 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 thenevery 2 weeks during the first 3 months of treatment. Thereafter, monitoring should be performedperiodically, since events may occur later than 3 months, with more frequent testing in patients whodevelop 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 describedin Table 2 (see section 4.2).

Severe myalgia and creatine phosphokinase (CPK) elevation

Myalgia or musculoskeletal pain was reported in patients in pivotal trials with Alecensa, including

Grade 3 events (see section 4.8).

Elevations of CPK occurred in pivotal trials with Alecensa, including Grade 3 events (see section 4.8).

Median time to Grade ≥ 3 CPK elevation was 15 days across clinical trials (BO40336, BO28984,

NP28761, NP28673).

Patients should be advised to report any unexplained muscle pain, tenderness, or weakness. CPKlevels should be assessed every two weeks for the first month of treatment and as clinically indicatedin patients reporting symptoms. Based on the severity of the CPK elevation, Alecensa should bewithheld, then resumed or dose reduced (see section 4.2).

Bradycardia

Symptomatic bradycardia can occur with Alecensa (see section 4.8). Heart rate and blood pressureshould be monitored as clinically indicated. Dose modification is not required in case of asymptomaticbradycardia (see section 4.2). If patients experience symptomatic bradycardia or life-threateningevents, concomitant medicinal products known to cause bradycardia, as well as anti-hypertensivemedicinal 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’).

Haemolytic anaemia

Haemolytic anaemia has been reported with Alecensa (see section 4.8). If haemoglobin concentrationis below 10 g/dL and haemolytic anaemia is suspected, Alecensa should be withheld and appropriatelaboratory testing should be initiated. If haemolytic anaemia is confirmed, Alecensa should beresumed at a reduced dose upon resolution as described in Table 2 (see section 4.2).

Gastrointestinal perforation

Cases of gastrointestinal perforations have been reported in patients at increased risk (e.g., history ofdiverticulitis, metastases to the gastrointestinal tract, concomitant use of medicinal product with arecognized risk of gastrointestinal perforation) treated with alectinib. Discontinuation of Alecensa inpatients who develop gastrointestinal perforation should be considered. Patients should be informed ofthe signs and symptoms of gastrointestinal perforations and advised to consult rapidly in case ofoccurrence.

Photosensitivity to sunlight has been reported with Alecensa administration (see section 4.8). Patientsshould be advised to avoid prolonged sun exposure while taking Alecensa, and for at least 7 days afterdiscontinuation of treatment. Patients should also be advised to use a broad-spectrum Ultraviolet A(UVA)/ Ultraviolet B (UVB) sunscreen and lip balm (sun protection factor [SPF] ≥50) to help protectagainst potential sunburn.

Embryo-foetal toxicity

Alecensa may cause foetal harm when administered to a pregnant woman. Female patients ofchild-bearing potential receiving Alecensa, must use highly effective contraceptive methods duringtreatment and for at least 5 weeks following the last dose of Alecensa (see sections 4.5, pct. 4.6 and 5.3).

Male patients with female partners of child-bearing potential must use highly effective contraceptivemethods during treatment and for at least 3 months following the last dose of Alecensa (seesections 4.6 and 5.3).

This medicinal product contains lactose. Patients with rare hereditary problems of galactoseintolerance, a congenital lactase deficiency or glucose-galactose malabsorption should not take thismedicinal product.

This medicinal product contains 48 mg sodium per daily dose (1200 mg), equivalent to 2.4% of the

WHO recommended maximum daily intake of 2 g sodium for an adult.

Effects of other medicinal products on alectinib

Based on in vitro data, CYP3A4 is the primary enzyme mediating the metabolism of both alectiniband its major active metabolite M4, and CYP3A contributes to 40% − 50% of total hepaticmetabolism. M4 has shown similar in vitro potency and activity against ALK.

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 thecombined 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 adjustmentsare required when Alecensa is co-administered with CYP3A inducers. Appropriate monitoring isrecommended for patients taking concomitant strong CYP3A inducers (including, but not limited to,carbamazepine, phenobarbital, phenytoin, rifabutin, rifampicin and St. John’s Wort (Hypericumperforatum)).

Co-administration of multiple oral doses of 400 mg posaconazole twice daily, a strong CYP3Ainhibitor, with a single oral dose of 300 mg alectinib increased alectinib exposure Cmax and AUCinf by1.18 and 1.75-fold respectively, and reduced M4 Cmax and AUCinf by 71% and 25% respectively. Theeffect 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 doseadjustments are required when Alecensa is co-administered with CYP3A inhibitors. Appropriatemonitoring is recommended for patients taking concomitant strong CYP3A inhibitors (including, butnot 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 noclinically relevant effect on the combined exposure of alectinib and M4. Therefore, no doseadjustments are required when Alecensa is co-administered with proton pump inhibitors or othermedicinal products which raise gastric pH (e.g. H2 receptor antagonists or antacids).

Effect of transporters on alectinib disposition

M4 is a substrate of P-glycoprotein (P-gp). As alectinib inhibits P-gp, it is not expected thatco-medication with P-gp inhibitors has a relevant effect on M4 exposure.

Effects of alectinib on other medicinal products

In vitro, alectinib and M4 show weak time-dependent inhibition of CYP3A4, and alectinib exhibits aweak 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 pregnane X receptor (PXR) regulated enzymes apart from

CYP3A4 cannot be completely excluded. The effectiveness of concomitant administration of oralcontraceptives may be reduced.

In vitro, alectinib and its major active metabolite M4 are inhibitors of the efflux transporter

P-gp. Therefore, alectinib and M4 may have the potential to increase plasma concentrations ofco-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), appropriatemonitoring is recommended.

Breast cancer resistance protein (BCRP) substrates

In vitro, alectinib and M4 are inhibitors of the efflux transporter BCRP. Therefore, alectinib and M4may 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, topotecanand lapatinib), appropriate monitoring is recommended.

Women of childbearing potential must be advised to avoid pregnancy while on Alecensa (seesection 4.4).

Contraception in female patients

Female patients of child-bearing potential receiving Alecensa must use highly effective contraceptivemethods during treatment and for at least 5 weeks following the last dose of Alecensa (see sections 4.4and 4.5).

Contraception in male patients

Male patients with female partners of child-bearing potential must use highly effective contraceptivemethods during treatment and for at least 3 months following the last dose of Alecensa (seesection 4.4).

There are no or limited amount of data from the use of alectinib in pregnant women. Based on itsmechanism of action, alectinib 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 5 weeks following the lastdose of Alecensa must contact their doctor and should be advised of the potential harm to the foetus.

Male patients with female partners who become pregnant while the male patient is taking Alecensa, orduring the 3 months following the last dose of Alecensa, must contact their doctor, and their femalepartner should seek medical advice due to the potential harm to the foetus based on its aneugenicpotential (see section 5.3).

It is unknown whether alectinib and/or its metabolites are excreted in human milk. A risk to thenewborn/infant cannot be excluded. Mothers should be advised against breast-feeding while receiving

Alecensa.

No fertility studies in animals have been performed to evaluate the effect of alectinib. No adverseeffects on male and female reproductive organs were observed in general toxicology studies (seesection 5.3).

Alecensa has minor influence on the ability to drive and use machines. Caution should be exercisedwhen 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).

The data described below reflect exposure to Alecensa in 533 patients with resected or advanced

ALK-positive NSCLC. These patients received Alecensa at the recommended dose of 600 mg twicedaily in pivotal clinical trials for adjuvant treatment of resected NSCLC (BO40336, ALINA) or fortreatment of advanced NSCLC (BO28984, ALEX; NP28761; NP28673). See section 5.1 for furtherinformation on clinical trial participants.

In BO40336 (ALINA; N=128), the median duration of exposure to Alecensa was 23.9 months. In

BO28984 (ALEX; N=152) the median duration of exposure to Alecensa was 28.1 months. In thephase II clinical trials (NP28761, NP28673; N=253), the median duration of exposure to Alecensa was11.2 months.

The most common adverse drug reactions (ADRs) (≥ 20%) were constipation, myalgia, oedema,anaemia, rash, increased bilirubin, increased ALT and increased AST.

Tabulated list of adverse drug reactions

Table 3 lists the ADRs occurring in patients who received Alecensa across clinical trials (BO40336,

BO28984, NP28761, NP28673).

The ADRs listed in Table 3 are presented by system organ class and frequency categories, definedusing 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 system organclass, undesirable effects are presented in order of decreasing frequency and severity. Within the samefrequency and severity grouping, undesirable effects are presented in order of decreasing seriousness.

Table 3 ADRs reported in Alecensa clinical trials (BO40336, BO28984, NP28761, NP28673;

N=533)

System organ class Alecensa

ADRs (MedDRA) N=533

Frequency category Frequency category(all grades) (grades 3-4)

Anaemia1) Very common Common

Haemolytic anaemia2) Common -*

Dysgeusia3) Common Uncommon

Vision disorders4) Common -*

Bradycardia5) Very common -*

System organ class Alecensa

ADRs (MedDRA) N=533

Frequency category Frequency category(all grades) (grades 3-4)

Interstitial lung disease /

Common Uncommonpneumonitis

Diarrhoea Very common Uncommon

Vomiting Very common Uncommon

Constipation Very common Uncommon

Nausea Very common Uncommon

Stomatitis6) Common Uncommon

Increased AST Very common Common

Increased ALT Very common Common

Increased bilirubin7) Very common Common

Increased alkaline

Very Common Uncommonphosphatase

Drug-induced liver injury8) Uncommon Uncommon

Rash9) Very common Common

Photosensitivity Common Uncommon

Musculoskeletal and connective tissues disorders

Myalgia10) Very common Uncommon

Increased blood creatine

Very common Commonphosphokinase

Acute kidney injury Uncommon Uncommon**

Blood creatinine increased Common Uncommon**

Oedema11) Very common Uncommon

Weight increased Very common Uncommon

Metabolism and Nutrition Disorders

Hyperuricaemia12) Common -*

* No Grade 3-4 ADRs were observed.

** Includes one Grade 5 event (observed in the advanced NSCLC setting).1) includes cases of anaemia, haemoglobin decreased and normochromic normocytic anaemia.2) cases reported in study BO40336 (N=128).3) includes cases of dysgeusia, hypogeusia, and taste disorder.4) includes cases of blurred vision, visual impairment, vitreous floaters, reduced visual acuity, asthenopia,diplopia, photophobia, and photopsia.5) includes cases of bradycardia and sinus bradycardia.6) includes cases of stomatitis and mouth ulceration.7) includes cases of blood bilirubin increased, hyperbilirubinaemia, bilirubin conjugated increased, and bloodbilirubin unconjugated increased.8) includes two patients with reported MedDRA term of drug-induced liver injury as well as one patient withreported Grade 4 increased AST and ALT who had documented drug-induced liver injury by liver biopsy.9) includes cases of rash, rash maculopapular, dermatitis acneiform, erythema, rash generalised, rash papular,rash pruritic, rash macular, exfoliative rash, and rash erythematous.10) includes cases of myalgia, musculoskeletal pain, and arthralgia.11) includes cases of oedema peripheral, oedema, generalised oedema, eyelid oedema, periorbital oedema, faceoedema, localised oedema, peripheral swelling, face swelling, lip swelling, swelling, joint swelling and eyelidswelling.12) includes cases of hyperuricaemia and increased blood uric acid.

Description of selected adverse drug reactions

Across clinical trials, ILD/pneumonitis occurred in 1.3% of patients treated with Alecensa, 0.4% ofthese cases were Grade 3 and treatment discontinuations due to ILD/pneumonitis occurred in 0.9% ofpatients. In the phase III clinical trial BO28984, Grade 3 or 4 ILD/pneumonitis was not observed inpatients receiving Alecensa versus 2.0% of patients receiving crizotinib. There were no fatal cases of

ILD in any of the clinical trials. Patients should be monitored for pulmonary symptoms indicative ofpneumonitis (see sections 4.2 and 4.4).

Across clinical trials, three patients had a documented drug-induced liver injury (including twopatients with the reported term drug-induced liver injury and one patient with reported Grade 4increased AST and ALT who had documented drug-induced liver injury by liver biopsy). Adversereactions of increased AST and ALT levels (22.7% and 20.1% respectively) were reported in patientstreated with Alecensa across clinical trials. The majority of these events were of Grade 1 and 2intensity, and events of Grade ≥ 3 were reported in 3.0% and 3.2% of the patients for increased ASTand ALT levels, respectively. The events generally occurred during the first 3 months of treatment,were usually transient and resolved upon temporary interruption of Alecensa treatment (reported for2.3% and 3.6% of the patients, respectively) or dose reduction (1.7% and 1.5%, respectively). In 1.1%and 1.3% of the patients, AST and ALT elevations, respectively, led to withdrawal from Alecensatreatment. Grade 3 or 4 ALT or AST elevations were each observed in 5% of patients receiving

Alecensa versus 16% and 11% of patients receiving crizotinib in the phase III clinical trial BO28984.

Adverse reactions of bilirubin elevations were reported in 25.1% of the patients treated with Alecensaacross clinical trials. The majority of the events were of Grade 1 and 2 intensity; Grade ≥ 3 eventswere reported in 3.4% of the patients. The events generally occurred during the first 3 months oftreatment, were usually transient and the majority resolved upon dose modification. In 7.7% ofpatients, bilirubin elevations led to dose modifications and in 1.5% of patients, bilirubin elevations ledto withdrawal from Alecensa treatment. In the phase III clinical trial BO28984, Grade 3 or 4 bilirubinelevations occurred in 3.9% of patients receiving Alecensa versus no patient receiving crizotinib.

Concurrent elevations in ALT or AST greater than or equal to three times the ULN and total bilirubingreater 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 insection 4.4 and managed as recommended in section 4.2.

Bradycardia

Cases of bradycardia (11.1%) of Grade 1 or 2 have been reported in patients treated with Alecensaacross clinical trials. No patients had events of Grade  3 severity. There were 102 of 521 patients(19.6%) treated with Alecensa, for whom serial ECGs were available, had post-dose heart rate valuesbelow 50 beats per minute (bpm). In the phase III clinical trial BO28984 15% of patients treated with

Alecensa had post-dose heart rate values below 50 bpm versus 21% of patients treated with crizotinib.

Patients who develop symptomatic bradycardia should be managed as recommended in sections 4.2and 4.4. No case of bradycardia led to withdrawal from Alecensa treatment.

Severe myalgia and CPK elevations

Cases of myalgia (34.9%) including myalgia events (24.0%), arthralgia (16.1%), and musculoskeletalpain (0.9%) have been reported in patients treated with Alecensa across clinical trials. The majority ofevents were Grades 1 or 2 and five patients (0.9%) had a Grade 3 event. Dose modifications of

Alecensa treatment due to these adverse events were required for nine patients (1.7%); Alecensatreatment was not withdrawn due to these events of myalgia. Elevations of CPK occurred in 55.6% of491 patients with CPK laboratory data available across clinical trials with Alecensa. The incidence of

Grade ≥ 3 elevations of CPK was 5.5%. Median time to Grade ≥ 3 CPK elevation was 15 days acrosstrials. Dose modifications for elevation of CPK occurred in 5.3% of patients; withdrawal from

Alecensa treatment did not occur due to CPK elevations. In the clinical trial BO28984, severearthralgia was reported in one patient (0.7%) in the alectinib arm and in two patients (1.3%) in thecrizotinib arm. Grade ≥ 3 elevation of CPK was reported for 3.9% of patients receiving Alecensa and3.3% of patients receiving crizotinib.

Haemolytic anaemia

Haemolytic anaemia has been observed in 3.1% of patients treated with Alecensa in the clinical trialsetting. These cases were Grade 1 or 2 (non-serious) and did not lead to treatment discontinuation (seesections 4.2 and 4.4).

Constipation (38.6%), nausea (17.4%), diarrhoea (17.4%) and vomiting (12.0%) were the mostcommonly reported gastrointestinal (GI) reactions. Most of these events were of mild or moderateseverity; Grade 3 events were reported for diarrhoea (0.9%), nausea (0.4%), vomiting (0.2%), andconstipation (0.4%). These events did not lead to withdrawal from Alecensa treatment. Median time toonset for constipation, nausea, diarrhoea, and/or vomiting events across clinical trials was 21 days.

The events declined in frequency after the first month of treatment. In the phase III clinical trial

BO28984, Grade 3 and 4 events of nausea, diarrhoea and constipation were reported in one patienteach (0.7%) in the alectinib arm and the incidence of Grade 3 and 4 events of nausea, diarrhoea andvomiting was 3.3%, 2.0% and 3.3%, respectively, in the crizotinib arm.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V

Patients who experience overdose should be closely supervised and general supportive care instituted.

There is no specific antidote for overdose with Alecensa.

Pharmacotherapeutic group: anti-neoplastic agents, protein kinase inhibitor; ATC code: L01ED03.

Alectinib is a highly selective and potent ALK and rearranged during transfection (RET) tyrosinekinase inhibitor. In pre-clinical studies, inhibition of ALK tyrosine kinase activity led to blockage ofdownstream signalling pathways including signal transducer and activator of transcription 3 (STAT 3)and phosphoinositide 3-kinase (PI3K)/protein kinase B (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-gp or BCRP, which are both effluxtransporters in the blood brain barrier, and is therefore able to distribute into and be retained within thecentral nervous system.

Adjuvant treatment of resected ALK-positive NSCLC

The efficacy of Alecensa for the adjuvant treatment of patients with ALK-positive NSCLC followingcomplete tumour resection was established in a global randomised Phase III open-label clinical trial(BO40336; ALINA). Eligible patients were required to have Stage IB (tumours ≥ 4 cm) - Stage IIIA

NSCLC per the Union for International Cancer Control/American Joint Committee on Cancer(UICC/AJCC) Staging System, 7th Edition, with ALK-positive disease identified by a locallyperformed CE-marked ALK test, or centrally performed by the Ventana ALK (D5F3)immunohistochemistry (IHC) assay.

The following selection criteria define patients with high risk of recurrence who are included in thetherapeutic indication and are reflective of the patient population with Stage IB(tumours ≥ 4 cm) - IIIA NSCLC according to the 7th Edition UICC/AJCC staging criteria:

Tumour size ≥ 4 cm; or tumours of any size that are either accompanied by N1 or N2 status; ortumours that are invasive of thoracic structures (directly invade the parietal pleura, chest wall,diaphragm, phrenic nerve, mediastinal pleura, parietal pericardium, mediastinum, heart, great vessels,trachea, recurrent laryngeal nerve, oesophagus, vertebral body, carina); or tumours that involve themain bronchus < 2 cm distal to the carina but without involvement of the carina; or tumours that areassociated with atelectasis or obstructive pneumonitis of the entire lung; or tumours with separatenodule(s) in the same lobe or different ipsilateral lobe as the primary.

The study did not include patients who had N2 status with tumours also invading the mediastinum,heart, great vessels, trachea, recurrent laryngeal nerve, oesophagus, vertebral body, carina, or withseparate tumour nodule(s) in a different ipsilateral lobe.

Patients were randomised (1:1) to receive Alecensa or platinum-based chemotherapy followingtumour resection. Randomisation was stratified by race (Asian and non-Asian) and stage of disease(IB, II and IIIA). Alecensa was administered at the recommended oral dose of 600 mg twice daily fora total of 2 years, or until disease recurrence or unacceptable toxicity. Platinum-based chemotherapywas administered intravenously for 4 cycles, with each cycle lasting 21 days, according to one of thefollowing regimens:

Cisplatin 75 mg/m2 on Day 1 plus vinorelbine 25 mg/m2 on Days 1 and 8

Cisplatin 75 mg/m2 on Day 1 plus gemcitabine 1250 mg/m2 on Days 1 and 8

Cisplatin 75 mg/m2 on Day 1 plus pemetrexed 500 mg/m2 on Day 1

In the event of intolerance to a cisplatin-based regimen, carboplatin was administered instead ofcisplatin in the above combinations at a dose of area under the free carboplatin plasma versus timecurve (AUC) 5 mg/mL/min or AUC 6 mg/mL/min.

The primary efficacy endpoint was disease-free survival (DFS) as assessed by the Investigator. DFSwas defined as the time from date of randomisation to the date of occurrence of any of the following:

first documented recurrence of disease, new primary NSCLC, or death due to any cause, whicheveroccurred first. The secondary and exploratory efficacy endpoints were overall survival (OS) and timeto CNS recurrence or death (CNS-DFS).

A total of 257 patients were studied: 130 patients were randomised to the Alecensa arm, and127 patients were randomised to the chemotherapy arm. Overall, the median age was 56 years (range:

26 to 87), and 24% were ≥ 65 years old, 52% were female, 56% were Asian, 60% were never smokers,53% had an ECOG PS of 0, 10% of patients had Stage IB, 36% had Stage II and 54% had Stage IIIAdisease.

ALINA demonstrated a statistically significant improvement in DFS for patients treated with Alecensacompared to patients treated with chemotherapy in the Stage II-IIIA and the Stage IB (≥ 4 cm) - IIIA(ITT) patient populations. OS data were not mature at the time of DFS analysis with 2.3% of deathsreported overall. The median duration of survival follow-up was 27.8 months in the Alecensa arm and28.4 months in the chemotherapy arm.

The DFS efficacy results are summarised in Table 4 and Figure 1.

Table 4 Investigator assessed DFS results in ALINA

Stage II-IIIA ITT Population

Efficacy Parameter

Alecensa Chemotherapy Alecensa Chemotherapy

N=116 N=115 N=130 N=127

Number of DFS Events (%) 14 (12.1) 45 (39.1) 15 (11.5) 50 (39.4)

Median DFS, months NE 44.4 NE 41.3(95% CI) (NE, NE) (27.8, NE) (NE, NE) (28.5, NE)

Stratified HR 0.24 0.24(95% CI)* (0.13, 0.45) (0.13, 0.43)p-value (log-rank)* <0.0001 <0.0001

DFS = Disease-Free Survival; ITT = Intent-to-Treat; CI = Confidence Interval; NE = Not Estimable; HR = Hazard Ratio

*Stratified by race in Stage II-IIIA, stratified by race and stage in Stage IB-IIIA.

Figure 1: Kaplan-Meier curve of investigator assessed DFS in the ITT population

Treatment of advanced ALK-positive NSCLC

The safety and efficacy of Alecensa were studied in a global randomised Phase III open label clinicaltrial (BO28984, ALEX) in ALK-positive NSCLC patients who were treatment naïve. Central testingfor ALK protein expression positivity of tissue samples from all patients by Ventana anti-ALK (D5F3)immunohistochemistry was required before randomisation into the study.

A total of 303 patients were included in the Phase III trial, 151 patients randomised to the crizotinibarm and 152 patients randomised to the Alecensa arm receiving Alecensa orally, at the recommendeddose of 600 mg twice daily.

Eastern Cooperative Oncology Group performance status ((ECOG PS) (0/1 vs. 2)), race(Asian vs. non-Asian), and central nervous system (CNS) metastases at baseline (yes vs. no) werestratification factors for randomisation. The primary endpoint of the trial was to demonstratesuperiority of Alecensa versus crizotinib based on Progression Free survival (PFS) as per investigatorassessment using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Baselinedemographic and disease characteristics for Alecensa were median age 58 years (54 years forcrizotinib), 55% female (58% for crizotinib), 55% non-Asian (54% for crizotinib), 61% with nosmoking history (65% for crizotinib), 93% ECOG PS of 0 or 1 (93% for crizotinib), 97% Stage IVdisease (96% for crizotinib), 90% adenocarcinoma histology (94% for crizotinib), 40% CNSmetastases at baseline (38% for crizotinib) and 17% having received prior CNS radiation (14% forcrizotinib).

The trial met its primary endpoint at the primary analysis, demonstrating a statistically significantimprovement in PFS by investigator. Efficacy data are summarised in Table 5 and the Kaplan-Meiercurve for investigator assessed PFS is shown in Figure 2.

Table 5 Summary of efficacy results from study BO28984 (ALEX)

Crizotinib Alecensa

N=151 N=15217.6 18.6

Median duration of follow-up (months)(range 0.3 - 27.0) (range 0.5 - 29.0)

Primary efficacy parameter

PFS (INV)

Number of patients with event n (%) 102 (68%) 62 (41%)

Median (months) 11.1 NE[95% CI] [9.1; 13.1] [17.7; NE]

HR 0.47[95% CI] [0.34, 0.65]

Stratified log-rank p-value p <0.0001

Secondary efficacy parameters

PFS (IRC)*

Number of patients with event n (%) 92 (61%) 63 (41%)

Median (months) 10.4 25.7[95% CI] [7.7; 14.6] [19.9; NE]

HR 0.50[95% CI] [0.36; 0.70]

Stratified log-rank p-value p < 0.0001

Time to CNS progression (IRC)*, **

Number of patients with event n (%) 68 (45%) 18 (12%)

Cause-specific HR 0.16[95% CI] [0.10; 0.28]

Stratified log-rank p-value p < 0.0001

Crizotinib Alecensa

N=151 N=15212-month cumulative incidence of CNSprogression (IRC) 41.4% 9.4%[95% CI] [33.2; 49.4] [5.4; 14.7]

ORR (INV)*, ***

Responders n (%) 114 (75.5%) 126 (82.9%)[95% CI] [67.8; 82.1] [76.0; 88.5]

Overall survival*

Number of patients with event n (%) 40 (27%) 35 (23%)

Median (months) NE NE[95% CI] [NE; NE] [NE; NE]

HR 0.76[95% CI] [0.48; 1.20]

Duration of response (INV) N=114 N=126

Median (months) 11.1 NE[95 % CI] [7.9; 13.0] [NE; NE]

CNS-ORR in patients with measurable CNS N=22 N=21metastases at baseline

CNS responders n (%) 11 (50.0%) 17 (81.0%)[95% CI] [28.2; 71.8] [58.1; 94.6]

CNS-CR n (%) 1 (5%) 8 (38%)

CNS-DOR, median (months) 5.5 17.3[95% CI] [2.1, 17.3] [14.8, NE]

CNS-ORR in patients with measurable and N=58 N=64non-measurable CNS metastases at baseline(IRC)

CNS responders n (%) 15 (25.9%) 38 (59.4%)[95% CI] [15.3; 39.0] [46.4; 71.5]

CNS-CR n (%) 5 (9%) 29 (45%)

CNS-DOR, median (months) 3.7 NE[95% CI] [3.2, 6.8] [17.3, NE]

* Key secondary endpoints part of the hierarchical testing

** Competing risk analysis of CNS progression, systemic progression and death as competing events

*** 2 patients in the crizotinib arm and 6 patients in the alectinib arm had CR

CI = confidence interval; CNS = central nervous system; CR = complete response; DOR = duration of response;

HR = hazard ratio; IRC = Independent Review Committee; INV = investigator; NE = not estimable;

ORR = objective response rate; PFS = progression free survival

The PFS benefit was consistent for patients with CNS metastases at baseline (hazard ratio(HR) = 0.40, 95% confidence interval (CI): 0.25-0.64, median PFS for Alecensa = not estimable (NE),95% CI: 9.2-NE, median PFS for crizotinib = 7.4 months, 95%CI: 6.6-9.6) and without CNSmetastases at baseline (HR = 0.51, 95% CI: 0.33-0.80, median PFS for Alecensa = NE, 95% CI: NE,

NE, median PFS for crizotinib = 14.8 months, 95% CI:10.8-20.3), indicating benefit of Alecensa overcrizotinib in both subgroups.

Figure 2: Kaplan Meier plot of INV assessed PFS in BO28984 (ALEX)

Crizotinib pre-treated patients

The safety and efficacy of Alecensa in ALK-positive NSCLC patients pre-treated with crizotinib werestudied 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 additionto crizotinib, patients may have received previous treatment with chemotherapy. A total of138 patients were included in the phase II part of the study and received Alecensa orally, at therecommended dose of 600 mg twice daily.

The primary endpoint was to evaluate the efficacy of Alecensa by Objective Response Rate (ORR) asper central Independent Review Committee (IRC) assessment using RECIST version 1.1 in the overallpopulation (with and without prior exposure of cytotoxic chemotherapy treatments). The co-primaryendpoint was to evaluate the ORR as per central IRC assessment using RECIST 1.1 in patients withprior exposure of cytotoxic chemotherapy treatments. A lower confidence limit for the estimated ORRabove the pre-specified threshold of 35% would achieve a statistically significant result.

Patient demographics were consistent with that of a NSCLC ALK positive population. Thedemographic 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 PS at baseline was 0 or 1 in 90.6% of patients and 2 in 9.4% of patients. At the time ofentry in the study, 99% of patients had stage IV disease, 61% had brain metastases and in 96% ofpatients tumours were classified as adenocarcinoma. Among patients included in the study, 20% of thepatients had previously progressed on crizotinib treatment only, and 80% had previously progressedon 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 positiveadvanced 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 wereincluded in the phase II part of the study and received Alecensa orally, at the recommended dose of600 mg twice daily.

The primary endpoint was to evaluate the efficacy of Alecensa by ORR as per central IRC assessmentusing RECIST version 1.1. A lower confidence limit for the estimated ORR above the pre-specifiedthreshold of 35% would achieve a statistically significant result.

Patient demographics were consistent with that of a NSCLC ALK positive population. Thedemographic 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 PS at baseline was 0 or 1 in 89.7% of patients and 2 in 10.3% of patients. At the time of entryin the study, 99% of patients had stage IV disease, 60% had brain metastases and in 94% of patientstumours were classified as adenocarcinoma. Among the patients included in the study, 26% of thepatients had previously progressed on crizotinib treatment only, and 74% had previously progressedon crizotinib and at least one chemotherapy treatment.

The main efficacy results from studies NP28673 and NP28761 are summarised in Table 6. A summaryof pooled analysis of CNS endpoints is presented in Table 7.

Table 6 Efficacy results from studies NP28673 and NP28761

NP28673 NP28761

Alecensa 600 mg Alecensa 600 mgtwice daily twice daily21 17

Median duration of follow-up (months)(range 1 - 30) (range 1 - 29)

Primary efficacy parameters

ORR (IRC) in RE population N=122 a N = 67 b

Responders N (%) 62 (50.8%) 35 (52.2%)[95% CI] [41.6%, 60.0%] [39.7%, 64.6%]

ORR (IRC) in patients pre-treated with N = 96chemotherapy

Responders N (%) 43 (44.8%)[95% CI] [34.6%, 55.3%]

Secondary efficacy parameters

DOR (IRC) N = 62 N = 35

Number of patients with events N (%) 36 (58.1%) 20 (57.1%)

Median (months) 15.2 14.9[95% CI] [11.2, 24.9] [6.9, NE]

PFS (IRC) N = 138 N = 87

Number of patients with events N (%) 98 (71.0%) 58 (66.7%)

Median duration (months) 8.9 8.2[95% CI] [5.6, 12.8] [6.3, 12.6]

CI = confidence interval; DOR = duration of response; IRC = independent review committee; NE = notestimable; ORR = objective response rate; PFS = progression free survival; RE = response evaluablea 16 patients did not have measurable disease at baseline according to the IRC and were not included in the IRCresponse evaluable population.b 20 patients did not have measurable disease at baseline according to the IRC and were not included in the IRCresponse evaluable population

ORR results for studies NP28673 and NP28761 were consistent across subgroups of baseline patientcharacteristics such as age, gender, race, ECOG PS, CNS metastasis and prior chemotherapy use,especially when considering the small number of patients in some subgroups.

Table 7 Summary of the pooled analysis of CNS endpoints from studies NP28673 and NP28761

CNS Parameters (NP28673 and NP28761) Alecensa 600 mg twice daily

Patients with measurable CNS lesions at baseline N=50

CNS ORR (IRC)

Responders (%) 32 (64.0%)[95% CI] [49.2%, 77.1%]

Complete response 11 (22.0%)

Partial response 21 (42.0%)

CNS DOR (IRC) N=32

Number of patients with events (%) 18 (56.3%)

Median (months) 11.1[95%CI] [7.6, NE]

CI = confidence interval; DOR = duration of response; IRC = independent review committee; ORR = objectiveresponse rate; NE = not estimable

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 cellcarcinoma) (see section 4.2 for information on paediatric use).

The pharmacokinetic parameters for alectinib and its major active metabolite (M4) have beencharacterised in ALK-positive NSCLC patients and healthy subjects. Based on populationpharmacokinetic 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%) and7430 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.

Following oral administration of 600 mg twice daily under fed conditions in ALK-positive NSCLCpatients, 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. Theaccumulation ratio for the twice-daily 600 mg regimen was approximately 6-fold. Population PKanalysis supports dose proportionality for alectinib across the dose range of 300 to 900 mg under fedconditions.

The absolute bioavailability of alectinib capsules was 36.9% (90% CI: 33.9%, 40.3%) under fedconditions in healthy subjects.

Following a single oral administration of 600 mg with a high-fat, high-calorie meal, alectinib and M4exposure was increased by around 3-fold relative to fasted conditions (see section 4.2).

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-plasmaconcentration ratios of alectinib and M4 are 2.64 and 2.50, respectively, at clinically relevantconcentrations.

The geometric mean volume of distribution at steady state (Vss) of alectinib following intravenous (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.

In vitro metabolism studies showed that CYP3A4 is the main CYP isozyme mediating alectinib and itsmajor 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 maincirculating 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 healthysubjects. Formation of metabolite M1b and its minor isomer M1a is likely to be catalyzed by acombination 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 notinhibit OATP1B1/OATP1B3, OAT1, OAT3 or OCT2 at clinically relevant concentrations in vitro.

Following administration of a single dose of 14C-labeled alectinib administered orally to healthysubjects the majority of radioactivity was excreted in faeces (mean recovery 97.8%) with minimalexcretion in urine (mean recovery 0.46%). In faeces, 84% and 5.8% of the dose was excreted asunchanged alectinib or M4, respectively.

Based on a population PK analysis, the apparent clearance (CL/F) of alectinib was 81.9 L/hour. Thegeometric mean of the individual elimination half-life estimates for alectinib was 32.5 hours. Thecorresponding values for M4 were 217 L/hour and 30.7 hours, respectively.

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 similarin patients with mild and moderate renal impairment and normal renal function. The pharmacokineticsof alectinib has not been studied in patients with severe renal impairment.

As elimination of alectinib is predominantly through metabolism in the liver, hepatic impairment mayincrease the plasma concentration of alectinib and/or its major metabolite M4. Based on a populationpharmacokinetic analysis, alectinib and M4 exposures were similar in patients with mild hepaticimpairment and normal hepatic function.

Following administration of a single oral dose of 300 mg alectinib in subjects with severe(Child-Pugh C) hepatic impairment, alectinib Cmax was the same and AUCinf was 2.2-fold highercompared with the same parameters in matched healthy subjects. M4 Cmax and AUCinf was 39% and34% lower respectively, resulting in a combined exposure of alectinib and M4 (AUCinf) 1.8-foldhigher in patients with severe hepatic impairment compared with matched healthy subjects.

The hepatic impairment study also included a group with moderate (Child-Pugh B) hepaticimpairment, and a modestly higher alectinib exposure was observed in this group compared withmatched healthy subjects. The subjects in the Child Pugh B group however did in general not sufferfrom abnormal bilirubin, albumin or prothrombin time, indicating that they may not be fullyrepresentative of moderately hepatically impaired subjects with decreased metabolic capacity.

Effects of age, body weight, race and gender

Age, body weight, race and gender had no clinically meaningful effect on the systemic exposure ofalectinib 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).

Carcinogenicity studies have not been performed to establish the carcinogenic potential of alectinib.

Alectinib was not mutagenic in vitro in the bacterial reverse mutation (Ames) assay but induced aslight 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. Themechanism of micronucleus induction was abnormal chromosome segregation (aneugenicity), and nota clastogenic effect on chromosomes.

No fertility studies in animals have been performed to evaluate the effect of alectinib. No adverseeffects on male and female reproductive organs were observed in general toxicology studies. Thesestudies 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 area under the curve (AUC), at the recommendeddose of 600 mg twice daily.

Alectinib caused embryo-foetal toxicity in pregnant rats and rabbits. In pregnant rats, alectinib causedtotal embryo-foetal loss (miscarriage) at exposures 4.5-fold of the human AUC exposure and smallfoetuses with retarded ossification and minor abnormalities of the organs at exposures 2.7-fold of thehuman AUC exposure. In pregnant rabbits, alectinib caused embryo-foetal loss, small fetuses andincreased incidence of skeletal variations at exposures 2.9-fold of the human AUC exposure at therecommended dose.

Alectinib absorbs ultraviolet (UV) light between 200 and 400 nm and demonstrated a phototoxicpotential 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 toxicologystudies included, but were not limited to the erythroid system, gastrointestinal tract, and hepatobiliarysystem.

Abnormal erythrocyte morphology was observed at exposures equal or greater than 10-60% thehuman exposure by AUC at the recommended dose. Proliferative zone extension in gastrointestinal(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 directbilirubin as well as vacuolation/degeneration/necrosis of bile duct epithelium and enlargement/focalnecrosis of hepatocytes was observed in rats and/or monkeys at exposures equal to or greater than20-30% of the human exposure by AUC at the recommended dose.

A mild hypotensive effect has been observed in monkeys at around clinically relevant exposures.

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5 years.

Store in the original package in order to protect from moisture.

Store in the original package and keep the bottle tightly closed in order to protect from moisture.

Aluminium/aluminium (PA/Alu/PVC/Alu) blisters containing 8 hard capsules.

Pack size: 224 (4 packs of 56) hard capsules.

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Pack size: 240 hard capsules.

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Roche Registration GmbH

Emil-Barell-Strasse 179639 Grenzach-Wyhlen

Germany

EU/1/16/1169/001

EU/1/16/1169/002

Date of first authorisation: 16 February 2017

Date of latest renewal: 15 July 2022

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.