1. description - pompionas.pom.go.id/sites/default/files/obat_baru/alecensa...withhold alecensa and...

Draft_Alecensa 1L-2L_PI_new drug application_CDS6.0_EN_v6

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________________________________________________________________

ALECENSA

Alectinib

_____________________________________________________

1. DESCRIPTION

1.1 THERAPEUTIC/PHARMACOLOGIC CLASS OF DRUG

Antineoplastic agent, protein kinase inhibitor

ATC Code: L01XE36

1.2 TYPE OF DOSAGE FORM

Hard capsule

1.3 ROUTE OF ADMINISTRATION

Oral

1.4 STERILE/RADIOACTIVE STATEMENT

Not applicable

1.5 QUALITATIVE AND QUANTITATIVE COMPOSITION

Active ingredient: Alectinib

Each hard capsule contains: Alectinib 150 mg (equivalent to 161.3 mg alectinib

hydrochloride).

Excipients: Lactose monohydrate, hydroxypropylcellulose, sodium lauryl sulphate,

carboxymethylcellulose calcium, magnesium stearate.

2. CLINICAL PARTICULARS

2.1 THERAPEUTIC INDICATION(S)

Alecensa is indicated for treatment naive patients with anaplastic lymphoma kinase (ALK)-

positive locally advanced or metastatic non-small cell lung cancer (NSCLC).

Alecensa is indicated for the treatment of patients with anaplastic lymphoma kinase

(ALK)-positive, locally advanced (not amenable to curative therapy) or metastatic non-

small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib.

DISETUJUI OLEH BPOM : 15/05/2019 EREG10036411800010


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2.2 DOSAGE AND ADMINISTRATION

General

A validated ALK assay such as immunohistochemistry or FISH test is required for the

selection of ALK-positive NSCLC patients. ALK-positive NSCLC status should be

established prior to initiation of Alecensa therapy.

Alecensa hard capsules should be taken with food, swallowed whole and must not be

opened or dissolved.

The recommended dose of Alecensa is 600 mg (four 150 mg capsules) given orally, twice

daily (total daily dose of 1200 mg) (see section 3.2 Pharmacokinetic Properties).

Patients with underlying severe hepatic impairment should receive a dose of 450 mg given

orally twice daily (total daily dose of 900 mg) (see sections 2.2.1 Special Dosing

Instructions and 3.2.5 Pharmacokinetics in Special Populations).

Duration of Treatment

It is recommended that patients are treated with Alecensa until disease progression or

unmanageable 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. If vomiting occurs after taking a dose of Alecensa, patients

should take the next dose at the scheduled time.

Dose Modifications

Management of adverse events may require temporary interruption, dose reduction, 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.

Table 1 below gives general dose modification advice for Alecensa.

Table 1 Dose Reduction Schedule

Dose reduction schedule Dose level

Dose 600 mg twice daily

First dose reduction 450 mg twice daily



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Second dose reduction 300 mg twice daily

Table 2 Dose modification advice for specified Adverse Drug Reactions (see sections

2.4.1 Warnings and Precautions and 2.6 Undesirable Effects):

Grade Alecensa Treatment

Interstitial Lung Disease

(ILD)/Pneumonitis (all Grades)

Immediately interrupt and permanently

discontinue 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 hemolysis

Permanently discontinue Alecensa

Bradycardiaa Grade 2 or Grade 3

(symptomatic, may be severe and

medically significant, medical

intervention indicated)


Grade 1 (asymptomatic) bradycardia or

to a heart rate of ≥ 60 bpm. Evaluate

concomitant medications known to cause

bradycardia, as well as anti-hypertensive

medications.

If contributing concomitant medication 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 medication

is identified, or if contributing concomitant

medications 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 medication is identified.

If contributing concomitant medication is

identified and discontinued, or its dose is

adjusted, resume at reduced dose (see



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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 same dose

CPK elevation >10 times ULN or second

occurrence of CPK elevation of > 5 times

ULN


baseline or to 2.5 times ULN, then

resume at reduced dose as per Table 1

ALT = alanine transaminase; AST = aspartate transaminase; ULN = upper limit of normal a Heart

rate less than 60 beats per minute (bpm)

2.2.1 Special Dosage Instructions

Pediatric use

The safety and efficacy of Alecensa in children and adolescents (< 18 years) have not been

studied.

Geriatric use

No dose adjustment of Alecensa is required in patients ≥ 65 years of age.

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 sections 2.5 Use in Special Populations and 3.2.5

Pharmacokinetics in Special Populations).

Hepatic Impairment

No dose adjustment is required in patients with underlying mild or moderate hepatic

impairment. Patients with underlying severe hepatic impairment should receive a dose of

450 mg given orally twice daily (total daily dose of 900 mg) (see section 3.2.5

Pharmacokinetics in Special Populations).

2.3 CONTRAINDICATIONS

Alecensa is contraindicated in patients with a known hypersensitivity to alectinib or any

of the excipients.



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2.4 WARNINGS AND PRECAUTIONS

2.4.1 General

Interstitial lung disease (ILD)/Pneumonitis

Cases of ILD/pneumonitis have been reported in clinical trials with Alecensa (see section

2.6.1 Undesirable Effects). 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 2.2 Dosage and

Administration).

Hepatotoxicity

Elevations in alanine aminotransferase (ALT) and aspartate aminotransferase (AST)

greater than 5 times the upper limit of normal (ULN) as well as bilirubin elevations of more

than 3 times the ULN occurred in patients in pivotal clinical trials with Alecensa (see

section 2.6.1 Undesirable Effects). The majority of these events occurred during the first 3

months of treatment. In the pivotal Alecensa clinical trials it was reported 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 to three times the ULN and total bilirubin greater than

or equal to two times the ULN, with normal alkaline phosphatase, occurred in 1 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, and then periodically, since

events may occur later than 3 months, with more frequent testing in patients who develop

transaminase and bilirubin elevations. Based on the severity of the adverse drug reaction,

withhold Alecensa and resume at a reduced dose, or permanently discontinue Alecensa as

described in Table 2 (see section 2.2 Dosage and Administration).

Severe Myalgia and Creatine Phosphokinase (CPK) elevation

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

including Grade 3 events.

Elevations of CPK occurred in pivotal trials with Alecensa, including Grade 3 events.

Median time to Grade 3 CPK elevation was 14 days in the pivotal phase II trials (NP28761,

NP28673). Median time to Grade 3 CPK elevation was 27.5 days in the pivotal phase III

clinical trial (BO28984) (see section 2.6.1. Undesirable Effects).

Advise patients to report any unexplained muscle pain, tenderness, or weakness. Assess

CPK levels 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, withhold

Alecensa, then resume or reduce dose (see section 2.2 Dosage and Administration).



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Bradycardia

Cases of bradycardia and sinus bradycardia have been reported in patients treated with

alectinib in pivotal clinical trials. All of these events were Grade 1 or 2 and generally

asymptomatic; none was reported as serious. In two patients, bradycardia/sinus bradycardia

led to dose reduction.

Treatment was interrupted due to bradycardia and sinus bradycardia in two patients.

Symptomatic bradycardia can occur with Alecensa (see 2.6 Undesirable Effects).

Alecensa treatment resulted in a decrease in heart rate (HR) of approximately 11 to 13 bpm

at Week 2 in the Phase I/II studies with crizotinib pre-treated patients, which was

maintained throughout the treatment period. The decrease in HR was reversible upon

discontinuation. In the Phase III study with treatment-naïve patients, the median decrease

in HR reached a plateau of approximately 17 bpm at Week 4. Overall, 20% of patients in

the Phase I/II studies and 15% of the patients in the Phase III study displayed lowest post-

baseline HRs below 50 bpm. The reduction on HR appears to be correlated to alectinib

plasma concentration. Patients presenting with baseline symptomatic bradycardia or QTc

interval > 470 millisecond (msec) were not studied in the pivotal clinical trials.

Co-administration of medicines that lower HR should be avoided to the extent possible

(see section 2.8 Interactions with Other Medicinal Products and Other Forms of

Interaction). If avoidance is not possible, patients should be closely monitored.

Heart rate and blood pressure should be monitored at baseline and regularly during

treatment (see 2.4 Warnings and Precautions). Dose modification is not required in case

of asymptomatic bradycardia (see 2.2 Dosage and Administration). If patients experience

symptomatic bradycardia or life-threatening events, Alecensa treatment should be

withheld, then reinstituted at a reduced dose or permanently discontinued (see 2.2 Dosage

and Administration).

Caution should be exercised in patients with a low heart rate at baseline (< 60 bpm), a

history of syncope or arrhythmia, sick sinus syndrome, sinoatrial block, atrioventricular

(AV) block, ischemic heart disease, or congestive heart failure. Cardiology consultation

may be required.

Patients should be informed that symptoms of bradycardia including dizziness,

lightheadedness, and syncope can occur while taking Alecensa. Advise patients to contact

their healthcare provider to report these symptoms and to inform their healthcare provider

about the use of any heart or blood pressure medications.

Photosensitivity

Photosensitivity to sunlight has been reported with Alecensa administration (see section

2.6 Undesirable Effects). Patients should be advised to avoid prolonged sun exposure while



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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.

Embryo-fetal toxicity

Alecensa may cause fetal harm when administered to a pregnant woman. When

administrated to pregnant rats and rabbits, alectinib caused embryo-fetal toxicity. Female

patients of child-bearing potential, or women of child-bearing potential who are partners

of male patients receiving Alecensa, must use highly effective contraceptive methods

during treatment and for at least 3 months following the last dose of Alecensa (see section

2.5 Use in Special Populations).

Gastrointestinal perforation

Across all pivotal clinical trials, one case of gastrointestinal perforation (0.2%) occurred

and had a fatal outcome. In the post-market setting cases of gastrointestinal perforation

were also reported with Alecensa.

In patients at risk for gastrointestinal perforation (e.g. concomitant use of medications with

a risk of gastrointestinal perforation, history of diverticulitis, metastases to the

gastrointestinal tract) Alecensa should be used with caution. Patients should be informed

of potential signs of gastrointestinal perforations and seek consultation rapidly in case of

occurrence.

Discontinue Alecensa permanently in patients who develop gastrointestinal perforation

(see 2.2 Dosage and Administration).

Renal Impairment

Renal impairment was reported in the pivotal clinical trials with Alecensa (see 2.6

Undesirable Effects) with grades above or equal to 3. Based on the severity of the renal

impairment, Alecensa may need to be withheld, resumed at a reduced dose, or permanently

discontinued (see 2.2 Dosage and Administration).

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

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.

2.4.2 Drug Abuse and Dependence

Not applicable.



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2.4.3 Ability to Drive and Use Machines

No studies on the effects on the ability to drive and to use machines have been performed.

2.5 USE IN SPECIAL POPULATIONS

2.5.1 Females and Males of Reproductive Potential

Contraception

Female patients of child-bearing potential, or women of child-bearing potential who are

partners of male patients receiving Alecensa, must use highly effective contraceptive

methods during treatment and for at least 3 months following the last dose of Alecensa.

2.5.2 Pregnancy

Women of childbearing potential must be advised to avoid pregnancy while on Alecensa.

No clinical studies of Alecensa in pregnant women have been performed. Based on its

mechanism of action, Alecensa may cause fetal harm when administered to a pregnant

woman.

Female patients or women who are partners of male patients receiving Alecensa, 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 fetus.

Animal data

In animal studies, alectinib caused embryo-fetal toxicity (see section 3.3 Nonclinical

Safety).

Labor and Delivery

The safe use of Alecensa during labor and delivery has not been established.

2.5.3 Lactation

It is not known whether Alecensa is excreted in human breast milk. No studies have been

conducted to assess the impact of Alecensa on milk production or its presence in breast

milk. As many drugs are excreted in human milk and because of the potential harm to the

infant, mothers should be advised against breastfeeding while receiving Alecensa.

2.5.4 Pediatric Use

Safety and efficacy in pediatric patients below the age of 18 have not been established.

2.5.5 Geriatric Use

See sections 2.2.1 Special Dosage Instructions and 3.2.5 Pharmacokinetics in Special

Populations.



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2.5.6 Renal Impairment


Populations.

2.5.7 Hepatic Impairment


Populations.

2.6 UNDESIRABLE EFFECTS

2.6.1 Clinical Trials

Patients not previously treated systemically for advanced or metastatic NSCLC

The safety of Alecensa 600 mg twice daily compared to crizotinib 250 mg twice daily were

evaluated in 152 and 151 patients with ALK-positive NSCLC, respectively, in the Phase

III clinical trial, Study BO28984 (ALEX) and evaluated in 125 and 62 Asian patients with

treatment-naïve ALK-positive, respectively in Study YO29449 (Alesia). The median

duration of exposure to Alecensa and crizotinib were 17.9 and 10.7 months in Alex Study

and 14.7 and 12.6 months in Alesia Study, respectively. Patients presenting with baseline

symptomatic bradycardia were not studied in this trial.

The most common adverse drug reactions for Alecensa (≥ 10%) in the pivotal phase III

trial were: constipation, myalgia, fatigue, edema, increased bilirubin, anemia, rash, alanine

aminotransferase increased, aspartate aminotransferase increased, nausea, diarrhoea,

arthralgia and bradycardia.

Serious adverse reactions occurred in 28% and 29% of patients treated with Alecensa and

crizotinib, respectively in Alex Study. The most frequently reported serious adverse

reactions were pneumonia (3.3%) and acute kidney injury (2.6%) for patients treated with

Alecensa, and pneumonia, pneumonitis and elevated ALT (2.6% each) for patients treated

with crizotinib. Grade ≥ 3 adverse events were reported for 41% of patients in the Alecensa

arm and 50% in the crizotinib arm. Fatal adverse events occurred in both treatment arms:

5 (3.3%), all unrelated in the Alecensa arm, and 7 (4.6%), 2 related in the crizotinib arm.

In Alesia study, serious adverse event occurred in 25.8% and 15.2% of patients treated with

crizotinib and Alecensa, respectively. The most common serious adverse events (≥ 2%

incidence in any arm) were lung infection, pneumonia, blood creatinine phosphokinase

increased, interstitial lung disease, bradycardia, hepatic function abnormal for patients

treated with crizotinib and blood uric acid increased for patients treated with Alecensa.

In Alex study, permanent treatment discontinuation for adverse reactions occurred in 11%

of patients treated with Alecensa, and in 13% of crizotinib-treated patients. Acute kidney

injury was the most commonly reported adverse drug reaction leading to study drug

discontinuation in the Alecensa arm (2.0%) and elevated ALT (5.3%), AST (4.0%) and

pneumonitis (2.6%) in the crizotinib arm. Dose modifications (dose reductions and drug

interruption, respectively) were required in 16% and 19% of patients in the Alecensa arm

and in 21% and 25% in the crizotinib arm, respectively. The most frequent adverse



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reactions that led to dose modifications in the Alecensa arm were pneumonia, elevation in

ALT and AST and in the crizotinib arm were elevated ALT, AST, neutropenia and

vomiting.

Table 3 Adverse Drug Reactions in > 10% for all NCI CTCAE Grades or ≥ 2%

for Grades 3-4 of patients in either treatment arm in Study 3 (ALEX)

Alecensa

N 152

Crizotinib

N 151

MedDRA System Organ Class

Adverse Reaction

All Grades (%) Grades 3-4

(%)

All Grades

(%)

Grades 3-4

(%)

Gastrointestinal disorders

Constipation 34 0 33 0

Nausea 14 0.7 48 3.3

Diarrhoea 12 0 45 2.0

Vomiting 7.2 0 38 3.3

General disorders and administration site conditions

Oedemaa 22 0.7 34 0.7

Musculoskeletal and connective tissue disorders

Myalgiab 23 0 4.0 0

Skin and subcutaneous tissue disorders

Rashc 15 0.7 13 0

Nervous system disorders

Dysgeusiad 3.3 0.7 19 0

Eye disorders

Vision disorderse 4.6 0 23 0

Cardiac disorders

Bradycardiaf 11 0 15 0

Renal and urinary disorders

Acute kidney injury 2.6 2.6* 0 0

NCI CTCAE National Cancer Institute Common Terminology Criteria for Adverse Events;

MedDRA Medical Dictionary for Regulatory Activities. a Includes cases of peripheral oedema, oedema, eyelid oedema, localised oedema, and face oedema. b Includes cases of myalgia and musculoskeletal pain. c Includes cases of rash, rash maculo-papular, dermatitis acneiform, erythema, generalised rash, rash

macular, rash papular, exfoliative rash, and pruritic rash. d Includes cases of dysgeusia and hypogeusia. e Includes cases of blurred vision, visual impairment, vitreous floaters, reduced visual acuity, and diplopia. f Includes cases of bradycardia and sinus bradycardia.

* Includes one Grade 5 event.

Additional adverse drug reactions in patients treated with Alecensa compared to crizotinib

respectively include weight increased (9.9% vs 0%), photosensitivity reaction (5.3% vs

0%), stomatitis (3.3% vs 2.6%, which includes cases of stomatitis and mouth ulceration),

interstitial lung disease (1.3% vs 6.0%, which includes cases of interstitial lung disease and

pneumonitis), and hepatotoxicity (1.4% vs 0.7%, which includes cases of drug-induced

liver injury, 0.7% vs 0.7, and hepatotoxicity).

Crizotinib pre-treated patients

The safety of Alecensa has been evaluated in 253 patients in pivotal phase I/II clinical trials

(NP28761, NP28673) with ALK-positive non-small cell lung cancer (NSCLC) treated with



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the recommended dose of 600 mg twice daily. The median duration of exposure to

Alecensa was 11 months (range 0-35 months).

The most common adverse reactions (≥ 20%) were fatigue (44%, includes fatigue and

asthenia), constipation (36%), edema (34% includes peripheral, generalised, eyelid,

periorbital), myalgia (31% includes myalgia and musculoskeletal pain), nausea (22%),

cough (21%), rash (20%, includes rash, maculopapular rash, acneiform dermatitis,

erythema, generalized rash, papular rash, pruritic rash and macular rash) and headache

(20%).

Serious adverse events occurred in 22% of patients. The most frequent reported serious

adverse events were pulmonary embolism (1.2%), dyspnoea (1.2%) and

hyperbilirubinaemia (1.2%). Fatal adverse reactions occurred in 2.8% of patients and

included haemorrhage (0.8%), intestinal perforation (0.4%), dyspnea (0.4%), pulmonary

embolism (0.4%), endocarditis (0.4%) and unknown adverse reaction (0.4%).

Adverse events led to permanent discontinuation of Alecensa in 6% of patients, most

frequently due to hyperbilirubinaemia (1.6%), increased ALT levels (1.6%), and increased

AST levels (1.2%). At least one dose reduction or interruption was required for 33% of

patients initiating treatment at the recommended dose, and the median time to first dose

reduction or interruption was 56 days. The most frequent adverse reactions that led to dose

changes were elevations in bilirubin (6.3%), CPK (4.3%), ALT (4.0%) or AST (2.8%), and

vomiting (3.2%).

Table 4 summarizes the adverse reactions (ARs) occurring in patients who received

Alecensa in pivotal phase II clinical trials (NP28761, NP28673). The following categories

of frequency have been used: 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).

Table 4 Summary of Adverse Reactions Occurring in Patients Treated with Alecensa

in the pivotal Phase I/II Clinical Trials (NP28761 and NP28673)

Adverse Reactions (MedDRA) ALECENSA

N=253

(NP28761, NP28763)

System Organ Class All Grades

n (%)

Grade 3 – 4*

n (%)

Blood and Lymphatic System Disorders

Anemia1 40 (16) 5 (2.0)

Neutropenia 9 (3.6) 1 (0.4)

Leukopenia 9 (3.6) 0

Cardiac Disorders

Bradycardia2 20 (7.9) 0

Eye Disorders

Vision Disorders3 29 (12) 0

Gastrointestinal Disorders

Constipation 90 (36) 0



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Nausea 55 (22) 1 (0.4)

Diarrhoea 46 (18) 3 (1.2)

Vomiting 34 (13) 1 (0.4)

Stomatitis4 7 (2.8) 0

General Disorders and Administration Site Conditions

Fatigue5 112 (44) 4 (1.6)

Edema6 85 (34) 2 (0.8)

Mucosal Inflammation 7 (3) 0

Investigations

Increased Bilirubin7 42 (17) 8 (3.2)

Aspartate Aminotransferase Increased 41 (16) 7 (2.8)

Alanine Aminotransferase Increased 35 (14) 8 (3.2)

Blood Creatine Phosphokinase Increased 34 (13) 9 (3.6)

Weight Increased 34 (13) 2 (0.8)

Blood Alkaline Phosphatase Increased 19 (7.5) 1 (0.4)

Blood Creatinine Increased 17 (6.7) 1 (0.4)

Musculoskeletal and Connective Tissue Disorders

Myalgia8 78 (31) 3 (1.2)

Arthralgia

28 (11) 0

Muscular Weakness 17 (6.7) 1 (0.4)

Nervous System Disorders

Headache 50 (20) 3 (1.2)

Dizziness 29 (12) 0

Dysgeusia 16 (6.3) 0

Neuropathy peripheral 11 (4.3) 0

Skin and Subcutaneous Tissue Disorders

Rash9 51 (20) 1 (0.4)

Photosensitivity Reaction 29 (12) 0

Dry Skin 17 (6.7) 0

Alopecia 13 (5.1) 0

Pruritus 11 (4.3) 0 * no Grade 5 events observed 1 includes cases of anemia and haemoglobin decreased 2 includes cases of bradycardia and sinus bradycardia 3 includes cases of vision blurred, visual impairment, vitreous floaters, visual acuity reduced, asthenopia,

and diplopia 4 includes cases of stomatitis and mouth ulceration 5 includes cases of fatigue and asthenia 6 includes cases of edema peripheral, edema, generalised edema, eyelid edema, periorbital edema

7 includes cases of blood bilirubin increased, hyperbilirubinemia and bilirubin conjugated increased 8 includes cases of myalgia and musculoskeletal pain

9 includes cases of rash, rash maculopapular, dermatitis acneiform, erythema, rash generalized, rash

papular, rash pruritic and rash macular



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Further information on selected adverse drug reactions:

The safety profile of Alecensa was generally consistent across the phase III clinical trial

(BO28984) and the pivotal phase II trials (NP28761, NP28673); however, relevant

differences between studies are described below.

Interstitial Lung Disease (ILD)/pneumonitis

Severe ILD/pneumonitis occurred in patients treated with Alecensa. Across clinical trials,

1 patient had ILD event, which was Grade 3, leading to withdrawal from Alecensa

treatment. There were no fatal cases of ILD in any of the clinical trials. Patients should be

monitored for pulmonary symptoms indicative of pneumonitis (see sections 2.2 Dosage

and administration and 2.4 Warning and Precautions).

Hepatotoxicity

Across clinical trials, two patients with Grade 3-4 AST/ALT elevations had documented

drug induced liver injury by liver biopsy. In addition, one patient experienced a Grade 4

adverse event of drug-induced liver injury. Two of these cases led to withdrawal from

Alecensa treatment. Adverse reactions of increased AST and ALT levels (15% and 14%

respectively) were reported in patients treated with Alecensa across clinical trials. The

majority of these events were of Grade 1 and 2 intensity, and events of Grade ≥ 3 were

reported in 3.7% and 3.7% 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 1.5% and 3.0% of the patients, respectively)

or dose reduction (2.2% and 1.2% respectively). In 1.2% and 1.5% of the patients, AST

and ALT elevations, respectively, led to withdrawal from Alecensa treatment.

Adverse reactions of bilirubin elevations were reported in 18% of the patients treated with

Alecensa across clinical trials. 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 the majority resolved upon dose

modification. In 5.2% of the patients, bilirubin elevations led to dose modifications and in

1.5% of patients, 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 2.4 Warning and Precautions and managed as recommended in section

2.2 Dosage and administration.

Bradycardia

Cases of bradycardia (8.9%) of Grade 1 or 2 have been reported in patients treated with

Alecensa across clinical trials. No patients had events of Grade ≥ 3 severity. There were



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66 of 365 patients (18%) treated with Alecensa who had post-dose heart rate values below

50 beats per minutes [bpm]. Patients who develop symptomatic bradycardia should be

managed as recommended in sections 2.2 Dosage and Administration and 2.4 Warning and

Precautions. No case of bradycardia led to withdrawal from Alecensa treatment.

Severe Myalgia and CPK elevation

Cases of myalgia (28%) including myalgia events (22%) and musculoskeletal pain (7.4%)

have been reported in patients treated with Alecensa across clinical trials. The majority of

events were Grades 1 or 2 and three patients (0.7%) had a Grade 3 event. Dose

modifications of Alecensa treatment due to these adverse events were only required for

two patients (0.5%); Alecensa treatment was not withdrawn due to these events of myalgia.

Elevations of CPK occurred in 43% of 362 patients with CPK laboratory data available

across clinical trials with Alecensa. The incidence of Grade 3 elevations of CPK was 3.7%.

Median time to Grade 3 CPK elevation was 14 days across trials. Dose modifications for

elevation of CPK occurred in 3.2% of patients; withdrawal from Alecensa treatment did

not occur due to CPK elevations.

Gastrointestinal effects

Constipation (35%), nausea (19%), diarrhoea (16%) and vomiting (11%) were the most

commonly reported gastrointestinal (GI) reactions. Most of these events were of mild or

moderate severity; Grade 3 events were reported for diarrhoea (0.7%), nausea (0.5%), and

vomiting (0.2%). These events did not lead to withdrawal from Alecensa treatment. Median

time to onset 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.

Laboratory Abnormalities

The following table displays treatment-emergent shifts in laboratory abnormalities

occurring in patients treated with Alecensa in phase II clinical trials (NP28761, NP28673)

and phase III trial BO28984.

Table 5 Alecensa Treatment-emergent shifts in key laboratory abnormalities

Parameter Alectinib

N= 250*/N=152#

All Grade (%) Grade 3 -4(%)°

Chemistry

Increased Blood Creatinine** 38# 3.4#

Increased AST 53* 6.2#

Increased ALT 40# 6.1#

Increased Blood Creatine Phosphokinase 46* 5.0*

Increased Blood Bilirubin 53# 5.5#



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Hematology

Decreased Hemoglobin 62# 6.8#

AST - Aspartate Aminotransferase, ALT - Alanine Aminotransferase

Note: Laboratory abnormalities were based on the normal ranges of the NCI CTCAE. * Rate reported in NP28761 and NP28673 studies, N= 219 for Creatine Phosphokinase. ** Only patients with creatinine increases based on ULN definition (CTCAE grading). # Rate reported in trial BO28984; Patients with missing baseline and/or no post-baseline lab assessments

were excluded from analyses; N=147 for Blood Creatinine, ALT and Hemoglobin; N=145 for AST;

N=146 for Blood Bilirubin.

° No Grade 5 laboratory abnormalities were reported.

2.6.2 Postmarketing Experience

The adverse drug reaction of increased alkaline phosphatase was reported with Alecensa

in the post marketing period. Cases of increased alkaline phosphatase have been reported

in Alecensa clinical trials (7.5% in patients treated with Alecensa in pivotal phase II clinical

trials (NP28761, NP28673)).

2.7 OVERDOSE

No experience with overdosage is available from the pivotal clinical trials and there is no

specific antidote for overdosage with Alecensa. Patients who experience overdose should

be closely supervised and supportive care instituted. Alectinib is > 99% bound to plasma

proteins and haemodialysis is likely to be ineffective in the treatment of overdose.

2.8 INTERACTIONS WITH OTHER MEDICINAL PRODUCTS AND OTHER FORMS OF INTERACTION

Effects of alectinib on others drugs

CYP substrates

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 and M4 show weak time-dependent inhibition of CYP3A4. In vitro, alectinib

exhibits a weak induction potential of CYP3A4 and CYP2B6 at clinical concentrations.

Results from a clinical drug-drug interaction study in ALK-positive NSCLC patients

demonstrated that multiple doses of alectinib had no influence on the exposure of

midazolam, a sensitive CYP3A substrate. Therefore, no dose adjustment is required for co-

administered CYP3A substrates.

In vitro studies indicate that alectinib is an inhibitor of CYP2C8. Alectinib may increase

plasma concentrations of co-administered CYP2C8 substrates. Alectinib and CYP2C8

substrates should be co-administered with caution and patients should be monitored.

P-gp and BCRP substrates

In vitro, alectinib and M4 are inhibitors of the efflux transporters P-glycoprotein (P-gp)

and Breast Cancer Resistance Protein (BCRP). Therefore, alectinib may have the potential

to increase plasma concentrations of co-administered substrates of P-gp or BCRP



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transporters (the increase in exposure is not expected to be more than 2-fold). When

alectinib is co-administered with P-gp or BCRP substrates with narrow therapeutic index

(e.g. digoxin, dabigatran, methotrexate), appropriate monitoring is recommended.

Effects of other drugs 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 to alectinib

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

Although the aqueous solubility of alectinib in vitro is pH dependent, a dedicated clinical

drug-drug interaction study with 40 mg esomeprazole once daily, a proton pump inhibitor,

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 drugs which raise gastric pH (e.g. H2 receptor antagonists or

antacids).



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Effect of transporters on alectinib disposition

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

contrast, M4 is a substrate of P-gp. Alectinib inhibits P-gp, and therefore, it is not expected

that co-medication with P-gp inhibitors has a relevant effect on M4 exposure.

3. PHARMACOLOGICAL PROPERTIES AND EFFECTS

3.1 PHARMACODYNAMIC PROPERTIES

3.1.1 Mechanism of Action

Alectinib is a highly selective and potent ALK and RET tyrosine kinase inhibitor. In

nonclinical studies, inhibition of ALK tyrosine kinase activity led to blockage of

downstream signalling pathways including STAT 3 and PI3K/AKT and induces tumor 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 nonclinical data, alectinib is not a substrate of p-glycoprotein (P-gp) or Breast

Cancer Resistance Protein (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.

3.1.2 Clinical/Efficacy Studies

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, multicenter 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) 1.1 in the overall population (with and

without prior exposure of cytotoxic chemotherapy treatments). The co-primary endpoint



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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 tumors 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 at least one and

chemotherapy treatment.

Study NP28761

Study NP28761 was a Phase I/II single arm, multicenter 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 tumors were classified

as adenocarcinoma. Among patients included in the study, 26% 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 6.

A summary of pooled analysis of CNS endpoints is presented in Table 7.



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Table 6 Efficacy results from Studies NP28673 and NP28761 NP28673

Alecensa 600 mg

twice daily

NP28761

Alecensa 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]

ORR (IRC) in patients pre-treated with

chemotherapy

Responders N (%)

[95% CI]

N=122 a

62 (50.8%)

[41.6%, 60.0%]

N = 96

43 (44.8%)

[34.6%, 55.3%]

N 67b

35 (52.2%)

[39.7%, 64.6%]

Secondary Efficacy Parameters

DOR (IRC)

Number of patients with events N (%)

Median (months)

[95% CI]

PFS (IRC)

Number of patients with events N (%)

Median duration (months)

[95% CI]

N = 62

36 (58.1%)

15.2

[11.2, 24.9]

N = 138

98 (71.0%)

8.9

[5.6, 12.8]

N 35

20 (57.1%)

14.9

[6.9, NE]

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 7 Summary of the pooled analysis for CNS endpoints from NP28673 and

NP286761 studies

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

Patients with Measurable CNS Lesions at Baseline

CNS ORR (IRC)

Responders (%)

[95% CI] Complete Response Partial Response

N = 50

32 (64.0%)

[49.2%, 77.1%]

11 (22.0%)

21 (42.0%)



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CNS DOR (IRC)

Number of patients with events (%)

Median (months)

[ 95% CI]

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

Treatment-naïve patients

The safety and efficacy of Alecensa were studied in a global randomized Phase III open

label clinical trial (BO28984) in ALK-positive NSCLC patients who were treatment naïve.

Central testing for ALK protein expression positivity of tissue samples from all patients by

Ventana anti-ALK (D5F3) immunohistochemistry (IHC) was required before

randomization into the study.

A total of 303 patients were included in the Phase III trial, 151 patients randomized to the

crizotinib arm and 152 patients randomized to the Alecensa arm receiving Alecensa orally,

at the recommended dose of 600 mg twice daily.

ECOG PS (0/1 vs 2), race (Asian vs non-Asian), and CNS metastases at baseline (yes vs

no) were stratification factors for randomization. The primary endpoint of the trial was to

demonstrate superiority of Alecensa versus crizotinib based on Progression Free survival

(PFS) as per investigator assessment using RECIST 1.1. Baseline demographic and disease

characteristics for Alecensa were median age 58 years (54 years for crizotinib), 55% female

(58% for crizotinib), 55% non-Asian (54% for crizotinib), 61% with no smoking history

(65% for crizotinib), 93% ECOG PS of 0 or 1 (93% for crizotinib), 97% Stage IV disease

(96% for crizotinib), 90% adenocarcinoma histology (94% for crizotinib), 40% CNS

metastases at baseline (38% for crizotinib) and 17% having received prior CNS radiation

(14% for crizotinib).

The trial met its primary endpoint at the primary analysis. Efficacy data are summarized in

Table 8 and the Kaplan-Meier curves for investigator and IRC-assessed PFS are shown in

Figures 1 and 2.

Table 8 Summary of efficacy results from study BO28984

Crizotinib

N=151

Alecensa

N=152

Median duration of follow-up (months) 17.6

(range 0.3 – 27.0)

18.6

(range 0.5 – 29.0)

Primary Efficacy Parameter

PFS (INV)

Number of patients with event n (%)

Median (months)

[95% CI]

102 (68%)

11.1

[9.1; 13.1]

62 (41%)

NE

[17.7; NE]

HR 0.47



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[95% CI]

Stratified log-rank p-value

[0.34, 0.65]

p <0.0001

Secondary efficacy parameters

PFS (IRC)*


Median (months)

[95% CI]

92 (61%)

10.4

[7.7; 14.6]

63 (41%)

25.7

[19.9; NE]

HR

[95% CI]


0.50

[0.36; 0.70]

p < 0.0001

Time to CNS progression (IRC)*

(without prior systemic PD**)


68 (45%)

18 (12%)

Cause-Specific HR

[95% CI]


0.16

[0.10; 0.28]

p < 0.0001

12-month cumulative incidence of

CNS progression (IRC)

% (95% CI)

41.4%

[33.2; 49.4]

9.4%

[5.4; 14.7]

ORR (INV)*, ***

Responders n (%)

[95% CI]

114 (75.5%)

[67.8; 82.1]

126 (82.9%)

[76.0; 88.5]

Overall survival*

Number of patients with event n (%)*

Median (months)

[95% CI]

40 (27%)

NE

[NE; NE]

35 (23%)

NE

[NE; NE]

HR

[95% CI]

0.76

[0.48; 1.20]

Duration of response (INV)

Median (months)

95 % CI

N=114

11.1

[7.9; 13.0]

N=126

NE

[NE; NE]

CNS-ORR in patients with measurable CNS

metastases at baseline

CNS responders n (%)

[95% CI]

CNS-CR n (%)

CNS-DOR , median (months)

95% CI

N=22

11 (50.0%)

[28.2; 71.8]

1 (5%)

5.5

[2.1, 17.3]

N=21

17 (81.0%)

[58.1; 94.6]

8 (38%)

17.3

[14.8, NE]

CNS-ORR in patients with measurable and

non-measurable CNS metastases at baseline

(IRC)

CNS responders n (%)

[95% CI]

CNS-CR n (%)

N=58

15 (25.9%)

[15.3%; 39.0%]

5 (9%)

N=64

38 (59.4%)

[46.4%; 71.5%]

29 (45%)



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*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 magnitude of PFS benefit was consistent for patients with CNS metastases at baseline

(HR=0.40, 95% CI: 0.25-0.64, median PFS for Alecensa = NE, 95% CI: 9.2-NE, median

PFS for crizotinib = 7.4 months, 95% CI: 6.6-9.6) and without CNS metastases 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 over

crizotinib in both subgroups.

Figure 1: Kaplan Meier Plot of INV Assessed PFS in BO28984

CNS-DOR , median (months)

95% CI

3.7

[3.2, 6.8]

NE

[17.3, NE]



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Figure 2: Kaplan Meier Plot of IRC Assessed PFS in BO28984

3.1.3 Immunogenicity

Not applicable.

3.2 PHARMACOKINETIC PROPERTIES

The pharmacokinetic parameters for alectinib and its major active metabolite (M4), have

been characterized in ALK-positive NSCLC patients and healthy subjects. 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.

3.2.1 Absorption

Following oral administration of 600 mg twice daily under fed conditions in ALK-positive

NSCLC patients, alectinib was rapidly absorbed reaching Tmax after approximately 4 to 6

hours.

Alectinib steady-state is reached by Day 7 with continuous 600 mg twice daily dosing and

remains stable thereafter. The geometric mean accumulation ratio estimated by population

PK analysis for the twice-daily 600 mg regimen is 5.6. Population PK analysis supports

dose proportionality for alectinib across the dose range of 300 to 900 mg under fed

conditions.



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The absolute bioavailability of alectinib 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, the

alectinib and M4 exposure increased by around 3-fold relative to fasted conditions.

3.2.2 Distribution

Alectinib and its major metabolite M4 are highly bound to human plasma proteins (> 99%),

independent of drug 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.

3.2.3 Metabolism

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 in human hepatocytes. Results from the human mass balance study

demonstrated that alectinib and M4 were the main circulating moieties in plasma with

alectinib and M4 together constituting approximately 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.

3.2.4 Elimination

Following administration of a single dose of 14C-labeled alectinib administered orally to

healthy subjects the majority of radioactivity was excreted in feces (mean recovery 97.8%,

range 95.6%-100%) with minimal excretion in urine (mean recovery 0.46%, range 0.30%-

0.60%). In feces, 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.



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3.2.5 Pharmacokinetics in Special Populations

Pediatric population

No studies have been conducted to investigate the pharmacokinetics of Alecensa in this

population.

Geriatric population

Age does not have an effect on Alecensa exposure.

Renal impairment

Negligible amounts of alectinib and the active metabolite M4 are excreted unchanged in

urine (< 0.2% of the dose). Data obtained in patients with mild and moderate renal

impairment show that the pharmacokinetics of alectinib are not significantly affected in

renal impairment. No formal pharmacokinetic study has been conducted and no population

PK data was collected 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 active

metabolite M4. Based on a population pharmacokinetic analysis, alectinib and M4

exposures were similar in patients with mild hepatic impairment (baseline total bilirubin

less than or equal to ULN and baseline AST greater than ULN or baseline total bilirubin

greater than 1.0 to 1.5 times ULN and any baseline AST) and normal hepatic function (total

bilirubin less than or equal to ULN and AST less than or equal to ULN).

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

higher compared with the same parameters in matched healthy subjects. M4 Cmax and

AUCinf was 39% and 34% lower respectively, resulting in a combined exposure of alectinib

and M4 (AUCinf) 1.8-fold higher in patients with severe hepatic impairment compared with

matched healthy subjects.

The hepatic impairment study also included a group with moderate (Child-Pugh B) hepatic

impairment, and a modestly higher alectinib exposure was observed in this group compared

with matched healthy subjects. The subjects in the Child Pugh B group however did in

general not suffer from abnormal bilirubin, albumin or prothrombin time, indicating that

they may not be fully representative of moderately hepatically impaired subjects with

decreased metabolic capacity.

No dose adjustments are required for Alecensa in patients with underlying mild or

moderate hepatic impairment. Patients with underlying severe hepatic impairment should

receive a dose of 450 mg given orally twice daily (total daily dose of 900 mg).



of 27

3.3 NONCLINICAL SAFETY

3.3.1 Carcinogenicity

No carcinogenicity studies have been performed to establish the carcinogenic potential of

Alecensa.

3.3.2 Genotoxicity

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.

3.3.3 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 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.

3.3.4 Reproductive Toxicity

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.

3.3.5 Other

Alectinib absorbs UV light between 200 and 400 nm and demonstrated 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



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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.

Alectinib crossed the blood brain barrier in rats and was retained within brain tissue with a

CNS-to-plasma radio-concentration ratio ranging from 0.9 to 1.5 at 24 hours post-dose.

4. PHARMACEUTICAL PARTICULARS

4.1 STORAGE

Storage: Do not store above 30o C. Keep in the original container to protect from light and

moisture.

Keep container tightly closed, protect from light and moisture.

This medicine should not be used after the expiry date (EXP) shown on the pack.

4.2 SPECIAL INSTRUCTIONS FOR USE, HANDLING AND DISPOSAL

Disposal of unused/expired medicines

The release of pharmaceuticals in the environment should be minimized. Medicines should

not be disposed of via wastewater and disposal through household waste should be avoided.

Use established “collection systems”, if available in your location.

4.3 PACK

Capsule 150 mg

Box, 4 boxes @ 7 blisters @ 8 capsules Reg. No: DKI1957508001A1

Box, 7 blisters @ 8 capsules Reg. No: DKI1957508001A1

Made for:

F.Hoffmann-La Roche Ltd, Basel, Switzerland

Manufactured by:

Excella GmbH & Co. KG, Feucht, Germany

Imported by:

PT Boehringer Ingelheim Indonesia,

Bogor, Indonesia

Distributed by:

PT Roche Indonesia,

Jakarta, Indonesia

Medicine: Keep out of reach and sight of children

On Medical Prescription Only

Harus Dengan Resep Dokter


Draft_Alecensa 1L-2L_PIL_new drug application_CDS6.0_ID_v6

Halaman 1 dari 9

INFORMASI PRODUK BAGI PASIEN

ALECENSA®

Alectinib

Kapsul 150 mg

Obat ini harus diberikan pemantauan tambahan. Hal ini memungkinkan identifikasi informasi

keamanan yang baru secara cepat. Anda dapat membantu dengan melaporkan efek samping yang

mungkin Anda alami. Lihat bagian akhir bagian 4 untuk pelaporan efek samping.

Baca keseluruhan brosur ini dengan saksama sebelum Anda mulai menggunakan obat ini

– karena terdapat informasi yang penting untuk Anda.

Simpan brosur ini. Anda mungkin perlu untuk membacanya lagi.

Bila Anda memiliki pertanyaan lebih lanjut, tanyakan pada dokter, apoteker atau perawat

Anda.

Obat ini hanya diresepkan untuk Anda. Jangan berikan obat ini ke orang lain. Hal itu dapat

membahayakan mereka, meskipun tanda-tanda penyakitnya sama dengan Anda.

Bila Anda mengalami efek samping, hubungi dokter, apoteker atau perawat Anda. Hal ini

termasuk kemungkinan efek samping apapun yang tidak tercantum dalam brosur ini. Lihat

bagian 4.

Apa yang terdapat dalam brosur ini

1. Apa itu Alencensa dan kegunaannya

2. Apa yang perlu Anda ketahui sebelum menggunakan Alecensa

3. Bagaimana cara penggunaan Alecensa

4. Efek samping yang mungkin terjadi

5. Bagaimana cara penyimpanan Alecensa

6. Isi dalam kemasan dan informasi lainnya

1. Apa itu Alecensa dan kegunaannya

Apa itu Alecensa

Alecensa adalah obat kanker yang mengandung zat aktif alectinib.

Apa kegunaan Alecensa

Alecensa digunakan untuk mengobati kanker paru jenis “non-small cell lung cancer”

(‘NSCLC’) pada orang dewasa. Obat ini digunakan jika kanker paru Anda:

ALK positif – artinya sel kanker Anda memiliki kecacatan pada gen yang menghasilkan

enzim ALK (‘anaplastic lymphoma kinase’), lihat ‘Bagaimana Alecensa bekerja’, di

bawah ini

dalam stadium lanjut (tidak dapat ditangani dengan terapi kuratif)

DISETUJUI OLEH BPOM: 17/06/2019 EREG10036411800010


Halaman 2 dari 9

Alecensa diberikan kepada Anda yang mengalami kanker paru tahap lanjut dan telah menyebar

yang belum pernah mendapatkan terapi kanker paru, atau pernah mendapatkan terapi dengan

obat mengandung crizotinib sebelumnya.

Bagaimana Alecensa bekerja

Alecensa menghambat kerja enzim ALK tirosin kinase. Bentuk abnormal dari enzim ini

(karena kecacatan dari gen yang menghasilkannya) membantu pertumbuhan sel kanker.

Alecensa dapat memperlambat atau menghentikan pertumbuhan kanker Anda. Alecensa juga

dapat membantu memperkecil ukuran kanker Anda.

Jika Anda memiliki pertanyaan tentang cara kerja Alecensa atau mengapa obat ini diresepkan

untuk Anda, tanyakan pada dokter, apoteker atau perawat Anda.

2. Apa yang perlu Anda ketahui sebelum menggunakan Alecensa

Jangan menggunakan Alecensa:

Bila Anda alergi terhadap alectinib atau bahan lain yang terkandung dalam obat ini

(tercantum pada bagian 6).

Bila Anda tidak yakin, diskusikan dengan dokter, apoteker atau perawat Anda sebelum

menggunakan Alecensa.

Peringatan dan perhatian:

Diskusikan dengan dokter, apoteker atau perawat Anda sebelum menggunakan Alecensa:

Bila Anda memiliki penyakit turunan berupa intoleransi galaktosa, defisiensi laktase

kongenital atau malabsorpsi glukosa-galaktosa.

Bila Anda tidak yakin, hubungi dokter, apoteker atau perawat Anda sebelum mengonsumsi

Alecensa.

Alecensa dapat menyebabkan efek samping yang harus Anda beri tahukan segera kepada

dokter Anda. Efek samping tersebut mencakup:

Gangguan hati (hepatotoksisitas). Dokter Anda akan melakukan tes darah sebelum Anda

memulai pengobatan, lalu diulang setiap 2 minggu untuk 3 bulan pertama dan kemudian

dengan frekuensi yang lebih jarang. Hal ini bertujuan untuk memeriksa bahwa Anda tidak

mengalami gangguan hati selama mengonsumsi Alecensa. Segera hubungi dokter Anda

jika Anda mengalami tanda-tanda berikut ini: kulit atau bagian putih mata menjadi

kekuningan, nyeri pada bagian perut sebelah kanan, urin berwarna gelap, gatal-gatal pada

kulit, kurang nafsu makan dibandingkan biasanya, mual atau muntah, merasa lelah,

perdarahan dan lebam dibandingkan keadaan normal.

Denyut jantung yang lambat (bradikardia)

Radang paru (pneumonitis). Alecensa dapat mengakibatkan pembengkakan (inflamasi)

paru yang berat atau mengancam jiwa selama masa pengobatan. Tanda-tanda tersebut



Halaman 3 dari 9

mungkin mirip dengan tanda-tanda akibat kanker paru yang Anda alami. Segera hubungi

dokter Anda jika Anda mengalami tanda-tanda yang baru atau yang memburuk seperti

kesulitan bernapas, napas tersengal-sengal, atau batuk dengan atau tanpa dahak, ataupun

demam.

Nyeri hebat, nyeri tekan, dan kelemahan pada otot (mialgia). Dokter Anda akan melakukan

tes darah setidaknya setiap 2 minggu untuk 1 bulan pertama dan selanjutnya jika diperlukan

selama Anda menjalani pengobatan dengan Alecensa. Segera hubungi dokter Anda jika

Anda mengalami tanda-tanda gangguan otot yang baru atau yang memburuk, seperti nyeri

otot yang tidak dapat dijelaskan atau tidak kunjung hilang, nyeri tekan, atau kelemahan.

Waspadailah hal-hal tersebut saat Anda mengonsumsi Alecensa. Lihat Efek samping pada

bagian 4 untuk informasi lebih lanjut.

Sensitivitas terhadap sinar matahari

Hindari diri Anda terhadap paparan sinar matahari dalam jangka waktu lama saat Anda

mengonsumsi Alecensa dan selama 7 hari setelah Anda berhenti. Anda perlu memakai tabir

surya dan pelembab bibir dengan Sun Protection Factor (SPF) 50 atau lebih untuk membantu

mencegah kulit Anda terbakar sinar matahari.

Penggunaan pada anak-anak dan remaja

Penggunaan Alecensa belum diteliti pada anak dan remaja. Jangan berikan obat ini pada anak

atau remaja di bawah usia 18 tahun.

Uji dan pemeriksaan

Sebelum Anda mengonsumsi Alecensa, dokter Anda akan melakukan tes darah, lalu diulang

setiap 2 minggu untuk 3 bulan pertama, dan kemudian dengan frekuensi yang lebih jarang. Hal

ini bertujuan untuk memeriksa bahwa Anda tidak mengalami gangguan hati dan otot saat

menggunakan Alecensa.

Obat-obatan lain dan Alecensa

Beri tahu dokter atau apoteker Anda jika Anda belakangan ini, sedang, atau berencana untuk

menggunakan obat lain. Ini termasuk obat-obatan yang dijual bebas dan obat herbal. Hal ini

perlu dilakukan karena Alecensa dapat memengaruhi cara kerja beberapa obat lain. Selain itu,

beberapa obat lain juga dapat memengaruhi cara kerja Alecensa.

Secara khusus, beri tahu pada dokter atau apoteker Anda jika Anda sedang mengonsumsi obat

di bawah ini:

digoksin, obat yang digunakan untuk mengatasi gangguan jantung

dabigatran eteksilat, obat yang digunakan untuk mengatasi gangguan pembekuan darah

metotreksat, obat yang digunakan untuk mengatasi beberapa jenis kanker atau penyakit

autoimun (seperti artritis reumatoid)

nilotinib, obat yang digunakan untuk mengatasi beberapa jenis kanker

lapatinib, obat yang digunakan untuk mengatasi beberapa jenis kanker payudara



Halaman 4 dari 9

mitoksantron, obat yang digunakan untuk mengatasi beberapa jenis kanker atau penyakit

autoimun (seperti sklerosis multipel)

everolimus, obat yang digunakan untuk mengatasi beberapa jenis kanker atau mencegah

sistem kekebalan tubuh menolak ginjal, jantung, atau hati yang ditransplantasi

sirolimus, obat yang digunakan untuk mencegah sistem kekebalan tubuh menolak ginjal,

jantung, atau hati yang ditransplantasi

topotecan, obat yang digunakan untuk mengatasi beberapa jenis kanker

obat-obat yang digunakan untuk mengobati HIV/AIDS (seperti ritonavir, sakuinavir)

obat-obat yang digunakan untuk mengobati infeksi. Hal ini mencakup obat-obat yang

digunakan untuk mengobati infeksi jamur (antijamur seperti ketokonazol, itrakonazol,

vorikonazol, posakonazol) dan obat-obat yang digunakan untuk mengatasi beberapa jenis

infeksi bakteri (antibiotik seperti telitromisin)

St. John’s Wort, obat herbal yang digunakan untuk mengatasi depresi

obat-obat yang digunakan untuk menghentikan kejang (antiepilepsi seperti fenitoin,

karbamazepin, atau fenobarbital)

obat-obat yang digunakan untuk mengatasi tuberkulosis (seperti rifampisin, rifabutin)

nefazodon, obat yang digunakan untuk mengobati depresi.

Kontrasepsi oral

Jika Anda menggunakan Alecensa saat menggunakan kontrasepsi oral, kontrasepsi oral Anda

dapat menjadi kurang efektif.

Alecensa dengan makanan dan minuman

Anda harus berhati-hati saat meminum jus grapefruit atau mengonsumsi grapefruit atau Seville

orange saat sedang menggunakan Alecensa karena buah-buahan tersebut dapat mengubah

kadar Alecensa yang ada dalam tubuh Anda.

Kontrasepsi, kehamilan, dan menyusui – informasi untuk wanita

Kontrasepsi – informasi untuk wanita

Anda tidak boleh hamil saat menggunakan obat ini. Jika Anda memiliki potensi untuk hamil,

Anda harus menggunakan kontrasepsi yang sangat efektif selama pengobatan dan setidaknya

selama 3 bulan setelah pengobatan berhenti. Tanyakan pada dokter Anda tentang metode

kontrasepsi yang tepat untuk Anda dan pasangan Anda. Jika Anda menggunakan Alecensa

saat menggunakan kontrasepsi oral, kontrasepsi oral Anda dapat menjadi kurang efektif.

Kehamilan

Jangan menggunakan Alecensa jika Anda sedang hamil. Hal ini dapat membahayakan janin

Anda.

Jika Anda hamil saat menggunakan obat ini atau dalam 3 bulan setelah mengonsumsi dosis

terakhir, segera hubungi Dokter Anda.



Halaman 5 dari 9

Menyusui

Jangan menyusui selama menggunakan obat ini. Belum diketahui apakah Alecensa dapat

diekskresikan melalui air susu ibu sehingga dapat membahayakan bayi Anda.

Mengemudi dan menggunakan mesin

Selama menggunakan Alecensa, berhati-hatilah saat mengemudi dan menggunakan mesin

karena Anda dapat mengalami gangguan penglihatan atau perlambatan denyut jantung atau

tekanan darah rendah yang dapat menyebabkan pingsan atau pusing.

Alecensa mengandung laktosa

Alecensa mengandung laktosa (suatu jenis gula). Jika Anda telah diberitahu oleh seorang

dokter Anda bahwa Anda tidak bisa menoleransi atau mencerna beberapa jenis gula,

sampaikan pada dokter Anda sebelum mengonsumsi obat ini.

Alecensa mengandung natrium

Dosis harian Alecensa yang direkomendasikan (1200 mg) mengandung 48 mg natrium.

Perhatikan jumlah ini jika Anda sedang menjalani diet natrium terkontrol.

3. Bagaimana cara penggunaan Alecensa

Selalu gunakan obat ini sesuai dengan instruksi dokter atau apoteker Anda. Pastikan kepada

dokter, apoteker atau perawat Anda jika Anda tidak yakin.

Jumlah Alecensa yang dikonsumsi

Dosis yang direkomendasikan adalah 4 kapsul (600 mg) dua kali sehari.

Ini berarti Anda mengonsumsi 8 kapsul (1200 mg) dalam sehari.

Terkadang dokter Anda dapat menurunkan dosis Anda, menghentikan pengobatan untuk

jangka pendek atau menghentikan pengobatan Anda sepenuhnya jika Anda merasa sakit.

Pasien dengan gangguan hati yang berat harus menerima dosis 450 mg yang diberikan

secara oral dua kali sehari (total dosis harian 900 mg)

Bagaimana cara mengonsumsi Alecensa

Alecensa dikonsumsi secara oral. Kapsul Alecensa harus ditelan secara utuh, tidak boleh

dibuka atau dilarutkan.

Anda harus mengonsumsi Alecensa bersama dengan makanan.

Bila Anda muntah setelah mengonsumsi Alecensa

Jika Anda muntah setelah mengonsumsi satu dosis Alecensa, jangan mengonsumsi dosis

tambahan, minumlah dosis selanjutnya sesuai jadwal.



Halaman 6 dari 9

Bila Anda mengonsumsi Alecensa lebih banyak daripada yang seharusnya

Jika Anda mengonsumsi Alecensa lebih banyak daripada yang seharusnya, segera hubungi

dokter atau pergi ke rumah sakit. Bawa kemasan obat dan brosur ini bersama Anda.

Bila Anda lupa mengonsumsi Alecensa

Jika terdapat waktu lebih dari 6 jam hingga dosis selanjutnya, konsumsi dosis yang

terlupakan secepatnya.

Jika kurang dari 6 jam hingga dosis selanjutnya, lewati dosis yang terlupakan, lalu

konsumsi dosis selanjutnya sesuai jadwal.

Jangan mengonsumsi obat dengan dosis ganda untuk mengganti dosis yang terlewatkan.

Bila Anda berhenti mengonsumsi Alecensa

Jangan berhenti menggunakan obat ini tanpa menghubungi dokter Anda terlebih dahulu.

Penting untuk mengonsumsi Alecensa dua kali sehari selama jangka waktu yang diresepkan

oleh dokter Anda.

Jika Anda memiliki pertanyaan tentang penggunaan obat ini, tanyakan pada dokter, apoteker

atau perawat Anda.

4. Efek samping yang mungkin terjadi

Sebagaimana halnya dengan obat-obatan lainnya, Alecensa juga dapat menyebabkan efek

samping, meskipun tidak semua pasien mengalaminya.

Beberapa efek samping dapat bersifat serius.

Segera hubungi dokter Anda jika Anda menjumpai efek samping di bawah ini.

Dokter Anda dapat menurunkan dosis Anda, menghentikan pengobatan Anda untuk jangka

pendek atau menghentikan pengobatan Anda sepenuhnya bila:

Kulit atau bagian putih mata menjadi kekuningan, nyeri pada bagian perut sebelah kanan,

urin berwarna gelap, gatal-gatal pada kulit, merasa lebih jarang lapar dibandingkan

biasanya, mual atau muntah, merasa lelah, lebih mudah berdarah dan lebam dibandingkan

keadaan normal (gejala potensial dari gangguan hati).

Gejala baru atau perburukan dari gangguan otot, termasuk nyeri otot yang tidak bisa

dijelaskan atau yang tidak kunjung hilang, nyeri tekan, atau kelemahan (gejala potensial

dari gangguan otot).

Pingsan, pusing dan tekanan darah rendah (gejala potensial dari detak jantung yang

lambat).

Gejala-gejala baru atau perburukan termasuk kesulitan bernapas, napas tersengal-sengal,

atau batuk dengan atau tanpa dahak, ataupun demam – tanda-tanda ini mungkin mirip

dengan gejala akibat kanker paru yang Anda alami (gejala potensial radang paru –

pneumonitis). Alecensa dapat menimbulkan radang paru berat atau mengancam jiwa

selama pengobatan.



Halaman 7 dari 9

Efek samping yang lain

Hubungi dokter, apoteker atau perawat Anda jika Anda menjumpai efek samping di bawah ini:

Sangat umum: dapat terjadi pada lebih dari 1 dari 10 orang

Hasil tes darah yang abnormal untuk pemeriksaan gangguan hati (kadar alanin

aminotransferase, aspartat aminotransferase, dan bilirubin yang tinggi)

Hasil yang abnormal dari tes darah untuk memeriksa kerusakan otot (kadar kreatin

fosfokinase yang tinggi)

Hasil tes darah yang abnormal untuk pemeriksaan fungi ginjal (kadar kreatinin yang

tinggi).

Anda dapat merasa lelah, lemah atau napas tersengal-sengal akibat berkurangnya jumlah

sel darah merah, yang dikenal dengan anemia.

Pandangan kabur, kebutaan, titik hitam atau titik putih dalam penglihatan Anda, dan

pandangan ganda (gangguan pada mata Anda)

Muntah – jika Anda muntah setelah mengonsumsi Alecensa, jangan mengonsumsi dosis

tambahan, konsumsi dosis selanjutnya sesuai jadwal

Konstipasi

Diare

Mual

Ruam

Sensitivitas terhadap sinar matahari - jangan paparkan diri Anda pada sinar matahari dalam

jangka waktu lama saat Anda mengonsumsi Alecensa dan selama 7 hari setelah Anda

berhenti. Anda perlu memakai tabir surya dan pelembab bibir dengan Sun Protection

Factor (SPF) 50 atau lebih untuk membantu mencegah kulit Anda terbakar sinar matahari.

Pembengkakan akibat akumulasi cairan di dalam tubuh (edema).

Peningkatan berat badan

Nyeri otot

Umum (dapat terjadi pada hingga 1 dari 10 orang):

Hasil yang abnormal dari tes darah untuk memeriksa penyakit hati atau gangguan tulang

(kadar alkalin fosfatase yang tinggi)

Pelaporan efek samping

Bila Anda mengalami efek samping, beri tahu dokter, apoteker atau perawat Anda. Ini termasuk

semua efek samping apapun yang mungkin terjadi namun tidak tercantum pada brosur ini. Anda

juga dapat melaporkan efek samping langsung melalui:

PT Roche Indonesia – Local Safety Unit

Email: [email protected]

Tel: 0-800-140-1579 (bebas pulsa)

Fax: +62-21-2253-2720


mailto:[email protected]


Halaman 8 dari 9

Pusat Farmakovigilans

c.q. Direktorat Pengawasan Keamanan, Mutu dan Ekspor Impor Obat Narkotika, Psikotropika,

Prekusor dan Zat Adiktif

Badan Pengawas Obat dan Makanan Republik Indonesia

Melalui pos: Jl. Percetakan Negara No. 23, Jakarta Pusat, 10560

Email: [email protected]

Tel: +62-21-4244755 Ext. 111; 4244691 Ext. 1072

Fax: +62-21-42883485

Website: http://e-meso.pom.go.id/

Dengan melaporkan efek samping, Anda dapat membantu memberikan lebih banyak informasi

mengenai keamanan obat ini.

5. Bagaimana cara penyimpanan Alecensa

Jauhkan obat ini dari pandangan dan jangkauan anak-anak.

Jangan menggunakan obat ini setelah melewati tanggal kedaluwarsa yang tertera pada dus

dan blister setelah tulisan EXP. Tanggal kedaluwarsa mengacu pada hari terakhir di bulan

tersebut.

Simpan obat dalam kemasan aslinya agar tidak lembab.

Jangan membuang obat apapun melalui saluran air atau tempat sampah rumah tangga.

Tanyakan kepada apoteker Anda tentang cara membuang obat yang sudah tidak Anda pakai

lagi. Hal ini akan membantu melindungi lingkungan.

6. Isi dari kemasan dan informasi lainnya

Apakah kandungan Alecensa:

Zat aktif berupa alectinib. Setiap kapsul mengandung alectinib hidroklorida yang setara

dengan alectinib 150 mg.

Komposisi lainnya adalah:

- Isi kapsul: laktosa monohidrat (lihat butir nomor 2 ‘Alecensa mengandung laktosa’),

hidroksi propil selulosa, natrium lauril sulfat (lihat butir nomor 2 ‘Alecensa

mengandung natrium’), magnesium stearat dan carboxy methyl cellulose calcium.

- Cangkang kapsul: hypromellose, karagenan, kalium klorida, titanium dioksida

(E171), pati jagung, dan carnauba wax.

- Tinta pencetak: red iron oxide (E172), yellow iron oxide (E172), indigo carmine

aluminium lake (E132), carnauba wax, white shellac dan gliseril monooleat.


mailto:[email protected]

http://e-meso.pom.go.id/


Halaman 9 dari 9

Tampilan Alecensa dan isi kemasan

Kapsul keras Alecensa berwarna putih, dengan tulisan ALE yang dicetak dengan tinta hitam

pada kepala kapsul dan tulisan 150 mg yang dicetak dengan tinta hitam pada badan kapsul.

Kapsul dikemas dalam blister dan tersedia dalam dus yang berisi:

- 224 kapsul (4 dus masing-masing berisi 56 kapsul).

- 56 kapsul (1 dus berisi 7 blister, masing-masing blister berisi 8 kapsul).

Kemasan yang terdaftar

Kapsul, 150 mg

Dus, 4 dus @ 7 blister @ 8 kapsul Reg.No: DKI1957508001A1

Dus, 7 blister @ 8 kapsul Reg.No: DKI1957508001A1

Dibuat oleh:

Excella GmbH & Co. KG, Feucht, Jerman

Untuk F. Hoffmann-La Roche Ltd., Basel, Swiss

Diimpor oleh:

PT Boehringer Ingelheim Indonesia, Bogor, Indonesia

Didistribusikan oleh:

PT Roche Indonesia, Jakarta, Indonesia

Obat: Jauhkan dari jangkauan dan penglihatan anak-anak

Harus dengan resep dokter


1. description - pompionas.pom.go.id/sites/default/files/obat_baru/alecensa...withhold alecensa and...

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