Posology : מינונים

4.2     Posology and method of administration

Treatment with Alecensa should be initiated and supervised by a physician experienced in the use of anticancer medicinal products.


A validated ALK assay is necessary for the selection of ALK-positive NSCLC patients. ALK-positive NSCLC status should be established prior to initiation of Alecensa therapy.

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

Patients with underlying severe hepatic impairment (Child-Pugh C) should receive a starting dose of 450 mg taken twice daily with food (total daily dose of 900 mg).
Duration of treatment

Adjuvant treatment of resected NSCLC
Treatment with Alecensa should be continued until disease recurrence, unacceptable toxicity or for 2 years.

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

Delayed or missed doses
If a planned dose of Alecensa is missed, patients can make up that dose unless the next dose is due within 6 hours. Patients should not take two doses at the same time to make up for a missed dose. If vomiting occurs after taking a dose of Alecensa, patients should take the next dose at the scheduled time.

Dose adjustments
Management of adverse events may require dose reduction, temporary interruption, or discontinuation of treatment with Alecensa. The dose of Alecensa should be reduced in steps of 150 mg twice daily based on tolerability. Alecensa treatment should be permanently discontinued if patients are unable to tolerate the 300 mg twice daily dose.

Dose modification advice is provided in Tables 1 and 2 below.

Table 1 Dose reduction schedule
Dose reduction schedule                                      Dose level Dose                                                                600 mg twice daily First dose reduction                                                450 mg twice daily Second dose reduction                                               300 mg twice daily 
Table 2 Dose modification advice for specified adverse drug reactions (see sections 4.4 and 4.8) 
CTCAE grade                                          Alecensa treatment 
ILD/pneumonitis of any severity grade                Immediately interrupt and permanently discontinue Alecensa if no other potential causes of ILD/pneumonitis have been identified.

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


CTCAE grade                                         Alecensa treatment 
ALT or AST elevation of Grade ≥ 2 (> 3 times        Permanently discontinue Alecensa.
ULN) with total bilirubin elevation > 2 times
ULN in the absence of cholestasis or haemolysis
Bradycardiaa Grade 2 or Grade 3 (symptomatic,       Temporarily withhold until recovery to  Grade 1 may be severe and medically significant,            (asymptomatic) bradycardia or to a heart rate of medical intervention indicated)                     ≥ 60 bpm. Evaluate concomitant medicinal products known to cause bradycardia, as well as anti-hypertensive medicinal products.

If a contributing concomitant medicinal product is identified and discontinued, or its dose is adjusted, resume at previous dose upon recovery to  Grade 1 (asymptomatic) bradycardia or to a heart rate of ≥ 60 bpm.

If no contributing concomitant medicinal product is identified, or if contributing concomitant medicinal products are not discontinued or dose modified, resume at reduced dose (see Table 1) upon recovery to ≤ Grade 1 (asymptomatic) bradycardia or to a heart rate of ≥ 60 bpm.
Bradycardiaa Grade 4 (life-threatening              Permanently discontinue if no contributing consequences, urgent intervention indicated)        concomitant medicinal product is identified.

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

Permanently discontinue in case of recurrence.
CPK elevation > 5 times ULN                         Temporarily withhold until recovery to baseline or to ≤ 2.5 times ULN, then resume at the same dose.

CPK elevation > 10 times ULN or second              Temporarily withhold until recovery to baseline occurrence of CPK elevation of > 5 times ULN        or to ≤ 2.5 times ULN, then resume at reduced dose 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 = upper limit of normal a
Heart rate less than 60 beats per minute (bpm).

Special populations

Hepatic impairment
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) is advised, see section 4.4.

Renal impairment
No dose adjustment is required in patients with mild or moderate renal impairment. Alecensa has not been studied in patients with severe renal impairment. However, since alectinib elimination via the kidney is negligible, no dose adjustment is required in patients with severe renal impairment (see section 5.2).

Elderly (≥ 65 years)
The limited data on the safety and efficacy of Alecensa in patients aged 65 years and older do not suggest that a dose adjustment is required in elderly patients (see section 5.2). There are no available data on patients over 80 years of age.

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

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

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