Posology : מינונים

3   DOSAGE AND ADMINISTRATION

3.1 Patient Selection
Select patients for the treatment of metastatic NSCLC with ALUNBRIG based on the presence of ALK positivity in tumor specimens [see Clinical Studies (13)].

3.2 Recommended Dosage
The recommended dosage for ALUNBRIG is:
•    90 mg orally once daily for the first 7 days; then increase the dose to 180 mg orally once daily.

Administer ALUNBRIG until disease progression or unacceptable toxicity.
If ALUNBRIG is interrupted for 14 days or longer for reasons other than adverse reactions, resume treatment at 90 mg once daily for 7 days before increasing to the previously tolerated dose.
ALUNBRIG may be taken with or without food. Instruct patients to swallow tablets whole. Do not crush or chew tablets, as the tablets are film-coated.
If a dose of ALUNBRIG is missed or vomiting occurs after taking a dose, do not administer an additional dose and take the next dose of ALUNBRIG at the scheduled time.

3.3 Dosage Modifications for Adverse Reactions
ALUNBRIG dosage reductions for adverse reactions are summarized in Table 1.

Table 1: Recommended ALUNBRIG Dosage reductions
Dosage Reduction
Dosage
First                       Second                      Third
90 mg once daily           60 mg once daily           permanently                         N/A* 180 mg once daily          120 mg once daily             90 mg once daily              60 mg once daily **Not applicable

Once reduced for adverse reactions, do not subsequently increase the dosage of ALUNBRIG.
Permanently discontinue ALUNBRIG if patients are unable to tolerate the 60 mg once daily dose.
Recommendations for dosage modifications of ALUNBRIG for the management of adverse reactions are provided in Table 2.


Table 2: Recommended ALUNBRIG Dosage Modifications for Adverse Reactions 
Adverse Reaction       Severity*                     Dosage Modifications • If new pulmonary symptoms occur during the first
7 days of treatment, withhold ALUNBRIG until recovery to baseline, then resume at same dose and do not escalate to 180 mg if ILD/pneumonitis is suspected.
Grade 1
• If new pulmonary symptoms occur after the first 7 days of treatment, withhold ALUNBRIG until recovery to baseline, then resume at same dose.
• If ILD/pneumonitis recurs, permanently
Interstitial                                     discontinue ALUNBRIG.
Lung                                         • If new pulmonary symptoms occur during the first 7 Disease                                          days
(ILD)/                                           of treatment, withhold ALUNBRIG until recovery Pneumonitis                                      to baseline. Resume at next lower dose (Table [see Warnings                                    1) and do not dose escalate if ILD/pneumonitis is and                                              suspected.
Precautions
(6.1)]          Grade 2                      • If new pulmonary symptoms occur after the first 7 days of treatment, withhold ALUNBRIG until recovery to baseline. If ILD/pneumonitis is suspected, resume at next lower dose (Table 1);
otherwise, resume at same dose.
• If ILD/pneumonitis recurs, permanently discontinue ALUNBRIG.

Grade 3 or 4                 Permanently discontinue ALUNBRIG for
ILD/pneumonitis.

Grade 3 hypertension         • Withhold ALUNBRIG until hypertension has (SBP greater than or             recovered to Grade 1 or less (SBP less than 140 equal to 160 mmHg or             mmHg and DBP less than 90 mmHg), then DBP greater than or              resume ALUNBRIG at the same dose.
equal to 100 mmHg,           • Recurrence: withhold ALUNBRIG until recovery to medical intervention             Grade 1 or less, and resume at next lower dose Hypertension indicated, more than one         (Table 1) or permanently discontinue treatment.
[see Warnings   anti-hypertensive drug, or and more intensive therapy
Precautions     than previously used
(6.2)] indicated)

• Withhold ALUNBRIG until recovery to Grade 1 or less, and resume at next lower dose (Table 1) or
Grade 4 hypertension             permanently discontinue treatment.
(life- threatening consequences, urgent         • Recurrence: permanently discontinue intervention indicated)          ALUNBRIG for recurrence of Grade 4 hypertension.
                                                 • Withhold ALUNBRIG until recovery to asymptomatic bradycardia or to a resting heart rate of 60 bpm or above.
• If a concomitant medication known to cause bradycardia is identified and discontinued or dose-
Symptomatic bradycardia          adjusted, resume ALUNBRIG at same dose upon recovery to asymptomatic bradycardia or to resting heart rate of 60 bpm or above.
• If no concomitant medication known to cause bradycardia is identified, or if contributing concomitant medications are not discontinued or dose-adjusted, resume ALUNBRIG at next lower dose (Table 1) upon recovery to asymptomatic
Bradycardia (HR bradycardia or to resting heart rate of 60 bpm or less than 60 bpm) above.
[see Warnings and                                              • Permanently discontinue ALUNBRIG if no Precautions                                          contributing concomitant medication is (6.3)]                                               identified.
Bradycardia with life-       • If contributing concomitant medication is identified threatening                      and discontinued or dose-adjusted, resume consequences, urgent             ALUNBRIG at next lower dose (Table 1) upon intervention indicated           recovery to asymptomatic bradycardia or to a resting heart rate of 60 bpm or above, with frequent monitoring as clinically indicated.
• Recurrence: permanently discontinue ALUNBRIG.



Withhold ALUNBRIG until recovery to Grade 1 or
Visual              Grade 2 or 3 visual baseline, then resume at the next lower dose (Table
Disturbance         disturbance
1).
[see Warnings and
Precautions
(6.4)]              Grade 4 visual disturbance Permanently discontinue ALUNBRIG.


•   Withhold ALUNBRIG until recovery to Grade 1
Creatine                                                  or less (less than or equal to 2.5 × ULN) CPK Phosphokinase                                             elevation or to baseline, then resume (CPK) Elevation     Grade 3 or 4 CPK elevation            ALUNBRIG at same dose.
[see Warnings       (greater                          •   Recurrence: Withhold ALUNBRIG until and                 than 5 × ULN)                         recovery to Grade 1 or less (less than or Precautions                                               equal to 2.5 × ULN) CPK elevation or to (6.5)]                                                    baseline, then resume ALUNBRIG at the next lower dose (Table 1).
Grade 3 lipase or                   •   Withhold ALUNBRIG until recovery to Grade amylase elevation                       1 or less (less than or equal to 1.5 × ULN) or Lipase/Amyl
(greater than 2 x ULN)                  to baseline, then resume ALUNBRIG at ase same dose.
Elevation
[see Warnings                                            •   Recurrence: Withhold ALUNBRIG until and                                                          recovery to Grade 1 or less (less than or Precautions                                                  equal to 1.5 × ULN) or to baseline, then (6.6)]                                                       resume ALUNBRIG at next lower dose (Table 1).

Grade 4 lipase or
Withhold ALUNBRIG until recovery to Grade 1 or amylase elevation less (less than or equal to 1.5 x ULN) or to baseline,
(greater than 5 x ULN) then resume ALUNBRIG at next lower dose (Table
1).

Grade 3 or 4 elevation        Withhold ALUNBRIG until recovery to Grade 1 or (greater than 5 × ULN) of      less (less than or equal to 3x ULN) or to baseline, either ALT or AST with         then resume ALUNBRIG at next lower dose Hepatotoxicity                                       (Table 1).
bilirubin less than or equal
(Elevation of alanine to 2 × ULN aminotransferase
(ALT) or aspartate
Permanently discontinue ALUNBRIG.
aminotransferase       Grade 2 to 4 elevation
(AST))                (greater than 3 × ULN) of
ALT or AST with concurrent
[see Warnings and total bilirubin elevation
Precautions (6.7)]    greater than 2 × ULN in the absence of cholestasis or hemolysis

If adequate hyperglycemic control cannot be
Hyperglycemia        Grade 3 (greater than 250 achieved with optimal medical management,
[see Warnings        mg/dL or 13.9 mmol/L) or withhold ALUNBRIG until adequate hyperglycemic and Precautions      4 control is achieved and resume at the next lower
(6.8)] dose (Table 1) or permanently discontinue
ALUNBRIG.

• Withhold ALUNBRIG until recovery to baseline, then resume at same dose.
Grade 3                        • Recurrence: withhold ALUNBRIG until recovery to baseline, then resume at next lower dose or
Other                                                   discontinue ALUNBRIG (Table 1).

• Withhold     ALUNBRIG until recovery to baseline and resume at next lower dose
Grade 4                            (Table 1).
• Recurrence: Permanently discontinue ALUNBRIG.
 bpm = beats per minute; DBP = diastolic blood pressure; HR = heart rate; SBP = systolic blood pressure; ULN = upper limit of normal


*Graded per National Cancer Institute Common Terminology Criteria for Adverse Events. Version 4.0 (NCI CTCAE v4)

3.4 Dosage Modifications for Strong or Moderate CYP3A Inhibitors
Avoid coadministration of strong or moderate CYP3A inhibitors during treatment with ALUNBRIG [see Drug Interactions (8.1), Clinical Pharmacology (11.3)]. If coadministration of a strong CYP3A inhibitor cannot be avoided, reduce the ALUNBRIG once daily dose by approximately 50% (i.e., from 180 mg to 90 mg, or from 90 mg to 60 mg). If coadministration of a moderate CYP3A inhibitor cannot be avoided, reduce the ALUNBRIG once daily dose by approximately 40% (i.e. from 180 mg to 120 mg, 120 mg to 90 mg, or from 90 mg to 60 mg). After discontinuation of a strong or moderate CYP3A inhibitor, resume the ALUNBRIG dose that was tolerated prior to initiating the CYP3A inhibitor.

3.5 Dosage Modifications for Moderate CYP3A Inducers
Avoid coadministration of moderate CYP3A inducers during treatment with ALUNBRIG [see Drug Interactions (8.1), Clinical Pharmacology (11.3)]. If coadministration of a moderate CYP3A inducer cannot be avoided, increase the ALUNBRIG once daily dose in 30 mg increments after 7 days of treatment with the current ALUNBRIG dose as tolerated, up to a maximum of twice the ALUNBRIG dose that was tolerated prior to initiating the moderate CYP3A inducer.

After discontinuation of a moderate CYP3A inducer, resume the ALUNBRIG dose that was tolerated prior to initiating the moderate CYP3A inducer.

3.6 Dosage Modifications for Patients with Severe Hepatic Impairment
Reduce the ALUNBRIG once daily dose by approximately 40% (i.e. from 180 mg to 120 mg, 120 mg to 90 mg, or from 90 mg to 60 mg) for patients with severe hepatic impairment (Child-Pugh C) [see Use in Specific Populations (9.6), Clinical Pharmacology (11.3)].

3.7 Dosage Modifications for Patients with Severe Renal Impairment
Reduce the ALUNBRIG once daily dose by approximately 50% (i.e. from 180 mg to 90 mg, or from 90 mg to 60 mg) for patients with severe renal impairment [creatinine clearance (CLcr) 15 to 29 mL/min by Cockcroft-Gault] [see Use in Specific Populations (9.7), Clinical Pharmacology (11.3)].

4   DOSAGE FORMS AND STRENGTHS
•   30 mg, round, white to off-white film-coated tablets with “U3” debossed on one side and plain on the other side
•   90 mg, oval, white to off-white film-coated tablets with “U7” debossed on one side and plain on the other side