Dosing
Dose Modifications

Recommended Dose Reductions for Adverse Reactions

• Once reduced for adverse reactions, do not subsequently increase the dose of ALUNBRIG^® (brigatinib)
• Permanently discontinue ALUNBRIG if patients are unable to tolerate the 60-mg once-daily dose
• Avoid concomitant use of strong CYP3A inhibitors during treatment with ALUNBRIG
  • If concomitant use cannot be avoided, reduce the ALUNBRIG once-daily dose by approximately 50% (ie, from 180 mg to 90 mg, or from 90 mg to 60 mg)
  • After discontinuation of a strong CYP3A inhibitor, resume the ALUNBRIG dose that was tolerated prior to initiating the strong CYP3A inhibitor

Recommended Dose Modifications for Adverse Reactions

ADVERSE REACTION AND SEVERITYa	DOSE MODIFICATION
Interstitial Lung Disease (ILD)/Pneumonitis Grade 1	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 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 discontinue ALUNBRIG
Interstitial Lung Disease (ILD)/Pneumonitis Grade 2	If new pulmonary symptoms occur during the first 7 days of treatment, withhold ALUNBRIG until recovery to baseline. Resume at next lower dose and do not dose escalate if ILD/pneumonitis is suspected 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; otherwise, resume at same dose If ILD/pneumonitis recurs, permanently discontinue ALUNBRIG
Interstitial Lung Disease (ILD)/Pneumonitis Grade 3 or 4	Permanently discontinue ALUNBRIG for ILD/pneumonitis
Hypertension Grade 3 hypertension (SBP ≥160 mmHg or DBP ≥100 mmHg, medical intervention indicated, more than one antihypertensive drug, or more intensive therapy than previously used indicated)	Withhold ALUNBRIG until hypertension has recovered to ≤ Grade 1 (SBP <140 mmHg and DBP <90 mmHg), then resume ALUNBRIG at the next lower dose Recurrence: withhold ALUNBRIG until recovery to ≤ Grade 1, and resume at next lower dose or permanently discontinue treatment
Hypertension Grade 4 hypertension (life-threatening consequences, urgent intervention indicated)	Withhold ALUNBRIG until recovery to ≤ Grade 1 and resume at next lower dose or permanently discontinue treatment Recurrence: permanently discontinue ALUNBRIG for recurrence of Grade 4 hypertension
Bradycardia (HR <60 bpm) Symptomatic bradycardia	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-adjusted, resume ALUNBRIG at same dose upon recovery to asymptomatic bradycardia or to a 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 the next lower dose level upon recovery to asymptomatic bradycardia or to a resting heart rate of 60 bpm or above
Bradycardia (HR <60 bpm) Bradycardia with life-threatening consequences, urgent intervention indicated	Permanently discontinue ALUNBRIG, if no contributing concomitant medication is identified If contributing concomitant medication is identified and discontinued or dose-adjusted, resume ALUNBRIG at next lower dose upon 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
Visual Disturbance Grade 2 or 3	Withhold ALUNBRIG until recovery to Grade 1 or baseline, then resume at the next lower dose
Visual Disturbance Grade 4	Permanently discontinue ALUNBRIG
Creatine Phosphokinase (CPK) Elevation Grade 3 elevation of CPK (>5.0 X ULN)	Withhold ALUNBRIG until recovery to ≤ Grade 1 (≤2.5 X ULN) or to baseline, then resume ALUNBRIG at same dose
Creatine Phosphokinase (CPK) Elevation Grade 4 elevation of CPK (>10.0 X ULN) OR recurrence of Grade 3 elevation	Withhold ALUNBRIG until recovery to ≤ Grade 1 (≤2.5 X ULN) or to baseline, then resume ALUNBRIG at next lower dose
Lipase/Amylase Elevation Grade 3 of lipase or amylase elevation (>2.0 X ULN)	Withhold ALUNBRIG until recovery to ≤ Grade 1 (≤1.5 X ULN) or to baseline, then resume ALUNBRIG at same dose
Lipase/Amylase Elevation Grade 4 lipase or amylase elevation (>5.0 X ULN) OR recurrence of Grade 3	Withhold ALUNBRIG until recovery to ≤ Grade 1 (≤1.5 X ULN) or to baseline, then resume ALUNBRIG at next lower dose
Hyperglycemia Grade 3 (>250 mg/dL or 13.9 mmol/L) or greater	If adequate hyperglycemic control cannot be achieved with optimal medical management, withhold ALUNBRIG until adequate hyperglycemic control is achieved and consider reduction to the next dose or permanently discontinue ALUNBRIG
Other Grade 3	Withhold ALUNBRIG until recovery to baseline, then resume at same dose Recurrence: withhold ALUNBRIG until recovery to baseline, then resume at the next lower dose or discontinue ALUNBRIG
Other Grade 4	First occurrence: either withhold ALUNBRIG until recovery to baseline and resume at the next lower dose or permanently discontinue Permanently discontinue ALUNBRIG for recurrence

bpm, beats per minute; DBP, diastolic blood pressure; HR, heart rate; SBP, systolic blood pressure; ULN, upper limit of normal.

^aPer National Cancer Institute Common Terminology Criteria for Adverse Events. Version 4.0 (NCI CTCAE v4).