DOSE MODIFICATIONS

Recommended Dosage 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 Coadministration of Strong or Moderate CYP3A Inhibitors During Treatment With ALUNBRIG

  • 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

Avoid Coadministration of Moderate CYP3A Inducers During Treatment With ALUNBRIG

  • 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

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).

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].

Dosage Modifications for Adverse Reactions

ADVERSE REACTION AND SEVERITYa DOSAGE 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 same 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 or 4 CPK elevation (greater than 5 X ULN) with Grade 2 or higher muscle pain or weakness
  • Withhold ALUNBRIG until recovery to ≤Grade 1 (≤2.5 X ULN) or to baseline, then resume ALUNBRIG at same dose
  • Recurrence: Withhold ALUNBRIG until recovery to ≤Grade 1 (≤2.5 X ULN) CPK elevation or to baseline, then resume ALUNBRIG at the next lower dose
Lipase/Amylase Elevation
Grade 3 of lipase or amylase elevation (>2 X ULN)
  • Withhold ALUNBRIG until recovery to ≤Grade 1 (≤1.5 X ULN) or to baseline, then resume ALUNBRIG at same dose
  • Recurrence: Withhold ALUNBRIG until recovery to ≤Grade 1 (≤1.5 X ULN) or to baseline, then resume ALUNBRIG at next lower dose
Lipase/Amylase Elevation
Grade 4 lipase or amylase elevation (>5 X ULN)
  • 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 4
  • If adequate hyperglycemic control cannot be achieved with optimal medical management, withhold ALUNBRIG until adequate hyperglycemic control is achieved and resume at the next lower 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
  • Withhold ALUNBRIG until recovery to baseline and resume at next lower dose
  • Recurrence: Permanently discontinue ALUNBRIG

aGraded per National Cancer Institute Common Terminology Criteria for Adverse Events. Version 4.0 (NCI CTCAE v4.0).

 

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

 


 

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In Vitro: ALUNBRIG Inhibited 17
ALK-Inhibitor—Resistant Mutations1,2

ALUNBRIG exhibited in vivo antitumor activity against 4 mutant forms of EML4-ALK, including the G1202R and L1196M mutants identified in NSCLC tumors in patients who had progressed on crizotinib.


 
 

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