Alunbrig

2 DOSAGE AND ADMINISTRATION 90 mg orally once daily for the first 7 days; then increase to 180 mg orally once daily. May be taken with or without food. ( 2.2 ) 2.1 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 (14) ] . Information on FDA-approved tests for the detection of ALK rearrangements in NSCLC is available at http://www.fda.gov/CompanionDiagnostics. 2.2 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. 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. 2.3 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 discontinue N/A Not applicable 180 mg once daily 120 mg once daily 90 mg once daily 60 mg once daily 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 Graded per National Cancer Institute Common Terminology Criteria for Adverse Events. Version 4.0 (NCI CTCAE v4). Dosage Modifications bpm = beats per minute; DBP = diastolic blood pressure; HR = heart rate; SBP = systolic blood pressure; ULN = upper limit of normal Interstitial Lung Disease (ILD) /Pneumonitis [see Warnings and Precautions (5.1 )] 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. 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 (Table 1) 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 (Table 1); otherwise, resume at same dose. If ILD/pneumonitis recurs, permanently discontinue ALUNBRIG. Grade 3 or 4 Permanently discontinue ALUNBRIG for ILD/pneumonitis. Hypertension [see Warnings and Precautions (5.2) ] Grade 3 hypertension (SBP greater than or equal to 160 mmHg or DBP greater than or equal to 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 or less (SBP less than 140 mmHg and DBP less than 90 mmHg), then resume ALUNBRIG at the same dose. Recurrence: withhold ALUNBRIG until recovery to Grade 1 or less, and resume at next lower dose (Table 1) or permanently discontinue treatment. Grade 4 hypertension (life-threatening consequences, urgent intervention indicated) Withhold ALUNBRIG until recovery to Grade 1 or less, and resume at next lower dose (Table 1) or permanently discontinue treatment. Recurrence: permanently discontinue ALUNBRIG for recurrence of Grade 4 hypertension. Bradycardia (HR less than 60 bpm) [see Warnings and Precautions (5.3) ] 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 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 or to resting heart rate of 60 bpm or above. 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 (Table 1) 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 [see Warnings and Precautions (5.4) ] Grade 2 or 3 visual disturbance Withhold ALUNBRIG until recovery to Grade 1 or baseline, then resume at the next lower dose (Table 1). Grade 4 visual disturbance Permanently discontinue ALUNBRIG. Creatine Phosphokinase (CPK) Elevation [see Warnings and Precautions (5.5) ] Grade 3 or 4 CPK elevation (greater than 5× ULN) with Grade 2 or higher muscle pain or weakness Withhold ALUNBRIG until recovery to Grade 1 or less (less than or equal to 2.5× ULN) CPK elevation or to baseline, then resume ALUNBRIG at same dose. Recurrence: Withhold ALUNBRIG until recovery to Grade 1 or less (less than or equal to 2.5× ULN) CPK elevation or to baseline, then resume ALUNBRIG at the next lower dose (Table 1). Lipase/Amylase Elevation [see Warnings and Precautions (5.6) ] Grade 3 lipase or amylase elevation (greater than 2× ULN) Withhold ALUNBRIG until recovery to Grade 1 or less (less than or equal to 1.5× ULN) or to baseline, then resume ALUNBRIG at same dose. Recurrence: Withhold ALUNBRIG until recovery to Grade 1 or less (less than or equal to 1.5× ULN) or to baseline, then resume ALUNBRIG at next lower dose (Table 1). Grade 4 lipase or amylase elevation (greater than 5× ULN) Withhold ALUNBRIG until recovery to Grade 1 or less (less than or equal to 1.5× ULN) or to baseline, then resume ALUNBRIG at next lower dose (Table 1). Hepatotoxicity (Elevation of alanine aminotransferase (ALT) or aspartate aminotransferase (AST)) [see Warnings and Precautions (5.7) ] Grade 3 or 4 elevation (greater than 5 × ULN) of either ALT or AST with bilirubin less than or equal to 2 × ULN Withhold ALUNBRIG until recovery to Grade 1 or less (less than or equal to 3× ULN) or to baseline, then resume ALUNBRIG at next lower dose (Table 1). Grade 2 to 4 elevation (greater than 3 × ULN) of ALT or AST with concurrent total bilirubin elevation greater than 2 × ULN in the absence of cholestasis or hemolysis Permanently discontinue ALUNBRIG. Hyperglycemia [see Warnings and Precautions (5.8) ] Grade 3 (greater than 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 (Table 1) 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 next lower dose or discontinue ALUNBRIG (Table 1). Grade 4 Withhold ALUNBRIG until recovery to baseline and resume at next lower dose (Table 1). Recurrence: Permanently discontinue ALUNBRIG. 2.4 Dosage Modifications for Strong or Moderate CYP3A Inhibitors Avoid coadministration of strong or moderate CYP3A inhibitors during treatment with ALUNBRIG [see Drug Interactions (7.1) , Clinical Pharmacology (12.3) ] . 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. 2.5 Dosage Modifications for Moderate CYP3A Inducers Avoid coadministration of moderate CYP3A inducers during treatment with ALUNBRIG [see Drug Interactions (7.1) , Clinical Pharmacology (12.3) ] . 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. 2.6 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 (8.6) , Clinical Pharmacology (12.3) ] . 2.7 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 (8.7) , Clinical Pharmacology (12.3) ] .

See official label

1 INDICATIONS AND USAGE ALUNBRIG is indicated for the treatment of adult patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) as detected by an FDA-approved test [see Dosage and Administration (2.1) ] .