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 SEVERITY^a	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.

Learn About Useful Resources for ALUNBRIG

Indication

ALUNBRIG^® (brigatinib) 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.

Important safety Information

Warnings and Precautions

Interstitial Lung Disease (ILD)/Pneumonitis
Severe, life-threatening, and fatal pulmonary adverse reactions consistent with interstitial lung disease (ILD)/pneumonitis have occurred with ALUNBRIG. In ALTA 1L, ILD/pneumonitis occurred in 5.1% of patients receiving ALUNBRIG. ILD/pneumonitis occurred within 8 days of initiation of ALUNBRIG in 2.9% of patients, with Grade 3 to 4 reactions occurring in 2.2% of patients. In ALTA, ILD/pneumonitis occurred in 3.7% of patients in the 90 mg group (90 mg once daily) and 9.1% of patients in the 90180 mg group (180 mg once daily with 7-day lead-in at 90 mg once daily). Adverse reactions consistent with possible ILD/pneumonitis occurred within 9 days of initiation of ALUNBRIG (median onset was 2 days) in 6.4% of patients, with Grade 3 to 4 reactions occurring in 2.7% of patients. Monitor for new or worsening respiratory symptoms (dyspnea, cough, etc.), particularly during the first week of initiating ALUNBRIG. Withhold ALUNBRIG in any patient with new or worsening respiratory symptoms, and promptly evaluate for ILD/pneumonitis or other causes of respiratory symptoms (e.g., pulmonary embolism, tumor progression, and infectious pneumonia). For Grade 1 or 2 ILD/pneumonitis, either resume ALUNBRIG with dose reduction according to Table 1 of the full Prescribing Information after recovery to baseline or permanently discontinue ALUNBRIG. Permanently discontinue ALUNBRIG for Grade 3 or 4 ILD/pneumonitis or recurrence of Grade 1 or 2 ILD/pneumonitis.

Hypertension
In ALTA 1L, hypertension was reported in 32% of patients receiving ALUNBRIG; 13% of patients experienced Grade 3 hypertension. In ALTA, hypertension was reported in 11% of patients in the 90 mg group and 21% of patients in the 90180 mg group. Grade 3 hypertension occurred in 5.9% of patients overall. Control blood pressure prior to treatment with ALUNBRIG. Monitor blood pressure after 2 weeks and at least monthly thereafter during treatment with ALUNBRIG. Withhold ALUNBRIG for Grade 3 hypertension despite optimal antihypertensive therapy. Upon resolution or improvement to Grade 1, resume ALUNBRIG at the same dose. Consider permanent discontinuation of treatment with ALUNBRIG for Grade 4 hypertension or recurrence of Grade 3 hypertension. Use caution when administering ALUNBRIG in combination with antihypertensive agents that cause bradycardia.

Bradycardia
In ALTA 1L, heart rates less than 50 beats per minute (bpm) occurred in 8.1% of patients receiving ALUNBRIG; one patient (0.7%) experienced Grade 3 bradycardia. In ALTA, heart rates less than 50 beats per minute (bpm) occurred in 5.7% of patients in the 90 mg group and 7.6% of patients in the 90180 mg group. One patient (0.9%) in the 90 mg group experienced Grade 2 bradycardia. Monitor heart rate and blood pressure during treatment with ALUNBRIG. Monitor patients more frequently if concomitant use of drug known to cause bradycardia cannot be avoided. For symptomatic bradycardia, withhold ALUNBRIG and review concomitant medications for those known to cause bradycardia. If a concomitant medication known to cause bradycardia is identified and discontinued or dose adjusted, resume ALUNBRIG at the same dose following resolution of symptomatic bradycardia; otherwise, reduce the dose of ALUNBRIG following resolution of symptomatic bradycardia. Discontinue ALUNBRIG for life-threatening bradycardia if no contributing concomitant medication is identified.

Visual Disturbance
In ALTA 1L, Grade 1 or 2 adverse reactions leading to visual disturbance, including blurred vision, photophobia, photopsia, and reduced visual acuity, were reported in 7.4% of patients receiving ALUNBRIG. In ALTA, adverse reactions leading to visual disturbance, including blurred vision, diplopia, and reduced visual acuity, were reported in 7.3% of patients treated with ALUNBRIG in the 90 mg group and 10% of patients in the 90180 mg group. Grade 3 macular edema and cataract occurred in one patient each in the 90180 mg group. Advise patients to report any visual symptoms. Withhold ALUNBRIG and obtain an ophthalmologic evaluation in patients with new or worsening visual symptoms of Grade 2 or greater severity. Upon recovery of Grade 2 or Grade 3 visual disturbances to Grade 1 severity or baseline, resume ALUNBRIG at a reduced dose. Permanently discontinue treatment with ALUNBRIG for Grade 4 visual disturbances.

Creatine Phosphokinase (CPK) Elevation
In ALTA 1L, creatine phosphokinase (CPK) elevation occurred in 81% of patients who received ALUNBRIG. The incidence of Grade 3 or 4 CPK elevation was 24%. Dose reduction for CPK elevation occurred in 15% of patients. In ALTA, CPK elevation occurred in 27% of patients receiving ALUNBRIG in the 90 mg group and 48% of patients in the 90180 mg group. The incidence of Grade 3 to 4 CPK elevation was 2.8% in the 90 mg group and 12% in the 90180 mg group. Dose reduction for CPK elevation occurred in 1.8% of patients in the 90 mg group and 4.5% of patients in the 90180 mg group. Advise patients to report any unexplained muscle pain, tenderness, or weakness. Monitor CPK levels during ALUNBRIG treatment. Withhold ALUNBRIG for Grade 3 or 4 CPK elevation with Grade 2 or higher muscle pain or weakness. Upon resolution or recovery to Grade 1 CPK elevation or baseline, resume ALUNBRIG at the same dose or at a reduced dose per Table 2 of the full Prescribing Information.

Pancreatic Enzyme Elevation
In ALTA 1L, amylase elevation occurred in 52% of patients and Grade 3 or 4 amylase elevation occurred in 6.8% of patients who received ALUNBRIG. Lipase elevations occurred in 59% of patients and Grade 3 or 4 lipase elevation occurred in 17% of patients. In ALTA, amylase elevation occurred in 27% of patients in the 90 mg group and 39% of patients in the 90180 mg group. Lipase elevations occurred in 21% of patients in the 90 mg group and 45% of patients in the 90180 mg group. Grade 3 or 4 amylase elevation occurred in 3.7% of patients in the 90 mg group and 2.7% of patients in the 90180 mg group. Grade 3 or 4 lipase elevation occurred in 4.6% of patients in the 90 mg group and 5.5% of patients in the 90180 mg group. Monitor lipase and amylase during treatment with ALUNBRIG. Withhold ALUNBRIG for Grade 3 or 4 pancreatic enzyme elevation. Upon resolution or recovery to Grade 1 or baseline, resume ALUNBRIG at the same dose or at a reduced dose.

Hepatotoxicity
In ALTA 1L, aspartate aminotransferase (AST) elevations occurred in 72% of patients and Grade 3 or 4 AST elevations occurred in 4.5% of patients who received ALUNBRIG. Alanine aminotransferase (ALT) elevations occurred in 52% of patients and Grade 3 or 4 ALT elevations occurred in 5.2% of patients. One patient (0.7%) had a serious adverse reaction of hepatocellular injury. In ALTA, AST elevations occurred in 38% of patients in the 90 mg group and 65% of patients in the 90180 mg group. ALT elevations occurred in 34% of patients in the 90 mg group and 40% of patients in the 90180 mg group. Grade 3 or 4 AST elevations occurred in 0.9% of patients in the 90 mg group and did not occur in any patients in the 90180 mg group. Grade 3 or 4 ALT elevations did not occur in any patients in the 90 mg group and in 2.7% of patients in the 90180 mg group. Monitor AST, ALT and total bilirubin during treatment with ALUNBRIG, especially during the first 3 months. Withhold ALUNBRIG for Grade 3 or 4 hepatic enzyme elevation with bilirubin less than or equal to 2 × ULN. Upon resolution or recovery to Grade 1 or less (less than or equal to 3 × ULN) or to baseline, resume ALUNBRIG at a next lower dose per Table 2 of the full Prescribing Information. Permanently discontinue ALUNBRIG for Grade 2 to 4 hepatic enzyme elevation with concurrent total bilirubin elevation greater than 2 times the ULN in the absence of cholestasis or hemolysis.

Hyperglycemia
In ALTA 1L, 56% of patients who received ALUNBRIG experienced new or worsening hyperglycemia. Grade 3 hyperglycemia, based on laboratory assessment of serum fasting glucose levels, occurred in 7.5% of patients. In ALTA, 43% of patients who received ALUNBRIG experienced new or worsening hyperglycemia. Grade 3 hyperglycemia, based on laboratory assessment of serum fasting glucose levels, occurred in 3.7% of patients. Two of 20 (10%) patients with diabetes or glucose intolerance at baseline required initiation of insulin while receiving ALUNBRIG. Assess fasting serum glucose prior to initiation of ALUNBRIG and monitor periodically thereafter. Initiate or optimize anti-hyperglycemic medications as needed. If adequate hyperglycemic control cannot be achieved with optimal medical management, withhold ALUNBRIG until adequate hyperglycemic control is achieved and consider reducing the dose of ALUNBRIG dosage per Table 1 of the full Prescribing Information or permanently discontinuing ALUNBRIG.

Photosensitivity
In ALTA 1L, 3.7% of patients who received ALUNBRIG experienced photosensitivity, with 0.7% of patients experiencing Grade 3 to 4 reactions. In ALTA, 0.9% of patients who received ALUNBRIG in the 90 mg group and 0.9% of patients in the 90180 mg group experienced photosensitivity. Grade 3 to 4 photosensitivity was not reported in patients in the 90 mg group or in the 90180 mg group. Advise patients to limit sun exposure while taking ALUNBRIG, and for at least 5 days after discontinuation of treatment. Advise patients, when outdoors, to wear a hat and protective clothing, and use a broad-spectrum Ultraviolet A (UVA)/ Ultraviolet B (UVB) sunscreen and lip balm (SPF ≥30) to help protect against sunburn. Based on the severity, withhold ALUNBRIG, then resume at the same dose, or reduce the dose, or permanently discontinue.

Embryo-Fetal Toxicity
Based on its mechanism of action and findings in animals, ALUNBRIG can cause fetal harm when administered to pregnant women. There are no clinical data on the use of ALUNBRIG in pregnant women. Advise women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with ALUNBRIG and for at least 4 months following the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment and for at least 3 months after the last dose of ALUNBRIG.

Adverse Reactions

The most common adverse reactions (≥25%) with ALUNBRIG were diarrhea, fatigue, nausea, rash, cough, myalgia, headache, hypertension, vomiting, and dyspnea.

DRUG INTERACTIONS

CYP3A Inhibitors: Avoid coadministration of ALUNBRIG with strong or moderate CYP3A inhibitors. If coadministration of a strong or moderate CYP3A inhibitor is unavoidable, reduce the dose of ALUNBRIG.

CYP3A Inducers: Avoid coadministration of ALUNBRIG with strong or moderate CYP3A inducers. If coadministration of a moderate CYP3A inducer is unavoidable, increase the dose of ALUNBRIG.

Use in Specific Populations

Females and Males of Reproductive Potential
Verify pregnancy status in females of reproductive potential prior to initiating ALUNBRIG. Advise females of reproductive potential to use effective contraception during treatment with ALUNBRIG and for at least 4 months after the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with ALUNBRIG and for at least 3 months after the final dose. ALUNBRIG may cause reduced fertility in males.

Lactation: Advise patients not to breastfeed.

Hepatic Impairment: Reduce the dose of ALUNBRIG for patients with severe hepatic impairment.

Renal Impairment: Reduce the dose of ALUNBRIG for patients with severe renal impairment.

To report SUSPECTED ADVERSE REACTIONS, contact Takeda Pharmaceuticals U.S.A., Inc. at 1-844-217-6468 or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Please see full Prescribing Information.

DOSE MODIFICATIONS

Recommended Dosage Reductions for Adverse Reactions

Avoid Coadministration of Strong or Moderate CYP3A Inhibitors During Treatment With ALUNBRIG

Avoid Coadministration of Moderate CYP3A Inducers During Treatment With ALUNBRIG

Dosage Modifications for Adverse Reactions

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In Vitro: ALUNBRIG Inhibited 17
ALK-Inhibitor—Resistant Mutations^1,2