Dosing
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% (ie, 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% (ie, 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% (ie, 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% (ie, 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]

Recommended 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 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 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 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 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 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 4	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).

Indication

ALUNBRIG^® (brigatinib) is indicated for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib.

This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

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 Trial ALTA (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 early (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%. Monitor for new or worsening respiratory symptoms (e.g., 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 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, hypertension was reported in 11% of patients in the 90 mg group who received ALUNBRIG 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 severity, resume ALUNBRIG at a reduced 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: Bradycardia can occur with ALUNBRIG. 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. Grade 2 bradycardia occurred in 1 (0.9%) patient in the 90 mg group. 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, 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, creatine phosphokinase (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 3‑4 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% 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. Upon resolution or recovery to Grade 1 or baseline, resume ALUNBRIG at the same dose or at a reduced dose.

Pancreatic Enzyme Elevation: 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.

Hyperglycemia: 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 or permanently discontinuing ALUNBRIG.

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 pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective non-hormonal 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

Serious adverse reactions occurred in 38% of patients in the 90 mg group and 40% of patients in the 90180 mg group. The most common serious adverse reactions were pneumonia (5.5% overall, 3.7% in the 90 mg group, and 7.3% in the 90180 mg group) and ILD/pneumonitis (4.6% overall, 1.8% in the 90 mg group and 7.3% in the 90180 mg group). Fatal adverse reactions occurred in 3.7% of patients and consisted of pneumonia (2 patients), sudden death, dyspnea, respiratory failure, pulmonary embolism, bacterial meningitis and urosepsis (1 patient each).

The most common adverse reactions (≥25%) in the 90 mg group were nausea (33%), fatigue (29%), headache (28%), and dyspnea (27%) and in the 90180 mg group were nausea (40%), diarrhea (38%), fatigue (36%), cough (34%), and headache (27%).

Drug Interactions

CYP3A Inhibitors: Avoid coadministration of ALUNBRIG with strong or moderate CYP3A inhibitors. Avoid grapefruit or grapefruit juice as it may also increase plasma concentrations of brigatinib. If coadministration of a strong or moderate CYP3A inhibitor cannot be avoided, reduce the dose of ALUNBRIG.
CYP3A Inducers: Avoid coadministration of ALUNBRIG with strong or moderate CYP3A inducers. If coadministration of moderate CYP3A inducers cannot be avoided, increase the dose of ALUNBRIG.
CYP3A Substrates: Coadministration of ALUNBRIG with sensitive CYP3A substrates, including hormonal contraceptives, can result in decreased concentrations and loss of efficacy of sensitive CYP3A substrates.

Use in Specific Populations

Pregnancy: ALUNBRIG can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus.
Lactation: There are no data regarding the secretion of brigatinib in human milk or its effects on the breastfed infant or milk production. Because of the potential adverse reactions in breastfed infants, advise lactating women not to breastfeed during treatment with ALUNBRIG.
Females and Males of Reproductive Potential:
Pregnancy Testing: Verify pregnancy status in females of reproductive potential prior to initiating ALUNBRIG.
Contraception: Advise females of reproductive potential to use effective non-hormonal 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.
Infertility: ALUNBRIG may cause reduced fertility in males.
Pediatric Use: The safety and effectiveness of ALUNBRIG in pediatric patients have not been established.
Geriatric Use: Clinical studies of ALUNBRIG did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger patients.
Hepatic or Renal Impairment: No dose adjustment is recommended for patients with mild or moderate hepatic impairment or mild or moderate renal impairment. Reduce the dose of ALUNBRIG for patients with severe hepatic impairment or severe renal impairment.

You may report side effects to the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. You may also report side effects directly to Takeda Oncology at 1-844-T1POINT (1-844-817-6468) or GlobalOncologyMedInfo@takeda.com.

Please see full Prescribing Information.

Dosing
Dose Modifications

Recommended Dosage Reductions for Adverse Reactions

Recommended Dosage Modifications for Adverse Reactions

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