Interstitial Lung Disease (ILD)/Pneumonitis

: Monitor for new or worsening respiratory symptoms, particularly during the first week of treatment. Withhold ALUNBRIG for new or worsening respiratory symptoms and promptly evaluate for ILD/pneumonitis. Upon recovery, either dose reduce or permanently discontinue ALUNBRIG. (

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/ANot 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	SeverityGraded 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 [seeWarnings 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 [seeWarnings 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.
Hypertension [seeWarnings and Precautions (5.2)]	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) [seeWarnings 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 [seeWarnings 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).
Visual Disturbance [seeWarnings and Precautions (5.4)]	Grade 4 visual disturbance	Permanently discontinue ALUNBRIG.
Creatine Phosphokinase (CPK) Elevation [seeWarnings 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 [seeWarnings 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)) [seeWarnings 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 [seeWarnings 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).
Other	Grade 4	Withhold ALUNBRIG until recovery to baseline and resume at next lower dose (Table 1). Recurrence: Permanently discontinue ALUNBRIG.

5.1 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 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 Trial 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 90→180 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%.

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 according to Table 1 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

[seeDosage and Administration (2.3),Adverse Reactions (6.1)]

)

Hypertension

: Monitor blood pressure after 2 weeks and then at least monthly during treatment. For severe hypertension, withhold ALUNBRIG, then dose reduce or permanently discontinue. (

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/ANot 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	SeverityGraded 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 [seeWarnings 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 [seeWarnings 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.
Hypertension [seeWarnings and Precautions (5.2)]	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) [seeWarnings 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 [seeWarnings 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).
Visual Disturbance [seeWarnings and Precautions (5.4)]	Grade 4 visual disturbance	Permanently discontinue ALUNBRIG.
Creatine Phosphokinase (CPK) Elevation [seeWarnings 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 [seeWarnings 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)) [seeWarnings 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 [seeWarnings 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).
Other	Grade 4	Withhold ALUNBRIG until recovery to baseline and resume at next lower dose (Table 1). Recurrence: Permanently discontinue ALUNBRIG.

5.2 Hypertension

In ALTA 1L, hypertension was reported in 32% of patients receiving ALUNBRIG; Grade 3 hypertension occurred in 13% of patients.

In ALTA, hypertension was reported in 11% of patients in the 90 mg group who received ALUNBRIG and 21% of patients in the 90→180 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

[seeDosage and Administration (2.3),Adverse Reactions (6.1)]

Use caution when administering ALUNBRIG in combination with antihypertensive agents that cause bradycardia

[seeWarnings and Precautions (5.3)]

)

Bradycardia

: Monitor heart rate and blood pressure regularly during treatment. If symptomatic, withhold ALUNBRIG, then dose reduce or permanently discontinue. (

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/ANot 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	SeverityGraded 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 [seeWarnings 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 [seeWarnings 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.
Hypertension [seeWarnings and Precautions (5.2)]	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) [seeWarnings 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 [seeWarnings 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).
Visual Disturbance [seeWarnings and Precautions (5.4)]	Grade 4 visual disturbance	Permanently discontinue ALUNBRIG.
Creatine Phosphokinase (CPK) Elevation [seeWarnings 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 [seeWarnings 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)) [seeWarnings 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 [seeWarnings 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).
Other	Grade 4	Withhold ALUNBRIG until recovery to baseline and resume at next lower dose (Table 1). Recurrence: Permanently discontinue ALUNBRIG.

5.3 Bradycardia

In ALTA 1L, heart rates less than 50 beats per minute (bpm) occurred in 8.1% of patients receiving ALUNBRIG. Grade 3 bradycardia occurred in 1 patient (0.7%).

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 90→180 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

[seeWarnings and Precautions (5.2)]

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

[seeDosage and Administration (2.3)]

)

Visual Disturbance

: Advise patients to report visual symptoms. Withhold ALUNBRIG and obtain ophthalmologic evaluation, then dose reduce or permanently discontinue ALUNBRIG. (

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/ANot 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	SeverityGraded 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 [seeWarnings 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 [seeWarnings 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.
Hypertension [seeWarnings and Precautions (5.2)]	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) [seeWarnings 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 [seeWarnings 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).
Visual Disturbance [seeWarnings and Precautions (5.4)]	Grade 4 visual disturbance	Permanently discontinue ALUNBRIG.
Creatine Phosphokinase (CPK) Elevation [seeWarnings 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 [seeWarnings 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)) [seeWarnings 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 [seeWarnings 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).
Other	Grade 4	Withhold ALUNBRIG until recovery to baseline and resume at next lower dose (Table 1). Recurrence: Permanently discontinue ALUNBRIG.

5.4 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 receiving ALUNBRIG in the 90 mg group and 10% of patients in the 90→180 mg group. Grade 3 macular edema and cataract occurred in 1 patient each in the 90→180 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

[seeDosage and Administration (2.3),Adverse Reactions (6.1)]

)

Creatine Phosphokinase (CPK) Elevation

: Monitor CPK levels regularly during treatment. Based on the severity and with muscle pain or weakness, withhold ALUNBRIG, then resume or reduce dose. (

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/ANot 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	SeverityGraded 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 [seeWarnings 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 [seeWarnings 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.
Hypertension [seeWarnings and Precautions (5.2)]	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) [seeWarnings 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 [seeWarnings 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).
Visual Disturbance [seeWarnings and Precautions (5.4)]	Grade 4 visual disturbance	Permanently discontinue ALUNBRIG.
Creatine Phosphokinase (CPK) Elevation [seeWarnings 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 [seeWarnings 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)) [seeWarnings 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 [seeWarnings 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).
Other	Grade 4	Withhold ALUNBRIG until recovery to baseline and resume at next lower dose (Table 1). Recurrence: Permanently discontinue ALUNBRIG.

5.5 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 90 mg→180 mg group. The incidence of Grade 3 to 4 CPK elevation was 2.8% in the 90 mg group and 12% in the 90→180 mg group.

Dose reduction for CPK elevation occurred in 1.8% of patients in the 90 mg group and 4.5% in the 90→180 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 as described in Table 2

[seeDosage and Administration (2.3),Adverse Reactions (6.1)]

)

Pancreatic Enzymes Elevation

: Monitor lipase and amylase levels regularly during treatment. Based on the severity, withhold ALUNBRIG, then resume or reduce dose. (

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/ANot 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	SeverityGraded 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 [seeWarnings 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 [seeWarnings 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.
Hypertension [seeWarnings and Precautions (5.2)]	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) [seeWarnings 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 [seeWarnings 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).
Visual Disturbance [seeWarnings and Precautions (5.4)]	Grade 4 visual disturbance	Permanently discontinue ALUNBRIG.
Creatine Phosphokinase (CPK) Elevation [seeWarnings 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 [seeWarnings 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)) [seeWarnings 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 [seeWarnings 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).
Other	Grade 4	Withhold ALUNBRIG until recovery to baseline and resume at next lower dose (Table 1). Recurrence: Permanently discontinue ALUNBRIG.

5.6 Pancreatic Enzymes Elevation

In ALTA 1L, amylase elevation occurred in 52% of patients and Grade 3 or 4 amylase elevation occurred in 6.8% of patients. 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 90→180 mg group. Lipase elevations occurred in 21% of patients in the 90 mg group and 45% of patients in the 90→180 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 90→180 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 90→180 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 as described in Table 2

[seeDosage and Administration (2.3),Adverse Reactions (6.1)]

)

Hepatotoxicity

: Monitor alanine aminotransferase (ALT), aspartate aminotransferase (AST) and total bilirubin levels regularly during treatment. Based on severity, withhold dose, then resume at lower level. (

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/ANot 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	SeverityGraded 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 [seeWarnings 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 [seeWarnings 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.
Hypertension [seeWarnings and Precautions (5.2)]	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) [seeWarnings 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 [seeWarnings 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).
Visual Disturbance [seeWarnings and Precautions (5.4)]	Grade 4 visual disturbance	Permanently discontinue ALUNBRIG.
Creatine Phosphokinase (CPK) Elevation [seeWarnings 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 [seeWarnings 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)) [seeWarnings 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 [seeWarnings 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).
Other	Grade 4	Withhold ALUNBRIG until recovery to baseline and resume at next lower dose (Table 1). Recurrence: Permanently discontinue ALUNBRIG.

5.7 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. 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 90→180 mg group. ALT elevations occurred in 34% of patients in the 90 mg group and 40% of patients in the 90→180 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 90→180 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 90→180 mg group.

Monitor AST, ALT and total bilirubin during treatment with ALUNBRIG, especially during 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 as described in Table 2. 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

[seeDosage and Administration (2.3),Adverse Reactions (6.1)]

)

Hyperglycemia

: Assess fasting serum glucose prior to starting ALUNBRIG and regularly during treatment. If not adequately controlled with optimal medical management, withhold ALUNBRIG, then consider dose reduction or permanently discontinue, based on severity. (

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/ANot 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	SeverityGraded 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 [seeWarnings 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 [seeWarnings 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.
Hypertension [seeWarnings and Precautions (5.2)]	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) [seeWarnings 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 [seeWarnings 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).
Visual Disturbance [seeWarnings and Precautions (5.4)]	Grade 4 visual disturbance	Permanently discontinue ALUNBRIG.
Creatine Phosphokinase (CPK) Elevation [seeWarnings 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 [seeWarnings 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)) [seeWarnings 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 [seeWarnings 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).
Other	Grade 4	Withhold ALUNBRIG until recovery to baseline and resume at next lower dose (Table 1). Recurrence: Permanently discontinue ALUNBRIG.

5.8 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 antihyperglycemic 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 as described in Table 1 or permanently discontinuing ALUNBRIG

[seeDosage and Administration (2.3),Adverse Reactions (6.1)]

)

Photosensitivity

: Advise patients to limit sun exposure. Based on severity withhold ALUNBRIG, then resume at the same dose, reduce the dose, or permanently discontinue. (

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/ANot 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	SeverityGraded 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 [seeWarnings 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 [seeWarnings 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.
Hypertension [seeWarnings and Precautions (5.2)]	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) [seeWarnings 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 [seeWarnings 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).
Visual Disturbance [seeWarnings and Precautions (5.4)]	Grade 4 visual disturbance	Permanently discontinue ALUNBRIG.
Creatine Phosphokinase (CPK) Elevation [seeWarnings 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 [seeWarnings 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)) [seeWarnings 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 [seeWarnings 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).
Other	Grade 4	Withhold ALUNBRIG until recovery to baseline and resume at next lower dose (Table 1). Recurrence: Permanently discontinue ALUNBRIG.

5.9 Photosensitivity

In ALTA 1L, photosensitivity occurred in 3.7% of patients who received ALUNBRIG, with 0.7% Grade 3 to 4.

In ALTA, 0.9% of patients who received ALUNBRIG in the 90 mg group experienced photosensitivity and 0.9% of patients in the 90 mg→180 mg group. Grade 3 to 4 photosensitivity was not reported in patients in the 90 mg group or in the 90→180 mg group.

Advise patients to limit sun exposure while taking brigatinib, 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 as described in Table 2

[seeDosage and Administration (2.3),Adverse Reactions (6.1)]

)

Embryo-Fetal Toxicity
: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception. (
5.10 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. Administration of brigatinib to pregnant rats during the period of organogenesis resulted in dose-related skeletal anomalies at doses as low as 12.5 mg/kg/day (approximately 0.7 times the human exposure by AUC at 180 mg once daily), as well as increased post-implantation loss, malformations, and decreased fetal body weight at doses of 25 mg/kg/day (approximately 1.26 times the human exposure at 180 mg once daily) or higher.
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
[seeUse in Specific Populations (8.1,8.3),Clinical Pharmacology (12.1)]
.
,
8.1 Pregnancy
Risk Summary
Based on its mechanism of action and findings in animals, ALUNBRIG can cause fetal harm when administered to a pregnant woman
[seeClinical Pharmacology (12.1)]
. There are no clinical data on the use of ALUNBRIG in pregnant women. Administration of brigatinib to pregnant rats during the period of organogenesis resulted in dose-related skeletal anomalies at doses as low as 12.5 mg/kg/day (approximately 0.7 times the human exposure by AUC at 180 mg once daily) as well as increased post-implantation loss, malformations, and decreased fetal body weight at doses of 25 mg/kg/day (approximately 1.26 times the human exposure at 180 mg once daily) or greater
(seeData)
. Advise pregnant women of the potential risk to a fetus.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Data
Animal Data
In an embryo-fetal development study in which pregnant rats were administered daily doses of brigatinib during organogenesis, dose-related skeletal (incomplete ossification, small incisors) and visceral anomalies were observed at doses as low as 12.5 mg/kg/day (approximately 0.7 times the human exposure by AUC at 180 mg once daily). Malformations observed at 25 mg/kg/day (approximately 1.26 times the human AUC at 180 mg once daily) included anasarca (generalized subcutaneous edema), anophthalmia (absent eyes), forelimb hyperflexion, small, short and/or bent limbs, multiple fused ribs, bent scapulae, omphalocele (intestine protruding into umbilicus), and gastroschisis (intestines protruding through a defect in the abdominal wall) along with visceral findings of moderate bilateral dilatation of the lateral ventricles.
,
8.3 Females and Males of Reproductive Potential
Pregnancy Testing
Verify pregnancy status in females of reproductive potential prior to initiating ALUNBRIG
[seeUse in Specific Populations (8.1)]
.
Contraception
ALUNBRIG can cause fetal harm
[seeUse in Specific Populations (8.1)]
.
Females
Advise females of reproductive potential to use effective contraception during treatment with ALUNBRIG and for at least 4 months after the final dose.
Males
Because of the potential for genotoxicity, 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
[seeNonclinical Toxicology (13.1)]
.
Infertility
Based on findings in male reproductive organs in animals, ALUNBRIG may cause reduced fertility in males
[seeNonclinical Toxicology (13.1)]
.
)

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