ALUNBRIG- brigatinib tablet, film coatedALUNBRIG- brigatinib kit
For Healthcare Providers >

1. Patient Information
2. Before You Take Alunbrig, Tell Your Healthcare Provider About All Of Your Medical Conditions, Including If You:
3. How Should I Take Alunbrig?
4. What Should I Avoid While Taking Alunbrig?
5. Alunbrig May Cause Serious Side Effects, Including:
6. Active Ingredient:
7. Inactive Ingredients:

Patient Information ⮝

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Interstitial Lung Disease (ILD)/Pneumonitis

Inform patients of the symptoms and risks of serious pulmonary adverse reactions such as ILD/pneumonitis. Advise patients to immediately report any new or worsening respiratory symptoms[
ALUNBRIG is a prescription medicine used to treat people with non-small cell lung cancer (NSCLC):

• that has a certain type of abnormal anaplastic lymphoma kinase (ALK) gene,and
• that has spread to other parts of your body,and
• who have taken the medicine crizotinib, but their NSCLC worsened or they cannot tolerate taking crizotinib.

It is not known if ALUNBRIG is safe and effective in children.

Before You Take Alunbrig, Tell Your Healthcare Provider About All Of Your Medical Conditions, Including If You: ⮝

• have lung or breathing problems
• have high blood pressure
• have a slow heartbeat
• have any vision problems
• have or have had pancreatitis
• have diabetes mellitus or glucose intolerance
• have liver problems
• have kidney problems or are on dialysis
• are pregnant or plan to become pregnant. ALUNBRIG can harm your unborn baby. Your healthcare provider will determine whether or not you are pregnant before you start treatment with ALUNBRIG. Tell your healthcare provider right away if you become pregnant during treatment with ALUNBRIG or think you may be pregnant.
  • Femaleswho are able to become pregnant should use effective non-hormonal birth control during treatment with ALUNBRIG and for at least 4 months after the final dose of ALUNBRIG. Birth control pills (oral contraceptives) and other hormonal forms of birth control may not be effective if used during treatment with ALUNBRIG. Talk to your healthcare provider about birth control choices that are right for you during treatment with ALUNBRIG.
  • Maleswho have female partners that are able to become pregnant should use effective birth control during treatment with ALUNBRIG and for at least 3 months after the final dose of ALUNBRIG.
• are breastfeeding or plan to breastfeed. It is not known if ALUNBRIG passes into your breast milk. Do not breastfeed during treatment with ALUNBRIG and for 1 week after the final dose of ALUNBRIG.

Tell your healthcare provider about all the medicines you take,including prescription medicines, over-the-counter medicines, vitamins, or herbal supplements.

How Should I Take Alunbrig? ⮝

• Take ALUNBRIG exactly as your healthcare provider tells you to take it. Do not change your dose or stop taking ALUNBRIG unless your healthcare provider tells you to.
• Your healthcare provider will start you on a low dose (90 mg) of ALUNBRIG for the first 7 days of treatment. If you tolerate this dose of ALUNBRIG well, your healthcare provider may increase your dose after the first 7 days of treatment.
• Your healthcare provider may change your dose, temporarily stop, or permanently stop treatment with ALUNBRIG if you develop side effects.
• Take ALUNBRIG 1 time each day.
• Take ALUNBRIG with or without food.
• Swallow ALUNBRIG tablets whole. Do not crush or chew tablets.
• If you miss a dose of ALUNBRIG, do not take the missed dose. Take your next dose at your regular time.
• If you vomit after taking a dose of ALUNBRIG, do not take an extra dose. Take your next dose at your regular time.

What Should I Avoid While Taking Alunbrig? ⮝

• Avoid eating grapefruit or drinking grapefruit juice during treatment with ALUNBRIG. Grapefruit may increase the amount of ALUNBRIG in your blood.

What are the possible side effects of ALUNBRIG?

Alunbrig May Cause Serious Side Effects, Including: ⮝

• • Store ALUNBRIG at room temperature 20 C to 25 C (68 F to 77 F).
  Keep ALUNBRIG and all medicines out of the reach of children.General information about the safe and effective use of ALUNBRIG.
  Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use ALUNBRIG for a condition for which it was not prescribed. Do not give ALUNBRIG to other people, even if they have the same symptoms you have. It may harm them.
  You can ask your healthcare provider or pharmacist for information about ALUNBRIG that is written for health professionals.

Active Ingredient: ⮝

brigatinib

Inactive Ingredients: ⮝

lactose monohydrate, microcrystalline cellulose, sodium starch glycolate (Type A), magnesium stearate, and hydrophobic colloidal silica. The tablet coating consists of talc, polyethylene glycol, polyvinyl alcohol, and titanium dioxide.
Manufactured for:Takeda Pharmaceutical Company Limited, 40 Landsdowne Street, Cambridge, MA 02139-4234. ALUNBRIGis a registered trademark of ARIAD Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. 2017-2018 ARIAD Pharmaceuticals, Inc. All rights reserved.
For more information, go to www.alunbrig.com or call 1-844-A-1POINT (1-844-217-6468).

1. Highlights Of Prescribing Information
2. Recent Major Changes
3. Indications And Usage
4. Dosage And Administration
5. Dosage Forms And Strengths
6. Contraindications
7. Warnings And Precautions
8. Adverse Reactions
9. Drug Interactions
10. Use In Specific Populations
11. 1 Indications And Usage
12. 2 Dosage And Administration
13. 3 Dosage Forms And Strengths
14. 4 Contraindications
15. 5 Warnings And Precautions
16. 6 Adverse Reactions
17. 7 Drug Interactions
18. 8 Use In Specific Populations
19. 11 Description
20. 12 Clinical Pharmacology
21. 13 Nonclinical Toxicology
22. 14 Clinical Studies
23. 16 How Supplied/storage And Handling
24. Principal Display Panel - 30 Mg Tablet Bottle Carton
25. Principal Display Panel - 90 Mg Tablet Bottle Carton
26. Principal Display Panel - 180 Mg Tablet Bottle Carton
27. Principal Display Panel - Kit Carton

Highlights Of Prescribing Information ⮝

These highlights do not include all the information needed to use ALUNBRIG safely and effectively. See full prescribing information for ALUNBRIG.

ALUNBRIG (brigatinib) tablets, for oral use
Initial U.S. Approval: 2017

Recent Major Changes ⮝

Dosage and Administration
Dosage Modifications for Strong or Moderate CYP3A Inhibitors (2.3)	12/2018
Dosage Modifications for Moderate CYP3A Inducers (2.4)	12/2018
Dosage Modifications for Patients with Severe Hepatic Impairment (2.5)	12/2018
Dosage Modifications for Patients with Severe Renal Impairment (2.6)	12/2018

Indications And Usage ⮝

ALUNBRIG is a kinase inhibitor 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. (1, 14)

Dosage And Administration ⮝

90 mg orally once daily for the first 7 days; if tolerated, increase to 180 mg orally once daily. May be taken with or without food. (2.1)

Dosage Forms And Strengths ⮝

Tablets: 180 mg, 90 mg, or 30 mg. (3)

Contraindications ⮝

None. (4)

Warnings And Precautions ⮝

• Interstitial Lung Disease (ILD)/Pneumonitis: Occurred in 9.1% of patients at the recommended dose. 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. (2.2, 5.1)
• 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. (2.2, 5.2)
• Bradycardia: Monitor heart rate and blood pressure regularly during treatment. If symptomatic, withhold ALUNBRIG, then dose reduce or permanently discontinue. (2.2, 5.3)
• Visual Disturbance: Advise patients to report visual symptoms. Withhold ALUNBRIG and obtain ophthalmologic evaluation, then dose reduce or permanently discontinue ALUNBRIG. (2.2, 5.4)
• Creatine Phosphokinase (CPK) Elevation: Monitor CPK levels regularly during treatment. Based on the severity, withhold ALUNBRIG, then resume or reduce dose. (2.2, 5.5)
• Pancreatic Enzymes Elevation: Monitor lipase and amylase levels regularly during treatment. Based on the severity, withhold ALUNBRIG, then resume or reduce dose. (2.2, 5.6)
• 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. (2.2, 5.7)
• Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use a non-hormonal method of effective contraception. (5.8, 8.1, 8.3)

Adverse Reactions ⮝

The most common adverse reactions ( 25%) with ALUNBRIG were nausea, diarrhea, fatigue, cough, and headache. (6)

To report SUSPECTED ADVERSE REACTIONS, contact Takeda Pharmaceutical Company Limited at 1-844-A-1POINT (1-844-217-6468) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Drug Interactions ⮝

• CYP3A Inhibitors: Avoid coadministration of ALUNBRIG with strong or moderate CYP3A inhibitors. If coadministration of a strong or moderate CYP3A inhibitor is unavoidable, reduce the dose of ALUNBRIG. (2.3, 7.1)
• CYP3A Inducers: Avoid coadministration of ALUNBRIG with strong or moderate CYP3A inducers. If coadministration of a moderate CYP3A inducer is unavoidable, increase the dose of ALUNBRIG. (2.4, 7.1)

Use In Specific Populations ⮝

• Hepatic Impairment: Reduce the dose of ALUNBRIG for patients with severe hepatic impairment. (2.5, 8.6)
• Renal Impairment: Reduce the dose of ALUNBRIG for patients with severe renal impairment. (2.6, 8.7)
• Lactation: Advise not to breastfeed. (8.2)

See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.

Revised: 12/2018

1 Indications And Usage ⮝

ALUNBRIG 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 [see Clinical Studies (14)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

2 Dosage And Administration ⮝

2.1 Recommended Dosage

The recommended dosage for ALUNBRIG is:

• 90 mg orally once daily for the first 7 days;
• if 90 mg is tolerated during the first 7 days, increase the dose to 180 mg orally once daily.

Administer ALUNBRIG until disease progression or unacceptable toxicity.

If ALUNBRIG is interrupted for 14 days or longer for reasons other than adverse reactions, resume treatment at 90 mg once daily for 7 days before increasing to the previously tolerated dose.

ALUNBRIG may be taken with or without food. Instruct patients to swallow tablets whole. Do not crush or chew tablets.

If a dose of ALUNBRIG is missed or vomiting occurs after taking a dose, do not administer an additional dose and take the next dose of ALUNBRIG at the scheduled time.

2.2 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
* Not applicable
90 mg once daily	60 mg once daily	permanently discontinue	N/A*
180 mg once daily	120 mg once daily	90 mg once daily	60 mg once daily

Once reduced for adverse reactions, do not subsequently increase the dosage of ALUNBRIG. Permanently discontinue ALUNBRIG if patients are unable to tolerate the 60 mg once daily dose.

Recommendations for dosage modifications of ALUNBRIG for the management of adverse reactions are provided in Table 2.

Table 2: Recommended ALUNBRIG Dosage Modifications for Adverse Reactions

Adverse Reaction	Severity*	Dosage Modifications
bpm = beats per minute; DBP = diastolic blood pressure; HR = heart rate; SBP = systolic blood pressure; ULN = upper limit of normal
* Graded per National Cancer Institute Common Terminology Criteria for Adverse Events. Version 4.0 (NCI CTCAE v4).
Interstitial Lung Disease (ILD) /Pneumonitis [see Warnings and Precautions (5.1)]	Grade 1	If new pulmonary symptoms occur during the first 7 days of treatment, withhold ALUNBRIG until recovery to baseline, then resume at same dose and do not escalate to 180 mg if ILD/pneumonitis is suspected. If new pulmonary symptoms occur after the first 7 days of treatment, withhold ALUNBRIG until recovery to baseline, then resume at same dose. If ILD/pneumonitis recurs, permanently discontinue ALUNBRIG.
	Grade 2	If new pulmonary symptoms occur during the first 7 days of treatment, withhold ALUNBRIG until recovery to baseline. Resume at next lower dose (Table 1) and do not dose escalate if ILD/pneumonitis is suspected. If new pulmonary symptoms occur after the first 7 days of treatment, withhold ALUNBRIG until recovery to baseline. If ILD/pneumonitis is suspected, resume at next lower dose (Table 1); otherwise, resume at same dose. If ILD/pneumonitis recurs, permanently discontinue ALUNBRIG.
	Grade 3 or 4	Permanently discontinue ALUNBRIG for ILD/pneumonitis.
Hypertension [see Warnings and Precautions (5.2)]	Grade 3 hypertension (SBP greater than or equal to 160 mmHg or DBP greater than or equal to 100 mmHg, medical intervention indicated, more than one antihypertensive drug, or more intensive therapy than previously used indicated)	Withhold ALUNBRIG until hypertension has recovered to Grade 1 or less (SBP less than 140 mmHg and DBP less than 90 mmHg), then resume ALUNBRIG at next lower dose (Table 1). Recurrence: withhold ALUNBRIG until recovery to Grade 1 or less, and resume at next lower dose (Table 1) or permanently discontinue treatment.
	Grade 4 hypertension (life-threatening consequences, urgent intervention indicated)	Withhold ALUNBRIG until recovery to Grade 1 or less, and resume at next lower dose (Table 1) or permanently discontinue treatment. Recurrence: permanently discontinue ALUNBRIG for recurrence of Grade 4 hypertension.
Bradycardia (HR less than 60 bpm) [see Warnings and Precautions (5.3)]	Symptomatic bradycardia	Withhold ALUNBRIG until recovery to asymptomatic bradycardia or to a resting heart rate of 60 bpm or above. If a concomitant medication known to cause bradycardia is identified and discontinued or dose-adjusted, resume ALUNBRIG at same dose upon recovery to asymptomatic bradycardia or to resting heart rate of 60 bpm or above. If no concomitant medication known to cause bradycardia is identified, or if contributing concomitant medications are not discontinued or dose-adjusted, resume ALUNBRIG at next lower dose (Table 1) upon recovery to asymptomatic bradycardia or to resting heart rate of 60 bpm or above.
	Bradycardia with life-threatening consequences, urgent intervention indicated	Permanently discontinue ALUNBRIG if no contributing concomitant medication is identified. If contributing concomitant medication is identified and discontinued or dose-adjusted, resume ALUNBRIG at next lower dose (Table 1) upon recovery to asymptomatic bradycardia or to a resting heart rate of 60 bpm or above, with frequent monitoring as clinically indicated. Recurrence: permanently discontinue ALUNBRIG.
Visual Disturbance [see Warnings and Precautions (5.4)]	Grade 2 or 3 visual disturbance	Withhold ALUNBRIG until recovery to Grade 1 or baseline, then resume at the next lower dose (Table 1).
	Grade 4 visual disturbance	Permanently discontinue ALUNBRIG.
Creatine Phosphokinase (CPK) Elevation [see Warnings and Precautions (5.5)]	Grade 3 CPK elevation (greater than 5 ULN)	Withhold ALUNBRIG until recovery to Grade 1 or less (less than or equal to 2.5 ULN) or to baseline, then resume ALUNBRIG at same dose.
	Grade 4 CPK elevation (greater than 10 ULN) or recurrence of Grade 3 elevation	Withhold ALUNBRIG until recovery to Grade 1 or less (less than or equal to 2.5 ULN) or to baseline, then resume ALUNBRIG at next lower dose (Table 1).
Lipase/Amylase Elevation [see Warnings and Precautions (5.6)]	Grade 3 lipase or amylase elevation (greater than 2 ULN)	Withhold ALUNBRIG until recovery to Grade 1 or less (less than or equal to 1.5 ULN) or to baseline, then resume ALUNBRIG at same dose.
	Grade 4 lipase or amylase elevation (greater than 5 ULN) or recurrence of Grade 3 elevation	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).
Hyperglycemia [see Warnings and Precautions (5.7)]	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 consider reduction to the next dose (Table 1) or permanently discontinue ALUNBRIG.
Other	Grade 3	Withhold ALUNBRIG until recovery to baseline, then resume at same dose. Recurrence: withhold ALUNBRIG until recovery to baseline, then resume at next lower dose or discontinue ALUNBRIG (Table 1).
	Grade 4	First occurrence: either withhold ALUNBRIG until recovery to baseline and resume at next lower dose (Table 1) or permanently discontinue. Permanently discontinue ALUNBRIG for recurrence.

2.3 Dosage Modifications for Strong or Moderate CYP3A Inhibitors

Avoid coadministration of strong or moderate CYP3A inhibitors during treatment with ALUNBRIG [see Drug Interactions (7.1), Clinical Pharmacology (12.3)]. If coadministration of a strong CYP3A inhibitor cannot be avoided, reduce the ALUNBRIG once daily dose by approximately 50% (i.e. from 180 mg to 90 mg, or from 90 mg to 60 mg). If coadministration of a moderate CYP3A inhibitor cannot be avoided, reduce the ALUNBRIG once daily dose by approximately 40% (i.e. from 180 mg to 120 mg, 120 mg to 90 mg, or from 90 mg to 60 mg). After discontinuation of a strong or moderate CYP3A inhibitor, resume the ALUNBRIG dose that was tolerated prior to initiating the CYP3A inhibitor.

2.4 Dosage Modifications for Moderate CYP3A Inducers

Avoid coadministration of moderate CYP3A inducers during treatment with ALUNBRIG [see Drug Interactions (7.1), Clinical Pharmacology (12.3)]. If coadministration of a moderate CYP3A inducer cannot be avoided, increase the ALUNBRIG once daily dose in 30 mg increments after 7 days of treatment with the current ALUNBRIG dose as tolerated, up to a maximum of twice the ALUNBRIG dose that was tolerated prior to initiating the moderate CYP3A inducer.

After discontinuation of a moderate CYP3A inducer, resume the ALUNBRIG dose that was tolerated prior to initiating the moderate CYP3A inducer.

2.5 Dosage Modifications for Patients with Severe Hepatic Impairment

Reduce the ALUNBRIG once daily dose by approximately 40% (i.e. from 180 mg to 120 mg, 120 mg to 90 mg, or from 90 mg to 60 mg) for patients with severe hepatic impairment (Child-Pugh C) [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].

2.6 Dosage Modifications for Patients with Severe Renal lmpairment

Reduce the ALUNBRIG once daily dose by approximately 50% (i.e. from 180 mg to 90 mg, or from 90 mg to 60 mg) for patients with severe renal impairment [creatinine clearance (CLcr) 15 to 29 mL/min by Cockcroft-Gault] [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)].

3 Dosage Forms And Strengths ⮝

• 180 mg: oval, white to off-white film-coated tablets with "U13" debossed on one side and plain on the other side
• 90 mg: oval, white to off-white film-coated tablets with "U7" debossed on one side and plain on the other side
• 30 mg: round, white to off-white film-coated tablets with "U3" debossed on one side and plain on the other side

4 Contraindications ⮝

None.

5 Warnings And Precautions ⮝

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 (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 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 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 [see Dosage and Administration (2.2), Adverse Reactions (6.1)].

5.2 Hypertension

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 severity, resume ALUNBRIG at a reduced dose. Consider permanent discontinuation of treatment with ALUNBRIG for Grade 4 hypertension or recurrence of Grade 3 hypertension [see Dosage and Administration (2.2), Adverse Reactions (6.1)].

Use caution when administering ALUNBRIG in combination with antihypertensive agents that cause bradycardia [see Warnings and Precautions (5.3)].

5.3 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 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 [see Warnings 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 [see Dosage and Administration (2.2)].

5.4 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 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 [see Dosage and Administration (2.2), Adverse Reactions (6.1)].

5.5 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 90 mg 180 mg group. The incidence of Grade 3-4 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. 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 [see Dosage and Administration (2.2), Adverse Reactions (6.1)].

5.6 Pancreatic Enzymes Elevation

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 [see Dosage and Administration (2.2), Adverse Reactions (6.1)].

5.7 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 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 [see Dosage and Administration (2.2), Adverse Reactions (6.1)].

5.8 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 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 [see Use in Specific Populations (8.1, 8.3), Clinical Pharmacology (12.1)].

6 Adverse Reactions ⮝

The following adverse reactions are discussed in greater detail in other sections of the prescribing information:

• Interstitial Lung Disease (ILD)/Pneumonitis [see Warnings and Precautions (5.1)]
• Hypertension [see Warnings and Precautions (5.2)]
• Bradycardia [see Warnings and Precautions (5.3)]
• Visual Disturbance [see Warnings and Precautions (5.4)]
• Creatine Phosphokinase (CPK) Elevation [see Warnings and Precautions (5.5)]
• Pancreatic Enzymes Elevation [see Warnings and Precautions (5.6)]
• Hyperglycemia [see Warnings and Precautions (5.7)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of ALUNBRIG was evaluated in 219 patients with locally advanced or metastatic ALK-positive non-small cell lung cancer (NSCLC) who received at least 1 dose of ALUNBRIG in ALTA after experiencing disease progression on crizotinib. Patients received ALUNBRIG 90 mg once daily continuously (90 mg group) or 90 mg once daily for 7 days followed by 180 mg once daily (90 180 mg group). The median duration of treatment was 7.5 months in the 90 mg group and 7.8 months in the 90 180 mg group. A total of 150 (68%) patients were exposed to ALUNBRIG for greater than or equal to 6 months and 42 (19%) patients were exposed for greater than or equal to 1 year.

The study population characteristics were: median age 54 years (range: 18 to 82), age less than 65 years (77%), female (57%), White (67%), Asian (31%), Stage IV disease (98%), NSCLC adenocarcinoma histology (97%), never or former smoker (95%), ECOG Performance Status (PS) 0 or 1 (93%), and brain metastases at baseline (69%) [see Clinical Studies (14)].

Serious adverse reactions occurred in 38% of patients in the 90 mg group and 40% of patients in the 90 180 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 90 180 mg group) and ILD/pneumonitis (4.6% overall, 1.8% in the 90 mg group and 7.3% in the 90 180 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).

In ALTA, 2.8% of patients in the 90 mg group and 8.2% of patients in the 90 180 mg group permanently discontinued ALUNBRIG for adverse reactions. The most frequent adverse reactions that led to discontinuation were ILD/pneumonitis (0.9% in the 90 mg group and 1.8% in the 90 180 mg group) and pneumonia (1.8% in the 90 180 mg group only).

In ALTA, 14% of patients required a dose reduction due to adverse reactions (7.3% in the 90 mg group and 20% in the 90 180 mg group). The most common adverse reaction that led to dose reduction was increased creatine phosphokinase for both regimens (1.8% in the 90 mg group and 4.5% in the 90 180 mg group).

Table 3 and Table 4 summarize the common adverse reactions and laboratory abnormalities observed in ALTA.

Table 3: Adverse Reactions in 10% (All Grades*) or 2% (Grades 3-4) of Patients by Dose Group in ALTA (N=219)

Adverse Reactions	90 mg once daily N = 109		90 180 mg once daily N = 110
	All Grades (%)	Grades 3-4 (%)	All Grades (%)	Grades 3-4 (%)
* Per National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 Includes abdominal distension, abdominal pain, and epigastric discomfort Includes asthenia and fatigue Includes dyspnea and exertional dyspnea Includes one Grade 5 event # Includes headache and sinus headache Includes peripheral sensory neuropathy and paresthesia Includes acneiform dermatitis, exfoliative rash, rash, pruritic rash, and pustular rash Includes musculoskeletal pain and myalgia Includes diplopia, photophobia, blurred vision, reduced visual acuity, visual impairment, vitreous floaters, visual field defect, macular edema, and vitreous detachment
Gastrointestinal Disorders
Nausea	33	0.9	40	0.9
Diarrhea	19	0	38	0
Vomiting	24	1.8	23	0
Constipation	19	0.9	15	0
Abdominal Pain	17	0	10	0
General Disorders And Administration Site Conditions
Fatigue	29	1.8	36	0
Pyrexia	14	0	6.4	0.9
Respiratory, Thoracic And Mediastinal Disorders
Cough	18	0	34	0
Dyspnea	27	2.8	21	1.8
ILD/Pneumonitis	3.7	1.8	9.1	2.7
Hypoxia	0.9	0	2.7	2.7
Nervous System Disorders
Headache#	28	0	27	0.9
Peripheral Neuropathy	13	0.9	13	1.8
Skin And Subcutaneous Tissue Disorders
Rash	15	1.8	24	3.6
Vascular Disorders
Hypertension	11	5.5	21	6.4
Musculoskeletal And Connective Tissue Disorders
Muscle Spasms	12	0	17	0
Back pain	10	1.8	15	1.8
Myalgia	9.2	0	15	0.9
Arthralgia	14	0.9	14	0
Pain in extremity	11	0	3.6	0.9
Metabolism And Nutrition Disorders
Decreased Appetite	22	0.9	15	0.9
Eye Disorders
Visual Disturbance	7.3	0	10	0.9
Infections
Pneumonia	4.6	2.8	10	5.5
Psychiatric Disorders
Insomnia	11	0	7.3	0

Table 4: Laboratory Abnormalities in 20% (All Grades*) of Patients by Regimen in ALTA (N=219)

Laboratory Abnormality	90 mg once daily N= 109		90 180 mg once daily N=110
	All Grades (%)	Grades 3-4 (%)	All Grades (%)	Grades 3-4 (%)
* Per CTCAE version 4.0 Elevated blood insulin was also observed in both regimens
Chemistry
Increased aspartate aminotransferase	38	0.9	65	0
Hyperglycemia	38	3.7	49	3.6
Increased creatine phosphokinase	27	2.8	48	12
Increased lipase	21	4.6	45	5.5
Increased alanine aminotransferase	34	0	40	2.7
Increased amylase	27	3.7	39	2.7
Increased alkaline phosphatase	15	0.9	29	0.9
Decreased phosphorous	15	1.8	23	3.6
Prolonged activated partial thromboplastin time	22	1.8	20	0.9
Hematology
Anemia	23	0.9	40	0.9
Lymphopenia	19	2.8	27	4.5

7 Drug Interactions ⮝

7.1 Effect of Other Drugs on ALUNBRIG

Strong or Moderate CYP3A Inhibitors

Coadministration of ALUNBRIG with a strong or moderate CYP3A inhibitor increased brigatinib plasma concentrations, which may increase the incidence of adverse reactions [see Clinical Pharmacology (12.3)]. Avoid coadministration of ALUNBRIG with strong or moderate CYP3A inhibitors. If coadministration of strong or moderate CYP3A inhibitors cannot be avoided, modify dose as recommended [see Dosage and Administration (2.3)].

Strong or Moderate CYP3A Inducers

Coadministration of ALUNBRIG with a strong or moderate CYP3A inducer decreased brigatinib plasma concentrations, which may decrease the efficacy of ALUNBRIG [see Clinical Pharmacology (12.3)]. Avoid coadministration of ALUNBRIG with strong or moderate CYP3A inducers. If coadministration of moderate CYP3A inducers cannot be avoided, modify dose as recommended [see Dosage and Administration (2.4)].

7.2 Effect of ALUNBRIG on Other Drugs

CYP3A Substrates

Brigatinib may decrease the concentrations of sensitive CYP3A substrates. Coadministration of ALUNBRIG with CYP3A substrates, including hormonal contraceptives, can result in decreased concentrations and loss of efficacy of sensitive CYP3A substrates [see Use in Specific Populations (8.3)].

8 Use In Specific Populations ⮝

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 [see Clinical 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 (see Data). 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.

8.2 Lactation

Risk Summary

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 for adverse reactions in breastfed infants, advise lactating women not to breastfeed during treatment with ALUNBRIG and for 1 week following the final dose.

8.3 Females and Males of Reproductive Potential

Pregnancy Testing

Verify pregnancy status in females of reproductive potential prior to initiating ALUNBRIG [see Use in Specific Populations (8.1)].

Contraception

ALUNBRIG can cause fetal harm [see Use in Specific Populations (8.1)].

Females

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. Counsel patients to use a non-hormonal method of contraception since ALUNBRIG can render some hormonal contraceptives ineffective [see Drug Interactions (7.2)].

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 [see Nonclinical Toxicology (13.1)].

Infertility

Based on findings in male reproductive organs in animals, ALUNBRIG may cause reduced fertility in males [see Nonclinical Toxicology (13.1)].

8.4 Pediatric Use

The safety and effectiveness of ALUNBRIG in pediatric patients have not been established.

8.5 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.

8.6 Hepatic Impairment

No dose adjustment is recommended for patients with mild hepatic impairment (Child-Pugh A) or moderate hepatic impairment (Child-Pugh B). Reduce the dose of ALUNBRIG for patients with severe hepatic impairment (Child-Pugh C) [see Dosage and Administration (2.5), Clinical Pharmacology (12.3)].

8.7 Renal Impairment

No dose adjustment is recommended for patients with mild or moderate renal impairment [creatinine clearance (CLcr) 30 to 89 mL/min by Cockcroft-Gault]. Reduce the dose of ALUNBRIG for patients with severe renal impairment (CLcr 15 to 29 mL/min) [see Dosage and Administration (2.6), Clinical Pharmacology (12.3)].

11 Description ⮝

Brigatinib is a kinase inhibitor. The chemical name for brigatinib is 5-chloro-N4-[2-(dimethylphosphoryl)phenyl]-N2-{2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}pyrimidine-2,4-diamine. The molecular formula is C29H39ClN7O2P which corresponds to a formula weight of 584.10 g/mol. Brigatinib has no chiral centers. The chemical structure is shown below:

Brigatinib is an off-white to beige/tan solid. The pKas were determined to be: 1.73 0.02 (base), 3.65 0.01 (base), 4.72 0.01 (base), and 8.04 0.01 (base).

ALUNBRIG is supplied for oral use as film-coated tablets containing 180 mg, 90 mg or 30 mg of brigatinib and the following inactive ingredients: lactose monohydrate, microcrystalline cellulose, sodium starch glycolate (Type A), magnesium stearate, and hydrophobic colloidal silica. The tablet coating consists of talc, polyethylene glycol, polyvinyl alcohol, and titanium dioxide.

12 Clinical Pharmacology ⮝

12.1 Mechanism of Action

Brigatinib is a tyrosine kinase inhibitor with in vitro activity at clinically achievable concentrations against multiple kinases including ALK, ROS1, insulin-like growth factor-1 receptor (IGF-1R), and FLT-3 as well as EGFR deletion and point mutations. Brigatinib inhibited autophosphorylation of ALK and ALK-mediated phosphorylation of the downstream signaling proteins STAT3, AKT, ERK1/2, and S6 in in vitro and in vivo assays. Brigatinib also inhibited the in vitro proliferation of cell lines expressing EML4-ALK and NPM-ALK fusion proteins and demonstrated dose-dependent inhibition of EML4-ALK-positive NSCLC xenograft growth in mice.

At clinically achievable concentrations ( 500 nM), brigatinib inhibited the in vitro viability of cells expressing EML4-ALK and 17 mutant forms associated with resistance to ALK inhibitors including crizotinib, as well as EGFR-Del (E746-A750), ROS1-L2026M, FLT3-F691L, and FLT3-D835Y. Brigatinib exhibited in vivo antitumor activity against 4 mutant forms of EML4-ALK, including G1202R and L1196M mutants identified in NSCLC tumors in patients who have progressed on crizotinib. Brigatinib also reduced tumor burden and prolonged survival in mice implanted intracranially with an ALK-driven tumor cell line.

12.2 Pharmacodynamics

Brigatinib exposure-response relationships and the time course of the pharmacodynamic response are unknown.

Cardiac Electrophysiology

The QT interval prolongation potential of ALUNBRIG was assessed in 123 patients following once daily ALUNBRIG doses of 30 mg (0.16 times the recommended dose of 180 mg) to 240 mg (1.3 times the recommended dose of 180 mg). ALUNBRIG did not prolong the QT interval to a clinically relevant extent.

12.3 Pharmacokinetics

The geometric mean (CV%) steady-state maximum concentration (Cmax) of brigatinib at ALUNBRIG doses of 90 mg and 180 mg once daily was 552 (65%) ng/mL and 1452 (60%) ng/mL, respectively, and the corresponding area under the concentration-time curve (AUC0-Tau) was 8165 (57%) ng h/mL and 20276 (56%) ng h/mL. After a single dose and multiple dosing of ALUNBRIG, systemic exposure of brigatinib was dose proportional over the dose range of 60 mg (0.3 times the recommended dose of 180 mg) to 240 mg (1.3 times the recommended dose of 180 mg) once daily. The mean accumulation ratio after repeat dosing was 1.9 to 2.4.

Absorption

Following administration of single oral doses of ALUNBRIG of 30 mg to 240 mg, the median time to peak concentration (Tmax) ranged from 1 to 4 hours.

Effect of Food

Brigatinib Cmax was reduced by 13% with no effect on AUC in healthy subjects administered ALUNBRIG after a high fat meal (approximately 920 calories, 58 grams carbohydrate, 59 grams fat and 40 grams protein) compared to the Cmax and AUC after overnight fasting.

Distribution

Brigatinib is 91% bound to human plasma proteins and the binding is not concentration-dependent. The blood-to-plasma concentration ratio is 0.69. Following oral administration of ALUNBRIG 180 mg once daily, the mean apparent volume of distribution (Vz/F) of brigatinib at steady-state was 153 L.

Elimination

Following oral administration of ALUNBRIG 180 mg once daily, the mean apparent oral clearance (CL/F) of brigatinib at steady-state is 12.7 L/h and the mean plasma elimination half-life is 25 hours.

Metabolism

Brigatinib is primarily metabolized by CYP2C8 and CYP3A4 in vitro. Following oral administration of a single 180 mg dose of radiolabeled brigatinib to healthy subjects, N-demethylation and cysteine conjugation were the two major metabolic pathways. Unchanged brigatinib (92%) was the major circulating radioactive component.

Excretion

Following oral administration of a single 180 mg dose of radiolabeled brigatinib to healthy subjects, 65% of the administered dose was recovered in feces and 25% of the administered dose was recovered in urine. Unchanged brigatinib represented 41% and 86% of the total radioactivity in feces and urine, respectively.

Specific Populations

Age, race, sex, body weight, and albumin concentration have no clinically meaningful effect on the pharmacokinetics of brigatinib.

Patients with Hepatic Impairment

Following a single dose of ALUNBRIG 90 mg, unbound brigatinib systemic exposure (AUC0-INF) was 37% higher in subjects with severe hepatic impairment (Child-Pugh C) compared to subjects with normal hepatic function. Unbound brigatinib systemic exposure (AUC0-INF) was similar between subjects with mild (Child-Pugh A) to moderate (Child-Pugh B) hepatic impairment and subjects with normal hepatic function [see Dosage and Administration (2.5)].

Patients with Renal Impairment

Following a single dose of ALUNBRIG 90 mg, unbound brigatinib systemic exposure (AUC0-INF) was 86% higher in subjects with severe renal impairment [creatinine clearance (CLcr) 15 to 29 mL/min] compared to subjects with normal renal function.

Based on a population pharmacokinetic analysis, brigatinib exposures were similar among 125 subjects with mild renal impairment (CLcr 60 to 89 mL/min), 34 subjects with moderate renal impairment (CLcr 30 to 59 mL/min) and 270 subjects with normal renal function (CLcr 90 mL/min) [see Dosage and Administration (2.6)].

Drug Interaction Studies

Clinical Studies

Effect of Strong and Moderate CYP3A Inhibitors on Brigatinib:

Coadministration of 200 mg twice daily doses of itraconazole (a strong CYP3A inhibitor) with a single 90 mg dose of ALUNBRIG increased brigatinib Cmax by 21% and AUC0-INF by 101%, relative to a 90 mg dose of ALUNBRIG administered alone [see Dosage and Administration (2.3), Drug Interactions (7.1)]. A moderate CYP3A inhibitor is predicted to increase the AUC of brigatinib by approximately 40%.

Effect of Strong CYP2C8 Inhibitors on Brigatinib:

Coadministration of 600 mg twice daily doses of gemfibrozil (a strong CYP2C8 inhibitor) with a single 90 mg dose of ALUNBRIG decreased brigatinib Cmax by 41% and AUC0-INF by 12%, relative to a 90 mg dose of ALUNBRIG administered alone. The effect of gemfibrozil on the pharmacokinetics of brigatinib is not clinically meaningful and the underlying mechanism for the decreased exposure of brigatinib is unknown.

Effect of Strong and Moderate CYP3A Inducers on Brigatinib:

Coadministration of 600 mg daily doses of rifampin (a strong CYP3A inducer) with a single 180 mg dose of ALUNBRIG decreased brigatinib Cmax by 60% and AUC0-INF by 80%, relative to a 180 mg dose of ALUNBRIG administered alone [see Dosage and Administration (2.4), Drug Interactions (7.1)]. A moderate CYP3A inducer is predicted to decrease the AUC of brigatinib by approximately 50%.

In Vitro Studies

Effect of Brigatinib on CYP Enzymes:

Brigatinib, at clinically relevant plasma concentrations, induced CYP3A via activation of the pregnane X receptor (PXR). Brigatinib may also induce CYP2C enzymes via the same mechanism at clinically relevant concentrations.

Brigatinib did not inhibit CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4/5 at clinically relevant concentrations.

Effect of P-glycoprotein and BCRP Inhibitors on Brigatinib:

Brigatinib is a substrate of the efflux transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Given that brigatinib exhibits high solubility and high permeability in vitro, P-gp and BCRP inhibitors are unlikely to increase plasma concentrations of brigatinib.

Effect of Other Transporters on Brigatinib:

Brigatinib is not a substrate of organic anion transporting polypeptide (OATP1B1, OATP1B3), organic anion transporter (OAT1, OAT3), organic cation transporter (OCT1, OCT2), multidrug and toxin extrusion protein (MATE1, MATE2K), or bile salt export pump (BSEP).

Effect of Brigatinib on Transporters:

Brigatinib is an inhibitor of P-gp, BCRP, OCT1, MATE1, and MATE2K in vitro. Therefore, brigatinib may have the potential to increase concentrations of coadministered substrates of these transporters. Brigatinib at clinically relevant concentrations did not inhibit OATP1B1, OATP1B3, OAT1, OAT3, OCT2 or BSEP.

13 Nonclinical Toxicology ⮝

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies have not been performed with brigatinib.

Treatment with brigatinib resulted in chromosomal damage in an in vivo mammalian erythrocyte micronucleus in the rat, but was not mutagenic in the Ames or in vitro mammalian chromosome aberration tests.

Dedicated animal fertility studies were not conducted with brigatinib. Testicular toxicity was observed in repeat-dose animal studies at doses resulting in exposure as low as 0.2 times the exposure in patients at the 180 mg dose. In rats, findings included lower weight of testes, seminal vesicles and prostate gland, and testicular tubular degeneration; these effects were not reversible during the 2 month recovery period. In monkeys, findings included reduced size of testes along with microscopic evidence of hypospermatogenesis; these effects were reversible during the recovery period.

14 Clinical Studies ⮝

The efficacy of ALUNBRIG was demonstrated in a two-arm, open-label, multicenter trial (ALTA, NCT02094573) in adult patients with locally advanced or metastatic ALK-positive non-small cell lung cancer (NSCLC) who had progressed on crizotinib. The study required patients to have a documented ALK rearrangement based on an FDA-approved test or a different test with adequate archival tissue to confirm ALK arrangement by the Vysis ALK Break-Apart fluorescence in situ hybridization (FISH) Probe Kit test. Key eligibility criteria included an ECOG Performance Status of 0-2 and progression on crizotinib. Neurologically stable patients with central nervous system (CNS) metastases were permitted to enroll. Patients with a history of interstitial lung disease or drug-related pneumonitis or who had received crizotinib within 3 days of the first dose of brigatinib were excluded. The major efficacy outcome measure was confirmed overall response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1) as evaluated by an Independent Review Committee (IRC). Additional efficacy outcome measures included Investigator-assessed ORR, duration of response (DOR), intracranial ORR, and intracranial DOR.

A total of 222 patients were randomized to receive ALUNBRIG either 90 mg once daily (90 mg arm; n=112) or 180 mg once daily following a 7-day lead-in at 90 mg once daily (90 180 mg arm; n=110). Randomization was stratified by brain metastases (present vs absent) and best prior response to crizotinib (complete or partial response vs any other response/unevaluable).

Baseline demographic characteristics of the overall study population were: median age 54 years (range 18 to 82, 23% 65 and over), 67% White and 31% Asian, 57% female, 36% ECOG PS 0 and 57% ECOG PS 1, and 95% never or former smokers. The disease characteristics of the overall study population were: Stage IV disease in 98%, adenocarcinoma histology in 97%, prior systemic chemotherapy in 74%, metastatic disease to the brain in 69% (61% had received prior radiation to the brain), bone metastases in 39%, and liver metastases in 26% of patients. Sixty-four percent of patients had an objective response to prior crizotinib.

The median duration of follow-up was 8 months (range: 0.1-20.2). Efficacy results from ALTA are summarized in Table 5.

Table 5: ALTA Efficacy Results

Efficacy Parameter	IRC Assessment		Investigator Assessment
	90 mg once daily (N=112)	90 180 mg once daily (N=110)	90 mg once daily (N=112)	90 180 mg once daily (N=110)
CI = Confidence Interval; NE = Not Estimable
Overall Response Rate (95% CI)	48% (39,58)	53% (43,62)	45% (35,54)	54% (44,63)
Complete Response, n (%)	4 (3.6%)	5 (4.5%)	1 (0.9%)	4 (3.6%)
Partial Response, n (%)	50 (45%)	53 (48%)	49 (44%)	55 (50%)
Duration of Response, median in months (95% CI)	13.8 (7.4,NE)	13.8 (9.3,NE)	13.8 (5.6,13.8)	11.1 (9.2,13.8)

IRC assessment of intracranial ORR and intracranial DOR according to RECIST v1.1 in the subgroup of 44 patients with measurable brain metastases ( 10 mm in longest diameter) at baseline are summarized in Table 6. Duration of intracranial response was measured from date of first intracranial response until intracranial disease progression (new lesions, intracranial target lesion diameter growth 20% from nadir, or unequivocal progression of intracranial nontarget lesions) or death.

Table 6: Intracranial Overall Response in Patients with Measurable Brain Metastases in ALTA

Efficacy Parameter	IRC Assessment
	90 mg once daily (N=26)	90 180 mg once daily (N=18)
CI = Confidence Interval
Intracranial Overall Response Rate, (95 % CI)	42% (23,63)	67% (41,87)
Complete Response, n (%)	2 (7.7%)	0
Partial Response, n (%)	9 (35%)	12 (67%)
Duration of Intracranial Response
Number of Responders	11	12
Intracranial Response Duration 6 months	7 (64%)	6 (50%)
Intracranial Response Duration 12 months	4 (36%)	3 (25%)

16 How Supplied/storage And Handling ⮝

180 mg tablets: oval, white to off-white film-coated tablets with "U13" debossed on one side and plain on the other side; available in:

Bottle of 23 tablets	NDC 63020-180-23
Bottle of 30 tablets	NDC 63020-180-30

90 mg tablets: oval, white to off-white film-coated tablets with "U7" debossed on one side and plain on the other side; available in:

Bottle of 7 tablets	NDC 63020-090-07
Bottle of 30 tablets	NDC 63020-090-30

30 mg tablets: round, white to off-white film-coated tablets with "U3" debossed on one side and plain on the other side; available in:

Bottle of 30 tablets

NDC 63020-113-30

90 mg / 7 count tablets (NDC 63020-090-07) and 180 mg / 23 count tablets (NDC 63020-180-23) are also available in a single carton as a one-month initiation pack:

One carton containing one bottle of 90 mg tablets (7 count) and one bottle of 180 mg tablets (23 count)

NDC 63020-198-30

Store at controlled room temperature 20 C to 25 C (68 F to 77 F); excursions permitted between 15 C to 30 C (59 F to 86 F) (see USP).

Principal Display Panel - 30 Mg Tablet Bottle Carton ⮝

NDC 63020-113-30

ALUNBRIG
(brigatinib) tablets

30 mg

Rx Only

30 Tablets

Principal Display Panel - 90 Mg Tablet Bottle Carton ⮝

NDC 63020-090-30

ALUNBRIG
(brigatinib) tablets

90 mg

Rx Only

30 Tablets

Principal Display Panel - 180 Mg Tablet Bottle Carton ⮝

NDC 63020-180-30

ALUNBRIG
(brigatinib) tablets

180 mg

Rx Only

30 Tablets

Principal Display Panel - Kit Carton ⮝

NDC 63020-198-30
INITIATION PACK

ALUNBRIG
(brigatinib) tablets

Rx Only | Oral Use

Usual Dose: One 90 mg tablet orally once daily for the first 7 days;
if tolerated, increase to one 180 mg tablet orally once daily.
See accompanying full Prescribing Information for complete details.

90 mg

7 Tablets

Take 1 tablet on
Day 1 - Day 7

180 mg

23 Tablets

Take 1 tablet on
Day 8 - Day 30

ALUNBRIG brigatinib tablet, film coated

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:63020-113 Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength brigatinib (UNII: HYW8DB273J) (brigatinib - UNII:HYW8DB273J) brigatinib 30 mg

Inactive Ingredients Ingredient Name Strength Lactose monohydrate (UNII: EWQ57Q8I5X) Microcrystalline cellulose (UNII: OP1R32D61U) SODIUM STARCH GLYCOLATE TYPE A POTATO (UNII: 5856J3G2A2) SILICON DIOXIDE (UNII: ETJ7Z6XBU4) Magnesium stearate (UNII: 70097M6I30)

Product Characteristics Color WHITE Score no score Shape ROUND Size 7mm Flavor Imprint Code U3 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:63020-113-18 180 in 1 BOTTLE; Type 0: Not a Combination Product 10/02/2017 2 NDC:63020-113-21 21 in 1 BOTTLE; Type 0: Not a Combination Product 10/02/2017 3 NDC:63020-113-30 30 in 1 BOTTLE; Type 0: Not a Combination Product 10/02/2017

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA208772 04/28/2017

ALUNBRIG brigatinib tablet, film coated

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:63020-090 Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength brigatinib (UNII: HYW8DB273J) (brigatinib - UNII:HYW8DB273J) brigatinib 90 mg

Inactive Ingredients Ingredient Name Strength Lactose monohydrate (UNII: EWQ57Q8I5X) Microcrystalline cellulose (UNII: OP1R32D61U) SODIUM STARCH GLYCOLATE TYPE A POTATO (UNII: 5856J3G2A2) SILICON DIOXIDE (UNII: ETJ7Z6XBU4) Magnesium stearate (UNII: 70097M6I30)

Product Characteristics Color WHITE Score no score Shape OVAL Size 15mm Flavor Imprint Code U7 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:63020-090-30 30 in 1 BOTTLE; Type 0: Not a Combination Product 10/02/2017 2 NDC:63020-090-07 7 in 1 BOTTLE; Type 0: Not a Combination Product 10/02/2017

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA208772 04/28/2017

ALUNBRIG brigatinib tablet, film coated

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:63020-180 Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength brigatinib (UNII: HYW8DB273J) (brigatinib - UNII:HYW8DB273J) brigatinib 180 mg

Inactive Ingredients Ingredient Name Strength Lactose monohydrate (UNII: EWQ57Q8I5X) Microcrystalline cellulose (UNII: OP1R32D61U) SODIUM STARCH GLYCOLATE TYPE A POTATO (UNII: 5856J3G2A2) SILICON DIOXIDE (UNII: ETJ7Z6XBU4) Magnesium stearate (UNII: 70097M6I30)

Product Characteristics Color WHITE Score no score Shape OVAL Size 19mm Flavor Imprint Code U13 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:63020-180-30 30 in 1 BOTTLE; Type 0: Not a Combination Product 10/02/2017

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA208772 04/28/2017

ALUNBRIG brigatinib kit

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:63020-198

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:63020-198-30 1 in 1 CARTON 10/02/2017

Quantity of Parts Part # Package Quantity Total Product Quantity Part 1 1 BOTTLE 7 Part 2 1 BOTTLE 23

Part 1 of 2 ALUNBRIG brigatinib tablet, film coated

Product Information Item Code (Source) NDC:63020-090 Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength brigatinib (UNII: HYW8DB273J) (brigatinib - UNII:HYW8DB273J) brigatinib 90 mg

Inactive Ingredients Ingredient Name Strength Lactose monohydrate (UNII: EWQ57Q8I5X) Microcrystalline cellulose (UNII: OP1R32D61U) SODIUM STARCH GLYCOLATE TYPE A POTATO (UNII: 5856J3G2A2) SILICON DIOXIDE (UNII: ETJ7Z6XBU4) Magnesium stearate (UNII: 70097M6I30)

Product Characteristics Color WHITE Score no score Shape OVAL Size 15mm Flavor Imprint Code U7 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:63020-090-07 7 in 1 BOTTLE; Type 1: Convenience Kit of Co-Package

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA208772 04/28/2017

Part 2 of 2 ALUNBRIG brigatinib tablet, film coated

Product Information Item Code (Source) NDC:63020-180 Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength brigatinib (UNII: HYW8DB273J) (brigatinib - UNII:HYW8DB273J) brigatinib 180 mg

Inactive Ingredients Ingredient Name Strength Lactose monohydrate (UNII: EWQ57Q8I5X) Microcrystalline cellulose (UNII: OP1R32D61U) SODIUM STARCH GLYCOLATE TYPE A POTATO (UNII: 5856J3G2A2) SILICON DIOXIDE (UNII: ETJ7Z6XBU4) Magnesium stearate (UNII: 70097M6I30)

Product Characteristics Color WHITE Score no score Shape OVAL Size 19mm Flavor Imprint Code U13 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:63020-180-23 23 in 1 BOTTLE; Type 1: Convenience Kit of Co-Package

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA208772 04/28/2017

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA208772 04/28/2017

Labeler - Millennium Pharmaceuticals, Inc. (804148757)

Revised: 4/2019 Document Id: 9445e6d4-c5b5-499f-9f9e-16fb635408cc 34391-3 Set id: 0fe9ff20-d402-41f3-bc1e-7002ea7007db Version: 5 Effective Time: 20190423 Millennium Pharmaceuticals, Inc.