ADVERSE REACTIONS SECTION.

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)] Photosensitivity [see Warnings and Precautions (5.8)] 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)] Photosensitivity [see Warnings and Precautions (5.8)] The most common adverse reactions (>=25%) with ALUNBRIG were diarrhea, fatigue, nausea, rash, cough, myalgia, headache, hypertension, vomiting, and dyspnea. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Takeda Pharmaceuticals at 1-844-217-6468 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.. Advanced ALK-positive NSCLC Without Prior ALK-targeted TherapyIn ALTA 1L, the safety of ALUNBRIG was evaluated in 136 patients with advanced ALK-positive NSCLC who had not previously received an ALK-targeted therapy [see Clinical Studies (14)]. The median duration of treatment with ALUNBRIG when administered as 90 mg orally once daily for the first days; then increased to 180 mg orally once daily, was 24.3 months. total of 106 (78%) patients were exposed to ALUNBRIG for greater than or equal to months including 92 (68%) patients exposed for greater than or equal to year. The median relative dose intensity was 97% for ALUNBRIG.The study population (N 275) characteristics were: median age 59 years (range: 27 to 89), age less than 65 years (68%), female (55%), White (59%), Asian (39%), Stage IV disease (93%), NSCLC adenocarcinoma histology (96%), never smoker (58%), ECOG Performance Status (PS) or (95%), and CNS metastases at baseline (30%) [see Clinical Studies (14)].Serious adverse reactions occurred in 33% of patients receiving ALUNBRIG. The most common serious adverse reactions were pneumonia (4.4%), ILD/pneumonitis (3.7%), pyrexia (2.9%), dyspnea (2.2%), pulmonary embolism (2.2%), and asthenia (2.2%). Fatal adverse reactions occurred in 2.9% of patients and included pneumonia (1.5%), cerebrovascular accident (0.7%), and multiple organ dysfunction syndrome (0.7%).In ALTA 1L, 13% of patients receiving ALUNBRIG permanently discontinued ALUNBRIG for adverse reactions. The most frequent adverse reactions that led to discontinuation were ILD/pneumonitis (3.7%) and pneumonia (2.2%).In ALTA 1L, 38% of patients required dose reduction due to adverse reactions. The most common adverse reaction that led to dose reduction was increased creatine phosphokinase (15%), increased lipase (6.6%), increased amylase (4.4%), increased aspartate aminotransferase (2.2%), ILD/pneumonitis (2.2%) and hypertension (2.2%).Table and Table summarize the common adverse reactions and laboratory abnormalities observed in ALTA 1L.Table 3: Adverse Reactions in >=10% (All GradesPer National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.03) or >=2% (Grades 3-4) of Patients by Arm in ALTA 1L (N 273)Adverse ReactionsALUNBRIGN 136CrizotinibN 137All Grades (%)Grades 3-4 (%)All Grades (%)Grades 3-4(%)Gastrointestinal Disorders Diarrhea532.2572.9 Nausea302.2582.9 Abdominal painIncludes abdominal discomfort, abdominal distension, abdominal pain, abdominal pain lower, abdominal pain upper, and epigastric discomfort 240.7333.6 Vomiting210.7442.2 Constipation180420 StomatitisIncludes aphthous ulcer, mouth ulceration, oral mucosal blistering and stomatitis 130.78.80 Dyspepsia80160.7 Gastroesophageal reflux disease0.70110Skin and Subcutaneous Tissue Disorders RashIncludes dermatitis, dermatitis acneiform, dermatitis bullous, dermatitis contact, drug eruption, erythema, palmar-plantar erythrodysesthesia syndrome, rash, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pruritic, rash pustular, toxic skin eruption, urticaria 402.9170 PruritusIncluded pruritus, allergic pruritus, and generalized pruritus 200.75.80.7Respiratory, Thoracic and Mediastinal Disorders Cough350200 DyspneaInclude dyspnea and exertional dyspnea 252.922Includes Grade events 3.6 ILD/Pneumonitis5.12.92.20.7 Pulmonary embolism2.22.25.8 2.9Vascular Disorders Hypertension Includes hypertension and systolic hypertension 321382.9General Disorders and Administration Site Conditions FatigueIncludes asthenia and fatigue 321.5402.2 EdemaIncludes angioedema, eye swelling, eyelid edema, face edema, generalized edema, lip swelling, peripheral edema, periorbital edema, peripheral swelling, skin swelling, swelling and swelling face 180.7480.7 Pyrexia150.7150Musculoskeletal and Connective Tissue Disorders MyalgiaIncludes muscle spasms, muscle twitching, musculoskeletal discomfort, musculoskeletal pain, and myalgia 280230 Back pain210.7171.5 Arthralgia140120 Pain in extremity5.10150.7Nervous System Disorders HeadacheIncludes headache and migraine 222.2170 Dizziness150.7200.7 Peripheral neuropathyIncludes burning sensation, dysesthesia, hyperesthesia, hypoesthesia, neuralgia, peripheral neuropathy, paraesthesia, peripheral sensory neuropathy and polyneuropathy 110.7180 Dysgeusia2.90140Investigations Increased Blood cholesterolIncludes blood cholesterol increased, hypercholesterolaemia 1300.70Cardiac Disorders BradycardiaIncludes bradycardia, heart rate decreased, sinus bradycardia 120.7230Infections and Infestations PneumoniaIncludes lower respiratory tract infection, lung infection, pneumonia, aspiration pneumonia, and cryptococcal pneumonia 15 5.16.6 2.9 Upper respiratory tract infectionIncludes upper respiratory tract infection and viral upper respiratory tract infection 120100 Nasopharyngitis80110 Urinary tract infection5.90.78.82.2Metabolism and Nutrition Disorders Decreased Appetite8.80.7192.9Eye Disorders Visual DisturbanceIncludes cataract, glaucoma, hypermetropia, night blindness, papilloedema, photophobia, photopsia, blurred vision, reduced visual acuity, visual field defect, visual impairment, and vitreous floaters 7.40530.7Table 4: Laboratory Abnormalities in >=20% (All GradesPer CTCAE version 4.03) of Patients by Arm in ALTA 1L (N 273)Laboratory AbnormalityALUNBRIGN 136Denominator for each laboratory parameter may vary and is defined as the number of patients who had both, baseline and post-baseline test CrizotinibN 137 All Grades (%)Grades 3-4(%)All Grades (%)Grades 3-4 (%)Chemistry Increased creatine phosphokinase8124684.8 Increased aspartate aminotransferase724.5705.2 Increased lipase5917369.8 HyperglycemiaElevated blood insulin was also observed in both arms 567.5373.7 Increased alanine aminotransferase525.27713 Increased amylase526.8253 Decreased phosphorous413.7396 Increased alkaline phosphatase363491.5 Increased creatinine250330 Potassium increased241.5313.7 Increased calcium2201.50 Decreased magnesium2106.90 Decreased albumin150.8523.7 Decreased calcium150671.5Hematology Hemoglobin decreased412.3361.5 Lymphocyte count decreased429.3305.4 Neutrophil count decreased120346.8Clinically relevant adverse reactions in patients who received ALUNBRIG included photosensitivity (3.7%).. ALK-positive Advanced or Metastatic NSCLC Previously Treated with CrizotinibThe safety of ALUNBRIG was evaluated in 219 patients with locally advanced or metastatic ALK-positive NSCLC who received at least 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 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. total of 150 (68%) patients were exposed to ALUNBRIG for greater than or equal to months and 42 (19%) patients were exposed for greater than or equal to year.The study population (N 222) 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) or (93%), and CNS 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 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 and Table summarize the common adverse reactions and laboratory abnormalities observed in ALTA.Table 5: Adverse Reactions in >=10% (All GradesPer National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0) or >=2% (Grades 3-4) of Patients by Dose Group in ALTA (N 219)Adverse Reactions90 mg once dailyN 10990->180 mg once dailyN 110All Grades(%)Grades 3-4(%)All Grades (%)Grades 3-4 (%)Gastrointestinal Disorders Nausea330.9400.9 Diarrhea190380 Vomiting241.8230 Constipation190.9150 Abdominal PainIncludes abdominal distension, abdominal pain, and epigastric discomfort 170100General Disorders and Administration Site Conditions FatigueIncludes asthenia and fatigue 291.8360 Pyrexia1406.40.9Respiratory, Thoracic and Mediastinal Disorders Cough180340 DyspneaIncludes dyspnea and exertional dyspnea 272.8211.8Includes one Grade event ILD/Pneumonitis3.71.89.12.7 Hypoxia0.902.72.7Nervous System Disorders HeadacheIncludes headache and sinus headache 280270.9 Peripheral NeuropathyIncludes peripheral sensory neuropathy and paresthesia 130.9131.8Skin and Subcutaneous Tissue Disorders RashIncludes acneiform dermatitis, exfoliative rash, rash, pruritic rash, and pustular rash 151.8243.6Vascular Disorders Hypertension115.5216.4Musculoskeletal and Connective Tissue Disorders Muscle Spasms120170 Back pain101.8151.8 MyalgiaIncludes musculoskeletal pain and myalgia 9.20150.9 Arthralgia140.9140 Pain in extremity1103.60.9Metabolism and Nutrition Disorders Decreased Appetite220.9150.9Eye Disorders Visual DisturbanceIncludes diplopia, photophobia, blurred vision, reduced visual acuity, visual impairment, vitreous floaters, visual field defect, macular edema, and vitreous detachment 7.30100.9Infections Pneumonia4.62.8 105.5 Psychiatric Disorders Insomnia1107.30Table 6: Laboratory Abnormalities in >=20% (All GradesPer CTCAE version 4.0) of Patients by Regimen in ALTA (N 219)Laboratory Abnormality90 mg once dailyN 10990->180 mg once dailyN 110All Grades(%)Grades 3-4(%)All Grades(%)Grades 3-4(%)Chemistry Increased aspartate aminotransferase380.9650 HyperglycemiaElevated blood insulin was observed in both regimens 383.7493.6 Increased creatine phosphokinase272.84812 Increased lipase214.6455.5 Increased alanine aminotransferase340402.7 Increased amylase273.7392.7 Increased alkaline phosphatase150.9290.9 Decreased phosphorous151.8233.6 Prolonged activated partial thromboplastin time221.8200.9Hematology Anemia230.9400.9 Lymphopenia192.8274.5Clinically relevant adverse reactions in patients who received ALUNBRIG included photosensitivity (0.9%).. Other Adverse Reactions from Multiple Clinical TrialsIn pooled clinical trial population consisting of three studies with 274 patients treated with ALUNBRIG at the recommended dose, the following adverse reactions and laboratory abnormalities were reported: white blood cell count decreased (28%), hyponatremia (20%), hypokalemia (19%), decreased platelet count (10%), dry skin (4.7%), pain (3.3%), and musculoskeletal stiffness (1.1%).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

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 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.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Brigatinib is 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 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 ElectrophysiologyThe 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 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 (49%) ng/mL and 1452 (60%) ng/mL, respectively, and the corresponding area under the concentration-time curve (AUC0-Tau) was 8165 (45%) ngoh/mL and 20276 (62%) ngoh/mL. After 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.. AbsorptionFollowing administration of single oral doses of ALUNBRIG of 30 mg to 240 mg, the median time to peak concentration (Tmax) ranged from to hours.. Effect of FoodBrigatinib Cmax was reduced by 13% with no effect on AUC in healthy subjects administered ALUNBRIG after 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.. DistributionBrigatinib 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 307 L.. EliminationFollowing oral administration of ALUNBRIG 180 mg once daily, the mean apparent oral clearance (CL/F) of brigatinib at steady-state is 8.9 L/h and the mean plasma elimination half-life is 25 hours.. MetabolismBrigatinib is primarily metabolized by CYP2C8 and CYP3A4 in vitro. Following oral administration of 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.. ExcretionFollowing oral administration of 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 PopulationsAge, race, sex, body weight, and albumin concentration have no clinically meaningful effect on the pharmacokinetics of brigatinib.. Patients with Hepatic ImpairmentFollowing 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 (2.6)].. Patients with Renal ImpairmentFollowing 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 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 (2.7)].. 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 single 90 mg dose of ALUNBRIG increased brigatinib Cmax by 21% and AUC0-INF by 101%, relative to 90 mg dose of ALUNBRIG administered alone [see Dosage and Administration (2.4), Drug Interactions (7.1)]. 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 single 90 mg dose of ALUNBRIG decreased brigatinib Cmax by 41% and AUC0-INF by 12%, relative to 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 single 180 mg dose of ALUNBRIG decreased brigatinib Cmax by 60% and AUC0-INF by 80%, relative to 180 mg dose of ALUNBRIG administered alone [see Dosage and Administration (2.5), Drug Interactions (7.1)]. moderate CYP3A inducer is predicted to decrease the AUC of brigatinib by approximately 50%.. Effect of Brigatinib on CYP3A Substrates:Coadministration of 180 mg daily doses of ALUNBRIG with single mg oral dose of midazolam (a sensitive CYP3A substrate) decreased midazolam Cmax by 16% and AUC0-INF by 26%, relative to 3 mg oral dose of midazolam administered alone. Brigatinib is considered weak inducer of CYP3A.. In Vitro Studies. Effect of Brigatinib on CYP Enzymes:Brigatinib, at clinically relevant plasma concentrations, induced CYP3A via activation of the pregnane 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 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 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.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. TKI-naive Advanced ALK-positive NSCLC (ALTA 1L Study)The efficacy of ALUNBRIG was demonstrated in randomized (1:1), open-label, multicenter trial (ALTA 1L, NCT02737501) in adult patients with advanced ALK-positive NSCLC who had not previously received an ALK-targeted therapy. The study required patients to have an ALK rearrangement based on local standard of care testing. Eligible patients were allowed to have up to prior regimen of chemotherapy in the locally advanced or metastatic setting and were required to have an ECOG Performance Status of 0-2. Neurologically stable patients with treated or untreated central nervous system (CNS) metastases, including leptomeningeal metastases, were eligible. Patients with history of interstitial lung disease, drug-related pneumonitis, or radiation pneumonitis were excluded. The major efficacy outcome measure was progression-free survival (PFS) as evaluated by Blinded Independent Review Committee (BIRC) according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1). Additional efficacy outcome measures as evaluated by the BIRC include confirmed overall response rate (ORR), duration of response (DOR), intracranial ORR, and intracranial DOR.A total of 275 patients were randomized to receive ALUNBRIG 180 mg orally once daily with 7-day lead-in at 90 mg once daily (n 137) or crizotinib 250 mg orally twice daily (n 138). Of the 275 enrolled patients, 239 had positive results using the companion diagnostic test, the Vysis ALK Break Apart FISH Probe Kit; central results were negative for 20 patients and unavailable for 16 patients.Randomization was stratified by CNS metastases (present vs absent) and prior chemotherapy use for locally advanced or metastatic disease (yes, no).Baseline demographic characteristics of the overall study population were: median age 59 years (range: 27 to 89, 32% 65 and over), 59% White and 39% Asian, 55% female, 39% ECOG PS and 56% ECOG PS 1, and 58% never smokers. The disease characteristics of the overall study population were: 93% with Stage IV disease; 27% received chemotherapy in the locally advanced or metastatic setting; 14% had received CNS radiation; 31% had bone metastases; and 20% had liver metastases. CNS metastases were present in 35% (n 96) of patients; 41 of those patients had measurable CNS lesions.ALTA 1L demonstrated statistically significant improvement in PFS by BIRC. Efficacy results from this study are described in Table and Figure 1.At the data cutoff point overall survival data was not mature.Table 7: Efficacy Results by BIRC Assessment in ALTA 1LEfficacy ParametersALUNBRIGN 137CrizotinibN 138CI Confidence Interval, NR Not Reached, NE Not EstimableProgression-Free Survival Number of Events, (%)63 (46%)87 (63%) Median (months) (95% CI)24.0 (18.5, NE)11.0 (9.2, 12.9) Hazard ratio (95% CI)0.49 (0.35, 0.68) p-valueStratified by presence of iCNS metastases at baseline and prior chemotherapy for locally advanced or metastatic disease for log-rank test and Cochran Mantel-Haenszel test, respectively <.0001Tumor Responses Confirmed Overall Response Rate, (95% CI)74% (66, 81)62% (53, 70) p-value 0.0342 Complete Response, (95% CI)15% (9, 22)9% (5, 15) Partial Response, (95% CI)59% (50, 67)53% (44, 61)Duration of Response Number of Confirmed respondersn 101n 85 Median (months) (95% CI)NR (19.4, NE)13.8 (9.3, 20.8) Response duration >=24 months51%30%Figure 1: Kaplan-Meier Plot of Progression-Free Survival by BIRC in ALTA 1LBIRC assessment of confirmed intracranial ORR and intracranial DOR according to RECIST v1.1 in the subgroup of 41 patients with measurable CNS metastases (>=10 mm in longest diameter) at baseline are summarized in Table 8. 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 8: Intracranial Overall Response in Patients with Measurable CNS Metastases in ALTA 1LEfficacy ParameterALUNBRIG(N 18)Crizotinib(N 23)CI Confidence Interval; NE Not EstimableConfirmed Intracranial Overall Response Rate, (95% CI)78% (52, 94)26% (10, 48) Complete Response, (95% CI)28% (10, 53)0 (0, 15) Partial Response, (95% CI)50% (26, 74)26% (10, 48)Duration of Intracranial Response Number of Confirmed Respondersn 14n 6 Intracranial Response Duration >=24 months64%NE. Figure 1. ALK-positive Advanced or Metastatic NSCLC Previously Treated with CrizotinibThe efficacy of ALUNBRIG was demonstrated in 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 documented ALK rearrangement based on an FDA-approved test or different test with adequate archival tissue to confirm ALK arrangement by the Vysis(R) 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 history of interstitial lung disease or drug-related pneumonitis or who had received crizotinib within 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; = 112) or 180 mg once daily following 7-day lead-in at 90 mg once daily (90->180 mg arm; = 110). Randomization was stratified by CNS 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 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%, CNS metastases in 69% (61% had received prior CNS radiation), 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 months (range: 0.1 to 20.2). Efficacy results from ALTA are summarized in Table 9.Table 9: ALTA Efficacy ResultsEfficacy ParameterIRC AssessmentInvestigator Assessment90 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 EstimableOverall Response Rate (95% CI)48% (39,58)53% (43,62)45% (35,54)54% (44,63) Complete Response, (%)4 (3.6%)5 (4.5%)1 (0.9%)4 (3.6%) Partial Response, (%)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 CNS metastases (>=10 mm in longest diameter) at baseline are summarized in Table 10. 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 10: Intracranial Overall Response in Patients with Measurable CNS Metastases in ALTAEfficacy ParameterIRC Assessment90 mg once daily(N 26)90->180 mg once daily(N 18)CI Confidence IntervalIntracranial Overall Response Rate, (95 CI)42% (23,63)67% (41,87) Complete Response, (%)2 (7.7%)0 Partial Response, (%)9 (35%)12 (67%)Duration of Intracranial Response Number of Responders1112 Intracranial Response Duration >=6 months7 (64%)6 (50%) Intracranial Response Duration >=12 months4 (36%)3 (25%).

CLINICAL TRIALS EXPERIENCE SECTION.

6.1Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.. Advanced ALK-positive NSCLC Without Prior ALK-targeted TherapyIn ALTA 1L, the safety of ALUNBRIG was evaluated in 136 patients with advanced ALK-positive NSCLC who had not previously received an ALK-targeted therapy [see Clinical Studies (14)]. The median duration of treatment with ALUNBRIG when administered as 90 mg orally once daily for the first days; then increased to 180 mg orally once daily, was 24.3 months. total of 106 (78%) patients were exposed to ALUNBRIG for greater than or equal to months including 92 (68%) patients exposed for greater than or equal to year. The median relative dose intensity was 97% for ALUNBRIG.The study population (N 275) characteristics were: median age 59 years (range: 27 to 89), age less than 65 years (68%), female (55%), White (59%), Asian (39%), Stage IV disease (93%), NSCLC adenocarcinoma histology (96%), never smoker (58%), ECOG Performance Status (PS) or (95%), and CNS metastases at baseline (30%) [see Clinical Studies (14)].Serious adverse reactions occurred in 33% of patients receiving ALUNBRIG. The most common serious adverse reactions were pneumonia (4.4%), ILD/pneumonitis (3.7%), pyrexia (2.9%), dyspnea (2.2%), pulmonary embolism (2.2%), and asthenia (2.2%). Fatal adverse reactions occurred in 2.9% of patients and included pneumonia (1.5%), cerebrovascular accident (0.7%), and multiple organ dysfunction syndrome (0.7%).In ALTA 1L, 13% of patients receiving ALUNBRIG permanently discontinued ALUNBRIG for adverse reactions. The most frequent adverse reactions that led to discontinuation were ILD/pneumonitis (3.7%) and pneumonia (2.2%).In ALTA 1L, 38% of patients required dose reduction due to adverse reactions. The most common adverse reaction that led to dose reduction was increased creatine phosphokinase (15%), increased lipase (6.6%), increased amylase (4.4%), increased aspartate aminotransferase (2.2%), ILD/pneumonitis (2.2%) and hypertension (2.2%).Table and Table summarize the common adverse reactions and laboratory abnormalities observed in ALTA 1L.Table 3: Adverse Reactions in >=10% (All GradesPer National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.03) or >=2% (Grades 3-4) of Patients by Arm in ALTA 1L (N 273)Adverse ReactionsALUNBRIGN 136CrizotinibN 137All Grades (%)Grades 3-4 (%)All Grades (%)Grades 3-4(%)Gastrointestinal Disorders Diarrhea532.2572.9 Nausea302.2582.9 Abdominal painIncludes abdominal discomfort, abdominal distension, abdominal pain, abdominal pain lower, abdominal pain upper, and epigastric discomfort 240.7333.6 Vomiting210.7442.2 Constipation180420 StomatitisIncludes aphthous ulcer, mouth ulceration, oral mucosal blistering and stomatitis 130.78.80 Dyspepsia80160.7 Gastroesophageal reflux disease0.70110Skin and Subcutaneous Tissue Disorders RashIncludes dermatitis, dermatitis acneiform, dermatitis bullous, dermatitis contact, drug eruption, erythema, palmar-plantar erythrodysesthesia syndrome, rash, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pruritic, rash pustular, toxic skin eruption, urticaria 402.9170 PruritusIncluded pruritus, allergic pruritus, and generalized pruritus 200.75.80.7Respiratory, Thoracic and Mediastinal Disorders Cough350200 DyspneaInclude dyspnea and exertional dyspnea 252.922Includes Grade events 3.6 ILD/Pneumonitis5.12.92.20.7 Pulmonary embolism2.22.25.8 2.9Vascular Disorders Hypertension Includes hypertension and systolic hypertension 321382.9General Disorders and Administration Site Conditions FatigueIncludes asthenia and fatigue 321.5402.2 EdemaIncludes angioedema, eye swelling, eyelid edema, face edema, generalized edema, lip swelling, peripheral edema, periorbital edema, peripheral swelling, skin swelling, swelling and swelling face 180.7480.7 Pyrexia150.7150Musculoskeletal and Connective Tissue Disorders MyalgiaIncludes muscle spasms, muscle twitching, musculoskeletal discomfort, musculoskeletal pain, and myalgia 280230 Back pain210.7171.5 Arthralgia140120 Pain in extremity5.10150.7Nervous System Disorders HeadacheIncludes headache and migraine 222.2170 Dizziness150.7200.7 Peripheral neuropathyIncludes burning sensation, dysesthesia, hyperesthesia, hypoesthesia, neuralgia, peripheral neuropathy, paraesthesia, peripheral sensory neuropathy and polyneuropathy 110.7180 Dysgeusia2.90140Investigations Increased Blood cholesterolIncludes blood cholesterol increased, hypercholesterolaemia 1300.70Cardiac Disorders BradycardiaIncludes bradycardia, heart rate decreased, sinus bradycardia 120.7230Infections and Infestations PneumoniaIncludes lower respiratory tract infection, lung infection, pneumonia, aspiration pneumonia, and cryptococcal pneumonia 15 5.16.6 2.9 Upper respiratory tract infectionIncludes upper respiratory tract infection and viral upper respiratory tract infection 120100 Nasopharyngitis80110 Urinary tract infection5.90.78.82.2Metabolism and Nutrition Disorders Decreased Appetite8.80.7192.9Eye Disorders Visual DisturbanceIncludes cataract, glaucoma, hypermetropia, night blindness, papilloedema, photophobia, photopsia, blurred vision, reduced visual acuity, visual field defect, visual impairment, and vitreous floaters 7.40530.7Table 4: Laboratory Abnormalities in >=20% (All GradesPer CTCAE version 4.03) of Patients by Arm in ALTA 1L (N 273)Laboratory AbnormalityALUNBRIGN 136Denominator for each laboratory parameter may vary and is defined as the number of patients who had both, baseline and post-baseline test CrizotinibN 137 All Grades (%)Grades 3-4(%)All Grades (%)Grades 3-4 (%)Chemistry Increased creatine phosphokinase8124684.8 Increased aspartate aminotransferase724.5705.2 Increased lipase5917369.8 HyperglycemiaElevated blood insulin was also observed in both arms 567.5373.7 Increased alanine aminotransferase525.27713 Increased amylase526.8253 Decreased phosphorous413.7396 Increased alkaline phosphatase363491.5 Increased creatinine250330 Potassium increased241.5313.7 Increased calcium2201.50 Decreased magnesium2106.90 Decreased albumin150.8523.7 Decreased calcium150671.5Hematology Hemoglobin decreased412.3361.5 Lymphocyte count decreased429.3305.4 Neutrophil count decreased120346.8Clinically relevant adverse reactions in patients who received ALUNBRIG included photosensitivity (3.7%).. ALK-positive Advanced or Metastatic NSCLC Previously Treated with CrizotinibThe safety of ALUNBRIG was evaluated in 219 patients with locally advanced or metastatic ALK-positive NSCLC who received at least 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 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. total of 150 (68%) patients were exposed to ALUNBRIG for greater than or equal to months and 42 (19%) patients were exposed for greater than or equal to year.The study population (N 222) 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) or (93%), and CNS 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 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 and Table summarize the common adverse reactions and laboratory abnormalities observed in ALTA.Table 5: Adverse Reactions in >=10% (All GradesPer National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0) or >=2% (Grades 3-4) of Patients by Dose Group in ALTA (N 219)Adverse Reactions90 mg once dailyN 10990->180 mg once dailyN 110All Grades(%)Grades 3-4(%)All Grades (%)Grades 3-4 (%)Gastrointestinal Disorders Nausea330.9400.9 Diarrhea190380 Vomiting241.8230 Constipation190.9150 Abdominal PainIncludes abdominal distension, abdominal pain, and epigastric discomfort 170100General Disorders and Administration Site Conditions FatigueIncludes asthenia and fatigue 291.8360 Pyrexia1406.40.9Respiratory, Thoracic and Mediastinal Disorders Cough180340 DyspneaIncludes dyspnea and exertional dyspnea 272.8211.8Includes one Grade event ILD/Pneumonitis3.71.89.12.7 Hypoxia0.902.72.7Nervous System Disorders HeadacheIncludes headache and sinus headache 280270.9 Peripheral NeuropathyIncludes peripheral sensory neuropathy and paresthesia 130.9131.8Skin and Subcutaneous Tissue Disorders RashIncludes acneiform dermatitis, exfoliative rash, rash, pruritic rash, and pustular rash 151.8243.6Vascular Disorders Hypertension115.5216.4Musculoskeletal and Connective Tissue Disorders Muscle Spasms120170 Back pain101.8151.8 MyalgiaIncludes musculoskeletal pain and myalgia 9.20150.9 Arthralgia140.9140 Pain in extremity1103.60.9Metabolism and Nutrition Disorders Decreased Appetite220.9150.9Eye Disorders Visual DisturbanceIncludes diplopia, photophobia, blurred vision, reduced visual acuity, visual impairment, vitreous floaters, visual field defect, macular edema, and vitreous detachment 7.30100.9Infections Pneumonia4.62.8 105.5 Psychiatric Disorders Insomnia1107.30Table 6: Laboratory Abnormalities in >=20% (All GradesPer CTCAE version 4.0) of Patients by Regimen in ALTA (N 219)Laboratory Abnormality90 mg once dailyN 10990->180 mg once dailyN 110All Grades(%)Grades 3-4(%)All Grades(%)Grades 3-4(%)Chemistry Increased aspartate aminotransferase380.9650 HyperglycemiaElevated blood insulin was observed in both regimens 383.7493.6 Increased creatine phosphokinase272.84812 Increased lipase214.6455.5 Increased alanine aminotransferase340402.7 Increased amylase273.7392.7 Increased alkaline phosphatase150.9290.9 Decreased phosphorous151.8233.6 Prolonged activated partial thromboplastin time221.8200.9Hematology Anemia230.9400.9 Lymphopenia192.8274.5Clinically relevant adverse reactions in patients who received ALUNBRIG included photosensitivity (0.9%).. Other Adverse Reactions from Multiple Clinical TrialsIn pooled clinical trial population consisting of three studies with 274 patients treated with ALUNBRIG at the recommended dose, the following adverse reactions and laboratory abnormalities were reported: white blood cell count decreased (28%), hyponatremia (20%), hypokalemia (19%), decreased platelet count (10%), dry skin (4.7%), pain (3.3%), and musculoskeletal stiffness (1.1%).

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. None.. None. (4).

DESCRIPTION SECTION.

11 DESCRIPTION. Brigatinib is 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]phenylpyrimidine-2,4-diamine. The molecular formula is C29H39ClN7O2P which corresponds to 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.. Chemical Structure.

RENAL IMPAIRMENT SUBSECTION.

8.7Renal 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 (2.7), Clinical Pharmacology (12.3)].

SPL PATIENT PACKAGE INSERT SECTION.

This Patient Information has been approved by the U.S. Food and Drug Administration.Revised: September 2021PATIENT INFORMATIONALUNBRIG (uh-lun-brig)(brigatinib) tabletsWhat is the most important information should know about ALUNBRIGALUNBRIG can cause serious side effects, including:Lung problems. ALUNBRIG may cause severe or life-threatening swelling (inflammation) of the lungs any time during treatment, and can lead to death. These lung problems happen especially within the first week of treatment with ALUNBRIG. Symptoms may be similar to those symptoms from lung cancer. Tell your healthcare provider right away if you have any new or worsening symptoms, including:trouble breathing or shortness of breathchest paincough with or without mucusfeverHigh blood pressure (hypertension). ALUNBRIG may cause high blood pressure. Your healthcare provider will check your blood pressure before starting and during treatment with ALUNBRIG. Tell your healthcare provider right away if you get headaches, dizziness, blurred vision, chest pain or shortness of breath.Slow heart rate (bradycardia). ALUNBRIG may cause very slow heartbeats that can be severe. Your healthcare provider will check your heart rate during treatment with ALUNBRIG. Tell your healthcare provider right away if you feel dizzy, lightheaded, or faint during treatment with ALUNBRIG. Tell your healthcare provider if you take any heart or blood pressure medicines.Vision problems. ALUNBRIG may cause vision problems. Your healthcare provider may stop ALUNBRIG and refer you to an eye specialist if you develop severe vision problems during treatment with ALUNBRIG. Tell your healthcare provider right away if you have any loss of vision or any change in vision, including:double visionseeing flashes of lightblurry visionlight hurting your eyesnew or increased floatersMuscle pain, tenderness, and weakness (myalgia). ALUNBRIG may increase the level of an enzyme in your blood called creatine phosphokinase (CPK), which may be sign of muscle damage. Your healthcare provider will do blood tests to check your blood levels of CPK during treatment with ALUNBRIG. Tell your healthcare provider right away if you get new or worsening signs and symptoms of muscle problems, including unexplained muscle pain or muscle pain that does not go away, tenderness, or weakness.Inflammation of the pancreas (pancreatitis). ALUNBRIG may increase enzymes in your blood called amylase and lipase, which may be sign of pancreatitis. Your healthcare provider will do blood tests to check your pancreatic enzyme blood levels during treatment with ALUNBRIG. Tell your healthcare provider right away if you get new or worsening signs and symptoms of pancreatitis, including upper abdominal pain that may spread to the back and get worse with eating, weight loss, or nausea.High blood sugar (hyperglycemia). ALUNBRIG may increase your blood sugar levels. Your healthcare provider will do blood tests to check your blood sugar levels before starting and during treatment with ALUNBRIG. Your healthcare provider may need to start or change your blood sugar medicine to control your blood sugar levels. Tell your healthcare provider right away if you get new or worsening signs and symptoms of hyperglycemia, including:feeling very thirstyneeding to urinate more than usualfeeling very hungryfeeling sick to your stomachfeeling weak or tiredfeeling confusedSee What are the possible side effects of ALUNBRIG for information about side effects.What is ALUNBRIGALUNBRIG is prescription medicine used to treat adults with non-small cell lung cancer (NSCLC):that has certain type of abnormal anaplastic lymphoma kinase (ALK) gene, and that has spread to other parts of your bodyIt 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 problemshave high blood pressurehave slow heartbeathave any vision problemshave or have had pancreatitishave diabetes mellitus or glucose intolerancehave liver problemshave kidney problems or are on dialysisare 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.Females who are able to become pregnant should use effective birth control during treatment with ALUNBRIG and for at least months after the final dose of ALUNBRIG. Talk to your healthcare provider about birth control choices that are right for you during treatment with ALUNBRIG.Males who have female partners that are able to become pregnant should use effective birth control during treatment with ALUNBRIG and for at least 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 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 take ALUNBRIGTake 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 low dose (90 mg) of ALUNBRIG for the first days of treatment. If you tolerate this dose of ALUNBRIG well, your healthcare provider may increase your dose after the first 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 time each day.Take ALUNBRIG with or without food.Swallow ALUNBRIG tablets whole. Do not crush or chew tablets.If you miss dose of ALUNBRIG, do not take the missed dose. Take your next dose at your regular time.If you vomit after taking dose of ALUNBRIG, do not take an extra dose. Take your next dose at your regular time.What should avoid while taking ALUNBRIGLimit your time in the sun during treatment with ALUNBRIG and for at least days after your final dose. ALUNBRIG may make your skin sensitive to sunlight. You may burn more easily and get severe sunburns. When you are in the sun, wear hat and protective clothing, and use broad -spectrum sunscreen and lip balm with Sun Protection Factor (SPF) of 30 or greater to protect against sunburn.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 ALUNBRIGALUNBRIG may cause serious side effects, including: See What is the most important information should know about ALUNBRIG.The most common side effects of ALUNBRIG include:diarrheafatiguenausearashcoughmuscle painheadachehigh blood pressurevomitingdifficulty breathingALUNBRIG may cause fertility problems in males. This may affect your ability to father child. Talk to your healthcare provider if you have concerns about fertility.These are not all of the possible side effects of ALUNBRIG. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store ALUNBRIGStore ALUNBRIG at room temperature between 68F to 77F (20C to 25C).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 Patient Information leaflet. Do not use ALUNBRIG for 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.What are the ingredients in ALUNBRIGActive 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. Distributed by: Takeda Pharmaceuticals America, Inc., Lexington, MA 02421 ALUNBRIG(R) is registered trademark of ARIAD Pharmaceuticals, Inc. (C)2021 ARIAD Pharmaceuticals, Inc. All rights reserved. For more information, go to www.alunbrig.com or call 1-844-217-6468. ABG346 R4. Lung problems. ALUNBRIG may cause severe or life-threatening swelling (inflammation) of the lungs any time during treatment, and can lead to death. These lung problems happen especially within the first week of treatment with ALUNBRIG. Symptoms may be similar to those symptoms from lung cancer. Tell your healthcare provider right away if you have any new or worsening symptoms, including:. trouble breathing or shortness of breath. chest pain. cough with or without mucus. fever. High blood pressure (hypertension). ALUNBRIG may cause high blood pressure. Your healthcare provider will check your blood pressure before starting and during treatment with ALUNBRIG. Tell your healthcare provider right away if you get headaches, dizziness, blurred vision, chest pain or shortness of breath.. Slow heart rate (bradycardia). ALUNBRIG may cause very slow heartbeats that can be severe. Your healthcare provider will check your heart rate during treatment with ALUNBRIG. Tell your healthcare provider right away if you feel dizzy, lightheaded, or faint during treatment with ALUNBRIG. Tell your healthcare provider if you take any heart or blood pressure medicines.. Vision problems. ALUNBRIG may cause vision problems. Your healthcare provider may stop ALUNBRIG and refer you to an eye specialist if you develop severe vision problems during treatment with ALUNBRIG. Tell your healthcare provider right away if you have any loss of vision or any change in vision, including:. double vision. seeing flashes of light. blurry vision. light hurting your eyes. new or increased floaters. Muscle pain, tenderness, and weakness (myalgia). ALUNBRIG may increase the level of an enzyme in your blood called creatine phosphokinase (CPK), which may be sign of muscle damage. Your healthcare provider will do blood tests to check your blood levels of CPK during treatment with ALUNBRIG. Tell your healthcare provider right away if you get new or worsening signs and symptoms of muscle problems, including unexplained muscle pain or muscle pain that does not go away, tenderness, or weakness.. Inflammation of the pancreas (pancreatitis). ALUNBRIG may increase enzymes in your blood called amylase and lipase, which may be sign of pancreatitis. Your healthcare provider will do blood tests to check your pancreatic enzyme blood levels during treatment with ALUNBRIG. Tell your healthcare provider right away if you get new or worsening signs and symptoms of pancreatitis, including upper abdominal pain that may spread to the back and get worse with eating, weight loss, or nausea.. High blood sugar (hyperglycemia). ALUNBRIG may increase your blood sugar levels. Your healthcare provider will do blood tests to check your blood sugar levels before starting and during treatment with ALUNBRIG. Your healthcare provider may need to start or change your blood sugar medicine to control your blood sugar levels. Tell your healthcare provider right away if you get new or worsening signs and symptoms of hyperglycemia, including:. feeling very thirsty. needing to urinate more than usual. feeling very hungry. feeling sick to your stomach. feeling weak or tired. feeling confused. that has certain type of abnormal anaplastic lymphoma kinase (ALK) gene, and that has spread to other parts of your body. have lung or breathing problems. have high blood pressure. have 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.Females who are able to become pregnant should use effective birth control during treatment with ALUNBRIG and for at least months after the final dose of ALUNBRIG. Talk to your healthcare provider about birth control choices that are right for you during treatment with ALUNBRIG.Males who have female partners that are able to become pregnant should use effective birth control during treatment with ALUNBRIG and for at least months after the final dose of ALUNBRIG. Females who are able to become pregnant should use effective birth control during treatment with ALUNBRIG and for at least months after the final dose of ALUNBRIG. Talk to your healthcare provider about birth control choices that are right for you during treatment with ALUNBRIG.. Males who have female partners that are able to become pregnant should use effective birth control during treatment with ALUNBRIG and for at least 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 week after the final dose of 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 low dose (90 mg) of ALUNBRIG for the first days of treatment. If you tolerate this dose of ALUNBRIG well, your healthcare provider may increase your dose after the first 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 time each day.. Take ALUNBRIG with or without food.. Swallow ALUNBRIG tablets whole. Do not crush or chew tablets.. If you miss dose of ALUNBRIG, do not take the missed dose. Take your next dose at your regular time.. If you vomit after taking dose of ALUNBRIG, do not take an extra dose. Take your next dose at your regular time.. Limit your time in the sun during treatment with ALUNBRIG and for at least days after your final dose. ALUNBRIG may make your skin sensitive to sunlight. You may burn more easily and get severe sunburns. When you are in the sun, wear hat and protective clothing, and use broad -spectrum sunscreen and lip balm with Sun Protection Factor (SPF) of 30 or greater to protect against sunburn.. Avoid eating grapefruit or drinking grapefruit juice during treatment with ALUNBRIG. Grapefruit may increase the amount of ALUNBRIG in your blood.. See What is the most important information should know about ALUNBRIG.. diarrhea. fatigue. nausea. rash. cough. muscle pain. headache. high blood pressure. vomiting. difficulty breathing. Store ALUNBRIG at room temperature between 68F to 77F (20C to 25C).

SPL UNCLASSIFIED SECTION.

2.1Patient Selection. Select patients for the treatment of metastatic NSCLC with ALUNBRIG based on the presence of ALK positivity in tumor specimens [see Clinical Studies (14)]. Information on FDA-approved tests for the detection of ALK rearrangements in NSCLC is available at http://www.fda.gov/CompanionDiagnostics.

STORAGE AND HANDLING SECTION.

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

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Hepatic Impairment: Reduce the dose of ALUNBRIG for patients with severe hepatic impairment. (2.6, 8.6)Renal Impairment: Reduce the dose of ALUNBRIG for patients with severe renal impairment. (2.7, 8.7)Lactation: Advise not to breastfeed. (8.2). Hepatic Impairment: Reduce the dose of ALUNBRIG for patients with severe hepatic impairment. (2.6, 8.6). Renal Impairment: Reduce the dose of ALUNBRIG for patients with severe renal impairment. (2.7, 8.7). Lactation: Advise not to breastfeed. (8.2). 8.1 Pregnancy. Risk SummaryBased on its mechanism of action and findings in animals, ALUNBRIG can cause fetal harm when administered to 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 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 DataIn 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 defect in the abdominal wall) along with visceral findings of moderate bilateral dilatation of the lateral ventricles.. 8.2 Lactation. Risk SummaryThere 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 week following the final dose.. 8.3 Females and Males of Reproductive Potential. Pregnancy TestingVerify pregnancy status in females of reproductive potential prior to initiating ALUNBRIG [see Use in Specific Populations (8.1)].. ContraceptionALUNBRIG can cause fetal harm [see Use in Specific Populations (8.1)].. FemalesAdvise females of reproductive potential to use effective contraception during treatment with ALUNBRIG and for at least months after the final dose.. MalesBecause 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 months after the final dose [see Nonclinical Toxicology (13.1)].. InfertilityBased 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. Of the 359 patients enrolled in the ALTA 1L ALUNBRIG arm and in ALTA, 26.7% were 65 and older and 7.5% were 75 and older. No overall differences in safety or effectiveness were observed between patients >=65 years and younger patients.. 8.6Hepatic 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 (2.6), Clinical Pharmacology (12.3)].. 8.7Renal 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 (2.7), Clinical Pharmacology (12.3)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. 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, 5.1)Hypertension: Monitor blood pressure after weeks and then at least monthly during treatment. For severe hypertension, withhold ALUNBRIG, then dose reduce or permanently discontinue. (2.3, 5.2)Bradycardia: Monitor heart rate and blood pressure regularly during treatment. If symptomatic, withhold ALUNBRIG, then dose reduce or permanently discontinue. (2.3, 5.3)Visual Disturbance: Advise patients to report visual symptoms. Withhold ALUNBRIG and obtain ophthalmologic evaluation, then dose reduce or permanently discontinue ALUNBRIG. (2.3, 5.4)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, 5.5)Pancreatic Enzymes Elevation: Monitor lipase and amylase levels regularly during treatment. Based on the severity, withhold ALUNBRIG, then resume or reduce dose. (2.3, 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. (2.3, 5.7)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, 5.8)Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to fetus and to use effective contraception. (5.9, 8.1, 8.3). 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, 5.1). Hypertension: Monitor blood pressure after weeks and then at least monthly during treatment. For severe hypertension, withhold ALUNBRIG, then dose reduce or permanently discontinue. (2.3, 5.2). Bradycardia: Monitor heart rate and blood pressure regularly during treatment. If symptomatic, withhold ALUNBRIG, then dose reduce or permanently discontinue. (2.3, 5.3). Visual Disturbance: Advise patients to report visual symptoms. Withhold ALUNBRIG and obtain ophthalmologic evaluation, then dose reduce or permanently discontinue ALUNBRIG. (2.3, 5.4). 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, 5.5). Pancreatic Enzymes Elevation: Monitor lipase and amylase levels regularly during treatment. Based on the severity, withhold ALUNBRIG, then resume or reduce dose. (2.3, 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. (2.3, 5.7). 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, 5.8). Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to fetus and to use effective contraception. (5.9, 8.1, 8.3). 5.1Interstitial 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 days of initiation of ALUNBRIG in 2.9% of patients, with Grade to 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 days of initiation of ALUNBRIG (median onset was days) in 6.4% of patients, with Grade to 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 or ILD/pneumonitis, either resume ALUNBRIG with dose reduction according to Table after recovery to baseline or permanently discontinue ALUNBRIG. Permanently discontinue ALUNBRIG for Grade or ILD/pneumonitis or recurrence of Grade or ILD/pneumonitis [see Dosage and Administration (2.3), Adverse Reactions (6.1)].. 5.2Hypertension. In ALTA 1L, hypertension was reported in 32% of patients receiving ALUNBRIG; Grade 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 hypertension occurred in 5.9% of patients overall.Control blood pressure prior to treatment with ALUNBRIG. Monitor blood pressure after weeks and at least monthly thereafter during treatment with ALUNBRIG. Withhold ALUNBRIG for Grade 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 hypertension or recurrence of Grade hypertension [see Dosage and Administration (2.3), Adverse Reactions (6.1)]. Use caution when administering ALUNBRIG in combination with antihypertensive agents that cause bradycardia [see Warnings and Precautions (5.3)].. 5.3Bradycardia. In ALTA 1L, heart rates less than 50 beats per minute (bpm) occurred in 8.1% of patients receiving ALUNBRIG. Grade bradycardia occurred in 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 bradycardia occurred in (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 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 (2.3)]. 5.4Visual Disturbance. In ALTA 1L, Grade or 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 macular edema and cataract occurred in 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 or greater severity. Upon recovery of Grade or Grade visual disturbances to Grade severity or baseline, resume ALUNBRIG at reduced dose. Permanently discontinue treatment with ALUNBRIG for Grade visual disturbances [see Dosage and Administration (2.3), Adverse Reactions (6.1)]. 5.5Creatine Phosphokinase (CPK) Elevation. In ALTA 1L, creatine phosphokinase (CPK) elevation occurred in 81% of patients who received ALUNBRIG. The incidence of Grade or 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 to 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 or CPK elevation with Grade or higher muscle pain or weakness. Upon resolution or recovery to Grade CPK elevation or baseline, resume ALUNBRIG at the same dose or at reduced dose as described in Table [see Dosage and Administration (2.3), Adverse Reactions (6.1)]. 5.6Pancreatic Enzymes Elevation. In ALTA 1L, amylase elevation occurred in 52% of patients and Grade or amylase elevation occurred in 6.8% of patients. Lipase elevations occurred in 59% of patients and Grade or 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 or 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 or 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 or pancreatic enzyme elevation. Upon resolution or recovery to Grade or baseline, resume ALUNBRIG at the same dose or at reduced dose as described in Table [see Dosage and Administration (2.3), Adverse Reactions (6.1)]. 5.7Hyperglycemia. In ALTA 1L, 56% of patients who received ALUNBRIG experienced new or worsening hyperglycemia. Grade 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 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 or permanently discontinuing ALUNBRIG [see Dosage and Administration (2.3), Adverse Reactions (6.1)].. 5.8Photosensitivity. In ALTA 1L, photosensitivity occurred in 3.7% of patients who received ALUNBRIG, with 0.7% Grade 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 to 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 days after discontinuation of treatment. Advise patients, when outdoors to wear hat and protective clothing, and use broad-spectrum Ultraviolet (UVA)/ Ultraviolet (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 [see Dosage and Administration (2.3), Adverse Reactions (6.1)].. 5.9Embryo-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 fetus. Advise females of reproductive potential to use effective contraception during treatment with ALUNBRIG and for at least months following the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment and for at least months after the last dose of ALUNBRIG [see Use in Specific Populations (8.1, 8.3), Clinical Pharmacology (12.1)].

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. 90 mg orally once daily for the first days; then increase to 180 mg orally once daily. May be taken with or without food. (2.2). 2.1Patient Selection. Select patients for the treatment of metastatic NSCLC with ALUNBRIG based on the presence of ALK positivity in tumor specimens [see Clinical Studies (14)]. Information on FDA-approved tests for the detection of ALK rearrangements in NSCLC is available at http://www.fda.gov/CompanionDiagnostics.. 2.2Recommended Dosage. The recommended dosage for ALUNBRIG is:90 mg orally once daily for the first days; then increase the dose to 180 mg orally once daily.Administer ALUNBRIG until disease progression or unacceptable toxicity.If ALUNBRIG is interrupted for 14 days or longer for reasons other than adverse reactions, resume treatment at 90 mg once daily for 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 dose of ALUNBRIG is missed or vomiting occurs after taking dose, do not administer an additional dose and take the next dose of ALUNBRIG at the scheduled time.. 90 mg orally once daily for the first days; then increase the dose to 180 mg orally once daily.. 2.3Dosage Modifications for Adverse Reactions. ALUNBRIG dosage reductions for adverse reactions are summarized in Table 1.Table 1: Recommended ALUNBRIG Dosage ReductionsDosage ReductionDosageFirstSecondThird90 mg once daily60 mg once dailypermanently discontinueN/ANot applicable 180 mg once daily120 mg once daily90 mg once daily60 mg once dailyOnce 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 ReactionsAdverse ReactionSeverityGraded per National Cancer Institute Common Terminology Criteria for Adverse Events. Version 4.0 (NCI CTCAE v4). Dosage Modificationsbpm beats per minute; DBP diastolic blood pressure; HR heart rate; SBP systolic blood pressure; ULN upper limit of normalInterstitial Lung Disease (ILD) /Pneumonitis [see Warnings and Precautions (5.1)] Grade 1If new pulmonary symptoms occur during the first 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 days of treatment, withhold ALUNBRIG until recovery to baseline, then resume at same dose.If ILD/pneumonitis recurs, permanently discontinue ALUNBRIG.Grade 2If new pulmonary symptoms occur during the first 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 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 or 4Permanently discontinue ALUNBRIG for ILD/pneumonitis.Hypertension [see Warnings and Precautions (5.2)] Grade 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 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 or less, and resume at next lower dose (Table 1) or permanently discontinue treatment.Grade hypertension (life-threatening consequences, urgent intervention indicated)Withhold ALUNBRIG until recovery to Grade or less, and resume at next lower dose (Table 1) or permanently discontinue treatment.Recurrence: permanently discontinue ALUNBRIG for recurrence of Grade hypertension.Bradycardia (HR less than 60 bpm) [see Warnings and Precautions (5.3)] Symptomatic bradycardiaWithhold ALUNBRIG until recovery to asymptomatic bradycardia or to resting heart rate of 60 bpm or above.If 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 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 or visual disturbanceWithhold ALUNBRIG until recovery to Grade or baseline, then resume at the next lower dose (Table 1).Grade visual disturbancePermanently discontinue ALUNBRIG.Creatine Phosphokinase (CPK) Elevation [see Warnings and Precautions (5.5)] Grade or CPK elevation (greater than 5x ULN) with Grade or higher muscle pain or weaknessWithhold ALUNBRIG until recovery to Grade or less (less than or equal to 2.5x ULN) CPK elevation or to baseline, then resume ALUNBRIG at same dose.Recurrence: Withhold ALUNBRIG until recovery to Grade or less (less than or equal to 2.5x ULN) CPK elevation or to baseline, then resume ALUNBRIG at the next lower dose (Table 1).Lipase/Amylase Elevation [see Warnings and Precautions (5.6)] Grade lipase or amylase elevation (greater than 2x ULN)Withhold ALUNBRIG until recovery to Grade or less (less than or equal to 1.5x ULN) or to baseline, then resume ALUNBRIG at same dose.Recurrence: Withhold ALUNBRIG until recovery to Grade or less (less than or equal to 1.5x ULN) or to baseline, then resume ALUNBRIG at next lower dose (Table 1).Grade lipase or amylase elevation (greater than 5x ULN)Withhold ALUNBRIG until recovery to Grade or less (less than or equal to 1.5x ULN) or to baseline, then resume ALUNBRIG at next lower dose (Table 1).Hyperglycemia [see Warnings and Precautions (5.7)] Grade (greater than 250 mg/dL or 13.9 mmol/L) or 4If 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.OtherGrade 3Withhold 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 4Withhold ALUNBRIG until recovery to baseline and resume at next lower dose (Table 1).Recurrence: Permanently discontinue ALUNBRIG.. If new pulmonary symptoms occur during the first 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 days of treatment, withhold ALUNBRIG until recovery to baseline, then resume at same dose.. If ILD/pneumonitis recurs, permanently discontinue ALUNBRIG.. If new pulmonary symptoms occur during the first 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 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.. Withhold ALUNBRIG until hypertension has recovered to Grade 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 or less, and resume at next lower dose (Table 1) or permanently discontinue treatment.. Withhold ALUNBRIG until recovery to Grade or less, and resume at next lower dose (Table 1) or permanently discontinue treatment.. Recurrence: permanently discontinue ALUNBRIG for recurrence of Grade hypertension.. Withhold ALUNBRIG until recovery to asymptomatic bradycardia or to resting heart rate of 60 bpm or above.. If 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.. 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 resting heart rate of 60 bpm or above, with frequent monitoring as clinically indicated.. Recurrence: permanently discontinue ALUNBRIG.. Withhold ALUNBRIG until recovery to Grade or less (less than or equal to 2.5x ULN) CPK elevation or to baseline, then resume ALUNBRIG at same dose.. Recurrence: Withhold ALUNBRIG until recovery to Grade or less (less than or equal to 2.5x ULN) CPK elevation or to baseline, then resume ALUNBRIG at the next lower dose (Table 1).. Withhold ALUNBRIG until recovery to Grade or less (less than or equal to 1.5x ULN) or to baseline, then resume ALUNBRIG at same dose.. Recurrence: Withhold ALUNBRIG until recovery to Grade or less (less than or equal to 1.5x ULN) or to baseline, then resume ALUNBRIG at next lower dose (Table 1).. 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).. Withhold ALUNBRIG until recovery to baseline and resume at next lower dose (Table 1).. Recurrence: Permanently discontinue ALUNBRIG.. 2.4Dosage 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 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 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 strong or moderate CYP3A inhibitor, resume the ALUNBRIG dose that was tolerated prior to initiating the CYP3A inhibitor.. 2.5Dosage 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 moderate CYP3A inducer cannot be avoided, increase the ALUNBRIG once daily dose in 30 mg increments after days of treatment with the current ALUNBRIG dose as tolerated, up to maximum of twice the ALUNBRIG dose that was tolerated prior to initiating the moderate CYP3A inducer.After discontinuation of moderate CYP3A inducer, resume the ALUNBRIG dose that was tolerated prior to initiating the moderate CYP3A inducer.. 2.6Dosage 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)].. 2.7Dosage 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)].

DOSAGE FORMS & STRENGTHS SECTION.

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 side90 mg: oval, white to off-white film-coated tablets with U7 debossed on one side and plain on the other side30 mg: round, white to off-white film-coated tablets with U3 debossed on one side and plain on the other side. 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. Tablets: 180 mg, 90 mg, or 30 mg. (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. CYP3A Inhibitors: Avoid coadministration of ALUNBRIG with strong or moderate CYP3A inhibitors. If coadministration of strong or moderate CYP3A inhibitor is unavoidable, reduce the dose of ALUNBRIG. (2.4, 7.1)CYP3A Inducers: Avoid coadministration of ALUNBRIG with strong or moderate CYP3A inducers. If coadministration of moderate CYP3A inducer is unavoidable, increase the dose of ALUNBRIG. (2.5, 7.1). CYP3A Inhibitors: Avoid coadministration of ALUNBRIG with strong or moderate CYP3A inhibitors. If coadministration of strong or moderate CYP3A inhibitor is unavoidable, reduce the dose of ALUNBRIG. (2.4, 7.1). CYP3A Inducers: Avoid coadministration of ALUNBRIG with strong or moderate CYP3A inducers. If coadministration of moderate CYP3A inducer is unavoidable, increase the dose of ALUNBRIG. (2.5, 7.1). 7.1Effect of Other Drugs on ALUNBRIG. Strong or Moderate CYP3A InhibitorsCoadministration of ALUNBRIG with 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 (2.4)].. Strong or Moderate CYP3A InducersCoadministration of ALUNBRIG with 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 (2.5)].

FEMALES & MALES OF REPRODUCTIVE POTENTIAL SECTION.

8.3 Females and Males of Reproductive Potential. Pregnancy TestingVerify pregnancy status in females of reproductive potential prior to initiating ALUNBRIG [see Use in Specific Populations (8.1)].. ContraceptionALUNBRIG can cause fetal harm [see Use in Specific Populations (8.1)].. FemalesAdvise females of reproductive potential to use effective contraception during treatment with ALUNBRIG and for at least months after the final dose.. MalesBecause 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 months after the final dose [see Nonclinical Toxicology (13.1)].. InfertilityBased on findings in male reproductive organs in animals, ALUNBRIG may cause reduced fertility in males [see Nonclinical Toxicology (13.1)].

GERIATRIC USE SECTION.

8.5 Geriatric Use. Of the 359 patients enrolled in the ALTA 1L ALUNBRIG arm and in ALTA, 26.7% were 65 and older and 7.5% were 75 and older. No overall differences in safety or effectiveness were observed between patients >=65 years and younger patients.

HEPATIC IMPAIRMENT SUBSECTION.

8.6Hepatic 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 (2.6), Clinical Pharmacology (12.3)].

HOW SUPPLIED SECTION.

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 tabletsNDC 63020-180-23Bottle of 30 tabletsNDC 63020-180-3090 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 tabletsNDC 63020-090-07Bottle of 30 tabletsNDC 63020-090-3030 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 tabletsNDC 63020-113-3090 mg 7 count tablets (NDC 63020-090-07) and 180 mg 23 count tablets (NDC 63020-180-23) are also available in single carton as 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 20C to 25C (68F to 77F); excursions permitted between 15C to 30C (59F to 86F) (see USP).

INDICATIONS & USAGE SECTION.

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

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Patient Information). Interstitial Lung Disease (ILD)/PneumonitisInform 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 [see Warnings and Precautions (5.1)].. HypertensionAdvise patients of risks of hypertension and to promptly report signs or symptoms of hypertension [see Warnings and Precautions (5.2)].. BradycardiaAdvise patients to report any symptoms of bradycardia and to inform their healthcare provider about the use of heart and blood pressure medications [see Warnings and Precautions (5.3)].. Visual DisturbanceAdvise patients to inform their healthcare provider of any new or worsening vision symptoms [see Warnings and Precautions (5.4)].. Creatine Phosphokinase (CPK) ElevationInform patients of the signs and symptoms of creatinine phosphokinase (CPK) elevation and the need for monitoring during treatment. Advise patients to inform their healthcare provider of any new or worsening symptoms of unexplained muscle pain, tenderness, or weakness [see Warnings and Precautions (5.5)].. Pancreatic Enzymes ElevationInform patients of the signs and symptoms of pancreatitis and the need to monitor for amylase and lipase elevations during treatment [see Warnings and Precautions (5.6)].. HyperglycemiaInform patients of the risks of new or worsening hyperglycemia and the need to periodically monitor glucose levels. Advise patients with diabetes mellitus or glucose intolerance that antihyperglycemic medications may need to be adjusted during treatment with ALUNBRIG [see Warnings and Precautions (5.7)].. Photosensitivity Inform patients of the signs and symptoms of photosensitivity. Advise patients to limit sun exposure while taking ALUNBRIG and for at least days after the final dose. Advise patients to wear hat, protective clothing, and to use broad-spectrum Ultraviolet (UVA)/ Ultraviolet (UVB) sunscreen and lip balm (SPF >=30) to protect against sunburn [see Warnings and Precautions (5.8)].. Females and Males of Reproductive Potential. Embryo-Fetal ToxicityAdvise females and males of reproductive potential that ALUNBRIG can cause fetal harm [see Warnings and Precautions (5.9), Use in Specific Populations (8.1)]. Advise females of reproductive potential to inform their healthcare provider of known or suspected pregnancy and to use effective contraception during treatment with ALUNBRIG and for at least months after the final dose [see Use in Specific Populations (8.3)]. Advise males with female partners of reproductive potential to use effective contraception during treatment with ALUNBRIG and for at least months after the final dose [see Use in Specific Populations (8.3)].. Advise females of reproductive potential to inform their healthcare provider of known or suspected pregnancy and to use effective contraception during treatment with ALUNBRIG and for at least months after the final dose [see Use in Specific Populations (8.3)]. Advise males with female partners of reproductive potential to use effective contraception during treatment with ALUNBRIG and for at least months after the final dose [see Use in Specific Populations (8.3)].. LactationAdvise females not to breastfeed during treatment with ALUNBRIG and for at least week following the final dose [see Use in Specific Populations (8.2)].. InfertilityAdvise males of reproductive potential of the potential for reduced fertility from ALUNBRIG [see Use in Specific Populations (8.3), Nonclinical Toxicology (13.1)].. Drug InteractionsAdvise patients to inform their healthcare provider of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products. Inform patients to avoid grapefruit or grapefruit juice while taking ALUNBRIG [see Drug Interactions (7)].. Dosing and AdministrationInstruct patients to start with 90 mg of ALUNBRIG once daily for the first days and if tolerated, increase the dose to 180 mg once daily. Advise patients to take ALUNBRIG with or without food [see Dosage and Administration (2.2)].. Missed DoseAdvise patients that if dose of ALUNBRIG is missed or if the patient vomits after taking dose of ALUNBRIG, not to take an extra dose, but to take the next dose at the regular time [see Dosage and Administration (2.2)].

LACTATION SECTION.

8.2 Lactation. Risk SummaryThere 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 week following the final dose.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Brigatinib is 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 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.

NONCLINICAL TOXICOLOGY SECTION.

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 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.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 30 mg Tablet Bottle Carton. NDC 63020-113-30ALUNBRIG(TM)(brigatinib) tablets30 mgRx Only30 Tablets. PRINCIPAL DISPLAY PANEL 30 mg Tablet Bottle Carton.

PEDIATRIC USE SECTION.

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

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Brigatinib exposure-response relationships and the time course of the pharmacodynamic response are unknown. Cardiac ElectrophysiologyThe 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 clinically relevant extent.

PHARMACOKINETICS SECTION.

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 (49%) ng/mL and 1452 (60%) ng/mL, respectively, and the corresponding area under the concentration-time curve (AUC0-Tau) was 8165 (45%) ngoh/mL and 20276 (62%) ngoh/mL. After 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.. AbsorptionFollowing administration of single oral doses of ALUNBRIG of 30 mg to 240 mg, the median time to peak concentration (Tmax) ranged from to hours.. Effect of FoodBrigatinib Cmax was reduced by 13% with no effect on AUC in healthy subjects administered ALUNBRIG after 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.. DistributionBrigatinib 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 307 L.. EliminationFollowing oral administration of ALUNBRIG 180 mg once daily, the mean apparent oral clearance (CL/F) of brigatinib at steady-state is 8.9 L/h and the mean plasma elimination half-life is 25 hours.. MetabolismBrigatinib is primarily metabolized by CYP2C8 and CYP3A4 in vitro. Following oral administration of 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.. ExcretionFollowing oral administration of 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 PopulationsAge, race, sex, body weight, and albumin concentration have no clinically meaningful effect on the pharmacokinetics of brigatinib.. Patients with Hepatic ImpairmentFollowing 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 (2.6)].. Patients with Renal ImpairmentFollowing 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 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 (2.7)].. 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 single 90 mg dose of ALUNBRIG increased brigatinib Cmax by 21% and AUC0-INF by 101%, relative to 90 mg dose of ALUNBRIG administered alone [see Dosage and Administration (2.4), Drug Interactions (7.1)]. 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 single 90 mg dose of ALUNBRIG decreased brigatinib Cmax by 41% and AUC0-INF by 12%, relative to 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 single 180 mg dose of ALUNBRIG decreased brigatinib Cmax by 60% and AUC0-INF by 80%, relative to 180 mg dose of ALUNBRIG administered alone [see Dosage and Administration (2.5), Drug Interactions (7.1)]. moderate CYP3A inducer is predicted to decrease the AUC of brigatinib by approximately 50%.. Effect of Brigatinib on CYP3A Substrates:Coadministration of 180 mg daily doses of ALUNBRIG with single mg oral dose of midazolam (a sensitive CYP3A substrate) decreased midazolam Cmax by 16% and AUC0-INF by 26%, relative to 3 mg oral dose of midazolam administered alone. Brigatinib is considered weak inducer of CYP3A.. In Vitro Studies. Effect of Brigatinib on CYP Enzymes:Brigatinib, at clinically relevant plasma concentrations, induced CYP3A via activation of the pregnane 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 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 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.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryBased on its mechanism of action and findings in animals, ALUNBRIG can cause fetal harm when administered to 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 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 DataIn 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 defect in the abdominal wall) along with visceral findings of moderate bilateral dilatation of the lateral ventricles.

RECENT MAJOR CHANGES SECTION.

Warnings and Precautions, Photosensitivity (5.8)9/2021.