PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. The pharmacokinetics of alectinib and its major active metabolite M4 have been characterized in patients with ALK-positive NSCLC and healthy subjects. In patients with ALK-positive NSCLC, the geometric mean (coefficient of variation %) steady-state maximal concentration (Cmax,ss) for alectinib was 665 ng/mL (44%) and for M4 was 246 ng/mL (45%) with peak to trough concentration ratio of 1.2. The geometric mean steady-state area under the curve from to 12 hours (AUC0-12h,ss) for alectinib was 7,430 ngh/mL (46%) and for M4 was 2,810 ngh/mL (46%). Alectinib exposure is dose proportional across the dose range of 460 mg to 900 mg (i.e., 0.75 to 1.5 times the approved recommended dosage) under fed conditions. Alectinib and M4 reached steady-state concentrations by day 7. The geometric mean accumulation was approximately 6-fold for both alectinib and M4.. AbsorptionAlectinib reached maximal concentrations at hours following administration of ALECENSA 600 mg twice daily under fed conditions in patients with ALK-positive NSCLC. The absolute bioavailability of alectinib was 37% (90% CI: 34%, 40%) under fed conditions.A high-fat, high-calorie meal increased the combined exposure (AUC0-inf) of alectinib plus M4 by 3.1-fold (90% CI: 2.7, 3.6) following oral administration of single 600 mg dose of ALECENSA. DistributionThe apparent volume of distribution is 4,016 for alectinib and 10,093 for M4.Alectinib and M4 are bound to human plasma proteins greater than 99%, independent of drug concentration. Alectinib concentrations in the cerebrospinal fluid in patients with ALK-positive NSCLC approximate estimated alectinib free concentrations in the plasma.In vitro studies suggest that alectinib is not substrate of P-glycoprotein (P-gp), but M4 is substrate of P-gp. Alectinib and M4 are not substrates of breast cancer resistance protein (BCRP), organic anion-transporting polypeptide (OATP) 1B1, or OATP1B3.. EliminationThe apparent clearance (CL/F) is 81.9 L/hour for alectinib and 217 L/hour for M4. The geometric mean elimination half-life is 33 hours for alectinib and 31 hours for M4 in patients with ALK-positive NSCLC.. MetabolismAlectinib is metabolized by CYP3A4 to its major active metabolite M4. The geometric mean metabolite/parent exposure ratio at steady-state is 0.40. M4 is subsequently metabolized by CYP3A4. Alectinib and M4 were the main circulating moieties in plasma, constituting 76% of the total radioactivity. ExcretionNinety-eight percent of the radioactivity was excreted in feces following oral administration of single radiolabeled dose of alectinib under fed conditions. Eighty-four percent of the dose was excreted in the feces as unchanged alectinib, and 6% of the dose was excreted as M4. Excretion of radioactivity in urine was less than 0.5% of administered radiolabeled dose of alectinib.. Specific PopulationsAge (21 to 83 years), body weight (38 to 128 kg), mild hepatic impairment (total bilirubin <= ULN and AST ULN or total bilirubin to <= 1.5 ULN and AST any value), mild to moderate renal impairment (creatinine clearance 30 to 89 mL/min), race (White, Asian, and Other), and sex had no clinically meaningful effect on the systemic exposure of alectinib and M4. The pharmacokinetics of alectinib have not been studied in patients with severe renal impairment (creatinine clearance 30 mL/min), or end-stage renal disease .. Hepatic Impairment: Following administration of single oral dose of 300 mg ALECENSA, the geometric mean ratio [90% confidence interval] for the combined AUCinf of alectinib and M4 in subjects with moderate hepatic impairment (Child-Pugh B) was 1.36 [0.947, 1.96] and in subjects with severe hepatic impairment (Child-Pugh C) was 1.76 [0.984, 3.15] as compared to that in subjects with normal hepatic function. The combined Cmax of alectinib and M4 was comparable among the three groups. No dose adjustment is recommended for patients with mild or moderate hepatic impairment. The recommended dose of ALECENSA in patients with severe hepatic impairment is 450 mg orally twice daily [see Dosage and Administration (2.2) and Use in Specific Populations (8.7)].. Drug Interactions. Effect of Other Drugs on Alectinib No clinically meaningful effect on the combined exposure of alectinib plus M4 was observed in clinical studies following co-administration of ALECENSA with strong CYP3A inhibitor (posaconazole), strong CYP3A inducer (rifampin), or an acid-reducing agent (esomeprazole).. Effect of Alectinib on Other DrugsNo clinically meaningful effect on the exposure of midazolam (sensitive CYP3A substrate) or repaglinide (sensitive CYP2C8 substrate) is expected following co-administration with ALECENSA. In vitro studies suggest that alectinib and M4 do not inhibit CYP1A2, 2B6, 2C9, 2C19 or 2D6.In vitro studies suggest that alectinib and M4 inhibit P-gp and BCRP. Alectinib did not inhibit OATP1B1, OATP1B3, OAT1, OAT3, or OCT2 transport activity in vitro.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following adverse reactions are discussed in greater detail in other sections of the label:Hepatotoxicity [see Warnings and Precautions (5.1)] Interstitial Lung Disease (ILD)/Pneumonitis [see Warnings and Precautions (5.2)] Renal Impairment [see Warnings and Precautions (5.3)] Bradycardia [see Warnings and Precautions (5.4)] Severe Myalgia and Creatine Phosphokinase (CPK) Elevation [see Warnings and Precautions (5.5)] Hemolytic Anemia [see Warnings and Precautions (5.6)] Embryo-Fetal Toxicity [see Warnings and Precautions (5.7)] Hepatotoxicity [see Warnings and Precautions (5.1)] Interstitial Lung Disease (ILD)/Pneumonitis [see Warnings and Precautions (5.2)] Renal Impairment [see Warnings and Precautions (5.3)] Bradycardia [see Warnings and Precautions (5.4)] Severe Myalgia and Creatine Phosphokinase (CPK) Elevation [see Warnings and Precautions (5.5)] Hemolytic Anemia [see Warnings and Precautions (5.6)] Embryo-Fetal Toxicity [see Warnings and Precautions (5.7)] The most common adverse reactions (incidence >=20%) were fatigue, constipation, edema, myalgia, and anemia. (6)To report SUSPECTED ADVERSE REACTIONS, contact Genentech at 1-888-835-2555 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.. Previously Untreated ALK-Positive Metastatic NSCLC The safety of ALECENSA was evaluated in 152 patients with ALK-positive NSCLC in the ALEX study. The median duration of exposure to ALECENSA was 17.9 months. Patient characteristics of the ALEX study population (n=303) were: median age 56 years, age less than 65 (77%), female (56%), Caucasian (50%), Asian (46%), adenocarcinoma histology (92%), never smoker (63%), and ECOG PS or (93%). Serious adverse reactions occurred in 28% of patients treated with ALECENSA; serious adverse reactions reported in 2% or more of patients treated with ALECENSA were pneumonia (4.6%), and renal impairment (3.9%). Grade >= adverse events were reported for 41% of patients in the ALECENSA arm. Fatal adverse reactions occurred in 3.3% of patients treated with ALECENSA; these were renal impairment (2 patients), sudden death, cardiac arrest, and pneumonia (1 patient each). Permanent discontinuation of ALECENSA for adverse reactions occurred in 11% of patients. Adverse drug reactions that led to discontinuation of ALECENSA in 1% or more of patients were renal impairment (2.0%), hyperbilirubinemia (1.3%), increased ALT (1.3%), and increased AST (1.3%). Dose reductions and drug interruption due to adverse reactions occurred in 16% and 19% of patients, respectively, in the ALECENSA arm. The most frequent adverse reactions that led to dose modifications in the ALECENSA arm were hyperbilirubinemia (6%), increased AST (5%), increased ALT (4.6%), and pneumonia (3.3%). Tables and summarize the common adverse reactions and laboratory abnormalities observed in ALEX.Table 3: Adverse Drug Reactions (>10% for all NCI CTCAE Grades or >=2% for Grades 3-4) in Patients Treated with ALECENSA in ALEXAdverse ReactionALECENSAN 152CrizotinibN= 151All Grades (%)Grades 3-4 (%)All Grades (%)Grades 3-4 (%)NCI CTCAE= National Cancer Institute Common Terminology Criteria for Adverse Events; MedDRA Medical Dictionary for Regulatory Activities; SOC System Organ Class.Gastrointestinal Constipation340330 Nausea140.7483.3 Diarrhea120452.0 Vomiting70383.3General FatigueIncludes fatigue and asthenia. 261.3230.7 EdemaIncludes peripheral edema, edema, eyelid edema, localized edema, and face edema. 220.7340.7Musculoskeletal MyalgiaIncludes myalgia and musculoskeletal pain. 2304.00Skin RashIncludes rash, rash maculo-papular, dermatitis acneiform, erythema, generalized rash, rash macular, rash papular, exfoliative rash, and pruritic rash. 150.7130Nervous system DysgeusiaIncludes dysgeusia and hypogeusia. 3.30.7190Eye Vision disordersIncludes blurred vision, visual impairment, vitreous floaters, reduced visual acuity, and diplopia. 4.60230Cardiac BradycardiaIncludes reported cases of bradycardia and sinus bradycardia but is not based on serial ECG assessment. 110150Renal Renal impairmentIncludes increased blood creatinine, creatinine renal clearance decreased, glomerular filtration rate decreased, and acute kidney injury. 123.9Includes two Grade events. 00The following additional clinically significant adverse drug reactions were observed in patients treated with ALECENSA: weight gain (9.9%), photosensitivity reaction (5.3%), stomatitis (3.3%), interstitial lung disease (1.3%), and drug-induced liver injury (1.3%).Table 4: Treatment-Emergent Worsening in Laboratory Values Occurring in 10% of Patients in ALEXParameterALECENSAN= 152CrizotinibN=151All Grades (%)Grades 3-4 (%)All Grades (%)Grades 3-4 (%)Note: Based on National Cancer Institute Common Terminology Criteria for Adverse Events v4.03.Excludes patients with no post-baseline lab assessments.Chemistry Hyperbilirubinemian=147 for alectinib (with baseline values missing for of these patients), n=148 for crizotinib. 5454.70 Increased ASTn=147 for alectinib (with baseline values missing for of these patients), n=148 for crizotinib. 5065611 Increased alkaline phosphatasen=147 for alectinib, n=148 for crizotinib. 500440 Increased ALT 4066216 Increased creatinine Only patients with creatinine increases based on ULN definition. 384.1230.7 Increased CPKn=143 for alectinib (with baseline values missing for 14 of these patients), n=143 for crizotinib (with baseline values missing for 13 of these patients). 372.8521.4 Hypocalcemia 290611.4 Hyperglycemian=134 for alectinib (with baseline values missing for 18 of these patients), n=131 for crizotinib (with baseline values missing for of these patients). 222.2192.3 Hyponatremian=147 for alectinib, n=148 for crizotinib (with baseline values missing for of these patients). 186204.1 Hypokalemia 172120.7 Hypoalbuminemian=146 for alectinib (with baseline values missing for of these patients), n=148 for crizotinib (with baseline values missing for of these patients). 140573.4 Hyperkalemia 121.4161.4 Hypophosphatemian=145 for alectinib (with baseline values missing for of these patients), n=148 for crizotinib (with baseline values missing for of these patients). 91.4252.7 Increased gamma glutamyl transferasen=143 for alectinib (with baseline values missing for of these patients), n=148 (with baseline values missing for of these patients). 70.7394.1Hematology Anemia 627360.7 Lymphopenia 141.4344.1 Neutropenia 140367. ALK-Positive Metastatic NSCLC Previously Treated with Crizotinib The safety of ALECENSA was evaluated in 253 patients with ALK-positive non-small cell lung cancer (NSCLC) treated with ALECENSA in two clinical trials, Studies NP28761 and NP28673. The median duration of exposure to ALECENSA was 9.3 months. One hundred sixty-nine patients (67%) were exposed to ALECENSA for more than months, and 100 patients (40%) for more than one year. The population characteristics were: median age 53 years, age less than 65 (86%), female (55%), White (74%), Asian (18%), NSCLC adenocarcinoma histology (96%), never or former smoker (98%), ECOG Performance Status (PS) or (91%), and prior chemotherapy treatment (78%). Serious adverse reactions occurred in 19% of patients; the most frequently reported serious adverse reactions were pulmonary embolism (1.2%), dyspnea (1.2%), and hyperbilirubinemia (1.2%). Fatal adverse reactions occurred in 2.8% of patients and included hemorrhage (0.8%), intestinal perforation (0.4%), dyspnea (0.4%), pulmonary embolism (0.4%), and endocarditis (0.4%). Permanent discontinuation of ALECENSA for adverse reactions occurred in 6% of patients. The most frequent adverse reactions that led to permanent discontinuation were hyperbilirubinemia (1.6%), increased ALT levels (1.6%), and increased AST levels (1.2%). Overall, 23% of patients initiating treatment at the recommended dose required at least one dose reduction. The median time to first dose reduction was 48 days. The most frequent adverse reactions that led to dose reductions or interruptions were elevations in bilirubin (6%), CPK (4.3%), ALT (4.0%), AST (2.8%), and vomiting (2.8%). Tables and summarize the common adverse reactions and laboratory abnormalities observed in Studies NP28761 and NP28673.Table 5: Adverse Reactions in >= 10% (All Grades) or >= 2% (Grades 3-4) of Patients in Studies NP28761 and NP28673Adverse ReactionsALECENSA N=253All Grades (%)Grades 3-4 (%)Per Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 FatigueIncludes fatigue and asthenia. 411.2Constipation340EdemaIncludes peripheral edema, edema, generalized edema, eyelid edema, and periorbital edema. 300.8MyalgiaIncludes myalgia and musculoskeletal pain. 291.2Cough190RashIncludes rash, maculopapular rash, acneiform dermatitis, erythema, generalized rash, papular rash, pruritic rash, and macular rash. 180.4Nausea180Headache170.8Diarrhea161.2Dyspnea163.6Includes one Grade event. Back pain120Vomiting120.4Increased weight110.4Vision disorderIncludes blurred vision, vitreous floaters, visual impairment, reduced visual acuity, asthenopia, and diplopia. 100An additional clinically significant adverse drug reaction was photosensitivity, which occurred in 9.9% of patients exposed to ALECENSA in Studies NP28761 and NP28673. Patients were advised to avoid sun exposure and to use broad-spectrum sunscreen. The incidence of Grade photosensitivity was 0.4%; the remaining events were Grade in severity. Table 6: Treatment-Emergent Worsening in Laboratory Values Occurring in 20% of Patients in Studies NP28761 and NP28673ParameterALECENSA N=250All Grades (%)Grades 3-4 (%)Per CTCAE version 4.0 Chemistry Increased AST513.6 Increased Alkaline Phosphatase471.2 Increased CPKn=218 for CPK (with baseline values missing for 91 of these patients). 434.6 Hyperbilirubinemia392.4 Hyperglycemian=152 for fasting blood glucose (with baseline values missing for of these patients). 362.0 Increased ALT 344.8 Hypocalcemia 320.4 Hypokalemia294.0 Increased CreatinineOnly patients with creatinine increases based on ULN definition. 280 Hypophosphatemia 212.8 Hyponatremia 202.0Hematology Anemia562.0 Lymphopenian=217 for lymphocytes (with baseline values missing for of these patients). 224.6. 6.2 Postmarketing Experience. The following adverse reactions have been identified during postapproval use of ALECENSA. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.. Blood and lymphatic system disorders: hemolytic anemia.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Alectinib is tyrosine kinase inhibitor that targets ALK and RET. In nonclinical studies, alectinib inhibited ALK phosphorylation and ALK-mediated activation of the downstream signaling proteins STAT3 and AKT, and decreased tumor cell viability in multiple cell lines harboring ALK fusions, amplifications, or activating mutations. The major active metabolite of alectinib, M4, showed similar in vitro potency and activity.Alectinib and M4 demonstrated in vitro and in vivo activity against multiple mutant forms of the ALK enzyme, including some mutations identified in NSCLC tumors in patients who have progressed on crizotinib. In mouse models implanted with tumors carrying ALK fusions, administration of alectinib resulted in antitumor activity and prolonged survival, including in mouse models implanted intracranially with ALK-driven tumor cell lines. 12.2 Pharmacodynamics. Cardiac ElectrophysiologyThe ability of alectinib to prolong the QT interval was assessed in 221 patients administered ALECENSA 600 mg twice daily in clinical studies. ALECENSA did not prolong the QTc (QT corrected for heart rate) interval to any clinically relevant extent. One patient had maximum post-baseline QTcF value of greater than 500 msec, and one patient had maximum QTcF change from baseline of greater than 60 msec.. 12.3 Pharmacokinetics. The pharmacokinetics of alectinib and its major active metabolite M4 have been characterized in patients with ALK-positive NSCLC and healthy subjects. In patients with ALK-positive NSCLC, the geometric mean (coefficient of variation %) steady-state maximal concentration (Cmax,ss) for alectinib was 665 ng/mL (44%) and for M4 was 246 ng/mL (45%) with peak to trough concentration ratio of 1.2. The geometric mean steady-state area under the curve from to 12 hours (AUC0-12h,ss) for alectinib was 7,430 ngh/mL (46%) and for M4 was 2,810 ngh/mL (46%). Alectinib exposure is dose proportional across the dose range of 460 mg to 900 mg (i.e., 0.75 to 1.5 times the approved recommended dosage) under fed conditions. Alectinib and M4 reached steady-state concentrations by day 7. The geometric mean accumulation was approximately 6-fold for both alectinib and M4.. AbsorptionAlectinib reached maximal concentrations at hours following administration of ALECENSA 600 mg twice daily under fed conditions in patients with ALK-positive NSCLC. The absolute bioavailability of alectinib was 37% (90% CI: 34%, 40%) under fed conditions.A high-fat, high-calorie meal increased the combined exposure (AUC0-inf) of alectinib plus M4 by 3.1-fold (90% CI: 2.7, 3.6) following oral administration of single 600 mg dose of ALECENSA. DistributionThe apparent volume of distribution is 4,016 for alectinib and 10,093 for M4.Alectinib and M4 are bound to human plasma proteins greater than 99%, independent of drug concentration. Alectinib concentrations in the cerebrospinal fluid in patients with ALK-positive NSCLC approximate estimated alectinib free concentrations in the plasma.In vitro studies suggest that alectinib is not substrate of P-glycoprotein (P-gp), but M4 is substrate of P-gp. Alectinib and M4 are not substrates of breast cancer resistance protein (BCRP), organic anion-transporting polypeptide (OATP) 1B1, or OATP1B3.. EliminationThe apparent clearance (CL/F) is 81.9 L/hour for alectinib and 217 L/hour for M4. The geometric mean elimination half-life is 33 hours for alectinib and 31 hours for M4 in patients with ALK-positive NSCLC.. MetabolismAlectinib is metabolized by CYP3A4 to its major active metabolite M4. The geometric mean metabolite/parent exposure ratio at steady-state is 0.40. M4 is subsequently metabolized by CYP3A4. Alectinib and M4 were the main circulating moieties in plasma, constituting 76% of the total radioactivity. ExcretionNinety-eight percent of the radioactivity was excreted in feces following oral administration of single radiolabeled dose of alectinib under fed conditions. Eighty-four percent of the dose was excreted in the feces as unchanged alectinib, and 6% of the dose was excreted as M4. Excretion of radioactivity in urine was less than 0.5% of administered radiolabeled dose of alectinib.. Specific PopulationsAge (21 to 83 years), body weight (38 to 128 kg), mild hepatic impairment (total bilirubin <= ULN and AST ULN or total bilirubin to <= 1.5 ULN and AST any value), mild to moderate renal impairment (creatinine clearance 30 to 89 mL/min), race (White, Asian, and Other), and sex had no clinically meaningful effect on the systemic exposure of alectinib and M4. The pharmacokinetics of alectinib have not been studied in patients with severe renal impairment (creatinine clearance 30 mL/min), or end-stage renal disease .. Hepatic Impairment: Following administration of single oral dose of 300 mg ALECENSA, the geometric mean ratio [90% confidence interval] for the combined AUCinf of alectinib and M4 in subjects with moderate hepatic impairment (Child-Pugh B) was 1.36 [0.947, 1.96] and in subjects with severe hepatic impairment (Child-Pugh C) was 1.76 [0.984, 3.15] as compared to that in subjects with normal hepatic function. The combined Cmax of alectinib and M4 was comparable among the three groups. No dose adjustment is recommended for patients with mild or moderate hepatic impairment. The recommended dose of ALECENSA in patients with severe hepatic impairment is 450 mg orally twice daily [see Dosage and Administration (2.2) and Use in Specific Populations (8.7)].. Drug Interactions. Effect of Other Drugs on Alectinib No clinically meaningful effect on the combined exposure of alectinib plus M4 was observed in clinical studies following co-administration of ALECENSA with strong CYP3A inhibitor (posaconazole), strong CYP3A inducer (rifampin), or an acid-reducing agent (esomeprazole).. Effect of Alectinib on Other DrugsNo clinically meaningful effect on the exposure of midazolam (sensitive CYP3A substrate) or repaglinide (sensitive CYP2C8 substrate) is expected following co-administration with ALECENSA. In vitro studies suggest that alectinib and M4 do not inhibit CYP1A2, 2B6, 2C9, 2C19 or 2D6.In vitro studies suggest that alectinib and M4 inhibit P-gp and BCRP. Alectinib did not inhibit OATP1B1, OATP1B3, OAT1, OAT3, or OCT2 transport activity in vitro.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. Previously Untreated ALK-Positive Metastatic NSCLC The efficacy of ALECENSA for the treatment of patients with ALK-positive NSCLC who had not received prior systemic therapy for metastatic disease was established in an open-label, randomized, active-controlled, multicenter study (ALEX: NCT02075840). Patients were required to have an ECOG performance status of 0-2 and ALK-positive NSCLC as identified by the VENTANA ALK (D5F3) CDx assay. Neurologically stable patients with treated or untreated central nervous system (CNS) metastases, including leptomeningeal metastases, were eligible; patients with neurologic signs and symptoms due to CNS metastases were required to have completed whole brain radiation or gamma knife irradiation at least 14 days prior to enrollment and be clinically stable. Patients with baseline QTc 470 ms were ineligible.Patients were randomized 1:1 to receive ALECENSA 600 mg orally twice daily or crizotinib 250 mg orally twice daily. Randomization was stratified by ECOG performance status (0/1 vs. 2), race (Asian vs. non-Asian), and the presence or absence of CNS metastases at baseline. Treatment on both arms was continued until disease progression or unacceptable toxicity. The major efficacy outcome measure was progression-free survival (PFS) as determined by investigator assessment according to RECIST v1.1. Additional efficacy outcome measures were PFS as determined by independent review committee (IRC), time to CNS progression by IRC based on RECIST v1.1, objective response rate (ORR) and duration of response (DOR), and overall survival (OS). Additional exploratory outcome measures were CNS objective response rate (CNS-ORR) and CNS duration of response (CNS-DOR) by IRC in patients with CNS metastases at baseline.A total of 303 patients were randomized to ALECENSA (n=152) or crizotinib (n=151). The demographic characteristics of the study population were 56% female, median age 56 years (range: 18 to 91 years), 50% White, 46% Asian, 1% Black, and 3% other races. The majority of patients had adenocarcinoma (92%) and never smoked (63%). CNS metastases were present in 40% (n=122) of patients: of these, 43 patients had measurable CNS lesions as determined by an IRC. The ALEX study demonstrated significant improvement in PFS. The time to cause-specific CNS progression as assessed by IRC was also significantly improved; there was lower incidence of progression in the CNS as the first site of disease progression, alone or with concurrent systemic progression, in the ALECENSA arm (12%) as compared to the crizotinib arm (45%). Efficacy results from ALEX are summarized in Table and Figure . Table 7: Efficacy Results in ALEX per IRC AssessmentALECENSAN=152CrizotinibN=151CNS: central nervous system, ORR: overall response rate, IRC: independent review committee, CI: confidence interval, NE: not estimable. Progression-Free Survival Number of events (%)63 (41%)92 (61%) Progressive disease (%)51 (34%)82 (54%) Death (%)12 (8%)10 (7%) Median in months (95% CI)25.7 (19.9, NE)10.4 (7.7, 14.6) Hazard ratio (95% CI) Stratified by race (Asian vs. non-Asian) and CNS metastases at baseline (yes vs. no) for Cox model, log-rank test and Cochran Mantel-Haenszel test, respectively 0.53 (0.38, 0.73) P-value 0.0001Overall Response Rate Overall response rate, (95% CI) Clopper and Pearson exact binomial 95% confidence interval. 79% (72, 85)72% (64, 79) P-value 0.1652 Complete response, %13%6% Partial response, %66%66%Duration of Response Number of respondersn=120n=109 Response duration >=6 months82%57% Response duration >=12 months64%36% Response duration >=18 months37%14%Figure 1: Kaplan-Meier Plot of Progression-Free Survival (IRC) in ALEX Results for PFS as determined by investigator assessment (HR=0.48 [95% CI: 0.35-0.66], stratified log-rank p<0.0001) were similar to that observed by IRC. At the data cutoff point overall survival data was not mature.The results of prespecified exploratory analyses of CNS response rate in patients with measurable CNS lesions at baseline are summarized in Table 8.Table 8: IRC-Assessed CNS Responses in Patients with Measurable CNS Lesions at Baseline in ALEXALECENSACrizotinibIRC: Independent Review Committee; CI: Confidence Interval; NE: Not EstimableCNS Tumor Response AssessmentN 21N 22CNS Objective Response Rate, (95% CIClopper and Pearson exact binomial 95% confidence interval)81% (58, 95)50% (28,72) Complete Response38%5%Duration of CNS Response Number of responders1711 CNS response duration >= 12 months59%36%. Figure 1. ALK-Positive Metastatic NSCLC Previously Treated with CrizotinibThe safety and efficacy of ALECENSA were established in two single-arm, multicenter clinical trials: NP28761 (NCT01588028) and NP28673 (NCT01801111). Patients with locally advanced or metastatic ALK-positive NSCLC, who have progressed on crizotinib, with documented ALK-positive NSCLC based on an FDA-approved test, and ECOG PS of 0-2 were enrolled in both studies. Eligibility criteria permitted enrollment of patients with prior chemotherapy and prior CNS radiotherapy provided that CNS metastases were stable for at least two weeks. All patients received ALECENSA 600 mg orally twice daily. The major efficacy outcome measure in both studies was objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1) as evaluated per Independent Review Committee (IRC). Additional outcome measures as evaluated by the IRC included duration of response (DOR), CNS ORR, and CNS DOR.NP28761 was conducted in North America and enrolled 87 patients. Baseline demographic and disease characteristics in NP28761 were median age 54 years old (range 29 to 79, 18% 65 and over), 84% White and 8% Asian, 55% female, 35% ECOG PS and 55% ECOG PS 1, 100% never or former smokers, 99% Stage IV, 94% adenocarcinoma, and 74% prior chemotherapy. The most common sites of extra-thoracic metastasis included 60% CNS (of whom 65% had received CNS radiation), 43% lymph nodes, 36% bone, and 34% liver.NP28673 was conducted internationally and enrolled 138 patients. Baseline demographic and disease characteristics in NP28673 were median age 52 years old (range 22 to 79, 10% 65 and over), 67% White and 26% Asian, 56% female, 32% ECOG PS and 59% ECOG PS 1, 98% never or former smokers, 99% Stage IV, 96% adenocarcinoma, and 80% prior chemotherapy. The most common sites of extra-thoracic metastasis included 61% CNS (of whom 73% had received CNS radiation), 51% bone, 38% lymph nodes, and 30% liver.Efficacy results from NP28761 and NP28673 in all treated patients are summarized in Table 9. The median duration of follow-up on Study NP28761 was 4.8 months for both IRC and Investigator assessments and on Study NP28673, 10.9 months for IRC assessment and 7.0 months for Investigator assessment. All responses were partial responses.Table 9: Efficacy Results in Studies NP28761 and NP28673 Efficacy ParameterNP28761 (N=87)NP28673 (N=138)IRC18 patients in NP28761 and 16 patients in NP28673 did not have measurable disease at baseline as per IRC assessment and were classified as non-responders in the IRC analysis. AssessmentInvestigator AssessmentIRC AssessmentInvestigator AssessmentObjective Response Rate (95% CI)38%(28; 49)46%(35; 57)44%(36; 53)48%(39; 57)Number of Responders33406166Duration of Response, median in months (95% CI)7.5(4.9, Not Estimable)NE(4.9, Not Estimable)11.2 (9.6, Not Estimable)7.8(7.4, 9.2)An assessment of ORR and duration of response for CNS metastases in the subgroup of 51 patients in NP28761 and NP28673 with baseline measurable lesions in the CNS according to RECIST v1.1 are summarized in Table 10. Thirty-five (69%) patients with measurable CNS lesions had received prior brain radiation, including 25 (49%) who completed radiation treatment at least months before starting treatment with ALECENSA. Responses were observed irrespective of prior brain radiation status.Table 10: CNS Objective Response in Patients with Measurable CNS Lesions in Studies NP28761 and NP28673Efficacy ParameterN=51CNS Objective Response Rate (95% CI)61%(46, 74) Complete Response18% Partial Response43%CNS Duration of Response, median in months (95% CI)9.1(5.8, Not Estimable).

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. 600 mg orally twice daily. Administer ALECENSA with food. (2.2). 2.1Patient Selection. Select patients for the treatment of metastatic NSCLC with ALECENSA based on the presence of ALK positivity in tumor tissue or plasma specimens [see Indications and Usage (1) and Clinical Studies (14)]. If ALK rearrangements are not detected in plasma specimen, test tumor tissue if feasible.Information on FDA-approved tests for the detection of ALK rearrangements in NSCLC is available at http://www.fda.gov/CompanionDiagnostics.. 2.2Dosing and Administration. The recommended dose of ALECENSA is 600 mg orally twice daily [see Clinical Pharmacology (12.3)]. Administer ALECENSA until disease progression or unacceptable toxicity.The recommended dose of ALECENSA in patients with severe hepatic impairment (Child-Pugh C) is 450 mg orally twice daily [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)]. ALECENSA should be taken with food. Do not open or dissolve the contents of the capsule. If dose of ALECENSA is missed or vomiting occurs after taking dose of ALECENSA, take the next dose at the scheduled time.. 2.3Dose Modifications for Adverse Reactions. The dose reduction schedule for ALECENSA is provided in Table 1.Table 1: ALECENSA Dose Reduction ScheduleDose reduction scheduleDose levelStarting dose600 mg taken orally twice dailyFirst dose reduction450 mg taken orally twice dailySecond dose reduction300 mg taken orally twice dailyDiscontinue if patients are unable to tolerate the 300 mg twice daily dose.Recommendations for dose modifications of ALECENSA in case of adverse reactions are provided in Table 2.Table 2: ALECENSA Dose Modifications for Adverse ReactionsCriteriaALT alanine transaminase; AST aspartate transaminase; ULN upper limit of normal; ILD interstitial lung disease; CPK blood creatine phosphokinase ALECENSA Dose ModificationALT or AST elevation of greater than times upper limit of normal (ULN) with total bilirubin less than or equal to times ULNTemporarily withhold until recovery to baseline or to less than or equal to times ULN, then resume at reduced dose as per Table 1. ALT or AST elevation greater than times ULN with total bilirubin elevation greater than times ULN in the absence of cholestasis or hemolysisPermanently discontinue ALECENSA.Total bilirubin elevation of greater than times ULNTemporarily withhold until recovery to baseline or to less than or equal to 1.5 times ULN, then resume at reduced dose as per Table 1.Any grade treatment-related interstitial lung disease (ILD)/pneumonitisPermanently discontinue ALECENSA.Grade renal impairmentTemporarily withhold until serum creatinine recovers to less than or equal to 1.5 times ULN, then resume at reduced dose.Grade renal impairmentPermanently discontinue ALECENSA.Symptomatic bradycardiaWithhold ALECENSA until recovery to asymptomatic bradycardia or to heart rate of 60 bpm or above.If contributing concomitant medication is identified and discontinued, or its dose is adjusted, resume ALECENSA at previous dose upon recovery to asymptomatic bradycardia or to heart rate of 60 bpm or above. If no contributing concomitant medication is identified, or if contributing concomitant medications are not discontinued or dose modified, resume ALECENSA at reduced dose (see Table 1) upon recovery to asymptomatic bradycardia or to heart rate of 60 bpm or above.BradycardiaHeart rate less than 60 beats per minute (bpm) (life-threatening consequences, urgent intervention indicated)Permanently discontinue ALECENSA if no contributing concomitant medication is identified.If contributing concomitant medication is identified and discontinued, or its dose is adjusted, resume ALECENSA at reduced dose (see Table 1) upon recovery to asymptomatic bradycardia or to heart rate of 60 bpm or above, with frequent monitoring as clinically indicated. Permanently discontinue ALECENSA in case of recurrence.CPK elevation greater than times ULNTemporarily withhold until recovery to baseline or to less than or equal to 2.5 times ULN, then resume at same dose. CPK elevation greater than 10 times ULN or second occurrence of CPK elevation of greater than times ULNTemporarily withhold until recovery to baseline or to less than or equal to 2.5 times ULN, then resume at reduced dose as per Table 1.Hemolytic AnemiaWithhold ALECENSA if hemolytic anemia is suspected.Upon resolution, resume at reduced dose or permanently discontinue.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Patient Information).Inform patients of the following:. HepatotoxicityInform patients of the signs and symptoms of bilirubin and hepatic transaminase elevations. Advise patients to contact their healthcare provider immediately for signs or symptoms of bilirubin and hepatic transaminase elevations [see Warnings and Precautions (5.1)]. Interstitial Lung Disease (ILD)/PneumonitisInform patients of the risks of severe ILD/pneumonitis. Advise patients to contact their healthcare provider immediately to report new or worsening respiratory symptoms [see Warnings and Precautions (5.2)]. Renal ImpairmentInform patients of the risk of severe and potentially fatal renal impairment. Advise patients to contact their healthcare provider for change in urine color, reduced urine output, or swelling in the legs and feet [see Warnings and Precautions (5.3)].. BradycardiaInform patients that symptoms of bradycardia including dizziness, lightheadedness, and syncope can occur while taking ALECENSA. Advise patients to contact their healthcare provider to report these symptoms and to inform their healthcare provider about the use of any heart or blood pressure medications [see Warnings and Precautions (5.4)].. Severe Myalgia/CPK ElevationInform patients of signs and symptoms of myalgia, including unexplained and/or persistent muscle pain, tenderness, or weakness. Advise patients to contact their healthcare provider immediately to report new or worsening symptoms of muscle pain or weakness [see Warnings and Precautions (5.5)].. Hemolytic AnemiaAdvise patients to contact their healthcare provider if they develop any signs or symptoms of hemolytic anemia [see Warnings and Precautions (5.6)]. PhotosensitivityInform patients of the signs and symptoms of photosensitivity. Advise patients to avoid prolonged sun exposure while taking ALECENSA and for at least days after study drug discontinuation and to use proper protection from the sun. Advise patients to use broad spectrum ultraviolet (UVA)/ultraviolet (UVB) sunscreen and lip balm (SPF >= 50) to help protect against potential sunburn [see Adverse Reactions (6.1)].. Embryo-Fetal ToxicityALECENSA can cause fetal harm if taken during pregnancy. Advise pregnant woman of the potential risk to fetus [see Warnings and Precautions (5.6) and Use in Specific Populations (8.1, 8.3)].Advise females of reproductive potential to use effective contraception during treatment with ALECENSA and for at least week after the last dose of ALECENSA. Advise patients to inform their healthcare provider of known or suspected pregnancy [see Warnings and Precautions (5.6) and Use in Specific Populations (8.1, 8.3)]. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with ALECENSA and for months after the last dose [see Use in Specific Populations (8.3) and Nonclinical Toxicology (13.1)]. LactationAdvise women not to breastfeed during treatment with ALECENSA and for one week after the last dose [see Use in Specific Populations (8.2)]. AdministrationInstruct patients to take ALECENSA twice day. Advise patients to take ALECENSA with food and to swallow ALECENSA capsules whole [see Dosage and Administration (2.2)]. Missed DoseAdvise patients that if dose of ALECENSA is missed or if the patient vomits after taking dose of ALECENSA, patients should be advised not to take an extra dose, but to take the next dose at the regular time [see Dosage and Administration (2.2)].

SPL PATIENT PACKAGE INSERT SECTION.

This Patient Information has been approved by the U.S. Food and Drug Administration.Revised: 09/2021 PATIENT INFORMATIONALECENSA(R) (a-le-sen-sah)(alectinib)capsulesWhat is the most important information should know about ALECENSAALECENSA may cause serious side effects, including:Liver problems (hepatotoxicity). ALECENSA may cause liver injury. Your healthcare provider will do blood tests at least every weeks for the first months, and then time each month and as needed during treatment with ALECENSA. Tell your healthcare provider right away if you get any of the following signs and symptoms: feeling tiredfeeling less hungry than usualyellowing of your skin or the whites of your eyesdark urineitchy skinnausea or vomitingpain on the right side of your stomach areableeding or bruising more easily than normalLung problems. ALECENSA may cause severe or life-threatening swelling (inflammation) of the lungs during treatment. 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, shortness of breath, cough, or fever.Kidney problems. ALECENSA may cause severe or life-threatening kidney problems. Tell your healthcare provider right away if you have change in the amount or color of your urine, or if you get new or worsening swelling in your legs or feet.Slow heartbeat (bradycardia). ALECENSA may cause very slow heartbeats that can be severe. Your healthcare provider will check your heart rate and blood pressure during treatment with ALECENSA. Tell your healthcare provider right away if you feel dizzy, lightheaded, or if you faint during treatment with ALECENSA. Tell your healthcare provider if you take any heart or blood pressure medicines.Muscle pain, tenderness, and weakness (myalgia). Muscle problems are common with ALECENSA and can be severe. Your healthcare provider will do blood tests at least every weeks for the first month and as needed during treatment with ALECENSA. 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. Breakdown of healthy red blood cells earlier than normal (hemolytic anemia). Hemolytic anemia can happen in some people who take ALECENSA. If this happens, you may not have enough healthy red blood cells. Your healthcare provider may temporarily stop ALECENSA and do blood tests, if needed, to check for this problem. If you develop hemolytic anemia, your healthcare provider may either restart you on ALECENSA at lower dose when the hemolytic anemia goes away, or may stop your treatment with ALECENSA. Tell your healthcare provider right away if you experience yellow skin (jaundice), weakness or dizziness, or shortness of breath.See What are the possible side effects of ALECENSA for more information about side effects.What is ALECENSAALECENSA is prescription medicine used to treat people with non-small cell lung cancer (NSCLC):that is caused by an abnormal anaplastic lymphoma kinase (ALK) gene, and that has spread to other parts of your bodyIt is not known if ALECENSA is safe and effective in children.Before you take ALECENSA, tell your healthcare provider about all of your medical conditions, including if you:have liver problemshave lung or breathing problemshave slow heartbeatare pregnant or plan to become pregnant. ALECENSA can harm your unborn baby. Tell your healthcare provider right away if you become pregnant during treatment with ALECENSA or think you may be pregnant.Females who are able to become pregnant should use effective birth control during treatment with ALECENSA and for week after the final dose of ALECENSA.Males who have female partners that are able to become pregnant should use effective birth control during treatment with ALECENSA and for months after the final dose of ALECENSA. are breastfeeding or plan to breastfeed. It is not known if ALECENSA passes into your breast milk. Do not breastfeed during treatment with ALECENSA and for week after the final dose of ALECENSA. Talk to your healthcare provider about the best way to feed your baby during this time. Tell your healthcare provider about all the medicines you take, including prescription medicines, over-the-counter medicines, vitamins, or herbal supplements.How should take ALECENSATake ALECENSA exactly as your healthcare provider tells you to take it. Do not change your dose or stop taking ALECENSA unless your healthcare provider tells you to.Your healthcare provider may change your dose, temporarily stop, or permanently stop treatment with ALECENSA if you have side effects.Take ALECENSA times day. Take ALECENSA with food.Swallow ALECENSA capsules whole. Do not open or dissolve the capsule contents.If you miss dose of ALECENSA, do not take the missed dose. Take your next dose at your regular time.If you vomit after taking dose of ALECENSA, do not take an extra dose. Take your next dose at your regular time.What should avoid while taking ALECENSAAvoid spending time in the sunlight during treatment with ALECENSA and for days after the final dose of ALECENSA. You may burn more easily and get severe sunburns. Use sunscreen and lip balm with an SPF 50 or greater to help protect against sunburn.What are the possible side effects of ALECENSAALECENSA may cause serious side effects, including:See What is the most important information should know about ALECENSAThe most common side effects of ALECENSA include:tirednessconstipationswelling in your hands, feet, ankles, face and eyelidsmuscle pain, tenderness, and weakness (myalgia). See What is the most important information should know about ALECENSA anemiaThese are not all of the possible side effects of ALECENSA. For more information, ask your healthcare provider or pharmacist.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store ALECENSADo not store ALECENSA at temperatures above 86F (30C).Store ALECENSA capsules in the original container.Keep ALECENSA capsules dry and away from light.Keep ALECENSA and all medicines out of the reach of children.General information about the safe and effective use of ALECENSA.Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use ALECENSA for condition for which it was not prescribed. Do not give ALECENSA to other people, even if they have the same symptoms that you have. It may harm them. You can ask your healthcare provider or pharmacist for information about ALECENSA that is written for health professionals.What are the ingredients in ALECENSAActive ingredient: alectinibInactive ingredients: lactose monohydrate, hydroxypropylcellulose, sodium lauryl sulfate, magnesium stearate and carboxymethylcellulose calcium. Capsule shell contains: hypromellose, carrageenan, potassium chloride, titanium dioxide, corn starch, and carnauba wax. Printing ink contains: red iron oxide (E172), yellow iron oxide (E172), FD&C Blue No. aluminum lake (E132), carnauba wax, white shellac, and glyceryl monooleate.Distributed by: Genentech, Inc., Member of the Roche Group, DNA Way, South San Francisco, CA 94080-4990ALECENSA(R) is registered trademark of Chugai Pharmaceutical Co., Ltd., Tokyo, Japan(C)2021 Genentech, Inc. For more information, go to www.ALECENSA.com or call 1-800-253-2367.. Liver problems (hepatotoxicity). ALECENSA may cause liver injury. Your healthcare provider will do blood tests at least every weeks for the first months, and then time each month and as needed during treatment with ALECENSA. Tell your healthcare provider right away if you get any of the following signs and symptoms: feeling tired. feeling less hungry than usual. yellowing of your skin or the whites of your eyes. dark urine. itchy skin. nausea or vomiting. pain on the right side of your stomach area. bleeding or bruising more easily than normal. Lung problems. ALECENSA may cause severe or life-threatening swelling (inflammation) of the lungs during treatment. 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, shortness of breath, cough, or fever.. Kidney problems. ALECENSA may cause severe or life-threatening kidney problems. Tell your healthcare provider right away if you have change in the amount or color of your urine, or if you get new or worsening swelling in your legs or feet.. Slow heartbeat (bradycardia). ALECENSA may cause very slow heartbeats that can be severe. Your healthcare provider will check your heart rate and blood pressure during treatment with ALECENSA. Tell your healthcare provider right away if you feel dizzy, lightheaded, or if you faint during treatment with ALECENSA. Tell your healthcare provider if you take any heart or blood pressure medicines.. Muscle pain, tenderness, and weakness (myalgia). Muscle problems are common with ALECENSA and can be severe. Your healthcare provider will do blood tests at least every weeks for the first month and as needed during treatment with ALECENSA. 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. Breakdown of healthy red blood cells earlier than normal (hemolytic anemia). Hemolytic anemia can happen in some people who take ALECENSA. If this happens, you may not have enough healthy red blood cells. Your healthcare provider may temporarily stop ALECENSA and do blood tests, if needed, to check for this problem. If you develop hemolytic anemia, your healthcare provider may either restart you on ALECENSA at lower dose when the hemolytic anemia goes away, or may stop your treatment with ALECENSA. Tell your healthcare provider right away if you experience yellow skin (jaundice), weakness or dizziness, or shortness of breath.. that is caused by an abnormal anaplastic lymphoma kinase (ALK) gene, and that has spread to other parts of your body. have liver problems. have lung or breathing problems. have slow heartbeat. are pregnant or plan to become pregnant. ALECENSA can harm your unborn baby. Tell your healthcare provider right away if you become pregnant during treatment with ALECENSA or think you may be pregnant.Females who are able to become pregnant should use effective birth control during treatment with ALECENSA and for week after the final dose of ALECENSA.Males who have female partners that are able to become pregnant should use effective birth control during treatment with ALECENSA and for months after the final dose of ALECENSA. Females who are able to become pregnant should use effective birth control during treatment with ALECENSA and for week after the final dose of ALECENSA.. Males who have female partners that are able to become pregnant should use effective birth control during treatment with ALECENSA and for months after the final dose of ALECENSA.. are breastfeeding or plan to breastfeed. It is not known if ALECENSA passes into your breast milk. Do not breastfeed during treatment with ALECENSA and for week after the final dose of ALECENSA. Talk to your healthcare provider about the best way to feed your baby during this time. Take ALECENSA exactly as your healthcare provider tells you to take it. Do not change your dose or stop taking ALECENSA unless your healthcare provider tells you to.. Your healthcare provider may change your dose, temporarily stop, or permanently stop treatment with ALECENSA if you have side effects.. Take ALECENSA times day. Take ALECENSA with food.. Swallow ALECENSA capsules whole. Do not open or dissolve the capsule contents.. If you miss dose of ALECENSA, do not take the missed dose. Take your next dose at your regular time.. If you vomit after taking dose of ALECENSA, do not take an extra dose. Take your next dose at your regular time.. Avoid spending time in the sunlight during treatment with ALECENSA and for days after the final dose of ALECENSA. You may burn more easily and get severe sunburns. Use sunscreen and lip balm with an SPF 50 or greater to help protect against sunburn.. See What is the most important information should know about ALECENSA. tiredness. constipation. swelling in your hands, feet, ankles, face and eyelids. muscle pain, tenderness, and weakness (myalgia). See What is the most important information should know about ALECENSA . anemia. Do not store ALECENSA at temperatures above 86F (30C).. Store ALECENSA capsules in the original container.. Keep ALECENSA capsules dry and away from light.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Lactation: Do not breastfeed. (8.2). 8.1 Pregnancy. Risk SummaryBased on animal studies and its mechanism of action, ALECENSA can cause fetal harm when administered to pregnant woman [see Clinical Pharmacology (12.1)]. There are no available data on ALECENSA use in pregnant women. Administration of alectinib to pregnant rats and rabbits by oral gavage during the period of organogenesis resulted in embryo-fetal toxicity and abortion at maternally toxic doses with exposures approximately 2.7 times those observed in humans treated with alectinib at 600 mg twice daily (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 preliminary rabbit embryo-fetal study, administration of alectinib by oral gavage during the period of organogenesis resulted in abortion or complete embryo-fetal mortality at maternally toxic dose of 27 mg/kg/day (approximately 2.9-fold the estimated area under the curve (AUC0-24h,ss) in humans treated with alectinib 600 mg BID) in three of six pregnant rabbits. The remaining three pregnant rabbits in this group had few live fetuses, decreased fetal and placental weights, and retroesophageal subclavian artery. In rat preliminary embryo-fetal development study, administration of alectinib during organogenesis resulted in complete litter loss in all pregnant rats at 27 mg/kg/day (approximately 4.5-fold the estimated AUC0-24h,ss in humans treated with alectinib 600 mg BID). Doses greater than or equal to mg/kg/day (approximately 2.7-fold the estimated human AUC0-24h,ss in humans treated with alectinib 600 mg BID), resulted in maternal toxicity as well as developmental toxicities including decreased fetal weight, dilated ureter, thymic cord, small ventricle and thin ventricle wall, and reduced number of sacral and caudal vertebrae.. 8.2 Lactation. Risk SummaryThere are no data on the presence of alectinib or its metabolites in human milk, the effects of alectinib on the breastfed infant, or its effects on milk production. Because of the potential for serious adverse reactions in breastfed infants from alectinib, advise lactating woman not to breastfeed during treatment with ALECENSA and for week after the final dose. 8.3 Females and Males of Reproductive Potential. Contraception. FemalesALECENSA can cause fetal harm when administered to pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with ALECENSA and for week after the final dose [see Use in Specific Populations (8.1)].. MalesBased on genotoxicity findings, advise males with female partners of reproductive potential to use effective contraception during treatment with ALECENSA and for months following the final dose [see Nonclinical Toxicology (13.1)]. 8.4 Pediatric Use. The safety and effectiveness of ALECENSA in pediatric patients have not been established.. Animal DataJuvenile animal studies have not been conducted using alectinib. In general toxicology studies, treatment of rats with doses of alectinib resulting in exposures greater than or equal to approximately 4.5 times those in humans treated with alectinib at 600 mg twice daily resulted in changes in the growing teeth and bones. Findings in teeth included discoloration and changes in tooth size along with histopathological disarrangement of the ameloblast and odontoblast layers. There were also decreases in the trabecular bone and increased osteoclast activity in the femur and sternum.. 8.5 Geriatric Use. Clinical studies of ALECENSA did not include sufficient number of subjects aged 65 and older to determine whether they respond differently from younger subjects. 8.6Renal Impairment. No dose adjustment is recommended for patients with mild or moderate renal impairment. The safety of ALECENSA in patients with severe renal impairment (creatinine clearance less than 30 mL/min) or end-stage renal disease has not been studied [see Clinical Pharmacology (12.3)]. 8.7Hepatic Impairment. No dose adjustment is recommended for patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment. Increased exposure of alectinib occurred in patients with severe hepatic impairment (Child-Pugh C). The recommended dose of ALECENSA in patients with severe hepatic impairment (Child-Pugh C) is 450 mg orally twice daily [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Hepatotoxicity: Monitor liver laboratory tests every weeks during the first months of treatment, then once month and as clinically indicated, with more frequent testing in patients who develop transaminase and bilirubin elevations. In case of severe ALT, AST, or bilirubin elevations, withhold, then reduce dose, or permanently discontinue ALECENSA. (2.3, 5.1)Interstitial Lung Disease (ILD)/Pneumonitis: Immediately withhold ALECENSA in patients diagnosed with ILD/pneumonitis and permanently discontinue if no other potential causes of ILD/pneumonitis have been identified. (2.3, 5.2)Renal Impairment: Withhold ALECENSA for severe renal impairment, then resume ALECENSA at reduced dose upon recovery or permanently discontinue (2.3, 5.3). Bradycardia: Monitor heart rate and blood pressure regularly. If symptomatic, withhold ALECENSA then reduce dose, or permanently discontinue. (2.3, 5.4)Severe Myalgia and Creatine Phosphokinase (CPK) Elevation: Assess CPK every weeks during the first month of treatment and in patients reporting unexplained muscle pain, tenderness, or weakness. In case of severe CPK elevations, withhold, then resume or reduce dose. (2.3, 5.5)Hemolytic Anemia: If hemolytic anemia is suspected, withhold ALECENSA. If hemolytic anemia is confirmed, consider resuming at reduced dose upon resolution or permanently discontinue. (5.6)Embryo-Fetal Toxicity: ALECENSA can cause fetal harm. Advise females of reproductive potential of the potential risk to fetus and to use effective contraception. (5.7, 8.1, 8.3). Hepatotoxicity: Monitor liver laboratory tests every weeks during the first months of treatment, then once month and as clinically indicated, with more frequent testing in patients who develop transaminase and bilirubin elevations. In case of severe ALT, AST, or bilirubin elevations, withhold, then reduce dose, or permanently discontinue ALECENSA. (2.3, 5.1). Interstitial Lung Disease (ILD)/Pneumonitis: Immediately withhold ALECENSA in patients diagnosed with ILD/pneumonitis and permanently discontinue if no other potential causes of ILD/pneumonitis have been identified. (2.3, 5.2). Renal Impairment: Withhold ALECENSA for severe renal impairment, then resume ALECENSA at reduced dose upon recovery or permanently discontinue (2.3, 5.3). Bradycardia: Monitor heart rate and blood pressure regularly. If symptomatic, withhold ALECENSA then reduce dose, or permanently discontinue. (2.3, 5.4). Severe Myalgia and Creatine Phosphokinase (CPK) Elevation: Assess CPK every weeks during the first month of treatment and in patients reporting unexplained muscle pain, tenderness, or weakness. In case of severe CPK elevations, withhold, then resume or reduce dose. (2.3, 5.5). Hemolytic Anemia: If hemolytic anemia is suspected, withhold ALECENSA. If hemolytic anemia is confirmed, consider resuming at reduced dose upon resolution or permanently discontinue. (5.6). Embryo-Fetal Toxicity: ALECENSA can cause fetal harm. Advise females of reproductive potential of the potential risk to fetus and to use effective contraception. (5.7, 8.1, 8.3). 5.1Hepatotoxicity. Elevations of AST greater than times the upper limit of normal (ULN) occurred in 4.6% of patients, and elevations of ALT greater than times the ULN occurred in 5.3% of the 405 patients in Studies NP28761, NP28673 and ALEX who received ALECENSA at dose of 600 mg BID. Elevations of bilirubin greater than times the ULN occurred in 3.7% of patients. The majority (69% of the patients with hepatic transaminase elevations and 68% of the patients with bilirubin elevations) of these events occurred during the first months of treatment. Six patients discontinued ALECENSA for Grades 3-4 AST and/or ALT elevations, and patients discontinued ALECENSA for Grade bilirubin elevations. Concurrent elevations in ALT or AST greater than or equal to times the ULN and total bilirubin greater than or equal to times the ULN, with normal alkaline phosphatase, occurred in less than 1% of patients treated with ALECENSA across clinical trials. Three patients with Grades 3-4 AST/ALT elevations had drug-induced liver injury (documented by liver biopsy in two cases).Monitor liver function tests including ALT, AST, and total bilirubin every weeks during the first months of treatment, then once month and as clinically indicated, with more frequent testing in patients who develop transaminase and bilirubin elevations. Based on the severity of the adverse drug reaction, withhold ALECENSA and resume at reduced dose or permanently discontinue ALECENSA as described in Table [see Dosage and Administration (2.3)]. 5.2Interstitial Lung Disease (ILD)/Pneumonitis. ILD/pneumonitis occurred in three (0.7%) patients treated with ALECENSA in Studies NP28761, NP28673 and ALEX. One (0.2%) of these events was severe (Grade 3).Promptly investigate for ILD/pneumonitis in any patient who presents with worsening of respiratory symptoms indicative of ILD/pneumonitis (e.g., dyspnea, cough, and fever). Immediately withhold ALECENSA treatment in patients diagnosed with ILD/pneumonitis and permanently discontinue ALECENSA if no other potential causes of ILD/pneumonitis have been identified [see Dosage and Administration (2.3) and Adverse Reactions (6)].. 5.3 Renal Impairment. Renal impairment occurred in 8% of patients in Studies NP28761, NP28673, and ALEX. The incidence of Grade >= renal impairment was 1.7%, of which 0.5% were fatal events. Dose modifications for renal impairment were required in 3.2% of patients. Median time to Grade >= renal impairment was 3.7 months (range 0.5 to 14.7 months).Permanently discontinue ALECENSA for Grade renal toxicity. Withhold ALECENSA for Grade renal toxicity until recovery to less than or equal to 1.5 times ULN, then resume at reduced dose [see Dosage and Administration (2.3)].. 5.4Bradycardia Symptomatic bradycardia can occur with ALECENSA. Cases of bradycardia (8.6%) have been reported in patients treated with ALECENSA in Studies NP28761, NP28673 and ALEX. Eighteen percent of 365 patients treated with ALECENSA for whom serial ECGs were available had heart rates of less than 50 beats per minute (bpm).Monitor heart rate and blood pressure regularly. Dose modification is not required in cases of asymptomatic bradycardia. In cases of symptomatic bradycardia that is not life-threatening, withhold ALECENSA until recovery to asymptomatic bradycardia or to heart rate of 60 bpm or above and evaluate concomitant medications known to cause bradycardia, as well as anti-hypertensive medications. If attributable to concomitant medication, resume ALECENSA at reduced dose (see Table 1) upon recovery to asymptomatic bradycardia or to heart rate of 60 bpm or above, with frequent monitoring as clinically indicated. Permanently discontinue ALECENSA in case of recurrence. Permanently discontinue ALECENSA in cases of life-threatening bradycardia if no contributing concomitant medication is identified [see Dosage and Administration (2.3)]. 5.5Severe Myalgia and Creatine Phosphokinase (CPK) Elevation Myalgia or musculoskeletal pain occurred in 26% of patients in Studies NP28761, NP28673 and ALEX. The incidence of Grade myalgia/musculoskeletal pain was 0.7%. Dose modifications for myalgia/musculoskeletal pain were required in 0.5% of patients.Elevations of CPK occurred in 41% of 347 patients with CPK laboratory data available in Studies NP28761, NP28673 and ALEX. The incidence of Grade elevations of CPK was 4.0%. Median time to Grade CPK elevation was 14 days (interquartile range 13-28 days). Dose modifications for elevation of CPK occurred in 3.2 of patients.Advise patients to report any unexplained muscle pain, tenderness, or weakness. Assess CPK levels every weeks for the first month of treatment and as clinically indicated in patients reporting symptoms. Based on the severity of the CPK elevation, withhold ALECENSA, then resume or reduce dose [see Dosage and Administration (2.3)]. 5.6Hemolytic Anemia. Hemolytic anemia has been reported with ALECENSA, including cases associated with negative direct antiglobulin test (DAT) result. If hemolytic anemia is suspected, withhold ALECENSA and initiate appropriate laboratory testing. If hemolytic anemia is confirmed, consider resuming at reduced dose upon resolution or permanently discontinue ALECENSA [see Dosage and Administration (2.3)]. 5.7Embryo-Fetal Toxicity. Based on findings from animal studies and its mechanism of action, ALECENSA can cause fetal harm when administered to pregnant women. Administration of alectinib to pregnant rats and rabbits during the period of organogenesis resulted in embryo-fetal toxicity and abortion at maternally toxic doses with exposures approximately 2.7 times those observed in humans with alectinib 600 mg twice daily. Advise pregnant women of the potential risk to fetus. Advise females of reproductive potential to use effective contraception during treatment with ALECENSA and for week following the final dose [see Use in Specific Populations (8.1 and 8.3) and Clinical Pharmacology (12.1)].