Data from FDA (Food and Drug Administration, USA) - Curated by EPG Health - Last updated 06 July 2018

Indication(s)

1 INDICATIONS AND USAGE ALECENSA is indicated for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) as detected by an FDA-approved test. ALECENSA is a kinase inhibitor indicated for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) as detected by an FDA-approved test. (1)

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contraindications
4 CONTRAINDICATIONS None. None. (4)
Adverse reactions
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)] Embryo-Fetal Toxicity [see Warnings and Precautions (5.6)] 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. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. 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 0 or 1 (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 ≥ 3 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 3 and 4 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 ALEX Alecensa N = 152 Crizotinib N= 151 Adverse Reaction All 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 Constipation 34 0 33 0 Nausea 14 0.7 48 3.3 Diarrhea 12 0 45 2.0 Vomiting 7 0 38 3.3 General FatigueIncludes fatigue and asthenia. 26 1.3 23 0.7 EdemaIncludes peripheral edema, edema, eyelid edema, localized edema, and face edema. 22 0.7 34 0.7 Musculoskeletal MyalgiaIncludes myalgia and musculoskeletal pain. 23 0 4.0 0 Skin RashIncludes rash, rash maculo-papular, dermatitis acneiform, erythema, generalized rash, rash macular, rash papular, exfoliative rash, and pruritic rash. 15 0.7 13 0 Nervous system DysgeusiaIncludes dysgeusia and hypogeusia. 3.3 0.7 19 0 Eye Vision disordersIncludes blurred vision, visual impairment, vitreous floaters, reduced visual acuity, and diplopia. 4.6 0 23 0 Cardiac BradycardiaIncludes reported cases of bradycardia and sinus bradycardia but is not based on serial ECG assessment. 11 0 15 0 Renal Renal impairmentIncludes increased blood creatinine, creatinine renal clearance decreased, glomerular filtration rate decreased, and acute kidney injury. 12 3.9Includes two Grade 5 events. 0 0 The 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 ALEX Parameter ALECENSA N= 152 Crizotinib N=151 All 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 1 of these patients), n=148 for crizotinib. 54 5 4.7 0 Increased ASTn=147 for alectinib (with baseline valuesmissing for 2 of these patients), n=148 for crizotinib. 50 6 56 11 Increased alkaline phosphatasen=147 for alectinib, n=148 for crizotinib. 50 0 44 0 Increased ALT 40 6 62 16 Increased creatinine , Only patients with creatinine increases based on ULN definition. 38 4.1 23 0.7 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). 37 2.8 52 1.4 Hypocalcemia 29 0 61 1.4 Hyperglycemian=134 for alectinib (with baseline values missing for 18 of these patients), n=131 for crizotinib (with baseline values missing for 8 of these patients). 22 2.2 19 2.3 Hyponatremian=147 for alectinib, n=148 for crizotinib (with baseline values missing for 1 of these patients). 18 6 20 4.1 Hypokalemia 17 2 12 0.7 Hypoalbuminemian=146 for alectinib (with baseline values missing for 1 of these patients), n=148 for crizotinib (with baseline values missing for 1 of these patients). 14 0 57 3.4 Hyperkalemia 12 1.4 16 1.4 Hypophosphatemian=145 for alectinib (with baseline values missing for 2 of these patients), n=148 for crizotinib (with baseline values missing for 4 of these patients). 9 1.4 25 2.7 Increased gamma glutamyl transferasen=143 for alectinib (with baseline values missing for 4 of these patients), n=148 (with baseline values missing for 5 of these patients). 7 0.7 39 4.1 Hematology Anemia 62 7 36 0.7 Lymphopenia 14 1.4 34 4.1 Neutropenia 14 0 36 7 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 6 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) 0 or 1 (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%), and AST (2.8%), and vomiting (2.8%). Tables 5 and 6 summarize the common adverse reactions and laboratory abnormalities observed in Studies NP28761 and NP28673. Table 5: Adverse Reactions in ≥ 10% (All Grades) or ≥ 2% (Grade 3–4) of Patients in Studies NP28761 and NP28673 Adverse Reactions ALECENSA N=253 All Grades (%) Grades 3–4 (%)Per Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 FatigueIncludes fatigue and asthenia. 41 1.2 Constipation 34 0 EdemaIncludes peripheral edema, edema, generalized edema, eyelid edema, and periorbital edema. 30 0.8 MyalgiaIncludes myalgia and musculoskeletal pain. 29 1.2 Cough 19 0 RashIncludes rash, maculopapular rash, acneiform dermatitis, erythema, generalized rash, papular rash, pruritic rash, and macular rash. 18 0.4 Nausea 18 0 Headache 17 0.8 Diarrhea 16 1.2 Dyspnea 16 3.6Includes one Grade 5 event. Back pain 12 0 Vomiting 12 0.4 Increased weight 11 0.4 Vision disorderIncludes blurred vision, vitreous floaters, visual impairment, reduced visual acuity, asthenopia, and diplopia. 10 0 An 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 2 photosensitivity was 0.4%; the remaining events were Grade 1 in severity. Table 6: Treatment-Emergent Worsening in Laboratory Values Occurring in > 20% of Patients in Studies NP28761 and NP28673 Parameter ALECENSA N=250 All Grades (%) Grades 3–4 (%)Per CTCAE version 4.0 Chemistry Increased AST 51 3.6 Increased Alkaline Phosphatase 47 1.2 Increased CPKn=218 for CPK (with baseline values missing for 91 of these patients). 43 4.6 Hyperbilirubinemia 39 2.4 Hyperglycemian=152 for fasting blood glucose (with baseline values missing for 5 of these patients). 36 2.0 Increased ALT 34 4.8 Hypocalcemia 32 0.4 Hypokalemia 29 4.0 Increased CreatinineOnly patients with creatinine increases based on ULN definition. 28 0 Hypophosphatemia 21 2.8 Hyponatremia 20 2.0 Hematology Anemia 56 2.0 Lymphopenian=217 for lymphocytes (with baseline values missing for 5 of these patients). 22 4.6

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION 600 mg orally twice daily. Administer ALECENSA with food. (2.2) 2.1 Patient Selection Select patients for the treatment of metastatic NSCLC with ALECENSA based on the presence of ALK positivity in tumor specimens [see Indications and Usage (1) and Clinical Studies (14)]. Information on FDA-approved tests for the detection of ALK rearrangements in NSCLC is available at http://www.fda.gov/CompanionDiagnostics 2.2 Dosing 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 a dose of ALECENSA is missed or vomiting occurs after taking a dose of ALECENSA, take the next dose at the scheduled time. 2.3 Dose Modifications for Adverse Reactions The dose reduction schedule for ALECENSA is provided in Table 1. Table 1: ALECENSA Dose Reduction Schedule Dose reduction schedule Dose level Starting dose 600 mg taken orally twice daily First dose reduction 450 mg taken orally twice daily Second dose reduction 300 mg taken orally twice daily Discontinue 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 Reactions CriteriaALT = alanine transaminase; AST = aspartate transaminase; ULN = upper limit of normal; ILD = interstitial lung disease; CPK = blood creatine phosphokinase ALECENSA Dose Modification ALT or AST elevation of greater than 5 times upper limit of normal (ULN) with total bilirubin less than or equal to 2 times ULN Temporarily withhold until recovery to baseline or to less than or equal to 3 times ULN, then resume at reduced dose as per Table 1. ALT or AST elevation greater than 3 times ULN with total bilirubin elevation greater than 2 times ULN in the absence of cholestasis or hemolysis Permanently discontinue ALECENSA. Total bilirubin elevation of greater than 3 times ULN Temporarily 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)/pneumonitis Permanently discontinue ALECENSA. Grade 3 renal impairment Temporarily withhold until serum creatinine recovers to less than or equal to 1.5 times ULN, then resume at reduced dose. Grade 4 renal impairment Permanently discontinue ALECENSA. Symptomatic bradycardia Withhold ALECENSA until recovery to asymptomatic bradycardia or to a 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 a 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 a 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 a heart rate of 60 bpm or above, with frequent monitoring as clinically indicated. Permanently discontinue ALECENSA in case of recurrence. CPK elevation greater than 5 times ULN Temporarily 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 5 times ULN Temporarily 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.
Use in special populations
8 USE IN SPECIFIC POPULATIONS Lactation: Do not breastfeed. (8.2) 8.1 Pregnancy Risk Summary Based on animal studies and its mechanism of action, ALECENSA can cause fetal harm when administered to a 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 a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data In a 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 a 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 a 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 9 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 Summary There 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 a lactating woman not to breastfeed during treatment with ALECENSA and for 1 week after the final dose. 8.3 Females and Males of Reproductive Potential Contraception Females ALECENSA can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with ALECENSA and for 1 week after the final dose [see Use in Specific Populations (8.1)]. Males Based on genotoxicity findings, advise males with female partners of reproductive potential to use effective contraception during treatment with ALECENSA and for 3 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 Data Juvenile 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. 8.6 Renal 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)]. 8.7 Hepatic 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)].

More information

Category Value
Authorisation number NDA208434
Agency product number P9YY73LO6J
Orphan designation No
Product NDC 50242-130
Date Last Revised 14-06-2018
Type HUMAN PRESCRIPTION DRUG
RXCUI 1727485
Storage and handling Storage and stability: Do not store above 30°C (86°F). Store in the original container to protect from light and moisture.
Marketing authorisation holder Genentech, Inc.