ALECENSA

Alectinib.

ALECENSA is supplied as hard capsules containing 150 mg of alectinib (equivalent to 161.33 mg alectinib HCl).
ALECENSA (alectinib) is a kinase inhibitor for oral administration. The molecular formula for alectinib is C₃₀H₃₄N₄O₂·HCl. The molecular weight is 482.62 g/mol (free base form) and 519.08 g/mol (hydrochloride salt). Alectinib is described chemically as 9-ethyl-6, 6-dimethyl-8-[4-(morpholin-4-yl)piperidin-1-yl]-11-oxo-6, 11-dihydro-5H-benzo[b]carbazole-3-carbonitrile hydrochloride.
Alectinib HCl is a white to yellow white powder or powder with lumps with a pKa of 7.05 (base).
Excipients/Inactive Ingredients: Capsule Content: Lactose monohydrate, Hydroxypropylcellulose, Sodium lauryl sulfate, Carboxymethylcellulose calcium, Magnesium stearate.
Capsule Shell: Carrageenan, Potassium chloride, Titanium dioxide, Carnauba wax, Corn starch, Hypromellose.
Printing Ink: Red iron oxide (E172), Yellow iron oxide (E172), FD&C Blue No. 2 aluminum lake (E132), Carnauba wax, White shellac, Glyceryl monooleate, l-butanol, Dehydrated ethyl alcohol.

Pharmacology: Mechanism of Action: Alectinib is a 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.
Pharmacodynamics: Cardiac Electrophysiology: The 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 a maximum post-baseline QTcF value of greater than 500 msec, and one patient had a maximum QTcF change from baseline of greater than 60 msec.
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 a 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 a significant improvement in PFS. The time to cause-specific CNS progression as assessed by IRC was also significantly improved; there was a 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 1 and figure. (See Table 1 and figure.)

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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 2. (See Table 2.)

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ALK-Positive Metastatic NSCLC Previously Treated with Crizotinib: The 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 Tumours (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 were median age 54 years old (range 29 to 79, 18% 65 and over), 84% White and 8% Asian, 55% female, 35% ECOG PS 0 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 0 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 3. 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. (See Table 3.)

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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 4. Thirty-five (69%) patients with measurable CNS lesions had received prior brain radiation, including 25 (49%) who completed radiation treatment at least 6 months before starting treatment with ALECENSA. Responses were observed irrespective of prior brain radiation status. (See Table 4.)

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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 (C_max,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 0 to 12 hours (AUC_0-12h,ss) for alectinib was 7,430 ng*h/mL (46%) and for M4 was 2,810 ng*h/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.
Absorption: Alectinib reached maximal concentrations at 4 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 (AUC_0-inf) of alectinib plus M4 by 3.1-fold (90% CI: 2.7, 3.6) following oral administration of a single 600 mg dose of ALECENSA.
Distribution: The apparent volume of distribution is 4,016 L for alectinib and 10,093 L 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 a substrate of P-glycoprotein (P-gp), but M4 is a substrate of P-gp. Alectinib and M4 are not substrates of breast cancer resistance protein (BCRP), organic anion-transporting polypeptide (OATP) 1B1, or OATP1B3.
Elimination: The 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.
Metabolism: Alectinib 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.
Excretion: Ninety-eight percent of the radioactivity was excreted in feces following oral administration of a 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 Populations: Age (21 to 83 years), body weight (38 to 128 kg), mild hepatic impairment (total bilirubin ≤ ULN and AST > ULN or total bilirubin 1 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 a single oral dose of 300 mg ALECENSA, the geometric mean ratio [90% confidence interval] for the combined AUC_inf 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 C_max 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 & Administration and Hepatic Impairment under Precautions].
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 a strong CYP3A inhibitor (posaconazole), a strong CYP3A inducer (rifampin), or an acid-reducing agent (esomeprazole).
Effect of Alectinib on Other Drugs: No 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.
Toxicology: Nonclinical Toxicology: Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity studies with alectinib have not been conducted.
Alectinib was not mutagenic in vitro in the bacterial reverse mutation (Ames) assay, but was positive with an increased number of micronuclei in a rat bone marrow micronucleus test. The mechanism of micronucleus induction was abnormal chromosome segregation (aneugenicity) and not a clastogenic effect on chromosomes.
No studies in animals have been performed to evaluate the effect of alectinib on fertility. No adverse effects on male and female reproductive organs were observed in general toxicology studies conducted in rats and monkeys.

ALECENSA is indicated for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive, metastatic non-small cell lung cancer (NSCLC).

Patient 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/Uses and Pharmacology: Pharmacodynamics: Clinical Studies under Actions). If ALK rearrangements are not detected in a plasma specimen, test tumor tissue if feasible.
Dosing and Administration: The recommended dose of ALECENSA is 600 mg orally twice daily (see Pharmacology: Pharmacokinetics under Actions). 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: Hepatic Impairment under Precautions and Pharmacology: Pharmacokinetics under Actions).
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.
Dose Modifications for Adverse Reactions: The dose reduction schedule for ALECENSA is provided in Table 5. (See Table 5.)

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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 6. (See Table 6.)

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No experience with overdose is available. There is no specific antidote for overdose with ALECENSA. Alectinib and its major active metabolite M4 are > 99% bound to plasma proteins; therefore, hemodialysis is likely to be ineffective in the treatment of overdose.

None.

Hepatotoxicity: Elevations of AST greater than 5 times the upper limit of normal (ULN) occurred in 4.6% of patients, and elevations of ALT greater than 5 times the ULN occurred in 5.3% of the 405 patients in Studies NP28761, NP28673 and ALEX who received ALECENSA at a dose of 600mg BID. Elevations of bilirubin greater than 3 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 3 months of treatment. Six patients discontinued ALECENSA for Grades 3-4 AST and/or ALT elevations, and 4 patients discontinued ALECENSA for Grade 3 bilirubin elevations. Concurrent elevations in ALT or AST greater than or equal to 3 times the ULN and total bilirubin greater than or equal to 2 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 2 weeks during the first 3 months of treatment, then once a 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 a reduced dose, or permanently discontinue ALECENSA as described in Table 6 (see Dose Modifications for Adverse Reactions under Dosage & Administration).
Interstitial 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 Dose Modifications for Adverse Reactions under Dosage & Administration and Adverse Reactions).
Renal Impairment: Renal impairment occurred in 8% of patients in Studies NP28761, NP28673, and ALEX. The incidence of Grade ≥ 3 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 ≥ 3 renal impairment was 3.7 months (range 0.5 to 14.7 months).
Permanently discontinue ALECENSA for Grade 4 renal toxicity. Withhold ALECENSA for Grade 3 renal toxicity until recovery to less than or equal to 1.5 times ULN, then resume at reduced dose (see Dose Modifications for Adverse Reactions under Dosage & Administration).
Bradycardia: 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 a heart rate of 60 bpm or above and evaluate concomitant medications known to cause bradycardia, as well as anti-hypertensive medications. If attributable to a concomitant medication, resume ALECENSA at a reduced dose (see Table 5) 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. Permanently discontinue ALECENSA in cases of life-threatening bradycardia if no contributing concomitant medication is identified (see Dose Modifications for Adverse Reactions under Dosage & Administration).
Severe 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 3 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 3 elevations of CPK was 4.0%. Median time to Grade 3 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 2 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 Dose Modifications for Adverse Reactions under Dosage & Administration).
Hemolytic Anemia: Hemolytic anemia has been reported with ALECENSA, including cases associated with a 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 a reduced dose upon resolution or permanently discontinue ALECENSA (see Dose Modifications for Adverse Reactions under Dosage & Administration).
Embryo-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 a fetus.
Advise females of reproductive potential to use effective contraception during treatment with ALECENSA and for 1 week following the final dose (see Pregnancy under Use in Pregnancy & Lactation, Females and Males of Reproductive Potential as follows and Pharmacology: Mechanism of Action under Actions).
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 Pregnancy under Use in Pregnancy & Lactation).
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 Pharmacology: Toxicology: Nonclinical Toxicology under Actions).
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 Pharmacology: Pharmacokinetics under Actions).
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 Dosing and Administration under Dosage & Administration and Pharmacology: Pharmacokinetics under Actions).
Use in Children: 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.
Use in the Elderly: Clinical studies of ALECENSA did not include sufficient number of subjects aged 65 and older to determine whether they respond differently from younger subjects.

Pregnancy: Risk Summary: Based on animal studies and its mechanism of action, ALECENSA can cause fetal harm when administered to a pregnant woman (see Pharmacology: Mechanism of Action under Actions). 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 as follows). 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 (AUC_0-24h,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 AUC_0-24h,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 AUC_0-24h,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.
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.

The following adverse reactions are discussed in greater detail in Precautions: Hepatotoxicity; Interstitial Lung Disease (ILD)/Pneumonitis; Renal Impairment; Bradycardia; Severe Myalgia and Creatine Phosphokinase (CPK) Elevation; Hemolytic Anemia; Embryo-Fetal Toxicity.
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 7 and 8 summarize the common adverse reactions and laboratory abnormalities observed in ALEX. (See Table 7.)

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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%). (See Table 8.)

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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 9 and 10 summarize the common adverse reactions and laboratory abnormalities observed in Studies NP28761 and NP28673. (See Table 9.)

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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. (See Table 10.)

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Postmarketing Experience: The following adverse reactions have been identified during post approval use of ALECENSA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Blood and lymphatic system disorders: hemolytic anemia.

Do not store above 30°C. Store in the original container to protect from light and moisture.

Advise the patient to read the patient information leaflet. Inform patients of the following: Hepatotoxicity: Inform 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 Precautions).
Interstitial Lung Disease (ILD)/Pneumonitis: Inform patients of the risks of severe ILD/pneumonitis. Advise patients to contact their healthcare provider immediately to report new or worsening respiratory symptoms (see Precautions).
Renal Impairment: Inform 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 Precautions).
Bradycardia: Inform 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 Precautions).
Severe Myalgia/CPK elevation: Inform 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 Precautions).
Hemolytic Anemia: Advise patients to contact their healthcare provider if they develop any signs or symptoms of hemolytic anemia (see Precautions).
Photosensitivity: Inform patients of the signs and symptoms of photosensitivity. Advise patients to avoid prolonged sun exposure while taking ALECENSA and for at least 7 days after study drug discontinuation and to use proper protection from the sun. Advise patients to use a broad spectrum ultraviolet A (UVA)/ultraviolet B (UVB) sunscreen and lip balm (SPF ≥50) to help protect against potential sunburn (see Adverse Reactions).
Embryo-Fetal Toxicity: ALECENSA can cause fetal harm if taken during pregnancy. Advise a pregnant woman of the potential risk to a fetus (see Precautions and Use in Pregnancy & Lactation).
Advise females of reproductive potential to use effective contraception during treatment with ALECENSA and for at least 1 week after the last dose of ALECENSA. Advise patients to inform their healthcare provider of a known or suspected pregnancy (see Precautions and Use in Pregnancy & Lactation).
Advise male patients with female partners of reproductive potential to use effective contraception during treatment with ALECENSA and for 3 months after the last dose (see Precautions and Pharmacology: Toxicology: Nonclinical Toxicology: Carcinogenesis, Mutagenesis, Impairment of Fertility under Actions).
Lactation: Advise women not to breastfeed during treatment with ALECENSA and for one week after the last dose (see Use in Pregnancy & Lactation).
Administration: Instruct patients to take ALECENSA twice a day. Advise patients to take ALECENSA with food and to swallow ALECENSA capsules whole (see Dosage & Administration).
Missed Dose: Advise patients that if a dose of ALECENSA is missed or if the patient vomits after taking a 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 & Administration).

Targeted Cancer Therapy

L01ED03 - alectinib ; Belongs to the class of anaplastic lymphoma kinase (ALK) inhibitors. Used in the treatment of cancer.

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