Alecensa

Alecensa

Manufacturer:

Roche

Distributor:

DKSH

Marketer:

Roche
Full Prescribing Info
Contents
Alectinib.
Description
Each hard capsule contains: Alectinib 150 mg (equivalent to 161.3 mg alectinib hydrochloride).
Excipients/Inactive Ingredients: Lactose monohydrate, hydroxypropylcellulose, sodium lauryl sulfate, carboxymethylcellulose calcium, and magnesium stearate.
Action
Pharmacotherapeutic Group: Antineoplastic agent, Protein Kinase inhibitor. ATC Code: L01XE36.
Pharmacology: Pharmacodynamics: Mechanism of Action: Alectinib is a highly selective and potent ALK and RET tyrosine kinase inhibitor. In nonclinical studies, inhibition of ALK tyrosine kinase activity led to blockage of downstream signalling pathways including STAT 3 and PI3K/AKT and induces tumor cell death (apoptosis).
Alectinib demonstrated in vitro and in vivo activity against mutant forms of the ALK enzyme, including mutations responsible for resistance to crizotinib. The major metabolite of alectinib (M4) has shown similar in vitro potency and activity.
Based on nonclinical data, alectinib is not a substrate of p-glycoprotein (P-gp) or Breast Cancer Resistance Protein (BCRP), which are both efflux transporters in the blood brain barrier, and is therefore able to distribute into and be retained within the central nervous system. Alectinib induced tumor regression in preclinical mouse xenograft models, including antitumor activity in the brain, and prolonged survival in intracranial tumor animal models.
Clinical/Efficacy Studies: ALK positive non-small cell lung cancer: Treatment-naïve patients: The safety and efficacy of Alecensa were studied in a global randomized Phase III open label clinical trial (BO28984) in ALK-positive NSCLC patients who were treatment naïve [39, 40]. Central testing for ALK protein expression positivity of tissue samples from all patients by Ventana anti-ALK (D5F3) immunohistochemistry (IHC) was required before randomization into the study.
A total of 303 patients were included in the Phase III trial, 151 patients randomized to the crizotinib arm and 152 patients randomized to the Alecensa arm receiving Alecensa orally, at the recommended dose of 600 mg twice daily.
ECOG PS (0/1 vs. 2), race (Asian vs. non-Asian), and CNS metastases at baseline (yes vs. no) were stratification factors for randomization. The primary endpoint of the trial was to demonstrate superiority of Alecensa versus crizotinib based on Progression Free survival (PFS) as per investigator assessment using RECIST 1.1. Baseline demographic and disease characteristics for Alecensa were median age 58 years (54 years for crizotinib) , 55% female (58% for crizotinib), 55% non-Asian (54% for crizotinib), 61% with no smoking history (65% for crizotinib), 93% ECOG PS of 0 or 1 (93% for crizotinib), 97% Stage IV disease (96% for crizotinib), 90% adenocarcinoma histology (94% for crizotinib), 40% CNS metastases at baseline (38% for crizotinib) and 17% having received prior CNS radiation (14% for crizotinib).
The trial met its primary endpoint at the primary analysis. Efficacy data are summarized in Table 1 and the Kaplan-Meier curves for investigator and IRC-assessed PFS are shown in Figures 1 and 2. (See Table 1.)

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The magnitude of PFS benefit was consistent for patients with CNS metastases at baseline (HR=0.40, 95%CI: 0.25-0.64, median PFS for Alecensa = NE, 95% CI: 9.2-NE, median PFS for crizotinib = 7.4 months, 95%CI: 6.6-9.6) and without CNS metastases at baseline (HR = 0.51, 95%CI: 0.33-0.80, median PFS for Alecensa = NE, 95% CI: NE, NE, median PFS for crizotinib = 14.8 months, 95% CI:10.8-20.3), indicating benefit of Alecensa over crizotinib in both subgroups. (See Figure 1 and 2.)

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Crizotinib pre-treated patients: The safety and efficacy of Alecensa in ALK-positive NSCLC patients pre-treated with crizotinib were studied in two Phase I/II clinical trials (NP28761 and NP28673).
Study NP28761 was a Phase I/II single arm, multicenter study conducted in patients with ALK positive advanced NSCLC who have previously progressed on crizotinib treatment. In addition to crizotinib, patients may have received previous treatment with chemotherapy. A total of 87 patients were included in the phase II part of the study and received Alecensa orally, at the recommended dose of 600 mg twice daily.
The primary endpoint was to evaluate the efficacy of Alecensa by Objective Response Rate (ORR) as per central Independent Review Committee (IRC) assessment using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
Patient demographics were consistent with that of a NSCLC ALK positive population. The demographic characteristics of the overall study population were 84% Caucasian, 8% Asian, 55% females and a median age of 54 years. The majority of patients had no history of smoking (62%). The ECOG (Eastern Cooperative Oncology Group) performance status at baseline was 0 or 1 in 90% of patients and 2 in 10% of patients. At the time of entry in the study, 99% of patients had stage IV disease, 60% had brain metastases and in 94% of patients tumors were classified as adenocarcinoma. Among patients included in the study, 26% had previously progressed on crizotinib treatment only, and 74% had previously progressed on crizotinib and chemotherapy treatment. (See Table 2.)

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As shown in the waterfall plot in Figure 3, most patients experienced tumour shrinkage of their defined target lesions, as assessed by the IRC according to RECIST 1.1. (See Figure 3.)

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Quality of life (QoL): Of the QoL items analysed (QLQ-C30 and QLQ-LC13), clinically meaningful improvements (change from baseline of ≥10 points) were observed in the Global Health Status, Emotional Functioning, Social Functioning, Fatigue, and Pain subscales.
Study NP28673 was a Phase I/II single arm, international, multicenter study conducted in patients with ALK-positive advanced NSCLC who have previously progressed on crizotinib. In addition to crizotinib, patients may have received previous treatment with chemotherapy. A total of 138 patients were included in the phase II part of the study and received Alecensa orally, at the recommended dose of 600 mg twice daily.
The primary endpoint was to evaluate the efficacy of Alecensa by ORR as per central IRC assessment using RECIST 1.1 in the overall population (with and without prior exposure of cytotoxic chemotherapy treatments). The co-primary endpoint was to evaluate the ORR as per central IRC assessment using RECIST 1.1 in patients with prior exposure of cytotoxic chemotherapy treatments.
Patient demographics were consistent with that of a NSCLC ALK positive population. The demographic characteristics of the overall study population were 67% Caucasian, 26% Asian, 56% females and the median age was 52 years. The majority of patients had no history of smoking (70%). The ECOG performance status in patients at baseline was 0 or 1 in 91% of patients and 2 in 9% of patients. At the time of entry in the study, 99% of patients had stage IV disease, 61% had brain metastases and in 96% of patient tumors were classified as adenocarcinoma. Among patients included in the study, 20% had previously progressed on crizotinib treatment only, and 80% had previously progressed on crizotinib and chemotherapy treatment. (See Table 3.)

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As shown in the waterfall plot in Figure 4, most patients experienced tumour shrinkage of their defined target lesions, as assessed by the IRC according to RECIST 1.1. (See Figure 4.)

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A summary of the pooled analysis of the Central Nervous System (CNS) endpoints based on RECIST (IRC) performed on patients with measurable CNS lesions at baseline (N=50) included in the phase II NP28761 and NP28673 is presented in the below table. (See Table 4.)

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In 136 patients included in the phase II NP28761 and NP28673 with measurable and/or non-measurable CNS lesions at baseline, the CNS complete response rate was 28.7%. A CNS partial response cannot be established in non-measurable CNS lesions per RECIST. The CNS disease control rate was 86.0% [95% CI (79.1, 91.4)].
Immunogenicity: Not applicable.
Pharmacokinetics: The pharmacokinetic parameters for alectinib and its major active metabolite (M4), have been characterized in ALK-positive NSCLC patients and healthy subjects. The geometric mean (coefficient of variation %) steady-state Cmax, Cmin and AUC0-12hr for alectinib were approximately 665 ng/mL (44.3%), 572 ng/mL (47.8 %) and 7430 ng*h/mL (45.7 %), respectively. The geometric mean steady-state Cmax, Cmin and AUC0-12hr for M4 were approximately 246 ng/mL (45.4 %), 222 ng/mL (46.6 %) and 2810 ng*h/mL (45.9 %), respectively.
Absorption: Following oral administration of 600 mg twice daily under fed conditions in ALK-positive NSCLC patients, alectinib was rapidly absorbed reaching Tmax after approximately 4 to 6 hours.
Alectinib steady-state is reached by Day 7 with continuous 600 mg twice daily dosing and remains stable thereafter. The geometric mean accumulation ratio estimated by population PK analysis for the twice-daily 600 mg regimen is 5.6. Population PK analysis supports dose proportionality for alectinib across the dose range of 300 to 900 mg under fed conditions.
The absolute bioavailability of alectinib was 36.9% (90% CI: 33.9%, 40.3%) under fed conditions in healthy subjects.
Following a single oral administration of 600 mg with a high-fat, high-calorie meal, exposure increased by 3-fold relative to fasted conditions (geometric mean ratio [90% CI] of combined alectinib and M4: Cmax: 3.31 [2.79-3.93], AUCinf: 3.11 [2.73-3.55].
Distribution: Alectinib and its major metabolite M4 are highly bound to human plasma proteins (>99%), independent of drug concentration. The mean in vitro human blood-to-plasma concentration ratios of alectinib and M4 are 2.64 and 2.50, respectively, at clinically relevant concentrations.
The geometric mean volume of distribution at steady state (Vss) of alectinib following IV administration was 475 L, indicating extensive distribution into tissues.
Metabolism: In vitro metabolism studies showed that CYP3A4 is the main CYP isozyme mediating alectinib and its major metabolite M4 metabolism, and is estimated to contribute 40-50% of alectinib metabolism in human hepatocytes. Results from the human mass balance study demonstrated that alectinib and M4 were the main circulating moieties in plasma with alectinib and M4 together constituting approximately 76% of the total radioactivity in plasma. The geometric mean Metabolite/Parent ratio at steady state is 0.399.
Elimination: Following administration of a single dose of 14C-labeled alectinib administered orally to healthy subjects the majority of radioactivity was excreted in feces (mean recovery 97.8%, range 95.6%-100%) with minimal excretion in urine (mean recovery 0.46%, range 0.30%-0.60%). In feces, 84% and 5.8% of the dose was excreted as unchanged alectinib or M4, respectively.
Based on a population PK analysis, the apparent clearance (CL/F) of alectinib was 81.9 L/hour. The geometric mean of the individual elimination half-life estimates for alectinib was 32.5 hours. The corresponding values for M4 were 217 L/hour and 30.7 hours, respectively.
Special Populations: Pediatric population: No studies have been conducted to investigate the pharmacokinetics of Alecensa in this population.
Geriatric population: Age does not have an effect on Alecensa exposure.
Renal impairment: Negligible amounts of alectinib and the active metabolite M4 are excreted unchanged in urine (< 0.2 % of the dose). Data obtained in patients with mild and moderate renal impairment show that the pharmacokinetics of alectinib are not significantly affected in renal impairment. No formal pharmacokinetic study has been conducted and no population PK data was collected in patients with severe renal impairment, however since alectinib elimination via the kidney is negligible no dose adjustment is required in renal impairment.
Hepatic impairment: As elimination of alectinib is predominantly through metabolism in the liver, hepatic impairment may increase the plasma concentration of alectinib and/or its major active metabolite M4. Based on a population pharmacokinetic analysis, alectinib and M4 exposures were similar in patients with mild hepatic impairment (baseline total bilirubin less than or equal to ULN and baseline AST greater than ULN or baseline total bilirubin greater than 1.0 to 1.5 times ULN and any baseline AST) and normal hepatic function (total bilirubin less than or equal to ULN and AST less than or equal to ULN).
Following administration of a single oral dose of 300 mg alectinib in subjects with moderate (Child-Pugh B) hepatic impairment the combined exposure of alectinib and M4 was modestly increased compared with matched healthy subjects (geometric mean ratio [90% confidence interval] for moderate/healthy: Cmax: 1.16 [0.786 – 1.72], AUCinf: 1.36 [0.947 – 1.96]). Administration of a single oral dose of 300 mg alectinib in subjects with severe (Child-Pugh C) hepatic impairment resulted in a greater increase in the combined exposure of alectinib and M4 compared with matched healthy subjects (geometric mean ratio [90% confidence interval] for severe/healthy: Cmax: 0.981 [0.517 – 1.86], AUCinf: 1.76 [0.984 – 3.15]).
No dose adjustments are required for Alecensa in patients with underlying mild or moderate hepatic impairment. Patients with underlying severe hepatic impairment should receive a dose of 450 mg given orally twice daily (total daily dose of 900 mg).
Toxicity: Non-clinical Safety: Carcinogenicity: No carcinogenicity studies have been performed to establish the carcinogenic potential of Alecensa.
Genotoxicity: Alectinib was not mutagenic in vitro in the bacterial reverse mutation (Ames) assay but induced a slight increase in numerical aberrations in the in vitro cytogenetic assay using Chinese Hamster Lung (CHL) cells with metabolic activation, and 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.
Impairment of Fertility: No fertility studies in animals have been performed to evaluate the effect of Alecensa. No adverse effects on male and female reproductive organs were observed in general toxicology studies conducted in rats and monkeys at exposures equal to or greater than 2.6 and 0.5 fold, respectively, of the human exposure measured by AUC at the recommended dose of 600 mg twice daily.
Reproductive Toxicity: In animal studies, a maternal dose of alectinib equivalent to 2.7-times the recommended human dose of 600 mg twice-daily (based on AUC), caused embryo-fetal loss (miscarriage) in pregnant rabbits. The same equivalent dose given to pregnant rats resulted in small fetuses with retarded ossification and minor abnormalities of the organs.
Other: Alectinib absorbs UV light between 200 and 400 nm and demonstrated phototoxic potential in an in vitro photosafety test in cultured murine fibroblasts after UVA irradiation.
Target organs in both rat and monkey at clinically relevant exposures in the repeat-dose toxicology studies included, but were not limited to the erythroid system, gastrointestinal tract and hepatobiliary system.
Abnormal erythrocyte morphology was observed at exposures equal or greater than 10-60% the human exposure by AUC at the recommended dose. Proliferative zone extension in GI mucosa in both species was observed at exposures equal to or greater than 20-120% of the human AUC exposure at the recommended dose. Increased hepatic alkaline phosphatase (ALP) and direct bilirubin as well as vacuolation/degeneration/necrosis of bile duct epithelium and enlargement/focal necrosis of hepatocytes was observed in rats and/or monkeys at exposures equal to or greater than 20-30% of the human exposure by AUC at the recommended dose.
A mild hypotensive effect has been observed in monkeys at around clinically relevant exposures.
Alectinib crossed the blood brain barrier in rats and was retained within brain tissue with a CNS-to-plasma radio-concentration ratio ranging from 0.9 to 1.5 at 24 hrs post-dose.
Indications/Uses
Alecensa as monotherapy is indicated for the first-line treatment of adult patients with anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC).
Alecensa is indicated for the treatment of patients with ALK-positive, locally advanced or metastatic NSCLC who have progressed on or are intolerant to crizotinib.
Dosage/Direction for Use
General: A validated ALK assay is required for the selection of ALK-positive NSCLC patients. ALK-positive NSCLC status should be established prior to initiation of Alecensa therapy in first-line.
Alecensa hard capsules should be taken with food, swallowed whole and must not be opened or dissolved.
The recommended dose of Alecensa is 600 mg (four 150 mg capsules) given orally, twice daily (total daily dose of 1200 mg) (see Pharmacology: Pharmacokinetics under Actions).
Patients with underlying severe hepatic impairment should receive a dose of 450 mg given orally twice daily (total daily dose of 900 mg) (see Special Dosing Instructions in the following text and Pharmacology: Pharmacokinetics under Actions).
Duration of Treatment: It is recommended that patients are treated with Alecensa until disease progression or unmanageable toxicity.
Delayed or Missed Doses: If a planned dose of Alecensa is missed, patients can make up that dose unless the next dose is due within 6 hours. If vomiting occurs after taking a dose of Alecensa, patients should take the next dose at the scheduled time.
Dose Modifications: Management of adverse events may require temporary interruption, dose reduction, or discontinuation of treatment with Alecensa. The dose of Alecensa should be reduced in steps of 150 mg twice daily based on tolerability. Alecensa treatment should be permanently discontinued if patients are unable to tolerate the 300 mg twice daily dose.
Table 5 below gives general dose modification advice for Alecensa. (See Tables 5 and 6.)

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Special Dosage Instructions: Pediatric use: The safety and efficacy of Alecensa in children and adolescents (<18 years) have not been studied.
Geriatric use: No dose adjustment of Alecensa is required in patients ≥65 years of age.
Renal Impairment: No dose adjustment is required in patients with mild or moderate renal impairment. Alecensa has not been studied in patients with severe renal impairment, however since alectinib elimination via the kidney is negligible, no dose adjustment is required in patients with severe renal impairment (see Special Populations under Precautions and Pharmacology: Pharmacokinetics under Actions).
Hepatic Impairment: No dose adjustment is required in patients with mild hepatic impairment. Patients with underlying severe hepatic impairment should receive a dose of 450 mg given orally twice daily (total dose of 900 mg) (see Pharmacology: Pharmacokinetics under Actions).
Overdosage
There is no experience with overdosage in clinical trials NP28761, NP28673 and BO28984. Patients who experience overdose should be closely supervised and supportive care instituted. There is no specific antidote for overdose with Alecensa.
Contraindications
Alecensa is contraindicated in patients with a known hypersensitivity to alectinib or any of the excipients.
Special Precautions
General: Interstitial lung disease (ILD)/Pneumonitis: Cases of ILD/pneumonitis have been reported in clinical trials with Alecensa (see Adverse Reactions). Patients should be monitored for pulmonary symptoms indicative of pneumonitis. Alecensa should be immediately interrupted in patients diagnosed with ILD/pneumonitis and should be permanently discontinued if no other potential causes of ILD/pneumonitis have been identified (see Dosage & Administration).
Hepatotoxicity: Elevations in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) greater than 5 times the upper limit of normal (ULN) as well as bilirubin elevations of more than 3 times the ULN occurred in patients in pivotal clinical trials with Alecensa (see Adverse Reactions). The majority of these events occurred during the first 3 months of treatment. In the pivotal Alecensa clinical trials it was reported that three patients with Grade 3-4 AST/ALT elevations had drug induced liver injury. Concurrent elevations in ALT or AST greater than or equal to three times the ULN and total bilirubin greater than or equal to two times the ULN, with normal alkaline phosphatase, occurred in 1 patient treated in Alecensa clinical trials.
Liver function, including ALT, AST, and total bilirubin should be monitored at baseline and then every 2 weeks during the first 3 months of treatment, and then periodically, since events may occur later than 3 months, 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 5 (see Dosage & Administration).
Severe Myalgia and Creatine Phosphokinase (CPK) elevation: Myalgia or musculoskeletal pain was reported in patients in pivotal trials with Alecensa, including Grade 3 events.
Elevations of CPK occurred in pivotal trials with Alecensa, including Grade 3 events. Median time to Grade 3 CPK elevation was 14 days in the pivotal phase II trials (NP28761, NP28673). Median time to Grade 3 CPK elevation was 27.5 days in the pivotal phase III clinical trial (BO28984) (see Adverse Reactions).
Advise patients to report any unexplained muscle pain, tenderness, or weakness. Assess CPK levels every two 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 & Administration).
Bradycardia: Symptomatic bradycardia can occur with Alecensa (see Adverse Reactions). Heart rate and blood pressure should be monitored as clinically indicated. Dose modification is not required in case of asymptomatic bradycardia (see Dosage & Administration). If patients experience symptomatic bradycardia or life-threatening events, concomitant medications known to cause bradycardia, as well as anti-hypertensive medications should be evaluated and Alecensa treatment should be adjusted as described in Table 5 (see Dosage & Administration and Interactions).
Photosensitivity: Photosensitivity to sunlight has been reported with Alecensa administration (see Adverse Reactions). Patients should be advised to avoid prolonged sun exposure while taking Alecensa and for at least 7 days after discontinuation of treatment. Patients should also be advised to use a broad spectrum Ultraviolet A (UVA)/ Ultraviolet B (UVB) sun screen and lip balm (SPF ≥50) to help protect against potential sunburn.
Embryo-fetal toxicity: Alecensa may cause fetal harm when administered to a pregnant woman. When administrated to pregnant rats and rabbits, alectinib caused embryo-fetal toxicity. Female patients of child-bearing potential, or women of child-bearing potential who are partners of male patients receiving Alecensa, must use highly effective contraceptive methods during treatment and for at least 3 months following the last dose of Alecensa. (See Use in Pregnancy & Lactation.)
Drug Abuse and Dependence: Not applicable.
Effects on the Ability to Drive and Use Machines: No studies on the effects on the ability to drive and to use machines have been performed.
Renal Impairment: See Dosage & Administration and Pharmacology: Pharmacokinetics: Special Populations under Actions.
Hepatic Impairment: See Dosage & Administration and Pharmacology: Pharmacokinetics: Special Populations under Actions.
Contraception: Female patients of child-bearing potential, or women of child-bearing potential who are partners of male patients receiving Alecensa, must use highly effective contraceptive methods during treatment and for at least 3 months following the last dose of Alecensa.
Use in Children: The safety and efficacy of Alecensa in paediatric patients below the age of 18 years have not been established.
Use in Elderly: See Dosage & Administration and Pharmacology: Pharmacokinetics: Special Populations under Actions).
Use In Pregnancy & Lactation
Use in Pregnancy: Women of childbearing potential must be advised to avoid pregnancy while on Alecensa. No clinical studies of Alecensa in pregnant women have been performed. Based on its mechanism of action, Alecensa may cause fetal harm when administered to a pregnant woman.
Female patients or women who are partners of male patients receiving Alecensa, who become pregnant while taking Alecensa or during the 3 months following the last dose of Alecensa must contact their doctor and should be advised of the potential harm to the fetus.
Animal data: In animal studies, alectinib caused embryo-fetal toxicity (Pharmacology: Toxciology: Non-clinical Safety under Actions).
Labor and delivery: The safe use of Alecensa during labor and delivery has not been established.
Use in Lactation: It is not known whether Alecensa is excreted in human breast milk. No studies have been conducted to assess the impact of Alecensa on milk production or its presence in breast milk. As many drugs are excreted in human milk and because of the potential harm to the infant, mothers should be advised against breastfeeding while receiving Alecensa.
Adverse Reactions
Clinical Trials: For the clinical development program of Alecensa as a whole an estimated total of 928 patients have received Alecensa and 203 patients have received blinded Alecensa.
The safety of Alecensa has been evaluated in 253 patients in pivotal phase II clinical trials (NP28761, NP28673) with ALK-positive non-small cell lung cancer (NSCLC) treated with the recommended dose of 600 mg twice daily. The median duration of exposure to Alecensa was 11 months  (range 0-35 months). The safety of Alecensa was also evaluated in 152 patients with ALK-positive NSCLC treated with a dose of 600 mg twice daily in the phase III clinical trial BO28984. The median duration of exposure to Alecensa was 17.9 months.
The most common adverse reactions (≥20%) were constipation (36%), edema (34% including peripheral, generalized, eyelid, periorbital); myalgia (31% including myalgia and musculoskeletal pain), nausea (22%), increased bilirubin (21% including increased blood bilirubin, hyperbilirubinemia and increased bilirubin conjugated), anemia (20%, including anemia and hemoglobin decreased), and rash (20%, including rash, rash maculopapular, dermatitis acneiform, erythema, rash generalized, rash papular, rash pruritic and rash macular).
Table 7 lists the adverse drug reactions (ADRs) occurring in patients who received Alecensa in clinical trials (NP28761, NP28673) and phase III clinical trial BO28984. Adverse drug reactions from clinical trials are listed by MedDRA system organ class. The corresponding frequency category for each adverse drug reaction is based on the following convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1000), very rare (<1/10,000). (See Table 7.)

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Further information on selected adverse reactions: The safety profile of Alecensa was generally consistent across the phase III clinical trial (BO28984) and the pivotal phase II trials (NP28761, NP28673); however, relevant differences between studies are described below.
Interstitial Lung Disease (ILD)/pneumonitis:
Severe ILD/pneumonitis occurred in patients treated with Alecensa. In the pivotal phase II clincal trials (NP28761, NP28673), 1 out of 253 patients treated with Alecensa (0.4%) had a an ILD event, which was Grade 3, leading to withdrawal from Alecensa treatment. There were no fatal cases of ILD in any of the clinical trials.
Hepatotoxicity: In the pivotal phase II clinical trials (NP28761, NP28673) two patients with Grade 3-4 AST/ALT elevations had documented drug induced liver injury by liver biopsy. Adverse reactions of increased AST and ALT levels (16% and 14% respectively) were reported in patients treated with Alecensa in pivotal phase II clinical trials (NP28761, NP28673). The majority of these events were of Grade 1 and 2 intensity, and events of Grade ≥3 were reported in 2.8% and 3.2% of the patients, respectively. The events generally occurred during the first 3 months of treatment, were usually transient and resolved upon temporary interruption of Alecensa treatment (reported for 1.2% and 3.2% of the patients, respectively) or dose reduction (1.6% and 0.8%, respectively). In 1.2% and 1.6% of the patients, AST and ALT elevations, respectively, led to withdrawal from Alecensa treatment.
Adverse reactions of bilirubin elevations were reported in 17% of the patients treated with Alecensa in pivotal phase II clincal trials (NP28761, NP28673). The majority of the events were of Grade 1 and 2 intensity; Grade 3 events were reported in 3.2% of the patients. The events generally occurred during the first 3 months of treatment, were usually transient and resolved upon temporary interruption of Alecensa treatment (4.7% of the patients) or dose reduction (2.8%). In 4 patients (1.6%), bilirubin elevations led to withdrawal from Alecensa treatment.
Concurrent elevations in ALT or AST greater than or equal to three times the ULN and total bilirubin greater than or equal to two times the ULN, with normal alkaline phosphatase, occurred in 1 patient treated in Alecensa clinical trials.
Bradycardia: Cases of bradycardia (7.9%) have been reported in patients treated with Alecensa in pivotal phase II clinical trials (NP28761, NP28673); all cases were of Grade 1 or 2 intensity. There were 44 of 221 patients (20%) treated with Alecensa who had post-dose heart rate values below 50 beats per minutes [bpm].
Severe Myalgia and CPK elevation: Cases of myalgia (31%) including myalgia events (25%) and musculoskeletal pain (7.5%) have been reported in patients treated with Alecensa in pivotal phase II clinical trials (NP28761, NP28673). The majority of events were Grades 1 or 2 and three patients (1.2%) had a Grade 3 event. Dose modifications due to these events were only required for two patients (0.8%). Elevations of CPK occurred in 46% of 219 patients with CPK laboratory data available in pivotal phase II clinical trials (NP28761, NP28673) with Alecensa. The incidence of Grade 3 elevations of CPK was 5.0%. Median time to Grade 3 CPK elevation was 14 days in the pivotal phase II trials (NP28761, NP28673). Median time to Grade 3 CPK elevation was 27.5 days in the pivotal phase III clinical trial (BO28984). Dose modifications for elevation of CPK occurred in 4.0% of patients.
Laboratory Abnormalities: The following table displays treatment-emergent shifts in laboratory abnormalities occurring in patients treated with Alecensa in phase II clinical trials (NP28761, NP28673) and phase III trial BO28984. (See Table 8.)

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Postmarketing Experience: The adverse drug reaction of increased alkaline phosphatase was reported with Alecensa in the post marketing period. Cases of increased alkaline phosphatase have been reported in Alecensa clinical trials (7.5% in patients treated with Alecensa in pivotal phase II clinical trials (NP28761, NP28673)).
Drug Interactions
Effects of alectinib on others drugs: CYP substrates: In vitro studies indicate that neither alectinib nor its major active metabolite (M4) inhibits CYP1A2, CYP2B6, CYP2C9, CYP2C19, or CYP2D6 at clinically relevant concentrations. Alectinib and M4 show weak time-dependent inhibition of CYP3A4. In vitro, alectinib exhibits a weak induction potential of CYP3A4 and CYP2B6 at clinical concentrations.
Results from a clinical drug-drug interaction study in ALK-positive NSCLC patients demonstrated that multiple doses of alectinib had no influence on the exposure of midazolam, a sensitive CYP3A substrate. Therefore, no dose adjustment is required for co-administered CYP3A substrates.
Although in vitro studies indicate that alectinib is an inhibitor of CYP2C8, physiologically based pharmacokinetic (PBPK) modeling supports that at clinically relevant concentrations alectinib does not have the potential to increase plasma concentrations of co-administered substrates of CYP2C8.
P-gp and BCRP substrates: In vitro, alectinib and M4 are inhibitors of the efflux transporters P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP). Therefore, alectinib may have the potential to increase plasma concentrations of co-administered substrates of P-gp or BCRP transporters (the increase in exposure is not expected to be more than 2-fold). When alectinib is co-administered with P-gp or BCRP substrates with narrow therapeutic index (e.g. digoxin, dabigatran, methotrexate), appropriate monitoring is recommended.
Effects of other drugs on alectinib: Based on in vitro data, CYP3A4 is the primary enzyme mediating the metabolism of both alectinib and its major active metabolite M4, and CYP3A contributes to 40%-50% of total hepatic metabolism. M4 has shown similar in vitro potency and activity to alectinib against ALK.
CYP3A inducers: Co-administration of multiple oral doses of 600 mg rifampicin once daily, a strong CYP3A inducer, with a single oral dose of 600 mg alectinib exhibited a minor effect on combined exposure of alectinib and M4 (geometric mean ratio with/without rifampicin [90% confidence interval]: Cmax: 0.96 [0.88-1.05], AUCinf: 0.82 [0.74-0.90]). Therefore, no dose adjustments are required when Alecensa is co-administered with CYP3A inducers.
CYP3A inhibitors: Co-administration of multiple oral doses of 400 mg posaconazole twice daily, a strong CYP3A inhibitor, with a single oral dose of 300 mg alectinib had a minor effect on combined exposure of alectinib and M4 (geometric mean ratio with/without posaconazole [90% confidence interval]: Cmax: 0.93 [0.81-1.08], AUCinf: 1.36 [1.24-1.49]). Therefore, no dose adjustments are required when Alecensa is co-administered with CYP3A inhibitors.
Medicinal products that increase gastric pH: Although the aqueous solubility of alectinib in vitro is pH dependent, a dedicated clinical drug-drug interaction study with 40 mg esomeprazole once daily, a proton pump inhibitor, demonstrated no clinically relevant effect on the combined exposure of alectinib and M4. Therefore, no dose adjustments are required when Alecensa is co-administered with proton pump inhibitors or other drugs which raise gastric pH (e.g. H2 receptor antagonists or antacids).
Effect of transporters on alectinib disposition: Based on in vitro data, alectinib is not a substrate of P-gp. Alectinib and M4 are not substrates of BCRP or Organic anion-transporting polypeptide (OATP) 1B1/B3. In contrast, M4 is a substrate of P-gp. Alectinib inhibits P-gp, and therefore, it is not expected that co-medication with P-gp inhibitors has a relevant effect on M4 exposure.
Caution For Usage
Special Instructions for Use, Handling and Disposal: Disposal of unused/expired medicines: The release of pharmaceuticals in the environment should be minimized. Medicines should not be disposed of via wastewater and disposal through household waste should be avoided. Use established "collection systems", if available in the location.
Storage
Do not store above 30°C.
Keep container tightly closed, protect from light and moisture.
ATC Classification
L01ED03 - alectinib ; Belongs to the class of anaplastic lymphoma kinase (ALK) inhibitors. Used in the treatment of cancer.
Presentation/Packing
Hard cap 150 mg x 224's.
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