Alecensa
(alectinib)Dosage & Administration
600 mg orally twice daily. Administer ALECENSA with food.
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Alecensa Prescribing Information
Adjuvant Treatment of Resected ALK-Positive Non-Small Cell Lung Cancer (NSCLC)
ALECENSA is indicated as adjuvant treatment in adult patients following tumor resection of anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) (tumors ≥ 4 cm or node positive), as detected by an FDA-approved test [see Dosage & Administration (2.1)].
Treatment of Metastatic ALK-Positive NSCLC
ALECENSA is indicated for the treatment of adult patients with ALK-positive metastatic NSCLC as detected by an FDA-approved test [see Dosage & Administration (2.1)].
Patient Selection
Select patients with resectable tumors for the adjuvant treatment of NSCLC with ALECENSA based on the presence of ALK positivity in tumor tissue [see Indications and Usage (1.1) and Clinical Studies (14.1)].
Select patients for the treatment of metastatic NSCLC with ALECENSA based on the presence of ALK positivity in tumor tissue or plasma specimens [see Indications and Usage (1.2) and Clinical Studies (14.2)]. If ALK rearrangements are not detected in a plasma specimen, test tumor tissue if feasible.
Information on FDA-approved tests for the detection of ALK rearrangements in NSCLC is available at http://www.fda.gov/CompanionDiagnostics.
Dosing and Administration
The recommended dosage information for ALECENSA is provided in Table 1.
| Indication | Recommended Dosage of ALECENSA | Duration |
|---|---|---|
| Adjuvant treatment of resected NSCLC | 600 mg orally twice daily with food [see Clinical Pharmacology (12.3)] | For a total of 2 years or until disease recurrence or unacceptable toxicity |
| Metastatic NSCLC | Until disease progression or unacceptable toxicity | |
| ||
Recommended Dosage for Hepatic Impairment
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)].
Dose Modifications for Adverse Reactions
The dose reduction schedule for ALECENSA is provided in Table 2.
| 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 3.
| Criteria * | 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 2. |
| 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 2. |
| 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 2) upon recovery to asymptomatic bradycardia or to a heart rate of 60 bpm or above. |
| Bradycardia † (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 2) 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 2. |
| Hemolytic Anemia | Withhold ALECENSA if hemolytic anemia is suspected. Upon resolution, resume at reduced dose or permanently discontinue. |
150 mg hard capsules, white, with "ALE" printed in black ink on the cap and "150 mg" printed in black ink on the body.
Pregnancy
Risk Summary
Based on findings from 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-fold 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 twice daily) 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 twice daily). 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 twice daily), 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 child, or its effects on milk production. Because of the potential for serious adverse reactions in breastfed children from alectinib, advise a lactating woman not to breastfeed during treatment with ALECENSA and for 1 week after the last dose.
Females and Males of Reproductive Potential
ALECENSA can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].
Pregnancy Testing
Verify pregnancy status in females of reproductive potential prior to initiating ALECENSA [see Use in Specific Populations (8.1)].
Contraception
Females
Advise females of reproductive potential to use effective contraception during treatment with ALECENSA and for 5 weeks after the last 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 last dose [see Nonclinical Toxicology (13.1)].
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-fold 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.
Geriatric Use
Nineteen percent of the 533 patients studied in NP28761, NP28673, ALEX and ALINA were 65 years of age and older (3.2% were 75 years of age and older). No overall differences in effectiveness were observed based on age. Exploratory analysis suggests a higher incidence of serious adverse events (38% vs 25%), more frequent adverse events leading to treatment discontinuations (18% vs 6%) and dose modifications (48% vs 35%) in patients 65 years or older as compared to those younger than 65 years.
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)].
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 (2.3) and Clinical Pharmacology (12.3)].
None.
Hepatotoxicity
Severe hepatotoxicity, including drug-induced liver injury, occurred in patients treated with ALECENSA.
In the pooled safety population [see Adverse Reactions (6.1)] of patients who received ALECENSA, hepatotoxicity occurred in 41% of patients and the incidence of Grade ≥ 3 hepatotoxicity was 8%. In the ALINA study, hepatotoxicity occurred in 61% of patients treated with ALECENSA and the incidence of Grade ≥ 3 hepatotoxicity was 4.7%. The majority (72% of 136 patients) of elevated transaminases occurred during the first 3 months of treatment. Treatment discontinuation due to hepatotoxicity occurred in 3.6% of patients who received ALECENSA in the pooled safety population and 1.6% of patients treated in the ALINA study.
In the pooled safety population, 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. 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 3 [see Dosage and Administration (2.4)].
Interstitial Lung Disease (ILD)/Pneumonitis
ILD/pneumonitis occurred in patients treated with ALECENSA.
In the pooled safety population [see Adverse Reactions (6.1)], ILD/pneumonitis occurred in 1.3% of patients treated with ALECENSA with 0.4% of patients experiencing Grade 3 ILD/pneumonitis.
Five patients (0.9%) in the pooled safety population discontinued ALECENSA due to ILD/pneumonitis. The median time-to-onset of Grade 3 or higher ILD/pneumonitis was 2.1 months (range: 0.6 months to 3.6 months).
Promptly investigate for ILD/pneumonitis in any patient who presents with worsening of respiratory symptoms indicative of ILD/pneumonitis (e.g., dyspnea, cough, and fever). Immediately withhold ALECENSA treatment in patients diagnosed with ILD/pneumonitis and permanently discontinue ALECENSA if no other potential causes of ILD/pneumonitis have been identified [see Dosage and Administration (2.4) and Adverse Reactions (6)].
Renal Impairment
Renal impairment, including fatal cases, occurred in patients treated with ALECENSA.
In the pooled safety population [see Adverse Reactions (6.1)], renal impairment occurred in 12% of patients treated with ALECENSA, including Grade ≥ 3 in 1.7% of patients, of which 0.4% were fatal events. The median time to Grade ≥ 3 renal impairment was 3.7 months (range 0.5 to 31.8 months). Dosage modifications for renal impairment were required in 2.4% of patients.
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 Dosage and Administration (2.4)].
Bradycardia
Symptomatic bradycardia occurred in patients treated with ALECENSA.
In the pooled safety population [see Adverse Reactions (6.1)], bradycardia occurred in 11% of patients treated with ALECENSA. Twenty percent of 521 patients treated with ALECENSA, for whom serial electrocardiograms (ECGs) were available, had post-dose heart rates of less than 50 beats per minute (bpm).
Monitor heart rate and blood pressure regularly. For asymptomatic bradycardia dose modification is not required. For symptomatic bradycardia that is not life-threatening, withhold ALECENSA until recovery to asymptomatic bradycardia or to a heart rate ≥ 60 bpm and evaluate concomitant medications known to cause bradycardia, as well as anti-hypertensive medications. If bradycardia is attributable to a concomitant medication, resume ALECENSA at a reduced dose (see Table 2) upon recovery to asymptomatic bradycardia or to a heart rate of ≥ 60 bpm, with frequent monitoring as clinically indicated.
Permanently discontinue ALECENSA in cases of life-threatening bradycardia if no contributing concomitant medication is identified [see Dosage and Administration (2.4)]. Permanently discontinue ALECENSA for recurrence of life-threatening bradycardia.
Severe Myalgia and Creatine Phosphokinase (CPK) Elevation
Severe myalgia and creatine phosphokinase (CPK) elevation occurred in patients treated with ALECENSA.
In the pooled safety population [see Adverse Reactions (6.1)], myalgia (including muscle- and musculoskeletal-related reactions) occurred in 31% of patients treated with ALECENSA, including Grade ≥ 3 in 0.8% of patients. Dosage modifications for myalgia events were required in 2.1% of patients.
In the pooled safety population, of the 491 patients with CPK laboratory data available, elevated CPK occurred in 56% of patients treated with ALECENSA, including 6% Grade ≥ 3. The median time to Grade ≥ 3 CPK elevation was 15 days (interquartile range - 15 –337 days). Dosage modifications for elevation of CPK occurred in 5% of patients.
In the ALINA study, elevated CPK occurred in 77% of 128 patients with CPK laboratory data, including 6% Grade ≥ 3 elevations.
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 Dosage and Administration (2.4)].
Hemolytic Anemia
Hemolytic anemia occurred in patients treated with ALECENSA.
Hemolytic anemia was initially reported with ALECENSA in the postmarketing setting, including cases associated with a negative direct antiglobulin test (DAT) result. Assessments for the determination of hemolytic anemia were subsequently collected in the ALINA study, where hemolytic anemia was observed in 3.1% of patients treated with ALECENSA. 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 Dosage and Administration (2.4)].
Embryo-Fetal Toxicity
Based on findings from animal studies and its mechanism of action, ALECENSA can cause fetal harm when administered to pregnant women. Oral 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-fold those observed in humans with alectinib 600 mg twice daily. Advise pregnant women and females of reproductive potential of the potential risk to a fetus.
Advise females of reproductive potential to use effective contraception during treatment with ALECENSA and for 5 weeks following the last dose [see Use in Specific Populations (8.1 and 8.3) and Clinical Pharmacology (12.1)].