Dosing and uses of Alecensa (alectinib)
Adult dosage forms and strengths
capsule
- 150mg
Non-small Cell Lung Cancer
Indicated for anaplastic lymphoma kinase (ALK)-positive, metastatic non-small cell lung cancer (NSCLC) in patients who have progressed on or are intolerant to crizotiniB
600 mg PO BID until disease progression or unacceptable toxicity
Dosage modifications
Dose reduction schedule
- Starting dose: 600 mg PO BID
- First dose reduction: 450 mg PO BID
- Second dose reduction: 300 mg PO BID
- Discontinue if patients are unable to tolerate 300 mg PO BID
Renal impairment
- Mild-to-moderate: No dose adjustment required
- Severe (CrCl <30 mL/min) or ESRD: Not studied
Hepatic impairment
- Mild (TB ≤ULN and AST >ULN or TB >1-1.5 x ULN and any AST): No dose adjustment required
- Moderate-to-severe: Not studied
Hepatotoxicity
- ALT or AST elevation >5 x ULN with total bilirubin (TB) ≤2 x ULN: Temporarily withhold until recovery to baseline or to ≤3 times ULN, then resume at reduced dose
- ALT or AST elevation >3 x ULN with TB elevation >2 x ULN in absence of cholestasis or hemolysis: Permanently discontinue
- TB elevation >3 x ULN: Temporarily withhold until recovery to baseline or to ≤1.5 x ULN, then resume at reduced dose
Interstitial lung disease (ILD)/pneumonitis
- Any grade treatment-related ILD/pneumonitis: Permanently discontinue
Bradycardia
- Symptomatic bradycardia
- Withhold until recovery to asymptomatic bradycardia or to a heart rate ≥60 bpm
- If contributing concomitant medication is identified and discontinued, or its dose is adjusted, resume alectinib at previous dose upon recovery to asymptomatic bradycardia or to a heart rate ≥60 bpm
- If no contributing concomitant medication is identified, or if contributing concomitant medications are not discontinued or dose modified, resume alectinib at reduced dose upon recovery to asymptomatic bradycardia or to a heart rate ≥60 bpm
- Life-threatening bradycardia or urgent intervention indicated
- Permanently discontinue if no contributing concomitant medication is identified
- If contributing concomitant medication is identified and discontinued, or its dose is adjusted, resume alectinib at reduced dose upon recovery to asymptomatic bradycardia or to a heart rate ≥60 bpm, with frequent monitoring as clinically indicated
- Permanently discontinue in case of recurrence
Elevated CPK
- CPK >5 x ULN: Temporarily withhold until recovery to baseline or to ≤2.5 x ULN, then resume at same dose
- CPK >10 x ULN or second occurrence of >5 x ULN: Temporarily withhold until recovery to baseline or to ≤2.5 x ULN, then resume at reduced dose
Dosing Considerations
Indication is approved under accelerated approval based on tumor response rate and duration of response
Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory triaL
Pediatric dosage forms and strengths
Safety and efficacy not established
Alecensa (alectinib) adverse (side) effects
Percentages for adverse effects listed below are for all grades of toxicity unless otherwise stated
>10%
Anemia (56%)
Increased AST (51%)
Increased alkaline phosphatase (47%)
Increased CPK (43%)
Fatigue (41%)
Hyperbilirubinemia (39%)
Hyperglycemia (36%)
Increased ALT (34%)
Constipation (34%)
Hypocalcemia (32%)
Edema (30%)
Hypokalemia (29%)
Myalgia (29%)
Increased creatinine (28%)
Lymphopenia (22%)
Hypophosphatemia (21%)
Hyponatremia (20%)
Cough (19%)
Rash (18%)
Nausea (18%)
Headache (17%)
Diarrhea (16%)
Dyspnea (16%)
Back pain (12%)
Vomiting (12%)
Increased weight (11%)
1-10%
Vision disorder (10%)
Increased ALT, grades 3-4 (4.8%)
Increased CPK, grades 3-4 (4.6%)
Lymphopenia, grades 3-4 (4.6%)
Hypokalemia, grades 3-4 (4%)
Dyspnea, grades 3-4 (3.6%)
Increased AST, grades 3-4 (3.6%)
Hypophosphatemia, grades 3-4 (2.8%)
Hyperbilirubinemia, grades 3-4 (2.4%)
Hyperglycemia, grades 3-4 (2%)
Hyponatremia, grades 3-4 (2%)
Anemia, grades 3-4 (2%)
Fatigue, grades 3-4 (1.2%)
Myalgia, grades 3-4 (1.2%)
Diarrhea, grades 3-4 (1.2%)
Increased alkaline phosphatase, grades 3-4 (1.2%)
<1%
Edema, grades 3-4
Rash, grades 3-4
Headache, grades 3-4
Vomiting, grades 3-4
Increased weight, grades 3-4
Hypocalcemia, grades 3-4
Warnings
Contraindications
None
Cautions
Elevated liver enzymes reported; monitor liver function tests, including ALT, AST, and total bilirubin, q2weeks during the first 2 months of treatment, then periodically during treatment, with more frequent testing in patients who develop transaminase and bilirubin elevations (see Dosage modifications)
Interstitial lung disease (ILD) and pneumonitis reported; promptly investigate any patient who presents with worsening respiratory symptoms (eg, dyspnea, cough, fever) and immediately withhold treatment in patients diagnosed with ILD/pneumonitis (see Dosage modifications)
Symptomatic bradycardia may occur; monitor heart rate and blood pressure regularly (see Dosage modifications)
Severe myalgia and elevated CPK reported; advise patients to report any unexplained muscle pain, tenderness, or weakness; assess CPK levels q2weeks for the first month of treatment and as clinically indicated in patients reporting symptoms (see Dosage modifications)
Based on findings from animal studies and its mechanism of action, alectinib can cause fetal harm when administered to pregnant women (see Pregnancy)
Pregnancy and lactation
Pregnancy
Based on animal studies and its mechanism of action, can cause fetal harm when administered to a pregnant woman There are no available data on use in humans during pregnancy
Animal data
- Administration 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 BID
Contraception
- Females: Use effective contraception during treatment and for 1 week after the final dose
- Males: Use effective contraception during treatment and for 3 months following the final dose
Lactation
Unknown if distributed in human breast milk
Because of the potential for serious adverse reactions in breastfed infants from alectinib, advise a lactating woman not to breastfeed during treatment and for 1 week after the final dose
Pregnancy categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA: Information not available.
Pharmacology of Alecensa (alectinib)
Mechanism of action
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
Absorption
Absolute bioavailability: 37% (with food)
Peak plasma time: 4 hr (with food)
Peak plasma concentration: 665 ng/mL; 246 ng/mL (M4)
AUC: 7430 ng·h/mL; 2810 ng·h/mL (M4)
Steady-state reached: 7 days
Distribution
Protein bound (parent drug and M4 metabolite): >99%
Vd: 4016 L; 10,093 L (M4)
Metabolism
Alectinib is metabolized by CYP3A4 to its major active metabolite M4
M4 is subsequently metabolized by CYP3A4
M4 is a substrate of P-gp
Elimination
Half-life: 33 hr; 31 hr (M4)
Clearance: 81.9 L/hr; 217 L/hr (M4)
Excretion
- Feces: 84%; 6% (M4)
- Urine: <0.5%
Administration
Instructions
Take with food
Do not open or dissolve contents of capsule
If a dose is missed or vomited, take the next dose at the scheduled time (do not take an extra dose)
Storage
Do not store above 30°C (86°F)
Store in the original container to protect from light and moisture
