alectinib (Rx)

>10% (All Grades)

Anemia (56%)

Increased AST (51%)

Increased alkaline phosphatase (47%)

Increased CPK (43%)

Fatigue (26-41%)

Hyperbilirubinemia (39%)

Hyperglycemia (36%)

Increased ALT (34%)

Constipation (34%)

Hypocalcemia (32%)

Edema (22-30%)

Hypokalemia (29%)

Myalgia (23-29%)

Increased creatinine (28%)

Lymphopenia (22%)

Hypophosphatemia (21%)

Hyponatremia (20%)

Cough (19%)

Rash (15-18%)

Nausea (14-18%)

Headache (17%)

Diarrhea (12-16%)

Dyspnea (16%)

Back pain (12%)

Vomiting (7-12%)

Bradycardia (11%)

Increased weight (11%)

1-10% (All Grades

Vision disorder (10%)

1-10% (Grade 3 or 4)

Increased ALT (4.8%)

Increased CPK (4.6%)

Lymphopenia (4.6%)

Vision disorders (4.6%)

Hypokalemia (4%)

Renal impairment (3.9%)

Dyspnea (3.6%)

Increased AST (3.6%)

Dysgeusia (3.3%)

Hypophosphatemia (2.8%)

Hyperbilirubinemia (2.4%)

Hyperglycemia (2%)

Hyponatremia (2%)

Anemia (2%)

Fatigue (1.2%)

Myalgia (1.2%)

Diarrhea (1.2%)

Increased alkaline phosphatase (1.2%)

<1% (Grade 3 or 4)

Edema (0.7-0.8%)

Headache (0.8%)

Rash (0.4-0.7%)

Dysgeusia (0.7%)

Nausea (0.7%)

Vomiting (0.4%)

Increased weight (0.4%)

Hypocalcemia (0.4%)

Postmarketing Reports

Hemolytic anemia

Contraindications

None

Cautions

Elevated liver enzymes reported; 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 (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)

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)

Renal impairment occurred; incidence of Grade ≥3 renal impairment was 1.7%, of which 0.5% were fatal events (see Dosage Modifications)

Hemolytic anemia reported, including cases associated with a negative direct antiglobulin test (DAT) result; if hemolytic anemia is suspected, withhold therapy and initiate appropriate laboratory testing; if hemolytic anemia confirmed, consider resuming at a reduced dose upon resolution or permanently discontinue therapy

Bradycardia

• Symptomatic bradycardia can occur; 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 therapy 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 therapy at a reduced dose; upon recovery to asymptomatic bradycardia or to a heart rate of 60 bpm or above, with frequent monitoring as clinically indicated
• Permanently discontinue drug in case of recurrence; permanently discontinue drug in cases of life-threatening bradycardia if no contributing concomitant medication is identified

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.

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 at steady-state: 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%

Oral Administration

Take with food

Swallow capsule whole

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