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 Grade 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 Grade 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).
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.