Alectinib is a tyrosine kinase inhibitor that targets ALK and RET. It is used for the treatment of patients with ALK-positive, metastatic non-small cell lung cancer (NSCLC). Common adverse effects include fatigue, constipation, edema, myalgia, and anemia; serious adverse reactions include hepatotoxicity, pneumonitis, bradycardia, and elevated creatine phosphokinase (CPK).
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Emetic Risk
-Minimal/Low
-Administer prn antiemetics as necessary.
Route-Specific Administration
Oral Administration
-Administer alectinib with food.
-Do not open or dissolve the contents of the capsule.
-If a dose is missed, or if vomiting occurs after taking a dose, take the dose at the next scheduled time. Do not repeat doses or make up missed doses.
Elevated hepatic enzymes and hyperbilirubinemia have been reported in patients treated with alectinib in clinical trials. Increases in AST above 5 times the upper limit of normal (ULN) occurred in 4.6% of patients treated with alectinib at the recommended dose in 3 clinical trials (n = 405), while increases in ALT greater than 5 times ULN occurred in 5.3% of patients; bilirubin was increased more than 3 times ULN in 3.7% of patients. Most of these events (69% of patients with increased transaminases; 68% of patients with hyperbilirubinemia) occurred during the first 3 months of treatment. Concurrent transaminase elevations greater than or equal to 3 times ULN and total bilirubin greater than 2 times ULN (with normal alkaline phosphatase) occurred in less than 1% of patients across clinical trials. Three patients with grade 3 to 4 AST/ALT elevations had drug-induced liver injury, with 2 cases documented by liver biopsy. Drug-induced liver injury was reported in 1.3% of patients treated with alectinib (n = 152) in a randomized, open-label clinical trial. In this trial, treatment-emergent worsening in bilirubin (all grade, 54% vs. 4.7%; grade 3 or 4, 5% vs. 0%) and alkaline phosphatase (grade 1 or 2, 50% vs. 44%) occurred more often in the alectinib arm compared with crizotinib-treated patients (n = 151); increased AST (all grade, 50% vs. 56%; grade 3 or 4, 6% vs. 11%), increased ALT (all grade, 40% vs. 62%; grade 3 or 4, 6% vs. 16%), increased GGT (all grade, 7% vs. 39%; grade 3 or 4, 0.7% vs. 4.1%), and hypoalbuminemia (all grade, 14% vs. 57%; grade 3 or 4, 0% vs. 3.4%) occurred more frequently in the crizotinib arm. In 2 single-arm trials of patients previously treated with crizotinib (n = 250), increased AST occurred in 51% of alectinib-treated patients in these trials (grade 3 or 4, 3.6%), along with increased alkaline phosphatase (all grade, 47%; grade 3 or 4, 1.2%), hyperbilirubinemia (all grade, 39%; grade 3 or 4, 2.4%), and increased ALT (all grade, 34%; grade 3 or 4, 4.8%).
Interstitial lung disease (ILD)/pneumonitis occurred in 3 patients (0.7%) treated with alectinib in clinical trials (n = 405); one of these events was severe (grade 3, 0.2%). Worsening respiratory symptoms, including cough and dyspnea, should be promptly investigated; an interruption or discontinuation of therapy may be necessary. Interstitial lung disease was reported in 1.3% of patients treated with alectinib (n = 152) in a randomized, open-label clinical trial. In 2 single-arm trials of patients previously treated with crizotinib (n = 250), 16% of alectinib-treated patients experienced dyspnea (grade 3 or 4, 3.6%), including one fatality; mild (grade 1 to 2) cough occurred in 19% of patients.
Symptomatic bradycardia has been reported with alectinib therapy. Bradycardia occurred in 8.6% of patients treated with alectinib in clinical trials (n = 405); 18% of patients treated with alectinib who had serial ECGs available (n = 365) had heart rates of less than 50 beats per minute (bpm). A dose modification or interruption/discontinuation of therapy may be necessary for symptomatic bradycardia; asymptomatic bradycardia does not require a dose adjustment. Mild (grade 1 or 2) bradycardia was reported in 11% of patients treated with alectinib (n = 152) in a randomized, open-label clinical trial, compared with 15% of those treated with crizotinib (n = 151).
Sudden death and cardiac arrest each occurred in one patient treated with alectinib in a randomized, open label clinical trial (N = 152). In clinical studies (n = 221), alectinib did not cause QT prolongation to a clinically relevant extent in patients who received alectinib 600 mg twice daily. However, one patient had a maximum post-baseline QTcF value of greater than 500 msec, and one patient had a maximum QTcF change from baseline of greater than 60 msec.
Myalgia or musculoskeletal pain occurred in 26% (grade 3, 0.7%) of alectinib-treated patients in clinical trials (n = 405). Elevated creatine phosphokinase (CPK) was also reported in 41% (grade 3, 4%) of patients with CPK laboratory data available in these trials (n = 347). The median time to grade 3 CPK elevation was 14 days (interquartile range, 13 to 28 days). Any unexplained muscle pain, tenderness, or weakness should be reported immediately; a dose modification or interruption of therapy may be necessary. Mild (grade 1 or 2) myalgia was reported in 23% of patients treated with alectinib (n = 152) compared with 4% of those who received crizotinib (n = 151) in a randomized, open-label clinical trial; increased CPK occurred in 37% (grade 3 or 4, 2.8%) versus 52% (grade 3 or 4, 1.4%) of patients, respectively. In 2 single-arm trials of patients previously treated with crizotinib (n = 250), 29% of alectinib-treated patients experienced myalgia (grade 3 or 4, 1.2%), and CPK elevations were reported in 43% (grade 3 or 4, 4.6%) of patients.
In a randomized, open-label clinical trial, the following electrolyte disturbances were reported in patients with advanced NSCLC treated with alectinib (n = 152) compared with crizotinib (n = 151): hypocalcemia (all grade, 29% vs. 61%; grade 3 or 4, 0% vs. 1.4%), hyperglycemia (all grade, 22% vs. 19%; grade 3 or 4, 2.2% vs. 2.3%), hyponatremia (all grade, 18% vs. 20%; grade 3 or 4, 6% vs. 4.1%), hypokalemia (all grade, 17% vs. 12%; grade 3 or 4, 2% vs. 0.7%), hyperkalemia (all grade, 12% vs. 16%; grade 3 or 4, 1.4% vs. 1.4%), and hypophosphatemia (all grade, 9% vs. 25%; grade 3 or 4, 1.4% vs. 2.7%). In 2 single-arm trials of patients previously treated with crizotinib (n = 250), patients treated with alectinib reported hyperglycemia (all grade, 36%; grade 3 or 4, 2%), hypocalcemia (all grade, 32%; grade 3 or 4, 0.4%), hypokalemia (all grade, 29%; grade 3 or 4, 4%), hypophosphatemia (all grade, 21%; grade 3 or 4, 2.8%), and hyponatremia (all grade, 20%; grade 3 or 4, 2%).
Renal failure (unspecified) has been reported in patients treated with alectinib. In clinical trials (n = 405), renal impairment occurred in 8% of alectinib-treated patients (grade 3 or higher, 1.7%), with 0.5% of cases being fatal. The median time to grade 3 or higher renal impairment was 3.7 months. An interruption or discontinuation of therapy, or dose modification, may be necessary for renal impairment. Renal impairment (including increased blood creatinine, decreased creatinine clearance, decreased glomerular filtration rate, and acute kidney injury) was reported in 12% (grade 3 or higher, 3.9%) of patients treated with alectinib (n = 152) compared with 0% of patients who received crizotinib (n = 151) in a randomized, open-label clinical trial, including two grade 5 events. In this trial, increased creatinine was reported in 38% (grade 3 or 4, 4.1%) of alectinib-treated patients compared with 23% (grade 3 or 4, 0.7%) of patients in the crizotinib arm. In 2 single-arm trials of patients previously treated with crizotinib (n = 250), mildly increased creatinine (grade 1 or 2) occurred in 28% of patients who received alectinib.
In a randomized, open-label clinical trial of patients with advanced NSCLC, anemia was more common with alectinib treatment (n = 152) compared with treatment with crizotinib (n = 151) (all grade, 62% vs. 36%; grade 3 or 4, 7% vs. 0.7%); lymphopenia (all grade, 14% vs. 34%; grade 3 or 4, 1.4% vs. 4.1%) and neutropenia (all grade, 14% vs. 36%; grade 3 or 4, 0% vs. 7%) occurred more frequently in patients treated with crizotinib. In 2 single-arm trials of patients previously treated with crizotinib (n = 250), 56% of patients treated with alectinib reported anemia (grade 3 or 4, 2%) and 22% reported lymphopenia (grade 3 or 4, 4.6%). In postmarketing surveillance, hemolytic anemia has been reported in alectinib-treated patients. Some cases were associated with a negative direct antiglobulin test. If hemolytic anemia is suspected, hold alectinib therapy and initiate appropriate laboratory testing. Permanent discontinuation or a dosage reduction is necessary in patients who develop hemolytic anemia.
In a randomized, open-label clinical trial of patients with advanced NSCLC, rash (unspecified), including maculopapular rash, acneiform rash or dermatitis, erythema, exfoliative dermatitis or rash, and pruritic rash (pruritus) occurred with a similar frequency in patients treated with alectinib (n = 152) and in patients treated with crizotinib (n = 151) (all grade, 15% vs. 13%; grade 3 or 4, 0.7% vs. 0%). In 2 open-label, single-arm clinical trials (n = 250), 18% of alectinib-treated patients reported rash (grade 3 or 4, 0.4%), including maculopapular rash, acneiform dermatitis, erythema, and pruritic rash.
In a randomized, open-label clinical trial of patients with advanced NSCLC, 5.3% of patients treated with alectinib developed a clinically significant photosensitivity reaction (n = 152). In 2 open-label, single-arm clinical trials, photosensitivity occurred in 9.9% (grade 1, 9.5%; grade 2, 0.4%) of patients treated with alectinib (n = 250). Patients were advised to avoid sun exposure and use broad-spectrum sunscreen.
In a randomized, open-label clinical trial of patients with advanced NSCLC, alectinib (n = 152) was generally better tolerated than crizotinib (n = 151) with regard to gastrointestinal adverse reactions, including constipation (grade 1 or 2, 34% vs. 33%), nausea (all grade, 14% vs. 48%; grade 3 or 4, 0.7% vs. 3.3%), diarrhea (all grade, 12% vs. 45%; grade 3 or 4, 0% vs. 2%), and vomiting (all grade, 7% vs. 38%; grade 3 or 4, 0% vs. 3.3%); weight gain (9.9%) and stomatitis (3.3%) were also reported in alectinib-treated patients. In 2 open-label, single-arm clinical trials (n = 250), 34% of alectinib-treated patients reported mild (grade 1 or 2) constipation, along with nausea (grade 1 or 2, 18%), diarrhea (all grade, 16%; grade 3 or 4, 1.2%), vomiting (all grade, 12%; grade 3 or 4, 0.4%), and weight gain (all grade, 11%; grade 3 or 4, 0.4%); GI perforation also occurred and was fatal in 0.4% of patients in these trials.
In a randomized, open-label clinical trial of patients with advanced NSCLC, fatigue and asthenia were reported in 26% (grade 3 or 4, 1.3%) of patients treated with alectinib (n = 152) compared with 23% (grade 3 or 4, 0.7%) of those who received crizotinib (n = 151). In 2 open-label, single-arm clinical trials (n = 250), 41% of alectinib-treated patients reported fatigue and asthenia (grade 3 or 4, 1.2%), along with headache (all grade, 17%; grade 3 or 4, 0.8%) and mild (grade 1 or 2) back pain (12%).
In a randomized, open-label clinical trial of patients with advanced NSCLC, mild (grade 1 or 2) visual impairment, including blurred vision, vitreous floaters, reduced visual acuity, and diplopia, was reported in 4.6% of patients treated with alectinib (n = 152) compared with 23% of those who received crizotinib (n = 151). In 2 open-label, single-arm clinical trials (n = 250), 10% of alectinib-treated patients reported mild visual impairment, which also included asthenopia.
Pulmonary embolism occurred in 1.2% of alectinib-treated patients with ALK-positive non-small cell lung cancer (NSCLC) in 2 open-label, single-arm clinical trials (n = 250), and was fatal in 1 patient (0.4%).
Fatal hemorrhage (bleeding) occurred in 0.8% of alectinib-treated patients with ALK-positive non-small cell lung cancer (NSCLC) in 2 open-label, single-arm clinical trials (n = 250).
Fatal endocarditis (infection) occurred in 0.4% of alectinib-treated patients with ALK-positive non-small cell lung cancer (NSCLC) in 2 open-label, single-arm clinical trials (n = 250). In a randomized clinical trial, pneumonia was also reported in patients treated with alectinib (n = 152); it was serious in 4.6% of patients, resulted in a dose modification in 3.3% of patients, and was fatal in one patient.
In a randomized, open-label clinical trial of patients with advanced NSCLC, dysgeusia (including hypogeusia) was reported in 3.3% (grade 3 or 4, 0.7%) of patients treated with alectinib (n = 152) compared with 19% (grade 3 or 4, 0%) of those who received crizotinib (n = 151).
Edema, including peripheral edema, eyelid edema, localized edema, and facial edema, was reported in 22% (grade 3 or 4, 0.7%) of advanced NSCLC patients treated with alectinib (n = 152) compared with 34% (grade 3 or 4, 0.7%) of those who received crizotinib (n = 151) in a randomized, open-label clinical trial. Edema was also reported in 30% (grade 3 or 4, 0.8%) of alectinib-treated patients in 2 open-label, single-arm clinical trials (n = 250), which additionally included periorbital edema.
Elevated hepatic enzymes and bilirubin have occurred with alectinib therapy. Monitor liver function tests (including ALT, AST, and total bilirubin) every 2 weeks for the first 3 months of treatment, and then once monthly and as clinically indicated during treatment; monitor more frequently in patients who develop transaminase and bilirubin elevations. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary. Most cases of hepatotoxicity (69% of transaminase elevations and 68% of bilirubin elevation) occurred during the first 3 months of treatment. Use alectinib with caution in patients with pre-existing hepatic disease.
Pneumonitis or interstitial lung disease (ILD) has been reported in patients treated with alectinib in clinical trials. Hold alectinib therapy and promptly evaluate any patient with worsening respiratory symptoms (e.g., dyspnea, cough, and fever). Permanently discontinue alectinib if ILD/pneumonitis is diagnosed and no other potential cause is identified. Use alectinib with caution in patients with pre-existing pulmonary disease.
Symptomatic bradycardia has been reported in patients treated with alectinib. Monitor heart rate and blood pressure regularly; an interruption of therapy, dose reduction, or discontinuation of therapy may be necessary. Use alectinib with caution in patients with pre-existing cardiac disease, including those with cardiac arrhythmias or conduction disturbances (e.g., sick sinus syndrome, AV block, QT prolongation); hypotension or syncope may also be exacerbated.
Musculoskeletal adverse reactions, including severe myalgia and elevated serum creatine phosphokinase (CPK) levels, have been reported with alectinib therapy. Monitor CPK levels every 2 weeks for the first month of treatment, and then as clinically indicated in patients reporting symptoms; a dose reduction, interruption of therapy, or discontinuation of therapy may be necessary. Patients should be advised to promptly report any unexplained muscle pain, tenderness, or weakness, especially if accompanied by malaise or fever. The median time to grade 3 CPK elevation was 14 days (interquartile range, 13 to 28 days). Use alectinib with caution in patients with a history of myopathy (e.g., rhabdomyolysis).
Alectinib is associated with mild to moderate photosensitivity. Patients should be advised to avoid sunlight (UV) exposure, and to wear protective clothing, use a broad spectrum UVA/UVB sunscreen, and wear protective lip balm (SPF 50 or higher) when outdoors while on treatment and for at least 7 days after the last dose.
Renal impairment, including fatalities, has occurred with alectinib treatment; use alectinib with caution in patients with pre-existing renal disease. The median time to grade 3 or higher renal impairment was 3.7 months (range, 0.5 to 14.7 months); an interruption of therapy, dose reduction, or discontinuation of therapy may be necessary.
Although there are no adequate and well-controlled studies in pregnant women, alectinib may cause fetal harm when administered during pregnancy. When administered to pregnant rabbits during organogenesis, abortion or complete embryo-fetal mortality occurred in 3 of 6 rabbits exposed to 2.9-fold the estimated AUC in humans treated with the recommended dose of 600 mg twice daily; the remaining 3 rabbits had few live fetuses, decreased fetal and placental weights, and retroesophageal subclavian artery. In pregnant rats, administration of alectinib during organogenesis at approximately 4.5-fold the AUC in humans at the recommended dose resulted in complete litter loss. Exposures of approximately 2.7-fold the estimated human AUC in humans at the recommended dose resulted in maternal toxicity in addition to decreased fetal weight, dilated ureter, thymic cord, small ventricle, and thin ventricle wall, and reduced number of sacral and caudal vertebrae.
Counsel patients about the reproductive risk and contraception requirements during alectinib treatment. Alectinib can cause fetal harm if taken by the mother during pregnancy. Females should avoid pregnancy and use effective contraception during and for at least 1 week after treatment with alectinib. Due to the risk of male-mediated teratogenicity, males with female partners of reproductive potential should also use effective contraception during alectinib therapy and for at least 3 months after the last dose. It would be prudent for females of reproductive potential to undergo pregnancy testing prior to initiation of alectinib. Women who become pregnant while receiving alectinib should be apprised of the potential hazard to the fetus.
It is not known whether alectinib is present in human milk. Many drugs are excreted in human milk including antibodies. Due to the potential for serious adverse reactions in nursing infants from alectinib, advise women to discontinue breast-feeding during treatment and for 1 week after the final dose.
For the treatment of metastatic, ALK-positive non-small cell lung cancer (NSCLC):
NOTE: The FDA has designated alectinib as an orphan drug for the treatment of ALK-positive NSCLC.
NOTE: Patients should be selected based on the presence of ALK positivity in tumor specimens. Information on FDA-approved tests for the detection of ALK rearrangements in NSCLC is available at www.fda.gov/CompanionDiagnostics.
Oral dosage:
Adults: 600 mg orally twice daily, with food, until disease progression or unacceptable toxicity. First-line treatment with alectinib significantly improved progression-free survival (PFS) compared with crizotinib in a multicenter, open-label clinical trial of patients with ALK-positive NSCLC (34.8 months vs. 10.9 months) (the ALEX study). After 37% of events being reported, the median overall survival (OS) was not reached with alectinib versus 57.4 months with crizotinib; the 5-year OS rate was 62.5% compared with 45.5%, respectively. The overall response rate was 79% (complete response [CR] 13%) for those who received alectinib compared with 72% (CR, 6%) for patients treated with crizotinib; the CNS objective response rate was 81% (CR, 38%) versus 50% (CR, 5%), respectively. Patients with locally advanced or metastatic ALK-positive NSCLC who were treated with alectinib after progression on crizotinib had objective response rates of 38% to 48% in two multicenter, single-arm clinical trials (n = 225). In a multicenter, randomized, open-label phase 3 study, treatment with alectinib (n = 72) also significantly improved median progression-free survival compared with chemotherapy (n = 35) (9.6 months vs. 1.4 months) in patients with advanced ALK-positive NSCLC who progressed on, or were intolerant to, crizotinib. The CNS objective response rate was also significantly higher with alectinib versus chemotherapy in patients with measurable baseline CNS disease (54.2% vs. 0%).
Therapeutic Drug Monitoring:
Dosage Adjustments for Treatment-Related Toxicity:
Pulmonary Toxicity
-Pneumonitis / Interstitial Lung Disease (ILD) of any grade: Permanently discontinue alectinib.
Bradycardia
-Asymptomatic bradycardia: No dose adjustment necessary. Continue treatment.
-Symptomatic bradycardia, not life-threatening: Hold alectinib. When bradycardia becomes asymptomatic or recovers to a heart rate of 60 beats per minute (bpm) or higher, resume alectinib. If a contributing concomitant medication is identified and discontinued (or dose-adjusted), resume alectinib at the previous dose. If no contributing concomitant medication is identified, or if the contributing medication is not discontinued or dose modified, resume alectinib therapy at a reduced dose (1st dose reduction, 450 mg twice daily; 2nd dose reduction, 300 mg twice daily); discontinue alectinib if unable to tolerate a dose of 300 mg twice daily.
-Life-threatening bradycardia; urgent intervention required: Hold alectinib; permanently discontinue treatment if unable to identify a contributing concomitant medication. If a contributing concomitant medication is identified and discontinued (or dose-adjusted), resume alectinib upon recovery to asymptomatic bradycardia or to a heart rate of 60 bpm or higher at a reduced dose (1st dose reduction, 450 mg twice daily; 2nd dose reduction, 300 mg twice daily) with frequent monitoring as clinically indicated. Discontinue alectinib if unable to tolerate a dose of 300 mg twice daily; permanently discontinue alectinib if life-threatening bradycardia recurs after the first occurrence.
Creatine phosphokinase (CPK)
-CPK elevation greater than 5 times ULN: Hold alectinib. When CPK recovers to less than or equal to 2.5 times ULN or baseline, resume alectinib at the same dose for the first occurrence. For subsequent occurrences, resume alectinib at a reduced dose (1st dose reduction, 450 mg twice daily; 2nd dose reduction, 300 mg twice daily); discontinue alectinib if unable to tolerate a dose of 300 mg twice daily.
-CPK elevation greater than 10 times ULN: Hold alectinib. When CPK recovers to less than or equal to 2.5 times ULN or baseline, resume alectinib at a reduced dose (1st dose reduction, 450 mg twice daily; 2nd dose reduction, 300 mg twice daily); discontinue alectinib if unable to tolerate a dose of 300 mg twice daily.
Hemolytic Anemia
-Hold alectinib if hemolytic anemia is suspected. Upon resolution, permanently discontinue therapy or resume alectinib at a reduced dose as follows: 1st dose reduction, 450 mg twice daily; 2nd dose reduction, 300 mg twice daily (discontinue alectinib if unable to tolerate a dose of 300 mg twice daily).
Maximum Dosage Limits:
-Adults
600 mg by mouth twice daily.
-Geriatric
600 mg by mouth twice daily.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Baseline Hepatic Impairment
-Mild to moderate hepatic impairment (Child-Pugh A or B): No dosage adjustment necessary.
-Severe hepatic impairment (Child-Pugh C): Reduce the dose of alectinib to 450 mg PO twice daily.
Treatment-Related Hepatotoxicity
-AST/ALT more than 5 times the upper limit of normal (ULN) AND total bilirubin 2 times ULN or less: Hold alectinib. When AST/ALT recovers to less than or equal to 3 times ULN or baseline, resume alectinib at a reduced dose (1st dose reduction, 450 mg twice daily; 2nd dose reduction, 300 mg twice daily); discontinue alectinib if unable to tolerate a dose of 300 mg twice daily.
-AST/ALT greater than 3 times ULN AND total bilirubin greater than 2 times ULN (in the absence of cholestasis or hemolysis): Permanently discontinue alectinib.
-Total bilirubin greater than 3 times ULN: Hold alectinib. When total bilirubin recovers to less than or equal to 1.5 times ULN or baseline, resume alectinib at a reduced dose (1st dose reduction, 450 mg twice daily; 2nd dose reduction, 300 mg twice daily); discontinue alectinib if unable to tolerate a dose of 300 mg twice daily.
Patients with Renal Impairment Dosing
Baseline Renal Impairment
A dosage adjustment is not recommended for patients with mild to moderate renal impairment. The safety of alectinib in patients with severe renal impairment (CrCL less than 30 mL/min) or end-stage renal disease has not been studied. Alectinib is not likely to be removed by hemodialysis.
Treatment-Related Nephrotoxicity
-Grade 3 renal impairment: Hold alectinib. When serum creatinine (SCr) recovers to less than or equal to 1.5 times ULN, resume alectinib at a reduced dose (1st dose reduction, 450 mg twice daily; 2nd dose reduction, 300 mg twice daily); discontinue alectinib if unable to tolerate a dose of 300 mg twice daily.
-Grade 4 renal impairment: Permanently discontinue alectinib.
*non-FDA-approved indication
Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
Dengue Tetravalent Vaccine, Live: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the dengue virus vaccine. When feasible, administer indicated vaccines at least 2 weeks prior to initiating immunosuppressant medications. If vaccine administration is necessary, consider revaccination following restoration of immune competence. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure after receiving the vaccine.
Porfimer: (Major) Avoid coadministration of porfimer with alectinib due to the risk of increased photosensitivity. All patients treated with porfimer will be photosensitive. Concomitant use of other photosensitizing agents like alectinib may increase the risk of a photosensitivity reaction.
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Adenovirus Vector Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) mRNA Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Recombinant Spike Protein Nanoparticle Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
Verteporfin: (Moderate) Use caution if coadministration of verteporfin with alectinib is necessary due to the risk of increased photosensitivity. Verteporfin is a light-activated drug used in photodynamic therapy; all patients treated with verteporfin will be photosensitive. Concomitant use of other photosensitizing agents like alectinib may increase the risk of a photosensitivity reaction.
Alectinib is a tyrosine kinase inhibitor that targets anaplastic lymphoma kinase (ALK) and RET. Alectinib, a CNS-active and highly selective ALK inhibitor, inhibited ALK phosphorylation and ALK-mediated activation of the downstream signaling proteins STAT3 and AKT in nonclinical studies. It also decreased tumor cell viability in multiple cell lines harboring ALK fusions, amplifications, or activating mutations. The major active metabolite is M4, which has shown similar in vitro potency and activity. Alectinib and M4 have demonstrated in vitro and in vivo activity against multiple mutant forms of the ALK enzyme, including some mutations in NSCLC tumors in patients who have progressed on crizotonib. Administration of alectinib resulted in antitumor activity and prolonged survival in mouse models implanted with tumors carrying ALK fusions, including mouse models implanted intracranially with ALK-driven tumor cell lines.
Alectinib is administered orally. Alectinib and its major metabolite, M4, are greater than 99% bound to plasma proteins, independent of drug concentration. The apparent volume of distribution (Vd) is 4,016 liters for alectinib and 10,093 liters for M4; alectinib concentrations in the cerebrospinal fluid of patients with ALK-positive NSCLC approximate the estimated alectinib free concentrations in the plasma. The apparent clearance (CL/F) is 81.9 L/hour for alectinib and 217 L/hour for M4; the geometric mean elimination half-life is 33 hours for alectinib and 31 hours for M4. Steady-state concentrations are reached by day 7 of administration. The geometric mean accumulation was approximately 6-fold for both alectinib and M4. Ninety-eight percent of radioactivity was excreted in feces after oral administration of a single radiolabeled dose of alectinib under fed conditions; 84% of the dose was unchanged alectinib and 6% was M4. Excretion in the urine was less than 0.5% of the radiolabeled dose.
Affected cytochrome (CYP) 450 isoenzymes and drug transporters: CYP3A4, P-glycoprotein (P-gp), and BCRP
Alectinib is metabolized by CYP3A4 to its major active metabolite, M4; M4 is subsequently also metabolized by CYP3A4. The mean metabolite/parent exposure ratio is 0.4 at steady state; alectinib and M4 account for 76% of the total radioactivity after a dose. In vitro studies suggest that alectinib is not a substrate of P-gp, but M4 is. Additionally, both alectinib and M4 inhibit P-gp and BCRP in vitro. Pharmacokinetic drug interactions with alectinib requiring dosage adjustments have not been identified. Alectinib and M4 are not substrates of BCRP, OATP1B1, or OATP1B3, and do not inhibit CYP1A2, 2B6, 2C9, 2C19, or 2D6. Alectinib did not inhibit OATP1B1, OATP1B3, OAT1, OAT3, or OCT2 in vitro.
-Route-Specific Pharmacokinetics
Oral Route
The maximal concentration (Cmax) for alectinib at steady-state was 665 ng/mL (CV, 44%) and was 246 ng/mL (CV, 45%) for M4, with a peak to trough concentration ratio of 1.2; the time to maximal concentration (Tmax) was was 4 hours. The geometric mean AUC at steady-state from 0 to 12 hours was 7,430 ng x h/mL (CV, 46%) for alectinib and 2,810 ng x h/mL (CV, 46%) for M4. Alectinib exposure is dose proportional between 460 mg to 900 mg (i.e., 0.75 to 1.5 times the approved recommended dose) under fed conditions. The absolute bioavailability (F) of alectinib was 37% (90% CI, 34% to 40%) under fed conditions; a high fat, high-calorie meal increased the AUC of alectinib plus M4 by 3.1-fold (90% CI, 2.7 to 3.6-fold) after oral administration of a single 600-mg dose.
-Special Populations
Hepatic Impairment
Mild hepatic impairment (total bilirubin less than or equal to upper limit of normal (ULN) and AST greater than ULN, OR total bilirubin 1 to 1.5 times ULN and any AST) does not have a clinically meaningful effect on the systemic exposure of alectinib or M4. After administration of a single oral dose of alectinib (300 mg), the geometric mean ratio for the combined AUC of alectinib and M4 in subjects with moderate hepatic impairment (Child-Pugh B) was 1.36 (90% CI, 0.947 to 1.96) and in subjects with severe hepatic impairment (Child-Pugh C) was 1.76 (90% CI, 0.984 to 3.15) compared to subjects with normal hepatic function. The combined Cmax of alectinib and M4 was comparable among the 3 groups.
Renal Impairment
Mild to moderate renal impairment (CrCL 30 to 89 mL/min) does not have a clinically meaningful effect on the systemic exposure of alectinib or M4. Due to high protein binding, alectinib and its major active metabolite, M4, are unlikely to be removed by hemodialysis. The pharmacokinetics of alectinib have not been studied in patients with severe renal impairment (CrCL less than 30 mL/min) or end-stage renal disease (ESRD).
Geriatric
Age (range, 21 to 83 years) does not have a clinically meaningful effect on the systemic exposure of alectinib or M4.
Gender Differences
Gender does not have a clinically meaningful effect on the systemic exposure of alectinib or M4.
Ethnic Differences
Ethnicity (Caucasian, Asian, Other) does not have a clinically meaningful effect on the systemic exposure of alectinib or M4.
Obesity
Body weight (38 kg to 128 kg) does not have a clinically meaningful effect on the systemic exposure of alectinib or M4.