Version October 2024
Dosage guidance:
Clinical considerations: Select patients for treatment based on the presence of abnormal anaplastic lymphoma kinase (ALK) positivity in tumor tissue or plasma specimens; if ALK rearrangements are not detected in plasma, test tumor tissue if feasible.
Non–small cell lung cancer, ALK positive, adjuvant treatment: Oral: 600 mg twice daily for 2 years or until disease progression or unacceptable toxicity, whichever occurred first (Ref).
Non–small cell lung cancer, metastatic, ALK positive: Oral: 600 mg twice daily; continue until disease progression or unacceptable toxicity (Ref).
Missed doses: If a dose is missed or if vomiting occurs, administer the next dose at the regularly scheduled time.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Preexisting kidney impairment:
CrCl ≥30 mL/minute: No dosage adjustment is necessary.
CrCl <30 mL/minute or end-stage kidney disease: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).
Kidney toxicity during treatment:
Grade 3 kidney impairment: Withhold alectinib until serum creatinine recovers to ≤1.5 times ULN, then resume at reduced dose.
Grade 4 kidney impairment: Permanently discontinue alectinib.
Preexisting hepatic impairment:
Mild to moderate impairment (Child-Turcotte-Pugh class A or B): No dosage adjustment is necessary.
Severe impairment (Child-Turcotte-Pugh class C): 450 mg twice daily.
Acute hepatotoxicity during treatment:
ALT or AST >5 × ULN with total bilirubin ≤2 × ULN: Withhold alectinib until recovery to baseline or to ALT/AST ≤3 × ULN, then resume at a reduced dose.
ALT or AST >3 × ULN with total bilirubin >2 × ULN (in the absence of cholestasis or hemolysis): Permanently discontinue alectinib.
Total bilirubin >3 × ULN: Withhold alectinib until recovery to baseline or to total bilirubin ≤1.5 × ULN, then resume at a reduced dose.
|
Dose reduction schedule |
Dose level |
|---|---|
|
a Discontinue alectinib if unable to tolerate 300 mg twice daily. | |
|
Starting (usual) dose |
600 mg twice daily |
|
First dose reduction |
450 mg twice daily |
|
Second dose reduction |
300 mg twice dailya |
|
Adverse reaction |
Severity |
Alectin ib dose modification |
|---|---|---|
|
a bpm = beats per minute; ILD = interstitial lung disease. | ||
|
Cardiac toxicity: Bradycardia |
Symptomatic (non–life-threatening) |
Withhold alectinib until recovery to asymptomatic bradycardia or until the heart rate is ≥60 bpm. Evaluate concurrent medications; if a contributing concomitant medication is identified and discontinued (or dose adjusted), resume alectinib at the previous dose upon recovery to asymptomatic bradycardia or heart rate ≥60 bpm. If no contributing concomitant medication is identified, or concomitant medication cannot be discontinued or dose adjusted, resume alectinib at a reduced dose upon recovery to asymptomatic bradycardia or heart rate ≥60 bpm. |
|
Life-threatening, urgent intervention indicated, heart rate <60 bpm |
Permanently discontinue alectinib if no contributing concomitant medication is identified. If a contributing concomitant medication is identified and discontinued (or dose adjusted), resume alectinib at a reduced dose (with frequent monitoring) upon recovery to asymptomatic bradycardia or to a heart rate ≥60 bpm. Permanently discontinue for recurrent life-threatening bradycardia. | |
|
CPK elevation |
CPK >5 × ULN |
Withhold alectinib until recovery to baseline or to ≤2.5 × ULN, then resume alectinib at the same dose. |
|
CPK >10 × ULN or second occurrence of CPK >5 × ULN |
Withhold alectinib until recovery to baseline or to ≤2.5 × ULN, then resume alectinib at a reduced dose. | |
|
Hemolytic anemia |
Suspected |
Withhold alectinib if hemolytic anemia suspected; upon recovery, resume alectinib at a reduced dose or permanently discontinue. |
|
Pulmonary toxicity |
ILD/pneumonitis, any grade (treatment-related) |
Immediately withhold alectinib if ILD/pneumonitis is confirmed; permanently discontinue alectinib if no other potential cause is identified. |
Refer to adult dosing.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reactions reported in adults.
>10%:
Cardiovascular: Bradycardia (11% to 12%), edema (16% to 30%)
Dermatologic: Skin rash (15% to 23%)
Endocrine & metabolic: Hyperglycemia (22% to 36%), hyperkalemia (12%), hypoalbuminemia (14%), hypocalcemia (29% to 32%), hypokalemia (17% to 29%), hyponatremia (18% to 20%), hypophosphatemia (9% to 21%), increased uric acid (30%), weight gain (10% to 13%)
Gastrointestinal: Abdominal pain (13%), constipation (34% to 42%), diarrhea (12% to 16%; grades 3/4: ≤1%), dysgeusia (3% to 13%), nausea (8% to 18%; grades 3/4: <1%), vomiting (7% to 12%; grades 3/4: <1%)
Hematologic & oncologic: Anemia (56% to 62%; grades 3/4: 2% to 7%), lymphocytopenia (14% to 22%; grades 3/4: 1% to 5%), neutropenia (14%)
Hepatic: Hepatotoxicity (61%), hyperbilirubinemia (39% to 54%), increased serum alanine aminotransferase (34% to 57%), increased serum alkaline phosphatase (47% to 64%), increased serum aspartate aminotransferase (50% to 75%)
Nervous system: Asthenia (≤41%), fatigue (≤41%), headache (11% to 17%)
Neuromuscular & skeletal: Back pain (12%), increased creatine phosphokinase in blood specimen (37% to 77%), musculoskeletal pain (≤34%), myalgia (≤34%)
Renal: Increased serum creatinine (28% to 41%), kidney impairment (12% to 16%)
Respiratory: Cough (19% to 20%), dyspnea (13% to 16%)
1% to 10%:
Cardiovascular: Acute myocardial infarction (2%), pulmonary embolism (1%)
Dermatologic: Skin photosensitivity (4% to 10%)
Gastrointestinal: Appendicitis (3%), stomatitis (3% to 5%)
Hematologic & oncologic: Hemolytic anemia (3%)
Hepatic: Hepatic injury (1%), increased gamma-glutamyl transferase (7%)
Ophthalmic: Visual disturbances (5% to 10%; including asthenopia, blurred vision, decreased visual acuity, diplopia, photopsia, vitreous opacity)
Respiratory: Interstitial lung disease (1%), pneumonia (4% to 5%), pneumonitis (2%)
There are no contraindications listed in the manufacturer’s US labeling.
Canadian labeling: Known hypersensitivity to alectinib or any component of the formulation.
Concerns related to adverse effects:
• Bradycardia: Symptomatic bradycardia has occurred with alectinib; heart rate <50 beats per minute has been reported in 20% of patients.
• Hemolytic anemia: Hemolytic anemia has occurred with alectinib, including cases associated with a negative direct antiglobulin test result. While initially reported in the postmarketing setting, hemolytic anemia was observed in a small percentage of patients in a subsequent study.
• Hepatotoxicity: Severe hepatotoxicity, including drug-induced liver injury, has occurred with alectinib. Hepatotoxicity commonly occurred in alectinib-treated patients, including grade 3 events. Most transaminase elevations occurred during the first 3 months of treatment. Discontinuation due to hepatotoxicity occurred in a small percentage of patients. Concurrent ALT or AST elevations ≥3 × ULN and total bilirubin ≥2 × ULN, with normal alkaline phosphatase, occurred rarely. Liver biopsy demonstrated drug-induced liver injury in some patients with grade 3 to 4 AST or ALT elevations.
• Kidney toxicity: Kidney impairment has been reported, including grade 3 and rare fatal events. The median time to ≥ grade 3 renal impairment was 3.7 months (range: 0.5 to ~32 months). A small percentage of patients required dosage modification.
• Myalgia: Severe myalgia and creatine phosphokinase (CPK) elevation has occurred in alectinib-treated patients. Myalgia or musculoskeletal pain occurred in nearly one-third of patients treated with alectinib (including grade 3 events). Some patients with myalgia required dosage modifications. CPK elevations commonly occurred with alectinib; grade ≥3 elevations have been reported. The median time to ≥ grade 3 CPK elevations was 15 days. Some patients with elevated CPK required dose modifications. Advise patients to report unexplained muscle pain, tenderness, or weakness.
• Pulmonary toxicity: Interstitial lung disease (ILD)/pneumonitis has occurred with alectinib in a small percentage of patients; grade 3 ILD/pneumonitis has been observed, with some patients requiring alectinib discontinuation. The median time to onset of ≥ grade 3 pneumonitis was 2.1 months (range: 0.6 to 3.6 months). Signs/symptoms suggestive of ILD/pneumonitis include cough, dyspnea, and fever.
Special populations:
• Older adults: Patients ≥65 years of age may experience a higher incidence of serious adverse and more frequent dosage modifications or discontinuations due to adverse events, compared to patients <65 years of age.
Other warnings/precautions:
• Anaplastic lymphoma kinase testing: Select patients for treatment of metastatic disease based on the presence of abnormal anaplastic lymphoma kinase (ALK) positivity in tumor tissue or plasma specimens. If ALK rearrangements are not detected in plasma, test tumor tissue (if feasible). For adjuvant therapy, test for ALK positivity in tumor tissue. Information on tests approved for detection of ALK rearrangements in non–small cell lung cancer is available at https://www.fda.gov/CompanionDiagnostics.
• Photosensitivity: Patients should avoid sun exposure (during treatment and for 7 days after the final alectinib dose) and use a broad-spectrum sunscreen and lip balm (SPF ≥50).
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule, Oral:
Alecensa: 150 mg [contains corn starch]
No
Capsules (Alecensa Oral)
150 mg (per each): $92.69
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule, Oral:
Alecensaro: 150 mg [contains corn starch]
Available through specialty pharmacies and distributors. Further information may be obtained from the manufacturer, Genentech, at 1-888-249-4918 or at https://www.alecensa.com/.
Oral: Administer with food. Swallow capsules whole; do not open or dissolve the contents of the capsule. If vomiting occurs after taking the dose, do not administer an extra dose; administer the next dose at the regularly scheduled time.
Non–small cell lung cancer, ALK positive, adjuvant treatment: Adjuvant treatment following tumor resection in adults with anaplastic lymphoma kinase (ALK)-positive (as detected by an approved test), non–small cell lung cancer (NSCLC) (tumors ≥4 cm or node positive).
Non–small cell lung cancer, metastatic, ALK positive: Treatment of anaplastic lymphoma kinase ALK-positive, metastatic NSCLC as detected by an approved test.
Alectinib may be confused with abemaciclib, acalabrutinib, afatinib, alpelisib, asciminib, avapritinib, axitinib, binimetinib, brigatinib, ceritinib, crizotinib, entrectinib, larotrectinib, lorlatinib.
Alecensa may be confused with Alesse.
The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drug classes (chemotherapeutic agent, parenteral and oral) which have a heightened risk of causing significant patient harm when used in error (High-Alert Medications in Acute Care, Community/Ambulatory Care, and Long-Term Care Settings).
Substrate of CYP3A4 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the drug interactions program by clicking on the “Launch drug interactions program” link above.
Bradycardia-Causing Agents: May enhance the bradycardic effect of other Bradycardia-Causing Agents. Risk C: Monitor therapy
Ceritinib: Bradycardia-Causing Agents may enhance the bradycardic effect of Ceritinib. Management: If this combination cannot be avoided, monitor patients for evidence of symptomatic bradycardia, and closely monitor blood pressure and heart rate during therapy. Risk D: Consider therapy modification
Desmopressin: Hyponatremia-Associated Agents may enhance the hyponatremic effect of Desmopressin. Risk C: Monitor therapy
Etrasimod: May enhance the bradycardic effect of Bradycardia-Causing Agents. Risk C: Monitor therapy
Fexinidazole: Bradycardia-Causing Agents may enhance the arrhythmogenic effect of Fexinidazole. Risk X: Avoid combination
Fingolimod: Bradycardia-Causing Agents may enhance the bradycardic effect of Fingolimod. Management: Consult with the prescriber of any bradycardia-causing agent to see if the agent could be switched to an agent that does not cause bradycardia prior to initiating fingolimod. If combined, perform continuous ECG monitoring after the first fingolimod dose. Risk D: Consider therapy modification
Ivabradine: Bradycardia-Causing Agents may enhance the bradycardic effect of Ivabradine. Risk C: Monitor therapy
Lacosamide: Bradycardia-Causing Agents may enhance the AV-blocking effect of Lacosamide. Risk C: Monitor therapy
Midodrine: May enhance the bradycardic effect of Bradycardia-Causing Agents. Risk C: Monitor therapy
Ozanimod: May enhance the bradycardic effect of Bradycardia-Causing Agents. Risk C: Monitor therapy
Ponesimod: Bradycardia-Causing Agents may enhance the bradycardic effect of Ponesimod. Management: Avoid coadministration of ponesimod with drugs that may cause bradycardia when possible. If combined, monitor heart rate closely and consider obtaining a cardiology consult. Do not initiate ponesimod in patients on beta-blockers if HR is less than 55 bpm. Risk D: Consider therapy modification
Siponimod: Bradycardia-Causing Agents may enhance the bradycardic effect of Siponimod. Management: Avoid coadministration of siponimod with drugs that may cause bradycardia. If combined, consider obtaining a cardiology consult regarding patient monitoring. Risk D: Consider therapy modification
Tofacitinib: May enhance the bradycardic effect of Bradycardia-Causing Agents. Risk C: Monitor therapy
Patients who could become pregnant should use effective contraception during therapy and for 5 weeks after the last alectinib dose. Patients with partners who could become pregnant should use effective contraception during therapy and for 3 months after the last alectinib dose.
Based on data from animal reproduction studies and its mechanism of action, in utero exposure to alectinib may cause fetal harm.
It is not known if alectinib is present in breast milk.
Due to the potential for serious adverse reactions in the breastfed infant, the manufacturer does not recommend breastfeeding during therapy or for 1 week after the last alectinib dose.
Anaplastic lymphoma kinase positivity: For metastatic disease, test for anaplastic lymphoma kinase (ALK) positivity in tumor tissue or plasma specimens for metastatic disease; if ALK rearrangements are not detected in plasma, test tumor tissue if feasible. For adjuvant therapy, test for ALK positivity in tumor tissue.
LFTs (ALT, AST, total bilirubin) every 2 weeks during the first 3 months of therapy, then once monthly and as clinically necessary (monitor more frequently in patients who develop transaminase and bilirubin elevations; CPK levels every 2 weeks for the first month of therapy, then as clinically necessary in symptomatic patients. Monitor heart rate and blood pressure regularly. Monitor for signs/symptoms of cardiotoxicity, hemolytic anemia, hepatotoxicity, kidney toxicity, interstitial lung disease (ILD)/pneumonitis (evaluate promptly for ILD/pneumonitis in patients who present with worsening of respiratory symptoms or who have signs/symptoms suggestive of ILD/pneumonitis such as cough, dyspnea, or fever), and myalgia. Monitor adherence.
The American Society of Clinical Oncology hepatitis B virus (HBV) screening and management provisional clinical opinion (ASCO [Hwang 2020]) recommends HBV screening with hepatitis B surface antigen, hepatitis B core antibody, total Ig or IgG, and antibody to hepatitis B surface antigen prior to beginning (or at the beginning of) systemic anticancer therapy; do not delay treatment for screening/results. Detection of chronic or past HBV infection requires a risk assessment to determine antiviral prophylaxis requirements, monitoring, and follow-up.
Cardiovascular monitoring: Comprehensive assessment prior to treatment including a history and physical examination, screening for cardiovascular disease risk factors such as hypertension, diabetes, dyslipidemia, obesity, and smoking (ASCO [Armenian 2017]; ESC [Lyon 2022]).
Alectinib is a tyrosine kinase receptor inhibitor which inhibits anaplastic lymphoma kinase (ALK) and RET (with similar potency to ALK) (Ou 2016). ALK gene abnormalities due to mutations or translocations may result in expression of oncogenic fusion proteins (eg, ALK fusion protein) which alter signaling and expression and result in increased cellular proliferation and survival in tumors which express these fusion proteins. Inhibition of ALK phosphorylation and ALK-mediated activation of downstream signaling results in decreased tumor cell viability. Alectinib is more potent than crizotinib against ALK, and can inhibit most of the clinically observed acquired ALK resistance mutations to crizotinib (Ou 2016).
Absorption: A high-fat, high-calorie meal increased the combined exposure of alectinib plus its active metabolite M4 by 3.1-fold
Distribution: Parent drug: 4,016 L; M4 (active metabolite): 10,093 L; distributes in the CSF at approximately the free concentrations in plasma
Protein binding: >99% to plasma proteins
Metabolism: Hepatic via CYP3A4 to major active metabolite M4; M4 is also metabolized by CYP3A4
Bioavailability: 37% (under fed conditions)
Half-life elimination: Parent drug: 33 hours; M4: 31 hours
Time to peak: 4 hours
Excretion: Feces (98%; 84% as unchanged parent drug and 6% as M4); urine (<0.5%)
Hepatic function impairment: Following administration of a single 300 mg oral dose, the mean ratio for the combined AUC (parent drug and M4) was 1.36 in moderate impairment (Child-Turcotte-Pugh class B) and 1.76 in severe impairment (Child-Turcotte-Pugh class C) compared to subjects with normal hepatic impairment.
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