Pronunciation
(al EK ti nib)
Index Terms
AF802Alectinib HydrochlorideCH5424802RG7853RO5424802UNII-LIJ4CT1Z3Y
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule, Oral:
Alecensa: 150 mg
Brand Names: U.S.
Alecensa
Pharmacologic Category
Antineoplastic Agent, Anaplastic Lymphoma Kinase InhibitorAntineoplastic Agent, Tyrosine Kinase Inhibitor
Pharmacology
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
Metabolism
Hepatic via CYP3A4 to major active metabolite M4; M4 is also metabolized by CYP3A4
Excretion
Feces (98%; 84% as unchanged parent drug and 6% as M4); urine (<0.5%)
Time to Peak
4 hours
Half-Life Elimination
Parent drug: 33 hours; M4: 31 hours
Protein Binding
>99% to plasma proteins
Use: Labeled Indications
Non-small cell lung cancer, metastatic: Treatment of anaplastic lymphoma kinase (ALK)-positive, metastatic non-small cell lung cancer (NSCLC) as detected by an approved test.
Contraindications
There are no contraindications listed in the manufacturer’s US labeling.
Canadian labeling: Known hypersensitivity to alectinib or any component of the formulation.
Dosing: Adult
Non-small cell lung cancer (NSCLC), metastatic (ALK-positive): Oral: 600 mg twice daily; continue until disease progression or unacceptable toxicity (Ou 2016; Peters 2017)
Missed doses: If a dose is missed or if vomiting occurs, take the next dose at the regularly scheduled time.
Dosing: Geriatric
Refer to adult dosing.
Dosing: Renal Impairment
Preexisting renal impairment:
CrCl ≥30 mL/minute: No dosage adjustment is necessary.
CrCl <30 mL/minute or ESRD: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).
Renal toxicity during treatment:
Grade 3 renal impairment: Withhold alectinib until serum creatinine recovers to ≤1.5 times ULN, then resume at reduced dose (see Dosage Adjustment for Toxicity for recommended alectinib dosage reduction levels).
Grade 4 renal impairment: Permanently discontinue.
Dosing: Hepatic Impairment
Preexisting hepatic impairment:
Mild impairment (total bilirubin ≤ULN and AST >ULN or total bilirubin >1 to 1.5 times ULN and any AST): No dosage adjustment is necessary.
Moderate or severe impairment: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).
Hepatotoxicity during treatment:
ALT or AST >5 times ULN and total bilirubin ≤2 times ULN: Withhold alectinib; upon recovery to baseline or to ALT/AST ≤3 times ULN, may resume at a reduced dose (see Dosage Adjustment for Toxicity for recommended alectinib dosage reduction levels).
ALT or AST >3 times ULN and total bilirubin >2 times ULN (in the absence of cholestasis or hemolysis): Permanently discontinue.
Total bilirubin >3 times ULN: Withhold alectinib; upon recovery to baseline or to total bilirubin ≤1.5 times ULN, may resume at a reduced dose (see Dosage Adjustment for Toxicity for recommended alectinib dosage reduction levels).
Dosing: Adjustment for Toxicity
Recommended alectinib dosage reductions for toxicity:
Initial starting dose: 600 mg twice daily
First dose reduction: 450 mg twice daily
Second dose reduction: 300 mg twice daily
If unable to tolerate 300 mg twice daily, discontinue alectinib
Cardiac toxicity:
Symptomatic bradycardia: Withhold alectinib until recovery to asymptomatic bradycardia or until the heart rate is ≥60 beats per minutes (bpm). 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 cannot be discontinued or dose adjusted), resume alectinib at a reduced dose upon recovery (to asymptomatic bradycardia or heart rate ≥60 bpm).
Life-threatening bradycardia/heart rate <60 bpm (urgent intervention required): Permanently discontinue alectinib if no contributing concomitant medication is identified. If a contributing concomitant medication is identified and discontinued (or dose adjusted), resume alectinib (with frequent monitoring) at a reduced dose upon recovery to asymptomatic bradycardia or to a heart rate ≥60 bpm. Permanently discontinue for recurrent life-threatening bradycardia.
CPK elevation:
CPK >5 times ULN: Withhold alectinib; upon recovery to baseline or to ≤2.5 times ULN, may resume alectinib at the same dose.
CPK >10 times ULN or 2nd occurrence of CPK >5 times ULN: Withhold alectinib; upon recovery to baseline or to ≤2.5 times ULN, may resume alectinib at a reduced dose.
Pulmonary toxicity: Interstitial lung disease (ILD)/pneumonitis, any grade (treatment-related): Permanently discontinue
Administration
Administer with food. Swallow capsule 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.
Storage
Store at ≤30°C (86°F); store in original container to protect from light and moisture.
Drug Interactions
Bradycardia-Causing Agents: May enhance the bradycardic effect of other Bradycardia-Causing Agents.Monitor therapy
Bretylium: May enhance the bradycardic effect of Bradycardia-Causing Agents. Bretylium may also enhance atrioventricular (AV) blockade in patients receiving AV blocking agents. 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. Avoid combination
Ivabradine: Bradycardia-Causing Agents may enhance the bradycardic effect of Ivabradine. Monitor therapy
Lacosamide: Bradycardia-Causing Agents may enhance the AV-blocking effect of Lacosamide. Monitor therapy
Ruxolitinib: May enhance the bradycardic effect of Bradycardia-Causing Agents. Management: Ruxolitinib Canadian product labeling recommends avoiding use with bradycardia-causing agents to the extent possible. Monitor therapy
Terlipressin: May enhance the bradycardic effect of Bradycardia-Causing Agents. Monitor therapy
Tofacitinib: May enhance the bradycardic effect of Bradycardia-Causing Agents. Monitor therapy
Adverse Reactions
>10%:
Cardiovascular: Edema (30%), bradycardia (8% to 20%)
Central nervous system: Fatigue (≤41%), headache (17%)
Dermatologic: Skin rash (18%)
Endocrine & metabolic: Hyperglycemia (36%), hypocalcemia (32%), hypokalemia (29%), hypophosphatemia (21%), hyponatremia (20%), weight gain (11%)
Gastrointestinal: Constipation (34%), nausea (18%), diarrhea (16%), vomiting (12%)
Hematologic & oncologic: Anemia (56%, grades 3/4: 2%), lymphocytopenia (22%, grades 3/4: 5%)
Hepatic: Increased serum AST (51%, grades 3/4: 4%), increased serum alkaline phosphatase (47%), hyperbilirubinemia (39%, grades 3/4: 2% to 3%), increased serum ALT (34%, grades 3/4: 5%)
Neuromuscular & skeletal: Increased creatine phosphokinase (43%, grades 3/4: 5%), weakness (≤41%), musculoskeletal pain (≤29%), myalgia (≤29%), back pain (12%)
Renal: Increased serum creatinine (28%)
Respiratory: Cough (19%), dyspnea (16%)
1% to 10%:
Cardiovascular: Pulmonary embolism (1%)
Dermatologic: Photosensitivity dermatitis (10%)
Ophthalmic: Visual disturbances (10%)
<1% (Limited to important or life-threatening): Interstitial pulmonary disease, pneumonitis
Warnings/Precautions
Concerns related to adverse effects:
• Bradycardia: Symptomatic bradycardia may occur; heart rate <50 beats per minute has been reported in nearly 20% of patients treated with alectinib. Monitor heart rate and blood pressure regularly. If symptomatic bradycardia (non-life-threatening) occurs, withhold treatment until recovery to asymptomatic bradycardia or to a heart rate of ≥60 beats per minute, evaluate concurrent medications, and potentially reduce alectinib dose. Permanently discontinue for life-threatening bradycardia due to alectinib if no contributing concomitant medication is identified and for recurrent bradycardia. If life-threatening bradycardia occurs and concurrent medications associated with bradycardia can be discontinued or dose adjusted, restart alectinib at a reduced dose (with frequent monitoring).
• Hepatotoxicity: Liver function test abnormalities have been reported, including elevations of AST/ALT >5 times ULN and bilirubin >3 times ULN; most abnormalities occurred during the first 3 months of therapy. Concurrent ALT/AST elevations ≥3 times ULN and total bilirubin ≥2 times 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. Monitor liver function tests (ALT, AST, and total bilirubin) every 2 weeks during the first 3 months of therapy and then once a month and as clinically necessary; monitor more frequently in patients who develop transaminase and bilirubin elevations. May require therapy interruption, dose reduction, or permanent discontinuation.
• Myalgia: Myalgia or musculoskeletal pain occurred in over one-quarter of patients treated with alectinib (including grade 3 toxicity). Elevations of creatine phosphokinase (CPK) were commonly reported in clinical trials. The median time to grade 3 CPK elevations was 14 days. Monitor; advise patients to report unexplained muscle pain, tenderness, or weakness. Assess CPK every 2 weeks for the first month of therapy and then as clinically necessary. May require therapy interruption and/or dose reduction.
• Photosensitivity: Photosensitivity occurred in some patients. Patients should avoid sun exposure (during treatment and for 7 days after the final dose) and use a broad spectrum sunscreen and lip balm (SPF ≥50).
• Pulmonary toxicity: Severe interstitial lung disease (ILD) has been reported rarely. Monitor for ILD/pneumonitis; evaluate promptly in patients who present with worsening of respiratory symptoms or who have signs/symptoms suggestive of ILD/pneumonitis (eg, cough, dyspnea, fever). Immediately interrupt therapy for confirmed ILD/pneumonitis; permanently discontinue if alectinib is determined to be the causative factor.
• Renal toxicity: Renal impairment has been reported, including grade 3 and fatal events. May require therapy interruption, dose reduction, or permanent discontinuation.
Concurrent drug therapy issues:
• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.
Other warnings/precautions:
• Anaplastic lymphoma kinase testing: Approved for use only in patients with metastatic non-small cell lung cancer (NSCLC) who test positive for the abnormal anaplastic lymphoma kinase (ALK) gene.
Monitoring Parameters
Test for ALK positivity. Liver function tests (ALT, AST, total bilirubin) every 2 weeks during the first 3 months of therapy, then 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; monitor heart rate and blood pressure regularly; monitor for signs/symptoms of interstitial lung disease/pneumonitis and myalgia. Monitor adherence.
Pregnancy Considerations
Based on data from animal reproduction studies and its mechanism of action, alectinib may be expected to cause fetal harm if administered during pregnancy. Women of reproductive potential should use effective contraception during therapy and for 1 week after the final dose. Males with female partners of reproductive potential should use effective contraception during therapy and for 3 months after the last dose.
Patient Education
• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
• Patient may experience constipation, nausea, vomiting, headache, diarrhea, back pain, or weight gain. Have patient report immediately to prescriber signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), signs of a severe pulmonary disorder (lung or breathing problems like difficulty breathing, shortness of breath, or a cough that is new or worse), signs of high blood sugar (confusion, fatigue, increased thirst, increased hunger, polyuria, flushing, fast breathing, or breath that smells like fruit), signs of electrolyte problems (mood changes, confusion, muscle pain or weakness, abnormal heartbeat, seizures, lack of appetite, or severe nausea or vomiting), severe loss of strength and energy, bradycardia, dizziness, passing out, muscle pain, muscle weakness, edema, or vision changes (HCAHPS).
• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.
Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.
