Alectinib Hydrochloride (Monograph)

Brand name: Alecensa
Drug class: Antineoplastic Agents

Medically reviewed by Drugs.com on Nov 10, 2024. Written by ASHP.

Introduction

Antineoplastic agent; an inhibitor of several receptor tyrosine kinases, including anaplastic lymphoma kinase (ALK).

Uses for Alectinib Hydrochloride

Non-small Cell Lung Cancer (NSCLC)

Treatment of adults with metastatic ALK-positive NSCLC as detected by FDA-approved test ; (designated an orphan drug by FDA for this use).

Adjuvant treatment in adults following tumor resection of ALK-positive NSCLC (tumors ≥4 cm or node positive), as detected by FDA-approved test.

Guidelines for the treatment of stage IV NSCLC in patients with driver alterations in ALK generally support use of alectinib as an option in the first-line setting and in the second-line setting following therapy with crizotinib.

The International Association for the Study of Lung Cancer recommends adjuvant alectinib for patients with stage IB (tumors ≥4 cm) to IIIA disease with ALK alterations.

Confirmation of ALK rearrangement necessary prior to initiation of therapy.

Alectinib Hydrochloride Dosage and Administration

General

Pretreatment Screening

• Select patients for treatment of metastatic non-small cell lung cancer (NSCLC) with alectinib based on presence of ALK rearrangement in tumor tissue or plasma specimens. If undetected in plasma specimen, test tumor tissue for ALK rearrangement, if feasible.

• Select patients with resectable tumors for adjuvant treatment of NSCLC with alectinib based on presence of ALK rearrangement in tumor tissue.

• Verify pregnancy status in females of reproductive potential.

Patient Monitoring

• Monitor liver function tests (e.g., ALT, AST, and total bilirubin) every 2 weeks during the first 3 months of therapy, then once monthly and as clinically indicated. More frequent monitoring may be necessary in patients who experience elevated serum aminotransferase and bilirubin concentrations.

• Monitor heart rate and BP regularly. More frequent monitoring may be necessary as clinically indicated.

• Monitor serum creatine kinase (CK, creatine phosphokinase, CPK) every 2 weeks during the first month of treatment and as clinically indicated in symptomatic patients.

Administration

Oral Administration

Administer twice daily with food. Swallow capsules whole; do not dissolve or open capsules.

If a dose of alectinib is missed or vomiting occurs after administration of a dose, take the next dose at the regularly scheduled time.

Dosage

Available as alectinib hydrochloride; dosage expressed in terms of alectinib.

Adults

NSCLC

Oral

600 mg twice daily. Continue therapy until disease progression or unacceptable toxicity occurs for patients with metastatic disease. For patients receiving alectinib as adjuvant therapy, continue for a total of 2 years or until disease progression or unacceptable toxicity occurs.

Dosage Modification for Toxicity

Oral

If dosage reduction is necessary, initially reduce dosage to 450 mg twice daily. If further dosage reduction is needed, reduce dosage to 300 mg twice daily.

If a dosage of 300 mg twice daily is not tolerated, discontinue the drug.

Hepatic Toxicity

Oral

If ALT or AST concentrations >5 times ULN with total bilirubin concentrations ≤2 times ULN, interrupt therapy. When liver function tests return to baseline or ≤3 times ULN, may resume alectinib at reduced dosage.

If ALT or AST concentrations >3 times ULN with total bilirubin concentrations >2 times ULN occur without cholestasis or hemolysis, permanently discontinue drug.

If total bilirubin concentrations >3 times ULN, interrupt therapy. When bilirubin concentrations return to baseline or ≤1.5 times ULN, may resume alectinib at reduced dosage.

Interstitial Lung Disease/Pneumonitis

Oral

If treatment-related interstitial lung disease/pneumonitis of any grade occurs, permanently discontinue drug.

Renal Toxicity

Oral

If grade 3 renal impairment occurs, interrupt alectinib therapy until S_cr improves to ≤1.5 times ULN; may resume alectinib at reduced dosage.

If grade 4 renal impairment occurs, permanently discontinue alectinib.

Bradycardia

Oral

If symptomatic, but non-life-threatening, bradycardia occurs, interrupt alectinib therapy until recovery to asymptomatic bradycardia or to a heart rate of ≥60 beats/minute. If concomitant therapy includes drugs known to cause bradycardia or hypotension and such therapy is modified (dosage adjusted or drug discontinued), may resume alectinib at the previous dosage; if such modification is not possible or if no concomitant contributory drugs are identified, may resume alectinib at reduced dosage.

If life-threatening bradycardia or bradycardia requiring urgent intervention occurs in patients receiving concomitant drugs known to cause bradycardia or hypotension, interrupt alectinib therapy until recovery to asymptomatic bradycardia or to a heart rate of ≥60 beats/minute. If the concomitant therapy is modified (dosage adjusted or drug discontinued), may resume alectinib at a reduced dosage with frequent monitoring; discontinue alectinib in case of recurrence.

If life-threatening bradycardia or bradycardia requiring urgent intervention occurs in patients not receiving concomitant drugs known to cause bradycardia or hypotension, permanently discontinue alectinib.

CK Elevation

Oral

If serum CK concentrations >5 times ULN, interrupt therapy until CK concentrations return to baseline or ≤2.5 times ULN; may resume alectinib at previous dosage. If serum CK concentrations >5 times ULN recur, interrupt therapy until recovery; may resume alectinib at reduced dosage.

If serum CK concentrations >10 times ULN, interrupt therapy until CK concentrations return to baseline or ≤2.5 times ULN; may resume alectinib at reduced dosage.

Hemolytic Anemia

Oral

If hemolytic anemia is suspected, withhold alectinib and initiate appropriate testing.

If hemolytic anemia is confirmed, consider resuming alectinib at a reduced dosage upon resolution or permanently discontinue drug.

Special Populations

Hepatic Impairment

Mild or moderate hepatic impairment (Child-Pugh class A or B): No adjustment of initial dosage needed.

Severe hepatic impairment (Child-Pugh class C): Reduce dosage to 450 mg twice daily.

Renal Impairment

Mild or moderate renal impairment (Cl_cr 30–89 mL/minute): No adjustment of initial dosage needed.

Severe renal impairment (Cl_cr <30 mL/minute) or end-stage renal disease: Pharmacokinetics and safety not established.

Geriatric Patients

No specific dosage recommendations.

Cautions for Alectinib Hydrochloride

Contraindications

• None.

Warnings/Precautions

Hepatic Toxicity

Severe hepatotoxicity, including drug-induced liver injury, has occurred. AST/ALT elevations generally observed during first 3 months of treatment.

Monitor liver function tests, including ALT, AST, and total bilirubin, every 2 weeks for first 3 months, then once every month, and as clinically indicated. More frequent testing necessary in patients who develop aminotransferase or bilirubin elevations.

If hepatic toxicity occurs, temporary interruption followed by dosage reduction or discontinuance of therapy may be necessary depending on the severity.

Interstitial Lung Disease (ILD)/Pneumonitis

ILD/pneumonitis may occur.

Monitor patients for pulmonary symptoms indicative of ILD or pneumonitis. Exclude other potential causes of ILD or pneumonitis.

In patients diagnosed with treatment-related ILD or pneumonitis of any grade, permanently discontinue alectinib.

Renal Toxicity

Renal impairment, sometimes fatal, reported. Median time to grade 3 or 4 renal impairment was 3.7 months.

If renal impairment occurs, temporary interruption, subsequent dosage reduction, or discontinuance of therapy may be necessary depending on the severity.

Bradycardia

Bradycardia reported.

Monitor heart rate and BP regularly in all patients receiving alectinib.

If bradycardia occurs, temporary interruption, subsequent dosage reduction, or discontinuance of therapy may be necessary depending on the severity, concomitant use of drugs known to cause bradycardia or hypotension, and feasibility of modifying such concomitant therapy. Evaluate concomitant therapy to identify any drugs that may cause bradycardia or hypotension; adjust dosage or discontinue such drugs, if possible.

Severe Myalgia and CK Elevation

Severe myalgia and serum CK elevations reported. Median time to grade 3 or greater CK elevations was 15 days.

Monitor serum CK concentrations every 2 weeks for first month and as clinically indicated in patients with muscle symptoms.

If CK elevation occurs, temporary interruption followed by dosage reduction or permanent discontinuance of therapy may be necessary depending on the severity.

Hemolytic Anemia

Hemolytic anemia, including cases associated with a negative direct antiglobulin test result, reported.

Withhold alectinib if hemolytic anemia is suspected and initiate appropriate testing. If hemolytic anemia is confirmed, consider resuming alectinib at a reduced dosage upon resolution or permanently discontinue drug.

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; developmental toxicity, abortion, and embryolethality demonstrated in animals.

Avoid pregnancy during therapy. If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.

Specific Populations

Pregnancy

May cause fetal harm.

Lactation

Not known whether alectinib or its metabolites are distributed into milk. Females should not breast-feed during therapy and for 1 week after last dose.

Females and Males of Reproductive Potential

Verify pregnancy status in females of reproductive potential prior to initiation of therapy. Females of childbearing potential should use effective methods of contraception during therapy and for 5 weeks after last dose.

Males with female partners of reproductive potential should use effective methods of contraception during therapy and for 3 months after last dose.

Pediatric Use

Safety and efficacy not established in pediatric patients.

Changes in growing teeth and bones reported in animals.

Geriatric Use

No overall differences in effectiveness based on age. Patients ≥65 years of age may experience increased incidence of serious adverse events and more adverse events leading to treatment discontinuation or dose modifications.

Hepatic Impairment

Systemic exposure of total active forms of alectinib (i.e., alectinib plus M4) increased in patients with moderate (Child-Pugh class B) or severe (Child-Pugh class C) hepatic impairment; peak plasma concentration not altered. Dosage adjustment is necessary in patients with severe hepatic impairment.

Exposure not altered by mild hepatic impairment.

Renal Impairment

Exposure not altered by mild or moderate renal impairment.

Pharmacokinetics and safety not established in patients with severe renal impairment (Cl_cr <30 mL/minute).

Common Adverse Effects

Most common adverse effects (≥20%): hepatotoxicity, constipation, fatigue, myalgia, edema, rash, cough.

Drug Interactions

No clinically important interactions identified to date.

Metabolized to major active M4 metabolite by CYP3A4. In vitro, M4, but not alectinib, is a substrate of P-glycoprotein (P-gp); neither alectinib nor M4 is a substrate of breast cancer resistance protein (BCRP), organic anion transport protein (OATP) 1B1, or OATP1B3.

In vitro, alectinib and M4 do not inhibit CYP isoenzymes 1A2, 2B6, 2C9, 2C19, or 2D6. In vitro, alectinib does not inhibit OATP1B1 or OATP1B3, organic anion transporter (OAT) 1 and OAT3, or organic cation transporter (OCT) 2.

Alectinib and M4 inhibit P-gp and BCRP in vitro.

Drugs Associated with Bradycardia

Possible increased risk of bradycardia. If clinically important bradycardia occurs, discontinue or adjust dosage of the concomitant drug, if possible.

Specific Drugs

Alectinib Hydrochloride Pharmacokinetics

Absorption

Bioavailability

Peak plasma concentrations of alectinib attained 4 hours following oral administration with food.

Systemic exposure to alectinib is dose proportional over a dose range of 460–900 mg in the fed state.

Steady-state concentrations of alectinib and M4 achieved within 7 days.

Absolute oral bioavailability under fed conditions is 37%.

Food

High-fat, high-calorie meal increased AUC of alectinib and M4 by 3.1-fold compared with administration in the fasted state.

Special Populations

Mild hepatic impairment does not affect exposure to alectinib and M4.

Moderate (Child-Pugh class B) or severe (Child-Pugh class C) hepatic impairment increased AUC of total active forms of alectinib (i.e., alectinib plus M4) by 36 or 76%, respectively; peak plasma concentration of the total active forms of alectinib not affected.

Mild or moderate renal impairment (Cl_cr 30–89 mL/minute) does not affect exposure to alectinib and M4.

Effects of severe renal impairment or end-stage renal disease on alectinib pharmacokinetics not established.

Age, body weight, sex, and race do not affect exposure to alectinib and M4.

Distribution

Extent

CSF concentrations are similar to alectinib free plasma concentrations.

Not known whether alectinib or its metabolites distribute into milk.

Plasma Protein Binding

Alectinib and M4: >99%.

Elimination

Metabolism

Metabolized by CYP3A4 to its major active metabolite, M4, which also is metabolized by CYP3A4.

Elimination Route

Eliminated in feces (98%), mainly as unchanged drug (84%) and, to a lesser extent, as M4 (6%); <0.5% of dose eliminated in urine.

Half-life

Alectinib: 33 hours. M4: 31 hours.

Special Populations

Hemodialysis not expected to enhance clearance of alectinib and M4 because of extensive binding to plasma proteins.

Stability

Storage

Oral

Capsules

<30°C; store in original container to protect from light and moisture.

Actions

• Inhibits receptor tyrosine kinases ALK and ret proto-oncogene (RET).

• Inhibits ALK phosphorylation and ALK-mediated activation of the downstream signaling proteins signal transducer and activator of transcription 3 (STAT3) and AKT serine/threonine kinase.

• Activating mutations or translocations of the ALK gene identified in several malignancies and can result in the expression of oncogenic fusion proteins (e.g., echinoderm microtubule-associated protein-like 4 [EML4]-ALK). Formation of ALK fusion proteins results in activation and dysregulation of the gene's expression and signaling, which can contribute to increased cell proliferation and survival in tumors expressing these proteins.

• ALK rearrangements identified in approximately 3–7% of patients with NSCLC.

• Clinical resistance to crizotinib attributed to several possible mechanisms, including acquired resistance mutations of ALK, amplification of gene expression, and activation of alternate signaling pathways. CNS is a common site of disease progression in crizotinib-treated patients because of poor distribution of crizotinib into CSF.

• Alectinib is approximately fivefold more potent than crizotinib against ALK in vitro.

• Exhibits dose-dependent antitumor activity and increased survival in mice bearing NSCLC tumor xenografts expressing EML4-ALK, including several with demonstrated resistance to crizotinib. Active against several crizotinib-resistant ALK mutations (e.g., L1196M, C1156Y, G1269A, F1174L).

• Demonstrates antitumor activity and increased survival in mice bearing intracranial ALK-positive NSCLC tumor xenografts. Demonstrated antitumor activity in patients with crizotinib-resistant, ALK-positive NSCLC with baseline CNS metastases.

Advice to Patients

• Advise patients to read the manufacturer's patient information.

• Stress importance of taking alectinib exactly as prescribed and of not altering the dosage or discontinuing therapy unless advised to do so by a clinician. Advise patients to swallow alectinib capsules whole with food and not dissolve or open the capsules.

• If a dose is missed or if vomiting occurs after taking a dose, advise patients to take the next dose at the regularly scheduled time; do not take the missed dose or take an extra dose to replace the vomited dose.

• Risk of hepatotoxicity; stress importance of liver function test monitoring. Importance of immediately informing clinician if manifestations suggestive of hepatotoxicity (e.g., fatigue, anorexia, nausea, vomiting, right upper quadrant pain, jaundice, dark urine, generalized pruritus, unusual bleeding or bruising) occur.

• Risk of renal toxicity. Stress importance of informing clinician if manifestations of renal toxicity (e.g., decreased urine output, hematuria, peripheral edema) occur.

• Risk of severe or fatal ILD/pneumonitis. Symptoms may be similar to those of lung cancer. Immediately inform clinician if any new or worsening pulmonary symptoms (e.g., dyspnea, shortness of breath, cough, fever) occur.

• Risk of bradycardia. Immediately inform clinician if dizziness, lightheadedness, or faintness occurs.

• Risk of muscle problems or myalgia; importance of CK monitoring. Stress importance of promptly informing clinician if any unexplained or persistent muscle pain, tenderness, or weakness occurs.

• Risk of photosensitivity. Advise patients to avoid prolonged sun exposure during therapy and for ≥7 days after drug discontinuance and of using a broad-spectrum sunscreen and lip balm (minimum SPF of 50).

• Risk of fetal harm. Advise women of reproductive potential to use effective methods of contraception during therapy and for 5 weeks after the last dose. Advise men who are partners of such women to use adequate methods of contraception during therapy and for 3 months after the last dose.

• Advise women to avoid breast-feeding during therapy and for 1 week after the last dose.

• Stress importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs (e.g., cardiac or hypotensive agents) and dietary or herbal supplements, as well as any concomitant illnesses (e.g., hepatic impairment).

• Advise patients to inform their clinician of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Alectinib is available only from designated specialty distributors and pharmacies. The manufacturer should be contacted for additional information.

Reload page with references included

Frequently asked questions

• What is the mechanism of action for Alecensa (alectinib)?
• What is Alecensa used to treat?

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