Alectinib (Monograph)

Brand name: Alecensa
Drug class: Antineoplastic Agents
- ALK Tyrosine Kinase Inhibitors
- Anaplastic Lymphoma Kinase Inhibitors
- Kinase Inhibitors
- Receptor Tyrosine Kinase Inhibitors
- Tyrosine Kinase Inhibitors
Chemical name: 9-Ethyl-6,11-dihydro-6,6-dimethyl-8-[4-(4-morpholinyl)-1-piperidinyl]-11-oxo-5H-benzo[b]carbazole-3-carbonitrile hydrochloride
Molecular formula: C₃₀H₃₄N₄O₂ • HCl
CAS number: 1256589-74-8

Medically reviewed by Drugs.com on Jul 21, 2022. Written by ASHP.

Introduction

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

Uses for Alectinib

Non-small Cell Lung Cancer (NSCLC)

Treatment of ALK-positive stage IV NSCLC (designated an orphan drug by FDA for this use).

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.

Confirmation of ALK rearrangement necessary prior to initiation of therapy.

Alectinib Dosage and Administration

General

Pretreatment Screening

Select patients for treatment 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.

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.

Dosage Modification for Toxicity

Oral

In the principal efficacy studies, 16–23% of patients required ≥1 dosage reduction (most commonly for hepatic toxicity, CK elevations, pneumonia, or vomiting); median time to first dosage reduction was 48 days in patients with previously treated ALK-positive metastatic NSCLC.

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

Contraindications

Manufacturer states none known.

Warnings/Precautions

Hepatic Toxicity

Hepatotoxicity (AST, ALT, and/or total bilirubin elevations; biopsy-confirmed liver injury), sometimes requiring permanent drug discontinuance, has occurred. AST/ALT and bilirubin 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

Severe 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 severe or fatal, reported. Median time to grade 3 or 4 renal impairment was 3 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. (See Bradycardia under Dosage and Administration.)

Severe Myalgia and CK Elevation

Myalgia/musculoskeletal pain and serum CK elevations reported. Median time to grade 3 CK elevations was 14 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. (See Females and Males of Reproductive Potential under Cautions.)

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 drug discontinuance.

Females and Males of Reproductive Potential

Females of childbearing potential should use effective methods of contraception during therapy and for ≥1 week after drug discontinuance.

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

Pediatric Use

Safety and efficacy not established in pediatric patients.

Changes in growing teeth and bones reported in animals.

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether they respond differently than younger adults.

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

Fatigue, constipation, edema, myalgia, anemia.

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. (See Bradycardia under Dosage and Administration.)

Specific Drugs

Drug	Interaction
Esomeprazole	No clinically important effect on combined systemic exposure to alectinib and M4
Midazolam	Clinically important pharmacokinetic interaction unlikely
Posaconazole	No clinically important effect on combined systemic exposure to alectinib and M4
Repaglinide	Clinically important pharmacokinetic interaction unlikely
Rifampin	No clinically important effect on combined systemic exposure to alectinib and M4

Alectinib 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

Importance of reading the manufacturer's patient information.
Importance of taking alectinib exactly as prescribed and of not altering the dosage or discontinuing therapy unless advised to do so by clinician. Importance of swallowing alectinib capsules whole with food and not dissolving or opening the capsules.
If a dose is missed or if vomiting occurs after taking a dose, importance of taking 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; 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. 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. Importance of immediately informing clinician if any new or worsening pulmonary symptoms (e.g., dyspnea, shortness of breath, cough, fever) occur.
Risk of bradycardia. Importance of immediately informing clinician if dizziness, lightheadedness, or faintness occurs.
Risk of muscle problems or myalgia; importance of CK monitoring. Importance of promptly informing clinician if any unexplained or persistent muscle pain, tenderness, or weakness occurs.
Risk of photosensitivity. Importance of avoiding 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 ≥1 week after drug discontinuance. Advise men who are partners of such women to use adequate methods of contraception during therapy and for 3 months after drug discontinuance.
Importance of women informing their clinicians if they are or plan to become pregnant. If pregnancy occurs, advise patient of potential fetal risk.
Importance of advising women to avoid breast-feeding during therapy and for 1 week after drug discontinuance.
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. (See Cautions.)

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.