Alectinib

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule, Oral:

Alecensa: 150 mg [contains corn starch]

Pharmacology

Mechanism of Action

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).

Pharmacokinetics/Pharmacodynamics

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 in Specific Populations

Special Populations: 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-Pugh class B) and 1.76 in severe impairment (Child-Pugh class C) compared to subjects with normal hepatic impairment.

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.

Dosage and Administration

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: 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

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. Exceptions are discussed in separate monographs. Consider therapy modification

Fexinidazole [INT]: Bradycardia-Causing Agents may enhance the arrhythmogenic effect of Fexinidazole [INT]. 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

Midodrine: May enhance the bradycardic effect of Bradycardia-Causing Agents. 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

Siponimod: Bradycardia-Causing Agents may enhance the bradycardic effect of Siponimod. Management: Avoid coadministration of siponimod with drugs that may cause bradycardia. Consider therapy modification

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 18%)

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%), increased serum alkaline phosphatase (47%), hyperbilirubinemia (39%), increased serum ALT (34%)

Neuromuscular & skeletal: Increased creatine phosphokinase (43%), 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: Skin photosensitivity (10%)

Ophthalmic: Visual disturbances (10%)

Renal: Renal insufficiency (8%)

<1%, postmarketing, and/or case reports: 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 rare fatal events. The median time to ≥ grade 3 renal impairment was 3.7 months (range: 0.5 to 14.7 months). Renal toxicity 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

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. Females 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

What is this drug used for?

• It is used to treat lung cancer.

Frequently reported side effects of this drug

• Constipation
• Nausea
• Vomiting
• Headache
• Diarrhea
• Back pain
• Weight gain

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin
• Infection
• Severe pulmonary disorder like lung or breathing problems like trouble breathing, shortness of breath, or a cough that is new or worse
• Kidney problems like unable to pass urine, blood in the urine, change in amount of urine passed, or weight gain
• High blood sugar like confusion, fatigue, increased thirst, increased hunger, passing a lot of urine, flushing, fast breathing, or breath that smells like fruit
• Electrolyte problems like mood changes, confusion, muscle pain or weakness, abnormal heartbeat, seizures, lack of appetite, or severe nausea or vomiting
• Severe loss of strength and energy
• Slow heartbeat
• Dizziness
• Passing out
• Muscle pain
• Muscle weakness
• Swelling
• Vision changes
• Signs of a significant reaction like 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. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.