Alecensa

Approved Indications:

• Anaplastic Lymphoma Kinase (ALK)–Positive Non‑Small Cell Lung Cancer (NSCLC):
• First-Line Therapy: For treatment of patients with advanced ALK-positive NSCLC who have not received prior ALK inhibitor therapy.
• Previously Treated Disease: In patients with ALK-positive NSCLC whose disease has progressed on or who are intolerant to crizotinib.

Clinically Accepted Off‑Label / Additional Uses:

• CNS Metastases in ALK‑Positive NSCLC: Demonstrated activity against central nervous system (brain) metastases, including leptomeningeal disease.
• Other ALK‑Positive Tumors (investigational): Rare use in ALK-positive anaplastic large-cell lymphoma or inflammatory myofibroblastic tumor harboring ALK fusions (off-label, under clinical supervision).

Adults:

• Standard Dose: 600 mg orally twice daily (total 1200 mg/day), with food.
• Administration: Swallow capsules whole; do not chew or open.
• Duration: Continued until disease progression or unacceptable toxicity.

Elderly (≥65 years):

• Same dosing; monitor closely for hepatotoxicity and myalgia.

Pediatric Use:

• Not currently approved; pediatric use only in clinical trials or under compassionate use with dose based on body surface area or weight.

Special Populations:

• Hepatic Impairment (Child–Pugh):
• Moderate impairment: Reduce to 450 mg twice daily.
• Severe impairment: Avoid use unless benefit outweighs risk.
• Renal Impairment:
• For mild to moderate renal impairment, no dose adjustment.
• Limited data in severe renal impairment; use with caution and monitor.
• Drug-Related Adverse Event Dose Adjustments:
• For Grade ≥3 adverse events (e.g., transaminitis, myalgia), withhold until resolution to ≤Grade 1 or baseline, then resume at 450 mg twice daily.

Alectinib is a potent, selective small-molecule inhibitor of anaplastic lymphoma kinase (ALK) tyrosine kinase and certain mutant forms including L1196M. It binds to the ATP-binding site of the ALK protein, blocking phosphorylation and downstream signaling through pathways such as PI3K/AKT and MAPK/ERK. This inhibition suppresses malignant cell proliferation and survival in ALK-rearranged tumor cells, including those within the central nervous system due to its superior CNS penetration.

• Absorption: Well absorbed orally; peak plasma concentration reached in ~4 hours.
• Food Effect: Food significantly increases bioavailability; administration with a meal is advised.
• Bioavailability: Estimated high when taken with food (approximately 40 %–50 %).
• Distribution: High volume of distribution; extensively distributed into tissues including CNS.
• Protein Binding: >99.9% bound to plasma proteins.
• Metabolism: Primarily metabolized by CYP3A4 to an active metabolite (M4) with similar potency.
• Half-Life:
• Alectinib: ~32.5 hours.
• M4 metabolite: ~30.5 hours.
• Elimination: Excreted via feces (~98%) and urine (<1%) as metabolites.
• Steady State: Reached within ~7 days of twice-daily dosing; accumulation ratio ~1.5 – 2×.

• Pregnancy:
• No formal FDA pregnancy category (PLLR applied).
• Animal studies show developmental toxicity at high exposures.
• Use during pregnancy only if potential benefit justifies potential risk.
• Lactation:
• Unknown whether Alectinib or metabolites are excreted into human milk.
• Breastfeeding is not recommended during treatment and for at least 7 days after the final dose.
• Fertility:
• May impair male fertility; contraception advised during and after treatment (e.g., for at least 3 months in men, at least 2 weeks in women after last dose).

• Primary Class: Tyrosine Kinase Inhibitor (TKI)
• Subclass: ALK Inhibitor (Second-Generation)
• Pharmacologic Type: Oral small-molecule receptor tyrosine kinase inhibitor

• Known hypersensitivity to Alectinib or any excipients.
• Concurrent use of strong CYP3A4 inducers or inhibitors that cannot be managed with monitoring or dose adjustment.
• Limited hepatic reserve in severe liver disease where dose adjustment cannot be safely performed.

• Hepatotoxicity:
• Monitor ALT, AST, total bilirubin prior to treatment, then every 2 weeks for first 3 months, then monthly.
• Grade ≥3 elevations: withhold or dose reduce.
• Interstitial Lung Disease (ILD)/ Pneumonitis:
• Discontinue if suspected; rule out other causes.
• Bradycardia:
• Monitor heart rate; symptomatic bradycardia may require dose modification or discontinuation.
• Myalgia and CPK Elevation:
• Monitor creatine phosphokinase (CPK) monthly. Withhold if CPK ≥5× ULN or with symptoms; resume at reduced dose once resolved.
• Visual Disturbances:
• Blurred vision, diplopia may occur; evaluate if persistent.
• QT Prolongation:
• Although rare, monitor electrolytes and ECG in patients with risk factors or concomitant QT-prolonging drugs.
• Pregnancy and Lactation Counseling:
• Provide advice on effective contraception.

Common (≥10%):

• Musculoskeletal: Muscle pain/myalgia, elevated CPK
• Gastrointestinal: Constipation, nausea, vomiting, diarrhea
• Neurological: Headache, fatigue
• Dysgeusia: Altered taste sensation
• Edema: Peripheral edema

Less Common (1–10%):

• Rash, dyspnea, cough, dizziness, insomnia, anemia, and back pain.

Serious or Rare (<1%):

• Hepatotoxicity (AST/ALT elevation, rarely fulminant hepatic failure)
• Interstitial lung disease/pneumonitis
• Bradycardia requiring intervention
• Severe myalgia with CPK elevation
• Severe visual disturbances

Onset & Dose Dependence:

• Most side effects occur within the first 2–3 months; some (e.g., CPK elevation) may accumulate over time.
• Dose reduction or temporary interruption often resolves adverse events.

• CYP3A4 Interactions:
• Strong inhibitors (e.g., ketoconazole): May increase exposure—reduce dose to 450 mg twice daily and monitor.
• Strong inducers (e.g., rifampin, phenytoin): May decrease exposure—avoid co‑administration or monitor efficacy.
• Drug‑Drug:
• Combined use with other QT-prolonging drugs may increase risk of arrhythmia.
• Coadministration with statins or fibrates may exacerbate CPK elevation.
• Drug‑Food:
• High-fat meals increase absorption—always administer with food (small meal acceptable).
• Drug‑Alcohol:
• No direct known interaction; avoid excess alcohol due to potential hepatotoxicity.
• Enzyme Systems:
• Also involves CYP2C8 (minor), but major metabolism via CYP3A4.

• Regulatory Approvals:
• EMA and FDA reaffirmed first-line use in ALK-positive NSCLC in recent label updates.
• CNS Metastasis Guidance:
• Increased emphasis in guidelines on using Alectinib for patients with brain metastases based on high CNS penetration.
• Safety Labeling:
• New advice on CPK monitoring and myalgia management added in latest prescribing information (past 2 years).
• Real‑World Data:
• Updated long-term safety data showing low rates of discontinuation due to hepatotoxicity or ILD.

• Temperature: Store at 20 °C to 25 °C (68–77 °F); excursions permitted between 15 °C and 30 °C.
• Light & Humidity: Keep in dry conditions and protect from light.
• Handling:
• Store in original container.
• Keep capsules in blister packs until use to maintain integrity.
• Not sensitive to freezing.
• Reconstitution: Not applicable—capsule form only.