Alectinib is used as a single-agent therapy for the first-line treatment of adults with anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC). It is also indicated for patients with ALK-positive advanced NSCLC who have previously been treated with crizotinib.

Alectinib is a potent and selective inhibitor of ALK and RET tyrosine kinases. It works by blocking ALK kinase activity, which disrupts downstream signaling pathways such as STAT3 and PI3K/AKT, ultimately leading to tumor cell death (apoptosis).

It has demonstrated activity against mutated forms of the ALK enzyme, including those associated with resistance to crizotinib. Its primary metabolite (M4) also exhibits similar activity and potency.

Alectinib is not a substrate of P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP), allowing it to cross the blood-brain barrier effectively. It has shown significant anti-tumor activity in the central nervous system and has been associated with prolonged survival in preclinical brain tumor models.

Recommended dose: Alectinib is 600 mg (four 150 mg capsules) taken twice daily with food (total daily dose of 1200 mg). Patients with underlying severe hepatic impairment (Child-Pugh C) should receive a starting dose of 450 mg taken twice daily with food (total daily dose of 900 mg).

Duration of treatment: Treatment with Alectinib should be continued until disease progression or unacceptable toxicity.

Delayed or missed doses: If a planned dose of Alectinib is missed, patients can make up that dose unless the next dose is due within 6 hours. Patients should not take two doses at the same time to make up for a missed dose. If vomiting occurs after taking a dose of Alectinib, patients should take the next dose at the scheduled time.

Dose adjustments: Management of adverse events may require dose reduction, temporary interruption, or discontinuation of treatment with Alectinib. The dose of Alectinib should be reduced in steps of 150 mg twice daily based on tolerability. Alectinib treatment should be permanently discontinued if patients are unable to tolerate the 300 mg twice daily dose.

Method of administration: Alectinib is for oral use. The hard capsules should be swallowed whole, and must not be opened or dissolved. They must be taken with food.

Alectinib is primarily metabolized by CYP3A4, and its active metabolite (M4) also depends on CYP3A activity, contributing significantly to liver metabolism.

CYP3A Inducers: Strong inducers such as rifampicin can significantly lower Alectinib levels while increasing M4 exposure. However, the overall combined exposure changes are minimal, so dose adjustment is usually not required. Monitoring is advised when used with strong inducers like carbamazepine, phenobarbital, phenytoin, rifabutin, and St. John’s wort.

CYP3A Inhibitors: Strong inhibitors such as posaconazole can increase Alectinib exposure and reduce M4 levels. Despite these changes, overall exposure remains manageable, and dose adjustment is generally unnecessary. Careful monitoring is recommended when used with strong inhibitors like ritonavir, saquinavir, ketoconazole, itraconazole, voriconazole, clarithromycin, grapefruit, or Seville oranges.

Medicinal products increasing gastric pH: Drugs such as proton pump inhibitors (e.g., esomeprazole) or H2 blockers have no significant effect on Alectinib absorption; therefore, no dose changes are required.

Transporters: M4 is a substrate of P-gp. Since Alectinib inhibits P-gp, co-administration with P-gp inhibitors is not expected to have a meaningful clinical impact.

Alectinib is contraindicated in patients with known hypersensitivity to the drug or its components.

Common adverse effects include constipation, edema (including peripheral and eyelid swelling), muscle pain, nausea, increased bilirubin levels, anemia, and skin rash.

Pregnancy: Limited data are available. Alectinib may cause fetal harm; therefore, pregnant women should be informed of potential risks.

Breast-feeding: It is unknown whether Alectinib passes into breast milk. Breastfeeding should be avoided during treatment.

Fertility: No significant adverse effects on fertility have been observed in animal studies.

Interstitial Lung Disease (ILD)/Pneumonitis: Cases of ILD and pneumonitis have been observed during Alectinib treatment. Patients should be closely monitored for respiratory symptoms. If ILD or pneumonitis is confirmed, treatment should be immediately interrupted and permanently discontinued if no other cause is identified.

Hepatotoxicity: Significant increases in liver enzymes (ALT and AST) and bilirubin levels have been reported. Most cases occur within the first 3 months of therapy. Regular liver function monitoring is essential, and treatment adjustment may be required if severe abnormalities are detected.

Bradycardia: Alectinib may cause slow heart rate. Heart rate and blood pressure should be monitored when clinically necessary. In symptomatic cases or severe events, dose adjustment or evaluation of other contributing medications is required.

Photosensitivity: Sensitivity to sunlight may occur. Patients should avoid prolonged sun exposure during treatment and for at least 7 days after stopping therapy. Use of broad-spectrum sunscreen (UVA/UVB) and lip protection (SPF >50) is recommended.

Women of Childbearing Potential: Alectinib can harm the fetus. Women should use effective contraception during treatment and for at least 3 months after the last dose.

Lactose Intolerance: This medication contains lactose and should not be used in patients with rare hereditary conditions such as galactose intolerance, lactase deficiency, or glucose-galactose malabsorption.

Sodium Content: Each daily dose contains a small amount of sodium, which should be considered in patients on sodium-restricted diets.

Hepatic impairment: Mild to moderate impairment requires no dose adjustment; severe impairment requires dose reduction and monitoring.

Renal impairment: No dose adjustment is required; limited data in severe cases.

Elderly: No dose adjustment generally required.

Pediatric: Safety and efficacy not established below 18 years.

Extreme body weight: No significant impact observed, but limited data in very high body weight.

Overdose cases should be managed with supportive care and close monitoring. No specific antidote is available.

Antineoplastic agent, protein kinase inhibitor.

Store below 30°C, protected from light and moisture. Keep out of reach of children.