Alecnib Capsule

Alecnib as monotherapy is indicated for the first-line treatment of adult patients with anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC). Alecnib as monotherapy is indicated for the treatment of adult patients with ALK-positive advanced NSCLC previously treated with crizotinib.

Alectinib is a highly selective and potent ALK and RET tyrosine kinase inhibitor.In nonclinicalstudies, inhibition of ALK tyrosine kinase activity led to blockage of downstream signaling pathways including STAT 3 and PI3K/AKT and inducedtumor cell death (apoptosis).

Alectinib demonstratedin vitroand in vivoactivity against mutant forms of the ALK enzyme, including mutations responsible forresistance to crizotinib.The major metabolite of alectinib (M4) has shown similar in vitropotency and activity.

Based on nonclinicaldata, alectinib is not a substrate of p-glycoprotein (P-gp) or breast cancer resistance protein (BCRP), which are both efflux transporters in the blood brain barrier, and is therefore able to distribute into and be retained within the central nervous system. Alectinibinducedtumor regressionin nonclinicalmousexenograft models, including antitumor activity in the brain, and prolonged survival inintracranial tumor animal 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.

Based on in vitro data, CYP3A4 is the primary enzyme mediating the metabolism of both Alecnib and its major active metabolite M4, and CYP3A contributes to 40% - 50% of total hepatic metabolism. M4 has shown similar in vitro potency and activity against ALK.

CYP3A inducers: Co-administration of multiple oral doses of 600 mg rifampicin once daily, a strong CYP3A inducer, with a single oral dose of 600 mg Alecnib reduced Alecnib Cmax, and AUCinf by 51% and 73% respectively and increased M4 Cmax and AUCinf 2.20 and 1.79-fold respectively. The effect on the combined exposure of Alecnib and M4 was minor, reducing Cmax and AUCinf by 4% and 18%, respectively. Based on the effects on the combined exposure of Alecnib and M4, no dose adjustments are required when Alecnib is co-administered with CYP3A inducers. Appropriate monitoring is recommended for patients taking concomitant strong CYP3A inducers (including, but not limited to, carbamazepine, phenobarbital, phenytoin, rifabutin, rifampicin and St. John's Wort (Hypericum perforatum).

CYP3A inhibitors: Co-administration of multiple oral doses of 400 mg posaconazole twice daily, a strong CYP3A inhibitor, with a single oral dose of 300 mg Alecnib increased Alecnib exposure Cmax and AUCinf by 1.18 and 1.75-fold respectively, and reduced M4 Cmax and AUCinf by 71% and 25% respectively. The effect on the combined exposure of Alecnib and M4 was minor, reducing Cmax by 7% and increasing AUCinf 1.36-fold. Based on the effects on the combined exposure of Alecnib and M4, no dose adjustments are required when Alecnib is co-administered with CYP3A inhibitors. Appropriate monitoring is recommended for patients taking concomitant strong CYP3A inhibitors (including, but not limited to, ritonavir, saquinavir, telithromycin, ketoconazole, itraconazole, voriconazole, posaconazole nefazodone, grapefruit or Seville oranges).

Medicinal products that increase gastric pH: Multiple doses of esomeprazole, a proton pump inhibitor, 40 mg once daily, demonstrated no clinically relevant effect on the combined exposure of Alecnib and M4. Therefore, no dose adjustments are required when Alecnib is co-administered with proton pump inhibitors or other medicinal products which raise gastric pH (e.g. H2 receptor antagonists or antacids).

Effect of transporters on Alecnib disposition: M4 is a substrate of P-gp. As Alecnib inhibits P-gp, it is not expected that co-medication with P-gp inhibitors has a relevant effect on M4 exposure.

Alectinib is contraindicated in patients with a known hypersensitivity to alectinib or any of the excipients.

The most common adverse drug reactions were constipation, edema including peripheral, generalized, eyelid, periorbital; myalgia (31% including myalgia and musculoskeletal pain), nausea, increased bilirubin (21% including increased blood bilirubin, hyperbilirubinemia and increased bilirubin conjugated), anemia (20%, including anemia and hemoglobin decreased), and rash (20%, including rash, rash maculopapular, dermatitis acneiform, erythema, rash generalized, rash papular, rash pruritic and rash macular).

Pregnancy: There are no or limited amount of data from the use of Alectinib in pregnant women. Based on its mechanism of action, Alectinib may cause foetal harm when administered to a pregnant woman. Studies in animals have shown reproductive toxicity. Female patients, who become pregnant while taking Alectinib or during the 3 months following the last dose of Alectinib must contact their doctor and should be advised of the potential harm to the foetus.

Breast-feeding: It is unknown whether Alectinib and its metabolites are excreted in human milk. A risk to the newborn/infant cannot be excluded. Mothers should be advised against breast-feeding while receiving Alectinib.

Fertility: No fertility studies in animals have been performed to evaluate the effect of Alectinib. No adverse effects on male and female reproductive organs were observed in general toxicology studies.

Interstitial lung disease (ILD)/pneumonitis: Cases of ILD/pneumonitishave been reported in clinical trials with Alecnib. Patients should be monitored for pulmonary symptoms indicative of pneumonitis. Alecnib should be immediately interrupted in patients diagnosed with ILD/pneumonitis and should be permanently discontinued if no other potential causes of ILD/pneumonitis have been identified

Hepatotoxicity: Elevations in alanine amino transferase (ALT) and aspartate amino transferase (AST) greater than 5 times the upper limit of normal (ULN) as well as bilirubin elevations of more than 3 times the ULN occurred in patients in pivotal clinical trials with Alecnib. The majority of these events occurred during the first 3months of treatment. In the pivotal Alecnib clinical trials it was reported that three patients with Grade 3‒4 AST/ALT elevations had drug-induced liver injury. Concurrent elevations in ALT or AST greater than or equal to three times the ULN and total bilirubin greater than or equal to two times the ULN, with normal alkaline phosphatase, occurred in 1 patient treated in Alecnib clinical trials.

Bradycardia: Symptomatic bradycardia can occur with Alecnib. Heart rate and blood pressure should be monitored as clinically indicated. Dose modification is not required in case of asymptomatic bradycardia. If patients experience symptomatic bradycardia or life-threatening events, concomitant medicinal products known to cause bradycardia, as well as anti-hypertensive medicinal products should be evaluated and Alecnib treatment should be adjusted.

Photosensitivity: Photosensitivity to sunlight has been reported with Alecnib administration. Patients should be advised to avoid prolonged sun exposure while taking Alecnib, and for at least 7 days after discontinuation of treatment. Patients should also be advised to use a broad-spectrum Ultraviolet A (UVA)/ Ultraviolet B (UVB) sun screen and lip balm (SPF >50) to help protect against potential sunburn.

Women of child-bearing potential: Alecnib may cause foetal harm when administered to a pregnant woman. Female patients of child-bearing potential receiving Alecnib, must use highly effective contraceptive methods during treatment and for at least 3 months following the last dose of Alecnib.

Lactose intolerance: This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, a congenital lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Sodium content: This medicinal product contains 48 mg sodium per daily dose (1200 mg), equivalent to 2.4% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

Hepatic impairment: No starting dose adjustment is required in patients with underlying mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment. Patients with underlying severe hepatic impairment (Child-Pugh C) should receive a starting dose of 450 mg taken twice daily (total dose of 900 mg). For all patients with hepatic impairment, appropriate monitoring (e.g. markers of liver function) is advised.

Renal impairment: No dose adjustment is required in patients with mild or moderate renal impairment. Alecnib has not been studied in patients with severe renal impairment. However, since Alecnib elimination via the kidney is negligible, no dose adjustment is required in patients with severe renal impairment.

Elderly (>65 years): The limited data on the safety and efficacy of Alecnib in patients aged 65 years and older do not suggest that a dose adjustment is required in elderly patients. There are no available data on patients over 80 years of age.

Paediatric population: The safety and efficacy of Alecnib in children and adolescents below 18 years of age have not been established. No data are available.

Extreme body weight (>130 kg): Although PK simulations for Alecnib do not indicate a low exposure in patients with extreme body weight (i.e. >130 kg), Alecnib is widely distributed and clinical studies for Alecnib enrolled patients within a range of body weights of 36.9-123 kg. There are no available data on patients with body weight above 130 kg.

Patients who experience overdose should be closely supervised and general supportive care instituted. There is no specific antidote for overdose with Alecnib.

Anti neoplastic preparations, Protein kinase inhibitor

Keep below 30°C temperature, away from light & moisture. Keep out of the reach of children.