Osimatab

It is a kinase inhibitor indicated for the treatment of patients with metastatic epidermal growth factor receptor (EGFR) T790M mutationpositive non-small cell lung cancer (NSCLC),as detected by an FDAapproved test,who have progressed on or after EGFR TKI therapy. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials

Cytotoxic Chemotherapy

Osimertinib is kinase inhibitor of the epidermal growth factor receptor (EGFR), which binds irreversibly to certain mutant forms of EGFR (T790M, L858R, and exon 19 deletion) at approximately 9-fold lower concentrations than wild-type. In cultured cells and animal tumor implantation models, Osimertinib exhibited anti-tumor activity against NSCLC lines harboring EGFR-mutations (T790M/L858R, L858R, T790M/exon 19 deletion, and exon 19 deletion) and, to a lesser extent, wild-type EGFR amplifications. Two pharmacologically-active metabolites (AZ7550 and AZ5104 circulating at approximately 10% of the parent) with similar inhibitory profiles to Osimertinib have been identified in the plasma after oral administration of Osimertinib. AZ7550 showed a similar potency to Osimertinib, while AZ5104 showed greater potency against exon 19 deletion and T790M mutants (approximately 8-fold) and wild- type (approximately 15-fold) EGFR. In vitro, Osimertinib also inhibited the activity of HER2, HER3, HER4, ACK1, and BLK at clinically relevant concentrations. The area under the plasma concentration-time curve (AUC) and maximal plasma concentration (C max ) of Osimertinib increased dose proportionally over 20 to 240 mg dose range (i.e., 0.25 to 3 times the recommended dosage) after oral administration and exhibited linear pharmacokinetics (PK). Administration of Osimertinib orally once daily resulted in approximately 3-fold accumulation withsteady state exposures achieved after 15 days of dosing. At steady state, the C max to C min (minimal concentration) ratio was 1.6-fold. Absorption: The median time to C max of Osimertinib was 6 hours (range 3-24 hours). Following administration of a 20 mg Osimertinib tablets with a high-fat, high-calorie meal (containing approximately 58 grams of fat and 1000 calories), the C max and AUC of Osimertinib were compared to that under fasting conditions. Distribution: The mean volume of distribution at steady-state (Vss/F) of Osimertinib was 986 L. Plasma protein binding of Osimertinib was 95%. Elimination: Osimertinib plasma concentrations decreased with time and a population estimated mean half-life of Osimertinib was 48 hours, and oral clearance (CL/F) was 14.2 (L/h). Metabolism: The main metabolic pathways of Osimertinib were oxidation (predominantly CYP3A) and dealkylation in vitro. Two pharmacologically active metabolites (AZ7550 and AZ5104) have been identified in the plasma after Osimertinib oral administration. The geometric mean exposure (AUC) of each metabolite (AZ5104 and AZ7550) was approximately 10% of the exposure of Osimertinib at steady-state. Excretion: Osimertinib is primarily eliminated in the feces (68%) and to a lesser extent in the urine (14%). Unchanged Osimertinib accounted for approximately 2% of the elimination.

Confirm the presence of T790M mutation in tumor specimens prior to initiation of treatment with TAGRISSO. ? 80 mg orally once daily,with or without food.

Strong CYP3A Inhibitors: Avoid concomitant administration of Osimertinib with strong CYP3A inhibitors, including macrolide antibiotics (e.g., Telithromycin), antifungals (e.g., Itraconazole), antivirals (e.g., Ritonavir), Nefazodone, as concomitant use of strong CYP3A inhibitors may increase Osimertinib plasma concentrations. If no other alternative exists, monitor patients more closely for adverse reactions of Osimertinib. Strong CYP3A Inducers: Avoid concomitant administration of Osimertinib with strong CYP3A inducers (e.g., Phenytoin, Rifampicin, Carbamazepine, St. John's Wort) as strong CYP3A inducers may decrease Osimertinib plasma concentrations. Effect on other drugs: Avoid concomitant administration of Osimertinib with drugs that are sensitive substrates of CYP3A, breast cancer resistance protein (BCRP), or CYP1A2 with narrow therapeutic indices, including but not limited to Fentanyl, Cyclosporine, Quinidine, Ergot Alkaloids, Phenytoin, Carbamazepine, as Osimertinib may increase or decrease plasma concentrations of these drugs.

Precautions & Warnings Interstitial Lung Disease (ILD)/Pneumonitis: Interstitial lung disease (ILD)/pneumonitis occurred in 3.9% of the 1142 Osimertinib-treated patients; 0.4% of cases were fatal. QTc Interval Prolongation: Monitor electrocardiograms and electrolytes in patients who have a history or predisposition for QTc prolongation, or those who are taking medications that are known to prolong the QTc interval. Withhold then restart at a reduced dose or permanently discontinue Osimertinib. Cardiomyopathy: Occurred in 1.4% of patients. Assess left ventricular ejection fraction (LVEF) before treatment and then every 3 months thereafter. Embryo-Fetal Toxicity: Osimertinib can cause fetal harm. Advise females of potential risk to the fetus and to use effective contraception during treatment with Osimertinib and for 6 weeks after final dose. Advise males to use effective contraception for 4 months, after the last dose of Osimertinib.

Diarrhea,rash,dry skin,and nail toxicity

Use in Pregnancy: There are no or limited amount of data from the use of Osimertinib in pregnant women. Studies in animals have shown reproductive toxicity. Based on its mechanism of action and preclinical data,Osimertinib may cause foetal harm when administered to a pregnant woman. Administration of osimertinib to pregnant rats was associated with embryolethality,reduced foetal growth and neonatal death at exposures similar to what is expected in humans. Osimertinib is not recommended during pregnancy and in women of childbearing potential not using contraception. Use in Lactation: It is not known whether osimertinib or its metabolites are excreted in human milk. Administration to rats during gestation and early lactation was associated with adverse effects,including reduced growth rates and neonatal death. There is insufficient information on the excretion of osimertinib or its metabolites in animal milk. A risk to the suckling child cannot be excluded. Breast-feeding should discontinue during treatment with Osimertinib.

In TAGRISSO clinical studies a limited number of patients were treated with daily doses of up to 240 mg without dose limiting toxicities. In these studies, patients who were treated with TAGRISSO daily doses of 160 mg and 240 mg experienced an increase in the frequency and severity of a number of typical EGFR TKI-induced AEs (primarily diarrhoea and skin rash) compared to the 80 mg dose. There is limited experience with accidental overdoses in humans. All cases were isolated incidents of patients taking an additional daily dose of TAGRISSO in error, without any resulting clinical consequences. There is no specific treatment in the event of TAGRISSO overdose. In case of suspected overdose, TAGRISSO should be withheld and symptomatic treatment initiated.

Store below 30°C. Protect from moisture & light. Safely throw away medicine that is out of date or that you no longer need. Keep Osimertinib and all medicines out of the reach of children.

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