Product Name: Osimertinib Mesylate Tablets (Tagrisso)

[Active Ingredient] The active ingredient of this product is osimertinib mesylate.

[Description] Osimertinib Mesylate Tablets 80 mg.

[Indications/Therapeutic Uses] This product is indicated for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) who have progressed on or after prior therapy with an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), and whose tumors have been confirmed to harbor the EGFR T790M mutation.

[Specification] 80 mg × 30 tablets

[Dosage and Administration] The recommended dose of this product is 80 mg orally once daily until disease progression or unacceptable toxicity occurs. If a dose is missed, it should be taken as soon as possible, unless the next scheduled dose is within 12 hours. This product should be taken at the same time each day; it may be taken with or without food. Dose Adjustment: Based on individual patient safety and tolerability, dosing may be temporarily withheld or reduced. If dose reduction is required, the dose should be reduced to 40 mg once daily. Principles for dose reduction following the occurrence of adverse events (AEs) and toxicities are provided in Table 1. Table 1: Dose Adjustment Principles for Osimertinib Mesylate Tablets Following Adverse Events. Special Populations: No dose adjustment is required based on patient age, body weight, gender, race, or smoking status (see [Pharmacokinetics]). Hepatic Impairment: No dose adjustment is required for patients with mild hepatic impairment (total bilirubin < Upper Limit of Normal [ULN] and Aspartate Aminotransferase [AST] 1 to 1.5 × ULN; or total bilirubin 1 to 1.5 × ULN, any AST level); however, this product should be used with caution in such patients. The safety and efficacy of this product in patients with moderate to severe hepatic impairment have not been established. Until further information becomes available, the use of this product in patients with moderate to severe hepatic impairment is not recommended (see [Pharmacokinetics]). **Renal Impairment:** No dose adjustment is required for patients with mild to moderate renal impairment. Data regarding the use of this product in patients with severe renal impairment are limited. The safety and efficacy of this product have not been established in patients with end-stage renal disease (creatinine clearance [CLcr] <15 mL/min, calculated using the Cockcroft-Gault equation) or in patients undergoing dialysis. This product should be used with caution in patients with severe or end-stage renal impairment (see [Pharmacokinetics]). **Method of Administration:** This product is for oral use. The tablets should be swallowed whole with water and should not be crushed, broken, or chewed. If a patient is unable to swallow the tablet whole, it may be dispersed in 50 mL of non-carbonated water. The tablet should be placed in the water—without crushing—and stirred until dispersed; the resulting suspension should then be swallowed immediately. The glass should subsequently be rinsed with an additional half-glass of water to ensure no residue remains, and this rinse should also be swallowed immediately. No other liquids should be added. If administration via a gastric tube is required, the same procedure described above may be followed, except that 15 mL of water should be used for the initial dispersion of the tablet, and 15 mL of water should be used for the subsequent rinse to clear any residue. This total volume of 30 mL should be administered via the nasogastric tube in accordance with the tube manufacturer's instructions, followed by an appropriate amount of water to flush the tube. Both the dispersed solution and the rinse volume must be administered within 30 minutes of adding the tablet to the water.

**[Adverse Reactions] Summary of Safety Data (Regardless of Causality):** Safety data for this product were obtained from 411 previously treated patients with T790M mutation-positive NSCLC across two global single-arm clinical trials (the Phase II portion of the AURA extension study and the AURA 2 study); these patients received a dose of 80 mg daily. Of the 411 patients, 333 were exposed to treatment with this product for at least 6 months, and 97 patients were exposed for at least 9 months; however, no patients were exposed for 12 months. The most common (>20%) adverse events observed in patients treated with this product were diarrhea (42%), rash (41%), dry skin (31%), and nail toxicity (25%). The most common adverse events leading to dose reduction or treatment interruption were QTc interval prolongation on ECG (2.2%) and neutropenia (1.9%). Serious adverse events reported in 2% or more of patients were pneumonia and pulmonary embolism. In the treatment group receiving this product, 4 patients (1%) experienced fatal adverse events of interstitial lung disease/non-infectious pneumonia. Other fatal adverse events reported in more than one patient included infectious pneumonia (4 patients) and cerebrovascular accident/cerebral hemorrhage (2 patients). In the treatment group receiving this product, 5.6% of patients discontinued treatment due to adverse events. The most common adverse events leading to treatment discontinuation were interstitial lung disease/non-infectious pneumonia and cerebrovascular accident/cerebral infarction. Table 2: All NCI CTCAE* grade adverse events with an incidence >10%, and NCI CTCAE* Grade 3–4 adverse events with an incidence >2%, in two global single-arm studies. Summary of Safety Data (Adverse Drug Reactions) Table 3 lists the incidence of common adverse drug reactions (ADRs) observed in patients treated with this product. Adverse reactions are listed according to the MedDRA System Organ Class (SOC). Within each System Organ Class, ADRs are arranged by frequency of occurrence, with the most frequent ADRs listed first. Within each frequency category, ADRs are arranged in descending order of severity. Furthermore, the corresponding frequency of each ADR has been categorized according to the conventional concepts of CIOMS III; these frequency categories are: Very common (≥1/10); Common (>1/100 to <1/10); Uncommon (≥1/1,000 to <1/100); Rare (≥1/10,000 to <1/1,000); Very rare (<1/10,000); and Not known (cannot be estimated from available data). This section includes data obtained only from completed studies in which patient exposure is known. Table 3. Adverse Drug Reactions Reported During the AURAa Study. Summary of AURA 17 Safety Data: Safety data for the Asia-Pacific population treated with this product were obtained from a Phase II study conducted in the Asia-Pacific region (Table 4, AURA 17; see [Clinical Trials]), involving 171 previously treated patients with T790M mutation-positive NSCLC (of whom 148 were Chinese patients). These patients received a dose of 80 mg daily. The safety data from AURA 17 were consistent with the global Phase II safety data. The vast majority of adverse reactions were Grade 1 or 2 in severity. The most frequently reported adverse drug reactions (ADRs) were diarrhea (29%) and rash (20%). In the AURA 17 study, the incidence of adverse events of Grade 3 or higher (CTCAE) was 14%. Among patients treated with the 80 mg daily regimen, 0.6% required dose reduction due to ADRs. A total of 1.2% of patients discontinued treatment prematurely due to adverse reactions or laboratory abnormalities. Table 4. Adverse Drug Reactions Reported During the AURA 17a Study. Description of Specific Adverse Drug Reactions: Interstitial Lung Disease (ILD): During the Phase II studies, ILD occurred in 6.2% of Japanese patients, while the incidence rates for non-Japanese Asian patients and non-Asian patients were 1.2% and 2.4%, respectively. The median time to onset of ILD or ILD-like adverse reactions was 2.7 months (see [Precautions]). QTc Interval Prolongation: Among the 411 patients enrolled in the AURAex and AURA2 studies, one patient (0.2%) experienced a QTc interval prolongation exceeding 500 ms, and 11 patients (2.7%) experienced a QTc interval prolongation of more than 60 ms from baseline. A pharmacokinetic analysis of this product predicted a concentration-dependent increase in the incidence of QTc interval prolongation. No arrhythmic events were reported during the AURAex or AURA2 studies (see [Precautions]). **Altered Myocardial Contractility:** In the AURAex and AURA2 studies (N=411), among patients with baseline and at least one follow-up assessment of Left Ventricular Ejection Fraction (LVEF), a decrease in LVEF of >10%—dropping to <50%—occurred in 2.4% (9/375) of patients. **Geriatric Patients:** Among patients treated with osimertinib during clinical studies (N=411), 46% were aged 65 years or older, and 13% were aged 75 years or older. Compared to younger subjects (<65 years), a higher proportion of subjects aged ≥65 years experienced adverse reactions leading to study drug dose adjustments (interruption or reduction) (23% vs. 17%). Compared to younger patients, geriatric patients experienced a higher incidence of Grade 3 or higher adverse reactions (32% vs. 28%). **Reporting of Suspected Adverse Reactions:** Reporting suspected adverse reactions after the product has been approved is very important. This allows for continued monitoring of the benefit-risk balance of the product.

**[Contraindications]** Hypersensitivity to the active substance or to any of the excipients. This product must not be administered concomitantly with St. John's wort (see [Drug Interactions]).

**[Precautions]** **Assessment of EGFR T790M Mutation Status:** When considering the use of this product for the treatment of locally advanced or metastatic NSCLC, the EGFR T790M mutation status must first be determined. A validated testing method should be used to detect tumor DNA derived from tissue samples or circulating tumor DNA (ctDNA) obtained from plasma samples. When testing for the T790M mutation status in tumor DNA (via tissue or plasma samples), a robust, reliable, and sensitive testing method must be employed. If the T790M mutation is detected (positive result) via tissue or plasma testing, this indicates that treatment with this product is appropriate. However, if a plasma ctDNA test is performed and yields a negative result, a tissue-based test should be performed whenever possible, as plasma testing may yield false-negative results. Interstitial Lung Disease (ILD): In clinical studies, severe, life-threatening, or fatal interstitial lung disease (ILD) or ILD-like adverse reactions (e.g., non-infectious pneumonia) have been observed in patients receiving this product. Following discontinuation of the drug, the vast majority of these events improved or resolved. Clinical studies excluded patients with a history of ILD, drug-induced ILD, radiation pneumonitis requiring steroid treatment, or clinical evidence of active ILD (see [Adverse Reactions]). During clinical studies, among 1,221 patients treated with this product, 2.9% experienced ILD or ILD-like adverse reactions (e.g., non-infectious pneumonia), of whom 0.3% died. During two Phase II studies, 11 of the 411 patients (2.7%) treated with this product reported ILD or ILD-like adverse reactions; Grade 3 or 4 adverse events accounted for 0.7%, and 1% of patients died. During the studies, 6.2% of Japanese patients experienced ILD, whereas the incidence rates for other Asian patients and non-Asian patients were 1.2% and 2.4%, respectively (see [Adverse Reactions]). Patients presenting with acute onset and/or unexplained worsening of pulmonary symptoms (dyspnea, cough, fever) should be carefully evaluated to rule out ILD. Treatment with this product should be suspended while investigating the cause of these symptoms. If ILD is confirmed, this product should be permanently discontinued, and appropriate therapeutic measures should be initiated. QTc Interval Prolongation: QTc interval prolongation has been observed in patients taking this product. QTc interval prolongation may lead to an increased risk of ventricular tachyarrhythmias (e.g., Torsades de Pointes) or sudden death. No arrhythmic events were reported during the AURAex or AURA2 studies (see [Adverse Reactions]). These two studies excluded patients with clinically significant abnormalities in cardiac rhythm or conduction (e.g., QTc interval >470 ms), as assessed by resting electrocardiogram (ECG) (see [Adverse Reactions]). If possible, patients with congenital long QT syndrome should avoid using this product. Patients with congestive heart failure, electrolyte abnormalities, or those taking medications known to prolong the QTc interval should undergo regular monitoring of their electrocardiogram (ECG) and electrolytes. Patients whose QTc interval is >500 ms, as indicated by at least two independent ECG assessments, should temporarily discontinue this product until the QTc interval is <481 ms or returns to baseline levels (e.g., if the baseline QTc interval is ≥481 ms); at that point, treatment may be resumed, but with a dose reduction as outlined in Table 1. Patients who experience QTc interval prolongation concurrently with any of the following conditions must permanently discontinue this product: Torsades de Pointes, polymorphic ventricular tachycardia, or signs or symptoms of severe arrhythmia. Alterations in Myocardial Contractility: In the AURAex and AURA2 clinical trials, a decrease in left ventricular ejection fraction (LVEF) of >10%—dropping to a value of <50%—occurred in 2.4% (9/375) of patients treated with osimertinib who had both baseline and at least one follow-up LVEF assessment. Based on currently available clinical trial data, a causal relationship between alterations in myocardial contractility and this product has not been established. For patients with known cardiovascular risk factors or conditions that may affect LVEF, cardiac function monitoring—including LVEF assessment at baseline and during treatment—should be considered. For patients who develop signs or symptoms of a cardiac event during treatment with this product, cardiac monitoring—including LVEF assessment—should be considered. Effects on Ability to Drive and Use Machines: This product has no or negligible influence on the ability to drive and use machines. Use in Pregnant and Lactating Women: Contraception (Men and Women): Women of childbearing potential should avoid becoming pregnant while taking this product. Such patients should continue to use effective contraception for the following periods after completing treatment with this product: at least 2 months for women, and at least 4 months for men. When used concomitantly with this product, the risk of reduced exposure to hormonal contraceptives cannot be ruled out. Pregnancy: There are currently no data, or very limited data, regarding the use of this product in pregnant women. Animal studies suggest that this product possesses reproductive toxicity (causing embryo mortality, retarded embryonic growth, and neonatal mortality; see [Pharmacology and Toxicology]). Based on its mechanism of action and preclinical data, use of this product by pregnant women may cause harm to the fetus. Unless the patient's clinical condition necessitates treatment with this product, it should not be used during pregnancy. Lactation: It is currently unknown whether this product or its metabolites are excreted in human milk. Furthermore, there is currently insufficient information to indicate whether this product or its metabolites are excreted in animal milk. However, this product and its metabolites have been detected in nursing offspring, and adverse effects on the growth and survival of the offspring have been observed (see [Pharmacology and Toxicology]). Therefore, the potential for this product to affect nursing infants cannot be ruled out. Consequently, breastfeeding should be discontinued during treatment with this product. Fertility: There are currently no data regarding the effects of this product on human fertility. Results from animal studies suggest that this product affects both female and male reproductive organs and may impair fertility (see [Pharmacology and Toxicology]).

[Pediatric Use] The safety and efficacy of this product in pediatric or adolescent patients under 18 years of age have not been established. No data are currently available in this regard.

[Geriatric Use] In clinical trials, 187 of the 411 patients (45%) were 65 years of age or older, and 54 patients (13%) were 75 years of age or older. No overall differences in efficacy were observed based on age. Exploratory analyses indicated...