Osimertinib

1 INDICATIONS AND USAGE TAGRISSO is a kinase inhibitor indicated for: • adjuvant therapy after tumor resection in adult patients with non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test. ( 1.1 , 2.2 ) • the treatment of adult patients with locally advanced, unresectable (stage III) NSCLC whose disease has not progressed during or following concurrent or sequential platinum-based chemoradiation therapy and whose tumors have EGFR exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test. ( 1.2 , 2.2 ) • the first-line treatment of adult patients with metastatic NSCLC whose tumors have EGFR exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test. ( 1.3 , 2.2 ) • in combination with pemetrexed and platinum-based chemotherapy, the first-line treatment of adult patients with locally advanced or metastatic NSCLC whose tumors have EGFR exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test. ( 1.4 , 2.2 ) • the treatment of adult patients with metastatic EGFR T790M mutation-positive NSCLC, as detected by an FDA-approved test, whose disease has progressed on or after EGFR TKI therapy. ( 1.5 , 2.2 ) 1.1 Adjuvant Treatment of EGFR Mutation-Positive Non-Small Cell Lung Cancer (NSCLC) TAGRISSO is indicated as adjuvant therapy after tumor resection in adult patients with non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test [see Dosage and Administration (2.2) ] . 1.2 Locally Advanced, Unresectable (Stage III) EGFR Mutation-Positive NSCLC TAGRISSO is indicated for the treatment of adult patients with locally advanced, unresectable (stage III) NSCLC whose disease has not progressed during or following concurrent or sequential platinum-based chemoradiation therapy and whose tumors have EGFR exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test [see Dosage and Administration (2.2)]. 1.3 First-line Treatment of EGFR Mutation-Positive Metastatic NSCLC TAGRISSO is indicated for the first-line treatment of adult patients with metastatic NSCLC whose tumors have EGFR exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test [see Dosage and Administration (2.2) ]. 1.4 First-line Treatment of EGFR Mutation-Positive Locally Advanced or Metastatic NSCLC TAGRISSO in combination with pemetrexed and platinum-based chemotherapy is indicated for the first-line treatment of adult patients with locally advanced or metastatic NSCLC whose tumors have EGFR exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test [see Dosage and Administration (2.2) ]. 1.5 Previously Treated EGFR T790M Mutation-Positive Metastatic NSCLC TAGRISSO is indicated for the treatment of adult patients with metastatic EGFR T790M mutation-positive NSCLC, as detected by an FDA-approved test, whose disease has progressed on or after EGFR tyrosine kinase inhibitor (TKI) therapy [see Dosage and Administration (2.2) ] .

5 WARNINGS AND PRECAUTIONS • Interstitial Lung Disease (ILD)/Pneumonitis : Monitor for new or worsening pulmonary symptoms indicative of ILD/pneumonitis. For patients receiving TAGRISSO who have not received recent definite platinum-based chemoradiation therapy, permanently discontinue TAGRISSO in patients diagnosed with ILD/Pneumonitis. For patients who received recent definitive platinum-based chemoradiation therapy with Grade 1 ILD/pneumonitis continue TAGRISSO or interrupt and restart, as appropriate. Permanently discontinue TAGRISSO in patients diagnosed with Grade ≥2 ILD/pneumonitis. ( 2.5 , 5.1 ) • 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 TAGRISSO based on severity. ( 2.5 , 5.2 ) • Cardiomyopathy : Occurred in 3.8% of patients. Conduct cardiac monitoring, including left ventricular ejection fraction (LVEF) assessment in patients with cardiac risk factors. ( 2.5 , 5.3 ) • Keratitis : Promptly refer patients with signs and symptoms of keratitis to an ophthalmologist for evaluation. ( 5.4 ) • Erythema Multiforme Major, Stevens-Johnson Syndrome, and Toxic Epidermal Necrolysis : Withhold TAGRISSO if erythema multiforme major (EMM), Stevens-Johnson syndrome (SJS), or toxic epidermal necrolysis (TEN) is suspected and permanently discontinue if confirmed. ( 2.5 , 5.5 ) • Cutaneous Vasculitis : Withhold TAGRISSO if cutaneous vasculitis is suspected, evaluate for systemic involvement, and consider dermatology consultation. If no other etiology can be identified, consider permanent discontinuation based on severity. ( 5.6 ) • Aplastic Anemia : Withhold TAGRISSO if aplastic anemia is suspected and permanently discontinue TAGRISSO if confirmed. ( 2.5 , 5.7 ) • Embryo-Fetal Toxicity : TAGRISSO can cause fetal harm. Advise females of potential risk to the fetus and to use effective contraception during treatment with TAGRISSO and for 6 weeks after last dose. Advise males to use effective contraception for 4 months after the last dose of TAGRISSO. ( 5.8 , 8.1 , 8.3 ) 5.1 Interstitial Lung Disease/Pneumonitis TAGRISSO can cause severe and fatal ILD/pneumonitis. Across clinical trials, interstitial lung disease (ILD)/pneumonitis occurred in 4% of the 1813 patients treated with TAGRISSO monotherapy who had not received recent definitive chemoradiation therapy; 0.4% of cases were fatal. ILD/Pneumonitis with TAGRISSO in Combination with Pemetrexed and Platinum-based Chemotherapy In the FLAURA2 study, ILD/pneumonitis occurred in 3.3% of the 276 patients who received TAGRISSO in combination with pemetrexed and platinum-based chemotherapy; 0.4% of cases were fatal. ILD/Pneumonitis Following Definitive Platinum-based Chemoradiation Therapy In the LAURA study, following definitive platinum-based chemoradiation therapy, ILD/pneumonitis, including radiation pneumonitis, occurred in 80 of the 143 patients (56%) who received TAGRISSO monotherapy and 28 of the 73 patients (38%) who received placebo. There was one fatal case (0.7%), 3.5% Grade 3, 34% Grade 2, and 18% Grade 1 adverse reactions of ILD/pneumonitis in TAGRISSO-treated patients. For TAGRISSO-treated patients, ILD/pneumonitis led to permanent discontinuation of TAGRISSO in 7% of patients and dosage interruptions of TAGRISSO in 35% of patients. Among the 46 patients who were rechallenged with TAGRISSO, 11% had recurrence of ILD/pneumonitis. In the 80 TAGRISSO-treated patients, ILD/pneumonitis resolved in 40%, resolved with sequelae in 1.3%, were resolving in 16%, did not resolve in 41%, and resulted in death in 1.3%. For patients receiving TAGRISSO who have not received recent definitive platinum-based chemoradiation therapy, withhold TAGRISSO and promptly investigate for ILD in patients who present with worsening or respiratory symptoms which may be indicative of ILD (e.g., dyspnea, cough, and fever). Permanently discontinue TAGRISSO if ILD/pneumonitis is confirmed [see Dosage and Administration (2.5) and Adverse Reactions (6.1) ]. For patients who have received recent definitive platinum-based chemoradiation therapy with Grade 1 ILD/pneumonitis continue TAGRISSO or interrupt and restart, as appropriate. Permanently discontinue TAGRISSO in patients diagnosed with Grade ≥2 ILD/pneumonitis [see Dosage and Administration (2.5) and Adverse Reactions (6.1) ]. 5.2 QTc Interval Prolongation TAGRISSO can cause heart rate-corrected QT (QTc) interval prolongation. Of the 1813 patients treated with TAGRISSO monotherapy in clinical trials, 1.1% were found to have a QTc >500 msec, and 4.3% of patients had an increase from baseline QTc >60 msec [see Clinical Pharmacology (12.2) ]. Of the 276 patients treated with TAGRISSO in combination with pemetrexed and platinum-based chemotherapy in the FLAURA2 study, 1.8% were found to have a QTc >500 msec, and 10.5% of patients had an increase from baseline QTc >60 msec. No QTc-related arrhythmias were reported. Clinical trials of TAGRISSO did not enroll patients with baseline QTc of >470 msec. Conduct periodic monitoring with ECGs and electrolytes in patients with congenital long QTc syndrome, congestive heart failure, electrolyte abnormalities, or those who are taking medications known to prolong the QTc interval. Permanently discontinue TAGRISSO in patients who develop QTc interval prolongation with signs/symptoms of life-threatening arrhythmia [see Dosage and Administration (2.5) ]. 5.3 Cardiomyopathy TAGRISSO can cause cardiomyopathy, including cardiac failure, chronic cardiac failure, congestive heart failure, pulmonary edema or decreased ejection fraction. Across clinical trials, cardiomyopathy occurred in 3.8% of the 1813 TAGRISSO-treated patients; 0.1% of cardiomyopathy cases were fatal. In the FLAURA2 study, cardiomyopathy occurred in 9% of the 276 patients who received TAGRISSO in combination with pemetrexed and platinum-based chemotherapy; 1.1% of cardiomyopathy cases were fatal. A decline in left ventricular ejection fraction (LVEF) ≥10 percentage points from baseline and to less than 50% LVEF occurred in 4.2% of 1557 patients who had baseline and at least one follow-up LVEF assessment. In the ADAURA study, 1.5% (5/325) of patients treated with TAGRISSO experienced LVEF decreases greater than or equal to 10 percentage points and a drop to less than 50%. In the LAURA study, following platinum-based chemoradiation therapy, 3% (4/135) of patients treated with TAGRISSO and no patients treated with placebo experienced LVEF decreases greater than or equal to 10 percentage points and a drop to less than 50%. In the FLAURA2 study, 8% (21/262) of patients treated with TAGRISSO in combination with pemetrexed and platinum-based chemotherapy, who had baseline and at least one follow-up LVEF assessment, experienced LVEF decreases greater than or equal to 10 percentage points and a drop to less than 50%. For patients who will be receiving TAGRISSO monotherapy, conduct cardiac monitoring, including assessment of LVEF at baseline and during treatment, in patients with cardiac risk factors. For patients who will be receiving TAGRISSO in combination with pemetrexed and platinum-based chemotherapy, conduct cardiac monitoring, including assessment of LVEF at baseline and during treatment, in all patients. Assess LVEF in patients who develop relevant cardiac signs or symptoms during treatment. For symptomatic congestive heart failure, permanently discontinue TAGRISSO [see Dosage and Administration (2.5) ]. 5.4 Keratitis Keratitis was reported in 0.6% of 1813 patients treated with TAGRISSO monotherapy in clinical trials. Promptly refer patients with signs and symptoms suggestive of keratitis (such as eye inflammation, lacrimation, light sensitivity, blurred vision, eye pain and/or red eye) to an ophthalmologist. 5.5 Erythema Multiforme Major, Stevens-Johnson Syndrome, and Toxic Epidermal Necrolysis Postmarketing cases consistent with erythema multiforme major (EMM), Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported in patients receiving TAGRISSO [see Postmarketing (6.2) ] . Withhold TAGRISSO if EMM, SJS, or TEN is suspected and permanently discontinue if confirmed. 5.6 Cutaneous Vasculitis Postmarketing cases of cutaneous vasculitis including leukocytoclastic vasculitis, urticarial vasculitis, and IgA vasculitis have been reported in patients receiving TAGRISSO [see Postmarketing (6.2) ] . Withhold TAGRISSO if cutaneous vasculitis is suspected, evaluate for systemic involvement, and consider dermatology consultation. If no other etiology can be identified, consider permanent discontinuation of TAGRISSO based on severity. 5.7 Aplastic Anemia Aplastic anemia has been reported in patients treated with TAGRISSO in clinical trials (0.06% of 1813) and postmarketing [see Postmarketing (6.2) ] . Some cases had a fatal outcome. Inform patients of the signs and symptoms of aplastic anemia including but not limited to, new or persistent fevers, bruising, bleeding, and pallor. If aplastic anemia is suspected, withhold TAGRISSO and obtain a hematology consultation. If aplastic anemia is confirmed, permanently discontinue TAGRISSO [see Dosage and Administration (2.5) ] . Perform complete blood count with differential before starting TAGRISSO, periodically throughout treatment, and more frequently if indicated. 5.8 Embryo-Fetal Toxicity Based on data from animal studies and its mechanism of action, TAGRISSO can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, osimertinib caused post-implantation fetal loss when administered during early development at a dose exposure 1.5 times the exposure at the recommended clinical dose. When males were treated prior to mating with untreated females, there was an increase in preimplantation embryonic loss at plasma exposures of approximately 0.5 times those observed at the recommended dose of 80 mg once daily. Verify pregnancy status of females of reproductive potential prior to initiating TAGRISSO. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with TAGRISSO and for 6 weeks after the last dose. Advise males with female partners of reproductive potential to use effective contraception for 4 months after the last dose [see Use in Specific Populations (8.1 and 8.3) ].

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: • Interstitial Lung Disease/Pneumonitis [see Warnings and Precautions (5.1 )] • QTc Interval Prolongation [see Warnings and Precautions (5.2) ] • Cardiomyopathy [see Warnings and Precautions (5.3) ] • Keratitis [see Warnings and Precautions (5.4) ] • Erythema multiforme, Stevens-Johnson syndrome, and Toxic epidermal necrolysis [see Warnings and Precautions (5.5) ] • Cutaneous Vasculitis [see Warnings and Precautions (5.6) ] • Aplastic Anemia [see Warnings and Precautions (5.7) ] Most common (≥20%) adverse reactions, including laboratory abnormalities, were: • TAGRISSO monotherapy: leukopenia, lymphopenia, thrombocytopenia, anemia, diarrhea, rash, musculoskeletal pain, neutropenia, nail toxicity, dry skin, stomatitis, and fatigue. ( 6.1 ) • TAGRISSO monotherapy following platinum-based chemoradiation therapy: lymphopenia, leukopenia, ILD/pneumonitis, thrombocytopenia, neutropenia, rash, diarrhea, nail toxicity, musculoskeletal pain, cough and COVID-19. ( 6.1 ) • TAGRISSO in combination with pemetrexed and platinum-based chemotherapy: leukopenia, thrombocytopenia, neutropenia, lymphopenia, rash, diarrhea, stomatitis, nail toxicity, dry skin, and increased blood creatinine. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca at 1-800-236-9933 or www.TAGRISSO.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data in the WARNINGS AND PRECAUTIONS section reflect exposure to TAGRISSO in 1813 patients with EGFR mutation-positive NSCLC who received TAGRISSO monotherapy at the recommended dose of 80 mg orally once daily until disease progression or unacceptable toxicity in four randomized, controlled trials [ADAURA (n=337), FLAURA (n=338), FLAURA2 (monotherapy arm; n=275), and AURA3 (n=279)] [see Clinical Studies (14) ] , two single arm trials [AURA Extension (n=201) {NCT01802632} and AURA2 (n=210)]{NCT02094261}, and one dose-finding study, AURA1 (n=173). Among 1813 patients who received TAGRISSO monotherapy, 82% were exposed for 6 months or longer and 67% were exposed for greater than one year. In this pooled safety population, the most common adverse reactions in ≥20% of 1813 patients who received TAGRISSO monotherapy were diarrhea (47%), rash (46%), musculoskeletal pain (38%), nail toxicity (34%), dry skin (32%), stomatitis (24%), and fatigue (21%). The most common laboratory abnormalities in ≥20% of 1813 patients who received TAGRISSO monotherapy were leukopenia (65%), lymphopenia (64%), thrombocytopenia (53%), anemia (52%), and neutropenia (36%). In addition to the 1813 patients, certain subsections in the WARNINGS AND PRECAUTIONS describe adverse reactions observed with exposure to TAGRISSO monotherapy (80 mg orally once daily until disease progression or unacceptable toxicity) following definitive platinum-based chemoradiation therapy (n=143) in the LAURA study. The data described below reflect exposure to TAGRISSO (80 mg daily) in 337 patients with EGFR mutation-positive resectable NSCLC, 143 patients with EGFR mutation-positive locally advanced, unresectable (stage III) NSCLC, and 833 patients with EGFR mutation-positive locally advanced or metastatic NSCLC in five randomized, controlled trials [ADAURA (n=337), LAURA (n=143), FLAURA (n=279), FLAURA2 (monotherapy arm; n=275), and AURA3 (n=279)]. The data also reflect exposure to TAGRISSO at the recommended dose of 80 mg daily given in combination with pemetrexed and platinum-based chemotherapy in 276 patients with EGFR mutation-positive locally advanced or metastatic NSCLC in one randomized controlled trial [FLAURA2 (n=276)]. Patients with a history of interstitial lung disease, drug induced interstitial disease or radiation pneumonitis that required steroid treatment, serious arrhythmia or baseline QTc interval greater than 470 msec on electrocardiogram were excluded from enrollment in these studies. Adjuvant Treatment of EGFR Mutation-Positive NSCLC – Monotherapy The safety of TAGRISSO was evaluated in ADAURA, a randomized, double-blind, placebo-controlled trial for the adjuvant treatment of patients with EGFR exon 19 deletions or exon 21 L858R mutation-positive NSCLC who had complete tumor resection, with or without prior adjuvant chemotherapy. At time of DFS analysis, the median duration of exposure to TAGRISSO was 22.5 months. Serious adverse reactions were reported in 16% of patients treated with TAGRISSO. The most common serious adverse reaction (≥1%) was pneumonia (1.5%). Adverse reactions leading to dose reductions occurred in 9% of patients treated with TAGRISSO. The most frequent adverse reactions leading to dose reductions or interruptions were diarrhea (4.5%), stomatitis (3.9%), nail toxicity (1.8%) and rash (1.8%). Adverse reactions leading to permanent discontinuation occurred in 11% of patients treated with TAGRISSO. The most frequent adverse reactions leading to discontinuation of TAGRISSO were interstitial lung disease (2.7%), and rash (1.2%). Tables 4 and 5 summarize common adverse reactions and laboratory abnormalities which occurred in ADAURA. Table 4. Adverse Reactions Occurring in ≥10% of Patients Receiving TAGRISSO in ADAURA NCI CTCAE v4.0. Adverse Reaction TAGRISSO (N=337) PLACEBO (N=343) All Grades (%) Grade 3 or higher All events were grade 3. (%) All Grades (%) Grade 3 or higher (%) Gastrointestinal Disorders Diarrhea Includes diarrhea, colitis, enterocolitis, enteritis. 47 2.4 20 0.3 Stomatitis Includes aphthous ulcer, cheilitis, gingival ulceration, glossitis, tongue ulceration, stomatitis and mouth ulceration. 32 1.8 7 0 Abdominal Pain Includes abdominal discomfort, abdominal pain, abdominal lower pain, abdominal upper pain, epigastric discomfort, hepatic pain. 12 0.3 7 0 Skin Disorders Rash Includes rash, rash generalized, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pustular, rash pruritic, rash vesicular, rash follicular, erythema, folliculitis, acne, dermatitis, dermatitis acneiform, dermatitis bullous, dermatitis exfoliative generalized, drug eruption, eczema, eczema asteatotic, lichen planus, skin erosion, pustule. 40 0.6 19 0 Nail toxicity Includes nail bed disorder, nail bed inflammation, nail bed infection, nail discoloration, nail pigmentation, nail disorder, nail toxicity, nail dystrophy, nail infection, nail ridging, onychalgia, onychoclasis, onycholysis, onychomadesis, onychomalacia, paronychia. 37 0.9 3.8 0 Dry skin Includes dry skin, skin fissures, xerosis, eczema, xeroderma. 29 0.3 7 0 Pruritus Includes pruritus, pruritus generalized, eyelid pruritus. 19 0 9 0 Respiratory, Thoracic and Mediastinal Disorders Cough Includes cough, productive cough, upper-airway cough syndrome. 19 0 19 0 Musculoskeletal and Connective Tissue Disorders Musculoskeletal Pain Includes arthralgia, arthritis, back pain, bone pain, musculoskeletal chest pain, musculoskeletal pain, myalgia, neck pain, non-cardiac chest pain, pain in extremity, and spinal pain. 18 0.3 25 0.3 Infection and Infestation Disorders Nasopharyngitis 14 0 10 0 Upper respiratory tract infection 13 0.6 10 0 Urinary Tract Infection Includes cystitis, urinary tract infection, and urinary tract infection bacterial. 10 0.3 7 0 General Disorders and Administration Site Conditions Fatigue Includes asthenia, fatigue. 13 0.6 9 0.3 Metabolism and Nutrition Disorders Decreased appetite 13 0.6 3.8 0 Nervous System Disorders Dizziness Includes dizziness, vertigo, and vertigo positional. 10 0 9 0 Clinically relevant adverse reactions in ADAURA in 500 msec. Table 5. Laboratory Abnormalities Worsening from Baseline in ≥20% of Patients in ADAURA Laboratory Abnormality NCI CTCAE v4.0 Based on the number of patients with available follow-up laboratory data. TAGRISSO (N=337) PLACEBO (N=343) All Grades (%) Grade 3 or Grade 4 (%) All Grades (%) Grade 3 or Grade 4 (%) Hematology Leukopenia 54 0 25 0 Thrombocytopenia 47 0 7 0.3 Lymphopenia 44 3.4 14 0.9 Anemia 30 0 12 0.3 Neutropenia 26 0.6 10 0.3 Chemistry Hyperglycemia 25 2.3 30 0.9 Hypermagnesemia 24 1.3 14 1.5 Hyponatremia 20 1.8 16 1.5 Laboratory abnormalities in ADAURA that occurred in 1 patient were ILD/pneumonitis (7%) and pneumonia (1.4%). Dosage interruptions of TAGRISSO due to an adverse reaction occurred in 56% of patients. The adverse reactions requiring dosage interruption in ≥2% of patients were ILD/pneumonitis (35%), pneumonia (6%), COVID-19 (4.2%), neutropenia (2.1%), and QTc interval prolongation (2.1%). Dose reductions of TAGRISSO due to an adverse reaction occurred in 8% of patients. The most common adverse reactions, including laboratory abnormalities worsening from baseline, were lymphopenia, leukopenia, ILD/pneumonitis, thrombocytopenia, neutropenia, rash, diarrhea, nail toxicity, musculoskeletal pain, cough, and COVID-19. Tables 6 and 7 summarize common adverse reactions and laboratory abnormalities which occurred in LAURA. Table 6. Adverse Reactions in ≥10% of Patients Receiving TAGRISSO in LAURA NCI CTCAE v5.0 Adverse Reaction TAGRISSO (N=143) Placebo (N=73) Any Grade (%) Grade 3 or 4(%) Any Grade (%) Grade 3 or 4 (%) Respiratory, Thoracic and Mediastinal Disorders ILD/pneumonitis Includes radiation pneumonitis, radiation lung fibrosis, pneumonitis, interstitial lung disease (ILD), pulmonary fibrosis. 56 3.5 38 0 Cough Includes cough, productive cough. 20 0 15 0 Skin Disorders Rash Includes rash, maculo-papular rash, pustular rash, pruritic rash, folliculitis, papule, dermatitis, acneiform dermatitis, atopic dermatitis, eczema, asteatotic eczema, acne, urticaria. 39 0.7 19 0 Nail toxicity Includes nail bed disorder, nail disorder, nail discoloration, nail infection, onychoclasis, paronychia. 23 0 1.4 0 Dry skin Includes dry skin, skin fissures, senile xerosis, xeroderma. 17 0.7 5 0 Pruritus 13 0 7 0 Gastrointestinal Disorders Diarrhea Includes diarrhea, enteritis. 36 2.1 14 0 Stomatitis Includes stomatitis, aphthous ulceration, mouth ulceration. 15 0 5 0 Musculoskeletal and Connective Tissue Disorders Musculoskeletal pain Includes musculoskeletal chest pain, myalgia, arthritis, arthralgia, back pain, bone pain, musculoskeletal pain, neck pain, pain in extremity, spinal osteoarthritis. 20 0.7 26 0 Infection and Infestation Disorders COVID-19 Includes COVID-19 and COVID-19 pneumonia. 20 0.7 10 0 Pneumonia Includes pneumonia, aspiration pneumonia, viral pneumonia, Pneumocystis jiroveci pneumonia, Haemophilus pneumonia, lower respiratory tract infection. 15 3.5 10 5 Metabolism and Nutrition Disorders Decreased appetite 15 0.7 5 0 Clinically relevant adverse reactions in LAURA in 500 msec. Table 7. Laboratory Abnormalities Worsening from Baseline in ≥20% of Patients in LAURA Laboratory Abnormality NCI CTCAE v5.0 Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available (TAGRISSO arm: 142 and placebo arm: 72). TAGRISSO (N=143) Placebo (N=73) All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Hematology Lymphopenia 70 3.5 40 1.4 Leukopenia 66 2.8 24 0 Thrombocytopenia 51 1.4 8 1.4 Neutropenia 42 2.1 15 1.4 A clinically relevant laboratory abnormality in LAURA that occurred in <20% of patients receiving TAGRISSO was increased blood creatinine (19%). Previously Untreated EGFR Mutation-Positive Metastatic Non-Small Cell Lung Cancer – Monotherapy The safety of TAGRISSO was evaluated in FLAURA, a multicenter international double-blind randomized (1:1) active‑controlled trial conducted in 556 patients with EGFR exon 19 deletion or exon 21 L858R mutation-positive, unresectable or metastatic NSCLC who had not received previous systemic treatment for advanced disease. The median duration of exposure to TAGRISSO was 16.2 months. Serious adverse reactions were reported in 4% of patients treated with TAGRISSO; the most common serious adverse reactions (≥1%) were pneumonia (2.9%), ILD/pneumonitis (2.1%), and pulmonary embolism (1.8%). Dose reductions occurred in 2.9% of patients treated with TAGRISSO. The most frequent adverse reactions leading to dose reductions or interruptions were prolongation of the QT interval as assessed by ECG (4.3%), diarrhea (2.5%), and lymphopenia (1.1%). Adverse reactions leading to permanent discontinuation occurred in 13% of patients treated with TAGRISSO. The most frequent adverse reaction leading to discontinuation of TAGRISSO was ILD/pneumonitis (3.9%). Tables 8 and 9 summarize common adverse reactions and laboratory abnormalities which occurred in FLAURA. Table 8. Adverse Reactions Occurring in ≥10% of Patients Receiving TAGRISSO in FLAURA NCI CTCAE v4.0 Adverse Reaction TAGRISSO (N=279) EGFR TKI comparator (gefitinib or erlotinib) (N=277) Any Grade (%) Grade 3 or higher (%) Any Grade (%) Grade 3 or higher (%) Gastrointestinal Disorders Diarrhea One grade 5 (fatal) event was reported (diarrhea) for EGFR TKI comparator. 58 2.2 57 2.5 Stomatitis Includes stomatitis and mouth ulceration. 32 0.7 22 1.1 Nausea 14 0 19 0 Constipation 15 0 13 0 Vomiting 11 0 11 1.4 Skin Disorders Rash Includes rash, rash generalized, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pustular, rash pruritic, rash vesicular, rash follicular, erythema, folliculitis, acne, dermatitis, dermatitis acneiform, drug eruption, skin erosion, pustule. 58 1.1 78 7 Dry skin Includes dry skin, skin fissures, xerosis, eczema, xeroderma. 36 0.4 36 1.1 Nail toxicity Includes nail bed disorder, nail bed inflammation, nail bed infection, nail discoloration, nail pigmentation, nail disorder, nail toxicity, nail dystrophy, nail infection, nail ridging, onychalgia, onychoclasis, onycholysis, onychomadesis, onychomalacia, paronychia. 35 0.4 33 0.7 Pruritus Includes pruritus, pruritus generalized, eyelid pruritus. 17 0.4 17 0 General Disorders and Administration Site Conditions Fatigue Includes fatigue, asthenia. 21 1.4 15 1.4 Pyrexia 10 0 4 0.4 Metabolism and Nutrition Disorders Decreased appetite 20 2.5 19 1.8 Respiratory, Thoracic and Mediastinal Disorders Cough 17 0 15 0.4 Dyspnea 13 0.4 7 1.4 Neurologic Disorders Headache 12 0.4 7 0 Cardiac Disorders Prolonged QT Interval Includes prolonged QT interval reported as adverse reaction. 10 2.2 4 0.7 Infection and Infestation Disorders Upper Respiratory Tract Infection 10 0 7 0 Clinically relevant adverse reactions in FLAURA in 500 msec. Table 9. Laboratory Abnormalities Worsening from Baseline in ≥20% of Patients in FLAURA Laboratory Abnormality NCI CTCAE v4.0 Each test incidence, except for hyperglycemia, is based on the number of patients who had both baseline and at least one on-study laboratory measurement available (TAGRISSO range: 267 – 273 and EGFR TKI comparator range: 256 – 268). TAGRISSO (N=279) EGFR TKI comparator (gefitinib or erlotinib) (N=277) All Grades (%) Grade 3 or Grade 4 (%) All Grades (%) Grade 3 or Grade 4 (%) Hematology Lymphopenia 63 6 36 4.2 Anemia 59 0.7 47 0.4 Thrombocytopenia 51 0.7 12 0.4 Neutropenia 41 3 10 0 Chemistry Hyperglycemia Hyperglycemia is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: TAGRISSO (179) and EGFR comparator (191). 37 0 31 0.5 Hypermagnesemia 30 0.7 11 0.4 Hyponatremia 26 1.1 27 1.5 Increased AST 22 1.1 43 4.1 Increased ALT 21 0.7 52 8 Hypokalemia 16 0.4 22 1.1 Hyperbilirubinemia 14 0 29 1.1 A clinically relevant laboratory abnormality in FLAURA that occurred in <20% of patients receiving TAGRISSO was increased blood creatinine (9%). Previously Untreated EGFR Mutation-Positive Locally Advanced or Metastatic Non-Small Cell Lung Cancer – TAGRISSO in Combination with Pemetrexed and Platinum-based Chemotherapy The safety of TAGRISSO in combination with pemetrexed and platinum-based chemotherapy was evaluated in FLAURA2, a multicenter international open-label, randomized (1:1), active-controlled trial conducted in 557 patients with EGFR exon 19 deletion or exon 21 L858R mutation-positive, locally advanced or metastatic NSCLC who had not received previous systemic treatment for advanced disease. The median duration of exposure to TAGRISSO in combination with pemetrexed and platinum-based chemotherapy was 22.3 months and the median duration of exposure to TAGRISSO monotherapy was 19.3 months. Serious adverse reactions were reported in 38% of patients treated with TAGRISSO in combination with pemetrexed and platinum-based chemotherapy; the most frequently reported serious adverse reactions (≥2%) in the combination arm were anemia (3.3%), COVID-19 (2.5%), pneumonia (2.5%), febrile neutropenia (2.2%), thrombocytopenia (2.2%), and pulmonary embolism (2.2%). Fatal adverse reactions occurred in 7% of patients who received TAGRISSO in combination with pemetrexed and platinum-based chemotherapy including pulmonary embolism (1.1%), pneumonia (1.1%) and cardiomyopathy (1.1%). Dosage interruptions of TAGRISSO, when given with pemetrexed and platinum-based chemotherapy, due to an adverse reaction occurred in 44% of patients. Adverse reactions which required dosage interruption in ≥ 2% of patients included anemia (4.7%), neutropenia (4.3%), diarrhea (3.6%), febrile neutropenia (3.3%) and thrombocytopenia (2.9%). Permanent discontinuation of TAGRISSO when given in combination with pemetrexed and platinum-based chemotherapy due to an adverse reaction occurred in 11% of patients. Adverse reactions which resulted in permanent discontinuation of TAGRISSO in ≥1% of patients included ILD/pneumonitis (2.9%), pneumonia (1.4%), and decreased ejection fraction (1.1%). Adverse reactions leading to dose reduction of TAGRISSO occurred in 10% of patients treated with TAGRISSO in combination with pemetrexed and platinum-based chemotherapy. The most frequently reported adverse reactions leading to dose reduction of TAGRISSO in the combination arm in ≥1% of patients were diarrhea (1.1%) and rash (1.1%). The most common adverse reactions, including laboratory abnormalities worsening from baseline, were leukopenia, thrombocytopenia, neutropenia, rash, diarrhea, stomatitis, nail toxicity, dry skin, increased blood creatinine. Tables 10 and 11 summarize common adverse reactions and laboratory abnormalities which occurred in FLAURA2. Table 10. Adverse Reactions Occurring in ≥10% of Patients Receiving TAGRISSO in FLAURA2 NCI CTCAE v5.0 Adverse Reaction TAGRISSO with Pemetrexed and Platinum-based Chemotherapy (N=276) TAGRISSO (N=275) Any Grade (%) Grade 3 or higher (%) Any Grade (%) Grade 3 or higher (%) Skin Disorders Rash Includes rash, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pustular, rash pruritic, rash vesicular, rash follicular, erythema, folliculitis, acne, dermatitis, dermatitis acneiform, drug eruption, skin erosion, pustule. 49 2.5 44 1.5 Nail toxicity Includes nail bed disorder, nail bed inflammation, nail bed infection, nail discoloration, nail pigmentation, nail disorder, nail toxicity, nail dystrophy, nail infection, nail ridging, onychalgia, onychoclasis, onycholysis, onychomadesis, onychomalacia, paronychia. 27 0.7 32 0.4 Dry skin Includes dry skin, skin fissures, xerosis, eczema, xeroderma. 24 0 31 0 Pruritus Includes pruritus, eyelid pruritus. 8 0 11 0 Gastrointestinal Disorders Diarrhea 43 2.9 41 0.4 Stomatitis Includes stomatitis and mouth ulceration. 31 0.4 21 0.4 Clinically relevant adverse reactions in FLAURA2 in 500 msec. Table 11. Laboratory Abnormalities Worsening from Baseline in ≥20% of Patients in FLAURA2 NCI CTCAE v5.0 Findings based on test results presented as CTCAE grade shifts. Laboratory Abnormality Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available (TAGRISSO with pemetrexed and platinum-based chemotherapy arm: 275 and TAGRISSO monotherapy arm: 275). TAGRISSO with Pemetrexed and Platinum-based Chemotherapy (N=276) TAGRISSO (N=275) All Grades (%) Grade 3 or Grade 4 (%) All Grades (%) Grade 3 or Grade 4 (%) Hematology Leukopenia 88 20 53 3.3 Thrombocytopenia 85 16 44 1.8 Neutropenia 85 36 40 4.7 Lymphopenia 78 16 55 7 Chemistry Blood creatinine increased 22 0.4 8 0 Previously Treated EGFR T790M Mutation-Positive Metastatic Non-Small Cell Lung Cancer – Monotherapy The safety of TAGRISSO was evaluated in AURA3, a multicenter international open label randomized (2:1) controlled trial conducted in 419 patients with unresectable or metastatic EGFR T790M mutation-positive NSCLC who had progressive disease following first line EGFR TKI treatment. A total of 279 patients received TAGRISSO 80 mg orally once daily until intolerance to therapy, disease progression, or investigator determination that the patient was no longer benefiting from treatment. A total of 136 patients received pemetrexed plus either carboplatin or cisplatin every three weeks for up to 6 cycles; patients without disease progression after 4 cycles of chemotherapy could continue maintenance pemetrexed until disease progression, unacceptable toxicity, or investigator determination that the patient was no longer benefiting from treatment. Left Ventricular Ejection Fraction (LVEF) was evaluated at screening and every 12 weeks. The median duration of treatment was 8.1 months for patients treated with TAGRISSO and 4.2 months for chemotherapy-treated patients. The trial population characteristics were: median age 62 years, age less than 65 (58%), female (64%), Asian (65%), never smokers (68%), and ECOG PS 0 or 1 (100%). Serious adverse reactions were reported in 18% of patients treated with TAGRISSO and 26% in the chemotherapy group. No single serious adverse reaction was reported in 2% or more patients treated with TAGRISSO. One patient (0.4%) treated with TAGRISSO experienced a fatal adverse reaction (ILD/pneumonitis). Dose reductions occurred in 2.9% of patients treated with TAGRISSO. The most frequent adverse reactions leading to dose reductions or interruptions were prolongation of the QT interval as assessed by ECG (1.8%), neutropenia (1.1%), and diarrhea (1.1%). Adverse reactions resulting in permanent discontinuation of TAGRISSO occurred in 7% of patients treated with TAGRISSO. The most frequent adverse reaction leading to discontinuation of TAGRISSO was ILD/pneumonitis (3%). Tables 12 and 13 summarize common adverse reactions and laboratory abnormalities which occurred in TAGRISSO-treated patients in AURA3. Table 12. Adverse Reactions Occurring in ≥10% of Patients Receiving TAGRISSO in AURA3 NCI CTCAE v4.0. Adverse Reaction TAGRISSO (N=279) Chemotherapy (Pemetrexed/Cisplatin or Pemetrexed/Carboplatin) (N=136) All Grades No grade 4 events were reported. (%) Grade 3/4 (%) All Grades (%) Grade 3/4 (%) Gastrointestinal Disorders Diarrhea 41 1.1 11 1.5 Nausea 16 0.7 49 3.7 Stomatitis Includes stomatitis and mouth ulceration. 19 0 15 1.5 Constipation 14 0 35 0 Vomiting 11 0.4 20 2.2 Skin Disorders Rash Includes rash, rash generalized, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pustular, erythema, folliculitis, acne, dermatitis, acneiform dermatitis, pustule. 34 0.7 6 0 Dry skin Includes dry skin, eczema, skin fissures, xerosis. 23 0 4.4 0 Nail toxicity Includes nail disorders, nail bed disorders, nail bed inflammation, nail bed tenderness, nail discoloration, nail disorder, nail dystrophy, nail infection, nail ridging, nail toxicity, onychalgia, onychoclasis, onycholysis, onychomadesis, paronychia. 22 0 1.5 0 Pruritus Includes pruritus, pruritus generalized, eyelid pruritus. 13 0 5 0 General Disorders and Administration Site Conditions Fatigue Includes fatigue, asthenia. 22 1.8 40 5.1 Metabolism and Nutrition Disorders Decreased appetite 18 1.1 36 2.9 Respiratory, Thoracic and Mediastinal Disorders Cough 17 0 14 0 Musculoskeletal and Connective Tissue Disorders Back pain 10 0.4 9 0.7 Clinically relevant adverse reactions in AURA3 in 500 msec. Table 13. Laboratory Abnormalities Worsening from Baseline in ≥20% of Patients in AURA3 Laboratory Abnormality NCI CTCAE v4.0 Each test incidence, except for hyperglycemia, is based on the number of patients who had both baseline and at least one on-study laboratory measurement available (TAGRISSO 279, Chemotherapy comparator 131). TAGRISSO (N=279) Chemotherapy (Pemetrexed/Cisplatin or Pemetrexed/Carboplatin) (N=131) All Grades (%) Grade 3 or Grade 4 (%) All Grades (%) Grade 3 or Grade 4 (%) Hematology Anemia 43 0 79 3.1 Lymphopenia 63 8 61 10 Thrombocytopenia 46 0.7 48 7 Neutropenia 27 2.2 49 12 Chemistry Hypermagnesemia 27 1.8 9 1.5 Hyponatremia 26 2.2 36 1.5 Hyperglycemia Hyperglycemia is based on the number of patients who had both baseline and at least one on-study laboratory measurement available (TAGRISSO 270, Chemotherapy 5; fasting glucose was not a protocol requirement for patients in the chemotherapy arm). 20 0 NA NA Hypokalemia 9 1.4 18 1.5 NA=not applicable Clinically relevant laboratory abnormalities in AURA3 that occurred in <20% of patients receiving TAGRISSO included increased blood creatinine (7%). Other Clinical Trials Experience The following adverse reaction has been reported following administration of TAGRISSO: increased blood creatine phosphokinase. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of TAGRISSO. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. o Skin and subcutaneous tissue: Erythema multiforme major (EMM), Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), cutaneous vasculitis, erythema dyschromicum perstans o Blood and lymphatic system disorders: Aplastic anemia.

8 USE IN SPECIFIC POPULATIONS Lactation: Do not breastfeed. (8.2 ) 8.1 Pregnancy Risk Summary Based on data from animal studies and its mechanism of action [see Clinical Pharmacology (12.1) ] , TAGRISSO can cause fetal harm when administered to a pregnant woman. There are no available data on TAGRISSO use in pregnant women. Administration of osimertinib to pregnant rats was associated with embryolethality and reduced fetal growth at plasma exposures 1.5 times the exposure at the recommended clinical dose (see Data ) . Advise pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data When administered to pregnant rats prior to embryonic implantation through the end of organogenesis (gestation days 2-20) at a dose of 20 mg/kg/day, which produced plasma exposures of approximately 1.5 times the clinical exposure, osimertinib caused post-implantation loss and early embryonic death. When administered to pregnant rats from implantation through the closure of the hard palate (gestation days 6 to 16) at doses of 1 mg/kg/day and above (0.1 times the AUC observed at the recommended clinical dose of 80 mg once daily), an equivocal increase in the rate of fetal malformations and variations was observed in treated litters relative to those of concurrent controls. When administered to pregnant dams at doses of 30 mg/kg/day during organogenesis through lactation Day 6, osimertinib caused an increase in total litter loss and postnatal death. At a dose of 20 mg/kg/day, osimertinib administration during the same period resulted in increased postnatal death as well as a slight reduction in mean pup weight at birth that increased in magnitude between lactation days 4 and 6. 8.2 Lactation Risk Summary There are no data on the presence of osimertinib or its active metabolites in human milk, the effects of osimertinib on the breastfed infant or on milk production. Administration to rats during gestation and early lactation was associated with adverse effects, including reduced growth rates and neonatal death [see Use in Specific Populations (8.1) ] . Because of the potential for serious adverse reactions in breastfed infants from osimertinib, advise women not to breastfeed during treatment with TAGRISSO and for 2 weeks after the last dose. 8.3 Females and Males of Reproductive Potential Based on animal data, TAGRISSO can cause malformations, embryo lethality, and postnatal death at doses resulting in exposures 1.5 times or less the human exposure at the clinical dose of 80 mg daily [see Use in Specific Populations (8.1) ]. Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to initiating TAGRISSO. Contraception Females Advise females of reproductive potential to use effective contraception during treatment with TAGRISSO and for 6 weeks after the last dose [see Use in Specific Populations (8.1) ] . Males Advise male patients with female partners of reproductive potential to use effective contraception during and for 4 months following the last dose of TAGRISSO [see Nonclinical Toxicology (13.1) ] . Infertility Based on animal studies, TAGRISSO may impair fertility in females and males of reproductive potential. The effects on female fertility showed a trend toward reversibility. It is not known whether the effects on male fertility are reversible [see Nonclinical Toxicology (13.1) ] . 8.4 Pediatric Use The safety and effectiveness of TAGRISSO in pediatric patients have not been established. 8.5 Geriatric Use Monotherapy Of the 1813 patients with EGFR exon 19 deletion or exon 21 L858R mutation-positive NSCLC who were treated with TAGRISSO monotherapy, 770 patients were ≥65 years and 207 patients were ≥75 years of age [see Adverse Reactions (6.1) ] . Exploratory analysis suggests a higher incidence of Grade 3 or higher adverse reactions (43% vs 33%) and more frequent dosage modifications for adverse reactions (34% vs 23%) in patients 65 years or older as compared to those younger than 65 years. No overall differences in safety or effectiveness were observed between patients 65 years or older and younger patients. TAGRISSO Following Definitive Platinum-based Chemoradiation Therapy Of the 142 patients with EGFR exon 19 deletion or exon 21 L858R mutation-positive, locally advanced unresectable (Stage III) NSCLC treated with TAGRISSO following definitive platinum-based chemoradiation therapy, 62 patients were ≥65 years and 13 patients were ≥75 years of age [see Adverse Reactions (6.1)]. No overall differences in safety or effectiveness were observed between patients 65 years or older and younger patients. TAGRISSO in Combination with Pemetrexed and Platinum-based Chemotherapy Of the 276 patients with EGFR exon 19 deletion or exon 21 L858R mutation-positive, locally advanced or metastatic NSCLC treated with TAGRISSO in combination with pemetrexed and platinum-based chemotherapy, 104 patients were ≥65 years and 23 patients were ≥75 years of age [see Adverse Reactions (6.1) ] . Exploratory analysis suggests a higher incidence of Grade 3 or higher adverse reactions (68% vs 61%) and more frequent dosage modifications for adverse reactions (55% vs 43%) in patients 65 years or older as compared to those younger than 65 years. Clinical studies of TAGRISSO in combination with pemetrexed and platinum-based chemotherapy did not include sufficient numbers of patients age 65 and over to determine whether they respond differently from younger patients. 8.6 Renal Impairment No dose adjustment is recommended in patients with creatinine clearance (CLcr) 15 – 89 mL/min, as estimated by Cockcroft-Gault. There is no recommended dose of TAGRISSO for patients with end-stage renal disease (CLcr ULN or total bilirubin 1 to 3 times ULN and any AST). There is no recommended dose for TAGRISSO for patients with severe hepatic impairment (total bilirubin between 3 to 10 times ULN and any AST) [see Clinical Pharmacology (12.3) ] .

8.1 Pregnancy Risk Summary Based on data from animal studies and its mechanism of action [see Clinical Pharmacology (12.1) ] , TAGRISSO can cause fetal harm when administered to a pregnant woman. There are no available data on TAGRISSO use in pregnant women. Administration of osimertinib to pregnant rats was associated with embryolethality and reduced fetal growth at plasma exposures 1.5 times the exposure at the recommended clinical dose (see Data ) . Advise pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data When administered to pregnant rats prior to embryonic implantation through the end of organogenesis (gestation days 2-20) at a dose of 20 mg/kg/day, which produced plasma exposures of approximately 1.5 times the clinical exposure, osimertinib caused post-implantation loss and early embryonic death. When administered to pregnant rats from implantation through the closure of the hard palate (gestation days 6 to 16) at doses of 1 mg/kg/day and above (0.1 times the AUC observed at the recommended clinical dose of 80 mg once daily), an equivocal increase in the rate of fetal malformations and variations was observed in treated litters relative to those of concurrent controls. When administered to pregnant dams at doses of 30 mg/kg/day during organogenesis through lactation Day 6, osimertinib caused an increase in total litter loss and postnatal death. At a dose of 20 mg/kg/day, osimertinib administration during the same period resulted in increased postnatal death as well as a slight reduction in mean pup weight at birth that increased in magnitude between lactation days 4 and 6.