TAGRISSO

Osimertinib is a kinase inhibitor for oral use.

The molecular formula for osimertinib mesylate is C 28 H 33 N 7 O 2 •CH 4 O 3 S, and the molecular weight is 596 g/mol.

The chemical name is

N-(2-{2-dimethylaminoethyl-methylamino}-4-methoxy-5-{[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamide mesylate salt.

Osimertinib has the following structural formula (as osimertinib mesylate): TAGRISSO tablets contain 40 or 80 mg of osimertinib, equivalent to 47.7 and 95.4 mg of osimertinib mesylate, respectively.

Inactive ingredients in the tablet core are mannitol, microcrystalline cellulose, low-substituted hydroxypropyl cellulose and sodium stearyl fumarate.

The tablet coating consists of polyvinyl alcohol, titanium dioxide, macrogol 3350, talc, ferric oxide yellow, ferric oxide red and ferric oxide black. chem_structure.

• 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.

• 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.

• 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.

• 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.

• 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. 1.1 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. 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. 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. 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. 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.

Osimertinib is a kinase inhibitor of the epidermal growth factor receptor (EGFR), which binds irreversibly to certain mutant forms of EGFR (T790M, L858R, and exon 19 deletions) at approximately 9-fold lower concentrations than wild-type.

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.

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.

Osimertinib distributed to the brain in multiple animal species (monkey, rat, and mouse) with brain to plasma AUC ratios of approximately 2 following oral dosing.

These data are consistent with observations of tumor regression and increased survival in osimertinib.

• versus control-treated animals in a pre-clinical mutant-EGFR intracranial mouse metastasis xenograft model (PC9; exon 19 deletion). 12.2 Pharmacodynamics Based on an analysis of dose-exposure response relationships over the dose range of 20 mg (0.25 times the recommended dose) to 240 mg (3 times the recommended dose), no apparent relationship between osimertinib exposure and overall response rate, duration of response and progression-free survival was identified; however, there were limited data available at the 20 mg dose.

Over the same dose range, increased exposure led to increased probability of adverse reactions, specifically rash, diarrhea and ILD.

QTc interval prolongation potential of osimertinib was assessed in 210 patients who received TAGRISSO 80 mg daily in AURA2.

A central tendency analysis of the

QTcF data at steady-state demonstrated that the maximum mean change from baseline was 16.2 msec (upper bound of two-sided 90% confidence interval (CI) 17.6 msec).

A pharmacokinetic/pharmacodynamic analysis in AURA2 suggested a concentration-dependent QTc interval prolongation of 14 msec (upper bound of two-sided 90% CI: 16 msec) at a dose of TAGRISSO 80 mg. 12.3 Pharmacokinetics The area under the plasma concentration-time curve (AUC) and maximal plasma concentration (C max ) of osimertinib increased dose proportionally over 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

TAGRISSO orally once daily resulted in approximately 3-fold accumulation with steady-state exposures achieved after 15 days of dosing.

At steady state, the C max to C min (minimal concentration) ratio was 1.6-fold.

The pharmacokinetics in patients treated with osimertinib in combination with pemetrexed and platinum-based chemotherapy are similar to those in patients treated with osimertinib monotherapy.

Absorption The median time to

C max of osimertinib was 6 hours (range 3-24 hours).

Following administration of a 20 mg TAGRISSO tablet with a high-fat, high-calorie meal (containing approximately 58 grams of fat and 1000 calories), the C max and AUC of osimertinib were comparable to that under fasting conditions.

The mean volume of distribution at steady-state (V ss /F) of osimertinib was 918 L. Plasma protein binding of osimertinib was 95%.

PET brain imaging studies in healthy volunteers and in patients with brain metastases show that osimertinib is distributed to the brain following intravenous injection of a micro dose of 11 C-labeled osimertinib.

Osimertinib plasma concentrations decreased with time and a population estimated mean half-life of osimertinib was 48 hours, and oral clearance (CL/F) was 14.3 (L/h).

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 TAGRISSO oral administration.

The geometric mean exposure (AUC) of each metabolite (AZ5104 and AZ7550) was approximately 10% of the exposure of osimertinib at steady-state.

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.

No clinically significant differences in the pharmacokinetics of osimertinib were observed based on age, sex, ethnicity, body weight, baseline albumin, line of therapy, smoking status, renal function (creatinine clearance (CLcr) ≥15 mL/min by Cockcroft-Gault), or hepatic impairment (Child-Pugh A and B, or total bilirubin ≤ ULN and AST > ULN or total bilirubin between to 3 times ULN and any AST).

The pharmacokinetics of osimertinib in patients with end-stage renal disease (CLcr <15 mL/min) or severe hepatic impairment (total bilirubin to 10 times ULN and any AST) are unknown.

Drug Interaction Studies Effect of Other Drugs on TAGRISSO in Clinical Pharmacokinetic Studies Strong CYP3A Inducers: The steady-state AUC of osimertinib was reduced by 78% in patients when co-administered with rifampin (600 mg daily for 21 days) .

CYP3A Inhibitors: Co-administering TAGRISSO with 200 mg itraconazole twice daily (a strong CYP3A4 inhibitor) had no clinically significant effect on the exposure of osimertinib (AUC increased by 24% and C max decreased by 20%).

The exposure of osimertinib was not affected by concurrent administration of a single 80 mg TAGRISSO tablet following 40 mg omeprazole administration for 5 days.

Effect of Osimertinib on Other Drugs in Clinical Pharmacokinetic Studies BCRP substrates: Co-administering TAGRISSO with rosuvastatin (a BCRP substrate) increased rosuvastatin AUC by 35% and C max by 72% .

P-gp substrates

Co-administering TAGRISSO with fexofenadine (a P-gp substrate) increased fexofenadine AUC and C max by 56% and 76% after a single dose and 27% and 25% at steady state, respectively.

CYP3A4 substrates: Co-administering TAGRISSO with simvastatin (a CYP3A4 substrate) had no clinically significant effect on the exposure of simvastatin.

CYP450 Metabolic Pathways: Osimertinib does not inhibit CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6 and 2E1.

Osimertinib induced

CYP1A2 enzymes.

Osimertinib is a substrate of P-glycoprotein and BCRP and is not a substrate of OATP1B1 and OATP1B3.

Osimertinib is an inhibitor of BCRP and does not inhibit OAT1, OAT3, OATP1B1, OATP1B3, MATE1, MATE2K and OCT2.

• Erythema multiforme, Stevens-Johnson syndrome, and Toxic epidermal necrolysis.

• TAGRISSO monotherapy: leukopenia, lymphopenia, thrombocytopenia, anemia, diarrhea, rash, musculoskeletal pain, neutropenia, nail toxicity, dry skin, stomatitis, and fatigue.

• TAGRISSO monotherapy following platinum-based chemoradiation therapy: lymphopenia, leukopenia, ILD/pneumonitis, thrombocytopenia, neutropenia, rash, diarrhea, nail toxicity, musculoskeletal pain, cough and COVID-19.

• TAGRISSO in combination with pemetrexed and platinum-based chemotherapy: leukopenia, thrombocytopenia, neutropenia, lymphopenia, rash, diarrhea, stomatitis, nail toxicity, dry skin, and increased blood creatinine.

To report SUSPECTED ADVERSE

REACTIONS, contact AstraZeneca at 1-800-236-9933 or 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)] , 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.

• 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 and 5 summarize common adverse reactions and laboratory abnormalities which occurred in ADAURA.

Table 4.

Occurring in ≥10% of Patients Receiving TAGRISSO in ADAURA NCI CTCAE v4.0.

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 <10% of patients receiving TAGRISSO were alopecia (6%), epistaxis (6%), interstitial lung disease (3%), palmar-plantar erythrodysesthesia syndrome (1.8%), skin hyperpigmentation (1.8%), urticaria (1.5%), keratitis (0.6%), QTc interval prolongation (0.6%), and erythema multiforme (0.3%).

QTc interval prolongation represents the incidence of patients who had a QTcF prolongation >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 <20% of patients receiving TAGRISSO was increased blood creatinine (10%).

Advanced, Unresectable (Stage III) EGFR Mutation Positive NSCLC The safety of TAGRISSO was evaluated in LAURA, a double blind, randomized (2:1), placebo controlled study conducted in 216 patients with EGFR exon 19 deletions or exon 21 L858R mutation positive, locally advanced, unresectable (stage III) NSCLC, who had not progressed during or following definitive platinum based chemoradiation therapy.

Among patients who received

TAGRISSO, 81% were exposed for 6 months or longer and 74% were exposed for one year or longer.

Serious adverse reactions were reported in 38% of patients treated with TAGRISSO.

The most common serious adverse reactions (≥1%) included ILD/pneumonitis (13%), pneumonia (6%) and gastroenteritis (1.4%).

Fatal adverse reactions occurred in 1.4% of patients who received TAGRISSO due to pneumonia (0.7%) and ILD/pneumonitis (0.7%).

Permanent discontinuation of

TAGRISSO due to an adverse reaction occurred in 13% of patients.

The adverse reactions resulting in permanent discontinuation of TAGRISSO 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 and 7 summarize common adverse reactions and laboratory abnormalities which occurred in LAURA.

Table 6.

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 extremi.

Adjuvant treatment of early-stage

NSCLC: 80 mg orally once daily, with or without food, until disease recurrence, or unacceptable toxicity, or for up to 3 years.

Locally advanced, unresectable (stage III) NSCLC: Following platinum-based chemoradiation therapy, 80 mg orally once daily, with or without food, until disease progression or unacceptable toxicity.

NSCLC: 80 mg orally once daily, with or without food, until disease progression or unacceptable toxicity.

Locally advanced or metastatic

NSCLC: 80 mg orally once daily administered in combination with pemetrexed and platinum-based chemotherapy, with or without food, until disease progression or unacceptable toxicity due to TAGRISSO. 2.1 Recommended Evaluation and Testing Before Initiating TAGRISSO TAGRISSO Monotherapy.

• Before initiating TAGRISSO monotherapy in patients with cardiac risk factors, conduct cardiac monitoring, including assessment of left ventricular ejection fraction (LVEF) .

• Before initiating TAGRISSO, perform complete blood count with differential.

TAGRISSO in Combination with Pemetrexed and Platinum-based Chemotherapy.

• Before initiating TAGRISSO in combination with pemetrexed and platinum-based chemotherapy, conduct cardiac monitoring in all patients, including assessment of left ventricular ejection fraction (LVEF) .

• Before initiating TAGRISSO, perform complete blood count with differential. 2.2 Patient Selection Table 1 below presents the patient selection criteria for treatment with TAGRISSO.

Table 1: Patient Selection Select patients for treatment with TAGRISSO based on the presence of a mutation as detected by an FDA-approved test.

Indication Treatment Regimen Required Mutation Source for Testing Adjuvant Treatment of EGFR Mutation-Positive NSCLC TAGRISSO monotherapy EGFR exon 19 deletions or exon 21 L858R mutations Tumor Locally Advanced, Unresectable (Stage III) EGFR Mutation-Positive NSCLC Following completion of platinum-based chemoradiation therapy, TAGRISSO monotherapy EGFR exon 19 deletions or exon 21 L858R mutations Tumor First-line Treatment of EGFR Mutation-Positive Metastatic NSCLC TAGRISSO monotherapy EGFR exon 19 deletions or exon 21 L858R mutations Plasma or tumor First-line Treatment of EGFR Mutation-Positive Locally Advanced or Metastatic NSCLC TAGRISSO in combination with pemetrexed and platinum-based chemotherapy EGFR exon 19 deletions or exon 21 L858R mutations Plasma or tumor Previously Treated EGFR T790M Mutation-Positive Metastatic NSCLC TAGRISSO monotherapy EGFR T790M Mutation Plasma or tumor Information on FDA-approved tests for the detection of EGFR mutations is available at. 2.3 Recommended Dosage and Administration Recommended Dosage Table 2 provides the recommended dosage of TAGRISSO by indication.

Table 2: Recommended Dosage of TAGRISSO Indication Recommended Dosage of TAGRISSO Duration of Treatment Adjuvant Treatment of EGFR Mutation-Positive NSCLC 80 mg tablet orally once daily with or without food For a total of 3 years or until disease recurrence or unacceptable toxicity Locally Advanced, Unresectable (Stage III) EGFR Mutation-Positive NSCLC Following platinum-based chemoradiation therapy, 80 mg tablet orally once daily with or without food Until disease progression or unacceptable toxicity First-line Treatment of EGFR Mutation-Positive Metastatic NSCLC 80 mg tablet orally once daily with or without food Until disease progression or unacceptable toxicity First-line Treatment of EGFR Mutation-Positive Locally Advanced or Metastatic NSCLC 80 mg tablet orally once daily with or without food in combination with pemetrexed and platinum-based chemotherapy Refer to the Prescribing Information for pemetrexed and cisplatin or carboplatin for the respective dosing information.

Until disease progression or unacceptable toxicity due to TAGRISSO Previously Treated EGFR T790M Mutation-Positive Metastatic NSCLC 80 mg tablet orally once daily with or without food Until disease progression or unacceptable toxicity Administration Administer TAGRISSO 80 mg tablet orally once daily with or without food.

Tablets may be dispersed in water for patients who have difficulty swallowing, or for nasogastric tube administration.

Missed Dose If a dose of

TAGRISSO is missed, do not make up the missed dose and take the next dose as scheduled. 2.4 Administration to Patients Who Have Difficulty Swallowing Solids Disperse TAGRISSO tablet in 60 mL (2 ounces) of non-carbonated water only.

Stir until tablet is dispersed into small pieces (the tablet will not completely dissolve) and swallow immediately.

Do not crush, heat, or ultrasonicate during preparation.

Rinse the container with 120 mL to 240 mL (4 to 8 ounces) of water and immediately drink.

If administration via nasogastric tube is required, disperse the TAGRISSO tablet as above in 15 mL of non-carbonated water, and then use an additional 15 mL of water to transfer any residues to the syringe.

The resulting 30 mL liquid should be administered as per the nasogastric tube instructions with appropriate water flushes (approximately 30 mL).

Repeat this step until no pieces remain in the syringe.

This will help to ensure that the full prescribed dose of the TAGRISSO is given.

The dispersion and residues should be administered within 30 minutes of the addition of the tablets to water. 2.5 Dosage Modifications for Adverse Reactions The recommended dose reductions for adverse reactions are provided in Table 3.

Table 3.

Recommended Dosage Modifications for TAGRISSO Target Organ Adverse Reaction Adverse reactions graded by the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 (NCI CTCAE v5.0).

Pulmonary (Patients who have not received recent definitive platinum-based chemoradiation therapy) Any Grade Interstitial lung disease (ILD)/Pneumonitis Permanently discontinue TAGRISSO.

Pulmonary (Patients who have received recent definitive platinum-based chemoradiation therapy) Grade 1 ILD/Pneumonitis Withhold or continue TAGRISSO, as clinically indicated.

Grade ≥2 ILD/Pneumonitis Permanently discontinue TAGRISSO.

QTc = QT interval corrected for heart rate interval greater than 500 msec on at least 2 separate ECGs ECGs = Electrocardiograms Withhold TAGRISSO until QTc interval is less than 481 msec or recovery to baseline if baseline QTc is greater than or equal to 481 msec, then resume at 40 mg dose.

QTc interval prolongation with signs/symptoms of life-threatening arrhythmia Permanently discontinue TAGRISSO.

Symptomatic congestive heart failure Permanently discontinue

Major (EMM), Stevens-Johnson syndrome (SJS), and Toxic Epidermal Necrolysis (TEN) Withhold TAGRISSO if suspected and permanently discontinue if confirmed.

Blood and bone marrow Aplastic anemia Withhold TAGRISSO if aplastic anemia is suspected and permanently discontinue if confirmed.

Other Adverse reaction of

Grade 3 or greater severity Withhold TAGRISSO for up to 3 weeks.

If improvement to

Grade 0-2 within 3 weeks Resume at 80 mg or 40 mg daily.

If no improvement within 3 weeks Permanently discontinue TAGRISSO.

Dosage Modifications for Combination Therapy When

TAGRISSO is administered in combination with pemetrexed and platinum-based chemotherapy, modify the dose of any one of the treatments for the management of adverse reactions, as appropriate.

TAGRISSO dose modification instructions, see Table 3.

Withhold, reduce the dose or permanently discontinue pemetrexed, cisplatin or carboplatin according to their respective Prescribing Information.

CYP3A4 Inducers Avoid concomitant use of strong CYP3A4 inducers with TAGRISSO.

If concurrent use is unavoidable, increase TAGRISSO dosage to 160 mg daily when co-administering with a strong CYP3A inducer.

TAGRISSO at 80 mg 3 weeks after discontinuation of the strong CYP3A4 inducer.

mg tablets: beige, oval and biconvex tablet marked with “AZ 80” on one side and plain on the reverse and are available in bottles of 30 (NDC 0310-1350-30). 40 mg tablets: beige, round and biconvex tablet marked with “AZ 40” on one side and plain on the reverse and are available in bottles of 30 (NDC 0310-1349-30).

TAGRISSO bottles at 25°C (77°F).

Excursions permitted to 15-30°C (59-86°F) .

Based on data from animal studies and its mechanism of action, 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.

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.

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 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 and 6.

The safety and effectiveness of

TAGRISSO in pediatric patients have not been established.

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.

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.

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.

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 and over to determine whether they respond differently from younger patients.