KOSELUGO

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • Cardiomyopathy [see Warnings and Precautions (5.1) ] • Ocular toxicity [see Warnings and Precautions (5.2) ] • Gastrointestinal toxicity [see Warnings and Precautions (5.3) ] • Skin toxicity [see Warnings and Precautions (5.4) ] • Increased creatine phosphokinase [see Warnings and Precautions (5.5) ] Most common adverse reactions (≥ 40%) are: vomiting, rash (all), abdominal pain, diarrhea, nausea, dry skin, fatigue, musculoskeletal pain, pyrexia, acneiform rash, stomatitis, headache, paronychia, and pruritus. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca at 1-800-236-9933 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 reflects exposure to KOSELUGO in 74 pediatric patients who received a dosage ranging from 20 mg/m 2 to 30 mg/m 2 orally twice daily in SPRINT. Among these patients, the duration of KOSELUGO exposure, including dose interruptions, was 12 months or longer (91%), more than 2 years (74%), or more than 4 years (23%). The WARNINGS AND PRECAUTIONS also includes additional data from adult and pediatric patients who received KOSELUGO administered at various doses across a range of tumors in other clinical trials. Neurofibromatosis Type 1 (NF1) with Inoperable Plexiform Neurofibromas (PN) The safety of KOSELUGO was evaluated in SPRINT Phase II Stratum 1 [see Clinical Studies (14) ] . Eligible patients were 2-18 years of age with NF1 who had inoperable PN that was causing significant morbidity. Patients were excluded for abnormal LVEF, uncontrolled hypertension (blood pressure > the 95th percentile for age, height, and sex), any current or past history of RVO or RPED, intraocular pressure > 21 mmHg (or upper limit of normal adjusted by age), uncontrolled glaucoma, and inability to swallow whole capsules. Patients received KOSELUGO 25 mg/m 2 orally twice daily (n=50). Among these patients, 88% were exposed for 12 months or longer and 66% were exposed for greater than 2 years. Serious adverse reactions occurred in 24% of patients who received KOSELUGO. Serious adverse reactions that occurred in 2 or more patients were anemia, hypoxia and diarrhea. Permanent discontinuation due to an adverse reaction occurred in 12% of patients who received KOSELUGO. Adverse reactions resulting in permanent discontinuation of KOSELUGO included increased creatine, increased weight, diarrhea, paronychia, malignant peripheral nerve sheath tumor, acute kidney injury, and skin ulcer. Dosage interruptions and dose reductions due to adverse reactions occurred in 80% and 24% of patients who received KOSELUGO, respectively. Adverse reactions requiring a dosage interruption or reduction in ≥ 5% of patients were vomiting, paronychia, diarrhea, nausea, abdominal pain, rash, skin infection, influenza-like illness, pyrexia and weight gain. The most common adverse reactions (≥ 40%) were vomiting, rash (all), abdominal pain, diarrhea, nausea, dry skin, fatigue, musculoskeletal pain, pyrexia, acneiform rash, stomatitis, headache, paronychia, and pruritus. Table 6 presents the adverse reactions in SPRINT Phase II Stratum 1. Table 6 Adverse Reactions (≥ 20%) in Patients Who Received KOSELUGO in SPRINT Phase II Stratum 1 Adverse Reaction KOSELUGO N=50 All Grades (%) Grade ≥ 3 (%) * Gastrointestinal Vomiting 82 6 Abdominal pain Abdominal pain includes abdominal pain; abdominal pain upper 76 0 Diarrhea 70 16 Nausea 66 2 Stomatitis Stomatitis includes stomatitis; mouth ulceration 50 0 Constipation 34 0 Skin and Subcutaneous Tissue Rash (all) Rash (all) includes dermatitis acneiform; rash maculo-papular; erythema; rash pustular; rash; urticaria; exfoliative rash; rash pruritic; rash erythematous 80 6 Dry skin 60 0 Rash acneiform Rash (acneiform) includes dermatitis acneiform 50 4 Paronychia Paronychia includes paronychia; nail infection 48 6 Pruritus 46 0 Dermatitis Dermatitis includes dermatitis; dermatitis atopic; dermatitis diaper; eczema; seborrheic dermatitis; skin irritation 36 4 Hair changes Hair changes include alopecia; hair color change 32 0 Musculoskeletal and Connective Tissue Musculoskeletal pain Musculoskeletal pain includes pain in extremity; back pain; neck pain; musculoskeletal pain 58 0 General Fatigue Fatigue includes fatigue; malaise 56 0 Pyrexia 56 8 Edema Edema includes peripheral swelling; edema; localized edema 20 0 Nervous System Headache 48 2 Respiratory, Thoracic and Mediastinal Epistaxis 28 0 Renal and Urinary System Hematuria 22 2 Proteinuria 22 0 Metabolism and Nutrition Decreased appetite 22 0 Cardiac System Decreased ejection fraction 22 0 Sinus tachycardia 20 0 Infections Skin infection Skin infection includes skin infection; abscess; cellulitis; impetigo; staphylococcal skin infection 20 2 * All events were Grade 3. Clinically relevant adverse reactions that occurred < 20% of patients include: • Eye: visual impairment • Gastrointestinal Disorders: dry mouth • General Disorders: facial edema, including periorbital edema and face edema • Metabolism and Nutrition: increased weight • Renal and Urinary System: acute kidney injury • Respiratory, Thoracic & Mediastinal: dyspnea, including exertional dyspnea and dyspnea at rest • Vascular: hypertension Table 7 presents the laboratory abnormalities in SPRINT Phase II Stratum 1. Table 7 Select Laboratory Abnormalities (≥ 15%) Worsening from Baseline in Patients Who Received KOSELUGO in SPRINT Phase II Stratum 1 Laboratory Abnormality KOSELUGO All Grades (%) The denominator used to calculate the rate varied from 39 to 49 based on the number of patients with a baseline value and at least one post-treatment value. Grade ≥ 3 (%) Chemistry Increased creatine phosphokinase (CPK) 79 7 Includes one Grade 4 increased CPK and one Grade 4 increased potassium. Decreased albumin 51 0 Increased aspartate aminotransferase (AST) 41 2 Increased alanine aminotransferase (ALT) 35 4 Increased lipase 32 5 Increased potassium 27 4 Decreased potassium 18 2 § Increased alkaline phosphatase 18 0 Increased amylase 18 0 Increased sodium 18 0 Decreased sodium 16 0 Hematology Decreased hemoglobin 41 4 Decreased neutrophils 33 4 Decreased lymphocytes 20 2

4 CONTRAINDICATIONS None. None. ( 4 )

11 DESCRIPTION Selumetinib is a kinase inhibitor. The chemical name is 5-[(4-bromo-2-chlorophenyl)amino]-4-fluoro-6-[(2-hydroxyethoxy)carbamoyl]-1-methyl-1 H -benzimidazol-3-ium hydrogen sulfate. The molecular formula for selumetinib sulfate is C 17 H 17 BrClFN 4 O 7 S and the relative molecular mass is 555.76 g/mol. Selumetinib sulfate has the following structural formula: Selumetinib sulfate is a white to yellow monomorphic crystalline powder that exhibits a pH dependent solubility. Selumetinib sulfate is freely soluble at pH < 1.5, sparingly soluble in the pH range at 1.5 to 3 and slightly soluble at pH > 3. Selumetinib sulfate has two ionizable functions with pKa values of 2.8 and 8.4. KOSELUGO (selumetinib) 10 mg capsules for oral use, contain 10 mg selumetinib (equivalent to 12.1 mg selumetinib sulfate) and the excipient, vitamin E polyethylene glycol succinate. The capsule shell contains hypromellose, carrageenan, potassium chloride, titanium dioxide, carnauba wax, and purified water. The capsule is imprinted with black ink that contains shellac, iron oxide black, propylene glycol and ammonium hydroxide. KOSELUGO (selumetinib) 25 mg capsules for oral use, contain 25 mg selumetinib (equivalent to 30.25 mg selumetinib sulfate) and the excipient, vitamin E polyethylene glycol succinate. The capsule shell contains hypromellose, carrageenan, potassium chloride, titanium dioxide, FD&C blue 2, ferric oxide yellow, purified water, carnauba wax, and/or corn starch. The capsule is imprinted with black ink that contains ferric oxide red, ferric oxide yellow, FD&C Blue 2 aluminum lake, carnauba wax, shellac, and glyceryl monooleate. structure

2 DOSAGE AND ADMINISTRATION • The recommended dosage is 25 mg/m 2 taken orally twice daily on an empty stomach. Do not consume food 2 hours before each dose or 1 hour after each dose. ( 2.1 ) • Reduce the recommended dosage to 20 mg/m 2 orally twice daily for patients with moderate hepatic impairment (Child-Pugh B). The recommended dosage for use in patients with severe hepatic impairment (Child-Pugh C) has not been established. ( 2.2 , 8.7 ) 2.1 Recommended Dosage The recommended dosage of KOSELUGO is 25 mg/m 2 orally twice daily (approximately every 12 hours) until disease progression or unacceptable toxicity. Take KOSELUGO on an empty stomach. Do not consume food 2 hours before each dose or 1 hour after each dose [see Clinical Pharmacology (12.3) ] . The recommended dose of KOSELUGO based on body surface area (BSA) is shown in Table 1. Table 1 Recommended Dosage Based on Body Surface Area Body Surface Area The recommended dosage for patients with a BSA less than 0.55 m 2 has not been established. Recommended Dosage 0.55 – 0.69 m 2 20 mg in the morning and 10 mg in the evening 0.70 – 0.89 m 2 20 mg twice daily 0.90 – 1.09 m 2 25 mg twice daily 1.10 – 1.29 m 2 30 mg twice daily 1.30 – 1.49 m 2 35 mg twice daily 1.50 – 1.69 m 2 40 mg twice daily 1.70 – 1.89 m 2 45 mg twice daily ≥ 1.90 m 2 50 mg twice daily Swallow KOSELUGO capsules whole with water. Do not chew, dissolve or open capsule. Do not administer to patients who are unable to swallow a whole capsule. Do not take a missed dose of KOSELUGO unless it is more than 6 hours until the next scheduled dose. If vomiting occurs after KOSELUGO administration, do not take an additional dose, but continue with the next scheduled dose. 2.2 Dosage Modifications for Adverse Reactions The recommended dose reductions for adverse reactions are provided in Table 2. Table 2 Recommended Dose Reductions for KOSELUGO for Adverse Reactions Body Surface Area First Dose Reduction (mg/dose) Second Dose Reduction Permanently discontinue KOSELUGO in patients unable to tolerate KOSELUGO after two dose reductions. (mg/dose) Morning Evening Morning Evening 0.55 – 0.69 m 2 10 10 10 mg once daily 0.70 – 0.89 m 2 20 10 10 10 0.90 – 1.09 m 2 25 10 10 10 1.10 – 1.29 m 2 25 20 20 10 1.30 – 1.49 m 2 25 25 25 10 1.50 – 1.69 m 2 30 30 25 20 1.70 – 1.89 m 2 35 30 25 20 ≥ 1.90 m 2 35 35 25 25 Dosage modifications for adverse reactions are in Table 3. Table 3 Recommended Dosage Modifications for KOSELUGO for Adverse Reactions Severity of Adverse Reaction Recommended Dosage Modifications for KOSELUGO Cardiomyopathy [see Warnings and Precautions (5.1) ] • Asymptomatic decrease in left ventricular ejection fraction (LVEF) of 10% or greater from baseline and less than lower level of normal Withhold until resolution. Resume at reduced dose. • Symptomatic decreased LVEF • Grade 3 or 4 decreased LVEF Permanently discontinue. Ocular Toxicity [see Warnings and Precautions (5.2) ] • Retinal Pigment Epithelial Detachment (RPED) Withhold until resolution. Resume at reduced dose. • Retinal vein occlusion (RVO) Permanently discontinue. Gastrointestinal Toxicity [see Warnings and Precautions (5.3) ] • Grade 3 Diarrhea Withhold until improved to Grade 0 or 1. Resume at same dose. Permanently discontinue if no improvement within 3 days. • Grade 4 Diarrhea Permanently discontinue. • Grade 3 or 4 Colitis Permanently discontinue. Skin Toxicity [see Warnings and Precautions (5.4) ] • Grade 3 or 4 Withhold until improvement. Resume at reduced dose. Increased Creatine Phosphokinase (CPK) [see Warnings and Precautions (5.5) ] • Grade 4 Increased CPK • Any Increased CPK and myalgia Withhold until improved to Grade 0 or 1. Resume at reduced dose. Permanently discontinue if no improvement within 3 weeks. • Rhabdomyolysis Permanently discontinue. Other Adverse Reactions [see Adverse Reactions (6.1)] • Intolerable Grade 2 • Grade 3 Withhold KOSELUGO until improved to Grade 0 or 1. Resume at reduced dose. • Grade 4 Withhold KOSELUGO until improved to Grade 0 or 1. Resume at reduced dose. Consider discontinuation. * Per National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03 2.3 Dosage Modifications for Hepatic Impairment Reduce the recommended dosage of KOSELUGO to 20 mg/m 2 orally twice daily in patients with moderate hepatic impairment (Child-Pugh B). The recommended dosage of KOSELUGO for use in patients with severe hepatic impairment (Child-Pugh C) has not been established [see Use in Specific Populations (8.7) ] . Table 4 Recommended Dosage of KOSELUGO for Moderate Hepatic Impairment Body Surface Area Moderate Hepatic Impairment (Child-Pugh B) (mg/dose) Morning Evening 0.55 – 0.69 m 2 10 10 0.70 – 0.89 m 2 20 10 0.90 – 1.09 m 2 20 20 1.10 – 1.29 m 2 25 25 1.30 – 1.49 m 2 30 25 1.50 – 1.69 m 2 35 30 1.70 – 1.89 m 2 35 35 ≥ 1.90 m 2 40 40 2.4 Dosage Modifications for Drug Interactions Strong or Moderate CYP3A4 Inhibitors or Fluconazole Avoid coadministration of strong or moderate CYP3A4 inhibitors or fluconazole with KOSELUGO. If coadministration with strong or moderate CYP3A4 inhibitors or fluconazole cannot be avoided, reduce the KOSELUGO dosage as recommended in Table 5. After discontinuation of the strong or moderate CYP3A4 inhibitor or fluconazole for 3 elimination half-lives, resume the KOSELUGO dose that was taken prior to initiating the inhibitor or fluconazole [see Drug Interactions (7.1) ] . Table 5 Recommended Dosage of KOSELUGO for Coadministration with Strong or Moderate CYP3A4 Inhibitors or Fluconazole Body Surface Area If the current dosage is 25 mg/m 2 twice daily, reduce to 20 mg/m 2 twice daily (mg/dose) If the current dosage is 20 mg/m 2 twice daily, reduce to 15 mg/m 2 twice daily (mg/dose) Morning Evening Morning Evening 0.55 – 0.69 m 2 10 10 10 mg once daily 0.70 – 0.89 m 2 20 10 10 10 0.90 – 1.09 m 2 20 20 20 10 1.10 – 1.29 m 2 25 25 25 10 1.30 – 1.49 m 2 30 25 25 20 1.50 – 1.69 m 2 35 30 25 25 1.70 – 1.89 m 2 35 35 30 25 ≥ 1.90 m 2 40 40 30 30

1 INDICATIONS AND USAGE KOSELUGO is indicated for the treatment of pediatric patients 2 years of age and older with neurofibromatosis type 1 (NF1) who have symptomatic, inoperable plexiform neurofibromas (PN). KOSELUGO is a kinase inhibitor indicated for the treatment of pediatric patients 2 years of age and older with neurofibromatosis type 1 (NF1) who have symptomatic, inoperable plexiform neurofibromas (PN). ( 1 )

10 OVERDOSAGE Dialysis is not helpful as KOSELUGO is highly protein bound and is extensively metabolized.

7 DRUG INTERACTIONS • Strong or Moderate CYP3A4 Inhibitors or Fluconazole : Avoid coadministration of strong or moderate CYP3A4 inhibitors or fluconazole with KOSELUGO. If coadministration with strong or moderate CYP3A4 inhibitors or fluconazole cannot be avoided, reduce the dose of KOSELUGO. ( 2.4 , 7.1 ) • Strong or Moderate CYP3A4 Inducers : Avoid concomitant use of strong and moderate CYP3A4 inducers. ( 7.1 ) 7.1 Effect of Other Drugs on KOSELUGO Strong or Moderate CYP3A4 Inhibitors or Fluconazole Clinical Impact • Concomitant use of KOSELUGO with a strong or moderate CYP3A4 inhibitor or fluconazole increased selumetinib plasma concentrations [see Clinical Pharmacology (12.3) ] , which may increase the risk of adverse reactions. Management • Avoid coadministration of strong or moderate CYP3A4 inhibitors or fluconazole with KOSELUGO. If coadministration with strong or moderate CYP3A4 inhibitors or fluconazole cannot be avoided, reduce KOSELUGO dosage [see Dosage and Administration (2.4) ]. Strong or Moderate CYP3A4 Inducers Clinical Impact • Concomitant use of KOSELUGO with a strong or moderate CYP3A4 inducer decreased selumetinib plasma concentrations [see Clinical Pharmacology (12.3) ] , which may reduce KOSELUGO efficacy. Management • Avoid concomitant use of strong or moderate CYP3A4 inducers with KOSELUGO. Vitamin E Clinical Impact • KOSELUGO contains vitamin E and daily vitamin E intake that exceeds the recommended or safe limits may increase the risk of bleeding. An increased risk of bleeding may occur in patients taking a vitamin-K antagonist or an anti-platelet agent with KOSELUGO. Management • Supplemental vitamin E is not recommended if daily vitamin E intake (including the amount of vitamin E in KOSELUGO and supplement) will exceed the recommended or safe limits. • Monitor for bleeding in patients coadministered a vitamin-K antagonist or an anti-platelet agent with KOSELUGO. Increase INR monitoring, as appropriate, in patients taking a vitamin-K antagonist [see Warnings and Precautions (5.3) ] .

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Selumetinib is an inhibitor of mitogen-activated protein kinase kinases 1 and 2 (MEK1/2). MEK1/2 proteins are upstream regulators of the extracellular signal-related kinase (ERK) pathway. Both MEK and ERK are critical components of the RAS-regulated RAF-MEK-ERK pathway, which is often activated in different types of cancers. In genetically modified mouse models of NF1 that generate neurofibromas that recapitulate the genotype and phenotype of human NF1, oral dosing of selumetinib inhibited ERK phosphorylation, and reduced neurofibroma numbers, volume, and proliferation. 12.2 Pharmacodynamics The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of KOSELUGO have not been fully characterized. Cardiac Electrophysiology At a dose 1.5-times the maximum recommended dose, KOSELUGO does not prolong the QT/QTc interval to any clinically relevant extent. 12.3 Pharmacokinetics At the recommended dosage of 25 mg/m 2 twice daily in pediatric patients (2 to ≤ 18 years old), the mean maximum plasma concentration (C max ) (coefficient of variation [CV%]) following the first dose and at steady state was 731 (62%) ng/mL and 798 (52%) ng/mL, respectively. The mean area under the plasma drug concentration curve (AUC 0-12h ) following the first dose was 2009 (35%) ng•h/mL and the AUC 0-6h at steady state was 1958 (41%) ng•h/mL. Selumetinib AUC and C max increases proportionally over a dose range from 20 mg/m 2 to 30 mg/m 2 (0.8- to 1.2-times the recommended dose). The accumulation was 1.1-fold following administration of KOSELUGO 25 mg/m 2 twice daily. Absorption The mean absolute oral bioavailability of selumetinib was 62% in healthy adults. The median time to peak plasma concentrations (T max ) at steady-state in pediatric patients was 1 to 1.5 hours. Effect of Food Mean C max and AUC of selumetinib decreased by 50% and 16%, respectively, following a high-fat meal (1000 calories, 50% fat) in healthy adults administered a single-dose of 75 mg (1.5-times the approved maximum recommended dosage). T max was delayed by approximately 1.5 hours following a high-fat meal. Selumetinib C max and AUC decreased by 60% and 38%, respectively, following a low-fat meal (400 calories, 25% fat) in healthy adults administered a single-dose of 50 mg. T max was delayed by approximately 0.9 hours following a low-fat meal. Distribution The mean apparent volume of distribution at steady state (V ss ) of selumetinib across a dose range of 20 mg/m 2 to 30 mg/m 2 (0.8- to 1.2-times the recommended dosage) ranged from 78 L to 171 L in pediatric patients. The plasma protein binding was 98.4% in humans in vitro. Selumetinib binds to serum albumin (96%) and α-1 acid glycoprotein (< 35%). Elimination In pediatric patients, selumetinib had an apparent oral clearance (CL/F) of 8.8 L/hr and a mean elimination half-life of approximately 6.2 hours following a dose of 25 mg/m 2 . Metabolism Selumetinib is primarily metabolized by CYP3A4 and to a lesser extent by CYP2C19, CYP1A2, CYP2C9, CYP2E1, and CYP3A5. Selumetinib also undergoes glucuronidation by UGT1A1 and UGT1A3. It is estimated that 56% of the observed intrinsic clearance of selumetinib could be attributed to CYP metabolism and about 29% attributed to direct glucuronidation by UGT enzymes in vitro. The active metabolite, N-desmethyl selumetinib, is generated by CYP2C19 and CYP1A2 with additional contribution by CYP2C9 and CYP2A6, and metabolized through the same routes as selumetinib. N-desmethyl selumetinib represents less than 10% of selumetinib levels in human plasma, but is approximately 3- to 5-times more potent than the parent compound, contributing to about 21% to 35% of the overall pharmacologic activity. Excretion After a single oral dose of radiolabeled selumetinib 75 mg (1.5-times the recommended dose) to healthy adults, 59% of the dose was recovered in feces (19% as unchanged) and 33% in urine (< 1% as parent). Specific Populations Racial or Ethnic Groups No clinically meaningful effect on the pharmacokinetics of selumetinib or N-desmethyl selumetinib were observed based on race (White, Asian, Black). Patients with Renal Impairment Following administration of a single dose of 50 mg, selumetinib exposures were similar in subjects with End Stage Renal Disease (CLcr < 15 mL/min) who required dialysis compared to subjects with normal renal function (CLcr ≥ 90 mL/min). Patients with Hepatic Impairment Following administration of a single-dose of selumetinib, dose normalized total AUC 0-INF decreased by 14% in subjects with mild hepatic impairment (Child-Pugh A), and increased by 59% in subjects with moderate hepatic impairment (Child-Pugh B) and by 57% in subjects with severe hepatic impairment (Child-Pugh class C) compared to subjects with normal hepatic function. Selumetinib unbound AUC 0-INF decreased by 31% in subjects with mild hepatic impairment (Child-Pugh A), and increased by 41% in subjects with moderate hepatic impairment (Child-Pugh B), and 3.2-fold in subjects with severe hepatic impairment (Child-Pugh C) compared to subjects with normal hepatic function. Drug Interaction Studies Clinical Studies and Model-Informed Approaches Effect of Strong or Moderate CYP3A4 Inhibitors : Concomitant use of itraconazole (strong CYP3A4 inhibitor) increased selumetinib AUC by 49% and C max by 19%. Concomitant use of erythromycin (moderate CYP3A4 inhibitor) is predicted to increase selumetinib AUC by 41% and C max by 23%. Effect of Fluconazole : Concomitant use of fluconazole (strong CYP2C19 inhibitor and moderate CYP3A4 inhibitor) increased selumetinib AUC by 53% and C max by 26%. Effect of Strong or Moderate CYP3A4 Inducers : Concomitant use of rifampicin (strong CYP3A4 inducer) decreased selumetinib AUC by 51% and C max by 26%. Concomitant use of efavirenz (moderate CYP3A4 inducer) is predicted to decrease selumetinib AUC by 38% and C max by 22%. In Vitro Studies CYP Enzymes : Selumetinib does not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, or CYP2E1. Selumetinib does not induce CYP3A4, CYP1A2, or CYP2B6. Transporter Systems : Selumetinib does not inhibit breast cancer resistance protein (BCRP), P-glycoprotein (P-gp), OATP1B1, OATP1B3, OCT2, OAT1, OAT3, MATE1, or MATE2K transporters. Selumetinib is a substrate of BCRP and P-gp transporters.

12.1 Mechanism of Action Selumetinib is an inhibitor of mitogen-activated protein kinase kinases 1 and 2 (MEK1/2). MEK1/2 proteins are upstream regulators of the extracellular signal-related kinase (ERK) pathway. Both MEK and ERK are critical components of the RAS-regulated RAF-MEK-ERK pathway, which is often activated in different types of cancers. In genetically modified mouse models of NF1 that generate neurofibromas that recapitulate the genotype and phenotype of human NF1, oral dosing of selumetinib inhibited ERK phosphorylation, and reduced neurofibroma numbers, volume, and proliferation.

12.2 Pharmacodynamics The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of KOSELUGO have not been fully characterized. Cardiac Electrophysiology At a dose 1.5-times the maximum recommended dose, KOSELUGO does not prolong the QT/QTc interval to any clinically relevant extent.

12.3 Pharmacokinetics At the recommended dosage of 25 mg/m 2 twice daily in pediatric patients (2 to ≤ 18 years old), the mean maximum plasma concentration (C max ) (coefficient of variation [CV%]) following the first dose and at steady state was 731 (62%) ng/mL and 798 (52%) ng/mL, respectively. The mean area under the plasma drug concentration curve (AUC 0-12h ) following the first dose was 2009 (35%) ng•h/mL and the AUC 0-6h at steady state was 1958 (41%) ng•h/mL. Selumetinib AUC and C max increases proportionally over a dose range from 20 mg/m 2 to 30 mg/m 2 (0.8- to 1.2-times the recommended dose). The accumulation was 1.1-fold following administration of KOSELUGO 25 mg/m 2 twice daily. Absorption The mean absolute oral bioavailability of selumetinib was 62% in healthy adults. The median time to peak plasma concentrations (T max ) at steady-state in pediatric patients was 1 to 1.5 hours. Effect of Food Mean C max and AUC of selumetinib decreased by 50% and 16%, respectively, following a high-fat meal (1000 calories, 50% fat) in healthy adults administered a single-dose of 75 mg (1.5-times the approved maximum recommended dosage). T max was delayed by approximately 1.5 hours following a high-fat meal. Selumetinib C max and AUC decreased by 60% and 38%, respectively, following a low-fat meal (400 calories, 25% fat) in healthy adults administered a single-dose of 50 mg. T max was delayed by approximately 0.9 hours following a low-fat meal. Distribution The mean apparent volume of distribution at steady state (V ss ) of selumetinib across a dose range of 20 mg/m 2 to 30 mg/m 2 (0.8- to 1.2-times the recommended dosage) ranged from 78 L to 171 L in pediatric patients. The plasma protein binding was 98.4% in humans in vitro. Selumetinib binds to serum albumin (96%) and α-1 acid glycoprotein (< 35%). Elimination In pediatric patients, selumetinib had an apparent oral clearance (CL/F) of 8.8 L/hr and a mean elimination half-life of approximately 6.2 hours following a dose of 25 mg/m 2 . Metabolism Selumetinib is primarily metabolized by CYP3A4 and to a lesser extent by CYP2C19, CYP1A2, CYP2C9, CYP2E1, and CYP3A5. Selumetinib also undergoes glucuronidation by UGT1A1 and UGT1A3. It is estimated that 56% of the observed intrinsic clearance of selumetinib could be attributed to CYP metabolism and about 29% attributed to direct glucuronidation by UGT enzymes in vitro. The active metabolite, N-desmethyl selumetinib, is generated by CYP2C19 and CYP1A2 with additional contribution by CYP2C9 and CYP2A6, and metabolized through the same routes as selumetinib. N-desmethyl selumetinib represents less than 10% of selumetinib levels in human plasma, but is approximately 3- to 5-times more potent than the parent compound, contributing to about 21% to 35% of the overall pharmacologic activity. Excretion After a single oral dose of radiolabeled selumetinib 75 mg (1.5-times the recommended dose) to healthy adults, 59% of the dose was recovered in feces (19% as unchanged) and 33% in urine (< 1% as parent). Specific Populations Racial or Ethnic Groups No clinically meaningful effect on the pharmacokinetics of selumetinib or N-desmethyl selumetinib were observed based on race (White, Asian, Black). Patients with Renal Impairment Following administration of a single dose of 50 mg, selumetinib exposures were similar in subjects with End Stage Renal Disease (CLcr < 15 mL/min) who required dialysis compared to subjects with normal renal function (CLcr ≥ 90 mL/min). Patients with Hepatic Impairment Following administration of a single-dose of selumetinib, dose normalized total AUC 0-INF decreased by 14% in subjects with mild hepatic impairment (Child-Pugh A), and increased by 59% in subjects with moderate hepatic impairment (Child-Pugh B) and by 57% in subjects with severe hepatic impairment (Child-Pugh class C) compared to subjects with normal hepatic function. Selumetinib unbound AUC 0-INF decreased by 31% in subjects with mild hepatic impairment (Child-Pugh A), and increased by 41% in subjects with moderate hepatic impairment (Child-Pugh B), and 3.2-fold in subjects with severe hepatic impairment (Child-Pugh C) compared to subjects with normal hepatic function. Drug Interaction Studies Clinical Studies and Model-Informed Approaches Effect of Strong or Moderate CYP3A4 Inhibitors : Concomitant use of itraconazole (strong CYP3A4 inhibitor) increased selumetinib AUC by 49% and C max by 19%. Concomitant use of erythromycin (moderate CYP3A4 inhibitor) is predicted to increase selumetinib AUC by 41% and C max by 23%. Effect of Fluconazole : Concomitant use of fluconazole (strong CYP2C19 inhibitor and moderate CYP3A4 inhibitor) increased selumetinib AUC by 53% and C max by 26%. Effect of Strong or Moderate CYP3A4 Inducers : Concomitant use of rifampicin (strong CYP3A4 inducer) decreased selumetinib AUC by 51% and C max by 26%. Concomitant use of efavirenz (moderate CYP3A4 inducer) is predicted to decrease selumetinib AUC by 38% and C max by 22%. In Vitro Studies CYP Enzymes : Selumetinib does not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, or CYP2E1. Selumetinib does not induce CYP3A4, CYP1A2, or CYP2B6. Transporter Systems : Selumetinib does not inhibit breast cancer resistance protein (BCRP), P-glycoprotein (P-gp), OATP1B1, OATP1B3, OCT2, OAT1, OAT3, MATE1, or MATE2K transporters. Selumetinib is a substrate of BCRP and P-gp transporters.

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3 DOSAGE FORMS AND STRENGTHS Capsules: • 10 mg: white to off-white, opaque, hard capsule sealed with a clear band and marked with “SEL 10” in black ink. • 25 mg: blue, opaque, hard capsule sealed with a clear band and marked with “SEL 25” in black ink. Capsules: 10 mg and 25 mg. ( 3 )

KOSELUGO SELUMETINIB SELUMETINIB SELUMETINIB TOCOPHERSOLAN HYPROMELLOSE, UNSPECIFIED CARRAGEENAN POTASSIUM CHLORIDE TITANIUM DIOXIDE SHELLAC ISOPROPYL ALCOHOL FERROSOFERRIC OXIDE BUTYL ALCOHOL PROPYLENE GLYCOL AMMONIA WATER SEL;10 KOSELUGO SELUMETINIB SELUMETINIB SELUMETINIB TOCOPHERSOLAN HYPROMELLOSE, UNSPECIFIED CARRAGEENAN POTASSIUM CHLORIDE FD&C BLUE NO. 2 FERRIC OXIDE YELLOW TITANIUM DIOXIDE FERRIC OXIDE RED CARNAUBA WAX SHELLAC 1-BUTANOL, 4-(ETHENYLOXY)- ALCOHOL WATER GLYCERYL OLEATE SEL;25

13.2 Animal Toxicology and/or Pharmacology In a 26-week repeat-dose toxicology study, selumetinib at a dose of 20 mg/kg (approximately 33-times the human exposure based on AUC at the clinical dose of 25 mg/m 2 twice daily) led to significant urinary tract obstruction as well as inflammation and luminal hemorrhage of the urethra leading to early death in male mice.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity Selumetinib was not carcinogenic in a 6-month study in rasH2 transgenic mice at exposures 24-times (males) and 36-times (females) and in 2-year carcinogenicity study in rats at exposures 20-times (male) and 15-times the human exposure (AUC) at the clinical dose of 25 mg/m 2 . Mutagenicity Selumetinib was not mutagenic or clastogenic in vitro . Selumetinib did result in an increase in micronucleated immature erythrocytes (chromosome aberrations) in mouse micronucleus studies, predominantly via an aneugenic mode of action, but at doses > 160 mg/kg (~38-times the human C max at the clinical dose of 25 mg/m 2 ). Impairment of Fertility In a 6-month mouse study, selumetinib did not affect male mating performance at any dose up to 20 mg/kg twice daily (approximately 33-times the human exposure based on AUC at the clinical dose of 25 mg/m 2 twice daily). In female mice exposed to selumetinib at 12.5 mg/kg twice daily, mating performance and fertility were not affected. The NOAEL for both maternal toxicity and effects on reproductive performance was 2.5 mg/kg twice daily (approximately 5-times the human exposure based on AUC at the clinical dose of 25 mg/m 2 twice daily).

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity Selumetinib was not carcinogenic in a 6-month study in rasH2 transgenic mice at exposures 24-times (males) and 36-times (females) and in 2-year carcinogenicity study in rats at exposures 20-times (male) and 15-times the human exposure (AUC) at the clinical dose of 25 mg/m 2 . Mutagenicity Selumetinib was not mutagenic or clastogenic in vitro . Selumetinib did result in an increase in micronucleated immature erythrocytes (chromosome aberrations) in mouse micronucleus studies, predominantly via an aneugenic mode of action, but at doses > 160 mg/kg (~38-times the human C max at the clinical dose of 25 mg/m 2 ). Impairment of Fertility In a 6-month mouse study, selumetinib did not affect male mating performance at any dose up to 20 mg/kg twice daily (approximately 33-times the human exposure based on AUC at the clinical dose of 25 mg/m 2 twice daily). In female mice exposed to selumetinib at 12.5 mg/kg twice daily, mating performance and fertility were not affected. The NOAEL for both maternal toxicity and effects on reproductive performance was 2.5 mg/kg twice daily (approximately 5-times the human exposure based on AUC at the clinical dose of 25 mg/m 2 twice daily). 13.2 Animal Toxicology and/or Pharmacology In a 26-week repeat-dose toxicology study, selumetinib at a dose of 20 mg/kg (approximately 33-times the human exposure based on AUC at the clinical dose of 25 mg/m 2 twice daily) led to significant urinary tract obstruction as well as inflammation and luminal hemorrhage of the urethra leading to early death in male mice.

NDA213756

KOSELUGO

SELUMETINIB

0310-0625

HUMAN PRESCRIPTION DRUG

ORAL

PACKAGE/LABEL PRINCIPAL DISPLAY PANEL 10mg NDC 0310-0610-28 Koselugo ® (selumetinib) capsules 10 mg Rx only Dispense in original bottle. Do not remove desiccant . Protect from moisture. Keep the bottle tightly closed. 28 Capsules AstraZeneca 10mg 28count

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Cardiomyopathy Advise patients and caregivers that KOSELUGO can cause a reduction in LVEF and to immediately report any signs or symptoms of cardiomyopathy to their healthcare provider [see Warnings and Precautions (5.1) ] . Ocular Toxicity Advise patients and caregivers that KOSELUGO can cause ocular toxicity that can lead to blindness and to contact their healthcare provider if the patient experiences any changes in their vision [see Warnings and Precautions (5.2) ] . Gastrointestinal Toxicity Advise patients and caregivers that KOSELUGO can cause diarrhea and to contact their healthcare provider at the onset of diarrhea [see Warnings and Precautions (5.3) ] . Skin Toxicity Advise patients and caregivers that KOSELUGO can cause serious skin toxicities and to contact their healthcare provider for severe skin changes [see Warnings and Precautions (5.4) ] . Increased Creatine Phosphokinase Advise patients and caregivers that KOSELUGO can cause increased CPK and to report any signs and symptoms of muscle pain or weakness to their healthcare provider [see Warnings and Precautions (5.5) ] . Increased Vitamin E Levels and Risk of Bleeding Advise patients and caregivers to notify their healthcare provider if they are taking a supplement containing vitamin E, a vitamin-K antagonist or an anti-platelet agent [see Warnings and Precautions (5.6) ] . Embryo-Fetal Toxicity • Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.7) , Use in Specific Populations (8.1) ]. • Advise females of reproductive potential to use effective contraception during treatment with KOSELUGO and for 1 week after the last dose [see Use in Specific Populations (8.3) ] . • Advise males with female partners of reproductive potential to use effective contraception during treatment with KOSELUGO and for at least 1 week after the last dose [see Use in Specific Populations (8.3) , Nonclinical Toxicology (13.1) ] . Lactation Advise women not to breastfeed during treatment with KOSELUGO and for 1 week after the last dose [see Use in Specific Populations (8.2) ] . Drug Interactions Advise patients and caregivers to inform their healthcare provider of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products. Inform patients to avoid St. John’s wort, grapefruit or grapefruit juice while taking KOSELUGO [see Drug Interactions (7) ] . Dosing and Administration Inform patients and caregivers on how to take KOSELUGO with food and what to do for missed or vomited doses [see Dosage and Administration (2.1) ] . Distributed by: AstraZeneca Pharmaceuticals LP Wilmington, DE 19850 © AstraZeneca 2021

14 CLINICAL STUDIES 14.1 Neurofibromatosis Type 1 (NF1) with Inoperable Plexiform Neurofibromas (PN) The efficacy of KOSELUGO was evaluated in SPRINT Phase II Stratum 1, an open-label, multicenter, single arm trial (NCT01362803). Eligible patients were required to have NF1 with inoperable PN, defined as a PN that could not be completely removed without risk for substantial morbidity due to encasement of, or close proximity to, vital structures, invasiveness, or high vascularity of the PN. Patients were also required to have significant morbidity related to the target PN. Morbidities that were present in ≥ 20% of patients included disfigurement, motor dysfunction, pain, airway dysfunction, visual impairment, and bladder/bowel dysfunction. Patients received KOSELUGO 25 mg/m 2 orally twice daily until disease progression or unacceptable toxicity. The major efficacy outcome measure was overall response rate (ORR), defined as the percentage of patients with complete response (defined as disappearance of the target PN) or confirmed partial response (defined as ≥ 20% reduction in PN volume confirmed at a subsequent tumor assessment within 3-6 months). The target PN, defined as the PN that caused relevant clinical symptoms or complications (PN-related morbidities), was evaluated for response rate using centrally read volumetric magnetic resonance imaging (MRI) analysis per Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) criteria. Tumor response was evaluated at baseline and while on treatment after every 4 cycles for 2 years, and then every 6 cycles. An additional efficacy outcome measure was duration of response (DoR). A total of 50 pediatric patients received KOSELUGO. The median age was 10.2 years (range 3.5 to 17.4 years); 60% were male; and 84% were White, 8% were Black and 2% were Asian. Efficacy results are provided in Table 8. The median time to onset of response was 7.2 months (range: 3.3 months to 1.6 years). Table 8 Efficacy Results from SPRINT Phase II Stratum 1 The ORR assessment was conducted by a single National Cancer Institute reviewer who was a SPRINT investigator and who evaluated all PN imaging from patients enrolled at all trial sites. Efficacy Parameter SPRINT N = 50 Overall Response Rate Responses required confirmation at least 3 months after the criteria for first response were met. Overall Response Rate, n (%) 33 (66%) 95% CI (51, 79) Complete Response Complete response: disappearance of the target lesion; Partial response: decrease in target PN volume by ≥ 20% compared to baseline. 0 Confirmed Partial Response, n (%) 33 (66%) Duration of Response DoR ≥ 12 months, n (%) 27 (82%) CI – confidence interval, DoR – duration of response. An independent centralized review of tumor response per REiNS criteria resulted in an ORR of 44% (95% CI: 30, 59).

8.5 Geriatric Use Clinical studies did not include patients 65 years of age and older.

8.4 Pediatric Use The safety and effectiveness have been established in pediatric patients 2 years of age and older with NF1 who have inoperable PN and the information on this use is discussed throughout the labeling. The safety and effectiveness of KOSELUGO have not been established in pediatric patients younger than 2 years of age. Animal Toxicity Data In 3-month general toxicology studies, male rats receiving selumetinib at doses ≥ 10 mg/kg daily (~60-times the human exposure based on AUC at the clinical dose of 25 mg/m 2 twice daily) showed growth plate dysplasia.

8.1 Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action [see Clinical Pharmacology (12.1) ] , KOSELUGO can cause fetal harm when administered to a pregnant woman. There are no available data on the use of KOSELUGO in pregnant women to evaluate drug-associated risk. In animal reproduction studies, administration of selumetinib to mice during organogenesis caused reduced fetal weight, adverse structural defects, and effects on embryofetal survival at exposures approximately > 5 times the human exposure at the clinical dose of 25 mg/m 2 twice daily ( see Data ). Advise pregnant women of the potential risk to the 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 In embryo-fetal development studies in mice at doses > 2.5 mg/kg twice daily (~5-times the human exposure based on area under the curve [AUC] at the clinical dose of 25 mg/m 2 twice daily), selumetinib caused increases in post-implantation loss, a reduction in mean fetal and litter weights, and an increased occurrence of open eye and cleft palate, but did not induce significant maternal toxicity. Administration of selumetinib to pregnant mice from gestation Day 6 through lactation Day 20 resulted in reduced pup body weights and fewer pups met the pupil constriction criterion on day 21 post-partum. The incidence of malformations (e.g., prematurely open eye(s) and cleft palate) was increased even at the lowest dose of 0.5 mg/kg twice daily (maternal maximal concentration [C max ] of ~0.6 times the human C max at the clinical dose of 25 mg/m 2 twice daily).

8 USE IN SPECIFIC POPULATIONS • Lactation: Advise not to breastfeed. (8.2) 8.1 Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action [see Clinical Pharmacology (12.1) ] , KOSELUGO can cause fetal harm when administered to a pregnant woman. There are no available data on the use of KOSELUGO in pregnant women to evaluate drug-associated risk. In animal reproduction studies, administration of selumetinib to mice during organogenesis caused reduced fetal weight, adverse structural defects, and effects on embryofetal survival at exposures approximately > 5 times the human exposure at the clinical dose of 25 mg/m 2 twice daily ( see Data ). Advise pregnant women of the potential risk to the 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 In embryo-fetal development studies in mice at doses > 2.5 mg/kg twice daily (~5-times the human exposure based on area under the curve [AUC] at the clinical dose of 25 mg/m 2 twice daily), selumetinib caused increases in post-implantation loss, a reduction in mean fetal and litter weights, and an increased occurrence of open eye and cleft palate, but did not induce significant maternal toxicity. Administration of selumetinib to pregnant mice from gestation Day 6 through lactation Day 20 resulted in reduced pup body weights and fewer pups met the pupil constriction criterion on day 21 post-partum. The incidence of malformations (e.g., prematurely open eye(s) and cleft palate) was increased even at the lowest dose of 0.5 mg/kg twice daily (maternal maximal concentration [C max ] of ~0.6 times the human C max at the clinical dose of 25 mg/m 2 twice daily). 8.2 Lactation Risk Summary There are no data on the presence of selumetinib or its active metabolite in human milk or their effects on the breastfed child or milk production. Selumetinib and its active metabolite were present in the milk of lactating mice ( see Data ). Due to the potential for adverse reactions in a breastfed child, advise women not to breastfeed during treatment with KOSELUGO and for 1 week after the last dose. Data Animal Data Selumetinib and its active metabolite were present in milk from mice dosed with selumetinib throughout gestation and lactation, with a mean plasma/milk ratio of 1.5 in lactating dams dosed at 5 mg/kg twice daily. Administration of selumetinib to dams during gestation and early lactation was associated with adverse events in pups, including reduced growth rates and incidence of malformations [see Use in Specific Populations (8.1) ]. 8.3 Females and Males of Reproductive Potential KOSELUGO can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1) ] . Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to initiating KOSELUGO [see Use in Specific Populations (8.1) ] . Contraception Females Advise females of reproductive potential to use effective contraception during treatment and for 1 week after the last dose. Males Advise male patients with female partners of reproductive potential to use effective contraception during treatment with KOSELUGO and for 1 week after the last dose. 8.4 Pediatric Use The safety and effectiveness have been established in pediatric patients 2 years of age and older with NF1 who have inoperable PN and the information on this use is discussed throughout the labeling. The safety and effectiveness of KOSELUGO have not been established in pediatric patients younger than 2 years of age. Animal Toxicity Data In 3-month general toxicology studies, male rats receiving selumetinib at doses ≥ 10 mg/kg daily (~60-times the human exposure based on AUC at the clinical dose of 25 mg/m 2 twice daily) showed growth plate dysplasia. 8.5 Geriatric Use Clinical studies did not include patients 65 years of age and older. 8.6 Renal Impairment No dose adjustment is recommended in patients with renal impairment or those with End Stage Renal Disease [see Clinical Pharmacology (12.3) ]. 8.7 Hepatic Impairment Selumetinib exposures increased in patients with moderate or severe hepatic impairment [see Clinical Pharmacology (12.3) ] . Reduce the dose of KOSELUGO for patients with moderate hepatic impairment (Child-Pugh B). A recommended dosage of KOSELUGO for use in patients with severe hepatic impairment (Child-Pugh C) has not been established [see Dosage and Administration (2.3) ] .

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied Strength Description Capsules per Bottle NDC Number 10 mg White to off-white, opaque, hard capsule sealed with a clear band and marked with “SEL 10” in black ink. 60 0310-0610-60 28 0310-0610-28 25 mg Blue, opaque, hard capsule sealed with a clear band and marked with “SEL 25” in black ink. 60 0310-0625-60 28 0310-0625-28 Storage Store at 20°C to 25°C (68°F to 77°F) with excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Dispense in original bottle. Keep the bottle tightly closed. Do not remove desiccant. Protect from moisture.