Koselugo

Description for Koselugo

KOSELUGO contains selumetinib sulfate, a kinase inhibitor. The chemical name is 5-[(4-bromo-2-chlorophenyl)amino]- 4-fluoro-6-[(2-hydroxyethoxy)carbamoyl]-1-methyl-1H-benzimidazol-3-ium hydrogen sulfate. The molecular formula for selumetinib sulfate is C₁₇H₁₇BrClFN₄O₇S 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 carnauba wax, carrageenan, hypromellose, potassium chloride, purified water, and titanium dioxide. The capsule is imprinted with black ink that contains ammonium hydroxide, iron oxide black, propylene glycol, and shellac.

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 carnauba wax and/or cornstarch, carrageenan, FD&C blue 2, ferric oxide yellow, hypromellose, potassium chloride, purified water, and titanium dioxide. The capsule is imprinted with black ink that contains carnauba wax, FD&C Blue 2 aluminum lake, ferric oxide red, ferric oxide yellow, glyceryl monooleate, and shellac.

KOSELUGO (selumetinib) 5 mg oral granules contain 5 mg selumetinib (equivalent to 6.05 mg selumetinib sulfate). The uncoated cores contain selumetinib sulfate, glyceryl dibehenate, and stearoyl polyoxylglycerides. The granule coating contains acetone, hypromellose acetate succinate, and stearic acid. The capsule shell contains ferric oxide yellow, hypromellose, and titanium dioxide. The capsule shell is imprinted with black ink that contains butyl alcohol, dehydrated alcohol, ferric oxide black, isopropyl alcohol, potassium hydroxide, propylene glycol, purified water, shellac, and strong ammonia solution.

KOSELUGO (selumetinib) 7.5 mg oral granules contain 7.5 mg selumetinib (equivalent to 9.08 mg selumetinib sulfate). The uncoated cores contain selumetinib sulfate, glyceryl dibehenate, and stearoyl polyoxylglycerides. The granule coating contains acetone, hypromellose acetate succinate, and stearic acid. The capsule shell contains ferric oxide red, hypromellose, and titanium dioxide. The capsule shell is imprinted with black ink that contains butyl alcohol, dehydrated alcohol, ferric oxide black, isopropyl alcohol, potassium hydroxide, propylene glycol, purified water, shellac, and strong ammonia solution.

INDICATIONS AND USAGE

KOSELUGO is indicated for the treatment of pediatric patients 1 year of age and older with neurofibromatosis type 1 (NF1) who have symptomatic, inoperable plexiform neurofibromas (PN) [see Dosage and Administration (2)].

Dosage for Koselugo

Recommended Dosage

The recommended dosage of KOSELUGO capsules (see Table 1) and KOSELUGO oral granules (see Table 2) for pediatric patients 1 year of age and older, based on body surface area, is 25 mg/m² orally twice daily, until disease progression or unacceptable toxicity [see Dosage and Administration (2.2)].

Table 1 Recommended Dosage: KOSELUGO Capsules

Body Surface Area*	KOSELUGO Capsules
0.55 – 0.69 m2	20 mg in the morning and 10 mg in the evening
0.70 – 0.89 m2	20 mg twice daily
0.90 – 1.09 m2	25 mg twice daily
1.10 – 1.29 m2	30 mg twice daily
1.30 – 1.49 m2	35 mg twice daily
1.50 – 1.69 m2	40 mg twice daily
1.70 – 1.89 m2	45 mg twice daily
≥ 1.90 m2	50 mg twice daily
* The recommended dosage of KOSELUGO capsules for patients with a BSA less than 0.55 m2 has not been established.

Table 2 Recommended Dosage: KOSELUGO Oral Granules

Body Surface Area*	KOSELUGO Oral Granules
0.40 – 0.59 m2	12.5 mg twice daily
0.60 – 0.69 m2	15 mg twice daily
0.70 – 0.89 m2	20 mg twice daily
0.90 – 1.09 m2	25 mg twice daily
1.10 – 1.29 m2	30 mg twice daily
1.30 – 1.49 m2	35 mg twice daily
1.50 – 1.69 m2	40 mg twice daily
1.70 – 1.89 m2	45 mg twice daily
≥ 1.90 m2	50 mg twice daily
* The recommended dosage of KOSELUGO oral granules for patients with a BSA less than 0.40 m2 has not been established.

Administration

KOSELUGO is available in two dosage forms: KOSELUGO capsules and KOSELUGO oral granules. Prescribe KOSELUGO oral granules for patients who have difficulty swallowing whole capsules.

KOSELUGO Capsules

• Administer KOSELUGO capsules to patients who can swallow a whole capsule.
• Swallow KOSELUGO capsules whole. Do not open, chew or crush KOSELUGO capsules.
• KOSELUGO capsules may be administered with or without food.

KOSELUGO Oral Granules

• Administer KOSELUGO oral granules to patients who have difficulty swallowing a whole capsule.
• Sprinkle KOSELUGO oral granules on or mix with a small amount (about 1 to 3 teaspoons) of smooth yogurt, or fruit puree containing the following fruits: apple, banana, pear, or strawberry and consume within 30 minutes of preparation. If not consumed within 30 minutes of preparation, discard and prepare a new dose. If a dose has been partially consumed within 30 minutes of preparation, discard remainder of the dose and do not prepare a new dose, aim to complete dosing within 30 minutes next time.
• The KOSELUGO oral granules should be free-flowing. Do NOT use if the oral granules are clumped or stuck inside the capsule shell. Instruct the patient or caregiver to contact their pharmacy if this happens.
• Discard the empty capsule shells after use.
• Do NOT swallow, chew, or dissolve the capsule shells of KOSELUGO oral granules.
• Do NOT chew or crush the KOSELUGO oral Do NOT add oral granules to liquids.
• Do NOT mix KOSELUGO oral granules in grapefruit or any juice, fruit puree or jam containing Seville orange.

Missed Dose

If a dose of KOSELUGO capsules or KOSELUGO oral granules is missed, make up that dose unless the next dose is due within 6 hours.

Vomiting

If vomiting occurs after taking a dose of KOSELUGO capsules or KOSELUGO oral granules, do not take an additional dose. Take the next dose at the regular scheduled time.

Dosage Modifications for Adverse Reactions

The recommended dose reductions for adverse reactions for KOSELUGO capsules and KOSELUGO oral granules are provided in Tables 3 and 4, respectively.

Table 3 Recommended Dose Reductions for KOSELUGO Capsules for Adverse Reactions

Body Surface Area	First Dose Reduction (mg/dose)		Second Dose Reduction (mg/dose)
	Morning	Evening	Morning	Evening
0.55 – 0.69 m2	10	10	10 mg once daily
0.70 – 0.89 m2	20	10	10	10
0.90 – 1.09 m2	25	10	10	10
1.10 – 1.29 m2	25	20	20	10
1.30 – 1.49 m2	25	25	25	10
1.50 – 1.69 m2	30	30	25	20
1.70 – 1.89 m2	35	30	25	20
≥ 1.90 m2	35	35	25	25
Permanently discontinue KOSELUGO capsules in patients unable to tolerate two dose reductions.

Table 4 Recommended Dose Reductions for KOSELUGO Oral Granules for Adverse Reactions

Body Surface Area	First Dose Reduction (mg/dose)		Second Dose Reduction (mg/dose)
	Morning	Evening	Morning	Evening
0.40 – 0.59 m2	10	10	7.5	7.5
0.60 – 0.69 m2	12.5	12.5	10	10
0.70 – 0.89 m2	15	15	12.5	12.5
0.90 – 1.09 m2	20	20	15	15
1.10 – 1.29 m2	22.5	22.5	15	15
1.30 – 1.49 m2	25	25	25	10
1.50 – 1.69 m2	30	30	25	20
1.70 – 1.89 m2	35	30	25	20
≥ 1.90 m2	35	35	25	25
Permanently discontinue KOSELUGO oral granules in patients unable to tolerate two dose reductions.

The recommended dosage modifications of KOSELUGO capsules and KOSELUGO oral granules for adverse reactions are provided in Table 5.

Table 5 Recommended Dosage Modifications for Adverse Reactions

Severity of Adverse Reaction	Recommended Dosage Modifications for KOSELUGO capsules and KOSELUGO oral granules
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

Dosage Modifications for Hepatic Impairment

Severe Hepatic Impairment

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)].

Moderate Hepatic Impairment

The recommended dosage of KOSELUGO capsules (see Table 6) and KOSELUGO oral granules (see Table 7) for pediatric patients 1 year of age or older with moderate hepatic impairment (Child-Pugh B) is based on body surface area; 20 mg/m² orally twice daily, until disease progression or unacceptable toxicity [see Dosage and Administration (2.2)].

Table 6 Recommended Dosage of KOSELUGO Capsules for Moderate Hepatic Impairment

Body Surface Area	Moderate Hepatic Impairment (Child-Pugh B) (mg/dose)
	Morning	Evening
0.55 – 0.69 m2	10	10
0.70 – 0.89 m2	20	10
0.90 – 1.09 m2	20	20
1.10 – 1.29 m2	25	25
1.30 – 1.49 m2	30	25
1.50 – 1.69 m2	35	30
1.70 – 1.89 m2	35	35
≥ 1.90 m2	40	40

Table 7 Recommended Dosage of KOSELUGO Oral Granules for Moderate Hepatic Impairment

Body Surface Area	Moderate Hepatic Impairment (Child-Pugh B) (mg/dose)
	Morning	Evening
0.40 – 0.59 m2	10	10
0.60 – 0.69 m2	12.5	12.5
0.70 – 0.89 m2	15	15
0.90 – 1.09 m2	20	20
1.10 – 1.29 m2	25	25
1.30 – 1.49 m2	30	25
1.50 – 1.69 m2	35	30
1.70 – 1.89 m2	35	35
≥ 1.90 m2	40	40

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 8 (KOSELUGO capsules) and Table 9 (KOSELUGO oral granules). 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 8 Recommended Dosage of KOSELUGO Capsules for Coadministration with Strong or
Moderate CYP3A4 Inhibitors or Fluconazole

Body Surface Area	If the current dosage is 25 mg/m2 twice daily, reduce to 20 mg/m2 twice daily (mg/dose)		If the current dosage is 20 mg/m2 twice daily, reduce to 15 mg/m2 twice daily (mg/dose)
	Morning	Evening	Morning	Evening
0.55 – 0.69 m2	10	10	10 mg once daily
0.70 – 0.89 m2	20	10	10	10
0.90 – 1.09 m2	20	20	20	10
1.10 – 1.29 m2	25	25	25	10
1.30 – 1.49 m2	30	25	25	20
1.50 – 1.69 m2	35	30	25	25
1.70 – 1.89 m2	35	35	30	25
≥ 1.90 m2	40	40	30	30

Table 9 Recommended Dosage of KOSELUGO Oral Granules for Coadministration with Strong or
Moderate CYP3A4 Inhibitors or Fluconazole

Body Surface Area	If the current dosage is 25 mg/m2 twice daily, reduce to 20 mg/m2 twice daily (mg/dose)		If the current dosage is 20 mg/m2 twice daily, reduce to 15 mg/m2 twice daily (mg/dose)
	Morning	Evening	Morning	Evening
0.40 – 0.59 m2	10	10	7.5	7.5
0.60 – 0.69 m2	12.5	12.5	10	7.5
0.70 – 0.89 m2	15	15	10	10
0.90 – 1.09 m2	20	20	15	15
1.10 – 1.29 m2	25	25	25	10
1.30 – 1.49 m2	30	25	25	20
1.50 – 1.69 m2	35	30	25	25
1.70 – 1.89 m2	35	35	30	25
≥ 1.90 m2	40	40	30	30

HOW SUPPLIED

Dosage Forms And Strengths

Capsules:

• 10 mg selumetinib: white to off-white, opaque, hard capsule sealed with a clear band and marked with “SEL 10” in black ink.
• 25 mg selumetinib: blue, opaque, hard capsule sealed with a clear band and marked with “SEL 25” in black

Oral Granules:

• 5 mg selumetinib: Off-white to light-yellow free-flowing oral granules contained within capsules. The capsules have a yellow cap and white The cap is printed with “sel 5” in black ink, and body is printed with a sprinkle capsule image indicating opening.
• 7.5 mg selumetinib: Off-white to light-yellow free-flowing oral granules contained within capsules. The capsules have a pink cap and white body. The cap is printed with “sel 7.5” in black ink, and body is printed with a sprinkle capsule image indicating opening.

How Supplied

Selumetinib Capsules

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

Selumetinib Oral Granules

Strength	Description	Capsules per Bottle	NDC Number
5 mg	Off-white to light-yellow free-flowing oral granules contained within capsules. The capsules have a yellow cap and white body. The cap is printed with “sel 5” in black ink, and body is printed with a sprinkle capsule image indicating opening.	60	0310-0635-60
7.5 mg	Off-white to light-yellow free-flowing oral granules contained within capsules. The capsules have a pink cap and white body where the cap is printed with “sel 7.5” in black ink, and body is printed with a sprinkle capsule image indicating opening.	60	0310-0640-60

Storage

KOSELUGO Capsules

Store KOSELUGO capsules 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 and store in the original bottle to protect from light and moisture. Do not remove desiccant. Keep the bottle tightly closed after first opening.

KOSELUGO Oral Granules

Store and transport KOSELUGO oral granules refrigerated at 2°C to 8°C (36°F to 46°F). After receipt, patients may store at room temperature 20°C to 25°C (68°F to 77°F). Do NOT exceed 30°C (86°F). KOSELUGO oral granules may clump together or stick to the capsule shell if exposed to high temperatures, which may lead to underdose. Dispense and store in the original bottle to protect from light and moisture. Do not remove desiccant. Keep the bottle tightly closed after first opening.

AstraZeneca Pharmaceuticals LP Wilmington, DE 19850

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)]

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 pooled safety population described in the WARNINGS AND PRECAUTIONS reflect exposure to KOSELUGO in 134 pediatric patients at the recommended dose in SPRINKLE (N = 36) (NCT05309668), in SPRINT Phase I (N = 24), SPRINT Phase II Stratum 1 (N = 50), and Phase I Food Effect Study (N = 24). Among the 134 pediatric patients, the duration of KOSELUGO exposure, including dose interruptions, was 12 months or longer (80%), more than 2 years (44%), or more than 3 years (37%). In this pooled safety population, the most common adverse reactions of any grade (incidence ≥ 40%) were vomiting (64%), diarrhea (59%), increased creatine phosphokinase (55%), dry skin (51%), paronychia (50%), nausea (49%), dermatitis acneiform (47%), and pyrexia (46%).

Neurofibromatosis Type 1 (NF1) with Inoperable Plexiform Neurofibromas (PN)

Pediatrics 2-18 years of Age (SPRINT Phase II Stratum 1)

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 neurofibromatosis type 1 (NF1) who had inoperable plexiform neurofibromas (PN) that was causing significant morbidity. Patients were excluded for abnormal LVEF, uncontrolled hypertension (blood pressure ≥ the 95^th 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 Patients received KOSELUGO 25 mg/m² 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 blood creatinine, 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 10 presents the adverse reactions in SPRINT Phase II Stratum 1.

Table 10 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 pain1	76	0
Diarrhea	70	16
Nausea	66	2
Stomatitis2	50	0
Constipation	34	0
Skin and Subcutaneous Tissue
Rash (all)3	80	6
Dry skin	60	0
Rash acneiform4	50	4
Paronychia5	48	6
Pruritus	46	0
Dermatitis6	36	4
Hair changes7	32	0
Musculoskeletal and Connective Tissue
Musculoskeletal pain8	58	0
General
Fatigue9	56	0
Pyrexia	56	8
Edema10	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 infection11	20	2
* All events were Grade 3. 1 Abdominal pain includes abdominal pain; abdominal pain upper 2 Stomatitis includes stomatitis; mouth ulceration 3 Rash (all) includes dermatitis acneiform; rash maculo-papular; erythema; rash pustular; rash; urticaria; exfoliative rash; rash pruritic; rash erythematous 4 Rash (acneiform) includes dermatitis acneiform 5 Paronychia includes paronychia; nail infection 6 Dermatitis includes dermatitis; dermatitis atopic; dermatitis diaper; eczema; seborrheic dermatitis; skin irritation 7 Hair changes include alopecia; hair color change 8 Musculoskeletal pain includes pain in extremity; back pain; neck pain; musculoskeletal pain 9 Fatigue includes fatigue; malaise 10 Edema includes peripheral swelling; edema; localized edema 11 Skin infection includes skin infection; abscess; cellulitis; impetigo; staphylococcal skin infection

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 11 presents the laboratory abnormalities in SPRINT Phase II Stratum 1.

Table 11 Select Laboratory Abnormalities (≥ 15%) Worsening from Baseline in Patients Who
Received KOSELUGO in SPRINT Phase II Stratum 1

Laboratory Abnormality	KOSELUGO
	All Grades (%)*	Grade ≥ 3 (%)
Chemistry
Increased creatine phosphokinase (CPK)	79	7§
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
* 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. § Includes one Grade 4 increased CPK and one Grade 4 increased potassium.

Pediatrics > 1 year of Age on KOSELUGO Granules (SPRINKLE)

The safety of KOSELUGO oral granules was evaluated in SPRINKLE (NCT05309668), a dose-finding and activity estimating, single-arm, multicenter study in 36 pediatric patients ages 1 year to less than 7 years with a clinical diagnosis of NF1-related symptomatic, inoperable PN. The study evaluated the pharmacokinetics (PK), safety, efficacy, and tolerability of KOSELUGO oral granules. Study patients were to receive KOSELUGO oral granules for 25 cycles at a dose equivalent to 25 mg/m² BSA twice daily until disease progression or unacceptable toxicity. The median age was approximately 4 years (range: 1 to 7 years), 61% were male, 61% were White, 14% were Asian and 3% were Black or African American.

In the SPRINKLE study, the median duration of KOSELUGO oral granules treatment in pediatric patients with neurofibromatosis type 1 (NF1) plexiform neurofibromas (PN) was 11 months (range: 3-25 months). Serious adverse reactions occurred in 6% of patients who received KOSELUGO oral granules. Serious adverse reactions occurred in 1 patient each and included pyrexia, gastroenteritis and upper respiratory infection. A total of 31% of patients had an adverse reaction leading to a dosage interruption. Adverse reactions requiring a dosage interruption in ≥ 5% of patients were pyrexia. vomiting, diarrhea, upper respiratory infection, gastroenteritis and eczema. The most common adverse reactions (≥ 40%) were pyrexia. dry skin. and paronychia.

The observed safety profile of KOSELUGO oral granules in the SPRINKLE study was consistent with the known safety profile of KOSELUGO capsules.

Drug Interactions for Koselugo

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 selecimumab 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 selecimumab plasma concentrations (see Clinical Pharmacology (12.3)], which may reduce KOSELUGO efficacy.
Management	Avoid coadministration of strong or moderate CYP3A4 inducers with KOSELUGO.
Vitamin E
Clinical Impact	KOSELUGO capsules contain 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 capsules.
Management	Supplemental vitamin E is not recommended if daily vitamin E intake (including the amount of vitamin E in KOSELUGO capsules and supplement) will exceed the recommended or safe limits. Monitor for bleeding in patients co-administered a vitamin-K antagonist or an anti-platelet agent with KOSELUGO capsules. Increase INR monitoring, as appropriate, in patients taking a vitamin-K antagonist [see Warnings and Precautions (5.3)].

Warnings for Koselugo

Included as part of the PRECAUTIONS section.

Precautions for Koselugo

Cardiomyopathy

KOSELUGO can cause cardiomyopathy, defined as a decrease in left ventricular ejection fraction (LVEF) ≥10% below baseline. KOSELUGO has not been studied in patients with a history of clinically significant cardiac disease or LVEF less than 55% prior to treatment.

In the NF1 PN pediatric pool (N = 134), Grade 2 LVEF decrease [Grade 2 LVEF decrease (40%-50%; 10-19% drop from baseline)] occurred in 17% of evaluable patients. Decreased LVEF of ≥ 20% occurred in 0.7% of patients and resulted in dose interruption and dose reduction. Decreased LVEF resolved in 75% of these patients. The median time to first occurrence of LVEF decrease was approximately 12 months (median duration approximately 3 months) [see Adverse Reactions (6.1)].

Left ventricular dysfunction or decreased LVEF resulting in permanent discontinuation of KOSELUGO occurred in an unapproved population of adult patients with multiple tumor types who received KOSELUGO. Decreased LVEF resulting in permanent discontinuation of KOSELUGO occurred in a pediatric population with NF1 in an expanded access program.

Assess ejection fraction by echocardiogram prior to initiating treatment, every 3 months during the first year of treatment, every 6 months thereafter, and as clinically indicated. Withhold, reduce dose, or permanently discontinue KOSELUGO based on severity of adverse reaction [see Dosage and Administration (2.2)]. In patients who interrupt KOSELUGO for decreased LVEF, obtain an echocardiogram or a cardiac MRI every 3 to 6 weeks until resolution. Upon resolution of decreased LVEF to greater than or equal to the institutional LLN, obtain an echocardiogram or a cardiac MRI every 2 to 3 months or as directed by the cardiologist.

Ocular Toxicity

KOSELUGO can cause ocular toxicity, including blurred vision [see Adverse Reactions (6.1)].

In the NF1 PN pediatric pool (N = 134), blurred vision, photophobia, cataracts, ocular hypertension, and retinal tear occurred in 13% of pediatric patients receiving KOSELUGO. Blurred vision resulted in dose interruption in 1.5% of patients. Ocular toxicity resolved in 76% of these patients.

Serious ocular toxicities including retinal vein occlusion (RVO) and retinal pigment epithelial detachment (RPED), occurred in an unapproved population of adult patients with multiple tumor types who received KOSELUGO as a single agent or in combination with other anti-cancer agents. RPED occurred in the pediatric population during treatment with single agent KOSELUGO and resulted in permanent discontinuation.

Conduct comprehensive ophthalmic assessments prior to initiating KOSELUGO, at regular intervals during treatment, and for new or worsening visual changes. Permanently discontinue KOSELUGO in patients with RVO. Withhold KOSELUGO in patients with RPED, follow up with optical coherence tomography assessments every 3 weeks until resolution, and resume KOSELUGO at a reduced dose. For other ocular toxicities, withhold, reduce dose, or permanently discontinue KOSELUGO based on severity of the adverse reaction [see Dosage and Administration (2.2)].

Gastrointestinal Toxicity

KOSELUGO can cause gastrointestinal toxicities, including diarrhea, vomiting, nausea and stomatitis [see Adverse Reactions (6.1)].

In the NF1 PN pediatric pool (N = 134), diarrhea occurred in 59% patients who received KOSELUGO, including Grade 3 in 10% of patients. Diarrhea resulting in permanent discontinuation occurred in 0.7% of patients. Diarrhea resulting in dose interruption occurred in 10% of patients. The median time to first onset of diarrhea was approximately 2 months and the median duration was 5 days.

Serious gastrointestinal toxicities, including perforation, colitis, ileus, and intestinal obstruction, occurred in an unapproved population of adult patients with multiple tumor types who received KOSELUGO as a single agent or in combination with other anti-cancer agents. Colitis occurred in an unapproved population of pediatric patients with multiple tumor types who received KOSELUGO as a single agent.

Advise patients to start an anti-diarrheal agent (e.g., loperamide) immediately after the first episode of unformed, loose stool and to increase fluid intake during diarrhea episodes. Withhold, reduce dose, or permanently discontinue KOSELUGO based on severity of adverse reaction [see Dosage and Administration (2.2)].

Skin Toxicity

KOSELUGO can cause rashes, including dermatitis acneiform [see Adverse Reactions (6.1)].

In the NF1 PN pediatric pool (N = 134), rash occurred in 68% of patients who received KOSELUGO. The most frequent rashes included dermatitis acneiform (47%) and maculopapular rash (31%). Pruritus (30%), alopecia (26%), and eczema (24%) occurred in patients who received KOSELUGO. Grade 3 rash occurred in 5% of patients. Rash resulted in dose interruption in 8% of patients and dose reduction in 3.7% of patients.

Other skin toxicities, including severe palmar-plantar erythrodysesthesia syndrome, occurred in an unapproved population of adult patients with multiple tumor types who received KOSELUGO as a single agent or in combination with other anti-cancer agents.

Monitor for severe skin rashes. Withhold, reduce dose, or permanently discontinue KOSELUGO based on severity of adverse reaction [see Dosage and Administration (2.2)].

Increased Creatine Phosphokinase

KOSELUGO can cause increased creatine phosphokinase (CPK) [see Adverse Reactions (6.1)].

In the NF1 PN pediatric pool (N = 134), increased creatine phosphokinase (CPK) occurred in 55% of patients who received KOSELUGO, including Grade 3 or 4 in 6% of patients. Increased CPK resulted in dose interruption and dose reduction in 4% of patients. Increased CPK concurrent with myalgia occurred in 5% of patients, including one patient who permanently discontinued KOSELUGO for myalgia.

Rhabdomyolysis occurred in an unapproved adult population who received KOSELUGO as a single agent.

Obtain serum CPK prior to initiating KOSELUGO, periodically during treatment, and as clinically indicated. If increased CPK occurs, evaluate patients for rhabdomyolysis or other causes. Withhold, reduce dose, or permanently discontinue KOSELUGO based on severity of adverse reaction [see Dosage and Administration (2.2)].

Increased Levels of Vitamin E and Increased Risk of Bleeding (KOSELUGO Capsules)

KOSELUGO capsules can cause increased levels of vitamin E and increased risk of bleeding.

KOSELUGO capsules contain vitamin E (10 mg capsules contain 32 mg vitamin E as the excipient, D-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS); while KOSELUGO 25 mg capsules contain 36 mg vitamin E as TPGS). Vitamin E can inhibit platelet aggregation and antagonize vitamin K-dependent clotting factors. Daily vitamin E intake that exceeds the recommended or safe limits may increase the risk of bleeding. 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.

An increased risk of bleeding in patients may occur in patients who are co-administered vitamin-K antagonists or anti-platelet antagonists with KOSELUGO capsules. Monitor for bleeding in these patients. Increase international normalized ratio (INR) monitoring, as appropriate, in patients taking a vitamin-K antagonist. Perform anticoagulant assessments, including INR or prothrombin time, more frequently and adjust the dose of vitamin K antagonists or anti-platelet agents as appropriate.

KOSELUGO oral granules do not contain vitamin E [see Drug Interactions (7.1)].

Embryo-Fetal Toxicity

Based on findings from animal studies and its mechanism of action, KOSELUGO can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of selumetinib to mice during organogenesis caused reduced fetal weight, adverse structural defects, and effects on embryo-fetal survival at approximate exposures > 5-times the human exposure at the clinical dose of 25 mg/m² twice daily. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with KOSELUGO and for 1 week after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with KOSELUGO and for 1 week after the last dose [see Use in Specific Populations (8.1, 8.3)].

NONCLINICAL TOXICOLOGY

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/m².

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/m²).

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/m² 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/m² twice daily).

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/m² 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.

Use In Specific Populations

Pregnancy

Risk Summary

Based on findings from animal studies and its mechanism of action [see CLINICAL PHARMACOLOGY], 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/m² 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/m² 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 [Cmax] of ~0.6 times the human Cmax at the clinical dose of 25 mg/m² twice daily).

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].

Females And Males Of Reproductive Potential

KOSELUGO can cause fetal harm when administered to a pregnant woman [see Use In Specific Populations].

Pregnancy Testing

Verify the pregnancy status of females of reproductive potential prior to initiating KOSELUGO [see Use In Specific Populations].

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.

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 (~60­times the human exposure based on AUC at the clinical dose of 25 mg/m² twice daily) showed growth plate dysplasia.

Geriatric Use

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

Renal Impairment

No dose adjustment is recommended in patients with renal impairment or those with End Stage Renal Disease [see CLINICAL PHARMACOLOGY].

Hepatic Impairment

Selumetinib exposures increased in patients with moderate or severe hepatic impairment [see CLINICAL PHARMACOLOGY]. 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].

Overdose Information for Koselugo

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

Contraindications for Koselugo

None.

Clinical Pharmacology for Koselugo

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.

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.

Pharmacokinetics

At the recommended dosage of 25 mg/m² of KOSELUGO capsules 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/m² to 30 mg/m² (0.8- to 1.2-times the recommended dose). The accumulation was 1.1-fold following administration of KOSELUGO 25 mg/m² twice daily.

At the recommended dosage of 25 mg/m² of KOSELUGO oral granules (sprinkled on smooth yogurt, smooth fruit sauce, smooth fruit puree, or smooth fruit jam) twice daily in pediatric patients (> 1 year old to < 7 years old), the AUC_0-24h following the first dose of KOSELUGO oral granules was within the range of that in patients administered KOSELUGO capsules.

No clinically relevant differences in the pharmacokinetics of selumetinib were observed following administration of a single-dose of either the granule or capsule dosage forms of KOSELUGO at equivalent dosages, under fasted and fed conditions, in healthy adults.

Absorption

The mean absolute oral bioavailability of KOSELUGO capsules 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

KOSELUGO capsules C_max and AUC decreased by 24% and 8%, respectively, following a low-fat meal (400 calories, 25% fat) in adolescent patients with NF1 and inoperable PN administered multiple doses of 25 mg/m² twice daily and T_max was delayed by approximately 0.6 hours.

KOSELUGO oral granules C_max and AUC decreased by 39% and 4%, respectively, following a low-fat meal (400 to 500 calories, 25% fat) in healthy adults and T_max was delayed by approximately 1.3 hours.

A population PK analysis including children and adolescent patients with NF1 and inoperable PN, adult patients with cancers, and healthy adults showed that a low- or high-fat meal had no clinically relevant effect on the AUC of selumetinib.

Distribution

The mean apparent volume of distribution at steady state (V_ss) of selumetinib across a dose range of 20 mg/m² to 30 mg/m² (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/m².

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.

Clinical Studies

Neurofibromatosis Type 1 (NF1) with Inoperable Plexiform Neurofibromas (PN)

Pediatrics 2-18 years of Age (SPRINT Phase II Stratum 1)

The efficacy of KOSELUGO was evaluated in SPRINT Phase II Stratum 1, an open-label, multicenter, single arm trial. 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/m² 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. The median time to onset of response was 7.2 months (range: 3.3 months to 1.6 years).

Efficacy Results from SPRINT Phase II Stratum 1

Efficacy Parameter	SPRINT (N=50)
Overall Response Rate, n (%)	33 (66%)
95% CI	(51, 79)
Complete Response	0
Confirmed Partial Response, n (%)	33 (66%)
Duration of Response
Median (95% CI) months	NR (41.2-NE)
DoR = 24 months, n (%)	26 (79%)
DoR = 36 months, n (%)	21 (64%)

An independent centralized review of tumor response per REINS criteria (data cut-off June 2018) resulted in an ORR of 44% (95% CI: 30, 59).

Adults 18 years of Age (KOMET)

The efficacy of KOSELUGO in adult patients was evaluated in KOMET, a randomized, multicenter, double-blind, placebo-controlled trial. Eligible patients were required to be 18 years of age or older with neurofibromatosis type 1 (NF1) and symptomatic, inoperable plexiform neurofibroma (PN). Inoperable plexiform neurofibroma (PN) is 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.

A total of 145 patients were randomized (1:1) to KOSELUGO 25 mg/m² (BSA) or placebo twice daily for 12 cycles (28-day cycles). After the end of Cycle 12, or earlier if disease progression was confirmed by the Independent Central Review (ICR), patients initially randomized to placebo crossed over to receive KOSELUGO in the open-label treatment phase.

Treatment was discontinued if a patient was no longer deriving clinical benefit, experienced unacceptable toxicity, patient decision, PN progression, or at the discretion of the investigator. One target and when applicable one non-target PN was assessed by using volumetric MRI analysis and REINS criteria.

The major efficacy outcome measure was overall response rate (ORR) by the end of Cycle 16, as determined by ICR per REINS criteria. Duration of response was an additional efficacy outcome measure. The study demographics were 52% male, 56% White, 31% Asian, 6% Black or African American, 10% Hispanic or Latino ethnicity, and the median age was 29 years (range: 18 to 60 years). PN-related morbidities that were present in > 20% of patients included pain, motor dysfunction, and disfigurement.

The trial demonstrated statistically significant ORR in patients randomized to KOSELUGO compared to placebo by the end of Cycle 16. The median time to response was 3.7 months (range: 3.6 months to 11.2 months).

Efficacy Results from KOMET

Efficacy Parameters	KOSELUGO (N=71)	Placebo (N=74)
Overall Response Rate by the end of Cycle 16 (ORR)
ORR % (95% CI)	20 (11, 31)	5 (2, 13)
p value	0.011
Duration of Response
Median (95% CI) months	NR (11.5, NE)	ND
= 6 months, n (%)	12 (86%)	ND

KOSELUGO® (ko-SEL-u-go) (selumetinib) capsules, for oral use

KOSELUGO® (ko-SEL-u-go) (selumetinib) oral granules

What is KOSELUGO?

KOSELUGO is a prescription medicine that is used to treat adults and children 1 year of age and older with neurofibromatosis type 1 (NF1) who have plexiform neurofibromas that cause symptoms and cannot be completely removed by surgery.

It is not known if KOSELUGO is safe and effective in children under 1 year of age.

Before taking KOSELUGO, tell your healthcare provider about all of your medical conditions, including if you:

• have heart problems.
• have eye problems.
• have liver problems.
• are pregnant or plan to become pregnant. KOSELUGO can harm your unborn baby.

Females who are able to become pregnant:

• Your healthcare provider should check to see if you are pregnant before you begin treatment with KOSELUGO.
• You should use effective birth control (contraception) during treatment with KOSELUGO and for 1 week after your last dose.
• Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with KOSELUGO.

Males with female partners who are able to become pregnant:

• You should use effective birth control (contraception) during treatment with KOSELUGO and for 1 week after your last dose.

• are breastfeeding or plan to breastfeed. It is not known if KOSELUGO passes into your breast milk. Do not breastfeed during treatment with KOSELUGO and for 1 week after your last dose. Talk to your healthcare provider about the best way to feed your baby during this time.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, or herbal supplements. Certain medicines may affect the way KOSELUGO works. Especially tell your healthcare provider if you are taking a supplement containing vitamin E, aspirin, blood thinners, or other medicines to treat blood clots. KOSELUGO capsules contain vitamin E, which may increase your risk of bleeding.

How should I take KOSELUGO?

• Take or give KOSELUGO exactly as your healthcare provider tells you to.
• Do not change your dose or stop taking KOSELUGO unless your healthcare provider tells you to.
• Your healthcare provider will decide on the right dose of KOSELUGO based on your or your child's weight or size (body surface area).
• Take or give KOSELUGO 2 times a day.
• If you or your child miss a dose of KOSELUGO capsules or KOSELUGO oral granules, take or give the dose as soon as you remember, unless the next dose is due within 6 hours. If your scheduled dose is due within 6 hours, skip the dose and take or give the next dose at the regular time.
• If you or your child vomit after taking a dose of KOSELUGO capsules or KOSELUGO oral granules, do not take an additional dose. Take the next dose at the regular scheduled time.

If your healthcare provider prescribes KOSELUGO capsules:

• Take KOSELUGO capsules with or without food.
• Swallow KOSELUGO capsules whole. Do not open, chew, or crush the capsules.
• Tell your healthcare provider if you or your child has trouble swallowing capsules.

If your healthcare provider prescribes KOSELUGO oral granules:

• See the Instructions for Use for the instructions on how to prepare and take or give KOSELUGO oral granules.
• Prepare KOSELUGO oral granules by carefully opening the capsule and sprinkling all of the oral granules on a small amount (about 1 to 3 teaspoons) of smooth yogurt, or fruit puree containing the following fruits: apple, banana, pear, or strawberry.
• Take or give the KOSELUGO oral granules and food mixture within 30 minutes of preparing the dose.
• If the prepared dose of KOSELUGO oral granules and food mixture is not taken or given within 30 minutes, do not take or give the prepared dose. Throw away the mixture and prepare a new dose.
• If part of a dose is taken or given within 30 minutes of preparing, throw away the remainder of the mixture and do not prepare a new dose. Take or give the full dose within 30 minutes next time.
• The KOSELUGO oral granules should flow freely. Do not use if the oral granules are clumped or stuck inside the capsule shell. Contact your pharmacy if this happens.
• Throw away the empty capsule shells after use. Do not swallow, chew, or dissolve the capsule shells of KOSELUGO oral granules.
• Do not chew or crush the KOSELUGO oral granules. Do not add oral granules to liquids.
• Do not mix KOSELUGO oral granules in grapefruit or any juice, fruit puree or jam containing Seville orange.

What should I avoid while taking KOSELUGO?

Avoid St John's wort, grapefruit or grapefruit juice, and Seville orange during treatment with KOSELUGO.

What are the possible side effects of KOSELUGO?

KOSELUGO can cause serious side effects, including:

• Heart problems. KOSELUGO can lower the amount of blood pumped by your heart, which can be severe. Your healthcare provider will do tests before and during treatment with KOSELUGO to check how well your heart is working. Tell your healthcare provider right away if you get any of the following signs or symptoms:
  • persistent coughing or wheezing
  • shortness of breath
  • swelling of your ankles and feet
  • tiredness
  • increased heart rate
• Eye problems. KOSELUGO can cause eye problems that can lead to blindness. Your healthcare provider will check your vision before and during treatment with KOSELUGO. Tell your healthcare provider right away if you get new or worsening vision changes, including:
  • blurred vision
  • loss of vision
  • dark spots in your vision (floaters)
  • other changes to your vision
• Stomach, intestine, and mouth (gastrointestinal) problems. KOSELUGO can cause diarrhea, vomiting, nausea, and mouth sores. Diarrhea can be severe with KOSELUGO. Tell your healthcare provider right away the first time that you get diarrhea during treatment with KOSELUGO. Your healthcare provider may give you medicine to help control your diarrhea and may tell you to drink more fluids.
• Skin problems. KOSELUGO can cause severe skin rashes. Tell your healthcare provider if you get any of the following signs of skin problems:
  • rash that covers a large area of your body
  • flat skin rash
  • raised bumps on your skin
  • skin bumps that look like acne
  • blisters
  • peeling skin
  • itchy rash
  • hair thinning or hair loss (alopecia)
• Increased level of an enzyme called creatine phosphokinase (CPK) in your blood and muscle problems. KOSELUGO can cause severe muscle problems. Treatment with KOSELUGO may increase the level of enzyme in your blood called creatine phosphokinase (CPK), which may be a sign of muscle damage. Increased level of CPK in the blood are common during treatment with KOSELUGO and can also be severe. Your healthcare provider should do a blood test to check your blood levels of CPK before and during treatment with KOSELUGO. Tell your healthcare provider right away if you get any of the following signs or symptoms:
  • muscle aches or pain
  • dark, reddish urine
  • muscle spasms and weakness

The most common side effects of KOSELUGO in children include: vomiting, diarrhea, increased level of CPK in your blood, dry skin, redness around the fingernails, nausea, skin bumps that look like acne, and fever.

The most common side effects of KOSELUGO in adults include: rash, diarrhea, and skin bumps that look like acne.

Your healthcare provider may change your dose, temporarily stop, or permanently stop treatment with KOSELUGO if you have any of these side effects.

How should I store KOSELUGO?

• Store KOSELUGO capsules and KOSELUGO oral granules at room temperature between 68°F to 77°F (20°C to 25°C).
• Do not store KOSELUGO oral granules above 86°F (30°C). Store KOSELUGO oral granules in the refrigerator between 36°F to 46°F (2°C to 8°C) if the temperature is above 86°F (30°C).
• KOSELUGO oral granules may clump together or stick to the capsule shell if the medicine gets too hot, and you may not get your full dose.
• Keep KOSELUGO oral granules cold in a cooler bag with a cold pack if you need to take it anywhere.
• The bottle of KOSELUGO capsules and KOSELUGO oral granules contain a desiccant packet to reduce moisture. Do not throw away the desiccant packet.
• Keep KOSELUGO capsules and KOSELUGO oral granules in its original bottle to protect from light and moisture.
• Keep the bottle tightly closed.
• Keep KOSELUGO and all medicines out of the reach of children.

General information about the safe and effective use of KOSELUGO.

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use KOSELUGO for a condition for which it was not prescribed. Do not give KOSELUGO to other people, even if they have the same symptoms you have. It may harm them.

What are the ingredients in KOSELUGO?

Active ingredient: selumetinib

KOSELUGO capsule inactive ingredients:

• The 10 mg and 25 mg capsules contain: vitamin E polyethylene glycol succinate.
• The 10 mg capsule shell contains: carnauba wax, carrageenan, hypromellose, potassium chloride, purified water, and titanium dioxide.
• The 10 mg capsule printing ink contains: ammonium hydroxide, iron oxide black, propylene glycol, and shellac.
• The 25 mg capsule shell contains: carnauba wax and/or corn starch, carrageenan, FD&C blue 2, ferric oxide yellow, hypromellose, potassium chloride, purified water, and titanium dioxide.
• The 25 mg capsule printing ink contains: carnauba wax, FD&C Blue 2 aluminum lake, ferric oxide red, ferric oxide yellow, glyceryl monooleate, and shellac.

KOSELUGO oral granule inactive ingredients:

• The 5 mg and 7.5 mg uncoated cores contain: glyceryl dibehenate and stearoyl polyoxylglycerides.
• The 5 mg and 7.5 mg granule coatings contain: acetone, hypromellose acetate succinate, and stearic acid.
• The 5 mg shell contains: ferric oxide yellow, hypromellose, and titanium dioxide.
• The 5 mg printing ink contains: butyl alcohol, dehydrated alcohol, ferric oxide black, isopropyl alcohol, potassium hydroxide, propylene glycol, purified water, shellac, and strong ammonia solution.
• The 7.5 mg shell contains: ferric oxide red, hypromellose, and titanium dioxide.
• The 7.5 mg printing ink contains: butyl alcohol, dehydrated alcohol, ferric oxide black, isopropyl alcohol, potassium hydroxide, propylene glycol, purified water, shellac, and strong ammonia solution.