What is mechanism of action?

mechanism of action is Mitogen-Activated Protein Kinase Kinase 1 Inhibitors [MoA] or Mitogen-Activated Protein Kinase Kinase 2 Inhibitors [MoA]

Koselugo (Selumetinib)

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Dosage & administration

* •

KOSELUGO capsules:

The recommended dosage is 25 mg/m², swallowed whole, taken orally twice daily with or without food

(see Table 1)

2.1 Recommended Dosage

The recommended dosage of KOSELUGO capsules (

see Table 1

) and KOSELUGO oral granules (

see Table 2

) for adult and pediatric patients 1 year of age and older, based on body surface area, is 25 mg/m²orally twice daily, until disease progression or unacceptable toxicity

[see Dosage and Administration (2.2)].

Table 1 Recommended Dosage: KOSELUGO Capsules
Body Surface Area The recommended dosage of KOSELUGO capsules for patients with a BSA less than 0.55 m²has not been established.	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

Table 2 Recommended Dosage: KOSELUGO Oral Granules
Body Surface Area The recommended dosage of KOSELUGO oral granules for patients with a BSA less than 0.40 m²has not been established.	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

2.3 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)
Body Surface Area	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)
Body Surface Area	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
Left Ventricular Dysfunction [see Warnings and Precautions (5.1)]
*
Withhold until resolution. Resume at reduced dose.
*
Permanently discontinue.
Ocular Toxicity [see Warnings and Precautions (5.2)]
*
Withhold until resolution. Resume at reduced dose.
*
Permanently discontinue.
Gastrointestinal Toxicity [see Warnings and Precautions (5.3)]
*
Withhold until improved to Grade 0 or 1. Resume at same dose. Permanently discontinue if no improvement within 3 days.
*
Permanently discontinue.
*
Permanently discontinue.
Skin Toxicity [see Warnings and Precautions (5.4)]
*
Withhold until improvement. Resume at reduced dose.
Increased Creatine Phosphokinase (CPK) [see Warnings and Precautions (5.5)]
*
Withhold until improved to Grade 0 or 1. Resume at reduced dose. Permanently discontinue if no improvement within 3 weeks.
*
Permanently discontinue.
Other Adverse Reactions [see Adverse Reactions (6.1)]
*
Withhold KOSELUGO until improved to Grade 0 or 1. Resume at reduced dose.
*
Withhold KOSELUGO until improved to Grade 0 or 1. Resume at reduced dose. Consider discontinuation.

Asymptomatic decrease in left ventricular ejection fraction (LVEF) of 10% or greater from baseline and less than lower level of normalSymptomatic decreased LVEFGrade 3 or 4 decreased LVEFRetinal Pigment Epithelial Detachment (RPED)Retinal vein occlusion (RVO)Grade 3 DiarrheaGrade 4 DiarrheaGrade 3 or 4 ColitisGrade 3 or 4Grade 4 Increased CPKAny Increased CPK and myalgiaRhabdomyolysisIntolerable Grade 2Grade 3Grade 4

* Per National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03.

)
* •

KOSELUGO oral granules:

The recommended dosage is equivalent to 25 mg/m², sprinkled onto or mixed with soft food and taken orally twice daily

(see Table 2).

(

2.1 Recommended Dosage

The recommended dosage of KOSELUGO capsules (

see Table 1

) and KOSELUGO oral granules (

see Table 2

) for adult and pediatric patients 1 year of age and older, based on body surface area, is 25 mg/m²orally twice daily, until disease progression or unacceptable toxicity

[see Dosage and Administration (2.2)].

Table 1 Recommended Dosage: KOSELUGO Capsules
Body Surface Area The recommended dosage of KOSELUGO capsules for patients with a BSA less than 0.55 m²has not been established.	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

Table 2 Recommended Dosage: KOSELUGO Oral Granules
Body Surface Area The recommended dosage of KOSELUGO oral granules for patients with a BSA less than 0.40 m²has not been established.	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

2.3 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)
Body Surface Area	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)
Body Surface Area	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
Left Ventricular Dysfunction [see Warnings and Precautions (5.1)]
*
Withhold until resolution. Resume at reduced dose.
*
Permanently discontinue.
Ocular Toxicity [see Warnings and Precautions (5.2)]
*
Withhold until resolution. Resume at reduced dose.
*
Permanently discontinue.
Gastrointestinal Toxicity [see Warnings and Precautions (5.3)]
*
Withhold until improved to Grade 0 or 1. Resume at same dose. Permanently discontinue if no improvement within 3 days.
*
Permanently discontinue.
*
Permanently discontinue.
Skin Toxicity [see Warnings and Precautions (5.4)]
*
Withhold until improvement. Resume at reduced dose.
Increased Creatine Phosphokinase (CPK) [see Warnings and Precautions (5.5)]
*
Withhold until improved to Grade 0 or 1. Resume at reduced dose. Permanently discontinue if no improvement within 3 weeks.
*
Permanently discontinue.
Other Adverse Reactions [see Adverse Reactions (6.1)]
*
Withhold KOSELUGO until improved to Grade 0 or 1. Resume at reduced dose.
*
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.

)
* •

Moderate hepatic impairment (Child-Pugh B):

The recommended dosage is 20 mg/m² orally twice daily

(see Tables 6 and 7)

. (

2.3 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)
Body Surface Area	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)
Body Surface Area	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
Left Ventricular Dysfunction [see Warnings and Precautions (5.1)]
*
Withhold until resolution. Resume at reduced dose.
*
Permanently discontinue.
Ocular Toxicity [see Warnings and Precautions (5.2)]
*
Withhold until resolution. Resume at reduced dose.
*
Permanently discontinue.
Gastrointestinal Toxicity [see Warnings and Precautions (5.3)]
*
Withhold until improved to Grade 0 or 1. Resume at same dose. Permanently discontinue if no improvement within 3 days.
*
Permanently discontinue.
*
Permanently discontinue.
Skin Toxicity [see Warnings and Precautions (5.4)]
*
Withhold until improvement. Resume at reduced dose.
Increased Creatine Phosphokinase (CPK) [see Warnings and Precautions (5.5)]
*
Withhold until improved to Grade 0 or 1. Resume at reduced dose. Permanently discontinue if no improvement within 3 weeks.
*
Permanently discontinue.
Other Adverse Reactions [see Adverse Reactions (6.1)]
*
Withhold KOSELUGO until improved to Grade 0 or 1. Resume at reduced dose.
*
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.

2.5 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/m²twice daily, reduce to 20 mg/m²twice daily (mg/dose)		If the current dosage is 20 mg/m²twice daily, reduce to 15 mg/m²twice daily (mg/dose)
Body Surface Area	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/m²twice daily, reduce to 20 mg/m²twice daily (mg/dose)		If the current dosage is 20 mg/m²twice daily, reduce to 15 mg/m²twice daily (mg/dose)
Body Surface Area	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

)
* •

Severe hepatic impairment (Child-Pugh C):

The recommended dosage has not been established. (

2.5 Dosage Modifications for Drug Interactions

Strong or Moderate CYP3A4 Inhibitors or Fluconazole

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/m²twice daily, reduce to 20 mg/m²twice daily (mg/dose)		If the current dosage is 20 mg/m²twice daily, reduce to 15 mg/m²twice daily (mg/dose)
Body Surface Area	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/m²twice daily, reduce to 20 mg/m²twice daily (mg/dose)		If the current dosage is 20 mg/m²twice daily, reduce to 15 mg/m²twice daily (mg/dose)
Body Surface Area	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

8.6 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 (2.4)].

)
* •

Strong or Moderate CYP3A4 Inhibitors or Fluconazole:

If coadministration with strong or moderate CYP3A4 inhibitors or fluconazole cannot be avoided, reduce the dose of KOSELUGO

(see Tables 8 and 9)

. (

2.5 Dosage Modifications for Drug Interactions

Strong or Moderate CYP3A4 Inhibitors or Fluconazole

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/m²twice daily, reduce to 20 mg/m²twice daily (mg/dose)		If the current dosage is 20 mg/m²twice daily, reduce to 15 mg/m²twice daily (mg/dose)
Body Surface Area	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/m²twice daily, reduce to 20 mg/m²twice daily (mg/dose)		If the current dosage is 20 mg/m²twice daily, reduce to 15 mg/m²twice daily (mg/dose)
Body Surface Area	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

)

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Koselugo prescribing information

Indications and Usage (

1 INDICATIONS AND USAGE

KOSELUGO is indicated for the treatment of adult and 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)].

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

) 11/2025

Dosage and Administration (

2.1 Recommended Dosage

The recommended dosage of KOSELUGO capsules (

see Table 1

) and KOSELUGO oral granules (

see Table 2

) for adult and pediatric patients 1 year of age and older, based on body surface area, is 25 mg/m²orally twice daily, until disease progression or unacceptable toxicity

[see Dosage and Administration (2.2)].

Table 1 Recommended Dosage: KOSELUGO Capsules
Body Surface Area The recommended dosage of KOSELUGO capsules for patients with a BSA less than 0.55 m²has not been established.	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

Table 2 Recommended Dosage: KOSELUGO Oral Granules
Body Surface Area The recommended dosage of KOSELUGO oral granules for patients with a BSA less than 0.40 m²has not been established.	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

) 11/2025

Warnings and Precautions (

5.1 Left Ventricular Dysfunction

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.

Pediatric patients

In the NF1 PN pediatric safety pool (N = 134) [see Adverse Reactions (6.1)], Grade 2 LVEF decrease [Grade 2 LVEF decrease (40% to 50%; 10 to 19% drop from baseline)], based on reported adverse reactions, 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).

Adult Patients

In the KOMET adult NF1 PN study (N = 71) [see Adverse Reactions (6.1)], Grade 2 LVEF decrease [Grade 2 LVEF decrease (40% to 50%; 10 to 19% drop from baseline)], based on echocardiogram results, occurred in 14% of evaluable patients. Decreased LVEF resulted in dose interruption in 1.4% of patients. The median time to first occurrence of LVEF decrease was approximately 4 months (median duration approximately 4 months).

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 (2.3)]. 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.

5.2 Ocular Toxicity

KOSELUGO can cause ocular toxicity, including retinal vein occlusion (RVO), retinal pigment epithelial detachment (RPED), and blurred vision.

Pediatric Patients

In the NF1 PN pediatric safety pool (N = 134)

[see Adverse Reactions (6.1)

], 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. RPED occurred in the pediatric population during treatment with single agent KOSELUGO and resulted in permanent discontinuation.

Adult Patients

In the KOMET adult NF1 PN study (N = 71)

[see Adverse Reactions (6.1)

], blurred vision and vitreous floaters occurred in 6% of patients receiving KOSELUGO. Serious ocular toxicities including RVO and 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.

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 (2.3)].

5.3 Gastrointestinal Toxicity

KOSELUGO can cause gastrointestinal toxicities, including diarrhea and colitis.

Pediatric Patients

In the NF1 PN pediatric safety pool (N = 134)

[see

Adverse Reactions (6.1)

]

, diarrhea occurred in 59% of 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. Colitis occurred in an unapproved population of pediatric patients with multiple tumor types who received KOSELUGO as a single agent.

Adult Patients

In the KOMET adult NF1 PN study (N = 71)

[see

Adverse Reactions (6.1)

]

, diarrhea occurred in 42% patients who received KOSELUGO. Diarrhea resulting in dose interruption occurred in 1.4% of patients. The median time to first onset of diarrhea was approximately 1 month and the median duration was 7 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.

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 (2.3)].

5.4 Skin Toxicity

KOSELUGO can cause severe rashes, including dermatitis acneiform.

Pediatric Patients

In the NF1 PN pediatric safety pool (N = 134)

[see

Adverse Reactions (6.1)

]

, 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.

Adult Patients

In the KOMET adult NF1 PN study (N = 71)

[see

Adverse Reactions (6.1)

rash occurred in 85% of patients who received KOSELUGO. The most frequent rash included dermatitis acneiform (66%). Alopecia (18%) and pruritus (10%) occurred in patients who received KOSELUGO. Grade 3 rash occurred in 4.2% of patients. Rash resulted in dose interruption in 2.8% of patients, dose reduction in 2.8% of patients, and permanent discontinuation in 2.8% 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 (2.3)].

5.5 Increased Creatine Phosphokinase

KOSELUGO can cause increased creatine phosphokinase (CPK), myalgia, and rhabdomyolysis.

Pediatric Patients

In the NF1 PN pediatric safety pool (N = 134)

[see Adverse Reactions (6.1)]

, increased creatine phosphokinase (CPK), based on laboratory data, occurred in 73% of patients who received KOSELUGO, including Grade 3 or 4 in 8% 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.

Adults

In the KOMET adult NF1 PN study (N = 71)

[see Adverse Reactions (6.1)]

, increased creatine phosphokinase (CPK), based on laboratory data, occurred in 70% of patients who received KOSELUGO, including Grade 3 or 4 in 7% of patients. Increased CPK resulted in dose interruption and dose reduction in 4.2% and 2.8% of patients, respectively. Increased CPK concurrent with myalgia occurred in 1.4% of patients. 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 (2.3)]

5.7 Embryo-Fetal Toxicity

Based on findings from clinical trials, animal studies and its mechanism of action, KOSELUGO can cause fetal harm when administered to a pregnant woman. In KOMET, a first trimester spontaneous abortion was reported in a patient receiving KOSELUGO.

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/m²twice 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)]

) 11/2025

KOSELUGO is indicated for the treatment of adult and pediatric patients 1 year of age and older with neurofibromatosis type 1 (NF1) who have symptomatic, inoperable plexiform neurofibromas (PN)

[see

2 DOSAGE AND ADMINISTRATION

•
KOSELUGO capsules:
The recommended dosage is 25 mg/m², swallowed whole, taken orally twice daily with or without food
(see Table 1)
. (2.1, 2.2)
•
KOSELUGO oral granules:
The recommended dosage is equivalent to 25 mg/m², sprinkled onto or mixed with soft food and taken orally twice daily
(see Table 2).
•
Moderate hepatic impairment (Child-Pugh B):
The recommended dosage is 20 mg/m²orally twice daily
(see Tables 6 and 7)
.
•
Severe hepatic impairment (Child-Pugh C):
The recommended dosage has not been established.
•
Strong or Moderate CYP3A4 Inhibitors or Fluconazole:
If coadministration with strong or moderate CYP3A4 inhibitors or fluconazole cannot be avoided, reduce the dose of KOSELUGO
(see Tables 8 and 9)
.

2.1 Recommended Dosage

The recommended dosage of KOSELUGO capsules (

see Table 1

) and KOSELUGO oral granules (

see Table 2

) for adult and pediatric patients 1 year of age and older, based on body surface area, is 25 mg/m²orally twice daily, until disease progression or unacceptable toxicity

[see Dosage and Administration (2.2)].

Table 1 Recommended Dosage: KOSELUGO Capsules
Body Surface Area The recommended dosage of KOSELUGO capsules for patients with a BSA less than 0.55 m²has not been established.	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

Table 2 Recommended Dosage: KOSELUGO Oral Granules
Body Surface Area The recommended dosage of KOSELUGO oral granules for patients with a BSA less than 0.40 m²has not been established.	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

2.2 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 the 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 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.

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.

2.3 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)
Body Surface Area	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)
Body Surface Area	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.

Asymptomatic decrease in left ventricular ejection fraction (LVEF) of 10% or greater from baseline and less than lower level of normalSymptomatic decreased LVEF

Grade 3 or 4 decreased LVEFRetinal Pigment Epithelial Detachment (RPED)Retinal vein occlusion (RVO)Grade 3 DiarrheaGrade 4 DiarrheaGrade 3 or 4 ColitisGrade 3 or 4Grade 4 Increased CPK

Any Increased CPK and myalgiaRhabdomyolysisIntolerable Grade 2

Grade 3Grade 4

Table 5 Recommended Dosage Modifications for Adverse Reactions
Severity of Adverse Reaction	Recommended Dosage Modifications for KOSELUGO capsules and KOSELUGO oral granules
Left Ventricular Dysfunction [see Warnings and Precautions (5.1)]

Withhold until resolution. Resume at reduced dose.

Permanently discontinue.
Ocular Toxicity [see Warnings and Precautions (5.2)]

Withhold until resolution. Resume at reduced dose.

Permanently discontinue.
Gastrointestinal Toxicity [see Warnings and Precautions (5.3)]

Withhold until improved to Grade 0 or 1. Resume at same dose. Permanently discontinue if no improvement within 3 days.

Permanently discontinue.

Permanently discontinue.
Skin Toxicity [see Warnings and Precautions (5.4)]

Withhold until improvement. Resume at reduced dose.
Increased Creatine Phosphokinase (CPK) [see Warnings and Precautions (5.5)]

Withhold until improved to Grade 0 or 1. Resume at reduced dose. Permanently discontinue if no improvement within 3 weeks.

Permanently discontinue.
Other Adverse Reactions [see Adverse Reactions (6.1)]

Withhold KOSELUGO until improved to Grade 0 or 1. Resume at reduced dose.

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.

2.4 Recommended Dosage in Patients with 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 (8.6)

]

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/m²orally 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)
Body Surface Area	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)
Body Surface Area	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

2.5 Dosage Modifications for Drug Interactions

Strong or Moderate CYP3A4 Inhibitors or Fluconazole

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/m²twice daily, reduce to 20 mg/m²twice daily (mg/dose)		If the current dosage is 20 mg/m²twice daily, reduce to 15 mg/m²twice daily (mg/dose)
Body Surface Area	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/m²twice daily, reduce to 20 mg/m²twice daily (mg/dose)		If the current dosage is 20 mg/m²twice daily, reduce to 15 mg/m²twice daily (mg/dose)
Body Surface Area	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

•

KOSELUGO capsules:

The recommended dosage is 25 mg/m², swallowed whole, taken orally twice daily with or without food

(see Table 1)

2.1 Recommended Dosage

The recommended dosage of KOSELUGO capsules (

see Table 1

) and KOSELUGO oral granules (

see Table 2

) for adult and pediatric patients 1 year of age and older, based on body surface area, is 25 mg/m²orally twice daily, until disease progression or unacceptable toxicity

[see Dosage and Administration (2.2)].

Table 1 Recommended Dosage: KOSELUGO Capsules
Body Surface Area The recommended dosage of KOSELUGO capsules for patients with a BSA less than 0.55 m²has not been established.	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

Table 2 Recommended Dosage: KOSELUGO Oral Granules
Body Surface Area The recommended dosage of KOSELUGO oral granules for patients with a BSA less than 0.40 m²has not been established.	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

2.3 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)
Body Surface Area	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)
Body Surface Area	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.

Asymptomatic decrease in left ventricular ejection fraction (LVEF) of 10% or greater from baseline and less than lower level of normalSymptomatic decreased LVEF

Grade 3 or 4 decreased LVEFRetinal Pigment Epithelial Detachment (RPED)Retinal vein occlusion (RVO)Grade 3 DiarrheaGrade 4 DiarrheaGrade 3 or 4 ColitisGrade 3 or 4Grade 4 Increased CPK

Any Increased CPK and myalgiaRhabdomyolysisIntolerable Grade 2

Grade 3Grade 4

Table 5 Recommended Dosage Modifications for Adverse Reactions
Severity of Adverse Reaction	Recommended Dosage Modifications for KOSELUGO capsules and KOSELUGO oral granules
Left Ventricular Dysfunction [see Warnings and Precautions (5.1)]

Withhold until resolution. Resume at reduced dose.

Permanently discontinue.
Ocular Toxicity [see Warnings and Precautions (5.2)]

Withhold until resolution. Resume at reduced dose.

Permanently discontinue.
Gastrointestinal Toxicity [see Warnings and Precautions (5.3)]

Withhold until improved to Grade 0 or 1. Resume at same dose. Permanently discontinue if no improvement within 3 days.

Permanently discontinue.

Permanently discontinue.
Skin Toxicity [see Warnings and Precautions (5.4)]

Withhold until improvement. Resume at reduced dose.
Increased Creatine Phosphokinase (CPK) [see Warnings and Precautions (5.5)]

Withhold until improved to Grade 0 or 1. Resume at reduced dose. Permanently discontinue if no improvement within 3 weeks.

Permanently discontinue.
Other Adverse Reactions [see Adverse Reactions (6.1)]

Withhold KOSELUGO until improved to Grade 0 or 1. Resume at reduced dose.

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.

)

•

KOSELUGO oral granules:

The recommended dosage is equivalent to 25 mg/m², sprinkled onto or mixed with soft food and taken orally twice daily

(see Table 2).

(

2.1 Recommended Dosage

The recommended dosage of KOSELUGO capsules (

see Table 1

) and KOSELUGO oral granules (

see Table 2

) for adult and pediatric patients 1 year of age and older, based on body surface area, is 25 mg/m²orally twice daily, until disease progression or unacceptable toxicity

[see Dosage and Administration (2.2)].

Table 1 Recommended Dosage: KOSELUGO Capsules
Body Surface Area The recommended dosage of KOSELUGO capsules for patients with a BSA less than 0.55 m²has not been established.	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

Table 2 Recommended Dosage: KOSELUGO Oral Granules
Body Surface Area The recommended dosage of KOSELUGO oral granules for patients with a BSA less than 0.40 m²has not been established.	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

2.3 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)
Body Surface Area	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)
Body Surface Area	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.

Asymptomatic decrease in left ventricular ejection fraction (LVEF) of 10% or greater from baseline and less than lower level of normalSymptomatic decreased LVEF

Grade 3 or 4 decreased LVEFRetinal Pigment Epithelial Detachment (RPED)Retinal vein occlusion (RVO)Grade 3 DiarrheaGrade 4 DiarrheaGrade 3 or 4 ColitisGrade 3 or 4Grade 4 Increased CPK

Any Increased CPK and myalgiaRhabdomyolysisIntolerable Grade 2

Grade 3Grade 4

Table 5 Recommended Dosage Modifications for Adverse Reactions
Severity of Adverse Reaction	Recommended Dosage Modifications for KOSELUGO capsules and KOSELUGO oral granules
Left Ventricular Dysfunction [see Warnings and Precautions (5.1)]

Withhold until resolution. Resume at reduced dose.

Permanently discontinue.
Ocular Toxicity [see Warnings and Precautions (5.2)]

Withhold until resolution. Resume at reduced dose.

Permanently discontinue.
Gastrointestinal Toxicity [see Warnings and Precautions (5.3)]

Withhold until improved to Grade 0 or 1. Resume at same dose. Permanently discontinue if no improvement within 3 days.

Permanently discontinue.

Permanently discontinue.
Skin Toxicity [see Warnings and Precautions (5.4)]

Withhold until improvement. Resume at reduced dose.
Increased Creatine Phosphokinase (CPK) [see Warnings and Precautions (5.5)]

Withhold until improved to Grade 0 or 1. Resume at reduced dose. Permanently discontinue if no improvement within 3 weeks.

Permanently discontinue.
Other Adverse Reactions [see Adverse Reactions (6.1)]

Withhold KOSELUGO until improved to Grade 0 or 1. Resume at reduced dose.

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.

)

•

Moderate hepatic impairment (Child-Pugh B):

The recommended dosage is 20 mg/m² orally twice daily

(see Tables 6 and 7)

. (

2.3 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)
Body Surface Area	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)
Body Surface Area	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.

Asymptomatic decrease in left ventricular ejection fraction (LVEF) of 10% or greater from baseline and less than lower level of normalSymptomatic decreased LVEF

Grade 3 or 4 decreased LVEFRetinal Pigment Epithelial Detachment (RPED)Retinal vein occlusion (RVO)Grade 3 DiarrheaGrade 4 DiarrheaGrade 3 or 4 ColitisGrade 3 or 4Grade 4 Increased CPK

Any Increased CPK and myalgiaRhabdomyolysisIntolerable Grade 2

Grade 3Grade 4

Table 5 Recommended Dosage Modifications for Adverse Reactions
Severity of Adverse Reaction	Recommended Dosage Modifications for KOSELUGO capsules and KOSELUGO oral granules
Left Ventricular Dysfunction [see Warnings and Precautions (5.1)]

Withhold until resolution. Resume at reduced dose.

Permanently discontinue.
Ocular Toxicity [see Warnings and Precautions (5.2)]

Withhold until resolution. Resume at reduced dose.

Permanently discontinue.
Gastrointestinal Toxicity [see Warnings and Precautions (5.3)]

Withhold until improved to Grade 0 or 1. Resume at same dose. Permanently discontinue if no improvement within 3 days.

Permanently discontinue.

Permanently discontinue.
Skin Toxicity [see Warnings and Precautions (5.4)]

Withhold until improvement. Resume at reduced dose.
Increased Creatine Phosphokinase (CPK) [see Warnings and Precautions (5.5)]

Withhold until improved to Grade 0 or 1. Resume at reduced dose. Permanently discontinue if no improvement within 3 weeks.

Permanently discontinue.
Other Adverse Reactions [see Adverse Reactions (6.1)]

Withhold KOSELUGO until improved to Grade 0 or 1. Resume at reduced dose.

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.

2.5 Dosage Modifications for Drug Interactions

Strong or Moderate CYP3A4 Inhibitors or Fluconazole

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/m²twice daily, reduce to 20 mg/m²twice daily (mg/dose)		If the current dosage is 20 mg/m²twice daily, reduce to 15 mg/m²twice daily (mg/dose)
Body Surface Area	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/m²twice daily, reduce to 20 mg/m²twice daily (mg/dose)		If the current dosage is 20 mg/m²twice daily, reduce to 15 mg/m²twice daily (mg/dose)
Body Surface Area	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

)

•

Severe hepatic impairment (Child-Pugh C):

The recommended dosage has not been established. (

2.5 Dosage Modifications for Drug Interactions

Strong or Moderate CYP3A4 Inhibitors or Fluconazole

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/m²twice daily, reduce to 20 mg/m²twice daily (mg/dose)		If the current dosage is 20 mg/m²twice daily, reduce to 15 mg/m²twice daily (mg/dose)
Body Surface Area	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/m²twice daily, reduce to 20 mg/m²twice daily (mg/dose)		If the current dosage is 20 mg/m²twice daily, reduce to 15 mg/m²twice daily (mg/dose)
Body Surface Area	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

8.6 Hepatic Impairment

Selumetinib exposures increased in patients with moderate or severe hepatic impairment

[see Clinical Pharmacology (12.3)]

[see Dosage and Administration (2.4)].

)

•

Strong or Moderate CYP3A4 Inhibitors or Fluconazole:

If coadministration with strong or moderate CYP3A4 inhibitors or fluconazole cannot be avoided, reduce the dose of KOSELUGO

(see Tables 8 and 9)

. (

2.5 Dosage Modifications for Drug Interactions

Strong or Moderate CYP3A4 Inhibitors or Fluconazole

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/m²twice daily, reduce to 20 mg/m²twice daily (mg/dose)		If the current dosage is 20 mg/m²twice daily, reduce to 15 mg/m²twice daily (mg/dose)
Body Surface Area	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/m²twice daily, reduce to 20 mg/m²twice daily (mg/dose)		If the current dosage is 20 mg/m²twice daily, reduce to 15 mg/m²twice daily (mg/dose)
Body Surface Area	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

)

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 ink.

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 body. 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.

•Lactation: Advise not to breastfeed.
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)].

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