A demonstrated long-term safety profile: Koselugo has been studied in patients with NF1 PN for up to 7.7 years1*

Duration of exposure with Koselugo

At the DCO of June 2018 in the SPRINT Phase 2 Stratum 1 study,

88% (44/50)

of patients were exposed to Koselugo for ≥12 months2

66% (33/50)

of patients were exposed to Koselugo for ≥2 years2

Known selumetinib-related adverse reactions can develop years after treatment initiation, and therefore ongoing monitoring is needed while patients remain on Koselugo.1

Adverse reactions (≥20%) in patients who received Koselugo in SPRINT Phase 2 Stratum 12†

Koselugo N=50

Adverse Reaction
All Grades (%)
Grade 3 (%)‡

Gastrointestinal

Vomiting

82
6

Abdominal pain§

76
0

Diarrhea

70
16

Nausea

66
2

Stomatitis‖

50
0

Constipation

34
0

Skin and subcutaneous tissue

Rash (all)

80
6

Dry skin

60
0

Rash acneiform#**

50
4

Paronychia**

48
6

Pruritus

46
0

Dermatitis††

36
4

Hair changes‡‡

32
0

Musculoskeletal and connective tissue

Musculoskeletal pain§§

58
0

General

Fatigue‖‖

56
0

Pyrexia

56
8

Edema¶¶

20
0

Nervous system

Headache

48
2

Respiratory, thoracic, and mediastinal

Epistaxis

28
0

Renal and urinary system

Hematuria

22
2

Proteinuria

22
0

Metabolism and nutrition

Decreased appetite

22
0

Cardiac system

Decreased ejection fraction

22
0

Sinus tachycardia

20
0

Infections

Skin infection##

20
2

*This statement reflects exposure to Koselugo in 74 pediatric patients who received a dosage ranging from 20 mg/m² to 30 mg/m² orally twice daily in SPRINT. At the DCO of February 2021, the median duration of exposure with Koselugo was 4.4 years (range: 28 days to 7.7 years).1

†DCO June 2018.2

‡No AEs greater than Grade 3 were reported.2

§Abdominal pain includes abdominal pain, abdominal pain upper.

‖Stomatitis includes stomatitis, mouth ulceration.

Rash (all) includes dermatitis acneiform, rash maculopapular, erythema, rash pustular, rash, urticaria, exfoliative rash, rash pruritic, rash erythematous.

#Rash (acneiform) includes dermatitis acneiform.

**Paronychia includes paronychia, nail infection.

††Dermatitis includes dermatitis, dermatitis atopic, dermatitis diaper, eczema, seborrheic dermatitis, skin irritation

‡‡Hair changes include alopecia, hair color change.

§§Musculoskeletal pain includes pain in extremity, back pain, neck pain, musculoskeletal pain.

‖‖Fatigue includes fatigue, malaise.

¶¶Edema includes peripheral swelling, edema, localized edema.

##Skin infection includes skin infection, abscess, cellulitis, impetigo, staphylococcal skin infection.

AE=adverse event; DCO=data cutoff; NF1=neurofibromatosis type 1; PN=plexiform neurofibromas.

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Dosing & AE Management Guide

A guide that provides dosing information and presents how specific toxicities were managed in the SPRINT study, based on institutional policies and guidelines

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Adverse reactions are well characterized, can be manageable, and may not require discontinuation2

red bubble with numbers

were able to stay on a full dose of Koselugo, without the need for a dose reduction***

blue bubble with numbers

required a dose interruption but avoided discontinuation***

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.2

12% (6/50) of patients permanently discontinued due to an AE2

  • These AEs included increased blood creatinine, increased weight, diarrhea, paronychia, malignant peripheral nerve sheath tumor, acute kidney injury, and skin ulcer2
  • 10% (5/50) of patients discontinued due to treatment-related AEs3
  • The median time to discontinuation for those 5 patients was 277 days (range: 64 days to 636 days)3

Select laboratory abnormalities (≥15%) worsening from baseline in patients who received Koselugo in SPRINT Phase 2 Stratum 12

Koselugo

Laboratory Abnormality
All Grades (%)‡ ‡ ‡
Grade ≥3 (%)

Chemistry

Increased CPK

79
7‡‡‡

Decreased albumin

51
0

Increased AST

41
2

Increased 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

In the long-term follow-up, the median duration of exposure with Koselugo was 4.4 years. During this time, no new safety signals were identified.1*§§§

***Due to adverse reactions. DCO June 2018.2

†††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 posttreatment value.2

‡‡‡Includes one Grade 4 increased CPK and one Grade 4 increased potassium.2

§§§No new safety signals were identified compared to the earlier publications.

ALT=alanine aminotransferase; AST=aspartate aminotransferase; CPK=creatine phosphokinase.

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IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Cardiomyopathy. A decrease in left
ventricular ejection fraction (LVEF) ≥10% below baseline occurred in pediatric
patients who received Koselugo in SPRINT with some experiencing decreased LVEF below the institutional lower limit of normal
(LLN), including one patient with Grade 3.
All patients with decreased LVEF were asymptomatic and identified during routine echocardiography. The safety of Koselugo has not been established in patients with a history of impaired LVEF or a baseline ejection fraction that is below the institutional LLN. 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. In patients who interrupt Koselugo for decreased LVEF, obtain an echocardiogram or a cardiac MRI every 3 to 6 weeks. Upon resolution of decreased LVEF, obtain an echocardiogram or a cardiac MRI every 2 to 3 months.

Ocular Toxicity. Blurred vision,
photophobia, cataracts, and ocular hypertension occurred. Retinal pigment epithelial detachment (RPED) occurred in the pediatric population during treatment with single agent Koselugo and resulted in permanent discontinuation. Conduct ophthalmic assessments prior to initiating Koselugo, at regular intervals during treatment, and for new or worsening visual changes. Permanently discontinue Koselugo in patients with retinal vein occlusion (RVO). Withhold Koselugo in patients with RPED, conduct ophthalmic assessments every 3 weeks until resolution, and resume Koselugo at a reduced dose.

Gastrointestinal Toxicity. Diarrhea
occurred, including Grade 3. Diarrhea resulting in permanent discontinuation, dose interruption or dose reduction occurred. Advise patients to start an anti-diarrheal agent (eg, loperamide) and to increase fluid intake immediately after the first episode of diarrhea. Withhold, reduce dose, or permanently discontinue Koselugo based on severity of adverse reaction.

Skin Toxicity. Rash occurred in 91% of 74 pediatric patients. The most frequent rashes included dermatitis acneiform (54%), maculopapular rash (39%), and eczema (28%). Grade 3 rash occurred, in addition to rash resulting in dose interruption or dose reduction. Monitor for severe skin rashes. Withhold, reduce dose, or permanently discontinue Koselugo based on severity of adverse reaction.

Increased Creatine Phosphokinase (CPK). Increased CPK occurred, including Grade 3 or 4 resulting in dose reduction. Increased CPK concurrent with myalgia occurred, including one patient who permanently discontinued Koselugo for myalgia. Obtain serum CPK prior to initiating Koselugo, periodically during treatment, and as clinically indicated. If increased CPK occurs, evaluate for rhabdomyolysis or other causes. Withhold, reduce dose, or permanently discontinue Koselugo based on severity of adverse reaction.

Increased Levels of Vitamin E and Risk of Bleeding. Koselugo capsules contain
vitamin E which can inhibit platelet aggregation and antagonize vitamin K-dependent clotting factors. 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 due to increased risk of bleeding. An increased risk of bleeding may occur in patients who are coadministered vitamin-K antagonists or anti-platelet antagonists with Koselugo. Monitor for bleeding in these patients and increase international normalized ratio (INR) in patients taking a vitamin-K antagonist. Perform anticoagulant assessments more frequently and adjust the dose of vitamin K antagonists or anti-platelet agents as appropriate.

Embryo-Fetal Toxicity. Based on findings from animal studies, Koselugo can cause fetal harm when administered during pregnancy. In animal 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 patients of reproductive potential of the potential risk to a fetus and to use effective contraception during treatment with Koselugo and for 1 week after the last dose.

ADVERSE REACTIONS

Common adverse reactions ≥40% include vomiting, rash (all), abdominal pain, diarrhea, nausea, dry skin, musculoskeletal pain, fatigue, pyrexia, acneiform rash, stomatitis, headache, paronychia, and pruritus.

DRUG INTERACTIONS

Effect of Other Drugs on Koselugo

Concomitant use of Koselugo with a strong
or moderate CYP3A4 inhibitor or
fluconazole increased selumetinib plasma concentrations, which may increase the risk of adverse reactions. Avoid coadministration with Koselugo. If coadministration cannot be avoided, reduce Koselugo dosage.

Concomitant use of Koselugo with a strong or moderate CYP3A4 inducer decreased selumetinib plasma concentrations, which may reduce Koselugo efficacy. Avoid concomitant use with Koselugo.

SPECIAL POPULATIONS

Pregnancy & Lactation. Verify the
pregnancy status of patients of reproductive potential prior to initiating Koselugo. Due to the potential for adverse reactions in a breastfed child, advise patients not to breastfeed during treatment with Koselugo and for 1 week after the last dose.

INDICATION

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

To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca
1-800-236-9933 or at https://us-aereporting.astrazeneca.com or FDA at
1-800-FDA-1088 or www.fda.gov/
medwatch.

Please see full Prescribing Information for Koselugo® (selumetinib).

References:

1. Gross AM, Dombi E, Wolters PL, et al. Long-term safety and efficacy of selumetinib in children with neurofibromatosis type 1 on a phase 1/2 trial for inoperable plexiform neurofibromas. Neuro Oncol. 2023;25(10):1883-1894. doi:10.1093/
neuonc/noad086

2. Koselugo. Package insert. AstraZeneca Pharmaceuticals LP.

3. Data on File, REF-75729, AstraZeneca Pharmaceuticals LP.