Koselugo allows you to prescribe with the confidence of easy-to-maintain, continuous dosing1

Recommended dosage

25 mg/m2 | twice daily

Dosing is individualized based on BSA (mg/
m2) and is rounded to the nearest achievable 5-mg or 10-mg dose (up to a maximum single dose of 50 mg).

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It is important to monitor your patients and reassess dosage based on their BSA changes.

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Koselugo is available in 25-mg and 10-mg capsules and 28- and 60-count bottles

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Recommended administration of Koselugo:

  • Before prescribing, children should be assessed for the ability to swallow capsules
  • Orally twice daily (approximately every 12 hours) until disease progression

  • No fasting requirement

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  • Swallowed whole with water: Do not chew, dissolve, or open capsule

With 2 dosing strengths and the option to take with or without food, Koselugo offers dosing flexibility.1

Advise patients:

Do not take a missed dose unless it is more than 6 hours until the next scheduled dose

If vomiting occurs, do not take an additional dose but continue with the next scheduled dose

Testing requirements1

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Additional Evaluation Guidelines1:

Ejection Fraction by Echocardiogram: 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 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.

Ophthalmic Assessment: 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 adverse reaction.

Serum CPK: If increased CPK occurs, evaluate patients for rhabdomyolysis or other causes. Withhold, reduce dose, or permanently discontinue Koselugo based on severity of adverse reaction.

Pregnancy Test: Assess the pregnancy status of females of reproductive age. Advise pregnant women of the potential risk to a fetus.

BSA=body surface area; CPK=creatine phosphokinase; LLN=lower limit of normal; LVEF=left ventricular ejection fraction; MRI=magnetic resonance imaging; RPED=retinal pigment epithelial detachment; RVO=retinal vein occlusion.

Koselugo dosing is based on BSA1

Recommended dosage based on BSA

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Recommended dosage and dose reductions for adverse reactions on Koselugo

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*The recommended dosage for patients with a BSA less than 0.55 m2 has not been established.

†Permanently discontinue Koselugo in patients unable to tolerate Koselugo after 2 dose reductions.

BSA=body surface area; BID=twice daily.

Hepatic Impairment‡

Reduce the recommended dosage to 20 mg/m2 orally twice daily in patients with moderate hepatic impairment (Child-Pugh B). The recommended dosage of Koselugo for use in patients with severe hepatic impairment (Child-Pugh C) has not been established.

Drug Interactions‡

Avoid coadministration of strong or moderate CYP3A4 inhibitors or fluconazole with Koselugo. If coadministration with strong or moderate CYP3A4 inhibitors or fluconazole cannot be avoided, reduce the Koselugo dosage as recommended in Table 5 in the Prescribing Information. 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.

‡For recommended dosage in hepatic impairment and dosage modifications due to drug interactions, see Tables 4 and 5 in the Prescribing Information.

Dosage modifications1

Recommended dosage modifications for adverse reactions on Koselugo§

Severity of adverse reaction

Recommended dosage modifications for Koselugo

Cardiomyopathy

  • Asymptomatic decrease in LVEF of 10% or greater from baseline
    and less than LLN

Withhold until resolution.
Resume at reduced dose.

  • Symptomatic decreased LVEF
  • Grade 3 or 4 decreased LVEF

Permanently discontinue.

Ocular toxicity

  • RPED

Withhold until resolution. Resume at reduced dose.

  • RVO

Permanently discontinue.

Gastrointestinal toxicity

  • 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

  • Grade 3 or 4

Withhold until improvement.
Resume at reduced dose.

Increased CPK

  • 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

  • Intolerable Grade 2
  • Grade 3

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

  • Grade 4

Withhold 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.

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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. Koselugo. Package insert. AstraZeneca Pharmaceuticals LP.