Selumetinib (Koselugo) for Neurofibromatosis: Side Effects & Dosage

What is Koselugo (selumetinib), and what is it used for?

Brand name: Koselugo

Generic: selumetinib

Koselugo (selumetinib) is a prescription medicine that is used to treat children 2 years of age and older with neurofibromatosis type 1 (NF1) who have plexiform neurofibromas that cannot be completely removed by surgery.

It is not known if Koselugo is safe and effective in children under 2 years of age.

What are the side effects of Koselugo?

Koselugo may cause serious side effects, including:

  • Heart
    problems.     Koselugo can lower the amount of blood pumped by your heart which is common and can also 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:

  • 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 any of the following signs or symptoms:

  • Severe diarrhea. Diarrhea is common with Koselugo and can also be severe. 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
    rash.     Skin rashes are common with Koselugo and can also be severe. Tell your healthcare provider if you get any of the following signs or symptoms:

  • Muscle problems (rhabdomyolysis). Muscle problems are common with Koselugo and can also be severe. Treatment with Koselugo may increase the level of enzyme in your blood called creatine phosphokinase (CPK) and may be a sign of muscle damage. Your healthcare provider should do a blood test to check your blood levels of CPK before you start taking Koselugo and during treatment. Tell your healthcare provider right away if you get any of the following signs or symptoms:

Your healthcare provider may change your dose, temporarily stop, or permanently ask you to stop taking Koselugo if you have any of these side effects.

The most common side effects of Koselugo are:

These are not all the possible side effects of Koselugo.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA1088.

Is Koselugo addictive?

No information provided

What is the dosage for Koselugo?

Recommended Dosage

The recommended dosage of Koselugo is 25 mg/m2 orally twice daily (approximately every 12 hours) until disease progression or unacceptable toxicity.

Take Koselugo on an empty stomach. Do not consume food 2 hours before each dose or 1 hour after each dose. The recommended dose of Koselugo based on body surface area (BSA) is shown in Table 1.

Table 1 Recommended Dosage Based on Body Surface Area

Body Surface Area*
Recommended Dosage

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 for patients with a BSA less than 0.55m2 has not been established.

Swallow Koselugo capsules whole with water. Do not chew, dissolve or open capsule.

Do not administer to patients who are unable to swallow a whole capsule.

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

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

Dosage Modifications For Adverse Reactions

The recommended dose reductions for adverse reactions are provided in Table 2.

Table 2 Recommended Dose Reductions for Koselugo for Adverse Reactions

Body Surface Area
First Dose Reduction
(mg/dose)
Second Dose Reduction*
(mg/dose)

Morning
Evening
Morning
Evening

0.55 – 0.69 m2
10
10
10 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 in patients unable to tolerate Koselugo after two dose reductions.

Dosage modifications for adverse reactions are in Table 3.

Table 3 Recommended Dosage Modifications for Koselugo for Adverse Reactions

Severity of Adverse Reaction
Recommended Dosage Modifications for Koselugo

Cardiomyopathy

  • Asymptomatic decrease in left ventricular ejection (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

  • Retinal Pigment Epithelial Detachment (RPED)

Withhold until resolution. Resume at reduced dose.

Retinal vein occlusion (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 Creatinine Phosphokinase (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 Koselugo until improve 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

Reduce the recommended dosage of Koselugo 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 [see Use In Specific Populations].

Table 4 Recommended Dosage of Koselugo for Moderate Hepatic Impairment

Body Surface Area
Moderate Hepatic Impairment
(Child-Pugh B)
(mg/dose)

Morning
Evening

0.55 – 0.69 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

Dosage Modifications For Drug Interactions

Strong Or Moderate CYP3A4 Inhibitors Or Fluconazole

Avoid coadministration of strong or moderate CYP3A4 inhibitors or fluconazole with Koselugo. If coadministration with strong or moderate CYP3A4 inhibitors or fluconazole cannot be avoided, reduce the Koselugo dosage as recommended in Table 5. After discontinuation of the strong or moderate CYP3A4 inhibitor or fluconazole for 3 elimination half-lives, resume the Koselugo dose that was taken prior to initiating the inhibitor or fluconazole.

Table 5 Recommended Dosage of Koselugo for Coadministration with Strong or Moderate CYP3A4 Inhibitors or Fluconazole

Body Surface Area
If the current dosage is 25 mg/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 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

How should I take Koselugo?

  • Take 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 may change your dose, temporarily stop, or permanently stop treatment with Koselugo if you have side effects.
  • Your healthcare provider will decide on the right dose of Koselugo based on your weight or size (body surface area) and how many capsules of Koselugo to take.
  • Koselugo should be taken around the same time each day, about 12 hours apart.
  • Take Koselugo on an empty stomach. Do not eat food for 2 hours before your dose and 1 hour after your dose.
  • Swallow Koselugo capsules whole with water. Do not chew, dissolve, or open the capsules.
  • If you miss a dose of Koselugo, take it as soon as you remember. If it is less than 6 hours before your next scheduled dose, take your next dose at your regular time. Do not make up for the missed dose.
  • If you vomit at any time after taking Koselugo, do not take an additional dose. Take your next dose at your regular time.

What should I avoid while taking Koselugo?

  • Do not drink grapefruit juice, eat grapefruit or take supplements that contain grapefruit or St. John’s Wort during treatment with Koselugo.

What drugs interact with Koselugo?

Effect of Other Drugs on Koselugo

Strong or Moderate CYP3A4 Inhibitors or FluconazoleClinical Impact

  • 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.

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.

Strong or Moderate CYP3A4 InducersClinical Impact

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

Management

  • Avoid concomitant use of strong or moderate CYP3A4 inducers with
    Koselugo.

Vitamin EClinical Impact

  • Koselugo contains vitamin E and daily vitamin E intake that exceeds the recommended or safe limits may increase the risk of bleeding. An increased risk of bleeding may occur in patients taking a vitamin-K antagonist or an anti-platelet agent with
    Koselugo.

Management

  • Supplemental vitamin E is not recommended if daily vitamin E intake (including the amount of vitamin E in
    Koselugo and supplement) will exceed the recommended or safe limits.
  • Monitor for bleeding in patients coadministered a vitamin-K antagonist or an
    anti-platelet agent with Koselugo. Increase INR monitoring, as appropriate,
    in patients taking a vitamin-K antagonist.

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Koselugo contraindications, and pregnancy and breastfeeding safety

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

  • have heart problems.
  • have eye problems.
  • are pregnant or plan to become pregnant. Koselugo can harm your unborn baby.
    • Your healthcare provider should check to see if you are pregnant before you begin treatment with Koselugo.
    • Females who are able to become pregnant should use effective birth control (contraception) during treatment with Koselugo and for 1 week after your last dose.
    • Males with female partners who are able to become pregnant 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.
  • 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. Especially tell your healthcare provider if you are taking aspirin, blood thinners, or other medicines to treat blood clots. Koselugo contains vitamin E, which may increase your risk of bleeding.

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