Drug Detail:Selumetinib (Selumetinib [ sel-ue-met-i-nib ])
Drug Class: Multikinase inhibitors
Usual Pediatric Dose for Fibromatosis
Recommended dosage in pediatric patients ages 2 to 18 years old: 25 mg/m2 orally twice a day (approximately every 12 hours) until disease progression or unacceptable toxicity.
Recommended dosage to achieve 25 mg/m2 twice a day based on body surface area (BSA):
- BSA less than 0.55 mg/m2: No dose recommendation.
- BSA 0.55 to 0.69 m2: 20 mg orally in the morning and 10 mg in the evening
- BSA 0.7 to 0.89 m2: 20 mg orally twice a day
- BSA 0.9 to 1.09 m2: 25 mg orally twice a day
- BSA 1.1 to 1.29 m2: 30 mg orally twice a day
- BSA 1.3 to 1.49 m2: 35 mg orally twice a day
- BSA 1.5 to 1.69 m2: 40 mg orally twice a day
- BSA 1.7 to 1.89 m2: 45 mg orally twice a day
- BSA 1.9 mg/m2 or greater: 50 mg orally twice a day
Comments:
- Do not administer to patients who are unable to swallow.
Use: For the treatment of pediatric patients 2 years of age and older with neurofibromatosis type 1 (NF1) who have symptomatic, inoperable plexiform neurofibromas (PN).
Renal Dose Adjustments
No adjustment recommended.
Liver Dose Adjustments
MILD HEPATIC DYSFUNCTION (Child-Pugh A): No dose adjustment recommended.
MODERATE HEPATIC DYSFUNCTION (Child-Pugh B): Reduce starting dosage to 20 mg/m2 twice a day.
Recommended dosage to achieve 20 mg/m2 twice a day based on body surface area (BSA):
- BSA 0.55 to 0.69 m2: 10 mg orally twice a day
- BSA 0.7 to 0.89 m2: 20 mg orally in the morning and 10 mg in the evening
- BSA 0.9 to 1.09 m2: 20 mg orally twice a day
- BSA 1.1 to 1.29 m2: 25 mg orally twice a day
- BSA 1.3 to 1.49 m2: 30 mg orally in the morning and 25 mg in the evening
- BSA 1.5 to 1.69 m2: 35 mg orally in the morning and 30 mg in the evening
- BSA 1.7 to 1.89 m2: 35 mg orally twice a day
- BSA 1.9 m2 or greater: 40 mg orally twice a day
SEVERE HEPATIC DYSFUNCTION (Child-Pugh C): Recommended dosage is unknown or not established.
Dose Adjustments
RECOMMENDED DOSE REDUCTIONS FOR ADVERSE REACTIONS:
General: If patient is unable to tolerate therapy after 2 dose reductions, therapy should be permanently discontinued.
Dose reduction recommendations based on body surface area (BSA):
BSA 0.55 to 0.69 m2:
- First dose reduction: 10 mg orally twice a day
- Second dose reduction: 10 mg orally once a day
BSA 0.7 to 0.89 m2:
- First dose reduction: 20 mg orally in the morning and 10 mg in the evening
- Second dose reduction: 10 mg orally twice a day
BSA 0.9 to 1.09 m2:
- First dose reduction: 25 mg orally in the morning and 10 mg in the evening
- Second dose reduction: 10 mg orally twice a day
BSA 1.1 to 1.29 m2:
- First dose reduction: 25 mg orally in the morning and 20 mg in the evening
- Second dose reduction: 20 mg orally in the morning and 10 mg in the evening
BSA 1.3 to 1.49 m2:
- First dose reduction: 25 mg orally twice a day
- Second dose reduction: 25 mg orally in the morning and 10 mg in the evening
BSA 1.5 to 1.69 m2:
- First dose reduction: 30 mg orally twice a day
- Second dose reduction: 25 mg orally in the morning and 20 mg in the evening
BSA 1.7 to 1.89 m2:
- First dose reduction: 35 mg orally in the morning and 30 mg in the evening
- Second dose reduction: 25 mg orally in the morning and 20 mg in the evening
BSA 1.9 m2 or greater:
- First dose reduction: 35 mg orally twice a day
- Second dose reduction: 25 mg orally twice a day
RECOMMENDED DOSE MODIFICATIONS FOR ADVERSE REACTIONS:
Cardiomyopathy:
- Asymptomatic decrease in left ventricular ejection fraction (LVEF) of 10% or greater from baseline and less than lower level of normal: Withhold therapy until resolution; resume at reduced dose.
- Symptomatic decreased LVEF: Permanently discontinue therapy.
- Grade 3 or 4 decreased LVEF: Permanently discontinue therapy.
Ocular Toxicity:
- Retinal pigment epithelial detachment (RPED): Withhold therapy until resolution; resume at reduced dose.
- Retinal vein occlusion (RVO): Permanently discontinue therapy.
Gastrointestinal Toxicity:
- Grade 3 diarrhea: Withhold until improved to Grade 0 or 1, then resume at same dose. Permanently discontinue if no improvement within 3 days.
- Grade 4 diarrhea: Permanently discontinue therapy.
- Grade 3 or 4 colitis: Permanently discontinue therapy.
Skin Toxicity:
- Grade 3 or 4: Withhold therapy until improvement; resume at reduced dose.
Increased Creatine Phosphokinase (CPK):
- Grade 4 Increased CPK: Withhold therapy until improved to Grade 0 or 1, then resume at reduced dose. Permanently discontinue therapy if no improvement within 3 weeks.
- Any Increased CPK and myalgia: Withhold therapy until improved to Grade 0 or 1, then resume at reduced dose. Permanently discontinue therapy if no improvement within 3 weeks.
- Rhabdomyolysis: Permanently discontinue therapy.
Other Adverse Reactions:
- Grade 2 (intolerable) or Grade 3: Withhold therapy until improved to Grade 0 or 1; resume at reduced dose.
- Grade 4: Withhold therapy until improved to Grade 0 or 1; resume at reduced dose. Consider discontinuation of therapy.
RECOMMENDED DOSE REDUCTIONS FOR COADMINISTRATION WITH STRONG OR MODERATE CYP450 3A4 INHIBITORS OR FLUCONAZOLE:
General Recommendations:
- Avoid coadministration of strong or moderate CYP450 3A4 inhibitors or fluconazole with this drug.
- If coadministration with strong or moderate CYP450 3A4 inhibitors or fluconazole cannot be avoided, reduce the dose of this drug as recommended below.
- After the discontinuation of the strong or moderate CYP450 3A4 inhibitor or fluconazole for 3 elimination half-lives, resume this drug at the dose taken prior to initiating the inhibitor or fluconazole.
Dose Reduction Recommendations for Coadministration with CYP450 3A4 inhibitors or fluconazole:
- If the current dosage is based on 25 mg/m2 twice a day, reduce to 20 mg/m2 twice a day.
- If the current dosage is based on 20 mg/m2 twice a day, reduce to 15 mg/m2 twice a day.
Body surface area dosing recommendations to achieve 20 mg/m2 twice a day:
- BSA 0.55 to 0.69 m2: 10 mg orally twice a day
- BSA 0.7 to 0.89 m2: 20 mg orally in the morning and 10 mg in the evening
- BSA 0.9 to 1.09 m2: 20 mg orally twice a day
- BSA 1.1 to 1.29 m2: 25 mg orally twice a day
- BSA 1.3 to 1.49 m2: 30 mg orally in the morning and 25 mg in the evening
- BSA 1.5 to 1.69 m2: 35 mg orally in the morning and 30 mg in the evening
- BSA 1.7 to 1.89 m2: 35 mg orally twice a day
- BSA 1.9 m2 or greater: 40 mg orally twice a day
Body surface area dosing recommendations to achieve 15 mg/m2 twice daily:
- BSA 0.55 to 0.69 m2: 10 mg orally once daily
- BSA 0.7 to 0.89 m2: 10 mg orally twice a day
- BSA 0.9 to 1.09 m2: 20 mg orally in the morning and 10 mg in the evening
- BSA 1.1 to 1.29 m2: 25 mg orally in the morning and 10 mg in the evening
- BSA 1.3 to 1.49 m2: 25 mg orally in the morning and 20 mg in the evening
- BSA 1.5 to 1.69 m2: 25 mg orally twice a day
- BSA 1.7 to 1.89 m2: 30 mg orally in the morning and 25 mg in the evening
- BSA 1.9 m2 or greater: 30 mg orally twice a day
Precautions
CONTRAINDICATIONS: None
Safety and efficacy have not been established in patients younger than 2 years.
Consult WARNINGS section for additional precautions.
Dialysis
This drug is not dialyzable because it is highly protein bound and extensively metabolized.
Other Comments
Administration advice:
- The manufacturer product information should be consulted prior to product administration.
- This drug should be given on an empty stomach; food consumption should be avoided 2 hours before each dose or for 1 hour after each dose.
- Capsules should be swallowed whole with water, and should not be chewed, dissolved, or opened.
- Do not administer to patients who are unable to swallow a whole capsule.
- Do not take a missed dose unless it is more than 6 hours until the next scheduled dose.
- If vomiting occurs after administration, do not take an additional dose, but continue with the next scheduled dose.
Storage requirements:
- Store at 25C (77F); excursions permitted from 15C to 30C (59F to 86F).
- Dispense in original bottle and do not remove desiccant.
- Protect from moisture.
Monitoring:
- Cardiovascular: Assess left ventricular ejection fraction every 3 months during the first year, and then every 6 months thereafter, or as clinically indicated.
- Dermatologic: Monitor for severe skin rashes.
- Gastrointestinal: Monitor for diarrhea or loose stool.
- General: Review patient medication list regularly for potential drug interactions.
- Musculoskeletal: Assess creatine phosphokinase periodically during treatment and monitor for myalgia or muscle weakness.
- Ocular: Monitor vision for new or worsening changes at regular intervals during therapy.
Patient advice:
- Read the FDA-approved patient labeling (Medication Guide).
- Take this drug on an empty stomach; do not eat for 2 hours before dose and for 1 hour after dose.
- Use effective contraception during therapy and for 1 week after last dose.
- Report symptoms associated with cardiomyopathy and reduced ejection fraction.
- Inform healthcare provider of any new episodes of diarrhea or loose stool.
- Report new or worsening changes in vision.
- Notify healthcare provider of any changes in the skin or new rashes.
- Report symptoms of muscle pain or weakness immediately to healthcare provider.
- Avoid taking supplemental vitamin E
