Usage
Selumetinib is prescribed for the treatment of symptomatic, inoperable plexiform neurofibromas (PNs) in pediatric patients with neurofibromatosis type 1 (NF1) aged 2 years and older. It belongs to the pharmacological class of kinase inhibitors, specifically a MEK1/2 inhibitor. Selumetinib works by blocking the activity of MEK enzymes, which are part of a signaling pathway (RAS/RAF/MEK/ERK) involved in cell growth and division. By inhibiting this pathway, selumetinib helps to reduce the size and growth of PNs.
Alternate Names
Selumetinib is also known by its international nonproprietary name (INN), Selumetinib. It is marketed under the brand name Koselugo.
How It Works
Pharmacodynamics: Selumetinib inhibits the MEK1 and MEK2 kinases, key components of the RAS/RAF/MEK/ERK pathway, crucial for cell growth, proliferation, and survival. Inhibiting MEK reduces downstream ERK phosphorylation, thereby suppressing tumor growth. This targeted approach is particularly relevant in NF1, where the RAS pathway is often dysregulated.
Pharmacokinetics:
- Absorption: Selumetinib is administered orally and is absorbed relatively quickly. Food does not significantly affect absorption.
- Metabolism: Primarily metabolized in the liver, mainly via CYP3A4 and to a lesser extent by CYP2C19. The major active metabolite, N-desmethyl selumetinib, contributes to its overall pharmacological effect.
- Elimination: Selumetinib and its metabolites are excreted both in feces and urine.
Mode of Action: Selumetinib acts as an ATP-noncompetitive inhibitor of MEK1/2, binding to these kinases and preventing their activation. This, in turn, blocks the phosphorylation and activation of ERK, disrupting the downstream signaling cascade and ultimately reducing tumor growth.
Receptor binding, enzyme inhibition or neurotransmitter modulation: Selumetinib primarily exerts its effects through enzyme inhibition, specifically by targeting MEK1/2 kinases.
Elimination pathways: Selumetinib is eliminated through both hepatic (liver) and renal (kidney) pathways, with a significant portion being excreted unchanged in the feces.
Dosage
Standard Dosage
Adults: Selumetinib is not indicated for use in adults. Clinical trials in adults are ongoing but currently, there is no established dosage regimen.
Children:
The recommended dose for children aged 2 years and older is 25 mg/m² body surface area (BSA), administered orally twice daily, approximately every 12 hours. The dose is individualized based on BSA and rounded to the nearest achievable 5 mg or 10 mg dose, up to a maximum single dose of 50 mg. Dosage adjustments are necessary for children with moderate hepatic impairment.
Special Cases:
- Elderly Patients: No specific dosage recommendations for elderly patients as the drug isn’t indicated for adult use.
- Patients with Renal Impairment: No dose adjustment is necessary based on the degree of renal impairment.
- Patients with Hepatic Dysfunction:
- Mild hepatic impairment: No dose adjustment.
- Moderate hepatic impairment: Reduce the dose to 20 mg/m² BSA twice daily.
- Severe hepatic impairment: Selumetinib is contraindicated in patients with severe hepatic impairment.
- Patients with Comorbid Conditions: Careful monitoring for cardiac and ocular side effects is crucial, especially in patients with pre-existing heart or eye problems.
Clinical Use Cases
Selumetinib is specifically indicated for the treatment of inoperable PNs in pediatric NF1 patients. It is not currently used in settings like intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations.
Dosage Adjustments
Dose reductions may be necessary based on the severity of certain adverse reactions, particularly cardiomyopathy, ocular toxicity, gastrointestinal toxicity, and skin toxicity. Consult specific guidelines for detailed recommendations on dose modifications based on adverse events.
Side Effects
Common Side Effects:
Vomiting, rash, abdominal pain, diarrhea, nausea, dry skin, fatigue, musculoskeletal pain, fever, acne, stomatitis (inflammation of the mouth and lips), headache, paronychia (nail infection), itching.
Rare but Serious Side Effects:
Cardiomyopathy (decreased heart function), ocular toxicity (including blurred vision, retinal pigment epithelial detachment, retinal vein occlusion), severe skin reactions, gastrointestinal issues (severe diarrhea, colitis).
Long-Term Effects:
Long-term effects of selumetinib are still being studied. Regular monitoring for cardiac and ocular toxicity is essential during treatment.
Adverse Drug Reactions (ADR):
Serious ADRs requiring immediate intervention include severe cardiomyopathy, retinal detachment, retinal vein occlusion, severe diarrhea, colitis, and serious skin reactions.
Contraindications
- Severe hepatic impairment.
- Hypersensitivity to selumetinib or any of its components.
Drug Interactions
Selumetinib interacts with numerous medications, including:
- Strong CYP3A4 inhibitors and inducers: Avoid concomitant use. Dose adjustments might be necessary if co-administration is unavoidable.
- Moderate CYP3A4 inhibitors and inducers: Use with caution and consider dose adjustments.
- Anticoagulants and antiplatelet agents: Enhanced antiplatelet effects may occur. Close monitoring of coagulation parameters is necessary.
- Vitamin E supplements: Concurrent use is not recommended.
- Hormonal contraceptives: Selumetinib may reduce the effectiveness of oral contraceptives. A barrier method should be added.
- Refer to drug interaction checkers for a comprehensive list of potential interactions.
Pregnancy and Breastfeeding
- Pregnancy Safety Category: Selumetinib can cause fetal harm and is not recommended during pregnancy. Women of childbearing potential should use effective contraception during treatment and for at least one week after the last dose. A negative pregnancy test is recommended before starting treatment.
- Breastfeeding: It is unknown if selumetinib passes into breast milk. Breastfeeding should be discontinued during treatment and for at least one week after the last dose.
Drug Profile Summary
- Mechanism of Action: MEK1/2 inhibitor, blocking the RAS/RAF/MEK/ERK pathway.
- Side Effects: Vomiting, rash, abdominal pain, diarrhea, fatigue, cardiomyopathy, ocular toxicity.
- Contraindications: Severe hepatic impairment, hypersensitivity.
- Drug Interactions: Numerous, especially with CYP3A4 inhibitors/inducers, anticoagulants/antiplatelet agents.
- Pregnancy & Breastfeeding: Not recommended.
- Dosage: Children (2 years and older): 25 mg/m² BSA twice daily. Dosage modifications required for moderate hepatic impairment and based on adverse reactions.
- Monitoring Parameters: LVEF (echocardiogram), eye examinations, creatine phosphokinase (CPK) levels, liver function tests (LFTs).
Popular Combinations
Selumetinib is typically used as monotherapy for PN in NF1. Combination therapies are under investigation, but none are currently established for standard clinical practice.
Precautions
- General Precautions: Assess cardiac function (LVEF) and ocular health before starting treatment. Monitor regularly throughout treatment. Screen for hepatic dysfunction.
- Specific Populations: See “Dosage” section for details on children, patients with renal/hepatic impairment.
- Lifestyle Considerations: Alcohol and smoking should be avoided or minimized, as they can exacerbate some side effects. Driving restrictions may be necessary if visual disturbances occur.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Selumetinib?
A: For children aged 2 years and older, the recommended dosage is 25 mg/m² BSA twice daily, adjusted based on individual BSA and rounded to the nearest 5 or 10 mg increment, up to a maximum single dose of 50 mg. Dosages vary based on hepatic function and BSA. Refer to the dosage section for complete details.
Q2: How does Selumetinib work?
A: Selumetinib inhibits MEK1/2 kinases, key players in the RAS/RAF/MEK/ERK pathway, which is often dysregulated in NF1 and contributes to PN growth. By blocking this pathway, Selumetinib reduces cell growth and proliferation, shrinking tumor size.
Q3: What are the common side effects of Selumetinib?
A: Common side effects include vomiting, rash, abdominal pain, diarrhea, nausea, dry skin, fatigue, musculoskeletal pain, fever, acne, mouth sores, headache, and nail infection.
Q4: What are the serious side effects of Selumetinib?
A: Serious side effects can include heart problems (cardiomyopathy), eye problems (including retinal detachment and retinal vein occlusion), and severe gastrointestinal issues (colitis, severe diarrhea).
Q5: Can Selumetinib be used during pregnancy or breastfeeding?
A: Selumetinib can cause fetal harm and is not recommended during pregnancy. It’s also recommended to discontinue breastfeeding while on this medication. Appropriate contraception should be used during treatment and for at least one week after the last dose.
Q6: What are the contraindications for Selumetinib?
A: Selumetinib is contraindicated in patients with severe hepatic impairment and in patients with hypersensitivity to the drug or its components.
Q7: Does Selumetinib interact with other medications?
A: Yes, Selumetinib has several significant drug interactions, particularly with strong and moderate CYP3A4 inhibitors and inducers. Concomitant use of certain drugs may require dose adjustments or be contraindicated. Consult a comprehensive drug interaction resource for detailed information.
Q8: How should I monitor patients taking Selumetinib?
A: Regular monitoring of left ventricular ejection fraction (LVEF) by echocardiogram, ophthalmological examinations, creatine phosphokinase (CPK) levels, and liver function tests (LFTs) are essential for patients taking Selumetinib. Closely observe for signs of cardiac, ocular, or gastrointestinal toxicity.
Q9: What should I do if a patient experiences vomiting shortly after taking Selumetinib?
A: If a patient vomits shortly after taking a dose, do not administer another dose. Continue with the next scheduled dose as prescribed.
Q10: Are there any dietary restrictions while taking Selumetinib?
A: While food does not significantly affect absorption, it’s generally recommended to take Selumetinib on an empty stomach, either one hour before or two hours after a meal. This helps to ensure consistent drug levels.
