Koselugo (Selumetinib)

• Selumetinib is employed to inhibit the MAPK/ERK signaling cascade in patients with neurofibromatosis type 1.
• Neurofibromatosis type 1 with inoperable plexiform neurofibromas: reduces tumor volume and slows disease progression, offering a non‑surgical therapeutic option.
• Plexiform neurofibromas causing pain or functional impairment: may alleviate symptoms and improve daily activity by decreasing lesion size.
• Patients at risk of surgical complications: can delay or avoid the need for invasive surgery through tumor shrinkage and stabilization.

• Selumetinib selectively inhibits the serine/threonine kinases MEK1 and MEK2, key components of the MAPK/ERK pathway. By blocking MEK activity, the drug prevents downstream phosphorylation of ERK, thereby reducing cellular proliferation and survival signals in tumor cells. This targeted inhibition curtails the growth of neurofibromas associated with NF1. The inhibition is reversible and dose‑dependent, leading to decreased transcription of genes involved in cell cycle progression and angiogenesis.

Selumetinib may cause a range of adverse reactions, which are categorized by frequency and severity.

Common Side Effects

• Nausea: mild to moderate stomach upset.
• Diarrhea: loose stools that may require hydration.
• Vomiting: occasional episodes.
• Fatigue: persistent tiredness.
• Rash: skin redness or itching.
• Edema: swelling of hands, feet or ankles.

Serious or Rare Side Effects

• Interstitial lung disease: inflammation of lung tissue requiring medical attention.
• Cardiac dysfunction: reduced left ventricular ejection fraction or heart‑failure signs.
• Retinal vein occlusion: vision changes due to eye blood‑vessel blockage.
• Severe hypertension: high blood pressure that may need treatment.
• Hepatic toxicity: elevated liver enzymes or liver injury.
• Stevens‑Johnson syndrome: severe skin reaction with blistering.

Before initiating therapy, several precautions should be considered.

• Pregnancy: safety unknown; avoid use unless benefits outweigh risks.
• Breastfeeding: unknown safety; discontinue if nursing.
• Renal impairment: monitor kidney function and adjust as needed.
• Hepatic impairment: regular liver‑function testing is advised.
• Cardiac monitoring: obtain baseline and periodic ejection‑fraction assessments.
• Drug interactions: avoid concomitant strong CYP3A4 inhibitors.
• Store at ambient temperature: keep below 25 °C, retain original packaging, protect from moisture.

Selumetinib can interact with other medicines, requiring careful management.

Major Interactions (Avoid)

• Strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole): may increase selumetinib exposure.
• Strong CYP3A4 inducers (e.g., rifampin, carbamazepine): may reduce efficacy.
• Co‑administration with other MEK inhibitors: risk of overlapping toxicity.

Moderate Interactions (Monitor Closely)

• Moderate CYP3A4 inhibitors (e.g., erythromycin): monitor plasma levels.
• Moderate CYP3A4 inducers (e.g., phenytoin): observe for reduced response.
• Warfarin: watch INR for potential anticoagulant effect changes.
• Statins metabolised by CYP3A4: assess for myopathy risk.
• Oral contraceptives: possible reduction in hormonal efficacy.