SEMEDX 25 (Selumetinib)

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 Selumetinib is safe and effective in children under 2 years of age.

PEDIATRIC

Type 1 Neurofibromatosis

Indicated for neurofibromatosis type 1 (NF1) in patients aged ≥2 years who have symptomatic, inoperable plexiform neurofibromas (PN)

<2 years or body surface area (BSA) <0.55 m²: Safety and efficacy not established

≥2 years

• BSA ≥0.55 m²: 25 mg/m² PO BID (~q12hr)

• Recommended dosage based on BSA

  • 0.55-0.69 m²: 20 mg PO qAM and 10 mg PO qPM
  • 0.7-0.89 m²: 20 mg PO BID
  • 0.9-1.09 m²: 25 mg PO BID
  • 1.1-1.29 m²: 30 mg PO BID
  • 1.3-1.49 m²: 35 mg PO BID
  • 1.5-1.69 m²: 40 mg PO BID
  • 1.7-1.89 m²: 45 mg PO BID
  • ≥1.9 m²: 50 mg PO BID

Dosage Modifications

Dose reductions for adverse reactions based on BSA

• First dose reduction

  • 0.55-0.69 m²: 10 mg BID
  • 0.7-0.89 m²: 20 mg qAM and 10 mg qPM
  • 0.9-1.09 m²: 25 mg qAM and 10 mg qPM
  • 1.1-1.29 m²: 25 mg qAM and 20 mg qPM
  • 1.3-1.49 m²: 25 mg BID
  • 1.5-1.69 m²: 30 mg BID
  • 1.7-1.89 m²: 35 mg qAM and 30 mg qPM
  • ≥1.9 m²: 35 mg BID

• Second dose reduction

  • 0.55-0.69 m²: 10 mg qDay
  • 0.7-1.09 m²: 10 mg BID
  • 1.1-1.29 m²: 20 mg qAM and 10 mg qPM
  • 1.3-1.49 m²: 25 mg qAM and 10 mg qPM
  • 1.5-1.89 m²: 25 mg qAM and 20 mg qPM
  • ≥1.9 m²: 25 mg BID

• Subsequent dose reductions

  • Permanently discontinue in patients unable to tolerate selumetinib after 2 dose reductions

Cardiomyopathy

• Asymptomatic decrease in left ventricular ejection fraction (LVEF) ≥10% from baseline and lower level of normal (LLN): Withhold until resolution; resume at reduced dose
• Symptomatic decreased LVEF OR 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 <1; resume at same dose; permanently discontinue if no improvement within 3 days
• Grade 4 diarrhea OR Grade 3 or 4 colitis: Permanently discontinue

Skin toxicity

• Grade 3 or 4: Withhold until improvement; resume at reduced dose

Increased creatine phosphokinase (CPK)

• Grade 4 increased CPK OR any increased CPK and myalgia: Withhold until improved to Grade <1; resume at reduced dose; permanently discontinue if no improvement within 3 weeks

Other adverse reactions

• Intolerable Grade 2 OR Grade 3: Withhold until improved to Grade <1; resume at reduced dose
• Grade 4: Withhold until improved to Grade <1; resume at reduced dose; consider discontinuation

Dosage modifications for drug interactions

Strong or moderate CYP3A4 inhibitors or fluconazole

• Avoid coadministration
• If coadministration cannot be avoided, reduce selumetinib dosage based on the recommendations below
• Resume selumetinib after discontinuation of the strong or moderate CYP3A4 inhibitor or fluconazole for 3 elimination half-lives
• Reduce current dose by 5 mg/m2 (eg, 25 mg/m² to 20 mg/m² OR 20 mg/m² to 15 mg/m²)

• Dosage reduction to 20 mg/m2 based on BSA

  • 0.55-0.69 m²: 10 mg BID
  • 0.7-0.89 m²: 20 mg qAM and 10 mg qPM
  • 0.9-1.09 m²: 20 mg BID
  • 1.1-1.29 m²: 25 mg BID
  • 1.3-1.49 m²: 30 mg qAM and 25 mg qPM
  • 1.5-1.69 m²: 35 mg qAM and 30 mg qPM
  • 1.7-1.89 m²: 35 mg BID
  • ≥1.9 m²: 40 mg BID

• Dosage reduction to 15 mg/m2 based on BSA

  • 0.55-0.69 m²: 10 mg qDay
  • 0.7-0.89 m²: 10 mg BID
  • 0.9-1.09 m²: 20 mg qAM and 10 mg qPM
  • 1.1-1.29 m²: 25 mg qAM and 10 mg qPM
  • 1.3-1.49 m²: 25 mg qAM and 20 mg qPM
  • 1.5-1.69 m²: 25 mg BID
  • 1.7-1.89 m²: 30 mg qAM and 25 mg qPM
  • ≥1.9 m²: 30 mg BID

Renal impairment

• No dosage adjustment necessary

Hepatic impairment

• Mild (Child-Pugh A): No dosage adjustment necessary

• Moderate (Child-Pugh B): Reduce recommended dose to 20 mg/m2 BID

  • 0.55-0.69 m²: 10 mg BID
  • 0.7-0.89 m²: 20 mg qAM and 10 mg qPM
  • 0.9-1.09 m²: 20 mg BID
  • 1.1-1.29 m²: 25 mg BID
  • 1.3-1.49 m²: 30 mg qAM and 25 mg qPM
  • 1.5-1.69 m²: 35 mg qAM and 30 mg qPM
  • 1.7-1.89 m²: 35 mg BID
  • ≥1.9 m²: 40 mg BID
• Severe (Child-Pugh C): Selumetinib unbound AUC increased 3.2-fold in subjects with severe hepatic impairment compared with normal hepatic function; no dosage recommended