FDA Approves KOSELUGO (selumetinib) for the Treatment of Pediatric Patients 2 Years of Age and Older with Neurofibromatosis Type 1 who Have Symptomatic, Inoperable Plexiform Neurofibromas


On April 10, 2020, the U.S. Food and Drug Administration (FDA) approved KOSELUGO (selumetinib) for the treatment of pediatric patients 2 years of age and older with neurofibromatosis type 1 (NF1) who have symptomatic, inoperable plexiform neurofibromas (PN). The approved 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.

Additional information regarding dosage and administration, including dosage modifications for adverse reactions, as well as important warnings and precautions about cardiomyopathy, ocular toxicity, gastrointestinal toxicity, skin toxicity, increased creatinine phosphokinase, increased levels of vitamin E and risk of bleeding, and embryo-fetal toxicity can be found in the full prescribing information linked below.

Mechanism of Action (MOA), Pharmacokinetics (PK), and Pharmacodynamics (PD)

  • MOA: Selumetinib is an inhibitor of mitogen-activated protein kinase kinases 1 and 2 (MEK1/2).

     

  • General PK: At the recommended dosage of 25 mg/m2 twice daily in pediatric patients (2 to ≤ 18 years old), the mean Cmax (CV%) following the first dose was 731 (62%) ng/mL and at steady state was 798 (52%) ng/mL. The mean AUC0-12h following the first dose was 2009 (35%) ng•h/mL and the AUC0-6h at steady state was 1958 (41%) ng•h/mL. Selumetinib AUC and Cmax increases proportionally over a dose range from 20 mg/m2 to 30 mg/m2 (0.8 to 1.2 times the recommended dose). The accumulation was 1.1-fold following administration of KOSELUGO 25 mg/m2 twice daily.

     

  • Absorption: The mean absolute oral bioavailability of selumetinib was 62% in healthy adults. The median time to peak plasma concentrations (Tmax) at steady-state in pediatric patients was 1 to 1.5 hours.

     

  • Effect of Food: Mean Cmax and AUC of selumetinib decreased by 50% and 16%, respectively, following a high-fat meal (1000 calories, 50% fat) in healthy adults administered a single-dose of 75 mg (1.5 times the approved maximum recommended dosage). Tmax was delayed by approximately 1.5 hours following a high-fat meal. Selumetinib Cmax and AUC decreased by 60% and 38%, respectively, following a low-fat meal (400 calories, 25% fat) in healthy adults administered a single-dose of 50 mg. Tmax was delayed by approximately 0.9 hours following a low-fat meal.

     

  • Distribution: The mean apparent volume of distribution of selumetinib across a dose range of 20 mg/m2 to 30 mg/m2 (0.8 to 1.2 times the recommended dosage) at steady state ranged from 78 L to 171 L in pediatric patients. The plasma protein binding was 98.4% in humans in vitro. Selumetinib binds to serum albumin (96%) and α-1 acid glycoprotein (< 35%).

     

  • Elimination: In pediatric patients, selumetinib had a mean elimination half-life of approximately 6.2 hours and an apparent oral clearance of 8.8 L/hr.

     

  • Metabolism: Selumetinib is primarily metabolized by CYP3A4 and to a lesser extent by CYP2C19, CYP1A2, CYP2C9, CYP2E1, and CYP3A5. Selumetinib also undergoes glucuronidation by UGT1A1 and UGT1A3. The active metabolite, N-desmethyl selumetinib is approximately 3 to 5 times more potent than the parent compound, contributing to about 21% to 35% of the overall pharmacologic activity.

     

  • Excretion: After a single oral dose of radiolabeled selumetinib 75 mg (1.5 times the recommended dose) to healthy adults, 59% of the dose was recovered in feces (19% as unchanged) and 33% in urine (< 1% as parent).

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 dose of KOSELUGO. 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.

     

  • Strong or Moderate CYP3A4 Inducers: Avoid concomitant use of strong and moderate CYP3A4 inducers. Concomitant use of KOSELUGO with a strong or moderate CYP3A4 inducer decreased selumetinib plasma concentrations, which may reduce KOSELUGO efficacy.

     

  • Vitamin E: 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. 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.

Use in Specific Populations

No clinically meaningful effect on the pharmacokinetics of selumetinib or N-desmethyl selumetinib were observed based on race (White, Asian, Black), renal impairment, or end stage renal disease (CLcr < 15 mL/min) requiring dialysis. 

  • Hepatic Impairment: Reduce the dose of KOSELUGO for patients with moderate hepatic impairment (Child-Pugh B). A recommended dosage of KOSELUGO for use in patients with severe hepatic impairment (Child-Pugh C) has not been established. Selumetinib exposures increased in patients with moderate or severe hepatic impairment but did not show clinically meaningful change in patients with mild hepatic impairment (Child-Pugh A).

     

  • Lactation: Due to the potential for adverse reactions in a breastfed child, advise women not to breastfeed during treatment with KOSELUGO and for 1 week after the last dose.

Efficacy and Safety

Efficacy of KOSELUGO was demonstrated in an open-label, multicenter, single arm trial that enrolled pediatric patients who had NF1 with inoperable PN. The major efficacy outcome measure was overall response rate (ORR), defined as the percentage of patients with complete response (defined as disappearance of the target PN) or confirmed partial response (defined as ≥ 20% reduction in PN volume confirmed at a subsequent tumor assessment within 3-6 months). Additional information regarding the efficacy trial can be found in the full prescribing information linked below.

The most common adverse reactions (≥ 40%) are: vomiting, rash (all), abdominal pain, diarrhea, nausea, dry skin, fatigue, musculoskeletal pain, pyrexia, acneiform rash, stomatitis, headache, paronychia, and pruritus.

Full prescribing information is available at https://go.usa.gov/xvBnj. 

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This communication was prepared by Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.