KOSELUGO

Selumetinib pharmacokinetics were observed at steady state in adult and pediatric patients with NF1 and are presented as mean (CV%) unless otherwise indicated. The maximum plasma concentration (C max ) is 792 (49) ng/mL and systemic exposure (AUC) is 2141 (55) ng

• h/mL following KOSELUGO 25 mg/m 2 twice daily. Selumetinib AUC and C max increases in a dose proportional manner over a dose range from 20 mg/m 2 to 30 mg/m 2 (0.8 to 1.2 times the recommended dose). Selumetinib accumulation range is 1....

14.1 Neurofibromatosis Type 1 (NF1) with Inoperable Plexiform Neurofibromas (PN) Pediatrics 2 18 years of Age (SPRINT Phase II Stratum 1) The efficacy of KOSELUGO was evaluated in SPRINT Phase II Stratum 1, an-open label, multicenter, single arm trial (NCT01362803). Eligible patients were required to have NF1 with inoperable PN, defined as a PN that could not be completely removed without risk for substantial morbidity due to encasement of, or close proximity to, vital structures, invasiveness, or high vascularity of the PN. Patients were also required to have significant morbidity related to ...

The following clinically significant adverse reactions are described elsewhere in the labeling:

• Left Ventricular Dysfunction [see Warnings and Precautions (5.1) ]
• Ocular Toxicity [see Warnings and Precautions (5.2) ]
• Gastrointestinal Toxicity [see Warnings and Precautions (5.3) ]
• Skin Toxicity [see Warnings and Precautions (5.4) ]
• Increased Creatine Phosphokinase [see Warnings and Precautions (5.5) ] Most common adverse reactions in pediatric patients (≥ 40%) are: vomiting, diarrhea, i...

None. None. ( 4 )

• Left Ventricular Dysfunction : Assess ejection fraction prior to initiating treatment, every 3 months during the first year, then every 6 months thereafter and as clinically indicated. Withhold, reduce the dose, or permanently discontinue KOSELUGO based on severity of adverse reaction. ( 2.3 , 5.1 )
• Ocular Toxicity : Conduct ophthalmic assessments prior to initiating KOSELUGO, at regular intervals during treatment and for new or worsening visual changes. Permanently discontinue KOSELUGO for ...

7 DRUG INTERACTIONS

• Strong or Moderate CYP3A4 Inhibitors or Fluconazole : Avoid coadministration of strong or moderate CYP3A4 inhibitors or fluconazole with KOSELUGO. If coadministration cannot be avoided, reduce the dose of KOSELUGO. ( 2.5 , 7.1 )
• Strong or Moderate CYP3A4 Inducers : Avoid concomitant use of strong and moderate CYP3A4 inducers. ( 7.1 ) 7.1 Effect of Other Drugs on KOSELUGO St...