Cardiomyopathy. A decrease
in left
ventricular ejection fraction (LVEF) ≥10% below baseline occurred
in pediatric
patients who received Koselugo in SPRINT with some experiencing
decreased LVEF below the institutional lower limit of normal
(LLN), including one patient with Grade 3.
All patients with decreased LVEF were asymptomatic and identified
during routine echocardiography. The safety of Koselugo has not
been established in patients with a history of impaired LVEF or a
baseline ejection fraction that is below the institutional LLN.
Assess ejection fraction by echocardiogram prior to initiating
treatment, every 3 months during the first year of treatment,
every 6 months thereafter, and as clinically indicated. Withhold,
reduce dose, or permanently discontinue Koselugo based on severity
of adverse reaction. In patients who interrupt Koselugo for
decreased LVEF, obtain an echocardiogram or a cardiac MRI every 3
to 6 weeks. Upon resolution of decreased LVEF, obtain an
echocardiogram or a cardiac MRI every 2 to 3 months.
Ocular Toxicity. Blurred
vision,
photophobia, cataracts, and ocular hypertension occurred. Retinal
pigment epithelial detachment (RPED) occurred in the pediatric
population during treatment with single agent Koselugo and
resulted in permanent discontinuation. Conduct ophthalmic
assessments prior to initiating Koselugo, at regular intervals
during treatment, and for new or worsening visual changes.
Permanently discontinue Koselugo in patients with retinal vein
occlusion (RVO). Withhold Koselugo in patients with RPED, conduct
ophthalmic assessments every 3 weeks until resolution, and resume
Koselugo at a reduced dose.
Gastrointestinal Toxicity.
Diarrhea
occurred, including Grade 3. Diarrhea resulting in permanent
discontinuation, dose interruption or dose reduction occurred.
Advise patients to start an anti-diarrheal agent (eg, loperamide)
and to increase fluid intake immediately after the first episode
of diarrhea. Withhold, reduce dose, or permanently discontinue
Koselugo based on severity of adverse reaction.
Skin Toxicity. Rash
occurred in 91% of 74 pediatric patients. The most frequent rashes
included dermatitis acneiform (54%), maculopapular rash (39%), and
eczema (28%). Grade 3 rash occurred, in addition to rash resulting
in dose interruption or dose reduction. Monitor for severe skin
rashes. Withhold, reduce dose, or permanently discontinue Koselugo
based on severity of adverse reaction.
Increased Creatine Phosphokinase (CPK).
Increased CPK occurred, including Grade 3 or 4 resulting in dose
reduction. Increased CPK concurrent with myalgia occurred,
including one patient who permanently discontinued Koselugo for
myalgia. Obtain serum CPK prior to initiating Koselugo,
periodically during treatment, and as clinically indicated. If
increased CPK occurs, evaluate for rhabdomyolysis or other causes.
Withhold, reduce dose, or permanently discontinue Koselugo based
on severity of adverse reaction.
Increased Levels of Vitamin E and Risk of Bleeding.
Koselugo capsules contain
vitamin E which can inhibit platelet aggregation and antagonize
vitamin K-dependent clotting factors. 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 due to increased risk of bleeding. An increased
risk of bleeding may occur in patients who are coadministered
vitamin-K antagonists or anti-platelet antagonists with Koselugo.
Monitor for bleeding in these patients and increase international
normalized ratio (INR) in patients taking a vitamin-K antagonist.
Perform anticoagulant assessments more frequently and adjust the
dose of vitamin K antagonists or anti-platelet agents as
appropriate.
Embryo-Fetal Toxicity.
Based on findings from animal studies, Koselugo can cause fetal
harm when administered during pregnancy. In animal studies,
administration of selumetinib to mice during organogenesis caused
reduced fetal weight, adverse structural defects, and effects on
embryo-fetal survival at approximate exposures >5 times the human
exposure at the clinical dose of 25 mg/m2
twice daily. Advise patients of reproductive potential of the
potential risk to a fetus and to use effective contraception
during treatment with Koselugo and for 1 week after the last dose.
ADVERSE REACTIONS
Common adverse reactions ≥40% include
vomiting, rash (all), abdominal pain, diarrhea, nausea, dry skin,
musculoskeletal pain, fatigue, pyrexia, acneiform rash,
stomatitis, headache, paronychia, and pruritus.
DRUG INTERACTIONS
Effect of Other Drugs on 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. Avoid coadministration with
Koselugo. If coadministration cannot be avoided, reduce Koselugo
dosage.
Concomitant use of Koselugo with a strong or moderate CYP3A4
inducer
decreased selumetinib plasma concentrations, which may reduce
Koselugo efficacy. Avoid concomitant use with Koselugo.
SPECIAL POPULATIONS
Pregnancy & Lactation.
Verify the
pregnancy status of patients of reproductive potential prior to
initiating Koselugo. Due to the potential for adverse reactions in
a breastfed child, advise patients not to breastfeed during
treatment with Koselugo and for 1 week after the last dose.
INDICATION
KOSELUGO is indicated for the treatment of pediatric patients 2
years of age and older with neurofibromatosis type 1 (NF1) who
have symptomatic, inoperable PN neurofibromas (PN).
To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca
1-800-236-9933 or at
https://us-aereporting.astrazeneca.com
or FDA at
1-800-FDA-1088 or
www.fda.gov/
medwatch.
Please see full
Prescribing Information
for Koselugo® (selumetinib).
