Additions
and/or revisions underlined:
The
following clinically significant adverse reactions are described elsewhere in
the labeling:
.
. .
6.1
Clinical Trials Experience
.
. .
The
NF1 PN pediatric safety pool described in the WARNINGS AND PRECAUTIONS
reflects exposure to KOSELUGO at the recommended dosage in 134 pediatric
patients in SPRINKLE (N = 36) (NCT05309668), SPRINT Phase I (N = 24) (NCT01362803),
SPRINT Phase II Stratum 1 (N = 50) [see Clinical Studies (14.1)], and Phase I Food Effect Study (N
= 24) (NCT05101148). Among pediatric patients, the duration of KOSELUGO
exposure was 12 months or longer (80%), more than 2 years (44%), or more than 3
years (37%). The most common adverse reactions in pediatric patients
(greater than or equal to 40%) are vomiting, diarrhea, increased
creatine phosphokinase, dry skin, paronychia, nausea, dermatitis acneiform, and
pyrexia.
In
the KOMET adult NF1 PN study, 71 adult patients received KOSELUGO at the
recommended dosage [see Clinical
Studies (14.1)]. Among adult patients, the
duration of KOSELUGO exposure in the randomized period was 6 months or longer
(92%), and 11 months or longer (66%). The most common adverse reactions in
adult patients (greater than or equal to 40%) are rash (all), dermatitis
acneiform, and diarrhea.
Neurofibromatosis
Type 1 (NF1) with Inoperable Plexiform Neurofibromas (PN)
.
. .
Adults greater
than or equal to 18 years of Age (KOMET)
The
safety of KOSELUGO was evaluated in KOMET [see
Clinical Studies (14.1)]. Eligible patients were 18 years
of age or older with NF1 who had symptomatic, inoperable PN. Patients were
excluded for abnormal LVEF, uncontrolled hypertension, any current or past
history of RVO or RPED/CSR, intraocular pressure > 21 mmHg (or upper limit
of normal adjusted by age), uncontrolled glaucoma, and inability to swallow
whole capsules. Among the patients (N = 137) who have received KOSELUGO, the
median duration of KOSELUGO treatment was 11 months with a range of 10 days to
31 months.
Serious
adverse reactions occurred in 14% of patients who received KOSELUGO. Serious
adverse reactions occurring in more than one patient included cellulitis
(2.8%).
Permanent
discontinuation due to an adverse reaction occurred in 13% of patients who
received KOSELUGO. Adverse reactions resulting in permanent discontinuation of
KOSELUGO included dermatitis acneiform, cellulitis, nausea, wound,
neurofibrosarcoma, neurofibrosarcoma recurrent, psychiatric decompensation,
ulcerative keratitis, and nail disorder.
Dosage
interruptions and dose reductions due to adverse reactions occurred in 27% and
14% of patients who received KOSELUGO, respectively. Adverse reactions
requiring a dosage reduction in 2 or more patients were paronychia, increased
CPK, increased ALT, increased AST, rash, and alopecia. Adverse reactions
requiring a dosage interruption in 2 or more patients were increased CPK, rash,
headache, abdominal pain, nausea, and COVID-19.
The
most common adverse reactions (greater than or equal to 40%) were rash (all),
rash (acneiform), and diarrhea.
Table
12 presents the adverse reactions in the KOMET study. The 12 cycle (48 weeks)
randomization period for KOSELUGO versus placebo was followed by a single arm
treatment period where all patients received KOSELUGO (placebo patients crossed
over to KOSELUGO at end of the randomized period). No new adverse reactions
were identified during the open-label period.
Table 12 Adverse Reactions (greater than or equal to
20%) in Patients Who Received KOSELUGO Compared with Placebo in KOMET
Newly
added table; please refer to label for complete information.
Clinically
relevant adverse reactions in < 20% of patients who received KOSELUGO versus
placebo based on reported adverse reactions included hair changes (18% vs 11%),
paronychia (13% vs 4%), pyrexia (7% vs 4%), stomatitis (18% vs 5%), and skin
infection (6% vs 1%), respectively. Decreased ejection fraction in patients who
received KOSELUGO versus placebo based on reported echocardiogram results
occurred in 14% and 11% of patients, respectively.
Table
13 presents the laboratory abnormalities in the KOMET study.
Table 13 Select Laboratory Abnormalities (greater than
or equal to 15%) That Worsened from Baseline in Patients Who Received KOSELUGO
with a Difference Between Arms of > 10% Compared to Placebo in KOMET
Newly
added table; please refer to label for complete information.
. . .
8.1
Pregnancy
Additions
and/or revisions underlined:
Risk
Summary
Based
on findings from animal studies and its mechanism of action [see Clinical
Pharmacology (12.1)], KOSELUGO can cause fetal harm when administered to a
pregnant woman. There are no available data on the use of KOSELUGO in pregnant
women to evaluate drug-associated risk. In animal reproduction studies,
administration of selumetinib to mice during organogenesis caused reduced fetal
weight, adverse structural defects, and effects on embryofetal survival at
exposures approximately > 5 times the human exposure at the clinical dose of
25 mg/m2 twice daily (see Data).
Advise pregnant women of the potential risk to the fetus.
In
the U.S. general population, the estimated background risk of major birth
defects and miscarriage in clinically recognized pregnancies is 2% to 4% and
15% to 20%, respectively.
Data
Human Data
In
KOMET, a first trimester spontaneous abortion was reported in a patient
receiving KOSELUGO.
.
. .
8.5
Geriatric Use
Additions
and/or revisions underlined:
Clinical studies
of
KOSELUGO did not include
a sufficient number of patients
aged
65 and
over to determine whether they respond differently from younger
patients.
PATIENT
COUNSELING INFORMATION
Additions
and/or revisions underlined:
Advise
the patient to read the FDA-approved patient labeling (Patient Information and
Instructions for Use).
Left
Ventricular Dysfunction
Advise
patients and caregivers that KOSELUGO can cause a reduction in LVEF and to
immediately report any signs or symptoms of cardiomyopathy to their healthcare
provider [see Warnings and Precautions (5.1)].
.
. .
Gastrointestinal
Toxicity
Advise
patients and caregivers that KOSELUGO can cause diarrhea, nausea, vomiting.
and stomatitis and to contact their healthcare provider at the first
sign of gastrointestinal toxicity [see Warnings and
Precautions (5.3)].
.
. .
Increased
Creatine Phosphokinase
Advise
patients and caregivers that KOSELUGO can cause increased CPK and rhabdomyolysis
to report any signs and symptoms of muscle pain or weakness to their healthcare
provider [see Warnings and Precautions (5.5)].
.
. .
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