HIGHLIGHTS
OF
PRESCRIBING INFORMATION
These highlights
do
not include all the information needed to use
•
Administer as an intravenous infusion over
35
to 60 minutes
(2.1, 2.3)
•
Dilution required prior to administration (2.2)
EXONDYS
51™ safely and effectively. See full prescribing information
for EXONDYS
51.
Injection:
DOSAGE FORMS AND STRENGTHS
EXONDYS 51 (eteplirsen) injection, for intravenous
use
Initial U.S. Approval: 2016
INDICATIONS AND
USAGE
EXONDYS
51
is an antisense oligonucleotide indicated for the treatment of
Duchenne
muscular dystrophy (DMD) in patients who have a confirmed mutation of the DMD gene that is amenable to exon 51 skipping. This
indication is approved under accelerated approval based on an increase in
dystrophin in skeletal
muscle observed in some patients treated with
EXONDYS 51[see Clinical Studies
(14)].A clinical benefit of
EXONDYS 51 has not been established. Continued approval for
this indication may be contingent upon verification of
a clinical benefit in confirmatory trials. (1)
•
100 mg/2 mL (50 mg/mL)
in single-dose vial (3)
•
500 mg/10 mL (50 mg/mL)
in single-dose vial (3)
CONTRAINDICATIONS
None
(4)
ADVERSE REACTIONS
The
most common adverse reactions (incidence ≥35% and higher than
placebo)
were balance disorder
and
vomiting (6.1)
To
report SUSPECTED ADVERSE REACTIONS, contact Sarepta Therapeutics, Inc. at 1-888-SAREPTA (1-888-727-3782) or FDA at 1-800
FDA-1088 or www.fda.gov/medwatch.
DOSAGE
AND ADMINISTRATION
•
30 milligrams per
kilogram of
body weight once weekly (2.1)
Revised: 09/2016
FULL PRESCRIBING INFORMATION: CONTENTS*
FU
LL PRESCRIBING INFORMATION
1 INDICATIONS AND USAGE
EXONDYS 51 is
indicated for the treatment
of Duchenne muscular dystrophy (DMD) in
patients who have a confirmed mutation of
the DMD gene that is amenable to exon 51 skipping. This indication
is approved under accelerated approval based on an
increase in
dystrophin in skeletal muscle observed in some patients treated with
EXONDYS 51 [see Clinical Studies
(14)]. A clinical benefit of
EXONDYS 51 has
not been established.
Continued approval for this
indication may be contingent upon verification
of a clinical benefit in confirmatory trials.
2
D
OSAGE AND ADMINISTRATION
2.1
D
osing Information
The recommended dose
of EXONDYS
51 is 30 milligrams per kilogram administered once
weekly as a 35 to 60 minute intravenous infusion.
If a dose of EXONDYS 51 is missed, it may be administered as
soon as possible after the
scheduled time.
2.2
Pre
paration
Instructions
EXONDYS 51 is
supplied in single-dose vials as
a preservative-free concentrated solution that requires dilution prior to administration.
Parenteral drug products should be inspected visually for particulate matter and discoloration
prior to administration,
whenever solution
and container permit.
Use
aseptic technique.
a. Calculate the total
dose of EXONDYS
51 to be administered based
on the patient’s
weight and
the recommended
dose of 30 milligrams per kilogram. Determine the
volume of EXONDYS 51 needed and
the correct
number of vials to supply the full calculated dose.
b.
Allow vials to warm
to room temperature.
Mix the contents of each vial
by
gently inverting 2 or 3
times. Do
not shake.
c.
Visually inspect each vial of
EXONDYS 51. EXONDYS 51 is a clear, colorless solution that may have some opalescence. Do not use if the solution in the vials is discolored
or particulate matter is
present.
d.
With a syringe
fitted with
a 21-gauge or smaller non-coring needle,
withdraw the calculated volume
of EXONDYS 51 from
the appropriate number of vials.
e.
Dilute the withdrawn
EXONDYS 51 in 0.9% Sodium Chloride Injection,
USP, to make a total
volume of 100-150 mL. Visually inspect the
diluted solution for particulates.
f.
EXONDYS 51 contains no
preservatives
and should be administered immediately after dilution. Complete infusion
of diluted EXONDYS 51
solution within 4 hours of
dilution. If immediate use is not possible, the diluted
solution may be stored for up to
24 hours at 2ºC to 8ºC (36ºF to 46ºF).
Do not freeze. Discard unused
EXONDYS 51.
2.3
A
dministration
Instructions
Application of
a topical anesthetic cream to the infusion site prior to administration of EXONDYS 51 may be considered.
EXONDYS 51 is administered
via intravenous infusion. Flush
the intravenous access
line with 0.9% Sodium Chloride Injection,
USP, prior to and after infusion.
Infuse the diluted
EXONDYS 51 solution over 35 to 60 minutes. Do
not mix other medications with
EXONDYS 51 or infuse other medications concomitantly via the same intravenous access line.
3
D
OSAGE FORMS AND STRENGTHS
EXONDYS 51 is
a clear and
colorless solution that may have some opalescence, and is available
as follows:
•
Injection: 100 mg/2 mL (50
mg/mL) solution
in a single-dose vial
•
Injection: 500 mg/10 mL (50 mg/mL) solution
in a single-dose vial
4
C
ONTRAINDICATIONS
None.
6 ADVERSE REACTIONS
6.1 Clinical
Trials Experience
Because clinical
trials
are conducted under widely varying conditions,
adverse reaction
rates observed in clinical trials of a drug cannot be
directly compared to rates
in the clinical trials of another drug
and may not reflect the
rates observed
in practice.
In the EXONDYS
51 clinical development
program,
107 patients received at
least one intravenous dose of EXONDYS
51, ranging between 0.5 mg/kg (0.017 times the recommended dosage) and
50 mg/kg (1.7
times the recommended dosage). All
patients were male and had
genetically confirmed Duchenne muscular dystrophy.
Age
at study entry was
4 to 19 years. Most (89%) patients were Caucasian.
EXONDYS 51 was studied in a
double-blind, placebo-controlled
study
for 24 weeks (Study 1),
followed by an
open label extension
(Study 2). In Study 1, 12 patients
were randomized
to receive weekly intravenous
infusions of EXONDYS 51 (n=8) or placebo (n=4) for 24 weeks. All
12 patients continued in Study 2 and received open-label
EXONDYS 51
weekly for up
to 208 weeks.
In Study 1, 4 patients received placebo,
4 patients received EXONDYS
51 30 mg/kg, and 4
patients
received
EXONDYS 51 50 mg/kg (1.7
times
the recommended dosage). In
Study
2, 6
patients
received
EXONDYS 51 30 mg/kg/week and
6 patients received EXONDYS 51
50
mg/kg/week[see Clinical Studies
(14)].
Adverse reactions that
occurred in 2 or more patients
who received EXONDYS
51 and were more frequent
than in the placebo group in Study 1 are presented
in Table 1 (the 30 and
50 mg/kg groups are pooled). Because of the small numbers of
patients, these represent crude frequencies
that may not reflect
the frequencies observed
in practice. The 50 mg/kg once weekly
dosing regimen
of
EXONDYS 51 is not recommended [see Dosage and Administration (2.1)].
The most common adverse reactions were balance disorder and
vomiting.
Table 1. Adverse Reactions in DMD Patients
Treated with 30 or
50 mg/kg/week1
EXONDYS
51 with Incidence at Least 25% More than Placebo
(Study
1)
|
Adverse Reactions
|
EXONDYS 51 (N=8)
%
|
Placebo (N=4)
%
|
|
Balance disorder
|
38
|
0
|
|
Vomiting
|
38
|
0
|
|
Contact dermatitis
|
25
|
0
|
1 50 mg/kg/week = 1.7
times
the recommended dosage
In the 88 patients
who received
≥30 mg/kg/week of EXONDYS
51 for up to 208 weeks in clinical studies,
the following events
were reported
in ≥10% of patients and
occurred more
frequently than
on the same dose in
Study
1: vomiting, contusion,
excoriation,
arthralgia,
rash,
catheter site pain, and
upper respiratory tract infection.
There have been reports
of transient erythema,
facial flushing, and elevated temperature occurring on days
of EXONDYS 51 infusion.
8
US
E IN SPECIFIC POPULATIONS
8.1
Pre
gnancy
RiskSummary
There are no
human or animal
data available to
assess the
use of EXONDYS
51 during pregnancy.
In the
U.S. general population, major birth
defects occur in 2 to
4% and miscarriage occurs in 15 to 20% of clinically recognized
pregnancies.
8.2
Lactation
RiskSummary
There are no
human or animal
data to assess the
effect of EXONDYS 51 on milk production, the presence of eteplirsen in milk,
or the effects of
EXONDYS 51 on the breastfed
infant.
The developmental and health benefits of
breastfeeding should
be considered along with the mother’s clinical need for EXONDYS
51 and any potential adverse effects on
the breastfed infant
from EXONDYS 51 or
from the underlying maternal
condition.
8.4
Pe
diatric Use
EXONDYS 51 is indicated for the treatment of
Duchenne muscular dystrophy (DMD) in
patients who have a confirmed mutation of
the DMD gene that is amenable to exon 51 skipping,
including pediatric patients[see Clinical Studies
(14)].
Intravenous administration of
eteplirsen (0, 100,
300, or 900 mg/kg) to
juvenile male rats once weekly for 10 weeks beginning
on postnatal day 14
resulted in renal tubular necrosis
at the highest dose tested and decreased
bone
densitometry parameters
(mineral density, mineral
content, area) at
all doses. The kidney findings were associated with
clinical pathology changes (increased
serum urea nitrogen
and creatinine, decreased urine creatinine clearance). No
effects were observed
on the male reproductive system, neurobehavioral development, or
immune function. An
overall no-effect
dose was not identified.
Plasma eteplirsen
exposure (AUC) at
the lowest dose tested (100 mg/kg) was similar to that
in humans at the recommended human
dose (30 mg/kg).
8.5
Ger
iatric Use
DMD is largely a disease of children and young adults;
therefore, there is no geriatric experience with
EXONDYS 51.
8.6
P
atients with Renal
or Hepatic Impairment
EXONDYS 51 has not been
studied in patients with
renal
or hepatic impairment.
10
OVERDOSAGE
There is no experience with overdose of EXONDYS
51.
11
D
ESCRIPTION
EXONDYS 51 (eteplirsen) injection is a sterile, aqueous, preservative-free, concentrated solution
for
dilution prior to intravenous administration.
EXONDYS 51 is clear and colorless,
and may have some opalescence. EXONDYS
51 is supplied in single dose vials containing 100 mg or 500 mg eteplirsen
(50 mg/mL). EXONDYS 51 is formulated
as
an isotonic, phosphate buffered
saline solution with an osmolality of 260 to 320 mOsm and a pH of 7.5.
Each milliliter of EXONDYS 51 contains 50 mg eteplirsen;
0.2 mg potassium chloride, 0.2 mg
potassium phosphate monobasic,
8 mg sodium chloride,
and 1.14 mg sodium phosphate dibasic,
anhydrous, in water for injection.
The product may contain
hydrochloric acid or
sodium hydroxide to
adjust pH.
Eteplirsen is an
antisense oligonucleotide
of the phosphorodiamidate morpholino oligomer (PMO) subclass. PMOs
are
synthetic molecules
in which the five-membered
ribofuranosyl rings
found in natural
DNA
and RNA are replaced
by
a six-membered
morpholino ring. Each morpholino
ring is linked through an
uncharged phosphorodiamidate moiety rather than the
negatively charged phosphate linkage that
is present in natural
DNA
and RNA. Each phosphorodiamidate morpholino subunit contains one of the heterocyclic bases
found in DNA (adenine, cytosine, guanine,
or thymine). Eteplirsen
contains 30 linked subunits. The molecular
formula of eteplirsen
is C364H569N177O122P30 and the molecular weight is 10305.7 daltons.
The structure and base sequence of eteplirsen are:
[ 5' ]
Break A Break B
O O
Break C
O P
Break D
O
N N N
N O N
O C O C O G
N N N
O T [ 3' ]
N
O
N N N
Break A Break B Break C
N
Break D
|
N
|
N
|
|
N O
|
|
N
|
N NH2
|
N O
|
|
A
|
|
|
C
|
|
G
|
|
T (m5U)
|
|
|
Base: N N
N N NH NH
The sequence of bases f rom the 5' end to the 3' end is: CTCCAACATCAAGGAAGATGGCATTTCTAG
12
C
LINICAL PHARMACOLOGY
12.1
Mec
hanism of Action
Eteplirsen is designed to bind to exon 51 of dystrophin pre-mRNA, resulting in
exclusion of this exon during mRNA processing in patients with genetic mutations
that are amenable to
exon
51 skipping. Exon skipping is intended to allow for production of
an internally truncated dystrophin
protein, which was evaluated
in Study 2 and Study 3
[see Clinical studies
(14)].
12.2
P
harmacodynamics
All EXONDYS 51-treated patients evaluated (n=36) were found to produce messenger
ribonucleic acid (mRNA) for a truncated dystrophin protein by reverse transcription
polymerase chain reaction.
In Study 2,
the average dystrophin
protein level
in muscle tissue after 180 weeks
of treatment with
EXONDYS 51 was 0.93% of normal
(i.e.,
0.93%
of the dystrophin
level
in healthy subjects). Because of insufficient information
on dystrophin protein levels
before treatment with
EXONDYS 51 in Study 1,
it is not possible to estimate dystrophin production
in response to EXONDYS 51 in Study 1.
In Study 3, the average dystrophin protein level
was
0.16% of normal before treatment, and
0.44% of normal after 48 weeks of
treatment with EXONDYS 51[see Clinical studies
(14)].The median increase in truncated
dystrophin in Study 3 was
0.1%[see Clinical Studies
(14)].
12.3
P
harmacokinetics
Following single or multiple intravenous
infusions of EXONDYS 51 in male pediatric DMD patients, plasma concentration-time profiles
of eteplirsen were generally similar and
showed multi-phasic decline. The majority of drug elimination
occurred within
24 hours. Approximate
dose-proportionality and linearity in
PK properties were observed following multiple-dose
studies (0.5 mg/kg/week [0.017 times
the recommended dosage] to
50 mg/kg/week [1.7
times the
recommended
dosage]). There was
no significant drug accumulation following weekly dosing
across this dose range. The inter-subject
variability
for eteplirsen Cmax and AUC range from
20 to 55%.
Following single or multiple intravenous
infusions of EXONDYS 51, the peak plasma concentrations (Cmax) of eteplirsen
occurred near the end of
infusion (i.e.,
1.1 to 1.2 hours across a dose
range of 0.5 mg/kg/week to 50 mg/kg/week).
Distribution
In vitroinvestigation suggested that plasma protein
binding of eteplirsen in human
ranges between
6 to 17%. The mean
apparent volume of distribution (Vss) of eteplirsen was
600 mL/kg following weekly intravenous
infusion of EXONDYS 51 at
30 mg/kg.
Twenty-four hours after the end of
the infusion, mean concentrations of eteplirsen were 0.07% of Cmax. Accumulation of
eteplirsen during once weekly dosing has not been observed.
Elimination
The total
clearance of eteplirsen was
339 mL/hr/kg following 12 weeks of
therapy with 30 mg/kg/week.
Metabolism
Eteplirsen did not appear to
be metabolized
by
hepatic microsomes
of any species
tested, including humans.
Excretion
Renal
clearance of eteplirsen accounts
for
approximately two-thirds of the administered
dose within 24 hours of intravenous
administration. Elimination half-life (t1/2) of eteplirsen
was 3 to 4 hours.
SpecificPopulations
Age:
The pharmacokinetics
of eteplirsen have been evaluated in male pediatric DMD patients. There
is no experience with the
use of EXONDYS 51 in patients 65 years
of age or older.
Sex:
Sex effects
have not been evaluated;
EXONDYS 51
has not been studied in female patients.
Race:
Potential impact
of race is not known because 89% of the patients in studies were Caucasians.
Renal
or Hepatic Impairment:
EXONDYS 51 has not been
studied in patients with
renal
or hepatic impairment.
DrugInteractionStudies
In vitrodata showed that eteplirsen did not significantly inhibit
CYP1A2, CYP2B6, CYP2C8,
CYP2C9, CYP2C19, CYP2D6,
or CYP3A4/5. Eteplirsen
did not induce CYP2B6 or CYP3A4,
and induction of CYP1A2
was substantially less than the
prototypical
inducer,
omeprazole. Eteplirsen was
not a substrate nor did
it have any major inhibitory potential
for
any of the key human
transporters tested (OAT1,
OAT3, OCT1, OCT2, OATP1B1, OATP1B3,
P-gp, BCRP,
MRP2 and BSEP). Based on in vitrodata on
plasma protein binding, CYP or drug transporter interactions,
and microsomal metabolism, eteplirsen is expected to have a low potential
for drug-drug interactions
in humans.
13
N
ONCLINICAL TOXICOLOGY
13.1
C
arcinogenesis,
Mutagenesis,
Impairment of Fertility
Carcinogenesis
Carcinogenicity studies have not
been conducted with
eteplirsen. Mutagenesis
Eteplirsen was
negative in in vitro(bacterial reverse mutation
and chromosomal
aberration
in CHO cells) and in vivo(mouse bone marrow micronucleus) assays.
ImpairmentofFertility
Fertility studies in animals were not conducted with eteplirsen. No
effects on the male reproductive system were observed following intravenous
administration of eteplirsen (0,
5, 40, or 320 mg/kg) to
male monkeys
once weekly for 39
weeks. Plasma eteplirsen
exposure (AUC)
in monkeys at
the highest dose tested was
20 times that in humans at
recommended human
dose (30 mg/kg).
14
C
LINICAL STUDIES
EXONDYS 51 was evaluated in three clinical studies
in patients who have a confirmed
mutation of the DMD gene that
is amenable to exon 51 skipping.
In Study 1,
patients were randomized
to receive weekly infusions of EXONDYS 51 (30
mg/kg, n=4);
EXONDYS 51 (50 mg/kg, n=4), or placebo (n=4) for 24
weeks. The primary endpoint
was dystrophin production;
a clinical outcome measure, the
6-minute walk test
(6MWT), was
also assessed. The 6MWT measures
the distance that
a patient can
walk
on a flat, hard surface in a
period of 6 minutes. Patients had
a mean age of 9.4 years, a
mean 6-minute walk
distance (6MWD) at baseline of 363
meters,
and were on a stable dose of corticosteroids
for
at least 6 months. There was no significant
difference in
change in
6MWD
between patients
treated with EXONDYS 51 and those treated
with placebo.
All 12 patients
who participated
in Study 1 continued
treatment with open-label EXONDYS
51 weekly for an additional 4 years
in Study 2. The 4 patients who
had been randomized
to placebo were re-randomized 1:1 to EXONDYS 30 or 50 mg/kg/week such
that there were 6 patients on each
dose. Patients who participated
in Study 2 were compared
to an
external
control group. The primary clinical efficacy outcome measure was
the
6MWT. Eleven
patients in Study 2
had
a muscle biopsy after 180 weeks of
treatment with EXONDYS 51, which was
analyzed
for dystrophin protein level
by
Western blot. Study 2 failed to provide evidence of a clinical benefit of
EXONDYS 51 compared
to the external control
group.
The average dystrophin
protein level after 180
weeks
of treatment with
EXONDYS 51 was 0.93% of the dystrophin level in healthy subjects.
Because of insufficient information
on dystrophin
protein levels
before treatment with
EXONDYS 51 in Study 1,
it is not possible to estimate dystrophin production
in response to EXONDYS 51 in Study 1.
In Study 3,
13 patients were treated with
open-label
EXONDYS 51 (30 mg/kg) weekly for 48 weeks
and had a muscle biopsy at
baseline
and after 48 weeks
of treatment. Patients had
a mean
age of 8.9 years and
were on a stable dose of corticosteroids
for
at least 6 months. Dystrophin
levels
in muscle tissue were assessed
by
Western blot. In the 12
patients with evaluable results, the pre-treatment dystrophin level was
0.16% ± 0.12% (mean ± standard
deviation) of the
dystrophin level in a
healthy subject and
0.44%
± 0.43% after 48
weeks of treatment
with EXONDYS 51 (p< 0.05). The median increase after 48
weeks was 0.1%.
Individual patient
dystrophin
levels
from Study 3 are shown
in Table 2.
Table 2. Western Blot
Results: EXONDYS
51-Treated (Week 48)
vs Pre-treatment
Baseline (% Normal Dystrophin) (Study
301)
|
Patient
Number
|
Baseline
% normal dystrophin
|
Week 48
% normal dystrophin
|
Change from Baseline
% normal dystrophin
|
|
1
|
0.13
|
0.26
|
0.13
|
|
2
|
0.35
|
0.36
|
0.01
|
|
3
|
0.06
|
0.37
|
0.31
|
|
4
|
0.04
|
0.10
|
0.06
|
|
5
|
0.17
|
1.02
|
0.85
|
|
6
|
0.37
|
0.30
|
-0.07
|
|
7
|
0.17
|
0.42
|
0.25
|
|
8
|
0.24
|
1.57
|
1.33
|
|
9
|
0.11
|
0.12
|
0.01
|
|
10
|
0.05
|
0.47
|
0.43
|
|
11
|
0.02
|
0.09
|
0.07
|
|
12
|
0.18
|
0.21
|
0.03
|
|
Mean
|
0.16
|
0.44
|
0.28;p=0.008
|
16 HOW SUPPLIED/STORAGE AND HANDLING
16.1 How Supplied
EXONDYS 51 injection is
supplied in single-dose vials.
The
solution is clear and
colorless,
and may have some opalescence.
• Single-dose vials
containing
100 mg/2 mL (50
mg/mL) eteplirsen NDC 60923-363-02
• Single-dose vials
containing
500 mg/10 mL (50
mg/mL) eteplirsen NDC
60923-284-10
16.2
Storage and Handling
Store EXONDYS 51 at 2°C to 8°C (36°F to
46°F). Do
not freeze. Protect
from light and store EXONDYS
51 in the original
carton
until ready for use.
Manufactured for:
Sarepta
Therapeutics, Inc.
Cambridge, MA 02142 USA
P P
O A O A
O T O T
O O O
N O N O N O
O A O G O G O C
N N N O N
N O C O G
O G O T
N N N N N
O O O P O O
O C O A O A
P P P P
N O N O N O
N N N
N O N
P P P
N O N O N O N O
O O O
P P P
N O N O N O N O
O C O A O A O T
NH2 NH2 O O