Approved Drug Label (PDF)
5
Warnings and Precautions
5.8 Pulmonary Arterial Hypertension
(Newly added subsection)
Cases
of pulmonary arterial hypertension (PAH) have been reported in patients treated
with interferon beta products, including PLEGRIDY. PAH has occurred in patients
treated with interferon beta products in the absence of other contributory
factors. Many of the reported cases required
hospitalization, including one case with interferon beta in which
the patient underwent a lung transplant. PAH has
developed at various time points
after initiating therapy with interferon beta products and
may occur several years after starting treatment.
Patients who develop unexplained symptoms (e.g., dyspnea,
new or increasing fatigue) should
be assessed for PAH. If alternative etiologies have been ruled out and a
diagnosis of PAH is confirmed, discontinue treatment and manage as clinically
indicated.
6
Adverse Reactions
(Additions and/or revisions
underlined)
The following
serious adverse reactions
are discussed in more detail
in other sections
of labeling:
·
Hepatic Injury
[see Warnings and Precautions (5.1)]
·
Depression and Suicide [see
Warnings and Precautions (5.2)]
·
Anaphylaxis and Other Allergic
Reactions [see Warnings
and Precautions (5.3)]
·
Injection Site Reactions Including
Necrosis [see Warnings
and Precautions (5.4)]
·
Congestive Heart Failure [see
Warnings and Precautions (Section 5.5 )]
·
Decreased Peripheral Blood Counts [see
Warnings and Precautions (5.6)]
·
Thrombotic Microangiopathy [see Warnings and Precautions (5.7)]
·
Pulmonary Arterial Hypertension [see Warnings and Precautions (5.8)]
·
Autoimmune Disorders [see Warnings and Precautions (5.9)]
·
Seizures [see
Warnings and Precautions (5.10)]
6.3 Postmarketing Experience
(Additions and/or revisions
underlined)
The following
adverse reactions have been identified during post-approval use of PLEGRIDY. Because these reactions are
reported voluntarily from a population of uncertain size, it is not always
possible to reliably estimate their frequency or establish a causal
relationship to drug exposure.
…
Pulmonary Arterial
Hypertension
In postmarketing experience, pulmonary arterial
hypertension has been reported following PLEGRIDY administration [see
Warnings and Precautions (5.8)].
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION
(Additions and/or revisions
underlined)
Advise the patient
to read the FDA-approved patient
labeling (Medication Guide
and Instructions for Use).
…
Pulmonary Arterial
Hypertension
Inform patients
that PAH has occurred in patients treated
with interferon beta products, including PLEGRIDY. Instruct patients to
promptly report any new symptoms such as new or increasing fatigue or shortness
of breath to their healthcare provider [see Warnings and Precautions (5.8)].
Approved Drug Label (PDF)
5
Warnings and Precautions
5.3 Anaphylaxis and Other Allergic Reactions
(Additions and/or revisions underlined)
Serious allergic
reactions are rare
complications of treatment
with interferon beta;
anaphylaxis has been reported with
use of PLEGRIDY in the
postmarketing setting.
Less than 1% of PLEGRIDY-treated patients experienced a
serious allergic reaction
such as angioedema
or urticaria. Those who did have serious allergic
reactions recovered promptly after treatment
with antihistamines or
corticosteroids. Discontinue
PLEGRIDY if a
serious allergic reaction
occurs.
The protective rubber cover of the
PLEGRIDY prefilled syringe for intramuscular administration contains natural rubber latex which may
cause allergic reactions
and should not be handled by latex-sensitive individuals. The safe use of PLEGRIDY prefilled
syringe in latex-sensitive individuals has not been studied.
5.4 Injection Site Reactions
(Additions and/or revisions underlined)
Injection site reactions, including injection
site necrosis, can occur
with the use of
interferon beta.
In clinical studies
of subcutaneous PLEGRIDY, the incidence of injection site reactions (e.g., injection
site erythema, pain, pruritus, or edema) was 66%
in the PLEGRIDY group and 11%
in the placebo group; the incidence of severe injection site reactions was 3% in the
PLEGRIDY group and 0%
in the placebo group.
One patient out of 1468 patients
who received PLEGRIDY in clinical
studies experienced injection
site necrosis. The injury resolved
with standard medical
treatment.
In Study
3, which compared
single doses of intramuscular and subcutaneous PLEGRIDY [see Adverse Reactions (6.1)], the incidence of injection site reactions (e.g., injection site
erythema, pain, pruritus,
or edema) was 14% in the
intramuscular PLEGRIDY group and 32%
in the subcutaneous PLEGRIDY group.
6
Adverse Reactions
6.1 Clinical Trials Experience
(Newly
added information)
Comparison Between Subcutaneous and Intramuscular Administration
An open-label, crossover study analyzed findings from
130 healthy volunteers to assess
the bioequivalence of single
doses of 125 micrograms
of PLEGRIDY administered as a subcutaneous
and intramuscular injection (Study
3).
The most commonly reported adverse reactions (with >10% incidence in either arm) across both treatment periods were chills (36%
in IM vs 27% in SC), pain
(22% in IM vs 14% in
SC), headache (36% in IM vs 41% in SC),
injection site pain (11% in IM
vs 15% in SC), and injection
site erythema (2% in IM vs
25% in SC). Overall, injection site reactions were reported
in 14% via IM route
as compared to 32% via SC route.
6.2 Immunogenicity
(Additions and/or revisions underlined)
As with all therapeutic
proteins, there is a potential for immunogenicity.
The detection of antibody formation
is highly dependent on the sensitivity and
specificity of the assay. Additionally,
the observed incidence of antibody (including neutralizing antibody)
positivity in an assay
may be influenced by several factors
including assay methodology,
sample handling, timing of sample collection, concomitant medications,
and underlying disease.
For these reasons, comparison
of the incidence of antibodies
in the studies described below with the incidence
of antibodies in other studies
or to other interferon beta-1a products may be misleading.
In Study
1, fewer than 1% of patients treated with PLEGRIDY SC
every 14 days for 1 year developed neutralizing antibodies. Approximately 7% of
PLEGRIDY SC-treated patients developed
antibodies to the polyethylene glycol moiety.
No formal
studies have been conducted with regards to immunogenicity of the
intramuscular route of
administration of PLEGRIDY.
6.3 Postmarketing Experience
(Newly
added section)
The
following adverse reactions have been identified during post-approval use of PLEGRIDY. Because these reactions are reported voluntarily from
a population of uncertain size, it is not always
possible to reliably estimate their frequency or establish
a causal relationship to drug exposure.
Anaphylactic reactions
In post marketing
experience, serious hypersensitivity reactions,
including cases of anaphylaxis, have been
reported following PLEGRIDY administration
[see Warnings
and Precautions (5.3)].
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
Medication Guide
(Extensive
changes; please refer to label)
Patient Counseling Information
(Newly
added information)
For subcutaneous administration, the usual
injection sites are the abdomen, back of the upper arm, and thigh. For
intramuscular administration, alternate
injections between the left
and right thigh.
Inform latex-sensitive
patients that the PLEGRIDY prefilled syringe
for intramuscular administration contains natural
rubber latex [see Warnings and Precautions (5.3)].
Approved Drug Label (PDF)
8
Use in Specific Populations
8.1 Pregnancy
(PLLR coonversin)
Pregnancy
Exposure Registry
There
is a pregnancy exposure registry that monitors pregnancy outcomes in women
exposed to PLEGRIDY during pregnancy. Encourage patients to enroll by calling
1-866-810-1462 or visiting https://www.plegridypregnancyregistry.com/.
Risk
Summary
Data
from a large population-based cohort study, as well as other published studies
over several decades, have not identified a drug-associated risk of major birth defects with the use of
interferon beta products during early pregnancy. Findings regarding a potential
risk for low birth weight or miscarriage with the use of interferon beta
products in pregnancy have been inconsistent (see Data). In a study in pregnant monkeys, administration of
interferon beta during pregnancy resulted in an increased rate of abortion (see Data).
In
the U.S. general population, the estimated background risk of major birth
defects and miscarriage in clinically recognized pregnancies is 2-4% and
15-20%, respectively. The background risk of major birth defects and
miscarriage for the indicated population
is unknown.
Data
Human Data
The
majority of observational studies reporting on pregnancies exposed to
interferon beta products did not identify an association between the use of
interferon beta products during early pregnancy and an increased risk of major
birth defects.
In
a population-based cohort study conducted in Finland and Sweden, data were
collected from 1996--2014 in Finland and 2005--2014 in Sweden on 2,831
pregnancy outcomes from women with MS.
797 pregnancies were in women exposed to interferon beta only. No
evidence
was found of an increased risk of major birth defects among women with MS
exposed to interferon beta products compared to women with MS that were
unexposed to any non-steroid therapy for MS (n=1,647) within the study. No
increased risks were observed for miscarriages and ectopic pregnancies, though
there were limitations in obtaining complete data capture for these outcomes,
making the interpretation of the findings more difficult.
Two
small cohort studies that examined
pregnancies exposed to interferon beta products (without differentiating between subtypes of
interferon beta products) suggested that a decrease in mean birth weight may
be associated with interferon beta
exposure during pregnancy, but this finding was not confirmed in larger observational studies. Two small studies
observed an increased prevalence of miscarriage, although the finding was only statistically
significant in one study. Most studies enrolled patients later in pregnancy, which made it difficult to ascertain the true
percentage of miscarriages. In one small cohort study, a significantly increased risk of preterm
birth following interferon beta exposure during pregnancy was observed.
Animal Data
PLEGRIDY
has not been tested for developmental toxicity in pregnant animals. In monkeys
given interferon beta by subcutaneous injection every other day during early
pregnancy, no adverse effects on embryofetal development were observed.
Abortifacient activity was evident following 3 to 5 doses.
8.2 Lactation
(PLLR conversion)
Risk
Summary
Limited
published literature has described the presence of interferon beta-1a products
in human milk at low levels. There are no data on the effects of interferon
beta-1a on milk production.
Therefore,
the developmental and health benefits of breastfeeding should be considered
along with the mother’s clinical need for PLEGRIDY and any potential adverse
effects on the breastfed infant from PLEGRIDY or from the underlying maternal
condition.
8.5 Geriatric Use
(subsection
revised, additions underlined)
Clinical
studies of PLEGRIDY did not include sufficient numbers of subjects aged 65 and
over to determine whether they respond differently from younger subjects. Other
reported clinical experience has not identified differences in responses
between the elderly and younger patients.
PATIENT COUNSELING INFORMATION
(additions
underlined)
…
Pregnancy
and Pregnancy Registry
Advise
patients to notify their healthcare provider if they become pregnant during
treatment or plan to become pregnant.
Encourage
patients to enroll in the PLEGRIDY Pregnancy Registry if they become pregnant
while taking PLEGRIDY.
…
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDE
(additions
underlined)
…
Before using
PLEGRIDY, tell your healthcare provider about all of your medical conditions,
including if you:
…
- See the detailed Instructions for Use for
instructions on how to prepare and inject your dose of PLEGRIDY.
Your healthcare provider will tell you how much
PLEGRIDY to inject and how often to inject PLEGRIDY. Do not inject more than your
healthcare provider tells you to.
When
you use PLEGRIDY for the first time, your healthcare provider may tell you to
slowly increase your dose.
PLEGRIDY
is given by injection under the skin (subcutaneous injection) of your stomach
(abdomen), back of upper arm, or thigh 1 time every 14 days.
Change
(rotate) the site you choose with each injection to help decrease the chance
that you will have an injection site reaction. Do not inject into an area of the body where the skin is irritated,
reddened, bruised, infected, or scarred in any way.
After 2 hours check your injection site for redness,
swelling or tenderness. If you have a skin
reaction and it does not clear up in a few days, contact your healthcare
provider.
Always
use a new, PLEGRIDY prefilled pen or new, unopened single dose prefilled
syringe for each injection.
What are the
possible side effects of PLEGRIDY?
PLEGRIDY may cause
serious side effects, including:
…
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