Approved Drug Label (PDF)
5
Warnings and Precautions
5.2 Hepatic Injury
(Additions and/or revisions
underlined)
Severe
liver injury, including some cases of hepatic failure requiring liver
transplantation, has been reported rarely
in patients taking
REBIF. Symptoms of liver dysfunction began from one to
six months following the initiation of REBIF.
If jaundice or other symptoms of liver dysfunction appear, treatment with REBIF should be discontinued immediately due to the potential
for rapid progression to liver
failure.
Asymptomatic elevation of hepatic transaminases (particularly SGPT) is common with interferon
therapy [see Adverse Reactions (6.1)].
REBIF should be initiated with caution in patients with active liver
disease, alcohol abuse, increased serum SGPT (> 2.5 times ULN), or a history
of significant liver disease. Also,
the potential risk of REBIF used in combination with known hepatotoxic products
should be considered prior to REBIF administration, or when adding new agents
to the regimen of patients already on REBIF.
Reduction of REBIF dose should be considered if SGPT rises above 5 times
the upper limit of normal. The dose may be gradually re- escalated when enzyme levels have normalized [see Warnings and Precautions (5.9) and Dosage and
Administration (2.1)].
5.7 Pulmonary Arterial
Hypertension
(Newly added subsection)
Cases of pulmonary
arterial hypertension (PAH) have been reported with interferon beta products, including REBIF. 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 adverse
reactions are discussed
in more detail
in the Warnings and Precautions
section of the label:
-
Depression
and Suicide [see Warnings and
Precautions (5.1)]
-
Hepatic Injury [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)]
-
Decreased Peripheral Blood Counts [see Warnings
and
Precautions (5.5)]
-
Thrombotic Microangiopathy [see Warnings
and Precautions
(5.6)]
-
Pulmonary Arterial Hypertension [ see Warnings and Precautions (5.7)]
-
Seizures
[see Warnings and Precautions (5.8)]
-
Laboratory Tests [see Warnings and Precautions
(5.9)]
6.3 Postmarketing Experience
(Additions and/or revisions
underlined)
The following adverse reactions have been identified during
post-approval use of REBIF. 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.
Autoimmune
Disorders: Drug-induced lupus erythematosus, autoimmune hepatitis
Eye Disorders: Retinal vascular
disorders (i.e. retinopathy, cotton wool spots
or obstruction of retinal artery or vein)
Respiratory, Thoracic and mediastinal disorders: Pulmonary Arterial
Hypertension
Skin
and Subcutaneous Tissue Disorders: Erythema
multiforme, Stevens-Johnson syndrome
Blood
and Lymphatic System Disorders: Hemolytic anemia
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION
(Additions and/or revisions
underlined)
See
FDA-approved patient
labeling
(Medication Guide).
…
Pulmonary
Arterial Hypertension
Inform
patients that PAH has occurred in patients treated with interferon beta products, including
REBIF.
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 (5.7)].
Seizures
Instruct patients to report seizures
immediately to their
healthcare provider [see
Warnings and Precautions (5.8)].
MEDICATION
GUIDE
(Additions and/or revisions
underlined)
…
- See “What is the most important information I should know about
REBIF?”
- Blood problems. REBIF
can affect your bone marrow and cause low red and white blood cell, and platelet
counts. In some people, these blood cell counts may fall to dangerously low
levels. If your blood cell counts become very low, you can get infections and problems with bleeding and bruising. Your healthcare provider may
ask you to have regular blood tests to check for blood problems.
- Pulmonary
arterial hypertension. Pulmonary arterial
hypertension can occur with interferon beta products, including REBIF.
Symptoms may include new or increasing fatigue or shortness
of breath. Contact your healthcare provider right
away if you develop these symptoms.
- Seizures.
Some people have had seizures
while taking REBIF.
…
Approved Drug Label (PDF)
5
Warnings and Precautions
5.4 Injection Site Reactions Including Necrosis
Additions
and/or revisions underlined:
Injection site
reactions, including injection site necrosis, can occur with the use of
interferon beta products, including REBIF. In
controlled clinical trials, injection site reactions occurred more frequently
in REBIF-treated patients …
… Some cases of
injection site necrosis required treatment with intravenous antibiotics and
surgical intervention (debridement and skin grafting). Some cases of
injection site abscesses and cellulitis required treatment with hospitalization
for surgical drainage and intravenous antibiotics.
Patient understanding
and use of aseptic self-injection techniques and procedures should be
periodically evaluated, particularly if injection site necrosis has occurred …
… Patients
should be advised against injecting an area which is inflamed, edematous,
erythematous, ecchymotic, or has any other signs of infection. These signs
should be reported to a healthcare professional immediately. If multiple
lesions occur, change injection site or discontinue therapy until healing
occurs.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDE
What is the
most important information I should know about REBIF?
Additions
and/or revisions underlined:
Injection site
problems. REBIF may cause redness, pain, itching or swelling
at the place where your injection was given. Call your healthcare provider right
away if an injection site becomes swollen and painful or the area looks
infected. You may have a skin infection or an area of severe skin damage
(necrosis) requiring treatment by a healthcare provider.
Approved Drug Label (PDF)
8
Use in Specific Populations
8.1
Pregnancy
PLLR
conversion; additions and/or revisions underlined:
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 during early pregnancy. Findings regarding a potential risk for
low birth weight or miscarriage with the use of interferon beta in pregnancy
have been inconsistent (see Data). It
is unclear whether, as a class of products, administration of interferon beta
therapies to pregnant animals at doses greater than those used clinically
results in an increased rate of abortion. The potential for REBIF to have
adverse effects on embryofetal development has not been fully assessed in
animals [see Data].
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. 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 from
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
In a study in pregnant cynomolgus monkeys,
interferon beta was administered daily (intramuscular doses approximately 1, 2,
and 7 times the maximum recommended cumulative weekly human dose …
8.2
Lactation
PLLR
conversion; additions and/or revisions underlined:
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 REBIF and any potential adverse effects on
the breastfed child from REBIF or from the underlying maternal condition.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDE
Additions
and/or revisions underlined:
What should I tell my healthcare provider
before taking REBIF?
Before
you take REBIF, tell your healthcare provider if have or have had any of the
following conditions:
you
are pregnant or plan to become pregnant. It is not known if REBIF can harm
your unborn baby.
you
are breastfeeding or plan to breastfeed. REBIF may pass into your breastmilk.
Talk with your healthcare provider about the best way to feed your baby
if you take REBIF.
PATIENT COUNSELING INFORMATION
Pregnancy
Additions
and/or revisions underlined:
Advise patients to notify their healthcare
provider if they become pregnant during treatment or plan to become pregnant [see Pregnancy (8.1)].
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