Included as part of the PRECAUTIONS section.
Severe hepatic injury including cases of hepatic failure,
some of which have been due to autoimmune hepatitis, has been rarely reported
in patients taking BETASERON. In some cases, these events have occurred in the
presence of other drugs or comorbid medical conditions that have been
associated with hepatic injury. Consider the potential risk of
BETASERON used in combination with known hepatotoxic
drugs or other products (eg, alcohol) prior to BETASERON administration, or when
adding new agents to the regimen of patients already on BETASERON. Monitor
patients for signs and symptoms of hepatic injury. Consider discontinuing
BETASERON if serum transaminase levels significantly increase, or if they are
associated with clinical symptoms such as jaundice.
Asymptomatic elevation of serum transaminases is common
in patients treated with BETASERON. In controlled clinical trials, elevations
of SGPT to greater than five times baseline value were reported in 12% of
patients receiving BETASERON (compared to 4% on placebo), and increases of SGOT
to greater than five times baseline value were reported in 4% of patients
receiving BETASERON (compared to 1% on placebo), leading to dose-reduction or discontinuation
of treatment in some patients [see ADVERSE REACTIONS]. Monitor liver
function tests [see Monitoring for Laboratory Abnormalities].
Anaphylaxis And Other Allergic Reactions
Anaphylaxis has been reported as a rare complication of
BETASERON use. Other allergic reactions have included dyspnea, bronchospasm,
tongue edema, skin rash and urticaria [see ADVERSE REACTIONS].
Discontinue BETASERON if anaphylaxis occurs.
Depression And Suicide
Depression and suicide have been reported to occur with
increased frequency in patients receiving interferon beta products, including
BETASERON. Advise patients to report any symptom of depression and/or suicidal
ideation to their healthcare provider. If a patient develops depression,
discontinuation of BETASERON therapy should be considered.
In randomized controlled clinical trials, there were
three suicides and eight suicide attempts among the 1532 patients on BETASERON
compared to one suicide and four suicide attempts among 965 patients on
Congestive Heart Failure
Monitor patients with pre-existing congestive heart
failure (CHF) for worsening of their cardiac condition during initiation of and
continued treatment with BETASERON. While beta interferons do not have any
known direct-acting cardiac toxicity, cases of CHF, cardiomyopathy, and cardiomyopathy
with CHF have been reported in patients without known predisposition to these
events, and without other known etiologies being established. In some cases,
these events have been temporally related to the administration of BETASERON.
Recurrence upon rechallenge was observed in some patients. Consider
discontinuation of BETASERON if worsening of CHF occurs with no other etiology.
Injection Site Necrosis And Reactions
Injection site necrosis (ISN) was reported in 4% of
BETASERON-treated patients in controlled clinical trials (compared to 0% on
placebo) [see ADVERSE REACTIONS]. Typically, ISN occurs within the first
four months of therapy, although postmarketing reports have been received of
ISN occurring over one year after initiation of therapy. The necrotic lesions are
typically 3 cm or less in diameter, but larger areas have been reported.
Generally the necrosis has extended only to subcutaneous fat, but has extended
to the fascia overlying muscle. In some lesions where biopsy results are available,
vasculitis has been reported. For some lesions, debridement, and/or skin
grafting have been required. In most cases healing was associated with
Whether to discontinue therapy following a single site of
necrosis is dependent on the extent of necrosis. For patients who continue
therapy with BETASERON after injection site necrosis has occurred, avoid
administration of BETASERON into the affected area until it is fully healed. If
multiple lesions occur, discontinue therapy until healing occurs.
Periodically evaluate patient understanding and use of
aseptic self-injection techniques and procedures, particularly if injection
site necrosis has occurred.
In controlled clinical trials, injection site reactions
occurred in 78% of patients receiving BETASERON with injection site necrosis in
4%. Injection site inflammation (42%), injection site pain (16%), injection
site hypersensitivity (4%), injection site necrosis (4%), injection site mass
(2%), injection site edema (2%) and nonspecific reactions were significantly associated
with BETASERON treatment. The incidence of injection site reactions tended to
decrease over time. Approximately 69% of patients experienced injection site
reactions during the first three months of treatment, compared to approximately
40% at the end of the studies.
In controlled clinical trials, leukopenia was reported in
18% of patients receiving BETASERON (compared to 6% on placebo), leading to a
reduction of the dose of BETASERON in some patients [see ADVERSE REACTIONS].
Monitoring of complete blood and differential white blood cell counts is
recommended. Patients with myelosuppression may require more intensive
monitoring of complete blood cell counts, with differential and platelet
Cases of thrombotic microangiopathy (TMA), including
thrombotic thrombocytopenic purpura and hemolytic uremic syndrome, some fatal,
have been reported with interferon beta products, including BETASERON. Cases
have been reported several weeks to years after starting interferon beta
products. Discontinue BETASERON if clinical symptoms and laboratory findings
consistent with TMA occur, and manage as clinically indicated.
Flu-like Symptom Complex
In controlled clinical trials, the rate of flu-like symptom
complex for patients on BETASERON was 57% [see ADVERSE REACTIONS]. The
incidence decreased over time, with 10% of patients reporting flu-like symptom
complex at the end of the studies. The median duration of flu-like symptom
complex in Study 1 was 7.5 days [see Clinical Studies]. Analgesics
and/or antipyretics on treatment days may help ameliorate flu-like symptoms
associated with BETASERON use.
Seizures have been temporally associated with the use of
beta interferons in clinical trials and postmarketing safety surveillance. It
is not known whether these events were related to a primary seizure disorder,
the effects of multiple sclerosis alone, the use of beta interferons, other
potential precipitants of seizures (eg, fever), or to some combination of these.
Monitoring For Laboratory Abnormalities
In addition to those laboratory tests normally required
for monitoring patients with multiple sclerosis, complete blood and differential
white blood cell counts, platelet counts and blood chemistries, including liver
function tests, are recommended at regular intervals (one, three, and six
months) following introduction of BETASERON therapy, and then periodically thereafter
in the absence of clinical symptoms.
Patient Counseling Information
See FDA-approved patient labeling (Medication Guide
and Instructions for Use).
Instruct patients to carefully read the supplied
BETASERON Medication Guide and caution patients not to change the BETASERON
dose or schedule of administration without medical consultation.
Instruction on Self-Injection Technique and Procedures
Provide appropriate instruction for reconstitution of
BETASERON and methods of self-injection, including careful review of the
BETASERON Medication Guide. Instruct patients in the use of aseptic technique
when administering BETASERON.
Tell patients not to re-use needles or syringes and
instruct patients on safe disposal procedures. Advise patients of the importance
of rotating areas of injection with each dose, to minimize the likelihood of
severe injection site reactions, including necrosis or localized infection [see
Advise patients that severe hepatic injury, including hepatic
failure, has been reported during the use of BETASERON.
Inform patients of symptoms of hepatic dysfunction, and
instruct patients to report them immediately to their healthcare provider [see WARNINGS
Anaphylaxis and Other Allergic Reactions
Advise patients of the symptoms of allergic reactions and
anaphylaxis, and instruct patients to seek immediate medical attention if these
symptoms occur [see WARNINGS AND PRECAUTIONS].
Depression and Suicide
Advise patients that depression and suicidal ideation
have been reported during the use of BETASERON. Inform patients of the symptoms
of depression or suicidal ideation, and instruct patients to report them
immediately to their healthcare provider [see WARNINGS AND PRECAUTIONS].
Congestive Heart Failure
Advise patients that worsening of pre-existing congestive
heart failure have been reported in patients using BETASERON.
Advise patients of symptoms of worsening cardiac
condition, and instruct patients to report them immediately to their healthcare
provider [see WARNINGS AND PRECAUTIONS].
Injection Site Necrosis and Reactions
Advise patients that injection site reactions occur in
most patients treated with BETASERON, and that injection site necrosis may
occur at one or multiple sites. Instruct patients to promptly report any break
in the skin, which may be associated with blue-black discoloration, swelling,
or drainage of fluid from the injection site, prior to continuing their BETASERON
therapy [see WARNINGS AND PRECAUTIONS].
Flu-like Symptom Complex
Inform patients that flu-like symptoms are common
following initiation of therapy with BETASERON, and that concurrent use of
analgesics and/or antipyretics on treatment days may help ameliorate flu-like
symptoms associated with BETASERON use [see WARNINGS AND PRECAUTIONS and
DOSAGE AND ADMINISTRATION].
Instruct patients to report seizures immediately to their
healthcare provider [see WARNINGS AND PRECAUTIONS].
Advise patients that BETASERON should not be used during
pregnancy unless the potential benefit justifies the potential risk to the
fetus [see Use in Special Population]. Therefore, inform patients that
if a pregnancy is considered, or does occur, the risks and benefits of continuing
BETASERON should be discussed with their healthcare provider.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
BETASERON has not been tested for its carcinogenic
potential in animals.
BETASERON was not genotoxic in the in vitro Ames
bacterial test or the in vitro chromosomal aberration assay in human peripheral
blood lymphocytes. BETASERON treatment of mouse BALBc-3T3 cells did not result
in increased transformation frequency in an in vitro model of tumor
Impairment of Fertility
Administration of BETASERON (doses of up to 0.33
mg/kg/day) to normally cycling female rhesus monkeys had no apparent adverse
effects on either menstrual cycle duration or associated hormonal profiles
(progesterone and estradiol) when administered over three consecutive menstrual
cycles. The highest dose tested is approximately 30 times the recommended human
dose of 0.25 mg on a body surface area (mg/m²) basis. The potential for other
effects on fertility or reproductive performance was not evaluated.
Use In Specific Populations
Pregnancy Category C
There are no adequate and well-controlled studies in
pregnant women; however, spontaneous abortions while on treatment were reported
in four patients participating in the BETASERON RRMS clinical trial. BETASERON
should be used during pregnancy only if the potential benefit justifies the
potential risk to the fetus.
When BETASERON (doses ranging from 0.028 to 0.42
mg/kg/day) was administered to pregnant rhesus monkeys throughout the period of
organogenesis (gestation days 20 to 70), a dose-related abortifacient effect
was observed. The low-effect dose is approximately 3 times the recommended
human dose of 0.25 mg on a body surface area (mg/m²) basis. A no-effect dose
for embryo-fetal developmental toxicity in rhesus monkeys was not established.
It is not known whether BETASERON is excreted in human
milk. Because many drugs are excreted in human milk and because of the
potential for serious adverse reactions in nursing infants from BETASERON, a
decision should be made to either discontinue nursing or discontinue the drug,
taking into account the importance of drug to the mother.
Safety and efficacy in pediatric patients have not been
Clinical studies of BETASERON did not include sufficient
numbers of patients aged 65 and over to determine whether they respond
differently than younger patients.