WARNINGS AND PRECAUTIONS
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 (e.g., 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 Warnings and Precautions].
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 placebo.
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 three 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 scarring.
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 counts.
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 (e.g., 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.
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 established.
Clinical studies of Betaseron did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently than younger patients.