The following serious adverse reactions are discussed in more details in other sections of labeling:
- Hepatic Injury [see WARNINGS AND PRECAUTIONS]
- Anaphylaxis and Other Allergic-Reactions [see WARNINGS AND PRECAUTIONS]
- Depression and Suicide [see WARNINGS AND PRECAUTIONS]
- Congestive Heart Failure [see WARNINGS AND PRECAUTIONS]
- Injection Site Necrosis and Reactions [see WARNINGS AND PRECAUTIONS]
- Leukopenia [see WARNINGS AND PRECAUTIONS]
- Flu-Like Symptom Complex [see WARNINGS AND PRECAUTIONS]
- Seizures [see WARNINGS AND PRECAUTIONS]
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions and over varying lengths of time, adverse reaction rates observed in the clinical trials of Betaseron cannot be directly compared to rates in clinical trials of other drugs, and may not reflect the rates observed in practice.
Among 1407 patients with MS treated with Betaseron 0.25 mg every other day (including 1261 patients treated for greater than one year), the most commonly reported adverse reactions (at least 5% more frequent on Betaseron than on placebo) were injection site reaction, lymphopenia, flu-like symptoms, myalgia leukopenia, neutropenia, increased liver enzymes, headache, hypertonia, pain, rash, insomnia, abdominal pain, and asthenia. The most frequently reported adverse reactions resulting in clinical intervention (for example, discontinuation of Betaseron, adjustment in dosage, or the need for concomitant medication to treat an adverse reaction symptom) were depression, flu-like symptom complex, injection site reactions, leukopenia, increased liver enzymes, asthenia, hypertonia, and myasthenia.
Table 2 enumerates adverse reactions and laboratory abnormalities that occurred among patients treated with 0.25 mg of Betaseron every other day by subcutaneous injection in the pooled placebo-controlled trials (Study 1-4) at an incidence that was at least 2% more than that observed in the placebo-treated patients [see Clinical Studies].
Table 2: Adverse Reactions and Laboratory Abnormalities in Patients with MS in Pooled Studies 1, 2, 3, and 4
|Adverse Reaction||Placebo (N=965)||Betaseron (N=1407)|
|Blood and lymphatic system disorders|
|Lymphocytes count decreased ( < 1500/mm³ )||66%||86%|
|Absolute neutrophil count decreased ( < 1500/mm³ )||5%||13%|
|White blood cell count decreased ( < 3000/mm³ )||4%||13%|
|Nervous system disorders|
|Respiratory, thoracic and mediastinal disorders|
|Alanine aminotransferase increased (SGPT > 5 times baseline)||4%||12%|
|Aspartate aminotransferase increased (SGOT > 5 times baseline)||1%||4%|
|Skin and subcutaneous tissue disorders|
|Musculoskeletal and connective tissue disorders|
|Renal and urinary disorders|
|Reproductive system and breast disorders|
|General disorders and administration site conditions|
|Injection site reactiona||26%||78%|
|Flu-like symptoms (complex)b||37%||57%|
|Injection site necrosis||0%||4%|
|a"Injection site reaction" comprises all adverse reactions occurring at the injection site (except injection site necrosis), that is, the following terms: injection site reaction, injection site hemorrhage, injection site hypersensitivity, injection site inflammation, injection site mass, injection site pain, injection site edema and injection site atrophy.
b "Flu-like symptom (complex)" denotes flu syndrome and/or a combination of at least two adverse reactions from fever, chills, myalgia, malaise, sweating. In addition to the Adverse Reactions listed in Table 2, the following adverse reactions occurred more frequently on Betaseron than on placebo, but with a difference smaller than 2%: alopecia, anxiety, arthralgia, constipation, diarrhea, dizziness, dyspepsia, dysmenorrhea, leg cramps, menorrhagia, myasthenia, nausea, nervousness, palpitations, peripheral vascular disorder, prostatic disorder, tachycardia, urinary frequency, vasodilatation, and weight increase.
In the four clinical trials (Studies 1, 2, 3, and 4), leukopenia was reported in 18% and 6% of patients in Betaseron- and placebo-treated groups, respectively. No patients were withdrawn or dose reduced for neutropenia in Study 1. Three percent (3%) of patients in Studies 2 and 3 experienced leukopenia and were dose-reduced. Other abnormalities included increase of SGPT to greater than five times baseline value (12%), and increase of SGOT to greater than five times baseline value (4%). In Study 1, two patients were dose reduced for increased hepatic enzymes; one continued on treatment and one was ultimately withdrawn. In Studies 2 and 3, 1.5% of Betaseron patients were dose-reduced or interrupted treatment for increased hepatic enzymes. In Study 4, 1.7% of patients were withdrawn from treatment due to increased hepatic enzymes, two of them after a dose reduction. In Studies 1-4, nine (0.6%) patients were withdrawn from treatment with Betaseron for any laboratory abnormality, including four (0.3%) patients following dose reduction.
As with all therapeutic proteins, there is a potential for immunogenicity. Serum samples were monitored for the development of antibodies to Betaseron during Study 1. In patients receiving 0.25 mg every other day 56/124 (45%) were found to have serum neutralizing activity at one or more of the time points tested. In Study 4, neutralizing activity was measured every 6 months and at end of study. At individual visits after start of therapy, activity was observed in 17% up to 25% of the Betaseron-treated patients. Such neutralizing activity was measured at least once in 75 (30%) out of 251 Betaseron patients who provided samples during treatment phase; of these, 17 (23%) converted to negative status later in the study. Based on all the available evidence, the relationship between antibody formation and clinical safety or efficacy is not known.
These data reflect the percentage of patients whose test results were considered positive for antibodies to Betaseron using a biological neutralization assay that measures the ability of immune sera to inhibit the production of the interferon-inducible protein, MxA. Neutralization assays are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of neutralizing activity in an assay may be influenced by several factors including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Betaseron with the incidence of antibodies to other products may be misleading.
Anaphylactic reactions have been reported with the use of Betaseron [see WARNINGS AND PRECAUTIONS].
The following adverse reactions have been identified during postapproval use of Betaseron. 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.
Blood and lymphatic system disorders: Anemia, Thrombocytopenia
Endocrine disorders: Hypothyroidism, Hyperthyroidism, Thyroid dysfunction
Metabolism and nutrition disorders: Triglyceride increased, Anorexia, Weight decrease, Weight increase
Psychiatric disorders: Anxiety, Confusion, Emotional lability
Nervous system disorders: Convulsion, Dizziness, Psychotic symptoms
Cardiac disorders: Cardiomyopathy, Palpitations, Tachycardia
Vascular disorders: Vasodilatation
Respiratory, thoracic and mediastinal disorders: Bronchospasm
Gastrointestinal disorders: Diarrhea, Nausea, Pancreatitis, Vomiting
Hepatobiliary disorders: Hepatitis, Gamma GT increased
Skin and subcutaneous tissue disorders: Alopecia, Pruritus, Skin discoloration, Urticaria
Musculoskeletal and connective tissue disorders: Arthralgia
Reproductive system and breast disorder: Menorrhagia
General disorders and administration site conditions: Fatal capillary leak syndrome*