ADVERSE REACTIONS
In all studies, the most serious adverse reactions with Betaseron were depression, suicidal ideation and injection site necrosis (see WARNINGS). The incidence of depression of any severity was approximately 30% in both Betaseron-treated patients and placebo-treated patients. Anaphylaxis and other allergic reactions have been reported in patients using Betaseron (see WARNINGS). The most commonly reported adverse reactions were lymphopenia (lymphocytes<1500/mm3), injection site reaction, asthenia, flu-like symptom complex, headache, and pain. The most frequently reported adverse reactions resulting in clinical intervention (e.g., 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.
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. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.
The data described below reflect exposure to Betaseron in the four placebo controlled trials of 1407 patients with MS treated with 0.25 mg or 0.16 mg/m2, including 1261 exposed for greater than one year. The population encompassed an age range from 18—65 years. Sixty-four percent (64%) of the patients were female. The percentages of Caucasian, Black, Asian, and Hispanic patients were 94.8%, 3.5%, 0.1%, and 0.7%, respectively.
The safety profiles for Betaseron-treated patients with SPMS and RRMS were similar. Clinical experience with Betaseron in other populations (patients with cancer, HIV positive patients, etc.) provides additional data regarding adverse reactions; however, experience in non-MS populations may not be fully applicable to the MS population.
Table 2 enumerates adverse events and laboratory abnormalities that occurred among all patients treated with 0.25 mg or 0.16 mg/m2 Betaseron every other day for periods of up to three years in the four placebo controlled trials (Study 1-4) at an incidence that was at least 2.0% more than that observed in the placebo patients (System Organ Class, MedDRA v. 8.0).
Table 2 Adverse Reactions and Laboratory Abnormalities |
System Organ Class MedDRA v. 8.0
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% |
| Lymphadenopathy | 3% | 6% |
| | | |
| Nervous system disorders | | |
| Headache | 43% | 50% |
| Insomnia | 16% | 21% |
| Incoordination | 15% | 17% |
| | | |
| | | |
| Vascular disorders | | |
| Hypertension | 4% | 6% |
| | | |
| Respiratory, thoracic and mediastinal disorders | | |
| Dyspnea | 3% | 6% |
| | | |
| Gastrointestinal disorders | | |
| Abdominal pain | 11% | 16% |
| | | |
| Hepatobiliary disorders | | |
Alanine aminotransferase increased
(SGPT > 5 times baseline) | 4% | 12% |
Aspartate aminotransferase increased
(SGOT > 5 times baseline) | 1% | 4% |
| | | |
| Skin and subcutaneous tissue disorders | | |
| Rash | 15% | 21% |
| Skin disorder | 8% | 10% |
| | | |
| Musculoskeletal and connective tissue disorders | | |
| Hypertonia | 33% | 40% |
| Myalgia | 14% | 23% |
| | | |
| Renal and urinary disorders | | |
| Urinary urgency | 8% | 11% |
| | | |
| Reproductive system and breast disorders | | |
| Metrorrhagia
| 7% | 9% |
| Impotence
| 6% | 8% |
| | | |
| General disorders and administration site conditions | | |
| Injection site reaction (various kinds )
| 26% | 78% |
| Asthenia | 48% | 53% |
| Flu-like symptoms (complex)
| 37% | 57% |
| Pain | 35% | 42% |
| Fever | 19% | 31% |
| Chills | 9% | 21% |
| Peripheral edema | 10% | 12% |
| Chest pain | 6% | 9% |
| Malaise | 3% | 6% |
| Injection site necrosis | 0% | 4% |
Injection Site Reactions
In four 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 non-specific reactions were significantly associated with Betaseron treatment (see WARNINGS and PRECAUTIONS). The incidence of injection site reactions tended to decrease over time. Approximately 69% of patients experienced the event during the first three months of treatment, compared to approximately 40% at the end of the studies.
Flu-Like Symptom Complex
The rate of flu-like symptom complex was approximately 57% in the four controlled clinical trials. The incidence decreased over time, with only 10% of patients reporting flu-like symptom complex at the end of the studies. For patients who experienced a flu-like symptom complex in Study 1, the median duration was 7.5 days.
Laboratory Abnormalities
In the four clinical trials, 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. (see PRECAUTIONS, Laboratory Tests).
Menstrual Irregularities
In the four clinical trials, 97 (12%) of the 783 pre-menopausal females treated with Betaseron and 79 (15%) of the 528 pre-menopausal females treated with placebo reported menstrual disorders. One event was reported as severe, all other reports were mild to moderate severity. No patients withdrew from the studies due to menstrual irregularities.
Postmarketing Experience
The following adverse events have been observed during postmarketing experience with Betaseron and are classified within body system categories:
Blood and lymphatic system disorders: Anemia, Thrombocytopenia
Endocrine disorders: Hypothyroidism, Hyperthyroidism, Thyroid dysfunction
Metabolism and nutrition disorders: Hypocalcemia, Hyperuricemia, Triglyceride increased, Anorexia, Weight decrease, Weight increase
Psychiatric disorders: Anxiety, Confusion, Depersonalization, Emotional lability
Nervous system disorders: Ataxia, Convulsion, Dizziness, Paresthesia, Psychotic symptoms
Cardiac disorders: Cardiomyopathy, Palpitations, Tachycardia
Vascular disorders: Deep vein thrombosis, Pulmonary embolism, Vasodilatation
Respiratory, thoracic and mediastinal disorders: Bronchospasm, Pneumonia
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
Renal and urinary disorders: Urinary tract infection, Urosepsis
General disorders and administration site conditions: Fatal capillary leak syndrome*.
*The administration of cytokines to patients with a pre-existing monoclonal gammopathy has been associated with the development of this syndrome.
Immunogenicity
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 16.5% up to 25.2% of the Betaseron treated patients. Such neutralizing activity was measured at least once in 75 (29.9%) out of 251 Betaseron patients who provided samples during treatment phase; of these, 17 (22.7%) 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 rarely been reported with the use of Betaseron.
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