ADVERSE REACTIONS
Clinical Studies Experience
In all studies, the most serious adverse reactions with Interferon beta-1b were depression, suicidal ideation and injection site necrosis (see
Warnings and Precautions). The incidence of depression of any severity was approximately 30% in both Interferon beta-1b-treated patients and placebo-treated patients. Anaphylaxis and other allergic reactions have been reported in patients using Interferon beta-1b [ see
Warnings and Precautions
(5.
4
)]. 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 Interferon beta-1b, 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 Interferon beta-1b 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 Interferon beta-1b 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 Interferon beta-1b-treated patients with SPMS and RRMS were similar. Clinical experience with Interferon beta-1b 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 Interferon beta-1b 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) |
Interferon beta-1b (n=1407) |
|
Blood and lymphatic system disorders
|
|
|
| Lymphocytes count decreased (< 1500/mm3) x
|
66% |
86% |
| Absolute neutrophil count decreased (< 1500/mm3) x
|
5% |
13% |
| White blood cell count decreased (< 3000/mm3) x
|
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)x
|
4% |
12% |
| Aspartate aminotransferase increased(SGOT > 5 times baseline)x
|
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 ) 0
|
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% |
# except for "injection site reaction (various kinds)o" and "flu-like symptom complex§" the most appropriate MedDRA term is used to describe a certain reaction and its synonyms and related conditions.
x laboratory abnormality
* pre-menopausal women
** men
o "Injection site reaction (various kinds)" comprises all adverse events occurring at the injection site (except injection site necrosis), i.e., 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.
§ "Flu-like symptom complex" denotes flu syndrome and/or a combination of at least two AEs from fever, chills, myalgia, malaise, sweating. |
Laboratory Abnormalities
In the four clinical trials, leukopenia was reported in 18% and 6% of patients in Interferon beta-1b- 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. Monitoring of complete blood and differential white blood cell counts is recommended [ see Warnings and Precautions (5.6, 5.8) ].
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 Interferon beta-1b 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 Interferon beta-1b for any laboratory abnormality, including four (0.3%) patients following dose reduction. Monitoring of liver function tests is recommended [see Warnings and Precautions (5.7, 5.8)].
Postmarketing Experience
The following adverse events have been observed during postmarketing experience with Interferon beta-1b 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
Psychiatric disorders: Confusion, Depersonalization, Emotional lability
Nervous system disorders: Ataxia, Convulsion, Paresthesia, Psychotic symptoms
Cardiac disorders: Cardiomyopathy
Vascular disorders: Deep vein thrombosis, Pulmonary embolism
Respiratory, thoracic and mediastinal disorders: Bronchospasm, Pneumonia
Gastrointestinal disorders: Pancreatitis, Vomiting
Hepatobiliary disorders: Hepatitis, Gamma GT increased
Skin and subcutaneous tissue disorders: Pruritus, Skin discoloration, Urticaria
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 Interferon beta-1b during Study 1 [see Clinical Studies]. 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 [see Clinical Studies], 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 Interferon beta-1b treated patients. Such neutralizing activity was measured at least once in 75 (29.9%) out of 251 Interferon beta-1b 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 Interferon beta-1b 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 Interferon beta-1b with the incidence of antibodies to other products may be misleading.
Anaphylactic reactions have rarely been reported with the use of Interferon beta-1b [s
ee Warnings and Precautions].
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