EXTAVIA SIDE EFFECTS
- Generic Name: interferon beta-1b kit
- Brand Name: Extavia
- Drug Class: Immunomodulators
SIDE EFFECTS
The following serious adverse reactions are discussed in more details in other sections of labeling:
- Hepatic Injury
- Anaphylaxis and Other Allergic Reactions
- Depression and Suicide
- Congestive Heart Failure
- Injection Site Necrosis and Reactions
- Leukopenia
- Thrombotic Microangiopathy
- Flu-like Symptom Complex
- Seizures
- Drug-induced Lupus Erythematosus
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 interferon beta-1b 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 interferon beta-1b 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 interferon beta-1b 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 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.
Table 2 enumerates adverse reactions and laboratory abnormalities that occurred among patients treated with 0.25 mg of interferon beta-1b 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.
Table 1: Adverse Reactions and Laboratory Abnormalities in Patients with MS in Pooled Studies 1, 2, 3, and 4
| Adverse Reaction | Placebo (N = 965) |
Interferon beta-1b (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 reactiona | 26% | 78% |
| Asthenia | 48% | 53% |
| Flu-like symptoms (complex)b | 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% |
| 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. |
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In addition to the adverse reactions listed in Table 2, the following adverse reactions occurred more frequently on interferon beta-1b 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.
Laboratory Abnormalities
In the four clinical trials (Studies 1, 2, 3, and 4), leukopenia was reported in 18% and 6% of patients in interferon beta-1band 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 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.
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. 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 interferon beta-1b-treated patients. Such neutralizing activity was measured at least once in 75 (30%) out of 251 interferon beta-1b 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 interferon beta1b 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 been reported with the use of interferon beta-1b
Postmarketing Experience
The following adverse reactions have been identified during postapproval use of interferon beta-1b. 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, Hemolytic anemia
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, Drug-induced lupus erythematosus
Reproductive system and breast disorder: Menorrhagia
General disorders and administration site conditions: Fatal capillary leak syndrome*
*The administration of cytokines to patients with a preexisting monoclonal gammopathy has been associated with the development of this syndrome.
SRC: NLM .