Betaseron Side Effects

Generic Name: interferon beta-1b

Please note - some side effects for Betaseron may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA at http://www.fda.gov/medwatch/ or 1-800-FDA-1088 (1-800-332-1088).

Side Effects of Betaseron - for the Consumer

Betaseron Solution

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Betaseron Solution:

Constipation;changes in menstrual cycle; diarrhea; dizziness; drowsiness; flu-like symptoms (eg, low-grade fever, chills, general body discomfort); frequent urination; headache; joint pain; muscle pain or weakness; nausea; redness, pain, or swelling at the injection site; stomach upset; sweating; vomiting; weakness.

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); blue-black discoloration or skin breakdown around the injection site; chest pain; confusion; fast or irregular heartbeat; feeling cold or hot all the time; infection; mood or mental changes (eg, depression); persistent or high fever; seizures; severe anxiety or nervousness; severe headache or dizziness; severe stomach pain; suicidal thoughts or behaviors; unexplained swelling or weight gain; unusual bruising or bleeding; yellowing of the eyes or skin.

Betaseron Side Effects - for the Professional

Betaseron

In all studies, the most serious adverse reactions with Betaseron were depression, suicidal ideation and injection site necrosis. 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. 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).

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. 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..

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.

Side Effects by Body System

General

The use of interferon beta-1b in patients with multiple sclerosis is limited, therefore, it is probable that rarely occurring adverse effects may not have been reported to date.

Other

A flu-like syndrome, which includes fever, chills, myalgias, malaise or sweating, occurs in 50% of patients. This syndrome appears to occur most frequently during the first three months of therapy, and abates with continued treatment.

Local

Locally, interferon beta-1b injections may cause pain or inflammation at the injection site in 70% of patients. Severe necrotic lesions have occurred.

Hepatic

Hepatic effects of interferon beta-1b include transient elevation of liver function tests. Mild elevations have occurred in 11% of treated patients. Therapy has been discontinued in 1.2% of patients for abnormal liver enzymes.

Hematologic

Hematologic effects include mild neutropenia in 17% of patients receiving interferon beta-1b. Lymphopenia occurs at some time in up to 80% of treated patients.

Genitourinary

A 19-year-old white woman diagnosed with multiple sclerosis experienced severe vaginal bleeding when her dose of interferon beta-1b was increased, 1 month from the start of therapy, from 4 to 8 million intl units.

Effects on the genitourinary system include menstrual disorders in 13 to 28% of women treated with interferon beta-1b.

Cardiovascular

Cardiovascular effects of interferon beta-1b may include palpitations in 8% of treated patients, and less commonly, tachycardia and hypertension.

Nervous system

The nervous system may be adversely affected by interferon beta-1b administration. Somnolence, depression, anxiety, and confusion have been reported in 4% to 6% of patients. One suicide and four suicide attempts were reported in 372 patients treated with 1.6 or 8 million intl units every other day, while none were reported in patients on placebo.

Gastrointestinal

Gastrointestinal adverse effects may include nausea and vomiting.

Other

Sudden hearing loss, which was reversible within 7 to 14 days of drug discontinuation, has been reported.

Immunologic

Immunologically, some patients may develop antibodies against interferon beta, often as early as 3 months after the start of treatment. The antibodies may bind to and block the beneficial effect of interferon beta in MS. The overall clinical significance is unknown.

Results of a prospective study suggest that several autoimmune events may occur during interferon beta treatment of multiple sclerosis and recommends the close monitoring of thyroid, liver function and autoantibodies.

Neutralizing antibodies formation occurred after the 24-week treatment in 95% of patients treated with natural interferon beta compared to 27% of patients treated with recombinant interferon beta.

Dermatologic

A case of sarcoid-like dermatitis is reported in a 57-year-old white man diagnosed with multiple sclerosis. The cutaneous eruption that developed 2 months after initiation of interferon beta-1b therapy histologically resembled sarcoidal granulomas, but without distinctive features of true sarcoidosis.

A case of cutaneous necrosis in a 38-year-old woman diagnosed with relapsing-remitting multiple sclerosis is believed to be a result of an immunological response to the improperly dissolved lyophilized drug. The patient was rechallenged with the drug, after introducing changes to the way she reconstituted the drug, without any reports of scars.

Dermatologic side effects have included contact dermatitis, erythema nodosum, exfoliative dermatitis, furunculosis, hirsutism, leukoderma, lichenoid dermatitis, maculopapular rash, psoriasis, seborrhea, benign skin neoplasm, skin carcinoma, skin hypertrophy, skin necrosis, skin ulcer, urticaria, and vesiculobullous lesions.

Endocrine

Endocrine side effects have included changes in thyroid function.

Musculoskeletal

Musculoskeletal side effects reported in a study of 124 multiple sclerosis patients have included reports of myalgia (44%) and myasthenia (13%). A study of 19 patients with primary progressive multiple sclerosis reported frequent and clinically significant increase in spasticity that appeared approximately 2 months after start of interferon beta-1b.

Renal

Renal side effects have included postmarketing case reports of hemolytic uremic syndrome, and nephrotic syndrome with minimal histologic changes of the glomerulus. Upon withdrawal of interferon beta therapy these side effects subsided.

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