Side Effects of Betaseron (interferon beta-1b)

Betaseron (interferon beta-1b) is an immunological agent made from human proteins used to treat relapsing forms of multiple sclerosis to reduce the frequency of clinical exacerbations. Patients with multiple sclerosis in whom efficacy has been demonstrated include patients who have experienced a first clinical episode and have MRI features consistent with multiple sclerosis.

Common side effects of Betaseron include

• flu-like symptoms (fever, tiredness, sweating, chills, muscle aches when you first start to use it),
• low white blood cell count,
• the increased liver enzyme,
• problems sleeping,
• headache,
• increased muscle tension,
• weakness,
• pain,
• rash, and
• stomach pain.

Serious side effects of Betaseron include

• Heart problems. Symptoms of heart problems include
  • swollen ankles,
  • shortness of breath,
  • being unable to lay flat in the bed,
  • chest tightness,
  • decreased ability to exercise,
  • fast heartbeat,
  • increased need to urinate at night, and
  • injection site problems.
• Serious skin reactions (severe damage to the skin and the tissue below the skin),
• Injection site problems. Symptoms may include
  • swelling,
  • redness, or pain at the injection site,
  • fluid drainage from the injection site, and
  • breaks in the skin or blue-black skin discoloration 
• Seizures.

Betaseron may interact with other drugs. Do not take Betaseron if you are allergic to interferon beta-1b, to another interferon beta, human albumin, or mannitol.

There are no adequate and well-controlled studies of Betaseron in pregnant women; however, spontaneous abortions while on treatment were reported in four patients participating in the Betaseron RRMS clinical trial. Betaseron should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

It is unknown if Betaseron is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Betaseron, a decision should be made to either discontinue breastfeeding or discontinue the drug, taking into account the importance of the drug to the mother.

Betaseron may cause serious side effects. Call your healthcare provider right away if you have any of the serious side effects of Betaseron including:

Heart problems

Betaseron may worsen heart problems including congestive heart failure. Symptoms of heart problems may include:

• swollen ankles
• shortness of breath
• not being able to lay flat in bed
• tightness in chest
• decreased ability to exercise
• fast heartbeat
• increased need to urinate at night
• injection site problems.

Skin reactions

Serious skin reactions can happen in some people including areas of severe damage to the skin and the tissue below the skin (necrosis). These reactions can happen anywhere you inject Betaseron.

Symptoms of injection site problems may include:

• swelling,
• redness, or
• pain at the injection site,
• fluid drainage from the injection site, and
• breaks in your skin or
• blue-black skin discoloration.

Flu-like symptoms

Betaseron can cause flu-like symptoms including:

• fever
• tiredness
• sweating
• chills
• muscle aches when you first start to use it

These symptoms may decrease over time. Taking medicines for fever and pain relief on the days you are using Betaseron may help decrease these symptoms.

Seizures

Some people have had seizures while taking Betaseron, including people who have never had seizures before. It is not known if the seizures were related to their MS, Betaseron, or a combination of both.

If you have a seizure after taking Betaseron call your healthcare provider right away. The most common side effects of Betaseron include:

• low white blood cell count
• increases in your liver enzymes
• problems sleeping
• headache
• increases in your muscle tension
• weakness
• pain
• rash
• stomach pain

Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of Betaseron. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

The following serious adverse reactions are discussed in more detail in other sections of the 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

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 the 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.

Table 2: Adverse Reactions and Laboratory Abnormalities in Patients with MS in Pooled Studies 1, 2, 3, and 4

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.

Laboratory Abnormalities

• 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 the 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 an increase of SGPT to greater than five times baseline value (12%) and an 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.

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 the study.
• At individual visits after the 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 the 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 interferoninducible 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, the timing of sample collection, concomitant medications, and underlying disease.
• For these reasons, a 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.

Postmarketing Experience

The following adverse reactions have been identified during the 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 increase, Anorexia, Weight decreased, 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*

*The administration of cytokines to patients with a pre-existing monoclonal gammopathy has been associated with the development of this syndrome.

No information was provided.