Betaseron

— THERAPEUTIC CATEGORIES —
  • Multiple sclerosis
PAGE CONTENTS
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  • Generic Name & Formulations
  • Indications
  • Dosage and Administration
  • Contraindications
  • Boxed Warnings
  • Warnings/Precautions
  • Pharmacokinetics
  • Interactions
  • Adverse Reactions
  • Clinical Trials
  • Note
  • Patient Counseling

    • Betaseron Generic Name & Formulations

    Legal Class

    Rx

    General Description

    Interferon beta-1b 0.3mg; per vial; lyophilized pwd for SC inj after reconstitution; contains albumin (human), mannitol; preservative-free.

    Pharmacological Class

    Immunomodulator.

    How Supplied

    Single-use vials (w. prefilled diluent syringe, supplies)—5, 14

    Storage

    After reconstitution, if not used immediately, refrigerate the reconstituted Betaseron solution at 35°F to 46°F (2°C to 8°C) and use within 3 hours. Do not freeze.

    Manufacturer

    Bayer Corporation

    Generic Availability

    NO

    Mechanism of Action

    The mechanism of action of interferon beta-1b in patients with multiple sclerosis is unknown. Immunomodulatory effects of interferon beta-1b include the enhancement of suppressor T cell activity, reduction of proinflammatory cytokine production, down-regulation of antigen presentation, and inhibition of lymphocyte trafficking into the central nervous system. 

    Betaseron Indications

    Indications

    Relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease.

    Betaseron Dosage and Administration

    Adult

    Pre-medicate with analgesics and/or antipyretics on treatment days to ameliorate flu-like symptoms. May be administered by syringe and needle or Betaconnect autoinjector. Rotate inj sites. ≥18yrs: initially 0.0625mg (0.25mL) SC every other day; increase by 25% every 2 weeks to target dose of 0.25mg (1mL) SC every other day.

    Children

    <18yrs: not established.

    Administration

    Intended for use under the guidance and supervision of a physician. Initial injection should be performed under the supervision of a health care provider. 

    If patient/caregiver self-administration is appropriate, train on proper technique. Patients with severe neurological deficits should not self-administer without assistance.

    BETACONNECT autoinjector

    • Has 3 adjustable injection depth settings.
    • Determine proper depth setting and injection technique.
    • Use only the syringes in the Betaseron packaging with the BETACONNECT autoinjector.

    Rotate sites for subcutaneous injection to minimize the likelihood of severe injection site reactions.

    Missed Dose: Take as soon as remembered. Do not take Betaseron on 2 consecutive days. The next injection should be taken 48 hours after that dose. Instruct patients to immediately report if more than the prescribed dose is taken or if taken on 2 consecutive days.

    Betaseron Contraindications

    Not Applicable

    Betaseron Boxed Warnings

    Not Applicable

    Betaseron Warnings/Precautions

    Warnings/Precautions

    Monitor for hepatic injury; consider discontinuing if elevated transaminase levels or jaundice occurs. Depression. Suicidal ideation. Pre-existing CHF: monitor for worsening cardiac function at initiation and during treatment. Discontinue if thrombotic microangiopathy or signs/symptoms of drug-induced lupus erythematosus occurs. Risk for pulmonary arterial hypertension (PAH); evaluate and discontinue if PAH confirmed. Myelosuppression. Monitor CBCs, differential, platelets, blood chemistries; liver function tests (at 1, 3, and 6 months then periodically). Pregnancy. Nursing mothers.

    Warnings/Precautions

    Hepatic Injury

    • Severe hepatic injury has been rarely reported with Betaseron.
    • Consider potential risk of concomitant use with known hepatotoxic drugs or alcohol.
    • Monitor for signs/symptoms of hepatic injury.
    • Increased serum transaminase levels with symptoms (eg, jaundice): consider discontinuing Betaseron.
    • Asymptomatic elevation of serum transaminases is common with Betaseron; monitor liver function tests.

    Anaphylaxis and Other Allergic Reactions

    • Anaphylaxis is a rare complication with Betaseron.
    • Other allergic reactions may include dyspnea, bronchospasm, tongue edema, skin rash and urticaria.
    • Discontinue if anaphylaxis occurs.

    Depression and Suicide

    • Depression and suicide have been reported with interferon beta products.
    • Patients should reports symptoms of depression or suicidal ideation.
    • Consider discontinuing Betaseron if depression develops.
    • Clinical trials: 3 suicides and 8 attempts among 1532 patients on Betaseron vs 1 suicide and 4 attempts among 965 patients on placebo.

    Congestive Heart Failure

    • Monitor patients with pre-existing CHF for worsening during treatment with Betaseron.
    • Cases of CHF and cardiomyopathy have been reported; some cases were temporally related to Betaseron.
    • Recurrence upon rechallenge has been observed in some cases.
    • Consider discontinuing Betaseron if worsening of CHF occurs with no other etiology.

    Injection Site Reactions Including Necrosis

    • Injection site reactions, including injection site necrosis (ISN), have been reported with interferon beta products.
    • ISN occurs within the first 4 months of therapy, although postmarketing reports have been received of ISN occurring over 1 year after initiation of therapy.
    • Necrotic lesions are typically 3cm or less in diameter.
    • Necrosis generally extends only to subcutaneous fat, but has extended to the fascia overlying muscle.
    • Vasculitis has been reported where lesion biopsy results were available.
    • Clinical trials: Injection site reactions occurred in 78% of patients receiving Betaseron; ISN occurred in 4% of patients.
    • Injection site abscesses and cellulitis have been reported in the postmarketing setting; some cases required hospitalization for surgical drainage and IV antibiotics.
    • Periodically evaluate patient understanding and use of aseptic self-injection techniques and procedures, particularly if ISN has occurred.
    • For patients who continue therapy after ISN, avoid administration into the affected area until fully healed.

    Leukopenia

    • Leukopenia was reported in 18% of patients receiving Betaseron in clinical trials; a reduction in dose was required for some patients.
    • Monitor complete blood and differential white blood cell counts.
    • Myelosuppression: May require more intensive monitoring.

    Thrombotic Microangiopathy

    • Cases of thrombotic microangiopathy (TMA), including thrombotic thrombocytopenic purpura and hemolytic uremic syndrome, some fatal, have been reported with interferon beta products.
    • Cases were reported several weeks to years after initiating therapy.
    • Discontinue treatment if symptoms and lab findings are consistent with TMA.

    Pulmonary Arterial Hypertension

    • Cases of pulmonary arterial hypertension (PAH) have been reported, many of which have required hospitalization.

    • Assess for PAH in patients who develop unexplained symptoms (eg, dyspnea, new or increasing fatigue). Discontinue if PAH is confirmed and alternative etiologies have been ruled out.

    Flu-Like Symptom Complex

    • In clinical trials, the rate of flu-like symptom complex for Betaseron-treated patients was 57%; the incidence decreased over time.
    • Median duration was 7.5 days.
    • Analgesics and/or antipyretics on treatment days helped ameliorate symptoms.

    Seizures

    • Seizures have been temporally associated with the use of beta interferons.

    Drug-Induced Lupus Erythematosus

    • Cases of drug-induced lupus erythematosus have been reported with some interferon beta products.
    • Signs and symptoms of drug-induced lupus: rash, serositis, polyarthritis, nephritis, and Raynaud’s phenomenon.
    • Cases have occurred with positive serologic testing.
    • Betaseron should be stopped if signs/symptoms of drug-induced lupus develop.

    Monitoring for Laboratory Abnormalities

    • Recommended: Complete blood count and differential white blood cell counts, platelet counts and blood chemistries, liver function tests.
    • Monitor at regular intervals (1, 3, 6 months) following initiation of therapy and then periodically thereafter in the absence of clinical symptoms.

    Immunogenicity

    • As with all therapeutic proteins, there is a potential for immunogenicity.
    • Based on available evidence, the relationship between antibody formation and clinical safety or efficacy with Betaseron  is not known.

    Pregnancy Considerations

    Available data, which includes prospective observational studies, have not generally indicated a drug-associated risk of major birth defects with interferon beta-1b during pregnancy.

    Nursing Mother Considerations

    There are no data on the presence of Betaseron in human milk, the effects on the breastfed infant, or the effects of the drug on milk production. Consider the benefits to the mother vs the potential risks to the infant.

    Pediatric Considerations

    Safety and efficacy in pediatric patients have not been established.

    Geriatric Considerations

    Clinical studies did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently than younger patients.

    Betaseron Pharmacokinetics

    Absorption

    Following every other day subcutaneous administration of Betaseron 0.25mg, biologic response marker levels (neopterin, β2- microglobulin, MxA protein, and the immunosuppressive cytokine, IL-10) increased significantly above baseline 6-12 hours after the first dose. Biologic response marker levels peaked between 40 and 124 hours and remained elevated above baseline throughout the 7-day (168-hour) study. The relationship between serum interferon beta-1b levels or induced biologic response marker levels and the clinical effects of interferon beta-1b in multiple sclerosis is unknown.

    Elimination

    Half-life: 8 minutes–4.3 hours.

    Betaseron Interactions

    Interactions

    Risk of hepatic injury with concomitant hepatotoxic drugs or alcohol.

    Betaseron Adverse Reactions

    Adverse Reactions

    Inj site reactions (necrosis, cellulitis, abscess, inflammation, pain), lymphopenia, flu-like symptoms, myalgia, leukopenia, neutropenia, increased liver enzymes, headache, hypertonia, pain, rash, insomnia, abdominal pain, asthenia; rare: hepatic injury, anaphylaxis (discontinue if occurs), possible seizures.

    Betaseron Clinical Trials

    Clinical Trials

    Patients with Relapsing-Remitting Multiple Sclerosis

    • Study 1: Double-blind, multiclinic, randomized, parallel, placebo-controlled clinical study of 2 years duration.
    • Study included patients aged 18 to 50 years who were ambulatory, exhibited a relapsing-remitting clinical course, met Poser’s criteria for clinically definite and/or laboratory supported definite MS and had experienced at least 2 exacerbations over 2 years preceding the trial without exacerbation in the preceding month.
    • Patients were randomly assigned to Betaseron 0.05mg, Betaseron 0.25mg, or placebo administered subcutaneously every other day.
    • Primary outcomes: 1) frequency of exacerbations per patient and 2) proportion of exacerbation free patients. 
    • Annual exacerbation rate: 1.14, 0.9 and 1.31 for Betaseron 0.05mg, 0.25mg, and placebo, respectively.
    • Proportion of exacerbation-free patients: 18%, 25%, and 16% for Betaseron 0.05mg, 0.25mg, and placebo, respectively.
    • The average number of days of MS-related steroid use was 41 days in the 0.25mg Betaseron group and 55 days in the placebo group (P =.004).
    • In an evaluation of frequent MRI scans (every 6 weeks) on 52 patients at 1 site, the percent of scans with new or expanding lesions was 29% in the placebo group and 6% in the 0.25mg treatment group (P =.006).

    Patients with Secondary Progressive Multiple Sclerosis 

    • Two randomized, double-blind, placebo-controlled trials conducted to assess the effect of Betaseron in patients with secondary progressive MS.
    • Study 2: Patients randomly assigned to Betaseron 0.25mg (n=360) or placebo (n=358).
    • Study 3: Patients randomly assigned to Betaseron 0.25mg (n=317), Betaseron 0.16mg/m2 of body surface area (n=314) or placebo (n=308).
    • Primary outcome: Progression of disability, defined as a 1.0 point increase in the EDSS score, or a 0.5 point increase for patients with baseline EDSS ≥ 6.0.
    • Study 2: Time to progression in EDSS was longer in the Betaseron treatment group (P =.005), with estimated annualized rates of progression of 16% and 19% in the Betaseron and placebo groups, respectively. The mean annual relapse rates were 0.42 and 0.63 in the Betaseron and placebo groups, respectively (P <.001).
    • Study 3: Rates of progression did not differ significantly between treatment groups, with estimated annualized rates of progression of 12%, 14%, and 12% in the Betaseron fixed dose, surface area-adjusted dose, and placebo groups, respectively. The mean annual relapse rates were 0.16, 0.20, and 0.28, for the fixed dose, surface area-adjusted dose, and placebo groups, respectively (P <.02).
    • Smaller increases in T2 MRI lesion area and decreased number of active MRI lesions were observed in patients in the Betaseron groups vs the placebo group. 

    Patients with an Isolated Demyelinating Event and Typical MS Lesions on Brain MRI 

    • Study 4: 468 patients who had recently (within 60 days) experienced an isolated demyelinating event, and who had lesions typical of MS on brain MRI were randomized to receive either Betaseron 0.25mg (n=292) or placebo (n=176) subcutaneously every other day (ratio 5:3).
    • Primary outcome: Time to development of a second exacerbation with involvement of at least 2 distinct anatomical regions.
    • Time to development of a second exacerbation was significantly delayed in patients treated with Betaseron compared with patients treated with placebo (P <.0001).
    • Kaplan-Meier estimates of the percentage of patients developing an exacerbation within 24 months were 45% in the placebo group and 28% of the Betaseron group.
    • Risk for developing a second exacerbation in the Betaseron group was 53% of the risk in the placebo group (hazard ratio, 0.53; 95% CI, 0.39-0.73).
    • Patients treated with Betaseron demonstrated a lower number of newly active lesions during the course of the study. A significant difference between Betaseron and placebo was not seen in the absolute change in T2 lesion volume during the course of the study.

    Betaseron Note

    Not Applicable

    Betaseron Patient Counseling

    Patient Counseling

    Patients should be advised of the importance of rotating injection sites with each dose; periodically evaluate patient understanding and use of aseptic self-injection techniques and procedures.

    Promptly report any break in the skin, which may be associated with black-blue discoloration, swelling, or drainage of fluid from the injection site prior to continuing treatment.

    Instruct patients on the symptoms of hepatic dysfunction, allergic reactions/anaphylaxis, and depression/suicidal ideation. Patients should report symptoms immediately..

    Worsening pre-existing CHF is possible with Betaseron treatment; patients should report symptoms immediately. 

    Report seizures immediately.

    Analgesics and/or antipyretics on treatment days may help ameliorate flu-like symptoms associated with Betaseron use.

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