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BETASERON (interferon beta-1b) is a purified, sterile, lyophilized protein product produced by recombinant DNA techniques. Interferon beta-1b is manufactured by bacterial fermentation of a strain of Escherichia coli that bears a genetically engineered plasmid containing the gene for human interferon betaser17. The native gene was obtained from human fibroblasts and altered in a way that substitutes serine for the cysteine residue found at position 17. Interferon beta-1b has 165 amino acids and an approximate molecular weight of 18,500 daltons. It does not include the carbohydrate side chains found in the natural material.
The specific activity of BETASERON is approximately 32 million international units (IU)/mg interferon beta-lb. Each vial contains 0.3 mg of interferon beta-lb. The unit measurement is derived by comparing the antiviral activity of the product to the World Health Organization (WHO) reference standard of recombinant human interferon beta. Mannitol, USP and Albumin (Human), USP (15 mg each/vial) are added as stabilizers.
Lyophilized BETASERON is a sterile, white to off-white powder, for subcutaneous injection after reconstitution with the diluent supplied (Sodium Chloride, 0.54% Solution). Albumin (Human) USP and Mannitol, USP (15 mg each/vial) are added as stabilizers.
BETASERON is indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults.
The recommended starting dose is 0.0625 mg (0.25 mL) subcutaneously every other day, with dose increases over a six-week period to the recommended dose of 0.25 mg (1 mL) every other day (see Table 1).
Table 1: Schedule for Dose Titration
| BETASERON Dose1 | Percentage of recommended dose | Volume | |
| Weeks 1-2 | 0.0625 mg | 25% | 0.25 mL |
| Weeks 3-4 | 0.125 mg | 50% | 0.5 mL |
| Weeks 5-6 | 0.1875 mg | 75% | 0.75 mL |
| Week 7 and thereafter | 0.25 mg | 100% | 1 mL |
| 1 Dosed every other day, subcutaneously | |||
If a dose of BETASERON is missed, then it should be taken as soon as the patient remembers or is able to take it. The patient should not take BETASERON on two consecutive days. The next injection should be taken about 48 hours (two days) after that dose. If the patient accidentally takes more than their prescribed dose, or takes it on two consecutive days, they should be instructed to call their healthcare provider immediately.
Concurrent use of analgesics and/or antipyretics on treatment days may help ameliorate flu-like symptoms associated with BETASERON use [see WARNINGS AND PRECAUTIONS].
For injection: 0.3 mg lyophilized powder in a single-dose vial for reconstitution.
BETASERON is supplied as a lyophilized powder in a clear glass, single-dose vial (3 mL capacity). Each carton contains 5 single-dose cartons (NDC 50419-524-05) or 14 single-dose cartons (NDC 50419-524-35).
Each single-dose carton contains:
The optional BETACONNECT autoinjector is not supplied with BETASERON, but is available for patients with a prescription for BETASERON by calling the BETAPLUS patient support program toll-free number at 1-800-788-1467.
BETASERON and the diluent are for single-dose only. Discard unused portions. The reconstituted product contains no preservative. Store BETASERON vials between 36°F to 86°F (2°C to 30°C). After reconstitution, if not used immediately, refrigerate the reconstituted solution and use within three hours. Do not freeze.
 Manufactured for: Bayer HealthCare Pharmaceuticals Inc. Whippany, NJ 07981. Revised: Jul 2023
The following serious adverse reactions are discussed in more details in other sections of labeling:
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 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 [see Clinical Studies].
Table 2: Adverse Reactions and Laboratory Abnormalities in Patients with MS in Pooled Studies 1, 2, 3, and 4
| Adverse Reaction | Placebo (N=965) |
BETASERON (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 reaction1 | 26% | 78% |
| Asthenia | 48% | 53% |
| Flu-like symptoms (complex)2 | 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% |
| 1“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. 2“Flu-like symptom (complex)” denotes flu syndrome and/or a combination of at least two adverse reactions from fever, chills, myalgia, malaise, sweating. |
||
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.
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 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.
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 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 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 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 been reported with the use of BETASERON [see WARNINGS AND PRECAUTIONS].
The following adverse reactions have been identified during 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, 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, Pulmonary Arterial Hypertension
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 provided
Included as part of the PRECAUTIONS section.
Severe hepatic injury including cases of hepatic failure, some of which have been due to autoimmune hepatitis, has been rarely reported in patients taking BETASERON. In some cases, these events have occurred in the presence of other drugs or comorbid medical conditions that have been associated with hepatic injury. Consider the potential risk of BETASERON used in combination with known hepatotoxic drugs or other products (eg, alcohol) prior to BETASERON administration, or when adding new agents to the regimen of patients already on BETASERON. Monitor patients for signs and symptoms of hepatic injury. Consider discontinuing BETASERON if serum transaminase levels significantly increase, or if they are associated with clinical symptoms such as jaundice.
Asymptomatic elevation of serum transaminases is common in patients treated with BETASERON. In controlled clinical trials, elevations of SGPT to greater than five times baseline value were reported in 12% of patients receiving BETASERON (compared to 4% on placebo), and increases of SGOT to greater than five times baseline value were reported in 4% of patients receiving BETASERON (compared to 1% on placebo), leading to dose-reduction or discontinuation of treatment in some patients [see ADVERSE REACTIONS]. Monitor liver function tests [see WARNINGS AND PRECAUTIONS].
Anaphylaxis has been reported as a rare complication of BETASERON use. Other allergic reactions have included dyspnea, bronchospasm, tongue edema, skin rash and urticaria [see ADVERSE REACTIONS]. Discontinue BETASERON if anaphylaxis occurs.
Depression and suicide have been reported to occur with increased frequency in patients receiving interferon beta products, including BETASERON. Advise patients to report any symptom of depression and/or suicidal ideation to their healthcare provider. If a patient develops depression, discontinuation of BETASERON therapy should be considered.
In randomized controlled clinical trials, there were three suicides and eight suicide attempts among the 1532 patients on BETASERON compared to one suicide and four suicide attempts among 965 patients on placebo.
Monitor patients with pre-existing congestive heart failure (CHF) for worsening of their cardiac condition during initiation of and continued treatment with BETASERON. While beta interferons do not have any known direct-acting cardiac toxicity, cases of CHF, cardiomyopathy, and cardiomyopathy with CHF have been reported in patients without known predisposition to these events, and without other known etiologies being established. In some cases, these events have been temporally related to the administration of BETASERON. Recurrence upon rechallenge was observed in some patients. Consider discontinuation of BETASERON if worsening of CHF occurs with no other etiology.
Injection site reactions, including injection site necrosis, can occur with the use of interferon beta products, including BETASERON. Injection site necrosis (ISN) was reported in 4% of BETASERON-treated patients in controlled clinical trials (compared to 0% on placebo) [see ADVERSE REACTIONS]. Typically, ISN occurs within the first four months of therapy, although postmarketing reports have been received of ISN occurring over one year after initiation of therapy. The necrotic lesions are typically 3 cm or less in diameter, but larger areas have been reported. Generally the necrosis has extended only to subcutaneous fat, but has extended to the fascia overlying muscle. In some lesions where biopsy results are available, vasculitis has been reported. For some lesions, debridement, and/or skin grafting have been required. In most cases healing was associated with scarring.
In 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 nonspecific reactions were significantly associated with BETASERON treatment. The incidence of injection site reactions tended to decrease over time. Approximately 69% of patients experienced injection site reactions during the first three months of treatment, compared to approximately 40% at the end of the studies.
Injection site abscesses and cellulitis have been reported in the postmarketing setting with use of interferon beta products including BETASERON. Some cases required treatment with hospitalization for surgical drainage and intravenous antibiotics. Periodically evaluate patient understanding and use of aseptic self-injection techniques and procedures, particularly if injection site necrosis has occurred. Patients should be advised of the importance of rotating injection sites with each dose. Whether to discontinue therapy following a single site of necrosis is dependent on the extent of necrosis. For patients who continue therapy with BETASERON after injection site necrosis has occurred, avoid administration of BETASERON into the affected area until it is fully healed. If multiple lesions occur, change injection site or discontinue therapy until healing occurs.
In controlled clinical trials, leukopenia was reported in 18% of patients receiving BETASERON (compared to 6% on placebo), leading to a reduction of the dose of BETASERON in some patients [see ADVERSE REACTIONS]. Monitoring of complete blood and differential white blood cell counts is recommended. Patients with myelosuppression may require more intensive monitoring of complete blood cell counts, with differential and platelet counts.
Cases of thrombotic microangiopathy (TMA), including thrombotic thrombocytopenic purpura and hemolytic uremic syndrome, some fatal, have been reported with interferon beta products, including BETASERON.
Cases have been reported several weeks to years after starting interferon beta products. If clinical symptoms and laboratory findings consistent with TMA occur and a relationship to BETASERON is suspected, discontinue treatment and manage as clinically indicated.
Cases of pulmonary arterial hypertension (PAH) have been reported with interferon beta products, including BETASERON. PAH has occurred in patients treated with interferon beta products in the absence of other contributory factors. Many of the reported cases required hospitalization, including one case with interferon beta in which the patient underwent a lung transplant. PAH has developed at various time points after initiating therapy with interferon beta products and may occur several years after starting treatment.
Patients who develop unexplained symptoms (e.g., dyspnea, new or increasing fatigue) should be assessed for PAH. If alternative etiologies have been ruled out and a diagnosis of PAH is confirmed, discontinue treatment and manage as clinically indicated.
In controlled clinical trials, the rate of flu-like symptom complex for patients on BETASERON was 57% [see ADVERSE REACTIONS]. The incidence decreased over time, with 10% of patients reporting flu-like symptom complex at the end of the studies. The median duration of flu-like symptom complex in Study 1 was 7.5 days [see Clinical Studies]. Analgesics and/or antipyretics on treatment days may help ameliorate flu-like symptoms associated with BETASERON use.
Seizures have been temporally associated with the use of beta interferons in clinical trials and postmarketing safety surveillance. It is not known whether these events were related to a primary seizure disorder, the effects of multiple sclerosis alone, the use of beta interferons, other potential precipitants of seizures (eg, fever), or to some combination of these.
Cases of drug-induced lupus erythematosus have been reported with some interferon beta products, including BETASERON. Signs and symptoms of drug-induced lupus reported in BETASERON-treated patients have included rash, serositis, polyarthritis, nephritis, and Raynaud’s phenomenon. Cases have occurred with positive serologic testing (including positive anti-nuclear and/or anti-double-stranded DNA antibody testing). If BETASERON-treated patients develop new signs and symptoms characteristic of this syndrome, BETASERON therapy should be stopped.
In addition to those laboratory tests normally required for monitoring patients with multiple sclerosis, complete blood and differential white blood cell counts, platelet counts and blood chemistries, including liver function tests, are recommended at regular intervals (one, three, and six months) following introduction of BETASERON therapy, and then periodically thereafter in the absence of clinical symptoms.
See FDA-approved patient labeling (Medication Guide and Instructions for Use).
Instruct patients to carefully read the supplied BETASERON Medication Guide and caution patients not to change the BETASERON dose or schedule of administration without medical consultation.
Provide appropriate instruction for reconstitution of BETASERON and methods of self-injection, including careful review of the BETASERON Medication Guide. Instruct patients in the use of aseptic technique when administering BETASERON.
Tell patients not to re-use needles or syringes and instruct patients on safe disposal procedures. Advise patients of the importance of rotating areas of injection with each dose, to minimize the likelihood of severe injection site reactions, including necrosis or localized infection [see Medication Guide].
Advise patients that severe hepatic injury, including hepatic failure, has been reported during the use of BETASERON.
Inform patients of symptoms of hepatic dysfunction, and instruct patients to report them immediately to their healthcare provider [see WARNINGS AND PRECAUTIONS].
Advise patients of the symptoms of allergic reactions and anaphylaxis, and instruct patients to seek immediate medical attention if these symptoms occur [see WARNINGS AND PRECAUTIONS].
Advise patients that depression and suicidal ideation have been reported during the use of BETASERON. Inform patients of the symptoms of depression or suicidal ideation, and instruct patients to report them immediately to their healthcare provider [see WARNINGS AND PRECAUTIONS].
Advise patients that worsening of pre-existing congestive heart failure have been reported in patients using BETASERON.
Advise patients of symptoms of worsening cardiac condition, and instruct patients to report them immediately to their healthcare provider [see WARNINGS AND PRECAUTIONS].
Advise patients that injection site reactions occur in most patients treated with BETASERON, and that injection site necrosis may occur at one or multiple sites. Instruct patients to promptly report any break in the skin, which may be associated with blue-black discoloration, swelling, or drainage of fluid from the injection site, prior to continuing their BETASERON therapy [see WARNINGS AND PRECAUTIONS].
Inform patients that PAH has occurred in patients treated with interferon beta products, including BETASERON. Instruct patients to promptly report any new symptoms such as new or increasing fatigue or shortness of breath to their healthcare provider [see WARNINGS AND PRECAUTIONS].
Inform patients that flu-like symptoms are common following initiation of therapy with BETASERON, and that concurrent use of analgesics and/or antipyretics on treatment days may help ameliorate flu-like symptoms associated with BETASERON use [see WARNINGS AND PRECAUTIONS and DOSAGE AND ADMINISTRATION].
Instruct patients to report seizures immediately to their healthcare provider [see WARNINGS AND PRECAUTIONS].
Advise patients to notify their healthcare provider if they are pregnant or plan to become pregnant [see Use In Specific Populations].
Although there have been no well-controlled studies in pregnant women, 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. Administration of BETASERON to monkeys during gestation resulted in increased embryo-fetal death at or above exposures greater than 3 times the human therapeutic dose (see Animal Data).
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown.
Human Data
The majority of the observational studies reporting on pregnancies exposed to interferon beta-1b did not identify an association between the use of interferon beta-1b during pregnancy and an increased risk of major birth defects.
Animal Data
When BETASERON (doses ranging from 0.028 to 0.42 mg/kg/day) was administered to pregnant rhesus monkeys throughout the period of organogenesis (gestation days 20 to 70), a dose-related abortifacient effect was observed. The low-effect dose is approximately 3 times the recommended human dose of 0.25 mg on a body surface area (mg/m²) basis. A no-effect dose for embryo-fetal developmental toxicity in rhesus monkeys was not established.
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.
The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for BETASERON and any potential adverse effects on the breastfed child from BETASERON or from the underlying maternal condition.
Safety and efficacy in pediatric patients have not been established.
Clinical studies of BETASERON did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently than younger patients.
No Information provided
BETASERON is contraindicated in patients with a history of hypersensitivity to natural or recombinant interferon beta, Albumin (Human), or any other component of the formulation.
The mechanism of action of BETASERON (interferon beta-1b) in patients with multiple sclerosis is unknown.
Interferons (IFNs) are a family of naturally occurring proteins, produced by eukaryotic cells in response to viral infection and other biologic agents. Three major types of interferons have been defined: type 1 (IFN-alpha, beta, epsilon, kappa and omega), type II (IFN–gamma) and type III (IFN-lambda). Interferon-beta is a member of the type I subset of interferons. The type I interferons have considerably overlapping but also distinct biologic activities. The bioactivities of all IFNs, including IFN-beta, are induced via their binding to specific receptors on the membranes of human cells. Differences in the bioactivities induced by the three major subtypes of IFNs likely reflect differences in the signal transduction pathways induced by signaling through their cognate receptors.
Interferon beta-1b receptor binding induces the expression of proteins that are responsible for the pleiotropic bioactivities of interferon beta-1b. A number of these proteins (including neopterin, β2-microglobulin, MxA protein, and IL-10) have been measured in blood fractions from BETASERON-treated patients and BETASERON-treated healthy volunteers. Immunomodulatory effects of interferon beta-1b include the enhancement of suppressor T cell activity, reduction of pro-inflammatory cytokine production, down-regulation of antigen presentation, and inhibition of lymphocyte trafficking into the central nervous system. It is not known if these effects play an important role in the observed clinical activity of BETASERON in multiple sclerosis (MS).
Because serum concentrations of interferon beta-1b are low or not detectable following subcutaneous administration of 0.25 mg or less of BETASERON, pharmacokinetic information in patients with MS receiving the recommended dose of BETASERON is not available.
Following single and multiple daily subcutaneous administrations of 0.5 mg BETASERON to healthy volunteers (N=12), serum interferon beta-1b concentrations were generally below 100 IU/mL. Peak serum interferon beta-1b concentrations occurred between one to eight hours, with a mean peak serum interferon concentration of 40 IU/mL. Bioavailability, based on a total dose of 0.5 mg BETASERON given as two subcutaneous injections at different sites, was approximately 50%.
After intravenous administration of BETASERON (0.006 mg to 2 mg), similar pharmacokinetic profiles were obtained from healthy volunteers (N=12) and from patients with diseases other than MS (N=142). In patients receiving single intravenous doses up to 2 mg, increases in serum concentrations were dose proportional. Mean serum clearance values ranged from 9.4 mL/min•kg-1 to 28.9 mL/min•kg-1 and were independent of dose. Mean terminal elimination half-life values ranged from 8 minutes to 4.3 hours and mean steady-state volume of distribution values ranged from 0.25 L/kg to 2.88 L/kg. Three-times-a-week intravenous dosing for two weeks resulted in no accumulation of interferon beta-1b in sera of patients. Pharmacokinetic parameters after single and multiple intravenous doses of BETASERON were comparable.
Following every other day subcutaneous administration of 0.25 mg BETASERON in healthy volunteers, biologic response marker levels (neopterin, β2-microglobulin, MxA protein, and the immunosuppressive cytokine, IL-10) increased significantly above baseline six-twelve hours after the first BETASERON dose. Biologic response marker levels peaked between 40 and 124 hours and remained elevated above baseline throughout the seven-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.
No formal drug interaction studies have been conducted with BETASERON.
BETASERON has not been tested for its carcinogenic potential in animals.
BETASERON was not genotoxic in the in vitro Ames bacterial test or the in vitro chromosomal aberration assay in human peripheral blood lymphocytes. BETASERON treatment of mouse BALBc-3T3 cells did not result in increased transformation frequency in an in vitro model of tumor transformation.
Administration of BETASERON (doses of up to 0.33 mg/kg/day) to normally cycling female rhesus monkeys had no apparent adverse effects on either menstrual cycle duration or associated hormonal profiles (progesterone and estradiol) when administered over three consecutive menstrual cycles. The highest dose tested is approximately 30 times the recommended human dose of 0.25 mg on a body surface area (mg/m²) basis. The potential for other effects on fertility or reproductive performance was not evaluated.
The clinical effects of BETASERON were studied in four randomized, multicenter, double-blind, placebo-controlled studies in patients with multiple sclerosis (Studies 1, 2, 3, and 4).
The effectiveness of BETASERON in relapsing-remitting MS (RRMS) was evaluated in a double-blind, multiclinic, randomized, parallel, placebo controlled clinical study of two years duration (Study 1). The study enrolled MS patients, aged 18 to 50, who were ambulatory [Kurtzke Expanded Disability Status Scale (EDSS) of ≤ 5.5 – score 5.5 is ambulatory for 100 meters, disability precludes full daily activities], exhibited a relapsing-remitting clinical course, met Poser’s criteria for clinically definite and/or laboratory supported definite MS and had experienced at least two exacerbations over two years preceding the trial without exacerbation in the preceding month. The EDSS score is a method of quantifying disability in patients with MS and ranges from 0 (normal neurologic exam) to 10 (death due to MS). Patients who had received prior immunosuppressant therapy were excluded.
An exacerbation was defined as the appearance of a new clinical sign/symptom or the clinical worsening of a previous sign/symptom (one that had been stable for at least 30 days) that persisted for a minimum of 24 hours.
Patients selected for study were randomized to treatment with either placebo (N=123), 0.05 mg of BETASERON (N=125), or 0.25 mg of BETASERON (N=124) self-administered subcutaneously every other day. Outcome based on the 372 randomized patients was evaluated after two years.
Patients who required more than three 28-day courses of corticosteroids were removed from the study. Minor analgesics (acetaminophen, codeine), antidepressants, and oral baclofen were allowed ad libitum, but chronic nonsteroidal anti-inflammatory drug (NSAID) use was not allowed.
The primary protocol-defined outcome measures were 1) frequency of exacerbations per patient and 2) proportion of exacerbation free patients. A number of secondary clinical and magnetic resonance imaging (MRI) measures were also employed. All patients underwent annual T2 MRI imaging and a subset of 52 patients at one site had MRIs performed every six weeks for assessment of new or expanding lesions.
The study results are shown in Table 3.
Table 3: Two-Year RRMS Study Results of Primary and Secondary Clinical Outcomes (Study 1)
| Efficacy Parameters | Treatment Groups | Statistical Comparisons p-value | |||||
| Primary End Points | Placebo (N=123) |
BETASERON 0.05 mg (N=125) |
BETASERON 0.25 mg (N=124) |
Placebo vs 0.05 mg | 0.05 mg vs 0.25 mg | Placebo vs 0.25 mg | |
| Annual exacerbation rate | 1.31 | 1.14 | 0.9 | 0.005 | 0.113 | 0.0001 | |
| Proportion of exacerbation-free patientsi | 16% | 18% | 25% | 0.609 | 0.288 | 0.094 | |
| Exacerbation frequency per patient | 01 | 20% | 22% | 29% | 0.151 | 0.077 | 0.001 |
| 1 | 32% | 31% | 39% | ||||
| 2 | 20% | 28% | 17% | ||||
| 3 | 15% | 15% | 14% | ||||
| 4 | 15% | 7% | 9% | ||||
| > 5 | 21% | 16% | 8% | ||||
| Secondary Endpoints2 | |||||||
| Median number of months to first on-study exacerbation | 5 | 6 | 9 | 0.299 | 0.097 | 0.01 | |
| Rate of moderate or severe exacerbations per year | 0.47 | 0.29 | 0.23 | 0.02 | 0.257 | 0.001 | |
| Mean number of moderate or severe exacerbation days per patient | 44 | 33 | 20 | 0.229 | 0.064 | 0.001 | |
| Mean change in EDSS score3 at endpoint | 0.21 | 0.21 | -0.07 | 0.995 | 0.108 | 0.144 | |
| Mean change in Scripps score4 at endpoint | -0.53 | -0.5 | 0.66 | 0.641 | 0.051 | 0.126 | |
| Median duration in days per exacerbation | 36 | 33 | 36 | NDJ | NDJ | NDJ | |
| % change in mean MRI lesion area at endpoint | 21.4% | 9.8% | -0.9% | 0.015 | 0.019 | 0.0001 | |
| 114 exacerbation free patients (0 from placebo, six from 0.05 mg, and eight from 0.25 mg) dropped out of the study before completing six months of therapy. These patients are excluded from this analysis. 2Sequelae and Functional Neurologic Status, both required by protocol, were not analyzed individually but are included as a function of the EDSS. 3EDSS scores range from 1-10, with higher scores reflecting greater disability. 4Scripps neurologic rating scores range from 0-100, with smaller scores reflecting greater disability. 5ND = Not done. |
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Of the 372 RRMS patients randomized, 72 (19%) failed to complete two full years on their assigned treatments.
Over the two-year period in Study 1, there were 25 MS-related hospitalizations in the 0.25 mg BETASERON-treated group compared to 48 hospitalizations in the placebo group. In comparison, non-MS hospitalizations were evenly distributed among the groups, with 16 in the 0.25 mg BETASERON group and 15 in the placebo group. The average number of days of MS-related steroid use was 41 days in the 0.25 mg BETASERON group and 55 days in the placebo group (p=0.004).
MRI data were also analyzed for patients in this study. A frequency distribution of the observed percent changes in MRI area at the end of two years was obtained by grouping the percentages in successive intervals of equal width. Figure 1 displays a histogram of the proportions of patients, which fell into each of these intervals. The median percent change in MRI area for the 0.25 mg group was -1.1%, which was significantly smaller than the 16.5% observed for the placebo group (p=0.0001).
Figure 1: Distribution of Change in MRI Area in Patients with RRMS in Study 1
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In an evaluation of frequent MRI scans (every six weeks) on 52 patients at one site in Study 1, the percent of scans with new or expanding lesions was 29% in the placebo group and 6% in the 0.25 mg treatment group (p=0.006).
Studies 2 and 3 were multicenter, randomized, double-blind, placebo controlled trials conducted to assess the effect of BETASERON in patients with secondary progressive MS (SPMS). Study 2 was conducted in Europe and Study 3 was conducted in North America. Both studies enrolled patients with clinically definite or laboratory-supported MS in the secondary progressive phase, and who had evidence of disability progression (both Study 2 and 3) or two relapses (Study 2 only) within the previous two years. Baseline Kurtzke expanded disability status scale (EDSS) scores ranged from 3.0 to 6.5. Patients in Study 2 were randomized to receive BETASERON 0.25 mg (N=360) or placebo (N=358). Patients in Study 3 were randomized to BETASERON 0.25 mg (N=317), BETASERON 0.16 mg/m² of body surface area (N=314, mean assigned dose 0.3 mg), or placebo (N=308). Test agents were administered subcutaneously, every other day for three years.
The primary outcome measure was 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. In Study 2, time to progression in EDSS was longer in the BETASERON treatment group (p=0.005), with estimated annualized rates of progression of 16% and 19% in the BETASERON and placebo groups, respectively. In Study 3, the 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.
Multiple analyses, including covariate and subset analyses based on sex, age, disease duration, clinical disease activity prior to study enrollment, MRI measures at baseline and early changes in MRI following treatment were evaluated in order to interpret the discordant study results. No demographic or disease-related factors enabled identification of a patient subset where BETASERON treatment was predictably associated with delayed progression of disability.
In Studies 2 and 3, like Study 1, a statistically significant decrease in the incidence of relapses associated with BETASERON treatment was demonstrated. In Study 2, the mean annual relapse rates were 0.42 and 0.63 in the BETASERON and placebo groups, respectively (p<0.001). In Study 3, 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<0.02).
MRI endpoints in both Study 2 and Study 3 showed smaller increases in T2 MRI lesion area and decreased number of active MRI lesions in patients in the BETASERON groups compared to the placebo group.
In Study 4, 468 patients who had recently (within 60 days) experienced an isolated demyelinating event, and who had lesions typical of multiple sclerosis on brain MRI were randomized to receive either 0.25 mg BETASERON (N=292) or placebo (N=176) subcutaneously every other day (ratio 5:3). The primary outcome measure was time to development of a second exacerbation with involvement of at least two distinct anatomical regions. Secondary outcomes were brain MRI measures, including the cumulative number of newly active lesions, and the absolute change in T2 lesion volume. Patients were followed for up to two years or until they fulfilled the primary endpoint.
Eight percent of subjects on BETASERON and 6% of subjects on placebo withdrew from the study for a reason other than the development of a second exacerbation. Time to development of a second exacerbation was significantly delayed in patients treated with BETASERON compared to patients treated with placebo (p<0.0001). The 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 (Figure 2). The risk for developing a second exacerbation in the BETASERON group was 53% of the risk in the placebo group (Hazard ratio= 0.53; 95% confidence interval 0.39 to 0.73).
Figure 2: Onset of Second Exacerbation by Time in Patients with Isolated Demyelinating Eventwith Typical MS Lesions on Brain MRI in Study 4*
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*Kaplan-Meier Methodology
In Study 4, 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
(bay-ta-seer-on) interferon beta-1b (in-ter-feer-on beta-one-be)
What is the most important information I should know about BETASERON?
BETASERON can cause serious side effects, including:
Your healthcare provider will do blood tests to check for these problems while you take BETASERON.
What is BETASERON?
BETASERON is a prescription medicine used to treat relapsing forms of multiple sclerosis, to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults. BETASERON is similar to certain interferon proteins that are produced in the body.
It is not known if BETASERON is safe and effective in children.
Who should not take BETASERON?
Do not take BETASERON if you are allergic to interferon beta-1b, to another interferon beta, to human albumin, or mannitol. See the end of this leaflet for a complete list of ingredients in BETASERON.
What should I tell my healthcare provider before taking BETASERON?
Before you take BETASERON, tell your healthcare provider if you:
Tell your healthcare provider about all the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal supplements.
Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.
How should I take BETASERON?
What are the possible side effects of BETASERON?
BETASERON may cause serious side effects. Call your healthcare provider right away if you have any of the serious side effects of BETASERON including:
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.
The most common side effects of BETASERON include:
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.
How should I store BETASERON?
Keep BETASERON and all medicines out of the reach of children.
General information about the safe and effective use of BETASERON.
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use BETASERON for a condition for which it was not prescribed. Do not give BETASERON to other people, even if they have the same symptoms that you have. It may harm them.
This Medication Guide summarizes the most important information about BETASERON. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about BETASERON that is written for health professionals.
For more information, go to www.BETASERON.com or call BETAPLUS, the BETASERON patient support program, at 1-800788-1467.
What are the ingredients in BETASERON?
Active ingredient: interferon beta-1b
Inactive ingredients: albumin (human), mannitol Diluent contains sodium chloride solution.
This Medication Guide has been approved by the U.S. Food and Drug Administration
INSTRUCTIONS FOR USE
BETASERON
(bay-ta-seer-on)
interferon beta-1b
(in-ter-feer-on beta-one-be)
Read the Instructions for Use that come with your BETASERON before you start using it and each time you get a refill. There may be new information. This leaflet does not take the place of talking to your healthcare provider about your medical condition or treatment. Before you use BETASERON for the first time, make sure your healthcare provider shows you the right way to use it.
Supplies needed for your BETASERON Injection (See Figure A).
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Step 1: Preparing for Your BETASERON Injection
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Step 2: Mixing BETASERON
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Step 3: Preparing the Injection
You have completed the steps to prepare your BETASERON and are ready for the injection. The injection should be given immediately after mixing and allowing any foam in the solution to settle. If you must wait to give yourself the injection, you may refrigerate the solution and use within 3 hours of mixing your BETASERON. Do not freeze.
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Step 4: Choosing an Injection Site
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Step 5: Injecting BETASERON
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Step 6: Disposing of used syringes, needles, and vials
This Instructions for Use has been approved by the U.S. Food and Drug Administration
