Betaseron

Bayer HealthCare Pharmaceuticals Inc.

HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use BETASERON safely and effectively. See full prescribing information for BETASERON.BETASERON (interferon beta-1b) for injection, for subcutaneous useInitial U.S. Approval: 1993INDICATIONS AND USAGEBetaseron is an interferon beta indicated for the treatment of 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. (1)DOSAGE AND ADMINISTRATION •For subcutaneous use only (2.1) •The recommended dose is 0.25 mg every other day. Generally, start at 0.0625 mg (0.25 mL) every other day, and increase over a six week period to 0.25 mg (1 mL) every other day. (2.1) •Reconstitute lyophilized powder with supplied diluent (2.2) DOSAGE FORMS AND STRENGTHS For injection: 0.3 mg of lyophilized powder in a single-use vial for reconstitution (3)CONTRAINDICATIONSHistory of hypersensitivity to natural or recombinant interferon beta, albumin or mannitol (4)WARNINGS AND PRECAUTIONS • Hepatic Injury: Monitor liver function tests and signs and symptoms of hepatic injury; consider discontinuing Betaseron if serious hepatic injury occurs. (5.1, 5.9) • Anaphylaxis and Other Allergic Reactions: Discontinue if anaphylaxis occurs. (5.2) • Depression and Suicide: Advise patients to immediately report any symptom of depression and/or suicidal ideation; consider discontinuation of Betaseron if depression occurs. (5.3) • Congestive Heart Failure (CHF): Monitor patients with CHF for worsening of cardiac symptoms; consider discontinuation of Betaseron if worsening of CHF occurs. (5.4) • Injection Site Necrosis and Reactions: Do not administer Betaseron into affected area until fully healed; if multiple lesions occur, discontinue Betaseron until healing of skin lesions. (5.5) • Leukopenia: Monitor complete blood count. (5.6, 5.9) • Flu-Like Symptom Complex: Consider analgesics and/or antipyretics on injection days. (5.7) Side EffectsIn controlled clinical trials, the most common 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. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Bayer HealthCare Pharmaceuticals at 1-888-842-2937 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. USE IN SPECIFIC POPULATIONS Pregnancy: Based on animal data, may cause fetal harm. (8.1)

FULL PRESCRIBING INFORMATION: CONTENTS*

• 1 BETASERON INDICATIONS AND USAGE
• 2 BETASERON DOSAGE AND ADMINISTRATION
  • 2.1 Dosing Information
  • 2.2 Reconstitution of the Lyophilized Powder
  • 2.3 Important Administration Instructions
  • 2.4 Premedication for Flu-like Symptoms
• 3 DOSAGE FORMS AND STRENGTHS
• 4 BETASERON CONTRAINDICATIONS
• 5 WARNINGS AND PRECAUTIONS
  • 5.1 Hepatic Injury
  • 5.2 Anaphylaxis and Other Allergic-Reactions
  • 5.3 Depression and Suicide
  • 5.4 Congestive Heart Failure
  • 5.5 Injection Site Necrosis and Reactions
  • 5.6 Leukopenia
  • 5.7 Flu-Like Symptom Complex
  • 5.8 Seizures
  • 5.9 Monitoring for Laboratory Abnormalities
• 6 BETASERON ADVERSE REACTIONS
  • 6.1 Clinical Trials Experience
  • 6.2 Immunogenicity
  • 6.3 Postmarketing Experience
• 8 USE IN SPECIFIC POPULATIONS
  • 8.1 Pregnancy
  • 8.3 Nursing Mothers
  • 8.4 Pediatric Use
  • 8.5 Geriatric Use
• 11 BETASERON DESCRIPTION
• 12 CLINICAL PHARMACOLOGY
  • 12.1 Mechanism of Action
  • 12.2 Pharmacodynamics
  • 12.3 Pharmacokinetics
• 13 NONCLINICAL TOXICOLOGY
  • 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
• 14 CLINICAL STUDIES
• 16 HOW SUPPLIED/STORAGE AND HANDLING
  • 16.1 How Supplied
  • 16.2 Stability and Storage
• 17 PATIENT COUNSELING INFORMATION
• Medication Guide
• PACKAGE/LABEL PRINCIPAL DISPLAY PANEL

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

Betaseron® (interferon beta-1b) is indicated for the treatment of 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.

2 DOSAGE AND ADMINISTRATION

2.1 Dosing Information

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).

2.2 Reconstitution of the Lyophilized Powder

(a) Prior to reconstitution, verify that the vial containing lyophilized Betaseron is not cracked or damaged. Do not use cracked or damaged vials.

(b) To reconstitute lyophilized Betaseron for injection, attach the prefilled syringe containing the diluent (Sodium Chloride, 0.54% Solution) to the Betaseron vial using the vial adapter.

(c) Slowly inject 1.2 mL of diluent into the Betaseron vial.

(d) Gently swirl the vial to dissolve the lyophilized powder completely; do not shake. Foaming may occur during reconstitution or if the vial is swirled or shaken too vigorously. If foaming occurs, allow the vial to sit undisturbed until the foam settles.

(e) 1 mL of reconstituted Betaseron solution contains 0.25 mg of interferon beta-1b.

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

2.3 Important Administration Instructions

(a) Perform the first Betaseron injection under the supervision of an appropriately qualified healthcare professional. If patients or caregivers are to administer Betaseron, train them in the proper subcutaneous injection technique and assess their ability to inject subcutaneously to ensure the proper administration of Betaseron.

(b) Visually inspect the reconstituted Betaseron solution before use; discard if it contains particulate matter or is discolored.

(c) Keeping the syringe and vial adapter in place, turn the assembly over so that the vial is on top. Withdraw the appropriate dose of Betaseron solution. Remove the vial from the vial adapter before injecting Betaseron.

(d) Use safe disposal procedures for needles and syringes.

(e) Do not re-use needles or syringes.

(f) Advise patients and caregivers to rotate sites for subcutaneous injections to minimize the likelihood of severe injection site reactions, including necrosis or localized infection.

2.4 Premedication for Flu-like Symptoms

Concurrent use of analgesics and/or antipyretics on treatment days may help ameliorate flu-like symptoms associated with Betaseron use [see Warnings and Precautions (5.7)].

3 DOSAGE FORMS AND STRENGTHS

For injection: 0.3 mg lyophilized powder in a single use vial for reconstitution.

4 CONTRAINDICATIONS

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.

5 WARNINGS AND PRECAUTIONS

5.1 Hepatic Injury

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 (e.g., 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 (6.1)]. Monitor liver function tests [see Warnings and Precautions (5.9)].

5.2 Anaphylaxis and Other Allergic-Reactions

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 (6.1)]. Discontinue Betaseron if anaphylaxis occurs.

5.3 Depression and Suicide

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.

5.4 Congestive Heart Failure

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.

5.5 Injection Site Necrosis and Reactions

Injection site necrosis (ISN) was reported in 4% of Betaseron-treated patients in controlled clinical trials (compared to 0% on placebo) [see Adverse Reactions (6.1)]. 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 three 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.

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, discontinue therapy until healing occurs.

Periodically evaluate patient understanding and use of aseptic self-injection techniques and procedures, particularly if injection site necrosis has occurred.

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.

5.6 Leukopenia

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 (6.1)]. 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.

5.7 Flu-Like Symptom Complex

In controlled clinical trials, the rate of flu-like symptom complex for patients on Betaseron was 57% [see Adverse Reactions (6.1)]. 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 (14)]. Analgesics and/or antipyretics on treatment days may help ameliorate flu-like symptoms associated with Betaseron use.

5.8 Seizures

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 (e.g., fever), or to some combination of these.

5.9 Monitoring for Laboratory Abnormalities

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.

6 ADVERSE REACTIONS

The following serious adverse reactions are discussed in more details in other sections of labeling:

• •Hepatic Injury [see Warnings and Precautions (5.1)]
• •Anaphylaxis and Other Allergic-Reactions [see Warnings and Precautions (5.2)]
• •Depression and Suicide [see Warnings and Precautions (5.3)]
• •Congestive Heart Failure [see Warnings and Precautions (5.4)]
• •Injection Site Necrosis and Reactions [see Warnings and Precautions (5.5)]
• •Leukopenia [see Warnings and Precautions (5.6)]
• •Flu-Like Symptom Complex [see Warnings and Precautions (5.7)]
• •Seizures [see Warnings and Precautions (5.8)]

6.1 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 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 (14)].

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 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.

6.2 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 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 (5.2)].

6.3 Postmarketing Experience

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

Endocrine disorders: Hypothyroidism, Hyperthyroidism, Thyroid dysfunction

Metabolism and nutrition disorders: Triglycerideincreased, 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

Reproductive system and breast disorder: Menorrhagia

General disorders and administration site conditions: Fatal capillary leak syndrome¹

¹The administration of cytokines to patients with a pre-existing monoclonal gammopathy has been associated with the development of this syndrome.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C: There are no adequate and well-controlled studies 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.

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.

8.3 Nursing Mothers

It is not known whether 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 nursing or discontinue the drug, taking into account the importance of drug to the mother.

8.4 Pediatric Use

Safety and efficacy in pediatric patients have not been established.

8.5 Geriatric Use

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

11 DESCRIPTION

Betaseron® (interferon beta-lb) 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.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The mechanism of action of Betaseron (interferon beta-1b) in patients with multiple sclerosis is unknown.

12.2 Pharmacodynamics

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 inteferons 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).

12.3 Pharmacokinetics

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.

Drug Interaction Studies

No formal drug interaction studies have been conducted with Betaseron.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Betaseron has not been tested for its carcinogenic potential in animals.

Mutagenesis

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.

Impairment of Fertility

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.

14 CLINICAL STUDIES

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).

Patients with Relapsing-Remitting Multiple Sclerosis

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 Two Year RRMS Study Results of Primary and Secondary Clinical Outcomes (Study 1)

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 Distribution of Change in MRI Area in Patients with RRMS in Study 1