HIGHLIGHTS OF PRESCRIBING INFORMATION
`These 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 use
`Initial U.S. Approval: 1993
`
`
`-----------------------INDICATIONS AND USAGE-------------------
`Betaseron 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)
`
`
`------------------------CONTRAINDICATIONS----------------------
`History 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)
`
`
`------------------------------ADVERSE REACTIONS-------------------------------
`In 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)
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA-
`Approved Patient Labeling
`
`Revised: October 2012
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`1 INDICATIONS AND USAGE 
`2 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 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 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 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 
`
`*Sections or subsections omitted from the Full Prescribing Information are not
`listed.
`
`Reference ID: 3220464
`
`Page 1 of 17
`
`Coalition Exhibit 1070
`Coalition v. Biogen
`IPR201-01993
`
`

`
`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).
`Table 1. Schedule for Dose Titration
`
`
`
`Betaseron
`Dose1
`
`0.0625 mg
`Weeks 1-2
`0.125 mg
`Weeks 3-4
`0.1875 mg
`Weeks 5-6
`0.25 mg
`Week 7 and thereafter
`1 Dosed every other day, subcutaneously
`
`Percentage of
`recommended
`dose
`25%
`50%
`75%
`100%
`
`Volume
`
`0.25 mL
`0.5 mL
`0.75 mL
`1 mL
`
`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.
`
`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.
`
`Reference ID: 3220464
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`

`
`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)].
`
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`

`
`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.
`
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`

`
`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.
`
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`

`
`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)].
`
`Table 2 Adverse Reactions and Laboratory Abnormalities in Patients with MS in Pooled
`Studies 1, 2, 3, and 4
`
`Betaseron
`(N=1407)
`
`86%
`13%
`13%
`6%
`
`50%
`21%
`17%
`
`6%
`
`6%
`
`16%
`
`12%
`
`4%
`
`21%
`10%
`
`40%
`23%
`
`Placebo
`(N=965)
`
`66%
`5%
`4%
`3%
`
`43%
`16%
`15%
`
`4%
`
`3%
`
`11%
`
`4%
`
`1%
`
`
`15%
`8%
`
`
`33%
`14%
`
`
`Adverse Reaction
`
`Blood and lymphatic system disorders
`Lymphocytes count decreased (<1500/mm3)
`Absolute neutrophil count decreased (< 1500/mm3)b
`White blood cell count decreased (<3000/mm3)
`Lymphadenopathy
`Nervous system disorders
`Headache
`Insomnia
`Incoordination
`Vascular disorders
`Hypertension
`Respiratory, thoracic and mediastinal disorders
`Dyspnea
`Gastrointestinal disorders
`Abdominal pain
`Hepatobiliary disorders
`Alanine aminotransferase increased
`(SGPT > 5 times baseline)b
`Aspartate aminotransferase increased
`(SGOT > 5 times baseline)b
`Skin and subcutaneous tissue disorders
`Rash
`Skin disorder
`Musculoskeletal and
`connective tissue disorders
`Hypertonia
`Myalgia
`Renal and urinary disorders
`
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`

`
`Adverse Reaction
`
`Urinary urgency
`Reproductive system and breast disorders
`Metrorrhagia
`Impotence
`General disorders and administration site
`conditions
`Injection site reactiona
`Asthenia
`Flu-like symptoms (complex)b
`Pain
`Fever
`Chills
`Peripheral edema
`Chest pain
`Malaise
`Injection site necrosis
`
`
`
`Placebo
`(N=965)
`8%
`
`7%
`6%
`
`
`26%
`48%
`37%
`35%
`19%
`9%
`10%
`6%
`3%
`0%
`
`Betaseron
`(N=1407)
`11%
`
`9%
`8%
`
`78%
`53%
`57%
`42%
`31%
`21%
`12%
`9%
`6%
`4%
`
`a) "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.
`b)
` "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.
`
`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
`
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`
`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: 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
`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.
`
`Reference ID: 3220464
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`
`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.
`
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`
`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.
`
`Reference ID: 3220464
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`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