`
`
`
`
`
`
` 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, 5.11)
`
`
`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, 5.11)
`
`
`
`Thrombotic Microangiopathy Cases of thrombotic microangiopathy
`
`
`
`have been reported. Discontinue BETASERON if clinical symptoms and
`
`
`laboratory findings consistent with TMA occur. (5.7)
`
`
`Flu-like Symptom Complex Consider analgesics and/or antipyretics on
`
`
`
`
`injection days. (5.8)
`
`
`Drug-induced Lupus Erythematosus Cases of drug-induced lupus
`
`
`
`erythematosus have been reported. Discontinue BETASERON if
`
`
`
`
`patients develop new characteristic signs and symptoms. (5.10)
`
`
`------------------------------ 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.
`
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA-
`
`
`
`
`Approved Medication Guide
`
`
`Revised: 08/2018
`
`
`
`
`6.1 Clinical Trials Experience
`
`
`6.2 Immunogenicity
`
`6.3 Postmarketing Experience
`
`8 USE IN SPECIFIC POPULATIONS
`
`8.1 Pregnancy
`
`8.2 Lactation
`
`
`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.
`
`
`
`
`
`•
`
`
`
`•
`
`
`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 Thrombotic Microangiopathy
`
`5.8 Flu-like Symptom Complex
`
`5.9 Seizures
`
`5.10 Drug-induced Lupus Erythematosus
`
`
`5.11 Monitoring for Laboratory Abnormalities
`
`
`6 ADVERSE REACTIONS
`
`
`
`Reference ID: 4314901
`
`
`
` 1
`
`Biogen Exhibits 2156
`Mylan v. Biogen
`IPR 2018-01403
`
`Page 1 of 26
`
`

`

`
`
`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
`
`
`
`
`
`
`
` Weeks 1-2
`
` Weeks 3-4
`
` Weeks 5-6
`
`
` Week 7 and thereafter
`
` 1. Dosed every other day, subcutaneously
`
`
`
`
`
` BETASERON
`
` Dose1
`
` 0.0625 mg
` 0.125 mg
`
` 0.1875 mg
`
`
` 0.25 mg
`
` 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 pre-filled 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 35°F to 46°F (2°C
`
` to 8°C) and use within three hours. Do not freeze.
`
`
`
`
`
`
`
`
` 2.3 Important Administration Instructions
`
`
` (a) BETASERON is intended for use under the guidance and supervision of a physician. If patients or
`
`
`caregivers are to administer BETASERON, train them in the proper technique for self‐administering
`
`
`
`
`
`
`
`
`
` 2
`
`
`
`Reference ID: 4314901
`
`Page 2 of 26
`
`

`

`
`
` subcutaneous injections using the prefilled syringe or the optional injection device. The BETACONNECT
`
`
`
` autoinjector has three adjustable injection depth settings; the healthcare provider should determine the proper
`
`
`
` depth setting and injection technique. Use only the syringes in the BETASERON packaging with the
` BETACONNECT autoinjector.
`
`
`
` The initial BETASERON injection should be performed under the supervision of an appropriately qualified
` healthcare provider. Users should demonstrate competency in all aspects of the BETASERON injection prior to
`
`
`
`
`
`
`
`
`
`
`
`
`
`independent use. If a patient is to self‐administer BETASERON, the physical and cognitive ability of that
`patient to self‐administer and properly dispose of syringes should be assessed. Patients with severe neurological
`deficits should not self‐administer injections without assistance from a trained caregiver.
`Appropriate instruction for self‐injection or injection by another person should be provided to the patient or
`
`
`
`
`
`
`
`their caregiver, including careful review of the BETASERON Medication Guide, the prefilled syringe
`
`Instructions for Use, and the BETACONNECT autoinjector Instructions for Use that accompanies the product.
`
`
`
`
`
`(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 (5.8)].
`
`
`
`
`
`
`
` 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 (eg, alcohol) prior to BETASERON
`
`
`
`
` 3
`
`
`
`Reference ID: 4314901
`
`Page 3 of 26
`
`

`

`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 (5.11)].
`
`
` 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 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.
`
`
`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.
`
`
`
`
`
`Reference ID: 4314901
`
`
`
` 4
`
`Page 4 of 26
`
`

`

`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 Thrombotic Microangiopathy
`
`
` 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. Discontinue BETASERON if clinical symptoms
`
`
`
` and laboratory findings consistent with TMA occur, and manage as clinically indicated.
`
`
`
`
`
`
`
` 5.8 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.
`
`
` 5.9 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 (eg, fever), or to some combination of
`
`
`
` these.
`
`
`
`
`
` 5.10 Drug-induced Lupus Erythematosus
`
`
`
` 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.
`
`
`
`
`
`
`
`
` 5.11 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.
`
`
`
`
`
`
`Reference ID: 4314901
`
`
`
` 5
`
`Page 5 of 26
`
`

`

`
`
` 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)]
`
`
`
`
`• Thrombotic Microangiopathy [see Warnings and Precautions (5.7)]
`
`
`
`
`
`• Flu-like Symptom Complex [see Warnings and Precautions (5.8)]
`
`
`• Seizures [see Warnings and Precautions (5.9)]
`
`
`
`• Drug Induced Lupus Erythematosus [see Warnings and Precautions (5.10)]
`
`
`
`
`
` 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)].
`
`
`
`
`
`
`Table 2: Adverse Reactions and Laboratory Abnormalities in Patients with MS in
`
`
`
`Pooled Studies 1, 2, 3, and 4
`
`
`
`
`
` Adverse Reaction
`
`
`
`
`
` Blood and lymphatic system disorders
`
`
`
` Lymphocytes count decreased (<1500/mm3)
`
` Absolute neutrophil count decreased (<1500/mm3)
`
`White blood cell count decreased (<3000/mm3)
`
`
` Lymphadenopathy
` Nervous system disorders
`
` Headache
`
` Insomnia
` Incoordination
`
` Vascular disorders
`
`
` Hypertension
` Respiratory, thoracic and mediastinal disorders
`
`
`
`
` Placebo
`
` (N=965)
`
`
` 66%
` 5%
`
`
` 4%
`
` 3%
`
`
` 43%
`
` 16%
`
` 15%
`
`
`
` 4%
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` BETASERON
`
` (N=1407)
`
`
` 86%
`
` 13%
`
` 13%
` 6%
`
`
`
` 50%
`
` 21%
`
` 17%
`
`
`
` 6%
`
`
`
`Reference ID: 4314901
`
`
`
` 6
`
`Page 6 of 26
`
`

`

`
`
` Adverse Reaction
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Placebo
`
` (N=965)
`
` 3%
`
`
`
` 11%
`
`
`
` 4%
`
`
`
` 1%
`
`
` 15%
` 8%
`
`
`
` 33%
`
` 14%
`
`
`
` 8%
`
`
` 7%
`
` 6%
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` BETASERON
`
` (N=1407)
`
` 6%
`
`
`
` 16%
`
`
`
` 12%
`
`
`
` 4%
`
`
` 21%
`
` 10%
`
`
` 40%
`
` 23%
`
`
`
` 11%
`
`
` 9%
`
` 8%
`
` Dyspnea
`
` Gastrointestinal disorders
`
` Abdominal pain
` Hepatobiliary disorders
`
`
` Alanine aminotransferase increased
`
`
` (SGPT > 5 times baseline)
` Aspartate aminotransferase increased
`
` (SGOT > 5 times baseline)
` Skin and subcutaneous tissue disorders
`
` Rash
` Skin disorder
`
` Musculoskeletal and
`
` connective tissue disorders
`
` Hypertonia
`
` Myalgia
` Renal and urinary disorders
`
` Urinary urgency
` Reproductive system and breast disorders
`
`
` Metrorrhagia
`
` Impotence
` General disorders and administration site conditions
`
` Injection site reaction1
`
` 78%
`
` 26%
`
`
` 53%
`
` 48%
` Asthenia
` Flu-like symptoms (complex)2
`
` 57%
`
` 37%
`
`
` 42%
`
` 35%
` Pain
`
` Fever
`
` 31%
`
` 19%
`
` Chills
`
` 21%
` 9%
`
` Peripheral edema
`
` 12%
` 10%
`
`
` Chest pain
` 9%
`
` 6%
`
`
`
` 6%
`
` 3%
` Malaise
` Injection site necrosis
`
` 4%
`
` 0%
`
`
` 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.
`
`
`
`
`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
`
`
`
`
`
`Reference ID: 4314901
`
`
`
` 7
`
`Page 7 of 26
`
`

`

`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: 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
`
`
`
`
`
`
`
`Reference ID: 4314901
`
`
`
` 8
`
`Page 8 of 26
`
`

`

`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.
`
`
`
`
`
` 8 USE IN SPECIFIC POPULATIONS
`
`
`
`
`
` 8.1 Pregnancy
`
` Risk Summary
`
`
`
`
`
` 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.
`
`
`
`
`
` Data
`
`
`
` 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.
`
`
`
` 8.2 Lactation
`
`
` Risk Summary
` 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.
`
`
`
`
` 8.4 Pediatric Use
`
` Safety and efficacy in pediatric patients have not been established.
`
`
`
`
`
`
`
`
`Reference ID: 4314901
`
`
`
` 9
`
`Page 9 of 26
`
`

`

`
` 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-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-1b. Each
`
`vial contains 0.3 mg of interferon beta-1b. The unit measurement is derived by c