`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. Thyroid function tests are recommended every six months
`in patients with a history of thyroid dysfunction or as clinically indicated.
`Patients with myelosuppression may require more intensive monitoring of
`complete blood cell counts, with differential and platelet counts.
`Drug Interactions
`No formal drug interaction studies have been conducted with Betaseron. In the
`placebo controlled studies in MS, corticosteroids or ACTH were administered
`for treatment of relapses for periods of up to 28 days in patients (N=664)
`receiving Betaseron.
`Carcinogenesis, Mutagenesis, and Impairment of Fertility
`Carcinogenesis: Interferon beta-1b has not been tested for its carcinogenic
`potential in animals.
`Mutagenesis:Betaseron was not mutagenic when assayed for genotoxicity in the
`Ames bacterial test in the presence or absence of metabolic activation. Interferon
`beta-1b was not mutagenic to human peripheral blood lymphocytes in vitro, in
`the presence or absence of metabolic inactivation. Betaseron treatment of
`mouse BALBc-3T3 cells did not result in increased transformation frequency in
`an in vitromodel of tumor transformation.
`Impairment of fertility:Studies in normally cycling, female rhesus monkeys at
`doses up to 0.33 mg/kg/day (32 times the recommended human dose based on
`body surface area, body surface dose based on 70 kg female) 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 validity of extrapolating doses used in animal studies to
`human doses is not known. Effects of Betaseron on normally cycling human
`females are not known.
`Pregnancy - Teratogenic Effects
`Pregnancy Category C: Betaseron was not teratogenic at doses up to
`0.42 mg/kg/day when given to pregnant female rhesus monkeys on gestation
`days 20 to 70. However, a dose related abortifacient activity was observed in
`these monkeys when Interferon beta-1b was administered at doses ranging from
`0.028 mg/kg/day to 0.42 mg/kg/day (2.8 to 40 times the recommended human
`dose based on body surface area comparison). The validity of extrapolating
`doses used in animal studies to human doses is not known. Lower doses were
`not studied in monkeys. Spontaneous abortions while on treatment were
`reported in patients (n=4) who participated in the Betaseron RRMS clinical trial.
`Betaseron given to rhesus monkeys on gestation days 20 to 70 did not cause
`teratogenic effects; however, it is not known if teratogenic effects exist in
`humans. There are no adequate and well-controlled studies in pregnant women.
`If the patient becomes pregnant or plans to become pregnant while taking
`Betaseron, the patient should be apprised of the potential hazard to the fetus and
`it should be recommended that the patient discontinue therapy.
`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.
`Pediatric Use
`Safety and efficacy in pediatric patients have not been established.
`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.
`
`Table 2
`Adverse Reactions and Laboratory Abnormalities
`(Continued)
`
`Adverse Reaction
`
`Metabolic and Nutritional Disorders
`SGPT > 5 times baseline
`SGOT > 5 times baseline
`Weight gain
`Musculoskeletal System
`Myasthenia
`Arthralgia
`Myalgia
`Leg cramps
`Nervous System
`Hypertonia
`Dizziness
`Insomnia
`Incoordination
`Anxiety
`Nervousness
`Respiratory System
`Dyspnea
`Skin and Appendages
`Rash
`Skin disorder
`Sweating
`Alopecia
`Urogential System
`Urinary urgency
`Metrorrhagia*
`Menorrhagia*
`Impotence**
`Urinary frequency
`Dysmenorrhea*
`Prostatic disorder**
`* pre-menopausal women
`** male patients
`
`Placebo
`(n=789)
`
`Betaseron
`(n=1115)
`
`4%
`1%
`5%
`
`43%
`29%
`16%
`2%
`
`40%
`21%
`19%
`18%
`8%
`5%
`
`4%
`
`18%
`10%
`6%
`2%
`
`10%
`8%
`6%
`7%
`5%
`5%
`1%
`
`10%
`3%
`7%
`
`46%
`31%
`27%
`4%
`
`50%
`24%
`24%
`21%
`10%
`7%
`
`7%
`
`24%
`12%
`8%
`4%
`
`13%
`11%
`8%
`9%
`7%
`7%
`3%
`
`The following adverse events have been observed during postmarketing
`experience with Betaseron and are classified within body system categories:
`Body General: *fatal capillary leak syndrome; Cardiovascular: cardiomyopathy,
`deep vein thrombosis, pulmonary embolism; Digestive: hepatitis, pancreatitis,
`vomiting; Endocrine: hypothyroidism, hyperthyroidism, thyroid dysfunction;
`Hemic and Lymphatic System: anemia, thrombocytopenia; Metabolic and
`Nutritional: Gamma GT increase, hypocalcemia, hyperuricemia, triglyceride
`increase; Nervous: ataxia, confusion, convulsion, depersonalization, emotional
`lability, paresthesia; Respiratory: bronchospasm, pneumonia; Skin and
`Appendages: pruritus, skin discoloration, urticaria; Urogenital: urinary tract
`infection, urosepsis.
`*The administration of cytokines to patients with a pre-existing monoclonal
`gammopathy has been associated with the development of this syndrome.
`Immunogenicity
`As with all therapeutic proteins, there is a potential for immunogenicity. Serum
`samples were monitored for the development of antibodies to Betaseron during
`the RRMS study. 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. 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 rarely been reported with the use of Betaseron.
`
`DRUG ABUSE AND DEPENDENCE
`No evidence or experience suggests that abuse or dependence occurs with
`Betaseron therapy; however, the risk of dependence has not been systematically
`evaluated.
`
`OVERDOSAGE
`Safety of doses higher than 0.25 mg every other day has not been adequately
`evaluated. The maximum amount of Betaseron that can be safely administered
`has not been determined.
`
`DOSAGE AND ADMINISTRATION
`The recommended dose of Betaseron is 0.25 mg injected subcutaneously every
`other day. Generally, patients should be started at 0.0625 mg (0.25 mL)
`subcutaneously every other day, and increased over a six-week period to 0.25
`mg (1.0 mL) every other day (see Table 3).
`Table 3. Schedule for Dose Titration
`
`Volume
`
`6052800-10004938 (M) 101703 10/17/03 3:53 PM Page 1
`
`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).
`Distribution of Change in MRI Area
`Figure 1
`
`Median Change = –1.1%
`n=95
`
`Median Change = +16.5%
`n=100
`
`Betaseron 0.25 mg
`
`Placebo
`
`40
`
`30
`
`20
`
`10
`
`0
`
`40
`
`30
`
`20
`
`10
`
`% of Patients
`
`% of Patients
`
`Betaseron®
`Interferon beta-1b
`
`10004938
`
`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 colithat 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).
`
`CLINICAL PHARMACOLOGY
`General
`Interferons (IFNs) are a family of naturally occurring proteins, produced by
`eukaryotic cells in response to viral infection and other biologic agents. Three
`major groups of interferons have been distinguished: alpha, beta, and gamma.
`Interferons alpha and beta comprise the Type I interferons and interferon gamma
`is a Type II interferon. Type I interferons have considerably overlapping but also
`distinct biologic activities. The bioactivities of IFNs are mediated by their
`interactions with specific receptors found on the surfaces of human cells.
`Differences in bioactivites induced by IFNs likely reflect divergences in the signal
`transduction process induced by IFN-receptor binding.
`Biologic Activities
`The mechanism of action of Interferon beta-1b in patients with multiple sclerosis
`is unknown. 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, ß2–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).
`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 2.0 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 2.0 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 8.0 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, ß2–
`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.
`
`CLINICAL STUDIES
`The safety and efficacy of Betaseron have been assessed in three multicenter trials.
`Study 1 evaluated Betaseron in relapsing-remitting MS (RRMS) patients and
`Studies2 and3 assessed Betaseron in secondary progressive MS(SPMS) patients.
`The effectiveness of Betaseron in relapsing-remitting MS (Study 1) was
`evaluated in a double blind, multiclinic, randomized, parallel, placebo controlled
`clinical investigation of two years duration. The study enrolled MS patients,
`aged 18 to 50, who were ambulatory (EDSS of ≤ 5.5), exhibited a relapsing-
`remitting clinical course, met Poser’s criteria1 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.
`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 1.
`
`Efficacy
`Parameters
`
`TABLE 1
`Two Year RRMS Study Results
`Primary and Secondary Clinical Outcomes
`Treatment
`Statistical Comparisons
`Groups
`p-value
`Placebo 0.05 mg 0.25 mg Placebo 0.05 mg Placebo
`vs
`vs
`vs
`(N=123) (N=125) (N=124) 0.05 mg 0.25 mg 0.25 mg
`0.113 0.0001
`1.31
`1.14
`0.90
`0.005
`
`16%
`
`18%
`
`25%
`
`0.609
`
`0.288
`
`0.094
`
`0
`From
`To
`
`–60
`<–40
`
`–40
`<–20
`
`–20
` <0
`
`100
`<120
`
`120
`<140
`
`140+
`
`80
`60
`40
`20
`0
`<20
`<40
`<60
`<80
`<100
`Percent Change in MRI Area
`In an evaluation of frequent MRI scans (every six weeks) on 52 patients at one
`site, the percent of scans with new or expanding lesions was 29% in the placebo
`group and 6% in the 0.25 mg treatment group (p=0.006).
`The exact relationship between MRI findings and clinical status of patients is
`unknown. Changes in lesion area often do not correlate with changes in
`disability progression. The prognostic significance of the MRI findings in this
`study has not been evaluated.
`Studies 2 and 3 were multicenter, randomized, double-blind, placebo controlled
`trials conducted to assess the effect of Betaseron in patients with SPMS. Study
`2 was conducted in Europe and Study 3 was conducted in North America. Both
`studies enrolled patients with clinically definite or laboratory-supported MS in
`the secondary progressive phase, and who had evidence of disability
`progression (both Study 2 and 3) or two relapses (Study 2 only) within the
`previous two years. Baseline Kurtzke expanded disability status scale (EDSS)
`scores ranged from 3.0 to 6.5.2 Patients in Study 2 were randomized to receive
`Betaseron 0.25 mg (n=360) or placebo (n=358). Patients in Study 3 were
`randomized to Betaseron 0.25 mg (n=317), Betaseron 0.16 mg/m2 of body
`surface area (n=314, mean assigned dose 0.30 mg), or placebo (n=308). Test
`agents were administered subcutaneously, every other day for three years.
`The primary outcome measure was progression of disability, defined as a 1.0
`point increase in the EDSS score, or a 0.5 point increase for patients with
`baseline EDSS ≥ 6.0. In Study 2, time to progression in EDSS was longer in the
`Betaseron treatment group (p=0.005), with estimated annualized rates of
`progression of 16% and 19% in the Betaseron and placebo groups, respectively.
`In Study 3, the rates of progression did not differ significantly between treatment
`groups, with estimated annualized rates of progression of 12%, 14%, and 12%
`in the Betaseron fixed dose, surface area-adjusted dose, and placebo groups,
`respectively.
`Multiple analyses, including covariate and subset analyses based on sex, age,
`disease duration, clinical disease activity prior to study enrollment, MRI
`measures at baseline and early changes in MRI following treatment were
`evaluated in order to interpret the discordant study results. No demographic or
`disease-related factors enabled identification of a patient subset where Betaseron
`treatment was predictably associated with delayed progression of disability.
`In Studies 2 and 3, like Study 1, a statistically significant decrease in the
`incidence of relapses associated with Betaseron treatment was demonstrated. In
`Study 2, the mean annual relapse rates were 0.42 and 0.63 in the Betaseron and
`placebo groups, respectively (p<0.001). In Study 3, the mean annual relapse
`rates were 0.16, 0.20, and 0.28, for the fixed dose, surface area-adjusted dose,
`and placebo groups, respectively (p<0.02).
`MRI endpoints in both Study 2 and Study 3 showed lesser increases in T2 MRI
`lesion area and decreased number of active MRI lesions in patients in the
`Betaseron groups. The exact relationship between MRI findings and the clinical
`status of patients is unknown. Changes in MRI findings often do not correlate
`with changes in disability progression. The prognostic significance of the MRI
`findings in these studies is not known.
`Safety and efficacy of treatment with Betaseron beyond three years are not known.
`
`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.
`
`CONTRAINDICATIONS
`Betaseron is contraindicated in patients with a history of hypersensitivity to
`natural or recombinant interferon beta, Albumin (Human), USP, or any other
`component of the formulation.
`
`ADVERSE REACTIONS
`In all studies, the most serious adverse reactions with Betaseron were
`depression, suicidal ideation and injection site necrosis (see WARNINGS).
`The incidence of depression of any severity was approximately 34% in both
`Betaseron-treated patients and placebo-treated patients. Anaphylaxis and other
`allergic reactions have been reported in patients using Betaseron (see
`WARNINGS). The most commonly reported adverse reactions were
`lymphopenia (lymphocytes<1500/mm3), injection site reaction, asthenia, flu-
`like symptom complex, headache, and pain. The most frequently reported
`adverse reactions resulting in clinical intervention (e.g., 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.
`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. The adverse reaction
`information from clinical trials does, however, provide a basis for identifying the
`adverse events that appear to be related to drug use and for approximating rates.
`The data described below reflect exposure to Betaseron in the three placebo
`controlled trials of 1115 patients with MS treated with 0.25 mg or 0.16 mg/m2,
`including 1041 exposed for greater than one year. The population encompassed
`an age range from 18 - 65 years. Sixty-five percent (65%) of the patients were
`female. The percentages of Caucasian, Black, Asian, and Hispanic patients were
`94.0%, 4.3%, 0.2%, and 0.8%, respectively.
`The safety profiles for Betaseron-treated patients with SPMS and RRMS were
`similar. Clinical experience with Betaseron in other populations (patients with
`cancer, HIV positive patients, etc.) provides additional data regarding adverse
`reactions; however, experience in non-MS populations may not be fully
`applicable to the MS population.
`Injection Site Reactions
`In three controlled clinical trials, injection site reactions occurred in 86% of
`patients receiving Betaseron with injection site necrosis in 5%. Inflammation
`(53%), pain (18%), hypersensitivity (3%), necrosis (5%), mass (2%), edema
`(3%) and non-specific reactions were significantly associated with Betaseron
`treatment (see WARNINGS and PRECAUTIONS). The incidence of injection
`site reactions tended to decrease over time, with approximately 76% of patients
`experiencing the event during the first three months of treatment, compared to
`approximately 45% at the end of the studies.
`Flu-Like Symptom Complex
`The rate of flu-like symptom complex was approximately 60% in the three
`controlled clinical trials. The incidence decreased over time, with only 10% of
`patients reporting flu-like symptom complex at the end of the studies. For
`patients who experienced a flu-like symptom complex in Study 1, the median
`duration was 7.5 days.
`Laboratory Abnormalities
`In the three clinical trials, leukopenia was reported in 18% and 5% 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 laboratory abnormalities included SGPT greater than five times baseline
`value (10%), and SGOT greater than five times baseline value (3%). In Study 1,
`two patients were dose reduced for increased liver 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
`liver enzymes. Three (0.3%) patients were withdrawn from treatment with
`Betaseron for any laboratory abnormality including two (0.2%) patients
`following dose reduction (see PRECAUTIONS, Laboratory Tests).
`Menstrual Irregularities
`In the three clinical trials, 82 (14%) of the 577 pre-menopausal females treated
`with Betaseron and 74 (18%) of the 405 pre-menopausal females treated with
`placebo reported menstrual disorders. One event was reported as severe, all
`other reports were mild to moderate severity. No patients withdrew from the
`studies due to menstrual irregularities.
`Table 2 enumerates adverse events and laboratory abnormalities that occurred
`among all patients treated with 0.25 mg or 0.16 mg/m2 Betaseron every other
`day for periods of up to three years in the controlled trials at an incidence that
`was at least 2% more than that observed in the placebo patients.
`
`Table 2
`Adverse Reactions and Laboratory Abnormalities
`Adverse Reaction
`Placebo
`Betaseron
`(n=789)
`(n=1115)
`
`Body as a Whole
`Injection site reaction
`Asthenia
`Flu-like symptom complex
`Headache
`Pain
`Fever
`Chills
`Abdominal pain
`Chest pain
`Malaise
`Injection site necrosis
`Cardiovascular System
`Peripheral edema
`Vasodilation
`Hypertension
`Peripheral vascular disorder
`Palpitation
`Tachycardia
`Digestive System
`Nausea
`Constipation
`Diarrhea
`Dyspepsia
`Hemic and Lymphatic System
`Lymphocytes < 1500/mm3
`ANC < 1500/mm3
`WBC < 3000/mm3
`Lymphadenopathy
`
`29%
`54%
`41%
`48%
`42%
`22%
`11%
`13%
`7%
`4%
`0%
`
`12%
`6%
`4%
`4%
`2%
`2%
`
`25%
`18%
`16%
`12%
`
`70%
`5%
`4%
`4%
`
`85%
`61%
`60%
`57%
`51%
`36%
`25%
`19%
`11%
`8%
`5%
`
`15%
`8%
`7%
`6%
`4%
`4%
`
`27%
`20%
`19%
`14%
`
`88%
`14%
`14%
`8%
`
`(Continued)
`
`WARNINGS
`Depression and Suicide
`Betaseron (Interferon beta-1b) should be used with caution in patients with
`depression, a condition that is common in people with multiple sclerosis.
`Depression and suicide have been reported to occur with increased frequency in
`patients receiving interferon compounds, including Betaseron. Patients treated
`with Betaseron should be advised to report immediately any symptoms of
`depression and/or suicidal ideation to their prescribing physicians. If a patient
`develops depression, cessation of Betaseron therapy should be considered.
`In the three randomized controlled studies there were three suicides and eight
`suicide attempts among the 1240 patients in the Betaseron treated groups
`compared to one suicide and four suicide attempts among the 789 patients in
`the placebo groups.
`Injection Site Necrosis
`Injection site necrosis (ISN) has been reported in 5% of patients in controlled
`clinical trials (see ADVERSE REACTIONS). Typically, injection site necrosis
`occurs within the first four months of therapy, although post-marketing reports
`have been received of ISN occurring over one year after initiation of therapy.
`Necrosis may occur at a single or multiple injection sites. 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. However, there are
`also reports of necrosis extending to and including fascia overlying muscle. In
`some lesions where biopsy results are available, vasculitis has been reported.
`For some lesions debridement and, infrequently, skin grafting have been required.
`As with any open lesion, it is important to avoid infection and, if it occurs, to treat
`the infection. Time to healing was varied depending on the severity of the
`necrosis at the time treatment was begun. In most cases healing was associated
`with scarring.
`Some patients have experienced healing of necrotic skin lesions while Betaseron
`therapy continued; others have not. 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,
`Betaseron should not be administered into the affected area until it is fully healed.
`If multiple lesions occur, therapy should be discontinued until healing occurs.
`Patient understanding and use of aseptic self-injection techniques and
`procedures should be periodically reevaluated, particularly if injection site
`necrosis has occurred.
`Anaphylaxis
`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).
`Albumin (Human), USP
`This product contains albumin, a derivative of human blood. Based on effective
`donor screening and product manufacturing processes, it carries an extremely
`remote risk for transmission of viral diseases. A theoretical risk for transmission
`of Creutzfeldt-Jakob disease (CJD) also is considered extremely remote. No
`cases of transmission of viral diseases or CJD have ever been identified for
`albumin.
`
`PRECAUTIONS
`Information for Patients
`All patients should be instructed to carefully read the supplied Betaseron
`Medication Guide. Patients should be cautioned not to change the dose or
`schedule of administration without medical consultation.
`Patients should be made aware that serious adverse reactions during the use of
`Betaseron have been reported, including depression and suicidal ideation,
`injection site necrosis, and anaphylaxis (see WARNINGS). Patients should be
`advised of the symptoms of depression or suicidal ideation and be told to report
`them immediately to their physician. Patients should also be advised of the
`symptoms of allergic reactions and anaphylaxis.
`Patients should be advised to promptly report any break in the skin, which may
`be associated with blue-black discoloration, swelling, or drainage of fluid from
`the injection site, prior to continuing their Betaseron therapy.
`Patients should be informed that flu-like symptoms are common following
`initiation of therapy with Betaseron. In the controlled clinical trials, antipyretics
`and analgesics were permitted for relief of these symptoms. In addition, gradual
`dose titration during initiation of Betaseron treatment may reduce flu-like
`symptoms (see DOSAGE AND ADMINISTRATION).
`Female patients should be cautioned about the abortifacient potential of
`Betaseron (see PRECAUTIONS, Pregnancy - Teratogenic Effects).
`Instruction on Self-injection Technique and Procedures
`Patients should be instructed in the use of aseptic technique when administering
`Betaseron. Appropriate instruction for reconstitution of Betaseron and self-
`injection should be provided, including careful review of the Betaseron
`Medication Guide. The first injection should be performed under the
`supervision of an appropriately qualified health care professional.
`Patients should be cautioned against the re-use of needles or syringes and
`instructed in safe disposal procedures. A puncture resistant container for
`disposal of used needles and syringes should be supplied to the patient along
`with instructions for safe disposal of full containers.
`Patients should be advised of the importance of rotating areas of injection with
`each dose, to minimize the likelihood of severe injection site reactions, including
`necrosis or localized infection, (see Picking an Injection Site section of the
`Medication Guide).
`
`Betaseron
`Recommended
`Dose
`Titration
`0.25 mL
`0.0625 mg
`25%
`Weeks 1-2
`0.50 mL
`0.125 mg
`50%
`Weeks 3-4
`0.75 mL
`0.1875 mg
`75%
`Weeks 5-6
`Week 7+
`100%
`0.25 mg
`1.0 mL
`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. Slowly inject 1.2 mL of diluent into the Betaseron vial.
`Gently swirl the vial to dissolve the drug 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. Visually
`inspect the reconstituted product before use; discard the product if it contains
`particulate matter or is discolored. 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. One mL of reconstituted Betaseron solution contains 0.25 mg of
`Interferon beta-1b/mL.
`Betaseron is intended for use under the guidance and supervision of a physician.
`It is recommended that physicians or qualified medical personnel train patients
`in the proper technique for self-administering subcutaneous injections. Patients
`should be advised to rotate sites for subcutaneous injections (see
`PRECAUTIONS, Instruction on Self-injection Technique and
`Procedures). Concurrent use of analgesics and/or antipyretics may help
`ameliorate flu-like symptoms on treatment days. Betaseron should be visually
`inspected for particulate matter and discoloration prior to administration.
`Stability and Storage
`The reconstituted product contains no preservative. Before reconstitution with
`diluent, store Betaseron at room tem