Laboratory Tests
`In addition to those laboratory tests normally requi ed for monitoring patients
`w th multiple sclerosis, complete blood and diffe ential white blood cell counts,
`platelet counts and blood chemistries, including liver function tests, are
`recommended at regular intervals (one, th ee, and six months) following
`introduction o Betase on therapy, and then periodically thereafter in the absence
`of clinical symptoms. Thyroid function tests a e ecommended every six months
`in patients w th a history of thy oid dysfunction or as clinically indicated.
`Patients w th myelosuppression may require mo e intensive monitoring of
`complete blood cell counts, w th differential and platelet counts.
`Drug Interactions
`No formal drug interaction studies have been conducted w th Betaseron. In the
`placebo cont olled studies in MS, corticoste oids or ACTH were administe ed
`for t eatment of elapses for periods of up to 28 days in patients (N=664)
`receiving Betase on.
`Carcinogenesis, Mutagenesis, and Impairment of Fertility
`Carcinogenesis: Interferon beta-1b has not been tested for its ca cinogenic
`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 p esence or absence of metabolic inactivation. Betase on 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 hesus monkeys at
`doses up to 0 33 mg/kg/day (32 times the ecommended 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 th ee 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 a e not known.
`Pregnancy - Teratogenic Effects
`Pregnancy Category C: Betaseron was not teratogenic at doses up to
`0 42 mg/kg/day when given to p egnant female hesus 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 ecommended human
`dose based on body surface a ea 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 t eatment were
`reported in patients (n=4) who participated in the Betase on RRMS clinical trial.
`Betase on 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. The e are no adequate and well-cont olled studies in p egnant women.
`If the patient becomes pregnant or plans to become pregnant while taking
`Betase on, the patient should be apprised of the potential haza d to the fetus and
`it should be recommended that the patient discontinue therapy.
`Nursing Mothers
`It is not known whether Betase on is excreted in human milk. Because many
`drugs a e exc eted 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 o Betaseron did not include sufficient numbers of patients aged
`65 and over to determine whether they respond diffe ently 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
`Met orrhagia*
`Menor hagia*
`Impotence**
`Urinary f equency
`Dysmenor hea*
`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 w th Betase on and are classified within body system categories:
`Body General: *fatal capillary leak synd ome; Cardiovascular: cardiomyopathy,
`deep vein thrombosis, pulmonary embolism; Digestive: hepatitis, pancreatitis,
`vomiting; Endocrine: hypothyroidism, hyperthy oidism, thyroid dysfunction;
`Hemic and Lymphatic System: anemia, thrombocytopenia; Metabolic and
`Nutritional: Gamma GT inc ease, hypocalcemia, hyperuricemia, triglyceride
`increase; Nervous: ataxia, confusion, convulsion, depersonalization, emotional
`lability, pa esthesia; Respiratory: b onchospasm, pneumonia; Skin and
`Appendages: pruritus, skin discoloration, urticaria; Urogenital: urina y tract
`infection, urosepsis.
`*The administration of cytokines to patients with a pre-existing monoclonal
`gammopathy has been associated with the development of this synd ome.
`Immunogenicity
`As with all therapeutic p oteins, there is a potential for immunogenicity. Serum
`samples were monitored for the development of antibodies to Betase on during
`the RRMS study. In patients eceiving 0 25 mg eve y other day 56/124 (45%)
`we e found to have serum neutralizing activity at one or more of the time points
`tested. The elationship between antibody formation and clinical safety or
`efficacy is not known.
`These data eflect the pe centage of patients whose test results we e conside ed
`positive for antibodies to Betaseron using a biological neutralization assay that
`measu es the ability of immune sera to inhibit the p oduction of the interferon-
`inducible protein, MxA. Neutralization assays a e 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 easons, comparison of the incidence of
`antibodies to Betase on with the incidence of antibodies to other products may
`be misleading.
`Anaphylactic eactions have rarely been reported with the use of Betaseron.
`
`DRUG ABUSE AND DEPENDENCE
`No evidence or experience suggests that abuse or dependence occurs with
`Betase on 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 administe ed
`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 eve y other day, and inc eased 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
`
`
`
`
`
`
`
`
`
`
`
`
`
`The average number of days of MS-related ste oid use was 41 days in the
`0 25 mg Betaseron group and 55 days in the placebo group (p=0.004).
`MRI data we e 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 g oup
`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
`Betase on® (Interfe on beta-lb) is a purified, sterile, lyophilized p otein product
`produced by ecombinant DNA techniques. Interfe on beta-1b is manufactu ed
`by bacterial fermentation of a strain of Escherichia colithat bears a genetically
`engineered plasmid containing the gene for human interfe on betaser17. The
`native gene was obtained f om human fib oblasts and altered in a way that
`substitutes serine for the cysteine residue found at position 17. Interfe on beta-1b
`has 165 amino acids and an app oximate 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 app oximately 32 million international units
`(IU)/mg Interferon beta-lb. Each vial contains 0 3 mg of Interferon beta-lb. The
`unit measu ement is derived by comparing the antiviral activity of the product to
`the World Health O ganization (WHO) eference standard of ecombinant human
`interferon beta. Mannitol, USP and Albumin (Human), USP (15 mg each/vial)
`a e added as stabilizers.
`Lyophilized Betase on is a sterile, white to off-white powder, for subcutaneous
`injection after econstitution with the diluent supplied (Sodium Chloride,
`0 54% Solution).
`
`CLINICAL PHARMACOLOGY
`General
`Interferons (IFNs) a e a family of naturally occurring proteins, produced by
`euka yotic cells in response to viral infection and other biologic agents. Three
`major groups of interfe ons have been distinguished: alpha, beta, and gamma.
`Interferons alpha and beta comprise the Type I interferons and interferon gamma
`is a Type II interfe on. Type I interferons have considerably overlapping but also
`distinct biologic activities. The bioactivities of IFNs a e mediated by their
`interactions with specific receptors found on the surfaces of human cells.
`Diffe ences in bioactivites induced by IFNs likely eflect dive gences in the signal
`transduction p ocess induced by IFN- eceptor binding.
`Biologic Activities
`The mechanism of action of Interfe on 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 measu ed in blood fractions f om Betaseron-
`t eated patients and Betase on-t eated healthy volunteers. Immunomodulatory
`effects of Interfe on beta-1b include the enhancement of supp essor T cell
`activity, reduction of p o-inflammato y 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 ole in the
`observed clinical activity o Betase on 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 eceiving the recommended
`dose of Betaseron is not available. Following single and multiple daily
`subcutaneous administrations of 0 5 mg Betase on to hea thy volunteers (N=12),
`serum Interferon beta-1b concentrations we e generally below 100 IU/mL. Peak
`serum Interferon beta-1b concentrations occurred between one to eight hours,
`w th 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 Betase on (0 006 mg to 2 0 mg), similar
`pharmacokinetic p ofiles we e obtained f om healthy volunteers (N=12) and from
`patients w th 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 we e 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 eve y other day subcutaneous administration of 0.25 mg Betaseron in
`healthy volunteers, biologic response marker
`levels (neopterin, ß2–
`mic oglobulin, 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 elationship between serum Interferon beta-1b levels or induced biologic
`response marker levels and the clinical effects of Interfe on beta-1b in multiple
`sclerosis is unknown.
`
`CLINICAL STUDIES
`The safety and efficacy of Betase on have been assessed in th ee 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 Betase on in elapsing- emitting MS (Study 1) was
`evaluated in a double blind, multiclinic, randomized, parallel, placebo cont olled
`clinical investigation of two years duration. The study enrolled MS patients,
`aged 18 to 50, who were ambulato y (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 eceived prior immunosuppressant therapy were excluded.
`An exacerbation was defined as the appearance of a new clinical sign/symptom
`or the clinical worsening of a p evious sign/symptom (one that had been stable
`for at least 30 days) that persisted for a minimum of 24 hours.
`Patients selected for study we e randomized to t eatment w th either placebo
`(N=123), 0.05 mg o Betase on (N=125), or 0 25 mg o Betase on (N=124) self-
`administered subcutaneously every other day. Outcome based on the 372
`randomized patients was evaluated after two years.
`Patients who required mo e than th ee 28-day courses of corticoste oids were
`removed from the study. Minor analgesics (acetaminophen, codeine),
`antidepressants, and oral baclofen were allowed ad libitum, but ch onic
`nonsteroidal anti-inflammatory drug (NSAID) use was not allowed.
`The primary p otocol-defined outcome measures we e 1) frequency of
`exacerbations per patient and 2) proportion of exacerbation f ee patients. A
`number of seconda y clinical and magnetic resonance imaging (MRI) measures
`we e 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 esults 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
`
`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
`Pe cent Change in MRI A ea
`In an evaluation of frequent MRI scans (every six weeks) on 52 patients at one
`site, the percent of scans w th new or expanding lesions was 29% in the placebo
`group and 6% in the 0 25 mg treatment g oup (p=0 006).
`The exact relationship between MRI findings and clinical status of patients is
`unknown. Changes in lesion a ea often do not correlate with changes in
`disability prog ession. The prognostic significance of the MRI findings in this
`study has not been evaluated.
`Studies 2 and 3 were multicenter, randomized, double-blind, placebo cont olled
`trials conducted to assess the effect o Betase on in patients w th SPMS. Study
`2 was conducted in Europe and Study 3 was conducted in North America. Both
`studies en olled patients w th clinically definite or laboratory-supported MS in
`the seconda y p og essive phase, and who had evidence of disability
`prog ession (both Study 2 and 3) or two elapses (Study 2 only) within the
`previous two years. Baseline Kurtzke expanded disability status scale (EDSS)
`scores ranged f om 3 0 to 6 5.2 Patients in Study 2 were randomized to receive
`Betase on 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 a ea (n=314, mean assigned dose 0 30 mg), or placebo (n=308). Test
`agents we e administe ed subcutaneously, every other day for three years.
`The primary outcome measure was prog ession of disability, defined as a 1.0
`point increase in the EDSS score, or a 0 5 point inc ease for patients with
`baseline EDSS ≥ 6.0. In Study 2, time to p og ession in EDSS was longer in the
`Betase on treatment group (p=0 005), with estimated annualized rates of
`prog ession of 16% and 19% in the Betaseron and placebo groups, respectively.
`In Study 3, the rates of p ogression did not differ significantly between t eatment
`groups, w th 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
`measu es at baseline and early changes in MRI following treatment were
`evaluated in order to interp et the discordant study esults. No demographic or
`disease- elated factors enabled identification of a patient subset where Betaseron
`t eatment was predictably associated w th delayed prog ession of disability.
`In Studies 2 and 3, like Study 1, a statistically significant dec ease in the
`incidence of relapses associated with Betase on treatment was demonstrated. In
`Study 2, the mean annual relapse rates we e 0 42 and 0 63 in the Betase on and
`placebo g oups, respectively (p<0 001). In Study 3, the mean annual elapse
`rates were 0.16, 0 20, and 0 28, for the fixed dose, surface area-adjusted dose,
`and placebo groups, espectively (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
`Betase on groups. The exact elationship between MRI findings and the clinical
`status of patients is unknown. Changes in MRI findings often do not correlate
`w th changes in disability p ogression. The prognostic significance of the MRI
`findings in these studies is not known.
`Safety and efficacy of t eatment w th Betaseron beyond th ee years are not known.
`
`INDICATIONS AND USAGE
`Betase on (Interferon beta-1b) is indicated for the treatment of relapsing forms
`of multiple scle osis to reduce the frequency of clinical exacerbations.
`
`CONTRAINDICATIONS
`Betase on is contraindicated in patients w th a history of hypersensitivity to
`natural or ecombinant interfe on beta, Albumin (Human), USP, or any other
`component of the formulation.
`
`ADVERSE REACTIONS
`In all studies, the most serious adverse reactions w th Betase on were
`dep ession, suicidal ideation and injection site necrosis (see WARNINGS).
`The incidence of depression of any severity was approximately 34% in both
`Betase on-t eated patients and placebo-treated patients. Anaphylaxis and other
`alle gic reactions have been reported in patients using Betaseron (see
`WARNINGS). The most commonly reported adverse eactions were
`lymphopenia (lymphocytes<1500/mm3), injection site reaction, asthenia, flu-
`like symptom complex, headache, and pain. The most frequently reported
`adverse eactions esulting in clinical intervention (e g., discontinuation of
`Betase on, adjustment in dosage, or the need for concomitant medication to t eat
`an adverse eaction symptom) were depression, flu-like symptom complex,
`injection site eactions, leukopenia, increased liver enzymes, asthenia,
`hypertonia, and myasthenia.
`Because clinical trials a e conducted under widely varying conditions and over
`varying lengths of time, adverse reaction rates observed in the clinical trials of
`Betase on cannot be di ectly compared to rates in clinical trials of other drugs,
`and may not eflect 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 eflect exposu e to Betaseron in the three placebo
`controlled trials of 1115 patients w th MS treated with 0 25 mg or 0.16 mg/m2,
`including 1041 exposed for g eater 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 p ofiles for Betaseron-treated patients with SPMS and RRMS were
`similar. Clinical experience with Betase on 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 eactions occur ed in 86% of
`patients receiving Betase on w th injection site necrosis in 5%. Inflammation
`(53%), pain (18%), hypersensitivity (3%), necrosis (5%), mass (2%), edema
`(3%) and non-specific eactions we e significantly associated w th Betaseron
`t eatment (see WARNINGS and PRECAUTIONS). The incidence of injection
`site eactions tended to decrease over time, with approximately 76% of patients
`experiencing the event during the first three months of treatment, compared to
`app oximately 45% at the end of the studies.
`Flu-Like Symptom Complex
`The rate of flu-like symptom complex was app oximately 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 Betase on- and placebo-treated groups, espectively. No patients were
`w thdrawn or dose reduced for neut openia in Study 1. Three pe cent (3%) of
`patients in Studies 2 and 3 experienced leukopenia and were dose- educed.
`Other laborato y abnormalities included SGPT greater than five times baseline
`value (10%), and SGOT g eater than five times baseline value (3%). In Study 1,
`two patients were dose reduced for increased liver enzymes; one continued on
`t eatment and one was ultimately w thdrawn. In Studies 2 and 3, 1 5% of
`Betase on patients we e dose-reduced or interrupted treatment for increased
`liver enzymes. Th ee (0 3%) patients we e withdrawn f om t eatment with
`Betase on for any laboratory abnormality including two (0 2%) patients
`following dose eduction (see PRECAUTIONS, Laboratory Tests).
`Menstrual Irregularities
`In the three clinical trials, 82 (14%) of the 577 p e-menopausal females treated
`w th Betase on and 74 (18%) of the 405 p e-menopausal females t eated with
`placebo reported menstrual diso ders. One event was reported as severe, all
`other eports we e mild to moderate severity. No patients w thd ew from the
`studies due to menstrual irregularities.
`Table 2 enumerates adverse events and laboratory abnormalities that occur ed
`among all patients t eated w th 0.25 mg or 0.16 mg/m2 Betase on every other
`day for periods of up to th ee years in the controlled trials at an incidence that
`was at least 2% mo e 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 nec osis
`Cardiovascular System
`Peripheral edema
`Vasodilation
`Hypertension
`Peripheral vascular disorder
`Palpitation
`Tachycardia
`Digestive System
`Nausea
`Constipation
`Diar hea
`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
`Betase on (Interferon beta-1b) should be used w th caution in patients with
`dep ession, a condition that is common in people w th multiple sclerosis.
`Depression and suicide have been reported to occur with inc eased f equency in
`patients eceiving interferon compounds, including Betase on. Patients treated
`w th Betase on should be advised to eport immediately any symptoms of
`dep ession and/or suicidal ideation to their p escribing physicians. If a patient
`develops depression, cessation of Betaseron therapy should be conside ed.
`In the th ee randomized cont olled studies the e were three suicides and eight
`suicide attempts among the 1240 patients in the Betaseron treated g oups
`compared to one suicide and four suicide attempts among the 789 patients in
`the placebo g oups.
`Injection Site Necrosis
`Injection site necrosis ( SN) has been reported in 5% of patients in cont olled
`clinical trials (see ADVERSE REACTIONS). Typically, injection site necrosis
`occurs w thin the first four months of therapy, a though post-marketing reports
`have been eceived of ISN occurring over one year after initiation of therapy.
`Necrosis may occur at a single or multiple injection sites. The necrotic lesions
`a e typically three cm or less in diameter, but larger a eas have been reported.
`Generally the nec osis has extended only to subcutaneous fat. However, there are
`also reports of necrosis extending to and including fascia overlying muscle. In
`some lesions whe e biopsy esults are available, vasculitis has been reported.
`For some lesions debridement and, inf equently, skin grafting have been requi ed.
`As w th any open lesion, it is important to avoid infection and, if it occurs, to t eat
`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
`w th scarring.
`Some patients have experienced healing of nec otic 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 Betase on after injection site nec osis has occur ed,
`Betase on should not be administe ed into the affected area until it is fully healed.
`If multiple lesions occur, therapy should be discontinued unti healing occurs.
`Patient understanding and use of aseptic self-injection techniques and
`procedures should be periodically eevaluated, particularly if injection site
`necrosis has occurred.
`Anaphylaxis
`Anaphylaxis has been eported as a rare complication of Betaseron use. Other
`allergic reactions have included dyspnea, b onchospasm, 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 sc eening and product manufacturing p ocesses, it carries an ext emely
`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 ca efully 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 eactions during the use of
`Betase on have been reported, including depression and suicidal ideation,
`injection site nec osis, and anaphylaxis (see WARNINGS). Patients should be
`advised of the symptoms of dep ession or suicidal ideation and be told to report
`them immediately to their physician. Patients should also be advised of the
`symptoms of allergic eactions and anaphylaxis.
`Patients should be advised to p omptly eport 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 w th Betaseron. In the controlled clinical trials, antipyretics
`and analgesics were permitted for elief of these symptoms. In addition, gradual
`dose titration during initiation of Betase on t eatment may reduce flu-like
`symptoms (see DOSAGE AND ADMINISTRATION).
`Female patients should be cautioned about the abortifacient potential of
`Betase on (see PRECAUTIONS, Pregnancy - Teratogenic Effects).
`Instruction on Self-injection Technique and Procedures
`Patients should be instructed in the use of aseptic technique when administering
`Betase on. App opriate instruction for reconstitution of Betaseron and self-
`injection should be provided, including ca eful review of the Betaseron
`Medication Guide. The first injection should be performed under the
`supervision of an app opriately qualified health care professional.
`Patients should be cautioned against the e-use of needles or syringes and
`instructed in safe disposal p ocedu es. A puncture esistant container for
`disposal of used needles and syringes should be supplied to the patient along
`w th 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 likel hood 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 econstituted product befo e use; discard the p oduct if it contains
`particulate matter or is discolo ed. Keeping the syringe and vial adapter in place,
`turn the assembly over so that the vial is on top. Withdraw the app opriate dose
`of Betase on solution. Remove the vial from the vial adapter befo e injecting
`Betase on. One mL of reconstituted Betaseron solution contains 0 25 mg of
`Interferon beta-1b/mL.
`Betase on 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 t eatment days. Betaseron should be visually
`inspected for particulate matter and discoloration prior to administration.
`Stability and Storage
`The reconstituted product contains no preservative. Befo e reconstitution with
`diluent, store Betase on at oom temperature 25°C (77°F). Excursions of 15° to
`30°C (59° to 86°F) a e permitted. After reconstitution, if not