Interferon beta-1b, Betaseron
`
`DESCRIPTION
`
`Betaseron® (Interferon beta-lb) is a purified, sterile, lyophilized protein product produced by recombinant
`DNA techniques. Interferon beta-1b is manufactured by bacterial fermentation of a strain of Escherichia
`coli that bears a genetically engineered plasmid containing the gene for human interferon betaser17. The
`native gene was obtained from human fibroblasts and altered in a way that substitutes serine for the
`cystine 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 interferon-induced 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
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`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-12 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 Studies 2 and 3 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 primaryprotocol-defined outcome measures were 1) frequency of exacerbations per patient and 2)
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`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.
`
`TABLE 1
`Two Year RRMS Study Results
`Primary and Secondary Clinical Outcomes
`
`Efficacy Parameters
`
`Treatment Groups
`
`Statistical Comparisons
`p-value
`
`Placebo
`vs
`0.25 mg
`0.0001
`0.094
`
`0.001
`
`0.010
`
`0.001
`
`0.001
`
`0.144
`
`0.126
`
`ND
`
`0.0001
`
`Placebo
`
`0.05 mg
`
`0.25 mg
`
`(N=123)
`1.31
`16%
`
`(N=125)
`1.14
`18%
`
`(N=124)
`0.90
`25%
`
`Placebo
`vs
`0.05 mg
`0.005
`0.609
`
`0.05 mg
`vs
`0.25 mg
`0.113
`0.288
`
`0.151
`
`0.077
`
`0.299
`
`0.020
`
`0.229
`
`0.995
`
`0.641
`
`ND
`
`0.015
`
`0.097
`
`0.257
`
`0.064
`
`0.108
`
`0.051
`
`ND
`
`0.019
`
`29
`39
`17
`14
`
`98
`
`9
`
`0.23
`
`19.5
`
`-0.07
`
`0.66
`
`35.5
`
`-0.9%
`
`20
`32
`20
`15
`15
`21
`
`5
`
`0.47
`
`44.1
`
`0.21
`
`-0.53
`
`36
`
`21.4%
`
`22
`31
`28
`15
`7
`16
`
`6
`
`0.29
`
`33.2
`
`0.21
`
`-0.50
`
`33
`
`9.8%
`
`Primary End Points
`
`Annual exacerbation rate
`Proportion of exacerbation-free
`patients†
`Exacerbation frequency per
`patient
`
`0†
`
`1234
`
`5
`
`Secondary Endpoints††
`Median number of months to first
`on-study exacerbation
`Rate of moderate or severe
`exacerbations per year
`Mean number of moderate or severe
`exacerbation days per patient
`Mean change in EDSS score‡ at
`endpoint
`Mean change in Scripps score‡‡ at
`endpoint
`Median duration in days per
`exacerbation
`% change in mean MRI lesion
`area at endpoint
`
`†
`
`ND Not done
`14 exacerbation free patients (0 from placebo, six from 0.05 mg, and eight from 0.25 mg) dropped out of the study
`before completing six months of therapy. These patients are excluded from this analysis.
`Sequelae and Functional Neurologic Status, both required by protocol, were not analyzed individually but are included
`as a function of the EDSS.
`EDSS scores range from 1-10, with higher scores reflecting greater disability
`
`††
`
`‡
`
`‡‡
`
`Scripps neurologic rating scores range from 0-100, with smaller scores reflecting greater disability.
`
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`Of the 372 RRMS patients randomized, 72 (19%) failed to complete two full years on their assigned
`treatments.
`
`Over the two-year period, there were 25 MS-related hospitalizations in the 0.25 mg Betaseron-treated
`group compared to 48 hospitalizations in the placebo group. In comparison, non-MS hospitalizations
`were evenly distributed among the groups, with 16 in the 0.25 mg Betaseron group and 15 in the placebo
`group. The average number of days of MS-related steroid use was 41 days in the 0.25 mg Betaseron
`group and 55 days in the placebo group (p=0.004).
`
`MRI data were also analyzed for patients in this study. A frequency distribution of the observed percent
`changes in MRI area at the end of two years was obtained by grouping the percentages in successive
`intervals of equal width. Figure 1 displays a histogram of the proportions of patients, which fell into each
`of these intervals. The median percent change in MRI area for the 0.25 mg group was 1.1% which was
`significantly smaller than the 16.5% observed for the placebo group (p=0.0001).
`
`Distribution of Change in MRI Area
`
`n = 95
`
`n = 100
`
`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
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`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.
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`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 overlaying 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.
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`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 Rotating
`Injection Sites section of Medication Guide).
`
`Laboratory Tests
`
`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
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`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 vitro
`model 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.
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`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.
`
`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
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`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 3 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.
`
`Adverse Reaction
`
`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
`
`Table 3
`Adverse Reactions and Laboratory Abnormalities
`Placebo
`(n=789)
`
`Betaseron
`(n=1115)
`
`29%
`54%
`41%
`48%
`42%
`22%
`11%
`13%
`7%
`4%
`0%
`
`12%
`6%
`4%
`4%
`2%
`2%
`
`25%
`18%
`
`10 of 14
`
`85%
`61%
`60%
`57%
`51%
`36%
`25%
`19%
`11%
`8%
`5%
`
`15%
`8%
`7%
`6%
`4%
`4%
`
`27%
`20%
`
`

`

`Diarrhea
`Dyspepsia
`
`Hemic and Lymphatic System
`Lymphocytes < 1500/mm3
`ANC < 1500/mm3
`WBC < 3000/mm3
`Lymphadenopathy
`
`Metabolic and Nutritional Disorders
`SGPT > 5 times baseline
`SGOT > 5 times baseline
`Weight gain
`
`Musculoskeletal System
`Myasthenia
`Arthralgia
`Myalgia
`Leg cramps
`
`16%
`12%
`
`70%
`5%
`4%
`4%
`
`4%
`1%
`5%
`
`43%
`29%
`16%
`2%
`
`19%
`14%
`
`88%
`14%
`14%
`8%
`
`10%
`3%
`7%
`
`46%
`31%
`27%
`4%
`
`Adverse Reaction
`
`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)
`
`40%
`21%
`19%
`18%
`8%
`5%
`
`4%
`
`18%
`10%
`6%
`2%
`
`10%
`8%
`6%
`7%
`5%
`5%
`1%
`
`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:
`
`11 of 14
`
`

`

`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 Betaserontherapy; 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