Action And Clinical Pharmacology: General: Interferons are a family of naturally occurring proteins, which have molecular weights ranging from 15 000 to 21 000 daltons. Three major classes of interferons have been identified: alpha, beta and gamma. Interferon beta-1b, interferon alpha, and interferon gamma have overlapping yet distinct biologic activities. The activities of interferon beta-1b are species-restricted and, therefore, the most pertinent pharmacological information on interferon beta-1b is derived from studies of human cells in culture and in vivo.
Biologic Activities: Interferon beta-1b has been shown to possess both antiviral and immunomodulatory activities. The mechanisms by which interferon beta-1b exerts its actions in multiple sclerosis (MS) are not clearly understood. However, it is known that the biologic response-modifying properties of interferon beta-1b are mediated through its interactions with specific cell receptors found on the surface of human cells. The binding of interferon beta-1b to these receptors induces the expression of a number of interferon-induced gene products (e.g., 2, 5-oligoadenylate synthetase, protein kinase and indoleamine 2, 3-dioxygenase) that are believed to be the mediators of the biological actions of interferon beta-1b. A number of these interferon-induced products have been readily measured in the serum and cellular fractions of blood collected from patients treated with interferon beta-1b.
Clinical Trials: The effectiveness of interferon beta-1b in relapsing-remitting MS was evaluated in a double-blind, multiclinic (11 sites: 4 in Canada and 7 in the U.S.), randomized, parallel, placebo-controlled clinical investigation of 2 years’ duration. The study included MS patients, aged 18 to 50, who were ambulatory (Kurtzke expanded disability status scale [EDSS] of Â£5.5), exhibited a relapsing-remitting clinical course, met Poser’s criteria for clinically definite and/or laboratory supported definite MS and had experienced at least two exacerbations over 2 years preceding the trial without exacerbation in the preceding month. Patients who had received prior immunosuppressant therapy were excluded.
An exacerbation was defined, per protocol, 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 (1.6 MIU) of interferon beta-1b (n=125), or 0.25 mg (8 MIU) of interferon beta-1b (n=124) self-administered s.c. every other day. Outcome based on the first 372 randomized patients was evaluated after 2 years.
Patients who required more than three 28-day courses of corticosteroids were withdrawn from the study. Minor analgesics (e.g., acetaminophen), antidepressants and oral baclofen were allowed ad libitum, but chronic nonsteroidal anti-inflammatory drug (NSAID) use was not allowed.
The primary, protocol defined, outcome assessment measures were 1) frequency of exacerbations per patient and 2) proportion of exacerbation-free patients. A number of secondary outcome measures were also employed as described in Table I.
In addition to clinical measures, annual magnetic resonance imaging (MRI) was performed and quantitated for extent of disease as determined by changes in total area of lesions. In a substudy of patients (n=52) at one site, MRI was performed every 6 weeks and quantitated for disease activity as determined by changes in size and number of lesions.
Results at the protocol designated endpoint of 2 years (see Table I): In the 2-year analysis, there was a 31% reduction in annual exacerbation rate, from 1.31 in the placebo group to 0.9 in the 0.25 mg (8 MIU) group. The p-value for this difference was 0.0001. The proportion of patients free of exacerbations was 16% in the placebo group, compared with 25% in the interferon beta-1b 0.25 mg (8 MIU) group.
Of the first 372 patients randomized, 72 (19%) failed to complete 2 full years on their assigned treatments. The reasons given for withdrawal varied with treatment assignment. Excessive use of steroids accounted for 11 of the 26 placebo withdrawals. In contrast, among the 25 withdrawals from the 0.25 mg (8 MIU) assigned group, excessive steroid use accounted for only one withdrawal. Withdrawals for adverse events attributed to study article, however, were more common among interferon beta-1b-treated patients: 1 and 10 withdrew from the placebo and 0.25 mg (8 MIU) groups, respectively.
Over the 2-year period, there were 25 MS-related hospitalizations in the 0.25 mg (8 MIU) interferon beta-1b-treated group compared to 48 hospitalizations in the placebo group. In comparison, non-MS hospitalizations were evenly distributed between the groups, with 16 in the 0.25 mg (8 MIU) interferon beta-1b 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 (8 MIU) interferon beta-1b 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 2 years was obtained by grouping the percentages in successive intervals of equal width. Figure 1 (not shown) displays a histogram of the proportions of patients who fell into each of these intervals. The median percent change in MRI area for the 0.25 mg (8 MIU) group was -1.1% which was significantly smaller than the 16.5% observed for the placebo group (p=0.0001).
Figure 1 (not shown): Distribution of Change in MRI Area: Fifty-two patients at one site had frequent MRI scans (every 6 weeks). The percentage of scans with new or expanding lesions was 29% in the placebo group and 6% in the 0.25 mg (8 MIU) treatment group (p=0.006).
MRI scanning is viewed as a useful means to visualize changes in white matter that are believed to be a reflection of the pathologic changes that, appropriately located within the CNS, account for some of the signs and symptoms that typify relapsing-remitting MS. The exact relationship between MRI findings and the clinical status of patients is unknown. Changes in lesion area often do not correlate with clinical exacerbations probably because many of the lesions affect so-called “silent” regions of the CNS. Moreover, it is not clear what fraction of the lesions seen on MRI become foci of irreversible demyelinization (i.e., classic white matter plaques). The prognostic significance of the MRI findings in this study has not been evaluated.
At the end of 2 years on assigned treatment, patients in the study had the option of continuing on treatment under blinded conditions. Approximately 80% of patients in each treatment group accepted. Although there was a trend toward patient benefit in the interferon beta-1b groups during the third year, particularly in the 0.25 mg (8 MIU) group, there was no statistically significant difference between the interferon beta-1b-treated vs placebo-treated patients in exacerbation rate, or in any of the secondary endpoints described in Table I. As noted above, in the 2-year analysis, there was a 31% reduction in exacerbation rate in the 0.25 mg (8 MIU) group, compared to placebo. The p-value for this difference was 0.0001. In the analysis of the third year alone, the difference between treatment groups was 28%. The p-value was 0.065. The lower number of patients may account for the loss of statistical significance, and lack of direct comparability among the patient groups in this extension study make the interpretation of these results difficult. The third-year MRI data did not show a trend toward additional benefit in the interferon beta-1b arm compared with the placebo arm.
Throughout the clinical trial, serum samples from patients were monitored for the development of antibodies to interferon beta-1b. In patients receiving 0.25 mg (8 MIU) of interferon beta-1b (n=124) every other day, 45% were found to have serum neutralizing activity on at least one occasion. One third had neutralizing activity confirmed by at least two consecutive positive titres. This development of neutralizing activity may be associated with a reduction in clinical efficacy, although the exact relationship between antibody formation and therapeutic efficacy is not yet known.
Indications And Clinical Uses: For use in ambulatory patients with relapsing-remitting multiple sclerosis to reduce the frequency of clinical exacerbations (see Pharmacology, Clinical Trials). Relapsing-remitting MS is characterized by recurrent attacks of neurologic dysfunction followed by complete or incomplete recovery. The safety and efficacy of interferon beta-1b in chronic progressive MS has not been evaluated.
Contra-Indications: Patients with a history of hypersensitivity to natural or recombinant interferon beta, albumin human USP or any other component of the formulation.
Manufacturers’ Warnings In Clinical States: One suicide and 4 attempted suicides were observed among 372 study patients during a 3-year period. All 5 patients received interferon beta-1b (three in the 0.05 mg [1.6 MIU] group and two in the 0.25 mg [8.0 MIU] group). There were no attempted suicides in patients on study who did not receive interferon beta-1b. Depression and suicide have been reported to occur in patients receiving interferon alpha, a related compound. Patients treated with interferon beta-1b should be informed that depression and suicidal ideation may be a side effect of the treatment and should report these symptoms immediately to the prescribing physician. Patients exhibiting depression should be monitored closely and cessation of therapy should be considered.
Precautions: General: Patients should be instructed in injection techniques to assure the safe self-administration of interferon beta-1b. See Information for the Patient, Instruction on Self-injection Technique and Procedure below and Information for the Patient in the Blue Section.
Information for the Patient: Instruction on Self-Injection Technique and Procedures: It is recommended that the first injection be administered by, or under the direct supervision of, a physician. Appropriate instructions for reconstitution of interferon beta-1b and self-injection, using aseptic techniques, should be given to the patient. A careful review of the Betaseron Information for the Patient in the Blue Section is also recommended.
Patients should be cautioned against the re-use of needles or syringes and instructed in safe disposal procedures. Information on how to acquire a puncture-resistant container for disposal of used needles and syringes should be given to the patient along with instruction for safe disposal of full containers.
Eighty-five percent of patients in the controlled MS trial reported injection site reactions at one or more times during therapy. Post-marketing experience has been consistent with this finding, with infrequent reports of injection site necrosis.
The onset of injection site necrosis usually appears early in therapy with most cases reported to have occurred in the first 2 to 3 months of therapy. The number of sites where necrosis has been observed was variable.
Rarely, the area of necrosis has extended to s.c. fat or fascia. Response to treatment of injection site necrosis with antibiotics and/or steroids has been variable. In some of these patients elective debridement and, less frequently, skin grafting took place to facilitate healing which could take from 3 to 6 months.
Some patients experienced healing of necrotic skin lesions while interferon beta-1b therapy continued. In other cases new necrotic lesions developed even after therapy was discontinued.
The nature and severity of all reported reactions should be carefully assessed. Patient understanding and use of aseptic self-injection technique and procedures should be periodically re-evaluated.
Flu-like symptoms are not uncommon following initiation of therapy with interferon beta-1b. In the controlled MS clinical trial, acetaminophen was permitted for relief of fever or myalgia.
Patients should be cautioned not to change the dosage or the schedule of administration without medical consultation.
Awareness of Adverse Reactions: Patients should be advised about the common adverse events associated with the use of interferon beta-1b, particularly, injection site reactions and the flu-like symptom complex (see Adverse Effects).
Patients should be cautioned to report depression or suicidal ideation (see Warnings).
Patients should be advised about the abortifacient potential of interferon beta-1b (see Precautions, Pregnancy).
Laboratory Tests: The following laboratory tests are recommended prior to initiating interferon beta-1b therapy and at periodic intervals thereafter: thyroid function test, hemoglobin, complete and differential white blood cell counts, platelet counts and blood chemistries including liver function tests. A pregnancy test, chest roentgenogram and ECG should also be performed prior to initiating interferon beta-1b therapy. In the controlled MS trial, patients were monitored every 3 months. The study protocol stipulated that interferon beta-1b therapy be discontinued in the event the absolute neutrophil count fell below 750/mm When the absolute neutrophil count had returned to a value greater than 750/mm therapy could be restarted at a 50% reduced dose. No patients were withdrawn or dose-reduced for neutropenia or lymphopenia.
Similarly, if AST/ALT levels exceeded 10 times the upper limit of normal, or if the serum bilirubin exceeded 5 times the upper limit of normal, therapy was discontinued. In each instance during the controlled MS trial, hepatic enzyme abnormalities returned to normal following discontinuation of therapy. When measurements had decreased to below these levels, therapy could be restarted at a 50% dose reduction, if clinically appropriate. Dose was reduced in two patients due to increased liver enzymes; one continued on treatment and one was ultimately withdrawn.
Drug Interactions: Interactions between interferon beta-1b and other drugs have not been fully evaluated. Although studies designed to examine drug interactions have not been done, it was noted that interferon beta-1b patients (n=180) have received corticosteroid or ACTH treatment of relapses for periods of up to 28 days.
Interferon beta-1b administered in 3 cancer patients over a dose range of 0.025 mg (0.8 MIU) to 2.2 mg (71 MIU) led to a dose-dependent inhibition of antipyrine elimination. The effect of alternate-day administration of 0.25 mg (8 MIU) of interferon beta-1b on drug metabolism in MS patients is unknown.
Impairment of Fertility: Studies in female rhesus monkeys with normal menstrual cycles, at doses up to 0.33 mg (10.7 MIU)/kg/day (equivalent to 32 times the recommended human dose based on body surface area comparison) showed no apparent adverse effects on the menstrual cycle or on associated hormonal profiles (progesterone and estradiol) when administered over 3 consecutive menstrual cycles. The extrapolability of animal doses to human doses is not known. Effects of interferon beta-1b on women with normal menstrual cycles are not known.
Pregnancy: Interferon beta-1b was not teratogenic at doses up to 0.42 mg (13.3 MIU)/kg/day in rhesus monkeys, but demonstrated dose-related abortifacient activity when administered at doses ranging from 0.028 mg (0.89 MIU)/kg/day (2.8 times the recommended human dose based on body surface area comparison) to 0.42 mg (13.3 MIU)/kg/day (40 times the recommended human dose based on body surface area comparison). The extrapolation of animal doses 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 interferon beta-1b MS clinical trial. Interferon beta-1b 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. Women of childbearing potential should take appropriate contraceptive measures. If the patient becomes pregnant or plans to become pregnant while taking interferon beta-1b, the patient should discontinue therapy.
Lactation: It is not known whether interferon beta-1b is excreted in human milk. Given that many drugs are excreted in human milk, there is a potential for serious adverse reactions in nursing infants, therefore a decision should be made as to whether to discontinue nursing or discontinue interferon beta-1b treatment.
Children: Safety and efficacy in children under 18 years of age has not been established.
Dependence Liability: No evidence or experience suggests that abuse or dependence occurs with interferon beta-1b therapy; however, the risk of dependence has not been systematically evaluated.
Adverse Reactions: Experience with interferon beta-1b in patients with MS is limited to a total of 147 patients at the recommended dose of 0.25 mg (8 MIU) or more, every other day. Consequently, adverse events that are associated with the use of interferon beta-1b in MS patients at an incidence of 1% or less may not have been observed in premarketing studies. Clinical experience with interferon beta-1b in non-MS patients (e.g., cancer patients, HIV positive patients) provides additional safety data; however, this experience may not be fully applicable to MS patients.
Flu-like symptoms complex was reported in 76% of the patients treated with 0.25 mg (8 MIU) interferon beta-1b. A patient was defined as having a flu-like symptom complex if flu-like syndrome or at least two of the following symptoms were concurrently reported: fever, chills, myalgia, malaise or sweating. Only myalgia, fever and chills were reported as severe in more than 5% of the patients. The incidence rate for flu-like symptom complex was also calculated over the course of 3 years. The incidence rate of these events decreased over time, with 60% of patients experiencing the event during the first 3 months of treatment compared to 10% during the last 6 months. The median time to the first occurrence of flu-like symptom complex was 3.5 days and the median duration per patient was 7.5 days per year.
Laboratory abnormalities included: lymphocyte count 5 times baseline value (19%), absolute neutrophil count 2.5 times baseline value (6%).
Three patients were withdrawn from treatment with 0.25 mg (8 MIU) interferon beta-1b for abnormal liver enzymes including one following dose reduction (see Precautions, Laboratory Tests).
Twenty-one (28%) of the 76 females of childbearing age treated at 0.25 mg (8 MIU) interferon beta-1b and 10 (13%) of the 76 females of childbearing age treated with placebo reported menstrual disorders. All reports were of mild to moderate severity and included: intermenstrual bleeding and spotting, early or delayed menses, decreased days of menstrual flow, and clotting and spotting during menstruation.
Mental disorders such as depression, anxiety, emotional lability, depersonalization, suicide attempts and confusion were observed in this study. Two patients withdrew for confusion. One suicide and 4 attempted suicides were also reported. It is not known whether these symptoms may be related to the underlying neurological basis of MS, to interferon beta-1b treatment, or to a combination of both. Some similar symptoms have been noted in patients receiving interferon alpha and both interferons are thought to act through the same receptor. Patients who experience these symptoms should be monitored closely and cessation of therapy should be considered.
Additional common clinical adverse events and laboratory abnormalities associated with the use of interferon beta-1b are listed in the following paragraphs. These events occurred at an incidence of 5% or more in the 124 MS patients treated with 0.25 mg (8 MIU) of interferon beta-1b every other day for periods of up to 3 years in the controlled trial, and at an incidence that was at least twice that observed in the 123 placebo patients. Common clinical adverse events and laboratory abnormalities associated with the use of interferon beta-1b were: injection site reaction (85%), lymphocyte count 5 times baseline value (19%), absolute neutrophil count 2.5 times baseline value (6%), somnolence (6%), laryngitis (6%), pelvic pain (6%), menorrhagia (6%), injection site necrosis (5%) and peripheral vascular disorders (5%).
A total of 277 MS patients have been treated with interferon beta-1b in doses ranging from 0.025 mg (0.8 MIU) to 0.5 mg (16 MIU). During the first 3 years of treatment, withdrawals due to clinical adverse events or laboratory abnormalities not mentioned above included: fatigue (2%, 6 patients), cardiac arrhythmia.
Adverse events and laboratory abnormalities occurred at an incidence of 2% or more among the 124 MS patients treated with 0.25 mg (8 MIU) interferon beta-1b every other day for periods of up to 3 years in the controlled trial and at an incidence that was at least 2% more than that observed in the 123 placebo patients. Reported adverse events have been re-classified using the standard COSTART glossary to reduce the total number of terms employed in the table.
Other events observed during premarketing evaluation of various doses of interferon beta-1b in 1 440 patients are listed in the paragraphs that follow. Given that most of the events were observed in open and uncontrolled studies, the role of interferon beta-1b in their causation cannot be reliably determined.
Body as a Whole: abscess, adenoma, anaphylactoid reaction, ascites, cellulitis, hernia, hydrocephalus, hypothermia, infection, peritonitis, photosensitivity, sarcoma, sepsis and shock.
Cardiovascular: angina pectoris, arrhythmia, atrial fibrillation, cardiomegaly, cardiac arrest, cerebral hemorrhage, cerebral ischemia, endocarditis, heart failure, hypotension, myocardial infarct, pericardial effusion, postural hypotension, pulmonary embolus, spider angioma, subarachnoid hemorrhage, syncope, thrombophlebitis, thrombosis, varicose vein, vasospasm, venous pressure increased, ventricular extrasystoles and ventricular fibrillation.
Digestive: aphthous stomatitis, cardiospasm, cheilitis, cholecystitis, cholelithiasis, duodenal ulcer, dry mouth, enteritis, esophagitis, fecal impaction, fecal incontinence, flatulence, gastritis, gastrointestinal hemorrhage, gingivitis, glossitis, hematemesis, hepatic neoplasia, hepatitis, hepatomegaly, ileus, increased salivation, intestinal obstruction, melena, nausea, oral leukoplakia, oral moniliasis, pancreatitis, periodontal abscess, proctitis, rectal hemorrhage, salivary gland enlargement, stomach ulcer and tenesmus.
Endocrine: Cushing’s Syndrome, diabetes insipidus, diabetes mellitus, hypothyroidism and inappropriate ADH.
Hemic and Lymphatic: chronic lymphocytic leukemia, hemoglobin less than 9.4 g/100 mL, petechia, platelets less than 75 000/mmand splenomegaly.
Metabolic and Nutritional Disorders: alcohol intolerance, alkaline phosphatase greater than 5 times baseline value, BUN greater than 40 mg/dL, calcium greater than 11.5 mg/dL, cyanosis, edema, glucose greater than 160 mg/dL, glycosuria, hypoglycemic reaction, hypoxia, ketosis and thirst.
Musculoskeletal: arthritis, arthrosis, bursitis, leg cramps, muscle atrophy, myopathy, myositis, ptosis and tenosynovitis.
Nervous System: abnormal gait, acute brain syndrome, agitation, apathy, aphasia, ataxia, brain edema, chronic brain syndrome, coma, delirium, delusions, dementia, depersonalization, diplopia, dystonia, encephalopathy, euphoria, facial paralysis, foot drop, hallucinations, hemiplegia, hypalgesia, hyperesthesia, incoordination, intracranial hypertension, libido decreased, manic reaction, meningitis, neuralgia, neuropathy, neurosis, nystagmus, oculogyric crisis, ophthalmoplegia, papilledema, paralysis, paranoid reaction, psychosis, reflexes decreased, stupor, subdural hematoma, torticollis, tremor and urinary retention.
Respiratory: apnea, asthma, atelectasis, carcinoma of the lung, hemoptysis, hiccup, hyperventilation, hypoventilation, interstitial pneumonia, lung edema, pleural effusion, pneumonia and pneumothorax.
Skin and Appendages: contact dermatitis, erythema nodosum, exfoliative dermatitis, furunculosis, hirsutism, leukoderma, lichenoid dermatitis, maculopapular rash, psoriasis, seborrhea, skin benign neoplasm, skin carcinoma, skin hypertrophy, skin necrosis, skin ulcer, urticaria and vesiculobullous rash.
Special Senses: blepharitis, blindness, deafness, dry eyes, ear pain, iritis, keratoconjunctivitis, mydriasis, otitis externa, otitis media, parosmia, photophobia, retinitis, taste loss, taste perversion and visual field defect.
Urogenital: anuria, balanitis, breast engorgement, cervicitis, epididymitis, gynecomastia, hematuria, impotence, kidney calculus, kidney failure, kidney tubular disorder, leukorrhea, nephritis, nocturia, oliguria, polyuria, salpingitis, urethritis, urinary incontinence, uterine fibroids enlarged, uterine neoplasm and vaginal hemorrhage.
Dosage And Administration: For s.c. use only. The recommended dose for the treatment of ambulatory relapsing-remitting MS is 0.25 mg (8 MIU) injected s.c. every other day. Limited data regarding the activity of a lower dose are presented above (see Pharmacology, Clinical Trials).
Evidence of efficacy beyond 2 years is not known since the primary evidence of efficacy derives from a 2-year, double-blind, placebo-controlled clinical trial (see Pharmacology, Clinical Trials). Safety data are not available beyond the third year. Some patients were discontinued from this trial due to unremitting disease progression of 6 months or greater.
To reconstitute lyophilized interferon beta-1b for injection, use a sterile syringe and needle to inject 1.2 mL of the diluent supplied, Sodium Chloride, 0.54% Solution, into the vial. Gently swirl the vial of interferon beta-1b to dissolve the drug completely; do not shake. Inspect the reconstituted product visually and discard the product before use if it contains particulate matter or is discolored. After reconstitution with accompanying diluent, each mL of solution contains 0.25 mg (8 MIU) interferon beta-1b, 13 mg albumin human USP and 13 mg dextrose USP.
Withdraw 1 mL of reconstituted solution from the vial into a sterile syringe fitted with a 27-gauge needle and inject the solution s.c. Sites for self-injection include abdomen, buttocks and thighs. A vial is suitable for single use only; unused portions should be discarded 3 hours after reconstitution (see Information for the Patient).
Availability And Storage: Betaseron is a purified, sterile, lyophilized protein product produced by recombinant DNA techniques and formulated for use by injection. Interferon beta-1b is manufactured by bacterial fermentation of a strain of E. coli that bears a genetically engineered plasmid containing the gene for human interferon betaser17. The native gene was obtained from human fibroblasts and altered in a way that substitutes serine for the cysteine residue found at position 17. Interferon beta-1b is a highly purified protein that has 165 amino acids and an approximate molecular weight of 18 500 daltons. It does not include the carbohydrate side chains found in the natural material.
The specific activity of Betaseron is approximately 32 million international units (IU)/mg interferon beta-1b. Each vial contains 0.3 mg (9.6 MIU) of interferon beta-1b. 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. Dextrose and albumin human, USP (15 mg each/vial) are added as stabilizers. Prior to 1993, a different analytical standard was used to determine potency. It assigned 54 million IU to 0.3 mg interferon beta-1b.
Each 3 mL single-use vial of lyophilized powder contains: interferon beta-1b 0.3 mg (9.6 MIU). Nonmedicinal ingredients: albumin human USP and Dextrose USP as stabilizers. Preservative-free. Cartons of 15 vials of medication and 15 vials of diluent (2 mL of Sodium Chloride, 0.54% Solution/vial). If refrigeration is not possible, vials of Betaseron and diluent should be kept as cool as possible, below 30°C, away from heat and light, and used within 7 days. If not used immediately following reconstitution store under refrigeration at 2 to 8Â°C and use within 3 hours. Avoid freezing.
BETASERON® Berlex Canada Interferon beta-1b Immunomodulator
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