Description: Interferon beta-1a is available through recombinant DNA technology. Interferon beta-1a is a 166 amino acid glycoprotein produced by Chinese hamster ovarian cells into which the human interferon beta gene has been introduced. The amino acid sequence of interferon beta-1a is identical to endogenous interferon beta. Interferon beta-1a is glycosolated with a single N-linked complex carbohydrate moiety, similar to native interferon beta. The specific activity of interferon beta-1a is 200 million IU/mg interferon beta-1a. Interferon beta-1a is 10-times more active per milligram of protein than interferon beta-1b in standard antiviral assays. This increase in activity is due to glycosylation of interferon beta-1a, which appears to stabilize the molecule.[2830] Interferon beta-1a had been shown to decrease both the number and severity of multiple sclerosis (MS) attacks (i.e., relapses) and to significantly slow the progression of physical disability associated with relapsing-remitting MS. Interferon beta-1a has also been studied in the treatment of hepatitis C, various malignancies including non-small cell lung cancer, chronic myelogenous leukemia, hairy cell leukemia, melanoma, and arthritis. The FDA approved Avonex® on May 17, 1996 for the treatment of relapsing-remitting MS. A Biologics License Application for Rebif® was submitted to the FDA in April 1998. Positive results from an on-going comparative study of Rebif® and Avonex® are needed to meet the US Orphan Drug requirements, which allow market exclusivity for Avonex® and Betaseron® (interferon beta-1b). Rebif® is available outside of the United States and is indicated for the treatment of relapsing-remitting MS (see also Interferon Beta-1a, Recombinant, rh-INF-beta monograph in Investigational/New Drugs). Mechanism of Action: Interferon beta-1a acts similarly to native interferon beta. Interferon beta belongs to the class of interferons, which are species-specific proteins produced in response to viruses as well as a variety of other natural and synthetic stimuli. Interferon beta is a Type I interferon. Interferon beta has 30% amino-acid homology with interferon alpha but only 1% homology with interferon gamma. Both interferon beta and interferon alpha are encoded on chromosome 9. Interferon beta binds to the type 1 interferon receptor with greater affinity than interferon alpha. In addition, interferon beta may bind to a distinct receptor that does not interact with interferon alpha. Interferon beta is produced by various cells including fibroblasts and macrophages, and has both antiviral and immune regulatory activities. Interferon beta increases the levels of 2,5-oligo-adenylate (2-5A) synthetase, an intracellular enzyme that is capable of degrading viral RNA. This activity may contribute to the antiviral and antiproliferative effects of interferon beta. Interferon beta has antiviral activity against herpes virus, human papillomavirus, hepatitis B, hepatitis C, and human immunodeficiency syndrome virus. There is some evidence that interferon beta has greater in vitro antiproliferative effects against many solid tumor cell lines than interferon alpha. The immunoregulatory effects of interferon beta include decreased expression of class II major histocompatibility complex (MHC) antigens, inhibition of T-helper cells, decreased expression of pro-inflammatory cytokines including interleukin (IL)-1beta, tumor necrosis factor (TNF)- alpha and -beta, interferon gamma (INF-G) and IL-6, and upregulation of interleukin-10, which is an immunosuppressive cytokine that inhibits T-helper cells INF-G and TNF release. The biologic responses of interferon beta therapy may be evaluated via the following markers: Beta2-microglobulin, neopterin, and tryptophan, and inhibition of concanavalin-stimulated proliferation of peripheral blood mononuclear cells. Interferon beta inhibits the expression of pro-inflammatory cytokines including INF-G, which is believed to be a major factor responsible for triggering the autoimmune reaction leading to multiple sclerosis. It is thought that INF-G stimulates cytotoxic T-cells and induces macrophages to produce proteinases that degrade the myelin sheath around the spinal cord. INF-G causes upregulation of class II MHC antigens on nervous system tissue; cytotoxic T-cells recognize these antigens as receptor sites and attack the tissue. The result is a progressive neurologic dysfunction. Interferon beta therapy downregulates INF-G production and INF-G-stimulated class II MHC expression. Interferon beta reduces T-cell migration across the blood-brain barrier. Interferon beta has also been found to increase production of nerve growth factor (NGF), which promotes oligodendrocyte survival and differentiation and axonal recovery. This may have a favorable effect on remyelination. Pharmacokinetics: Interferon beta-1a is administered by intramuscular injection. Pharmacokinetic data from patients with multiple sclerosis are not available. Interferon beta is metabolized in the liver. Peak serum concentrations were achieved between 3 and 15 hours (mean = 9.8 hours) in healthy volunteers following a 60 µg IM dose. Serum concentrations of interferon beta may be sustained following IM administration because of prolonged absorption from the IM site. The elimination half-life is about 10 hours. Biologic response marker levels (e.g., neopterin, tryptophan, and beta2-microglobulin) increase within 12 hours of dosing and remain elevated for at least 4 days. Biologic response marker levels usually peak within 48 hours of dosing.

Indications...Dosage For the treatment of remitting-relapsing forms of multiple sclerosis (MS) to slow physical disability and decrease the frequency of exacerbations: NOTE: Interferon beta-1a (Avonex®) has been designated as an orphan drug by the FDA for this indication. Intramuscular dosage (Avonex®): Adults: 30 µg (6 million IU) IM once a week. If a dose is missed, it should be given as soon as possible. The regular schedule may then be continued, but do not give 2 injections within 2 days of each other.[1659] Data suggest that early initiation of interferon beta-1a therapy delays the onset of clinically definite MS in high-risk patients who have recently experienced a demyelinating event but do not yet have clinical MS.[2985] Doses of 60 µg IM once weekly do not provide any additional benefits versus the 30 µg dose. Subcutaneous dosage (Rebif®, not available in the US)†: Adults: The PRISMS trial has shown that Rebif® 22 µg or 44 µg SC three times weekly significantly reduces the number of relapses, delays disability progression, and reduced disease activity and burden as measured in MRI.[249] New 4-year data from the PRISMS trial presented at the Annual Meeting of the American Academy of Neurology (May 2000) show that the higher dose is statistically superior to the lower dose. In addtion, these data suggest that disease progression was most delayed in patients who started treatment 2 years earlier in the disease with the higher dose, as compared to delaying treatment with the lower dose. For the treatment of hepatitis C†: NOTE: Interferon beta-1a has been designated as an orphan drug by the FDA for this indication. Intramuscular dosage: Adults: Data regarding the efficacy of beta interferons for hepatitis C are conflicting. There is no established dosage regimen. In the majority of studies, beta interferon 3—6 million IU IM three times weekly was used to treat patients who are no longer responding to other therapies, such as alfa interferon. Patients with hepatic impairment: Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed. Patients with renal impairment: Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed. †non-FDA approved indication

Administration Intramuscular Administration •Premedication with acetaminophen or ibuprofen and administration of interferon beta-1a at bedtime may lessen the severity of flu-like symptoms. •Interferon beta-1a 30 µg is equivalent to 6 million IU. •The manufacturer of Avonex® offers free training on intramuscular injection administration for patients and their health care partners. Contact MS ActiveSource for more information (1-800-456-2255). •Visually inspect parenteral products for particulate matter and discoloration prior to administration. •Store under refrigeration between 2—8 degrees C (36—46 degrees F); do not freeze. If refrigeration is unavailable, Avonex® may be stored at or below 24 degrees C (77 degrees F) for a period up to 30 days. Do not expose to high temperatures. Reconstitution: •Slowly add 1.1 ml of sterile water for injection, USP, preservative-free (supplied by the manufacturer) to the vial. Rapid addition of the diluent may cause foaming, making it difficult to withdraw the solution. Gently swirl the vial to aid in dissolution; do not shake. The final concentration should be 30 µg/ml (i.e., 6 million IU/ml). •Use within 6 hours of reconstitution; store reconstituted solution at 2—8 degrees C (36—46 degrees F). Discard any unused solution. Intramuscular injection: •Withdraw 1 ml of the reconstituted solution into a syringe. •Inject IM into the deltoid muscle of the upper arm or the anterolateral portion of the upper thigh. Do not use the gluteal muscle as a routine injection site due to the risk of sciatic nerve injury. If the gluteal region is used, injection should be made only into the upper, outer quadrant. Aspirate prior to injection to avoid injection into a blood vessel. If a vessel is penetrated, withdraw the needle and use a new syringe and needle at a different injection site.

Contraindications Interferon beta-1a is classified as FDA pregnancy category C. No adequate or well-controlled pregnancy studies have been done. Use of interferons during pregnancy should be avoided due to the risk of spontaneous abortion. If the patient does become pregnant, she should be made aware of the risk. Discontinuation of therapy is recommended. Females of childbearing age should use appropriate birth control measures while receiving beta interferon therapy. The flu-like symptoms associated with interferon beta-1a can place stress on patients with cardiac disease. These drugs should be used cautiously in patients with a history of angina, cardiac arrhythmias, heart failure, or myocardial infarction. Interferon beta-1a is not directly cardiotoxic. Patients with pre-existing bone marrow suppression or who are receiving myelosuppression therapy may be at increased risk of developing hematologic toxicity during beta interferon therapy. Interferon beta-1a-induced hematologic toxicity is dose related and uncommon at doses used for the treatment of multiple sclerosis. Patients with bone marrow suppression may require more intensive monitoring of hematologic parameters. During clinical studies, monitoring of all patients included complete white blood cell counts with differential, platelet counts, and blood chemistries including liver function tests every 6 months. The formulation of interferon beta-1a contains human albumin. Thus, interferon beta-1a is contraindicated in patients with albumin hypersensitivity. Interferon beta-1a should not be used in patients with hamster protein hypersensitivity. The risks of interferon beta-1a during breast-feeding are not known. There is the potential for serious adverse reactions to the infant. Breast-feeding of infants should be avoided during beta interferon therapy. The safety and efficacy of interferon beta-1a have not been established in children 18 years of age or younger. Interferon beta-1a should be used with caution in patients with depression. Patients with a history of depression 2 weeks prior to starting interferon beta-1a therapy may be at increased risk for developing depression during the first 2 months of therapy.[2831] Depression and suicide have been known to occur with other interferon compounds. Patients treated with interferon beta should report immediately any symptoms of depression or suicidal ideation to their prescriber or health-care professional. If a patient develops depression, cessation of interferon beta therapy should be considered. Exercise caution when administering interferon beta-1a to patients with a pre-existing seizure disorder. Seizures occurred during placebo-controlled trials in 4 patients receiving interferon beta-1a. It is not known whether these events were related to the effects of multiple sclerosis alone, interferon beta-1a therapy, or a combination of both. The effect of interferon beta-1a on the medical management of patients with a seizure disorder is unknown.

Interactions Another inteferon beta product (interferon beta-1b, Betaseron®) has been shown to reduce zidovudine, ZDV, clearance by as much as 93%. The mechanism of this interaction is unknown, but beta interferon may interfere with the glucuronidation of zidovudine. A similar interaction may occur with interferon beta-1a and zidovudine. Dosage reduction of zidovudine may be necessary when interferon beta and zidovudine are coadministered. No drug interactions of interferon beta-1a with the cytochrome P450 system have been reported in the professional literature or to the manufacturer. Hepatic microsomes isolated from interferon beta-1a-treated monkeys showed no influence of interferon beta-1a on hepatic P450 enzyme activity; formal studies in humans have not been performed. Interferon beta-1a has been given in combination with corticosteroids, antidepressants, and oral contraceptives and no unexpected adverse events were associated with these concurrent therapies.

Adverse Reactions Flu-like symptoms occur frequently in most patients treated with interferon beta-1. Specific symptoms have include fever, chills, headache, myalgia, malaise, and asthenia. Chills, fever, and myalgia may be severe in up to 5% of patients. These symptoms are most prevalent 6—12 hours after dosage administration and usually resolve within 24 hours. Flu-like symptoms most commonly occur within the first three months of therapy and diminish over time. Premedication and treatment for 24 hours after the dose with an antipyretic (i.e., acetaminophen or ibuprofen) and administration at bedtime may lessen the severity of these adverse reactions. Clinically, flu-like symptoms may be worse in female patients and patients with low-body mass. Dosage reduction of 50—75% may be necessary if severe reactions occur; the dose may be slowly increased after 4—6 weeks. Relapse of multiple sclerosis may occur with dosage reduction or discontinuation. Injection site reactions occurred in about 3% of patients following intramuscular injection of interferon beta-1a. Ecchymosis (bruising) at the injection site was reported in a small number of patients (2%). Although not recommended for patients with multiple sclerosis, subcutaneous administration of interferon beta-1a (Avonex®) has resulted inflammation at the injection site in 52% of patients. Subcutaneous administration has also been associated with tissue necrosis, atrophy, edema, and hemorrhage at the injection site. Clinically, some patients experience a transient worsening of multiple sclerosis symptoms, including increased spasticity, deterioration visual acuity and more pronounced paresthesias. These effects usually occur within the first 3 months of beta interferon treatment. Symptoms may appear 3—24 hours after the dose and can last from several hours to several days. Patients with spasticity or temperature-related symptoms prior to therapy are at increased risk for these effects. Dosage adjustment of beta interferon is usually not required. During initial clinical trials with interferon beta-1a, depression occurred equally in interferon beta-treated patients and in placebo-treated patients. During initial controlled trials with interferon beta-1a, only one patient in the placebo group attempted suicide. Suicidal ideation was reported in 4% of interferon beta-1a-treated patients and 1% of placebo treated patients. Interferon beta therapy can cause gastrointestinal side effects, including diarrhea, dyspepsia, and nausea/vomiting. During initial clinical trials with interferon beta-1a, common adverse gastrointestinal effects were nausea (33%), diarrhea (16%), and dyspepsia (11%). Elevated hepatic enzymes, such as increases in AST, ALT, and/or hyperbilirubinemia, have also been observed. In patients treated with interferon beta-1a, 3% of patients developed AST concentrations of at least three times the upper limit of normal. In a placebo-controlled study, 4 patients receiving interferon beta-1a experienced seizures, while no seizures occurred in the placebo group. Three of these patients had no prior history of seizure. It is not known whether these events were related to the effects of multiple sclerosis alone, interferon beta-1a, or a combination of both. For patients with no prior history of seizure who develop seizures during therapy with interferon beta-1a, an etiologic basis should be established and appropriate anticonvulsant therapy started prior to considering continuation of interferon beta-1a treatment. During clinical trials, anemia occurred significantly more often in patients treated with interferon beta-1a (8%) than in placebo-treated patients (3%). Eosinophilia (eosinophils <= 10%) was reported in 5% of patients treated with interferon beta-1a, which was not significantly different than the incidence seen in placebo-treated patients (4%). There was no significant difference between placebo and interferon beta-1a groups in the incidence of leukopenia or thrombocytopenia. However, these are known to be dose-related adverse effects associated with interferon therapy. During clinical studies, neutralizing antibody formation was noted in 24% of patients treated with interferon beta-1a. Fifteen percent of interferon beta-1a treated patients tested positive for neutralizing activity at a level at which no placebo patient tested positive. The significance of the appearance of serum neutralizing activity is unknown. Cross-reactivity with interferon beta-1b and natural interferon beta has been reported. Additional adverse reactions reported with interferon beta-1a include alopecia (4%), arthralgia (9%), ataxia (2%), dizziness (15%), dyspnea (6%), hearing loss or decrease (3%), hypotension (4%), insomnia (19%), nevus (3%), sinusitis (18%), speech disorder (3%), syncope (4%), urticaria (5%), and vaginitis (4%). Autoimmune reactions have been associated with interferon beta therapy. Case reports of thyroiditis, capillary leak syndrome, and polyarthritis have been noted. Thyroid dysfunction (usually hypothyroidism) may be seen in patients with a family history of thyroid disease or baseline anti-thyroid autoantibodies.

Interferon Beta-1a Avonex®

2830. Runkel L, Meier R, Pepinsky RB, et al. Structural and functional differences between glycosylated and nonglycosylated forms of human interferon b (INF-beta). Pharm Res 1998;15:641-9.

1659. Jacobs LD, Cookfair DL, Rudick RA et al. Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. Ann Neurol 1996;39:285—94.

2985. Jacobs LD, Beck RW, Simon, JH, et al. Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis N Engl J Med 2000;343;898—904.

249. PRISMS (Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Mutiple Sclerosis) Study Group. Randomised double-blind placebo-controlled study of interferon beta-1a in relapsing/remitting multiple sclerosis. Lancet 1998;352:1498—504.

2831. Mohr DC, Likosky W, Dwyer P, et al. Course of depression during the initiation of interferon beta-1a treatment for multiple sclerosis. Arch Neurol 1999;56:1263—5.