INTERFERON BETA 1B EN VADEMECUM

INTERFERON BETA 1b

Description: Interferon beta-1b is available through recombinant DNA technology. Interferon beta 1b is produced by bacterial fermentation of a strain of Escherichia coli that has a genetically engineered plasmid containing the gene for human interferon beta-ser 17. The native beta interferon gene has been obtained from human fibroblasts and altered so that serine is substituted for cysteine at position 17. Interferon beta-1b contains 165 amino acids and is not glycosolated. The specific activity of interferon beta-1b is 32 million IU/mg interferon beta-1b. Interferon beta-1b has been shown to decrease both the number and severity of multiple sclerosis (MS) attacks in patients with relapsing-remitting MS. Interferon beta-1b has also been shown to be effective in secondary progressive MS and delays the time to disability. Interferon beta-1b 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 Betaseron� on July 23, 1993 for the treatment of relapsing-remitting MS. Betaseron� was approved in Europe in January 1999 for secondary progressive MS; a Biologic License Application was submitted to the US FDA in June 1998 for the treatment of secondary progressive MS. Mechanism of Action: Interferon beta-1b 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, and decrease expression of pro-inflammatory cytokines, and upregulation of interleukin-10, which is an immunosuppressive cytokine that inhibits T-helper cells and interferon gamma and tumor necrosis factor 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 interleukin (IL)-1beta, tumor necrosis factor- alpha and beta, interferon gamma (INF-G) and IL-6. Interferon gamma 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 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-1b is administered by subcutaneous injection. Pharmacokinetic data from patients with multiple sclerosis are not available. Interferon beta is metabolized in the liver. Peak serum concentrations were achieved between 1 and 8 hours in healthy volunteers who received higher than recommended doses. Bioavailability was approximately 50% after subcutaneous administration. After single IV doses, mean serum clearance was 9.4�28.9 ml/min/kg and the elimination half-life ranged between 8 minutes and 4.3 hours.

Indications...Dosage For the treatment of multiple sclerosis (MS): NOTE: Interferon beta-1b has been designated as an orphan drug by the FDA for this indication. �for the treatment of relapsing-remitting forms of MS to decrease the frequency of exacerbations: Subcutaneous dosage: Adults: 250 �g SC every other day for up to 2 years. Disease progression that lasts 6 months is reason to cease therapy. Alternatively, limited data have shown a lower dose (50 �g SC every other day) superior to placebo in regards to decreasing the overall exacerbation rate and rate of moderate and severe exacerbations.[395] [1083] �for the treatment of secondary progressive MS� to delay neurological deterioration: Subcutaneous dosage: Adults: In a randomized-double blind study, 250 �g SC every other day significantly delayed the time to neurological deterioration in patients with secondary progressive MS as compared to placebo. Interferon beta-1b delayed disease progression by 9�12 months during the 2�3 year study period. The beneficial effect was seen in patients with superimposed relapses and in patients who had only progressive disease without relapses.[2832] However, in a North American study, treatment with interferon beta-1b showed no effect on time to onset of sustained progressive disability, although significant reductions in the number, severity, and duration of relapses, hospitalizations, and need for steroid treatment were noted (data presented at the Annual Meeting of the American Academy of Neurology, May 2000). Differences in patient characteristics may account for the differences noted between these studies (i.e., patients with more advanced disease in the North American study). For the treatment of hepatitis C�: Subcutaneous dosage: Adults: Data regarding the efficacy of beta interferons in the treatment of hepatitis C are conflicting. There is no established dosage regimen. In the majority of studies, beta interferon 3�6 million IU SC three times weekly has been 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 Subcutaneous Administration �Interferon beta-1b is administered subcutaneously only. Rotate injection sites minimize injection site reactions. �The manufacturer of Betaseron� offers materials to assist with training on subcutaneous injection administration for patients and their health care partners. �Premedication with acetaminophen or ibuprofen and administration of interferon at bedtime may lessen the severity of flu-like symptoms. �Interferon beta-1b 300 �g (0.3 mg) is equivalent to 9.6 million IU. �Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. �Store vials with diluent at 2�8 degrees C (36�46 degrees F). If refrigeration is not possible, the vials and diluent should be kept as cool as possible, below 30 degrees C (86 degrees F), away from heat and light, and used within 7 days. Reconstitution: �Add 1.2 ml of 0.54% sodium chloride injection (supplied by the manufacturer) to the vial. Gently swirl the vial to aid in dissolution; do not shake. The final concentration should be 250 �g interferon beta-1b/ml; corresponding to 8 million IU/ml. �The reconstituted injection should be used within 3 hours and any unused portions should be discarded. Subcutaneous injection: �Withdraw 1 ml of the reconstituted solution into a syringe. �Inject subcutaneously into arms, abdomen, hips, or thighs. Take care not to inject intradermally.

Contraindications Interferon beta-1b 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 and discontinuation of therapy is recommended. Females of childbearing age should use appropriate birth control measures while receiving interferon beta. The flu-like symptoms associated with interferon beta-1b 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-1b is not directly cardiotoxic. Interferon beta-1b contains human albumin. Thus interferon beta-1b is contraindicated in patients with albumin hypersensitivity. Interferon beta-1b is also contraindicated in patients with E. coli protein hypersensitivity since it contains trace amounts of E. coli protein. The risks of interferon beta-1b 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 therapy with interferon beta. The safety and efficacy of interferon beta-1b have not been established in children 18 years of age or younger. Interferon beta-1b should be used with caution in patients with depression. Depression and suicide have been reported with interferon beta-1b treatment of multiple sclerosis. 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. Patients with pre-existing bone marrow suppression or who are receiving myelosuppression therapy may be at increased risk of developing hematologic toxicity during interferon beta-1b therapy. 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 3 months. The study protocol recommended that interferon beta-1b therapy be discontinued if the absolute neutrophil count (ANC) fell below 750/mm3. When the ANC was > 750/mm3, therapy could be restarted at with a 50% dose reduction.

Interactions Interferon beta-1b has been shown to reduce zidovudine, ZDV, clearance by as much as 93%. The mechanism of this interaction is unknown, but interferon beta may interfere with the glucuronidation of zidovudine. Dosage reduction of zidovudine may be necessary when interferon beta and zidovudine are coadministered. Interactions of interferon beta with the cytochrome P-450 system have not been reported in the professional literature or to the manufacturer.

Adverse Reactions Flu-like symptom complex occurs in about 76% of patients receiving interferon-1b. The symptom complex included at least 2 of the following: fever, chill, myalgia, malaise, and diaphoresis (sweating). Specific symptoms have included fever (59%), chills (46%), myalgia (44%), malaise (15%), and asthenia (49%). Chills, fever, and myalgia may be severe in up to 5% of patients. Fever can persist for up to 10 hours after a dose. Flu-like symptoms most commonly occur within the first three months of therapy and diminish over time. During initial clinical trials with interferon beta-1b, the median time to the first occurrence of flu-like symptoms was 3 days. 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 are the most commonly described adverse reaction to interferon beta-1b therapy and occur in about 85% of treated patients. Injection site reactions include erythema, inflammation, pain, skin discoloration, swelling, and tissue necrosis. Tissue necrosis occurs in 5% of patients and may occur at single or multiple sites. Typically, tissue necrosis occurs within the first 4 months of therapy, but has been reported after 1 year of treatment. The necrotic lesions are usually < 3 cm in diameter and only involve the subcutaneous fat, although larger and deeper lesions have been reported. For some lesions, debridement, and infrequently, skin grafting have been required. Some patients have experienced healing while interferon beta-1b therapy continues. For patients who continue interferon beta-1b therapy after tissue necrosis has occurred, therapy should not be continued until all sites are completely healed. The decision of whether to discontinue interferon beta-1b therapy is dependent upon the extent of necrosis. 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. Mental disorders including anxiety, confusion, depersonalization, depression, emotional lability, and suicide have been reported during clinical trials of interferon beta-1b. Suicidal ideation resulting in attempted suicide was reported in 2% of patients treated with interferon beta-1b. It is not known whether these symptoms are related to the underlying multiple sclerosis, interferon beta-1b therapy, or a combination of both. Patients who experience these symptoms should be closely monitored and cessation of therapy considered. The most common adverse gastrointestinal symptoms reported during interferon beta-1b therapy are diarrhea (35%), constipation (24%) and nausea/vomiting (21%), although nausea/vomiting occurred only slightly more often than in patients treated with placebo. Elevated hepatic enzymes, such as increases in AST, ALT, and/or hyperbilirubinemia, have also been observed. In patients treated with interferon beta-1b, 19% developed significant increases in ALT (> 5 times baseline), compared with 6% of placebo-treated patients; AST increased significantly in 4% of patients. Some patients have discontinued therapy with interferon beta-1b due to abnormal hepatic enzymes. During clinical trials, patients whose hepatic transaminases (AST/ALT) exceed 10-times the upper limit of normal or whose bilirubin exceeds 5-times the upper limit of normal discontinued treatment. Once the values normalized, interferon beta-1b could be restarted with a 50% dose reduction. Twenty eight percent of premenopausal women treated with interferon beta-1b experienced menstrual irregularity. All changes were mild to moderate in severity and included decreased days of menstrual flow, dysmenorrhea, early or delayed menses, intermenstrual bleeding and spotting, and menorrhagia. With interferon beta-1b therapy, palpitations (8%), hypertension (7%), and sinus tachycardia (6%) were the most common cardiovascular events reported. Headache in 85% of patients treated with interferon beta-1b. Migraine headache was reported in 12% of patients treated with interferon beta-1b (vs. 7% with placebo). Neutropenia (absolute neutrophil count (ANC) < 1500/mm3) has been reported in 18% of patients receiving interferon beta-1b. No patients had an ANC < 500/mm3. Leukopenia consisting of a WBC count < 3000/mm3 has been reported in 16% of patients. Other hematologic toxicities were reported rarely. Spontaneous fetal abortion has been reported during clinical trials with interferon beta-1b. Women who think they may be pregnant should stop interferon beta-1b therapy and contact their prescriber or health care professional immediately. Neutralizing antibody formation against interferon beta-1b has been noted in up to 42% of multiple sclerosis patients treated for more than 3 months. Antibodies cross-reacting with interferon beta-1a and natural interferon have also been found in patients with high titers of interferon beta-1b antibodies.[2833] Other adverse reactions reported with interferon beta-1b include (23%), edema (8%), proteinuria (5%), hypoglycemia (15%), sinusitis (36%), dyspnea (8%), conjunctivitis (12%), and visual impairment (7%). 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-1b Betaseron�

395. INFB Multiple Sclerosis Study Group. Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. Neurology 1993;43:655�61.

1083. The IFNB Multiple Sclerosis Study Group and the University of British Columbia MS/MRI Analysis Group. Interferon beta-1b in the treatment of multiple sclerosis: final outcome of the randomized controlled trial. Neurology 1995;45:1277�85.

2832. European Study Group of interferon beta-1b in secondary progressive MS. Placebo-controlled multicentre randomised trial of interferon beta-1b in treatment of secondary progressive multiple sclerosis. Lancet 1998;352:1491�7.

2833. Kivisakk P, Alm GV, Tian WZ, et al. Neutralising and binding anti-interferon-beta-1b (INF-beta-1b) antibodies during INF-beta-1b treatment of multiple sclerosis. Mult Scler 1997;3:184�90.