Rebif (Interferon beta-1a)

REBIF™

Serono

Interferon beta-1a

Immunomodulator

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, interferon alpha and interferon gamma have overlapping yet distinct biologic activities.

Interferon beta-1a acts through various mechanisms: Immunomodulation through the induction of cell membrane components of the major histocompatibility complex i.e., MHC Class I antigens, an increase in natural killer (NK) cell activity, and an inhibition of IFN-g induced MHC Class II antigen expression, as well as a sustained reduction in TNF level. Antiviral effect through the induction of proteins like 2-5 oligoadenylate synthetase and p78. Antiproliferative effect through direct cytostatic activity and indirect through antitumoral immune response enhancement.

The mechanism of action of interferon beta-1a in relapsing-remitting multiple sclerosis is still under investigation.

Relapsing-remitting Multiple Sclerosis: Two pivotal studies, including a total of 628 patients, evaluated the long-term safety and efficacy of interferon beta-1a when administered s.c. 3 times weekly to relapsing-remitting multiple sclerosis patients. The results indicate that interferon beta-1a alters the natural course of relapsing-remitting multiple sclerosis. Efficacy was demonstrated with respect to the 3 major aspects of this disease: disability (patients EDSS 0-5), exacerbations, and burden of disease and activity as measured by MRI scans.

Prisms Study: In the larger trial, a total of 560 patients diagnosed with clinically definite or laboratory-supported relapsing-remitting multiple sclerosis EDSS 0-5 with at least a 1-year history before study entry, were enrolled and randomized to the 3 treatments (placebo, 22 µg (6MIU) interferon beta-1a, or 44 µg (12MIU) interferon beta-1a) in a ratio of 1:1:1. About 90% of patients completed the 2 years of treatment, and very few patients withdrew from the study due to adverse events.

The main criteria for inclusion were: history of 2 or more acute exacerbations in the 2 years prior to study entry, no previous systemic treatment with interferons, no treatment with corticosteroids or ACTH in the 2 months preceding study entry and no exacerbation in the 8 weeks prior to study entry.

Patients were evaluated at 3-month periods, during exacerbations and coinciding with MRI scanning. Each patient underwent cranial proton density/T2-weighted (PD/T2) MRI scans at baseline and every 6 months during the study. A subset of patients underwent PD/T2 and T1-weighted (T1) Gd-MRI scans 1 month before the start of treatment, at baseline and then monthly until the end of the first 9 months of treatment. Of those, another subset of 39 continued with the monthly scans throughout the 24-month treatment period.

This study demonstrated that interferon beta-1a at a total dose of 66 or 132 µg weekly, significantly improved all 3 major outcomes, including exacerbation rate, disease activity and burden of disease as measured by MRI scanning and progression of disability. In addition, the study showed that interferon beta-1a is effective in delaying the progression in disability in patients with an EDSS of 4.0 or higher who are known to progress more rapidly. Also, the drug reduced the requirements for steroids to treat multiple sclerosis and, at 132 µg weekly interferon beta-1a reduced the number of hospitalizations for multiple sclerosis.

Requirement for Steroids: The proportion of patients requiring steroids for MS (excluding non-MS indications) was higher in the placebo group (more than 50%) than in either of the 2 interferon beta-1a groups (around 40% in each group).

Hospitalization for Multiple Sclerosis: The observed mean numbers of hospitalizations for MS in the interferon beta-1a 66 and 132 µg weekly groups represented reductions of 21% and 48%, respectively, from that in the placebo group.

Immunogenicity: Antibodies to IFN-beta were tested in all patients pre-entry, and at Months 6, 12, 18 and 24. The results of testing for the presence of neutralizing antibodies (NAb).

Due to concern about the potential impact of neutralizing antibody formation on efficacy, exacerbation counts (primary endpoint) were analyzed according to patients’ neutralizing antibody status. Over the 2 years of the study, there was no trend to a higher exacerbation rate in the neutralizing antibody-positive groups compared to the neutralizing antibody-negative groups. There is no clear indication that the development of serum neutralizing antibodies affected either safety or efficacy in either of the interferon beta-1a groups.

Cohort of Patients with High Baseline EDSS (baseline EDSS >3.5): Additional analyses were conducted in order to study the efficacy of interferon beta-1a in populations of patients with adverse predictive outcome factors, who were likely to be at higher risk for progression in disability. The primary predictive factor examined was baseline EDSS >3.5. Patients in this cohort have a more severe degree of disability and are at higher risk for progression than those with lower EDSS: natural history studies have shown that patients at EDSS levels of 4.0 to 5.0 spend less time at these EDSS levels than at lower levels of disability.

Treatment with interferon beta-1a at both doses significantly reduced the mean exacerbation count per patient compared to placebo treatment. Progression in this group of patients is of particular concern, as it involves development of difficulty in ambulation. The 132 µg weekly dose significantly prolonged time to confirmed progression whereas the 66 µg weekly dose did not. Both doses of interferon beta-1a significantly affected percent change from baseline in MRI burden of disease in the high-EDSS cohort, and the 132 µg weekly dose significantly reduced the number of T2 active lesions in this population. The efficacy results in this cohort of patients with established disability confirms that the 132 µg weekly dose has a marked effect on progression in disability and the underlying pathology of the disease.

Cross-over Study: The other study was an open cross-over design, with MRI evaluations conducted in a blinded fashion. Enrolled in this study were 68 patients between the ages of 15 and 45 years, with clinically definite and/or laboratory supported relapsing-remitting MS for up to 10 years in duration. The main inclusion criteria included: at least 2 relapses in the previous 2 years, EDSS score between 1 and 5, no corticosteroid or plasmapheresis treatments or administration of gamma globulins within the 3 months prior to study, no immunomodulating or immunosuppressive therapy for the 6 months prior to the study and absence of HBsAg and HIV antibodies. Once enrolled, patients remained under clinical observation for 6 months with assessments of their neurological status and other parameters, and extensive monitoring of exacerbations. Patients were then randomized to treatment with either 11 µg (3MIU) (n=35) or 33 µg (9MIU) (n=33) of interferon beta-1a, self-administered s.c. 3 times per week. The total dose was therefore 33 or 99 µg weekly.

Six-months Observation vs 6-months Treatment: Treatment with interferon beta-1a at both doses used in this study, achieved a statistically significant reduction in both the MRI evidence of MS activity in the brain and the clinical relapse rate versus the corresponding observation periods. This pattern of improvement was also reflected in additional MRI measures. In the biannual T2-weighted scans, a reduction in the mean number of new lesions and in the mean number of enlarging lesions was demonstrated.

Two-year Results: At the end of this study, 62 patients continued treatment for a further 18 months. Each of these patients continued to receive the dose to which they were randomized. Validation of the results of the 2-year treatment period is ongoing; however, the results from the continuation of treatment at both doses demonstrate that interferon beta-1a maintained its dose-dependent effect in reducing the relapse rate and the brain lesion volume detected by T2 weight MRI scans compared to the observation period, which corroborates the findings of the longer, placebo-controlled study.

Condyloma Acuminatum: The results from 4 double-blind, placebo-controlled studies, including 349 patients (aged 17 to 62), each reveal that interferon beta-1a, when injected intralesionally at a dose of 3.67 µg (1 MIU)/lesion 3 times per week for 3 weeks, is efficacious in the treatment of condyloma acuminatum in men and women. This efficacy is evidenced by both the induction of complete disappearance of lesions as well as the reduction in the area of lesions. The majority of treated patients in these studies had recurrent warts that had failed previous treatments. The number of lesions treated per patient was between 3 and 8.

Immunogenicity: The determination of the presence of antibodies to human IFN-b was performed in all 4 studies. A total of four patients had anti beta-interferon antibodies at pre-entry, and 6 other patients had at least a positive result for total binding antibodies at some point during the study. Antibodies were of low titer, and none of the antibodies were neutralizing to human IFN-b biological activity.

Indications And Clinical Uses: Multiple Sclerosis: For the treatment of relapsing-remitting multiple sclerosis in patients with an EDSS between 0 and 5.0, to reduce the number and severity of clinical exacerbations, slow the progression of physical disability, reduce the requirement for steroids, and reduce the number of hospitalizations for treatment of multiple sclerosis. The efficacy has been confirmed by T1-Gd enhanced and T2 (burden of disease) MRI evaluations. Evidence of efficacy beyond 2 years is not known since the primary evidence of efficacy derives from 2-year trials.

Condyloma Acuminatum: For the patient who has less than 9 lesions, and who has failed several prior treatments. In the case of patients with 9 or more lesions, if the first treatment is successful, the remaining lesions could be treated with a second course of therapy. Interferon beta-1a should also be considered for the treatment of condyloma acuminatum in patients for whom the side effects from other treatments, e.g., scarring, are of concern. While not all patients who were treated with interferon beta-1a attained a complete response, patients whose lesions decreased in size and had at least a partial response may have also benefitted from treatment because lesion shrinkage may facilitate subsequent management with other therapies, as has been reported with IFN-a.

Contra-Indications: Patients with a known hypersensitivity to natural or recombinant interferon beta, albumin (human), or any other component of the formulation. tag_WarningWarnings

Manufacturers’ Warnings In Clinical States: Interferon beta-1a should be used under the supervision of a physician.

Relapsing-remitting Multiple Sclerosis: Depression and suicidal ideation are known to occur at an increased frequency in the multiple sclerosis population. The use of interferon beta-1a has not been associated with an increase in the incidence and/or severity of depression, or with an increased incidence of suicide attempts or suicide. In the relapsing-remitting multiple sclerosis study, a similar incidence of depression was seen in the placebo-treated group and in the 2 interferon beta-1a patient groups. Nevertheless, patients with depression should be closely monitored for signs of significant worsening of depression or suicidal ideation.

The first injection should be performed under the supervision of an appropriately qualified health care professional.

Condyloma: All injections should be administered by a qualified health care professional.

Precautions: General: Patients should be informed of the most common adverse events associated with interferon beta administration, including symptoms of the flu-like syndrome (see Adverse Effects). These symptoms tend to be most prominent at the initiation of therapy and decrease in frequency and severity with continued treatment.

Serum neutralizing antibodies against interferon beta-1a may develop. The precise incidence and clinical significance of antibodies is as yet uncertain.

Intralesional injections can be painful to some patients treated for condyloma acuminata. In such cases an anesthetic cream such as lidocaine-prilocaine can be used.

Pregnancy and Lactation : Interferon beta-1a should not be administered in case of pregnancy and lactation. There are no studies of interferon beta-1a in pregnant women. At high doses in monkeys, abortifacient effects were observed with other interferons. Fertile women receiving interferon beta-1a should take appropriate contraceptive measures. Patients planning for pregnancy and those becoming pregnant should be informed of the potential hazards of interferons to the fetus and interferon beta-1a should be discontinued. It is not known whether interferon beta-1a is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants, a decision should be made either to discontinue nursing or to discontinue interferon beta-1a therapy.

Children: There is no experience with interferon beta-1a in children under 16 years of age with multiple sclerosis or condyloma, and therefore, interferon beta-1a should not be used in this population.

Patients with Special Diseases and Conditions: Caution should be used and close monitoring considered when administering interferon beta-1a to patients with severe renal and hepatic failure, patients with severe myelosuppression, and depressive patients.

Drug Interactions: No formal drug interaction studies have been conducted with interferon beta-1a in humans. Interferons have been reported to reduce the activity of hepatic cytochrome P450-dependent enzymes in humans and animals. Caution should be exercised when administering interferon beta-1a in combination with medicinal products that have a narrow therapeutic index and are largely dependent on the hepatic cytochrome P450 system for clearance, e.g., antiepileptics and some classes of antidepressants. The interaction of interferon beta-1a with corticosteroids or ACTH has not been studied systematically. Clinical studies indicate that multiple sclerosis patients can receive interferon beta-1a and corticosteroids or ACTH during relapses. Interferon beta-1a should not be mixed with other drugs in the same syringe.

Laboratory Tests: Relapsing-remitting Multiple Sclerosis: Laboratory abnormalities are associated with the use of interferons. Therefore, in addition to those laboratory tests normally required for monitoring patients with multiple sclerosis, complete and differential white blood cell counts, platelet counts and blood chemistries, including liver function tests are recommended during interferon beta-1a therapy.

Condyloma Acuminatum: Same as relapsing-remitting multiple sclerosis but tend not to be as severe because of dose and length of treatment.

Information to Be Provided to the Patient: Flu-like symptoms (fever, headache, chills, muscle aches) are not uncommon following initiation of therapy with interferon beta-1a. Acetaminophen may be used for relief of flu-like symptoms. Patients should contact their physician or pharmacist if they experience any undesirable effects.

Depression may occur in patients with relapsing-remitting multiple sclerosis and may occur while patients are taking interferon beta-1a. Patients should be asked to contact their physician should they feel depressed.

Patients should be advised not to stop or modify their treatment unless instructed by their physician.

Instruction on Self-Injection Technique and Procedures: Patients treated for relapsing-remitting multiple sclerosis should be instructed in the use of aseptic technique when administering interferon beta-1a. Appropriate instruction for reconstitution of interferon beta-1a and self-injection should be given including careful review of the interferon beta-1a patient leaflet. The first injection should be performed under the supervision of an appropriately qualified health care professional. Injection sites should be rotated at each injection. Injections may be given prior to bedtime as this may lessen the perception of side effects. 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.

In the controlled MS trial reported injection site reactions were commonly reported by patients at one or more times during therapy. In general, they did not require discontinuation of therapy, but 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.

Adverse Reactions: Multiple Sclerosis: As with other interferon preparations, flu-like symptoms are not uncommon. The use of interferon beta may cause flu-like syndrome, asthenia, pyrexia, chills, arthralgia, myalgia, headache, and injection site reactions.

Less frequent adverse reactions include cold sores, stuffy nose, light headedness, mucosal irritation, hematological disorders (leukopenia, lymphopenia, granulocytopenia), and alterations in liver function tests such as elevated AST and ALT. These effects are usually mild and reversible. Tachyphylaxis with respect to most side effects is well recognized. Fever and flu-like symptoms can be treated with acetaminophen. Depending on the severity and persistence of the side effects, the dose may be lowered or temporarily interrupted, at the discretion of the physician.

Most injection site reactions are mild to moderate. Rare cases of skin ulceration/necrosis at the site of injection have been reported with long-term treatment.

The most frequently reported adverse events and the most common laboratory abnormalities observed during the placebo-controlled study in relapsing-remitting multiple sclerosis (560 patients, 2 years’ treatment) are presented for patients on placebo and interferon beta-1a. The frequencies are patients who reported this event at least once during the study, as a percentage of the total number of patients, by study-arm.

The adverse events experienced during the study are listed below, by WHOART System Organ Class. The most common amongst the injection site reactions was in the form of mild erythema. The majority of the other injection site reactions were also mild in the 2 interferon beta-1a groups. Necrosis was reported in 8 patients treated with interferon beta-1a. Two of these patients were in the 66 µg weekly and 6 in the 132 µg weekly groups. All patients completed the planned treatment period, with only 1 requiring temporary dose reductions and another patient stopping treatment for 2 weeks. Those that required treatment, received antibiotics.

In addition to the above listed adverse events, the following events have been experienced less frequently, in one or both of the relapsing-remitting multiple sclerosis studies: asthenia, fluid retention, anorexia, gastroenteritis, heartburn, paradentium affections, dental abscess or extraction, stomatitis, glossitis, sleepiness, anxiety, irritability, confusion, lymphadenopathy, weight gain, bone fracture, dyspnea, cold sores, fissure at the angle of the mouth, menstrual disorders, cystitis and vaginitis.

Other adverse events were experienced by less than 5% of the patients, and included eye pain, skin disorder, rhinitis, bronchitis, coughing, diarrhea, abdominal pain, postural hypotension, palpitation, vasodilatation, rectal disorder, lymphocytosis, thrombocytopenia, delirium, somnolence, joint pain, joint stiffness, lightheadedness, paresthesia distal, disorientation, irritability, sleeplessness, lethargy, bruise, purpura, sweating increased, shortness of breath, upper respiratory tract infection, tachycardia, flushing, urethral pain, infection, chest pain, lymphadenopathy, PBI increased, arthralgia, dizziness, nervousness, tremor, abnormal vision, vulvovaginal disease, balanitis, penis disease, testis disease, urethritis, infection urinary tract, vaginitis, leukopenia, herpes simplex, pruritus, rash mac pap, skin neoplasia and rash.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: No case of overdose has thus far been described. However, in case of overdosage, patients should be hospitalized for observation and appropriate supportive treatment should be given.

Dosage And Administration: Relapsing-remitting Multiple Sclerosis: The recommended dosage of interferon beta-1a is 22 µg (6 MIU) given 3 times per week by s.c. injection. This dose is effective in the majority of patients to delay progression of the disease. Patients with a higher degree of disability (an EDSS of 4 or higher) may require a dose of 44 µg (12 MIU) 3 times per week.

Treatment should be initiated under supervision of a physician experienced in the treatment of the disease. When first starting treatment with interferon beta-1a, in order to allow tachyphylaxis to develop thus reducing adverse events, it is recommended that 20% of the total dose be administered during the initial 2 weeks of therapy, 50% of total dose be administered in week 3 and 4, and the full dose from the fifth week onwards.

At the present time, it is not known for how long patients should be treated. Safety and efficacy with interferon beta-1a have been demonstrated following 2 years of treatment. Therefore, it is recommended that patients should be evaluated after 2 years of treatment with interferon beta-1a and a decision for longer-term treatment be made on an individual basis by the treating physician.

Preparation of Solution: Lyophilized Formulation (Relapsing-remitting Multiple Sclerosis): Reconstitute the contents of a vial of interferon beta-1a with 0.5 mL of the accompanying sterile diluent. The reconstituted solution should be used immediately.

Liquid Formulation: The liquid formulation in a prefilled syringe is ready for use. These syringes are graduated to facilitate therapy initiation. The prefilled syringes contain 22 µg and 44 µg of interferon beta-1a respectively. The prefilled syringes are ready for s.c. use only.

Condyloma Acuminatum: The recommended dosage is 3.67 µg (1 MIU) per lesion 3 times per week for 3 weeks. The recommended route of administration is intra- or peri-lesional. The prefilled syringes are not to be used for this indication.

Preparation of Solution: Lyophilized Formulation (Condyloma Acuminatum): Reconstitute the contents of a vial of interferon beta-1a in sterile diluent in order to obtain a final concentration of 1 MIU per 0.1 mL solution. The reconstituted solution should be used immediately.

SuppliedSupplied: Rebif is a purified, sterile glycoprotein product produced by recombinant DNA techniques and formulated for use by injection. The active ingredient is produced by genetically engineered Chinese Hamster Ovary (CHO) cells. Interferon beta-1a is a highly purified glycoprotein that has 166 amino acids and an approximate molecular weight of 22 500 daltons. It contains a single N-linked carbohydrate moiety attached to Asn-80 similar to that of natural human interferon beta.

The specific activity of Rebif is approximately 0.27 million international units (MIU)/µg interferon beta-1a. The unit measurement is derived by comparing the antiviral activity of the product to an in-house natural hIFN-b NIH standard that is obtained from human fibroblasts (BILS 11), which has been calibrated against the NIH natural hIFN-b standard (GB 23-902-531).

Liquid: Each prefilled syringe with 0.5 mL of solution contains: interferon beta-1a 22 µg (6 MIU) or 44 µg (12 MIU). Nonmedicinal ingredients: albumin (human), mannitol and sodium acetate buffer. Preservative-free. Packs of 1, 3 and 12. Refer to the date indicated on the labels for the expiry date. Liquid in a prefilled syringe should be stored at 2 to 8°C. Do not freeze.

Lyophilized Powder: Each 3 mL of sterile, lyophilized powder contains: interferon beta-1a, 11 µg (3 MIU) or 44 µg (12 MIU). Nonmedicinal ingredients: albumin (human), mannitol and sodium acetate and sodium hydroxide. Each ampul of diluent contains: 2 mL of NaCl 0.9% in water for injection. Preservative-free. Cartons of 1, 3 and 12 with ampuls of diluent. Refer to the date indicated on the labels for the expiry date. Store at 2 to 8°C. The reconstituted solution should be administered immediately. Although not recommended, it may be used later during the day of reconstitution if stored in a refrigerator (2 to 8°C). Do not freeze. The reconstituted solution may have a yellow coloration which is a normal product characteristic.

REBIF™ Serono Interferon beta-1a Immunomodulator

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Multiple Sclerosis

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