Rebif

Interferon-β_1a.

Each 0.5-mL pre-filled syringe contains 22 mcg (6 MIU) or 44 mcg (12 MIU) of interferon-β_1a.

Pharmacotherapeutic Group: Cytokines. ATC Code: L03AB.
Pharmacology: Pharmacodynamics: Interferons (IFNs) are a group of endogenous glycoproteins endowed with immunomodulatory, antiviral and antiproliferative properties.
Rebif (interferon-β_1a) is composed of the native amino acid sequence of natural human interferon-β. It is produced in mammalian cells (Chinese hamster ovary) and is therefore glycosylated like the natural protein.
The precise mechanism of action of Rebif in multiple sclerosis is still under investigation.
The safety and efficacy of Rebif have been evaluated in patients with relapsing-remitting multiple sclerosis at doses ranging from 11-44 mcg (3-12 MIU) administered SC 3 times/week. At licensed posology, Rebif has been demonstrated to decrease the incidence (approximately 30% over 2 years) and severity of clinical relapses in patients with at least 2 exacerbations in the previous 2 years and with an expaned disability status state (EDSS) of 0-5 at entry. The proportion of patients with disability progression, as defined by at least 1 point increase in EDSS confirmed 3 months later, was reduced from 39% (placebo) to 30% (Rebif 22 mcg) and 27% (Rebif 44 mcg). Over 4 years, the reduction in the mean exacerbation rate was 22% in patients treated with Rebif 22 mcg and 29% in patients treated with Rebif 44 mcg compared with a group of patients treated with placebo for 2 years and then either Rebif 22 or 44 mcg for 2 years.
In a 3-year study in patients with secondary progressive multiple sclerosis (EDSS 3-6.5) with evidence of clinical progression in the preceding 2 years and who had not experienced relapses in the preceding 8 weeks, Rebif had no significant effect on progression of disability but relapse rate was reduced by approximately 30%. The patient population was divided into 2 subgroups (those with and those without relapses in the 2-year period prior to study entry). There was no effect on disability in patients without relapses, but in patients with relapses, the proportion with progression in disability at the end of the study was reduced from 70% (placebo) to 57% (Rebif 22 and 44 mcg combined). These results obtained in a subgroup of patients, a posteriori, should be interpreted cautiously.
Rebif has not yet been investigated in patients with primary progressive multiple sclerosis, and should not be used in such patient.
Pharmacokinetics: In healthy volunteers after IV administration, interferon-β_1a exhibits a sharp multiexponential decline with serum levels proportional to the dose. The initial half-life is in the order of min and the terminal half-life is several hrs, with the possible presence of a deep compartment. When administered by the SC or IM routes, serum levels of interferon-β remain low, but are still measurable up to 12-24 hrs post-dose. SC and IM administrations of Rebif produce equivalent exposure to interferon-β. Following a single 60-mcg dose, the maximum peak concentration, as measured by immunoassay, is around 6-10 IU/mL, occurring on average of around 3 hrs after the dose. After SC administration at the same dose repeated every 48 hrs for 4 doses, a moderate accumulation occurs [about 2.5 times for area under the curve (AUC)].
Regardless of the route of dosing, pronounced pharmacodynamic changes are associated with the administration of Rebif. After a single dose, intracellular and serum activity of 2-5A synthetase and serum concentrations of β₂-microglobulin and neopterin increase within 24 hrs, and start to decline within 2 days. IM and SC administrations produce fully superimposable responses. After repeated SC administration every 48 hrs for 4 doses, these biological responses remain elevated, with no signs of tolerance development.
Interferon-β_1a is mainly metabolised and excreted by the liver and by the kidneys.
Toxicology: Preclinical Safety Data: Nonclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated-dose toxicity, and genotoxicity.
Rebif has not been investigated for carcinogenicity.
A study on embryo/foetal toxicity in monkeys showed no evidence of reproductive disturbances. Based on observations with other α- and β-interferons, an increased risk of abortions cannot be excluded. No information is available on the effects of the interferon-β_1a on male fertility.

Treatment of relapsing multiple sclerosis.
In clinical trials, this was characterised by ≥2 acute exacerbations in the previous 2 years (see Pharmacology under Actions).
Rebif is not indicated in secondary progressive multiple sclerosis patients who no longer experience relapses.

Rebif is available in 2 strengths: 22 and 44 mcg.
Recommended Dose: 44 mcg given 3 times weekly by SC injection. Rebif 22 mcg is also given 3 times weekly by SC injection for patients who cannot tolerate the higher dose in view of the treating specialist.
Treatment should be initiated under the supervision of a physician experienced in the treatment of the disease.
When starting treatment with Rebif, it is recommended that the dose be gradually increased in order to allow development of tachyphylaxis; thus, reducing the risk of adverse reactions. It is recommended that 20% of the total dose be administered during the first 2 weeks of therapy; 50% of the total dose be administered in the 3rd and 4th weeks; and the full dose be administered from the 5th week and onwards.
Children and Adolescents: No formal clinical trials or pharmacokinetic studies have been conducted in children or adolescents. However, limited published data suggest that the safety profile in adolescents from 12-16 years receiving Rebif 22 mcg SC 3 times weekly is similar to that seen in adults. There is very limited information on the use of Rebif in children <12 years; therefore, Rebif should not be used in this population.
Prior to injection and for an additional 24 hrs after each injection, an antipyretic-analgesic is advised to decrease flu-like symptoms associated with Rebif administration.
At the present time, it is not known for how long patients should be treated. Safety and efficacy with Rebif have not been demonstrated beyond 4 years of treatment. It is recommended that patients should be evaluated at least every 2nd year in the 4-year period after initiation of treatment with Rebif, and a decision for long-term treatment should then be made on an individual basis by the treating physician.

In case of overdosage, patients should be hospitalized for observation and appropriate supportive treatment should be given.

History of hypersensitivity to natural or recombinant interferon-β, or to any of the excipients of Rebif.
Patients currently with severe depression and/or suicidal ideation (see Precautions and Adverse Reactions).

Patients should be informed of the most common adverse reactions associated with interferon-β administration; including symptoms of the flu-like syndrome (see Adverse Reactions). These symptoms tend to be most prominent at the initiation of therapy and decrease in frequency and severity with continued treatment.
Rebif should be administered with caution to patients with previous or current depressive disorders in particular to those with antecedents of suicidal ideation (see Contraindications). Depression and suicidal ideation are known to occur in increased frequency in the multiple sclerosis population and in association with interferon use. Patients treated with Rebif should be advised to immediately report any symptoms of depression and/or suicidal ideation to their prescribing physician. Patients exhibiting depression should be monitored closely during therapy with Rebif and treated appropriately. Cessation of therapy with Rebif should be considered (see Contraindications and Adverse Reactions).
Rebif should be administered with caution to patients with history of seizures and to those receiving treatment with antiepileptics particularly if their epilepsy is not adequately controlled with antiepileptics (see Adverse Reactions and Interactions).
Patients with cardiac disease eg, angina, congestive heart failure or arrhythmia should be closely monitored for worsening of their clinical condition during initiation of therapy with interferon-β_1a. Symptoms of the flu-like syndrome associated with interferon-β_1a therapy may prove stressful to patients with cardiac conditions.
Injection site necrosis (ISN) has been reported in patients using Rebif (see Adverse Reactions). To minimize the risk of ISN, patients should be advised to: Use an aseptic injection technique; rotate the injection sites with each dose.
The procedure for the self-administration by the patient should be reviewed periodically especially if injection site reactions have occurred.
If the patient experiences any break in the skin which may be associated with swelling or drainage of fluid from the injection site, the patient should be advised to consult with their physician before continuing injections with Rebif. If the patient has multiple lesions, Rebif should be discontinued until healing has occurred. Patients with single lesions may continue provided that the necrosis is not too extensive.
In clinical trials with Rebif, asymptomatic elevations of hepatic transaminases [particularly alanine aminotransferase (ALT)] were common and 1-3% of patients developed elevations of hepatic transaminases >5 times the upper limit of normal (ULN). In the absence of clinical symptoms, serum ALT levels should be monitored prior to the start of therapy, at months 1, 3 and 6 on therapy and periodically thereafter. Dose reduction of Rebif should be considered if ALT rises >5 times the ULN, and gradually re-escalated when enzyme levels have normalized. Rebif should be initiated with caution in patients with history of significant liver disease, clinical evidence of active liver disease, alcohol abuse or increased serum ALT (>2.5 times ULN). Treatment with Rebif should be stopped if icterus or other clinical symptoms of liver dysfunction appear (see Adverse Reactions).
Rebif, like other interferon-β, has a potential for causing severe liver injury (see Adverse Reactions) including acute hepatic failure. The mechanism for the rare symptomatic hepatic dysfunction is not known. No specific risk factors have been identified.
Laboratory abnormalities are associated with the use of interferons. Therefore, in addition to those laboratory tests normally required for monitoring patients with multiple sclerosis, liver enzyme monitoring and complete and differential blood cell counts and platelet counts are recommended at regular intervals (1, 3 and 6 months) following introduction of Rebif therapy and then periodically thereafter in the absence of clinical symptoms. These should be more frequent when initiating Rebif 44 mcg.
Patients being treated with Rebif may occasionally develop new or worsening thyroid abnormalities. Thyroid function testing is recommended at baseline and if abnormal, every 6-12 months following initiation of therapy. If tests are normal at baseline, routine testing is not needed but should be performed if clinical findings of thyroid dysfunction appear (see Adverse Reactions).
Caution should be used, and close monitoring be considered when administering interferon-β_1a to patients with severe renal and hepatic failure and to patients with severe myelosuppression.
Serum neutralising antibodies against interferon-β_1a may develop. The precise incidence of antibodies is uncertain yet. Clinical data suggest that after 24-48 months of treatment with Rebif 22 and 44 mcg, approximately 24% and 13-14% of patients, respectively, develop persistent serum antibodies to interferon-β_1a. The presence of antibodies has been shown to attenuate the pharmacodynamic response to interferon-β_1a (β₂-microglobulin and neopterin). Although the clinical significance of the induction of antibodies has not been fully elucidated, the development of neutralising antibodies is associated with reduced efficacy on clinical and MRI variables. If a patient responds poorly to Rebif therapy, and has neutralising antibodies, the treating physician should reassess the benefit/risk ratio of continued Rebif therapy.
The use of various assays to detect serum antibodies and differing definitions of antibody positivity limits the ability to compare antigenicity among different products.
Only sparse safety and efficacy data are available from non-ambulatory patients with multiple sclerosis.
Effects on the Ability to Drive or Operate Machinery: Less commonly reported central nervous system-related adverse events associated with the use of interferon beta might influence the patient's ability to drive or use machines (see Adverse Reactions).
Use in pregnancy: There is limited information on the use of Rebif in pregnancy. Available data indicates that there may be an increased risk of spontaneous abortion. Initiation of treatment is contraindicated during pregnancy.
Women of childbearing potential should take appropriate contraceptive measures. If the patient becomes pregnant or plans to become pregnant while taking Rebif, she should be informed of the potential hazards, and discontinuation of therapy should be considered (see Toxicology under Actions). The risk of a severe relapse following discontinuation of Rebif in the event of pregnancy should be weighed against a possible increased risk of spontaneous abortion in patients with a high relapse rate before the initiation of treatment.
Use in lactation: It is not known whether Rebif is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue breastfeeding or Rebif therapy.

Use in pregnancy: There is limited information on the use of Rebif in pregnancy. Available data indicates that there may be an increased risk of spontaneous abortion. Initiation of treatment is contraindicated during pregnancy.
Women of childbearing potential should take appropriate contraceptive measures. If the patient becomes pregnant or plans to become pregnant while taking Rebif, she should be informed of the potential hazards, and discontinuation of therapy should be considered (see Toxicology under Actions). The risk of a severe relapse following discontinuation of Rebif in the event of pregnancy should be weighed against a possible increased risk of spontaneous abortion in patients with a high relapse rate before the initiation of treatment.
Use in lactation: It is not known whether Rebif is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue breastfeeding or Rebif therapy.

General Description: The highest incidence of adverse reactions associated with Rebif therapy is related to flu-like syndrome. Flu-like symptoms tend to be most prominent at the initiation of therapy and decrease in frequency with continued treatment. Approximately 70% of patients treated with Rebif can expect to experience the typical interferon flu-like syndrome within the first 6 months after starting treatment. Approximately 30% of patients will also experience reactions at the injection site, predominantly mild inflammation or erythema. Asymptomatic increases in laboratory parameters of hepatic function and decreases in WBC are also common.
The majority of adverse reactions observed with interferon-β_1a are usually mild and reversible, and respond well to dose reductions.
In case of severe or persistent undesirable effects, the dose of Rebif may be temporarily lowered or interrupted at the discretion of the physician.
Adverse Reactions by Frequency: The adverse reactions reported as follows are classified according to frequency of occurrence as follows: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10,000 to <1/1000); very rare (<1/10,000). Within each frequency grouping, adverse reactions are presented in order of decreasing severity.
Infections and Infestations: Uncommon: Injection site abscess. Not Known*: Injection site infections, including cellulitis.
Blood and Lymphatic System Disorders: Very Common: Neutropenia, lymphopenia, leucopenia, thrombocytopenia, anaemia. Not Known*: Thrombotic thrombocytopenic purpura/haemolytic uremic syndrome.
Immune System Disorders: Not Known*: Anaphylactic reactions.
Endocrine Disorders: Uncommon: Thyroid dysfunction most often presenting as hypothyroidism or hyperthyroidism.
Psychiatric Disorders: Common: Depression, insomnia. Not Known*: Suicide attempt.
Nervous System Disorders: Very Common: Headache. Not Known*: Seizures, transient neurological symptoms (ie, hypoesthesia, muscle spasm, paraesthesia, difficulty in walking, musculoskeletal stiffness) that may mimic multiple sclerosis exacerbations.
Eye Disorders: Not Known*: Retinal vascular disorders (eg, retinopathy, cotton wool spots and obstruction of retinal artery or vein).
Vascular Disorders: Not Known*: Thromboembolic events.
Respiratory, Thoracic and Mediastinal Disorders: Not Known*: Dyspnoea.
Gastrointestinal Disorders: Common: Diarrhoea, vomiting, nausea.
Hepatobiliary Disorders: Not Known*: Hepatic failure, hepatitis with or without icterus.
Skin and Subcutaneous Tissue Disorders: Common: Pruritus, rash, erythematous rash, maculopapular rash. Not Known*: Angioedema, urticaria, erythema multiforme, erythema multiforme-like skin reactions, Stevens-Johnson syndrome, alopecia.
Musculoskeletal and Connective Tissue Disorders: Common: Myalgia, arthralgia.
General Disorders and Administration Site Conditions: Very Common: Injection site inflammation, injection site reaction, influenza-like symptoms. Common: Injection site pain, fatigue, rigors, fever. Uncommon: Injection site necrosis, injection site mass.
Investigations: Very Common: Increased asymptomatic transaminase. Common: Severe elevations of transaminase.
*Adverse reactions identified during post-marketing surveillance (frequency not known).
Information Characterizing Individual Serious and/or Frequently Occurring Adverse Reactions: Rebif, like other interferons β, has a potential for causing severe liver injury. The mechanism for the rare symptomatic hepatic dysfunction is not known. The majority of the cases of severe liver injury occurred within the first 6 months of treatment. No specific risk factors have been identified. Treatment with Rebif should be stopped if icterus or other clinical symptoms of liver dysfunction appear (see Precautions).
Adverse Reactions that Apply to the Pharmacological Class: The administration of interferons has been associated with anorexia, dizziness, anxiety, arrythmias, vasodilation and palpitation, menorrhagia and metrorrhagia.
An increased formation of autoantibodies may occur during treatment with interferon-β.

No drug interactions studies have been conducted with Rebif (interferon-β_1a) in humans.Interferons have been reported to reduce the activity of hepatic CYP450-dependent enzymes in humans and animals. Caution should be exercised when administering Rebif in combination with medicinal products that have a narrow therapeutic index and are largely dependent on the hepatic CYP450 system for clearance eg, antiepileptics and some classes of antidepressants.
The interaction of Rebif with corticosteroids or adrenocorticotropic hormones (ACTH) has not been studied systematically. Clinical studies indicate that multiple sclerosis patients can receive Rebif and corticosteroids or ACTH during relapses.
Incompatibilities: Not applicable.

Instruction for Use, Handling and Disposal: The solution for injection in a pre-filled syringe is ready for use. It may also be administered with a suitable auto-injector.
Any unused product or waste material should be disposed of in accordance with local requirements.
For single-use only.
Only clear to opalescent solution without particles and without visible signs of deterioration should be used.

Store at 2°-8°C. Do not freeze. Protect from light.

Vaccines, Antisera & Immunologicals

L03AB07 - interferon beta-1a ; Belongs to the class of interferons. Used as immunostimulants.

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