Rebif

/ Merck

When first starting treatment with this drug the dose should be gradually escalated in order to allow tachyphylaxis to develop thus reducing adverse reactions. It is recommended that patients be started according to the doctor recommended dose subcutaneously. When first starting treatment it is recommended that 8.8 micrograms be administered by subcutaneous injection three times per week during the initial 2 weeks of therapy. Thereafter, 22 micrograms be administered by subcutaneous injection three times per week in weeks 3 and 4, and the total of the 44 micrograms strength be administered from the fifth week onwards.
First demyelinating event: The posology for patients who have experienced a first demyelinating event is 44 micrograms given three times per week by subcutaneous injection.
Relapsing multiple sclerosis: The recommended posology is 44 micrograms given three times per week by subcutaneous injection. The 22 micrograms product, also given three times per week by subcutaneous injection, is recommended for patients who cannot tolerate the higher dose in view of the treating specialist.
Paediatric population: No formal clinical trials or pharmacokinetic studies have been conducted in children or adolescents. However, a paediatric retrospective cohort study collected safety data with this drug from medical records in children (n=52) and adolescents (n=255). The results of this study suggest that the safety profile in children (2 to 11 years old) and in adolescents (12 to 17 years old) receiving the 22 micrograms or 44 micrograms subcutaneous products three times per week is similar to that seen in adults.
The safety and efficacy in children below 2 years of age have not yet been established. This medicinal product should not be used in this age group.
Method of administration: This medicinal product is administered by subcutaneous injection, in a pre-filled-syringe or in cartridge. Prior to injection and for an additional 24 hours after each injection, an antipyretic analgesic is advised to decrease flu-like symptoms associated with the drug administration.
The solution for subcutaneous injection in cartridge is intended for multidose use with RebiSmart electronic injection device following adequate training of the patient and/or carer.
For administration, the instructions provided in the package leaflet and in the instruction manual provided with RebiSmart autoinjector should be followed.
At the present time, it is not known for how long patients should be treated. Safety and efficacy have not been demonstrated beyond 4 years of treatment. It is recommended that patients should be evaluated at least every second year in the 4-year period after initiation of treatment with this drug and a decision for longer term treatment should then be made on an individual basis by the treating physician.

• The 22/44 mcg products is indicated for the treatment of patients with relapsing forms of multiple sclerosis to decrease the frequency of clinical exacerbations and delay the accumulation of physical disability. Efficacy in chronic progressive multiple sclerosis has not been established.
• The 44 mcg product is indicated for the treatment of patients with a single demyelinating event with an active inflammatory process, if alternative diagnoses have been excluded, and if they are determined to be at high risk of developing clinically definite multiple sclerosis. These patients should have MRI findings which are compatible with the diagnosis of multiple sclerosis.
Efficacy has not been demonstrated in patients with secondary progressive multiple sclerosis without ongoing relapse activity.

• Hypersensitivity to natural or recombinant interferon beta or to any excipients.
• Current severe depression and/or suicidal ideation.

Traceability: In order to imporve the traceabilty of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.
General recommendations: Patients should be informed of the most frequent adverse reactions associated with interferon beta administration, including symptoms of the flu-like syndrome. These symptoms tend to be most prominent at the initiation of therapy and decrease in frequency and severity with continued treatment.
Thrombotic microangiopathy (TMA): Cases of thrombotic microangiopathy, manifested as thrombotic thrombocytopenic purpura (TTP) or haemolytic uraemic syndrome (HUS), including fatal cases, have been reported with interferon beta products. Events were reported at various time points during treatment and may occur several weeks to several years after starting treatment with interferon beta. Early clinical features include thrombocytopenia, new onset hypertension, fever, central nervous system symptoms (e.g. confusion, paresis) and impaired renal function. Laboratory findings suggestive of TMA include decreased platelet counts, increased serum lactate dehydrogenase (LDH) due to haemolysis and schistocytes (erythrocyte fragmentation) on a blood film. Therefore if clinical features of TMA are observed, further testing of blood platelet levels, serum LDH, blood films and renal function is recommended. If TMA is diagnosed, prompt treatment is required (considering plasma exchange) and immediate discontinuation of this drug is recommended.
Depression and suicidal ideation: The drug should be administered with caution to patients with previous or current depressive disorders in particular to those with antecedents of suicidal ideation. 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 this drug 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 this drug and treated appropriately. Cessation of therapy with this drug should be considered.
Seizure disorders: This medicinal product should be administered with caution to patients with a history of seizures, to those receiving treatment with anti-epileptics, particularly if their epilepsy is not adequately controlled with anti-epileptics.
Cardiac disease: Patients with cardiac disease, such as angina, congestive heart failure or arrhythmia, should be closely monitored for worsening of their clinical condition during initiation of therapy with interferon beta-1a. Symptoms of the flu-like syndrome associated with Interferon beta-1a therapy may prove stressful to patients with cardiac conditions.
Injection site necrosis: Injection site necrosis (ISN) has been reported in patients using this drug. To minimise the risk of injection site necrosis 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 this drug. If the patient has multiple lesions, this drug should be discontinued until healing has occurred. Patients with single lesions may continue provided that the necrosis is not too extensive.
Hepatic dysfunction: In clinical trials, asymptomatic elevations of hepatic transaminases (particularly alanine aminotransferase (ALT)) were common and 1-3% of patients developed elevations of hepatic transaminases above 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 should be considered if ALT rises above 5 times the ULN, and gradually re-escalated when enzyme levels have normalized. This medicinal product should be initiated with caution in patients with a history of significant liver disease, clinical evidence of active liver disease, alcohol abuse or increased serum ALT (>2.5 times ULN). Treatment with this drug should be stopped if icterus or other clinical symptoms of liver dysfunction appear.
This medicinal product, like other interferons beta, has a potential for causing severe liver injury including acute hepatic failure. The majority of the cases of severe liver injury occurred within the first six months of treatment. The mechanism for the rare symptomatic hepatic dysfunction is not known. No specific risk factors have been identified.
Renal and urinary disorders: Nephrotic syndrome:Cases of nephrotic syndrome with different underlying nephropathies including collapsing focal segmental glomerulosclerosis (FSGS), minimal change disease (MCD), membranoproliferative glomerulonephritis (MPGN) and membranous glomerulopathy (MGN) have been reported during treatment with interferon-beta products. Events were reported at various time points during treatment and may occur after several years of treatment with interferon-beta. Periodic monitoring of early signs or symptoms, e.g. oedema, proteinuria and impaired renal function is recommended, especially in patients at higher risk of renal disease. Prompt treatment of nephrotic syndrome is required and discontinuation of treatment with this drug should be considered.
Laboratory abnormalities: Laboratory abnormalities are associated with the use of interferons. The overall incidence of these is slightly higher with the 44 mcg product than the 22 mcg product. Therefore, in addition to those laboratory tests normally required for monitoring patients with multiple sclerosis, liver enzyme monitoring and complete and differential blood cell count, and platelet counts are recommended at regular intervals (1, 3 and 6 months) following introduction of therapy and then periodically thereafter in the absence of clinical symptoms. These should be more frequent when initiating the 44 micrograms product.
Thyroid disorders: Patients being treated with this drug 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.
Severe renal or hepatic failure and severe Myelosuppression: Caution should be used, and close monitoring considered when administering interferon beta-1a to patients with severe renal and hepatic failure and to patients with severe myelosuppression.
Neutralising antibodies: Serum neutralising antibodies against interferon beta-1a may develop. The precise incidence of antibodies is as yet uncertain. Clinical data suggest that after 24 to 48 months of treatment with the 22 micrograms product, approximately 24% of patients develop persistent serum antibodies to interferon beta-1a, with the 44 micrograms product, approximately 13 to 14% of patients develop persistent serum antibodies to interferon beta-1a. The presence of antibodies has been shown to attenuate the pharmacodynamic response to interferon beta-1a (beta-2 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 therapy with this drug, and has neutralising antibodies, the treating physician should reassess the benefit/risk ratio of continued interferon beta-1a 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.
Other forms of multiple sclerosis: Only sparse safety and efficacy data are available from non-ambulatory patients with multiple sclerosis. This medicinal product has not yet been investigated in patients with primary progressive multiple sclerosis and should not be used in these patients.
Excipients:
Sodium content: This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. it is essentially ‘sodium-free’.
Benzyl alcohol: This medicinal product contains benzyl alcohol per dose of 0.5 mL. Benzyl alcohol may cause toxic reactions and anaphylactoid reactions in infants and children up to 3 years old. Monitor patients less than 3 years of age for respiratory symptoms. Advise patients who are pregnant or breastfeeding of the potential risk from excipient benzyl alcohol, which might accumulate over time and cause metabolic acidosis. Use with caution in patients with hepatic or renal impairment, because of the potential risk from excipient benzyl alcohol which might accumulate over time and cause metabolic acidosis.

Blood and the lymphatic system disorders: Very common: Neutropenia, lymphopenia, leukopenia, thrombocytopenia, anaemia.
Hepatobiliary disorders: Very common: Asymptomatic transaminase increase. Common: Severe elevations in transaminases.
Psychiatric disorders: Common: Depression, insomnia.
Nervous system disorders: Very common: Headache.
Gastrointestinal disorders: Common: Diarrhoea, vomiting, nausea.
Skin and subcutaneous tissue disorders: Common: Pruritus, rash, erythematous rash, maculo-papular rash, alopecia.
Musculoskeletal and connective 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. for full details see prescribing information.

No interaction studies have been performed with Rebif (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 Rebif 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 Rebif with corticosteroids or ACTH has not been studied systematically. Clinical studies indicate that multiple sclerosis patients can receive Rebif and corticosteroids or ACTH during relapses.

Pregnancy
A large amount of data (more than 1,000 pregnancy outcomes) from registries and post-marketing experience indicates no increased risk of major congenital anomalies after pre-conception exposure to interferon beta or such exposure during the first trimester of pregnancy. However, the duration of exposure during the first trimester is uncertain, because data were collected when interferon beta use was contraindicated during pregnancy, and treatment likely interrupted when the pregnancy was detected and/or confirmed. Experience with exposure during the second and third trimester is very limited.
Based on animal data, there is a possibly increased risk for spontaneous abortion. The risk of spontaneous abortions in pregnant women exposed to interferon beta cannot adequately be evaluated based on the currently available data, but the data do not suggest an increased risk so far.
If clinically needed, the use of this drug may be considered during pregnancy.
Breast-feeding
Limited information available on the transfer of interferon beta-1a into breast milk, together with the chemical/physiological characteristics of interferon beta, suggests that levels of interferon beta-1a excreted in human milk are negligible. No harmful effects on the breastfed newborn/infant are anticipated.
This medicinal product can be used during breast-feeding.

In case of overdose, patients should be hospitalised for observation and appropriate supportive treatment should be given.