Rebif 44 mcg

The liquid formulation in a pre-filled cartridge is ready for use with the RebiSmart autoinjection device. For administration, follow the instructions given in the package leaflet and in the instructions manual which is provided with each RebiSmart autoinjection device. The pre-filled cartridge that contains 66 µg/1.5 mL is designed to deliver three doses of 22 µg/0.5 mL and the pre-filled cartridge that contains 132 µg/1.5 mL is designed to deliver three doses of 44 µg/0.5 mL of REBIF. The pre-filled cartridges are for subcutaneous use only.

The recommended dose is 44 µg given 3 times per week by subcutaneous injection. The dose can be reduced to 22 µg tiw if the patient is not able to tolerate the higher dose.

Treatment should be initiated under supervision of a physician experienced in the treatment of the disease. When first starting treatment with REBIF, 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.

Please also review the Warnings and Precautions section and ensure appropriate monitoring of patients with depression, hepatic dysfunction, a history of seizures, cardiac disease, renal dysfunction, thyroid dysfunction, myelosuppression, and female patients of child-bearing potential.

At the present time, it is not known for how long patients should be treated. Safety and efficacy with REBIF have been demonstrated following 4 years of treatment. Therefore, it is recommended that patients should be evaluated after 4 years of treatment with REBIF and a decision for longer-term treatment be made on an individual basis by the treating physician.

The liquid formulation in a pre-filled syringe is ready for use. These syringes are graduated to facilitate therapy initiation. The pre-filled syringes contain 8.8 µg, 22 µg and 44 µg of REBIF New HSA-free Formulation respectively. The pre-filled syringes are ready for subcutaneous use only.

Before initiating a patient on REBIF therapy, please review completely the Contraindications.

Patients should be advised of REBIF side-effects and instructed on the use of aseptic technique when administering REBIF. The REBIF Patient Leaflet should be carefully reviewed with all patients, and patients should be educated on self-care and advised to keep the Leaflet for continued reference during REBIF therapy.

Should a dose be missed, the patient should be advised to continue to inject from the day of the next scheduled dose. The patient should not take a double dose to make up for the missed dose.

The vast majority of the adverse reactions of REBIF in multiple sclerosis have been identified from the clinical trials and are summarized in the above placebo-controlled study tables. The adverse reactions reported with marketed use of REBIF that are not already mentioned in the clinical study tables are shown below. These reactions have been identified during post-marketing surveillance and their exact frequency is unknown.

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

injection site necrosis.

seizures, transient neurological symptoms (i.e. hypoesthesia, muscle spasm, paresthesia, difficulty in walking, musculoskeletal stiffness) that may mimic multiple sclerosis exacerbations.

angioedema (Quincke’s edema), urticaria, erythema multiforme, erythema multiforme-like skin reactions, hair loss, Stevens-Johnson Syndrome.

injection site infections, including cellulitis which could be severe and injection site abscesses.

In Study GF7480, adverse events were reported more frequently in patients assigned REBIF than in those assigned placebo. These events included injection-site inflammation (60% vs 12%), fever (28% vs 12%), myalgia (17% vs 9%) and chills (11% vs 5%). Serious adverse events were reported in five patients in the placebo group and six in the interferon beta-1a group.

hepatitis with or without icterus.

thromboembolic events.

The most common adverse reactions which can occur during REBIF therapy are mild to moderate flu-like symptoms, injection site reactions, reduction in white blood cell count and elevation of liver enzymes. Depending on the severity and persistence of the reactions, the dose may be lowered or temporarily interrupted, at the discretion of the physician.

Less common reactions include erythematous skin rash with pruritus, anemia, depression and thyroid dysfunction. Uncommonly, cases of infection and skin ulceration/necrosis at the site of injection have been reported with long term treatment (see Warnings and Precautions, Information to Be Provided to the Patient).

Serious adverse hepatic reactions such as hepatitis, with or without jaundice, have been rarely (≤1/1000 to ≥1/10 000) reported and isolated cases of acute hepatic failure have been reported (see Warnings and Precautions).

Thyroid dysfunction, may present as hypothyroidism or hyperthyroidism, is generally transient and mild, and may occur during the first year of treatment, particularly in patients with pre-existing thyroiditis (see Warnings and Precautions, Monitoring and Laboratory Tests).

Anaphylaxis has very rarely (≤1/10 000) been observed with the use of REBIF (see Warnings and Precautions).

anaphylactic reaction.

suicide attempt.

Asymptomatic laboratory abnormalities were reported frequently with interferon dosing over the 4 years. Of the abnormalities noted, the cytopenias and abnormalities of liver function showed dose-related differences. Lymphopenia occurred in 35% of high dose patients and 27% of low dose patients. Thrombocytopenia was seen in 2.6% of patients on low dose, and 8.2% of patients on high dose. Differences in the frequency of abnormal liver enzymes were seen which included elevated ALT (24% for low dose vs. 30% for high dose, p=0.07) and elevated AST (11% vs. 20%, p=0.03). Severe elevations are uncommon and not different between dose groups. These data suggest that there is only minimal evidence of significant dose-dependent lab abnormalities with interferon therapy in MS patients.

After 4 years of therapy, 23.7% of the low dose and 14.3% of the high-dose patients had developed persistent neutralising antibodies (p=0.024, 44 µg vs. 22 µg), the vast majority of which (91%) developed within 24 months. The lower incidence in the high dose group may be due to the phenomenon of high-zone tolerance. While continuing interferon treatment, 20.0% of low-dose NAb+ patients reverted, while 25.7% of high-dose NAb+ patients reverted. The neutralising antibodies were associated with reduced clinical efficacy during years 3 and 4 and reduced MRI efficacy over 4 years.

The safety and tolerability of the New HSA-free Formulation of interferon beta-1a was compared to the previously marketed HSA- and FBS-containing formulation of REBIF as a secondary objective of the study. Both formulations were well tolerated when administered in subcutaneous doses of 44 μg in this study. There were no deaths or SAEs. All subjects who were administered with either study drug experienced mild Treatment Emergent Adverse Events (TEAEs). Of those TEAEs reported, 59.3% and 65.7% were probably related to the administration of the previously marketed REBIF formulation and the New HSA-free Formulation of interferon beta-1a, respectively. The nature and severities of AEs were similar for both study drugs, and were consistent with the known safety profile of previously marketed REBIF formulation. There appeared to be a higher frequency of pain associated TEAEs after administration of previously marketed REBIF formulation, and more episodes of pyrexia, and associated symptoms, after administration of the HSA-free interferon beta-1a. Injection site reactions, particularly redness, were observed after administration of both of the study drugs. Pain at the administration site and the incidence of injection site reactions however lower after injection of the HSA-free interferon beta-1a compared to previously marketed REBIF formulation.

Studies with REBIF have included patients with Relapsing Remitting Multiple Sclerosis and secondary progressive forms of MS, disability ranging from none to severe, and age ranging from 18 to 60 at study start.

Each pre-filled cartridge of 1.5 mL of solution contains: interferon beta-1a 66 μg or 132 μg. Nonmedicinal ingredients: benzyl alcohol, mannitol, methionine, poloxamer-188 and sodium acetate buffer. The pre-filled cartridge that contains 66 μg/1.5 mL is designed to deliver three doses of 22 μg/0.5 mL and the pre-filled cartridge that contains 132 μg/1.5 mL is designed to deliver three doses of 44 μg/0.5 mL of REBIF. Boxes of 4. The pre-filled cartridge is ready for use with the RebiSmart autoinjection device for subcutaneous administration only.

Initiation packs are available for the initial 4 weeks of treatment (see Dosage and Administration). The initiation pack for the recommended therapeutic dose of 44 μg contains two cartridges of 132 μg/1.5 mL. The cartridges provided in the initiation pack will be injected with the RebiSmart autoinjection device. The RebiSmart autoinjection device is programmed to deliver 20% of the total dose during the initial 2 weeks of therapy (6 injections in total) and 50% of the total dose in the week 3 and 4 (6 injections in total).

The route of administration for Relapsing forms of Multiple Sclerosis is subcutaneous.

Each pre-filled syringe with 0.5 mL of solution contains: interferon beta-1a 22 µg or 44 µg. Nonmedicinal ingredients: benzyl alcohol, mannitol, methionine, poloxamer-188 and sodium acetate buffer. Packs of 3. The pre-filled syringes are for subcutaneous use only.

Initiation packs are available for the initial 4 weeks of treatment (see Dosage and Administration). The initiation pack contains six syringes of 8.8 μg/0.2 mL and six syringes of 22 μg/0.5 mL.

Caution should be exercised and close monitoring conducted when administering REBIF to patients with severe renal failure, or severe myelosuppression, or cardiac disease.

Caution should be exercised when administering REBIF (interferon-beta-1a) to patients with pre-existing seizures disorder. For patients without a pre-existing seizure disorder who develop seizures during therapy, an etiologic basis should be established and appropriate anti-convulsant therapy instituted prior to continuing treatment with REBIF. The effect of REBIF administration on the medical management of patients with seizure disorder is unknown.

There is limited experience with REBIF in children under 18 years of age with MS.

REBIF should not be administered in case of pregnancy and lactation. There are no adequate and well-controlled clinical studies of REBIF in pregnant women. In cynomolgous monkeys administered doses approximately 2 times the cumulative weekly human dose (based on either body weight or surface area), REBIF treatment was associated with significant increases in embryolethal or abortifacient effects either during the period of organogenesis (gestation day 21-89) or later in pregnancy. There were no fetal malformations or other evidence of teratogenesis noted in these studies; however, it is not known if teratogenic effects can occur in humans. These effects are consistent with the abortifacient effects of other type I interferons. Patients should be advised about the abortifacient potential of REBIF.

Patients should be instructed in the use of aseptic technique when administering REBIF. Appropriate instruction for self-injection should be given including careful review of the REBIF patient leaflet. The first injection should be performed under the supervision of an appropriately qualified health care professional. Patients should be advised of the importance of rotating sites of injection with each dose, to minimize the likelihood of severe injection site reactions or necrosis and not to inject into an area that appears abnormal. Patients should be advised to consult with their physician should they develop multiple lesions and/or experience any break in the skin, which may be associated with swelling or drainage of fluid from the injection site, as a decision may be required to discontinue REBIF until healing has occurred. Patients with single lesions may be advised to continue provided that necrosis is not too extensive. 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.

Certain laboratory tests may change. The number of white blood cells or platelets may decrease, but no increased risk of infections or bleeding has been observed.

As REBIF may cause changes in thyroid function, patients should be informed of the symptoms of thyroid dysfunction such as difficulty concentrating, feeling abnormally cold or hot, gaining or losing weight unexpectedly, feeling unusually tired or nervous and unusual very dry skin.

REBIF may cause skin reactions such as rash, hives or urticaria, and itching or pruritus associated with redness, which may be a local allergic reaction. Rarely (in less than 1% of patients) these skin and/or allergic reactions can become generalized and very severe, associated with difficulty breathing, cough, swelling of the mouth or throat, fainting, dizziness, low blood pressure, heart palpitations, hives, itching, abdominal pain, vomiting and diarrhea. Patients should be informed that if this occurs, REBIF should be discontinued and prompt medical care is needed, since severe allergic reactions may be potentially life threatening.

Isolated, life-threatening cases of acute hepatic failure have been reported with REBIF therapy. Symptomatic hepatic dysfunction, primarily presenting as jaundice, has been reported as a rare complication of REBIF therapy. Several possible mechanisms may explain the effect of REBIF on the liver (including direct toxicity, indirect toxicity via release of cytokines and/or autoimmunity). Asymptomatic elevations of transaminases (particularly ALT) is common with interferon therapy (see Adverse Reactions). In clinical trials with REBIF, the majority of these elevations were below 2.5 times the upper limit of normal [ULN] with 1-3% of patients developing elevations above 5 times ULN. In the absence of clinical symptoms, serum ALT levels should be monitored at baseline, every month for the first 6 months and every 6 months thereafter. REBIF 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). Dose reduction or discontinuation should be considered if ALT rises 5 times above the ULN and gradually re-escalated when enzyme levels have normalized. Treatment with REBIF should be stopped if icterus or other clinical symptoms of hepatic dysfunction appear.

There is no controlled clinical experience with REBIF in patients with multiple sclerosis over 65 years of age.

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

Patients with cardiac disease, such as angina, congestive heart failure or arrhythmia, should be closely monitored for worsening of their clinical condition during initiation and continued therapy with REBIF. Symptoms of the flu-like syndrome associated with REBIF may prove stressful to patients with cardiac conditions.

Laboratory abnormalities are associated with the use of interferons. Therefore, in addition to those laboratory tests normally required for monitoring patients with multiple sclerosis, when initiating REBIF therapy, liver enzymes should be monitored at baseline, every month for the first 6 months and every 6 months thereafter (see Warnings and Precautions, Hepatic/Biliary/Pancreatic). Complete blood cell counts with white blood cell differential, and platelet counts are also recommended at baseline 1, 3 and 6 months, and every 6 months thereafter in the absence of clinical symptoms. As patients being treated with REBIF may develop new or worsening thyroid abnormalities (see Warnings and Precautions, Endocrine and Metabolism), testing of thyroid function should be performed at baseline and every 6 months. In case of abnormal results or in patients with a past history of thyroid dysfunction, any necessary treatment should be administered and more frequent testing should be performed as clinically indicated (see Adverse Reactions).

Patients treated with REBIF may develop new or worsening thyroid laboratory abnormalities. Caution should be exercised when administering REBIF to patients with pre-existing thyroid disorders. Patients treated with REBIF should be carefully monitored for evidence of thyroid dysfunction (most often presenting as hypothyroidism or hyperthyroidism), and development of thyroid auto-antibodies. Thyroid testing is recommended at baseline and if abnormal, every 6-12 months following initiation of therapy. If normal, routine testing is not needed but should be performed if clinical findings of thyroid dysfunction appear.

REBIF should be used with caution in patients with depression, a condition that is common in people with multiple sclerosis. Depression, suicidal ideation, and suicide attempts have been reported to occur with increased frequency in patients receiving interferon products, including REBIF. Depressive symptoms associated with interferon beta may often be an atypical syndrome, occurring more frequently early in the course of treatment and not associated with all of the usual clinical symptoms of depression. Patients treated with REBIF should be advised to immediately report any symptoms of depression and/or suicidal ideation to their prescribing physician. Patients developing depression during REBIF therapy should be monitored closely and cessation of therapy should be considered.

Anaphylaxis has been reported as a rare complication of REBIF use. Other allergic reactions have included skin rash, angioedema, and urticaria, and have ranged from mild to severe without a clear relationship to dose or duration of exposure. Several allergic reactions, some severe, have occurred after prolonged use.

Neutralising antibodies (NAbs) to REBIF may develop during the first 24 months of therapy in a small proportion of patients, the precise incidence of which is uncertain. Neutralising antibodies have been associated with a reduced clinical benefit, as evaluated by MRI parameters and multiple sclerosis relapse rate; however, the clinical significance of NAbs development in individual patients remains uncertain. Treatment decisions should be based on the assessment of clinical efficacy by the clinician in view of available NAbs data. A poor clinical course associated with persistent NAbs should prompt reconsideration of REBIF therapy. Neutralising antibodies to REBIF are cross-reactive to different forms of interferon beta.

It is not known whether REBIF is excreted in human milk and is not known if interferon beta-1a can cross the gastrointestinal mucosa. Because of the potential for serious adverse reactions in nursing infants, a decision should be made either to discontinue nursing or to discontinue REBIF therapy.

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

Patients should be informed of the potential risk of liver injury during REBIF therapy, and be informed about the signs and symptoms of such injury, such as loss of appetite with malaise, fatigue, nausea, vomiting, abdominal pain, dark urine, jaundice or pruritus, and be informed of the requirement for frequent laboratory testing (see Warnings and Precautions, Hepatic/Biliary/Pancreatic). They should be advised to consult their physician immediately if such symptoms arise.

Flu-like symptoms (fever, headache, chills, muscle and joint aches, and fatigue) are the most common adverse reactions following initiation of therapy with REBIF. Acetaminophen or ibuprofen 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 multiple sclerosis and may occur while patients are taking REBIF. Patients receiving REBIF should be instructed to inform their doctor immediately if they have feelings of sadness, unusual tiredness, trouble concentrating, or if they think about committing suicide.

Female patients should be advised about the abortifacient potential of REBIF and instructed to take adequate contraceptive measures (see Contraindications and Warnings and Precautions).

Injection site reactions are commonly experienced by patients during therapy (see Adverse Reactions). In general, they do 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.

Interferon beta-1a acts through various mechanisms:

• Immunomodulation through an 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-γ 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 REBIF in relapsing forms of multiple sclerosis is still under investigation.

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, gamma. Interferon beta, Interferon alpha and Interferon gamma have overlapping yet distinct biologic activities.