Rebif (Emd Serono, A Division of Emd Inc., Canada, 22 mcg, ..., 132 mcg) Product Monograph

Recent Major Label Changes

Table of Contents

Certain sections or subsections that are not applicable at the time of the preparation of the most recent authorized product monograph are not listed.

Recent Major Label Changes ................................................................................................. 2

Table of Contents ................................................................................................................. 2

Part 1: Healthcare Professional Information.......................................................................... 4

1. 1.

   Indications..................................................................................................................... 4

   1.1. Pediatrics .................................................................................................................... 4

   1.2. Geriatrics .................................................................................................................... 4

2. 2. Contraindications .......................................................................................................... 4
3. 4.

   Dosage and Administration ............................................................................................ 5

   4.1. Dosing Considerations ............................................................................................... 5

   4.2. Recommended Dose and Dosage Adjustment .......................................................... 5

   4.4. Administration ........................................................................................................... 6

   4.5. Missed Dose ............................................................................................................... 6

4. 5. Overdose ....................................................................................................................... 6
5. 6. Dosage Forms, Strengths, Composition, and Packaging .................................................. 6
6. 7.

   Warnings and Precautions ............................................................................................. 7

   General ................................................................................................................................... 7

   Cardiovascular ........................................................................................................................ 8

   Endocrine and Metabolism .................................................................................................... 8

   Hepatic/Biliary/Pancreatic ..................................................................................................... 8

   Immune .................................................................................................................................. 9

   Monitoring and Laboratory Tests ........................................................................................... 9

   Neurologic .............................................................................................................................. 9

   Psychiatric ............................................................................................................................... 9

   Renal ..................................................................................................................................... 10

   7.1. Special Populations .................................................................................................. 11

   7.1.1. Pregnancy ......................................................................................................... 11

   7.1.2. Breastfeeding ................................................................................................... 12

   7.1.3. Pediatrics (<18 years of age) ............................................................................ 12

   7.1.4. Geriatrics (≥65 years of age) ............................................................................ 12

7. 8.

   Adverse Reactions ....................................................................................................... 12

   8.1. Adverse Reaction Overview ..................................................................................... 12

   8.2. Clinical Trial Adverse Reactions ............................................................................... 12

   8.3. Less Common Clinical Trial Adverse Reactions ........................................................ 60

   8.5. Post-Market Adverse Reactions ............................................................................... 68

8. 9.

   Drug Interactions ......................................................................................................... 69

   9.2. Drug Interactions Overview ..................................................................................... 69

   9.3. Drug-Behaviour Interactions .................................................................................... 69

   9.4. Drug-Drug Interactions ............................................................................................ 69

   9.5. Drug-Food Interactions ............................................................................................ 69

   9.6. Drug-Herb Interactions ............................................................................................ 69

   9.7. Drug-Laboratory Test Interactions........................................................................... 69

9. 10.

   Clinical Pharmacology .................................................................................................. 69

   10.1. Mechanism of Action ............................................................................................... 69

   10.2. Pharmacodynamics .................................................................................................. 70

   10.3. Pharmacokinetics ..................................................................................................... 70

   10.4. Immunogenicity ....................................................................................................... 72

10. 11. Storage, Stability, and Disposal .................................................................................... 72
11. 12. Special Handling Instructions ....................................................................................... 72

Part 2: Scientific Information .............................................................................................. 73

1. 13. Pharmaceutical Information ........................................................................................ 73
2. 14.

   Clinical Trials ............................................................................................................... 74

   14.1. Clinical Trials by Indication ...................................................................................... 74

3. 16. Non-Clinical Toxicology ................................................................................................ 99

Patient Medication Information ....................................................................................... 100

Patient Medication Information ....................................................................................... 109

Part 1: Healthcare Professional Information

1. Indications

REBIF (Interferon beta-1a Injection) is indicated for:

• The treatment of relapsing forms of multiple sclerosis (MS), to

  • reduce the number and severity of clinical exacerbations,
  • slow the progression of physical disability,
  • reduce the requirement for steroids,
  • reduce the number of hospitalizations for treatment of multiple sclerosis, and
  • reduce T1-Gd enhanced and T2 (burden of disease) lesions as seen on MRI.

• The treatment of patients who have experienced a single demyelinating event, accompanied by an active inflammatory process and an abnormal MRI scan with lesions typical of MS, who are determined to be at high risk of developing clinically definite multiple sclerosis.

  Before initiating treatment with REBIF, alternate diagnoses should be excluded.

  In a two-year clinical trial in patients with CIS, REBIF has been shown to delay the onset of McDonald MS (2005 criteria), and other MS features (see 14 Clinical Trials).

Relapsing forms of multiple sclerosis include the subgroups of MS in which patients still experience recurrent attacks of neurological dysfunction including traditional RRMS but also SPMS patients still experiencing relapses.

Although REBIF did not affect progression of disability in SPMS, the clinical trial has shown that secondary progressive MS patients who still experience relapses, had a statistically significant improvement on relapse rate and on MRI measures of disease activity as compared to patients on placebo.

REBIF has not yet been investigated in patients with primary progressive multiple sclerosis and should not be administered to such patients.

1.1. Pediatrics

Pediatrics (<18 years of age): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use.

1.2. Geriatrics

Geriatrics (≥65 years of age): There is no controlled clinical experience with REBIF in patients with multiple sclerosis over 65 years of age.

2. Contraindications

• REBIF is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see 6 Dosage Forms, Strengths, Composition, and Packaging.
• REBIF is contraindicated in patients with decompensated liver disease (see 7 Warnings and Precautions, Hepatic/Biliary/Pancreatic).

4. Dosage and Administration

4.1. Dosing Considerations

• Before initiating a patient on REBIF therapy, please review completely the2 Contraindications section of this Product Monograph.

4.2. Recommended Dose and Dosage Adjustment

Relapsing-Remitting Multiple Sclerosis (RRMS):

The recommended dose is 44 mcg given three times a week by subcutaneous injection. The dose can be reduced to 22 mcg three times a week if the patient is not able to tolerate the higher dose.

Single Demyelinating Event:

The recommended dose for patients who have experienced a first demyelinating event is 44 mcg of REBIF given three times a week by subcutaneous injection.

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 according to the following schedule:

Table 1 – Dosing Schedule After First Demyelinating Event

Prior to injection and for an additional 24 hours after each injection, an antipyretic analgesic is advised to decrease flu-like symptoms associated with REBIF administration.

Please also review the 7 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 childbearing 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.

4.4. Administration

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.

Preparation of Solution: Liquid formulation in a pre-filled syringe

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 22 mcg and 44 mcg of REBIF New HSA-free Formulation respectively. The pre-filled syringes are ready for subcutaneous use only.

Preparation of Solution: Liquid formulation in a pre-filled cartridge

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 device. The pre-filled cartridge that contains 66 mcg/1.5 mL is designed to deliver three doses of 22 mcg/0.5 mL and the pre-filled cartridge that contains 132 mcg/1.5 mL is designed to deliver three doses of 44 mcg/0.5 mL of REBIF. The pre-filled cartridges are for subcutaneous use only.

4.5. Missed Dose

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.

5. Overdose

One medically-confirmed case of REBIF overdose has been reported in over 450,000 patient-years of exposure to REBIF and concerned a subject who injected himself with seven syringes of REBIF 44 mcg (total dose of 308 mcg) in a suicide attempt. Symptoms included a modest rise in body temperature (to 37.5°C), diffuse erythema of the limbs and abdomen with rigors. The subject was treated with 500 mg of acetyl-salicylic acid dl-lysine intravenously, and haematologic screening revealed no abnormalities of hepatic function, thyroid function, or indices of inflammation. The event was not considered serious. There is no known antidote for an overdose of REBIF. The subject should be hospitalised for observation and appropriate supportive treatment administered.

For the most recent information in the management of a suspected drug overdose, contact your regional poison control centre or Health Canada’s toll-free number, 1-844 POISON-X (1-844-764-7669).

1. 6. Dosage Forms, Strengths, Composition, and Packaging

Table 2 – Dosage Forms, Strengths, and Composition

Description

Solution for injection in a pre-filled syringe

REBIF New HSA-free Formulation is available as a liquid formulation, in pre-filled syringes. Two package strengths are available: 22 mcg/0.5 mL and 44 mcg/0.5mL. The pre-filled syringes are supplied as 3-packs. The pre-filled syringes are for subcutaneous use only.

Solution for injection in a pre-filled cartridge

REBIF New HSA-free Formulation is available as a liquid formulation, in pre-filled cartridges. Two package strengths are available: 66 mcg/1.5 mL and 132 mcg /1.5 mL. The pre-filled cartridge that contains 66 mcg/1.5 mL is designed to deliver three doses of 22 mcg/0.5 mL and the pre-filled cartridge that contains 132 mcg/1.5 mL is designed to deliver three doses of 44 mcg/0.5 mL of REBIF. The pre-filled cartridges are supplied as 4 pre-filled cartridges per box.

The pre-filled cartridge is ready for use with the RebiSmart auto-injection device for subcutaneous administration only.

RebiSmart is an electronic injection device intended for subcutaenous injection of REBIF pre-filled cartridges.

The RebiSmart auto-injection 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).

7. Warnings and Precautions

General

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

Patients should be informed of the most common adverse reactions associated with interferon beta administration, including symptoms of the flu-like syndrome (see 8 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 Special Diseases and Conditions: Caution should be exercised and close monitoring conducted when administering REBIF to patients with severe renal failure, or severe myelosuppression, or cardiac disease.

Cardiovascular

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 and continued therapy with REBIF. Symptoms of the flu-like syndrome associated with REBIF may prove stressful to patients with cardiac conditions.

Pulmonary Arterial Hypertension

Cases of pulmonary arterial hypertension (PAH) have been reported with interferon beta products. Events were reported at various time points including up to several years after starting treatment with interferon beta.

Thrombotic Microangiopathy

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 after 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. If clinical features of TMA are observed, testing of blood platelet levels, serum lactate dehydrogenase (LDH), schistocytes (erythrocyte fragmentation) on a blood film with a negative Coombs test and renal function is recommended. Prompt treatment of TTP/HUS is required and immediate discontinuation of treatment with REBIF is recommended.

Endocrine and Metabolism

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.

Hepatic/Biliary/Pancreatic

REBIF, like other beta interferons, has a potential of causing severe liver injury including hepatic failure. 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). Severe elevations in transaminases are common with interferon therapy; asymptomatic elevations of transaminases (particularly ALT) are very common (see 8 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.

Immune

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.

Monitoring and Laboratory Tests

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 7 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 7 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 8 Adverse Reactions).

Neurologic

Caution should be exercised when administering REBIF 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.

Psychiatric

Depression

REBIF should be used with caution in patients with previous or current 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.

Renal

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 REBIF should be considered.

Information to be Provided to the Patient

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 7 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.

Injection site reactions are commonly experienced by patients during therapy (see 8 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.

Instruction on self-injection technique and procedures: 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.

7.1. Special Populations

7.1.1. Pregnancy

Women of childbearing potential receiving REBIF should be advised to take adequate contraceptive measures. Patients should be advised to discuss with their health care provider the potential risks and benefits of continued treatment while attempting to conceive. It is not known if interferons alter the efficacy of hormonal contraceptives.

There are no adequate and well-controlled clinical studies of REBIF in pregnant women. The administration of REBIF during confirmed pregnancy should be avoided, unless clearly needed.

A European registry study collected data on 948 prospective pregnancies in women with MS who were treated with one of five interferon beta medications. The rates of aggregated adverse pregnancy outcomes were in line with reference ranges published in the literature.

Data from a retrospective register-based study in Sweden and Finland have likewise not indicated an increased risk of major congenital anomalies after early pregnancy exposure. However, the duration of exposure during the first trimester was uncertain since data were collected when interferon beta use was contraindicated during pregnancy, and treatment was interrupted when the pregnancy was detected and/or confirmed. Experience with exposure during the second and third trimester was too limited to determine whether exposure affects maternal or fetal health.

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.

The risk of spontaneous abortions in pregnant women exposed to interferon beta cannot be evaluated based on the currently available data.

7.1.2. Breastfeeding

No studies have been conducted with REBIF in lactating women. Limited information available from published literature on the transfer of interferon beta-1a into breast milk suggests that levels of interferon beta-1a excreted in human milk are low. A risk to the nursing infant cannot be excluded.

The benefit and potential risk of breastfeeding should be considered along with the patient’s medical need for interferon beta-1a therapy.

7.1.3. Pediatrics (<18 years of age)

No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use.

7.1.4. Geriatrics (≥65 years of age)

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

8. Adverse Reactions

8.1. Adverse Reaction Overview

The most serious adverse reactions observed with REBIF are hepatic failure, hepatitis (including autoimmune hepatitis), suicide attempt, seizures, and injection site necrosis (see 7 Warnings and Precautions) as well as thrombocytopenic thrombotic purpura/haemolytic uremic syndrome, drug-induced lupus erythematosus and retinal vascular disorders.

The most common adverse reactions observed with REBIF are influenza-like symptoms, headache, injection site reactions, reduction in white blood cell count and elevation of liver enzymes and depression. Depending of the severity and persistence of the reactions, the dose of REBIF may need to be lowered and or treatment may need to be interrupted or discontinued.

Thyroid dysfunction may present as hypothyroidism and hyperthyroidism. It is commonly transient and mild, especially in the first year of treatment and in patients with pre-existing thyroiditis (see 7 Warnings and Precautions, Monitoring and Laboratory Tests).

Analphylaxis and other allergic reactions have been reported in patients using REBIF (see 7 Warnings and Precautions).

8.2. Clinical Trial Adverse Reactions

Clinical trials are conducted under very specific conditions. Therefore, the frequencies of adverse reactions observed in the clinical trials may not reflect frequencies observed in clinical practice and should not be compared to frequencies reported in clinical trials of another drug.

Study 25632 (REBIF HSA-free Formulation): Adverse Drug Reactions

Study 25632 was performed to assess the immunogenicity and safety of FBS-free/HSA-free Formulation of interferon beta-1a (REBIF HSA-free Formulation), administered subcutaneously three times per week in accordance with the current product label.

The adverse events experienced during ninety-six weeks of Study 25632 are listed below, by MedDRA (Version 8.0) System Organ Class.

(a)Treatment Emergent Adverse Events

No new or unexpected treatment emergent adverse events (TEAEs) were observed in the REBIF HSA-free Formulation Cohort compared to the Historical HSA-containing Formulation Cohort (Historical Cohort). The Historical Cohort consisted of patients from three phase III clinical trials (Study GF6789, Study GF6954 and Study 21125) who were administered identical dosing of the previous HSA- and FBS-containing formulation of interferon beta 1a (44 mcg three times a week) during the 24-month/96-week period. For the purposes of these comparisons, the Historical Cohort TEAE data for 24-months/96-weeks of treatment was recoded in MedDRA version 8.0 (Clinical Trial Report Study 25632: 96-week Analysis). Overall, the proportion of subjects experiencing TEAEs was similar between the REBIF HSA-free Formulation Cohort (95.0%) and the Historical Cohort (99.7%). With regard to severity, the majority (97%) of AEs in the REBIF HSA-free Formulation Cohort were mild (70%) or moderate (27%). To facilitate comparison of the REBIF HSA-free Formulation Cohort safety profile with that of the Historical Cohort the common AEs of interferon beta-1a were pre-specified into groups of MedDRA preferred terms. The pre-specified AE groups were “cytopenia”, “flu like syndrome”, “hepatic disorders”, “hypersensitivity reactions”, “injection site reactions”, “depression and suicidal ideation,” “skin rashes” and “thyroid disorders”. Specific differences were observed in some of these eight pre-specified AE groups known to be associated with interferon beta-1a. The adverse event profile of REBIF HSA-free Formulation was generally comparable with that observed in the historical trials with the original formulation of interferon-beta-1a. Events related to the flu-like syndrome were reported in 71.5% of REBIF HSA-free Formulation subjects and in 69.0%, 55.4% and 49.0% of subjects in protocols 6789, 6954 and 21125 respectively. Local injection site reactions were 30.8% in REBIF HSA-free Formulation Cohort and in 85.8% to 92.4% in the historical trials. Events related to depression and suicidal ideation were reported in 6.5% of REBIF HSA-free Formulation subjects compared with 22.7% to 36.3% in the historical trials.

Study 25827 (REBIF HSA-free Formulation): Adverse Drug Reactions

The safety and tolerability of the 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 mcg 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 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.

Study GF6789 (PRISMS): Adverse Reactions

The adverse events experienced during the first two years of Study GF6789 are listed below, by WHOART System Organ Class. The most common amongst the injection site reactions was in the form of injection site inflammation. The majority of the other injection site reactions were also mild in the 2 REBIF groups. Necrosis was reported in 8 patients treated with REBIF. Two of these patients were in the 66 mcg weekly and six in the 132 mcg 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 treatments, received antibiotics.

Long-term Follow-up (LTFU) data up to 8 years for the PRISMS study has been collected in the retrospective study 22930. LTFU was attended by 68.2% of the original PRISMS study cohort (382/560 patients). 72.0% (275/382) were still receiving IFNbeta-1a s.c., with 74.3% (101/136) of those originally randomized to receive the 44 mcg dose and 70.7% (87/123) the 22 mcg dose. Overall, 19.7% of patients progressed to secondary progressive MS between baseline and LTFU (75/381). No new safety concerns were identified and treatment was generally well tolerated.

After 2 years, the placebo patients were switched to REBIF, and along with the patients for the REBIF treatment groups, they were treated for an additional two years. Listed below by WHOART System Organ Class, are the proportion of patients reporting the most common adverse events ongoing from years 1 and 2 or started during years 3 and 4 of treatment. The results are similar to those obtained in the original phase of the study. The findings indicate that the incidence of interferon-related adverse events diminishes somewhat with continued exposure to the medication.

Cases of necrosis were rare and not a cause of drop-out. For REBIF 66 mcg weekly, there was one episode of skin necrosis per 92 years of exposure or per 14 100 injections. The comparable figures for REBIF 132 mcg weekly are 1 episode of necrosis per 61 years of exposure or per 9 300 injections.

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 mcg vs. 22 mcg), 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.

Study GF6954 (SPECTRIMS): Adverse Reactions

The table below presents adverse events that were reported in at least 1% of the patients in any treatment group of Study GF6954; the AEs are listed by WHOART system organ class and preferred term (sorted by preferred term in order of frequency). The most frequently reported adverse event was injection site inflammation, which occurred in 67% of both treated groups compared to 16% for placebo. Lower frequencies of the closely associated but more symptomatic injection site reactions were reported in 3 to 4 times as many treated patients as placebo patients. Injection site necrosis was seen in 3.3% and 6.9% of patients in the 22 mcg and 44 mcg groups respectively, but almost always as a single event per patient. The rate of necrosis was 1/3 800 injections for high-dose and 1/9 600 for low-dose therapy. Liver function abnormalities were also reported 3 to 4 times more commonly with active therapy. The haematopoietic system was also affected, with increased reports of leucopenia, granulocytopenia and lymphopenia associated with active therapy and most prominently with the higher dose. These haematopoietic abnormalities are expected side-effects of interferon therapy. Increased reports of anaemia and thrombocytopenia were noted with treatment, but these events occurred in less than 10% of patients.

Study GF7480 (ETOMS): Adverse Reactions

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.

Study 21125 (EVIDENCE): Adverse Reactions

Study 21125 was a direct comparative trial of IFN beta-1a 44 mcg three times a week (REBIF) vs. IFN beta-1a 30 mcg im qw (AVONEX®) in RRMS patients. Of the 677 patients randomized, 339 patients received REBIF 44 mcg sc three times a week and 338 patients were randomized to AVONEX 30 mcg im qw. The following tables present AE frequencies for only the REBIF-treated group coded in MedDRA version 8.0.

There were a total of 2682 AEs reported by the subjects who received REBIF, the majority of which were mild in severity. The most commonly reported AEs were injection site disorders, flu-like symptoms (headache, fever, chills, fatigue, malaise, arthralgia and myalgia), white blood cell abnormalities and elevated hepatic transaminases (AST and ALT), all of which are well-known reactions to interferon and are included in the product label for REBIF.

Study 27025 (REFLEX): Adverse Reactions

Study 27025 was a 2-year controlled clinical trial with REBIF HSA-free formulation in patients with a first clinical demyelinating event at high risk of converting to MS.

Patients were randomized in a double-blind manner to either REBIF 44 mcg three times a week (three times a week; n=171), once weekly (ow; n=175), or placebo (n =171). Upon conversion to clinically definite multiple sclerosis (CDMS), patients switched to open-label REBIF 44 mcg three times a week, including 59 out of 171 patients from the placebo group.

The table below presents adverse events that were reported in 1% or more of patients in the double-blind treatment period of Study 27025. The adverse events are listed by MedDRA (Version 13.0) System Organ Class.

During the DB treatment period, the most common AEs (reported by 10% of subjects or more) experienced in the RNF 44 mcg ow and three times a week treatment groups were typical IFN-beta related AEs such as influenza-like illness (Placebo 19.9%; RNF three times a week 70.3%, ow 70.5%) and injection site erythema (Placebo 1.8%; RNF three times a week 29.2%, ow 19.7%) and pyrexia (only reported in excess over Placebo (5.3%) in the RNF 44 mcg ow treatment group (12.7%)). In addition, the TEAEs headache (Placebo 26.9%; RNF three times a week 26.9%, ow 21.4%) and nasopharyngitis (Placebo 12.9%; RNF three times a week 9.9%, ow 13.3%) were commonly reported by the subjects, but their incidence was higher in the active treatment groups than in the Placebo group. A dose-dependent effect was observed on some pre-specified AEs: patients treated with RNF three times/week experienced more treatment-emergent adverse events compared to patients treated once weekly (ow) in the categories: injection site reactions (three times a week 35.7% vs. ow 24.3%), cytopenias (three times a week 11.1% vs. ow 5.2%), skin rash (three times a week 9.4% vs. ow 4.6%), thyroid (three times a week 6.4% vs. ow 2.9%), depression (three times a week 8.2% vs. ow 6.4%), hypersensitivity (three times a week 9.4% vs. ow 5.8%), and hepatic events - mainly transaminases elevations - (three times a week 11.1% vs. ow 9.2%). Whereas flu-like symptoms were more frequently observed in patients treated with RNF once weekly compared to patients treated three times/week (ow 70.5% vs. three times a week 54.4%). [SAEs were reported in few subjects: 12 in the Placebo treatment group, 8 in the RNF 44 mcg ow treatment, and 6 in the RNF 44 mcg three times a week treatment group.

During the OL treatment period, no new unexpected adverse reactions were observed. Incidences of influenza like illness and injection site erythema were highest in the subjects newly exposed to active treatment (i.e. subject initially treated with Placebo). Incidences of leukopenia and alanine aminotransferase increased were higher in the subjects with longer exposure to active treatment (i.e. subjects initially treated with RNF 44 mcg ow as well as those initially treated with RNF 44 mcg three times a week).

8.3. Less Common Clinical Trial Adverse Reactions

Study 25632 (REBIF HSA-free Formulation):

In addition to the above listed adverse events, the following events have been experienced less frequently (i.e. in less than 1% of the study population) during the 96 weeks of treatment:

Blood and Lymphatic System Disorders: lymphadenopathy.

Cardiac Disorders: angina pectoris, tachycardia, angina unstable.

Congenital, Familial and Genetic Disorders: seasonal allergy, factor VIII deficiency.

Ear and Labyrinth Disorders: ear discomfort, middle ear effusion.

Endocrine Disorders: goitre, Cushing’s syndrome, hypothyroidism, thyroiditis chronic.

Eye Disorders: blepharitis, eye irritation, conjunctivitis, diplopia, dry eye, myopia, retinal degeneration, visual brightness, vitreous disorder, vitreous floaters.

Gastrointestinal Disorders: coeliac disease, abdominal discomfort, abdominal distension, aerophagia, anal haemorrhage, colitis, faecal incontinence, food poisoning, gastritis erosive, gastroduodenitis, gingival bleeding, gingival oedema, gingivitis, mouth ulceration, odynophagia, odynophagia, pancreatitis, periodontitis, periproctitis, peritonitis, stomach discomfort, tongue discolouration, tooth impacted.

General Disorders and Administration Site Conditions: feeling cold, injection site inflammation, injection site irritation, oedema peripheral, chest pain, cyst, feeling hot, infusion site pain, injection site desquamation, injection site induration, injection site necrosis, injection site oedema, injection site reaction, malaise, non-cardiac chest pain, thirst.

Hepatobiliary Disorders: cholecystitis, cholecystitis chronic, hepatic function abnormal, hepatic pain, hepatic steatosis, hepatitis toxic, hepatotoxicity.

Infections and Infestations: bronchitis acute, gastroenteritis, otitis externa, pharyngitis streptococcal, pneumonia, pulpitis dental, salpingitis, acute sinusitis, acute tonsillitis, bacterial food poisoning, blister infected, bronchitis, campylobacter infection, cervictis, dry socket, furuncle, gastroenteritis escherichia coli, genital candidiasis, gingival abscess, hordeolum, injection site infection, kidney infection, laryngitis, localised infection, lower respiratory tract infection, nail candida, onychomycosis, oral fungal infection, osteomyelitis acute, paronychia, parotitis, penile infection, periodontal infection, peritonsillar abscess, pilonidal cyst, pyelonephritis, pyelonephritis acute, pyelonephritis chronic, tinea versicolour, tooth infection, tracheitis, vaginal candidiasis, vaginal mycosis.

Injury, Poisoning and Procedural Complications: fall, post procedural pain, arthropod bite, back injury, caustic injury, concussion, drug toxicity, excoriation, face injury, humerus fracture, injury, joint dislocation, ligament sprain, muscle strain, near drowning, radius fracture.

Investigations: lymphocyte count decreased, thyroid function test abnormal, weight increased, blood cholesterol increased, blood creatinine increased, blood thyroid stimulating hormone decreased, haemoglobin decreased, heart rate increased, hepatic enzyme abnormal, red blood cell count decreased, serum ferritin increased, thyroxine free decreased, tri-iodothyronine free decreased.

Metabolism and Nutrition Disorders: anorexia, dehydration, diabetes mellitus non-insulin-dependent, hyperglycaemia, hypokalaemia, lactose intolerance.

Muskuloskeletal and Connective Tissue Disorders: chest wall pain, musculoskeletal stiffness, sensation of heaviness, arthropathy, bone pain, bursitis, fibromyalgia, groin pain, joint stiffness, muscle fatigue, muscle tightness, muscle twitching, musculoskeletal pain, myositis, night cramps, osteoarthritis, osteopenia, osteoporosis, shoulder pain.

Neoplasms Benign, Malignant and Unspecified (including cysts and polyps): uterine leiomyoma, fallopian tube neoplasm, tracheal neoplasm.

Nervous System Disorders: coordination abnormal, hemiparesis, muscle spasticity, sinus headache, somnolence, syncope, amnesia, automonic nervous system imbalance, cognitive disorder, dysguesia, dysgraphia, lethargy, loss of consciousness, motor dysfunction, neuralgia, optic neuritis, restless leg syndrome, syncope vasovagal, tension headache.

Psychiatric Disorders: dyssomnia, panic attack, sleep disorder, hypomania, irritability, tension.

Renal and Urinary Disorders: nocturia, renal colic, dysuria, micturition urgency, neurogenic bladder, pollakiuria, proteinuria, urinary hesitation, urine odour abnormal.

Reproductive System and Breast Disorders: amenorrhoea, dysmenorrhoea, erectile dysfunction, menorrhagia, ovarian cyst, premenstrual syndrome, breast discharge, cervical polyp, endometriosis, fibrocystic breast disease, menometrorrhagia, menstrual disorder, ovarian cyst ruptured, uterine cervical erosion.

Respiratory, Thoracic and Mediastinal Disorders: cough, haemoptysis, increased upper airway secretion, pulmonary congestion, rhinitis allergic, rhinitis seasonal, rhinorrhoea, sleep apnoea syndrome, upper respiratory tract congestion.

Skin and Subcutaneous Tissue Disorders: acne, alopecia, dermatitis allergic, rash, anhidrosis, dermal cyst, dermatitis atopic, eczema, exanthem, haemorrhage subcutaneous, heat rash, hypotrichosis, livedo reticularis, pigmentation disorder, pityriasis, pruritus generalised, skin irritation, skin ulcer.

Vascular Disorders: essential hypertension, flushing, haematoma, hot flush, peripheral coldness, Reynaud’s phenomenon.

Study GF6789 (PRISMS): Adverse Reactions

In addition to the above listed adverse events, the following events have been experienced less frequently (i.e. in less than 1% of the study population) during years 1 and 2 of treatment:

Application Site Disorders: injection site atrophy.

Body As a Whole – General Disorders: scar, oedema, syncope, abdomen enlarged, anaphylactoid reaction, carpal tunnel syndrome, nasal polyp, oedema genital.

Cardiovascular Disorders, General: hypotension postural.

Central & Peripheral Nervous System Disorders: convulsions local, extrapyramidal disorder, hypotonia, nerve root lesion, neuralgia, optic neuritis, paralysis, paresis, scotoma, visual field defect.

Endocrine Disorders: hypothyroidism, sialoadenitis.

Foetal Disorders: hernia congenital, death foetal.

Gastro-intestinal System Disorders: appetite increased, saliva increased, tooth caries, colitis, Crohn's disease, gastroesophageal reflux, GI neoplasm benign, gum hyperplasia, hiccup, intestinal obstruction, irritable bowel syndrome, rectal prolapse, stomatitis, aphthous.

Hearing and Vestibular Disorders: hearing decreased, hyperacusis, motion sickness, deafness.

Heart Rate and Rhythm Disorders: arrhythmia, bradycardia, cardiac arrest, extrasystoles, sick sinus syndrome.

Liver and Biliary System Disorders: cholecystitis, cholelithiasis, gamma-gt increased.

Metabolic and Nutritional Disorders: hypercholesterolaemia, thirst, hyperlipaemia, hypernatraemia, oedema generalised.

Musculo-skeletal System Disorders: malformation foot, osteoporosis.

Myo Endo Pericardial & Valve Disorders: angina pectoris.

Neoplasm: basal cell carcinoma, colon carcinoma, lipoma.

Platelet, Bleeding & Clotting Disorders: disseminated intravascular coagulation, embolism arterial, embolism pulmonary, thrombosis arterial arm.

Psychiatric Disorders: apathy, dreaming abnormal, hallucination, psychosis manic-depressive, thinking abnormal.

Red Blood Cell Disorders: hyperhaemoglobinaemia, splenomegaly.

Reproductive Disorders, Female: cervicitis, endometriosis, lactation nonpuerperal, vaginal haemorrhage, bacterial growth genital asymptom, breast neoplasm benign female, cervical dysplasia, endometrial disorder, menopausal symptoms, ovarian disorder, premenstrual tension, uterovaginal prolapse.

Reproductive Disorders, Male: breast discharge, epididymitis, sexual function abnormal, testicular pain, testis disorder.

Resistance Mechanism Disorders: infection bacterial, moniliasis genital, sepsis.

Respiratory System Disorders: sputum increased, atelectasis, pneumonitis, stridor.

Secondary Terms: cyst nos, heat intolerance, spinal cord compression, abrasion nos, asthma extrinsic, cytomegalus virus infection, heat stroke, lumbar disc lesion, malaria.

Skin and Appendages Disorders: pigmentation abnormal, rosacea, bullous eruption, hair texture abnormal, hyperkeratosis, hypertrichosis, paronychia, rhagades, seborrhoea, skin reaction localised, skin ulceration, sweat gland disorder, vesicular rash.

Special Senses Other, Disorders: taste perversion.

Urinary System Disorders: pyelonephritis, polyuria.

Vascular (Extracardiac) Disorders: thrombophlebitis arm superficial, vein distended, claudication intermittent, thrombophlebitis, vascular malformation cerebral.

Vision Disorders: accommodation abnormal, conjunctival haemorrhage, blindness, blindness temporary, cataract, iritis, keratitis, meibomianitis, retinal disorder, uveitis.

White Cell and Res Disorders: immunoglobulins increased.

In addition to the above listed adverse events, the following events have been experienced less frequently (i.e. in less than 1% of the study population) ongoing from years 1 and 2 or started during years 3 and 4 of treatment:

Application Site Disorders: injection site atrophy, cellulitis, injection site fibrosis, skin necrosis.

Body As a Whole – General Disorders: chest pain substernal, sarcoidosis.

Cardiovascular Disorders, General: aneurysm, circulatory failure, heart murmur.

Central & Peripheral Nervous System Disorders: trigeminal neuralgia, dyskinesia, dysphonia, nerve root lesion, neuralgia, neuropathy, scotoma.

Collagen Disorders: antinuclear factor test positive.

Endocrine Disorders: glucocorticoids increased.

Gastro-Intestinal System Disorders: change in bowel habits, enanthema, haemorrhage rectum, hiccup, oesophageal ulceration, periodontal destruction, tongue ulceration, tooth caries.

Heart Rate and Rhythm Disorders: arrhythmia, extrasystoles.

Liver and Biliary System Disorders: cholelithiasis, hepatomegaly.

Metabolic and Nutritional Disorders: bun increased, diabetes mellitus, hypercalcaemia, oedema generalised, vitamin B12 deficiency.

Musculo-Skeletal System Disorders: myopathy, osteoporosis.

Myo Endo Pericardial & Valve Disorders: myocardial infarction.

Neoplasm: bladder carcinoma, ovarian carcinoma, renal carcinoma.

Platelet, Bleeding & Clotting Disorders: purpura.

Psychiatric Disorders: depression psychotic, drug dependence.

Red Blood Cell Disorders: hyperhaemoglobinaemia, packed cell volume increased.

Reproductive Disorders, Female: cervical uterine polyp, cervix lesion, fertility decreased female, premenstrual tension, vulva discomfort.

Reproductive Disorders, Male: hernia inguinal, semen abnormal, sexual function abnormal, testis disorder.

Resistance Mechanism Disorders: toxoplasmosis.

Respiratory System Disorders: pleural pain, pleurisy, pulmonary congestion.

Secondary Terms: abrasion nos, heat intolerance, lumbar disc lesion, medication reaction nos, nasal septum deviation.

Skin and Appendages Disorders: dermatitis contact, pigmentation abnormal, pityriasis rosea, hair texture abnormal, hypertrichosis, livedo reticularis, photosensitivity allergic react, rash pustular, rhagades, skin malformation, skin reaction localised, vesicular rash, vitiligo.

Urinary System Disorders: nocturia, cystitis haemorrhagic, polyuria, renal cyst, urethral disorder.

Vascular (Extracardiac) Disorders: claudication intermittent, ocular haemorrhage, vascular malformation cerebral, vascular malformation peripheral, vein distended.

Vision Disorders: blepharitis, corneal ulceration, herpes ocular, lacrimal gland disorder, mydriasis, retinal disorder, uveitis.

Study GF6954 (SPECTRIMS): Adverse Reactions

In addition to the above listed adverse events, the following events have been experienced less frequently (i.e. in less than 1% of the study population) during the 3 years of treatment:

Application Site Disorders: cellulitis, otitis externa, skin nodule.

Body As a Whole – General Disorders: allergy, choking, face oedema, carpal tunnel syndrome, condition aggravated, granulomatous lesion, halitosis, necrosis ischaemic, oedema, pallor.

Cardiovascular Disorders, General: heart murmur, cyanosis, oedema periorbital.

Central & Peripheral Nervous System Disorders: anaesthesia mouth, cramps legs, neuralgia, coma, dyskinesia, lower motor neurone lesion,, neuropathy, paralysis, paraplegia, convulsions grand mal, hemianopia, hyperaesthesia, nystagmus, optic atrophy, scotoma, stupor, visual field defect.

Collagen Disorders: auto-antibody response.

Endocrine Disorders: thyroid stim. hormone decreased, hypothyroidism, T3 increased, goitre, hyperthyroidism, T4 decreased, thyroiditis.

Foetal Disorders: hernia congenital.

Gastro-Intestinal System Disorders: stomatitis ulcerative, appendicitis, gastroesophageal reflux, haemorrhoids, change in bowel habits, enteritis, abdomen enlarged, colitis, gastric ulcer, haemorrhage rectum, melaena, tenesmus, tongue discolouration, abdominal adhesions, anus disorder, duodenal ulcer, faeces discoloured, GI haemorrhage, leukoplakia oral, mucositis nos, oesophagospasm, saliva altered, saliva increased, salivary duct obstruction, salivary gland enlargement, stomatitis, teeth-grinding, tongue ulceration.

Hearing and Vestibular Disorders: hearing decreased, deafness, motion sickness, vestibular disorder.

Heart Rate and Rhythm Disorders: fibrillation atrial, arrhythmia, bradycardia.

Liver and Biliary System Disorders: bilirubinaemia, hepatomegaly, cholangitis, gall bladder disorder, gamma-gt increased.

Metabolic and Nutritional Disorders: blood urea decreased, hypercalcaemia, hyperkalaemia, thirst, vitamin B12 deficiency, hypokalaemia, oedema generalised, dehydration, gout, hyperglycaemia, hyperuricaemia, hypocalcaemia, hypoglycaemia, hypoglycaemic reaction, lipodystrophy, npn increased.

Musculo-Skeletal System Disorders: osteoporosis, torticollis, avascular necrosis femoral head, myositis, synovitis.

Myo Endo Pericardial & Valve Disorders: angina pectoris.

Neoplasm: basal cell carcinoma, brain neoplasm benign, breast neoplasm malignant female, cervical uterine polyp, gi neoplasm benign, lipoma, thyroid neoplasm malignant.

Psychiatric Disorders: concentration impaired, aggressive reaction, paroniria, depersonalization, drug abuse, euphoria, paranoid reaction, sleep disorder, snoring.

Red Blood Cell Disorders: anaemia hypochromic, polycythaemia, packed cell volume increased, splenomegaly.

Reproductive Disorders, Female: cervical dysplasia, intermenstrual bleeding, mastitis, uterine fibroid, breast discharge, endometrial hyperplasia, ovarian cyst, uterine haemorrhage, uterovaginal prolapse, vaginal discomfort, vaginal neoplasm benign.

Reproductive Disorders, Male: prostatic disorder, semen abnormal, ejaculation failure, epididymitis, hernia inguinal, testicular pain.

Resistance Mechanism Disorders: infection bacterial, sepsis.

Respiratory System Disorders: asthma, bronchospasm, pneumonitis, chronic obstruct airways disease, pleurisy, pulmonary congestion, respiratory insufficiency, sleep apnoea, pleural effusion, pulmonary eosinophilia, pulmonary oedema, sputum increased, throat tightness.

Secondary Terms: post-operative haemorrhage, post-operative wound infection, surgical procedure, asthma extrinsic, bone metastases, lumbar disc lesion, nasal septum deviation, varicella.

Skin and Appendages Disorders: photosensitivity reaction, psoriasis, rash psoriaform, bullous eruption, rash pustular, hyperkeratosis, onychomycosis, dermatitis contact, hypertrichosis, skin odor abnormal, vesicular rash, chloasma, erythema induratum, erythema multiforme, erythema nodosum, folliculitis, hair disorder nos, heat rash, livedo reticularis, melanosis, nail discolouration, photosensitivity allergic react, piloerection, pilonidal cyst, pruritus genital, skin atrophy, skin hypertrophy, sweating decreased.

Special Senses Other, Disorders: parosmia.

Urinary System Disorders: polyuria, renal pain, nocturia, urethral disorder, urine abnormal, bladder discomfort, cystitis haemorrhagic, hydronephrosis, renal calculus, renal cyst, renal function abnormal.

Vascular (Extracardiac) Disorders: peripheral ischaemia, embolism pulmonary, vascular disorder, vasculitis, vein distended, cerebral haemorrhage, cerebrovascular disorder, phlebitis, subarachnoid haemorrhage, thrombophlebitis, vascular malformation peripheral, vein varicose.

Vision Disorders: blepharitis, photophobia, accommodation abnormal, cataract, retinal disorder, blindness, glaucoma, blepharospasm, blindness temporary, conjunctival discolouration, conjunctival haemorrhage, corneal deposits, corneal opacity, exophthalmos, eyelid retraction, herpes ocular, uveitis.

White Cell and Res Disorders: lymphadenopathy cervical, WBC abnormal nos, basophilia.

Study 21125 (EVIDENCE): Adverse Reactions

In addition to the above listed adverse events, the following events have been experienced less frequently (i.e. in less than 1% of the study population) during the 48 weeks of treatment:

Blood and Lymphatic System Disorders: neutropenia, lymphopenia, leukopenia, thrombocytopenia, anaemia, bone marrow depression, lymphadenitis, microcytic anaemia, monocytosis.

Cardiac Disorders: tachycardia, arrhythmia, bundle branch block right, supraventricular tachycardia.

Congenital, Familial and Genetic Disorders: colour blindness.

Ear and Labyrinth Disorders: ear disorder, ear pain, Meniere's disease, motion sickness, vertigo positional.

Endocrine Disorders: hypothyroidism, goitre.

Eye Disorders: photopsia, visual disturbance, diplopia, dry eye, eye disorder, vitreous floaters, accommodation disorder, conjunctivitis allergic, eye irritation, ocular hyperaemia, optic atrophy, visual acuity reduced.

Gastrointestinal Disorders: dry mouth, mouth ulceration, abdominal distension, abdominal pain lower, dysphagia, gastritis, abdominal tenderness, anorectal disorder, aphthous stomatitis, change of bowel habit, colitis, colonic polyp, diverticulum, enteritis, flatulence, gingivitis, halitosis, irritable bowel syndrome, oesophagitis, oral pain, salivary hypersecretion, stomatitis, tongue discolouration, tooth disorder.

General Disorders and Administration Site Conditions: chest discomfort, injection site discolouration, injection site rash, injection site swelling, nodule, feeling hot, injection site vesicles, temperature intolerance, thirst, circadian rhythm sleep disorder, cyst, difficulty in walking, drug withdrawal syndrome, facial pain, feeling jittery, hernia, injection site induration, injection site necrosis, injection site photosensitivity reaction, injection site ulcer, oedema peripheral.

Hepatobiliary Disorders: hepatitis, cholecystitis, hepatocellular damage.

Immune System Disorders: hypersensitivity, seasonal allergy.

Infections and Infestations: fungal infection, onychomycosis, vaginal mycosis, abscess limb, cystitis, dental caries, nasopharyngitis, paronychia, pharyngitis streptococcal, pneumonia, abscess, bacterial infection, bacteriuria, fungal skin infection, gastrointestinal fungal infection, herpes zoster, infection parasitic, injection site cellulitis, laryngitis, malaria, postoperative infection, skin candida, skin infection, tinea infection, tonsillitis, tooth infection, wound infection.

Injury, Poisoning and Procedural Complications: arthropod bite, excoriation, fall, pain trauma activated, animal bite, joint dislocation, joint injury, post procedural pain, tooth injury, accident, anaemia postoperative, ankle fracture, arthropod sting, foot fracture, hand fracture, injury, limb injury, muscle injury, muscle strain, nerve injury, post procedural complication, sunburn, thermal burn.

Investigations: anti-thyroid antibody, blood glucose increased, blood thyroid stimulating hormone decreased, blood urine present, blood albumin increased, blood thyroid stimulating hormone increased, glucose urine, haematocrit decreased, haemoglobin decreased, neutrophil count, thyroid function test abnormal, tri-iodothyronine increased, blood iron decreased, blood phosphorus decreased, blood potassium increased, lymphocyte count abnormal, monocyte count increased, neutrophil count increased, platelet count decreased, platelet count increased, protein total increased, thyroxine decreased, white blood cell count, white blood cell count increased.

Metabolism and Nutrition Disorders: hypokalaemia, diabetes mellitus, hypercholesterolaemia, hypertriglyceridaemia, hypocalcaemia, hypoglycaemia, increased appetite, ketoacidosis.

Musculoskeletal and Connective Tissue Disorders: muscle twitching, sensation of heaviness, arthropathy, bone pain, bursitis, intervertebral disc disorder, joint stiffness, bone disorder, costochondritis, flank pain, ganglion, joint effusion, osteoporosis, pain in jaw, periarthritis, spinal osteoarthritis, torticollis.

Neoplasms Benign, Malignant and Unspecified (Incl Cysts and Polyps): thyroid neoplasm, basal cell carcinoma, breast cancer, breast neoplasm, fibroadenoma of breast, uterine leiomyoma.

Nervous System Disorders: coordination abnormal, dysgeusia, neuralgia, restless legs syndrome, amnesia, carpal tunnel syndrome, cognitive disorder, disturbance in attention, hyperaesthesia, multiple sclerosis, sciatica, somnolence, syncope, aphasia, burning sensation, dizziness postural, dyskinesia, dystonia, head discomfort, lethargy, muscle contractions involuntary, myoclonus, sensory disturbance, syncope vasovagal.

Pregnancy, Puerperium and Perinatal Conditions: abortion spontaneous.

Psychiatric Disorders: apathy, confusional state, suicidal ideation, anxiety disorder, libido decreased, nightmare, suicide attempt, tension.

Renal and Urinary Disorders: glycosuria, dysuria, nocturia, urine odour abnormal, bladder disorder, ketonuria, proteinuria, renal colic, stress incontinence, urinary retention, urinary tract disorder.

Reproductive System and Breast Disorders: breast mass, sexual dysfunction, breast pain, endometriosis, genital disorder female, oligomenorrhoea, ovarian cyst, pelvic pain, pruritus genital, scrotal pain, vaginal discharge, vaginal prolapsed, vulvovaginal discomfort.

Respiratory, Thoracic and Mediastinal Disorders: rhinitis allergic, rhinorrhoea, asthma, dysphonia, postnasal drip, rales, wheezing, breath sounds decreased, nasal discomfort, nasopharyngeal disorder, pleurisy, productive cough, rhinitis seasonal, rhonchi.

Skin and Subcutaneous Tissue Disorders: acne, rash erythematous, dermatitis allergic, livedo reticularis, rash maculo-papular, skin disorder, urticaria, alopecia areata, blister, cold sweat, dermatitis, dermatitis bullous, dermatitis contact, eczema, ephelides, erythema, exanthem, hypotrichosis, nail disorder, onychorrhexis, palmar erythema, photosensitivity allergic reaction, pruritus allergic, rash scaly, rash vesicular, rosacea, skin discolouration, skin nodule.

Vascular Disorders: flushing, haematoma, phlebitis, varicose vein.

Study 27025 (REFLEX): Adverse Reactions

In addition to the above listed adverse events, the following events have been experienced less frequently (i.e. in less than 1% of the double-blind treatment period) during the 24 months of treatment:

Blood and Lymphatic System Disorders: iron deficiency anaemia, monocytopenia, monocytosis, pancytopenia.

Endocrine Disorders: autoimmune thyroiditis, hyperthyroidism, thyroid disorder.

Gastrointestinal Disorders: nausea, abdominal mass, diarrhoea.

General Disorders and Administration Site Conditions: injection site discolouration, injection site pruritus, feeling cold, injection site haemorrhage, injection site induration, injection site mass, injection site papule, injection site swelling, injection site urticaria, injection site warmth, irritability, pain.

Hepatobiliary Disorders: biliary dyskinesia, liver disorder.

Infections and Infestations: influenza, viral upper respiratory tract infection, bronchitis, furuncle, gastroenteritis viral, oral candidiasis, subcutaneous abscess.

Investigations: weight increased, gamma-glutamyltransferase increased, haematocrit decreased, haemoglobin decreased, red blood cell count decreased, serum ferritin increased, thyroid function test abnormal, white blood cell count decreased.

Musculoskeletal and Connective Tissue Disorders: arthralgia, musculoskeletal stiffness.

Nervous System Disorders: autonomic nervous system imbalance, dysaesthesia, extrapyramidal disorder, loss of consciousness, somnolence.

Psychiatric Disorders: anxiety, anxiety disorder, sleep disorder.

Reproductive System and Breast Disorders: erectile dysfunction, menstrual disorder, vaginal haemorrhage.

Skin and Subcutaneous Tissue Disorders: pruritus, rash.

8.5. Post-Market Adverse Reactions

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.

Blood and lymphatic system disorders: Pancytopenia, thrombotic microangiopathy including thrombotic thrombocytopenic purpura and haemolytic uraemic syndrome

Eye disorders: Retinal vascular disorders (i.e. retinopathy, cotton wool spots, obstruction of retinal artery or vein)

General disorders and administration site conditions: Injection site necrosis, increased sweating

Infections and infestations: Injection site infections, including cellulitis which could be severe and injection site abscesses

Hepatobiliary disorders: Hepatic failure, hepatitis with or without icterus, autoimmune hepatitis, asymptomatic transaminases increase

Immune system disorders: Anaphylactic reaction

Muskuloskeletal and connective tissue disorders: Drug-induced lupus erythematosus

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

Psychiatric disorders: Suicide attempt

Renal and urinary disorders: Rare: Nephrotic syndrome, glomerulosclerosis (see 7 Warnings and Precautions).

Skin and subcutaneous tissue disorders: Angioedema (Quincke’s edema), urticaria, erythema multiforme, erythema multiforme-like skin reactions, hair loss, Stevens-Johnson Syndrome

Vascular disorders: Thromboembolic events

9. Drug Interactions

9.2. Drug Interactions Overview

No formal drug interaction studies have been conducted with REBIF 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. REBIF should not be mixed with other drugs in the same syringe. It is not known if interferons alter the efficacy of hormonal contraceptives.

9.3. Drug-Behaviour Interactions

The interaction of REBIF with individual behavioural risks (e.g. cigarette smoking, cannabis use, and/or alcohol consumption) has not been studied.

9.4. Drug-Drug Interactions

Interactions with other drugs have not been established.

9.5. Drug-Food Interactions

This drug may be taken with or without food.

9.6. Drug-Herb Interactions

Interactions with herbal products have not been established.

9.7. Drug-Laboratory Test Interactions

Interactions with laboratory tests have not been established.

10. Clinical Pharmacology

10.1. Mechanism of Action

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.

10.2. Pharmacodynamics

2'-5'-oligoadenylate synthetase is an enzyme shown to be produced in response to exposure to IFN both in vitro and in vivo. In the above mentioned randomized study, it was found to increase following REBIF administration, however, the mean peak elevation was independent of the route of administration. The increase in (2-5A) synthetase levels was maximal at 24 h (earlier samples were not collected) and levels were still significantly elevated 72 h after REBIF injection.

Previous work has shown these biomarkers to be of value in assessing the pharmacodynamics of interferons, but the relationship between serum IFN-beta concentration, measurable pharmacodynamic response and the mechanism(s) by which REBIF exerts therapeutic effects in multiple sclerosis remains essentially unknown.

Additional studies investigated the importance of increased frequency of administration. The results confirmed that more frequent administration (i.e., three times per week vs. once per week) elicits the optimal pharmacologic response.

10.3. Pharmacokinetics

The following studies are based on the original REBIF formulation (HSA formulation). This formulation is being replaced with the REBIF HSA-free Formulation described below (see 10.3 Pharmacokinetics, Clinical Pharmacology Program with the HSA-free Formulation of Interferon beta-1a:).

In a randomized, double-blind, placebo-controlled, cross-over study, 12 healthy volunteers were injected with a single dose of 22 mcg REBIF by the IV, IM or SC route. The pharmacokinetic analysis showed that 22 mcg REBIF administered by the IV route follows a two-compartment model with a short distribution half-life of approximately 5 minutes and an elimination half-life of about 5 h, (similar results have also been reported for IFN-beta-1b). Following IM or SC administration, REBIF showed a rather flat plasma concentration/time curve, (similar to the data obtained in rats and monkeys), with an absolute bioavailability of about 15%.

The bioavailability of human interferon beta following single-dose subcutaneous and intramuscular administration of recombinant human interferon beta-1a was compared. The pharmacokinetic parameters showed a high intersubject variability, but intramuscular and subcutaneous routes of administration demonstrated equivalent bioavailability.

Clinical Pharmacology Program with the HSA-free Formulation of Interferon beta-1a:

Human Pharmacokinetics:

The clinical pharmacology program compared the HSA-free Formulation of REBIF to the previously marketed HSA-containing formulation of REBIF at a dose of 44 mcg interferon beta-1a. The biocomparability assessment that was performed as a secondary objective of the study was influenced by the high variability of the PK parameters. Standard bioequivalence criteria were not met for C_max or AUClast.

The table below represents summary of the results of a non-compartmental analysis between the previously marketed formulation of REBIF and the current HSA-free formulation of REBIF, based on Study 25394 and 25827.

Special Tolerance Studies in Human: In an open-label study in patients with malignant diseases unresponsive to standard therapies, REBIF was given as a bolus IV injection on day 1, followed one week later by daily subcutaneous injections for 28 consecutive days at the following dose levels: 5.5, 11, 22, 44, 66 or 88 mcg/m². Preliminary results indicate that the maximum tolerated dose is probably 44 mcg/m².

10.4. Immunogenicity

All therapeutic proteins have the potential for immunogenicity.

The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies in the studies described below with the incidences of antibodies in other studies or to other products may be misleading.

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 (see 7 Warnings and Precautions, Immune).

1. 11. Storage, Stability, and Disposal

Refer to the date indicated on the labels for the expiry date. REBIF New HSA-free Formulation liquid in a pre-filled syringe or pre-filled cartridge should be stored at 2°C - 8°C. REBIF New HSA-free Formulation in pre-filled syringes or pre-filled cartridges may be stored for a limited period at room temperature (up to 25°C), but not more than 1 month. Do not freeze.

12. Special Handling Instructions

The liquid in the pre-filled syringe is ready for use.

The liquid in the pre-filled cartridge is ready for use with the RebiSmart autoinjection device. Both devices should be stored in their respective device storage boxes, and when a REBIF pre-filled cartridge is inserted, the box should be stored as per product storage conditions (see 11 Storage, Stability, and Disposal).

Part 2: Scientific Information

13. Pharmaceutical Information

Drug Substance

Non-proprietary name of the drug substance(s): BAN: Interferon beta-1a

INN: Interferon beta-1a

USAN: Interferon beta-1a

Chemical name: [text]

Molecular formula and molecular mass: Approximately 22,500 daltons, identical to the natural human IFN-beta

Structure (for biologics)/Structural formula:

The full amino acid sequence is as follows:

* Asn-80 N-glycosylation site

Physicochemical properties: IFN-beta-1a is a glycoprotein of 166 amino acids, it has 3 cysteines at positions 17, 31 and 141, a single disulphide bridge and an N-linked carbohydrate moiety primarily of the biantennary complex type attached to Asn-80.

Bulk hIFN-beta-1a is a clear, colourless to yellowish solution.

pH: 3.5 – 4.5 for the pre-filled syringe/3.5 - 4.1 for the pre-filled cartridge

Pharmaceutical standard: Professed

Product Characteristics:

REBIF is a purified, sterile glycoprotein product produced by recombinant DNA techniques and formulated for use by injection. The active ingredient of REBIF 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)/mcg Interferon beta-1a. The unit measurement is derived by comparing the antiviral activity of the product to an in-house natural hIFN-β NIH standard that is obtained from human fibroblasts (BILS 11), which has been calibrated against the NIH natural hIFN-β standard (GB 23-902-531).

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

Solution for injection in a pre-filled cartridge

The liquid formulation is supplied in cartridges containing 1.5 mL of solution. Each cartridge contains Interferon beta-1a, mannitol, poloxamer-188, methionine, benzyl alcohol and 0.01 M sodium acetate buffer, as indicated in the table below.

Table 10 – Composition of REBIF Pre-filled Cartridges

14. Clinical Trials

14.1. Clinical Trials by Indication

REBIF (Interferon beta-1a Injection) has been tested in seven large, well-controlled studies of 3256 patients with 2296 on active therapy.

Study GF6789 (PRISMS: Prevention of Relapses and Disability by Interferon β-1a Subcutaneously in relapsing-remitting Multiple Sclerosis)

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 and a history of 2 or more acute exacerbations in the 2 years prior to study entry were enrolled and randomized to 3 treatments (placebo, 22 mcg REBIF, or 44 mcg REBIF) in a ratio of 1:1:1. About 90% of patients completed the 2 years of treatment, and entered the extension phase: 167 from the original 44 mcg three times a week group, 167 from the original 22 mcg three times a week group, and 172 from the original placebo group. Prior to the start of the extension phase and without knowledge of study results, all patients from the original placebo group were re-randomized to receive either 22 or 44 mcg three times a week (85 randomized to 22 mcg, and 87 randomized to 44 mcg). The patients from the original 22 and 44 mcg three times a week groups continued their treatment as originally randomized. Of the original 560 patients enrolled in the study, 445 (79%) remained in the study to the end of year 4. Less than 10 % of patients treated with active therapy withdrew for adverse events over 4 years.

REBIF 66 mcg weekly (22 mcg, 3x/week) and 132 mcg weekly (44 mcg, 3x/week) had a significant effect on the primary outcome measure by reducing relapse count compared to placebo. The relapse rate reduction continued during years 3 and 4 of therapy. Patients converting to REBIF from placebo demonstrated a 52-53% reduction in relapse rate compared to years on placebo. Over 4 years, REBIF 132 mcg weekly was superior to REBIF 66 mcgweekly in reducing relapses and although this difference did not achieve statistical significance (p= 0.069), neither was the study powered to demonstrate a significant difference between two active treatment arms. REBIF 132 mcgweekly reduced the time to onset of progression of disability by 18 months compared to placebo crossover patients. High dose REBIF also reduced the number of EDSS 1-point changes made by a patient compared to placebo and compared to REBIF 66 mcgweekly. Both doses strongly diminished the MRI active lesion development and the accumulation of lesion burden over time compared to placebo. REBIF 132 mcg weekly was significantly more effective on MRI outcomes than REBIF 66 mcg weekly. These data demonstrate a continued benefit of REBIF therapy up to 4 years and provide further evidence of a dose-effect relationship in MS. Whereas after two years of therapy, there had been a consistent trend in favour of the high dose which was statistically significant for MRI active lesions, further observation to 4 years showed that these trends continued and for the majority of endpoints became statistically significant. Finally, patients treated early (study start) attained more benefit at 4 years than those delaying treatment until the start of year 3.