Emaxem

Emaxem is indicated for the treatment of

- Patients diagnosed with relapsing multiple sclerosis (MS). In clinical trials, this was characterised by two or more acute exacerbations (relapses) in the previous three-years without evidence of continuous progression between relapses; Emaxem slows the progression of disability and decreases the frequency of relapses.

- Patients with a single demyelinating event with an active inflammatory process, if it is severe enough to warrant treatment with intravenous corticosteroids, if alternative diagnoses have been excluded, and if they are determined to be at high risk of developing clinically definite multiple sclerosis.

Emaxem should be discontinued in patients who develop progressive MS.

Emaxem is indicated for the treatment of

- patients with a single demyelinating event with an active inflammatory process, if it is severe enough to warrant treatment with intravenous corticosteroids, if alternative diagnoses have been excluded, and if they are determined to be at high risk of developing clinically definite multiple sclerosis.

- patients with relapsing-remitting multiple sclerosis and two or more relapses within the last two years.

- patients with secondary progressive multiple sclerosis with active disease, evidenced by relapses.

Initiation Pack & Emaxem 44

Emaxem is indicated for the treatment of

- patients with a single demyelinating event with an active inflammatory process, if alternative diagnoses have been excluded, and if they are determined to be at high risk of developing clinically definite multiple sclerosis

- patients with relapsing multiple sclerosis. In clinical trials, this was characterised by two or more acute exacerbations in the previous two years.

Efficacy has not been demonstrated in patients with secondary progressive multiple sclerosis without ongoing relapse activity.

Emaxem 22

Emaxem is indicated for the treatment of relapsing multiple sclerosis.

In clinical trials, this was characterised by two or more acute exacerbations in the previous two years.

Efficacy has not been demonstrated in patients with secondary progressive multiple sclerosis without ongoing relapse activity.

Treatment should be initiated under supervision of a physician experienced in the treatment of the disease.

Posology

Adults: The recommended dosage for the treatment of relapsing MS is 30 micrograms (0.5 ml solution), administered by intramuscular (IM) injection once a week. No additional benefit has been shown by administering a higher dose (60 micrograms) once a week.

Titration: To help patients reduce the incidence and severity of flu-like symptoms , titration can be performed at the initiation of treatment. Titration using the BIOSET or pre-filled syringe can be achieved by initiating therapy on ¼ dose increments per week reaching the full dose (30 micrograms/week) by the fourth week.

An alternative titration schedule can be achieved by initiating therapy on approximately a ½ dose of Emaxem once a week before increasing to the full dose. In order to obtain adequate efficacy, a dose of 30 micrograms once a week should be reached and maintained after the initial titration period.

The AVOSTARTCLIP titration kit is designed for use with the pre-filled syringe only. It can be used to achieve the ¼ or ½ dose increments. Each AVOSTARTCLIP should be used once and then discarded along with any remaining Emaxem in the syringe.

Prior to injection and for an additional 24 hours after each injection, an antipyretic analgesic is advised to decrease flu-like symptoms associated with Emaxem administration. These symptoms are usually present during the first few months of treatment.

Paediatric population: The safety and efficacy of Emaxem in adolescents aged 12 to 16 years have not yet been established.1 but no recommendation on a posology can be made.

The safety and efficacy of Emaxem in children below 12 years of age have not yet been established.

No data are available

Elderly: Clinical studies did not include a sufficient number of patients aged 65 and over to determine whether they respond differently than younger patients. However, based on the mode of clearance of the active substance there are no theoretical reasons for any requirement for dose adjustments in the elderly.

Method of administration

The intramuscular injection site should be varied each week.

Doctors may prescribe a 25 mm, 25 gauge needle to patients for whom such a needle is appropriate to administer an intramuscular injection.

At the present time, it is not known for how long patients should be treated. Patients should be clinically evaluated after two years of treatment and longer-term treatment should be decided on an individual basis by the treating physician. Treatment should be discontinued if the patient develops chronic progressive MS.

The treatment with Emaxem should be initiated under the supervision of a physician experienced in the treatment of the disease.

Posology

Adults

The recommended dose of Emaxem is 250 microgram (8.0 million IU), contained in 1 ml of the reconstituted solution , to be injected subcutaneously every other day.

Paediatric population

No formal clinical trials or pharmacokinetic studies have been conducted in children or adolescents. However, limited published data suggest that the safety profile in adolescents from 12 to 16 years of age receiving Emaxem 8.0 million IU subcutaneously every other day is similar to that seen in adults. There is no information on the use of Emaxem in children under 12 years of age. Therefore Emaxem should not be used in this population.

Generally, dose titration is recommended at the start of treatment.

Patients should be started at 62.5 microgram (0.25 ml) subcutaneously every other day, and increased slowly to a dose of 250 microgram (1.0 ml) every other day (see Table A). The titration period may be adjusted, if any significant adverse reaction occurs. In order to obtain adequate efficacy, a dose of 250 microgram (1.0 ml) every other day should be reached.

A titration pack composed of four triple packs is available for the titration period and the patient's initial treatment with Emaxem. This package meets the patient's needs for the first 12 injections. The triple packs are highlighted in different colours.

Table A: Schedule for dose titration*

* The titration period may be adjusted, if any significant adverse reaction occurs.

The optimal dose has not been fully clarified.

At the present time, it is not known how long the patient should be treated for. There are follow-up data under controlled clinical conditions for patients with relapsing-remitting MS for up to 5 years and for patients with secondary progressive MS for up to 3 years. For relapsing-remitting MS, efficacy has been demonstrated for therapy for the first two years. The available data for the additional three years are consistent with sustained treatment efficacy of Emaxem over the whole time period.

In patients with a single clinical event suggestive of multiple sclerosis, the progression to clinically definite multiple sclerosis was significantly delayed over a period of five years.

Treatment is not recommended in patients with relapsing-remitting multiple sclerosis who have experienced less than 2 relapses in the previous 2 years or in patients with secondary-progressive multiple sclerosis who have had no active disease in the previous 2 years.

If the patient fails to respond, for example a steady progression in EDSS for 6 months occurs or treatment with at least 3 courses of ACTH or corticosteroids during a one year period is required despite Emaxem therapy, treatment with Emaxem should be stopped.

Method of administration

For subcutaneous injection.

Treatment should be initiated under supervision of a physician experienced in the treatment of the disease.

Posology

The Emaxem initiation package corresponds to the patient needs for the first month of treatment. When first starting treatment with Emaxem, in order to allow tachyphylaxis to develop thus reducing adverse reactions, it is recommended that patients be started at 8.8 micrograms dose subcutaneously and the dose be increased over a 4 week period to the targeted dose, according to the following schedule:

First demyelinating event

The posology for patients who have experienced a first demyelinating event is 44 micrograms of Emaxem given three times per week by subcutaneous injection.

Relapsing multiple sclerosis

The recommended posology of Emaxem is 44 micrograms given three times per week by subcutaneous injection. A lower dose of 22 micrograms, also given three times per week by subcutaneous injection, is recommended for patients who cannot tolerate the higher dose in view of the treating specialist.

Paediatric population

No formal clinical trials or pharmacokinetic studies have been conducted in children or adolescents. However, a paediatric retrospective cohort study collected safety data with Emaxem from medical records in children (n=52) and adolescents (n=255). The results of this study suggest that the safety profile in children (2 to 11 years old) and in adolescents (12 to 17 years old) receiving Emaxem 22 micrograms or 44 micrograms subcutaneous three times per week is similar to that seen in adults.

The safety and efficacy of Emaxem in children below 2 years of age have not been established. Emaxem should not be used in this age group.

Method of administration

Emaxem solution for subcutaneous injection in a cartridge is intended for multidose use with either the RebiSmart electronic injection device or the RebiSlide manual pen-injector device following adequate training of the patient and/or carer. The physician should discuss with the patient which device is the most appropriate. Patients with poor vision should not use RebiSlide unless someone with good eyesight can provide support.

For administration, the instructions provided in the package leaflet and in the instruction manual (Instructions for Use) provided with RebiSmart and RebiSlide should be followed.

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

At the present time, it is not known for how long patients should be treated. Safety and efficacy with Emaxem have not been demonstrated beyond 4 years of treatment. It is recommended that patients should be evaluated at least every second year in the 4-year period after initiation of treatment with Emaxem and a decision for longer term treatment should then be made on an individual basis by the treating physician.

- Initiation of treatment in pregnancy.

- Patients with current severe depression and/or suicidal ideation.

- Initiation of treatment in pregnancy.

-

- Patients with current severe depression and/or suicidal ideation.

- Patients with decompensated liver disease.

- Current severe depression and/or suicidal ideation.

Emaxem should be administered with caution to patients with previous or current depressive disorders, in particular to those with antecedents of suicidal ideation. Depression and suicidal ideation are known to occur in increased frequency in the multiple sclerosis population and in association with interferon use. Patients should be advised to immediately report any symptoms of depression and/or suicidal ideation to their prescribing physician.

Patients exhibiting depression should be monitored closely during therapy and treated appropriately.8).

Emaxem should be administered with caution to patients with a history of seizures, to those receiving treatment with anti-epileptics, particularly if their epilepsy is not adequately controlled with anti-epileptics.

Caution should be used and close monitoring considered when administering Emaxem to patients with severe renal and hepatic failure and to patients with severe myelosuppression.

Thrombotic microangiopathy (TMA): Cases of thrombotic microangiopathy, manifested as thrombotic thrombocytopenic purpura (TTP) or haemolytic uraemic syndrome (HUS), including fatal cases, have been reported with interferon beta products. Events were reported at various time points during treatment and may occur several weeks to several years after starting treatment with interferon beta. Early clinical features include thrombocytopenia, new onset hypertension, fever, central nervous system symptoms (e.g. confusion, paresis) and impaired renal function. Laboratory findings suggestive of TMA include decreased platelet counts, increased serum lactate dehydrogenase (LDH) due to haemolysis and schistocytes (erythrocyte fragmentation) on a blood film. Therefore if clinical features of TMA are observed, further testing of blood platelet levels, serum LDH, blood films and renal function is recommended. If TMA is diagnosed, prompt treatment is required (considering plasma exchange) and immediate discontinuation of Emaxem is recommended.

Nephrotic Syndrome: Cases of nephrotic syndrome with different underlying nephropathies including collapsing focal segmental glomerulosclerosis (FSGS), minimal change disease (MCD), membranoproliferative glomerulonephritis (MPGN) and membranous glomerulopathy (MGN) have been reported during treatment with interferon-beta products. Events were reported at various time points during treatment and may occur after several years of treatment with interferon beta. Periodic monitoring of early signs or symptoms, e.g. oedema, proteinuria and impaired renal function is recommended, especially in patients at higher risk of renal disease. Prompt treatment of nephrotic syndrome is required and discontinuation of treatment with Emaxem should be considered.

Hepatic injury including elevated serum hepatic enzyme levels, hepatitis, autoimmune hepatitis and hepatic failure has been reported with interferon beta in post-marketing. In some cases, these reactions have occurred in the presence of other medicinal products that have been associated with hepatic injury. The potential of additive effects from multiple medicinal products or other hepatotoxic agents (e.g. alcohol) has not been determined. Patients should be monitored for signs of hepatic injury and caution exercised when interferons are used concomitantly with other medicinal products associated with hepatic injury.

Patients with cardiac disease, such as angina, congestive heart failure or arrhythmia, should be closely monitored for worsening of their clinical condition during treatment with Emaxem. Flu-like symptoms associated with Emaxem therapy may prove stressful to patients with underlying cardiac conditions.

Laboratory abnormalities are associated with the use of interferons. Therefore, in addition to those laboratory tests normally required for monitoring patients with MS, complete and differential white blood cell counts, platelet counts, and blood chemistry, including liver function tests, are recommended during Emaxem therapy. Patients with myelosuppression may require more intensive monitoring of complete blood cell counts, with differential and platelet counts.

Patients may develop antibodies to Emaxem. The antibodies of some of those patients reduce the activity of interferon beta-1a in vitro (neutralising antibodies). Neutralising antibodies are associated with a reduction in the in vivo biological effects of Emaxem and may potentially be associated with a reduction of clinical efficacy. It is estimated that the plateau for the incidence of neutralising antibody formation is reached after 12 months of treatment. Recent clinical studies with patients treated up to three years with Emaxem suggest that approximately 5% to 8% develop neutralising antibodies.

The use of various assays to detect serum antibodies to interferons limits the ability to compare antigenicity among different products.

Immune system disorders

The administration of cytokines to patients with a pre-existing monoclonal gammopathy has been associated with the development of systemic capillary leak syndrome with shock-like symptoms and fatal outcome.

Gastrointestinal disorders

In rare cases, pancreatitis was observed with Emaxem use, often associated with hypertriglyceridaemia.

Nervous system disorders

Emaxem should be administered with caution to patients with previous or current depressive disorders, in particular to those with antecedents of suicidal ideation.8).

Emaxem should be administered with caution to patients with a history of seizures and to those receiving treatment with anti-epileptics, particularly if their epilepsy is not adequately controlled with anti-epileptics.

This product contains human albumin and hence carries a potential risk for transmission of viral diseases. A risk for transmission of Creutzfeld-Jacob disease (CJD) cannot be excluded.

Laboratory test

Thyroid function tests are recommended regularly in patients with a history of thyroid dysfunction or as clinically indicated.

In addition to those laboratory tests normally required for monitoring patients with multiple sclerosis, complete blood and differential white blood cell counts, platelet counts, and blood chemistries, including liver function tests (e.g. AST (SGOT), ALT (SGPT) and γ-GT), are recommended prior to initiation and at regular intervals following introduction of Emaxem therapy, and then periodically thereafter in the absence of clinical symptoms.

Patients with anaemia, thrombocytopenia, leukopenia (alone or in any combination) may require more intensive monitoring of complete blood cell counts, with differential and platelet counts. Patients who develop neutropenia should be monitored closely for the development of fever or infection. There have been reports of thrombocytopenia, with profound decreases in platelet count.

Hepatobiliary disorders

Asymptomatic elevations of serum transaminases, in most cases mild and transient, occurred very commonly in patients treated with Emaxem during clinical trials. As for other beta interferons, severe hepatic injury, including cases of hepatic failure, has been reported rarely in patients treated with Emaxem. The most serious events often occurred in patients exposed to other drugs or substances known to be associated with hepatotoxicity or in the presence of comorbid medical conditions (e.g. metastasising malignant disease, severe infection and sepsis, alcohol abuse).

Patients should be monitored for signs of hepatic injury. The occurrence of elevations in serum transaminases should lead to close monitoring and investigation. Withdrawal of Emaxem should be considered if the levels significantly increase or if they are associated with clinical symptoms such as jaundice. In the absence of clinical evidence for liver damage and after normalisation of liver enzymes a reintroduction of therapy could be considered with appropriate follow-up of hepatic functions.

Renal and urinary disorders

Caution should be used and close monitoring considered when administering Interferon beta to patients with severe renal failure.

Nephrotic Syndrome

Cases of nephrotic syndrome with different underlying nephropathies including collapsing focal segmental glomerulosclerosis (FSGS), minimal change disease (MCD), membranoproliferative glomerulonephritis (MPGN) and membranous glomerulopathy (MGN) have been reported during treatment with interferon beta products. Events were reported at various time points during treatment and may occur after several years of treatment with interferon beta. Periodic monitoring of early signs or symptoms, e.g. oedema, proteinuria and impaired renal function is recommended, especially in patients at higher risk of renal disease. Prompt treatment of nephrotic syndrome is required and discontinuation of treatment with Emaxem should be considered.

Cardiac disorders

Emaxem should also be used with caution in patients who suffer from pre-existing cardiac disorders. Patients with pre-existing significant cardiac disease, such as congestive heart failure, coronary artery disease or arrhythmia, should be monitored for worsening of their cardiac condition, particularly during initiation of treatment with Emaxem.

While Emaxem does not have any known direct-acting cardiac toxicity, symptoms of the flu-like syndrome associated with beta interferons may prove stressful to patients with pre-existing significant cardiac disease. During the post-marketing period very rare reports have been received of worsening of cardiac status in patients with pre-existing significant cardiac disease temporarily associated with the initiation of Emaxem therapy.

Rare cases of cardiomyopathy have been reported. If this occurs and a relationship to Emaxem is suspected, treatment should be discontinued.

Thrombotic microangiopathy (TMA)

Cases of thrombotic microangiopathy, manifested as thrombotic thrombocytopenic purpura (TTP) or haemolytic uraemic syndrome (HUS), including fatal cases, have been reported with interferon beta products. Events were reported at various time points during treatment and may occur several weeks to several years after starting treatment with interferon beta. Early clinical features include thrombocytopenia, new onset hypertension, fever, central nervous system symptoms (e.g. confusion, paresis) and impaired renal function. Laboratory findings suggestive of TMA include decreased platelet counts, increased serum lactate dehydrogenase (LDH) due to haemolysis and schistocytes (erythrocyte fragmentation) on a blood film. Therefore if clinical features of TMA are observed, further testing of blood platelet levels, serum LDH, blood films and renal function is recommended. If TMA is diagnosed, prompt treatment is required (considering plasma exchange) and immediate discontinuation of Emaxem is recommended.

General disorders and administration site conditions

Serious hypersensitivity reactions (rare but severe acute reactions such as bronchospasm, anaphylaxis and urticaria) may occur. If reactions are severe, Emaxem should be discontinued and appropriate medical intervention instituted.

Injection site necrosis has been reported in patients using Emaxem. It can be extensive and may involve muscle fascia as well as fat and therefore can result in scar formation. Occasionally debridement and, less often, skin grafting are required and healing may take up to 6 months.

If the patient experiences any break in the skin, which may be associated with swelling or drainage of fluid from the injection site, the patient should be advised to consult with his/her physician before continuing injections with Emaxem.

If the patient has multiple lesions Emaxem should be discontinued until healing has occurred. Patients with single lesions may continue on Emaxem provided the necrosis is not too extensive, as some patients have experienced healing of injection site necrosis whilst on Emaxem.

To minimise the risk of injection site necrosis patients should be advised to:

- use an aseptic injection technique

- rotate the injection sites with each dose.

The incidence of injection site reactions may be reduced by the use of an autoinjector. In the pivotal study of patients with a single clinical event suggestive of multiple sclerosis an autoinjector was used in the majority of patients. Injection site reactions as well as injection site necroses were observed less frequently in this study than in the other pivotal studies.

The procedure for the self-administration by the patient should be reviewed periodically especially if injection site reactions have occurred.

Immunogenicity

As with all therapeutic proteins, there is a potential for immunogenicity. Serum samples in controlled clinical trials were collected every 3 months for monitoring of development of antibodies to Emaxem.

In the different controlled clinical trials in relapsing-remitting multiple sclerosis and secondary progressive multiple sclerosis, between 23% and 41% of the patients developed serum interferon beta-1b neutralising activity confirmed by at least two consecutive positive titres; of these patients, between 43% and 55% converted to a stable antibody negative status (based on two consecutive negative titres) during the subsequent observational period of the respective study.

The development of neutralising activity in these studies is associated with a reduction in clinical efficacy only with regard to relapse activity. Some analyses suggest that this effect might be larger in patients with higher titre levels of neutralising activity.

In the study of patients with a single clinical event suggestive of multiple sclerosis, neutralising activity measured every 6 months was observed at least once in 32% (89) of the patients treated immediately with Emaxem; of these, 60% (53) returned to negative status based on the last available assessment within the 5 year period. Within this period, the development of neutralising activity was associated with a significant increase in newly active lesions and T2 lesion volume on magnetic resonance imaging. However, this did not seem to be associated with a reduction in clinical efficacy (with regard to time to clinically definite multiple sclerosis (CDMS), time to confirmed EDSS progression and relapse rate).

New adverse events have not been associated with the development of neutralising activity.

It has been demonstrated in vitro that Emaxem cross-reacts with natural interferon beta. However, this has not been investigated in vivo and its clinical significance is uncertain.

There are sparse and inconclusive data on patients who have developed neutralising activity and have completed Emaxem therapy.

The decision to continue or discontinue treatment should be based on all aspects of the patient's disease status rather than on neutralising activity status alone.

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

Thrombotic microangiopathy (TMA)

Cases of thrombotic microangiopathy, manifested as thrombotic thrombocytopenic purpura (TTP) or haemolytic uraemic syndrome (HUS), including fatal cases, have been reported with interferon beta products. Events were reported at various time points during treatment and may occur several weeks to several years after starting treatment with interferon beta. Early clinical features include thrombocytopenia, new onset hypertension, fever, central nervous system symptoms (e.g. confusion, paresis) and impaired renal function. Laboratory findings suggestive of TMA include decreased platelet counts, increased serum lactate dehydrogenase (LDH) due to haemolysis and schistocytes (erythrocyte fragmentation) on a blood film. Therefore if clinical features of TMA are observed, further testing of blood platelet levels, serum LDH, blood films and renal function is recommended. If TMA is diagnosed, prompt treatment is required (considering plasma exchange) and immediate discontinuation of Emaxem is recommended.

Depression and suicidal ideation

Emaxem should be administered with caution to patients with previous or current depressive disorders in particular to those with antecedents of suicidal ideation. Depression and suicidal ideation are known to occur in increased frequency in the multiple sclerosis population and in association with interferon use. Patients treated with Emaxem should be advised to immediately report any symptoms of depression and/or suicidal ideation to their prescribing physician. Patients exhibiting depression should be monitored closely during therapy with Emaxem and treated appropriately. Cessation of therapy with Emaxem should be considered.

Seizure disorders

Emaxem should be administered with caution to patients with a history of seizures, to those receiving treatment with anti-epileptics, particularly if their epilepsy is not adequately controlled with anti-epileptics.

Cardiac disease

Patients with cardiac disease, such as angina, congestive heart failure or arrhythmia, should be closely monitored for worsening of their clinical condition during initiation of therapy with interferon beta-1a. Symptoms of the flu-like syndrome associated with interferon beta-1a therapy may prove stressful to patients with cardiac conditions.

Injection site necrosis

Injection site necrosis (ISN) has been reported in patients using Emaxem. To minimise the risk of injection site necrosis patients should be advised to:

- use an aseptic injection technique,

- rotate the injection sites with each dose.

The procedure for the self-administration by the patient should be reviewed periodically especially if injection site reactions have occurred.

If the patient experiences any break in the skin, which may be associated with swelling or drainage of fluid from the injection site, the patient should be advised to consult with their physician before continuing injections with Emaxem. If the patient has multiple lesions, Emaxem should be discontinued until healing has occurred. Patients with single lesions may continue provided that the necrosis is not too extensive.

Hepatic dysfunction

In clinical trials with Emaxem, asymptomatic elevations of hepatic transaminases (particularly alanine aminotransferase (ALT)) were common and 1-3% of patients developed elevations of hepatic transaminases above 5 times the upper limit of normal (ULN). In the absence of clinical symptoms, serum ALT levels should be monitored prior to the start of therapy, at months 1, 3 and 6 on therapy and periodically thereafter. Dose reduction of Emaxem should be considered if ALT rises above 5 times the ULN, and gradually re-escalated when enzyme levels have normalized. Emaxem should be initiated with caution in patients with a history of significant liver disease, clinical evidence of active liver disease, alcohol abuse or increased serum ALT (>2.5 times ULN). Treatment with Emaxem should be stopped if icterus or other clinical symptoms of liver dysfunction appear.

Emaxem, like other interferons beta, has a potential for causing severe liver injury including acute hepatic failure. The majority of the cases of severe liver injury occurred within the first six months of treatment. The mechanism for the rare symptomatic hepatic dysfunction is not known. No specific risk factors have been identified.

Renal and urinary disorders

Nephrotic syndrome

Cases of nephrotic syndrome with different underlying nephropathies including collapsing focal segmental glomerulosclerosis (FSGS), minimal change disease (MCD), membranoproliferative glomerulonephritis (MPGN) and membranous glomerulopathy (MGN) have been reported during treatment with interferon-beta products. Events were reported at various time points during treatment and may occur after several years of treatment with interferon-beta. Periodic monitoring of early signs or symptoms, e.g. oedema, proteinuria and impaired renal function is recommended, especially in patients at higher risk of renal disease. Prompt treatment of nephrotic syndrome is required and discontinuation of treatment with Emaxem should be considered.

Laboratory abnormalities

Laboratory abnormalities are associated with the use of interferons. The overall incidence of these is slightly higher with Emaxem 44 than Emaxem 22 micrograms. Therefore, in addition to those laboratory tests normally required for monitoring patients with multiple sclerosis, liver enzyme monitoring and complete and differential blood cell counts and platelet counts are recommended at regular intervals (1, 3 and 6 months) following introduction of Emaxem therapy and then periodically thereafter in the absence of clinical symptoms. These should be more frequent when initiating Emaxem 44 micrograms.

Thyroid disorders

Patients being treated with Emaxem may occasionally develop new or worsening thyroid abnormalities. Thyroid function testing is recommended at baseline and if abnormal, every 6-12 months following initiation of therapy. If tests are normal at baseline, routine testing is not needed but should be performed if clinical findings of thyroid dysfunction appear.

Severe renal or hepatic failure and severe myelosuppression

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

Neutralising antibodies

Serum neutralising antibodies against interferon beta-1a may develop. The precise incidence of antibodies is as yet uncertain. Clinical data suggest that after 24 to 48 months of treatment with Emaxem 22 micrograms, approximately 24% of patients develop persistent serum antibodies to interferon beta-1a and after 24 to 48 months of treatment with Emaxem 44 micrograms, approximately 13 to 14% of patients develop persistent serum antibodies to interferon beta-1a. The presence of antibodies has been shown to attenuate the pharmacodynamic response to interferon beta-1a (beta-2 microglobulin and neopterin). Although the clinical significance of the induction of antibodies has not been fully elucidated, the development of neutralising antibodies is associated with reduced efficacy on clinical and MRI variables. If a patient responds poorly to therapy with Emaxem, and has neutralising antibodies, the treating physician should reassess the benefit/risk ratio of continued Emaxem therapy.

The use of various assays to detect serum antibodies and differing definitions of antibody positivity limits the ability to compare antigenicity among different products.

Other forms of multiple sclerosis

Only sparse safety and efficacy data are available from non-ambulatory patients with multiple sclerosis. Emaxem has not yet been investigated in patients with primary progressive multiple sclerosis and should not be used in these patients.

Benzyl alcohol

Emaxem 8.8 mcg/0.1mL and Emaxem 22 mcg/0.25mL:

This medicinal product contains 0.5 mg benzyl alcohol per dose of 0.1 mL and 1.25 mg benzyl alcohol per dose of 0.25 mL.

It must not be given to premature babies or neonates. It may cause toxic reactions and anaphylactoid reactions in infants and children up to 3 years old.

Emaxem 22mcg/0.5mL:

Emaxem 44 mcg/0.5mL:

This medicinal product contains 2.5 mg benzyl alcohol per dose of 0.5 mL.

It must not be given to premature babies or neonates. It may cause toxic reactions and anaphylactoid reactions in infants and children up to 3 years old.

No studies on the effects of Emaxem on the ability to drive and use machines have been performed. Central nervous system-related adverse reactions may have a minor influence on the ability to drive and use machines in susceptible patients.

No studies of the effects on the ability to drive and use machines have been performed.

Central nervous system-related adverse events associated with the use of Emaxem might influence the ability to drive and use machines in susceptible patients.

Central nervous system-related adverse events associated with the use of interferon beta (e.g. dizziness) might influence the patient's ability to drive or use machines.

The highest incidence of adverse reactions associated with Emaxem therapy is related to flu-like symptoms. The most commonly reported flu-like symptoms are myalgia, fever, chills, sweating, asthenia, headache and nausea. Titrating Emaxem at the initiation of therapy has demonstrated a reduction in the severity and incidence of flu-like symptoms. Flu-like symptoms tend to be most prominent at the initiation of therapy and decrease in frequency with continued treatment.

Transient neurological symptoms that may mimic MS exacerbations may occur following injections. Transient episodes of hypertonia and/or severe muscular weakness that prevent voluntary movements may occur at any time during treatment. These episodes are of limited duration, temporally related to the injections and may recur after subsequent injections. In some cases these symptoms are associated with flu-like symptoms.

The frequencies of adverse reactions are expressed in patient-years, according to the following categories:

Very common (>1/10 patient-years);

Common (>1/100 to <1/10 patient-years);

Uncommon (>1/1, 000 to <1/100 patient-years);

Rare (>1/10, 000 to <1/1,000 patient-years);

Very rare (<1/10,000 patient-years);

Not known (cannot be estimated from the available data).

Patient-time is the sum of individual units of time that the patient in the study has been exposed to Emaxem before experiencing the adverse reaction. For example, 100 person-years could be observed in 100 patients who were on treatment for one year or in 200 patients who were on treatment for half a year.

Adverse reactions identified from studies (clinical trials and observational studies, with a period of follow-up ranging from two years to six years) and other adverse reactions identified through spontaneous reporting from the market, with unknown frequency, are provided in the table below.

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

*Class label for interferon beta products.

^┼ Class label for interferon products, see below Pulmonary arterial hypertension.

¹Injection site reactions including pain, inflammation and very rare cases of abscess or cellulitis that may require surgical intervention have been reported.

²The frequency of occurrence is higher at the beginning of treatment.

³A syncope episode may occur after Emaxem injection, it is normally a single episode that usually appears at the beginning of the treatment and does not recur with subsequent injections.

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.

Paediatric population

Limited published data suggest that the safety profile in adolescents from 12 to 16 years of age receiving Emaxem 30 micrograms IM once per week is similar to that seen in adults.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via:

Ireland

HPRA Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.hpra.ie

e-mail: [email protected]

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard

Summary of the safety profile

At the beginning of treatment adverse reactions are common but in general they subside with further treatment. The most frequently observed adverse reactions are a flu-like symptom complex (fever, chills, arthralgia, malaise, sweating, headache, or myalgia), which is mainly due to the pharmacological effects of the medicinal product, and injection site reactions. Injection site reactions occurred frequently after administration of Emaxem. Redness, swelling, discolouration, inflammation, pain, hypersensitivity, necrosis and non-specific reactions were significantly associated with 250 microgram (8.0 million IU) Emaxem treatment.

Generally, dose titration is recommended at the start of treatment in order to increase tolerability to Emaxem. Flu-like symptoms may also be reduced by administration of non-steroidal anti-inflammatory drugs. The incidence of injection site reactions may be reduced by the use of an autoinjector.

Tabulated list of adverse reactions

The following adverse event listing is based on reports from clinical trials (Table 1, adverse events and laboratory abnormalities) and from the post-marketing surveillance (Table 2, frequencies - where known- based on pooled clinical trials (very common >1/10, common >1/100 to <1/10, uncommon > 1/1,000 to < 1/100, rare >1/10,000 to <1/1,000, very rare < 1/10,000)) of Emaxem use. Experience with Emaxem in patients with MS is limited, consequently those adverse events which occur very rarely may not yet have been observed.

Table 1: Adverse events and laboratory abnormalities with incidence rates > 10% and the respective percentages under placebo; significantly associated side effects < 10% based on reports from clinical trials

The most appropriate MedDRA term is used to describe a certain reaction and its synonyms and related conditions.

Table 2: Adverse drug reactions (ADRs) identified during post-marketing surveillance (frequencies - where known - calculated based on pooled clinical trial data N= 1093)

The most appropriate MedDRA term is used to describe a certain reaction and its synonyms and related 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.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

Summary of the safety profile

The highest incidence of adverse reactions associated with Emaxem therapy is related to flu-like syndrome. Flu-like symptoms tend to be most prominent at the initiation of therapy and decrease in frequency with continued treatment. Approximately 70% of patients treated with Emaxem can expect to experience the typical interferon flu-like syndrome within the first six months after starting treatment. Approximately 30% of patients will also experience reactions at the injection site, predominantly mild inflammation or erythema. Asymptomatic increases in laboratory parameters of hepatic function and decreases in white blood cells are also common.

The majority of adverse reactions observed with interferon beta-1a are usually mild and reversible, and respond well to dose reductions. In case of severe or persistent undesirable effects, the dose of Emaxem may be temporarily lowered or interrupted, at the discretion of the physician.

List of adverse reactions

The adverse reactions presented have been identified from clinical studies as well as from post-marketing reports (an asterisk [*] indicates adverse reactions identified during post-marketing surveillance). The following definitions apply to the frequency terminology used hereafter:

- very common (>1/10)

- common (>1/100 to <1/10)

- uncommon (>1/1,000 to <1/100)

- rare (>1/10,000 to <1/1,000)

- very rare (<1/10,000)

- frequency not known (cannot be estimated from the available data).

Blood and the lymphatic system disorders

Very common: Neutropenia, lymphopenia, leukopenia, thrombocytopenia, anaemia

Rare: Thrombotic microangiopathy including thrombotic thrombocytopenic purpura/haemolytic uraemic syndrome* , pancytopenia*

Endocrine disorders

Uncommon: Thyroid dysfunction, most often presenting as hypothyroidism or hyperthyroidism

Immune system disorders

Rare: Anaphylactic reactions*

Hepatobiliary disorders

Very common: Asymptomatic transaminase increase

Common: Severe elevations in transaminases

Uncommon: Hepatitis with or without icterus*

Rare: Hepatic failure* , autoimmune hepatitis*

Psychiatric disorders

Common: Depression, insomnia

Rare: Suicide attempt*

Nervous system disorders

Very common: Headache

Uncommon: Seizures*

Frequency not known: Transient neurological symptoms (i.e. hypoesthesia, muscle spasm, paraesthesia, difficulty in walking, musculoskeletal stiffness) that may mimic multiple sclerosis exacerbations*

Eye disorders

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

Vascular disorders

Uncommon: Thromboembolic events*

Respiratory, thoracic and mediastinal disorders

Uncommon: Dyspnoea*

Not known: Pulmonary arterial hypertension* (class label for interferon beta products, see below Pulmonary arterial hypertension)

Gastrointestinal disorders

Common: Diarrhoea, vomiting, nausea

Skin and subcutaneous tissue disorders

Common: Pruritus, rash, erythematous rash, maculo-papular rash, alopecia*

Uncommon: Urticaria*

Rare: Quincke's oedema (angio-oedema)*, erythema multiforme*, erythema multiforme-like skin reactions*, Stevens Johnson syndrome*

Musculoskeletal and connective disorders

Common: Myalgia, arthralgia

Rare: Drug-induced lupus erythematosus*

Renal and urinary disorders

Rare: Nephrotic syndrome*, glomerulosclerosis*

General disorders and administration site conditions

Very common: Injection site inflammation, injection site reaction, influenza-like symptoms

Common: Injection site pain, fatigue, rigors, fever

Uncommon: Injection site necrosis, injection site mass, injection site abscess, injection site infections*, increased sweating*

Rare: Injection site cellulitis*

Paediatric population

No formal clinical trials or pharmacokinetic studies have been conducted in children or adolescents. Limited safety data suggest that the safety profile in children and adolescents (2 to 17 years old) receiving Emaxem 22 micrograms or 44 micrograms three times weekly is similar to that seen in adults.

Class effects

The administration of interferons has been associated with anorexia, dizziness, anxiety, arrhythmias, vasodilation and palpitation, menorrhagia and metrorrhagia.

An increased formation of auto-antibodies may occur during treatment with interferon beta.

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.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions (see details below).

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard

Ireland

HPRA Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.hpra.ie

e-mail: [email protected]

No case of overdose has been reported. However, in case of overdose, patients should be hospitalised for observation and appropriate supportive treatment given.

Interferon beta-1b has been given without serious adverse events compromising vital functions to adult cancer patients at individual doses as high as 5,500 microgram (176 million IU) intravenously three times a week.

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

Pharmacotherapeutic Group: Interferons, ATC code: L03 AB07.

Interferons are a family of naturally occurring proteins that are produced by eukaryotic cells in response to viral infection and other biological inducers. Interferons are cytokines that mediate antiviral, antiproliferative, and immunomodulatory activities. Three major forms of interferons have been distinguished: alpha, beta, and gamma. Interferons alpha and beta are classified as Type I interferons, and interferon gamma is a Type II interferon. These interferons have overlapping but clearly distinguishable biological activities. They can also differ with respect to their cellular sites of synthesis.

Interferon beta is produced by various cell types including fibroblasts and macrophages. Natural interferon beta and Emaxem (interferon beta-1a) are glycosylated and have a single N-linked complex carbohydrate moiety. Glycosylation of other proteins is known to affect their stability, activity, biodistribution, and half-life in blood. However, the effects of interferon beta that are dependent on glycosylation are not fully defined.

Mechanism of action

Emaxem exerts its biological effects by binding to specific receptors on the surface of human cells. This binding initiates a complex cascade of intracellular events that leads to the expression of numerous interferon-induced gene products and markers. These include MHC Class I, Mx protein, 2' / 5'-oligoadenylate synthetase, β₂-microglobulin, and neopterin. Some of these products have been measured in the serum and cellular fractions of blood collected from patients treated with Emaxem. After a single intramuscular dose of Emaxem, serum levels of these products remain elevated for at least four days and up to one week.

Whether the mechanism of action of Emaxem in MS is mediated by the same pathway as the biological effects described above is not known because the pathophysiology of MS is not well established.

Clinical efficacy and safety

The effects of lyophilised Emaxem in the treatment of MS were demonstrated in a placebo-controlled study of 301 patients (Emaxem n=158, placebo n=143) with relapsing MS characterised by at least 2 exacerbations in the previous 3 years or at least one exacerbation per year prior to entry when the duration of the disease was less than 3 years. Patients with an EDSS of 1.0 to 3.5 at entry were included in the clinical trial. Due to the design of the study, patients were followed for variable lengths of time. 150 Emaxem-treated patients completed one year on study and 85 completed two years on study. In the study, the cumulative percentage of patients who developed disability progression (by Kaplan-Meier life table analysis) by the end of two years was 35% for placebo-treated patients and 22% for Emaxem-treated patients. Disability progression was measured as an increase in the Expanded Disability Status Scale (EDSS) of 1.0 point, sustained for at least six months. It was also shown that there was a one-third reduction in annual relapse rate. This latter clinical effect was observed after more than one year of treatment.

A double-blind randomised dose comparison study of 802 relapsing MS patients (Emaxem 30 micrograms n=402, Emaxem 60 micrograms n=400) has shown no statistically significant differences or trends between the 30 micrograms and the 60 micrograms doses of Emaxem in clinical and general MRI parameters.

The effects of Emaxem in the treatment of MS were also demonstrated in a randomised double-blind study performed with 383 patients (Emaxem n=193, placebo n=190) with a single demyelinating event associated with at least two compatible brain MRI lesions. A reduction of the risk of experiencing a second event was noted in the Emaxem treatment group. An effect on MRI parameters was also seen. The estimated risk of a second event was 50% in three years and 39% in two years in the placebo group and 35% (three years) and 21% (two years) in the Emaxem group. In a post-hoc analysis, those patients with a baseline MRI with at least one Gd-enhancing lesion and nine T2 lesions had a two-year risk of suffering a second event of 56% in the placebo group and 21% in the Emaxem treatment group. However, the impact of early treatment with Emaxem is unknown even in this high-risk subgroup as the study was mainly designed to assess the time to the second event rather than the long-term evolution of the disease. Furthermore, for the time-being there is no well established definition of a high risk patient although a more conservative approach is to accept at least nine T2 hyperintense lesions on the initial scan and at least one new T2 or one new Gd-enhancing lesion on a follow-up scan taken at least three months after the initial scan. In any case, treatment should only be considered for patients classified at high risk.

Paediatric population

Limited data of the efficacy/safety of Emaxem 15 micrograms IM once per week (n=8) as compared to no treatment (n=8) with follow up for 4 years showed results in line to those seen in adults, although the EDSS scores increased in the treated group over the 4 year follow-up thus indicating disease progression. No direct comparison with the dose currently recommended in adults is available.

Pharmacotherapeutic group: Cytokines, Interferons,

ATC Code: L03 AB 08

Mechanism of action

Interferons belong to the family of cytokines, which are naturally occurring proteins. Interferons have molecular weights ranging from 15,000 to 21,000 Daltons. Three major classes of interferons have been identified: alpha, beta, and gamma. Interferon alpha, interferon beta, and interferon gamma have overlapping yet distinct biologic activities. The activities of interferon beta-1b are species-restricted and therefore, the most pertinent pharmacological information on interferon beta-1b is derived from studies of human cells in culture or in human in vivo studies.

Interferon beta-1b has been shown to possess both antiviral and immunoregulatory activities. The mechanisms by which interferon beta-1b exerts its actions in multiple sclerosis are not clearly understood. However, it is known that the biologic response-modifying properties of interferon beta-1b are mediated through its interactions with specific cell receptors found on the surface of human cells. The binding of interferon beta-1b to these receptors induces the expression of a number of gene products that are believed to be the mediators of the biological actions of interferon beta-1b. A number of these products have been measured in the serum and cellular fractions of blood collected from patients treated with interferon beta-1b. Interferon beta-1b both decreases the binding affinity and enhances the internalisation and degradation of the interferon-gamma receptor. Interferon beta-1b also enhances the suppressor activity of peripheral blood mononuclear cells.

No separate investigations were performed regarding the influence of Emaxem on the cardiovascular system, respiratory system and the function of endocrine organs.

Clinical efficacy and safety

RR-MS

One controlled clinical trial with Emaxem in patients with relapsing-remitting multiple sclerosis and able to walk unaided (baseline EDSS 0 to 5.5) was performed. Patients receiving Emaxem showed a reduction in frequency (30%) and severity of clinical relapses, as well as the number of hospitalisations due to disease. Furthermore, there was a prolongation of the relapse-free interval. There is no evidence of an effect of Emaxem on the duration of relapses or on symptoms in between relapses, and no significant effect was seen on the progression of the disease in relapsing-remitting multiple sclerosis.

SP-MS

Two controlled clinical trials with Emaxem involving a total of 1,657 patients with secondary progressive multiple sclerosis (baseline EDSS 3 to 6.5, i.e. patients were able to walk) were performed. Patients with mild disease and those unable to walk were not studied. The two studies showed inconsistent results for the primary endpoint time to confirmed progression, representing delay of disability progression:

One of the two studies demonstrated a statistically significant delay in the time to disability progression (Hazard Ratio = 0.69, 95% confidence interval (0.55, 0.86), p=0.0010, corresponding to a 31% risk reduction due to Emaxem) and in the time to becoming wheelchair bound (Hazard Ratio = 0.61, 95% confidence interval (0.44, 0.85), p=0.0036, corresponding to a 39% risk reduction due to Emaxem) in patients who received Emaxem. This effect continued over the observation period of up to 33 months. The treatment effect occurred in patients at all levels of disability investigated and independent of relapse activity.

In the second trial of Emaxem in secondary progressive multiple sclerosis, no delay in the time to disability progression was observed. There is evidence that the patients included in this study had overall less active disease than in the other study in secondary progressive multiple sclerosis.

In retrospective meta-analyses including the data of both studies, an overall treatment effect was found which was statistically significant (p=0.0076; 8.0 million IU Emaxem versus all placebo patients).

Retrospective analyses in subgroups showed that a treatment effect on disability progression is most likely in patients with active disease before treatment commences (Hazard Ratio 0.72, 95% confidence interval (0.59, 0.88), p=0.0011, corresponding to a 28 % risk reduction due to Emaxem in patients with relapses or pronounced EDSS progression, 8.0 million IU Emaxem versus all placebo patients).

From these retrospective subgroup analyses there was evidence to suggest that relapses as well as pronounced EDSS progression (EDSS >1 point or >0.5 point for EDSS >6 in the previous two years) can help to identify patients with active disease.

In both trials secondary progressive multiple sclerosis patients receiving Emaxem showed a reduction in frequency (30%) of clinical relapses. There is no evidence of Emaxem having an effect on the duration of relapses.

Single clinical event suggestive of MS

One controlled clinical trial with Emaxem was performed in patients with a single clinical event and MRI features suggestive of multiple sclerosis (at least two clinically silent lesions on the T2-weighted MRI). Patients with monofocal or multifocal onset of the disease were included (i.e. patients with clinical evidence for a single or at least two lesions, respectively, of the central nervous system). Any disease other than multiple sclerosis that could better explain signs and symptoms of the patient had to be excluded. This study consisted of two phases, a placebo-controlled phase followed by a pre-planned follow-up phase. The placebo-controlled phase lasted for 2 years or until the patient developed clinically definite multiple sclerosis (CDMS), whichever came first. After the placebo-controlled phase, patients entered a pre-planned follow-up phase with Emaxem to evaluate the effects of immediate versus delayed start of Emaxem treatment, comparing patients initially randomized to Emaxem ("immediate treatment group") or to placebo ("delayed treatment group"). Patients and investigators remained blinded to the initial treatment allocation.

Table 3: Primary efficacy results of the BENEFIT and the BENEFIT Follow-up study

In the placebo-controlled phase, Emaxem delayed the progression from the first clinical event to CDMS in a statistically significant and clinically meaningful manner. The robustness of the treatment effect was also shown by the delay of progression to multiple sclerosis according to McDonald criteria (Table 3).

Subgroup analyses according to baseline factors demonstrated evidence of efficacy on progression to CDMS in all subgroups evaluated. The risk for progression to CDMS within 2 years was higher in monofocal patients with at least 9 T2-lesions or Gd-enhancement on brain MRI at baseline. In multifocal patients, the risk for CDMS was independent from MRI findings at baseline, indicating a high risk for CDMS because of the dissemination of the disease based on clinical findings. For the time being there is no well established definition of a high risk patient, although a more conservative approach is to accept at least nine T2 hyperintense lesions on the initial scan and at least one new T2 or one new Gd-enhancing lesion on a follow-up scan taken at least 1 month after the initial scan. In any case, treatment should only be considered for patients classified as high risk.

Therapy with Emaxem was well accepted as indicated by a high rate of trial completion (93% in the Emaxem group). To increase tolerability of Emaxem, a dose titration was applied and non-steroidal anti-inflammatory drugs were administered at start of therapy. Moreover, an autoinjector was used by the majority of patients throughout the study.

In the open-label follow-up phase, the treatment effect on CDMS was still evident after 3 and 5 years (Table 3) even though the majority of patients from the placebo-group was treated with Emaxem at least from the second year onwards. EDSS progression (confirmed increase in EDSS of at least one point compared to baseline) was lower in the immediate treatment group (Table 3, significant effect after 3 years, no significant effect after 5 years). The majority of patients in both treatment groups had no disability progression over the 5-year period. Robust evidence for benefit on this outcome parameter could not be demonstrated for 'immediate' treatment. No benefit, attributable to immediate Emaxem treatment, in quality of life (as measured by FAMS - Functional Assessment of MS: Treatment Outcomes Index) was seen.

RR-MS, SP-MS and single clinical event suggestive of MS

Emaxem was effective in all multiple sclerosis studies to reduce disease activity (acute inflammation in the central nervous system and permanent tissue alterations) as measured by magnetic resonance imaging (MRI). The relation of multiple sclerosis disease activity as measured by MRI and clinical outcome is currently not fully understood.

Pharmacotherapeutic group: Immunostimulants, Interferons, ATC code: L03AB07.

Interferons are a group of endogenous glycoproteins endowed with immunomodulatory, antiviral and antiproliferative properties.

Emaxem (interferon beta-1a) shares the same amino acid sequence with endogenous human interferon beta. It is produced in mammalian cells (Chinese hamster ovary) and is therefore glycosylated like the natural protein.

Regardless of the route of dosing, pronounced pharmacodynamic changes are associated with the administration of Emaxem. After a single dose, intracellular and serum activity of 2'5'OAS synthetase and serum concentrations of beta-2 microglobulin and neopterin increase within 24 hours, and start to decline within 2 days. Intramuscular and subcutaneous administrations produce fully superimposable responses. After repeated subcutaneous administration every 48 hours for 4 doses, these biological responses remain elevated, with no signs of tolerance development.

Biological response markers (e.g., 2',5'-OAS activity, neopterin and beta 2-microglobulin) are induced by interferon beta-1a following subcutaneous doses administered to healthy volunteer subjects. Time to peak concentrations following a single subcutaneous injection were 24 to 48 hours for neopterin, beta-2-microglobulin and 2'5'OAS, 12 hours for MX1 and 24 hours for OAS1 and OAS2 gene expression. Peaks of similar height and time were observed for most of these markers after first and sixth administration.

The precise mechanism of action of Emaxem in multiple sclerosis is still under investigation.

Single clinical event suggestive of multiple sclerosis

One 2-year controlled clinical trial with Emaxem was performed in patients with a single clinical event suggestive of demyelination due to multiple sclerosis. The patients enrolled into the trial had at least two clinically silent lesions on the T2-weighted MRI scan, with a size of at least 3 mm, at least one of which is ovoid or periventricular or infratentorial. Any disease other than multiple sclerosis that could better explain signs and symptoms of the patient had to be excluded.

Patients were randomised in a double-blind manner to either Emaxem 44 micrograms given three times per week, Emaxem 44 micrograms once weekly, or placebo. If a second clinical demyelinating event occurred confirming definite multiple sclerosis, patients switched to the recommended posology of Emaxem 44 micrograms three times per week in an open label manner, while maintaining blinding as to initial randomisation. Efficacy results of Emaxem 44 micrograms given three times per week compared to placebo from this study are as follows:

For the time being there is no well established definition of a high risk patient, although a more conservative approach is to accept at least nine T2 hyperintense lesions on the initial scan and at least one new T2 or one new Gd-enhancing lesion on a follow-up scan taken at least 1 month after the initial scan. In any case, treatment should only be considered for patients classified as high risk.

Relapsing-remitting multiple sclerosis

The safety and efficacy of Emaxem has been evaluated in patients with relapsing-remitting multiple sclerosis at doses ranging from 11 to 44 micrograms (3-12 million IU), administered subcutaneously three times per week. At licensed posology, Emaxem 22 micrograms and Emaxem 44 micrograms have been demonstrated to decrease the incidence (approximately 30% over 2 years) and severity of clinical relapses in patients with at least 2 exacerbations in the previous 2 years and with an EDSS of 0-5.0 at entry. The proportion of patients with disability progression, as defined by at least one point increase in EDSS confirmed three months later, was reduced from 39% (placebo) to 30% (Emaxem 22 micrograms) and 27% (Emaxem 44 micrograms). Over 4 years, the reduction in the mean exacerbation rate was 22% in patients treated with Emaxem 22 micrograms, and 29% in patients treated with Emaxem 44 micrograms group compared with a group of patients treated with placebo for 2 years and then either Emaxem 22 or Emaxem 44 micrograms for 2 years.

Secondary progressive multiple sclerosis

In a 3-year study in patients with secondary progressive multiple sclerosis (EDSS 3-6.5) with evidence of clinical progression in the preceding two years and who had not experienced relapses in the preceding 8 weeks, Emaxem had no significant effect on progression of disability, but relapse rate was reduced by approximately 30%. If the patient population was divided into 2 subgroups (those with and those without relapses in the 2-year period prior to study entry), there was no effect on disability in patients without relapses, but in patients with relapses, the proportion with progression in disability at the end of the study was reduced from 70% (placebo) to 57% (Emaxem 22 micrograms and 44 micrograms combined). These results obtained in a subgroup of patients a posteriori should be interpreted cautiously.

Primary progressive multiple sclerosis

Emaxem has not yet been investigated in patients with primary progressive multiple sclerosis, and should not be used in these patients.

The pharmacokinetic profile of Emaxem has been investigated indirectly with an assay that measures interferon antiviral activity. This assay is limited in that it is sensitive for interferon but lacks specificity for interferon beta. Alternative assay techniques are not sufficiently sensitive.

Following intramuscular administration of Emaxem, serum antiviral activity levels peak between 5 and 15 hours post-dose and decline with a half-life of approximately 10 hours. With appropriate adjustment for the rate of absorption from the injection site, the calculated bioavailability is approximately 40%. The calculated bioavailability is greater without such adjustments. Subcutaneous administration cannot be substituted for intramuscular administration.

Emaxem serum levels were followed in patients and volunteers by means of a not completely specific bioassay. Maximum serum levels of about 40 IU/ml were found 1-8 hours after subcutaneous injection of 500 microgram (16.0 million IU) interferon beta-1b. From various studies mean clearance rates and half-lives of disposition phases from serum were estimated to be at most 30 ml·min^-1·kg^-1 and 5 hours, respectively.

Emaxem injections given every other day do not lead to serum level increases, and the pharmacokinetics do not seem to change during therapy.

The absolute bioavailability of subcutaneously administered interferon beta-1b was approxi-mately 50%.

Absorption

In healthy volunteers after intravenous administration, interferon beta-1a exhibits a sharp multi-exponential decline, with serum levels proportional to the dose. Subcutaneous and intramuscular administrations of Emaxem produce equivalent exposure to interferon beta.

Distribution

Following repeated subcutaneous injections of 22 and 44 micrograms doses of Emaxem maximum concentrations were typically observed after 8 hours, but this was highly variable.

Elimination

After repeated subcutaneous doses in healthy volunteers, the main PK parameters (AUC_tau and C_max) increased proportional to the increased in dose from 22 micrograms to 44 micrograms. The estimated apparent half-life is 50 to 60 hours, which is in line with the accumulation observed after multiple dosing.

Metabolism

Interferon beta-1a is mainly metabolised and excreted by the liver and the kidneys.

Carcinogenesis: No carcinogenicity data for interferon beta-1a are available in animals or humans.

Chronic Toxicity: In a 26-week repeated dose toxicity study in rhesus monkeys by intramuscular route once per week, administered in combination with another immunomodulating agent, an anti CD40 ligand monoclonal antibody, no immune response toward interferon beta-1a and no signs of toxicity were demonstrated.

Local Tolerance: Intramuscular irritation has not been evaluated in animals following repeated administration to the same injection site.

Mutagenesis: Limited but relevant mutagenesis tests have been carried out. The results have been negative.

Impairment of Fertility: Fertility and developmental studies in rhesus monkeys have been carried out with a related form of interferon beta-1a. At very high doses, anovulatory and abortifacient effects in test animals were observed. Similar reproductive dose-related effects have also been observed with other forms of alpha and beta interferons. No teratogenic effects or effects on foetal development have been observed, but the available information on the effects of interferon beta-1a in the peri- and postnatal periods is limited.

No information is available on the effects of interferon beta-1a on male fertility.

No acute toxicity studies have been carried out. As rodents do not react to human interferon beta, repeated dose studies were carried out with rhesus monkeys. Transitory hyperthermia was observed, as well as a significant rise in lymphocytes and a significant decrease in thrombocytes and segmented neutrophils.

No long-term studies have been conducted. Reproduction studies with rhesus monkeys revealed maternal toxicity and an increased rate of abortion, resulting in prenatal mortality. No malformations have been observed in the surviving animals.

No investigations on fertility have been conducted. No influence on the monkey oestrous cycle has been observed. Experience with other interferons suggest a potential for impairment of male and female fertility.

In one single genotoxicity study (Ames test), no mutagenic effect has been observed. Carcinogenicity studies have not been performed. An in vitro cell transformation test gave no indication of tumorigenic potential.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated-dose toxicity, and genotoxicity.

Emaxem has not been investigated for carcinogenicity.

A study on embryo/foetal toxicity in monkeys showed no evidence of reproductive disturbances. Based on observations with other alpha and beta interferons, an increased risk of abortions cannot be excluded. No information is available on the effects of the interferon beta-1a on male fertility.

Emaxem is provided as ready to use solution for injection in a pre-filled syringe.

Once removed from the refrigerator, Emaxem in a pre-filled syringe should be allowed to warm to room temperature (15°C - 30°C) for about 30 minutes.

Do not use external heat sources such as hot water to warm Emaxem 30 micrograms solution for injection.

If the solution for injection contains particulate matter or if it is any colour other than clear colourless, the pre-filled syringe must not be used. The injection needle for intramuscular injection is provided. The formulation does not contain a preservative. Each pre-filled syringe of Emaxem contains a single dose only. Discard the unused portion of any pre-filled syringe.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Reconstitution:

To reconstitute lyophilised interferon beta-1b for injection, connect the vial adapter with the attached needle on the vial. Connect the pre-filled syringe with solvent to the vial adapter and inject the 1.2 ml of the solvent (sodium chloride solution, 5.4 mg/ml (0.54% w/v)) into the Emaxem vial. Dissolve the powder completely without shaking.

After reconstitution, draw 1.0 ml from the vial into the syringe for the administration of 250 microgram Emaxem.

Remove the vial with the vial adapter from the pre-filled syringe before injection.

Emaxem may also be administered with a suitable autoinjector.

Inspection prior to use

Inspect the reconstituted product visually before use. The reconstituted product is colourless to light yellow and slightly opalescent to opalescent.

Discard the product before use if it contains particulate matter or is discoloured.

Disposal

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

The solution for injection in a pre-filled cartridge is ready for use with the RebiSmart electronic injection device or the RebiSlide manual pen-injector device. Not all injection devices may be available.

For multidose use. Only clear to opalescent solution without particles should be used and without visible signs of deterioration.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.