REBIF 22 interferon beta-1a (rch) 22 microgram/0.5mL injection pre-filled syringe autoinjector

Main information

  • Trade name:
  • REBIF 22 interferon beta-1a (rch) 22 microgram/0.5mL injection pre-filled syringe autoinjector
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • REBIF 22 interferon beta-1a (rch) 22 microgram/0.5mL injection pre-filled syringe autoinjector
    Australia
  • Language:
  • English

Status

  • Source:
  • Dept. of Health,Therapeutic Goods Administration - Australia
  • Authorization status:
  • Registered
  • Authorization number:
  • 174478
  • Last update:
  • 22-05-2019

Public Assessment Report

Public Summary

Summary for ARTG Entry:

174478

REBIF 22 interferon beta-1a (rch) 22 microgram/0.5mL injection pre-filled syringe autoinjector

ARTG entry for

Medicine Registered

Sponsor

Merck Serono Australia Pty Ltd

Postal Address

Units 3-4/25 Frenchs Forrest Road East,FRENCHS FOREST, NSW, 2086

Australia

ARTG Start Date

21/10/2010

Product category

Medicine

Status

Active

Approval area

Drug Safety Evaluation Branch

Conditions

Conditions applicable to all therapeutic goods as specified in the document "Standard Conditions Applying to Registered or Listed Therapeutic Goods

Under Section 28 of the Therapeutic Goods Act 1989" effective 1 July 1995.

Conditions applicable to the relevant category and class of therapeutic goods as specified in the document "Standard Conditions Applying to Registered

or Listed Therapeutic Goods Under Section 28 of the Therapeutic Goods Act 1989" effective 1 July 1995.

Products

1. REBIF 22 interferon beta-1a (rch) 22 microgram/0.5mL injection pre-filled syringe autoinjector

Product Type

Single Medicine Product

Effective date

29/09/2017

Warnings

See Product Information and Consumer Medicine Information for this product

Standard Indications

Specific Indications

REBIF is indicated for the treatment of:

? Patients with a single demyelinating event in the central nervous system 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. High risk can be inferred from cerebral MRI with

2 or more lesions suggestive of demyelination.,? Ambulatory patients with multiple sclerosis who have experienced two or more relapses within the last 2

years.

REBIF therapy should not be initiated in secondary progressive MS patients who no longer experience relapses.¾

Additional Product information

Container information

Type

Material

Life Time

Temperature

Closure

Conditions

Syringe

Glass Type I Clear

2 Years

Store at 2 to 8

degrees Celsius

Not recorded

Refrigerate

Protect from Light

Do not Freeze

Pack Size/Poison information

Pack Size

Poison Schedule

12 pre-filled syringes in single-use autoinjectors

(S4) Prescription Only Medicine

1 pre-filled syringe in single-use autoinjector

(S4) Prescription Only Medicine

3 pre-filled syringes in single-use autoinjectors

(S4) Prescription Only Medicine

Components

1. Medicine Component

Dosage Form

Injection, solution

Route of Administration

Subcutaneous

Visual Identification

Clear, colourless solution.

Active Ingredients

Interferon beta-1a

44 microgram/mL

© Commonwealth of Australia.This work is copyright.You are not permitted to re-transmit, distribute or commercialise the material without obtaining prior

written approval from the Commonwealth.Further details can be found at http://www.tga.gov.au/about/website-copyright.htm.

Public Summary

Page 1 of

Produced at 29.11.2017 at 03:18:54 AEDT

This is not an ARTG Certificate document.

The onus is on the reader to verify the current accuracy of the information on the document subsequent to the date shown.

Visit www.tga.gov.au for contact information

Summary of Product characteristics: dosage, interactions, side effects

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AUSTRALIAN PRODUCT INFORMATION

REBIF

(interferon beta-1a)

1.

NAME OF THE MEDICINE

Interferon beta-1a

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

REBIF is registered in two strengths of 22 microgram/0.5 mL (6 MIU) and 44 microgram/0.5

mL (12 MIU) of interferon beta-1a (rch) in pre-filled syringes for single dose use (0.5 mL) and

in cartridges for multidose use (1.5 mL). There is also a pre-filled syringe presentation which

includes a RebiDose® single use autoinjector (0.5 mL).

REBIF also contains mannitol, poloxamer, methionine, water for injections and benzyl alcohol.

Sodium hydroxide and acetic acid are used for pH adjustment.

For the full list of excipients, see Section 6.1 List of excipients

3.

PHARMACEUTICAL FORM

Solution for injection

Clear to opalescent solution, with pH 3.5 to 4.5 and osmolarity 250 to 450 mOsm/L.

4.

CLINICAL PARTICULARS

4.1.

THERAPEUTIC INDICATIONS

REBIF is indicated for the treatment of:

Patients with a single demyelinating event in the central nervous system 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. High risk can be inferred from cerebral MRI with 2 or more lesions

suggestive of demyelination.

Ambulatory patients with multiple sclerosis who have experienced two or more

relapses within the last 2 years.

REBIF therapy should not be initiated in secondary progressive MS patients who no longer

experience relapses.

4.2.

DOSE AND METHOD OF ADMINISTRATION

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

multiple sclerosis.

When first starting treatment with REBIF, it is recommended that the dose be gradually

increased in order to allow tachyphylaxis to develop thus reducing the risk of adverse reactions.

It is recommended that 20% of the total dose be administered during the first two weeks of

therapy, 50% of the total dose be administered in weeks three and four, and the full dose from

the fifth week onwards.

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.

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Dosage

First Demyelinating Event

The recommended dose for patients who have experienced a first demyelinating event is 44

micrograms (12 MIU) REBIF given three times per week by subcutaneous injection.

Upon conversion to relapsing multiple sclerosis these patients must be treated according to the

recommended dosage for relapsing multiple sclerosis.

Relapsing Multiple Sclerosis

The recommended dose for patients with relapsing multiple sclerosis is 44 microgram (12

MIU) REBIF given three times per week by subcutaneous injection. REBIF 22 microgram (6

MIU) given three times per week by subcutaneous injection is recommended for patients who

cannot tolerate the higher dose.

Please refer to Section 4.4 Special Warnings and Precautions for Use regarding regular liver

function test monitoring of patients.

At the present time, it is not known for how long patients should be treated with REBIF.

Safety and efficacy with REBIF have been demonstrated up to four years after initiation of

treatment. It is recommended that patients should be evaluated at least every second year in

the four-year period after initiation of treatment with REBIF, and a decision for longer term

treatment be made on an individual basis by the treating physician.

Paediatric population

There is limited experience with REBIF in children under 12 years of age with multiple

sclerosis.

No formal clinical trials or pharmacokinetic studies of REBIF 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 REBIF 22 micrograms subcutaneous three

times per week is similar to that seen in adults.

Method of Administration

Allow REBIF solution to reach room temperature before administration. The solution should

not be administered if it contains particles and is not clear.

REBIF cartridges intended for multidose use in one patient only must be used with RebiSmart

provided separately. Only validated needle sizes as specified in the Instructions for Use

supplied with the RebiSmart device should be used. Refer to the Instructions for Use provided

with RebiSmart. Cartridges should be discarded within 21 days after first use.

4.3.

CONTRAINDICATIONS

REBIF is contraindicated in patients with a known hypersensitivity to natural or recombinant

interferon beta, or to any other component of the formulation (listed under Section 2

Qualitative and Quantitative Composition).

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REBIF is contraindicated in women who are or plan to become pregnant while on therapy,

patients with severe depressive disorders and/or suicidal ideation, and in epileptic patients

with seizures not adequately controlled by treatment.

4.4.

SPECIAL WARNINGS AND PRECAUTIONS FOR USE

General

Patients should be informed of the most common adverse reactions associated with REBIF

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.

REBIF should be used under the supervision of a physician. The first injection should be

performed under the supervision of an appropriately qualified healthcare professional.

Caution must be used and close monitoring considered when administering REBIF to patients

with severe renal and hepatic failure, patients with severe myelosuppression and depressive

patients. There are currently no data available on the use of REBIF in patients with severe

hepatic or renal impairment or with myelosuppression.

Only sparse safety and efficacy data are available from non-ambulatory patients with multiple

sclerosis.

Thrombotic microangiopathy

Cases of thrombotic microangiopathy, manifested as thrombotic thrombocytopenic purpura

(TTP) or haemolytic uraemic syndrome (HUS) have been reported, including fatal cases.

Monitoring of early symptoms in all patients e.g. new onset hypertension, impaired renal

function and thrombocytopenia is recommended. Prompt treatment of TTP/HUS is required

and discontinuation of treatment with REBIF is recommended.

Depression and Suicidal Ideation

REBIF 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 at an increased frequency in the multiple sclerosis population and

in association with interferon use.

Patients treated with REBIF must be advised to immediately report any symptoms of depression

and/or suicidal ideation to their prescribing physician. Patients exhibiting depression must be

monitored closely during therapy with REBIF and treated appropriately. Cessation of therapy

with REBIF must be considered.

Hepatic Dysfunction and Injury

Interferon

therapy

frequently

associated

with

asymptomatic

elevations

hepatic

transaminases (particularly ALT). In clinical trials with REBIF, the majority of these elevations

are below 2.5 times the upper limit of normal [ULN] with 1 3% of patients developing

elevations above 5 times ULN. They are reversible with dose reduction or discontinuation of

therapy but may resolve while therapy continues. Serum ALT levels must be monitored prior

to the start of therapy, at months 1, 3 and 6 on therapy and periodically thereafter in the absence

of clinical symptoms. 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 with REBIF must be considered if ALT rises

above 5 times the ULN and gradually re-escalated when enzyme levels have normalised.

Treatment with REBIF must be stopped if icterus or other clinical symptoms of liver

dysfunction appear (see also Section 4.8 Adverse Effects (Undesirable Effects)).

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Beta-interferons including REBIF, have a potential for causing severe liver injury, including

acute hepatic failure. The mechanism for the rare symptomatic hepatic dysfunction is not

known. No specific risk factors have been identified.

Patients should be informed of the symptoms suggesting liver dysfunction, such as loss of

appetite accompanied by other symptoms such as malaise, fatigue, nausea, vomiting, abdominal

pain, dark urine, jaundice or pruritis. They should be advised to consult with a physician

immediately if such symptoms arise.

Seizure Disorder

Caution must be exercised when administering REBIF to patients with pre existing seizure

disorders (see also Section 4.5 Interactions With Other Medicines and Other Forms of

Interactions). For patients without a pre existing seizure disorder who develop seizures during

therapy with REBIF, an aetiological basis should be established and appropriate anti-convulsant

therapy instituted prior to resuming REBIF treatment.

Cardiac Disease

Patients with cardiac disease such as angina, congestive heart failure or arrhythmia, must be

monitored closely for worsening of clinical condition during initiation of therapy with REBIF.

Symptoms of the flu-like syndrome associated with REBIF therapy may prove to be stressful

to patients with cardiac conditions.

Injection Site Necrosis

Injection site necrosis has been reported in patients using REBIF. To minimise the risk patients

must be advised to:

use an aseptic injection technique

rotate the injection sites with each dose

The procedure for 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 must be

advised to consult with their physician before continuing injections with REBIF. If the patient

has multiple lesions, REBIF must be discontinued until healing has occurred. Patients with

single lesions may continue provided that the necrosis is not too extensive.

Immune Reactions (including hypersensitivity, autoimmunity, immunogenicity)

Anaphylaxis has been reported as a rare complication of REBIF use. Other allergic reactions

have included skin rash, angio-oedema, 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

In a controlled clinical study, between 14% and 23% of patients developed neutralising

antibodies against REBIF by the end of 4 years of therapy, most developing in the first 12 to

18 months.

Development of neutralising antibodies (NAb) has been associated with a reduced benefit, as

evaluated

parameters

clinical

relapse

rate.

full

significance

development in individual cases remains uncertain. Neutralising antibodies are cross-reactive

to different forms of interferon beta.

Treatment decisions should be based on the complete clinical assessment of efficacy by the

clinician in view of available data regarding NAb. A poor clinical course associated with the

presence of persistent NAb should prompt reconsideration of interferon therapy.

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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 interferon should be considered.

Effects on 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, liver

enzyme monitoring, complete and differential white blood cell counts, platelet counts and blood

chemistries, are recommended during REBIF therapy. Blood cell counts are recommended at

regular intervals (1, 3 and 6 months) following introduction of REBIF therapy and then

periodically thereafter in the absence of clinical symptoms.

Thyroid disorder

As with other interferons, patients being treated with REBIF may occasionally develop new or

worsening thyroid abnormalities. Thyroid function testing is recommended at baseline and if

abnormal, every 6-12 months following initiation of therapy. If normal, routine testing is not

needed but testing must be performed if clinical findings of thyroid dysfunction appear (see

also Section 4.8 Adverse Effects (Undesirable Effects)).

Paediatric Use

There is limited experience with REBIF in children under 12 years of age with multiple

sclerosis.

No formal clinical trials or pharmacokinetic studies of REBIF 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 REBIF 22 micrograms subcutaneous three times per week

is similar to that seen in adults.

Use in the Elderly

No dedicated studies have been conducted in elderly patients.

4.5.

INTERACTIONS

WITH

OTHER

MEDICINES

AND

OTHER

FORMS

OF

INTERACTIONS

No formal drug interaction studies relevant to approved indications have been conducted with

REBIF in humans.

Clinical trial experience indicates that patients with multiple sclerosis can receive concomitant

therapy with REBIF and corticosteroid or ACTH treatment during relapses. Antidepressant

and oral contraceptive therapy were co-administered in the clinical trial with no increase in

adverse effects.

However, interferons have been reported in the literature to reduce the activity of hepatic

cytochrome P450-dependent enzymes in humans and animals. Exploratory results from a study

in 8 normal volunteers on the effect of REBIF on the CYP450 system showed an effect on

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CYP1A2 only, however this study was of limited power. The effect of interferon beta on the

CYP450 system suggests a down-regulation of CYP1A1 and CYP1A2 in rats and of CYP1A1,

CYP2B1 and CYP3A and total hepatic cytochrome P450 in mice. Caution should be exercised

when administering REBIF in combination with medicinal products that have a narrow

therapeutic index and/or are dependent on the hepatic cytochrome P450 system for clearance,

for example:

antiepileptics, which may include phenytoin, carbamazepine, sodium valproate,

benzodiazepines (such as clonazepam); and

some classes of

antidepressants, which may include MAOI, SSRIs,

tricyclic

antidepressants, etc.

As with all interferon products, proper monitoring of patients is required if REBIF is given in

combination with myelosuppressive agents.

Immune response to influenza vaccine is maintained in patients with multiple sclerosis

receiving REBIF.

4.6.

FERTILITY, PREGNANCY AND LACTATION

Effects on Fertility

The effects of REBIF on fertility have not been investigated. However, in monkeys, exposure

to interferon beta-1a at more than 18 times the maximum likely clinical exposure (based on

AUC), had no effect on the menstrual cycle or serum oestradiol levels in females; or sperm

function, motility, count, morphology or serum testosterone levels in males.

Use in Pregnancy

Initiation of treatment with REBIF is contraindicated during pregnancy (Category D).

There are no studies of REBIF in pregnant women. At high doses in monkeys, abortifacient

effects were observed with other interferons. When administered to pregnant monkeys during

the period of organogenesis, interferon beta-1a was not teratogenic. However, the results of

this study may have been compromised by the production of low levels of antibodies to

interferon beta-1a in the test monkeys.

Fertile women receiving REBIF must take appropriate contraceptive measures. Patients

planning for pregnancy and those becoming pregnant should be informed of the potential

hazards of interferons to the foetus and REBIF should be discontinued.

Use in Lactation

It is not known whether interferon beta-1a is excreted in human milk. Because of the potential

for serious adverse reactions in breastfed infants, a decision should be made either to

discontinue breastfeeding or to discontinue REBIF therapy.

4.7.

EFFECTS ON ABILITY TO DRIVE AND USE MACHINES

Central nervous system-related adverse reactions associated with the use of interferon beta (e.g.

dizziness) might influence the patient’s ability to drive or use machines.

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4.8.

ADVERSE EFFECTS (UNDESIRABLE EFFECTS)

Summary of the safety profile

The highest incidence of adverse reactions associated with REBIF therapy is related to flu like

syndrome. Flu-like symptoms tend to be most prominent at the initiation of therapy and

decrease in frequency with continued treatment. Approximately 70% of patients treated with

REBIF can expect to experience the typical interferon-related flu-like syndrome within the first

six months after starting treatment. 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. 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 blood

cells are also common. This includes decreases in white blood cell counts (leucopenia,

lymphopenia, granulocytopenia), red cells and thrombocyte counts and alterations in liver

function tests such as elevated ALT and AST (see also Section 4.4 Special Warnings and

Precautions for Use). These effects are usually mild and reversible.

Tachyphylaxis with respect to most side effects is well recognised.

Injection site reactions are commonly encountered and are usually mild and reversible. Rare

cases of skin ulceration/necrosis at the site of injection have been reported with long term

REBIF treatment (see also Section 4.4 Special Warnings and Precautions for Use).

Occasional thyroid dysfunction, most often presenting as hypothyroidism or hyperthyroidism,

and generally transient and mild, may occur during the first year of treatment, particularly in

patients with pre-existing thyroiditis (see also Section 4.4 Special Warnings and Precautions

for Use).

In case of severe or persistent adverse reactions, the dose of REBIF may be temporarily lowered

or interrupted or the treatment discontinued, at the discretion of the physician.

Clinical Trials

PRISMS and SPECTRIMS Studies

A pooled analysis of the adverse events reported at a cut-off of 10% active vs. placebo in the

PRISMS and SPECTRIMS clinical studies with the original formulation during the 2 first

years of placebo-controlled treatment.

Table 1

System Organ Class

Preferred Term

Placebo Subjects

(n=392) n (%)

REBIF 22 mcg/tiw

(n=398) n (%)

REBIF 44 mcg/tiw

(n=388) n (%)

General disorders and

administration site conditions

Influenza like illness

155 (39.5)

156 (39.2)

166 (42.8)

Injection site erythema

52 (13.3)

205 (51.5)

205 (52.8)

Fatigue

128 (32.7)

137 (34.4)

163 (42.0)

Injection site reaction

25 (6.4)

99 (24.9)

128 (33.0)

Pyrexia

61 (15.6)

81 (20.4)

98 (25.3)

Injection site pain

64 (16.3)

82 (20.6)

91 (23.5)

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System Organ Class

Preferred Term

Placebo Subjects

(n=392) n (%)

REBIF 22 mcg/tiw

(n=398) n (%)

REBIF 44 mcg/tiw

(n=388) n (%)

Chills

26 (6.6)

37 (9.3)

48 (12.4)

Injection site inflammation

6 (1.5)

40 (10.1)

50 (12.9)

Injection site haematoma

43 (11.0)

20 (5.0)

27 (7.0)

Infections and infestations

Nasopharyngitis

117 (29.8)

105 (26.4)

94 (24.2)

Upper respiratory tract

infection

107 (27.3)

97 (24.4)

83 (21.4)

Urinary tract infection

75 (19.1)

89 (22.4)

73 (18.8)

Influenza

76 (19.4)

79 (19.8)

61 (15.7)

Rhinitis

78 (19.9)

76 (19.1)

58 (14.9)

Cystitis

44 (11.2)

37 ( 9.3)

27 (7.0)

Nervous system disorders

Headache

237 (60.5)

233 (58.5)

261 (67.3)

Dizziness

63(16.1)

49 (12.3)

59 (15.2)

Paraesthesia

49 (12.5)

40 (10.1)

37 ( 9.5)

Musculoskeletal and connective

tissue disorders

Back pain

72 (18.4)

77 (19.3)

78 (20.1)

Pain in extremity

77 (19.6)

63 (15.8)

64 (16.5)

Myalgia

46 (11.7)

72 (18.1)

69 (17.8)

Arthralgia

61 (15.6)

60 (15.1)

65 (16.8)

Muscular weakness

50 (12.8)

44 (11.1)

45 (11.6)

Muscle spasms

28 (7.1)

25 (6.3)

39 (10.1)

Gastrointestinal disorders

Nausea

103 (26.3)

108 (27.1)

87 (22.4)

Diarrhoea

59 (15.1)

68 (17.1)

62 (16.0)

Constipation

48 (12.2)

42 (10.6)

33 (8.5)

Vomiting

42 (10.7)

40 (10.1)

39 (10.1)

Psychiatric disorders

Depression

96 (24.5)

86 (21.6)

98 (25.3)

Insomnia

69 (17.6)

69 (17.3)

64 (16.5)

Investigations

Alanine aminotransferase

increased

19 (4.8)

76 (19.1)

101 (26.0)

Lymphocyte count decreased

32 (8.2)

45 (11.3)

56 (14.4)

Aspartate aminotransferase

increased

12 (3.1)

41 (10.3)

62 (16.0)

Respiratory, thoracic and

mediastinal disorders

Oropharyngeal pain

112 (28.6)

93 (23.4)

79 (20.4)

Cough

63 (16.1)

51 (12.8)

50 (12.9)

Blood and lymphatic system

disorders

Lymphopenia

19 (4.8)

36 (9.0)

54 (13.9)

Leukopenia

5 (1.3)

29 (7.3)

44 (11.3)

REBIF HSA-free Formulation

No new or unexpected treatment emergent adverse events (TEAEs) were observed in the

multicentre, single arm, open-label REBIF HSA-free formulation Cohort (Study 25632)

compared to a Historical Cohort.

The Historical Cohort consisted of patients from three phase III clinical trials (PRISMS Study

GF6789, SPECTRIMS Study GF6954 and EVIDENCE Study GF21125) who were

administered identical dosing of interferon beta-1a (44 mcg tiw) during the 96 week period,

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and for the purposes of these comparisons, the Historical Cohort TEAE data to week 96 of

treatment was recorded in MedDRA version 8.0.

Table 2 compares the REBIF HSA-free formulation Cohort with that of the Historical Cohort

based upon pre-specified MedDRA common AEs known to be associated with interferon

beta-1a.

Table 2

MedDRA preferred term

Adverse Events Incidence Rate

REBIF HSA-free formulation

Cohort (n=260)

Historical Cohort

(n=727)

Cytopenia

13.5%

13.0% to 39.7%

Flu-like syndrome

71.5%

49.0% to 69.0%

Hepatic disorders

14.2%

18.6% to 38.0%

Hypersensitivity reactions

5.8%

5.6% to 12.0%

Injection site reactions

30.8%

85.3% to 92.4%

Depression and suicidal ideation

6.5%

22.7% to 36.3%

Skin rashes

6.2%

16.5% to 25.5%

Thyroid disorders

4.2%

4.9 to 8.7%

Subjects in the REBIF HSA-free formulation Cohort experienced similar or lower rates of

incidence in the eight pre-specified AE groups compared to the Historical Cohort with the

exception of “flu-like syndrome”.

Study 27025: REFLEX

Study 27025 was a two year controlled study conducted to evaluate the efficacy, safety, and

immunogenicity of REBIF (HSA-free formulation) in subjects with a first clinical

demyelinating event at high risk of converting to MS. The safety analysis was performed on

the double-blind (DB) safety population (including all subjects who received at least one DB

study treatment injection [either active or placebo], whether randomized or not) and on the

open label (OL) safety population (including all subjects from the DB study population who

received at least one OL study treatment injection with REBIF 44 mcg three times a week

(tiw) after having converted the Clinically Definite Multiple Sclerosis (CDMS).

Table 3 presents treatment-emerging 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.

Table 3 Incidence of Most Common Related Treatment-Emergent Adverse Events

(a)

During the DB Treatment Period by MedDRA Preferred Term

System Organ Class

Preferred Term

(subjects with most

common events)

Placebo

(n=171)

n (%)

REBIF

44 mcg ow

(n=173)

n (%)

REBIF

44 mcg tiw

(n=171)

n (%)

Blood and lymphatic system

disorders

Neutropenia

1 (0.6)

5 (2.9)

13 (7.6)

Leukopenia

1 (0.6)

4 (2.3)

7 (4.1)

Thrombocytopenia

5 (2.9)

Lymphopenia

1 (0.6)

3 (1.8)

Lymphadenopathy

2 (1.2)

Ear and labyrinth disorders

Vertigo

2 (1.2)

3 (1.7)

2 (1.2)

Eye disorders

Eye pain

2 (1.2)

1 (0.6)

Gastrointestinal disorders

Vomiting

3 (1.7)

General disorders and

administration site conditions

Influenza like illness

34 (19.9)

121 (69.9)

92 (53.8)

Injection site

erythema

3 (1.8)

33 (19.1)

49 (28.7)

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System Organ Class

Preferred Term

(subjects with most

common events)

Placebo

(n=171)

n (%)

REBIF

44 mcg ow

(n=173)

n (%)

REBIF

44 mcg tiw

(n=171)

n (%)

Pyrexia

6 (3.5)

16 (9.2)

5 (2.9)

Injection site pain

6 (3.5)

4 (2.3)

8 (4.7)

Fatigue

5 (2.9)

2 (1.2)

8 (4.7)

Injection site

haematoma

3 (1.8)

5 (2.9)

7 (4.1)

Asthenia

4 (2.3)

6 (3.5)

4 (2.3)

Chills

2 (1.2)

7 (4.0)

5 (2.9)

Injection site

oedema

1 (0.6)

2 (1.2)

Injection site rash

3 (1.8)

Malaise

2 (1.2)

Infections and infestations

Upper respiratory

tract infection

6 (3.5)

2 (1.2)

6 (3.5)

Nasopharyngitis

5 (2.9)

1 (0.6)

1 (0.6)

Pharyngitis

1 (0.6)

3 (1.7)

Oral herpes

2 (1.2)

1 (0.6)

Injection site

infection

2 (1.2)

Urinary tract

infection

2 (1.2)

Investigations

Alanine

aminotransferase

increased

3 (1.8)

9 (5.2)

13 (7.6)

Aspartate

aminotransferase

increased

1 (0.6)

8 (4.6)

9 (5.3)

Body temperature

increased

4 (2.3)

Blood creatine

phosphokinase

increased

2 (1.2)

1 (0.6)

Hepatic enzyme

increased

2 (1.2)

Metabolism and nutrition

disorders

Decreased appetite

2 (1.2)

Musculoskeletal and

connective tissue disorders

Myalgia

3 (1.8)

8 (4.6)

10 (5.8)

Arthralgia

1 (0.6)

5 (2.9)

1 (0.6)

Pain in extremity

3 (1.8)

1 (0.6)

1 (0.6)

Muscle spasms

2 (1.2)

1 (0.6)

Musculoskeletal

stiffness

2 (1.2)

1 (0.6)

Nervous system disorders

Headache

14 (8.2)

14 (8.1)

21 (12.3)

Paraesthesia

6 (3.5)

1 (0.6)

Tremor

1 (0.6)

1 (0.6)

2 (1.2)

Hypoaesthesia

2 (1.2)

Psychiatric disorders

Depression

5 (2.9)

6 (3.5)

8 (4.7)

Insomnia

2 (1.2)

4 (2.3)

4 (2.3)

Anxiety

1 (0.6)

2 (1.2)

1 (0.6)

Respiratory, thoracic and

mediastinal disorders

Oropharyngeal pain

2 (1.2)

1 (0.6)

Skin and subcutaneous tissue

disorders

Alopecia

2 (1.2)

1 (0.6)

1 (0.6)

Dermatitis allergic

1 (0.6)

2 (1.2)

Erythema

1 (0.6)

2 (1.2)

Hypoaesthesia facial

2 (1.2)

Only TEAEs included that are possibly or probably related to study drug

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List of adverse reactions

Adverse reactions are listed below by frequency of occurrence and by MedDRA System

Organ Class.

The following definitions apply to the frequency terminology:

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

Adverse reactions, as identified in clinical trials, are presented by body system and by class of

frequency (in excess of placebo).

Blood and the lymphatic system disorders

Very common:

Neutropenia, lymphopenia, leucopenia, thrombocytopenia, anaemia

Endocrine disorders

Uncommon:

Thyroid dysfunction most often presenting as hypothyroidism or

hyperthyroidism

Hepatobiliary disorders

Very common:

Asymptomatic transaminase increase

Common:

Severe elevations of transaminase

Psychiatric disorders

Common:

Depression

Nervous system disorders

Very common:

Headache

Skin and subcutaneous tissue disorders

Common:

Pruritus, rash, erythematous rash, maculopapular rash

Musculoskeletal and connective disorders

Common:

Myalgia, arthralgia

General disorders and administration site conditions

Very common:

Injection site inflammation, injection site reactions (e.g. swelling, bruising,

redness), influenza-like symptoms

Common:

Injection site pain, fatigue, rigors, fever

Uncommon:

Injection site necrosis, injection site abscess

Post-Marketing Data

Adverse reactions identified during post-marketing surveillance:

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Immune system disorders

Rare:

Anaphylactic reactions

Blood and lymphatic system disorders

Rare:

Thrombotic microangiopathy including thrombotic thrombocytopenic

purpura/haemolytic uraemic syndrome, pancytopenia

Nervous system disorders

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)

Hepatobiliary disorders

Uncommon:

Hepatitis with or without icterus

Rare:

Hepatic failure, autoimmune hepatitis

Renal disorders

Frequency not known: Nephrotic syndrome

Skin and subcutaneous tissue disorders

Uncommon:

Urticaria

Rare:

Quincke’s oedema (angio-oedema), erythema multiforme,

Stevens-Johnson syndrome

Musculosketal and connective tissue disorder

Rare:

Drug-induced lupus erythematosus

General disorders and administration site conditions

Uncommon:

Injection site infections, which could be severe, increased sweating

Rare:

Injection site cellulitis, which could be severe

Reporting suspected adverse reactions

Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-

problems.

4.9.

OVERDOSE

A few cases of overdose have been reported, and the only adverse event observed in one case

was flu-like syndrome. However, in case of overdosage, patients should be hospitalised for

observation and appropriate supportive treatment should be given.

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For information on the management of overdose, contact the Poison Information Centre on 13

11 26 (Australia) or 0800 764 744 (New Zealand).

5.

PHARMACOLOGICAL PROPERTIES

5.1.

PHARMACODYNAMIC PROPERTIES

Pharmacotherapeutic group: Immunostimulants, Interferons ATC code: L03AB07

Interferons are a group of naturally occurring proteins that are produced by eukaryotic cells in

response to viral infection and other biological inducers. Interferon beta, one member of this

family, is produced by various cell types including fibroblasts and macrophages. Natural

interferon beta and interferon beta-1a are glycosylated with each containing a single N-linked

complex carbohydrate moiety.

Mechanism of action

Interferons are cytokines that mediate immunomodulatory, antiviral and antiproliferative

activities in response to viral infection and other biological inducers. Interferon beta 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, including 2’,5’-oligoadenylate synthetase, beta

2-microglobulin and neopterin. These products have been measured in the serum and cellular

fractions of blood collected from volunteers.

However, the relationship of these markers to any beneficial therapeutic effect of REBIF in

multiple sclerosis patients is not clear. The precise mechanism of action of REBIF in multiple

sclerosis is still under investigation. REBIF has not been studied in primary progressive disease

and should not be administered to such patients.

Clinical trials

PRISMS STUDY (Prevention of Relapses and Disability by Interferon beta-1a in

Relapsing-Remitting Multiple Sclerosis)

total

patients

diagnosed

with

clinically

definite

laboratory-supported

relapsing-remitting multiple sclerosis, Expanded Disability Status Scale (EDSS) 0-5 with at

least a 1-year history before study entry, were randomised to one of 3 treatments (placebo,

REBIF 22 mcg (6 MIU) three times a week (tiw), or REBIF 44 mcg (12 MIU) tiw) in a ratio of

1:1:1. About 90% of patients completed the 2 years of treatment and entered the extension

phase and 79% remained in the study to the end of year 4. The patients originally randomised

to 22 and 44 mcg tiw groups continued their treatment (years 1-4). Prior to the start of the

extension phase (years 3-4), all patients from the original placebo group were re-randomised to

receive, in blinded fashion, either REBIF 22 mcg (n=85) or REBIF 44 mcg (n=87) tiw. The

patients re-randomised from placebo (year 1-2) to treatment (years 3-4) on either REBIF 22

mcg tiw or REBIF 44 mcg tiw are referred to as placebo/REBIF 22 mcg tiw or placebo/REBIF

44 mcg tiw, respectively.

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The withdrawal rate due to adverse events for patients randomised to REBIF 22 mcg and

REBIF 44 mcg, from years 1-4, were 8 (4.2%) and 18 (9.8%), respectively.

Results of PRISMS study

Effect on exacerbations

REBIF 22 mcg tiw and 44 mcg tiw had a significant effect during Year 1 and Year 2 on the

primary outcome measure by reducing relapse count compared to placebo. The relapse rate

reduction continued during years 3 and 4 of therapy. REBIF 22 mcg tiw and 44 mcg tiw had a

significant effect in delaying relapses (median time to 1st exacerbation 7.6 and 9.6 months,

respectively compared to 4.5 months with placebo [years 1-2], and median time to 2nd

exacerbation 23.1 and 31.7 months compared to 14.8 months for placebo/treatment group [years

1-4], respectively).

Table 4 Effect on Exacerbations: Summary - Intention to Treat (ITT)

Exacerbation

Placebo/REBIF 22 mcg tiw

or

Placebo/REBIF 44 mcg tiw

REBIF 22

mcg tiw

REBIF 44

mcg tiw

p-value

Exacerbation rate

(years 1-4)

1.02

0.80

0.72

REBIF 44

vs

placebo=0.0001

REBIF 22

vs

placebo=0.0001

REBIF 44

vs

REBIF 22=0.0693

Proportion

exacerbation free

(year 4)

6.67%

14.36%

18.99%

REBIF 44

vs

placebo=0.0002

REBIF 22

vs

placebo=0.0158

REBIF 44

vs

REBIF 22=0.1596

Time (months) to

exacerbation

(years 1-2)

REBIF 44

vs

placebo<0.0001

REBIF 22

vs

placebo=0.0008

Time (months) to

exacerbation

(years 1-4)

14.8

23.1

31.7

REBIF 44

vs

placebo=0.0001

REBIF 22

vs

placebo=0.0058

REBIF 44

vs

REBIF 22=0.0460

Effect on time to first progression in disability

Analysis of the intent-to-treat (ITT) group shows that REBIF 44 mcg tiw significantly

prolonged time to progression compared to placebo/REBIF. This prolongation is 18 months

for REBIF 44 mcg tiw compared to placebo (p=0.0474) and 12 months for REBIF 22 mcg tiw

compared to placebo (p=0.2893), for the 40th percentile (median not reached). The time to first

progression was in favour of 44 mcg tiw compared to 22 mcg tiw (p=0.3333).

The reductions in the rate of Expanded Disability Status Scale (EDSS) change for 44 mcg tiw

were 29% (p=0.005) compared to placebo, 23% (p=0.030) compared to 22 mcg tiw, and

8% (ns) for 22 mcg tiw compared to placebo. The reduction rate of EDSS changes was

measured by the average number (a Poisson regression model) of EDSS changes per patient,

per year. An EDSS change was defined as a one point change in the EDSS scale (or 0.5 point

change above EDSS 5.5) occurring during the study.

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Table 5 Number of confirmed EDSS changes during years 1-4: ITT

Estimated confirmed annual progression rate†

Time Period

(years)

Placebo

(n=187)

REBIF 22 mcg tiw

(n=189)

REBIF 44 mcg tiw

(n=184)

0.24

0.22

0.17

Treatment comparison

p-value†

REBIF 44 mcg

vs

placebo

REBIF 22 mcg

vs

placebo

REBIF 44 mcg

vs

REBIF 22 mcg

0.0048

0.5227

0.0295

†The estimated rate for years 1-4 is from a Poisson Regression model with effects for treatment and

centre (treatment-by-centre interaction p=0.06)

prolongation

time

confirmed

progression

disability

illustrated

Kaplan-Meier curves by treatment group shown below (Figure 1). The curves demonstrate the

effect of total cumulative doses of REBIF on progression in disability over 4 years. The best

outcome is for patients receiving 44 mcg tiw for the entire study duration.

Figure 1 Time to Confirmed Progression in Disability: Kaplan-Meier Curves by Treatment

Group

Effect on multiple sclerosis pathology as detected by MRI scans

The MRI data show a highly significant effect of interferon therapy on burden of disease (BOD)

and MRI activity measures compared to placebo groups and a dose effect favouring patients

treated with 44 mcg tiw vs 22 mcg tiw after 4 years (p=0.009 and p<0.0001 respectively). There

is an overall net reduction in BOD of 6.2% over 4 years in patients treated with 44 mcg tiw,

and patients originally treated with the high dose of REBIF retain an overall significant benefit

on BOD (p=0.003) and T2 activity measure (p<0.0001) compared to patients treated with

placebo/REBIF 44 mcg tiw.

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Table 6 Percent change in burden of disease during years 1-4

Treatment Groups

Time Period

(years)

Statistic

Placebo/REBIF

22 mcg tiw

Placebo/REBIF

44 mcg tiw

REBIF 22 mcg

REBIF 44 mcg

Median

-6.2

Treatment Comparison

p-value

REBIF 44

vs

Placebo/REBIF 44

REBIF 22

vs

Placebo/REBIF 22

REBIF 44

vs

REBIF 22

0.0027

0.1125

0.0089

Table 7 Median of mean number of T2 active lesions per patient per scan during years 1-4

Treatment Groups

Time Period

(years)

Statistic

Placebo/REBIF

22 mcg tiw

Placebo/REBIF

44 mcg tiw

REBIF 22

mcg tiw

REBIF 44

mcg tiw

Median

Treatment Comparison

p-value

REBIF 44

vs

Placebo/REBIF 44

REBIF 22

vs

Placebo/REBIF 22

REBIF 44

vs

REBIF 22

< 0.0001

0.0009

< 0.0001

Conclusion

These data demonstrate a continued benefit of REBIF therapy up to 4 years and provide further

evidence of a dose-effect relationship in the treatment of multiple sclerosis with interferon beta-

1a. In the initial two year study, REBIF 44 mcg had a statistically significant benefit over

REBIF 22 mcg for the MRI endpoints (number of active T2 lesions and percentage of T2 active

scans per patient). However, in the extension phase (years 3-4) REBIF 44 mcg demonstrated

statistically significant benefits for a greater number of parameters. The parameters include:

exacerbation rate (years 3-4 only), time to second exacerbation (years 1-4), the number of

steroid courses (years 1-4 and years 3-4), time to confirmed progression in disability (years

3-4), number of confirmed EDSS changes (years 1-4) and mean Integrated Disability Status

Score (IDSS) for years 3-4, burden of disease (years 1-4), number of active T2 lesions (years

1-4 and years 3-4) and percentage of T2 active scans per patient (years 1-4 and years 3-4). A

trend was observed for REBIF 44 mcg over REBIF 22 mcg for: exacerbation (years 1-4),

number of confirmed EDSS changes (years 3-4) and patients not reaching EDSS 6.0 (year 4).

Finally, patients treated early (randomised to REBIF 22 or 44 mcg from years 1-4) attained

more benefit at 4 years than those delaying treatment until the start of year 3 (placebo/REBIF

groups).

High Disability Group (EDSS 3.5)

Additional analyses were performed in the group of patients with baseline EDSS>3.5 who are

at higher risk of evolving into the phase of disease characterised by steady progression of

disability (sometimes referred to as “Transitional MS”). Progression in this group of patients

is of particular concern, as progression involves development of difficulty in ambulation.

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Efficacy parameters were analysed for the cohort of patients with baseline EDSS>3.5. The low

number of patients in this cohort during the extension phase limits the comparisons for this

group. Both doses significantly reduced exacerbation count compared to placebo (p<0.0001),

however only REBIF 44 mcg tiw was statistically beneficial compared to placebo for time to

1st confirmed EDSS progression and number of confirmed EDSS changes.

SPECTRIMS STUDY (Secondary Progressive Efficacy Clinical Trial of Recombinant

Interferon beta-1a in Multiple Sclerosis)

A total of 618 patients (229 men and 389 women) aged 19-56 years with secondary progressive

MS (EDSS 3-6.5) were randomised to receive REBIF 22 mcg, 44 mcg, or matching placebo as

SC injections tiw for 3 years. A total of 506 patients (82%) completed the 3-year study

treatment. The proportions of patients completing the study were similar in the placebo

(90.7%), REBIF 22 mcg (93.3%), and REBIF 44 mcg (93.1%) groups. Of the 112 patients who

discontinued prematurely, only 47 (7.6% of the overall population) were lost to follow-up. All

analyses were based on intent-to-treat principles.

Clinical Endpoints

Primary Endpoint

The primary efficacy endpoint was the effect of treatment on the time to first confirmed

progression of disability with the main comparison being between REBIF 44 mcg tiw and

placebo. Time to progression of disability was prospectively defined as the time to at least 1.0

point progression on the EDSS, or a deterioration of 0.5 point if the baseline EDSS was ≥5.5,

confirmed at two consecutive visits three months apart. The time to progression (primary

outcome) was not significantly affected by treatment compared to placebo. The hazard ratio

for progression was 0.83 (95% CI [0.65, 1.07]; p=0.146), for 44 mcg tiw (high dose) and 0.88

(95% CI [0.69, 1.22]; p=0.305) for 22 mcg (low dose).

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Figure 2 Time to confirmed progression in disability: All patients

Figure 3 Patients with relapses

Secondary Endpoints

The three secondary endpoints were relapse rate, T2 active lesion count and the change in T2

burden of disease (BOD).

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Table 8 Secondary endpoints results

Placebo tiw

REBIF 22

mcg tiw

REBIF 44

mcg tiw

P value

22 mcg tiw

vs

placebo

P value

44 mcg tiw

vs

placebo

Relapse Rate

(number per year)

0.71

0.50

0.50

<0.001

<0.001

T2 Active lesions per patient

per scan (median)

0.67

0.20

0.17

<0.0001

<0.0001

% Change in BOD (median)

+10.0

-0.5

-1.3

<0.001

<0.001

Both doses of REBIF had significant benefits, reducing the relapse rate by approximately 30%

(p<0.001), reducing T2 activity by 70-75% (p<0.001), and the percentage change in BOD

increased by 10% in the placebo group while decreasing by 1.3% and 0.5% in the high and low

dose groups respectively (p<0.001 for both doses compared to placebo).

Subgroup Analyses

A retrospective analysis was performed to examine the differential effects of treatment based

on whether or not patients had relapses during the 2 years before entry to the study. These

results obtained a posteriori should be interpreted cautiously.

Primary Endpoints

The analysis indicated that the benefit for the combined treatment group, compared to placebo

was greater for relapsing patients (n=293) as opposed to non-relapsing patients (n=325),

p=0.055 and p=0.934, respectively. Among patients with pre-study relapses, those who

received REBIF 44 and 22 mcg tiw, were less likely to progress to disability than those on

placebo (hazard ratio 0.76 for 44 mcg and 0.71 for 22 mcg). Among patients without pre-study

relapses, treated patients were as likely to progress as placebo patients (hazard ratio 0.95 for

REBIF 44 mcg and 1.10 for REBIF 22 mcg). The corresponding odds ratios for progressing in

the treated relapsing and non-relapsing patients were 0.52 (95% CI [0.29, 0.93]; p=0.027) and

1.07 (95% CI [0.64, 1.78]; p=0.802), respectively.

Secondary Endpoints

The comparison of relapsing vs non-relapsing patients revealed differences in both baseline

MRI characteristics and on-study behaviour and treatment response. The relapsing group

achieved greater treatment benefit on the MRI measures (77 vs 48% reduction in T2 activity,

and 34% greater reduction in BOD change). In summary, treatment was more effective on the

secondary outcomes for patients with pre-study relapses compared to the non-relapsing

patients.

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Table 9 Summary of on-study behaviour of relapsing vs non-relapsing patients

Relapsing Pre-study

Non-relapsing Pre-study

Dose of REBIF

REBIF 44

mcg tiw

REBIF 22

mcg tiw

Placebo

REBIF

44 mcg

REBIF

22 mcg

Placebo

Total number of patients per group

% progressing at the end of the study

Relapse rate (number per year)

0.67***

0.57***

1.08

0.36

0.43

0.39

T2 activity (median)

0.17***

0.17***

1.17

0.17*

0.20

0.33

% Change in BOD (median)

-1.3***

-1.5***

11.8

-1.4***

***: p<0.001, **: p<0.01, *: p<0.05 compared with placebo

A treatment by sex interaction was seen for the primary outcome measure in which women had

a significant benefit on therapy whereas men did not. Exploration of study data could not

identify a reason for this interaction nor has such an interaction been previously reported in the

literature. A treatment by sex interaction was not seen on relapse count but was noted on the

MRI outcome measures. For the MRI measures, women had significant benefit compared to

placebo at both doses while men experienced significant benefit on 44 mcg tiw only.

Study 25632 (REBIF HSA-free formulation)

In a multi-national, single-arm, open-label study, patients with a relapsing form of MS received

HSA-free formulation of REBIF 44 mcg three times a week. The primary objective of the study

compare

antigenicity

FBS-free/HSA-free

interferon

beta-1a

(REBIF)

formulation to historical data. The data reported here represent the results following 96 weeks

of treatment. Patients with a relapsing form of MS according to the McDonald criteria, an

EDSS<6.0 and no prior interferon beta therapy were enrolled.

All 260 enrolled subjects received REBIF HSA-free formulation, 207 subjects (79.6%)

completed

treatment

subjects

(86.2%)

completed

trial.

Demographic

characteristics were similar to previous REBIF trials: median age of 34.0 years, 71.5% of

subjects were female. The vast majority of subjects (253 subjects or 97.3%) had relapsing-

remitting MS (RRMS), 6 (2.3%) had secondary progressive MS (SPMS) with superimposed

relapses and one (0.4%) had progressive relapsing MS (PRMS). The median time since first

attack was 5.45 years. EDSS scores at screening ranged from 0 to 6.5, with a median of 2.0.

The trial primary endpoint was the proportion of subjects with neutralising antibodies (NAb

positive) at Week 96, using LOCF for missing values. At Week 96 or last assessment, 45

subjects (17.4%) were NAb positive (95% CI: 13.0% 22.5%). The proportion of NAb positive

HSA-free formulation cohort subjects was lower than that observed in recent clinical studies

performed with REBIF.

One hundred and thirty eight subjects (53.3%) were relapse-free at Week 96 (95% CI: 47.0%,

59.5%). Median time to first relapse (Kaplan-Meier estimator) was not reached, as more than

50% of subjects were relapse-free (or censored) at Week 96/early termination; the first quartile

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(Q1) was 45.0 weeks. Among subjects with known relapse status at Week 96/early termination,

the estimated relapse rate per subject was 0.70 (95% CI: 0.48, 1.13) over 96 weeks. Overall,

95 subjects or 36.7% had experienced at least one relapse by Week 96/early termination. The

mean number of relapses per subject was 0.70. EDSS scores showed very little change over

the 2 years of the trial: median changes from baseline were zero at all time points examined.

Overall, the results in this study were consistent with past experience with the original

formulation of REBIF.

Study 27025 (REFLEX) - Single clinical event suggestive of multiple sclerosis

One 2-year controlled clinical trial with REBIF was performed in patients with a single clinical

event at risk of conversion to multiple sclerosis (i.e. with 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). Patients with monofocal or multifocal onset of the disease

were included (i.e. patients with clinical evidence for involvement of a single or at least two

locations, respectively, of the central nervous system). Patients recruited into the REFLEX

study

were

strictly/explicitly

stratified

degree

their

clinical

symptoms/manifestations, as assessed by the investigating clinician, into mild, moderate or

severe. Any disease other than MS that could better explain signs and symptoms of the patient

had to be excluded.

Patients were randomised in a double-blind (DB) manner to either REBIF 44 mcg given three

times per week, REBIF 44 mcg once weekly, or placebo. Upon conversion to clinically definite

multiple sclerosis (CDMS) patients switched to the recommended dosage of REBIF 44 mcg

three times per week in an open label manner, while maintaining blinding as to initial

randomisation.

Table 10 Efficacy results from Study 27025 (REFLEX)

Parameter

Statistics

Treatment

Treatment Comparison

Placebo

(n=171)

REBIF 44

mcg qw*

(n=175)

REBIF 44

mcg tiw**

(n=171)

REBIF

44 mcg tiw

versus

Placebo

REBIF 44

mcg qw

versus

Placebo

Time to McDonald (2005) Conversion (Primary Endpoint)

Number of events

KM Estimate

at 24 months

85.8%

75.5%

62.5%

Median Time (days)

Hazard Ratio [95% CI]

0.49

[0.38;0.64]

0.69

[0.54;0.87]

Log-rank p-value

<0.001

0.008

Time to CDMS Conversion

Number of events

KM Estimate

at 24 months

37.5%

21.6%

20.6%

Hazard Ratio [95% CI]

0.48

[0.31;0.73]

0.53

[0.35;0.79]

Log-rank p-value

<0.001

0.002

Mean Combined Unique Active (CUA) Lesions per Subject per Scan During the DB Period

Least Square Means (SE)

2.58 (0.30)

0.95 (0.11)

0.50 (0.06)

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Parameter

Statistics

Treatment

Treatment Comparison

Placebo

(n=171)

REBIF 44

mcg qw*

(n=175)

REBIF 44

mcg tiw**

(n=171)

REBIF

44 mcg tiw

versus

Placebo

REBIF 44

mcg qw

versus

Placebo

Rate Ratio [95% CI]

0.19

[0.14;0.26]

0.37

[0.27;0.50]

Non-parametric ANOVA

p-value

<0.001

<0.001

qw – once a week

tiw – three times per week

Kaplan-Meier estimate of the cumulative probability of developing McDonald MS (or CDMS) over 2 years

Multivariate Cox's proportional hazards model with treatment and randomisation stratification factors as covariates

Stratified Chi-square log-rank test controlling for randomisation stratification factors

Negative binomial model with treatment and randomisation stratification factors (f) as covariates and log number of

scans as an offset variable

2-sided stratified non-parametric ANOVA model on ranked data with effects for treatment group and the

randomisation stratification factors

Randomisation stratification factors: age (<30 years, ≥30 years), classification of first clinical demyelinating event

(monofocal, multifocal), steroid use at first clinical demyelinating event (yes, no), and presence of Gd Enhancing

Lesions at baseline (yes, no).

In the placebo-controlled phase, both REBIF 44 mcg given three times per week and REBIF 44

mcg given once per week delayed the progression from the first clinical event to MS according

to the McDonald (2005) criteria and to CDMS in a statistically significant and clinically

meaningful manner versus placebo.

The treatment effect of REBIF 44 mcg given three times per week was superior to the treatment

effect of REBIF 44 mcg given once per week in delaying the progression from the first clinical

event to MS according to the McDonald (2005) criteria and in reducing the number of combined

unique active (CUA) lesions. Treatment with REBIF 44 mcg given three times per week

resulted in a 51% reduction of risk of conversion to McDonald MS compared to placebo

(Hazard Ratio = 0.49, 95% CI [0.38, 0.64], p-value < 0.001, primary endpoint). The absolute

risk reduction at 24 Months for McDonald conversion based on KM estimates between placebo

and Rebif 44mcg tiw was 23.3% and the relative risk reduction at 24 Months was 27.2%.

Treatment with REBIF 44 mcg tiw resulted in a 52% relative reduction of risk of conversion to

CDMS compared to placebo (Hazard Ratio = 0.48, 95% CI [0.31, 0.73], p-value < 0.001). The

absolute risk reduction at 24 Months for CDMS conversion based on KM estimates was 16.9%

and the relative risk reduction at 24 Months was 45.1%.

Subgroup Analysis

Subsequent to the availability of revised McDonald (2010) criteria, a post hoc subgroup analysis

was performed whereby subjects of Study 27025 (REFLEX) were re-categorised according to

the new diagnostic criteria. Over one third of patients randomised had MS at baseline according

to McDonald (2010) criteria. Compared with placebo, REBIF 44 mcg given three times per

week significantly reduced the risk of MS according to McDonald (2005) and of CDMS at 2

years, irrespective of the McDonald (2010) status at baseline.

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5.2.

PHARMAKINETIC PROPERTIES

The pharmacokinetic and pharmacodynamic profiles of the REBIF HSA-free formulation were

investigated in phase I study 25827, a double-blind, randomised, 2 period, crossover study in

which 41 healthy subjects received single 44 microgram doses of REBIF (containing Human

Serum Albumin (HSA)) and the REBIF HSA-free formulation. The geometric mean C

(17.1

IU/mL) and AUC (54.0 IU·h/mL) of the current formulation were approximately 70% higher

than that of the previous formulation (10.2 IU/mL and 31.9 IU·h/mL, respectively). The median

was 0.25 h (vs 0.33 h for the previous formulation). There was high inter-patient

variability

pharmacokinetics

interferon

beta-1a

with

both

formulations.

Bioequivalence was not demonstrated for PK parameters. However, in this study, both REBIF

HSA and REBIF HSA-free formulations were shown to be bioequivalent on the basis of two

markers of biological activity, neopterin and

-2 microglobulin.

The raw neopterin responses measured for REBIF HSA and REBIF HSA-free formulations

were similar. Median t

was 24 hours after dosing for both formulations. Mean (± sd) C

was 42 ± 21 nmol/L for REBIF HSA-free formulation, and 40 ± 19 nmol/L for REBIF HSA

formulation. Mean AUC

last

were 3882 ± 1804 nmol·h/L for REBIF HSA-free formulation and

3581 ± 1475 nmol·h/L for the REBIF HSA formulation.

The β-2 microglobulin responses of REBIF HSA and REBIF HSA-free formulations were

similar. For both formulations the median t

was 48 hours after administration. Mean C

was 3017 ± 597ng/mL for REBIF HSA-free formulation, and 2970 ± 646 ng/mL for REBIF

HSA formulation. Mean AUC

last

were 401 ± 67 µg·h/mL and 392 ± 70 µg·h/mL for the REBIF

HSA-free and REBIF HSA formulations, respectively.

The following data were obtained from an earlier REBIF formulation, now replaced with the

REBIF Human Serum Albumin (HSA)-free formulation.

In a phase I study, 28 healthy volunteers were injected with increasing (22, 44 and 66

micrograms) intravenous (IV) injections, single 66 micrograms IV, subcutaneous (SC), and

intramuscular (IM) injections, and repeated SC injections. The pharmacokinetic analysis

showed that after intravenous injection, interferon beta followed a tri-exponential pattern of

decay, with three half-lives of 3 minutes, 41 minutes and 21.5 hours. Initial volume of

distribution was 5 L, volume of distribution at steady state was 380 L and clearance was 33-55

L/h.

After SC and IM administration, median absolute bioavailability was similar regardless of

route, at 27% and 30% respectively. The mean absorption time of interferon beta following

administration of REBIF by the SC and IM routes was approximately 7 hours. Following SC

administration, absorption appeared to be the rate-limiting step for elimination. This led to an

apparent terminal half-life of (median) 66 hours following multiple dosing with REBIF every

other day. An accumulation ratio of 2.4 was noted on the fourth dose (near steady state).

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

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Special populations

No studies have been conducted to evaluate the pharmacokinetics of REBIF in elderly or

paediatric MS patients, or in subjects with renal or hepatic impairment.

However, limited published data suggest that the safety profile in adolescents from 12 to 16

years of age receiving REBIF 22 micrograms subcutaneous three times per week is similar to

that seen in adults.

5.3.

PRECLINICAL SAFETY DATA

Carcinogenicity

The carcinogenic potential of REBIF has not been investigated in animals or humans.

Genotoxicity

Interferon beta-1a appeared to not be genotoxic when tested in in vitro and in vivo assays for

gene mutation and chromosomal damage.

6.

PHARMACEUTICAL PARTICULARS

6.1.

LIST OF EXCIPIENTS

Mannitol, poloxamer, methionine, water for injections and benzyl alcohol.

Sodium hydroxide and acetic acid are used for pH adjustment.

6.2.

INCOMPATIBILITIES

Incompatibilities were either not assessed or not identified as part of the registration of this

medicine.

6.3.

SHELF LIFE

In Australia, information on the shelf life can be found on the public summary of the

Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the

packaging. Do not use after the expiry date.

6.4.

SPECIAL PRECAUTIONS FOR STORAGE

REBIF should be stored at 2°C to 8°C (Refrigerate. Do not freeze) in the original packaging to

protect it from light. Should refrigeration be temporarily unavailable, REBIF can be stored at

or below 25ºC for up to 14 days, then put back in the refrigerator and used before the expiry

date.

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6.5.

NATURE AND CONTENTS OF CONTAINER

REBIF

registered

strengths

microgram/0.5

MIU)

44 microgram/0.5mL (12 MIU) of interferon beta-1a (rch). REBIF 22 microgram/0.5 mL

(6 MIU) is not currently supplied.

REBIF 44 microgram/0.5 mL is supplied in the following presentations:

pre-filled syringe for single dose use (0.5 mL)

pre-filled syringe in a RebiDose single use autoinjector (0.5 mL)

cartridge for multidose use (1.5 mL).

REBIF pre-filled syringe (Glass Type I Clear)

REBIF is available in packs of 12 pre-filled syringes (44 microgram/0.5 mL), ready for use.

REBIF pre-filled syringe is for single use in one patient only. Contains no antimicrobial agent.

Use once only and discard any residue. REBIF pre-filled syringe may also be administered with

a suitable autoinjector (Rebiject II

REBIF pre-filled syringe (Glass Type I Clear) in a RebiDose single use autoinjector

REBIF is available in packs of 12 pre-filled syringes (44 microgram/0.5 mL), each pre-

assembled in a disposable RebiDose autoinjector and ready for use. REBIF pre-filled syringe

in RebiDose single use autoinjector is for use in one patient only. Contains no antimicrobial

agent. Use once only and discard any residue.

REBIF multidose cartridge (Glass Type I Clear)

REBIF is available in packs of 4 cartridges (132 microgram/1.5 mL) for multidose use in one

patient only.

REBIF cartridge must be administered with a reusable autoinjection device, RebiSmart. The

autoinjection device containing a cartridge of REBIF must be stored in the device storage box

at 2°C to 8°C (Refrigerate. Do not freeze). Should refrigeration be temporarily unavailable, it

can be stored at or below 25ºC for up to 14 days. Cartridges should be discarded within 21

days after first use.

6.6.

SPECIAL PRECAUTIONS FOR DISPOSAL

In Australia, any unused medicine or waste material should be disposed of by taking to your

local pharmacy.

6.7.

PHYSICOCHEMICAL PROPERTIES

Chemical structure

REBIF (interferon beta-1a (rch)) is composed of the native amino acid sequence of natural

human interferon beta. Because it is produced in mammalian cells (Chinese Hamster Ovary),

it is glycosylated as is the natural protein. Interferon beta-1a has 166 amino acids and an

approximate molecular weight of 22,500 daltons.

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The specific activity of REBIF is approximately 0.27 million international units (MIU) of

antiviral activity per microgram interferon beta-1a.

CAS number

145258-61-3

7.

MEDICINE SCHEDULE (POISONS STANDARD)

Schedule 4 (Prescription Only Medicine)

8.

SPONSOR

Supplied in Australia by:

Merck Serono Australia Pty Ltd

3-4/25 Frenchs Forest Rd East

Frenchs Forest NSW 2086

9.

DATE OF FIRST APPROVAL

Pre-filled syringe: 5 December 2008

Pre-filled syringe autoinjector: 21 October 2010

Multidose cartridge: 21 January 2010

10.

DATE OF REVISION

20 February 2019

Summary table of changes

Section

changed

Summary of new information

New format

4.2 & 6.5

Deletion of Rebislide (device discontinued)

Addition of ARTG start date for each presentation