Consumer medicine information

Rebif

Interferon beta-1a

BRAND INFORMATION

Brand name

Rebif

Active ingredient

Interferon beta-1a

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Rebif.

What is in this leaflet

This leaflet answers some common questions about REBIF.

It does not contain all of the available information.

It does not take the place of talking to your doctor or pharmacist.

All medicines have benefits and risks. Your doctor has weighed the risks of you using REBIF against the benefits it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this information with your medicine. You may want to read it again later.

What REBIF is for

REBIF belongs to a class of medicines known as interferons. The active substance of REBIF is interferon beta-1a, a recombinant human interferon beta produced in Chinese hamster ovary cells.

REBIF is used in patients who have relapsing forms of multiple sclerosis (MS). It is also approved for use in patients who have experienced a single clinical event likely to be a first sign of multiple sclerosis.

REBIF has been shown to reduce the number of attacks that occur, decrease the severity of attacks and increase the time between attacks. Treatment with REBIF also delays the progression in disability and lowers the number of times people need to be hospitalised because of attacks.

Your doctor may prescribe REBIF for another reason. Ask your doctor if you have any questions about why REBIF has been prescribed for you.

REBIF is not addictive.

The effects of the disease or of REBIF treatment may influence your ability to drive a car or operate machinery. You should discuss this with your doctor if you are concerned.

This medicine is available only with a doctor's prescription.

Before you use REBIF

When you must not use it

Do not use REBIF if you have an allergy to:

  • interferon beta
  • any of the other ingredients listed at the end of this leaflet

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin

Do not use REBIF if:

  • you are feeling depressed (feeling of severe sadness and unworthiness) or have thoughts of suicide
  • you have epilepsy that is not adequately controlled by treatment

Tell your doctor if you are pregnant or intend to become pregnant. Women of childbearing age should take appropriate contraceptive measures while using REBIF.

If you want to have children, you should discuss this matter with your doctor.

Do not use REBIF after the expiry date (EXP) printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

There is limited experience with the use of REBIF in children.

If you are not sure whether you should start using REBIF, contact your doctor.

Before you start to use it

Tell your doctor before you start to use REBIF if you are breastfeeding or intend to breastfeed. It is not known whether REBIF passes into breast milk. Your doctor will discuss with you the risks and benefits of using REBIF while you are breastfeeding.

Before starting REBIF, tell your doctor if you have or have had any of the following:

  • seizures (fits or convulsions)
  • depression
  • heart disorders
  • kidney disease
  • liver disease
  • problems with your thyroid
  • blood disorder (e.g. low counts of platelets, red and white blood cells)
  • allergy to any other medicines, foods, dyes or preservatives
  • alcohol abuse

REBIF has a potential for causing severe liver injury. Therefore, it is recommended that serum liver enzymes should be checked whilst taking REBIF.

Taking other medicines

Tell your doctor if you are taking any other medicines, including:

  • all prescription medicines
  • all medicines, vitamins, herbal supplements or natural therapies that you buy without a prescription from your pharmacy, supermarket, naturopath or health food shop

REBIF may interact with some other medicines that are broken down by the liver:

  • medicine to treat epilepsy
  • medicine used for sedation or to treat anxiety
  • medicine to treat depression

Your doctor may have to adjust the dose of your other medicines while you are using REBIF.

If you are not sure if you are taking any of these medicines, ask your doctor or pharmacist. Your doctor and pharmacist have more information on medicines to be careful with or avoid while using REBIF.

The following medicines, which are commonly used by people with MS, may be taken while using REBIF:

  • corticosteroids such as hydrocortisone, prednisone or prednisolone
  • ACTH (adrenocorticotrophic hormone)
  • flu vaccine

How to use REBIF

Treatment with REBIF should be started under the supervision of a specialist doctor experienced in the treatment of MS.

Follow all directions given to you by your doctor, nurse or pharmacist carefully. They may differ from the information contained in this leaflet.

How to inject

REBIF is intended for you to inject yourself by subcutaneous (under the skin) injection.

Your doctor or nurse will instruct and assist you in the procedure and technique of self-injection.

Do not attempt self-injection until you are sure of how to do it.

You may be prescribed:

  • REBIF pre-filled syringe (REBIF PFS) for single injection. REBIF PFS can be used on its own or with a Rebiject II® injection device
  • REBIF PFS in a RebiDose® single use autoinjector (RebiDose). REBIF PFS is pre-assembled in the RebiDose injection device and is also for single injection
  • REBIF cartridge for multiple injections. The REBIF cartridge must be used with RebiSmart® re-usable autoinjection device

Follow the Directions for Use supplied in the pack with the Rebiject II, RebiDose or RebiSmart (See Product Description).

Before the injection, you should allow the cold REBIF solution to reach room temperature. This will minimise discomfort during administration.

Do not inject REBIF if it contains particles or is not clear.

Where to inject

The best areas for injection are loose and soft (flabby) skin away from joints and nerves.

Use a different injection site each time you inject to lessen the risk of damage to the fat and tissues under the skin.

Suitable injection sites are:

  • arms (upper back portion)
  • stomach (except around navel and waistline)
  • buttocks
  • thighs (front and sides except at groin and knee)

Do not inject into any areas that have lumps, firm knots, depressions, pain or discolouration.

Talk to your doctor if you experience anything unusual when injecting.

How much to inject

Your doctor will tell you how much REBIF to inject.

When first starting treatment with REBIF, it is recommended to start at a lower dose and then increase the dose gradually over the first few weeks until you reach your maintenance dose.

The usual dose for patients with multiple sclerosis or those who have experienced a single clinical event is 44 micrograms injected subcutaneously three times a week.

One REBIF PFS or RebiDose can only be used for a single injection and must be discarded after use.

At the usual maintenance dose, one cartridge of REBIF is enough for three injections. This is usually for one week of treatment. If you are on a lower dose, e.g. at the start of treatment, one cartridge can last for more than one week.

Discard the cartridge within 21 days after first use even if it is not empty.

If you are not sure what to do, ask your doctor, nurse or pharmacist.

If you forget to inject it

If you forget an injection by one day, administer it the day after the missed dose and push back the days of injection for the remainder of the week by one day. Resume your regular schedule the following week.

If you miss an injection by two days, skip the missed injection (do not double dose on any day) and resume regular schedule.

Ask your doctor if you are not sure what to do or have trouble remembering to inject your medicine.

If you inject too much

Immediately contact your doctor or the Poisons Information Centre (in Australia telephone 131 126) if you are concerned that you have given yourself too much REBIF.

While you are using REBIF

Things you must do

Tell your doctor immediately if you become pregnant while using REBIF.

Change the injection site each time you inject. Today's injection should not be given in the same area as the last one. Keep a record of where and when you last gave yourself an injection. You may use a site again after waiting one week, if the skin area is not red or irritated. If all areas become tender, talk to your doctor about choosing other injection sites.

Before starting any new medicine, tell your doctor and pharmacist that you are using REBIF.

Tell any doctors, dentists, and pharmacists who treat you that you are using REBIF.

If you become pregnant while using REBIF, tell your doctor immediately.

Things you must not do

Do not use REBIF to treat any other complaints unless your doctor tells you to.

Do not give this medicine to anyone else, even if they have the same condition as you.

Do not stop using REBIF without first checking with your doctor.

Do not change the dose unless your doctor tells you to.

Things to be careful of

Tell your doctor if you become depressed or have suicidal thoughts while using REBIF.

Side effects

Tell your doctor as soon as possible if you do not feel well while you are using REBIF.

REBIF helps most people with MS, but it may have unwanted side effects in some people. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

Tell your doctor if you notice any of the following and they worry you:

  • injection site reactions including redness, swelling, bruising, pain
  • flu-like symptoms including fever, chills, and muscular pain Flu-like symptoms can be reduced by taking a fever reducing painkiller, such as paracetamol, before you inject and for 24 hours after you inject REBIF
  • headache or fatigue
  • itching or rash
  • abdominal pain
  • diarrhoea or nausea
  • muscle pain or aches, back pain or painful joints
  • muscle stiffness or spasms, weakness, difficulty walking
  • increased sweating

Tell your doctor immediately if you experience any of the following:

  • infected area at site of injection (swollen and painful area, with or without discharge)
  • depression, problems with sleeping or suicidal thoughts
  • anxiety/nervousness
  • fits/convulsions
  • extreme feeling of tiredness, particularly if this occurs with other symptoms, such as fever, sore throat and/or mouth ulcers
  • problems with your eyes or vision
  • spontaneous bruising or bleeding from gums or spontaneous blisters on skin
  • fatigue, dizziness, shortness of breath, bruises, gum/nose bleeds, minor cuts bleed a lot, confusion, sleepiness, seizures, decreased urine, swollen legs or fever
    Some or all of these symptoms together may indicate a rare but serious disease of the blood.
  • persistent rapid heartbeat or palpitations, insomnia, weight loss or weight gain, hair loss, tremor, neck lumps, irritability, abnormal menstrual cycles
    These symptoms alone or in combination may mean that your thyroid gland is not working properly and needs to be checked by your doctor.
  • Severe swelling (oedema), particularly around your eyes and in your ankles and feet or weight gain due to fluid retention.
  • Foamy urine, which may be caused by excess protein in your urine.
  • loss of appetite accompanied by other symptoms such as nausea, vomiting, jaundice (yellow appearance to your skin colour)
    Such symptoms can be associated with a liver disorder and, rarely, liver failure.

Tell your doctor immediately or go to Accident and Emergency at your nearest hospital if you have:

  • shortness of breath, wheezing or difficulty breathing, swelling of the face, lips, tongue or other parts of the body, rash, itching or hives on the skin
    These may be signs of an allergic reaction

Some side effects may only be found when your doctor does laboratory tests to check your progress, e.g. decreased number of red blood cells, white blood cells or platelets, or the reduction in number of all blood cells, or disturbed liver function tests. These changes are usually reversible and mild, and most often do not require particular treatment.

There have been cases of lupus reported after treatment with medicines like REBIF. This occurs when the body's immune system doesn't recognise some part of the body as its own and attacks its own cells. This is uncommon to very rare.

Tell your doctor if you notice anything else that is making you feel unwell. Other side effects not listed above may also occur in some patients.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

After using REBIF

Storage

Keep REBIF in a refrigerator where the temperature is between 2°C to 8°C (Refrigerate. Do not freeze) and it is not exposed to light.

Should refrigeration be temporarily unavailable, REBIF can be stored at or below 25°C for up to 14 days, then put back in the refrigerator and used before the expiry date.

Do NOT store it in the freezer.

REBIF cartridge must be used with a RebiSmart reusable autoinjection device. The device containing a cartridge of REBIF must be stored in the device storage box.

Use REBIF PFS and RebiDose once only. After injecting, you should discard the syringe or RebiDose even if you have not injected all of the contents.

Discard the REBIF cartridge within 21 days after first use, even if you have not injected all of the contents.

Cartridge should be used for multiple injections by one person only.

Keep this medicine where young children cannot reach it.

Disposal

Discard all sharps into a disposal unit. Sharps are objects or devices having sharp points or edges capable of cutting or piercing the skin.

Ask your doctor or pharmacist what to do with any REBIF that has expired or is left over from your treatment.

Product description

What it looks like

REBIF is an injection solution available in REBIF PFS, RebiDose or REBIF cartridge.

REBIF PFS and RebiDose contain 0.5 mL of solution and must only be used for a single injection. They are available in packs of 12.

REBIF cartridge contains 1.5mL of solution and is used for multiple injections. REBIF cartridges are available in packs of 4.

RebiSmart autoinjection device and needles for REBIF are provided separately by Merck Serono via your neurologist, MS nurse or MS Australia. Only validated needle sizes as specified in the Instructions for Use supplied with the RebiSmart device should be used.

Ingredients

Active Ingredient:

  • interferon beta-1a (rch)

Inactive Ingredients:

  • mannitol
  • poloxamer
  • methionine
  • sodium hydroxide
  • acetic acid
  • water for injections
  • benzyl alcohol

REBIF does NOT contain lactose.

Sponsor

REBIF is supplied in Australia by:

Merck Healthcare Pty Ltd
Suite 1, Level 1, Building B
11 Talavera Road
Macquarie Park NSW 2113

For enquiries please call Merck Medical Information on 1800 633 463

Australian Registration Numbers

REBIF 44 PFS
44 micrograms per 0.5 mL:
AUST R 133813

REBIF 44 PFS in RebiDose single use autoinjector
44 micrograms per 0.5 mL:
AUST R 174479

REBIF 44 cartridge
132 micrograms per 1.5 mL
(88 microgram per mL):
AUST R 165746

This leaflet was revised on February 2020

A017-0220

® Registered trademark

Published by MIMS April 2020

BRAND INFORMATION

Brand name

Rebif

Active ingredient

Interferon beta-1a

Schedule

S4

 

1 Name of 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.

Dosage.

First demyelinating event.

The recommended dose for patients who have experienced a first demyelinating event is 44 microgram (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 see 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 microgram 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 (see Section 2 Qualitative and Quantitative Composition).
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 nonambulatory 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 is frequently associated with asymptomatic elevations of 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 Section 4.8 Adverse Effects (Undesirable Effects)).
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 pruritus. 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 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 anticonvulsant 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 by MRI parameters and clinical relapse rate. The full significance of NAb 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.

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 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 microgram 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 coadministered 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 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 MAOIs, 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.
(Category D)
Initiation of treatment with Rebif is contraindicated during pregnancy.
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.
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.

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 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 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 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 cutoff 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. See Table 1.

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 microgram tiw) during the 96 week period, 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 prespecified MedDRA common AEs known to be associated with interferon beta-1a.
Subjects in the Rebif HSA-free formulation cohort experienced similar or lower rates of incidence in the eight prespecified 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 microgram 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.

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, leukopenia, 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:

Immune system disorders.

Rare: anaphylactic reactions.

Blood and lymphatic system disorders.

Rare: thrombotic microangiopathy including thrombotic thrombocytopenic purpura/ haemolytic uraemic syndrome, pancytopenia. Frequency not known: haemolytic anaemia.

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.

Musculoskeletal 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.
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 lead 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).

A total of 560 patients diagnosed with clinically definite or 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 microgram (6 MIU) three times a week (tiw), or Rebif 44 microgram (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 microgram 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 rerandomised to receive, in blinded fashion, either Rebif 22 microgram (n = 85) or Rebif 44 microgram (n = 87) tiw. The patients rerandomised from placebo (year 1-2) to treatment (years 3-4) on either Rebif 22 microgram tiw or Rebif 44 microgram tiw are referred to as placebo/ Rebif 22 microgram tiw or placebo/ Rebif 44 microgram tiw, respectively.
The withdrawal rate due to adverse events for patients randomised to Rebif 22 microgram and Rebif 44 microgram, from years 1-4, were 8 (4.2%) and 18 (9.8%), respectively.

Results of PRISMS study.

Effect on exacerbations.

Rebif 22 microgram tiw and 44 microgram 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 microgram tiw and 44 microgram 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). (See Table 4.)

Effect on time to first progression in disability.

Analysis of the intent to treat (ITT) group shows that Rebif 44 microgram tiw significantly prolonged time to progression compared to placebo/ Rebif. This prolongation is 18 months for Rebif 44 microgram tiw compared to placebo (p = 0.0474) and 12 months for Rebif 22 microgram tiw compared to placebo (p = 0.2893), for the 40th percentile (median not reached). The time to first progression was in favour of 44 microgram tiw compared to 22 microgram tiw (p = 0.3333).
The reductions in the rate of Expanded Disability Status Scale (EDSS) change for 44 microgram tiw were 29% (p = 0.005) compared to placebo, 23% (p = 0.030) compared to 22 microgram tiw, and 8% (ns) for 22 microgram 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. (See Table 5.)
The prolongation of time to confirmed progression in disability is illustrated by the Kaplan Meier curves by treatment group shown in 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 microgram tiw for the entire study duration.

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 microgram tiw versus 22 microgram 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 microgram 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 microgram tiw. (See Tables 6 and 7.)

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 microgram had a statistically significant benefit over Rebif 22 microgram 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 microgram 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 microgram over Rebif 22 microgram 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 microgram 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.
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 microgram 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 microgram, 44 microgram, 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 microgram (93.3%), and Rebif 44 microgram (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 microgram 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 microgram tiw (high dose) and 0.88 (95% CI (0.69, 1.22); p = 0.305) for 22 microgram (low dose). (See Figures 2 and 3.)

Secondary endpoints.

The three secondary endpoints were relapse rate, T2 active lesion count and the change in T2 burden of disease (BOD). (See Table 8.)
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 nonrelapsing patients (n = 325), p = 0.055 and p = 0.934, respectively. Among patients with prestudy relapses, those who received Rebif 44 and 22 microgram tiw were less likely to progress to disability than those on placebo (hazard ratio 0.76 for 44 microgram and 0.71 for 22 microgram). Among patients without prestudy relapses, treated patients were as likely to progress as placebo patients (hazard ratio 0.95 Rebif 44 microgram and 1.10 for Rebif 22 microgram). The corresponding odds ratios for progressing in the treated relapsing and nonrelapsing 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 nonrelapsing 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 prestudy relapses compared to the nonrelapsing patients. (See Table 9.)
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 microgram tiw only.

Study 25632 (Rebif HSA-free formulation).

In a multinational, single arm, open label study, patients with a relapsing form of MS received HSA-free formulation of Rebif 44 microgram three times a week. The primary objective of the study was to compare the antigenicity of the 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 and 224 subjects (86.2%) completed the 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 (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 not strictly/ explicitly stratified by the degree of 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 microgram given three times per week, Rebif 44 microgram once weekly, or placebo. Upon conversion to clinically definite multiple sclerosis (CDMS) patients switched to the recommended dosage of Rebif 44 microgram three times per week in an open label manner, while maintaining blinding as to initial randomisation. (See Table 10.)
In the placebo controlled phase, both Rebif 44 microgram given three times per week and Rebif 44 microgram 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 microgram given three times per week was superior to the treatment effect of Rebif 44 microgram 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 microgram 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 44 microgram tiw was 23.3% and the relative risk reduction at 24 months was 27.2%.
Treatment with Rebif 44 microgram 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 recategorised 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 microgram 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.

5.2 Pharmacokinetic 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 Cmax (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 Tmax was 0.25 h (vs 0.33 h for the previous formulation). There was high interpatient variability in the pharmacokinetics of 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 β-2 microglobulin.
The raw neopterin responses measured for Rebif HSA and Rebif HSA-free formulations were similar. Median Tmax was 24 hours after dosing for both formulations. Mean (± sd) Cmax was 42 ± 21 nanomol/L for Rebif HSA-free formulation, and 40 ± 19 nanomol/L for Rebif HSA formulation. Mean AUClast were 3882 ± 1804 nanomol.h/L for Rebif HSA-free formulation and 3581 ± 1475 nanomol.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 Tmax was 48 hours after administration. Mean Cmax was 3017 ± 597 nanogram/mL for Rebif HSA-free formulation, and 2970 ± 646 nanogram/mL for Rebif HSA formulation. Mean AUClast were 401 ± 67 microgram.h/mL and 392 ± 70 microgram.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 microgram), intravenous (IV) injections, single 66 microgram IV, subcutaneous (SC), and intramuscular (IM) injections, and repeated SC injections. The pharmacokinetic analysis showed that after intravenous injection, interferon beta followed a triexponential 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.

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 microgram 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 25°C for up to 14 days, then put back in the refrigerator and used before the expiry date.

6.5 Nature and Contents of Container

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). 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 preassembled 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 25°C 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.
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).

Summary Table of Changes