Consumer medicine information

Roferon-A

Interferon alfa-2a

BRAND INFORMATION

Brand name

Roferon-A

Active ingredient

Interferon alfa-2a

Schedule

What is in this leaflet

This leaflet answers some common questions about Roferon-A pre-filled syringes.

It does not contain all the available information.

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

All medicines have risks and benefits. Your doctor has weighed the risks of you using Roferon-A against the benefits they expect it will have for you.

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

Keep this leaflet with the medicine. You may need to read it again.

What Roferon-A is used for

Roferon-A contains the active ingredient interferon alfa-2a.

Roferon-A belongs to a group of medicines called interferons.

Roferon-A is a similar form of interferon to one of the interferons made naturally by your own immune system as a defence against viruses and tumours. Roferon-A works by slowing the growth of certain tumour cells and viruses and also by boosting the effects of your own immune system to fight these.

Roferon-A is used in the treatment of viral infections of the liver (chronic active hepatitis B and chronic hepatitis C).

Roferon-A treatment will not prevent a hepatitis B or C infected person from giving another person hepatitis B or C.

Roferon-A may be used in combination with ribavirin for the treatment of chronic hepatitis C in patients who have relapsed to previous interferon monotherapy treatment.

Roferon-A is also used in the treatment of various types of cancer such as, kidney cancer (renal cell carcinoma), cancer of the lymph glands (cutaneous T-cell lymphoma), blood cancer (hairy cell leukaemia, chronic myelogenous leukaemia (CML) and other bone marrow conditions causing platelet disorders), AIDS-related cancer (Kaposi's sarcoma), and low-grade non-Hodgkin's lymphoma.

Roferon-A may be used in combination with AVASTIN for the treatment of kidney cancer.

Your doctor, however, may have prescribed Roferon-A for another reason.

Ask your doctor if you have any questions why Roferon-A has been prescribed for you.

Roferon-A is not addictive.

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

Before you use Roferon-A

Do not use Roferon-A if:

you have had an allergic reaction to interferon alfa or any ingredients listed at the end of this leaflet
Some symptoms of an allergic reaction include:

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

you have advanced liver disease or suffer from autoimmune hepatitis
the patient is a new born baby - one of the inactive ingredients of Roferon-A, benzyl alcohol, can be harmful to newborns
the package is torn or shows signs of tampering
the expiry date (EXP) printed on the pack has passed
If you use this medicine after the expiry date has passed it may have no effect at all, or worse, an unexpected effect.

Before starting Roferon-A, your doctor will discuss with you the possible benefits and possible side effects of treatment, to decide if Roferon-A is right for you. While taking Roferon-A, you will need to see your doctor regularly for medical examinations and blood tests to make sure your treatment is working and to check for side effects.

Use in children

Do not give Roferon-A to children under 18 years of age. Safety and effectiveness in children have not been established.

This product contains benzyl alcohol and should not be given to babies from birth up to the age of 3 years.

Before you start to use Roferon-A

Your doctor must know about all the following before you start to use Roferon-A.

Tell your doctor if:

you are pregnant or plan to become pregnant
It is not known whether Roferon-A is harmful to an unborn baby when used by a pregnant woman. If there is a need to use Roferon-A when you are pregnant your doctor will discuss the risks and benefits to you and the unborn baby.
you are breast-feeding or plan to breast-feed
Because interferon alfa-2a occurs naturally in the body, it has not been possible to determine whether Roferon-A passes into the breast milk following injection. Your doctor will discuss the risks and benefits of using Roferon-A if you are breast-feeding.
you have ever had any of the following medical conditions or problems, tell your doctor before you start taking Roferon-A:

history of, or current severe mental illness (such as depression or anxiety)
history of injecting drug use or excessive alcohol use
history of heart disease or previous heart attack
autoimmune disease (where the body's immune system attacks the body's own cells), such as psoriasis (a skin disease)
kidney problems
blood disorders
diabetes (high blood sugar)
problems with the thyroid gland
liver problems, other than hepatitis C
vision problems
an organ transplant (e.g. kidney or bone marrow) or an organ transplant is planned for you in the immediate future.

you are allergic to any other medicines, foods, dyes or preservatives.

Taking other medicines

Tell your doctor if you are taking any other medicines, including any that you have bought from a pharmacy, supermarket or health food shop.

Some medicines may interfere with Roferon-A or may affect how well it works. You may need to use different amounts of your medicine, or you may need to take different medicines. Your doctor will advise you.

You must tell your doctor if you are taking:

theophylline, a medicine used in the treatment of asthma, bronchitis, emphysema and related conditions.
sho-saiko-to, a Chinese herbal medicine, also known as Xiao-Chai-Hu-Tang

Your doctor or pharmacist has more information on medicines to be careful with or avoid while using Roferon-A.

If you have not told your doctor about any of the above, tell them before you start using Roferon-A.

How to use Roferon-A

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

How much to inject

The dosage of Roferon-A is expressed in millions of international units (MIU). If this unitage seems unusually high, it may be helpful to convert it into units that you are more familiar with. For example, 200 MIU adds up to only 1 milligram of Roferon-A.

The dose of Roferon-A will be determined by your doctor based on your condition. As a general rule, your dosage should not exceed 36 MIU per day.

Your dose may be adjusted by your doctor during therapy according to your response.

Your doctor will keep track of your response to Roferon-A by asking questions and performing occasional laboratory tests.

Do not exceed or change the dose recommended by your doctor. The dosage is generally adjusted depending on your response to treatment.

Directions for administration

Roferon-A is administered by a subcutaneous injection (under the skin).

If you are receiving other treatments for your disease (e.g. chemotherapy, AVASTIN), your Roferon-A injection may be given by a doctor or nurse whilst you are in hospital receiving your other treatment.

It may be appropriate and more convenient for you to receive your injections at home. Your doctor will discuss this with you. If this is the case, you or a family member will be instructed on how to give the injection properly. This is a simple procedure and many patients prefer to administer their treatment at home. Administration of the subcutaneous injection is described further on in this leaflet.

How long to use Roferon-A

Your treatment period could range from a few weeks up to 12 months depending on your illness.

If your injections are administered at a hospital with another treatment (e.g. chemotherapy, AVASTIN), your Roferon-A treatment might continue for several months after your other treatment has stopped. At this time, you may start to self-administer Roferon-A as described below. Your doctor will advise you.

Continue using Roferon-A until your doctor tells you to stop. Your doctor will determine when your treatment should be stopped.

Directions for self-administration

If you wish to administer Roferon-A yourself at home, please follow the instructions below.

Subcutaneous (sc) Injection

You should read these directions from beginning to end before starting so that each step of the procedure becomes familiar. These instructions must be carefully followed. Consult your doctor if you require further instructions.

Remember that cleanliness is vital.

How to inject

Before subcutaneous injection

Check the expiry date. Do not use Roferon-A after the expiry date shown on the pre-filled syringe label.
Check the dose that you have been prescribed.
Check the liquid has no discolouration, cloudiness or particles. The liquid should look clear and colourless to slightly yellow.
Let the syringe stand for 30 minutes at room temperature.
Wash your hands thoroughly.
Place everything you need within easy reach: the pre-filled syringe, the needle for subcutaneous injection, an alcohol swab and some cotton wool and a container for disposal of the needle and syringe.

How to prepare the syringe and needle for injection

A. Take the sealed needle in both hands and snap the grey cap backwards. Remove the cap. DO NOT remove the plastic needle shield.

B. Remove the rubber cap from the syringe. Do not touch the tip of the syringe.

C. Attach the needle with the plastic shield firmly to the syringe.

D. Remove the plastic cover from the needle while holding the syringe. Avoid pushing the plunger.

E. To remove air bubbles from the syringe, hold the syringe with the needle pointing up. Tap the syringe gently to bring the bubbles to the top. Push up the plunger slowly to the correct dose. Replace the needle guard and place the syringe in a horizontal position on a clean flat surface.

The syringe is now ready for use.

Performing subcutaneous injection

F. Select an injection site in the abdomen or thigh area (except your navel or waistline, see diagram). Change your injection site each time.

G. Remove an alcohol swab from one packet and clean and disinfect the site by wiping with the swab.

H. Remove the alcohol swab from the site. Allow the injection site to dry for 10 seconds.
I. Remove the needle guard

J. With one hand, pinch a fold of loose skin. With your other hand, hold the syringe as you would a pencil.

K. Gently insert the needle into the pinched skin at an angle of 45° to 90° (bevelled edge facing upwards). Half of the needle should still be visible.

L. Inject the solution by gently pushing the plunger all the way down, while keeping the skin grasped.
M. After injecting, remove the needle at the same angle so it does not hurt you, and release the skin.
Press gently over the injected area with some cotton wool. Don't worry if you see slight bleeding, it should not bleed a lot. If it does bleed, keep pressing on the area for a while. You may need to put a Band-Aid on. Check the site later for any signs of soreness, and if this occurs tell your doctor or nurse at the next opportunity.
Remember:
Most people can learn to give themselves a subcutaneous injection, but if you experience difficulty, please do not be afraid to ask for help and advice from your doctor, nurse or pharmacist.

How to dispose of used needles and syringes

The needle and syringe are to be used once only. Dispose of the needle and syringe immediately after injection into a sturdy glass or hard plastic container away from children. Do not replace the needle cover.
Never put used needles and syringes into your normal household waste bin. If you are not sure how to dispose of the needles and syringes, consult your doctor, nurse or pharmacist on how to properly dispose the syringes and needles.

When to inject Roferon-A

Your doctor will tell you how often to use this medicine. As a general rule, a maximum of one injection per day should be given.

If you are injecting this medicine yourself, use it at bedtime as Roferon-A may cause unusual tiredness or flu-like symptoms.

If you forget to use Roferon-A

If it is almost time for your injection, skip the injection you missed and use your next injection when you are meant to.

Otherwise, use it as soon as you remember, and then go back to using it as you would normally.

Do not use a double injection to make up for the injection that you missed.

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

If you have trouble remembering when to use your medicine, ask your pharmacist for some hints.

If you use too much Roferon-A (overdose)

Immediately telephone your doctor or Poisons Information Centre (telephone 13 11 26) for advice or go to Accident and Emergency at your nearest hospital if you think that you or anyone else may have used too much Roferon-A, even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

Keep telephone numbers for these places handy.

While you are using Roferon-A

Things you must do

Use Roferon-A exactly as your doctor has prescribed.

Tell all doctors, dentists and pharmacists who are treating you that you are using Roferon-A.

Do not take any other medicines whether they require a prescription or not without first telling your doctor or consulting with a pharmacist.

Tell your doctor if you become pregnant while using Roferon-A.

Tell your doctor if, for any reason, you have not used Roferon-A exactly as prescribed. Otherwise, your doctor may think that it was not effective and change your treatment unnecessarily.

Be sure to keep all of your appointments with your doctor so that your progress can be checked.

Things you must not do

Do not stop using Roferon-A or change the dose without first checking with your doctor.

Do not let yourself run out of medicine over the weekend or on holidays.

Do not give Roferon-A to anyone else even if they have the same condition as you.

Do not use Roferon-A to treat other complaints unless your doctor says to.

Do not switch to any other brands of interferon without consulting your doctor because a change in dosage may result.

Do not take any other medicines whether they require a prescription or not without first telling your doctor or consulting a pharmacist.

Things to be careful of

Be careful driving or operating machinery until you know how Roferon-A affects you.

Your doctor may want you to drink extra fluids, especially when you begin Roferon-A treatment.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are using Roferon-A.

Roferon-A helps most people but it may have unwanted side effects in a few 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.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor immediately or go to Accident and Emergency at your nearest hospital if you notice any of the following:

signs of anaemia, such as tiredness, shortness of breath when exercising, headaches, dizziness and looking pale
signs of mental health problems such as, irritability (getting easily upset), depression (feeling low, bad about yourself, hopeless, very depressed), suicidal, anxiety, aggressive behaviour
mania (episodes of overactivity, elation or irritability, excitement, over-activity and uninhibited behaviour)
chest pain or irregular heartbeat
confusion, depression, trouble sleeping, thinking or concentrating
numbness or tingling sensation
coughing and/or breathlessness
trouble breathing, pneumonia
fluid build up in body tissues (swelling)
visual disturbances such as blurred or loss of vision
convulsions (epileptic fits)
frequent infections such as fever, severe chills, sore throat or mouth ulcers; unusual bleeding, bruising more easily than usual or nosebleeds
symptoms of bowel inflammation including diarrhoea (usually with blood or mucus), stomach pain, fever

These are serious side effects. You may need urgent medical attention. Serious side effects are rare.

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

flu-like symptoms such as fever, tiredness, chills, muscle or joint pain and headache (these symptoms can usually be relieved by paracetamol)
loss of appetite, taste change or dry mouth
tiredness or sleepiness (may be less troublesome if you have your injection in the evening or before going to sleep)
dizziness
nausea (feeling as if you are about to vomit), vomiting or diarrhoea
heart burn
slight hair loss (usually temporary and reversible after finishing treatment)
mild or moderate abdominal (gut) pain
rash
dry or itchy skin
weight loss
night sweats
temporary impotence
reappearance of cold sores if previously infected with herpes virus

This is not a complete list of all possible side effects. Your doctor or pharmacist has a more complete list. Others may occur in some people and there may be some side effects not yet known.

Tell your doctor if you notice anything else that is making you feel unwell, even if it is not on this list.

Ask your doctor or pharmacist if you don't understand anything in this list.

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

After using Roferon-A

Storage

Always keep this medicine closed in its original pack. If you take the pre-filled syringes out of the pack they may not keep well.

Store Roferon-A pre-filled syringes in the fridge at 2°C to 8°C. Do not freeze.

Protect Roferon-A pre-filled syringes from light.

Do not leave it in the car or on window sills. Heat and dampness can destroy some medicines.

Keep Roferon-A where young children cannot reach it. The top shelf of the refrigerator is a good place to store this medicine.

Roferon-A pre-filled syringes are for single use only. The pre-filled syringe should be used once only and any remaining contents should be discarded with the needle.

Disposal

If your doctor tells you to stop using Roferon-A, or the pre-filled syringe has passed its expiry date, ask your pharmacist what to do with any pre-filled syringes that are left over.

If you use Roferon-A at home, you must throw away the syringes and needles in a sturdy glass or hard plastic container that will not let the needles stick through it. This will help protect you and other people from accidental needle stick injuries. Being struck by a needle can pass diseases onto other people.

Product description

Availability

Roferon-A pre-filled syringes come in packs of one.

What Roferon-A pre-filled syringes look like

Roferon-A solution for injection is contained in a disposable glass syringe. The solution is clear and colourless to slightly yellowish.

A stainless steel needle is also supplied with the syringe to allow for subcutaneous injection.

Ingredients

Active ingredient

interferon alfa-2a (rbe)

Roferon-A pre-filled syringes are available in the following strengths:

3.0 MIU in 0.5 mL solution
9.0 MIU in 0.5 mL solution

On the outer carton, these strengths are expressed as 3.0 x 10⁶ IU/0.5 mL, and 9.0 x 10⁶ IU/0.5 mL of interferon alfa-2a, respectively.

Inactive ingredients

Each pre-filled syringe also contains:

ammonium acetate
sodium chloride
benzyl alcohol
polysorbate 80
glacial acetic acid
sodium hydroxide
water for injections

Distributor

Roferon-A pre-filled syringes are distributed by:

Roche Products Pty Limited
ABN 70 000 132 865
Level 8, 30-34 Hickson Road
Sydney NSW 2000
Medical Enquiries: 1800 233 950

Please check with your pharmacist for the latest Consumer Medicine Information

Australian Registration Numbers
3.0 MIU: AUST R 58594
9.0 MIU: AUST R 58597

This leaflet was prepared on 27 September 2017

Published by MIMS November 2017

BRAND INFORMATION

Brand name

Roferon-A

Active ingredient

Interferon alfa-2a

Schedule

Name of the medicine

Recombinant interferon alfa-2a.

Excipients.

Sodium chloride, ammonium acetate, benzyl alcohol, polysorbate 80, glacial acetic acid, sodium hydroxide and water for injections.

Description

MW: approximately 19 kD. CAS: 76543-88-9. Roferon-A (interferon alfa-2a) is a sterile protein product for use by injection. Roferon-A is produced biosynthetically using recombinant DNA technology, and is the product of a cloned human leucocyte interferon gene inserted into and expressed in E. coli. Interferon alfa-2a is a highly purified protein containing 165 amino acids.
Fermentation is carried out in a defined nutrient medium containing the antibiotic tetracycline hydrochloride 5 mg/L. However, the presence of the antibiotic is not detectable in the final product.
The specific activity of interferon alfa-2a is approximately 270 MIU/mg protein. Roferon-A should be administered by subcutaneous injection.

Pharmacology

Pharmacodynamics.

Mechanism of action.

The mechanism by which interferon alfa-2a or any other interferon exerts antitumour activity is not clearly understood. However, it is believed that direct antiproliferative action against tumour cells and modulation of the host immune response play important roles in the antitumour activity.
Roferon-A exerts its antiviral effects by inducing a state of resistance to viral infections in cells and by modulating the effector arm of the immune system to neutralise viruses or eliminate virus infected cells.
The biological activities of interferon alfa-2a are species restricted, i.e. they are expressed in a very limited number of species other than humans. As a consequence, preclinical evaluation of interferon alfa-2a has involved in vitro experiments with human cells and some in vivo experiments. Using human cells in culture, interferon alfa-2a has been shown to have antiproliferative and immunomodulatory activities that are very similar to those of the mixture of interferon alfa subtypes produced by human leucocytes. In vivo, interferon alfa-2a has been shown to inhibit the growth of several human tumours growing in immunocompromised (nude) mice. Because of its species restricted activity, it has not been possible to demonstrate antitumour activity in immunologically intact syngeneic tumour model systems, where effects on the host immune system would be observable. However, such antitumour activity has been repeatedly demonstrated with, for example, mouse interferon alfa in transplantable mouse tumour systems. The clinical significance of these findings is unknown.
In a pharmacological study in 9 subjects, Roferon-A was shown to inhibit hepatic oxidative drug metabolism as measured by antipyrine clearance.

Pharmacokinetics.

Absorption.

The serum concentrations of interferon alfa-2a reflected a large intersubject variation in both healthy volunteers and patients with disseminated cancer. After intramuscular (IM) and subcutaneous (SC) administrations of 36 MIU, peak serum concentrations ranged from 1500-2580 picogram/mL (mean 2020 picogram/mL) at a mean time to peak of 3.8 h and from 1250-2320 picogram/mL (mean 1730 picogram/mL) at a mean time peak of 7.3 h, respectively. The apparent fraction of the dose absorbed after IM injection was greater than 80%. Multiple IM doses of interferon alfa-2a resulted in an accumulation of 2-4 times the single dose serum concentrations.

Distribution.

In healthy people, interferon alfa-2a exhibited a volume of distribution at steady state of 0.223-0.748 L/kg (mean 0.400 L/kg) after a 36 MIU (2.2 x 10⁸ picogram) intravenous (IV) infusion. Small amounts of radiolabelled interferon alfa-2a appear in the urine of isolated rat kidneys, suggesting near complete reabsorption of interferon alfa-2a catabolites.

Metabolism.

The metabolism of interferon alfa-2a is consistent with that of alfa interferons in general. Alfa interferons are totally filtered through the glomeruli and undergo rapid proteolytic degradation during tubular reabsorption, rendering a negligible reappearance of intact alfa interferon in the systemic circulation.

Elimination.

Renal catabolism is the major pathway for Roferon-A elimination. Liver metabolism and subsequent biliary excretion are considered minor pathways of elimination of Roferon-A. In healthy people, interferon alfa-2a exhibited an elimination half-life of 3.7-8.5 h (mean 5.1 h) and a total body clearance of 2.14-3.62 mL/min/kg (mean 2.79 mL/min/kg) after a 36 MIU (2.2 x 10⁸ picogram) IV infusion. Theophylline clearance has also been measured before and during interferon administration. Clearance decreased from 190 mL/min to 45 mL/min and correspondingly the elimination half-life increased from 4.7 h to 11.6 h.

Pharmacokinetics in special populations.

The pharmacokinetics of interferon alfa-2a after single IM doses to patients with disseminated cancer and chronic active hepatitis B were similar to those found in healthy volunteers. Dose proportional increases in serum concentrations were observed after single doses up to 198 MIU. There were no changes in the distribution or elimination of interferon alfa-2a during twice daily (0.5-36 MIU), once daily (1-54 MIU), or three times a week (1-136 MIU) dosing regimens up to 28 days of dosing.
Pharmacokinetic information in patients with hairy cell leukaemia or AIDS related Kaposi's sarcoma is presently unknown.
The acute parenteral toxicity of interferon alfa-2a has been studied in mice, rats, rabbits and ferrets at doses up to 30 MIU/kg IV and 500 MIU/kg IM. No treatment related mortality was noted in any species given interferon alfa-2a by any of the routes of administration.

Anti-interferon antibodies.

Neutralising antibodies to proteins may be formed in some subjects following homologous administration. Antibodies to all interferons, whether natural or recombinant, are therefore likely to be found in a certain proportion of patients. In certain clinical conditions (cancer, systemic lupus erythematosus, herpes zoster) antibodies to human leucocyte interferon may also occur spontaneously in patients who have never received exogenous interferon.
In clinical trials where Roferon-A which had been stored at 25°C was used, neutralising antibodies to Roferon-A have been detected in approximately one-fifth of patients. The significance of the appearance of serum neutralising antibodies on pharmacokinetics and efficacy is unclear. In most cases there appears to be no effect on efficacy. However, in a small proportion of cases loss of efficacy has been associated with detection of neutralising activity. In patients with hepatitis C, a trend for responding patients who develop neutralising antibodies to lose response while still on treatment and to lose it earlier than patients who do not develop such antibodies has been seen. No other clinical sequelae of the presence of antibodies to Roferon-A have been documented.

Clinical Trials

Studies have shown that Roferon-A can produce clinically meaningful regression or stabilisation of hairy cell leukaemia both in previously splenectomised and nonsplenectomised patients and can induce clinical responses in patients with advanced renal cell carcinoma (RCC), AIDS related Kaposi's sarcoma, chronic active hepatitis B, chronic hepatitis C, chronic myelogenous leukaemia and cutaneous T cell lymphoma. Studies have also shown that Roferon-A prolongs the time to relapse in patients with low grade non-Hodgkin's lymphoma when used as an adjunct to or concomitant with chemotherapy (with or without radiotherapy).

Chronic hepatitis C.

Roferon-A monotherapy.

Roferon-A has been shown to produce a decrease in biochemical markers maintained after completion of treatment in chronic active hepatitis C. However the percentage of cases with biochemical response maintained after completion of treatment varied markedly between studies. Histological indices of liver inflammation and detection of hepatitis C virus also decrease in a significant number of cases.

Roferon-A combination therapy.

Previously untreated patients.

A randomised, controlled trial was conducted to investigate the sustained efficacy of combining Roferon-A with ribavirin compared to Roferon-A alone. Sixty noncirrhotic patients with chronic hepatitis C participated in this trial for 24 weeks treatment with a 72 week treatment free follow-up period. Patients were followed up at 4 week intervals for the initial 24 weeks and every 8 weeks thereafter for a total of 96 weeks.
Patients were randomised to one of three treatment regimens: 21 patients received Roferon-A 3 MIU subcutaneous (SC) three times a week with ribavirin 1200 mg daily; 19 patients received Roferon-A 3 MIU SC; and 20 patients received no treatment.
Virological response, defined as negative HCV-RNA (determined by polymerase chain reaction using the COBAS-AMPLICOR version 2.0, sensitivity to 100 copies/mL) was measured at the end of treatment and during the follow-up period to determine sustained virological response (see Table 1).
Virological response was reported more frequently in those patients treated with Roferon-A with ribavirin combination therapy than those treated with Roferon-A alone. Patients receiving Roferon-A with ribavirin combination therapy maintained a significantly higher rate of sustained virological response for up to 2 years.

Histological response was measured in 28 out of 60 patients by the Knodell Histology Activity Index (HAI). Histological improvements were defined as a decrease in the inflammation score of at least 2 points. Histology changes indicated that there was no significant difference between treatment groups.

Relapsed patients.

Roferon-A in combination with ribavirin has been investigated in chronic hepatitis C patients who had relapsed after treatment with interferon alfa monotherapy. In a placebo controlled, double blind trial 99 patients were randomised into two treatment groups; 49 patients received Roferon-A 4.5 MIU SC three times a week with ribavirin 1000 mg daily in two divided doses and 50 patients received Roferon-A 4.5 MIU SC three times a week with placebo. The treatment duration was 24 weeks with a 24 week treatment free follow-up period.
Virological response, as defined for previously untreated patients, was measured at the end of treatment and during the treatment free follow-up period to determine sustained response (see Table 2).
Sustained responses were significantly higher for Roferon-A with ribavirin combination treated patients compared to Roferon-A with placebo.

Liver biopsies were conducted post-treatment to determine any improvements in histology. Histological improvements were defined as a decrease in the inflammation score of at least 2 points using the Knodell HAI (see Table 3). Fibrosis was graded according to the Metavir system in which a score of 0 indicated the absence of fibrosis and a score of 4 the presence of cirrhosis. Fibrosis was usually moderate, mild or absent in patients treated with Roferon-A with ribavirin combination therapy but usually severe, moderate or mild in patients treated with Roferon-A alone.

Advanced and/or metastatic renal cell carcinoma (RCC).

Combination therapy.

Evidence supporting the use of Roferon-A in advanced and/or metastatic RCC is derived from clinical trials investigating the combination of Roferon-A with vinblastine or bevacizumab.

Study M23935.

A total of 160 patients with advanced RCC were enrolled and randomised to treatment with vinblastine (n = 81) or with Roferon-A and vinblastine (n = 79). Roferon-A was injected SC at 3 MIU three times a week during the first week, and at 18 MIU three times a week for subsequent weeks. Vinblastine was given IV at 0.1 mg/kg once every 3 weeks to patients in both treatment groups. Treatment was continued for 1 year unless disease progression or intolerable side effects occurred. Where patients achieved a complete response, treatment was discontinued 3 months after detection of a complete response.
Median survival was 67.9 weeks in the Roferon-A + vinblastine group and 37.4 weeks in the vinblastine group (p < 0.01; log rank test). In addition, median time to progression was 13 weeks in the Roferon-A + vinblastine group and 9 weeks in the vinblastine group (p < 0.01; log rank test). Objective response rates (complete response + partial response) were 16.9% for Roferon-A + vinblastine and 2.5% for vinblastine (p < 0.01; Fisher's exact test).
During follow-up of this study, survival rates for patients treated with Roferon-A + vinblastine or vinblastine alone were, respectively, 55.7% and 38.3% after 1 year, 11.7% and 5.1% at 3 years, 8.1% and 1.3% at 4 years and 4.1% and 0% at 5 years.

Study O.10519.

A total of 178 patients with advanced RCC were randomised to Roferon-A (n = 87) or to Roferon-A and vinblastine therapy (n = 91). Roferon-A was given at a dose of 18 MIU IM three times a week. Vinblastine was injected IV at a dose of 0.1 mg/kg once every 3 weeks. The dose of both drugs was reduced if WHO grade 3 or 4 toxicity developed. Treatment duration was for 6 months. However, patients with progressive disease during treatment were withdrawn. Patients with a complete response continued treatment for 6 months after the first detection of complete response. Patients with a partial response or no change after the first 6 months of treatment continued therapy for a total of 12 months. Tumours were assessed at monthly intervals.
On an intention to treat analysis, overall response rates were 8% in the Roferon-A group and 19% in the Roferon-A + vinblastine group. The difference between treatments was statistically significant (p = 0.038). However, the difference may have resulted from a difference in performance status that existed between the two groups at baseline. Therefore it is not possible to conclude that vinblastine provides additional efficacy to that obtained with Roferon-A alone. The median overall survival was 338 days in the Roferon-A group and 386 days in the Roferon-A + vinblastine group (p = 0.29; log rank test).
Treatment with Roferon-A was tolerated by most patients in these studies, with reductions in dosage necessary for some. For those unable to tolerate the recommended dose of 18 MIU three times a week, halving the dose to 9 MIU did not appear to reduce the survival benefit in study M23935.

Study BO17705.

BO17705 was a multicentre, randomised, double blind phase III trial conducted to evaluate the efficacy and safety of Roferon-A in combination with bevacizumab (Avastin) versus Roferon-A alone as first-line treatment in metastatic RCC. Roferon-A (9 MIU three times a week) plus Avastin (10 mg/kg every two weeks) or placebo was given until disease progression. A lower starting Roferon-A dose (3 or 6 MIU) was permitted as long as the recommended 9 MIU dose was reached within the first 2 weeks of treatment. If 9 MIU was not tolerated, Roferon-A dosage reduction to a minimum of 3 MIU three times a week was also permitted.
In this study a benefit to patients with advanced and/or metastatic RCC was shown. A clinically relevant and statistically significant increase in progression-free survival, a trend towards an increase in overall survival and a statistically significant increase in the percentage of responders in the Avastin + Roferon-A arm compared with the placebo + Roferon-A arm were observed. However, the observed increase of 2 months in overall survival was not significant. The efficacy results are presented in Table 4.

Ninety-seven (97) patients in the Roferon-A arm and 131 patients in the Avastin arm reduced the dose of Roferon-A from 9 MIU to either 6 or 3 MIU three times a week as prespecified in the protocol.
For more information on the combination use with Avastin, refer to the Avastin product information.

Low grade non-Hodgkin's lymphoma.

The activity of interferon alfa-2a in low grade non-Hodgkin's lymphoma has been studied in 2 clinical trials when used as an adjunct to or concomitant with chemotherapy, with or without radiotherapy.

Interferon alfa-2a used as an adjunct to chemotherapy and radiotherapy.

In a prospective randomised trial (Western Europe, EORTC 20856), 347 previously untreated patients with stages III or IV (working formulation categories B and C) low grade malignant non-Hodgkin's lymphoma were treated with 8 cycles of CVP chemotherapy, followed by iceberg radiotherapy, if indicated. After induction chemo/ radiotherapy, 253 patients in remission (without progressive disease) were randomised to maintenance therapy with Roferon-A (126 patients) at 3 MIU SC or IM three times a week for 12 months, or to no further treatment. Patients were periodically assessed to determine the duration of remission and overall survival.
The median time to relapse was 135 weeks for patients treated with Roferon-A group versus 87 weeks for those who received no maintenance treatment; this difference was statistically significant (p = 0.036; log rank test). The median survival has not been reached, and the effects of treatment on overall survival have not yet been determined.

Interferon alfa-2a used concomitantly with chemotherapy.

In a prospective randomised trial (United States, ECOG 6484), 291 patients with low or intermediate grade NHL (working formulation categories A to E) were enrolled, and eligible patients were randomised to treatment with 8-10 cycles of COPA chemotherapy alone, or combined with Roferon-A at 6 MIU/m² IM on days 22-26 of each 28 day COPA cycle. Patients were periodically assessed for tumour responses, duration of response, time to treatment failure and survival. Patients with a partial response after 8 cycles or complete response during cycle 7 or 8 received a maximum of 2 additional treatment cycles.
After a median follow-up of 5.25 years, 81% of patients with COPA alone and 66% of patients treated with COPA plus Roferon-A had disease progression. This difference was statistically significant (p = 0.0013; Fisher's exact test). The study demonstrated no difference in response rate or in overall survival with addition of Roferon-A to induction chemotherapy with COPA.

Chronic active hepatitis B (CAHB).

Roferon-A has been shown to induce a decrease in biochemical markers and markers of viral replication and to result in an antiviral immune response in 20-30% of cases of chronic active hepatitis B in the dose range equivalent to 2.5-10 MIU/m² (4.5-18 MIU).
Histological changes do not show a response greater than that seen in untreated patients.
Response to therapy is signalled by a transient asymptomatic acute hepatitis ‘flare’ with a serum transaminase peak accompanied by a fall in the level of genomic and antigenic (especially HBe) markers of viral replication. Patients most likely to respond are those with mild to moderate levels of hepatitis B viral DNA.
Loss or reduction of HBs antigenaemia usually occurs over a period of many months. The appearance of anti-HBe and in some cases anti-HBs antibody in the serum signals antiviral immunity. By 12 months after treatment there is no difference in histological, biochemical or viral markers of the disease.

Chronic myelogenous leukaemia (CML).

Roferon-A produces haematological remission in 60% of patients with chronic phase CML, independent of prior treatment. Two-thirds of these patients have complete haematological responses which occur as late as 18 months after treatment start.

Cutaneous T cell lymphoma (CTCL).

Roferon-A produces objective tumour responses in approximately 60% of patients with CTCL. About one-third of these responses are complete responses with response duration of more than 12 months and ongoing responses after treatment discontinuation. These tumour regressions can also be achieved in patients who failed to respond or relapsed after having responded to other treatment modalities. Partial responses are usually seen within 3 months and complete responses within 6 months, although it may occasionally take more than 1 year to reach the best response.

Hairy cell leukaemia.

During the first 1-2 months of treatment of patients with hairy cell leukaemia, significant depression of haematopoiesis was likely to occur. Subsequently, there was an improvement in circulating blood cell counts.
Of the 75 patients who were evaluable for efficacy following at least 16 weeks of therapy, 46 (61%) achieved complete or partial response. Twenty-one patients (28%) had a minor remission, 8 (11%) remained stable, and none had worsening of disease. All patients who achieved either a complete or partial response had complete or partial normalisation of all peripheral blood elements including haemoglobin level, white blood cell, neutrophil, monocyte and platelet counts, with a concomitant decrease in peripheral blood and bone marrow hairy cells.
Responding patients also exhibited a marked reduction in red blood cell and platelet transfusion requirements, a decrease in infectious episodes and improvement in performance status. The probability of survival for 2 years in patients receiving Roferon-A (94%) showed a statistically significant increase compared to a historical control group (75%).

AIDS related Kaposi's sarcoma.

Patients with AIDS related Kaposi's sarcoma are more likely to respond to therapy if they have no history of opportunistic infection and no B symptoms (> 10% loss of bodyweight, fever > 38°C with no identified source of infection or night sweats). Of 182 such patients who were evaluable for efficacy, 22.5% achieved a complete or partial response.
At the recommended dose of 36 MIU, the response rate was 28.6%. Patients generally evidenced response after approximately 2-3 months of therapy. The response rate in patients with a prior history of opportunistic infections was less than 10%.
Responding patients experienced tumour regression. Twelve percent of responders experienced opportunistic infections during therapy whereas 20% of the poor prognosis group (B symptoms and prior opportunistic infections) had opportunistic infections during therapy on interferon. The median survival for responding patients was 51.5 months. The median survival time for nonresponders was 14 months.

Indications

Roferon-A is indicated for use in the treatment of the following.
AIDS related Kaposi's sarcoma.
Patients with histologically proven chronic active hepatitis B (but without evidence of cirrhosis of the liver) and raised ALT levels (> 3 x upper limit of reference range).
Chronic hepatitis C given in combination with ribavirin in previously untreated patients or patients who have relapsed following alfa interferon monotherapy. Patients must be 18 years of age and have compensated liver disease.
Patients 18 years or older with histologically proven chronic hepatitis due to hepatitis C and persistently elevated serum ALT for at least 6 months and without liver decompensation (Child's class A).
Hairy cell leukaemia.
Chronic myelogenous leukaemia (CML) and excessive thrombocytosis associated with CML and other myeloproliferative disorders, in people 18 years of age or older.
Cutaneous T cell lymphoma (mycosis fungoides and Sézary syndrome).
Patients with low grade non-Hodgkin's lymphoma (as per international working formulation) when used as an adjunct to or concomitant with chemotherapy (with or without radiotherapy).
Advanced and/or metastatic renal cell carcinoma.

Contraindications

Roferon-A is contraindicated in patients with the following.
Known hypersensitivity to alfa interferon or any component of the product.
Chronic hepatitis with advanced, decompensated hepatic disease or cirrhosis of the liver.
Patients with autoimmune hepatitis; or patients with chronic hepatitis who are being or have recently been treated with immunosuppressive agents, excluding short-term ‘steroid withdrawal’. In rare cases, severe hepatic dysfunction and liver failure with associated deaths have been reported after treatment with alfa interferon.
Neonates and infants up to the age of 3 years, because of the excipient benzyl alcohol.
Roferon-A given in combination with ribavirin must not be used in pregnant women or by men whose female partners are pregnant.

Precautions

In order to improve traceability of biological medicinal products, the trade name of the administered product should be clearly recorded in the patient medical record. Substitution of Roferon-A by any other biological similar product requires the consent of the prescribing physician.

General.

Roferon-A should be administered under the guidance of a qualified medical practitioner (see Dosage and Administration). Appropriate management of the therapy and its complications is possible only when adequate diagnostic and treatment facilities are readily available.
In all instances where the use of Roferon-A is considered for chemotherapy, the physician must evaluate the need and usefulness of the drug against the risk of adverse reactions. Most adverse reactions are reversible if detected early. If severe reactions occur, the drug should be reduced in dosage or discontinued and appropriate corrective measures should be taken according to the clinical judgement of the physician. Reinstitution of Roferon-A therapy should be carried out with caution and with adequate consideration of the further need for the drug and alertness as to possible recurrence of toxicity. Roferon-A may be immunogenic. Immunisation of the patient may have safety implications. As with other proteins, there is the possibility of a hypersensitivity reaction including anaphylaxis to Roferon-A administration.
Patients should be cautioned not to change brands of interferon without medical consultation, as a change in dosage may result. Patients should be informed regarding the potential benefits and risks associated with the use of Roferon-A. If home use is determined to be desirable by the physician, instructions on appropriate use should be given, including review of the contents of the consumer medicine information. Patients should be well hydrated, especially during the initial stages of treatment.
Roferon-A should be used with caution in patients with severe pre-existing cardiac disease, severe renal, hepatic or myeloid dysfunction, thyroid disease, seizure disorders, neuropsychiatric disorders and/or compromised central nervous system function.

Chronic myelogenous leukaemia.

Patients with chronic myelogenous leukaemia who have an HLA-identical relative, and for whom allogeneic bone marrow transplantation is planned or possible in the immediate future, should not take Roferon-A.

Cardiovascular.

Roferon-A should be administered with caution to patients with cardiac disease or with any history of cardiac illness. No direct cardiotoxic effect has been demonstrated. However, it is likely that acute, self limited toxicities (i.e. fever, chills) frequently associated with Roferon-A administration may exacerbate pre-existing cardiac conditions. Rarely, myocardial infarction has occurred in patients receiving Roferon-A. It is recommended that these patients are monitored.

Hepatic impairment.

Caution is recommended when administering Roferon-A to chronic hepatitis patients with a history of autoimmune disease. Consequently, any patients developing liver function abnormalities during Roferon-A treatment should be closely monitored and if necessary treatment should be discontinued. Use of alfa interferons has been rarely associated with severe hepatic dysfunction and liver failure.

Bone marrow suppression.

Extreme caution should be exercised when administering Roferon-A to patients with severe myelosuppression as it has a suppressive effect on the bone marrow, leading to a fall in the white blood count (particularly granulocytes), platelet count and, less commonly, haemoglobin concentration. This can lead to increased risk of infection or haemorrhage. It is important to monitor closely these events in patients and perform a full blood count before, and at regular appropriate intervals during, Roferon-A treatment.

Infections.

While fever may be associated with the flu-like syndrome reported commonly during interferon therapy, other causes of persistent fever must be ruled out particularly in patients with neutropenia. Serious infections (bacterial, viral, fungal) have been reported during treatment with alfa interferons including Roferon-A. Appropriate anti-infective therapy should be started immediately and discontinuation of therapy should be considered.

Neuropsychiatric.

Severe psychiatric adverse reactions may manifest in patients receiving therapy with interferons, including Roferon-A. Depression, suicidal ideation and suicide may occur in patients with and without previous psychiatric illness. Roferon-A should be used with caution in patients who report a history of depression and physicians should monitor all patients treated with Roferon-A for evidence of depression. Physicians should inform patients of the possible development of depression prior to initiation of therapy, and patients should report any sign or symptoms of depression immediately. Psychiatric intervention and/or drug discontinuation should be considered in such cases.

Ophthalmologic.

As with other interferons, retinopathy including retinal haemorrhages, cotton wool spots, papilloedema, retinal artery or vein thrombosis and optic neuropathy which may result in loss of vision have been reported after treatment with Roferon-A. Any patient complaining of decreased or loss of vision must have an eye examination. Because these ocular events may occur in conjunction with other disease states, a visual examination prior to initiation of Roferon-A is recommended in patients with diabetes mellitus or hypertension. Roferon-A should be discontinued in patients who develop new or worsening ophthalmologic disorders.

Hypersensitivity.

Serious, acute hypersensitivity reactions, e.g. urticaria, angioedema, bronchoconstriction and anaphylaxis have been rarely observed during Roferon-A therapy. If such a reaction develops during treatment of Roferon-A, discontinue treatment and institute appropriate medical therapy immediately. Transient rashes do not necessitate interruption of treatment.

Endocrine.

Hyperglycaemia has been observed rarely in patients treated with Roferon-A. Symptomatic patients should have their blood glucose measured and followed up accordingly. Patients with diabetes mellitus may require adjustment of their antidiabetic regimen.

Autoimmune.

The development of different autoantibodies has been reported during treatment with alfa interferons. Clinical manifestations of autoimmune disease during interferon therapy occur more frequently in subjects predisposed to the development of autoimmune disorders. Autoimmune phenomena such as vasculitis, arthritis, haemolytic anaemia, thyroid dysfunction and lupus erythematosus syndrome, have been observed rarely in patients receiving Roferon-A.
Use of alfa interferon has rarely been associated with exacerbation or provocation of psoriasis.
In transplant patients (e.g. kidney or bone marrow transplant), therapeutic immunosuppression may be weakened because interferons also exert an immunostimulatory action. As with other alfa interferons, graft rejections have been reported in patients taking Roferon-A.

Effects on fertility.

Roferon-A has been studied for its effect on fertility in Macaca mulatta (rhesus monkeys). Nonpregnant rhesus females treated with Roferon-A at doses of 5 and 25 MIU/kg/day have shown menstrual cycle irregularities, including prolonged or shortened menstrual periods and erratic bleeding; these cycles were considered to be anovulatory.
These monkeys returned to a normal menstrual rhythm following discontinuation of treatment.

Use in pregnancy.

(Category B3)
As with the use of other anticancer drugs, men and women receiving Roferon-A should practise effective contraception. In pregnancy, Roferon-A should be administered only if the benefit to the woman justifies the potential risk to the foetus. Although animal tests do not indicate that Roferon-A is a teratogen, harm to the foetus from use during pregnancy cannot be excluded. When doses greatly in excess of the recommended clinical dose were administered to pregnant rhesus monkeys in the early to midfoetal period, an abortifacient effect was observed.
Male fertility and teratologic evaluations have yielded no significant adverse effects to date.
Roferon-A given in combination with ribavirin must not be used in pregnant women or by men whose female partners are pregnant. Fertile women and partners of fertile women should not receive ribavirin combination therapy unless the patient and his/her partner are taking efficacious contraceptive measures. Ribavirin has demonstrated significant teratogenic and/or embryocidal potential in all animal species in which adequate studies have been conducted. Based on the multiple dose half-life of ribavirin of 12 days, effective contraception must be used for 6 months post-treatment (see Contraindications).

Use in lactation.

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Roferon-A, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Paediatric use.

Safety and effectiveness in children under 18 years of age have not been established.
This product contains benzyl alcohol and should not be used in neonates and infants up to the age of 3 years. There have been rare reports of death in neonates and infants associated with excessive exposure to benzyl alcohol. The amount of benzyl alcohol at which toxicity or adverse effects may occur in neonates or infants is not known (see Contraindications).

Carcinogenesis and mutagenesis.

Roferon-A has not been tested for its carcinogenic potential.

A. Internal studies.

Ames tests using 6 different tester strains, with and without metabolic activation, were performed with Roferon-A up to a concentration of 1920 microgram/ plate. There was no evidence of mutagenicity.
Human lymphocyte cultures were treated in vitro with Roferon-A at noncytotoxic concentrations. No increase in the incidence of chromosomal damage was noted.

B. Published studies.

There are no published studies on the mutagenic potential of Roferon-A. However, a number of studies on the genotoxicity of human leucocyte interferon have been reported.
A chromosomal defect following the addition of human leucocyte interferon to lymphocyte cultures from a patient suffering from a lymphoproliferative disorder has been reported.
In contrast, other studies have failed to detect chromosomal abnormalities following treatment of lymphocyte cultures from healthy volunteers with human leucocyte interferon.
It has also been shown that human leucocyte interferon protects primary chick embryo fibroblasts from chromosomal aberrations produced by gamma rays.

Effects on laboratory tests.

Periodic complete blood counts and liver function tests should be performed during the course of Roferon-A treatment. They should be performed prior to therapy and at appropriate periods during therapy. Since response of hairy cell leukaemia or AIDS related Kaposi's sarcoma is not generally observed for 1-3 months after initiation of treatment, very careful monitoring for severe depression of blood cell counts is warranted during the initial phase of treatment.
For patients with hairy cell leukaemia, tests should be performed to quantitate peripheral hairy cells and bone marrow hairy cells prior to initiation of therapy.
For patients with AIDS related Kaposi's sarcoma, indicator lesion measurements and total lesion count should be performed before initiation of therapy. These parameters should be monitored periodically (e.g. monthly) during treatment to determine whether response to treatment or disease stabilisation has occurred.
Those patients who have pre-existing cardiac abnormalities and/or are in advanced stages of cancer should have electrocardiograms taken prior to and during the course of treatment.
Thyroid abnormalities were detected in patients treated for chronic hepatitis C with Roferon-A therapy in approximately 1% of patients with no thyroid function abnormalities at baseline. A third of these patients with pre-existing abnormalities worsened during therapy. In patients treated for chronic hepatitis C, thyroid functions should be assessed prior to the initiation of Roferon-A and re-evaluated during the course of therapy if symptoms consistent with thyroid dysfunction develop.
A liver biopsy should be performed in all patients considered for treatment of hepatitis. Patients with causes of hepatitis other than chronic hepatitis B or chronic hepatitis C should be excluded. Patients treated with Roferon-A for chronic hepatitis B or C should be appropriately monitored because of the increased risks of hepatic decompensation in association with a flare of aminotransaminases.

Effects on ability to drive and operate machinery.

Depending on the dose and schedule as well as the sensitivity of the individual patient, Roferon-A may have an effect on reaction times, which could impair certain operations, such as driving or operating machinery.

Interactions

Interactions between Roferon-A and other drugs have not been fully evaluated.
Since alfa interferons alter cellular metabolism, the potential exists for Roferon-A to modify the activity of other drugs. In a small study, Roferon-A was shown to have an effect on specific microsomal enzyme systems. The clinical relevance of these findings is unknown (see Pharmacology).
Alfa interferons may affect the oxidative metabolic process by reducing the activity of hepatic microsomal cytochrome enzymes in the P450 group. Although the clinical relevance is still unclear, this should be taken into account when prescribing concomitant therapy with drugs metabolised by this route. Reduced clearance of theophylline following the concomitant administration of alfa interferons has been reported.
It has been observed that the neurotoxic, haematotoxic or cardiotoxic effects of previously or concurrently administered drugs may be increased by interferons. Interactions could occur following concurrent administration of centrally acting drugs.
Pulmonary symptoms have been reported more frequently when sho-saiko-to, a Chinese herbal medicine, also known as Xiao-Chai-Hu was given with interferon alfa-2a. This herb should not be taken by patients receiving interferon.
Results from a controlled clinical study demonstrated no significant effect of bevacizumab on the pharmacokinetics of interferon alfa-2a.

Adverse Effects

Roferon-A monotherapy.

The following data on adverse reactions are based on information derived from the treatment of cancer patients with a wide variety of malignancies and often refractory to previous therapy and suffering from advanced disease, patients with chronic hepatitis B and patients with chronic hepatitis C. Most cancer patients received doses that were significantly higher than the dose now recommended, and this probably explains the higher frequency and severity of adverse reactions in this patient group compared with patients with hepatitis B where adverse reactions are usually transient, and patients return to pretreatment status within 1-2 weeks after the end of therapy.

Haematopoietic system.

Common. Transient leucopenia rarely requires restriction of dosage, in myelosuppressed patients, thrombocytopenia and decreased haemoglobin. Uncommon. In nonmyelosuppressed patients, thrombocytopenia. Rare. Decrease of haemoglobin and haematocrit. Recovery of severe haematological deviations to pretreatment levels usually occurred within 7 to 10 days after discontinuing Roferon-A treatment. Very rare. Idiopathic thrombocytopenic purpura (ITP).

Vision disorders.

Uncommon. Visual disturbances. Rare. Ischaemic retinopathy. Very rare. Retinopathy including retinal haemorrhages and cotton wool spots, papilloedema, retinal artery and vein thrombosis and optic neuropathy.

Gastrointestinal tract.

Frequent. About two-thirds of cancer patients experienced anorexia and one-half nausea. Common. Emesis, taste alterations, mouth dryness, weight loss, diarrhoea and mild or moderate abdominal pain. Rare. Constipation, flatulence, hypermotility, heartburn, reactivation of peptic ulcer, nonlife-threatening gastrointestinal bleeding as well as reversible pancreatic reactions, i.e. amylase/ lipase increase with or without abdominal pain.

General symptoms.

Frequent. Patients experienced flu-like symptoms, e.g. fatigue, fever, chills, appetite loss, myalgia, headache, arthralgia and diaphoresis. These acute side effects can usually be reduced or eliminated by concurrent administration of paracetamol and tend to diminish with continued therapy or dose moderation. Continuing therapy can lead to lethargy, weakness and fatigue.

Alterations of hepatic function.

Uncommon. Elevation of ALT, but also of alkaline phosphatase, lactate dehydrogenase and bilirubin, which generally did not require dosage adjustment. In rare cases, jaundice, hepatitis, hepatic failure and hepatic encephalopathy were reported. Rare. In hepatitis B, changes in transaminases usually signal clinical improvement.

Abnormal laboratory test values.

Common. Mild and less commonly moderate declines in neutrophils and leucocytes, declines in haemoglobin, haematocrit and platelets. Rare. Severe declines in haemoglobin, haematocrit and platelets, abnormalities in serum SGOT of mild to moderate degree, increases in alkaline phosphatase and LDH, proteinuria, hypocalcaemia, hyperbilirubinaemia, hyperglycaemia and abnormalities of serum uric acid, BUN and creatinine. These effects tend to be dose dependent and improve spontaneously or with dose attenuation or discontinuation of therapy.

Central nervous system.

Uncommon. Dizziness, vertigo, decreased mental status, forgetfulness, depression, drowsiness, confusion, behavioural disturbances, such as anxiety and nervousness, sleep disturbances. Rare. Suicidal ideation, suicide attempt, suicide, severe somnolence, convulsions, coma, cerebrovascular adverse events and transient impotence.

Peripheral nervous system.

Uncommon. Paraesthesia, numbness, neuropathy, itching and tremor.

Renal and urinary system.

Rare. Decreased renal function, acute renal failure, mainly in cancer patients with renal diseases and/or nephrotoxic comedications as concomitant risk factors, electrolyte disturbances, generally in association with anorexia or dehydration, proteinuria and increased cell count in sediment, elevation of BUN, serum creatinine and uric acid.

Cardiovascular and pulmonary systems.

Common. Disorders were seen in about one-fifth of cancer patients and consisted of transient hypotensive and hypertensive episodes, oedema, cyanosis, arrhythmias, palpitations and chest pain. Rare. Coughing, mild dyspnoea, pneumonia, pulmonary oedema, congestive heart failure, cardiorespiratory arrest and myocardial infarction. Very rare. Cardiovascular problems in patients with hepatitis B.

Skin, mucous membranes and adnexa.

Common. Mild to moderate alopecia occurred in up to one-fifth of patients, but this was reversible on discontinuation of treatment. Note that alopecia may continue for several weeks after discontinuation of treatment. Rare. Re-exacerbation of herpes labialis, rash, pruritus, dryness of skin and mucous membranes, rhinorrhoea and epistaxis.
If Roferon-A is used concomitantly with combination chemotherapy, haematological toxicity may be exacerbated, requiring reduction of doses of other myelosuppressive drugs in the chemotherapy regimen.

Other.

Rare. Hyperglycaemia, diabetes mellitus, injection site reactions including, very rarely, necrotic site reactions, autoimmune phenomena, i.e. vasculitis, arthritis, haemolytic anaemia, thyroid dysfunction and lupus erythematosus syndrome. Very rare. Asymptomatic hypocalcaemia, sarcoidosis, elevated serum glucose, hypertriglyceridaemia/ hyperlipidaemia.

Roferon-A combination therapy.

The following adverse reactions are based on clinical experience of Roferon-A in combination with ribavirin in chronic hepatitis C patients.
Rarely, alfa interferons, including Roferon-A, used in combination with ribavirin may be associated with pancytopenia and, very rarely, aplastic anaemia (see Table 5).

Laboratory test values.

In clinical trials conducted with Roferon-A with ribavirin, the majority of cases of abnormal laboratory values were managed with dose modifications.
Thyroid function test abnormalities requiring clinical intervention occur in less than 5% of patients with no previous thyroid disorder.
An increase in uric acid and indirect bilirubin values associated with haemolysis were observed in some patients treated Roferon-A in combination with ribavirin and values returned to baseline levels within 4 weeks after end of therapy. In no case was this associated with clinical manifestations and values returned to baseline levels within 4 weeks after the end of treatment.
Anaemia was the primary reason for ribavirin dose reductions during clinical trials, which occurred in 19% of patients treated with ribavirin in combination with interferon alfa-2a.

Postmarketing experience.

The following adverse reactions have been identified during postmarketing use of Roferon-A. As these events are reported from a population of uncertain size, it is not always possible to reliably estimate their frequency.

Immune system disorders.

As with other alfa interferons, graft rejections have been reported in patients taking Roferon-A.

Psychiatric disorders.

Mania has been reported.

Gastrointestinal disorders.

Haemorrhagic/ ischemic colitis and ulcerative colitis have been reported.