INTRON A Interferon alfa-2b (HSA-free) 18 million IU/3mL injection

Australia - English - Department of Health (Therapeutic Goods Administration)

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Active ingredient:
Interferon alfa-2b
Available from:
Merck Sharp & Dohme (Australia) Pty Ltd
INN (International Name):
Interferon alfa-2b
Authorization status:
Registered
Authorization number:
60021

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INTRON A

Interferon alfa-2b

Consumer Medicine Information

What is in this leaflet

This leaflet answers some common

questions about INTRON A. 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 risks and

benefits. Your doctor has weighed

the risks of you using INTRON 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 want to read it again.

What INTRON A is

used for

INTRON A belongs to a group of

medicines called interferons.

Interferons are a family of naturally

occurring, small protein molecules.

They are produced and secreted by

cells in response to viral infections or

various synthetic and biological

inducers.

Interferons modify the body's

immune system response.

INTRON A is used to treat patients

with the following conditions:

Hairy cell leukaemia

Kaposi's sarcoma in AIDS

Chronic myelogenous leukaemia

Multiple myeloma

Follicular non-Hodgkin's

lymphoma

Malignant melanoma

Chronic hepatitis B

Chronic hepatitis C

Your doctor, however, may prescribe

INTRON A for another purpose.

Before you use

INTRON A

When you must not use it:

Do not use INTRON A if you are

allergic to:

interferon alfa-2b or any of the

ingredients listed at the end of

this leaflet.

Do not use INTRON A if you are

pregnant or breastfeeding unless

your doctor says so. Ask your

doctor about the risks and benefits

involved.

If you are a woman of childbearing

age make sure you do not become

pregnant while using INTRON A.

Do not use INTRON A if

packaging is torn or shows signs of

tampering.

Do not use INTRON A after the

expiry date (EXP) printed on the

pack.

If you use it after the expiry date it

may have no effect at all, or worse,

an unexpected effect.

If you are not sure whether you

should start using INTRON A, talk

to your doctor.

Before you start to use it

You must tell your doctor:

1.

if you are allergic to:

any other medicines or any food,

dyes or preservatives

2.

if you have any of these medical

conditions:

heart disease, high blood pressure

or you have ever had a heart

attack

poor kidney or liver function

advanced liver disease

hepatitis and have been treated

recently with medicines that

suppress the immune system

a history of convulsions or mental

disorder

you have ever been treated for

depression or any other

psychiatric disorder

a history of autoimmune disease

or skin disease (psoriasis)

a history of diabetes, lung disease

or respiratory disease

thyroid disease or blood clotting

disorder

3.

you are taking any other

medicines, including medicines

that you buy without a

prescription from a pharmacy,

supermarket or health food

shop.

Be sure to tell your doctor if

you are taking theophylline for

asthma, as you may need to

take different amounts of your

medicine.

Use in Children

There is limited experience with the

use of INTRON A in children.

INTRON A is not intended for use in

premature infants or neonates.

INTRON A

Effect on Fertility

Fertile women should not use

INTRON A unless effective

contraception is used during

treatment with INTRON A.

INTRON A should be used with

caution in fertile men.

How to use INTRON A

How much to inject

Your doctor has determined the exact

schedule according to your needs.

Your dose may be adjusted by your

doctor during therapy according to

your response.

Do not exceed the recommended

dosage.

How to inject

Your doctor or nurse will tell you

how to give the injection under the

skin if you are injecting this medicine

yourself.

INTRON A can also be injected into

a vein. This would normally be

carried out by your doctor.

How to use INTRON A

INTRON A Injectable Solution is

available in single dose vials.

The solution may be injected directly

under the skin after withdrawal of the

appropriate doses from the vial with

a sterile syringe and needle.

When to inject

If you are injecting this medicine

yourself, use it at bedtime as

interferons may cause unusual

tiredness and flu-like symptoms.

How long to use it

Do not stop using this medicine

without first checking with your

doctor.

Your doctor will determine when

your treatment should be stopped.

If you forget to use it

If it is almost time for your

injection, skip the injection you

missed and take 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 take a double injection to

make up for the injection that you

missed.

If you have trouble remembering

when to use your medicine, ask your

pharmacist for some hints.

If you use too much

(overdose)

Immediately telephone your doctor

or Poisons Information Centre

(telephone 13 11 26) for advice, or

go to casualty at your nearest

hospital, if you think you or

anyone else may have used too

much INTRON A. Do this 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

INTRON A

Things you must do

Use INTRON A exactly as your

doctor has prescribed.

Tell all doctors, dentists and

pharmacists who are treating you

that you are using INTRON A.

Tell your doctor immediately if

you become pregnant while you

are using INTRON A.

Things you must not do

INTRON A may cause dizziness

and drowsiness in some people. If

you become drowsy from this

medicine do not drive or use

machinery.

Do not use it to treat any other

complaints unless your doctor says

to.

Do not give this medicine to anyone

else, even if their symptoms seem

similar to yours.

Do not switch to any other brands

of interferon unless advised by

your doctor as your response to

other interferons may be different.

Things to be careful of

Check with your doctor about

drinking alcoholic beverages or

taking sleeping pills, sedatives or

strong painkillers.

Your doctor may want you to

drink extra fluids.

This will help prevent low blood

pressure while you are using

INTRON A.

Check with your doctor if you

think you are developing

symptoms associated with a cold or

other respiratory infection.

While receiving INTRON A, you

may temporarily have a greater risk

of getting an infection.

Check with your doctor

immediately if you notice unusual

bleeding or bruising.

Your blood may temporarily take a

longer time to clot.

Tell your doctor if you notice

any changes in your eyes or

eyesight

worsening psoriasis

psychiatric symptoms,

depression, irritability,

aggressive behaviour

Side effects

Tell your doctor or pharmacist as

soon as possible if you do not feel

well while you are using INTRON

A.

All medicines have side effects.

Sometimes they are serious, most of

the time they are not. You may need

INTRON A

medical treatment if you get some of

the side effects.

Ask your doctor or pharmacist any

questions you may have.

Check with your doctor

immediately if any of the following

side effects occur:

an allergic reaction such as hives

or difficulty in breathing

chest pain or irregular heartbeat

confusion, aggressive behaviour,

suicidal feelings, depression,

trouble sleeping, thinking or

concentrating

numbness or tingling sensation

black or tar-like stools, blood in

stool or urine, painful or difficult

urination

severe nosebleed

fever or chills beginning after a

few weeks of treatment

lower back or side pain

visual disturbances

unusual bruising or bleeding

You may need urgent medical

attention.

Tell your doctor if you notice any

of the following and they worry

you:

flu symptoms including muscle

ache, fever, chills and headache

loss of appetite, taste change or

dry mouth

tiredness, sleepiness or dizziness

feeling sick, vomiting or

diarrhoea

hair loss

increased sweating

irritability

itching

low blood pressure

These side effects may go away as

your body adjusts to the medicine.

Tell your doctor, if they continue

or are severe.

Other side effects not listed above

may also occur in some patients.

Check with your doctor as soon as

possible if you have any problems

while using INTRON A even if you

do not think the problems are

connected with the medicine or the

side effects are not listed in this

leaflet.

Do not be alarmed by this list of

possible side effects. You may not

experience any of them.

After using INTRON A

Storage

Keep INTRON A where children

cannot reach it.

Before use: Store in the

refrigerator (2°C to 8°C). Do not

freeze. Do not leave it in the car.

Use each vial once and discard any

residue.

Disposal

Discard after the last dose is used.

Return any unused medicine to

your pharmacist.

Product description

What it looks like

INTRON A Injectable Solution is a

clear colourless solution.

Ingredients

Each vial contains:

interferon alfa-2b

sodium phosphate dibasic

sodium phosphate monobasic

disodium edetate

sodium chloride

polysorbate 80

water

m-cresol as preservative

Manufacturer

Merck Sharp & Dohme (Australia)

Pty Limited

Level 1, Building A

26 Talavera Road

Macquarie Park, NSW 2113

Australia

Australian Registration

Number

10 MIU/1 mL AUST R 63274

18 MIU/3 mL AUST R 60021

25 MIU/2.5 mL AUST R 60024

Date of Preparation

02 July 2019

INTRON A

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Page 1

PRODUCT INFORMATION

INTRON A

NAME OF THE MEDICINE

Interferon alfa-2b (rbe)

DESCRIPTION

INTRON A is a sterile, stable formulation of highly purified interferon alfa-2b produced by

recombinant DNA techniques. Recombinant interferon alfa-2b is a water soluble protein with

a molecular weight of approximately 19,300 daltons. It is obtained from a clone of E. coli

which has a genetically engineered plasmid containing an interferon alfa-2 gene from human

leucocytes.

The activity of INTRON A is expressed in terms of International Units (IU). The specific

activity of INTRON A is approximately 2.6 x 10

IU/mg protein.

INTRON A Injectable (HSA-free) Solution

INTRON A HSA-free Injectable Solution is a clear, colourless solution and is available in

single dose vials. Each single dose vial of INTRON A HSA-free Injectable Solution contains,

10 million IU/1 mL, 18 million IU/3 mL or 25 million IU/2.5 mL of recombinant interferon alfa-

vials

also

contain

sodium

phosphate

dibasic,

sodium

phosphate

monobasic,

disodium edetate, sodium chloride, polysorbate 80, water for injections and m-cresol.

PHARMACOLOGY

Interferons are

a family of naturally occurring, small protein molecules produced and

secreted by cells in response to viral infections or various synthetic and biological inducers.

Interferons exert their cellular activities by binding to specific membrane receptors on the cell

surface. Preliminary studies to characterise these membrane receptors and to determine the

subsequent fate of the human interferon-receptor complex have been carried out using

labelled recombinant interferon alfa-2b. Human interferon receptors, as isolated from human

lymphoblastoid (Daudi) cells, appear to be highly asymmetric membrane proteins. They

exhibit selectivity for human but not murine interferons, suggesting species specificity.

Studies with other interferons have demonstrated species specificity.

The results of several studies suggest that, once bound to the cell membrane, the interferon

initiates a complex sequence of intracellular events which include the induction of certain

enzymes. It is thought that this process, at least in part, is responsible for the various cellular

responses to interferons, including inhibition of virus replication in virus-infected cells,

suppression of cell proliferation and such immunomodulating activities as enhancement of

the phagocytic activity of macrophages and augmentation of the specific cytotoxicity of

lymphocytes for target cells. These activities possibly contribute to the therapeutic effects of

interferons.

Recombinant interferon alfa-2b has exhibited antiproliferative effects in preclinical studies

employing both cell culture systems and human tumour xenografts in animals, and has

demonstrated significant immunomodulatory activity in vitro. Recombinant interferon alfa-2b

also inhibits viral replication in vitro and in vivo.

Page 2

The antiproliferative activity of recombinant interferon alfa-2b was evaluated in vitro using

mouse and human leukaemia cell lines, and human osteosarcoma, melanoma, and normal

amnion

cells.

antiproliferative activity

recombinant

interferon alfa-2b

was most

pronounced against human osteosarcoma cells and the human lymphocytic leukaemia cell

line RPMI-8402; growth of both cell lines was inhibited 80-100%. No activity was seen in

mouse leukaemia cells, which again suggests species specificity.

The immunomodulating activity of recombinant interferon alfa-2b was demonstrated in vitro

by its augmentation of the spontaneous "natural killer" activity of human lymphocytes, its

enhancement of the tumoricidal activity of human monocytes against human tumour cells

and its induction of Class I histocompatibility antigens on the surface of a number of cell

types. These effects appear to be dose-dependent.

Subcutaneous administration of recombinant interferon alfa-2b at a dose of 0.2 million

IU/day inhibited the growth of implanted human breast tumour xenografts in athymic mice by

about 50% after 23 days. However, intra-peritoneal administration of recombinant interferon

alfa-2b (0.1 - 1 million IU for 9 days) demonstrated no effect on the growth of human tumour

xenografts in athymic mice or on murine leukaemia cells implanted in BDFI mice.

human

tumour

stem

cell

assay

used

study

effects

recombinant

interferon alfa-2b in combination with doxorubicin. Study results suggested that a schedule-

dependent

synergistic

effect

exhibited

when

doxorubicin

recombinant

interferon alfa-2b were combined in the cell lines tested. Antagonistic effects or cell growth

enhancement over control levels were not observed.

Preliminary studies with isolated and perfused rabbit kidneys have shown that the kidney

may be the main site of interferon alfa catabolism.

CLINICAL TRIALS

Kaposi's

Sarcoma:

patients

with

AIDS-related

Kaposi's

sarcoma,

measures

immunologic competence, commonly characterised by the baseline T4 count or T4/T8 ratio,

have been noted to be highly predictive of the status of AIDS patients and their likelihood of

response to INTRON A treatment. In patients with baseline T4 counts above 400, the overall

response rate to INTRON A can be expected to be as high as 78%. Few patients with

baseline T4 counts less than 200 can be expected to respond to INTRON A.

Chronic hepatitis B: Studies in patients with compensated liver disease and evidence of

chronic hepatitis B virus infection (serum HBsAg positive) and HBV replication (serum

HBeAg positive and serum HBV-DNA positive) have demonstrated that INTRON A therapy

can produce virological remission of this disease (loss of serum HBeAg) and normalisation

of serum aminotransferases.

In clinical studies, 39% (15/38) of responding patients lost HBeAg 1 to 6 months following

the end of INTRON A therapy. Virological response was associated with a reduction in

serum ALT to normal or near normal (

1.5 times the upper limit of normal) in 87% (13/15) of

patients responding to INTRON A therapy at 5 million IU daily. Of responding patients who

lost HBsAg, 58% (7/12) did so 1 to 6 months post-treatment.

Chronic hepatitis C: Studies in patients with compensated liver disease and a history of

blood or blood product exposure and/or positive HCV antibody demonstrated that INTRON A

therapy

produce

clinically

meaningful

effects

this

disease,

manifested

normalisation of serum ALT and reduction in liver necrosis and degeneration.

Page 3

A multicentre study comparing treatment of chronic hepatitis C using INTRON A (i) 3 million

IU three times weekly for a duration of 18 months, (ii) 3 million IU three times weekly for

6 months then 1 million IU three times weekly for 12 months and (iii) 3 million IU three times

weekly for 6 months showed that treatment with 3 million IU three times weekly for a

duration of 18 months produced significantly superior histological improvement, virological

response and sustained ALT response than the regimens involving a lower dose or shorter

duration of treatment.

Similarly, an Australian multicentre study evaluated the efficacy of INTRON A (i) 3 million IU

three times weekly for 6 months, (ii) 5 million IU three times weekly for 6 months and (iii)

3 million IU three times weekly for 24 months. Treatment for a duration of up to 24 months

significantly improved the sustained response in patients who achieved normalisation of ALT

at 24 weeks of therapy compared to the two 6-month treatment regimens. Sustained ALT

response

associated

with

virological

response

improvement

hepatic

inflammation. This study confirmed that INTRON A 3 million IU three times weekly remains

the optimal dose; increasing the dose to 5 million IU three times weekly did not significantly

improve the ALT response rate or sustained ALT response.

Malignant melanoma: The safety and efficacy of INTRON A was evaluated as adjuvant to

surgical treatment in patients with melanoma who were free of disease (post-surgery) but at

high risk for systemic recurrence. These included patients with lesions of Breslow thickness

>4 mm, or patients with lesions of any Breslow thickness with primary or recurrent nodal

involvement. In a randomised, controlled trial in 280 patients, 143 patients received INTRON

A therapy at 20 million IU/m

intravenously five times per week for 4 weeks (induction phase)

followed

million

IU/m

subcutaneously

three

times

week

weeks

(maintenance phase). INTRON A therapy was begun

56 days after surgical resection. The

remaining 137 patients were observed.

INTRON A therapy produced a significant increase in relapse-free and overall survival.

Median time to relapse for the INTRON A treated patients versus observation patients was

1.72 years versus 0.98 years (p<0.01, stratified Log Rank). The estimated 5-year relapse-

free survival rate, using the Kaplan-Meier method, was 37% for INTRON A treated patients

versus 26% for observation patients. Median overall survival time for INTRON A treated

patients was 3.82 years versus 2.78 years (p=0.047, stratified Log Rank). The estimated 5-

year overall survival rate, using the Kaplan-Meier method, was 46% for INTRON A treated

patients versus 37% for observation patients.

The INTRON A dose was modified because of adverse events in 65% (n=93) of the patients.

INTRON A therapy was discontinued because of adverse events in 8% of the patients during

induction and 18% of the patients during maintenance. The most frequently reported

adverse reaction was fatigue which was observed in 96% of patients. Other adverse

reactions that were recorded in >20% of INTRON A treated patients included neutropenia

(92%), fever (81%), myalgia (75%), anorexia (69%), vomiting/nausea (66%), increased

SGOT (63%), headache (62%), chills (54%), depression (40%), diarrhoea (35%), alopecia

(29%), altered taste sensation (24%), dizziness/vertigo (23%), and anaemia (22%).

Adverse reactions classified as severe or life-threatening (ECOG Toxicity Criteria grade 3 or

4) were recorded in 66% and 14% of INTRON A treated patients, respectively. Severe

adverse

reactions

recorded

>10%

INTRON

treated

patients

included

neutropenia/leucopenia (26%), fatigue (23%), fever (18%), myalgia (17%), headache (17%),

chills (16%), and increased SGOT (14%). Grade 4 fatigue was recorded in 4% and grade 4

depression was recorded in 2% of INTRON A treated patients. No other grade 4 adverse

event was reported in more than 2 INTRON A treated patients. Lethal hepatotoxicity

occurred in 2 INTRON A treated patients early in the clinical trial. No subsequent lethal

hepatotoxicities were observed with adequate monitoring of liver function tests.

Page 4

Pharmacokinetics

pharmacokinetics

INTRON

after

single

doses

administered

subcutaneously,

intramuscularly and as a 30-minute intravenous infusion has been studied in healthy male

volunteers.

study

involving

subjects,

single

million

IU/m

doses

were

administered

three

routes.

Serum

concentrations

interferon

alfa-2b

were

determined by a radio-immunoassay (RIA) with a detection limit of 10 IU/mL. The mean

serum interferon concentrations following subcutaneous and intramuscular injections were

comparable. Maximum serum levels (18-116 IU/mL) occurred at 3 to 12 hours post-injection.

The elimination half-lives of interferon following both injections were 2 to 3 hours. Serum

levels were below the detection limit 16 hours post-injection.

After intravenous administration, serum interferon levels peaked (135-273 IU/mL) at the end

of the infusion, then declined at a slightly more rapid rate than after subcutaneous or

intramuscular

administration,

becoming

undetectable

hours

after

infusion.

elimination half-life was approximately 2 hours.

In another study also involving 12 subjects, single 10 million IU doses were administered by

the same three routes of administration. Mean serum interferon concentrations were again

comparable following intramuscular and subcutaneous injections, with maximum serum

levels (150-180 IU/mL) occurring at 6 to 8 hours post-injection. The elimination half-lives

following both injections were 6 to 7 hours. Serum levels were below the detection limit of 25

IU/mL 24 hours post-injection.

As with the other study, after intravenous administration, serum interferon levels peaked

(546

IU/mL)

infusion,

then

declined

rapidly

with

time,

becoming

undetectable 4 hours after the infusion.

Urine levels of interferon were below the detection limit following each of the three routes of

administration in both studies.

Interferon neutralising factor assays were performed on serum samples of patients who

received INTRON A in Schering-Plough monitored clinical trials. The clinical incidence of

neutralising

factors

developing in cancer patients treated systemically is 2.9% and in

hepatitis patients, 6.9%. The detected titres are low in almost all cases and have not been

regularly associated with loss of response or any other autoimmune phenomenon.

INDICATIONS

Hairy cell leukaemia: INTRON A is indicated for the treatment of hairy cell leukaemia in

splenectomised or non-splenectomised patients.

Kaposi’s sarcoma in AIDS: INTRON A is indicated for the treatment of Kaposi’s sarcoma in

patients with acquired immune deficiency syndrome (AIDS).

Chronic myelogenous leukaemia: INTRON A is indicated for the treatment of Philadelphia

chromosome positive chronic myelogenous leukaemia in the chronic phase.

Multiple myeloma:

INTRON

indicated

maintenance of

control

multiple

myeloma once control has been achieved by chemotherapy. The effect on overall survival

has not as yet been determined.

Follicular non-Hodgkin's lymphoma: INTRON A is indicated as an adjuvant treatment of high

tumour burden Stage III or IV follicular non-Hodgkin's lymphoma in conjunction with an

appropriate

chemotherapy

regimen.

controlled

clinical

trials

which

efficacy

demonstrated anthracycline chemotherapy was employed.

Page 5

Malignant Melanoma: INTRON A is indicated as an adjuvant therapy of malignant melanoma

following surgery in patients who are at high risk of recurrence. The potential benefit to the

patient should be assessed carefully. Although toxicity of the treatment may be substantial,

for most patients, the benefit of therapy outweighed the risk.

Chronic hepatitis B: INTRON A injection is indicated for the treatment of adults with

histologically proven compensated chronic active hepatitis B. Patients should be serum

HBsAg positive and have evidence of HBV replication (such as serum HBeAg positive) and

raised

serum

alanine

aminotransferase

(ALT)

levels

(>3 times

upper

limit

reference range) for at least 6 months. [See Pharmacology for response rate].

Chronic hepatitis C: INTRON A is indicated for the treatment of histologically proven

compensated chronic hepatitis due to hepatitis C (HCV antibody positive) in adult patients

with persistently elevated serum alanine aminotransferase (ALT). Studies in these patients

demonstrate that INTRON A Injection therapy can produce normalisation of serum ALT,

clearance of serum HCV RNA and improvement in liver histology.

CONTRAINDICATIONS

A history of hypersensitivity to recombinant interferon alfa-2b or any other components of

INTRON A contraindicates its use. Hypersensitivity to other forms of interferon alfa should

lead to extreme caution with the use of INTRON A.

Patients with decompensated liver disease, autoimmune hepatitis or a history of autoimmune

liver disease, and patients who are immunosuppressed transplant recipients should not be

treated with INTRON A for chronic hepatitis. There are reports of worsening liver disease,

including jaundice, hepatic encephalopathy, hepatic failure and death following INTRON A

therapy in such patients.

Patients with severe renal dysfunction or creatinine clearance <50 mL/min must not be

treated with INTRON A Injection when used in combination with ribavirin.

INTRON A is not intended for use in premature infants or neonates.

PRECAUTIONS

Acute, serious hypersensitivity reactions (eg urticaria, angioedema, bronchoconstriction,

anaphylaxis) to INTRON A have been observed rarely during INTRON A therapy. If any such

reaction

develops,

drug

should

discontinued

appropriate

medical

therapy

instituted immediately. Transient rashes do not necessitate interruption of treatment.

Moderate to severe adverse experiences may require modification of the patient's dosage

regimen, or in some cases, termination of INTRON A therapy.

INTRON A should be used cautiously in patients with debilitating medical conditions, such as

those with a history of pulmonary disease (e.g. chronic obstructive pulmonary disease) or

diabetes mellitus prone to ketoacidosis. Caution should be observed also in patients with

coagulation

disorder

(e.g.

thrombophlebitis,

pulmonary

embolism)

severe

myelosuppression.

Page 6

Administration of INTRON A in combination with other chemotherapeutic agents may lead to

increased risk of toxicity (severity and duration), which may be life-threatening or fatal as a

result of the concomitantly administered drug. The most commonly reported potentially life-

threatening

fatal

adverse

events

include

mucositis,

diarrhoea,

neutropenia,

renal

impairment and electrolyte disturbance. Because of the risk of increased toxicity, careful

adjustments of doses are required for INTRON A and for the concomitant chemotherapeutic

agents.

While

fever

associated

with the

flu-like syndrome

reported

commonly

during

interferon therapy, other causes of persistent fever should not be overlooked.

In patients with liver disease, exacerbation of hepatic enzyme abnormalities may occur.

Monitoring of liver function tests is advised. Hepatotoxicity resulting in fatality has been

observed rarely. INTRON A increases the risk of hepatic decompensation and death in

patients with cirrhosis. Therefore, any patient developing liver function abnormalities during

treatment with INTRON A should be monitored closely and treatment discontinued if signs

and symptoms progress.

In patients considered for treatment of hepatitis, a liver biopsy should be performed to

document diagnosis and extent of disease. Patients with causes of chronic hepatitis other

than chronic hepatitis B or chronic hepatitis C, including autoimmune hepatitis, should be

excluded. Prior to initiation of INTRON A therapy, the physician should establish that the

patient has compensated liver disease. INTRON A should not be used in patients with

decompensated liver disease.

Patients with chronic hepatitis B with evidence of decreasing hepatic synthetic function (e.g.

decreasing albumin or prolongation of prothrombin time), who nevertheless meet the criteria

therapy,

increased

risk

clinical

decompensation

flare

aminotransferases

occurs

during

INTRON

treatment

[see

Laboratory

Tests

under

Precautions]. In considering these patients for INTRON A therapy, the potential risks must

be evaluated against the potential benefits of treatment.

Results of two studies indicate that the efficacy of interferon therapy remains uncertain in

chronic active hepatitis B in children or in adults where the presumed route of transmission is

vertical.

Infrequently, patients treated for chronic hepatitis C with INTRON A developed thyroid

abnormalities (hypothyroid or hyperthyroid). In clinical trials <1% (4/426) developed thyroid

abnormalities.

abnormalities

were

controlled

conventional

therapy

thyroid

dysfunction. The mechanism by which INTRON A may alter thyroid status is unknown. Prior

to initiation of INTRON A therapy for the treatment of chronic hepatitis C, serum thyroid-

stimulating hormone (TSH) levels should be evaluated. Any thyroid abnormality detected at

that time should be treated with conventional therapy. INTRON A treatment may be initiated

if TSH levels can be maintained in the normal range by medication.

Monitor hepatic function with serum bilirubin, ALT (alanine transaminase), AST (aspartate

aminotransferase), alkaline phosphatase and LDH (lactate dehydrogenase) at 2, 8, and 12

weeks following initiation of INTRON A, then every 6 months while receiving INTRON A.

Permanently discontinue INTRON A for evidence of severe (Grade 3) hepatic injury or

hepatic decompensation (Child-Pugh score >6 [class B and C]).

If, during the course of INTRON A therapy, a patient develops symptoms consistent with

possible thyroid dysfunction, TSH levels should be evaluated. In the presence of thyroid

dysfunction, INTRON A treatment may be continued only if TSH levels can be maintained in

the normal range by medication. Discontinuation of INTRON A therapy has not reversed

thyroid dysfunction occurring during treatment.

Page 7

Hypertriglyceridaemia and aggravation of hypertriglyceridaemia, sometimes severe, have

been observed. Monitoring of lipid levels is, therefore, recommended.

Due to reports of interferon alfa exacerbating pre-existing psoriatic disease and sarcoidosis,

use of INTRON A in patients with psoriasis or sarcoidosis is recommended only if the

potential benefit justifies the potential risk.

Hypotension may occur during INTRON A administration or up to two days post-therapy and

may require supportive therapy. Adequate hydration should be maintained in patients

undergoing INTRON A therapy since hypotension related to fluid depletion has been seen in

some patients. Fluid replacement to maintain intravascular volume may be necessary.

Patients with a history of cardiac disease (e.g.,congestive heart failure, myocardial infarction

and/or previous or current arrhythmic disorders), or with AIDS-related Kaposi’s sarcoma who

require

INTRON

therapy,

should

closely

monitored.

Transient

reversible

cardiomyopathy has been reported rarely in AIDS- related Kaposi’s sarcoma patients treated

with INTRON A 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. Cardiac arrhythmias (primarily supraventricular) occurred rarely and

appeared to be correlated with pre-existing conditions and prior therapy with cardiotoxic

agents. These adverse experiences usually respond to conventional therapy but may require

discontinuation of INTRON A therapy.

Cardiomyopathy was reported in approximately 2% of the AIDS-related Kaposi's sarcoma

patients treated with INTRON A. Cardiomyopathy has also been reported in AIDS patients

not receiving INTRON A therapy. Baseline chest X-rays are suggested and should be

repeated if clinically indicated.

Pulmonary infiltrates, pneumonitis and pneumonia, including fatality, have been observed

rarely in patients treated with interferon alfa including those treated with INTRON A. The

aetiology has not been defined. Any patient developing fever, cough, dyspnoea or other

respiratory symptoms should have a chest X-ray taken. If the chest X-ray shows pulmonary

infiltrates or there is evidence of pulmonary function impairment, the patient should be

monitored closely, and if appropriate, interferon alfa treatment should be discontinued. While

this has been reported more often in patients with chronic hepatitis C treated with interferon

alfa, it has also been reported in patients with oncological diseases treated with interferon

alfa.

Prompt

discontinuation

interferon

alfa

administration

treatment

with

corticosteroids

appear

associated

with resolution of

pulmonary

adverse

events.

Moreover, these symptoms have been reported more frequently when shosaikoto, a Chinese

herbal medicine, is administered concomitantly with interferon-alfa.

Patients with a pre-existing psychiatric condition or a history of severe psychiatric disorder

should not be treated with INTRON A.

Treatment with interferons may be associated with exacerbated symptoms of psychiatric

disorders in HCV infected patients with co-occurring psychiatric and substance use disorders.

If treatment with interferons is judged necessary in patients with prior history or existence of

psychiatric condition or with substance use disorders, in order to reach successful adherence

to treatment with interferons, adequate management of psychiatric symptoms and substance

use requires individualized screening strategies and frequent psychiatric symptom monitoring.

Early

intervention

re-emergence

development

neuropsychiatric

symptoms

substance use is recommended.

If severe central nervous system (CNS) effects, particularly depression, are observed,

INTRON A therapy should be discontinued. Severe central nervous system (CNS) effects

particularly depression, homicidal ideation, suicidal ideation, suicide or attempted suicide have

been observed in some patients during INTRON A therapy. Other CNS effects including

aggressive behaviour, sometimes directed towards others, psychosis including hallucinations,

Page 8

confusion and alterations of mental status have been observed

These adverse effects have

occurred in patients treated with recommended doses, as well as in patients treated with

higher

INTRON

doses.

More

significant

obtundation

coma,

including

cases

encephalopathy, have been observed in some patients, usually elderly, treated at higher

doses. While these effects are generally reversible, in a few patients full resolution took up to

three weeks. Very rarely seizures have occurred with high doses of INTRON A. If patients

develop psychiatric or CNS problems, including clinical depression, it is recommended that

the patients be carefully monitored by the prescribing physician during treatment and in the 6

month

follow-up

period.

such

symptoms

appear,

potential

seriousness

these

undesirable

effects

must

borne

mind

prescribing

physician

psychiatric

symptoms persist or worsen, or suicidal or homicidal ideation or aggressive behaviour

towards

others

identified,

recommended

that

treatment

with

INTRON

discontinued, and the patient followed with psychiatric intervention as appropriate.

Narcotics,

hypnotics or

sedatives should be

administered with caution if administered

concomitantly with INTRON A.

Because of reports of exacerbating pre-existing psoriatic disease, INTRON A should be

used in patients with psoriasis only if the potential benefit justifies the potential risk.

The use of INTRON A has been associated with the exacerbation of autoimmune disease,

therefore, when administering INTRON A to patients with a history of, or predisposition to

autoimmune disease, this should be considered.

In patients with AIDS-related Kaposi's Sarcoma, INTRON A therapy should not be used in

the presence of rapidly progressive visceral disease. With the exception of zidovudine, there

is a lack of safety data for the combination of INTRON A with reverse transcriptase

inhibitors.

Patients

receiving

concomitant

zidovudine

have

higher

incidence

neutropenia than that expected with zidovudine alone. The effects of INTRON A when

combined with other drugs used in the treatment of AIDS-related disease are unknown.

Ophthalmologic disorders, including retinal haemorrhages, cotton wool spots, retinal artery or

vein obstruction and serous retinal detachment have been reported in rare instances after

treatment with alfa interferons (see ADVERSE EFFECTS). All patients should have a baseline

eye examination. Any patient complaining of ocular symptoms, including loss of visual acuity or

visual field must have a prompt and complete eye examination. Because these ocular events

may occur in conjunction with other disease states, periodic visual examinations during

INTRON A therapy are recommended in patients with disorders that may be associated with

retinopathy, such as diabetes mellitus or hypertension. Discontinuation of INTRON A should be

considered in patients who develop new or worsening opthalmological disorders.

Preliminary data indicated that interferon alfa therapy may be associated with an increased

rate of kidney graft rejection. Liver graft rejection has also been reported but a causal

association with interferon alfa therapy has not been established.

Effect on Fertility

Interferon

impair

fertility.

studies

interferon

non-human

primates,

abnormalities of the menstrual cycle have been observed. Decreased serum oestradiol and

progesterone concentrations have been reported in women treated with human leucocyte

interferon. Therefore, fertile women should not receive INTRON A unless they are using

effective contraception during the treatment period. INTRON A should be used with caution

in fertile men.

Page 9

Use in Pregnancy (Category B3)

Results of animal reproduction studies indicate that recombinant interferon alfa-2b was not

teratogenic in rats or rabbits, nor did it adversely affect pregnancy, foetal development or

reproductive capacity in the offspring of treated rats. Animal studies have also shown that

interferons do not cross the placental barrier.

Interferon

been

shown to have abortifacient

effects

in rhesus monkeys

(Macaca

mulatta). Abortion was observed in all dose groups (7.5, 15 and 30 million IU/day IM from

Day 20 to Day 80 of gestation), and was statistically significant versus control in the mid- and

high-dose groups.

There are no adequate and well controlled studies in pregnant women. INTRON A should be

used during pregnancy only if the potential benefit justifies the potential risk to the foetus.

Use during 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 adverse reactions from INTRON A

nursing

infants,

decision

should

made

whether

discontinue

nursing

discontinue the drug, taking into account the importance of the drug to the mother.

Use in Children

Experience in patients below 18 years of age has been limited and in such cases the

expected benefits should be carefully weighed against potential hazards. Results of two

studies indicate that the efficacy of interferon therapy remains uncertain in children with

chronic active hepatitis B where the presumed route of transmission is vertical.

INTERACTIONS WITH OTHERS MEDICINES

Interactions between INTRON A and other drugs have not been fully evaluated. Caution

should be exercised when administering INTRON A in combination with other potentially

myelosuppressive agents.

A synergistic adverse effect on the white blood cell count may occur when INTRON A is

administered concomitantly with zidovudine. Patients receiving the two agents concomitantly

have

dose-dependent

higher

incidence

neutropaenia

than

expected

when

zidovudine

administered

alone

[See

Concomitant

Therapy

under

Dosage

Administration].

Laboratory Tests

following

laboratory

tests

should

conducted

prior

periodically

during

INTRON A treatment for all patients:

Standard haematological tests including complete blood counts (CBC), differential

white blood cell counts and platelet;

Blood chemistry including electrolytes, liver function tests, serum creatinine, serum

protein and TSH.

The haematological parameters of the patients should be followed closely as part of the

treatment because a certain degree of myelodepression has been reported in some patients

treated with INTRON A.

Page 10

Patients with pre-existing thyroid abnormalities may be treated if thyroid stimulating hormone

(TSH) levels can be maintained in the normal range by medication. TSH levels must be

within normal limits upon initiation of INTRON A treatment and TSH testing should be

repeated at 3 and 6 months.

Those patients who have pre-existing cardiac abnormalities and/or who are in advanced

stages of cancer should have electrocardiograms taken prior to and during the course of

treatment.

Multiple myeloma: Since multiple myeloma may impair renal function, patients should have

renal tests performed periodically.

Malignant melanoma: Liver function and white blood cell (WBC) count and differential should

monitored

weekly

during

induction

phase

therapy

monthly

during

maintenance phase of therapy.

Chronic hepatitis B: CBC and platelet counts should be evaluated prior to initiation of

INTRON A therapy in order to establish baselines for monitoring potential toxicity. These

tests should be repeated at treatment Weeks 1, 2, 4, 8, 12 and 16. Liver function tests,

including serum ALT, albumin and bilirubin, should be evaluated at treatment Weeks 1, 2, 4,

8, 12 and 16. HBeAg, HBsAg and ALT should be evaluated at the end of therapy as well as

3 and 6 months post therapy, since patients may become virological responders during the 6

month period following the end of treatment.

A transient increase in ALT

2 times baseline value (flare) can occur during INTRON A

therapy for chronic hepatitis B. In clinical trials, this flare generally occurred 8 to 12 weeks

after initiation of therapy and was more frequent in responders (63%, 24/38) than in non-

responders (27%, 13/48). Elevations in bilirubin

3 mg/dL (51.3

mol/L) occurred infrequently

(2%, 2/86) during therapy.

When ALT flare occurs, in general, INTRON A therapy should be continued unless signs

and symptoms of liver failure are observed. During ALT flare, clinical symptomatology and

liver function tests including ALT, prothrombin time, alkaline phosphatase, albumin and

bilirubin should be monitored at approximately 2-week intervals.

Chronic hepatitis C: Prior to initiation of INTRON A therapy, CBC and platelet counts should

be evaluated in order to establish baselines for monitoring potential toxicity. These tests

should be repeated at Weeks 1 and 2 following initiation of INTRON A therapy, and monthly

thereafter. Serum ALT should be evaluated after 2, 16 and 24 weeks of therapy to assess

response to treatment.

ADVERSE EFFECTS

Adverse reactions of INTRON A are dose-related. Haematological, hepatic, cardiovascular

and neurological toxicities are more common with higher doses.

The most frequently reported adverse reactions were flu-like symptoms, primarily fever,

fatigue, headache, myalgia, rigors/chills and malaise which occurred in almost all patients

treated. These effects were reversible within 72 hours of interruption or cessation of

treatment and were dose-related.

Page 11

Other less frequent adverse reactions reported with INTRON A therapy include:

Cardiovascular System

Less common: Hypotension

Rarely reported: Tachycardia, hypertension, peripheral ischaemia, chest pain,

cardiomyopathy (see below)

Very rarely reported: Palpitations, postural hypotension, bradycardia, cardiac failure, atrial

fibrillation, arrhythmia, extrasystole, angina pectoris, thrombophlebitis, cardiac ischaemia,

myocardial infarction, cerebrovascular haemorrhage, cerebrovascular ischaemia,

pericarditis.

Cardiovascular adverse reactions, particularly arrhythmia appeared to be correlated mostly

with pre-existing CVS disease and prior cardiotoxic therapy (see Precautions).

Cardiomyopathy that may be reversible upon discontinuation of interferon alfa has been

reported rarely in patients without prior evidence of cardiac disease.

Central and Peripheral Nervous System (including psychiatric adverse reactions)

Less common: Dizziness, somnolence, insomnia, confusion, impaired concentration,

depression, irritability, suicidal ideation, suicide attempts, suicide.

Rarely reported: Paraesthesia, impaired consciousness (including cases of encephalopathy,

see PRECAUTIONS), migraine, hypo-aesthesia, nervousness, anxiety, seizures, agitation,

emotional lability, flushing, neuropathy, peripheral neuropathy, polyneuropathy, psychosis

including hallucinations, aggressive behaviour towards others, vertigo.

Very rarely reported: Amnesia, stupor, convulsions, hypertonia, hyperaesthesia, hot flushes,

encephalopathy, tremor, coma, extrapyramidal disorder, paresis, speech disorder, syncope,

tinnitus, abnormal coordination, ataxia, aphasia, CNS dysfunction, abnormal gait,

hyperkinesia, dystonia, paralysis, impotence, personality disorder, abnormal thinking,

paroniria, apathy, aggravated depression, neurosis, feeling of ebriety, dementia.

Endocrine System

Rarely reported: Hyperthyroidism, hypothyroidism, diabetes mellitus/hyperglycaemia.

Very rarely reported: Gynaecomastia, virilism, aggravation of diabetes, pancreatitis.

Gastrointestinal System

Common: Nausea

Less common: Vomiting, diarrhoea

Rarely reported: Abdominal pain, dyspepsia, loose stool, taste perversion, gingival bleeding,

stomatitis, constipation, right upper quadrant (RUQ) pain, glossitis.

Very rarely reported: Eructation, tenesmus, ileus, colitis, thirst, melena, increased saliva,

esophagitis, rectal bleeding after stool, dysphagia, gastrointestinal haemorrhage, gastric

ulcer, gingivitis, gum hyperplasia, rectal haemorrhage, oral leucoplakia, gastrointestinal

mucosal discolouration, abdominal distention, flatulence, tongue discolouration, taste loss,

tongue pigmentation.

Haematological System [See Laboratory Values under Adverse Effects]

Very rarely reported: Haemolytic anaemia, increased gamma globulins, coagulation disorder

Very rarely, alfa interferons, including INTRON A used alone or in combination with Rebetol

may be associated with aplastic anaemia or pure red cell aplasia.

Page 12

Liver and Biliary System

Rarely reported: Hepatotoxicity including fatality.

Very rarely reported: Abnormal hepatic function tests, bilirubinaemia, jaundice,

hepatospleno-megaly, splenomegaly, hepatic encephalopathy.

Musculo-Skeletal System

Common: Arthralgia, back pain.

Less Common: Musculoskeletal pain.

Rarely reported: Rhabdomyolysis (sometimes serious) myositis.

Very rarely reported: Bone pain, muscle weakness, arthritis, arthrosis, myopathy.

Reproductive System

Rarely reported: Menstrual disorders eg. menorrhagia, amenorrhoea.

Very rarely reported: Leucorrhoea, uterine bleeding, vaginal haemorrhage.

Resistant Mechanism Disorders

Rarely reported: Resistance mechanism disorders (e.g.: altered resistance to infection; these

effects rarely have been life-threatening or fatal), viral infections, conjunctivitis.

Very rarely reported: Sty, fungal infections, moniliasis, sepsis.

Respiratory System

Rarely reported: Coughing, pharyngitis, dyspnoea, pulmonary infiltrates, pneumonitis,

pneumonia nasal congestion, sinusitis, rhinitis, respiratory disorder.

Very rarely reported: Hypoxia, stridor, bronchospasm, cyanosis, wheezing, pleural pain,

sneezing, nonproductive coughing, pulmonary embolism, pulmonary oedema, laryngitis,

pulmonary fibrosis

Skin and Appendages

Less common: Alopecia, increased sweating.

Rarely reported: Rash (e.g. erythematous and maculopapular), injection site disorders ,

pruritus, dermatitis, dry skin, erythema.

Very rarely reported: Urticaria, acne, nail disorders, purpura, peripheral ischaemia,

furunculosis, non-herpetic cold sores, epidermal necrolysis, lacrimal gland disorder,

photosensitivity, skin discolouration, chloasma, abnormal hair texture, increased hair growth,

skin depigmentation, dermatitis lichenoides, melanosis, vitiligo, injection site necrosis, toxic

epidermal necrolysis, erythema multiforme, Steven Johnson syndrome.

Urinary System

Rarely reported: Renal insufficiency, renal failure, hyperuricaemia.

Very rarely reported: Micturition disorder, nocturia, polyuria, haematuria, micturition

frequency, cystitis, oliguria, nephrosis, urinary incontinence, nephrotic syndrome.

Page 13

Visual and Auditory Disorders

Rarely reported: Eye pain, hearing disorder abnormal/blurred vision, hearing loss, retinal

haemorrhage, retinopathies (including macular oedema), cotton wool spots, and retinal

artery or vein obstruction, loss of visual acuity or visual field, optic neuritis and papilloedema,

lacrimal gland disorder.

Very rarely reported: Conjunctivitis, photophobia, blurred vision, diplopia, dry eyes,

oculomotor nerve paralysis, retinal disorder, night blindness, serous retinal detachment,

earache, deafness, hyperacusis.

General

Common: Anorexia

Less common: Asthenia, dry mouth, flu-like symptoms (unspecified), pain, taste alteration.

Rarely reported: Herpes simplex, epistaxis, weight decrease, increased appetite, decreased

libido, weakness, leg cramps, face oedema.

Very rarely reported: Dehydration, hypercalcaemia, cachexia, peripheral oedema,

lymphadenopathy, periorbital oedema, malignant hyperpyrexia, transplant rejection, acidosis,

hypertriglyceridaemia sarcoidosis or exacerbation of sarcoidosis, hepatitis B reactivation in

HCV/HBV co-infected patients.

A wide variety of autoimmune and immune-mediated disorders have been reported with alfa

interferons including idiopathic thrombocytopenic purpura and thrombotic thrombocytopenic

purpura, rheumatoid arthritis, systemic lupus erythematosus, vasculitis, and Vogt-Koyanogi-

Harada syndrome.

Cases of acute hypersensitivity reactions, including anaphylaxis, urticaria, and angioedema

have been reported.

Asthenic

conditions

(including

asthenia,

malaise

fatigue),

homicidal

ideation,

dehydration,

palpitations,

psoriasis,

fungal

infection,

bacterial

infection

(including

sepsis), have been reported.

When INTRON A is used with hydroxyurea, the occurrence of cutaneous vasculitides may be

increased.

Laboratory Values

Clinically significant laboratory abnormalities, most frequently occurring at doses greater

than 10 million IU

daily,

include reduction in granulocyte and white blood cell counts;

decreases in haemoglobin level and platelet count; increases in alkaline phosphatase,

lactate dehydrogenase (LDH), serum creatinine, serum urea nitrogen levels and TSH levels.

Moderate and usually reversible reduction in all three blood elements – white blood cells, red

blood cells and platelets, have been reported. Increase in serum ALT/AST levels have been

noted as an abnormality in some non-hepatitis subjects and also in some patients with

hepatitis particularly those with chronic hepatitis B coincident with clearance of viral DNAp.

DOSAGE AND ADMINISTRATION

INTRON A may be administered using either sterilised glass or plastic disposable syringes.

Page 14

During the course of treatment with INTRON A for any indication, if adverse reactions

develop, the dosage should be modified or therapy should be discontinued temporarily until

adverse

reactions

abate.

persistent

recurrent

intolerance

develops

following

adequate dosage adjustment, or disease progresses, the treatment with INTRON A should

be discontinued.

For maintenance dosage regimens administered subcutaneously, at the discretion of the

physician, the patient may self-administer the dose.

Hairy Cell Leukaemia

The recommended dosage of INTRON A is 2 million IU/m

administered subcutaneously

3 times a week (every other day). Higher doses are not recommended. Normalisation of one

or more haematological variables usually begins within 2 months of therapy. Improvement in

all three haematological variables (granulocyte count, platelet count and haemoglobin level)

require

months

more.

Non-splenectomised

patients

responded

similarly

splenectomised

patients

showed

similar

demonstrable improvement

in transfusion

requirements. This dosage regimen should be maintained unless the disease progresses

rapidly or severe intolerance is manifested.

The minimum effective dose of INTRON A has not been established.

Kaposi's Sarcoma

The recommended dosage for INTRON A is 30 million IU/m

three times a week, to be

administered

subcutaneously.

Alternatively,

INTRON

administered

intravenous infusion in a dose of 50 million IU/m

over a 30-minute period for 5 consecutive

days

every

other

week

(refer

"Preparation

of

INTRON

A

(HSA-free)

Solution

for

Intravenous Infusion"). The minimum interval between treatments is 9 days. Either dosage

regimen should be maintained indefinitely unless the disease progresses rapidly or severe

intolerance is manifested.

Chronic Myelogenous Leukaemia

The recommended dosage of INTRON A is 2 to 6 million IU/m

administered daily by

subcutaneous injection. When the white blood cell count is controlled, the dosage may be

administered

three

times

week

(every

other

day).

dosage

regimen

should

maintained unless the disease progresses rapidly or severe intolerance is manifested.

Multiple Myeloma

The recommended dosage is 3 million IU/m

administered three times a week (every other

day) by subcutaneous injection. The dosage regimen should be maintained unless the

disease progresses rapidly or severe intolerance is manifested.

Follicular Non-Hodgkin's Lymphoma

The recommended dosage is 3 to 5 million IU administered three times a week (every other

day) by subcutaneous injection for a duration of up to 18 months. The dosage should be

adjusted according to the patient's response and tolerance of the medication.

Malignant Melanoma

As induction therapy, INTRON A is administered intravenously at a dose of 20 million IU/m

daily for five days a week over a four-week period (refer to "Preparation of INTRON A (HSA-

free) Solution for Intravenous Infusion"). As maintenance treatment, the recommended dose

is 10 million IU/m

administered subcutaneously three days a week (every other day) for 48

weeks.

Page 15

If severe adverse reactions develop during INTRON A treatment, particularly if granulocytes

decrease to <500/mm

or ALT/AST rises to >5x upper limit of normal, treatment should be

temporarily discontinued until the adverse reactions abates. INTRON A treatment should be

restarted at 50% of the previous dose. If intolerance persists after dose adjustment or if

granulocytes decrease to <250/mm

or ALT/AST rises to >10x upper limit of normal,

INTRON A therapy should be discontinued.

There

evidence

that

dose

modifications

beyond

those

described

will

result

maintenance of clinical benefit. For full clinical benefit, patients should be treated at the

recommended doses, with dose modification for toxicity as described.

Chronic Hepatitis B

Prior to initiation of INTRON A therapy, it is recommended that a liver biopsy be performed

to establish the presence of chronic hepatitis and the extent of liver damage. Patients with

causes of chronic hepatitis other than chronic hepatitis B or chronic hepatitis C should not be

treated with INTRON A. The physician should establish that the patient has compensated

liver disease.

The lowest effective dose of INTRON A is 3 million IU three times a week, administered

subcutaneously. Patients who do not respond within one month may be treated at doses of

5 million IU three times a week or up to 10 million IU three times a week or 5 million IU daily.

The dosage may be adjusted according to the patient's tolerance to the medication. With a

response, the selected dosage regimen should be maintained for up to four months unless

severe intolerance develops.

[See Laboratory Tests under Precautions for various tests to be conducted and timing of

these tests.]

Chronic Hepatitis C

Prior to initiation of INTRON A therapy, it is recommended that a liver biopsy be performed

to establish the diagnosis of chronic hepatitis and the extent of liver damage. Patients should

be tested for the presence of antibody to HCV. Patients with causes of chronic hepatitis

other than chronic hepatitis B or chronic hepatitis C should not be treated with INTRON A.

The physician should establish that the patient has compensated liver disease.

The recommended dose is 3 million IU administered subcutaneously three times a week.

Most patients who respond demonstrate improvement in ALT levels within 12-16 weeks. In

these patients, therapy should be continued with 3 million IU three times a week for up to 18

months.

In patients who fail to respond after 12-16 weeks of treatment, use of INTRON A Injection

should be discontinued.

Current clinical experience in patients who remain on INTRON A Injection for 12-18 months

indicates that a higher proportion of patients demonstrated a sustained response after longer

durations of therapy than those who discontinued therapy after six months.

[See Laboratory Tests under Precautions for tests to be conducted and timing of these

tests.]

Concomitant Therapy

Paracetamol has been used successfully to alleviate the symptoms of fever and headache

which can occur with INTRON A therapy. The recommended paracetamol dosage is 500 mg

to 1 g given 30 minutes before administration of INTRON A. The maximum dosage of

paracetamol to be given is 1 g four times daily.

Page 16

Preparation of INTRON A (HSA-free) Solution for Intravenous Infusion

NO OTHER DRUG CAN BE INFUSED CONCOMITANTLY WITH INTRON A SOLUTION

FOR INJECTION.

The infusion should be prepared immediately prior to use. Any size vial of the INTRON A

(HSA-free) solution may be used to prepare the infusion, but the aim should be to minimise

handling.

The INTRON A solution can be diluted in sterile normal saline (0.9%). However, the final

concentration of diluted INTRON A solution must not be less than 0.3 million IU/mL.

For Kaposi’s Sarcoma

Prior to administration of each INTRON A infusion, the patient should have a 21-gauge

butterfly inserted or other intravenous access provided. An infusion of sterile normal saline

(at 200 mL/hr) should be started approximately 10 minutes before drug administration. This

normal saline infusion should be stopped just prior to the administration of INTRON A.

The calculated amount of interferon for the appropriate dose should be withdrawn from the

vial(s) and added to 50 mL of sterile normal saline. The diluted INTRON A solution should be

infused over a 30-minute period. After drug administration has been completed, the normal

saline infusion should be restarted for a 10-minute period at the original rate of 200 mL/hr.

For Malignant Melanoma

The appropriate dose should be withdrawn from the vials and added to 50 mL of sterile

normal saline solution in a PVC bag or glass bottle for intravenous use and administered

over 20 minutes.

Stability of Injectable Solution

Single dose vials: After opening, use once and discard any residue.

As with all parenteral drug products, the solution should be inspected visually for particulate

matter and discolouration prior to administration.

OVERDOSAGE

Most adverse reactions to recombinant interferon alfa-2b listed are dose-related. There is no

specific antidote in the event of overdose. Symptomatic treatment with frequent monitoring

of vital signs and close observation of the patient is indicated.

PRESENTATION AND STORAGE CONDITIONS

Injectable Solution (HSA-free):

Single dose vials

Page 17

10 million IU/1 mL: 1s, 3s*, 5s, 6s* and 10s*

18 million IU/3 mL; 25 million IU/2.5 mL: 1s and 5s*

Note: Presentations marked with an asterisk are not marketed.

Store at 2° to 8

C. (Refrigerate. Do not freeze.)

NAME AND ADDRESS OF THE SPONSOR

Merck Sharp & Dohme (Australia) Pty Limited

Level 1 – Building A

26 Talavera Road

Macquarie Park NSW 2113

AUSTRALIA

POISON SCHEDULE

Schedule 4 – Prescription Only Medicine

DATE OF FIRST INCLUSION IN THE AUSTRALIAN REGISTER OF THERAPEUTIC

GOODS (ARTG)

29 May 1997

DATE OF MOST RECENT AMENDMENT

05 December 2017

Read the complete document

Public Summary

Summary for ARTG Entry:

60021

INTRON A Interferon alfa-2b (HSA-free) 18 million IU/3mL injection

ARTG entry for

Medicine Registered

Sponsor

Merck Sharp & Dohme (Australia) Pty Ltd

Postal Address

North Ryde Post Business Centre,Locked Bag 2234,NORTH RYDE BC, NSW, 1670

Australia

ARTG Start Date

29/05/1997

Product category

Medicine

Status

Active

Approval area

Drug Safety Evaluation Branch

Conditions

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

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

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

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

Products

1. INTRON A Interferon alfa-2b (HSA-free) 18 million IU/3mL injection

Product Type

Single Medicine Product

Effective date

11/05/2017

Warnings

See Product Information and Consumer Medicine Information for this product

Standard Indications

Specific Indications

Hairy cell leukaemia: for the treatment of hairy cell leukaemia in splenectomised or non-splenectomised patients. Kaposi's sarcoma in AIDS: for the

treatment of Kaposi's sarcoma in patients with acquired immune deficiency syndrome (AIDS). Chronic myelogenous leukaemia: for the treatment of

Philadelphia chromosome positive chronic myelogenous leukaemia in the chronic phase. Multiple myeloma: for the maintenance of control of multiple

myeloma once control has been achieved by chemotherapy. The effect on overall survival has not as yet been determined. Follicular non-Hodgkin's

lymphoma: as an adjuvant treatment of high tumour burden Stage III or IV follicular non-Hodgkin's lymphoma in conjunction with an appropriate

chemotherapy regimen. In controlled clinical trials in which efficacy was demonstrated, anthracycline chemotherapy was employed. Malignant

melanoma: as an adjuvant therapy of malignant melanoma following surgery in patients who are at high risk of recurrence. The potential benefit to the

patient should be assessed carefully. Although toxicity of the treatment may be substantial, for most patients, the benefit of therapy outweighed the risk.

Chronic hepatitis B: for the treatment of adults with histologically proven compensated chronic active hepatitis B. Patients should be serum HBsAg

positive and have evidence of HBV replication (such as serum HBeAg positive) and raised serum alanine aminotransferase (ALT) levels (>3 times the

upper limit of the reference range) for at least 6 months. [See Pharmacology for response rate]. Chronic hepatitis C: for the treatment of histologically

proven compensated chronic hepatitis due to hepatitis C (HCV antibody positive) in adult patients with persistently elevated serum alanine

aminotransferase (ALT). Studies in these patients demonstrate that Intron A Injection therapy can produce normalisation of serum ALT, clearance of

serum HCV RNA and improvement in liver histology.

Additional Product information

Container information

Type

Material

Life Time

Temperature

Closure

Conditions

Vial

Glass

2 Years

Store at 2 to 8

degrees Celsius

Not recorded

Refrigerate

Do not Freeze

Pack Size/Poison information

Pack Size

Poison Schedule

1 x 3ml

(S4) Prescription Only Medicine

5 x 3mL

(S4) Prescription Only Medicine

Components

1. Medicine Component

Dosage Form

Injection, solution

Route of Administration

Subcutaneous

Intravenous

Visual Identification

Clear to opalescent, colourless to light yellow solution, essentially free of

visible particles.

Active Ingredients

Interferon alfa-2b

6 million IU/mL

Public Summary

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Produced at 02.11.2017 at 11:36:11 AEDT

This is not an ARTG Certificate document.

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

Visit www.tga.gov.au for contact information

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

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

Public Summary

Page 2 of

Produced at 02.11.2017 at 11:36:11 AEDT

This is not an ARTG Certificate document.

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

Visit www.tga.gov.au for contact information

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