Binocrit

New Zealand - English - Medsafe (Medicines Safety Authority)

Buy It Now

Active ingredient:
Epoetin alfa 336 µg/mL
Available from:
Novartis New Zealand Ltd
INN (International Name):
Epoetin alfa 336 µg/mL
Dosage:
336 mcg/mL
Pharmaceutical form:
Solution for injection
Composition:
Active: Epoetin alfa 336 µg/mL Excipient: Dibasic sodium phosphate dihydrate Glycine Hydrochloric acid Monobasic sodium phosphate dihydrate Nitrogen Polysorbate 80 Sodium chloride Sodium hydroxide Water for injection
Units in package:
Syringe, glass, 0.5 mL x1, 0.5 mL
Class:
Prescription
Prescription type:
Prescription
Manufactured by:
Rentschler Biotechnologie GmbH
Therapeutic indications:
Binocrit is indicated for: · the treatment of severe anaemia of renal origin accompanied by clinical symptoms in patients with renal insufficiency not yet undergoing dialysis · anaemia associated with chronic renal failure in paediatric and adult patients on dialysis · anaemia in patients with non-myeloid malignancies where anaemia is due to the effect of concomitantly administered chemotherapy · adult patients with mild-to-moderate anaemia (haemoglobin > 100 to < 130 g/L) scheduled for elective surgery with an expected moderate blood loss (2-4 units or 900 to 1800 mL) to reduce exposure to allogeneic blood transfusion and to facilitate erythropoietic recovery · to augment autologous blood collection and to limit the decline in haemoglobin in anaemic adult patients undergoing major surgery who are not expected to pre-deposit their complete peri-operative blood needs.
Product summary:
Package - Contents - Shelf Life: Syringe, glass, 0.5 mL x1 - 0.5 mL - 24 months from date of manufacture stored at 2° to 8°C (Refrigerate, do not freeze) protect from light. up to 3 days at or below 25°C - Syringe, glass, 0.75 mL x1 - 0.75 mL - 24 months from date of manufacture stored at 2° to 8°C (Refrigerate, do not freeze) protect from light. up to 3 days at or below 25°C - Syringe, glass, 1 mL x1 - 1 mL - 24 months from date of manufacture stored at 2° to 8°C (Refrigerate, do not freeze) protect from light. up to 3 days at or below 25°C - Syringe, glass, 0.5 mL x6 - 3 mL - 24 months from date of manufacture stored at 2° to 8°C (Refrigerate, do not freeze) protect from light. up to 3 days at or below 25°C - Syringe, glass, 0.75 mL x6 - 4.5 mL - 24 months from date of manufacture stored at 2° to 8°C (Refrigerate, do not freeze) protect from light. up to 3 days at or below 25°C - Syringe, glass, 1 mL x6 - 6 mL - 24 months from date of manufacture stored at 2° to 8°C (Refrigerate, do not freeze) protect from light. up to 3 days at or below 25°C
Authorization number:
TT50-8872b
Authorization date:
2011-07-22

Binocrit

Binocrit

Epoetin alfa (rch) solution for injection (prefilled syringes)

Consumer Medicine Information

WHAT IS IN THIS LEAFLET

This leaflet answers some common questions about Binocrit.

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 taking this medicine

against the benefits they expect it will have for you.

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

Keep this leaflet .

You may need to read it again.

WHAT BINOCRIT IS USED FOR

The prefilled syringes contain the active ingredient epoetin alfa, a protein that stimulates bone marrow to

produce more red blood cells.

Red blood cells are responsible for carrying oxygen to all parts of your body. A decrease in the number of

red blood cells can cause anaemia. Some symptoms of anaemia are tiredness, breathlessness when

exercising and feeling cold. Anaemia may have many causes including decreased production of a

hormone called erythropoietin by the kidneys due to kidney failure or as a result of chemotherapy

treatments for cancer. This medicine is virtually identical to your body’s erythropoietin, and has a similar

effect to naturally occurring erythropoietin in your body.

This medicine is used to treat:

anaemia associated with kidney disease. If you have kidney disease, your kidney may not produce

enough erythropoietin (necessary for red blood cell production) and your doctor may wish to correct

this by prescribing this medicine. This medicine stimulates your bone marrow to produce more red

blood cells, helping to treat your anaemia.

anaemia and reduce the need for a blood transfusion if you are receiving chemotherapy for cancer and

your doctor decides you may need a blood transfusion.

mildly anaemic patients who are going to have surgery and donate blood before surgery, so that their

own blood can be given to them during or after surgery. Because this medicine stimulates the

production of red blood cells, a higher volume of blood can be taken from these patients.

adult patients about to undergo major orthopaedic (bone) surgery, as an alternative to a blood

transfusion, where there is a potentially high risk from blood transfusion complications.

Ask your doctor if you have any questions about why this medicine has been prescribed for you.

Your doctor may have prescribed it for another reason.

This medicine is not addictive.

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

Binocrit

BEFORE YOU USE BINOCRIT

When you must not use it

Do not use this medicine if you have an allergy to:

epoetin alfa, the active ingredient, or to any of the other ingredients listed at the end of this leaflet

under Product Description

any other similar medicines, such as other erythropoietins

any medicines that are manufactured using mammalian cells.

Some of the symptoms of an allergic reaction may include:

shortness of breath

wheezing or difficulty breathing

swelling of the face, lips, tongue or other parts of the body

rash, itching or hives on the skin

Do not use this medicine if you:

have high blood pressure that is not properly controlled with blood pressure-lowering medication

are a surgery patient who should not be given medicines to thin the blood

are due to have elective surgery and have severe heart disease, disorders of the veins or arteries, or

have recently had a heart attack or stroke

have been diagnosed with Pure Red Cell Aplasia (your bone marrow cannot produce enough red

blood cells) after previous treatment with an erythropoietin product, including Binocrit

if you cannot have transfusions with your own blood during or after surgery.

Do not use this medicine after the expiry date printed on the pack or if the packaging is torn or

shows signs of tampering.

If it has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start to use this medicine, talk to your doctor.

Before you start to use it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you have or have had any of the following medical conditions:

high blood pressure

heart disease (such as angina)

disorders of blood circulation resulting in pins and needles or cold hands or feet or muscle cramps in

the legs

blood clotting disorders

seizures or epileptic fits

cancer. If you are a cancer patient be aware that erythropoietins like this medicine, may act as a

growth factor and therefore in theory may affect the progression of your cancer. Please discuss this

with your doctor.

anaemia from other causes

liver disease

gout

porphyria (a rare blood pigment disorder).

Tell your doctor if you are pregnant or plan to become pregnant or are breastfeeding.

Your doctor can discuss with you the risks and benefits involved.

Binocrit

In many women with severe kidney failure, their monthly periods may stop. In these women,

erythropoietin may restart the monthly cycle. Before starting this medicine, you should discuss the need

for contraception with your doctor.

Make sure you tell your doctor if you have any other medical problems since these may affect the use of

this medicine.

If you have used this medicine or another erythropoietin in the past, and you lose the good response you

were having, tell your doctor about this.

If you have not told your doctor about any of the above, tell him/her before you start using

Binocrit.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including any that you get

without a prescription from your pharmacy, supermarket or health food shop.

Some medicines and Binocrit may interfere with each other. These include:

cyclosporin

iron supplementation. Iron is also a constituent of red blood cells, therefore iron supplements and

other blood stimulating medicines may increase your response to this medicine.

These medicines may be affected by Binocrit or may affect how well it works. You may need different

amounts of your medicines, or you may need to take different medicines.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while you

are given this medicine.

HOW TO USE BINOCRIT

Follow all directions given to you by your doctor or pharmacist carefully.

They may differ from the information contained in this leaflet.

If you do not understand the instructions, ask your doctor or pharmacist for help.

How much to use

Your doctor will determine the correct dose of this medicine. The injection is administered either into a

vein (intravenously) or just under the skin (subcutaneously). After instruction, you can administer it under

the skin yourself if you wish. Your doctor can discuss with you whether injection into the vein or under

the skin is preferable.

In patients with anaemia due to kidney failure, Binocrit should be given intravenously (into a vein or a

tube that goes into a vein) if intravenous access is routinely available (haemodialysis patients). The

usual starting dose is 50 IU/kg three times per week for adults and 25 IU/kg three times per week for

children, after which the dose may be changed by your doctor as needed.

In patients who are scheduled for surgery and who are not storing their own blood, the usual dose is

300 IU/kg body weight for 10 days before surgery, on the day of surgery and for 4 days after.

Alternatively a dose of 600 IU/kg may be administered weekly for 3 weeks before surgery and on the

day of surgery. The subcutaneous route is used.

Binocrit

In anaemic cancer patients receiving chemotherapy, the initial dose is 150 IU/kg three times per week.

After 4 weeks your doctor will check your response and increase the dose to 300 IU/kg three times

weekly if response has been insufficient. If at any stage, this medicine has produced too many red

cells, your doctor will stop the drug and later re-start it at a lower dose. The subcutaneous route is

used.

Injecting Binocrit under the skin yourself

At the start of your therapy, this medicine may be injected by medical or nursing staff. However, your

doctor may decide that it is right for you to learn how to inject this medicine under the skin

(subcutaneously) yourself. You will receive appropriate training for you to do this.

Under no circumstances should you attempt to inject yourself unless you have been trained to do

so.

If this medicine is injected under the skin (subcutaneously), the amount injected is not normally more

than one millilitre (1 mL) in a single injection.

This medicine is given alone and not mixed with other liquids for injection.

Only use this medicine if the solution is clear, colourless and free of visible particles.

Do not shake Binocrit prefilled syringes.

Prolonged vigorous shaking may damage this medicine. If it has been shaken vigorously, don’t use it.

Ask your doctor or pharmacist if you are unsure of the correct dose for you.

They will tell you exactly how much to take.

Follow the instructions they give you.

If you take the wrong dose, Binocrit may not work as well and your problem may not improve.

How to inject it

Take a syringe out of the refrigerator.

The liquid needs to come to room temperature. This usually

takes between 15 to 30 minutes.

Check the syringe,

to make sure it is the right dose, has not passed its expiry date, is not damaged

and the liquid is clear and not frozen.

Choose an injection site.

Good sites are the top of the thigh and around the tummy (abdomen) but

away from the navel. Vary the site from day to day.

Wash your hands.

Use an antiseptic swab on the injection site, to disinfect it.

Take the cover off the syringe

by holding the barrel and pulling the cover off carefully without

twisting it. Don’t push the plunger, touch the needle or shake the syringe.

Pinch a fold of skin

between your thumb and index finger. Don’t squeeze it.

Push the needle in fully.

Your doctor or nurse may have shown you how to do this.

Check that you haven’t punctured a blood vessel.

Pull back slightly on the plunger. If you see

blood, take the syringe out and try somewhere else.

Push the plunger with your thumb as far as it will go to inject all of the liquid.

Push it slowly

and evenly, keeping the skin-fold pinched.

When the plunger is pushed as far as it will go,

take out the needle and let go of the skin.

Take your thumb off the plunger.

Press an antiseptic swab

over the injection site for a few seconds after the injection.

Dispose of your used syringe

in a safe container.

Only take one dose of Binocrit from each syringe. If any liquid remains in the syringe after an injection,

the syringe should be properly disposed of and not reused. Binocrit prefilled syringes do not contain

Binocrit

preservatives. Therefore, once a syringe has been opened, any remaining solution must be discarded.

If you do not understand the instructions provided with this medicine, ask your doctor or pharmacist for

help.

If you forget to use it

Administer your dose as soon as you remember, and continue to take it as you would normally.

If it is almost time for your next dose, skip the dose you missed and administer your next dose when you

are meant to.

Do not administer a double dose to make up for the dose that you missed.

This may increase the chance of you getting an unwanted side effect.

If you have missed more than one dose or 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 have used too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone Australia 13 11

26 or New Zealand 0800 POISON or 0800 764766) for advice, or go to Accident and Emergency at

the nearest hospital, if you think that you or anyone else may have taken too much Binocrit.

Do this even if there are no signs of discomfort or poisoning.

You may need urgent medical attention.

WHILE YOU ARE USING BINOCRIT

Things you must do

Always follow your doctor’s instructions carefully.

If you are about to be started on any new medicine, remind your doctor and pharmacist that you

are using Binocrit.

Tell any other doctors, dentists and pharmacists who treat you that you are using this medicine.

If you are receiving dialysis treatment when you begin treatment with this medicine, your dialysis

regimen may need to be adjusted.

Your doctor will decide this.

If you are going to have surgery, tell the surgeon or anaesthetist that you are using this medicine.

It may affect other medicines used during surgery. Your doctor will give you a medicine to reduce the

risk of abnormal clotting.

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

If you are about to have any blood tests, tell your doctor that you are using this medicine.

It may interfere with the results of some tests.

Keep all of your doctor’s appointments so that your progress can be checked.

Your doctor may do some tests (i.e. blood pressure, blood tests) regularly to make sure the medicine is

working and to prevent unwanted side effects. If your haemoglobin levels are above 120 g/L, discuss

Binocrit

reducing your Binocrit dose with your doctor. An increase in levels of small cells (platelets) in your blood

may occur, particularly when starting haemodialysis treatment.

If you become increasingly tired, dizzy or breathless, you should talk to your doctor at once.

Your doctor can decide whether this medicine is not working properly for you and will end the treatment

if necessary.

Tell your doctor if you received Binocrit or another erythropoietin-like medicine in the past and

you experienced a worsening in your anaemia.

Take special care with other products that stimulate red blood cell production

This medicine is one of a group of products that stimulate the production of red blood cells like the

human protein erythropoietin dose. If you are given a product in this group other than the one prescribed

by your doctor during your treatment, speak to your doctor before using it. It is important that you

continue to use the same product in the group unless your doctor says otherwise.

Things you must not do

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

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

Things to be careful of

If you have kidney failure be careful driving or operating machinery until you know how Binocrit

affects you.

This medicine may cause dizziness in some people. If you have this symptom, do not drive, operate

machinery or do anything else that could be dangerous.

If you feel dizzy when getting out of bed or standing up, get up slowly.

Standing up slowly, especially when you get up from bed or chairs, will help your body get use to the

change in position and blood pressure. If this problem continues or gets worse, talk to your doctor.

SIDE EFFECTS

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

Binocrit.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may

need medical attention if you get some of the side effects.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

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

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

flu-like symptoms such as dizziness, drowsiness, fever, chills, headache, muscle and joint pain and

weakness

cough or congested airways such as stuffy nose and sore throat

redness, burning and pain at the site this medicine is given

nausea, diarrhoea and vomiting.

If any of the following happen, tell your doctor immediately or go to Accident and Emergency at

your nearest hospital:

Binocrit

severe, sudden, stabbing migraine-like headaches

seizures, confusion or epileptic fits

raised blood pressure, which may require treatment with medication or adjustment of the doses of

medication you already take for high blood pressure

clotting of your blood in the haemodialysis system or blockage of your fistula if you are on dialysis.

There may be a need to increase your heparin dose during dialysis.

chest pain, breathlessness, painful swelling in the leg that may be symptoms of a blood clot

(thrombosis)

skin rashes and accumulation of fluid under the skin of the eyelids (oedema), which may result from

an allergic reaction

signs of allergy such as rash, itching or hives on the skin; shortness of breath, wheezing or difficulty

breathing; swelling of the face, lips, tongue or other parts of the body

sudden tiredness, dizziness or sudden shortness of breath.

Your doctor will want to investigate this. These symptoms may be caused by a condition called pure red

cell aplasia (PRCA). PRCA has been rarely reported after months to years of treatment with this

medicine. PRCA means the absence of very young red blood cells in the bone marrow. If this condition

develops, you suddenly lose the good response you have been having to this medicine. Due to product

improvements PRCA is now very rare but as the previous cases occurred mainly with subcutaneous

administration, it is preferable that this medicine be administered intravenously in haemodialysis patients.

Although PRCA is rare, you should be informed that if it develops, you will need to have regular blood

transfusions to treat your anaemia and Binocrit would have to be stopped.

The above list includes very serious side effects. You may need urgent medical attention or

hospitalisation.

Tell your doctor or pharmacist if you notice anything else that is making you feel unwell.

Other side effects not listed above may also occur in some people.

AFTER USING BINOCRIT

Storage

Keep your medicine in the original container.

If you take it out of its original container it may not keep well.

Keep your medicine in a cool dry place where the temperature stays between 2ºC and 8ºC in the

refrigerator. Do not freeze and protect from light.

Immediately prior to use, Binocrit may be stored in a room that stays below 25ºC for a maximum single

period of three days.

Do not store Binocrit or any other medicine in the bathroom or near a sink. Do not leave it on a window

sill or in the car.

Heat and dampness can destroy some medicines.

Keep it where children cannot reach it.

A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop using this medicine or the expiry date has passed, ask your pharmacist

what to do with any medicine that is left over.

Binocrit

PRODUCT DESCRIPTION

What it looks like

Binocrit solution for injection is a clear, colourless solution, presented in a glass graduated syringe. Each

pack of Binocrit contains 1 or 6 syringes.

Ingredients

Active ingredients:

Binocrit

1,000 IU / 0.5 mL

- 1,000IU epoetin alfa (rch)

Binocrit

2,000 IU / 1.0 mL

- 2,000IU epoetin alfa (rch)

Binocrit

3,000 IU / 0.3 mL

- 3,000IU epoetin alfa (rch)

Binocrit

4,000 IU / 0.4 mL

- 4,000IU epoetin alfa (rch)

Binocrit

5,000 IU / 0.5 mL

- 5,000IU epoetin alfa (rch)

Binocrit

6,000 IU / 0.6 mL

- 6,000IU epoetin alfa (rch)

Binocrit

7,000 IU / 0.7 mL

- 7,000IU epoetin alfa (rch)

Binocrit

8,000 IU / 0.8 mL

- 8,000IU epoetin alfa (rch)

Binocrit

9,000 IU / 0.9 mL

- 9,000IU epoetin alfa (rch)

Binocrit

10,000 IU / 1.0 mL

-10,000IU epoetin alfa (rch)

Binocrit

20,000 IU / 0.5 mL

-20,000IU epoetin alfa (rch)

Binocrit

30,000 IU / 0.75 mL -30,000IU epoetin alfa (rch)

Binocrit

40,000 IU / 1.0 mL

-40,000IU epoetin alfa (rch)

Inactive ingredients:

sodium dihydrogen-phosphate dihydrate

disodium hydrogen-phosphate dihydrate

sodium chloride

glycine

polysorbate 80

nitrogen

hydrochloric acid

sodium hydroxide

water for injections.

This medicine does not contain lactose, sucrose, gluten, tartrazine or any other azo dyes.

Supplier

Sandoz Pty Ltd

ABN 60 075 449 553

54 Waterloo Road

Macquarie Park, NSW 2113

Australia

Tel: 1800 634 500

Novartis New Zealand Ltd

PO Box 99102

Newmarket

Auckland 1149

New Zealand

Tel: 0800 354 335

Binocrit

This leaflet was prepared in November 2018.

New Zealand Data sheet

180702-Binocrit

-dds

Page 1 of 18

1

PRODUCT NAME

Binocrit 1,000 IU/0.5 mL solution for injection in pre-filled syringe.

Binocrit 2,000 IU/1.0 mL solution for injection in pre-filled syringe.

Binocrit 3,000 IU/0.3 mL solution for injection in pre-filled syringe.

Binocrit 4,000 IU/0.4 mL solution for injection in pre-filled syringe.

Binocrit 5,000 IU/0.5 mL solution for injection in pre-filled syringe.

Binocrit 6,000 IU/0.6 mL solution for injection in pre-filled syringe.

Binocrit 7,000 IU/0.7 mL solution for injection in pre-filled syringe.

Binocrit 8,000 IU/0.8 mL solution for injection in pre-filled syringe.

Binocrit 9,000 IU/0.9 mL solution for injection in pre-filled syringe.

Binocrit 10,000 IU/1.0 mL solution for injection in pre-filled syringe.

Binocrit 20,000 IU/0.5 mL solution for injection in pre-filled syringe.

Binocrit 30,000 IU/0.75 mL solution for injection in pre-filled syringe.

Binocrit 40,000 IU/1.0 mL solution for injection in pre-filled syringe.

Binocrit is a biosimilar medicine.

2

QUALITATIVE AND QUANTITATIVE COMPOSITION

Binocrit is a sterile, clear and colourless, preservative-free buffered protein solution of epoetin alfa

(rch).

Table 1. Binocrit dose strengths and the corresponding quantity of epoetin alpha per mL

Binocrit dose strength

Filled volume

Total content of active

Concentration

1000 IU

0.5 mL

8.4 microgram

16.8 microgram/mL

2000 IU

1.0 mL

16.8 microgram

16.8 microgram/mL

3000 IU

0.3 mL

25.2 microgram

84.0 microgram/mL

4000 IU

0.4 mL

33.6 microgram

84.0 microgram/mL

5000 IU

0.5 mL

42.0 microgram

84.0 microgram/mL

6000 IU

0.6 mL

50.4 microgram

84.0 microgram/mL

7000 IU

0.7 mL

58.8 microgram

84.0 microgram/mL

8000 IU

0.8 mL

67.2 microgram

84.0 microgram/mL

9000 IU

0.9 mL

75.6 microgram

84.0 microgram/mL

10,000 IU

1.0 mL

84.0 microgram

84.0 microgram/mL

20,000 IU

0.5 mL

168.0 microgram

336.0 microgram/mL

30,000 IU

0.75 mL

252.0 microgram

336.0 microgram/mL

40,000 IU

1.0 mL

336.0 microgram

336.0 microgram/mL

For the full list of excipients, see Section 6.1.

New Zealand Data sheet

180702-Binocrit

-dds

Page 2 of 18

Binocrit is a biosimilar medicine. Prior to dispensing Binocrit the prescribing physician should review

the bioequivalence data (see section 5) to determine whether Binocrit is interchangeable with the

reference medicine epoetin alfa (rch) marketed in New Zealand. Erythropoiesis-stimulating agents

(ESAs) are not necessarily equivalent. Therefore, it should be emphasised that patients should only be

switched from one ESA (such as epoetin alfa) to another ESA with the authorisation of the treating

physician. For further information refer to http://www.medsafe.govt.nz/profs/RIss/Biosimilars.asp

3

PHARMACEUTICAL FORM

Solution for injection in a pre-filled syringe (injection).

Clear, colourless solution.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications

Binocrit is indicated for:

the treatment of severe anaemia of renal origin accompanied by clinical symptoms in patients with

renal insufficiency not yet undergoing dialysis

anaemia associated with chronic renal failure in paediatric and adult patients on dialysis

anaemia in patients with non-myeloid malignancies where anaemia is due to the effect of

concomitantly administered chemotherapy

adult patients with mild-to-moderate anaemia (haemoglobin > 100 to < 130 g/L) scheduled for

elective surgery with an expected moderate blood loss (2-4 units or 900 to 1800 mL) to reduce

exposure to allogeneic blood transfusion and to facilitate erythropoietic recovery

to augment autologous blood collection and to limit the decline in haemoglobin in anaemic adult

patients undergoing major surgery who are not expected to pre-deposit their complete peri-operative

blood needs.

4.2

Dose and method of administration

During

therapy,

haematological

parameters

should

monitored

regularly.

Doses

must

individualised to ensure that haemoglobin is maintained at an appropriate level for each patient.

As a single anaphylactic reaction was observed in one patient during the course of clinical testing, it is

recommended that the first dose be administered under medical supervision.

Method of Administration

Parenteral medicine products should be visually inspected for particulate matter and discolouration

prior to administration. Product exhibiting particulate matter or discolouration must not be used.

Do not shake, as shaking may denature the glycoprotein, rendering it inactive.

Binocrit in single use syringes contains no preservatives. Do not re-use syringe. Discard unused

portion.

Prepare Binocrit for injection from the prefilled syringe.

Administer as i.v. or s.c. injection over 1-2 minutes. In patients on dialysis the injection should

follow the dialysis procedure. Slow injection over 5 minutes may be beneficial to those who

experience flu-like symptoms. For subcutaneous dosing a maximum volume of 1 mL at any one

injection site should not be exceeded. In the case of larger volumes, the injection should be divided

between more than one site.

New Zealand Data sheet

180702-Binocrit

-dds

Page 3 of 18

Do not dilute or transfer to any other container. Do not administer by intravenous infusion or in

conjunction with other medicine solutions.

The pre-filled syringes are fitted with or without a needle safety guard. The needle safety guard device

helps prevent needle stick injuries after use. The Binocrit Consumer Medicine Information includes full

instructions for the use and handling of pre-filled syringes.

For treatment of anaemia associated with renal insufficiency or chronic renal failure

In patients with chronic renal failure, where intravenous access is routinely available (haemodialysis

patients) administration of Binocrit by the intravenous route is preferable. Where intravenous access is

not readily available (patient not yet on dialysis and peritoneal dialysis patients) Binocrit may be

administered subcutaneously (See section 4.4, Pure Red Cell Aplasia).

In patients maintained on haemodialysis, Binocrit should always be administered after completion of

dialysis.

Adults

The recommended starting dose of epoetin alfa (rch) is 50 IU/kg, three times per week, administered as

i.v. or s.c injection over 1-2 minutes. Further dose increments should depend upon the initial response

(proposed rate < 20 g/L per month). Because of the length of time required for erythropoiesis - several

days for erythroid progenitors to mature and be released into the circulation - a clinically significant

increase in haematocrit is usually not observed in less than 2 weeks and may require up to 6 weeks in

some patients.

If required, dose increments in steps of 25 IU/kg in intervals of four weeks are recommended. If the

rate of haemoglobin (Hb) rise exceeds 20 g/L per month at 50 IU/kg, three times per week, downward

dosage adjustments should be made in the amount administered in each dose and by omitting one of the

weekly doses. Similar downward dose adjustments should be made if the Hb level exceeds 120 g/L.

Maximum dose should generally not exceed 200 IU/kg three times per week.

When a target haemoglobin concentration of 100-120 g/L (95 to 110 g/L in paediatric patients) has been

achieved, the total maintenance weekly dose (average 100-300 IU/kg) can be apportioned in two or

three injections. Caution should be exercised with escalation of epoetin alfa doses in patients with

chronic renal failure.

In patients with chronic renal failure, maintenance haemoglobin concentration should not exceed the

upper limit of the haemoglobin concentration range.

Available data indicate that patients starting treatment at very low Hb levels (< 60g/L) may require

higher maintenance dosages than those starting therapy with Hb above 80 g/L; the latter group of

patients may need weekly doses as low as 100 IU/kg.

Children

For paediatric haemodialysis patients:

The treatment is divided into 2 stages:

Correction phase

50 IU/kg/3 times per week by the intravenous or subcutaneous route. When a dose adjustment is

necessary, this should be done in steps of 25 IU/kg/3 times per week at intervals of at least 4 weeks

until the desired goal is achieved.

Maintenance phase

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Appropriate adjustment of the dose should be made in order to maintain the haemoglobin concentration

within the desired range between 5.9 to 6.8 mmol/L. Generally, children under 30 kg require higher

maintenance doses than children over 30 kg and adults. For example, the following maintenance doses

were observed in clinical trials after 6 months of treatment.

Weight (kg)

Median

Dose (IU/kg given 3 x /week)

Usual maintenance dose

< 10

75 – 150

10-30

60 – 150

> 30

30 – 100

The clinical data available suggest that those patients whose initial haemoglobin is very low (<6.8 g/dL)

may require higher maintenance doses than those whose initial anaemia is less severe (>6.8 g/dL).

For treatment of anaemia associated with non-myeloid malignancies

Adults

The haemoglobin concentration range should be between 100 to 120 g/L in men and women, and it

should not be exceeded.

Starting dose

The recommended starting dose of Binocrit is 150 lU/kg as a subcutaneous injection three times per

week for 4 weeks.

Increase dose

If the haemoglobin has increased by at least 10 g/L (0.62 mmol/L) or the reticulocyte count has

increased ≥ 40,000 cells/microlitre above baseline after 4 weeks of treatment, the dose should remain

at 150 IU/kg. If the haemoglobin increase is < 10 g/L (< 0.62 mmol/L) and the reticulocyte count has

increased < 40,000 cells/microlitre above baseline, increase the dose to 300 IU/kg.

If after an additional 4 weeks of therapy at 300 IU/kg, the haemoglobin has increased ≥ 10 g/L (≥ 0.62

mmol/L) or the reticulocyte count has increased ≥ 40,000 cells/microlitre the dose should remain at 300

IU/kg. However, if the haemoglobin has increased < 10 g/L (< 0.62 mmol/L) and the reticulocyte count

has increased < 40,000 cells/microlitre above baseline, response is unlikely and treatment should be

discontinued.

A rate of rise in haemoglobin of greater than 10 g/L per 2 week or 20 g/L per month, or haemoglobin

levels of > 120 g/L should be avoided. If the haemoglobin is rising by more than 10 g/L per two week

or 20 g/L per month, or haemoglobin is approaching 120 g/L, reduce the epoetin alfa (rch) dose by

about 25-50% depending on the rate of rise of haemoglobin. If the haemoglobin exceeds 120g/L,

withhold therapy until it falls below 120 g/L and then reinitiate epoetin alfa (rch) at a dose 25% below

the previous dose.

Patients should be monitored closely to ensure that the lowest approved dose of epoetin alpha (rch) is

used to provide adequate control of the symptoms of anaemia.

Adult patients scheduled for elective surgery

The subcutaneous route of administration should be used.

The recommended dose regimen is 600 IU/kg Binocrit given weekly for three weeks (Days -21, -14,

and -7) prior to surgery and on the day of surgery. In cases where there is a medical need to shorten the

lead time before surgery to less than three weeks, 300 IU/kg Binocrit should be given daily for 10

consecutive days prior to surgery, on the day of surgery, and for four days immediately thereafter. The

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administration of Binocrit should be stopped as soon as the haemoglobin level reaches 150 g/L in the

pre-operative period, even if not all the planned Binocrit doses have been given.

Anaemic adult surgery patients in an Autologous Pre-donation Programme (ABD)

The intravenous route should be used. The recommended dose is 300 - 600 IU/kg twice weekly for

three weeks, together with at least 200 mg oral elemental iron daily.

4.3

Contraindications

Binocrit is contraindicated in patients with uncontrolled hypertension, known sensitivity to

mammalian cell derived products, and/or hypersensitivity to any component of the product.

Patients who develop Pure Red Cell Aplasia (PRCA) following treatment with any erythropoietin

product should not receive Binocrit or any other erythropoietin.

The use of Binocrit in patients scheduled for elective surgery (and who are not participating in an

autologous blood pre deposit programme), is contraindicated in patients with severe coronary,

peripheral arterial, carotid, or cerebral vascular disease, including patients with recent myocardial

infarction or cerebral vascular accident.

Surgery patients who for any reason cannot receive adequate antithrombotic prophylaxis or

treatment.

All contraindications associated with autologous blood predonation programs should be respected

in patients being supplemented with Binocrit

4.4

Special warnings and precautions for use

Cardiovascular and Thrombotic Events / Increased Mortality

Cardiovascular and thrombotic events such as myocardial ischaemia and infarction, cerebrovascular

haemorrhage and infarction, transient ischaemic attacks, deep venous thrombosis, arterial thrombosis,

pulmonary emboli, retinal thrombosis and haemodialysis graft occlusion have been reported in patients

receiving erythropoiesis stimulating agents such as epoetin alfa.

An increased incidence of thrombotic vascular events (TVEs) has been observed in patients receiving

Erythropoiesis-stimulating agents ESAs (see section 4.8). These include venous and arterial thromboses

and embolism (including some with fatal outcomes), such as deep venous thrombosis, pulmonary

emboli,

retinal

thrombosis

myocardial

infarction.

Additionally,

cerebrovascular

accidents

(including cerebral infarction, cerebral haemorrhage and transient ischaemic attacks) have been

reported.

The reported risk of TVEs should be carefully weighed against the benefits to be derived from treatment

with epoetin alfa particularly in patients with pre-existing risk factors.

Epoetin alfa (rch) and other erythropoiesis-stimulating agents increased the risk for death and for serious

cardiovascular events in controlled clinical trials when administered to target a haemoglobin of greater

than 120 g/L. There was an increased risk of serious arterial and venous thromboembolic events,

including myocardial infarction, stroke, congestive heart failure and haemodialysis graft occlusion. A

rate of haemoglobin rise of greater than 10 g/L over 2 weeks may also contribute to these risks.

In all patients, haemoglobin concentrations should be closely monitored due to a potential increased

risk

thromboembolic

events

fatal

outcomes

when

patients

treated

haemoglobin

concentrations above the range for the indication of use.

Growth Factor Potential / Increased Tumour Progression

Epoetin alfa is a growth factor that primarily stimulates red blood cell production. Like all growth

factors there is a theoretical concern that epoetin alfa could act as a growth factor for any tumour type,

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particularly myeloid malignancies. Erythropoiesis-stimulating agents (ESAs), when administered to

target a haemoglobin of greater than 120 g/L, shortened the time to tumour progression in patients with

advanced head and neck cancer receiving radiation therapy. ESAs also shortened survival in patients

with metastatic breast cancer receiving chemotherapy when administered to a target haemoglobin

greater than 120 g/L.

Use in Cancer Patients

Cancer patients on epoetin alfa (rch) should have haemoglobin levels measured on a regular basis until

a stable level is achieved and periodically thereafter.

ESAs are growth factors that primarily stimulate red blood cell production. Erythropoietin receptors

may be expressed on the surface of a variety of tumour cells. As with all growth factors, there is a

concern that ESAs could stimulate the growth of tumours.

In controlled clinical studies, use of epoetin alfa (rch) and other ESAs have shown:

decreased locoregional control in patients with advanced head and neck cancer receiving radiation

therapy when administered to a haemoglobin target of greater than 140 g/L

shortened overall survival and increased deaths attributed to disease progression at 4 months in

patients with metastatic breast cancer receiving chemotherapy when administered to a haemoglobin

target of 120-140 g/L

Another ESA (darbepoetin alfa) increased risk of death when administered to target a haemoglobin

of 120 g/L in patients with active malignant disease receiving neither chemotherapy nor radiation

therapy. ESAs are not indicated for use in this patient population.

In view of the above, the decision to administer recombinant erythropoietin treatment should be based

on a benefit-risk assessment with the participation of the individual patient, which should take into

account the specific clinical context. Factors to consider in this assessment include: the type of tumour

and its stage; the degree of anaemia; life-expectancy; the environment in which the patient is being

treated; and patient preference.

Use in Chronic Renal Failure Patients

Chronic renal failure patients being treated with epoetin alfa (rch) should have haemoglobin levels

measured on a regular basis until a stable level is achieved, and periodically thereafter.

In chronic renal failure patients, the rate of increase in haemoglobin should be approximately 10 g/L

per month and should not exceed 20 g/L per month to minimise risks of an increase in hypertension.

Dose should be reduced when haemoglobin approaches 120 g/L.

In patients with chronic renal failure, maintenance haemoglobin concentration should not exceed the

upper limit of the target haemoglobin concentration range as recommended under Dosage and

Administration. Haemoglobin levels targeted to 130 g/L or higher may be associated with a higher risk

of cardiovascular events or cerebrovascular events, including stroke and death.

Patients with chronic renal failure and insufficient haemoglobin response to ESA therapy may be at

even greater risk for cardiovascular events and mortality than other patients.

Shunt thromboses have occurred in haemodialysis patients, especially in those who have a tendency to

hypotension or whose arteriovenous fistulae exhibit complications (e.g. stenoses, aneurysms, etc.).

Early shunt revision and thrombosis prophylaxis by administration of acetylsalicylic acid (aspirin), for

example, is recommended in these patients.

Hyperkalaemia has been observed in isolated cases, though causality has not been established. Serum

electrolytes should be monitored in chronic renal failure patients. If an elevated or rising serum

potassium level is detected, then in addition to the appropriate treatment of the hyperkalaemia,

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consideration should be given to ceasing epoetin alfa (rch) administration until the serum potassium

level has been corrected.

As a result of an increase in packed cell volume, haemodialysis patients receiving epoetin alfa (rch)

frequently require an increase in heparin dose during dialysis. If heparinisation is not optimal, occlusion

of the dialysis system is possible.

In some female chronic renal failure patients, menses have resumed following epoetin alfa (rch) therapy;

the possibility of potential pregnancy should be discussed and the need for contraception evaluated.

Hypertension

Patients with uncontrolled hypertension should not be treated with epoetin alfa (rch); blood pressure

should be controlled adequately before initiation of therapy. Blood pressure may rise during treatment

of anaemia with epoetin alfa (rch). Hypertensive crisis with encephalopathy and seizures, requiring the

immediate attention of a physician and intensive medical care, have also occurred during epoetin alfa

(rch) treatment in patients with previously normal or low blood pressure. Particular attention should be

paid to sudden stabbing migraine-like headaches as a possible warning signal (see section 4.8).

Special care should be taken to closely monitor and control blood pressure in patients treated with

epoetin alfa (rch). During epoetin alfa (rch) therapy, patients should be advised of the importance of

compliance with antihypertensive therapy and dietary restrictions. If blood pressure is difficult to

control after initiation of appropriate measures, the dose of epoetin alfa (rch) should be reduced or

temporarily withheld until haemoglobin begins to decrease (see section 4.2).

Pure Red Cell Aplasia

In chronic renal failure patients, antibody-mediated pure red cell aplasia (PRCA) (erythroblastopaenia)

has been rarely reported after months to years of treatment with erythropoietins. Most cases of PRCA

associated with epoetin alfa (rch) occurred in patients receiving subcutaneous (SC) administration. The

SC route should only be used when intravenous (IV) access is not readily available. Cases also have

been rarely reported in patients with hepatitis C treated with interferon and ribavirin, when ESAs are

used concomitantly. ESAs are not approved in the management of anaemia associated with hepatitis C.

In most of these PRCA patients, antibodies to erythropoietins have been reported. In patients developing

sudden lack of efficacy typical causes of non-response should be investigated. If no cause is identified,

a bone marrow examination should be considered.

If pure red cell aplasia (PRCA) is diagnosed, epoetin alfa (rch) must be immediately discontinued and

testing for erythropoietin antibodies should be considered. If antibodies to erythropoietin are detected,

patients should not be switched to another ESA product as anti-erythropoietin antibodies cross-react

with other ESAs. Other causes of pure red cell aplasia should be excluded, and appropriate therapy

instituted.

Seizures

Epoetin alfa (rch) should be used with caution in patients with epilepsy, history of seizures, or medical

conditions associated with a predisposition to seizure activity such as CNS infections and brain

metastases.

lron Supplementation

Other causes of anaemia (iron, folate or Vitamin B12 deficiency, aluminium intoxication, infection or

inflammation, blood loss, haemolysis and bone marrow fibrosis of any origin) should be evaluated and

treated prior to initiating therapy with epoetin alfa (rch), and when deciding to increase the dose. In

most cases, the ferritin values in the serum fall simultaneously with the rise in packed cell volume. In

order to ensure optimum response to epoetin alfa (rch), adequate iron stores should be assured and iron

supplementation should be administered if necessary:

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For chronic renal failure patients, iron supplementation (elemental iron 200-300 mg/day orally for

adults and 100-200 mg/day orally for paediatrics) is recommended if serum ferritin levels are below

100 ng/mL.

For cancer patients, iron supplementation (elemental iron 200-300 mg/day orally) is recommended

if transferrin saturation is below 20%.

For patients in an autologous predonation programme, iron supplementation (elemental iron 200

mg/day orally) should be administered several weeks prior to initiating the autologous predeposit

in order to achieve high iron stores prior to starting epoetin alfa therapy, and throughout the course

of epoetin alfa (rch) therapy.

For patients scheduled for major elective orthopaedic surgery, iron supplementation (elemental iron

200 mg/day orally) should be administered throughout the course of epoetin alfa (rch) therapy. If

possible, iron supplementation should be initiated prior to starting epoetin alfa (rch) therapy to

achieve adequate iron stores.

General

Epoetin alfa (rch) should be used with caution in those patients with pre-existing hypertension,

ischaemic vascular disease, epilepsy, history of seizures, or medical conditions associated with a

predisposition to seizure activity such as CNS infections and brain metastases.

The safety and effectiveness of epoetin alfa has not been established in patients with underlying

haematologic diseases (e.g. haemolytic anaemia, sickle cell disease, thalassemia, porphyria).

Erythropoiesis-stimulating agents (ESAs) are not necessarily equivalent. Therefore, it should be

emphasised that patients should only be switched from one ESA (such as epoetin alfa) to another ESA

with the authorisation of the treating physician.

There may be a moderate dose-dependent rise in the platelet count, within the normal range, during

treatment with epoetin alfa (rch). This regresses during the course of continued therapy. In addition,

thrombocythaemia above the normal range has been reported. It is recommended that the platelet count

should be regularly monitored during the first 8 weeks of therapy.

Very rarely, exacerbation of porphyria has been observed in epoetin alfa (rch) treated patients with

chronic renal failure. Epoetin alfa (rch) has not caused increased urinary excretion of porphyrin

metabolites in normal volunteers, even in the presence of a rapid erythropoietic response.

Nevertheless, epoetin alfa (rch) should be used with caution in patients with known porphyria.

Increased serum uric acid may occur in patients whose haemoglobin is rising more than approximately

20 g/L per month. Consequently epoetin alfa (rch) should be used with caution in patients with a history

of gout.

Epoetin alfa (rch) should also be used with caution in patients with chronic liver failure. The safety and

dosage regime of epoetin alfa (rch) has not been established in the presence of hepatic dysfunction. Due

to decreased metabolism, patients with hepatic dysfunction may have increased erythropoiesis with

epoetin alfa (rch).

Blistering

skin

exfoliation

reactions

including

erythema

multiforme

Stevens-Johnson

Syndrome (SJS)/toxic epidermal necrolysis (TEN), have been reported in a small number of patients

treated with epoetin alpha (rch). Discontinue epoetin alpha (rch) therapy immediately if a severe

cutaneous reaction, such as SJS/TEN, is suspected.

Renal dialysis

Correction of anaemia with epoetin alfa (rch) does not appear to affect dialysis efficiency. However, an

increase in appetite could lead to increased potassium intake and hyperkalaemia in both dialysis and

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pre-dialysis patients. This and other alterations in serum chemistry should be managed by dietary

alterations and modifications of the dialysis prescription, if appropriate.

Serum electrolytes should be monitored in chronic renal failure patients. If an elevated (or rising) serum

potassium level is detected then in addition to appropriate treatment of the hyperkalaemia consideration

should be given to ceasing epoetin alfa treatment until hyperkalaemia has been corrected.

In some pre-clinical toxicological studies in dogs and rats, but not in monkeys, epoetin alfa (rch) therapy

was associated with subclinical bone marrow fibrosis. Bone marrow fibrosis is a known complication

of chronic renal failure in humans and may be related to secondary hyperparathyroidism or unknown

factors. The incidence of bone marrow fibrosis was not increased in a study of dialysis patients who

were treated with epoetin alfa (rch) for 12-19 months compared with the incidence of bone marrow

fibrosis in a matched control group of dialysis patients who had not been treated with epoetin alfa (rch).

In a 13-week study, dogs were treated subcutaneously or intravenously with 80, 240 or 520 IU/kg/day.

The majority of dogs treated subcutaneously and 50% of dogs treated intravenously developed anaemia

with or without bone marrow hypoplasia. The cause of these observations is unknown, however, no

cases of paradoxical anaemia have been reported in haematologically normal humans treated with

epoetin alfa (rch), making the significance of the findings in dogs unclear.

As a result of an increase in packed cell volume, haemodialysis patients receiving Binocrit frequently

require an increase in heparin dose during dialysis. If heparinisation is not optimal, occlusion of the

dialysis system is possible.

In some female chronic renal failure patients, menses have resumed following epoetin alpha (rch)

therapy; the possibility of potential pregnancy should be discussed and the need for contraception

evaluated.

Use in Patients Scheduled for Elective Surgery

Potentially correctable anaemia should be investigated and appropriately treated before considering

therapy with epoetin alfa (rch) prior to elective surgery.

In patients with a baseline haemoglobin of > l30 g/L (8.1 mmol/L), the possibility that epoetin alfa (rch)

treatment may be associated with an increased risk of postoperative thrombotic vascular events cannot

be excluded. Therefore, it should not be used in patients with a baseline haemoglobin > l30 g/L (8.1

mmol/L).

Use in Surgery Patients in an Autologous Pre-Donation Programme (ABD)

All special precautions associated with autologous pre-donation programmes, especially routine volume

replacement, should be respected.

Good blood management practices should always be used in the perisurgical setting.

Paediatric Use

Efficacy:

Clinical trials of epoetin alfa in children supported the following effects - correction of

anaemia; reduction or elimination of transfusion-requirements; improvement of the bleeding tendency

in uraemia; increased weight and appetite; and the reduction of cytotoxic antibodies. Possible but not

conclusive effects were an improvement in exercise capacity and short-term cardiovascular effects.

Long-term cardiovascular effects, effects on growth rate, improved prospects for renal transplantation

and improved quality of life were unproved.

Safety:

Incomplete information is available, particularly on the rate of change of haemoglobin and

blood pressure.

Dose:

Available data supports a dose of 25 IU/kg/3 times a week rather than 50 IU/kg/3 times a week.

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4.5

Interaction with other medicines and other forms of interaction

There are no known clinically significant medicine interactions, but the effect of epoetin alfa (rch) may

be potentiated by the simultaneous therapeutic administration of a haematinic agent such as ferrous

sulphate when a deficiency state exists.

Drugs that decrease erythropoiesis may decrease the response to epoetin alfa (rch).

No evidence exists that indicates that treatment with epoetin alfa (rch) alters the metabolism of other

drugs. However, since cyclosporin is bound by RBC’s there is potential for a drug interaction. If epoetin

alfa (rch) is given concomitantly with cyclosporin, blood levels of cyclosporin should be monitored and

the dose of cyclosporin adjusted as the haematocrit rises.

No evidence exists that indicates an interaction between epoetin alfa (rch) and G-CSF or GM-CSF with

regard to haematological differentiation or proliferation of tumour biopsy specimens

in vitro

In patients with metastatic breast cancer, subcutaneous co-administration of 40,000 IU/mL epoetin alfa

(rch) with trastuzumab (6 mg/kg) had no effect on the pharmacokinetics of trastuzumab.

4.6

Fertility, pregnancy and lactation

Pregnancy

The drug is classed as Category B3. Epoetin alfa (rch) should be administered during pregnancy only

if clearly needed and if the potential benefit justifies the potential risk to the foetus. It is not known

whether epoetin alfa (rch) crosses the placenta or whether it can cause foetal harm when administered

to a pregnant woman. Animal studies have shown no evidence of teratogenic activity in rats or rabbits

at epoetin alfa (rch) dosages up to 55 IU/kg/day administered intravenously. However, intravenous

administration of epoetin alfa (rch) at dose levels of 20-500 IU/kg/day in rats causes decreased fertility,

increased pre- and post-implantation loss, decreased foetal weight and retardation of ossification.

In pregnant or lactating surgical patients participating in an autologous blood predonation programme,

the use of epoetin alfa (rch) is not recommended.

Breastfeeding

Epoetin alfa (rch) should be administered during lactation only if clearly needed. It is not known

whether epoetin alfa (rch) is excreted in breast milk or whether it can cause harm to the infant when

administered to a lactating woman. Intravenous administration of the drug to lactating rats at 500

IU/kg/day causes retardation of growth and development of the offspring.

In lactating surgical patients participating in an autologous blood predonation programme, the use of

epoetin lambda (rch) is not recommended.

4.7

Effects on ability to drive and use machines

Due to the increased risk of hypertension during the initial phase of epoetin alfa (rch) treatment, patients

with chronic renal failure should use caution when performing potentially hazardous activities, such as

driving or operating machinery, until the optimal maintenance dose of epoetin alfa (rch) has been

established.

4.8

Undesirable effects

The most frequent adverse drug effects during treatment with epoetin alfa (rch) is a dose-dependent

increase in blood pressure or aggravation of existing hypertension. Monitoring of the blood pressure

should be performed, particularly at the start of therapy. The most frequently occurring adverse drug

effects observed in clinical trials of epoetin alfa are diarrhoea, nausea, vomiting, pyrexia and headache.

Influenza-like illness may occur especially at the start of treatment.

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An increased incidence of thrombotic vascular events (TVEs), has been observed in patients receiving

ESAs (See section 4.4).

Hypersensitivity reactions, including cases of rash (including urticaria, anaphylactic reaction and angio-

oedema have been reported).

Hypertensive crisis with encephalopathy and seizures, requiring the immediate attention of a physician

and intensive medical care, have occurred also during epoetin alfa treatment in patients with previously

normal or low blood pressure. Particular attention should be paid to sudden stabbing migraine-like

headaches as a possible warning signal.

Clinical Trial Experience

Of a total 3559 subjects in 27 randomised, double-blinded, placebo or standard of care controlled

studies, the overall safety profile of epoetin alfa (rch) was evaluated in 2136 anaemic subjects. Included

were 228 epoetin alfa-treated CRF subjects in 4 chronic renal failure studies (2 studies in predialysis

[N=131 exposed CRF subjects not yet on dialysis] and 2 in dialysis [N=97 exposed CRF subjects on

dialysis]; 1404 exposed cancer subjects in 16 studies of anaemia due to chemotherapy; 144 exposed

subjects in 4 HIV-infection studies; 147 exposed subjects in 2 studies for autologous blood donation;

and 213 exposed subjects in 1 study in the perisurgical setting. Adverse drug effects reported by ≥ 1%

of subjects treated with epoetin alfa (rch) in these trials are shown in Tables 2-3.

Table 2: Summary of Adverse Drug Effects Reported by ≥ 1% of Subjects in Clinical Registration Trials

with epoetin alfa (rch): Chronic Renal Failure

System/Organ Class

Adverse Drug Effect

Chronic Renal Failure

Predialysis

Dialysis

N=131

n (%)

Placebo

N=79

n (%)

N=97

n (%)

Placebo

N=46

n (%)

Gastrointestinal disorders

Nausea

14 (11)

10 (13)

23 (24)

13(28)

Diarrhoea

16 (12)

8 (10)

7 (7)

4 (9)

Vomiting

12 (9)

6 (8)

9 (9)

8 (17)

General disorders and administration site conditions

Chills

6 (5)

2 (3)

10 (10)

3 (7)

Influenza like illness

1 (1)

9 (9)

6 (13)

Injection site reaction

14 (11)

16 (20)

1 (1)

Pyrexia

4 (3)

4 (5)

9 (9)

6 (13)

Peripheral oedema

9 (7)

10 (3)

Metabolism and nutrition disorders

Hyperkalaemia

3 (2)

3 (4)

10 (10)

2 (4)

Musculoskeletal and connective tissue disorders

Arthralgia

16 (12)

6 (8)

23 (24)

3 (7)

Bone pain

1 (1)

6 (6)

1 (2)

Myalgia

3 (2)

1 (1)

6 (6)

Pain in extremity

7 (5)

7 (9)

15 (15)

2 (4)

Nervous system disorders

Convulsion

1 (1)

2 (3)

2 (2)

Headache

22 (17)

14 (18)

33 (34)

20 (43)

Respiratory, thoracic and mediastinal disorders

Cough

5 (4)

1 (1)

9 (9)

8 (17)

Respiratory tract congestion

9 (9)

2 (4)

Skin and subcutaneous tissue disorders

Rash

8 (6)

6 (8)

11 (11)

2 (4)

Vascular disorders

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System/Organ Class

Adverse Drug Effect

Chronic Renal Failure

Predialysis

Dialysis

N=131

n (%)

Placebo

N=79

n (%)

N=97

n (%)

Placebo

N=46

n (%)

Embolism and thrombosis

2 (2)

15 (15)

2 (4)

Deep vein thrombosis

Thrombosis

4 (4)

1 (2)

Hypertension

35 (27)

20 (25)

32 (33)

5 (11)

EPO = epoetin alfa (rch)

NR = not reported

Rash includes urticaria and angioedema

Includes arterial and venous, fatal and non fatal events such as deep venous thrombosis, pulmonary

emboli, retinal thrombosis, arterial thrombosis (including myocardial infarction), cerebrovascular

accidents (i.e. stroke, including cerebral infarction and cerebral haemorrhage), transient ischaemic

attacks and shunt thrombosis (including dialysis equipment) and thrombosis within arteriovenous shunt

aneurisms

Hypertension includes hypertensive crisis and hypertensive

Table 3: Summary of Adverse Drug Effects Reported by ≥ 1% of Subjects in Clinical Registration Trials

with epoetin alfa (rch): Oncology, HIV, Autologous blood donation, Surgery

System/Organ Class

Adverse Drug Effect

Oncology

HIV

Autologous blood

donation

Surgery

N=1404

n (%)

Non-

N=930

n (%)

N=144

n (%)

Placebo

N=153

n (%)

N=147

n (%)

Non-

N=112

n (%)

N=213

n (%)

Placebo

N=103

n (%)

Gastrointestinal disorders

Nausea

265(19)

193(21)

36(25)

39(25)

26(18)

11(10)

96(45)

46(45)

Diarrhoea

168(12)

102(11)

43(30)

51(33)

5(3)

7(6)

18(8)

12(12)

Vomiting

173(12)

134(14)

21(15)

24(16)

7(5)

1(1)

36(17)

14(14)

General disorders and administration site conditions

Chills

33(2)

32(3)

5(3)

14(9)

8(5)

4(4)

12(6)

1(1)

Influenza like illness

23(2)

10(1)

3(2)

1(1)

4(3)

1(1)

1(<1)

Injection site reaction

42(3)

31(3)

14(10)

13(9)

1(1)

39(18)

19(18)

Pyrexia

189(13)

130(14)

61(42)

52(34)

7(5)

3(3)

37(17)

27(26)

Peripheral oedema

72(5)

34(4)

7(5)

5(3)

2(1)

2(2)

14(7)

4(4)

Metabolism and nutrition disorders

Hyperkalaemia

2(<1)

2(<1)

1(1)

Musculoskeletal and connective tissue disorders

Arthralgia

45(3)

43(5)

5(3)

11(7)

3(2)

3(3)

5(2)

3(3)

Bone pain

47(3)

26(3)

3(2)

1(1)

1(<1)

Myalgia

46(3)

25(3)

8(6)

9(6)

2(1)

3(3)

2(1)

Pain in extremity

37(3)

19(2)

10(7)

13(8)

6(4)

2(2)

7(3)

4(4)

Nervous system disorders

Convulsion

12(1)

4(<1)

2(1)

2(1)

Headache

98(7)

50(5)

28(19)

32(21)

17(12)

16(14)

25(12)

9(9)

Respiratory, thoracic and mediastinal disorders

Cough

98(7)

66(7)

37(26)

22(14)

2(1)

2(2)

10(5)

Respiratory tract

congestion

1(1)

Skin and subcutaneous tissue disorders

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System/Organ Class

Adverse Drug Effect

Oncology

HIV

Autologous blood

donation

Surgery

N=1404

n (%)

Non-

N=930

n (%)

N=144

n (%)

Placebo

N=153

n (%)

N=147

n (%)

Non-

N=112

n (%)

N=213

n (%)

Placebo

N=103

n (%)

Rash

93(7)

47(5)

36(25)

19(12)

3(2)

2(2)

8(4)

2(2)

Vascular disorders

Embolism and

thrombosis

76(5)

33(4)

7(5)

1(1)

6(4)

3(3)

18(8)

6(6)

Deep vein thrombosis

24(2)

6(1)

2(1)

2(2)

10(5)

3(3)

Thrombosis

18(1)

6(1)

2(1)

3(1)

Hypertension

43(3)

24(3)

3(2)

4(3)

2(2)

23(11)

9(9)

EPO = epoetin alfa (rch)

Non-ESA = non-erythropoiesis-stimulating agent

NR = not reported

Rash includes urticaria and angioedema

Includes arterial and venous, fatal and non fatal events such as deep venous thrombosis, pulmonary

emboli, retinal thrombosis, arterial thrombosis (including myocardial infarction), cerebrovascular

accidents (i.e. stroke, including cerebral infarction and cerebral haemorrhage), transient ischaemic

attacks and shunt thrombosis (including dialysis equipment) and thrombosis within arteriovenous shunt

aneurisms

Hypertension includes hypertensive crisis and hypertensive

Post-marketing Experience

Adverse drug effects identified during the post-marketing experience with epoetin alfa (rch) are

included in Table 4. In the table, the frequencies are provided according to the following convention:

Very common

≥ 1/10

Common

≥ 1/100 and < 1/10

Uncommon

≥ 1/1,000 and < 1/100

Rare

≥ 1/10,000 and < 1/1,000

Very rare

< 1/10,000, including isolated reports

Antibody-mediated pure red cell aplasia has been very rarely reported (<1/10,000 cases per patient-

year) after months to years of treatment with epoetin alfa.

Table 4: Adverse Drug Effects Identified During Post-marketing Experience with epoetin alfa (rch) by

Frequency Category Estimated from Spontaneous Reporting Rates

System/Organ Class

Frequency

Adverse Drug Effect

Nervous system disorders

Common

Stroke

Cardiac disorders

Frequency not known

Mycocardial infarction

Blood and Lymphatic System Disorders

Very rare

Erythropoietin Antibody-Mediated Pure Red Cell Aplasia

Thrombocythaemia

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4.9

Overdose

Contact the Poisons Information Centre on (telephone Australia 13 11 26 or New Zealand 0800

POISON or 0800 764766) for advice on management of overdose.

Response to epoetin alfa (rch) is dose-related and individualised. In case of excessive erythropoietic

response from an overdose of epoetin alfa (rch), dosing should be stopped and phlebotomy can be

considered. Supportive care should be provided for hypertensive or convulsive events that may be

related to overdosing with epoetin alfa (rch).

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: antianaemic, ATC code: B03XA01.

Erythropoietin (EPO) is a glycoprotein hormone produced primarily by the kidney in response to

hypoxia and is the key regulator of red blood cell (RBC) production. EPO is involved in all phases of

erythroid development, and has its principal effect at the level of erythroid precursors. After EPO binds

to its cell surface receptor, it activates signal transduction pathways that interfere with apoptosis and

stimulates erythroid cell proliferation.

Recombinant human EPO (Epoetin alfa), produced by genetically engineered Chinese hamster ovary

cells (rch), has a 165 amino acid sequence identical to that of human urinary EPO; the two are

indistinguishable on the basis of functional assays.

The primary pharmacodynamics of Binocrit were assessed

in vitro

using an ELISA, by surface plasmon

resonance spectroscopy and by use of a cell-based assay assessing the response to an erythropoietic

stimulus. Comparable responses of Binocrit and the reference product epoetin alfa (rch) were obtained.

The biological efficacy of Binocrit has been demonstrated

in vivo

using a normocythaemic mouse assay.

After administration of Binocrit, the reticulocyte counts increased similar to the reference product

epoetin alfa.

A 5-day

in vivo

pharmacodynamic-pharmacokinetic study in Beagle dogs was performed which used

reticulocyte pharmacodynamics as biomarker. After three to four days of Binocrit injection a clear rise

in reticulocytes was observed, which was reversible upon cessation of treatment. There was no

remarkable difference between Binocrit and the reference product epoetin alfa (rch).

Phase I studies investigating haematological pharmacodynamic parameters following intravenous and

subcutaneous single and repeated dosing have demonstrated comparable pharmacodynamics of Binocrit

to the reference product epoetin alfa (rch) preparation.

Table 5: Study results from an open, randomized, pivotal IV Phase I study

AUEC

Test medicine

(Binocrit)- Epoetin alfa

(N=37)

Reference medicine -

Epoetin alfa

(N=39)

Ratio [%] and 90% CI*

Haemoglobin [g*h/dL]

10056 ± 354

10071 ± 365

99.9 [98.5 – 101.2]

Red blood cells [h/pL]

3322 ± 181

3303 ± 175

100.6 [98.5 – 102.7]

Haematocrit [h]

288 ± 12

289 ± 10

99.6 [98.2 – 101.0]

Reticulocytes [%*h]

1740 ± 186

1788 ± 253

96.8 [92.4 – 101.9]

* based on a parametric approach (ANOVA) for all parameters except for reticulocytes

Table 6: Study results from an open, randomized, pivotal SC Phase I study

AUEC

Test medicine

(Binocrit) -Epoetin alfa

(N=37)

Reference medicine -

Epoetin alfa

(N=37)

Ratio [%] and 90% CI*

Haemoglobin [g*h/dL]

10248 ± 494

10469 ± 495

98.9 [97.7 – 100.2]

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Red blood cells [h/pL]

3378 ± 184

3511 ± 207

98.7 [97.5 – 99.8]

Haematocrit [h]

300 ± 14

308 ± 13

98.7 [97.3 – 100.0]

Reticulocytes [%*h]

1525 ± 267

1660 ± 274

93.4 [88.3 – 98.8]

* based on a parametric approach (baseline-adjusted ANCOVA)

A randomised, double-blind, multi-centre phase III study (study number 2003-29-INJ-9) was conducted

to evaluate therapeutic equivalence in terms of haemoglobin response of Binocrit versus the reference

product epoetin alfa (rch) in the long-term intravenous treatment of anaemia in haemodialysis patients

after a 1:1 dose conversion from reference product epoetin alfa (rch) to Binocrit. The study included

478 haemodialysis patients with CRF that were treated with the reference product at time of inclusion

to the study.

In the first part (double-blind) of the study patients were randomly assigned to continue treatment with

their original therapy (N=164) or to switch to Binocrit (N=314).

In the evaluation phase (weeks 25-28) patients treated with Binocrit showed a comparable Hb-level

after treatment with Binocrit to their Hb-level at start of the treatment. No relevant differences regarding

dosing could be observed. Binocrit has shown to be therapeutically equivalent to reference product

epoetin alfa (rch) with respect to Hb response in haemodialysis patients after a 1:1 switch.

In the second (open) part of the study patients of the reference group were changed to Binocrit and

treated for another 28 weeks. The switch to Binocrit did not demonstrate any safety relevant changes.

The long-term safety profiles of Binocrit and reference medicine epoetin alfa (rch) were comparable.

No formation of anti-epoetin antibodies was detected. The safety and efficacy of subcutaneous

administration of Binocrit in patients with chronic renal failure has not been studied.

A randomised, double-blind,

multi-centre

phase

III study

(study

number 2003-31-INJ-11) was

conducted to assess the efficacy and safety of Binocrit in the treatment of chemotherapy-induced,

symptomatic anaemia in patients with solid tumours.

114 patients were treated with Binocrit or reference medicine epoetin alfa (rch) three times a week

subcutaneously for 12 weeks. Doses were raised in case of insufficient increase of Hb respectively

reticulocytes after 4 or 8 weeks.

In 62% of patients under Binocrit treatment the Hb level increased by ≥ 20g/L with the confidence

interval being entirely above the predefined threshold of 30%. In the Binocrit group, 32% of patients

required transfusions versus 38% in the reference medicine epoetin alfa (rch) group. None of the

secondary efficacy endpoints showed relevant differences between the treatment groups and also the

safety profiles were similar.

Binocrit was shown to be efficacious in the treatment of chemotherapy-associated anaemia in solid

tumour patients with a safety profile not differing from what is expected in this therapeutic area.

Binocrit has not been studied in patients scheduled for elective surgery, either to treat moderate anaemia

or to augment autologous blood collection (see INDICATIONS). However, comparable efficacy and

safety can be expected in these patients since comparable efficacy and safety to reference medicine

epoetin alfa (rch) has been demonstrated in the anaemia of chronic renal failure (IV administration) and

chemotherapy-induced anaemia settings.

5.2

Pharmacokinetic properties

Erythropoietin stimulates erythropoiesis in anaemic patients with chronic renal failure in whom the

endogenous production of erythropoietin is impaired. Because of the length of time required for

erythropoiesis - several days for erythroid progenitors to mature and be released into the circulation - a

New Zealand Data sheet

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clinically significant increase in haemoglobin is usually not observed in less than two weeks and may

require up to ten weeks in some patients.

Measurement of epoetin alfa (rch) following intravenous administration showed 10% excretion by the

kidneys with the major routes of elimination not determined. After intravenous administration, the mean

half lives in normal volunteers ranged from 4.0 to 6.1 hours and in patients with chronic renal failure

from 6.5 to 9.3 hours. Following subcutaneous injection, serum levels are much lower than the levels

achieved following IV injection; the levels increase slowly and reach a peak between 12 and 18 hours

post-dose.

The peak is always well below the peak achieved using the IV route (approximately 1/20th of the value).

Following subcutaneous injection, erythropoietin serum levels remain elevated above baseline for about

72 hours. There is no accumulation when thrice weekly dosing is used: the levels remain the same,

whether they are determined 24 hours after the first injection or 24 hours after the last injection. The

half-life is difficult to evaluate for the subcutaneous route and is estimated about 24 hours. The

bioavailability of subcutaneous injectable erythropoietin is much lower than that of the intravenous

drug: approximately 20-30%. No information is available in the young and in the elderly. Due to

decreased metabolism, patients with hepatic dysfunction may have increased erythropoiesis with

epoetin alfa (rch).

Erythropoiesis-stimulating

agents

(ESAs)

growth

factors

that

primarily

stimulate

cell

production. Erythropoietin receptors may be expressed on the surface of a variety of tumour cells.

Bioequivalence. Phase I studies investigating pharmacokinetic parameters following intravenous and

subcutaneous repeated dosing have demonstrated the bioequivalence of Binocrit to the reference

medicine epoetin alfa (rch) preparation.

Bioequivalence after multiple intravenous administration was demonstrated in an open, randomised,

parallel study in 80 healthy volunteers receiving 100IU/kg body weight 3 times per week for 4 weeks.

The pharmacokinetic parameters are summarised below.

Ratio

90% Confidence

interval

Mean±SD

[Test Medicine (Binocrit) -

Epoetin alpha (rch)]

Mean ± SD

[Reference Medicine- Epoetin

alfa (rch)]

Cmax

97.5%

91.1 – 104.5

2189mIU/mL ± 393.7

2262mIU/mL ± 422.0

89.2%

82.5 – 96.2

8422mIU/mL

h ± 2419

9224mIU/mL

h ± 1850

t1/2

87.8%

75.3 – 100.0

4.14h ± 1.71

4.74h ± 2.00

Bioequivalence after multiple subcutaneous administration was demonstrated in an open, randomised,

parallel study in 80 healthy volunteers receiving 100IU/kg body weight 3 times per week for 4 weeks.

The pharmacokinetic parameters are summarised below.

Ratio

90% Confidence

interval

Mean±SD

[Test Medicine (Binocrit) -

Epoetin alpha (rch)]

Mean ± SD

[Reference Medicine - Epoetin

alfa (rch)]

Cmax

97.6%

84.2 – 113.1

82.410mIU/mL ± 48.69

82.817mIU/mL ± 34.06

96.9%

88.2 – 106.5

2044.9mIU/mL

h± 587.9

2095.0mIU/mL

h ± 486.4

t1/2

97.9%

81.0 – 118.2

18.28h ± 8.50

18.16h ± 7.52

These results demonstrate that Binocrit is bioequivalent to the reference medicine epoetin alfa (rch)

preparation with respect to the pharmacokinetic parameters AUC and Cmax after multiple intravenous

and multiple subcutaneous application.

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5.3

Preclinical safety

Carcinogenesis, mutagenesis

Long-term carcinogenicity studies have not been carried out. There are conflicting reports in the

literature regarding whether erythropoietins may play a role as tumour proliferators.

These reports, based on

in vitro

findings from human tumour samples, are of uncertain significance in

the clinical situation. In a standard series of assays for genotoxic potential, epoetin alfa (rch) did not

induce gene mutations or cause chromosomal damage.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Binocrit contains the following inactive ingredients: sodium dihydrogen-phosphate dihydrate, disodium

hydrogen-phosphate dihydrate, sodium chloride, glycine, polysorbate 80, nitrogen and water for

injection. Hydrochloric acid and sodium hydroxide may be used for pH adjustment.

6.2

Incompatibilities

Not applicable

6.3

Shelf life

24 months

6.4

Special precautions for storage

Store at 2°C to 8°C. Do not freeze or shake. This temperature range should be closely maintained until

administration to the patient. Store in original package in order to protect from light.

When the product is about to be used, it may be removed from the refrigerator and stored at room

temperature (below 25ºC) for a maximum single period of three days.

The product should not be used, and discarded

if the seal is broken,

if the liquid is coloured or you can see particles floating in it,

if you know, or think that it may have been accidentally frozen, or

if there has been a refrigeration failure.

6.5

Nature and contents of container

1 pre-filled syringe per pack

6 pre-filled syringes per pack

1 pre-filled syringe per pack with a needle safety guard

6 pre-filled syringes per pack with a needle safety guard

Not all pack sizes may be marketed.

6.6

Special precautions for disposal

Any waste material should be disposed of in accordance with local requirements.

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7

MEDICINE SCHEDULE

Prescription Medicine

8

SPONSOR

Novartis New Zealand Limited

PO Box 99102

Newmarket

Auckland 1149

Telephone: 0800 354 335

9

DATE OF FIRST APPROVAL

19 April 2012

10

DATE OF REVISION OF THE TEXT

02 July 2018

11

SUMMARY TABLE OF CHANGES

Section

Summary of new information

Reformatted

4.4 & 4.6

Safety updates

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