Consumer medicine information

Eprex Prefilled Syringes

Epoetin alfa

BRAND INFORMATION

Brand name

Eprex

Active ingredient

Epoetin alfa

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Eprex Prefilled Syringes.

What is in this leaflet

This leaflet answers some common questions about EPREX prefilled syringes. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits.

Current and updated information about benefits and side effects of EPREX is contained in this leaflet.

Your doctor has weighed the risks of you using EPREX against the benefits this medicine is expected to have for you.

If you have any concerns about using EPREX ask your doctor or pharmacist.

It is important that you read this leaflet.

Keep this leaflet with your medicine.

What EPREX is used for

EPREX 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. EPREX is virtually identical to your body's erythropoietin, and has a similar effect to naturally occurring erythropoietin in your body.

EPREX is used to treat the 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 EPREX. This medicine stimulates your bone marrow to produce more red blood cells, helping to treat your anaemia.

EPREX can also be used to treat anaemia if you are receiving chemotherapy for cancer and your doctor decides that a blood transfusion is not appropriate.

Doctors can also prescribe EPREX for 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 EPREX stimulates the production of red blood cells, a higher volume of blood can be taken from these patients.

EPREX can be used as an alternative to a blood transfusion in adult patients about to undergo major orthopaedic (bone) surgery where there is a potentially high risk from blood transfusion complications.

EPREX is not addictive.

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

Before you use EPREX

When you must not use it

Do not use EPREX

  • If you have an allergy to EPREX or any of the ingredients. See Product Description at the end of this leaflet for a list of ingredients.
    Symptoms of an allergic or hypersensitivity reaction may include:
    - 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
  • If you have high blood pressure that is not properly controlled with blood pressure-lowering drugs.
  • If you are a surgery patient who should not be given medicines to thin the blood.
  • If you are due to have elective surgery and you have severe heart disease, disorders of the veins or arteries, or have recently had a heart attack or stroke.
  • If you 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 EPREX.
  • If you cannot have transfusions with your own blood during or after surgery.

Do not use EPREX if the packaging is torn or shows signs of tampering.

Do not use EPREX beyond the expiry date (month and year) printed on the pack.

Before you start to use it

You must tell your doctor if you have or have had:

  • 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 EPREX 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).

Also, tell your doctor if you are:

  • pregnant or planning to become pregnant
  • breastfeeding or wish to breastfeed.

In many women with severe kidney failure, their monthly periods may stop. In these women, erythropoietin may restart the monthly cycle. Before starting EPREX, 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 EPREX.

If you have used EPREX or another erythropoietin in the past, and you lost the good response you were having, tell your doctor about this.

If you have not told your doctor or pharmacist about any of the above, tell them before you start using or are given EPREX.

Your doctor will advise you whether or not to use EPREX or if you need to adjust the dose or adapt your treatment.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including medicines you can buy without a prescription from a pharmacy, supermarket or health food shop.

Iron is also a constituent of red blood cells. Therefore, iron supplements and other blood stimulating drugs may increase your response to EPREX treatment. Your doctor will decide whether you should take other medicines while using EPREX.

Using EPREX

How much to use:

  • Your doctor will determine the correct dose of EPREX. EPREX 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.
  • For patients with anaemia due to kidney failure, EPREX should be given intravenously, (into a vein or a tube that goes into a vein) if intravenous access is routinely available (haemodialysis patients). For patients not yet on dialysis and those on peritoneal dialysis EPREX can be administered subcutaneously. 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.
  • For 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.
  • For 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 EPREX 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 EPREX under the skin yourself

At the start of your therapy, EPREX may be injected by medical or nursing staff. However, your doctor may decide that it is right for you to learn how to inject EPREX 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 EPREX is injected under the skin (subcutaneously), the amount injected is not normally more than one millilitre (1 mL) in a single injection.

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

Only use EPREX if the solution is clear and colourless.

Do not shake EPREX prefilled syringes. Prolonged vigorous shaking may damage EPREX. If EPREX has been shaken vigorously, don't use it.

How to inject EPREX

The pre-filled syringes are fitted with the PROTECS™ needle guard device to help prevent needle stick injuries after use. This is indicated on the packaging.

  • Take a syringe out of the refrigerator.
    The liquid needs to come to room temperature. This usually takes between 15 to 30 minutes. Do not remove the syringe's needle cover while allowing it to reach room temperature.
  • 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.
  • Hold the pre-filled syringe by the body of the syringe with the covered needle pointing upward.
  • Do not hold by the plunger head, needle guard wings, or needle cover.
  • Do not pull back on the plunger at any time.
  • Do not remove the needle cover from the pre-filled syringe until you are ready to inject your EPREX.
  • 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.
  • 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 skinfold pinched. The PROTECS needle guard will not activate unless the entire dose is given. You may hear a click when the PROTECS needle guard has been activated.
  • When the plunger is pushed as far as it will go,
    take out the needle and let go of the skin.
  • Slowly take your thumb off the plunger.
    Allow the syringe to move up until the entire needle is covered by the needle guard.
  • When the needle is pulled out of your skin, there may be a little bleeding at the injection site.
    This is normal. You can 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 EPREX from each syringe. If any liquid remains in the syringe after an injection, the syringe should be properly disposed of, not reused. EPREX prefilled syringes do not contain 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 then continue to use it as you would normally.
  • Do not administer a double dose to make up for the dose you missed.

If you have missed more than one dose, or are not sure what to do, check with 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 for advice, or go to Accident and Emergency at your nearest hospital.

Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

Poisons Information Centre telephone numbers:

  • Australia: 13 11 26
  • New Zealand: 0800 POISON or 0800 764 766

Keep these telephone numbers handy.

While you are using EPREX

Things you must do

  • Always follow your doctor's instructions carefully.

If you are receiving dialysis treatment when you begin treatment with EPREX, your dialysis regimen may need to be adjusted. Your doctor will decide this.

You will need to have regular blood tests while you are using EPREX to see how you respond to treatment with EPREX. Your doctor will order regular blood tests to ensure that your medicine is continuing to work properly. If your haemoglobin levels are above 120 g/L, discuss reducing your EPREX dose with your doctor.

Your doctor will need to monitor your blood pressure regularly, especially at the beginning of treatment.

An increase in levels of small cells (called platelets) in your blood may occur, particularly when starting haemodialysis treatment.

  • Tell your doctor if you become pregnant while using EPREX.
  • If you experience a severe skin reaction, a rash, which may be severe, may cover your whole body and can also include blisters or areas of skin coming off, stop using EPREX and call your doctor or get medical help right away.
  • If you are about to start taking a new medicine, tell your doctor and pharmacist that you are using EPREX.
  • If you become increasingly tired, dizzy or breathless, you should talk to your doctor at once. Your doctor can decide whether EPREX is not working properly for you and will end the treatment if necessary.
  • If you are due to have major surgery, your doctor will give you a medicine to reduce the risk of abnormal blood clotting.
  • Remember to tell your doctor if you received EPREX 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: EPREX is one of a group of products that stimulate the production of red blood cells like the human protein erythropoietin does. 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 EPREX to treat any other complaint unless your doctor says so.
  • Do not give this medicine to anyone else, even if their symptoms seem similar to yours.

Side Effects

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some side effects. Do not be alarmed by this list of possible 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

  • Nausea, vomiting or diarrhoea
  • Cough or congested airways such as stuffy nose and sore throat
  • Flu-like symptoms such as dizziness, drowsiness, fever, chills, headache, muscle and joint pain and weakness.
  • Redness, burning and pain at the site EPREX is given.

Tell your doctor immediately if you notice any of the following, as you may need urgent medical care

  • Severe, sudden, stabbing migraine-like headaches.
  • Seizures, confusion or epileptic fits.
  • Raised blood pressure, which may require treatment with drugs or adjustment of the doses of drugs 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 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 EPREX. 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 EPREX. As the previous cases of PRCA occurred mainly with subcutaneous administration it is preferable that EPREX be administered intravenously whenever possible. Although PRCA is rare, you should be informed that if it develops, you would need to have regular blood transfusions to treat your anaemia, and EPREX would have to be stopped.

Other side effects not listed above may also occur in some people. Tell your doctor if you notice any other effects.

After using EPREX

Storage

Store EPREX between 2°C and 8°C in the refrigerator. Do not freeze and protect from light. Immediately prior to use, EPREX may be stored in a room that stays below 25°C, for a maximum single period of seven days. Keep your medicine out of reach of children.

Do not store EPREX, or any other medicine, in the bathroom or near a sink. Do not leave medicines in the car or on windowsills. Heat and dampness can destroy some medicines.

Disposal

If your doctor tells you to stop using EPREX, or your medicine has passed its expiry date, ask your pharmacist what to do with any medicine that may be left over.

Product Description

What it looks like

EPREX injection is a clear, colourless solution in prefilled syringes of 1000 IU in 0.5 mL, 2000 IU in 0.5 mL, 3000 IU in 0.3 mL, 4000 IU in 0.4 mL, 5000 IU in 0.5 mL, 6000 IU in 0.6 mL, 8000 IU in 0.8 mL, 10000 IU in 1.0 mL, 20,000 IU in 0.5 mL, 30,000 IU in 0.75 mL and 40,000 IU in 1.0 mL. Each box contains 6 prefilled syringes (1 syringe for 40,000 IU).

Australian Registration numbers:

Phosphate buffered syringes:

EPREX 1000 0.5 mL
AUST R 65442

EPREX 2000 0.5 mL
AUST R 65443

EPREX 3000 0.3 mL
AUST R 65444

EPREX 4000 0.4 mL
AUST R 65445

EPREX 5000 0.5 mL
AUST R 76970

EPREX 6000 0.6 mL
AUST R 76971

EPREX 8000 0.8 mL
AUST R 76973

EPREX 10000 1.0 mL
AUST R 65446

EPREX 20000 0.5 mL
AUST R 73486

EPREX 30000 0.75 mL
AUST R 135069

EPREX 40000 1.0 mL
AUST R 73487

Ingredients

EPREX is the tradename in Australia and New Zealand for Epoetin alfa (rch) (r-HuEPO).

EPREX injection in prefilled syringes is stabilised with glycine (5 mg/mL) and polysorbate 80 (0.3 mg/mL). All formulations also contain sodium chloride at 1.7 - 5.8 mg, monobasic sodium phosphate dihydrate at 0.35 - 1.16 mg, dibasic sodium phosphate dihydrate at 0.67 - 2.22 mg, sodium citrate at less than 5 mmol and water for injections.

The prefilled syringes are fitted with the PROTECS™ needle guard device to help prevent needle stick injuries after use.

EPREX does not contain lactose or gluten.

Sponsor

JANSSEN-CILAG Pty Ltd
1-5 Khartoum Road
Macquarie Park NSW 2113 Australia
Telephone: (02) 8875 3333

NZ Office: Auckland New Zealand

Telephone: 0800 800 806

This leaflet was prepared in November 2019.

Published by MIMS February 2020

BRAND INFORMATION

Brand name

Eprex

Active ingredient

Epoetin alfa

Schedule

S4

 

1 Name of Medicine

Epoetin alfa (rch).

6.7 Physicochemical Properties

Most common abbreviation: r-HuEPO.

CAS number.

113427-24-0.

2 Qualitative and Quantitative Composition

Eprex epoetin alfa (rch) 1,000 IU/0.5 mL injection syringe.
Eprex epoetin alfa (rch) 2,000 IU/0.5 mL injection syringe.
Eprex epoetin alfa (rch) 3,000 IU/0.3 mL injection syringe.
Eprex epoetin alfa (rch) 4,000 IU/0.4 mL injection syringe.
Eprex epoetin alfa (rch) 5,000 IU/0.5 mL injection syringe.
Eprex epoetin alfa (rch) 6,000 IU/0.6 mL injection syringe.
Eprex epoetin alfa (rch) 8,000 IU/0.8 mL injection syringe.
Eprex epoetin alfa (rch) 10,000 IU/1.0 mL injection syringe.
Eprex epoetin alfa (rch) 20,000 IU/0.5 mL injection syringe.
Eprex epoetin alfa (rch) 30,000 IU/0.75 mL injection syringe.
Eprex epoetin alfa (rch) 40,000 IU/1.0 mL injection syringe.
Epoetin alfa is recombinant human erythropoietin (EPO). It is expressed in Chinese hamster ovary cells (rch) and has a 165 amino acid sequence identical to that of human urinary EPO; the two are indistinguishable on the basis of functional assays. The apparent molecular weight of erythropoietin is about 30,400 daltons.
Eprex is a sterile preservative-free phosphate buffered protein solution of Epoetin alfa (rch) in pre-filled syringes of 1,000 IU in 0.5 mL, 2,000 IU in 0.5 mL, 3,000 IU in 0.3 mL, 4,000 IU in 0.4 mL, 5000 IU in 0.5 mL, 6000 IU in 0.6 mL, 8000 IU in 0.8 mL, 10,000 IU in 1.0 mL, 20,000 IU in 0.5 mL, 30,000 IU in 0.75 mL and 40,000 IU (336 micrograms) in 1 mL. The formulation is stabilised with glycine and polysorbate 80.
For a full list of excipients, see Section 6.1.

3 Pharmaceutical Form

Solution for injection in pre-filled syringe.
Clear, colourless solution.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Anti-anaemic, ATC code: B03XA01.

Mechanism of action.

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 erythoid cell proliferation.
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 clinically significant increase in haemoglobin is usually not observed in less than two weeks and may require up to ten weeks in some patients.
Erythropoiesis stimulating agents ESAs are growth factors that primarily stimulate red cell production. Erythropoietin receptors may be expressed on the surface of a variety of tumour cells (see Section 4.4, Use in cancer patients).

Clinical trials.

Eprex has been studied in a series of placebo controlled, double blind trials in a total of 131 anaemic cancer patients. Within this group, 72 patients were treated with concomitant noncisplatin containing chemotherapy regimens and 59 patients were treated with concomitant cisplatin containing chemotherapy regimens. Patients were randomised to Eprex 150 IU/kg or placebo subcutaneously (three times a week) for 12 weeks.
Eprex therapy was associated with a significantly (p < 0.008) greater haematocrit response than in the corresponding placebo treated patients (see Table 3).
In the two types of chemotherapy studies (utilising an Eprex dose of 150 IU/kg three times weekly) the mean number of units of blood transfused per patient after the first month of therapy was significantly (p < 0.02) lower in patients treated with Eprex (0.71 units in months 2, 3) than in corresponding placebo treated patients (1.84 units in months 2, 3). Moreover, the proportion of patients transfused during months 2 and 3 of therapy combined was significantly (p < 0.03) lower in the patients treated with Eprex than in the corresponding placebo treated patients (22% versus 43%).
Comparable intensity of chemotherapy in the Eprex and placebo groups in the chemotherapy trials was suggested by a similar area under the neutrophil time curve in patients treated with Eprex and placebo treated patients as well as by a similar proportion of patients in groups treated with Eprex and placebo treated groups whose absolute neutrophil counts fell below 1,000 cells/microlitre. Available evidence suggests that patients with lymphoid and solid cancers respond equivalently to Eprex therapy and that patients with or without tumour infiltration of the bone marrow respond equivalently to Eprex therapy.
A randomized, open label, multicenter study was conducted in 2098 anemic women with metastatic breast cancer, who received first line or second line chemotherapy. This was a noninferiority study designed to rule out a 15% risk increase in tumor progression or death of epoetin alfa plus standard of care (SOC) as compared with SOC alone. The median progression free survival (PFS) per investigator assessment of disease progression was 7.4 months in each arm (HR 1.09, 95% CI: 0.99, 1.20), indicating the study objective was not met. Median PFS with disease progression assessed by the Independent Review Committee was 7.6 months in each arm (HR 1.03, 95% CI: 0.92, 1.15). At clinical cutoff, 1337 deaths were reported. Median overall survival in the epoetin alfa plus SOC group was 17.2 months compared with 17.4 months in the SOC alone group (HR 1.06, 95% CI: 0.95, 1.18). Significantly fewer patients received RBC transfusions in the epoetin alfa plus SOC arm (5.8% versus 11.4%); however, significantly more patients had thrombotic vascular events in the epoetin alfa plus SOC arm (2.8% versus 1.4%). At the final analysis, 1653 deaths were reported. Median overall survival in the epoetin alfa plus SOC group was 17.8 months compared with 18.0 months in the SOC alone group (HR 1.07, 95% CI: 0.97, 1.18). The median time to progression (TTP) based on investigator-determined progressive disease (PD) was 7.5 months in the epoetin alfa plus SOC group and 7.5 months in the SOC group (HR 1.099, 95% CI: 0.998, 1.210). The median TTP based on IRC-determined PD was 8.0 months in the epoetin alfa plus SOC group and 8.3 months in the SOC group (HR 1.033, 95% CI: 0.924, 1.156).
Efficacy and safety of Eprex in the prevention and treatment of anaemia of cancer has not been demonstrated in children.
Epoetin alfa has been studied in a placebo controlled, double blind trial enrolling 316 patients scheduled for major, elective orthopaedic hip or knee surgery who were expected to require ≥ 2 units of blood. Patients were randomly assigned to receive 300 IU/kg epoetin alfa, 100 IU/kg epoetin alfa or placebo by subcutaneous injection for 10 days before surgery, on the day of surgery and for four days after surgery. All patients received oral iron and a low dose postoperative warfarin regimen.
Treatment with epoetin alfa 300 IU/kg significantly (p = 0.024) reduced the risk of allogeneic transfusion in patients with a pretreatment haemoglobin of > 100 to ≤ 130 g/L; 5/31 (16%) of epoetin alfa 300 IU/kg, 6/26 (23%) of epoetin alfa 100 IU/kg and 13/29 (45%) of placebo treated patients were transfused.
In the > 100 to ≤ 130 g/L pretreatment stratum, the mean number of units transfused per epoetin alfa treated patient (0.45 units blood for 300 IU/kg, 0.42 units blood for 100 IU/kg) was less than the mean transfused per placebo treated patient (1.14 units) (overall p = 0.028). In addition, mean haemoglobin, haematocrit and reticulocyte counts increased significantly during the presurgery period in epoetin alfa treated patients.
Epoetin alfa was also studied in an open label, parallel group trial enrolling 145 subjects with a pretreatment haemoglobin level of ≥ 100 to ≤ 130 g/L who were scheduled for major orthopaedic hip or knee surgery and who were not participating in an autologous program.
Subjects were randomly assigned to receive one of two subcutaneous dosing regimens of epoetin alfa (600 IU/kg once weekly for three weeks prior to surgery and on the day of surgery or 300 IU/kg once daily for ten days prior to surgery, on the day of surgery and for four days after surgery). All subjects received oral iron and appropriate pharmacologic anticoagulation therapy.
From pretreatment to presurgery, the mean increase in haemoglobin in 600 IU/kg weekly group (14.4 g/L) was greater than observed in the 300 IU/kg daily group.
The erythropoietic response observed in both treatment groups resulted in similar transfusion rates [11/169 (16%) in the 600 IU/kg weekly group and 14/71 (20%) in the 300 IU/kg daily group]. The mean number of units transfused per subject was approximately 0.3 units in both treatment groups.
Using linear logistic models it can be calculated that for a patient with an entry haemoglobin level of 100 g/L, use of 300 IU/kg daily or 600 IU/kg weekly would reduce the probability of transfusion to about 38%, compared to 58% in the same patient receiving a 100 IU/kg daily regimen, or 81% in a patient given no Eprex therapy.
Similarly, at a higher entry haemoglobin of 120 g/L, the 300 IU/kg daily or 600 IU/kg weekly regimens would reduce the probability of transfusion to about 18%, compared to 35% in the same patient receiving 100 IU/kg daily, or 61% in a patient receiving no Eprex.
In autologous blood donation, a double blind study was conducted in 204 patients scheduled to undergo elective orthopaedic surgery with haematocrits ≤ 39% and no underlying anaemia due to iron deficiency. On average, patients treated with Eprex 600 IU/kg twice weekly for three weeks were able to predeposit significantly more units of blood (4.5 units) than placebo treated patients (3.0 units) (p < 0.001). Also, significantly more patients treated with Eprex (p < 0.05) were able to predeposit between 3 and 6 units, inclusively, of autologous blood than the corresponding placebo treated patients. Virtually all (98%) of Eprex treated patients predeposited 3 or more units, compared with 69% of placebo treated patients. While 37% of placebo patients were able to predeposit 4 or 5 units, 81% of Eprex patients predeposited 4 or more units. Among the evaluable patients, fewer patients who received Eprex required allogeneic transfusions (19.8%) than placebo patients (31%).
In a second placebo controlled study, 55 patients with low haematocrits were enrolled 2:2:1 to receive Eprex 600 IU/kg, Eprex 300 IU/kg or placebo twice weekly for three weeks. A significantly greater amount of autologous blood (p < 0.005) was donated by the Eprex treated patients (4.68 vs 4.42 vs 2.89 units). Likewise 84, 79 and 11% of patients were able to donate four or more units over the three week study.

5.2 Pharmacokinetic Properties

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 postdose. 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 Eprex.

5.3 Preclinical Safety Data

Genotoxicity.

In a standard series of assays for genotoxic potential, epoetin alfa (rch) did not induce gene mutations or cause chromosomal damage.

Carcinogenicity.

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 (see Section 4.4, Use in cancer patients).

4 Clinical Particulars

4.1 Therapeutic Indications

Eprex is indicated for the treatment of patients with symptomatic or transfusion requiring anaemia associated with chronic renal failure to improve their quality of life by improving energy levels, exercise performance, fatigue and sleep patterns and by reducing the need for blood transfusions.
Eprex is also indicated for the treatment of anaemia in patients with nonmyeloid malignancies where anaemia develops as a result of concomitantly administered chemotherapy, and where blood transfusion is not considered appropriate.
Eprex is also indicated in 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 1,800 mL) to reduce exposure to allogeneic blood transfusion and to facilitate erythropoietic recovery.
Eprex is also indicated to augment autologous blood collection and to limit the decline in haemoglobin in anaemic adult patients who are scheduled for major elective surgery and who are not expected to predeposit their complete perioperative blood needs.

4.3 Contraindications

Eprex is contraindicated in patients with the following.
1. Uncontrolled hypertension.
2. Known sensitivity to mammalian cell derived products.
3. Hypersensitivity to the active substance or to any of the excipients.
4. Patients scheduled for elective surgery, who are not participating in an autologous blood predeposit programme and who have severe coronary, peripheral arterial, carotid or cerebral vascular disease, including patients with recent myocardial infarction or cerebral vascular accident.
5. All contraindications associated with autologous blood predonation programs should be respected in patients being supplemented with Eprex.
6. Surgery patients who for any reason cannot receive adequate antithrombotic prophylaxis or treatment.
7. Patients who develop pure red cell aplasia (PRCA) following treatment with any erythropoietin should not receive Eprex or any other erythropoietin (see Section 4.4, Pure red cell aplasia).

4.4 Special Warnings and Precautions for Use

Cardiovascular and thrombotic events/ increased mortality.

An increased incidence of thrombotic vascular events (TVEs) has been observed in patients receiving ESAs such as epoetin alfa (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 and myocardial infarction. Additionally, cerebrovascular accidents (including cerebral infarction, cerebral haemorrhage and transient ischaemic attacks) have been reported (see Section 4.4, Use in chronic renal failure patients).
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.
In all patients, haemoglobin concentrations should be closely monitored due to a potential increased risk of thromboembolic events and fatal outcomes when patients are treated at haemoglobin concentrations above the range for the indication of use.

Use in cancer patients.

Cancer patients on Eprex should have haemoglobin levels measured on a regular basis until a stable level is achieved and periodically thereafter.
As with all growth factors, there is a concern that ESAs could stimulate the growth of tumours. In controlled clinical studies, use of Eprex 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.
Eprex should only be used to treat cancer patients with anaemia where the anaemia has arisen as a result of concomitantly administered chemotherapy. A haemoglobin concentration of 120 g/L should not be exceeded.

Use in chronic renal failure patients.

Chronic renal failure patients being treated with epoetin alfa 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 (see Section 4.2). In controlled trials, haemoglobin levels targeted to 130 g/L were associated with a higher risk of cardiovascular events, including death.
Patients with chronic renal failure and insufficient haemogloblin 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, for example, is recommended in these patients.
Hyperkalaemia has been observed in isolated cases. 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, consideration should be given to ceasing Eprex administration until the serum potassium level has been corrected.
As a result of an increase in packed cell volume, haemodialysis patients receiving Eprex 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 Eprex therapy; the possibility of potential pregnancy should be discussed and the need for contraception evaluated.
In some preclinical 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 for 12-19 months compared to the incidence of bone marrow fibrosis in a matched control group of dialysis patients who had not been treated with epoetin alfa. 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 Eprex, making the significance of the findings in dogs unclear.

Use in patients scheduled for elective surgery.

In patients with a baseline haemoglobin of > 130 g/L (8.1 mmol/L), the possibility that Eprex 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 > 130 g/L (8.1 mmol/L).
Good blood management practices should always be used in the perisurgical setting.

Use in surgery patients in an autologous predonation programme (ABD).

All special precautions associated with autologous predonation programmes, especially routine volume replacement, should be respected.

Hypertension.

Patients with uncontrolled hypertension should not be treated with Eprex; blood pressure should be controlled adequately before initiation of therapy. Blood pressure may rise during treatment of anaemia with Eprex. Hypertensive encephalopathy and seizures have been observed.
Special care should be taken to closely monitor and control blood pressure in patients treated with Eprex. During Eprex 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 Eprex should be reduced or temporarily withheld until haemoglobin begins to decrease (see Section 4.2).
Hypertensive crisis with encephalopathy and seizures, requiring the immediate attention of a physician and intensive medical care, have also occurred during Eprex 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).

Pure red cell aplasia.

Antibody mediated pure red cell aplasia (PRCA) (erythroblastopaenia) has been reported after treatment with erythropoietins. Most cases of PRCA associated with Eprex 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 nonresponse should be investigated. If no cause is identified, a bone marrow examination should be considered.
If pure red cell aplasia (PRCA) is diagnosed, Eprex 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 antierythropoietin antibodies cross react with other ESAs. Other causes of pure red cell aplasia should be excluded and appropriate therapy instituted.

Seizures.

Seizures have occurred in patients receiving Eprex. Therefore, Eprex 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.

Iron 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 Eprex, 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 Eprex, adequate iron stores should be assured and iron supplementation should be administered if necessary:
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 nanogram/mL.
For cancer patients, iron supplementation (elemental iron 200-300 mg/day orally) is recommended if transferring 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 Eprex therapy, and throughout the course of Eprex therapy.
For patients scheduled for major elective orthopaedic surgery, iron supplementation (elemental iron 200 mg/day orally) should be administered throughout the course of Eprex therapy. If possible, iron supplementation should be initiated prior to starting Eprex therapy to achieve adequate iron stores.

General.

Eprex should be used with caution in those patients with pre-existing hypertension, ischaemic vascular disease, or suspected allergy to any components of the product, porphyria or gout.
The safety and efficacy of Eprex therapy have not been established in patients with underlying haematological diseases (e.g. haemolytic anaemia, sickle cell anaemia, 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 Eprex) 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 Eprex. 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 is regularly monitored during the first 8 weeks of therapy.
Very rarely, exacerbation of porphyria has been observed in Eprex treated patients with chronic renal failure. Eprex has not caused increased urinary excretion of porphyrin metabolites in normal volunteers, even in the presence of a rapid erythropoietic response. Nevertheless, Eprex 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 Eprex should be used with caution in patients with a history of gout.
Blistering and skin exfoliation reactions including erythema multiforme and Stevens-Johnson Syndrome (SJS)/toxic epidermal necrolysis (TEN), have been reported in patients treated with Eprex. Discontinue Eprex therapy immediately if a severe cutaneous reaction, such as SJS/TEN, is suspected.

Use in hepatic impairment.

Eprex should also be used with caution in patients with chronic liver failure. The safety and dosage regime of Eprex has not been established in the presence of hepatic dysfunction. Due to decreased metabolism, patients with hepatic dysfunction may have increased erythropoiesis with Eprex.

Use in the elderly.

No data available.

Paediatric use.

Efficacy.

Clinical trials of Eprex 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 three times a week rather than 50 IU/kg three times a week.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

There are no known clinically significant drug interactions but the effect of Eprex 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 Eprex.
Since cyclosporin is bound by red blood cells, there is potential for a drug interaction. If Eprex is given concomitantly with cyclosporin, blood levels of cyclosporin should be monitored and the dose of cyclosporin adjusted as the haematocrit rises.
In patients with metastatic breast cancer, subcutaneous coadministration of 40,000 IU/mL epoetin alfa with trastuzumab (6 mg/kg) had no effect on the pharmacokinetics of trastuzumab.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

The effect of Eprex on human fertility has not been studied.
(Category B3)
Eprex 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 fetal 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 fetal weight and retardation of ossification.
In pregnant or lactating surgical patients participating in an autologous blood predonation programme, the use of Eprex is not recommended.
Eprex 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.

4.8 Adverse Effects (Undesirable Effects)

The most frequent adverse drug reaction during treatment with epoetin alfa 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 reactions observed in clinical trials of Eprex are diarrhoea, nausea, vomiting, pyrexia, and headache. Influenza-like illness may occur especially at the start of treatment.
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 angioedema have been reported.
Hypertensive crises with encephalopathy and seizures, requiring the immediate attention of a physician and intensive medical care, have also occurred 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 3,559 subjects in 27 randomized, double blinded, placebo or standard of care controlled studies, the overall safety profile of Eprex was evaluated in 2,136 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); 1,404 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 reactions reported by ≥ 1% of Eprex treated subjects in these trials are shown in Table 1.

Postmarketing data.

Adverse drug reactions identified during postmarketing experience with epoetin alfa are included in Table 2. 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.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.2 Dose and Method of Administration

During therapy, haematological parameters should be monitored regularly. Doses must be 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.

Adult patients scheduled for elective surgery.

Before considering therapy with Eprex prior to elective surgery, it is important to investigate and provide appropriate treatment for potentially correctable anaemia.
In patients scheduled for elective surgery adequate antithrombotic prophylaxis is strongly recommended.
The subcutaneous route of administration should be used.
The recommended dose regimen is 600 IU/kg Eprex 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 Eprex should be given daily for 10 consecutive days prior to surgery, on the day of surgery, and for four days immediately thereafter. The administration of Eprex should be stopped as soon as the haemoglobin level reaches 150 g/L in the preoperative period, even if not all the planned Eprex doses have been given.
All patients being treated with Eprex should receive adequate iron supplementation (e.g. 200 mg oral elemental iron daily) throughout the course of Eprex treatment. If possible, iron supplementation should be started prior to Eprex therapy, to achieve adequate iron stores.

Anaemic adult surgery patients in an autologous predonation 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.

Chronic renal failure patients.

In patients with chronic renal failure, where intravenous access is routinely available (haemodialysis patients) administration of Eprex by the intravenous route is preferable. Where intravenous access is not readily available (patient not yet on dialysis and peritoneal dialysis patients) Eprex may be administered subcutaneously (see Section 4.4, Pure red cell aplasia).
In patients maintained on haemodialysis, Eprex should always be administered after completion of dialysis.
Treatment with Eprex is divided into two stages:

Correction phase.

The initial dosage is 50 IU/kg bodyweight three times a week IV/SC. If haemoglobin does not increase by 10 g/L after 1 month of treatment, the dosage may be raised to 75 IU/kg three times per week, and if further increments are needed, they should be at 25 IU/kg, three times per week, at monthly intervals, to achieve a haemoglobin not to exceed 120 g/L. This level should not be exceeded in patients with chronic renal failure. The maximum dosage should not exceed 3 x 200 IU/kg per week.

Maintenance phase.

The IV/SC dose has to be adjusted individually to maintain a haemoglobin not to exceed 120 g/L.
The maintenance dose should be individualised for each chronic renal failure patient. The recommended total weekly dose is between 75 and 300 IU/kg.
For patients who are converted from the subcutaneous to intravenous route, the same dose should be used, and the haemoglobin should be followed carefully (e.g. weekly) so that appropriate changes in Eprex dose can be made to keep the haemoglobin within the target range.

Dose adjustment.

If the haemoglobin is increasing and approaching 120 g/L, the dose should be reduced by approximately 25%. If the haemoglobin continues to increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at which point therapy should be reinitiated at a dose approximately 25% below the previous dose. If the haemoglobin increases by more than 10 g/L in any 2 week period, the dose should be decreased by approximately 25%. If dose reduction is needed the amount given per dose should be reduced or the number of weekly injections reduced or both.

Adult patients with cancer.

Treatment should not be commenced unless haemoglobin falls below 100-110 g/L. The target haemoglobin concentration should be up to 120 g/L in men and women and it should not be exceeded.
The initial dose is 150 IU/kg given subcutaneously 3 times per week. 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.
The recommended dosing regimen is described in Figure 1.

Dose adjustment.

In oncology patients, rapid increases in haemoglobin concentrations or the use of erythropoietins in subjects with normal haemoglobin concentrations, may result in an increased risk of thrombotic adverse events (see Section 4.4, Cardiovascular and thrombotic events/ increased mortality).
Therefore, a rate of rise in haemoglobin of greater than 10 g/L per two week period 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 2 week period or 20 g/L per month or haemoglobin is approaching 120 g/L, reduce Eprex dose by about 25-50%. If the haemoglobin exceeds 120 g/L, discontinue therapy until it falls to below 120 g/L and then reinstitute Eprex at a dose 25% below the previous dose.

Administration instructions.

Parenteral drug 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, shaking may denature the glycoprotein, rendering it inactive.
Epoetin alfa in single use syringes contains no preservatives. Do not reuse syringe. Discard unused portion.
Prepare Eprex for IV/SC injection from the prefilled syringe.
Administer as IV/SC 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.
Do not dilute or transfer to any other container. Do not administer by intravenous infusion or in conjunction with other drug solutions.
For subcutaneous route a maximum volume of 1 mL at one injection site should generally not be exceeded. In case of larger volumes, more than one site should be chosen for the injection. Subcutaneous injections are given in the limbs or the anterior abdominal wall.
The prefilled syringes are fitted with the Protecs needle guard device to help prevent needle stick injuries after use. The Eprex Consumer Medicine Information includes full instructions for the use and handling of prefilled syringes.

4.7 Effects on Ability to Drive and Use Machines

No studies on the effects of epoetin alfa on the ability to drive and use machines have been performed.

4.9 Overdose

Signs and symptoms.

The maximum amount of Eprex that can be safely administered in single or multiple doses has not been determined with respect to the direct effect of epoetin alfa (rch) as distinct from its effect on red cell mass.The response to Eprex is dose related and individual.

Treatment.

With excessive erythropoietic response to Eprex, dosing should be stopped and treatment begun as described above (see Section 4.4, Hypertension, Seizures). Phlebotomy may be performed if excessively high haemoglobin levels occur. Additional supportive care should be provided as necessary.
For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Glycine (5 mg/mL); Polysorbate 80 (0.30 mg/mL); Sodium chloride (1.7 - 5.8 mg); Monobasic sodium phosphate dihydrate (0.35 - 1.16 mg); Dibasic sodium phosphate dihydrate (0.67 - 2.22 mg); Sodium citrate (at less than 5 mmol); Water for injections.

6.2 Incompatibilities

Do not dilute or transfer to any other container. Do not administer by intravenous infusion or in conjunction with other drug solutions.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

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 25°C) for a maximum single period of seven days.

6.5 Nature and Contents of Container

Pre-filled syringe fitted with the Protecs needle guard device.
Each package contains 6 pre-filled syringes, except the 40,000 IU syringe that is sold singly.

6.6 Special Precautions for Disposal

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

Summary Table of Changes