Consumer medicine information

Novicrit

Epoetin lambda

BRAND INFORMATION

Brand name

Novicrit

Active ingredient

Epoetin lambda

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Novicrit.

What is in this leaflet

This leaflet answers some common questions about Novicrit.

It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

The information in this leaflet was last updated on the date listed on the final page. More recent information on the medicine may be available.

You should ensure that you speak to your pharmacist or doctor to obtain the most up to date information on the medicine. You can also download the most up to date leaflet from www.sandoz.com.au. Those updates may contain important information about the medicine and its use of which you should be aware.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking Novicrit 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 with the medicine. You may need to read it again.

What Novicrit is used for

Novicrit is used:

  • to treat anaemia associated with kidney disease
  • to treat anaemia in patients receiving chemotherapy for certain types of cancer
  • in patients with anaemia who are about to undergo surgery as an alternative to a blood transfusion where there is the likelihood of moderate blood loss
  • in patients with anaemia who face major elective surgery and who, prior to it, donate blood so that their own blood can be given to them during and after surgery. Novicrit stimulates the production of red blood cells and hence, a higher volume of blood can be taken from these patients.

Novicrit contains the active ingredient epoetin lambda (rch). Epoetin lambda (rch) is man-made and works in exactly the same way as the natural hormone produced in your kidneys.

Epoetin lambda is a hormone which works by stimulating the production of red blood cells. It is used to treat anaemia, a condition in which there is a decreased number of red blood cells.

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.

Novicrit is available only with a doctor's prescription and is not addictive.

Before you use Novicrit

When you must not use it

Do not use Novicrit if you have an allergy to:

  • epoetin lambda (rch), the active ingredient in Novicrit
  • any of the other ingredients listed at the end of this leaflet
  • 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 or have had high blood pressure which is not properly controlled
  • you have a medical condition where the production of red blood cells is reduced or stopped (Pure Red Cell Aplasia) which developed following treatment with any erythropoietin
  • you are due to have surgery and for any reason cannot receive medication to reduce the risk of abnormal blood clotting
  • you are due to have elective surgery and you do not donate your own blood before surgery and you have severe disorders of the veins and arteries.

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 using this medicine, talk to your doctor.

Before you start to use it

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

  • high blood pressure
  • heart disease
  • disorders of blood circulation resulting in pins and needles or cold hands and feet or muscle cramps in the legs
  • cancer
  • seizures
  • gout
  • porphyria, a rare blood pigment disorder
  • chronic liver disease
  • blood clots in the legs or lungs
  • stroke or transient ischaemic attack (TIA).
  • an allergy to latex

Tell your doctor if you are pregnant or plan to become pregnant. Your doctor can discuss with you the risks and benefits involved.

Tell your doctor if you are breast-feeding. It is not known whether Novicrit passes into breast milk and could affect your baby.

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes. Your doctor will want to know if you are prone to allergies.

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

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 Novicrit may interfere with each other. These include:

  • iron supplements
  • cyclosporin, an immunosuppresant.

Such medicines may be affected by Novicrit 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 taking this medicine.

How to use Novicrit

Follow all directions given to you by your doctor 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.

Your doctor will conduct investigations, for example blood tests, to help decide whether it is necessary for you to have Novicrit. They will work out the correct dose of Novicrit for you to use, how long the treatment should continue and how it will be given. This decision will be influenced by the cause of your anaemia. The dose you receive is based on your body weight in kilograms.

Novicrit is administered either into a vein (intravenously) or under the skin (subcutaneously). Your doctor will know which route of administration is preferable in your case.

How much to use

  • In patients with kidney failure Novicrit will usually be administered by the intravenous route but may also be given by the subcutaneous route. The recommended initial dose is 50IU/kg bodyweight 3 times a week. The starting dose may be adjusted by your doctor as needed to properly control your condition.
  • The initial dose for cancer patients is 150IU/kg bodyweight given subcutaneously 3 times a week. The starting dose may be adjusted by your doctor depending on how your anaemia responds to treatment.
  • In patients who are scheduled for elective surgery, the subcutaneous route is used. The usual dose is 600IU/kg bodyweight for 3 weeks prior to surgery and on the day of surgery. Alternatively, 300 IU/kg may be administered for 10 consecutive days prior to surgery, on the day of surgery and for 4 days immediately after.
  • In patients who donate blood prior to major surgery the recommended dose is 300IU to 600IU/kg bodyweight twice a week for 3 weeks. The intravenous route is used.

Iron is an important constituent of red blood cells. It is important that levels of iron in your blood are normal throughout Epoetin lambda treatment. Where appropriate you will receive iron tablets or injections to ensure that the iron in your body will not be used up as more red blood cells are produced.

How to inject Novicrit yourself

At the start of your therapy, Novicrit may be injected by medical staff. However, your doctor may decide that it is right for you to learn how to inject it under the skin yourself. You will receive appropriate training for you to do this.

Under no circumstances should you attempt to inject yourself before you have been trained to do so.

The Novicrit pre-filled syringe is ready for use. Only use solutions which are clear, colourless and free of visible particles.

Do not shake the syringes.

Ask your doctor if you are unsure of the correct dose for you. They will tell you exactly how much to use.

Follow the instructions they give you. If you inject the wrong dose, Epoetin lambda may not work as well and your problem may not improve.

Instructions on how to inject yourself

For patients with symptomatic anaemia caused by kidney disease, for adult patients receiving chemotherapy, adult patients scheduled for orthopaedic surgery, or adult patients with myelodysplastic syndromes only).

This section contains information on how to give yourself an injection of Novicrit. It is important that you do not try to give yourself the injection unless you have received special training from your doctor or nurse. Novicrit is provided with or without a needle safety guard and you will be shown how to use this by your doctor or nurse. If you are not sure about giving the injection or you have any questions, please ask your doctor or nurse for help.

  1. Wash your hands.
  2. Remove one syringe from the pack and remove the protective cap from the injection needle. Syringes are embossed with graduation rings in order to enable partial use if required. Each graduation ring corresponds to a volume of 0.1 mL. If partial use of a syringe is required, remove unwanted solution before injection.
  3. Clean the skin at the injection site using an alcohol wipe.
  4. Form a skin fold by pinching the skin between thumb and forefinger.
  5. Insert the needle into the skin fold with a quick, firm action. Inject the Novicrit solution as you have been shown by your doctor. You should check with your doctor or pharmacist if you are not sure.

Pre-filled syringe without needle safety guard

  1. Always keeping your skin pinched, depress the plunger slowly and evenly.
  2. After injecting the liquid, remove the needle and let go of your skin. Apply pressure over the injection site with a dry, sterile pad.
  3. Discard any unused product or waste material. Only use each syringe for one injection.

Pre-filled syringe with needle safety guard

  1. Always keeping your skin pinched, depress the plunger slowly and evenly until the entire dose has been given and the plunger cannot be depressed any further. Do not release the pressure on the plunger!
  2. After injecting the liquid, remove the needle while maintaining pressure on the plunger and then let go of your skin. Apply pressure over the injection site with a dry, sterile pad.
  3. Let go of the plunger. The needle safety guard will rapidly move to cover the needle.
  4. Discard any unused product or waste material. Only use each syringe for one injection.

How long to use it

Do not stop using this medicine without first checking with your doctor. Your doctor will determine when your treatment should be stopped.

If you forget to use it

Inject your dose as soon as you remember, and continue to use 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 inject 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 are not sure what to do, ask your doctor or pharmacist.

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

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice, or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have used too much Novicrit. Do this even if there are no signs of discomfort or poisoning.

While you are using Novicrit

Things you must do

Keep all of your doctor's appointments so that your progress can be checked. Your doctor may do tests from time to time to make sure the medicine is working and to prevent unwanted side effects.

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

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

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

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

If you are about to have any blood tests, tell your doctor that you are taking this medicine. It may interfere with the results of some tests.

Things you must not do

Do not use Novicrit 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 Novicrit affects you.

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 used 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 taking Novicrit.

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 or pharmacist if you notice any of the following and they worry you:

  • flu-like symptoms such as headache, fever, sore throat, chills, difficulty swallowing, runny nose and cough, sore red eyes, muscle and joint pain and weakness, dizziness, drowsiness
  • mild skin rashes
  • skin reactions such as redness or burning at the injection site
  • nausea, diarrhoea or vomiting.

If any of the following happen, tell your doctor immediately:

  • symptoms of an allergic reaction such as 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
  • skin rashes and accumulation of fluid under the skin of the eyelids (oedema), which may result from an allergic reaction.
  • sudden onset of a tender/painful red skin rash starting on the trunk
  • seizures, 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)
  • severe, sudden, stabbing migraine-like headaches
  • paralysis or weakness of an arm, leg and one side of the face, numbness, difficulty speaking, impaired vision, loss of balance or coordination
  • pain in the foot or calf
  • sudden tiredness, severe dizziness and light-headedness or sudden shortness of breath. There have been rare reports of patients developing antibodies against erythropoietins resulting in a failure of red blood cell development. This condition is called antibody-mediated Pure Red Cell Aplasia (PRCA). If you develop PRCA your Novicrit therapy will be discontinued and your doctor will decide how best to treat your anaemia.

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

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

Other side effects not listed here or not yet known may happen in some people. Some of these side effects can only be found by laboratory testing.

After using Novicrit

Storage

Keep the syringes in the original container until it is time to use them.

Keep your medicine in a cool dry place where the temperature stays between 2 and 8°C. Do not freeze. Novicrit may be removed from the refrigerator and stored at up to 25°C for one single period of up to 3 days.

Keep it where children cannot reach it.

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.

Product description

What it looks like

Novicrit solution for injection is a clear, colourless solution, presented in a glass syringe. Each pack of Novicrit contains 6 syringes.

Ingredients

Novicrit syringes contain 1,000IU; 2,000IU; 3,000IU; 4,000IU; 5,000IU; 6,000IU; 8,000IU or 10,000IU epoetin lambda (rch) as the active ingredient.

They also contain:

  • dibasic dihydrate sodium phosphate
  • monobasic dihydrate sodium phosphate
  • sodium chloride
  • glycine
  • polysorbate 80
  • hydrochloric acid
  • sodium hydroxide
  • water for injections.

The needle cover of the pre-filled syringe contains a derivative of latex (FM27)

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

Sponsor

Novicrit is supplied in Australia by:

Sandoz Pty Ltd
ABN 60 075 449 553
54 Waterloo Road
Macquarie Park, NSW 2113
Australia
Tel: 1800 726 369

®= Registered Trademark

This leaflet was revised in August 2022.

Australian Registration Numbers:

1,000IU/0.5mL: - AUST R 147847

2,000IU/1.0mL: - AUST R 147833

3,000IU/0.3mL: - AUST R 147849

4,000IU/0.4mL: - AUST R 147843

5,000IU/0.5mL: - AUST R 147859

6,000IU/0.6mL: - AUST R 147844

8,000IU/0.8mL: - AUST R 147837

10,000IU/1.0mL: - AUST R 147842

Published by MIMS September 2022

BRAND INFORMATION

Brand name

Novicrit

Active ingredient

Epoetin lambda

Schedule

S4

 

1 Name of Medicine

Epoetin lambda (rch).

2 Qualitative and Quantitative Composition

The active ingredient of Novicrit Solution for Injection is Epoetin lambda (rch).
Erythropoietin is an endogenous glycoprotein that stimulates red blood cell production. It is normally produced by the kidney and regulated by the level of tissue oxygenation. Epoetin lambda (rch) (CHO) is purified from a Chinese hamster ovary (CHO) cell line into which the gene coding for human erythropoietin has been inserted. Epoetin lambda (rch) is indistinguishable from human erythropoietin in biological activity and immunological reactivity.
Epoetin lambda (rch) has been developed as a similar biological medicinal product to epoetin alfa.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Novicrit is supplied in a pre-filled syringe as a clear, colourless solution for injection.

4 Clinical Particulars

4.1 Therapeutic Indications

Novicrit 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.
Novicrit is 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.
Novicrit 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 (two to four units or 900 to 1,800 mL) to reduce exposure to allogeneic blood transfusion and to facilitate erythropoietic recovery.
Novicrit 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.

4.2 Dose and Method of Administration

Dosage.

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 Novicrit 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 Novicrit 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 Novicrit should be given daily for ten consecutive days prior to surgery, on the day of surgery and for four days immediately thereafter. The administration of Novicrit should be stopped as soon as the haemoglobin level reaches 150 g/L in the preoperative period, even if not all the planned Novicrit doses have been given.
All patients being treated with Novicrit should receive adequate iron supplementation (e.g. oral elemental iron 200 mg daily) throughout the course of Novicrit treatment. If possible, iron supplementation should be started prior to Novicrit therapy, to achieve adequate iron stores.
Anaemic adult surgery patients in an autologous predonation program. The intravenous route should be used. The recommended dose is 300 to 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 by the intravenous route is preferable. Where intravenous access is not readily available (patient not yet on dialysis and peritoneal dialysis patients) Novicrit may be administered subcutaneously (see Section 4.4 Special Warnings and Precautions for Use, Pure red cell aplasia).
In patients maintained on haemodialysis, Novicrit should always be administered after completion of dialysis.
Treatment with Novicrit is divided into the following two stages:

Correction phase.

The initial dose of Novicrit is 50 IU/kg bodyweight three times a week, by intravenous or subcutaneous injection. If the haemoglobin does not increase by 10 g/L after one month of treatment, the dosage may be raised to 75 IU/kg three times/week. If further increments are needed, they should be at 25 IU/kg, three times/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. Maximum dose should not exceed 3 x 200 IU/kg per week.

Maintenance phase.

The intravenous or subcutaneous 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 route to intravenous route, the same dose should be used, and the haemoglobin should be followed carefully (e.g. weekly) so that appropriate changes in Novicrit dose can be made to keep the haemoglobin within the target range.
Adult patients with cancer. Treatment should not be commenced unless haemoglobin falls below 100 to 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 three times/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/microliter above baseline after four 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/microliter above baseline, increase the dose to 300 IU/kg. If after an additional four 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/microliter 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/microliter above baseline, response is unlikely and treatment should be discontinued.
The recommended dosing regimen is described in Figure 1.
Patients should be monitored closely to ensure that the lowest approved dose of epoetin lambda (rch) is used to provide adequate control of the symptoms of anaemia.
Evaluation of iron status. Iron status should be assessed in all patients prior to therapy. See Section 4.4 Special Warnings and Precautions for Use, Iron supplementation for further information.
Delayed or diminished response. Delayed or diminished response to Novicrit therapy should prompt a search for causative factors such as iron, folate or cyanocobalamin (vitamin B12) deficiency; aluminium intoxication; intercurrent infections; inflammatory or traumatic episodes; occult blood loss; haemolysis; and bone marrow fibrosis of any origin.

Method of administration.

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.
Syringes are embossed with graduation rings in order to enable partial use if required. Each graduation ring corresponds to a volume of 0.1 mL.
Administer as an intravenous or subcutaneous injection over one to two minutes. In patients on dialysis the injection should follow the dialysis procedure. Slow injection over five 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 medicine solutions.
For the 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.
In those situations in which the physician determines that a patient or caregiver can safely and effectively administer Novicrit subcutaneously, instruction as to the proper dose and administration should be provided.

Injecting Novicrit.

Do not shake Novicrit syringes. Prolonged vigorous shaking may damage the product. If the product has been shaken vigorously, don't use it.
The Novicrit consumer medicine information includes full instructions for the use and handling of pre-filled syringes.

Dosage adjustment.

Renal impairment.

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.

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 Special Warnings and Precautions for Use, 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 two week period or 20 g/L per month, or haemoglobin is approaching 120 g/L, reduce Novicrit dose by about 25 to 50%. If the haemoglobin exceeds 120 g/L, discontinue therapy until it falls to below 120 g/L and then reinstitute Novicrit at a dose 25% below the previous dose.

4.3 Contraindications

Novicrit is contraindicated in patients with:
Uncontrolled hypertension.
Known sensitivity to mammalian cell derived products.
Hypersensitivity to the active substance or to any of the excipients.
Patients scheduled for elective surgery, who are not participating in an autologous blood predeposit program and who have severe coronary, peripheral arterial, carotid or cerebral vascular disease, including patients with recent myocardial infarction or cerebral vascular accident.
All contraindications associated with autologous blood predonation programmes should be respected in patients being supplemented with epoetin lambda (rch).
Surgery patients who for any reason cannot receive adequate antithrombotic prophylaxis or treatment.
Patients who develop pure red cell aplasia (PRCA) following treatment with any erythropoietin should not receive epoetin lambda (rch) or any other erythropoietin (see Section 4.4 Special Warnings and Precautions for Use).

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 lambda (rch) (see Section 4.8 Adverse Effects (Undesirable Effects)). These include venous and arterial thromboses and embolism (including some with fatal outcomes), such as deep venous thrombosis, pulmonary emboli, retinal thrombosis, haemodialysis graft occlusion, myocardial ischaemia and myocardial infarction. Additionally, cerebrovascular accidents (including cerebral infarction, cerebral haemorrhage and transient ischaemic attacks) have been reported (see Section 4.4 Special Warnings and Precautions for Use, Use in renal impairment).
The reported risk of TVEs should be carefully weighed against the benefits to be derived from treatment with epoetin lambda (rch) particularly in patients with pre-existing risk factors for TVE, including obesity and prior history of TVEs (e.g. deep venous thrombosis, pulmonary embolism, and cerebral vascular accident). Epoetin lambda (rch) and other erythropoiesis-stimulating agents increased the risk for death and for serious cardiovascular events in controlled 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 levels should be closely monitored due to potential increased risk of thromboembolic events and fatal outcomes when patients are treated at haemoglobin levels above the target range for the indication for use.

Use in cancer patients.

In some studies, use of Erythropoiesis Stimulating Agents (ESAs) to treat anaemia in patients with cancer has been associated with increased mortality. ESAs should only be used to treat anaemia that has developed as a result of concomitantly administered chemotherapy, and only when blood transfusion is not considered appropriate. Haemoglobin levels should not exceed 120 g/L.
Epoetin lambda (rch) is a growth factor that primarily stimulates red cell production. Like all growth factors there is a theoretical concern that epoetin lambda (rch) could act as a growth factor for any tumour type, particularly myeloid malignancies.
Cancer patients on Novicrit 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 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.
A study comparing another erythropoiesis stimulating agent with placebo in patients with anaemia of cancer who were not being treated with chemotherapy demonstrated no benefit in terms of reduced transfusion requirements. In addition, there were an increased number of deaths in the active group (26% vs. 20%).
Epoetin lambda (rch) should only be used to treat cancer patients with anaemia where the anaemia has arisen as a result of concomitantly administered chemotherapy. The target haemoglobin should be up to 120 g/L in men and women and it should not be exceeded.

Severe cutaneous adverse reactions.

Severe cutaneous adverse reactions (SCARs) including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), which can be life-threatening or fatal, have been reported in association with epoetin treatment. More severe cases have been observed with long-acting epoetins.
At the time of prescription patients should be advised of the signs and symptoms and monitored closely for skin reactions. If signs and symptoms suggestive of these reactions appear, epoetin alfa should be withdrawn immediately and an alternative treatment considered.
If the patient has developed a severe cutaneous skin reaction such as SJS or TEN due to the use of epoetin alfa, treatment with epoetin alfa must not be restarted in this patient at any time.

Hypertension.

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

Pure red cell aplasia.

In chronic renal failure patients, antibody mediated pure red cell aplasia (PRCA) (erythroblastopenia) has been rarely reported after months to years of treatment with erythropoietins. 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 PRCA is diagnosed, epoetin lambda (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 antierythropoietin antibodies cross react with ESAs. Other causes of pure red cell aplasia should be excluded, and appropriate therapy instituted.
PRCA most commonly occurs in patients with chronic renal failure who have received erythropoietins via the subcutaneous route. The subcutaneous route should only be used when intravenous access is not readily available.
No other ESA therapy should be commenced because of the risk of cross reaction.

Seizures.

Seizures have occurred in patients with CRF receiving epoetin lambda (rch) with a frequency of 3 to 7%, usually during the first 90 days of treatment. Therefore, Novicrit 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. Blood pressure and premonitory neurological symptoms should be closely monitored. Patients should be cautioned to avoid potentially hazardous activities such as driving or operating heavy machinery during this period.

Iron supplementation.

Iron status should be assessed in all patients prior to therapy. Further monitoring of serum iron, ferritin and total iron binding capacity is indicated monthly for the first three months of therapy and three monthly thereafter. Virtually all patients will eventually need supplemental iron therapy.
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 Novicrit, 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 Novicrit, 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 Novicrit therapy, and throughout the course of Novicrit therapy.
For patients scheduled for major elective orthopaedic surgery, iron supplementation (elemental iron 200 mg/day orally) should be administered throughout the course of Novicrit therapy. If possible, iron supplementation should be initiated prior to starting Novicrit therapy to achieve adequate iron stores.

General.

Epoetin lambda (rch) 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 epoetin lambda (rch) 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 epoetin lambda) to another ESA with the authorisation of the treating physician. In order to improve the traceability of ESAs, the trade name of the administered ESA should be clearly recorded (or stated) in the patient file.
There may be a moderate dose dependent rise in the platelet count within the normal range during treatment with epoetin lambda (rch). This regresses during the course of continued therapy. Development of thrombocytosis is very rare. It is recommended that the platelet count is regularly monitored during the first eight weeks of therapy.
Rarely, development of or exacerbation of porphyria has been observed in epoetin alfa treated patients with chronic renal failure. Epoetin alfa has not caused increased urinary excretion of porphyrin metabolites in normal volunteers, even in the presence of a rapid erythropoietic response. Nevertheless, epoetin lambda (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 lambda (rch) should be used with caution in patients with a history of gout.
The needle shield on the Novicrit pre-filled syringe contains a derivative of latex (FM27), which may cause allergic reactions in individuals sensitive to latex.

Renal dialysis.

Correction of anaemia with epoetin lambda (rch) does not appear to affect dialysis efficiency.
Hyperkalaemia has been observed in isolated cases. However, an increase in appetite could lead to increased potassium intake and hyperkalaemia in both dialysis and predialysis 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 lambda (rch) administration until hyperkalaemia has been corrected.
As a result of an increase in packed cell volume, haemodialysis patients receiving Novicrit 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.
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 (rch) for 12 to 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 (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.

Use in patients scheduled for elective surgery.

Potentially correctable anaemia should be investigated and appropriately treated before considering therapy with epoetin lambda (rch) prior to elective surgery. In patients with a baseline haemoglobin of > 130 g/L (8.1 mmol/L), the possibility that epoetin lambda (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 > 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 programs, especially routine volume replacement, should be respected.

Use in hepatic impairment.

Novicrit should also be used with caution in patients with chronic liver failure. The safety and dosage regime of epoetin lambda (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 lambda (rch).

Use in renal impairment.

Chronic renal failure patients being treated with epoetin lambda 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 Dose and Method of Administration. In controlled trials, haemoglobin levels targeted to 130 g/L were associated with a higher risk of cardiovascular or cerebrovascular events, including stroke and death.
Patients with chronic renal failure and insufficient haemogloblin response to ESA therapy may be at even greater risk for cardiovascular or cerebrovascular 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.

Use in the elderly.

No data available.

Paediatric use.

Efficacy.

Clinical trials of epoetin alfa (rch) 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 support 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 interactions with other medicines but the effect of epoetin lambda (rch) may be potentiated by the simultaneous therapeutic administration of a haematinic agent such as ferrous sulfate when a deficiency state exists.
Drugs that decrease erythropoiesis may decrease the response to Novicrit.
Since cyclosporin is bound by red blood cells, there is potential for a medicine interaction. If epoetin lambda (rch) 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 co-administration 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.

Intravenous administration of epoetin alfa (rch) at dose levels of 20 to 500 IU/kg/day in rats caused decreased fertility.
(Category B3)
Epoetin lambda (rch) should be administered during pregnancy only if clearly needed and if the potential justifies the potential risk to the foetus. It is not known whether epoetin lambda (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 to 500 IU/kg/day in rats caused decreased fertility, increased preimplantation and postimplantation loss, decreased foetal weight and retardation of ossification.
In pregnant surgical patients participating in an autologous blood predonation program, the use of epoetin lambda (rch) is not recommended.
 Epoetin lambda (rch) should be administered during lactation only if clearly needed. It is not known whether epoetin lambda (rch) is excreted in breast milk or whether it can cause harm to the infant when administered to a lactating woman. Intravenous administration of epoetin alfa (rch) 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 lambda (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 lambda (rch) has been established.

4.8 Adverse Effects (Undesirable Effects)

Epoetin lambda has been demonstrated to have equivalent pharmacokinetics and pharmacodynamics to epoetin alfa. The adverse effects observed with epoetin alfa would therefore be expected to occur with epoetin lambda.

Adverse effects observed with epoetin alfa.

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. Other common adverse drug reactions observed in clinical trials of epoetin alfa are diarrhoea, nausea, headache, influenza-like illness, pyrexia, rash, and vomiting. Influenza-like illness including headaches, joint pains, myalgia, and pyrexia may occur especially at the start of treatment.
Serious adverse drug reactions include venous and arterial thromboses and embolism (including some with fatal outcomes), such as deep venous thrombosis, pulmonary emboli, arterial thrombosis, retinal thrombosis, and shunt thrombosis (including dialysis equipment). In a cumulative analysis of 10 double blind, randomised, placebo controlled trials in subjects with cancer receiving chemotherapy, deep venous thrombosis was reported in 2.1% and pulmonary embolism in 1.2% of the 1564 subjects exposed to epoetin alfa, compared to 1.2% and 1.2%, respectively, of the 1207 subjects exposed to placebo. Additionally, cerebrovascular accidents (including cerebral infarction and cerebral haemorrhage) and transient ischaemic attacks have been reported in clinical trials of epoetin alfa.
Hypersensitivity reactions, including cases of rash, urticaria, anaphylactic reaction, and angioneurotic oedema have been reported.
Hypertensive crisis 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.
Hyperkalaemia, cough, respiratory congestion, bone pain, porphyria, bone pain in extremity, have also been reported.
The overall safety profile of epoetin alfa was evaluated in 142 subjects with chronic renal failure (CRF) and in 765 subjects with cancer who participated in placebo controlled, double blind clinical registration trials. Adverse drug reactions reported by ≥ 0.2% of epoetin alfa treated subjects in these trials are shown in Table 1.
Additional adverse drug reactions with unknown incidence rates identified through other controlled and non-controlled clinical trials with epoetin alfa are shown in Table 2.

Renal failure patients.

In chronic renal failure patients, haemoglobin levels greater than 120 g/L may be associated with a higher risk of cardiovascular events, including death (see Section 4.4 Special Warnings and Precautions for Use).
Shunt thromboses have occurred in haemodialysis patients, especially in those who have a tendency to hypotension or whose arteriovenous fistulae exhibit complications.

Cancer patients.

Thromboembolic events (see Section 4.4 Special Warnings and Precautions for Use) have been reported in cancer patients receiving erythropoietic agents, including epoetin alfa. An investigational study in women with metastatic breast cancer intended to determine whether erythropoietin treatment that extended beyond the correction of anaemia could improve treatment outcomes. However, in that study overall mortality, mortality attributed to disease progression, and incidence of fatal thromboembolic events were all higher in patients receiving epoetin alfa than in those receiving placebo.

Post-marketing data.

Adverse drug reactions identified during post-marketing experience with epoetin alfa are included in Table 3. 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, < 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.

Adverse effects observed in clinical trials with epoetin lambda.

Adverse effects identified during clinical trials with epoetin lambda are shown in Table 4.
Cases of pure red cell aplasia/ antierythropoietin neutralising antibody development have been reported following subcutaneous administration of epoetin lambda to patients with chronic renal failure.
Severe cutaneous adverse reactions (SCARs) including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), which can be life-threatening or fatal, have been reported in association with epoetin treatment.
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 http://www.tga.gov.au/reporting-problems.

4.9 Overdose

The maximum amount of epoetin lambda (rch) that can be safely administered in single or multiple doses has not been determined with respect to the direct effect of epoetin lambda (rch) as distinct from its effect on red cell mass.
The response to epoetin lambda (rch) is dose related and individual. With excessive erythropoietic response to Novicrit, dosing should be stopped and treatment begun as described above (see Section 4.4 Special Warnings and Precautions for Use, 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).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

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.
The primary pharmacodynamics of epoetin lambda (rch) 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 epoetin lambda (rch) and the reference product epoetin alfa (rch) were obtained.
The biological efficacy of epoetin lambda (rch) has been demonstrated in vivo using a normocythaemic mouse assay. After administration of epoetin lambda (rch), 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 epoetin lambda (rch) injection a clear rise in reticulocytes was observed, which was reversible upon cessation of treatment. There was no remarkable difference between epoetin lambda (rch) 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 epoetin lambda (rch) to a reference epoetin alfa (rch) preparation. See Tables 5 and 6.

Clinical trials.

Comparable safety and efficacy of epoetin lambda (rch) to epoetin alfa (rch) has been demonstrated in anaemia of chronic renal failure (IV administration) and chemotherapy induced anaemia.
Epoetin alfa (rch) 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 epoetin alfa (rch) 150 IU/kg or placebo subcutaneously three times a week for 12 weeks.
Epoetin alfa (rch) therapy was associated with a significantly (p < 0.008) greater haematocrit response than in the corresponding placebo treated patients (see Table 7).
In the two types of chemotherapy studies (utilising an epoetin alfa (rch) 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 epoetin alfa (rch) (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 epoetin alfa (rch) than in the corresponding placebo treated patients (22 versus 43%).
Comparable intensity of chemotherapy in the epoetin alfa (rch) and placebo groups in the chemotherapy trials was suggested by a similar area under the neutrophil time curve in patients treated with epoetin alfa (rch) and placebo treated patients as well as by a similar proportion of patients in groups treated with epoetin alfa (rch) and placebo treated groups whose absolute neutrophil counts fell below 1,000 cells/microliter. Available evidence suggests that patients with lymphoid and solid cancers respond equivalently to epoetin alfa (rch) therapy and that patients with or without tumour infiltration of the bone marrow respond equivalently to epoetin alfa (rch) therapy.
Efficacy and safety of epoetin alfa (rch) in the prevention and treatment of anaemia of cancer have not been demonstrated in children.
Epoetin alfa (rch) 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 epoetin alfa (rch) 300 IU/kg, epoetin alfa (rch) 100 IU/kg or placebo by subcutaneous injection for ten 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 (rch) 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 (rch) 300 IU/kg, 6/26 (23%) of epoetin alfa (rch) 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 (rch) 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 (rch) treated patients.
Epoetin alfa (rch) 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 (rch) (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 pharmacological anticoagulation therapy.
From pretreatment to presurgery, the mean increase in haemoglobin in the 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 epoetin alfa (rch) 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 epoetin alfa (rch).
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 epoetin alfa (rch) 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 epoetin alfa (rch) (p < 0.05) were able to predeposit between three and six units, inclusively, of autologous blood than the corresponding placebo treated patients. Virtually all (98%) of epoetin alfa (rch) treated patients predeposited three or more units, compared with 69% of placebo treated patients. While 37% of placebo patients were able to predeposit four or five units, 81% of epoetin alfa (rch) patients predeposited four or more units. Among the evaluable patients, fewer patients who received epoetin alfa (rch) 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 epoetin alfa (rch) 600 IU/kg, epoetin alfa (rch) 300 IU/kg or placebo twice weekly for three weeks. A significantly greater amount of autologous blood (p < 0.005) was donated by the epoetin alfa (rch) 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.
A randomised, double blind, multicentre phase III study (study number 2003-29-INJ-9) was conducted to evaluate therapeutic equivalence in terms of haemoglobin response of epoetin lambda (rch) 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 epoetin alfa (rch) to epoetin lambda (rch).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 epoetin lambda (rch) (N = 314).
In the evaluation phase (weeks 25-28) patients treated with epoetin lambda (rch) showed a comparable Hb level after treatment with epoetin lambda (rch) to their Hb level at start of the treatment. No relevant differences regarding dosing could be observed. Epoetin lambda (rch) has shown to be therapeutically equivalent to 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 epoetin lambda and treated for another 28 weeks. The switch to epoetin lambda did not demonstrate any safety relevant changes.
The long-term safety profiles of epoetin lambda (rch) and epoetin alfa (rch) were comparable. No formation of antiepoetin antibodies was detected. The safety and efficacy of subcutaneous administration of epoetin lambda (rch) in patients with chronic renal failure has not been studied.
A randomised, double blind, multicentre phase III study (study number 2003-31-INJ-11) was conducted to assess the efficacy and safety of epoetin lambda (rch) in the treatment of chemotherapy induced, symptomatic anaemia in patients with solid tumours.
114 patients were treated with epoetin lambda (rch) or 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 epoetin lambda (rch) treatment the Hb level increased by ≥ 20 g/L with the confidence interval being entirely above the predefined threshold of 30%. In the epoetin lambda (rch) group, 32% of patients required transfusions versus 38% in the epoetin alfa (rch) group. None of the secondary efficacy endpoints showed relevant differences between the treatment groups and also the safety profiles were similar.
An open label, single arm, multicentre phase III study (study number HX575-308) was conducted to evaluate the safety and immunogenicity of HX575 epoetin lambda administered subcutaneously in the treatment of anaemia associated with chronic kidney disease in pre-dialysis and dialysis patients.
Patient eligibility was assessed during a 4-week screening period, after which patients entered a 52 week treatment period. A 6-month safety follow-up was conducted for patients with binding, non-neutralising anti-erythropoietin antibodies. Doses were individually titrated to maintain haemoglobin concentrations in the range between 10 and 12 g/dL, and the dosing frequency was adjusted as required. A total of 416 patients were included in the safety population and 303 in the per protocol population.
For ESA naïve patients the starting dose for correcting anaemia was 25 IU/kg of body weight 3 times per week or 75 IU/kg of body weight once per week from analysis week 1 to week 5. After analysis week 5 dose adjustments were possible.
Binding anti-epoetin antibodies were detected via radioimmunoprecipitation (RIP) assay in seven (1.7%, incidence rate of 0.019) of patients in the safety population at some time during the study. No patient developed neutralising antibodies as tested in a cell-based neutralising anti-erythropoietin antibody assay. The 'detected by RIP assay binding antibodies' had no clinical impact on the treatment efficacy. There were no clinical signs of immunogenicity or hypersensitivity.
Prior to study treatment, binding anti-epoetin antibodies were detected in thirteen (eight ESA naïve and 5 ESA pre-treated) of 993 patients (1.3%) via RIP assay during screening. Therefore, given the high sensitivity of the RIP assay, with a potential 1% false-positive rate, the low antibody titres of most positive samples and the fact there was no increase in titer over consecutive visits with continued HX575 treatment, a persistent anti-drug antibody response can be excluded.
Epoetin lambda (rch) 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.
Epoetin lambda (rch) has not been studied in patients scheduled for elective surgery, either to treat moderate anaemia or to augment autologous blood collection (see Section 4.1 Therapeutic Indications). However, comparable efficacy and safety can be expected in these patients since comparable efficacy and safety to epoetin alfa (rch) has been demonstrated in the anaemia of chronic renal failure (IV administration) and chemotherapy induced anaemia settings.

5.2 Pharmacokinetic Properties

Absorption.

Following subcutaneous injection, erythropoietin serum levels remain elevated above baseline for about 72 hours. There is no accumulation when three times 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. Following subcutaneous injection, serum levels are much lower than the levels achieved following intravenous injection; the levels increase slowly and reach a peak between 6 and 24 hours post-dose. The peak is always well below the peak achieved using the intravenous route (approximately 1/20 of the value).

Distribution.

The bioavailability of subcutaneous injectable erythropoietin is much lower than that of the intravenous medicine (approximately 20 to 30%).

Metabolism.

Metabolism data was not studied for epoetin lambda.

Excretion.

After intravenous administration, the mean half-lives in normal volunteers ranged from 2.5 to 6.7 hours. The half-life is difficult to evaluate for the subcutaneous route and is estimated to be about 24 hours.

PK in special populations.

No information is available in young or elderly patients. Due to decreased metabolism, patients with hepatic dysfunction may have increased erythropoiesis with epoetin lambda (rch).

Bioequivalence.

Phase I studies investigating pharmacokinetic parameters following intravenous and subcutaneous repeated dosing have demonstrated the bioequivalence of Novicrit to a reference epoetin alfa (rch) preparation.
Bioequivalence after multiple intravenous administration was demonstrated in an open, randomised, parallel study in 80 healthy volunteers receiving 100 IU/kg body weight 3 times per week for 4 weeks. The pharmacokinetic parameters are summarised in Table 8.
Bioequivalence after multiple subcutaneous administration was demonstrated in an open, randomised, parallel study in 80 healthy volunteers receiving 100 IU/kg body weight 3 times per week for 4 weeks. The pharmacokinetic parameters are summarised in Table 9.
These results demonstrate that Novicrit is bioequivalent to a reference epoetin alfa (rch) preparation with respect to the pharmacokinetic parameters AUC and Cmax after multiple intravenous and multiple subcutaneous application.

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. These reports, based on in vitro findings from human tumour samples, are of uncertain significance in the clinical situation.

6 Pharmaceutical Particulars

6.1 List of Excipients

Dibasic dihydrate sodium phosphate, monobasic dihydrate sodium, phosphate, sodium chloride, glycine, polysorbate 80, hydrochloric acid, sodium hydroxide and water for injections. Novicrit pre-filled syringes contain no preservatives.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.
For information on interactions with other medicines and other forms of interactions, see Section 4.5.

6.3 Shelf Life

For the purpose of ambulatory use for one single period of up to 3 days.

6.4 Special Precautions for Storage

Store and transport refrigerated (2°C - 8°C). Do not freeze.
Keep the pre-filled syringe in the outer carton in order to protect from light.
For the purpose of ambulatory use, the patient may remove Novicrit from the refrigerator and store it not above 25°C.

6.5 Nature and Contents of Container

Novicrit is supplied as a clear, colourless solution in a single-dose, pre-filled syringe. The prefilled syringes are ready-to-use. The pre-filled syringes are fitted with a needle shield device. The needle cover contains a derivative of latex (FM27) (see Section 4.4 Special Warnings and Precautions for Use).
Packs of 1 syringe or 6 syringes.
Not all presentations are marketed in Australia.

6.6 Special Precautions for Disposal

The pre-filled syringes are for single use in one patient only. Discard any unused portion.

6.7 Physicochemical Properties

Chemical structure.

The chemical name of Novicrit is Epoetin lambda (rch). Its empirical formula is C809H1299N229O239S5. (Molecular weight: About 28,000 Daltons. The protein moiety, a single chain polypeptide of 165 amino acids, has a molecular weight of 18,243 Daltons. The carbohydrate moiety with three N-linked and one O-linked carbohydrate groups corresponds to a weight fraction of approximately 40%) and its chemical structure is:

CAS number.

No data available.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes