Consumer medicine information

Aranesp

Darbepoetin alfa

BRAND INFORMATION

Brand name

Aranesp

Active ingredient

Darbepoetin alfa

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Aranesp.

SUMMARY CMI

Aranesp®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

WARNING: Important safety information is provided in a boxed warning in the full CMI. Read before using this medicine.

1. Why am I using Aranesp?

Aranesp contains the active ingredient darbepoetin alfa. Aranesp is used to treat anaemia that is associated with chronic renal failure (kidney failure) and anaemia in cancer patients who are receiving chemotherapy.

For more information, see Section 1. Why am I using Aranesp? in the full CMI.

2. What should I know before I use Aranesp?

Do not use if you have ever had an allergic reaction to Aranesp or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use Aranesp? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with Aranesp and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use Aranesp?

  • Following blood tests, your doctor will prescribe the strength of Aranesp that is best for you.
  • Aranesp can be self-administered by injection under the skin after training from your doctor or nurse. It can also be injected into a vein by a doctor or nurse.

More instructions can be found in Section 4. How do I use Aranesp? in the full CMI.

5. What should I know while using Aranesp?

Things you should do
  • Tell your doctor if you are pregnant, think you may be pregnant or are planning to have a baby.
  • Keep all of your doctor's appointments so that your progress can be monitored.
  • Remind your doctor, dentist, nurse or pharmacist on your visit that you are using Aranesp.
Things you should not do
  • Do not stop using this medicine suddenly.
  • Do not inject Aranesp into a vein yourself.
Looking after your medicine
  • Store Aranesp in the refrigerator (between 2 to 8°C). Do not freeze.
  • Keep in the original box to protect it from light until it's time to inject it. Do not shake.

For more information, see Section 5. What should I know while using Aranesp? in the full CMI.

6. Are there any side effects?

Serious side effects include serious allergic or hypersensitivity reaction, severe skin reactions, sudden rise in blood pressure, seizures or fits, stroke, heart attack, blood clots, pure red cell aplasia (PRCA), problems with dialysis shunt and high blood pressure.

Very common side effects include redness, swelling, pain or itching at the injection site, tiredness, chest or throat infection, difficulty breathing, cough, itching, fast heart rate, shortness of breath, and chest tightness, fever, flu-like feeling, headache, dizziness, nausea, vomiting, diarrhoea, constipation, loss of appetite, stomach pain, pins and needles, diminished sense of touch, pain in joints, limbs, muscles or bones and fluid retention.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.

WARNING FOR CANCER PATIENTS: Your doctor can use Aranesp to treat anaemia if you are receiving chemotherapy for cancer and your doctor decides that blood transfusion is not an option for you. In some clinical studies, the use of Aranesp to treat anaemia was associated with increased risk of death in patients receiving chemotherapy for cancer.



FULL CMI

Aranesp®

Active ingredient(s): darbepoetin alfa

Consumer Medicine Information (CMI)

This leaflet provides important information about using Aranesp. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using Aranesp.

Where to find information in this leaflet:

1. Why am I using Aranesp?
2. What should I know before I use Aranesp?
3. What if I am taking other medicines?
4. How do I use Aranesp?
5. What should I know while using Aranesp?
6. Are there any side effects?
7. Product details

1. Why am I using Aranesp?

Aranesp contains the active ingredient darbepoetin alfa. Aranesp is recombinant erythropoietic protein produced by special mammalian cells.

Aranesp is used to treat anaemia. Anaemia is a condition where the blood does not contain a sufficient amount of red blood cells. The symptoms of anaemia may include fatigue, dizziness, increased heart rate, depression, nausea, loss of appetite, feeling cold, shortness of breath and pale skin colour.

Aranesp works in exactly the same way as the natural hormone erythropoietin. Erythropoietin is produced in the kidneys and encourages bone marrow to produce more red blood cells. It will take your body some time to make more red blood cells, so it can take about four weeks before you notice any effect.

Aranesp is used to treat:

  • anaemia that is associated with chronic renal failure (kidney failure).
    In kidney failure, the kidney does not produce enough of the natural hormone erythropoietin which can often cause anaemia. If you are on dialysis, your normal dialysis routine will not affect the ability of Aranesp to treat your anaemia.
  • anaemia in cancer patients who are receiving chemotherapy.
    Some chemotherapy medicines can affect the bone marrow's ability to produce enough red blood cells.

2. What should I know before I use Aranesp?

Warnings

Do not use Aranesp if:

  • you have high blood pressure that is not controlled by other medicines.
  • you are allergic to other erythropoietin products, Aranesp, medicines made using mammalian cells, or to any of the ingredients listed at the end of this leaflet. Always check the ingredients to make sure you can use this medicine.

Do not misuse Aranesp.

Misuse by healthy people can cause life-threatening problems with the heart or blood vessels.

Check with your doctor if you:

  • have any blood clotting diseases,
  • have epilepsy or convulsions (fits or seizures),
  • have an allergy to latex. The needle shield on the pre-filled pen and the needle cover on pre-filled syringe contain a derivative of latex,
  • have any other illness or health problems, a number of conditions such as infections, vitamin deficiencies or cancers may affect how well you respond to Aranesp,
  • take any medicines for any other condition

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Patients with cancer

In some clinical studies, the use of Aranesp to treat anaemia was associated with increased risk of death in patients receiving chemotherapy for cancer. Discuss this with your doctor.

Pregnancy

Check with your doctor if you are pregnant or intend to become pregnant.

Breastfeeding

Talk to your doctor if you are breastfeeding or intend to breastfeed. It is not known if Aranesp passes into breast milk.

Use in children

Do not give Aranesp to a child.

3. What if I am taking other medicines?

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

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect Aranesp.

4. How do I use Aranesp?

How much to use

  • Following blood tests, your doctor has prescribed the strength of Aranesp that is best for you. You need to inject the full contents of the syringe.
  • While you are taking Aranesp, your doctor will take blood samples to measure how well your anaemia is responding and may change the strength if necessary.
  • Follow the instructions provided and use Aranesp until your doctor tells you to stop.

When to use Aranesp

  • Your doctor will decide which injection frequency is best for you. Aranesp should be used once a week, once every two weeks, once every three weeks, or once a month.

How to inject Aranesp

Aranesp can be injected either:

  • under the skin (subcutaneous injection) using either the pre-filled pen, the pre-filled syringe or the pre-filled syringe with automatic needle guard; or
  • into a vein (intravenous injection) using the pre-filled syringe or the pre-filled syringe with automatic needle guard.

You can give yourself a subcutaneous injection after you have received training from your doctor or nurse. Intravenous injections are given by a doctor or nurse.

Never inject Aranesp into a vein yourself.

If you have any questions regarding injecting instructions, please ask your doctor, nurse or pharmacist for assistance.

If you forget to use Aranesp

If you have forgotten to inject Aranesp, contact your doctor or nurse to discuss when you should next inject.

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

If you use too much Aranesp

If you think that you have injected too much Aranesp, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while using Aranesp?

Things you should do

  • Tell your doctor if you are pregnant, think you may be pregnant or are planning to have a baby.
  • If you are about to start a new medicine, remind your doctor, nurse and pharmacist that you are taking Aranesp.
  • If you are going to have surgery, tell the surgeon that you are taking this medicine.
  • Keep all of your doctor's appointments so that your progress can be monitored. While you are taking Aranesp, your doctor will take blood samples to measure how your anaemia is responding and may change the strength if necessary. Your doctor will check your blood pressure regularly.

Always follow your doctor's instructions carefully.

Call your doctor straight away if you have:

  • Serious allergic or hypersensitivity reactions such as drop in blood pressure (faintness), fast pulse, difficulty breathing, sweating, swelling of the face, lips, mouth tongue or throat which may cause difficulty in swallowing or breathing, shortness of breath, skin rash, including rash over the whole body, hives.
  • Severe skin reactions such as a rash, which may be severe, may cover your whole body and can also include blisters or areas of skin coming off.
  • Signs of a sudden rise in blood pressure such as sudden, stabbing, migraine-like headaches, confusion, seizures or fits.
  • Signs of stroke such as tingling of the extremities, slight weakness on one side of the body, speech difficulties, double vision, dizziness, headache, imbalance.
  • Signs of a heart attack such as chest pain.
  • Sudden severe headache, loss of vision, loss of coordination, slurred speech, shortness of breath, chest pain, numbness, heat or swelling in the arms and legs.
  • If you have symptoms which include unusual tiredness and a lack of energy this could mean you have pure red cell aplasia (PRCA), which has been reported in patients with chronic kidney failure. PRCA means the absence of very young red blood cells in the bone marrow.

Remind any doctor, dentist or pharmacist you visit that you are using Aranesp.

Things you should not do

  • Do not inject Aranesp into a vein yourself.
  • Do not stop using this medicine suddenly.
  • Do not use Aranesp to treat any other condition unless your doctor says so.
  • Do not give Aranesp to anyone else, even if their symptoms seem similar to yours.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how Aranesp affects you.

The effects on your ability to drive or use machines whilst taking Aranesp are not known.

Looking after your medicine

  • Keep Aranesp in the refrigerator (between 2 and 8°C). You can use Aranesp if it has been left out of the refrigerator, for no longer than 2 days at room temperature (up to 30°C).
  • Do not freeze. You can use Aranesp if accidentally left frozen for less than 2 days.
  • Always keep Aranesp in the original box to protect it from light.
  • Do not shake.

Follow the instructions on the carton on how to take care of your medicine properly.

The pre-filled syringe with automatic needle guard can be taken out of the refrigerator 30 minutes before injection, provided it is kept in the carton. This may make the injection more comfortable.

The pre-filled pen can be taken out of the refrigerator at least 30 minutes before injection, provided it is kept in the carton.

Do not use this medicine after the expiry date.

Keep it where young children cannot reach it.

When to discard your medicine

Do not use Aranesp if it has been left out of the refrigerator at room temperature for longer than 2 days.

Do not use Aranesp if it has been frozen for longer than 2 days.

Disposal of used syringes

Do not attempt to put the needle cover back onto the used syringe.

Put used pre-filled pens and pre-filled syringes into the puncture-resistant sharps container and keep it out of the reach and sight of children.

Never put the used pre-filled pens or used pre-filled syringes into your normal household rubbish bin.

Dispose of the full puncture-resistant sharps container as instructed by your doctor, nurse or pharmacist.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may be serious and need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effectsWhat to do
Injection site:
  • redness
  • swelling
  • pain
  • itching
Lung and upper airways:
  • chest or throat infection
  • shortness of breath or difficulty breathing
  • chest tightness or pain (non-cardiac)
  • cough
  • flu-like symptoms
  • bleeding from the nose
Brain and nerves:
  • headache
  • dizziness, light-headedness
  • pins and needles
  • diminished sense of touch
Skin:
  • itching
  • hair loss
Gut and digestion:
  • nausea (feeling sick)
  • stomach pain
  • diarrhoea, constipation
  • vomiting
  • decreased appetite
Muscle and skeleton:
  • pain in joints, limbs, back, muscles or bones
Urinary:
  • urinary tract infection (pain in abdomen or pelvic region, stinging or burning urine, more frequent need to pass urine)
General:
  • tiredness and weakness
  • fever, chills
  • fast heart rate
  • trouble sleeping
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
Signs of a condition called pure red cell aplasia (PRCA)
  • more tiredness than usual
Signs of problems with your dialysis shunt:
  • bleeding, infection or clotting in your shunt (a channel that bypasses normal blood circulation) if you are receiving haemodialysis
Signs of high blood pressure:
  • headache
  • bleeding from the nose
Call your doctor straight away if you notice any of these serious side effects.
Signs of a serious allergic or hypersensitivity reaction:
  • drop in blood pressure (faintness)
  • fast pulse
  • difficulty breathing
  • sweating
  • swelling of the face, lips, mouth tongue or throat which may cause difficulty in swallowing or breathing
  • shortness of breath
  • skin rash, including rash over the whole body, hives
Signs of severe skin reactions:
  • a rash, which may be severe, may cover your whole body and can also include blisters or areas of skin coming off
Signs of a sudden rise in blood pressure:
  • sudden, stabbing, migraine-like headaches
  • confusion
  • seizures or fits
Signs of stroke:
  • tingling of the extremities
  • slight weakness on one side of the body
  • speech difficulties
  • double vision
  • dizziness
  • headache
  • imbalance
Signs of a heart attack:
  • chest pain
  • dizziness
  • shortness of breath or difficulty breathing
Other side effects:
  • sudden severe headache
  • loss of vision
  • loss of coordination
  • slurred speech, shortness of breath
  • chest pain
  • numbness, heat or swelling in the arms and legs
  • convulsions, fits or seizures
Call your doctor straight away or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

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

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

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

What Aranesp contains

Active ingredient
(main ingredient)		darbepoetin alfa
Other ingredients
(inactive ingredients)		polysorbate 80
monobasic sodium phosphate monohydrate
dibasic sodium phosphate
sodium chloride
water for Injection

Do not take this medicine if you are allergic to any of these ingredients.

What Aranesp looks like

Aranesp is a clear, colourless liquid available as:

  • Pre-filled pens containing from 20 to 150 microgram of darbepoetin alfa in each pre-filled pen. Aranesp SureClick is available in packs containing 1 pre-filled pen.
  • Pre-filled syringes with automatic needle guard, containing from 20 to 150 microgram of darbepoetin alfa in each pre-filled syringe. Aranesp is available in packs containing 4 pre-filled syringes.
  • Pre-filled syringe containing 10 microgram of darbepoetin alfa. Aranesp is available in packs containing 4 pre-filled syringes.

Australian Registration Numbers

Pre-filled pen:

Aranesp 20 microgram/0.5 mL (AUST R 122853)
Aranesp 40 microgram/0.4 mL (AUST R 122851)
Aranesp 60 microgram/0.3 mL (AUST R 122849)
Aranesp 80 microgram/0.4 mL (AUST R 122855)
Aranesp 100 microgram/0.5 mL (AUST R 122852)
Aranesp 150 microgram/0.3 mL (AUST R 122854)

Pre-filled syringe with automatic needle guard:

Aranesp 20 microgram/0.5 mL (AUST R 166090)
Aranesp 30 microgram/0.3 mL (AUST R 166092)
Aranesp 40 microgram/0.4 mL (AUST R 166094)
Aranesp 50 microgram/0.5 mL (AUST R 166095)
Aranesp 60 microgram/0.3 mL (AUST R 166688)
Aranesp 80 microgram/0.4 mL (AUST R 166097)
Aranesp 100 microgram/0.5 mL (AUST R 166087)
Aranesp 150 microgram/0.3 mL (AUST R 166089)

Pre-filled syringe:

Aranesp 10 microgram/0.4 mL (AUST R 77950)

Who distributes Aranesp

Amgen Australia Pty Ltd
Level 11, 10 Carrington St
Sydney NSW 2000
Ph: 1800 803 638
www.amgenmedinfo.com.au

This leaflet was prepared in October 2024.

Published by MIMS January 2025

BRAND INFORMATION

Brand name

Aranesp

Active ingredient

Darbepoetin alfa

Schedule

S4

 

1 Name of Medicine

Darbepoetin alfa.

2 Qualitative and Quantitative Composition

Aranesp darbepoetin alfa (rch) 10 microgram/0.4 mL injection syringe within a pen injector.
Aranesp darbepoetin alfa (rch) 15 microgram/0.38 mL injection syringe within a pen injector.
Aranesp darbepoetin alfa (rch) 20 microgram/0.5 mL injection syringe within a pen injector.
Aranesp darbepoetin alfa (rch) 30 microgram/0.3 mL injection syringe within a pen injector.
Aranesp darbepoetin alfa (rch) 40 microgram/0.4 mL injection syringe within a pen injector.
Aranesp darbepoetin alfa (rch) 50 microgram/0.5 mL injection syringe within a pen injector.
Aranesp darbepoetin alfa (rch) 60 microgram/0.3 mL injection syringe within a pen injector.
Aranesp darbepoetin alfa (rch) 80 microgram/0.4 mL injection syringe within a pen injector.
Aranesp darbepoetin alfa (rch) 100 microgram/0.5 mL injection syringe within a pen injector.
Aranesp darbepoetin alfa (rch) 150 microgram/0.3 mL injection syringe within a pen injector.
Aranesp darbepoetin alfa (rch) 200 microgram/0.4 mL injection syringe within a pen injector.
Aranesp darbepoetin alfa (rch) 300 microgram/0.6 mL injection syringe within a pen injector.
Aranesp darbepoetin alfa (rch) 500 microgram/1.0 mL solution for injection syringe within a pen injector.
Aranesp darbepoetin alfa (rch) 15 microgram/0.38 mL injection syringe with automatic needle guard.
Aranesp darbepoetin alfa (rch) 20 microgram/0.5 mL injection syringe with automatic needle guard.
Aranesp darbepoetin alfa (rch) 30 microgram/0.3 mL injection syringe with automatic needle guard.
Aranesp darbepoetin alfa (rch) 40 microgram/0.4 mL injection syringe with automatic needle guard.
Aranesp darbepoetin alfa (rch) 50 microgram/0.5 mL injection syringe with automatic needle guard.
Aranesp darbepoetin alfa (rch) 60 microgram/0.3 mL injection syringe with automatic needle guard.
Aranesp darbepoetin alfa (rch) 80 microgram/0.4 mL injection syringe with automatic needle guard.
Aranesp darbepoetin alfa (rch) 100 microgram/0.5 mL injection syringe with automatic needle guard.
Aranesp darbepoetin alfa (rch) 150 microgram/0.3 mL injection syringe with automatic needle guard.
Aranesp darbepoetin alfa (rch) 200 microgram/0.4 mL injection syringe with automatic needle guard.
Aranesp darbepoetin alfa (rch) 300 microgram/0.6 mL injection syringe with automatic needle guard.
Aranesp darbepoetin alfa (rch) 500 microgram/1.0 mL solution for injection syringe with automatic needle guard.
Aranesp darbepoetin alfa (rch) 10 microgram/0.4 mL injection syringe.
Aranesp darbepoetin alfa (rch) 15 microgram/0.38 mL injection syringe.
Aranesp darbepoetin alfa (rch) 20 microgram/0.5 mL injection syringe.
Aranesp darbepoetin alfa (rch) 30 microgram/0.3 mL injection syringe.
Aranesp darbepoetin alfa (rch) 40 microgram/0.4 mL injection syringe.
Aranesp darbepoetin alfa (rch) 50 microgram/0.5 mL injection syringe.
Aranesp darbepoetin alfa (rch) 60 microgram/0.3 mL injection syringe.
Aranesp darbepoetin alfa (rch) 80 microgram/0.4 mL injection syringe.
Aranesp darbepoetin alfa (rch) 100 microgram/0.5 mL injection syringe.
Aranesp darbepoetin alfa (rch) 150 microgram/0.3 mL injection syringe.
Aranesp darbepoetin alfa (rch) 200 microgram/0.4 mL injection syringe.
Aranesp darbepoetin alfa (rch) 300 microgram/0.6 mL injection syringe.
Aranesp darbepoetin alfa (rch) 500 microgram/1.0 mL solution for injection syringe.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Aranesp is a sterile, clear, colourless, preservative-free aqueous solution for injection.

4 Clinical Particulars

4.1 Therapeutic Indications

Aranesp is indicated for the treatment of anaemia associated with chronic renal failure (CRF).
Aranesp is also indicated for the treatment of anaemia in patients with non-myeloid malignancies where anaemia develops as a result of concomitantly administered chemotherapy, and where blood transfusion is not considered appropriate.

4.2 Dose and Method of Administration

Dosage (dose and interval).

Use the lowest dose of Aranesp that will gradually increase the haemoglobin concentration to approach a target of not more than 120 g/L; the rate of haemoglobin increase should not exceed 10 g/L in any 2-week period.
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).

CRF patients.

For patients where intravenous (IV) access is routinely available (haemodialysis patients), administration of Aranesp by the IV route is preferable. Where IV access is not readily available (patients not yet undergoing dialysis and peritoneal dialysis patients) Aranesp may be administered as a subcutaneous (SC) injection.
The dose should be started and titrated slowly (e.g. once every 4 weeks) based on individual haemoglobin levels. The haemoglobin target, regardless of the treatment population, should not exceed 120 g/L (see Section 4.2 Dose and Method of Administration, Dose adjustment in CRF patients). Clinical studies have shown interpatient response to be variable. If a patient fails to respond, or maintain a response, other aetiologies should be considered and evaluated (see Section 4.4 Special Warnings and Precautions for Use, General). Haemoglobin levels should be monitored frequently until stable. Thereafter, haemoglobin levels can be monitored less frequently. In clinical studies that were used for approval of Aranesp in patients with CRF, haemoglobin levels were measured every 1 to 2 weeks.
Dosing instructions are provided for two phases of treatment: correction of anaemia and maintenance of the target haemoglobin level. Instructions for dose adjustment and for conversion from recombinant human erythropoietin (r-HuEPO) to Aranesp are also provided.

Correction of anaemia.

The initial or starting dose of Aranesp for patients on dialysis is 0.45 microgram/kg body weight administered as a single SC or IV injection once weekly.
Patients not on dialysis may receive any of the following initial doses:
0.45 microgram/kg as a single SC injection once weekly; or
0.75 microgram/kg as a single SC injection once every 2 weeks; or
1.5 microgram/kg as a single SC injection once monthly.
If the increase in haemoglobin is inadequate (less than 10 g/L in 4 weeks) and iron stores are adequate (see Section 4.4 Special Warnings and Precautions for Use, General), the dose of Aranesp may be increased by approximately 25%. Further increases may be made at 4-week intervals, until the desired response is attained.

Maintenance of haemoglobin concentration.

For patients on dialysis, Aranesp may be dosed once weekly or once every 2 weeks at the titrated dose to maintain the target haemoglobin.
For patients not on dialysis, Aranesp may be dosed once weekly, once every 2 weeks or once monthly at the titrated dose to maintain the target haemoglobin.
Patients not on dialysis receiving Aranesp once every 2 weeks may be dosed once monthly using twice the once every 2-week dose. Thereafter, the monthly dose should be titrated as necessary to maintain the haemoglobin target. If a dose adjustment is required to maintain a target haemoglobin, the individual dose may be adjusted at 4-week intervals until the appropriate haemoglobin level is achieved (see Section 4.2 Dose and Method of Administration, Dose adjustment in CRF patients).
Dose changes in the maintenance phase of treatment should not be made more frequently than every 2 weeks.
When changing the route of administration, the same dose should be used and the haemoglobin monitored so that the appropriate Aranesp dose adjustments can be made to keep the haemoglobin at a target not to exceed 120 g/L. Data from 809 patients receiving Aranesp in Australian and European clinical studies were analysed to assess the dose required to maintain haemoglobin; no difference was observed between the average weekly dose administered via the IV and SC routes of injection.

Conversion from recombinant human erythropoietin to Aranesp.

Due to its longer serum half-life, Aranesp can be administered less frequently than r-HuEPO. Clinical experience has shown that patients receiving r-HuEPO 2 or 3 times weekly may change to once weekly Aranesp. Those receiving r-HuEPO once weekly may change to Aranesp administered once every 2 weeks. The substitution of Aranesp for r-HuEPO should be based on the patient's r-HuEPO dose at the time of substitution, and the same route of administration should be used. The initial SC dose of Aranesp (microgram/week) can be determined by dividing the total weekly SC dose of r-HuEPO (U/week) by 200, while the initial IV dose can be determined by dividing the total weekly IV dose of r-HuEPO (U/week) by 240. Because of individual variability, doses should be titrated as described above to maintain the haemoglobin at the desired concentration.

Patients with non-myeloid malignancies receiving chemotherapy.

Treatment should not be commenced unless haemoglobin falls below 100-110 g/L. The recommended initial dose is 500 microgram or 6.75 microgram/kg body weight given once every 3 weeks as a single SC injection. If the clinical response of the patient (fatigue, haemoglobin response) is inadequate after nine weeks, further therapy may not be effective. Alternatively, once-weekly SC dosing can be given at 2.25 microgram/kg body weight.
The aim of treatment is to increase haemoglobin concentration to a target not to exceed 120 g/L and to reduce the requirement for blood transfusions. The therapy should be continued for approximately 4 weeks after the end of chemotherapy or until haemoglobin concentrations approach 120 g/L.

Method of administration.

Aranesp may be administered by either a pre-filled syringe, pre-filled syringe with automatic needle guard or pre-filled pen (SureClick).
Aranesp may be administered SC by a patient or caregiver after being trained by a doctor, nurse or pharmacist.
Do not shake Aranesp. Prolonged vigorous shaking may denature any protein, rendering it biologically inactive.
Parenteral drug products should be inspected visually for particulate matter and discolouration prior to administration. Do not use any products exhibiting particulate matter or discolouration.
Do not dilute or administer Aranesp in conjunction with other drug solutions.
Aranesp contains no antimicrobial agent. Aranesp is for single use in one patient only. Discard any residue.
Allow Aranesp to reach room temperature before injecting.
The Aranesp pre-filled pen (SureClick) delivers the complete dose by SC administration.

Dosage adjustment.

Dose adjustment in CRF patients.

The dose should be adjusted for each patient to achieve and maintain a target haemoglobin not to exceed 120 g/L. Dose adjustment instructions should be followed to achieve and maintain a target haemoglobin or in response to an excessive rate of rise of haemoglobin.
If the haemoglobin is increasing and approaching 120 g/L, the dose should be reduced by approximately 25%. If after a dose reduction, 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 rise in haemoglobin is more than 10 g/L in 2 weeks, reduce the dose by 25%.

Dose adjustment in cancer patients.

If the haemoglobin approaches 120 g/L, the dose should be reduced by 25 to 50%. For both once weekly and once every 3-week dosing schedules, if the haemoglobin exceeds 120 g/L treatment should be temporarily withheld until the haemoglobin decreases to approximately 110 g/L, at which point therapy should be re-initiated at 25 to 50% below the previous dose.
If haemoglobin increases by more than 10 g/L in a 2-week period, the dose should be reduced by 25 to 50%.
For patients receiving Aranesp on a weekly basis, if the increase in haemoglobin is inadequate (less than 10 g/L after approximately 1 month of therapy), or if the response is not satisfactory in terms of reducing red blood cell (RBC) transfusion requirements, the dose should be doubled to 4.5 microgram/kg given once weekly.

4.3 Contraindications

Aranesp is contraindicated in patients with:
1. Uncontrolled hypertension.
2. Known sensitivity to products derived from mammalian cells.
3. Known hypersensitivity to darbepoetin alfa or any of the excipients found in Aranesp.

4.4 Special Warnings and Precautions for Use

Cardiovascular and thrombotic events/ increased mortality.

Cardiovascular and thrombotic events such as myocardial ischaemia and infarction, cerebrovascular haemorrhage and infarction, transient ischaemic attacks, deep venous thrombosis, arterial thrombosis, pulmonary emboli, retinal thrombosis and haemodialysis graft occlusion have been reported in patients receiving erythropoiesis stimulating agents (ESAs) such as Aranesp.
ESAs have been associated with an increased risk of death, serious cardiovascular events or stroke in controlled clinical trials when administered to target a haemoglobin of greater than 120 g/L. There was an increased risk of serious arterial and venous thromboembolic events, including myocardial infarction, stroke, congestive heart failure and haemodialysis graft occlusion. A rate of haemoglobin rise of greater than 10 g/L over 2 weeks may also contribute to these risks.
To reduce cardiovascular risks, use the lowest dose of Aranesp that will gradually increase the haemoglobin concentration. The haemoglobin concentration should aim not to exceed a target of 120 g/L; the rate of haemoglobin increase should not exceed 10 g/L in any 2-week period (see Section 4.2 Dose and Method of Administration).
CRF patients with relative hyporesponsiveness to ESAs may be at increased risk for mortality and cardiovascular events. These patients should be evaluated for treatable conditions and caution should be used when increasing the dose (see Section 4.4 Special Warnings and Precautions for Use, General).
In a randomised prospective trial, 1432 anaemic CRF patients who were not undergoing dialysis were assigned to epoetin alfa treatment targeting a maintenance haemoglobin concentration of 135 g/L or 113 g/L. A major cardiovascular event (death, myocardial infarction, stroke, or hospitalisation for congestive heart failure) occurred among 125 (18%) of the 715 patients in the higher haemoglobin group compared to 97 (14%) among the 717 patients in the lower haemoglobin group (HR 1.3, 95% CI: 1.0, 1.7, p = 0.03).
Increased risk for serious cardiovascular events was also reported from a randomised, prospective trial of 1265 haemodialysis patients with clinically evident cardiac disease (ischaemic heart disease or congestive heart failure). In this trial, patients were assigned to epoetin alfa treatment targeted to a maintenance haemoglobin of either 140 ± 10 g/L or 100 ± 10 g/L. Higher mortality (35% versus 29%) was observed in the 634 patients randomised to a target haemoglobin of 140 g/L than in the 631 patients assigned a target haemoglobin of 100 g/L. The reason for the increased mortality observed in this study is unknown; however, the incidence of nonfatal myocardial infarction, vascular access thrombosis and other thrombotic events was also higher in the group randomised to a target haemoglobin of 140 g/L.
In a randomised, double-blind, placebo-controlled study of 4,038 patients called TREAT, there was an increased risk of stroke (HR 1.92, 95% CI: 1.38, 2.68) when Aranesp was administered to anaemic patients with type 2 diabetes and CRF not on dialysis to target a haemoglobin level of 130 g/L compared with placebo-treated patients who received Aranesp when their haemoglobin levels were less than 90 g/L.
In a post hoc subgroup analysis of TREAT, more deaths from any cause were observed in those patients who indicated a prior history of malignancy and were treated with Aranesp to target a haemoglobin level of 130 g/L (60 deaths out of 188 patients randomised to Aranesp versus 37 deaths out of 160 patients randomised to placebo; HR: 1.38, 95% CI: 0.91, 2.07).
An increased incidence of thrombotic events has also been observed in patients with cancer treated with ESAs such as Aranesp (see Section 4.8 Adverse Effects (Undesirable Effects), Adverse events in cancer patients, Thrombotic events in cancer patients).
In a randomised controlled study (referred to as the 'BEST' study) with another ESA in 939 women with metastatic breast cancer receiving chemotherapy, patients received either weekly epoetin alfa or placebo for up to a year. This study was designed to show that survival was superior when an ESA was administered to prevent anaemia (maintain haemoglobin levels between 120 and 140 g/L or haematocrit between 36% and 42%). The trial was terminated prematurely when interim results demonstrated that a higher mortality at 4 months (8.7% versus 3.4%) and a higher rate of fatal thrombotic events (1.1% versus 0.2%) in the first 4 months of the study were observed among patients treated with epoetin alfa. Based on Kaplan-Meier estimates, at the time of study termination, the 12-month survival was lower in the epoetin alfa group than in the placebo group (70% versus 76%; HR 1.37, 95% CI: 1.07, 1.75; p = 0.012).
A systematic review of 57 randomised controlled trials (including the BEST and ENHANCE studies) evaluating 9353 patients with cancer compared ESAs plus RBC transfusion with RBC transfusion alone for prophylaxis or treatment of anaemia in cancer patients with or without concurrent antineoplastic therapy. An increased relative risk of thromboembolic events (RR 1.67, 95% CI: 1.35, 2.06; 35 trials and 6769 patients) was observed in ESA treated patients. An overall survival hazard ratio of 1.08 (95% CI: 0.99, 1.18; 42 trials and 8167 patients) was observed in ESA treated patients.

Growth factor potential/increased tumour progression.

Aranesp is a growth factor that primarily stimulates RBC production. Like all growth factors, there is a theoretical concern that Aranesp could act as a growth factor for any tumour type, particularly myeloid malignancies.
ESAs have been associated with shortened time to tumour progression in patients with advanced head and neck cancer receiving radiation therapy when administered to a haemoglobin between 140 to 155 g/L. Aranesp should only be used to treat cancer patients with anaemia where the anaemia has arisen as a result of concomitantly administered chemotherapy.
The ENHANCE study was a randomised controlled study in 351 head and neck cancer patients where epoetin beta or placebo was administered to achieve target haemoglobins of 140 and 150 g/L for women and men, respectively. Locoregional progression-free survival was significantly shorter in patients receiving epoetin beta, hazard ratio 1.62 (95% CI: 1.22, 2.14; p = 0.0008) with a median of 406 days epoetin beta versus 745 days placebo.
The DAHANCA 10 study, conducted in 522 patients with primary squamous cell carcinoma of the head and neck receiving radiation therapy were randomised to Aranesp or placebo. An interim analysis in 484 patients demonstrated a 10% increase in locoregional failure rate among Aranesp-treated patients (p = 0.01). At the time of study termination, there was a trend toward worse survival in the Aranesp-treated arm (p = 0.08).
ESAs have been associated with shortened survival in patients with metastatic breast cancer receiving chemotherapy when administered to a target haemoglobin of greater than 120 g/L.
The BEST study was previously described (see Section 4.4 Special Warnings and Precautions for Use, Cardiovascular and thrombotic events/ increased mortality). Mortality at 4 months (8.7% versus 3.4%) was significantly higher in the epoetin alfa arm. The most common investigator attributed cause of death within the first 4 months was disease progression; 28 of 41 deaths in the epoetin alfa arm and 13 of 16 deaths in the placebo arm were attributed to progressive disease. Investigator assessed time to tumour progression was not different between the two groups.

Use in cancer patients.

ESAs have been associated with an increased risk of death when administered to a haemoglobin target of 120 to 140 g/L in patients with active malignant disease receiving neither chemotherapy nor radiation therapy. Aranesp is not indicated for this population. Aranesp should only be used to treat cancer patients with anaemia where the anaemia has arisen as a result of concomitantly administered chemotherapy.
In a Phase 3, double-blind, randomised (Aranesp versus placebo), 16-week study in 989 anaemic patients with active malignant disease neither receiving nor planning to receive chemotherapy or radiation therapy, there was no evidence of a statistically significant reduction in proportion of patients receiving RBC transfusions. In addition, there were more deaths in the Aranesp treatment group [26% (136/515)] than the placebo group [20% (94/470)] at 16 weeks (completion of treatment phase). With a median survival follow-up of 4.3 months, the absolute number of deaths was greater in the Aranesp treatment group [49% (250/515)] compared with the placebo group [46% (216/470); HR 1.29, 95% CI: 1.08, 1.55].
In a Phase 3, multicentre, randomised (epoetin alfa versus placebo), double-blind study, patients with advanced non-small cell lung cancer unsuitable for curative therapy were treated with epoetin alfa targeting haemoglobin levels between 120 and 140 g/L. Following an interim analysis of 70 of 300 patients planned, a significant difference in median survival in favour of patients in the placebo group was observed (63 versus 129 days; HR 1.84; p = 0.04).

Hypertension.

Patients with uncontrolled hypertension should not be treated with Aranesp; blood pressure should be controlled adequately before initiation of therapy. Blood pressure may rise during treatment of anaemia with Aranesp. Hypertensive encephalopathy and seizures have been observed in patients with CRF treated with Aranesp or epoetin alfa.
Special care should be taken to closely monitor and control blood pressure in patients treated with Aranesp. During Aranesp therapy patients should be advised of the importance of compliance with antihypertensive therapy and dietary/fluid restriction. If blood pressure is difficult to control after initiation of appropriate antihypertensive measures, the dose of Aranesp should be reduced or temporarily withheld until haemoglobin begins to decrease (see Section 4.2 Dose and Method of Administration). A clinically significant change in haemoglobin may occur, but may not be observed for several weeks.

Pure red cell aplasia.

Pure red cell aplasia (PRCA) in association with neutralising antibodies to native erythropoietin has been observed in patients treated with ESAs, including Aranesp. This has been reported predominantly in patients with CRF and in patients with hepatitis C treated with interferon and ribavirin. Most cases have been associated with SC administration of ESAs.
Any patient with loss of response to Aranesp should be investigated for the typical causes of loss of effect (see Section 4.4 Special Warnings and Precautions for Use, General). Aranesp should be discontinued in any patient with evidence of PRCA and the patient evaluated for the presence of binding and neutralising antibodies to Aranesp, native erythropoietin and any other ESA administered to the patient. In patients with PRCA secondary to neutralising antibodies to any ESA, Aranesp should not be administered. Patients should not be switched to other ESA as antibodies may cross-react with other erythropoietins.

Convulsions.

Aranesp should be used with caution in patients with a history of convulsions. Cases of convulsions have been very rarely reported in patients receiving Aranesp.

General.

In order to ensure effective erythropoiesis, iron status should be evaluated for all patients before and during treatment, as the majority of patients will eventually require supplemental iron therapy. As per CARI Guidelines (Caring for Australians with Renal Impairment), supplemental iron therapy is recommended for all CRF patients whose serum ferritin is below 100 microgram/L or serum transferrin saturation is below 20%.
A lack of response or failure to maintain a haemoglobin response with Aranesp doses within the recommended dosing range should prompt a search for causative factors. Deficiencies of folic acid or vitamin B12 should be excluded or corrected. Intercurrent infections, inflammatory or malignant processes, osteofibrosis cystica, occult blood loss, haemolysis, severe aluminium toxicity or bone marrow fibrosis may compromise an erythropoietic response. A reticulocyte count should be considered as part of the evaluation. If typical causes of non-response are excluded and the patient has reticulocytopenia and a bone marrow biopsy demonstrates pure red cell aplasia, testing for anti-erythropoietin antibodies should be conducted. If patients do not respond to Aranesp and no causal factor can be found consider discontinuing Aranesp.
Misuse or abuse of Aranesp by healthy persons, including athletes, may lead to an excessive increase in packed cell volume. This may be associated with life threatening complications of the cardiovascular system.
The safety and efficacy of Aranesp therapy have not been established in patients with underlying haematologic diseases (e.g. haemolytic anaemia, sickle cell anaemia, thalassaemia and porphyria).

Severe cutaneous reactions.

Blistering and skin exfoliation reactions including erythema multiforme and Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN), have been reported in patients treated with Aranesp in the post-marketing environment. Discontinue Aranesp therapy immediately if a severe cutaneous reaction, such as SJS/TEN, is suspected.

Allergic reactions.

There have been reports of serious allergic reactions, including anaphylactic reaction, angioedema, dyspnoea, skin rash and urticaria, associated with Aranesp. Symptoms have recurred with rechallenge, suggesting a causal relationship exists in some cases.
Precautions should be taken when administering Aranesp in case allergic or other untoward reactions occur. If a serious allergic or anaphylactic reaction occurs, Aranesp should be immediately discontinued and appropriate therapy administered.

Use in the elderly.

See Section 5.1 Pharmacodynamic Properties, Clinical trials, Geriatric use.

Paediatric use.

The safety and efficacy of Aranesp in paediatric patients have not been established.

Effects on laboratory tests.

In clinical studies, no treatment effect was observed for biochemistry parameters. Generally, values remained within the expected range for patients with CRF. Changes in haematology (red blood cells, reticulocytes) were consistent with the pharmacologic effects of Aranesp.

4.5 Interactions with Other Medicines and Other Forms of Interactions

The theoretical risk of any drug interaction is low due to the clearance and mechanism of action of Aranesp (see Section 5.1 Pharmacodynamic Properties; Section 5.2 Pharmacokinetic Properties). No evidence of drug interactions with Aranesp was observed during the course of clinical studies.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No adverse effects on fertility were observed in male and female rats at IV darbepoetin alfa doses of up to 10 microgram/kg 3 times weekly. Systemic exposure (plasma AUC times number of doses/week) at the highest dose was about 4 times greater than that in humans at the recommended initial SC dose of 2.25 microgram/kg in cancer patients. An increase in postimplantation loss was seen at darbepoetin alfa doses of 0.5 microgram/kg/day and higher, but this was considered to be associated with polycythaemia in the dams and is therefore unlikely to be of clinical relevance.
(Category B3)
Reproductive studies in rats showed no significant placental transfer of darbepoetin alfa. Studies in pregnant rats and rabbits showed no evidence of direct embryotoxic, foetotoxic or teratogenic properties of darbepoetin alfa at IV doses of up to 20 microgram/kg/day. Systemic exposure (AUC/dose) at the highest dose was about 4 times (rats) and 20 times (rabbits) than that in humans at the recommended initial SC dose of 2.25 microgram/kg in cancer patients. Reductions in foetal weights were observed in both species and were probably associated with polycythaemia in the dams. IV injection of Aranesp to female rats every other day from day 6 of gestation through day 23 of lactation at doses of 2.5 microgram/kg/dose and higher resulted in offspring (F1 generation) with decreased body weights, which correlated with a low incidence of deaths, as well as delayed eye opening and delayed preputial separation. No adverse effects were seen in the F2 offspring.
Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human foetus having been observed. Studies in animals have shown evidence of an increased occurrence of foetal damage, the significance of which is considered uncertain in humans.
No studies have been conducted in pregnant women. Aranesp should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.
 It is not known whether darbepoetin alfa is excreted in human milk, although many drugs are excreted in human milk. In a reproductive study in rats, IV administration of darbepoetin alfa during gestation and lactation at doses of up to 10 microgram/kg/day caused decreases in pup viability during lactation and delays in pup development, in addition to reductions in pup birthweights. Although these effects were probably due to polycythaemia and associated toxicity in the dams, caution should be exercised when Aranesp is administered to a breastfeeding woman.

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.

4.8 Adverse Effects (Undesirable Effects)

Adverse events in CRF patients.

Data from clinical studies.

Aranesp was well tolerated in clinical studies involving 1578 patients, with an exposure of 942 patient years. The adverse events reported are typical sequelae of CRF and are not necessarily attributable to Aranesp therapy. The adverse events reported in ≥ 5% of patients treated with Aranesp compared with r-HuEPO are shown in Table 1. Adverse events reported in < 5% of patients treated with Aranesp that are considered to be of interest are shown in Table 2. The incidence of deaths was 7% in the Aranesp-treated patients and 6% in the r-HuEPO-treated patients.
The data described in Table 3 reflect exposure to Aranesp and placebo in 4,023 patients who received at least one dose of investigational product from the TREAT study; a randomised placebo controlled clinical study in adult CRF patients not on dialysis with type 2 diabetes (see Section 4.4 Special Warnings and Precautions for Use).
Treatment-related events were defined as those occurring in > 0.5% of patients treated with Aranesp (n = 1598) and/or occurring in ≥ 0.2% compared to r-HuEPO (n = 600).

Subject incidence.

1 to 10%: hypertension, injection site pain, headache, thrombosis vascular access.
< 1%: fatigue, anaemia, pruritus, dizziness, hypotension, nausea, arrhythmia, influenza-like symptoms, somnolence, dyspnoea, pain chest, convulsions, pain abdominal, epistaxis.

Thrombotic events in CRF patients.

Vascular access thrombosis occurred in CRF clinical studies at an annualised rate of 0.19 events per patient year of Aranesp therapy and 0.40 events per patient year of r-HuEPO. Rates of thrombotic events (e.g. vascular access thrombosis, venous thrombosis and pulmonary emboli) with Aranesp therapy were similar to those observed in r-HuEPO therapy in these studies.

Adverse events in cancer patients.

Data from clinical studies.

The Aranesp clinical program included evaluation of a total of 1087 patients with cancer receiving chemotherapy in double-blind, placebo-controlled or open-label, active controlled (r-HuEPO) studies of up to 6 months duration. Death, primarily due to disease progression, occurred on study in 9% of Aranesp, 10% of placebo and 13% of r-HuEPO subjects. Common adverse events reported by the treating physicians as severe are shown in Table 4.
The data in Table 5 reflect the adverse events reported in at least 5% of cancer patients treated with Aranesp and receiving concomitant chemotherapy in these controlled studies. In general, adverse experiences reported in clinical trials with Aranesp in patients with cancer receiving chemotherapy were consistent with the underlying disease and its treatment with chemotherapy.
Clinically significant adverse reactions occurring in < 1% of cancer patients treated with Aranesp include: injection site reaction, headache, myalgia, arthralgia and thromboembolic events.
In clinical trials of Aranesp (n = 873) versus placebo (n = 221), one adverse reaction was reported in ≥ 1% of cancer patients: injection site pain (Aranesp 4% versus placebo 3%).

Thrombotic events in cancer patients.

In cancer patients, the incidence of thrombotic events was 6% for Aranesp, 5% for r-HuEPO and 4% for placebo. The following events were reported more frequently in Aranesp-treated patients than in placebo controls, but at a rate comparable to r-HuEPO: pulmonary embolism, thromboembolism, thrombosis and thrombophlebitis (deep and/or superficial).

Adverse events, all patients.

Post-marketing experience.

Cases of convulsions have been very rarely reported in patients receiving Aranesp.
Rarely, serious allergic reactions have been reported with Aranesp (see Section 4.4 Special Warnings and Precautions for Use). In patients treated with Aranesp the following skin and SC tissue adverse reactions have been reported: blistering, skin exfoliation, erythema multiforme, SJS/TEN.
Hypersensitivity reactions have been reported with Aranesp.
In CKD patients on haemodialysis, events of vascular access thrombosis (such as vascular access complication, arteriovenous fistula thrombosis, graft thrombosis, shunt thrombosis, arteriovenous fistula site complication, etc) have been reported.

Immunogenicity.

As with all therapeutic proteins, there is a potential for immunogenicity. Radioimmuno-precipitation (RIP) assays were performed on sera from 1534 CRF patients and 833 cancer patients treated with Aranesp in clinical studies. Antibodies were not detected in the CRF patients; however reactivity, not considered antibody-related, was detected in 3 cancer patients. The patients responded to Aranesp therapy and there was no evidence of PRCA.
The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay. Antibody positivity in an assay may also be influenced by sample handling, timing of sample collection, concomitant medications and underlying disease. Therefore, comparison of the incidence of antibodies to Aranesp with the incidence of antibodies to other products may be misleading.
Cases of PRCA associated with neutralising antibodies to erythropoietin have been reported in patients receiving Aranesp (see Section 4.4 Special Warnings and Precautions for Use, Pure red cell aplasia).

Reporting of 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 https://www.tga.gov.au/reporting-problems.

4.9 Overdose

The maximum amount of Aranesp that can be safely administered in single or multiple doses has not been determined. Doses over 3.0 microgram/kg/week for up to 28 weeks have been administered to CRF patients without any direct toxic effects of Aranesp itself. Doses up to 8.0 microgram/kg/week and 15.0 microgram/kg/3 weeks have been safely administered to cancer patients for up to 22 weeks.
Aranesp can result in polycythaemia if the haemoglobin is not carefully monitored and the dose appropriately adjusted. Cases of severe hypertension have been observed following overdose with Aranesp. If the suggested haemoglobin target range is exceeded, Aranesp should be reduced or temporarily withheld until the haemoglobin returns to the suggested target range. If withheld, Aranesp therapy may then be resumed using a lower dose (see Section 4.2 Dose and Method of Administration). If clinically indicated, phlebotomy may be performed.
For advice on the management of overdose contact the Poisons Information Centre on 131126.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Erythropoietin is a glycoprotein that is the primary regulator of erythropoiesis. The production of erythropoietin primarily occurs in the kidney and is regulated in response to changes in tissue oxygenation. Endogenous erythropoietin production is impaired in patients with CRF and erythropoietin deficiency is the primary cause of their anaemia.
Erythropoietin acts through specific interaction with the erythropoietin receptor on erythroid progenitor cells in the bone marrow. Using a panel of human tissues, neither darbepoetin alfa nor r-HuEPO (or their desialylated forms) bound to human tissues other than those expressing the erythropoietin receptor.
Aranesp has been shown to stimulate erythropoiesis in anaemic CRF and cancer patients, resulting in the correction and maintenance of haemoglobin. Treatment of anaemia of CRF and cancer has been associated with a reduction in RBC transfusions and improved quality of life.
In patients with cancer receiving concomitant chemotherapy, the aetiology of anaemia is multifactorial, with erythropoietin deficiency and a blunted response of erythroid progenitor cells to endogenous erythropoietin contributing significantly towards their anaemia.
Due to its increased sialic acid containing carbohydrate content, Aranesp has an approximately 3-fold longer terminal half-life than erythropoietin and consequently a greater in vivo biologic activity when administered by either the SC or IV route.
In cancer patients with anaemia (mean ± SD haemoglobin 99 ± 9 g/L), a range of weekly SC doses of Aranesp from 0.5 to 8.0 microgram/kg were assessed, beginning on day 1 of chemotherapy (before starting chemotherapy) and continuing for 12 weeks. Data from these studies indicate that there is a dose relationship with respect to haemoglobin response. The minimally effective starting dose with respect to reducing transfusion requirements was 1.5 microgram/kg/week with a plateau observed at 4.5 microgram/kg/week.

Preclinical experience.

Aranesp undergoes extensive metabolism with less than 2% of intact Aranesp being excreted renally in rats, while degradation products are recovered in the urine (57% dose) and faeces (24% dose). Metabolism of Aranesp may involve desialylation by blood/tissue sialidases, with subsequent rapid removal of the desialylated form by hepatic receptors, and/or reuptake via bone marrow cells.

Clinical trials.

Clinical experience in CRF patients.

Ten clinical studies were conducted, involving SC and IV administration of Aranesp to a total of 1578 adult CRF patients with an exposure of 942 patient years. Response to Aranesp was consistent across all studies. The time to reach the target haemoglobin is a function of the baseline haemoglobin and the rate of haemoglobin rise. The rate of increase in haemoglobin is dependent upon the dose of Aranesp administered and individual patient variation.

Maintenance in CRF patients.

Aranesp was at least equivalent to r-HuEPO in the maintenance of a target haemoglobin (haemoglobin between 90 to 130 g/L and between -10 and +15 g/L of baseline) in 2 trials in which adult dialysis patients were randomised to either stay on r-HuEPO or switch to Aranesp.
One trial evaluated 224 Aranesp-treated patients and 112 r-HuEPO-treated patients. The median Aranesp dose was 30 microgram/week and the median r-HuEPO dose was 6000 U/week. The drugs were administered either IV or SC at frequencies varying from 3 times weekly to once every 2 weeks. Ninety-seven percent of patients in the Aranesp group received their treatment at a lower frequency than they had previously received r-HuEPO, in most cases once weekly instead of 2 to 3 times weekly. The mean difference for change in haemoglobin from baseline (Aranesp minus r-HuEPO) was 0.3 g/L (95% confidence interval [CI]: -1.6, 2.1).
In the second trial, 121 Aranesp-treated patients and 240 r-HuEPO-treated patients were evaluated. Both drugs were administered IV, Aranesp once weekly and r-HuEPO 3 times weekly. The median Aranesp dose was 38 microgram/week and the median r-HuEPO dose 9900 U/week. The mean difference for change in haemoglobin from baseline (Aranesp minus r-HuEPO) was 1.6 g/L (95% CI: -0.8, 3.3).
There were no significant differences between the drugs in the proportion of patients with unstable haemoglobin and proportion receiving blood transfusions, in either trial.
Clinical studies in CRF patients not on dialysis have demonstrated that Aranesp has similar effectiveness when administered as a single SC monthly injection in patients stabilised on once every 2-week SC dosing, without any increase in total dose requirements.

Correction of anaemia in CRF patients.

In a trial in adult predialysis CRF patients with anaemia (haemoglobin concentration < 110 g/L), Aranesp produced a similar response to r-HuEPO with 87% (95% CI: 80, 92) of Aranesp-treated patients (n = 129) and 86% (95% CI: 71, 95) of r-HuEPO-treated patients (n = 37) achieving the haemoglobin target (> 110 g/L and > 10 g/L increase from baseline) after 16 weeks. The drugs were administered by the SC route. The starting dose of Aranesp was 0.45 microgram/kg once weekly (approximately equivalent to 90 U/kg of r-HuEPO weekly). The starting dose of r-HuEPO was 50 U/kg twice weekly (100 U/kg total weekly dose). The doses were adjusted in ± 25% increments at 2 to 4-week intervals as required. The median time to response was 7 weeks in each group and the median doses at response were similar to the starting doses, 0.46 microgram/kg/week for Aranesp and 100 U/kg/week for r-HuEPO. The median dose after 16 weeks of treatment was 0.45 microgram/kg/week for Aranesp and 100 U/kg/week for r-HuEPO.
In a second trial, in adult dialysis CRF patients with anaemia (haemoglobin < 100 g/L), r-HuEPO was started at a higher dose than Aranesp based on protein mass, 50 U/kg 3 times weekly (150 U/kg total weekly dose) compared with 0.45 microgram/kg once weekly (approximately equivalent to 90 U/kg of r-HuEPO weekly). The drugs were administered either IV or SC. A similar regime of dosage adjustments and a similar haemoglobin target were employed to the previous trial. Of patients receiving at least one dose of drug, 95% (95% CI: 77, 100) of r-HuEPO-treated patients (n = 22) and 71% (95% CI: 59, 82) of Aranesp-treated patients (n = 70) reached the haemoglobin target by 20 weeks. The median time to response was 8 weeks in the r-HuEPO group and 9 weeks in the Aranesp group and the median doses at response were 150 U/kg/week and 0.55 microgram/kg/week, respectively. The median dose after 20 weeks of treatment was 0.56 microgram/kg/week for Aranesp and 150 U/kg/week for r-HuEPO.
A randomised, double-blind non-inferiority (non-inferiority margin -5 g/L) correction study (n = 358) compared Aranesp once every 2 weeks SC and once monthly SC dosing schedules in CRF patients with anaemia not on dialysis. The initial Aranesp dose for once every 2 weeks and once monthly was 0.75 microgram/kg and 1.5 microgram/kg respectively. Dose adjustments were monthly, if required to correct and maintain a haemoglobin level within the target 100-120 g/L. Aranesp once monthly dosing was non-inferior to once every 2-week dosing for correcting anaemia. The median (Q1, Q3) time to achieve haemoglobin correction (≥ 100 g/L and ≥ 10 g/L increase from baseline) was 5 weeks for both once every 2 weeks (3, 7 weeks) and once monthly dosing (3, 9 weeks). During the evaluation period (weeks 29-33), the median (Q1, Q3) weekly equivalent dose was 0.23 (0.14, 0.36) microgram/kg in the once every 2-week arm and 0.30 (0.18, 0.51) microgram/kg in the once monthly arm.

Treatment of anaemia in cancer patients receiving chemotherapy.

A randomised, double-blind, placebo-controlled, parallel-group trial was conducted in anaemic patients with lung cancer receiving multicycle platinum containing chemotherapy. Randomisation was stratified by tumour type (small cell, non-small cell) and region (Australia, Canada, Central and Eastern Europe, Western Europe). The starting dose was 2.25 microgram/kg/week as a single SC injection commencing on day 1 prior to administration of chemotherapy. The dose could be increased after 6 weeks up to 4.5 microgram/kg/week if patients failed to achieve an increase in haemoglobin of > 10 g/L. The duration of treatment was 12 weeks.
Efficacy was determined by a reduction in the proportion of patients who were transfused over the 12-week treatment period. A significantly lower proportion of patients in the Aranesp arm, 26% (95% CI: 20, 33) required transfusion compared to 60% (95% CI: 52, 68) in the placebo arm (Kaplan-Meier estimate of proportion; p < 0.001 by Cochran Mantel Haenszel test) (see Table 6). There was a trend in favour of Aranesp in FACT/F, a fatigue related quality of life score.
There were 67 patients in the Aranesp arm who had their dose increased from 2.25 to 4.5 microgram/kg/week, at any time during the treatment period. Of the 67 patients who received a dose increase, 28% had a 20 g/L increase in haemoglobin over baseline, generally occurring between weeks 8 to 13. Of the 89 patients who did not receive a dose increase, 69% had a 20 g/L increase in haemoglobin over baseline, generally occurring between weeks 6 to 13.
In the same study, the effect of Aranesp on tumour progression and survival was evaluated through long-term surveillance of patients. After a median observation period of approximately 1 year, the median time to disease progression in the Aranesp group (n = 155) was 29 weeks (95% CI: 22, 33) compared with 22 weeks (95% CI: 18, 25) in the placebo group (n = 159). The median time to death in the Aranesp group was 43 weeks (95% CI: 37, not estimable) compared with 35 weeks (95% CI: 29, 48) in the placebo group.
Clinical studies in cancer patients have demonstrated that darbepoetin alfa has similar effectiveness when administered as a single SC injection either once every three weeks or weekly without any increase in total dose requirements.

Geriatric use.

More than 1500 Aranesp-treated patients with CRF have been studied; 28% were 65 to 74 years of age and 15% were 75 years or older. Of the 781 cancer patients in clinical studies receiving Aranesp and concomitant chemotherapy, 31% were 65 to 74 years of age, while 12% were 75 and over. No differences in dose requirements, safety or efficacy were observed between geriatric and younger adult patients.

5.2 Pharmacokinetic Properties

General.

The concentration of Aranesp in the circulation remains above the minimum stimulatory concentration for erythropoiesis for longer than an equivalent molar dose of r-HuEPO. This allows Aranesp to be administered less frequently to achieve the same biological response. The pharmacokinetic properties of Aranesp have been studied in healthy adult subjects, in adult and paediatric CRF patients, and in adult cancer patients. In all cases Aranesp exhibits dose linearity over the therapeutic dose range.

Absorption.

Following SC administration in adult CRF patients, the absorption is slow and rate limiting. The peak concentration occurs at 34 hours (range 24 to 72 hours) post-SC administration in adult CRF patients, and bioavailability is approximately 37% (range 30 to 50%). After SC administration of 2.25 microgram/kg to adult cancer patients, Aranesp reached peak concentration at a median of 94.5 hours (range 70.8 to 123 hours).

Distribution.

Distribution following IV administration of Aranesp in adult CRF patients is predominantly confined to the vascular space (approximately 60 mL/kg). The distribution half-life following IV administration is 1.4 hours.

Excretion.

In adult CRF patients, the terminal half-life of Aranesp following IV administration is approximately 21 hours (range: 12 to 40 hours). Following monthly SC administration in CRF patients and once every 3-week SC dosing in cancer patients, the terminal half-life was 70 hours (range: 35 to 139 hours) in CRF patients and 74 hours (range: 24 to 144 hours) in cancer patients, respectively, reflecting the long absorption half-life.

Multiple dosing.

With once weekly dosing in adult CRF patients, steady-state serum concentrations are achieved within 4 weeks with < 2-fold increase in peak concentration. Accumulation was negligible following both SC and IV dosing over 1 year of treatment.
In adult cancer patients, the pharmacokinetic properties did not change with multiple dosing over 12 weeks (dosing every week or every 2 weeks). The expected moderate increases (less than 2-fold) in Aranesp serum concentrations upon multiple dosing were observed as steady state was approached. No unexpected accumulation was observed upon repeated administration of Aranesp across a wide range of doses at once weekly and once every 2-week dosing schedules.

Special populations.

Paediatric.

The pharmacokinetic parameters of Aranesp in paediatric CRF patients are similar to adult CRF patients. Following SC or IV administration in children 7 to 16 years old, the terminal half-life was 21 hours (range: 12 to 25 hours) for IV administration and 33 hours (range: 16 to 44 hours) for SC administration. The SC bioavailability was 52% (range: 32 to 70%).

Hepatic dysfunction.

The efficacy and safety of Aranesp have not been established in patients with hepatic dysfunction.

5.3 Preclinical Safety Data

Genotoxicity.

Darbepoetin alfa was not mutagenic in assays for gene mutations (bacterial and Chinese hamster ovary (CHO) cells) and was not clastogenic in the mouse micronucleus assay.

Carcinogenicity.

Darbepoetin alfa has not been evaluated in standard carcinogenicity bioassays, but there was no evidence from preclinical studies of a proliferative response of any tissue type, other than erythroid progenitor cells, to the drug.

6 Pharmaceutical Particulars

6.1 List of Excipients

Aranesp is formulated at pH 6.2 with 0.05 mg polysorbate 80, 2.12 mg monobasic sodium phosphate monohydrate, 0.66 mg dibasic sodium phosphate and 8.18 mg sodium chloride in water for injection (to 1.0 mL).

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

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. (Refrigerate. Do not freeze.) Protect from light. Do not shake.
Aranesp kept within the pre-filled syringe does not show any observable decrease or change in activity and protein integrity if stored outside the recommended temperature range (not below -20°C or above 30°C) for up to 2 days.
The function of the pre-filled pen when stored beyond the recommended storage condition is not known.

6.5 Nature and Contents of Container

Aranesp is provided in a glass syringe with a stainless steel 27-gauge needle and is available in the following presentations and packages:

Pre-filled pen.

The needle shield for the pre-filled pen contains dry natural rubber (a derivative of latex).
Aranesp pre-filled pens contain a pre-filled syringe within a sealed, single use pre-filled pen assembly and are available in a pack containing 1 pen, in the following doses:
Presentations available in Australia:
20 microgram/0.50 mL, 40 microgram/0.40 mL, 60 microgram/0.30 mL, 80 microgram/0.40 mL, 100 microgram/0.50 mL, 150 microgram/0.30 mL.
Presentations not available in Australia:
10 microgram/0.40 mL, 15 microgram/0.38 mL, 30 microgram/0.30 mL, 50 microgram/0.50 mL, 200 microgram/0.40 mL, 300 microgram/0.60 mL, 500 microgram/1.0 mL.

Pre-filled syringe with automatic needle guard.

The needle cover for the pre-filled syringe with automatic needle guard contains dry natural rubber (a derivative of latex).
Aranesp pre-filled syringes with automatic needle guard consist of the pre-filled syringe preassembled inside a single use, disposable, automatic needle guard and are available in a pack containing 4 syringes, in the following doses:
Presentations available in Australia:
20 microgram/0.50 mL, 30 microgram/0.30 mL, 40 microgram/0.40 mL, 50 microgram/0.50 mL, 60 microgram/0.30 mL, 80 microgram/0.40 mL, 100 microgram/0.50 mL, 150 microgram/0.30 mL.
Presentations not available in Australia:
15 microgram/0.38 mL, 200 microgram/0.40 mL, 300 microgram/0.60 mL, 500 microgram/1.0 mL.
Pack containing 1 syringe.

Pre-filled syringe.

The needle cover for the pre-filled syringe contains dry natural rubber (a derivative of latex).
Aranesp pre-filled syringes are available in a pack containing 4 syringes, in the following doses:
Presentations available in Australia:
10 microgram/0.40 mL.
Presentations not available in Australia:
15 microgram/0.38 mL, 20 microgram/0.50 mL, 30 microgram/0.30 mL, 40 microgram/0.40 mL, 50 microgram/0.50 mL, 60 microgram/0.30 mL, 80 microgram/0.40 mL, 100 microgram/0.50 mL, 150 microgram/0.30 mL, 200 microgram/0.40 mL, 300 microgram/0.60 mL, 500 microgram/1.0 mL.
Pack containing 1 syringe.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Chemical structure.

Aranesp (darbepoetin alfa) is produced in CHO cells by recombinant DNA technology. Aranesp stimulates RBC production (erythropoiesis) by the same mechanism as recombinant human erythropoietin (r-HuEPO). Aranesp is a 165 amino acid protein containing 5 N-linked oligosaccharide chains, whereas erythropoietin contains only 3. The additional carbohydrate chains increase the molecular weight of the glycoprotein from approximately 30,000 to 37,000 daltons.

CAS number.

209810-58-2.

7 Medicine Schedule (Poisons Standard)

Schedule 4 Prescription Medicine.

Summary Table of Changes