Consumer medicine information

Eligard

Leuprorelin acetate

BRAND INFORMATION

Brand name

Eligard

Active ingredient

Leuprorelin acetate

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Eligard.

SUMMARY CMI

ELIGARD®

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.

 This medicine is subject to additional monitoring due to approval of an extension of indications. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. You can report side effects to your doctor, or directly at www.tga.gov.au/reporting-problems.

1. Why am I being given ELIGARD?

ELIGARD contains the active ingredient leuprorelin acetate. ELIGARD is used to reduce the symptoms of advanced cancer of the prostate gland, or to treat high-risk localised prostate cancer in combination with radiotherapy. ELIGARD is also used to treat early puberty in children 2 years of age and older (central precocious puberty).

For more information, see Section 1. Why am I being given ELIGARD? in the full CMI.

2. What should I know before am I given ELIGARD?

Do not use ELIGARD if you have ever had an allergic reaction to leuprorelin acetate 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 am I given ELIGARD? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with ELIGARD 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 am I given ELIGARD?

  • Your doctor will decide what dose of ELIGARD you will receive.
  • ELIGARD should only be given to you by a doctor or nurse.

More instructions can be found in Section 4. How am I given ELIGARD? in the full CMI.

5. What should I know while being given ELIGARD?

Things you should do
  • Remind any doctor or dentist you visit that you are using ELIGARD.
  • Keep all of your doctor's appointments so that your progress can be checked.
Things you should not do
  • Do not stop treatment with your medicine without checking with your doctor.
Driving or using machines
  • Be careful driving or operating machinery until you know how ELIGARD affects you.
Drinking alcohol
  • There is no information on the use of ELIGARD with alcohol.
Looking after your medicine
  • Keep ELIGARD in a place where the temperature stays below 25°C.

For more information, see Section 5. What should I know while being given ELIGARD? in the full CMI.

6. Are there any side effects?

Swelling of face, lips, throat; chest pain; tingling/numbness in arms or legs; headache; vision problems; unconsciousness.

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.

 This medicine is subject to additional monitoring due to approval of an extension of indications. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. You can report side effects to your doctor, or directly at www.tga.gov.au/reporting-problems.



FULL CMI

ELIGARD®

Active ingredient: Leuprorelin acetate


Consumer Medicine Information (CMI)

This leaflet provides important information about using ELIGARD. 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 ELIGARD.

Where to find information in this leaflet:

1. Why am I being given ELIGARD?
2. What should I know before I am given ELIGARD?
3. What if I am taking other medicines?
4. How am I given ELIGARD?
5. What should I know about being given ELIGARD?
6. Are there any side effects?
7. Product details

1. Why am I being given ELIGARD?

ELIGARD contains the active ingredient leuprorelin acetate.

In men, ELIGARD is used to reduce the symptoms of advanced cancer of the prostate gland, or to treat high-risk localised prostate cancer in combination with radiotherapy.

In children 2 years of age and older, ELIGARD is used to treat early puberty (central precocious puberty).

2. What should I know before am I given ELIGARD?

Warnings

ELIGARD should not be given if:

  • you are allergic to leuprorelin acetate, or any of the ingredients listed at the end of this leaflet. Always check the ingredients to make sure you can use this medicine.
  • you are allergic to any other similar medicines (such as goserelin).
  • you had surgical removal of your testes, as in that case ELIGARD does not lead to further decrease in serum testosterone levels
  • you are pregnant or plan to become pregnant or are breastfeeding. If used during pregnancy, it may affect the developing baby.

Check with your doctor if you:

  • have allergies to any other medicines, foods, preservatives or dyes
  • have history of epilepsy, fits or seizures
  • have tumour in your pituitary gland.
  • have a history of mental (psychiatric) problems.

In Men

  • have nerve problems caused by bone lesions in the spine, problems passing urine or blood in your urine. These conditions may get worse for a short time after treatment is started. Your doctor may prescribe another medicine when you first receive ELIGARD to reduce the likelihood of this occurring.
  • have diabetes
  • have cardiovascular disease, heart problems or blood vessel conditions, including heart rhythm problems (arrhythmia), or are being treated with medicines for these conditions. The risk of you having further heart rhythm problems may increase with ELIGARD

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?

Pregnancy and breastfeeding

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

Talk to your doctor if you are breastfeeding or intend to breastfeed.

You must not be given this medicine if you are pregnant or plan to become pregnant or are breastfeeding.

This medicine has not been studied in women.

If used during pregnancy, it may affect the developing baby.

Fertility

Talk to your doctor about the effects ELIGARD may have on fertility.

This medicine may impair fertility in men. Use of this medicine for a short time has shown a full return to fertility after stopping the medicine. Fertility suppression may or may not be permanent when the medicine is given for a long time.

In Children

In the first few weeks after your child receives their first ELIGARD injection, ELIGARD can cause an increase in some hormones. During this time, you may notice more signs of puberty in your child including vaginal bleeding. Call your doctor straight away if signs of puberty continue after 2 months of receiving ELIGARD.

Some people given gonadotropin releasing hormone like ELIGARD have had new or worsened mental (psychiatric) problems. Call your doctor straight away if your child has any new or worsening emotional symptoms while taking ELIGARD.

Pseudotumor Cerebri/Idiopathic Intracranial Hypertension (in children)

A condition characterised by increased pressure inside the head has been reported in children receiving this medicine.

Monitor your child for symptoms, including headache, eye problems, including blurred vision, double vision and decreased eyesight, eye pain, ringing in the ears, dizziness and nausea. Contact your doctor immediately if your child has any of these symptoms during treatment with Eligard.

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.

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

ELIGARD may interfere with some medicines used to treat heart rhythm problems, such as:

  • quinidine
  • disopyramide
  • amiodarone
  • sotalol.

ELIGARD may increase the risk of heart rhythm problems when used with other medicines which also have the same risk, such as:

  • methadone (used for pain relief and part of drug addiction detoxification)
  • moxifloxacin (an antibiotic)
  • antipsychotics used for serious mental illness.

ELIGARD has not been found to interact with other commonly used medicines.

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

4. How am I given ELIGARD?

How much to use

Your doctor will decide what dose of ELIGARD you will receive.

The recommended dose of ELIGARD for prostate cancer is one of:

  • 7.5 mg injection every month or
  • 22.5 mg injection every three months or
  • 30 mg injection every four months or
  • 45 mg injection every six months.

For central precocious puberty, the recommended dose is one 45mg injection every six months.

When am I given ELIGARD

  • Continue treatment with your medicine for as long as your doctor tells you.

How am I given ELIGARD

  • ELIGARD should only be given to you by a doctor or nurse.
  • The content of the two syringes in the ELIGARD kit (one containing the active ingredient and the other containing the delivery system) will be mixed together, then injected underneath the skin. The site of the injection should be varied from time to time.

If you forget to use ELIGARD

If you have missed your injection, contact your doctor or pharmacist to find out what to do.

If you use too much ELIGARD (overdose)

As ELIGARD will be given to you under the supervision of your doctor, it is very unlikely that you will receive an overdose. However, if you think that you or anyone else may have been given too much ELIGARD, 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 being given ELIGARD?

Things you should do

  • Keep all of your doctor's appointments so that your progress can be checked. Your doctor may do some blood and other tests from time to time to make sure the medicine is working.

Call your doctor straight away if:

  • your condition worsens
  • you are about to be started on any new medicine.
  • you are about to have any blood tests. It may interfere with the results of some tests.
  • your child feels unwell (when being treated for central precocious puberty).

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

Things you should not do

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

Do not stop treatment with your medicine without checking with your doctor.

Driving or using machines

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

ELIGARD may cause fatigue, dizziness and visual disturbances in some people. If you have any of these symptoms, do not drive, operate machinery or do anything else that could be dangerous.

Drinking alcohol

Tell your doctor if you drink alcohol.

Looking after your medicine

  • ELIGARD is usually stored in the refrigerator (below 8°C) in doctor's surgery or clinic, or at the pharmacy
  • However, if ELIGARD is dispensed to you, keep it in a place where the temperature stays below 25°C. It may be stored in this manner for a period of up to 8 weeks prior to administration

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

Store it in a cool dry place away from moisture, heat or sunlight; for example, do not store it:

  • in the bathroom or near a sink, or
  • in the car or on window sills.

Keep it where young children cannot reach it.

Getting rid of any unwanted medicine

Any ELIGARD which is not used will be disposed in a safe manner by your doctor.

Do not use this medicine after the expiry date.

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 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
Prostate cancer:
  • short-lived burning, stinging, pain, redness or itching at the injection site
  • mild bruising at the injection site
  • fatigue
  • dizziness
  • feelings of warmth or periods of excessive sweating
  • pain or a decrease in size of the testicles
  • nausea, vomiting or diarrhoea
  • hair loss
  • more frequent urination
  • decreased libido
  • depression
  • changes in your breasts.
Central Precocious puberty:
  • injection site pain
  • nasal congestion, sore throat, and runny nose (nasopharyngitis)
  • headache
  • cough
  • abdominal pain
  • nausea
  • constipation
  • vomiting
  • upper respiratory tract infection
  • sudden shortness of breath or wheezing (bronchospasm)
  • productive cough
  • fever (pyrexia)
  • sudden strong feelings of heat and sweating (hot flush).
Speak to your doctor, nurse or pharmacist if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
Prostate cancer:
  • backache
  • tingling or numbness of the hands and feet
  • difficulty in passing urine
  • blood in your urine
  • bone pain or fractures (this may be a sign of weakening of the bones).
Central Precocious puberty:
  • vaginal irritation, bleeding or discharge
  • changes in mood, irritability, restlessness, aggression, anger
  • tearfulness, crying
  • seizures, fits or convulsions.
  • headache, eye problems, including blurred/double vision, and decreased eyesight, eye pain, ringing in the ears, dizziness and nausea.
Call your doctor, nurse or pharmacist straight away, you may require medical attention.

Very serious side effects

Very serious side effectsWhat to do
  • signs 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
  • headache and vomiting, eye problems, altered mental state, or collapse
  • chest pain.
Call your doctor, nurse or pharmacist immediately, or go straight to the Emergency Department at your nearest hospital if you notice any of these very serious side effects.
You may need urgent medical attention or hospitalisation.

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 for injection by a doctor or nurse.

What ELIGARD contains

Active ingredient
(main ingredient)
Leuprorelin acetate
Other ingredients
(inactive ingredients)
The Atrigel® delivery system consists of a biodegradable polymer, dissolved in a solvent (N-methyl-2-pyrrolidone).
Each presentation of ELIGARD contains a different mixture and volume of the polymer.

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

What ELIGARD looks like

ELIGARD is available in a single use kit, containing a cardboard frame and two removable sealed plastic trays. The tray containing syringe A contains a syringe filled with the delivery system, known as the Atrigel® Delivery System, plus a long white replacement plunger rod and a desiccant pack (to absorb moisture). The tray containing syringe B contains a syringe filled with a powder which is the active ingredient, plus a needle and a desiccant pack (to absorb moisture).

Once the contents of syringe A and syringe B have been mixed together (prior to injection), the colour of the resulting liquid will be:

  • light tan to tan for ELIGARD 1 month
  • colourless to pale yellow for ELIGARD 3 month, ELIGARD 4 month and ELIGARD 6 month.

The mixed solution may appear slightly grey due to tiny air bubbles. This is acceptable and not representative of product quality.

ELIGARD comes in single packs.

ELIGARD comes in the following strengths:

ELIGARD 1 month 7.5 mg (AUST R 97449)

ELIGARD 3 month 22.5 mg (AUST R 97450)

ELIGARD 4 month 30 mg (AUST R 97451)

ELIGARD 6 month 45 mg (AUST R 101581)

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

Who distributes ELIGARD

Mundipharma Pty Limited
ABN 87 081 322 509
10 Carrington Street
SYDNEY NSW 2000
Phone: 1800 188 009

This leaflet was prepared in July 2022.

® ELIGARD and ATRIGEL are trademarks of Tolmar Therapeutics, Inc. used under licence.

ELIGARD CMI v1 (CCDS 17)

Published by MIMS September 2022

BRAND INFORMATION

Brand name

Eligard

Active ingredient

Leuprorelin acetate

Schedule

S4

 

1 Name of Medicine

Leuprorelin acetate.

2 Qualitative and Quantitative Composition

Eligard is a sterile polymeric matrix formulation of leuprorelin acetate for subcutaneous injection. It is designed to deliver leuprorelin acetate at a controlled rate over a therapeutic period.
Leuprorelin acetate is a synthetic nonapeptide analogue of naturally occurring gonadotropin releasing hormone (GnRH or LHRH) that, when given continuously, inhibits pituitary gonadotropin secretion and suppresses testicular steroidogenesis. The analogue possesses greater potency than the natural hormone.
Eligard 1 month contains 10.6 mg of lyophilised leuprorelin acetate. Eligard 1 month delivers 7.5 mg of leuprorelin acetate (equivalent to approximately 7.0 mg leuprorelin free base) dissolved in 160 mg N-methyl-2-pyrrolidone and 82.5 mg polyglactin. The approximate weight of the administered formulation is 250 mg. It is designed to deliver 7.5 mg of leuprorelin acetate at a controlled rate over a 1 month therapeutic period.
Eligard 3 month contains 29.2 mg lyophilised leuprorelin acetate. Eligard 3 month delivers 22.5 mg of leuprorelin acetate (equivalent to approximately 21 mg leuprorelin free base) dissolved in 193.9 mg N-methyl-2-pyrrolidone and 158.6 mg polyglactin. The approximate weight of the administered formulation is 375 mg. It is designed to deliver 22.5 mg of leuprorelin acetate at a controlled rate over a 3 month therapeutic period.
Eligard 4 month contains 37.2 mg lyophilised leuprorelin acetate. Eligard 4 month delivers 30 mg of leuprorelin acetate (equivalent to approximately 28 mg leuprorelin free base) dissolved in 258.5 mg N-methyl-2-pyrrolidone and 211.5 mg polyglactin. The approximate weight of the administered formulation is 500 mg. It is designed to deliver 30 mg of leuprorelin acetate at a controlled rate over a 4 month therapeutic period.
Eligard 6 month contains 59.2 mg of lyophilised leuprorelin acetate. Eligard 6 month delivers 45 mg of leuprorelin acetate (equivalent to approximately 42 mg leuprorelin free base) dissolved in 165 mg N-methyl-2-pyrrolidone and 165 mg polyglactin. The approximate weight of the administered formulation is 375 mg. It is designed to deliver 45 mg of leuprorelin acetate at a controlled rate over a 6 month therapeutic period.
The Atrigel delivery system is a polymeric (nongelatin containing) delivery system consisting of a biodegradable polyglactin. The polymer is dissolved in a biocompatible solvent, N-methyl-2-pyrrolidone. The polyglactin mixture and volume differ with each presentation of Eligard.
Eligard contains no antimicrobial agent. Eligard does not contain: lactose, sucrose, gluten, tartrazine, or any other azo dyes.

3 Pharmaceutical Form

Eligard is a modified release suspension syringe, available in a single use kit.
Eligard is prefilled and supplied in two separate, sterile syringes whose contents are mixed immediately prior to administration. The two syringes are joined and the single dose product is mixed until it is homogenous. Eligard is administered subcutaneously where it forms a solid drug delivery depot.

4 Clinical Particulars

4.1 Therapeutic Indications

Prostate cancer.

Eligard 7.5 mg 1 month, Eligard 22.5 mg 3 month, Eligard 30 mg 4 month and Eligard 45 mg 6 month are indicated for the:
Palliative treatment of advanced prostate cancer.
Treatment of high-risk localised and locally advanced hormone-dependent prostate cancer in combination with radiotherapy1.

Central precocious puberty (CPP).

Eligard 45 mg 6 month is indicated for the treatment of children 2 years of age and older with central precocious puberty (CPP).
1 Not indicated for Bi Eligard cp combination pack.

4.2 Dose and Method of Administration

Important.

Allow the product to reach room temperature before using. Once mixed, Eligard must be administered within 30 minutes. Discard the constituted product if not administered within 30 minutes.
The two syringes are coupled and the product is mixed by transferring the contents from syringe to syringe immediately before administration to the patient. Refer to the instruction leaflet contained in the packaging titled Eligard Mixing Procedure. The syringes are uncoupled and the needle is attached prior to injection. The product is injected subcutaneously into areas with adequate amounts of subcutaneous tissue (such as the abdomen) and that do not have excessive pigment, nodules, lesions, or hair. As with other drugs administered by subcutaneous injection, the injection site should be varied periodically.
Eligard must be administered by healthcare professional.

Prostate cancer.

When thoroughly mixed, the suspension will appear a light tan to tan colour (Eligard 1 month) or a colourless to pale yellow colour (Eligard 3 month, Eligard 4 month and Eligard 6 month). The mixed solution colour is not representative of product quality. An occasional slightly grey appearance of the mixed solution may be due to tiny air bubbles and will not affect the product quality.
Eligard should not be injected in the arm.
The recommended dose of Eligard 7.5 mg 1 month is one injection every month.
The recommended dose of Eligard 22.5 mg 3 month is one injection every three months.
The recommended dose of Eligard 30 mg 4 month is one injection every four months.
The recommended dose of Eligard 45 mg 6 month is one injection every six months.
Eligard 7.5 mg 1 month, 22.5 mg 3 month, 30 mg 4 month and 45 mg 6 month presentations have different release characteristics and therefore, fractional, multiple and/or combinational doses are not equivalent to each other and should not be given.
Eligard contains no antimicrobial agent and is for single use in one patient only. Discard any residue.
The injection delivers leuprorelin acetate, incorporated in a polymer formulation. It is administered subcutaneously and provides continuous release of leuprorelin for one month for Eligard 7.5 mg 1 month, three months for Eligard 22.5 mg 3 month, four months for Eligard 30 mg 4 month and six months for Eligard 45 mg 6 month.

Central precocious puberty.

Clinical evidence of onset of breast development in girls < 8 years or bilateral testicular enlargement > 4 mL in boys < 9 years plus raised LH/FSH, oestradiol or testosterone.
In paediatric patients, monitor response to Eligard with a GnRH agonist stimulation test, basal serum luteinizing hormone (LH) levels or serum concentration of sex steroid levels at 1 to 2 months following initiation of therapy and as needed to confirm adequate suppression of pituitary gonadotropins, sex steroids, and progression of secondary sexual characteristics. Measure height (for calculation of growth velocity) every 3 to 6 months and monitor bone age periodically. Noncompliance with drug regimen or inadequate dosing may lead to gonadotropins and/or sex steroids increasing above prepubertal levels resulting in inadequate control of the pubertal process. If the dose of Eligard is not adequate, switching to an alternative GnRH agonist for the treatment of CPP with the ability for dose adjustment may be necessary.

4.3 Contraindications

Prostate cancer.

Eligard is contraindicated in patients with hypersensitivity to GnRH, GnRH agonist analogues or any of the components of Eligard. Anaphylactic reactions to synthetic GnRH or GnRH agonist analogues have been reported in the literature.
Eligard is contraindicated in women who are breastfeeding, pregnant or intending to become pregnant and in paediatric patients. Eligard was not studied in women or children. Moreover, leuprorelin acetate can cause foetal harm when administered to a pregnant woman. Major foetal abnormalities were observed in rabbits but not in rats after administration of leuprorelin acetate throughout gestation. There were increased foetal mortality and decreased foetal weights in rats and rabbits. The effects on foetal mortality are expected consequences of the alterations in hormonal levels brought about by this drug. The possibility exists that spontaneous abortion may occur.
Eligard is contraindicated in patients who previously underwent orchiectomy (as with other GnRH agonists, Eligard does not result in further decrease of serum testosterone in case of surgical castration). Eligard is contraindicated as a sole treatment in prostate cancer patients with spinal cord compression or evidence of spinal metastases.

Central precocious puberty.

Eligard is contraindicated in patients with hypersensitivity to GnRH, GnRH agonist analogues or any of the components of Eligard. Anaphylactic reactions to synthetic GnRH or GnRH agonist analogues have been reported in the literature.
Eligard is contraindicated in pregnancy (see Section 4.6 Fertility, Pregnancy and Lactation).

4.4 Special Warnings and Precautions for Use

Prostate cancer.

Eligard, like other LHRH agonists, causes a transient increase in serum concentrations of testosterone during the first week of treatment. Patients may experience worsening of symptoms or onset of new signs and symptoms during the first few weeks of treatment, including bone pain, neuropathy, haematuria or bladder outlet obstruction. Isolated cases of ureteral obstruction and/or spinal cord compression, which may contribute to paralysis with or without fatal complications, have been observed in the palliative treatment of advanced prostate cancer using LHRH agonists.
Initiating therapy with a nonsteroidal antiandrogen at the same time as leuprorelin acetate therapy has proven benefit in reducing flare reactions in 'at risk' patients (e.g. those with thecal indentation or at risk of cord compression and patients with bladder neck obstruction). Additional administration of an appropriate antiandrogen should be considered beginning 3 days prior to leuprorelin therapy and continuing for the first two to three weeks of treatment. This has been reported to prevent the sequelae of an initial rise in serum testosterone.
If spinal cord compression or renal impairment develops, standard treatment of these complications should be instituted.
Long-term administration of leuprorelin will cause suppression of pituitary gonadotropins and gonadal hormone production with clinical symptoms of hypogonadism. These changes have been observed to reverse on discontinuation of therapy. However, whether the clinical symptoms of induced hypogonadism will reverse in all patients has not yet been established.

General.

Patients with metastatic vertebral lesions and/or with urinary tract obstruction should be closely observed during the first few weeks of therapy.
Response to Eligard should be monitored by measuring serum concentrations of testosterone and prostate specific antigen periodically.
Results of testosterone determinations are dependent on assay methodology. It is advisable to be aware of the type and precision of the assay methodology to make appropriate clinical and therapeutic decisions.
Following surgical castration, Eligard does not lead to a further decrease in serum testosterone levels in male patients.
A proportion of patients will have tumors which are not sensitive to hormone manipulation. This is termed castrate resistant prostate cancer. Signs and/or symptoms of tumor progression despite adequate testosterone suppression are diagnostic of this condition. Current treatment paradigms recommend continued GnRH therapy along with other therapeutic regimes for this circumstance.

Hyperglycemia and diabetes.

Hyperglycemia and an increased risk of developing diabetes have been reported in men receiving GnRH agonists. Hyperglycemia may represent development of diabetes mellitus or worsening of glycemic control in patients with diabetes. Monitor blood glucose and/or glycosylated hemoglobin (HbA1c) periodically in patients receiving a GnRH agonist and manage with current practice for treatment of hyperglycemia or diabetes.

Cardiovascular diseases.

Increased risk of developing myocardial infarction, sudden cardiac death and stroke has been reported in association with use of GnRH agonists in men. The risk appears low based on the reported odds ratios, and should be evaluated carefully along with cardiovascular risk factors when determining a treatment for patients with prostate cancer. Patients receiving a GnRH agonist should be monitored for symptoms and signs suggestive of development of cardiovascular disease and be managed according to current clinical practice.

Effect on QT/QTc interval.

Androgen deprivation therapy may prolong the QT interval. Physicians should consider whether the benefits of androgen deprivation therapy outweigh the potential risks in patients with congenital long QT syndrome, congestive heart failure, frequent electrolyte abnormalities, and in patients taking drugs known to prolong the QT interval. Electrolyte abnormities should be corrected. Consider periodic monitoring of electrocardiograms and electrolytes.

Changes in bone density.

Bone loss can be expected as part of natural aging and can also be anticipated during the hypo-androgenic state caused by long-term use of leuprorelin acetate. In patients with significant risk factors for decreased bone mineral content and/or bone mass such as family history of osteoporosis, chronic use of corticosteroids or anticonvulsants or chronic abuse of alcohol or tobacco, leuprorelin acetate may pose additional risk. In these patients, risk versus benefit must be weighed carefully before initiation of leuprorelin acetate therapy.

Convulsions.

Post marketing reports of convulsions have been observed in patients on leuprorelin acetate therapy with or without a history of predisposing factors. These included patients in the female and paediatric populations, patients with a history of seizures, epilepsy, cerebrovascular disorders, central nervous system anomalies or tumours, and in patients on concomitant medications that have been associated with convulsions such as bupropion and SSRIs. Convulsions have also been reported in patients in the absence of any of the conditions mentioned above. Convulsions are to be managed according to the current clinical practice.

Respiratory.

There have been post-marketing reports of interstitial pneumonitis associated with leuprorelin use. Treatment should be discontinued immediately if the patient develops any signs or symptoms suggestive of interstitial lung disease.

Use in hepatic impairment.

Eligard was not studied in hepatically and renally impaired patients.

Use in renal impairment.

Eligard was not studied in hepatically and renally impaired patients.

Use in the elderly.

The majority of the patients (approximately 70%) studied in the clinical trials were age 70 and older.

Paediatric use.

The safety and effectiveness of Eligard 7.5 mg 1 month, 22.5 mg 3 month and 30 mg 4 month in paediatric patients have not been established (see Section 4.3 Contraindications).
The management of CPP is in the specialist field of paediatric endocrinology.

Central precocious puberty.

The safety and effectiveness of Eligard 45 mg 6 month for the treatment of CPP has been established in paediatric patients 2 years of age and older.

Psychiatric events.

Psychiatric events have been reported in patients taking GnRH agonists, including leuprorelin acetate. Postmarketing reports with this class of drugs include symptoms of emotional lability, such as crying, irritability, impatience, anger, and aggression. Monitor for development or worsening of psychiatric symptoms during treatment with Eligard.

Initial rise of gonadotropins and sex steroid levels.

During the early phase of therapy, gonadotropins and sex steroids rise above baseline because of the initial stimulatory effect of the drug. Therefore, an increase in clinical signs and symptoms of puberty including vaginal bleeding may be observed during the first weeks of therapy or after subsequent doses. Instruct patients and caregivers to notify the physician if these symptoms continue beyond the second month after Eligard administration.

Convulsions.

Postmarketing reports of convulsions have been observed in patients receiving GnRH agonists, including leuprorelin acetate. These included patients with a history of seizures, epilepsy, cerebrovascular disorders, central nervous system anomalies or tumours, and patients on concomitant medications that have been associated with convulsions such as bupropion and SSRIs. Convulsions have also been reported in patients in the absence of any of the conditions mentioned above.

Pseudotumor cerebri (idiopathic intracranial hypertension).

Pseudotumor cerebri (idiopathic intracranial hypertension) have been reported in paediatric patients receiving GnRH agonists, including leuprorelin acetate. Monitor patients for signs and symptoms of pseudotumor cerebri, including headache, papilledema, blurred vision, diplopia, loss of vision, pain behind the eye or pain with eye movement, tinnitus, dizziness, and nausea.

Effects on laboratory tests.

In the majority of non-orchiectomised patients, testosterone levels increased during the first week of treatment. They then decreased and by day 14 had returned to baseline levels or below. Castrate levels were reached in 2 to 4 weeks. Once achieved, castrate levels were maintained as long as the patient received their injections. Transient increases in acid phosphatase levels may occur early in the treatment period; however, by the fourth week the elevated levels usually decreased to values at or near normal. Therapy with leuprorelin results in suppression of the pituitary gonadal system. Results of diagnostic tests of pituitary gonadotropic and gonadal functions conducted during and after leuprorelin therapy may be affected.

4.5 Interactions with Other Medicines and Other Forms of Interactions

There are no reports of drug interactions with leuprorelin acetate to date.
Since androgen deprivation treatment may prolong the QT interval, the concomitant use of Eligard with medicinal products known to prolong the QT interval or medicinal products able to induce torsades de pointes such as class IA (e.g. quinidine, disopyramide) or class III (e.g. amiodarone, sotalol) antiarrhythmic medicinal products, methadone, moxifloxacin, antipsychotics, etc. should be carefully evaluated (see Section 4.4 Special Warnings and Precautions for Use).
In paediatric use, no pharmacokinetic drug-drug interaction studies have been conducted with Eligard.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Preclinical studies with leuprorelin acetate in rats demonstrated reversible, expected effects (given that leuprorelin acetate has known pharmacological effects on reproductive endocrinology) on the reproductive system of both sexes.
Leuprorelin acetate did not show teratogenicity in rats.
Clinical and pharmacological studies in adults (> 18 years) with leuprorelin acetate and similar analogues have shown full reversibility of fertility suppression when the drug is discontinued after continuous administration for periods of up to 24 weeks.
(Category D)
(See Section 4.3 Contraindications).
Leuprorelin acetate is contraindicated in pregnancy due to its embryotoxic effects.
Eligard is contraindicated for use in breastfeeding women.

4.7 Effects on Ability to Drive and Use Machines

No studies on the effects of Eligard on the ability to drive and use machines have been performed. The ability to drive and operate machines may be impaired due to fatigue, dizziness and visual disturbances being possible side effects of treatment or resulting from the underlying disease.

4.8 Adverse Effects (Undesirable Effects)

Prostate cancer.

Eligard, like other LHRH analogues, caused a transient increase in serum testosterone concentrations during the first two weeks of treatment. Therefore, potential exacerbations of signs and symptoms of the disease during the first few weeks of treatment are of concern in patients with vertebral metastases and/or urinary obstruction or haematuria. If these conditions are aggravated, it may lead to neurological problems such as weakness and/or paraesthesia of the lower limbs or worsening of urinary symptoms (see Section 4.4 Special Warnings and Precautions for Use).

'Flare' phenomenon.

The initial increase in circulating levels of pituitary gonadotropins and gonadal steroids leads in some patients to a transient exacerbation of symptoms and signs ('flare' phenomenon). The exacerbation may include worsened bone pain, ureteric obstruction and spinal cord compression. This possibility should be taken into account in deciding to initiate leuprorelin acetate therapy in patients with existing obstructive uropathy or vertebral metastases. Early symptoms of spinal cord compression such as paraesthesia should alert the physician to the need for intensive monitoring and possible treatment.
There is no information available on the clinical effects of interrupting leuprorelin acetate therapy and whether this will produce a withdrawal 'flare'.
Initiating therapy with a nonsteroidal antiandrogen at the same time as leuprorelin acetate therapy has proven benefit in reducing flare reactions in 'at risk' patients.
The safety of Eligard was evaluated in open label, multicentre studies. In Eligard clinical studies conducted, patient injection sites were closely monitored. The adverse reactions from injection sites are summarised in Table 1.
The majority (84%) of transient burning/stinging events for Eligard 1 month were reported as mild. Pain was generally reported as brief in duration and mild in intensity. Erythema were all reported as mild and generally resolved within a few days postinjection.
The majority (86%) of transient burning/stinging events for Eligard 3 month were reported as mild. Pain was generally reported as brief in duration and mild in intensity. One of the reports characterized the erythema as mild and resolved within 7 days. The other was moderate and resolved within 15 days. Neither patient experienced erythema at multiple injections.
All (100%) of transient burning/stinging events for Eligard 4 month were reported as mild. Pain was generally reported as brief in duration and mild in intensity. Erythema was reported as mild in all cases and generally resolved within a few days postinjection.
The majority (91%) of transient burning/stinging events for Eligard 6 month were reported as mild. Pain was generally reported as brief in duration and mild in intensity. Mild bruising was reported following five (2.3%) study injections and moderate bruising was reported following two (< 1%) study injections.
The following possibly or probably related systemic adverse events occurred during clinical trials of up to six months of treatment with Eligard 1 month and Eligard 3 month, up to eight months of treatment with Eligard 4 month and up to 12 months of treatment with Eligard 6 month, and were reported in ≥ 2% and < 2% of patients (see Tables 2 and 3, respectively). Often, causality is difficult to assess in patients with metastatic prostate cancer. Reactions considered not drug related were excluded.
More common reactions (incidence ≥ 2%). See Table 2.
Less common reactions (incidence < 2%). See Table 3.

Eligard in combination with radiotherapy.

The addition of ADT in the form of leuprorelin acetate to radiotherapy unequivocally resulted in an increased range of acute and late toxicities. Some of these pivotal studies employed half of the currently recommended dose of leuprorelin. Long term safety data on the combination therapy was limited due to long term use of an anti-androgen in some studies, but limited use of leuprorelin.

Central precocious puberty.

The following are serious adverse events (see Section 4.4 Special Warnings and Precautions for Use):
Initial rise in gonadotropin and sex steroid levels.
Psychiatric events.
Convulsions.
Pseudotumor cerebri (idiopathic intracranial hypertension).
Eligard 6 month was evaluated in an uncontrolled, open-label, single-arm clinical trial in which 64 paediatric patients with CPP received at least one dose of Eligard 6 month. The age ranged from 4 to 9 years at start of treatment; 62 patients were female and 2 were male. Adverse events that occurred in ≥ 5% of patients are shown in Table 4.
Other adverse events.

Psychiatric.

Emotional disorder (2%) and irritability (2%).

Post-marketing experiences.

Pituitary apoplexy. During postmarketing surveillance, rare cases of pituitary apoplexy (a clinical syndrome secondary to infarction of the pituitary gland) have been reported after the administration of gonadotropin releasing hormone agonists, with a majority occurring within two weeks of the first dose, and some within the first hour. In these cases, pituitary apoplexy has presented as a sudden headache, vomiting, visual changes, ophthalmoplegia, altered mental status, and sometimes cardiovascular collapse. Immediate medical attention has been required.
Other adverse effects. During post-market surveillance with LHRH agonists; diabetes mellitus, myocardial infarction, cerebrovascular accident and sudden cardiac death have also been reported (see Section 4.4 Special Warnings and Precautions for Use).
Anaphylactic/anaphylactoid reactions have been reported after GnRH agonist analog administration.
Postmarketing reports of convulsions have been observed in patients on leuprorelin acetate with or without a history of predisposing factors. Convulsions are to be managed according to the current clinical practice.
Muscular atrophy has been observed with long term use of products in this class.
Interstitial lung disease has been reported with an unknown frequency.
Central precocious puberty. The following adverse events have been observed during post-approval use of leuprorelin acetate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Allergic reactions.

Anaphylactic, rash, urticaria, and photosensitivity reactions.

General.

Chest pain, weight increase, weight decrease, decreased appetite, fatigue.

Laboratory abnormalities.

Decreased WBC.

Metabolic.

Diabetes mellitus.

Musculoskeletal and connective tissue.

Arthralgia, epiphysiolysis, muscle spasms, myalgia.

Neurologic.

Neuropathy peripheral, convulsion, paralysis, insomnia, pseudotumor cerebri (idiopathic intracranial hypertension).

Psychiatric.

Emotional lability, such as crying, irritability, impatience, anger and aggression. Depression, including rare reports of suicidal ideation and attempt. Many, but not all, of these patients had a history of psychiatric illness or other comorbidities with an increased risk of depression.

Skin and subcutaneous tissue.

Injection site reactions including induration and abscess, flushing, hyperhidrosis.

Reproductive system.

Vaginal bleeding, breast enlargement.

Vascular.

Hypertension, hypotension.

Respiratory.

Dyspnea.

Reporting suspected adverse effects.

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

4.9 Overdose

In clinical trials using daily subcutaneous leuprorelin acetate in patients with prostate cancer, doses as high as 20 mg/day for up to two years caused no adverse effects differing from those observed with the 1 mg/day dose.
There is no clinical experience with the effects of an acute overdose. Because the acute animal toxicity of the drug is low, adverse effects are not expected. In the event of an overdose the patient should be monitored and supportive treatment given, if considered necessary.
In paediatric use, no specific antidotes for Eligard are known.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Prostate cancer.

Leuprorelin acetate, an LHRH agonist, acts as a potent inhibitor of gonadotropin secretion when given continuously in therapeutic doses. Animal and human studies indicate that after an initial stimulation, chronic administration of leuprorelin acetate results in suppression of testicular steroidogenesis. This effect is reversible upon discontinuation of drug therapy.
Administration of leuprorelin acetate has resulted in inhibition of the growth of certain hormone dependent tumours (prostatic tumours in Noble and Dunning male rats and DMBA induced mammary tumours in female rats) as well as atrophy of the reproductive organs.
In humans, administration of leuprorelin acetate results in an initial increase in circulating levels of luteinizing hormone (LH) and follicle stimulating hormone (FSH), leading to a transient increase in levels of the gonadal steroids (testosterone and dihydrotestosterone in males and oestrone and oestradiol in premenopausal females). However, continuous administration of leuprorelin acetate results in decreased levels of LH and FSH. In males, testosterone is reduced to below castrate threshold (≤ 50 nanogram/dL). These decreases occur within two to six weeks after initiation of treatment.
Leuprorelin acetate is not active when given orally.

Central precocious puberty.

In paediatric patients, leuprorelin acetate, a GnRH agonist, acts as a potent inhibitor of gonadotropin secretion (LH and follicle stimulating hormone (FSH)) when given continuously in therapeutic doses. Following an initial stimulation of GnRH receptors, chronic administration of leuprorelin acetate results in downregulation of GnRH receptors, reduction in release of LH, FSH and consequent suppression of ovarian and testicular production of oestradiol and testosterone, respectively. This inhibitory effect is reversible upon discontinuation of drug therapy.
In the clinical trial evaluating Eligard 6 month in paediatric patients with CPP, there was a transient surge in circulating levels of LH, FSH, oestradiol and testosterone following the first administration. A decrease in basal and GnRH agonist-stimulated LH and FSH levels along with reductions in basal oestradiol and testosterone were observed after repeat administration.

Clinical trials.

Prostate cancer. In the open label, multicentre studies conducted with Eligard patients with advanced prostate cancer were treated with monthly injections of Eligard 1 month for 6 months, a single injection of Eligard 3 month, given once every three months for 6 months, a single injection of Eligard 4 month, given once every four months for 8 months or a single injection of Eligard 6 month, given once every six months for 12 months. Patient stages in the open label, multicentre studies are described in Table 5. The Eligard 1 month and Eligard 3 month studies evaluated the achievement and maintenance of serum testosterone suppression over six months of therapy. The Eligard 4 month study evaluated the achievement and maintenance of serum testosterone suppression over eight months of therapy. The Eligard 6 month study evaluated the achievement and maintenance of serum testosterone suppression over twelve months of therapy.
Patients with brain metastases, spinal cord compression and/or urinary tract obstruction, serum testosterone levels below 150 nanogram/dL at screening, uncontrolled congestive heart failure, myocardial infarction or a coronary vascular procedure, symptomatic cardiovascular disease, venous thrombosis, uncontrolled hypertension, symptomatic hypotension, insulin dependent diabetes, a history of drug and alcohol abuse, other serious intercurrent illness (for example, haematological, renal, hepatic, respiratory, endocrine) were excluded from the studies.

Eligard 1 month.

The mean testosterone concentration increased from 361.3 nanogram/dL at baseline to 574.6 nanogram/dL at day 3 following the initial subcutaneous injection. The mean serum testosterone concentration then decreased to below baseline by day 10 and was 21.8 nanogram/dL on day 28. At the conclusion of the study (month 6), mean testosterone concentration was 6.1 nanogram/dL (see Figure 1), comparable to levels following bilateral orchiectomy.
Serum testosterone was suppressed to below the castrate threshold (≤ 50 nanogram/dL) by day 28 (week 4) in 112 of 119 (94.1%) patients remaining in the study. The remaining seven patients all attained the castrate threshold by day 42. A high proportion of patients (97% at day 42), achieved testosterone suppression levels of ≤ 20 nanogram/dL, although the full benefit of these low levels has not yet been established. Once testosterone suppression at or below serum concentrations of 50 nanogram/dL was achieved, no patients (0%) demonstrated breakthrough (concentration above 50 nanogram/dL) at any time in the study. All 117 evaluable patients in the study at month 6 (two patients withdrew for reasons unrelated to drug) had testosterone concentrations of ≤ 50 nanogram/dL.

Eligard 3 month.

The mean testosterone concentration increased from 367.1 nanogram/dL at baseline to 588.0 nanogram/dL at day 2 following the initial subcutaneous injection. The mean serum testosterone concentration then decreased to below baseline by day 14 and was 27.7 nanogram/dL on day 21. At the conclusion of the study (month 6), mean testosterone concentration was 10.1 nanogram/dL (see Figure 2), comparable to levels following bilateral orchiectomy.
Of the original 117 patients, one received less than a full dose of Eligard 3 month at baseline, never suppressed, and was withdrawn at day 73 and given an alternate treatment. In the remaining 116 patients who did receive the full dose at baseline, serum testosterone was suppressed to below the castrate threshold (≤ 50 nanogram/dL) by day 28 (week 4) in 115 of 116 (99%). By day 35, all 116 patients (100%) who received a full dose at baseline attained the castrate threshold. A high proportion of patients (84% at day 28 and 92% at day 42), achieved testosterone suppression levels of ≤ 20 nanogram/dL, although the full benefit of these low levels has not yet been established. Once testosterone suppression at or below serum concentrations of 50 nanogram/dL was achieved, only one patient (< 1%) demonstrated breakthrough (concentration above 50 nanogram/dL) following initial injection; that patient remained below the castrate threshold following the second injection. All 111 evaluable patients in the study at month 6 had testosterone concentrations of ≤ 50 nanogram/dL.

Eligard 4 month.

The mean testosterone concentration increased from 385.5 nanogram/dL at baseline to 610.0 nanogram/dL at day 2 following the initial subcutaneous injection. The mean serum testosterone concentration then decreased to below baseline by day 14 and was 17.2 nanogram/dL on day 28. At the conclusion of the study (month 8), mean testosterone concentration was 12.4 nanogram/dL (see Figure 3), comparable to levels following bilateral orchiectomy.
Serum testosterone was suppressed to below the castrate threshold (≤ 50 nanogram/dL) by day 28 in 85 of 89 (96%) patients remaining in the study. All 89 (100%) of patients remaining in the study attained the castrate threshold by day 42. A high proportion of patients (67% at day 28 and 90% at day 42), achieved testosterone suppression levels of ≤ 20 nanogram/dL, although the full benefit of these low levels has not yet been established. Once testosterone suppression at or below serum concentrations of 50 nanogram/dL was achieved, three patients (3%) demonstrated breakthrough (concentration above 50 nanogram/dL) during the study. These patients again reached castrate suppression following the second injection of study drug. Of 82 evaluable patients in the study at month 8, 81 had testosterone concentrations of ≤ 50 nanogram/dL.

Eligard 6 month.

The mean testosterone concentration increased from 367.7 nanogram/dL at baseline to 588.6 nanogram/dL at day 2 following the initial subcutaneous injection. The mean serum testosterone concentration then decreased to below baseline by day 14 and was 16.7 nanogram/dL on day 28. At the conclusion of the study (month 12), mean testosterone concentration was 12.6 nanogram/dL (see Figure 4), comparable to levels following bilateral orchiectomy.
Serum testosterone was suppressed to below the castrate threshold (≤ 50 nanogram/dL) by day 28 in 108 of 109 (99%) patients remaining in the study. One patient (< 1%) did not achieve castrate suppression and was withdrawn from the study on day 85. A high proportion of patients remaining in the study (84% at day 28 and 95% at day 42), achieved testosterone suppression levels of ≤ 20 nanogram/dL, although the full benefit of these low levels has not yet been established. Once testosterone suppression at or below serum concentrations of 50 nanogram/dL was achieved, one patient (< 1%) demonstrated breakthrough (concentration above 50 nanogram/dL) during the study. This patient reached castrate suppression at day 21 and remained suppressed until day 308 when his testosterone level rose to 112 nanogram/dL. At month 12, his testosterone was 210 nanogram/dL. Of 103 evaluable patients in the study at month 12, 102 had testosterone concentrations of ≤ 50 nanogram/dL.
All five nonevaluable patients who had achieved castration by day 28 maintained castration at each timepoint, up to and including the time of withdrawal.
Serum PSA decreased in all patients whose baseline values were elevated above the normal limit. Mean values were reduced 94% from baseline to month 6 for Eligard 1 month, 98% from baseline to month 6 for Eligard 3 month, 86% from baseline to month 8 for Eligard 4 month and 97% from baseline to month 12 for Eligard 6 month.
At month 6, PSA levels had decreased to within normal limits in 94% of patients who presented with elevated levels at baseline for Eligard 1 month. At month 6, PSA levels had decreased to within normal limits in 91% of patients who presented with elevated levels at baseline for Eligard 3 month. At month 8, PSA levels had decreased to within normal limits in 93% of patients who presented with elevated levels at baseline for Eligard 4 month. At month 12, PSA levels had decreased to within normal limits in 95% of patients who presented with elevated levels at baseline for Eligard 6 month.
Other secondary efficacy endpoints evaluated included WHO performance status, bone pain, urinary pain and urinary signs and symptoms.
At baseline, 88% of patients using Eligard 1 month, 94% of patients using Eligard 3 month, 90% of patients using Eligard 4 month and 90% of patients using Eligard 6 month were classified as "fully active" by the WHO performance status scale (status = 0). Eleven percent of patients using Eligard 1 month, 6% of patients using Eligard 3 month, 10% of patients using Eligard 4 month and 7% of patients using Eligard 6 month were "restricted in strenuous activity but ambulatory and able to carry out work of a light or sedentary nature" (status = 1).
Three percent of patients using Eligard 6 month were classified as "ambulatory but unable to carry out work activities" (status 2).
These percentages were unchanged at month 6 for Eligard 1 month. At month 6, 96% of patients using Eligard 3 month, 87% of patients using Eligard 4 month at month 8 and 94% of patients using Eligard 6 month at month 12 were classified as "fully active" by the WHO performance status scale (status = 0). Four percent of patients using Eligard 3 month at month 6, 12% of patients using Eligard 4 month at month 8 and 5% of patients using Eligard 6 month at month 12 were "restricted in strenuous activity but ambulatory and able to carry out work of a light or sedentary nature" (status = 1). One percent of patients using Eligard 4 month at month 8 and 1% of patients using Eligard 6 month at month 12 were "ambulatory but unable to carry out work activities" (status 2).
At baseline and at month 6 for Eligard 1 month and Eligard 3 month, at month 8 for Eligard 4 month and at month 12 for Eligard 6 month, patients experienced little bone pain. Urinary pain was also low both at baseline and at month 6, 8 or 12, respectively. Urinary signs and symptoms were similarly low at baseline and decreased modestly for Eligard 1 month, Eligard 4 month and Eligard 6 month at month 6, 8 or 12, respectively. Urinary signs and symptoms were similarly low at baseline and increase modestly for Eligard 3 month at month 6. In addition, there was a reduction in patients with prostate abnormalities detected during physical exam from 102 (85%) at screening to 77 (64%) at month 6 for Eligard 1 month, from 96 (82%) at screening to 76 (65%) at month 6 for Eligard 3 month, from 66 (73%) at screening to 54 (60%) at month 8 for Eligard 4 month and from 89 (80%) at screening to 60 (58%) at month 12 for Eligard 6 month.

Eligard in combination with radiotherapy.

Evidence for the indication of high-risk localised prostate cancer is based on published studies of radiotherapy combined with androgen deprivation therapy (ADT). The ADT included LHRH agonists, including leuprorelin acetate given at various dosing regimens in the neoadjuvant, concomitant and adjuvant settings, but also clinical experience of nonsteroidal antiandrogens as well as surgical castration.
Clinical data from 8 published studies was analysed for efficacy (Mottet et al., Eur Urol. 2012, Widmark et al., Lancet 2009, Heymann et al., J Clin Oncol. 2007, Solberg et al., I J Radiation Oncol. Biol. Phys. 2011, Nguyen et al., Cancer 2013, Stone et al., Mol Urol. 2000, Stone et al., Mol Urol. 1999, Zelefsky et al., Urology 1997) which demonstrated a clinical benefit for the combination of ADT with radiotherapy, compared to ADT alone. Clear differentiation of the respective study populations for the indications of locally advanced prostate cancer and high-risk prostate cancer was not possible in all the published studies.
Central precocious puberty. The efficacy of Eligard 6 month was evaluated in an uncontrolled, open-label, single arm clinical trial in which 64 paediatric patients (62 females and 2 males, naïve to previous GnRH agonist treatment) with CPP received at least one dose of Eligard 6 month at a dosing interval of 24 weeks and were observed for 12 months. The mean age was 7.5 years (range 4 to 9 years) at the start of treatment. In paediatric patients with CPP, Eligard reduced stimulated and basal gonadotropins to prepubertal levels. Suppression of peak stimulated LH concentrations to < 4 IU/L was achieved in 87% of paediatric patients by month 6 and in 86% of patients by month 12. Suppression of oestradiol or testosterone concentration to prepubertal levels at the 6-month assessment was achieved in 97% and 100% of patients, respectively. Suppression of oestradiol or testosterone was maintained at the 12-month assessment with 98% (55/56 females) and 50% (1/2 males) maintaining suppression. Eligard arrested or reversed progression of clinical signs of puberty with reductions in growth velocity and bone age. Mean growth velocity decreased from 8.9 ± 13.1 cm/yr at 1 month to 6.9 ± 3.1 cm/yr at 6 months and to 6.4 ± 1.9 cm/yr at 12 months. See Table 6.
Eight female patients out of 62 did not meet the primary efficacy criteria for LH < 4 IU/L at 6 months. In four of the eight patients, the LH level at 6 months was between 4.2 and 4.8 IU/L. The remaining four patients had LH levels > 5 IU/L. However, post stimulation oestradiol was suppressed to prepubertal levels (< 20 picogram/mL) in seven of the eight patients at month 6 and was maintained through month 12.

5.2 Pharmacokinetic Properties

Absorption.

The absorption pharmacokinetic parameters determined for Eligard are presented in Table 7.
After the initial increase following each injection, mean serum concentrations remained relatively constant: 0.28-2.0 nanogram/mL for Eligard 1 month, 0.2-2.0 nanogram/mL for Eligard 3 month, 0.1-1.0 nanogram/mL for Eligard 4 month and 0.2-2.0 nanogram/mL for Eligard 6 month. There was no evidence of significant accumulation during repeated dosing. Nondetectable leuprorelin serum concentrations have been observed during chronic Eligard administration, but testosterone levels were maintained at castrate levels.

Central precocious puberty.

After an initial subcutaneous injection of Eligard 45 mg in paediatric patients 4 to 9 years of age with CPP, leuprorelin levels peaked 4 hours post dose with a mean Cmax of 212.3 nanogram/mL. Absorption occurred in two phases, a burst phase followed by a plateau phase. The mean plateau serum leuprorelin level from 4 to 48 weeks was approximately 0.37 nanogram/mL with a range of 0.18 to 0.63 nanogram/mL. There was no accumulation of leuprorelin after the second dose.

Distribution.

The mean steady-state volume of distribution of leuprorelin following intravenous bolus administration to healthy male volunteers was 27 L.
In vitro binding to human plasma proteins ranged from 43% to 49%.
The distribution of leuprorelin following Eligard administration was not evaluated in paediatric patients.

Metabolism.

In healthy male volunteers, a 1 mg bolus of leuprorelin administered intravenously revealed that the mean systemic clearance was 7.6 L/h, with a terminal elimination half-life of approximately 3 hours based on a two compartment model.
Drug metabolism studies were not conducted with Eligard. Upon administration with different leuprorelin acetate formulations, the major metabolite of leuprorelin acetate is a pentapeptide (M-1) metabolite.

Excretion.

Drug excretion studies were not conducted with Eligard.

Special populations.

Geriatrics.

The majority of the patients (approximately 70%) studied in these clinical trials were age 70 and older.

Paediatrics.

The safety and effectiveness of Eligard 7.5 mg 1 month, 22.5 mg 3 month and 30 mg 4 month in paediatric patients have not been established (see Section 4.3 Contraindications).

Renal and hepatic insufficiency.

The pharmacokinetics of Eligard in hepatically and renally impaired adult and paediatric patients have not been determined.

5.3 Preclinical Safety Data

Genotoxicity.

Mutagenicity studies have been performed with leuprorelin acetate using bacterial and mammalian systems and with Eligard 1 month in bacterial systems. These studies provided no evidence of a genotoxic potential.

Carcinogenicity.

Two year carcinogenicity studies were conducted with leuprorelin acetate in rats and mice. In rats, a dose related increase of benign pituitary hyperplasia and benign pituitary adenomas was noted at 24 months when the drug was administered subcutaneously at high daily doses (0.6 to 4 mg/kg). There was a significant but not dose related increase of pancreatic islet cell adenomas in females and of testicular interstitial cell adenomas in males (highest incidence in the low dose group). In mice, no leuprorelin acetate induced tumours or pituitary abnormalities were observed at a dose as high as 60 mg/kg for two years. Patients have been treated with leuprorelin acetate for up to three years with doses as high as 10 mg/day and for two years with doses as high as 20 mg/day without demonstrable pituitary abnormalities.
No carcinogenicity studies have been conducted with Eligard in paediatric use.

6 Pharmaceutical Particulars

6.1 List of Excipients

See Section 2 Qualitative and Quantitative Composition.

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

Eligard should be stored below 8°C (refrigerate). The patient may store Eligard below 25°C in intact packaging for a period of 8 weeks prior to administration.

6.5 Nature and Contents of Container

Eligard is available in a single use kit. The kit consists of a two syringe mixing system, a 20-gauge 5/8 inch needle (for Eligard 1 month, Eligard 3 month and Eligard 4 month) or a 18-gauge 5/8 inch needle (for Eligard 6 month), a silica desiccant pouch to control moisture uptake, and package insert for constitution and administration procedures. Each syringe is individually packaged. Syringe B, made of cyclic olefin copolymer and sealed with a chlorobutyl closure, contains aseptically filled, lyophilized leuprorelin acetate. Syringe A, constructed of polypropylene and sealed with a polypropylene or polyethylene cap, contains the Atrigel delivery system.

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

Leuprorelin acetate is a white to near white powder, freely soluble in water and glacial acetic acid.

Chemical structure.


Chemical name: 5-oxo-L-prolyl-L-histidyl- L-tryptophyl-L-seryl- L-tyrosyl-D-leucyl- L-leucyl-L-arginyl- N-ethyl-L-prolinamide acetate (salt).

CAS number.

74381-53-6.

7 Medicine Schedule (Poisons Standard)

Schedule 4.

Summary Table of Changes