ELITYRAN 3 DCS 11.25 MG POWDER AND SOLVENT FOR PROLONGED-RELEASE SUSPENSION FOR INJECTION IN PRE-FIL, PROSTAP 3 DCS 11.25 MG POWDER AND SOLVENT FOR PROLONGED-RELEASE SUSPENSION FOR INJECTION IN PRE-FILL - patient leaflet, side effects, dosage

- if you get any side effects talk to your doctor or pharmacist. this includes any possible side effects not listed in this leaflet. see section 4.

Your medicine is available using the above name but will be referred to as PROSTAP 3 throughout this leaflet.

In this leaflet:

• 1. What PROSTAP 3 is and what it is used for

• 2. What you need to know before you use PROSTAP 3

• 3. How to take PROSTAP 3

• 4. Possible side effects

• 5. How to store PROSTAP 3

• 6. Contents of the pack and other information

1. what prostap 3 is and what it is used for

PROSTAP 3 is a synthetic hormone which can be used to reduce the levels of testosterone and estrogen circulating in the body.

PROSTAP 3 is used to treat prostate cancer in men and to treat hormone responsive early stage breast cancer in pre and perimenopausal women at higher risk of recurrence and hormone responsive advanced breast cancer in pre and perimenopausal wo­men.

PROSTAP 3 can also be used in women to treat endometriosis.

Use in children:

PROSTAP 3 is a synthetic hormone which can be used to reduce the levels of testosterone and estrogen circulating in the body. PROSTAP 3 is used to treat premature puberty which is caused by a release of certain hormones from the pituitary gland (central precocious puberty) in girls under 9 years of age and boys under 10 years of age.

2. what you need to know before you use prostap 3 use in children: your doctor will make a precise diagnosis of central precocious puberty.

Do not take PROSTAP 3:

• - If you are allergic (hypersensitive) to leuprorelin acetate (PROSTAP SR or PROSTAP 3) or any of the other ingredients of PROSTAP 3 (listed in section 6).

• - If you are pregnant, planning to become pregnant or are breastfeeding.

• - If you have abnormal vaginal bleeding which you have not discussed with your doctor.

• - In pre and perimenopausal women receiving PROSTAP 3 for the treatment of breast cancer:

• - your estrogen levels must have been adequately suppressed with PROSTAP 3 before you start treatment with an aromatase inhibitors such as exemestane and should be checked every three months during combination treatment with PROSTAP 3 and an aromatase inhibitor (see ‘Warnings and precautions’ section below for more information)

• - In girls with central precocious puberty

• - if the girl to be treated is pregnant or breast-feeding.

• - if the girl has undiagnosed vaginal bleeding.

Warnings and Precautions:

Both men and women:

• - If you are diabetic PROSTAP 3 can aggravate existing diabetes therefore diabetes patients may need more frequent monitoring of the blood glucose levels.

• - If you have diabetes or suffer from heart problems you should tell your doctor.

• - If you are at an increased risk of thinning of the bones (osteoporosis) you should tell your doctor before taking PROSTAP 3. Risk factors include:

• - If you or any of your close family have thinning of the bones.

• - If you drink excessive amounts of alcohol, and/or smoke heavily.

• - If you take drugs for epilepsy or have taken steroids such as hydrocortisone or prednisolone for a long time.

• - There have been reports of depression in patients taking PROSTAP 3 which may be severe. If you are taking PROSTAP 3 and develop depressed mood, inform your doctor.

Women only:

• - If you are a woman with submucous fibroids (benign tumours in the muscle underneath the lining of the womb), PROSTAP 3 can cause severe bleeding when the fibroids break-down. Contact your doctor immediately if you experience severe or unusual bleeding or pain.

• - If you are a woman and continue to have periods (menstruate) after starting treatment with PROSTAP 3 you should tell your doctor.

• - If you are a woman of child-bearing age, you should use non hormonal contraception whilst receiving PROSTAP 3. Although PROSTAP 3 causes periods to stop, it is not itself a contraceptive. If you are unsure about this talk to your doctor.

• – If you are being given PROSTAP 3 for the treatment of breast cancer:

• - Your doctor may assess your bone density and ovarian function before you start treatment with PROSTAP 3 and monitor your bone density and ovarian function throughout treatment.

• - PROSTAP 3 must be started at least 6–8 weeks before you start treatment with an aromatase inhibitor and should continue throughout treatment with the aromatase inhibitor.

• - If you have had chemotherapy, PROSTAP 3 treatment should only commence once you have completed chemotherapy and premenopausal status has been confirmed.

• - The recommended duration of treatment with PROSTAP 3 in combination with other hormone treatments for breast cancer is up to 5 years.

• - If you are being given PROSTAP 3 in combination with an aromatase inhibitor, your doctor may monitor your blood pressure, heart function and blood glucose levels during treatment. If you have depression or a history of depression, please inform you doctor so that they can additionally monitor your symptoms of depression during treatment with PROSTAP 3.

• - If you are unsure about this, speak to your doctor.

Men only:

• - In the rare event of an abscess occurring at the injection site your doctor may measure your testosterone levels as there could be reduced absorption of leuprorelin from the injection site.

• - If you are a man with urinary obstruction or spinal cord compression. Your doctor will supervise you closely for the first few weeks of treatment.

• - If you are a man with prostate cancer, and have had injections of a synthetic hormone in the past that has not worked, or you have had an operation to remove your testicles you should tell your doctor.

• - Please tell your doctor if you have any of the following: Any heart or blood vessel conditions, including heart rhythm problems (arrhythmia), or are being treated with medicines for these conditions. The risk of heart rhythm problems may be increased when using PROSTAP 3.

In children:

• - In the event of a sterile abscess at the injection site (mostly reported after injection into the muscle) your doctor will monitor your hormone levels as there could be reduced absorption of leuprorelin from the injection site.

• - If the child has progressive brain tumour your doctor will decide if treatment with leuprorelin is appropriate.

In girls with central precocious puberty:

• - After the first injection vaginal bleeding (spotting) and discharge may occur as a sign of hormone withdrawal. Vaginal bleeding beyond the first/second month of treatment needs to be investigated.

• - Bone density may decrease during treatment of central precocious puberty with Leuprorelin 3 Month Depot. However, after treatment is stopped, subsequent bone mass growth is preserved and peak bone mass in late adolescence does not seem to be affected by treatment.

• - Often sterile abscesses at the injection site occurred when Leuprorelin

3 Month Depot is administered in higher dosages than recommended and when it is administered into the muscle. Your doctor will therefore administer the medicinal product under the skin of e.g. abdomen, bottom or thigh.

• - Discontinuation of treatment may lead to a slipping of the growth plate of the thigh bone. A possible cause could be a weakness of the growth plate due to a lower concentration of female sexual hormones during treatment.

Other medicines and PROSTAP 3

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription.

PROSTAP 3 might interfere with some medicines used to treat heart rhythm problems (e.g. quinidine, procainamide, amiodarone and sotalol) or might increase the risk of heart rhythm problems when used with some other drugs (e.g. methadone (used for pain relief and part of drug addiction detoxification), moxifloxacin (an antibiotic), antipsychotics used for serious mental illnesses).

PROSTAP 3 with food and drink

PROSTAP 3 can be taken with or without food.

Pregnancy and breastfeeding

PROSTAP 3 must not be administered in pregnant or breast-feeding women or girls (see also section “Do not use PROSTAP 3’).

Driving and using machines

Do not drive or operate machinery if you experience drowsiness, dizziness or visual disturbances whilst being treated with PROSTAP 3.

3. how to take prostap 3

PROSTAP 3 should only be administered by your doctor or a nurse who will also take care of the preparation of the product.

The doctor or nurse will give you an injection of PROSTAP 3. The injection will normally be given in your arm, thigh or abdomen. The injection site should be varied at regular intervals.

You will normally be given an injection once every 3 months.

If you have early breast cancer, you will be given PROSTAP 3 every three months in combination with tamoxifen or an aromatase inhibitor. A minimum of one injection of PROSTAP 3 should be given before you start treatment with an aromatase inhibitor or tamoxifen.

If you have advanced breast cancer, you will be given PROSTAP 3 every three months as an add-on to your other breast cancer treatment.

If you have endometriosis you will be given an injection of PROSTAP 3 for a period of 6 months only and treatment will be initiated during the first five days of the menstrual cycle.

Use in children

Treatment of children should be under the overall supervision of the paediatric endocrinologist.

The dosing scheme needs to be adapted individually.

The recommended starting dose is dependent on the body weight:

• a) Children with a body weight 20 kg or more

Unless prescribed otherwise, 1 ml PROSTAP 3 (11,25 mg leuprorelin acetate) is administered every 3 months under the skin of e.g. abdomen, bottom or thigh as a single injection.

• b) Children with a body weight less than 20 kg

Taking into account the clinical activity of the central precocious puberty in these rare cases, the following applies:

Unless prescribed otherwise, 0,5 ml PROSTAP 3 (5,625 mg leuprorelin acetate) is administered every 3 months under the skin of e.g. abdomen, bottom or thigh as a single injection. The remainder of the suspension should be discarded. Your doctor will monitor the child’s weight ga­in.

Depending on the central precocious puberty activity, your doctor may increase the dosage in the presence of inadequate suppression (e.g. vaginal bleeding). Your doctor will determine the minimal effective dose with the help of a blood test.

The duration of treatment depends on the clinical signs at the start of treatment or during the course of treatment and is decided by your doctor together with the legal guardian and, if appropriate, the treated child. Your doctor will determine the bone age of the child in regular intervals.

In girls with bone maturation of older than 12 years and boys with bone maturation of older than 13 years your doctor will consider discontinuing the treatment, depending on the clinical effects in your child.

In girls, pregnancy should be excluded before the start of treatment. The occurrence of pregnancy during treatment cannot be generally excluded. In such cases, please talk to your doctor.

The therapy is a long-term treatment, adjusted individually. Please arrange with your doctor that PROSTAP 3 is administered as precisely as possible in regular 3-monthly periods. An exceptional delay of the injection date for a few days (90 ± 2 days) does not influence the result of the therapy.

If you miss an injection

As soon as you realise you have missed an injection, contact your doctor who will be able to give you your next injection.

Women only:

If a PROSTAP 3 injection is missed, breakthrough bleeding or ovulation may occur with the potential for conception. If you think you may be pregnant you should stop using PROSTAP 3 and contact your doctor immediately.

If you stop using PROSTAP 3

If you are being given PROSTAP 3 for the treatment of advanced or early breast cancer, you must not stop your treatment with PROSTAP 3 whilst you are taking an aromatase inhibitor.

If you are going to discontinue treatment with PROSTAP 3, your aromatase inhibitor treatment must also be discontinued within 3 months of your last PROSTAP 3 injection.

4. possible side effects

Like all medicines, PROSTAP 3 can cause side effects, although not everybody gets them.

Contact your doctor immediately or go to hospital:

• - If you develop a severe rash, itching or shortness of breath or difficulty breathing. These could be symptoms of a severe allergic reaction.

Tell your doctor:

• - If you get a severe headache which does not get better when you take painkillers.

• - If you suffer from any unexplained bruising or bleeding or feel generally unwell whilst taking PROSTAP 3. Although rare, these could be symptoms of changes in the number of red or white blood cells.

If any of the following side effects get serious, or if you notice any side effects not listed in this leaflet, speak to your doctor or pharmacist:

Men:

• - When men with prostate cancer first start treatment with PROSTAP 3, levels of testosterone can increase and in some people this may cause a temporary increase in local pain. In some cases, to prevent this from happening, your doctor may give you another type of drug such as cyproterone acetate or flutamide before and just after your first PROSTAP 3 injection. If you do get worsening pain, weakness or loss of feeling in your legs or difficulty passing urine, contact your doctor immediately.

• - If you have an existing pituitary lesion, there may be an increased risk of loss of blood to the area, which may cause permanent damage. This is very rare (may affect more than 1 in 10,000 people).

• - Blood sugar levels may be altered during treatment with PROSTAP 3, which may affect control in diabetic patients and require more frequent monitoring.

• - If you have a blood test your doctor may notice a change in blood lipid (cholesterol) levels or in values for tests on how the liver is working. These changes do not usually cause any symptoms.

Very common (may affect more than 1 in 10 people)

Weight changes, hot flushes, sweating, muscle weakness, bone pain, loss of interest in sexual intercourse, inability to have an erection, a reduction in size and function of the testes, tiredness or skin reactions at the injection site (these include skin hardening, redness, pain, abscesses, swelling, nodules, ulcers and skin damage).

Common (may affect up to 1 in 10 people)

Loss of appetite, difficulty sleeping, depression, mood changes (with longterm use), headache, nausea, abnormalities in liver function or liver blood tests, joint pain, swelling of the breast tissue or swelling in your ankles.

Uncommon (may affect up to 1 in 100 people)

Mood changes (with short-term use), dizziness, tingling in the hands or feet, diarrhoea, vomiting, muscle ache or weakness in the legs.

Not known (frequency cannot be estimated from the available data) Blood tests may show anaemia (low red cell counts), low counts in white cells or platelets, allergic reactions (may include symptoms of rash, itching, wheals or a serious allergic reaction which causes difficulty breathing or dizziness), changes in blood lipids (cholesterol) or blood sugar, paralysis, seizure, altered vision, pounding heartbeats, changes in ECG (QT prolongation), blood clots in lungs, high or low blood pressure, jaundice, fracture of the spine, thinning of bone, difficulty passing urine, fever, chills, inflammation of lungs or lung disease.

Women:

• - Many of the side effects of PROSTAP 3 are related to the decrease in oestrogen level. Oestrogen level returns to normal after treatment is stopped. Common side effects include hot flushes, mood swings, depression and vaginal dryness. As can happen naturally when women reach the menopause, PROSTAP 3 can cause a small amount of bone thinning. Vaginal bleeding may occur during treatment.

• - If you have an existing pituitary lesion, there may be an increased risk of loss of blood to the area, which may cause permanent damage. This is very rare (may affect more than 1 in 10,000 people).

• - Blood sugar levels may be altered during treatment with PROSTAP 3, which may affect control in diabetic patients and require more frequent monitoring.

• - If you have a blood test your doctor may notice a change in blood lipid (cholesterol) levels or in values for tests on how the liver is working. These changes do not usually cause any symptoms.

Very common (may affect more than 1 in 10 people)

Difficulty sleeping, headaches or hot flushes

Common (may affect up to 1 in 10 people)

Weight changes, mood changes, depression, tingling in hands or feet, dizziness, nausea, joint pain, muscle weakness, breast tenderness, changes in breast size, vaginal dryness, swelling in ankles or skin reactions at the injection site (these include skin hardening, redness, pain, abscesses, swelling, nodules, ulcers and skin damage)

Uncommon (may affect up to 1 in 100 people)

Loss of appetite, changes in blood lipids (cholesterol), altered vision, pounding heartbeats, diarrhoea, vomiting, abnormalities in liver blood tests, hair loss, muscle aches, fever, chills or tiredness

Not known (frequency cannot be estimated from the available data) Blood tests may show anaemia (low red cell counts), low counts in white cells or platelets, allergic reactions (may include symptoms of rash, itching, wheals or a serious allergic reaction causing difficulty breathing or dizziness), changes in blood sugar, paralysis, blood clots in the lungs, high or low blood pressure, jaundice, abnormalities in liver function, fracture of the spine, seizure, thinning of bone, vaginal bleeding, inflammation of lungs or lung disease.

Side effects when used for breast cancer in combination with either tamoxifen or an aromatase inhibitor

The following side effects have been seen when a similar class of medicine called GnRH analogues (Gonadotrophin Releasing Hormone analogues) has been used for breast cancer in combination with either tamoxifen or an aromatase inhibitor:

Very common (may affect more than 1 in 10 people)

Nausea, feeling very tired, joint and muscle pain, osteoporosis, hot flushes, excessive sweating, difficulty in sleeping, depression, decreased libido, dryness of the vagina, pain during or after sexual intercourse, urinary incontinence, increased blood pressure.

Common (may affect up to 1 in 10 people)

Diabetes, high blood sugar (hyperglycaemia), pain, bruising, redness and swelling at injection site, allergic reaction, bone fractures, blood clot in a blood vessel.

Uncommon (may affect up to 1 in 100 people)

Bleed in the brain, lack of blood supply to the brain or the heart.

Rare (may affect up to 1 in 1000 people)

Change in ECG (QT prolongation).

Children

In the initial phase of treatment, a short-term rise in the sex hormone levels occurs, followed by a fall to values within the prepuberty range. Due to this effect, side effects may occur particularly at the start of treatment.

Common (may affect up to 1 in 10 people):

• - mood swings

• - headache

• - abdominal pain / abdominal cramps

• - feeling sick / vomiting

• - acne

• - vaginal bleeding

• - spotting

• - discharge

• - injection site reactions

Very rare (may affect up to 1 in 10,000 people):

• - general allergic reactions (fever, rash, itching)

• - serious allergic reaction which causes difficulty in breathing or dizziness

• - As with other medicinal products of this class: if you have an existing pituitary lesion, there may be an increased risk of loss of blood to the area, which may cause permanent damage.

Not known (frequency cannot be estimated from the available data)

• - seizure

• - inflammation of lungs

• - lung disease

Notes:

In general, if vaginal bleeding (spotting) occurs with continued treatment (after possible withdrawal bleeding in the first month of treatment), this may be a sign of potential underdosage. Please tell your doctor if vaginal bleeding occurs.

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the Yellow Card Scheme Website: or search for MHRA Yellow Card in the Google Play or Apple App Store. By reporting side effects, you can help provide more information on the safety of this medicine.

5. how to store prostap 3

• – Keep out of the sight and reach of children

• – Do not store above 25oC.

• – Do not refrigerate or freeze.

• – Store in the original container in order to protect from light.

• – Do not use this medicine after the expiry date stated on the packaging.

• – The expiry date refers to the last day of that month.

• – Once mixed with the Sterile Solvent, the suspension must be used immediately.

• – If the pack has been opened or damaged, return it to your pharmacist.

• – If the medicines become discoloured or show any other signs of deterioration, consult your pharmacist who will tell you what to do.

• – Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.

6. CONTENTS OF THE PACK AND OTHER INFORMATION

What PROSTAP 3 contains:

The active ingredient in PROSTAP 3 Powder is leuprorelin acetate (11.25 mg)

Leuprorelin acetate 11.25 mg equivalent to 10.72 mg leuprorelin base.

When reconstituted with the solvent, the solution contains 11.25 mg/ml of leuprorelin acetate.

The other ingredients are:

Powder- polylactic acid, mannitol

Sterile solvent- carmellose sodium, mannitol, polysorbate 80, and water for injections.

What PROSTAP 3 looks like and contents of the pack:

One dual chamber pre-filled syringe with a needle and needle cap containing a white powder in the front chamber and 1 ml of sterile solvent (clear liquid) in the rear chamber, with a red end stopper.

The pack also contains a 1 × 23 gauge syringe needle and 1 x syringe plunger.

Manufacturer and product licence holder

Manufactured by DELPHARM NOVARA S.r.l., Via Crosa 86, 28065 Cerano, I­taly.

Procured from within EU by product licence holder: Star Pharmaceuticals Ltd, 5 Sandridge Close, Harrow, Middlesex, HA1 1XD. Repackaged by Servipharm Ltd.

POM PL 20636/3042

Leaflet revision and issue date (Ref): 18.01.21[10]

Prostap is a trademark of Takeda Pharmaceutical Company Limited.

Blind or partially sighted?

Is this leaflet hard to see or read? Call 020 8423 2111 to obtain the leaflet in a format suitable for you.

HEALTH PROFESSIONALS’ USER LEAFLET

Prostap

- if you get any side effects talk to your doctor or pharmacist. this includes any possible side effects not listed in this leaflet. see section 4.

Your medicine is available using the above name but will be referred to as ELITYRAN 3 throughout this leaflet.

In this leaflet:

• 1. What ELITYRAN 3 is and what it is used for

• 2. What you need to know before you use ELITYRAN 3

• 3. How to take ELITYRAN 3

• 4. Possible side effects

• 5. How to store ELITYRAN 3

• 6. Contents of the pack and other information

1. what elityran 3 is and what it is used for

ELITYRAN 3 is a synthetic hormone which can be used to reduce the levels of testosterone and estrogen circulating in the body.

ELITYRAN 3 is used to treat prostate cancer in men and to treat hormone responsive early stage breast cancer in pre and perimenopausal women at higher risk of recurrence and hormone responsive advanced breast cancer in pre and perimenopausal wo­men.

ELITYRAN 3 can also be used in women to treat endometriosis.

Use in children:

ELITYRAN 3 is a synthetic hormone which can be used to reduce the levels of testosterone and estrogen circulating in the body. ELITYRAN 3 is used to treat premature puberty which is caused by a release of certain hormones from the pituitary gland (central precocious puberty) in girls under 9 years of age and boys under 10 years of age.

2. what you need to know before you use elityran 3 use in children: your doctor will make a precise diagnosis of central precocious puberty.

Do not take ELITYRAN 3:

• - If you are allergic (hypersensitive) to leuprorelin acetate (ELITYRAN SR or ELITYRAN 3) or any of the other ingredients of ELITYRAN 3 (listed in section 6).

• - If you are pregnant, planning to become pregnant or are breastfeeding.

• - If you have abnormal vaginal bleeding which you have not discussed with your doctor.

• - In pre and perimenopausal women receiving ELITYRAN 3 for the treatment of breast cancer:

• - your estrogen levels must have been adequately suppressed with ELITYRAN 3 before you start treatment with an aromatase inhibitors such as exemestane and should be checked every three months during combination treatment with ELITYRAN 3 and an aromatase inhibitor (see ‘Warnings and precautions’ section below for more information)

• - In girls with central precocious puberty

• - if the girl to be treated is pregnant or breast-feeding.

• - if the girl has undiagnosed vaginal bleeding.

Warnings and Precautions:

Both men and women:

• - If you are diabetic ELITYRAN 3 can aggravate existing diabetes therefore diabetes patients may need more frequent monitoring of the blood glucose levels.

• - If you have diabetes or suffer from heart problems you should tell your doctor.

• - If you are at an increased risk of thinning of the bones (osteoporosis) you should tell your doctor before taking ELITYRAN 3. Risk factors include:

• - If you or any of your close family have thinning of the bones.

• - If you drink excessive amounts of alcohol, and/or smoke heavily.

• - If you take drugs for epilepsy or have taken steroids such as hydrocortisone or prednisolone for a long time.

• - There have been reports of depression in patients taking ELITYRAN 3 which may be severe. If you are taking ELITYRAN 3 and develop depressed mood, inform your doctor.

Women only:

• - If you are a woman with submucous fibroids (benign tumours in the muscle underneath the lining of the womb), ELITYRAN 3 can cause severe bleeding when the fibroids break-down. Contact your doctor immediately if you experience severe or unusual bleeding or pain.

• - If you are a woman and continue to have periods (menstruate) after starting treatment with ELITYRAN 3 you should tell your doctor.

• - If you are a woman of child-bearing age, you should use non hormonal contraception whilst receiving ELITYRAN 3. Although ELITYRAN 3 causes periods to stop, it is not itself a contraceptive. If you are unsure about this talk to your doctor.

• – If you are being given ELITYRAN 3 for the treatment of breast cancer:

• - Your doctor may assess your bone density and ovarian function before you start treatment with ELITYRAN 3 and monitor your bone density and ovarian function throughout treatment.

• - ELITYRAN 3 must be started at least 6–8 weeks before you start treatment with an aromatase inhibitor and should continue throughout treatment with the aromatase inhibitor.

• - If you have had chemotherapy, ELITYRAN 3 treatment should only commence once you have completed chemotherapy and premenopausal status has been confirmed.

• - The recommended duration of treatment with ELITYRAN 3 in combination with other hormone treatments for breast cancer is up to 5 years.

• - If you are being given ELITYRAN 3 in combination with an aromatase inhibitor, your doctor may monitor your blood pressure, heart function and blood glucose levels during treatment. If you have depression or a history of depression, please inform you doctor so that they can additionally monitor your symptoms of depression during treatment with ELITYRAN 3.

• - If you are unsure about this, speak to your doctor.

Men only:

• - In the rare event of an abscess occurring at the injection site your doctor may measure your testosterone levels as there could be reduced absorption of leuprorelin from the injection site.

• - If you are a man with urinary obstruction or spinal cord compression. Your doctor will supervise you closely for the first few weeks of treatment.

• - If you are a man with prostate cancer, and have had injections of a synthetic hormone in the past that has not worked, or you have had an operation to remove your testicles you should tell your doctor.

• - Please tell your doctor if you have any of the following: Any heart or blood vessel conditions, including heart rhythm problems (arrhythmia), or are being treated with medicines for these conditions. The risk of heart rhythm problems may be increased when using ELITYRAN 3.

In children:

• - In the event of a sterile abscess at the injection site (mostly reported after injection into the muscle) your doctor will monitor your hormone levels as there could be reduced absorption of leuprorelin from the injection site.

• - If the child has progressive brain tumour your doctor will decide if treatment with leuprorelin is appropriate.

In girls with central precocious puberty:

• - After the first injection vaginal bleeding (spotting) and discharge may occur as a sign of hormone withdrawal. Vaginal bleeding beyond the first/second month of treatment needs to be investigated.

• - Bone density may decrease during treatment of central precocious puberty with Leuprorelin 3 Month Depot. However, after treatment is stopped, subsequent bone mass growth is preserved and peak bone mass in late adolescence does not seem to be affected by treatment.

• - Often sterile abscesses at the injection site occurred when Leuprorelin

• 3 Month Depot is administered in higher dosages than recommended and when it is administered into the muscle. Your doctor will therefore administer the medicinal product under the skin of e.g. abdomen, bottom or thigh.

• - Discontinuation of treatment may lead to a slipping of the growth plate of the thigh bone. A possible cause could be a weakness of the growth plate due to a lower concentration of female sexual hormones during treatment.

Other medicines and ELITYRAN 3

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription.

ELITYRAN 3 might interfere with some medicines used to treat heart rhythm problems (e.g. quinidine, procainamide, amiodarone and sotalol) or might increase the risk of heart rhythm problems when used with some other drugs (e.g. methadone (used for pain relief and part of drug addiction detoxification), moxifloxacin (an antibiotic), antipsychotics used for serious mental illnesses).

ELITYRAN 3 with food and drink

ELITYRAN 3 can be taken with or without food.

Pregnancy and breastfeeding

ELITYRAN 3 must not be administered in pregnant or breast-feeding women or girls (see also section “Do not use ELITYRAN 3’).

Driving and using machines

Do not drive or operate machinery if you experience drowsiness, dizziness or visual disturbances whilst being treated with ELITYRAN 3.

3. how to take elityran 3

ELITYRAN 3 should only be administered by your doctor or a nurse who will also take care of the preparation of the product.

The doctor or nurse will give you an injection of ELITYRAN 3. The injection will normally be given in your arm, thigh or abdomen. The injection site should be varied at regular intervals.

You will normally be given an injection once every 3 months.

If you have early breast cancer, you will be given ELITYRAN 3 every three months in combination with tamoxifen or an aromatase inhibitor. A minimum of one injection of ELITYRAN 3 should be given before you start treatment with an aromatase inhibitor or tamoxifen.

If you have advanced breast cancer, you will be given ELITYRAN 3 every three months as an add-on to your other breast cancer treatment.

If you have endometriosis you will be given an injection of ELITYRAN 3 for a period of 6 months only and treatment will be initiated during the first five days of the menstrual cycle.

Use in children

Treatment of children should be under the overall supervision of the paediatric endocrinologist.

The dosing scheme needs to be adapted individually.

The recommended starting dose is dependent on the body weight:

• a) Children with a body weight 20 kg or more

Unless prescribed otherwise, 1 ml ELITYRAN 3 (11,25 mg leuprorelin acetate) is administered every 3 months under the skin of e.g. abdomen, bottom or thigh as a single injection.

• b) Children with a body weight less than 20 kg

Taking into account the clinical activity of the central precocious puberty in these rare cases, the following applies:

Unless prescribed otherwise, 0,5 ml ELITYRAN 3 (5,625 mg leuprorelin acetate) is administered every 3 months under the skin of e.g. abdomen, bottom or thigh as a single injection. The remainder of the suspension should be discarded. Your doctor will monitor the child’s weight ga­in.

Depending on the central precocious puberty activity, your doctor may increase the dosage in the presence of inadequate suppression (e.g. vaginal bleeding). Your doctor will determine the minimal effective dose with the help of a blood test.

The duration of treatment depends on the clinical signs at the start of treatment or during the course of treatment and is decided by your doctor together with the legal guardian and, if appropriate, the treated child. Your doctor will determine the bone age of the child in regular intervals.

In girls with bone maturation of older than 12 years and boys with bone maturation of older than 13 years your doctor will consider discontinuing the treatment, depending on the clinical effects in your child.

In girls, pregnancy should be excluded before the start of treatment. The occurrence of pregnancy during treatment cannot be generally excluded. In such cases, please talk to your doctor.

The therapy is a long-term treatment, adjusted individually. Please arrange with your doctor that ELITYRAN 3 is administered as precisely as possible in regular 3-monthly periods. An exceptional delay of the injection date for a few days (90 ± 2 days) does not influence the result of the therapy.

If you miss an injection

As soon as you realise you have missed an injection, contact your doctor who will be able to give you your next injection.

Women only:

If a ELITYRAN 3 injection is missed, breakthrough bleeding or ovulation may occur with the potential for conception. If you think you may be pregnant you should stop using ELITYRAN 3 and contact your doctor immediately.

If you stop using ELITYRAN 3

If you are being given ELITYRAN 3 for the treatment of advanced or early breast cancer, you must not stop your treatment with ELITYRAN 3 whilst you are taking an aromatase inhibitor.

If you are going to discontinue treatment with ELITYRAN 3, your aromatase inhibitor treatment must also be discontinued within 3 months of your last ELITYRAN 3 injection.

4. possible side effects

Like all medicines, ELITYRAN 3 can cause side effects, although not everybody gets them.

Contact your doctor immediately or go to hospital:

• - If you develop a severe rash, itching or shortness of breath or difficulty breathing. These could be symptoms of a severe allergic reaction.

Tell your doctor:

• - If you get a severe headache which does not get better when you take painkillers.

• - If you suffer from any unexplained bruising or bleeding or feel generally unwell whilst taking ELITYRAN 3. Although rare, these could be symptoms of changes in the number of red or white blood cells.

If any of the following side effects get serious, or if you notice any side effects not listed in this leaflet, speak to your doctor or pharmacist:

Men:

• - When men with prostate cancer first start treatment with ELITYRAN 3, levels of testosterone can increase and in some people this may cause a temporary increase in local pain. In some cases, to prevent this from happening, your doctor may give you another type of drug such as cyproterone acetate or flutamide before and just after your first ELITYRAN 3 injection. If you do get worsening pain, weakness or loss of feeling in your legs or difficulty passing urine, contact your doctor immediately.

• - If you have an existing pituitary lesion, there may be an increased risk of loss of blood to the area, which may cause permanent damage. This is very rare (may affect more than 1 in 10,000 people).

• - Blood sugar levels may be altered during treatment with ELITYRAN 3, which may affect control in diabetic patients and require more frequent monitoring.

• - If you have a blood test your doctor may notice a change in blood lipid (cholesterol) levels or in values for tests on how the liver is working. These changes do not usually cause any symptoms.

Very common (may affect more than 1 in 10 people)

Weight changes, hot flushes, sweating, muscle weakness, bone pain, loss of interest in sexual intercourse, inability to have an erection, a reduction in size and function of the testes, tiredness or skin reactions at the injection site (these include skin hardening, redness, pain, abscesses, swelling, nodules, ulcers and skin damage).

Common (may affect up to 1 in 10 people)

Loss of appetite, difficulty sleeping, depression, mood changes (with longterm use), headache, nausea, abnormalities in liver function or liver blood tests, joint pain, swelling of the breast tissue or swelling in your ankles.

Uncommon (may affect up to 1 in 100 people)

Mood changes (with short-term use), dizziness, tingling in the hands or feet, diarrhoea, vomiting, muscle ache or weakness in the legs.

Not known (frequency cannot be estimated from the available data) Blood tests may show anaemia (low red cell counts), low counts in white cells or platelets, allergic reactions (may include symptoms of rash, itching, wheals or a serious allergic reaction which causes difficulty breathing or dizziness), changes in blood lipids (cholesterol) or blood sugar, paralysis, seizure, altered vision, pounding heartbeats, changes in ECG (QT prolongation), blood clots in lungs, high or low blood pressure, jaundice, fracture of the spine, thinning of bone, difficulty passing urine, fever, chills, inflammation of lungs or lung disease.

Women:

• - Many of the side effects of ELITYRAN 3 are related to the decrease in oestrogen level. Oestrogen level returns to normal after treatment is stopped. Common side effects include hot flushes, mood swings, depression and vaginal dryness. As can happen naturally when women reach the menopause, ELITYRAN 3 can cause a small amount of bone thinning. Vaginal bleeding may occur during treatment.

• - If you have an existing pituitary lesion, there may be an increased risk of loss of blood to the area, which may cause permanent damage. This is very rare (may affect more than 1 in 10,000 people).

• - Blood sugar levels may be altered during treatment with ELITYRAN 3, which may affect control in diabetic patients and require more frequent monitoring.

• - If you have a blood test your doctor may notice a change in blood lipid (cholesterol) levels or in values for tests on how the liver is working. These changes do not usually cause any symptoms.

Very common (may affect more than 1 in 10 people)

Difficulty sleeping, headaches or hot flushes

Common (may affect up to 1 in 10 people)

Weight changes, mood changes, depression, tingling in hands or feet, dizziness, nausea, joint pain, muscle weakness, breast tenderness, changes in breast size, vaginal dryness, swelling in ankles or skin reactions at the injection site (these include skin hardening, redness, pain, abscesses, swelling, nodules, ulcers and skin damage)

Uncommon (may affect up to 1 in 100 people)

Loss of appetite, changes in blood lipids (cholesterol), altered vision, pounding heartbeats, diarrhoea, vomiting, abnormalities in liver blood tests, hair loss, muscle aches, fever, chills or tiredness

Not known (frequency cannot be estimated from the available data) Blood tests may show anaemia (low red cell counts), low counts in white cells or platelets, allergic reactions (may include symptoms of rash, itching, wheals or a serious allergic reaction causing difficulty breathing or dizziness), changes in blood sugar, paralysis, blood clots in the lungs, high or low blood pressure, jaundice, abnormalities in liver function, fracture of the spine, seizure, thinning of bone, vaginal bleeding, inflammation of lungs or lung disease.

Side effects when used for breast cancer in combination with either tamoxifen or an aromatase inhibitor

The following side effects have been seen when a similar class of medicine called GnRH analogues (Gonadotrophin Releasing Hormone analogues) has been used for breast cancer in combination with either tamoxifen or an aromatase inhibitor:

Very common (may affect more than 1 in 10 people)

Nausea, feeling very tired, joint and muscle pain, osteoporosis, hot flushes, excessive sweating, difficulty in sleeping, depression, decreased libido, dryness of the vagina, pain during or after sexual intercourse, urinary incontinence, increased blood pressure.

Common (may affect up to 1 in 10 people)

Diabetes, high blood sugar (hyperglycaemia), pain, bruising, redness and swelling at injection site, allergic reaction, bone fractures, blood clot in a blood vessel.

Uncommon (may affect up to 1 in 100 people)

Bleed in the brain, lack of blood supply to the brain or the heart.

Rare (may affect up to 1 in 1000 people)

Change in ECG (QT prolongation).

Children

In the initial phase of treatment, a short-term rise in the sex hormone levels occurs, followed by a fall to values within the prepuberty range. Due to this effect, side effects may occur particularly at the start of treatment.

Common (may affect up to 1 in 10 people):

• - mood swings

• - headache

• - abdominal pain / abdominal cramps

• - feeling sick / vomiting

• - acne

• - vaginal bleeding

• - spotting

• - discharge

• - injection site reactions

Very rare (may affect up to 1 in 10,000 people):

• - general allergic reactions (fever, rash, itching)

• - serious allergic reaction which causes difficulty in breathing or dizziness

• - As with other medicinal products of this class: if you have an existing pituitary lesion, there may be an increased risk of loss of blood to the area, which may cause permanent damage.

Not known (frequency cannot be estimated from the available data)

• - seizure

• - inflammation of lungs

• - lung disease

Notes:

In general, if vaginal bleeding (spotting) occurs with continued treatment (after possible withdrawal bleeding in the first month of treatment), this may be a sign of potential underdosage. Please tell your doctor if vaginal bleeding occurs.

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the Yellow Card Scheme Website: or search for MHRA Yellow Card in the Google Play or Apple App Store. By reporting side effects, you can help provide more information on the safety of this medicine.

5. how to store elityran 3

• – Keep out of the sight and reach of children

• – Do not store above 25oC.

• – Do not refrigerate or freeze.

• – Store in the original container in order to protect from light.

• – Do not use this medicine after the expiry date stated on the packaging.

• – The expiry date refers to the last day of that month.

• – Once mixed with the Sterile Solvent, the suspension must be used immediately.

• – If the pack has been opened or damaged, return it to your pharmacist.

• – If the medicines become discoloured or show any other signs of deterioration, consult your pharmacist who will tell you what to do.

• – Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.

6. CONTENTS OF THE PACK AND OTHER INFORMATION

What ELITYRAN 3 contains:

The active ingredient in ELITYRAN 3 Powder is leuprorelin acetate (11.25 mg)

Leuprorelin acetate 11.25 mg equivalent to 10.72 mg leuprorelin base.

When reconstituted with the solvent, the solution contains 11.25 mg/ml of leuprorelin acetate.

The other ingredients are:

Powder- polylactic acid, mannitol

Sterile solvent- carmellose sodium, mannitol, polysorbate 80, and water for injections.

What ELITYRAN 3 looks like and contents of the pack:

One dual chamber pre-filled syringe with a needle and needle cap containing a white powder in the front chamber and 1 ml of sterile solvent (clear liquid) in the rear chamber, with a red end stopper.

The pack also contains a 1 × 23 gauge syringe needle and 1 x syringe plunger.

Manufacturer and product licence holder

Manufactured by DELPHARM NOVARA S.r.l., Via Crosa 86, 28065 Cerano, I­taly.

Procured from within EU by product licence holder: Star Pharmaceuticals Ltd, 5 Sandridge Close, Harrow, Middlesex, HA1 1XD. Repackaged by Servipharm Ltd.

POM PL 20636/3042

Leaflet revision and issue date (Ref): 18.01.21[10]

Elityran is a trademark of Takeda Pharmaceutical Company Limited.

Blind or partially sighted?

Is this leaflet hard to see or read? Call 020 8423 2111 to obtain the leaflet in a format suitable for you.

Elityran

(leuprorelin acetate)

• 1. NAME OF THE MEDICINAL PRODUCT

Elityran 3 DCS 11.25 mg Powder and Solvent for Prolonged-release Suspension for Injection in Pre-filled Syringe

• 2. QUALITATIVE AND QUANTITATIVE COMPOSITION

ELITYRAN 3 Powder : contains 11.25 mg leuprorelin acetate (equivalent to 10.72 mg base).

Sterile Solvent: Each ml contains carmellose sodium 5 mg, mannitol (E421) 50 mg, polysorbate 80 1 mg, acetic acid, glacial up to 0.05 mg and water for injections.

When reconstituted with Sterile Solvent, the suspension contains 11.25 mg/ml leuprorelin acetate.

For the full list of excipients, see section 6.1

• 3. PHARMACEUTICAL FORM

Powder and solvent for suspension for injection in pre-filled syringe

Powder: A sterile, lyophilised, white, odourless powder.

Solvent: A clear, odourless, slightly viscous, sterile solvent.

• 4. CLINICAL PARTICULARS

  • 4.1 Therapeutic indications

• (i) Metastatic prostate cancer.

• (ii) Locally advanced prostate cancer, as an alternative to surgical castration.

• (iii) As an adjuvant treatment to radiotherapy in patients with high-risk localised or locally advanced prostate cancer.

• (iv) As an adjuvant treatment to radical prostatectomy in patients with locally advanced prostate cancer at high risk of

disease progression.

• (v) As neo-adjuvant treatment prior to radiotherapy in patients with high-risk localised or locally advanced prostate cancer.

• (vi) Management of endometriosis, including pain relief and reduction of endometriotic lesions.

• (vii) As treatment in pre- and perimenopausal women with advanced breast cancer suitable for hormonal manipulation.

• (viii) As adjuvant treatment in combination with tamoxifen or an aromatase inhibitor, of endocrine responsive early stage breast

cancer in pre- and perimenopausal women at higher risk of disease recurrence (young age, high grade tumour, lymph node involvement). In women who have received chemotherapy, premenopausal status must be confirmed after completion of chemotherapy.

In children:

Treatment of central precocious puberty (girls under 9 years of age, boys under 10 years of age). (See Section 5.1)

• 4.2 Posology and method of administration

Posology

Prostate Cancer : The usual recommended dose is 11.25 mg presented as a three month depot injection and administered as a single subcutaneous injection at intervals of three months. The majority of patients will respond to this dosage. ELITYRAN 3 therapy should not be discontinued when remission or improvement occurs. As with other drugs administered regularly by injection, the injection site should be varied periodically.

Response to ELITYRAN 3 therapy should be monitored by clinical parameters and by measuring prostate-specific antigen (PSA) serum levels.

Clinical studies with leuprorelin acetate have shown that testosterone levels increased during the first 4 days of treatment in the majority of non-orchidectomised patients. They then decreased and reached castrate levels by 2–4 weeks. Once attained, castrate levels were maintained as long as drug therapy continued. If a patient's response appears to be sub-optimal, then it would be advisable to confirm that serum testosterone levels have reached or are remaining at castrate levels. Transient increases in acid phosphatase levels sometimes occur early in the treatment period but usually return to normal or near normal values by the 4th week of treatment.

In patients treated with GnRH analogues for prostate cancer, treatment is usually continued upon development of castrateresistant prostate cancer.

Reference should be made to relevant guidelines.

Endometriosis : The recommended dose is 11.25 mg administered as a single intramuscular injection every 3 months for a period of 6 months only.

Treatment should be initiated during the first 5 days of the menstrual cycle.

In women receiving GnRH analogues for the treatment of endometriosis, the addition of hormone replacement therapy (HRT – an estrogen and progestogen) has been shown to reduce bone mineral density loss and vasomotor symptoms. Therefore if appropriate, HRT should be co-administered with ELITYRAN 3 taking into account the risks and benefits of each treatment. Advanced breast cancer : The recommended dose is 11.25 mg administered as a single subcutaneous injection every 3 months. Early breast cancer : The recommended dose is 11.25 mg administered as a single subcutaneous injection every 3 months in combination with tamoxifen or an aromatase inhibitor.

In women receiving chemotherapy, leuprorelin should be commenced after completion of chemotherapy, once pre-menopausal status has been confirmed (see section 4.4).

The recommended treatment duration for adjuvant treatment in combination with other hormonotherapy is up to 5 years.

In combination with aromatase inhibitor for advanced and early breast cancer:

Treatment with leuprorelin must be initiated at least 6–8 weeks before starting aromatase inhibitor treatment. A minimum of one injection of ELITYRAN 3 should be administered before commencement of aromatase inhibitor treatment.

Ovarian suppression should be confirmed by low blood concentrations of FSH and estradiol prior to starting aromatase inhibitor treatment and measurements should be repeated every three months during combination therapy with leuprorelin and an aromatase inhibitor (see Section 4.4).

During treatment with an aromatase inhibitor, leuprorelin must not be interrupted to avoid rebound increases in circulating estrogens in premenopausal wo­men.

ELITYRAN 3 should not be used for preservation of ovarian function (see Section 5.1).

Elderly : As for adults.

Paediatric population:

The treatment of children with leuprorelin acetate should be under the overall supervision of the paediatric endocrinologist.

The dosing scheme needs to be adapted individually.

The recommended starting dose is dependent on the body weight.

Children with a body weight > 20 kg

• 1 ml (11.25 mg leuprorelin acetate) suspension of 130.0 mg sustained-release microcapsules in 1 ml vehicle solution are administered every 3 months as a single subcutaneous injection.

Children with a body weight < 20 kg

In these rare cases the following dosage should be administered according to the clinical activity of the central precocious puberty: 0.5 ml (5.625 mg leuprorelin acetate) suspension of 130.0 mg sustained-release microcapsules in 1 ml vehicle solution are administered every 3 months as a single subcutaneous injection.

The remainder of the suspension should be discarded. The child’s weight gain should be monitored.

Depending on the activity of the central precocious puberty, it may be necessary to increase the dosage in the presence of inadequate suppression (clinical evidence e.g. spotting or inadequate gonadotropin suppression in the LHRH test). The minimal effective 3-monthly dose to be administered should then be determined by means of the LHRH test.

Sterile abscesses at the injection site often occurred when leuprorelin acetate was administered intramuscularly at higher than the recommended dosages. Therefore, in such cases, the medicinal product should be administered subcutaneously (see 4.4).

It is recommended to use the lowest volumes possible for injections in children in order to decrease the inconvenience which is associated with the intramuscular/sub­cutaneous injection.

The duration of treatment depends on the clinical parameters at the start of treatment or during the course of treatment (final height prognosis, growth velocity, bone age and/or bone age acceleration) and is decided by the treating paediatrician together with the legal guardian and, if appropriate, the treated child. The bone age should be monitored during treatment at 6–12 month intervals. In girls with bone maturation of older than 12 years and boys with bone maturation of older than 13 years discontinuation of treatment should be considered taking into account the clinical parameters.

In girls, pregnancy should be excluded before the start of treatment. The occurrence of pregnancy during treatment cannot be generally excluded. In such cases, medical advice should be sought.

Note : The administration interval should be 90 ± 2 days in order to prevent the recurrence of precocious puberty symptoms.

Method of Administration

ELITYRAN 3 should be prepared, reconstituted and administered only by healthcare professionals who are familiar with these procedures.

Administration

INSTRUCTIONS ON HOW TO MIX AND ADMINISTER

mood changes (long term use: frequency of ‘common’ and short term use: frequency of ‘uncommon’)

Women : Those adverse events occurring most frequently with ELITYRAN 3 are associated with hypo-estrogenism; the most frequently reported are hot flushes, mood swings including depression (occasionally severe), and vaginal dryness. Estrogen levels return to normal after treatment is discontinued. The induced hypo-estrogenic state results in a small loss in bone density over the course of treatment, some of which may not be reversible (see Section 4.4).

Vaginal haemorrhage may occur during therapy due to acute degeneration of submucous fibroids (see Section 4.4).

TABULATED LIST OF ADVERSE REACTIONS

In women with early breast cancer treated with a GnRH agonist, in combination with tamoxifen or an aromatase inhibitor, the most commonly observed adverse reactions included hot flush, musculoskeletal disorders, fatigue, insomnia, hyperhidrosis, vulvovaginal dryness and depression.

• 5. PHARMACOLOGICAL PROPERTIES

  • 5.1 Pharmacody­namic properties

Pharmacotherapeutic group: Gonadotrophin Releasing Hormone Analogues

ATC code: L02AE 02

ELITYRAN 3 contains leuprorelin acetate, a synthetic nonapeptide analogue of naturally occurring gonadotrophin releasing hormone (GnRH) which possesses greater potency than the natural hormone. Leuprorelin acetate is a peptide and therefore unrelated to the steroids. Chronic administration results in an inhibition of gonadotrophin production and subsequent suppression of ovarian and testicular steroid secretion.

This effect is reversible on discontinuation of therapy.

Administration of leuprorelin acetate results in an initial increase in circulating levels of gonadotrophins which leads to a transient increase in gonadal steroid levels in both men and women. Continued administration of leuprorelin acetate results in a decrease of gonadotrophin and sex steroid levels. In men serum testosterone levels, initially raised in response to early luteinising hormone (LH) release, fall to castrate levels in about 2–4 weeks.

Leuprorelin acetate is inactive when given orally.

A randomised, open-label, comparative multi-centre study was performed to compare the efficacy and safety of the 3.75 mg and 11.25 mg depots of leuprorelin acetate. 48% of patients included had locally advanced disease (T3N0M0), 52% of patients had metastatic disease. Mean serum testosterone level fell below the threshold for chemical castration (0.5 ng/ml) at one month of treatment, continuing to decrease thereafter and stabilising at a value below the castration threshold. The decline in serum PSA mirrored that of serum testosterone in both groups.

In an open, prospective clinical trial involving 205 patients receiving 3.75 mg leuprorelin acetate on a monthly basis as treatment for metastatic prostate cancer, the long-term efficacy and safety of leuprorelin acetate was assessed. Testosterone levels were maintained below the castrate threshold over the 63-month follow up period. Median survival time exceeded 42.5 months for those receiving monotherapy and 30.9 months for those receiving leuprorelin acetate in combination with anti-androgens (this difference relating to baseline differences between groups).

In a meta-analysis involving primarily patients with metastatic disease, no statistically significant difference in survival was found for patients treated with LHRH analogues compared with patients treated with orchidectomy.

In another randomised, open-label, multi-centre comparative trial, leuprorelin acetate in combination with flutamide has been shown to significantly improve disease-free survival and overall survival when used as an adjuvant therapy to radiotherapy in 88 patients with high-risk localised (T1-T2 and PSA of at least

10 ng/mL or a Gleason score of at least 7), or locally advanced (T3-T4) prostate cancer. The optimum duration of adjuvant therapy has not been established.

This US study used a higher dose of leuprorelin acetate (7.5 mg/month) which is therapeutically equivalent to the European licensed dose.

The use of a LHRH agonist may be considered after prostatectomy in selected patients considered at high risk of disease progression.

There are no disease-free survival data or survival data with leuprorelin acetate in this setting.

Neoadjuvant leuprorelin acetate prior to radiotherapy has been shown to reduce prostate volume.

There are no data demonstrating effectiveness of the 3-monthly formulation of leuprorelin for ovarian function preservation in premenopausal women undergoing chemotherapy treatment.

In children:

Reversible suppression of pituitary gonadotropin release occurs, with a subsequent decrease in oestradiol (E2) or testosterone levels to values in the pre-pubertal range.

Initial gonadal stimulation (flare-up) may cause vaginal bleeding in girls who are already post-menarchal at start of treatment. Withdrawal bleeding may occur at the start of treatment. The bleeding normally stops as treatment continues.

The following therapeutic effects can be demonstrated:

• – Suppression of basal and stimulated gonadotropin levels to pre-pubertal levels.

• – Suppression of prematurely increased sexual hormone levels to pre-pubertal levels and arrest of premature menstruation;

• – Arrest/involution of somatic pubertal development (Tanner stages);

• – Improvement/nor­malisation of the ratio of chronological age to bone age;

• – Prevention of progressive bone age acceleration;

• – Decrease of growth velocity and its normalization;

• – Increase in final height.

Treatment result is the suppression of the pathologically, prematurely activated hypothalamic-pituitary-gonadal axis according to pre-pubertal age. In a long-term clinical trial in children treated with leuprorelin at doses up to 15mg monthly for > 4 years resumption of pubertal progression were observed after cessation of treatment. Follow up of 20 female subjects to adulthood showed normal menstrual cycles in 80% and 12 pregnancies in 7 of the 20 subjects including multiple pregnancies for 4 subjects.

• 5.2 Pharmacoki­netic properties

Leuprorelin acetate is well absorbed after subcutaneous and intramuscular injections. It binds to the LHRH receptors and is rapidly degraded. An initially high plasma level of leuprorelin acetate peaks at around 3 hours after a ELITYRAN 3 subcutaneous injection, followed by a decrease to maintenance levels in 7 to 14 days. ELITYRAN 3 provides continuous plasma levels for up to 117 days resulting in suppression of testosterone to below castration level within 4 weeks of the first injection in the majority of patients.

The metabolism, distribution and excretion of leuprorelin acetate in humans have not been fully determined.

In children:

• Figure 1 presents the leuprorelin serum levels in children during the first 6 months of treatment following s.c. administration of leuprorelin acetate 3-month depot (two injections).

From the first injection, the leuprorelin serum levels increase reaching maximal serum levels at month 4 (294.79 pg/ml ± 105.42) and slightly decrease until month 6 (229.02 pg/ml ± 103.33).

Figure 1: Leuprorelin serum levels during the first six months of treatment with the leuprorelin acetate 3-month depot formulation (two s.c. injections) (n=42–43)

• 5.3 Preclinical safety data

Animal studies have shown that leuprorelin acetate has a high acute safety factor. No major overt toxicological problems have been seen during repeated administration. Whilst the development of pituitary adenomas has been noted in chronic toxicity studies at high doses in some animal species, this has not been observed in long-term clinical studies. No evidence of mutagenicity or teratogenicity has been shown.

Animal reproductive studies showed increased foetal mortality and decreased foetal weights reflecting the pharmacological effects of this LHRH agonist.

• 6. PHARMACEUTICAL PARTICULARS

  • 6.1 List of excipients

The other ingredients are:

Powder- poly lactic acid, mannitol (E421)

Sterile solvent- carmellose sodium, mannitol, polysorbate 80 and water for injections.

• 6.2 Incompati­bilities

Not applicable.

• 6.3 Shelf life

3 years unopened.

Once reconstituted with sterile solvent, the suspension should be administered immediately.

• 6.4 Special precautions for storage

Do not store above 25oC.

Do not refrigerate or freeze.

Store in the original container in order to protect from light.

• 6.5 Nature and contents of container

One dual chamber pre-filled syringe with a needle and needle cap containing a white powder in the front chamber and 1 ml of sterile solvent (clear liquid) in the rear chamber, with a red end stopper.

The pack also contains a 1 × 23 gauge syringe needle and 1 x syringe plunger.

• 6.6 Special precautions for disposal and other handling

Always ensure that the safety device to prevent needle-stick injury is deployed after injection. Any unused product or waste material should be disposed of in accordance with local requirements.

• 7. PRODUCT LICENCE HOLDER