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

Prostap® 3 DCS 11.25 mg Powder and Solvent for Prolonged-release Suspension for Injection in Prefilled Syringe

Your medicine is known by the above name but will be referred to as Prostap 3 throughout this leaflet.

Read all of this leaflet carefully before you start using this medicine because it contains important information for you.

• – Keep this leaflet. You may need to read it again.

• – If you have any further questions, ask your doctor or pharmacist.

• – This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.

• – 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.

What is 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 pre-menopausal 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

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

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

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.
• 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 long-term 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.

• mood swings
• headache
• abdominal pain / abdominal cramps
• feeling sick / vomiting
• acne
• vaginal bleeding
• spotting
• discharge
• injection site reactions
• 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.
• 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 at: 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 use this medicine after the expiry date which is stated on the packaging.
• The expiry date refers to the last day of that month.
• Do not refrigerate or freeze.
• Store in the original package in order to protect from light.
• Do not store above 25°C.
• 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 your medicine shows signs of deterioration or discolouration seek the advice of your pharmacist who will tell you what to do.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help to protect the environment.

6. contents of the pack and other information

What Prostap 3 contains:

• Each syringe contains 11.25 mg leuprorelin acetate.
• Also includes polylactic acid, which controls the release of the active ingredient into the body, and mannitol.
• The Sterile Solvent contains mannitol, carmellose sodium, polysorbate, glacial acetic acid and water for injections.

What Prostap 3 looks like and contents of the pack:

A dual chamber pre-filled syringe containing sterile, white powder in the front chamber and sterile, clear solvent in the rear chamber. The powder is mixed with the solvent before injection.

Each pack contains:

1 x dual chamber pre-filled syringe containing 11.25 mg leuprorelin acetate powder in the front chamber and 1 ml sterile solvent in the rear chamber.

1 × 23 gauge syringe needle.

1 x syringe plunger.

Who Manufactured your medicine

Manufactured by Takeda Italia S.p.A. Via Crosa 86, Cerano, Italy.

or

Delpharm Novara S.r.l. Via Crosa 86, Cerano, Italy.

Procured from within the EU and repackaged by Product Licence Holder Ennogen Healthcare Ltd, Unit G4 Riverside Industrial Estate, Riverside Way, Dartford, Kent, DA1 5BS.

PL 40739/0102 POM

Leaflet date: 12 November 2020 Ref: Pro3/UT1

This leaflet does not contain the complete information about your medicine. If you have any questions or you are not sure about anything you should ask your doctor or pharmacist who can give you more information.

The information in this leaflet applies only to Prostap 3.

Prostap is a registered trademark of Takeda Pharmaceutical Company Ltd

Blind or partially sighted?

Is this leaflet hard to see or read?

Call 01322 629220 to obtain the leaflet in a format suitable for you.

INSTRUCTIONS ON HOW TO MIX AND ADMINISTER

Note: The suspension settles out very quicklyfollowin­greconstituti­on and therefore the product should be mixed and used immediately.

Vascular disorders	hot flush					pulmonary embolism, hypertension, hypotension (see Section 4.4)
Gastrointestinal disorders		nausea	diarrhoea, vomiting
Hepatobiliary disorders		hepatic function abnormal, liver function test abnormal (usually transient)				jaundice
Skin and subcutaneous tissue disorders	hyperhydrosis
Musculoskeletal, connective tissue and bone disorders	muscle weakness, bone pain	arthralgia	myalgia, weakness of lower extremities			spinal fracture (see Section 4.4), reduction in bone mass which may occur with the use of GnRH agonists
Respiratory, thoracic and mediastinal disorders						Interstitial lung disease
Renal and urinary disorders						urinary tract obstruction
Reproductive system and breast disorders	Libido decreased, erectile dysfunction, testicular atrophy	gynaecomastia
General disorders and administration site conditions	Fatigue, injection site reaction, e.g., induration, erythema, pain, abscesses, swelling, nodules, ulcers and necrosis	oedema peripheral				pyrexia

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

Women: Those adverse events occurring most frequently with Prostap 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

SOC	Very common	Common	Uncommon	Rare	Very rare	Not known
Blood and lymphatic system disorders						Anaemia (reported in medicinal products of this class), thrombocytopaenia, leucopenia
Immune system disorders						hypersensitivity reactions (including rash, pruritus, urticaria and rarely, wheezing and interstitial pneumonitis, anaphylactic reactions)
Metabolism and nutrition disorders		weight fluctuation	decreased appetite, lipids abnormal			glucose tolerance abnormal, which may affect diabetic control
Psychiatric disorders	insomnia	mood altered depression (see Section 4.4),
Nervous system disorders	headache (occasionally severe)	parasthesiae, dizziness			pituitary haemorrhage has been reported following initial administration in patients with pituitary adenoma.	paralysis (see Section 4.4), seizure
Eye disorders			visual impairment
Cardiac disorders			palpitations
Vascular disorders	hot flush					pulmonary embolism, hypertension, hypotension (see Section 4.4)
Gastrointestinal disorders		nausea	diarrhoea, vomiting
Hepatobillary disorders			liver function test abnormal, (usually transient)			hepatic function abnormal, jaundice
Skin and subcutaneous tissue disorders			hair loss
Musculoskeletal, connective tissue and bone disorders		arthralgia, muscle weakness	myalgia			spinal fracture (see section 4.4), reduction in bone mass which may occur with the use of GnRH agonists
Respiratory, thoracic and mediastinal disorders						Interstitial lung disease
Reproductive system and breast disorders		breast tenderness, breast atrophy, vulvovaginal dryness				vaginal haemorrhage
General disorders and administration site conditions		Oedema peripheral, injection site reaction, e.g., injection site induration, erythema, pain, abscessess, swelling, nodules, ulcers and necrosis	pyrexia, fatigue

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.

In Children: In the initial phase of therapy, a short-term increase as flare-up of the sex hormone level occurs, followed by a decrease to values within the prepubertal range. Due to this pharmacological effect, adverse events may occur particularly at the beginning of treatment.

Tabulated list of adverse reactions

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 prepubertal 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 Prostap 3 subcutaneous injection, followed by a decrease to maintenance levels in 7 to 14 days. Prostap 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).

—■— Leuprorelin

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

PROSTAP 3 Powder

Polylactic acid

Mannitol

Sterile Solvent

Carmellose sodium

Mannitol

Polysorbate 80

Glacial acetic acid

Water for Injections

• 6.2 Incompati­bilities

Not applicable.

• 6.3 Shelf life

The expiry date is stated on the packaging. The expiry date refers to the last day of that month.

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

• 6.4 Special precautions for storage

Do not refrigerate or freeze.

Store in the original container in order to protect from light. Do not store above 25°C.

• 6.5 Nature and contents of container

One dual chamber pre-filled syringe containing 11.25 mg leuprorelin acetate powder in the front chamber and 1 ml of Sterile Solvent in the rear chamber.

• 1 × 23 gauge syringe needle fitted with safety device

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

Procured from within the EU and repackaged by Product Licence Holder Ennogen Healthcare Ltd, Unit G4 Riverside Industrial Estate, Riverside Way, Dartford, Kent, DA1 5BS.

• 8 PRODUCT LICENCE NUMBER:

PL 40739/0102

• 9 DATE OF REVISION OF THE TEXT