Document: leaflet MAH BRAND_PLPI 16378-0583 change

• leaflet MAH BRAND HEALTH PROFESSIONAL_PL 16189-0013
• leaflet MAH BRAND_PL 16189-0013
• leaflet MAH BRAND_PLPI 16378-0583
• leaflet MAH BRAND_PLPI 18799-2820
• leaflet MAH BRAND_PLPI 20636-2583

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Package Leaflet: Information for the user

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

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. 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.

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 endometriosis in women.

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 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.

•    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.

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 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:

at 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.

bt 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) are 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.

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 more than 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 or chills.

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 more than 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 or vaginal bleeding.

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 less than 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 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: www.mhra.aov.uk/vellowcard.

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.

Do not store above 25°C.

Do not refrigerate or freeze.

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

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.

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. When reconstituted with the solvent, the solution contains 11,25mg/2ml of leuprorelin acetate.

•    The excipients in Prostap® 3 are: Polylactic acid which controls the release of the active ingredient into the body, and mannitol.

•    The Sterile Solvent contains carmellose sodium, mannitol (E421), polysorbate 80 and water for injections.

What Prostap® 3 looks like and contents of the pack:

Prostap® 3 is a prolonged release powder for use in an injection.

The Sterile Solvent is a clear liquid, which is mixed with the Prostap® 3 Powder before injection.

One dual chamber pre-filled syringe containing a sterile white powder in the front chamber and a clear sterile solvent in the rear chamber. The syringe contains a syringe plunger and a 23 gauge syringe needle fitted with a safety device. The pack contains 2 swabs soaked in alcohol.

Product Licence Holder and Manufacturer:

Manufactured by Takeda Pharmaceutical Company Ltd., Japan and Procured from the EU and repackaged by Product Licence Holder: Beachcourse Limited., 20 Alliance Court, Alliance Road,

London W3 ORB, UK.

PL 16378/0583    |POM|

Revision date: 10.10.2016 Leaflet reference: PROST3 PIL

Prostap® is a registered trademark of Takeda Pharmaceutical Company Limited.

Patients at risk of ureteric obstruction or spinal cord compression should be considered carefully and closely supervised in the first few weeks of treatment. These patients should be considered for prophylactic treatment with anti-androgens. Should urological/neurological complications occur, these should be treated by appropriate specific measures.

Long-term androgen deprivation either by bilateral orchiectomy or administration of GnRH analogues is associated with increased risk of bone loss which, in patients with additional risk factors, may lead to osteoporosis and increased risk of bone fracture. If an anti-androgen is used over a prolonged period, due attention should be paid to the contra-indications and precautions associated with its extended use.

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 with leuprorelin acetate.

Androgen deprivation therapy may prolong the QT interval.

In patients with a history of or risk factors for QT prolongation and in patients receiving concomitant medicinal products that might prolong the QT interval (see section 4.5) physicians should assess the benefit risk ratio including the potential for Torsade de pointes prior to initiating Prostap® 3.

Women: During the early phase of endometriosis therapy, sex steroids temporarily rise above baseline because of the physiological effect of the drug. Therefore, a worsening of clinical signs and symptoms may be observed during the initial days of therapy, but these will dissipate with continued therapy.

When receiving GnRH analogues for the treatment of endometriosis, the addition of HRT (an estrogen and progestogen) has been shown to reduce bone mineral density loss and vasomotor symptoms (see ‘Posology and Method of Administration' section 4.2 for further information).

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. The extent of bone demineralisation due to hypo-estrogenaemia is proportional to time and, consequently, is the adverse event responsible for limiting the duration of therapy to 6 months. The generally accepted level of bone loss with LHRH analogues such as Prostap® 3 is 5%. In clinical studies with Prostap® 3 the levels varied between 2.3% and 15.7% depending on the method of measurement. During one six-month treatment period, this bone loss should not be important. In patients with major risk factors for decreased bone mineral content such as chronic alcohol and/or tobacco use, strong family history of osteoporosis, or chronic use of drugs that can reduce bone mass such as anticonvulsants or corticosteroids, Prostap® 3 therapy may pose an additional risk. In these patients, the risks and benefits must be weighed carefully before therapy with Prostap® 3 is instituted.

In women with submucous fibroids there have been reports of severe bleeding following administration of Prostap® 3 as a consequence of the acute degeneration of the fibroids. Patients should be warned of the possibility of abnormal bleeding or pain in case earlier surgical intervention is required.

Prostap® 3 may cause an increase in uterine cervical resistance, which may result in difficulty in dilating the cervix for intrauterine surgical procedures.

Precautions

Men: Patients with urinary obstruction and patients with metastatic vertebral lesions should begin Prostap® 3 therapy under close supervision for the first few weeks of treatment.

Women: Since menstruation should stop with effective doses of Prostap® 3, the patient should notify her physician if regular menstruation persists.

In girls with central precocious puberty: Before starting the therapy, a precise diagnosis of idiopathic and/or neurogenic central precocious puberty is necessary.

The therapy is a long-term treatment, adjusted individually. Prostap^® 3 should be 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 results of the therapy.

In the event of a sterile abscess at the injection site (mostly reported after i.m. injection of higher than the recommended dosage) the absorption of leuprorelin acetate from the depot can be decreased. In this case the hormonal parameters (testosterone, oestradiol) should be monitored at 2-week intervals (see 4.2).

The treatment of children with progressive brain tumours should follow a careful individual appraisal of the risks and benefits.

The occurrence of vaginal bleeding, spotting and discharge after the first injection may occur as a sign of hormone withdrawal in girls. Vaginal bleeding beyond the first/second month of treatment needs to be investigated.

Bone mineral density (BMD) may decrease during GnRH therapy for central precocious puberty. However, after cessation of treatment subsequent bone mass accrual is preserved, and peak bone mass in late adolescence does not seem to be affected by treatment.

Slipped femoral epiphysis can be seen after withdrawal of GnRH treatment. The suggested theory is that the low concentrations of estrogen during treatment with GnRH agonists weakens the epiphysial plate. The increase in growth velocity after stopping the treatment subsequently results in a reduction of the shearing force needed for displacement of the epiphysis.

4.5    Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed.

Since androgen deprivation treatment may prolong the QT interval, the concomitant use of Prostap^® 3 with medicinal products known to prolong the QT interval or medicinal products able to induce Torsade de pointes such as class IA (e.g. quinidine, disopyramide) or class III (e.g. amiodarone, sotalol, dofetilide, ibutilide) antiarrhythmic medicinal products, methadone, moxifloxacin, antipsychotics, etc. should be carefully evaluated (see section 4.4).

4.6    Fertility, Pregnancy and lactation

Safe use of leuprorelin acetate in pregnancy has not been established clinically.

Studies in animals have shown reproductive toxicity (see section 5.3). Before starting treatment with Prostap® 3, pregnancy must be excluded. There have been reports of foetal malformation when Prostap^® 3 has been given during pregnancy.

Prostap® 3 should not be used in women who are breastfeeding.

When used 3-monthly at the recommended dose, Prostap® 3 usually inhibits ovulation and stops menstruation. Contraception is not ensured, however, by taking Prostap^® 3 and therefore patients should use non-hormonal methods of contraception during treatment.

Patients should be advised that if they miss successive doses of Prostap® 3, breakthrough bleeding or ovulation may occur with the potential for conception. Patients should be advised to see their physician if they believe they may be pregnant. If a patient becomes pregnant during treatment, the drug must be discontinued. The patient must be apprised of this evidence and the potential for an unknown risk to the foetus.

In girls with central precocious puberty: See section 4.3 Contraindications.

4.7    Effects on ability to drive and use machines

Prostap® 3 can influence the ability to drive and use machines due to visual disturbances and dizziness.

4.8    Undesirable effects

Adverse reactions seen with Prostap® 3 are due mainly to the specific pharmacological action, namely increases and decreases in certain hormone levels.

The following tables list adverse reactions with leuprorelin based on experience from clinical trials as well as from post-marketing experience. Adverse reactions are grouped by MedDRA System Organ Classes and frequency classification. Frequencies are defined as: very common (>1/10); common (>1/100 to <1/10); uncommon (>1/1,000 to <1/100); rare (>1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data).

Men: In cases where a “tumour flare” occurs after Prostap® 3 therapy, an exacerbation may occur in any symptoms or signs due to disease, for example, bone pain, urinary obstruction, weakness of the lower extremities and paraesthesia. These symptoms subside on continuation of therapy.

SEE MIL-2 FOR THE REST OF INFORMATION

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).

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

A teratogenic effect has been observed in rabbits but not in rats.

6. PHARMACEUTICAL PARTICULARS

6.1    List of excipients

The other ingredients are:

Powder- Polylactic acid, mannitol

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 25^oC.

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 containing a sterile white powder in the front chamber and a clear sterile solvent in the rear chamber. The syringe contains a syringe plunger and a 23 gauge syringe needle fitted with a safety device. The pack contains 2 swabs soaked in alcohol.

6.6    Special precautions for disposal and other handling

Any unused product or waste material should be disposed of in accordance with local requirements.

Product Licence Holder and Manufacturer:

Manufactured by Takeda Pharmaceutical Company Ltd., Japan and Procured from the EU and repackaged by Product Licence Holder: Beachcourse Limited., 20 Alliance Court, Alliance Road, London W3 0RB, UK.

PL 16378/0583    |POM|

Revision date: 10.10.2016 Leaflet reference: PROST3 MIL-2

Prostap^® is a registered trademark of Takeda Pharmaceutical Company Limited.

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