Document: leaflet MAH BRAND_PLPI 18799-2820 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

(leuprorelin acetate)

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.

The name of your medicine is Prostap® 3 DCS but it will be referred to as Prostap throughout this leaflet.

In this leaflet:

1.    What Prostap is and what it is used for

2.    What you need to know before you use Prostap

3.    How to take Prostap

4.    Possible side effects

5.    How to store Prostap

6.    Contents of the pack and other information

1.    WHAT PROSTAP IS AND WHAT IT IS USED FOR

Prostap is a synthetic hormone which can be used to reduce the levels of testosterone and estrogen circulating in the body. Prostap is used to treat prostate cancer in men and endometriosis in women.

Use in children:

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

Use in children: Your doctor will make a precise diagnosis of central precocious puberty.

Do not take Prostap:

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

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

•    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 can aggravate existing diabetes therefore diabetes patients may need more frequent monitoring ofthe 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. Risk factors include:

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

o lf you drink excessive amounts of alcohol, and/or smoke heavily.

o lf 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 which may be severe. If you are taking Prostap 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 can cause severe bleeding when the fibroids breakdown. 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 you should tell your doctor.

•    If you are a woman of child-bearing age, you should use non hormonal contraception whilst receiving Prostap. Although Prostap 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.

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

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

Prostap 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 with food and drink Prostap can be taken with or without food.

Pregnancy and breast-feeding

Prostap must not be administered in pregnant or breast-feeding women or girls (see also section 'Do not use Prostap').

Driving and using machines Do not drive or operate machinery if you experience drowsiness, dizziness or visual disturbances whilst being treated with Prostap.

3. HOW TO TAKE PROSTAP

The doctor or nurse will give you an injection of Prostap.

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 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 20kg or more

Unless prescribed otherwise, 1ml Prostap (11.25mg 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 20kg

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

Unless prescribed otherwise, 0.5ml Prostap (5.625mg 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 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 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 and contact your doctor immediately.

4. POSSIBLE SIDE EFFECTS

Like all medicines, Prostap 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. 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, 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 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, 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 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 heart beats, 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 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 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, 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 heart beats, 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, pharmacist or nurse. 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.gov.uk/yellowcard.

By reporting side effects you can help provide more information on the safety of this medicine.

5.    HOW TO STORE PROSTAP

Keep out of the sight and reach of children.

Do not store above 25°C. Do not refrigerate or freeze.

Keep pre-filled syringes in the outer carton in order to protect from light.

However, it is recommended to administer the product immediate after reconstitution.

Do not use Prostap after the expiry date which is stated on the carton after 'Exp'. The expiry date refers to the last day of that month.

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 INFROMATION What Prostap contains:

The active substance is leuprorelin as leuprorelin acetate (11.25mg).

Each syringe contains 11.25mg leuprorelin acetate.

The other ingredients are: polylactic acid, mannitol and sterile solvent: (sodium carboxymethylcellulose, mannitol, polysorbate 80, glacial acetic acid for pH adjustment, water for injections) What Prostap looks like and content of the pack:

It is a plastic tray which holds one dual chamber pre-filled syringe with a needle and needle cap containing 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 1 x syringe plunger and 1 x alcoholic swab.

Prostap: 1 pre-filled syringe.

The alcohol swab is soaked in 70% isopropyl alcohol. Manufacturer by:

ABBOTT Laboratories SA, Avenida de Burgos 91, 28050 Madrid, Spain.

Or

AbbVie Logistics BV, Meeuwenlaan 4, 8011 BZ-Zwolle,

Holland.

Procured from within the EU and repackaged by the Product Licence holder: B&S Healthcare, Unit 4,

Bradfield Road, Ruislip, Middlesex, HA4 0NU, UK.

Prostap® 3 DCS; PL 18799/2820 pqm]

Leaflet date: 11.04.2016

5 PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Pharmacotherapeutic group: Gonadotrophin-Releasing Hormone Analogues ATC code: L02AE 02

Prostap 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 3.75mg and 11.25mg 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 (0.5ng/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 3.75mg 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 10ng/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 (7.5mg/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.

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

6.6 Special precautions for disposal and other handling

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

7    MARKETING AUTHORISATION HOLDER

Procured from within the EU and repackaged by the Product Licence holder: B&S Healthcare, Unit 4, Bradfield Road, Ruislip, Middlesex, HA4 0NU, Uk.

8    MARKETING AUTHORISATION NUMBER(S): PLPI 18799/2820

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION:

10    DATE OF REVISION OF THE TEXT: 11/04/2016

6 PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Prostap Powder Polylactic acid,

Mannitol Sterile solvent carboxymethylcellulose Mannitol Polysorbate 80 Acetic acid, glacial 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 11.25mg leuprorelin acetate powder in the front chamber and 1ml of sterile solvent in the rear chamber.

1 x syringe needle.

1 x syringe plunger