Document: leaflet MAH BRAND_PLPI 19488-1785 change

• leaflet MAH BRAND_PLPI 19488-1785
• leaflet MAH BRAND_PLPI 20636-2582

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S1785 LEAFLET Prostap 20160714

PACKAGE LEAFLET: INFORMATION FOR THE USER Prostap® SR DCS

3.75 mg powder and solvent for prolonged-release suspension for injection in pre-filled syringe

(leuprorelin acetate)

Your medicine is known as Prostap® SR DCS 3.75 mg powder and solvent for prolonged-release suspension for injection in pre-filled syringe but will be referred to as Prostap SR throughout the following patient information 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. 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 SR is and what it is used for

2.    What you need to know before you use Prostap SR

3.    How to take Prostap SR

4.    Possible side effects

5.    How to store Prostap SR

6.    Contents of the pack and other information

1. WHAT PROSTAP SR IS AND WHAT IT IS USED FOR

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

Prostap SR is used to treat prostate cancer in men and endometriosis and uterine fibroids in women. It can also be used to reduce the thickness of the lining (endometrium) of the womb (uterus) in preparation for surgery.

Use in children:

Prostap SR is a synthetic hormone which can be used to reduce the levels of testosterone and estrogen circulating in the body. Leuprorelin 1 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 SR

Use in children: Your doctor will make a precise diagnosis of

central precocious puberty.

Do not take Prostap SR:

•    If you are allergic (hypersensitive) to leuprorelin acetate (Prostap SR or Prostap 3) or any of the other ingredients of Prostap SR (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 SR 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 SR. Risk factors include:

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

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

o 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 SR which may be severe. If you are taking Prostap SR 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 SR 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 SR you should tell your doctor.

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

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 1 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 1 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 SR

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription. Prostap SR 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 SR with food and drink

Prostap SR can be taken with or without food.

Pregnancy and breastfeeding

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

Driving and using machines

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

3. HOW TO TAKE PROSTAP SR

The doctor or nurse will give you an injection of Prostap SR. 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 a month. If you are to be given Prostap SR prior to intrauterine surgery you will receive a single injection 5-6 weeks before your surgery.

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

If you have uterine fibroids you will be given an injection of Prostap SR once a month usually for 3-4 months before surgery.

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 SR (3.75 mg leuprorelin acetate) is administered once a month 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 SR (1.88 mg leuprorelin acetate) are administered once a month 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 SR is administered as precisely as possible in regular monthly periods. An exceptional delay of the injection date for a few days (30 ± 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 SR 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 SR and contact your doctor immediately.

4. POSSIBLE SIDE EFFECTS

Like all medicines, Prostap SR 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 SR. 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 SR, 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 SR 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 SR, 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 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 SR 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 SR 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 SR, 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.gov.uk/yellowcard.

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

5. HOW TO STORE PROSTAP SR

•    KEEP OUT OF THE SIGHT AND REACH OF CHILDREN.

•    Do not store above 25°C.

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

•    Do not refrigerate or freeze.

•    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 use this medicine after the expiry date which is stated on the packaging. The expiry date refers to the last day of that month.

•    If the medicine becomes discoloured or shows any other signs of deterioration, you should seek the advice of your pharmacist who will tell you what to do.

•    Do not throw away 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 SR contains:

•    Each syringe contains 3.75mg leuprorelin acetate.

•    The other ingredients in Prostap SR are: gelatin, copolymer (DL-lactic acid/glycolic acid 75:25) and mannitol.

•    The sterile solvent contains carmellose sodium, mannitol, polysorbate 80 and water for Injections.

What Prostap SR looks like and contents of the pack:

Prostap SR is 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 3.75 mg leuprorelin acetate powder in the front chamber and 1 ml sterile solvent in the rear chamber.

•    1 x 23 gauge syringe needle.

•    1 x syringe plunger and 2 x alcohol swabs.

Product Licence holder

Procured from within the EU and repackaged by the Product Licence holder: S&M Medical Ltd, Chemilines House,

Alperton Lane, Wembley, HA0 1Dx.

Manufacturer

This product is manufactured by Takeda Pharmaceutical Company Ltd, Japan.

| POM | PL: 19488/1785 Leaflet revision date: 14 July 2016

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

S1785 LEAFLET Prostap 20160714

S1785 MIL LEAFLET Prostap 20160714

HEALTH PROFESSIONALS’ USER LEAFLET Prostap® SR DCS

3.75 mg powder and solvent for prolonged-release suspension for injection in pre-filled syringe

(leuprorelin acetate)

1.    NAME OF THE MEDICINAL PRODUCT

Prostap® SR DCS 3.75 mg powder and solvent for prolonged-release suspension for injection in pre-filled syringe

2.    QUALITATIVE AND QUANTITATIVE COMPOSITION

PROSTAP SR Powder: Each syringe contains 3.75 mg leuprorelin acetate

Sterile Solvent: Each ml contains carmellose sodium, mannitol, polysorbate 80, water for injections.

When reconstituted with sterile solvent, the suspension contains 3.75 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)    Endometrial preparation prior to intrauterine surgical procedures including endometrial ablation or resection.

(viii)    Preoperative management of uterine fibroids to reduce their size and associated bleeding.

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 3.75 mg presented as a one month depot injection and administered as a single subcutaneous or intramuscular injection every month. The majority of patients will respond to a 3.75 mg dose. PROSTAP SR therapy should not be discontinued when remission or improvement occurs. As with other drugs administered chronically by injection, the injection site should be varied periodically.

Response to PROSTAP SR therapy may be monitored by clinical parameters and by measuring serum levels of testosterone and acid phosphatase. 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 castrate-resistant prostate cancer. Reference should be made to relevant guidelines.

Endometriosis: The recommended dose is 3.75 mg administered as a single subcutaneous or intramuscular injection every month 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 PROSTAP SR taking into account the risks and benefits of each treatment.

Endometrial preparation prior to intrauterine surgery: A single 3.75 mg subcutaneous or intramuscular injection 5-6 weeks prior to surgery. Therapy should be initiated during days 3 to 5 of the menstrual cycle.

Preoperative management of uterine fibroids: The recommended dose is 3.75 mg administered as a single subcutaneous or intramuscular injection every month, usually for 3-4 months but for a maximum of six months.

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 (3.75 mg leuprorelin acetate) suspension of 44.1 mg sustained-release microcapsules in 1 ml vehicle solution are administered once a month 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 (1.88 mg leuprorelin acetate) is administered once a month 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 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 30 ± 2 days in order to prevent the recurrence of precocious puberty symptoms.

Administration_

INSTRUCTIONS ON HOW TO MIX AND ADMINISTER

4.4    Special warnings and precautions for use

As would be expected with this class of drug, development or aggravation of diabetes may occur, therefore diabetic patients may require more frequent monitoring of blood glucose during treatment with PROSTAP SR.

Epidemiological data have shown that during androgen deprivation therapy changes in the metabolic condition (e.g. reduction in glucose tolerance or aggravation of pre-existing diabetes) as well as an increased risk for cardiovascular diseases may occur. However, prospective data did not confirm the link between treatment with GnRH analogues and an increase in cardiovascular mortality. Patients at high risk for metabolic or cardiovascular diseases should be appropriately monitored.

Hepatic dysfunction and jaundice with elevated liver enzyme have been reported. Therefore, close observation should be made and appropriate measures taken if necessary.

Spinal fracture, paralysis and hypotension have been reported.

There is an increased risk of incident depression (which may be severe) in patients undergoing treatment with GnRH agonists, such as leuprorelin. Patients should be informed accordingly and treated as appropriate if symptoms occur.

Postmarketing reports of seizures have been observed in patients treated with leuprorelin acetate and these events have been reported in both children and adults, and in those with or without a history of epilepsy, seizure disorders or risk disorders for seizures.

Men: In the initial stages of therapy, a transient rise in levels of testosterone, dihydrotestosterone and acid phosphatase may occur. In some cases, this may be associated with a “flare” or exacerbation of the tumour growth resulting in temporary deterioration of the patient's condition. These symptoms usually subside on continuation of therapy. “Flare” may manifest itself as systemic or neurological symptoms in some cases. In order to reduce the risk of “flare”, an anti-androgen may be administered beginning 3 days prior to leuprorelin acetate therapy and continuing for the first two to three weeks of treatment. This has been reported to prevent the sequelae of an initial rise in serum testosterone. In the rare event of an abscess occurring at the injection site, testosterone level should be monitored as there may be inadequate absorption of leuprorelin from the depot formulation.

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 SR.

Women: When considering the preoperative treatment of fibroids it is mandatory to confirm the diagnosis of fibroids and exclude an ovarian mass, either visually by laparoscopy or by ultrasonography or other investigative technique, as appropriate, before PROSTAP SR therapy is instituted. During the early phase of therapy, sex steroids temporarily rise above baseline because of the physiological effect of the drug. Therefore, an increase in clinical signs and symptoms may be observed during the initial days of therapy, but these will dissipate with continued therapy. 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 SR is 5%. In clinical studies with PROSTAP Sr 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 SR therapy may pose an additional risk. In these patients, the risks and benefits must be weighed carefully before therapy with PROSTAP SR is instituted. This is particularly important in women with uterine fibroids where age related bone loss may have already begun to occur.

Therefore, before using PROSTAP SR for the preoperative treatment of uterine fibroids, patients with major risk factors for decreased bone mineral content (see above) should have their bone density measured and where results are below the normal (5th percentile by DEXA scan) range, PROStAp SR therapy should not be started.

In women with submucous fibroids there have been reports of severe bleeding following the administration of PROSTAP SR 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 SR may cause an increase in uterine cervical resistance, which may result in difficulty in dilating the cervix for intrauterine surgical procedures.

In women 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.

Precautions

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

Women: Since menstruation should stop with effective doses of PROSTAP SR, 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 SR should be administered as precisely as possible in regular monthly periods. An exceptional delay of the injection date for a few days (30 ± 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 SR 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 SR, pregnancy must be excluded. There have been reports of foetal malformation when PROSTAP SR has been given during pregnancy.

PROSTAP SR should not be used in women who are breastfeeding.

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

Patients should be advised that if they miss successive doses of PROSTAP SR, 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 SR can influence the ability to drive and use machines due to visual disturbances and dizziness.

4.8    Undesirable effects

Adverse reactions seen with PROSTAP SR 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 SR 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.

Women: Those adverse events occurring most frequently with PROSTAP SR 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 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 pre-pubertal range. Due to this pharmacological effect, adverse events may occur particularly at the beginning of treatment.

Tabulated list of adverse reactions

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9 Overdose

No case of overdose has been reported.

In animal studies, doses of up to 500 times the recommended human dose resulted in dyspnoea, decreased activity and local irritation at the injection site. In cases of overdose, the patients should be monitored closely and management should be symptomatic and supportive.

5. PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

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

PROSTAP SR contains leuprorelin acetate, a synthetic nonapeptide analogue of naturally occurring 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. Estradiol levels will decrease to postmenopausal levels in premenopausal women within one month of initiating treatment.

The drug is well absorbed from the subcutaneous or intramuscular route, binds to luteinising hormone releasing hormone (LHRH) receptors and is rapidly degraded. In this dose form, an initial high level of leuprorelin acetate in the plasma is achieved within 3 hours followed by a drop over 24-48 hours to maintenance levels of 0.3-0.8ng/ml and a slow decline thereafter. Effective levels persist for 30-40 days after a single dose. 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 highrisk 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 (7.5mg/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 prepubertal 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

Studies submitted show that single intramuscular or subcutaneous doses of leuprorelin acetate over the dose range 3.75 to 15 mg results in detectable levels of leuprorelin acetate for more than 28 days, good bioavailability, a consistent and predictable pharmacokinetic profile, and biological efficacy at plasma levels of less than 0.5 ng/ml. The pharmacokinetic profile is similar to that seen in animal studies using the compound, with an initial high level of drug released from the microcapsules during reconstitution and injection followed by a plateau over a 2-3 week period before levels gradually become undetectable. There appears to be no significant difference between the routes of administration (im vs sc) in biological effectiveness or pharmacokinetics.

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

In children:

Figure 1 presents leuprorelin serum levels after a single s.c. administration of leuprorelin acetate depot at a dosage of 30 gg/kg body weight.

Peak serum levels are reached sixty minutes after administration (7.81 ± 3.59 ng/m)l. The AUC₀-₆72 is 105.78 ± 52.40 ng x hr/ml.

Figure 1: Leuprorelin serum levels after single s.c. administration of 30 gg/kg body weight of leuprorelin acetate as depot formulation (n=6) (Mean ± SD)

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

PROSTAP SR Powder gelatin

copolymer (DL-lactic acid/glycolic acid 75:25)

mannitol

Sterile Solvent

carmellose sodium

mannitol

polysorbate 80

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°C.

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

Do not refrigerate or freeze.

6.5    Nature and contents of container

One dual chamber pre-filled syringe containing 3.75 mg leuprorelin acetate powder in the front chamber and 1 ml of sterile solvent in the rear chamber.

1 x 23 gauge syringe needle fitted with safety device 1 x syringe plunger and 2 x alcohol swabs.

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 the Product Licence holder: S&M Medical Ltd, Chemilines House, Alperton Lane, Wembley,

HA0 1DX.

8    PRODUCT LICENCE NUMBER: PL 19488/1785

9    DATE OF REVISION OF THE TEXT: 14 July 2016

S1785 MIL LEAFLET Prostap 20160714

1

In general, the occurrence of vaginal spotting with continued treatment (subsequent to possible withdrawal bleeding in the first month of treatment) should be assessed as a sign of potential underdosage. The pituitary suppression should then be determined by an LHRH test.