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PROSTAP SR DCS 3.75MG POWDER AND SOLVENT SUSPENSION FOR INJECTION IN PRE-FILLED SYRINGE

Active substance(s): LEUPRORELIN ACETATE / LEUPRORELIN ACETATE / LEUPRORELIN ACETATE

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Add/Amend to correct the statement of active from "...the solution
contains 3.75 mg/ml..." to "...the solution contains 3.75 mg/2 ml...".

Previously assessed against UK PIL dated February 2016

Package Leaflet: Information for the user
®
By Aneela Mahmood at 9:43 am, Oct 11, 2016 Prostap SR DCS 3.75 mg Powder and Solvent for Prolonged-release
Suspension for Injection in Pre-filled Syringe

Mock up 

(leuprorelin acetate)
Women only:
Your medicine is known by the above name, but will be referred to as
Prostap® SR throughout this leaflet.
 If you are a woman with submucous fibroids (benign tumours in the
muscle underneath the lining of the womb), Prostap® SR can cause
Read all of this leaflet carefully before you start using this medicine
severe bleeding when the fibroids break-down.
because it contains important information for you.
Contact your doctor immediately if you experience severe or unusual
bleeding or pain.
 Keep this leaflet. You may need to read it again.
 If you are a woman and continue to have periods (menstruate) after
 If you have any further questions, ask your doctor or pharmacist.
starting treatment with Prostap® SR you should tell your doctor.
 This medicine has been prescribed for you. Do not pass it on to others.
 If you are a woman of child-bearing age, you should use non hormonal
It may harm them, even if their signs of illness are the same as yours.
contraception whilst receiving Prostap® SR. Although Prostap® SR
 If you get any side effects talk to your doctor or pharmacist. This
causes periods to stop, it is not itself a contraceptive. If you are unsure
includes any possible side effects not listed in this leaflet. See section
about this talk to your doctor.
4.
Men only:
In this leaflet:
 In the rare event of an abscess occurring at the injection site your
1. What Prostap® SR is and what it is used for
doctor may measure your testosterone levels as there could be
reduced absorption of leuprorelin from the injection site.
2. What you need to know before you use Prostap® SR
 If you are a man with urinary obstruction or spinal cord compression.
3. How to take Prostap® SR
Your doctor will supervise you closely for the first few weeks of treatment.
4. Possible side effects
 If you are a man with prostate cancer, and have had injections of a
®
5. How to store Prostap SR
synthetic hormone in the past that has not worked, or you have had an
6. Contents of the pack and other information
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),
1. WHAT PROSTAP® SR IS AND WHAT IT IS USED FOR
or are being treated with medicines for these conditions. The risk of
heart rhythm problems may be increased when using Prostap® SR.
Prostap® SR is a synthetic hormone which can be used to reduce the
In children:
levels of testosterone and estrogen circulating in the body.
 In the event of a sterile abscess at the injection site (mostly reported
Prostap® SR is used to treat prostate cancer in men and endometriosis
after injection into the muscle) your doctor will monitor your hormone
and uterine fibroids in women. It can also be used to reduce the thickness
levels as there could be reduced absorption of leuprorelin from the
of the lining (endometrium) of the womb (uterus) in preparation for
injection site.
surgery.
 If the child has progressive brain tumour your doctor will decide if
Use in children:
treatment with leuprorelin is appropriate.
In girls with central precocious puberty:
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
 After the first injection vaginal bleeding (spotting) and discharge may
used to treat premature puberty which is caused by a release of certain
occur as a sign of hormone withdrawal. Vaginal bleeding beyond the
hormones from the pituitary gland (central precocious puberty) in girls
first/second month of treatment needs to be investigated.
under 9 years of age and boys under 10 years of age.
 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
2. WHAT YOU NEED TO KNOW BEFORE YOU USE PROSTAP® SR
mass in late adolescence does not seem to be affected by treatment.
 Often sterile abscesses at the injection site occurred when Leuprorelin
Use in children: Your doctor will make a precise diagnosis of central
1 Month Depot is administered in higher dosages than recommended
precocious puberty.
and when it is administered into the muscle. Your doctor will therefore
administer the medicinal product under the skin of e.g. abdomen,
Do not take Prostap® SR:
bottom or thigh.
®
 If you are allergic (hypersensitive) to leuprorelin acetate (Prostap SR
 Discontinuation of treatment may lead to a slipping of the growth plate
®
®
or Prostap 3) or any of the other ingredients of Prostap SR (listed in
of the thigh bone. A possible cause could be a weakness of the growth
section 6).
plate due to a lower concentration of female sexual hormones during
 If you are pregnant, planning to become pregnant or are breastfeeding.
treatment.
 If you have abnormal vaginal bleeding which you have not discussed
Other medicines and Prostap® SR
with your doctor.
 In girls with central precocious puberty
Please tell your doctor or pharmacist if you are taking or have recently
 if the girl to be treated is pregnant or breast-feeding.
taken any other medicines, including medicines obtained without a
 if the girl has undiagnosed vaginal bleeding.
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).

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:
 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® SR
which may be severe. If you are taking Prostap® SR and develop
depressed mood, inform your doctor.

4

Revision date: 10.10.2016
Leaflet reference:
PROSTSR PIL

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.

1

3. HOW TO TAKE PROSTAP® SR

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:

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.

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.

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.

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® 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.

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.

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

Contact your doctor immediately or go to hospital:

Difficulty sleeping, headaches or hot flushes

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

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)

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.

2

Uncommon (may affect more than 1 in 100 people)

6. CONTENTS OF THE PACK AND OTHER INFORMATION

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

What Prostap® SR contains:
 Each syringe contains 3.75 mg leuprorelin acetate. When reconstituted
with the solvent, the solution contains 3.75mg/2ml of leuprorelin
acetate.
 The excipients in Prostap® SR are: Gelatin, copolymer (DL-lactic
acid/glycolic acid 75:25), mannitol.
 The Sterile Solvent contains carmellose sodium, mannitol (E421),
polysorbate 80 and water for injections.

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.

What Prostap® SR looks like and contents of the pack:
Prostap® SR is a prolonged release powder for use in an injection.
The Sterile Solvent is a clear liquid, which is mixed with the Prostap® SR
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.

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):










Product Licence Holder and Manufacturer:

mood swings
headache
abdominal pain / abdominal cramps
feeling sick / vomiting
acne
vaginal bleeding
spotting
discharge
injection site reactions

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 16378/0582

POM

Revision date: 10.10.2016
Leaflet reference: PROSTSR PIL

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.

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

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 use this medicine after the expiry date which is stated on the
packaging.
The expiry date refers to the last day of that month.
Do not store above 25oC.
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 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.

3

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)

Revision date: 10.10.2016

Ref: PROSTSR MIL-1
Administration

1 NAME OF THE MEDICINAL PRODUCT

INSTRUCTIONS ON HOW TO MIX AND ADMINISTER

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. When reconstituted with the solvent,
the solution contains 3.75mg/2ml of leuprorelin acetate.
Sterile Solvent: Each ml contains carmellose sodium 5 mg, mannitol (E421) 50 mg, polysorbate 80 1 mg, acetic
acid, glacial up to 0.05 mg and water for injections.
When reconstituted with Sterile Solvent, the suspension contains 3.75 mg/ml leuprorelin acetate.
For the full list of excipients, see section 6.1
3 PHARMACEUTICAL FORM

1.To prepare for injection,
screw the plunger
rod into the end stopper until
the stopper
begins to turn.

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.

2. Remember to check if
the needle is tight by
twisting the needle cap
clockwise.
Do not overtighten.

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)

3. Holding the syringe upright, release
the diluents by SLOWLY PUSHING
the plunger until the middle stopper is
at the blue line in the middle of the
barrel.
NOTE: Pushing the plunger rod
quickly or over the blue line will cause
leakage of the suspension from the
needle.

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.

4. Gently tap the syringe on the palm keeping the
syringe upright to thoroughly mix the particles to form
a uniform suspension. The suspension will appear
milky.
NOTE: Avoid hard tapping to prevent the generation
of bubbles.

5. Remove the needle cap and advance
the plunger to expel the air from the
syringe.

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.

6. At the time of injection, check the direction of the
safety device (with round mark face up), as
illustrated, and inject the entire contents of the
syringe subcutaneously or intramuscularly as you
would for a normal injection.

7. Withdraw the needle from the patient.
Immediately activate the safety
device by pushing the arrow forward with
the thumb or finger until the device is fully
extended and a CLICK is heard or felt.

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.

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

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.

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.

4.3 Contraindications
Hypersensitivity to the active substance, any of the excipients listed in section 6.1 or to synthetic gonadotrophin
releasing homone (Gn-RH) or Gn-RH derivatives.
Women: Prostap® SR is contra-indicated in women who are or may become pregnant while receiving the drug.
Prostap® SR should not be used in women who are breastfeeding or have undiagnosed abnormal vaginal
bleeding.
Men: There are no known contra-indications to the use of Prostap® SR in men.
In girls with central precocious puberty:
- Pregnancy and lactation
- Undiagnosed vaginal bleeding.

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.

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.

1

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.

Tabulated list of adverse reactions
SOC

Very
common

Common

Uncommon

Rare

Very rare

Blood
and
lymphatic
system
disorders

Anaemia
(reported in
medicinal products
of this class),
thrombocytopaenia,
leucopenia
hypersensitivity
reactions
(including rash,
pruritus,
urticaria and rarely,
wheezing
or interstitial
pneumonitis,
anaphylactic
reactions)
Lipids abnormal,
glucose
tolerance abnormal

Immune
system
disorders

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.

Metabolism
and
nutrition
disorders
Psychiatric
disorders

weight
fluctuation

decreased
appetite

insomnia,
depression
(see Section
4.4), mood
changes
(long-term
use)**
headache
(occasionaly
severe)

Nervous
system
disorders

mood
changes
(short term
use)**

dizziness,
parasthesiae

Eye
disorders
Cardiac
disorders

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.

Vascular
disorders

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.

paralysis (see
Section 4.4),
seizure

palpitations,
electrocardiogram
QT
prolonged (see
Sections 4.4
and 4.5)
pulmonary
embolism,
hypertension,
hypotension
(see Section 4.4)

hot flush

nausea

Hepatobiliary
disorders

hepatic
function
abnormal,
liver
function test
abnormal
(usually
transient)

General
disorders
and
administration
site
conditions

pituitary
apoplexy
has
been
reported
following
initial
administration
in patients
with
pituitary
adenoma

visual impairment

Gastrointestinal
disorders

Skin and
subcutan
eous
tissue
disorders
Musculoskeletal,
Connective
tissue
and bone
disorders
Renal and
urinary
disorders
Reproductive
system
and
breast
disorders

Not known

diarrhoea,
vomiting
jaundice

Hyperhydrosis

muscle
weakness,
bone pain

arthralgia

Libido
decreesed,
erectile
dysfunction,
testicular
atrophy
Fatigue,
injection
site
reaction,
e.g.,
induration,
erythema,
pain,
abscesses,
swelling,
nodules,
ulcers and
necrosis

Gynaecomastia

oedema
peripheral

myalgia,
weakness
of lower
extremities

spinal fracture (see
Section
4.4), reduction in
bone mass which
may occur with the
use of GnRH
agonists
urinary tract
obstruction

pyrexia

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

SEE MIL-2 FOR THE REST OF INFORMATION

2

Revision date: 10.10.2016

Women: Those adverse events occurring most frequently with Prostap® SR are associated with hypoestrogenism; the most frequently reported are hot flushes, mood swings including depression (occasionally
severe), and vaginal dryness. Estrogen levels return to normal after treatment is discontinued.
The induced hypo-estrogenic state results in a small loss in bone density over the course of treatment, some of
which may not be reversible (see Section 4.4).
Vaginal haemorrhage may occur during therapy due to acute degeneration of submucous fibroids (see Section
4.4).
Tabulated list of adverse reactions
SOC

Very
common

Common

Uncommon

Rare

Very rare

Blood and
lymphatic
system
disorders

Immune
system
disorders

Metabolism
and
nutrition
disorders

weight
fluctuation

Psychia-tric
disorders

insomnia

Nervous
system
disorders

headache
(occasiona
ly severe)

Eye
disorders
Cardiac
disorders
Vascular
disorders

Gastrointes
tinal
disorders

mood
altered
depression
(see Section
4.4)
Parasthesiae,
dizziness

General
disorders
and
administrati
on
site conditions

pituitary
haemorrha
ge
has been
reported
following
initial
administra
tion
in patients
with
pituitary
adenoma

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

Not known

SOC

Anaemia
(reported in
medicinal products
of this class),
thrombocytopaenia,
leucopenia
hypersensitivity
reactions
(including rash,
pruritus,
urticaria and
rarely, wheezing
or interstitial
pneumonitis,
anaphylactic
reactions)
glucose tolerance
abnormal, which
may
affect diabetic
control

Immune system
disorders

paralysis (see
Section 4.4),
seizure

hot flush

arthralgia,
muscle
weakness

breast
tenderness,
breast
atrophy,
vulvovaginal
dryness
Oedema
peripheral,
injection site
reaction
e.g.injection
site
induration,
erythema,
pain,
abscesses,
swelling,
nodules,
ulcers and
necrosis

Common

Uncommon

Rare

Very rare

Not
known

Hypersensitivity
(fever, rash,
e.g. itching,
anaphylactic
reactions)

Psychiatric
disorders

emotional
lability

Nervous
system
disorders

headache

Gastrointestinal
disorders

abdominal pain
/
abdominal
cramps,
nausea/vomiting

Skin and
subcutaneous
tissue
disorders
Reproductive
system
and breast
disorders

acne

pituitary
haemorrhage
following initial
administration
in patients with
pituitary
adenoma

seizure

vaginal
haemorrhage,
spotting**,
vaginal
discharge
injection site
reactions

** 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.
pulmonary
embolism,
hypertension,
hypotension
(see Section 4.4)

nausea

Very
common

General
disorders and
administration
site
conditions

visual
impairment
palpitations

Hepatobilia
ry
disorders

Skin and
Subcutaneous
tissue
disorders
Musculosk
eletal,
Connective
tissue and
bone
disorders
Reproductive
system and
breast
disorders

decreased
appetite,
lipids
abnormal

Ref: PROSTSR MIL-2

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

diarrhoea,
vomiting
liver function
test
abnormal
(usually
transient)
hair loss

hepatic function
abnormal,
jaundice

myalgia

spinal fracture
(see Section
4.4), reduction in
bone mass which
may occur with the
use of GnRH
agonists
vaginal
haemorrhage

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 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. 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 0.30.8ng/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 (7.5 mg/month) which
is therapeutically equivalent to the European licensed dose.
The use of a LHRH agonist may be considered after prostatectomy in selected patients considered at high risk of
disease progression. There are no disease-free survival data or survival data with leuprorelin acetate in this
setting.
Neoadjuvant leuprorelin acetate prior to radiotherapy has been shown to reduce prostate volume.
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.

pyrexia,
fatigue

3

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

Figure 1: Leuprorelin serum levels after single s.c. administration of 30 µg/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) 72:25 mol%, Mannitol (E421)
Sterile Solvent
Carmellose sodium, Mannitol (E421), 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 25oC.
Do not refrigerate or freeze.
Store in the original container in order to protect from light.
6.5 Nature and contents of container
One dual chamber pre-filled syringe 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 16378/0582

POM

Revision date: 10.10.2016
Leaflet reference: PROSTSR MIL-2
Prostap® is a registered trademark of Takeda Pharmaceutical Company Limited.

4

Expand Transcript

Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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