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PROSTAP SR DCS 3.75 MG PROLONGED-RELEASE SUSPENSION FOR INJECTION

Active substance(s): LEUPRORELIN ACETATE / LEUPRORELIN ACETATE

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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)

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.
Read all of this leaflet carefully before you start using this medicine • Bone density may decrease during treatment of central precocious puberty
with Leuprorelin 1 Month Depot. However, after treatment is stopped,
because it contains important information for you
subsequent bone mass growth is preserved and peak bone mass in late
• Keep this leaflet. You may need to read it again.
adolescence does not seem to be affected by treatment.
• 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 • Often sterile abscesses at the injection site occurred when Leuprorelin 1
Month Depot is administered in higher dosages than recommended and
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
when it is administered into the muscle. Your doctor will therefore administer
any possible side effects not listed in this leaflet. See section 4.
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
In this leaflet:
thigh bone. A possible cause could be a weakness of the growth plate due to
1. What PROSTAP SR is and what it is used for
a lower concentration of female sexual hormones during treatment.
2. What you need to know before you use PROSTAP SR
3. How to take PROSTAP SR
Other medicines and Prostap SR
4. Possible side effects
Please tell your doctor or pharmacist if you are taking or have recently taken
5. How to store PROSTAP SR
any other medicines, including medicines obtained without a prescription.
6. Contents of the pack and other information
Prostap SR might interfere with some medicines used to treat heart rhythm
problems (e.g. quinidine, procainamide, amiodarone and sotalol) or might
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 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),
testosterone and estrogen circulating in the body.
moxifloxacin (an antibiotic), antipsychotics used for serious mental illnesses).
Prostap SR is used to treat prostate cancer in men and endometriosis and
Prostap SR with food and drink
uterine fibroids in women. It can also be used to reduce the thickness of the
Prostap SR can be taken with or without food.
lining (endometrium) of the womb (uterus) in preparation for surgery.
Pregnancy and breastfeeding
Use in children:
Prostap SR is a synthetic hormone which can be used to reduce the levels of Prostap SR must not be administered in pregnant or breast-feeding women or
girls (see also section “Do not use Prostap SR’).
testosterone and estrogen circulating in the body.
Leuprorelin 1 Month Depot is used to treat premature puberty which is caused Driving and using machines
by a release of certain hormones from the pituitary gland (central precocious
Do not drive or operate machinery if you experience drowsiness, dizziness or
puberty) in girls under 9 years of age and boys under 10 years of age.
visual disturbances whilst being treated with Prostap SR.
2. WHAT YOU NEED TO KNOW BEFORE YOU USE PROSTAP SR
3. HOW TO TAKE PROSTAP SR
Use in children: Your doctor will make a precise diagnosis of central
The doctor or nurse will give you an injection of Prostap SR. The injection will
precocious puberty.
normally be given in your arm, thigh or abdomen. The injection site should be
varied at regular intervals.
Do not take Prostap SR:
You will normally be given an injection once a month. If you are to be given
• If you are allergic (hypersensitive) to leuprorelin acetate (Prostap SR or
Prostap SR prior to intrauterine surgery you will receive a single injection 5-6
Prostap 3) or any of the other ingredients of Prostap SR (listed in section 6).
weeks before your surgery.
• If you are pregnant, planning to become pregnant or are breastfeeding.
If you have endometriosis you will be given an injection of Prostap SR for a
• If you have abnormal vaginal bleeding which you have not discussed with
period of 6 months only and treatment will be initiated during the first five days
your doctor.
of the menstrual cycle.
• In girls with central precocious puberty
-- if the girl to be treated is pregnant or breast-feeding.
If you have uterine fibroids you will be given an injection of Prostap SR once a
-- if the girl has undiagnosed vaginal bleeding.
month usually for 3-4 months before surgery.
Warnings and Precautions:
Use in children
Both men and women:
Treatment of children should be under the overall supervision of the paediatric
• If you are diabetic Prostap SR can aggravate existing diabetes therefore
endocrinologist.
diabetes patients may need more frequent monitoring of the blood glucose levels. The dosing scheme needs to be adapted individually.
• If you have diabetes or suffer from heart problems you should tell your doctor.
The recommended starting dose is dependent on the body weight:
• If you are at an increased risk of thinning of the bones (osteoporosis) you
a) Children with a body weight 20 kg or more
should tell your doctor before taking Prostap SR. Risk factors include:
Unless prescribed otherwise, 1 ml Prostap SR (3.75 mg leuprorelin acetate) is
ooIf you or any of your close family have thinning of the bones.
administered once a month under the skin of e.g. abdomen, bottom or thigh as
ooIf you drink excessive amounts of alcohol, and/or smoke heavily.
a single injection.
ooIf you take drugs for epilepsy or have taken steroids such as
hydrocortisone or prednisolone for a long time.
b) Children with a body weight less than 20 kg
• There have been reports of depression in patients taking Prostap SR which Taking into account the clinical activity of the central precocious puberty in these
may be severe. If you are taking Prostap SR and develop depressed mood, rare cases, the following applies:
inform your doctor.
Unless prescribed otherwise, 0.5 ml Prostap SR (1.88 mg leuprorelin acetate)
Women only:
are administered once a month under the skin of e.g. abdomen, bottom or thigh
• If you are a woman with submucous fibroids (benign tumours in the muscle as a single injection. The remainder of the suspension should be discarded.
underneath the lining of the womb), Prostap SR can cause severe bleeding Your doctor will monitor the child’s weight gain.
when the fibroids break-down. Contact your doctor immediately if you
Depending on the central precocious puberty activity, your doctor may increase
experience severe or unusual bleeding or pain.
the dosage in the presence of inadequate suppression (e.g. vaginal bleeding).
• If you are a woman and continue to have periods (menstruate) after starting Your doctor will determine the minimal effective dose with the help of a blood
treatment with Prostap SR you should tell your doctor.
test.
• If you are a woman of child-bearing age, you should use non hormonal
The duration of treatment depends on the clinical signs at the start of treatment
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 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
to your doctor.
determine the bone age of the child in regular intervals.
Men only:
• In the rare event of an abscess occurring at the injection site your doctor
In girls with bone maturation of older than 12 years and boys with bone
may measure your testosterone levels as there could be reduced absorption maturation of older than 13 years your doctor will consider discontinuing the
of leuprorelin from the injection site.
treatment, depending on the clinical effects in your child.
• If you are a man with urinary obstruction or spinal cord compression. Your
In girls, pregnancy should be excluded before the start of treatment. The
doctor will supervise you closely for the first few weeks of treatment.
occurrence of pregnancy during treatment cannot be generally excluded. In
• If you are a man with prostate cancer, and have had injections of a synthetic such cases, please talk to your doctor.
hormone in the past that has not worked, or you have had an operation to
The therapy is a long-term treatment, adjusted individually. Please arrange with
remove your testicles you should tell your doctor.
your doctor that Prostap SR is administered as precisely as possible in regular
• Please tell your doctor if you have any of the following: Any heart or blood
monthly periods. An exceptional delay of the injection date for a few days
vessel conditions, including heart rhythm problems (arrhythmia), or are
(30 ± 2 days) does not influence the result of the therapy.
being treated with medicines for these conditions. The risk of heart rhythm
problems may be increased when using Prostap SR.
If you miss an injection
In children:
As soon as you realise you have missed an injection, contact your doctor who
• In the event of a sterile abscess at the injection site (mostly reported after
will be able to give you your next injection.
injection into the muscle) your doctor will monitor your hormone levels as
Women only:
there could be reduced absorption of leuprorelin from the injection site.
If a Prostap SR injection is missed, breakthrough bleeding or ovulation may
• If the child has progressive brain tumour your doctor will decide if treatment
occur with the potential for conception. If you think you may be pregnant you
with leuprorelin is appropriate.
should stop using Prostap SR and contact your doctor immediately.

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

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 use this medicine after the expiry date which is stated on the packaging.
The expiry date refers to the last day of that month.
Do not refrigerate or freeze.
Store in the original package in order to protect from light.
Do not store above 25°C.
Once mixed with the Sterile Solvent, the suspension must be used immediately.
If the pack has been opened or damaged, return it to your pharmacist.
If your medicine shows signs of deterioration or discolouration seek the advice
of your pharmacist who will tell you what to do.
Do not throw away any medicines via wastewater or household waste. Ask your
pharmacist how to throw away medicines you no longer use. These measures
will help to protect the environment.
6. CONTENTS OF THE PACK AND OTHER INFORMATION
What Prostap SR contains:
• Each syringe contains 3.75 mg leuprorelin acetate.
• Also includes gelatin, copolymer (DL-lactic acid/glycolic acid), which controls
the release of the active ingredient into the body, and mannitol.
• The Sterile Solvent contains mannitol, carmellose sodium, polysorbate 80
and water for injections.
What Prostap SR looks like and contents of the pack:
A dual chamber pre-filled syringe containing sterile, white powder in the front
chamber and sterile, clear solvent in the rear chamber. The powder is mixed
with the solvent before injection.
Each pack contains:
1 x dual chamber pre-filled syringe containing 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
Who Manufactured your medicine
Manufactured by Takeda Italia S.p.A. Via Crosa 86, Cerano, Italy.
or
Delpharm Novara S.r.l. Via Crosa 86, Cerano, Italy.
Procured from within the EU and repackaged by Product Licence Holder
Ennogen Healthcare Ltd, Unit G4 Riverside Industrial Estate, Riverside Way,
Dartford, Kent, DA1 5BS.
PL 40739/0117
Leaflet date: 8 May 2017

POM
Ref: ProSR/v1

Prostap is a registered trademark of Takeda Pharmaceutical Company Ltd

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HEALTH PROFESSIONALS’ USER LEAFLET

Prostap® SR DCS 3.75 mg Powder and Solvent
for Suspension for Injection
(leuprorelin acetate)
1

NAME OF THE MEDICINAL PRODUCT
Prostap® SR DCS 3.75 mg Powder and Solvent for Suspension for Injection

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Prostap SR Powder: contains 3.75 mg leuprorelin acetate (equivalent to 3.57 mg base).
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 regularly 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

Administration

INSTRUCTIONS ON HOW TO MIX AND ADMINISTER

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.
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 3 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 3-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.

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

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

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.

Tabulated list of adverse reactions
SOC

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

Common

Uncommon

Rare

Very rare

anaemia (reported in medicinal
products of this class),
thrombocytopaenia,
leucopenia

Immune system
disorders

hypersensitivity reactions
(including rash, pruritus,
urticaria and rarely, wheezing
or interstitial pneumonitis,
anaphylactic reactions)
weight fluctuation

decreased appetite

Lipids abnormal, glucose
tolerance abnormal

Psychiatric
disorders

insomnia,
depression (see
Section 4.4.) mood
changes (long-term
use)**

mood changes
(short term use)**

Nervous system
disorders

headache
(occasionally severe)

dizziness,
parasthesiae

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

visual impairment

Cardiac disorders

palpitations, electrocardiogram
QT prolonged (see Sections 4.4
and 4.5)

Vascular
disorders

skin

Round mark

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.

AFTER 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.

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

paralysis (see Section 4.4),
seizure

Eye disorders

NOTE: Avoid hard tapping to prevent the generation of bubbles.

upside

Not known

Blood and
lymphatic system
disorders

Metabolism and
nutrition disorders

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.

Very common

hot flush

pulmonary embolism
hypertension, hypotension (see
Section 4.4)

Gastrointestinal
disorders

nausea

Hepatobiliary
disorders

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

Skin and
subcutaneous
tissue disorders

hyperhydrosis

Musculoskeletal
connective tissue
and bone disorders

muscle weakness,
bone pain

arthralgia

diarrhoea, vomiting
jaundice

myalgia, weakness
of lower extremities

Renal and
urinary disorders

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

Reproductive
system and
breast disorders

Libido decreased,
erectile dysfunction,
testicular atrophy

gynaecomastia

General
disorders and
administration
site conditions

Fatigue, injection
site reaction,
e.g., induration,
erythema, pain,
abscesses,
swelling, nodules,
ulcers and necrosis

oedema peripheral

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

pyrexia

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).

In children:
Figure 1 presents the 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/m)l. The AUC0-672 is 105.78 ± 52.40 ng x hr/ml.

(ng/ml)
10

Tabulated list of adverse reactions
SOC

Very common

Common

Uncommon

Rare

Very rare

Not known

Blood and lymphatic
system disorders

Anaemia (reported in medicinal products of
this class), thrombocytopaenia, leucopenia

Immune system
disorders

hypersensitivity reactions (including rash,
pruritus, urticaria and rarely, wheezing and
interstitial pneumonitis,
anaphylactic reactions)

Metabolism and nutrition
disorders

weight
fluctuation

Psychiatric
disorders

insomnia

mood altered
depression
(see Section
4.4),

Nervous system
disorders

headache
(occasionally
severe)

parasthesiae,
dizziness

Eye disorders

glucose tolerance abnormal, which may
affect diabetic control

pituitary
haemorrhage
has been
reported
following initial
administration
in patients
with pituitary
adenoma.

paralysis (see Section 4.4),
seizure

0.1

palpitaitions
hot flush

Gastrointestinal
disorders

nausea

Skin and subcutaneous
tissue disorders

hair loss

Musculoskeletal
connective tissue and
bone disorders

arthralgia,
muscle
weakness

Reproductive system and
breast disorders

breast
tenderness,
breast atrophy,
vulvovaginal
dryness

General disorders and
administration site
conditions

Oedema
peripheral,
injection site
reaction, e.g.,
injection site
induration,
erythema, pain,
abscesses,
swelling,
nodules, ulcers
and necrosis

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

pyrexia, fatigue

Immune system disorders
emotional lability

Nervous system disorders

headache

acne

Reproductive system and
breast disorders

vaginal haemorrhage,
spotting**, vaginal
discharge

General disorders and
administration site
conditions

injection site reactions

6
PHARMACEUTICAL PARTICULARS
6.1 List of excipients
PROSTAP SR Powder
Gelatin
Copolymer (DL-lactic acid/glycolic acid)
Mannitol
Sterile Solvent
Carmellose sodium
Mannitol
Polysorbate 80
Water for Injections

6.4 Special precautions for storage
Do not refrigerate or freeze.
Store in the original container in order to protect from light.

Uncommon

Rare

Very rare

Not known

pituitary haemorrhage following
initial administration in patients with
pituitary adenoma

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
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

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

8

PRODUCT LICENCE NUMBER:
PL 40739/0117

9

DATE OF REVISION OF THE TEXT
8 May 2017

seizure

abdominal pain /
abdominal cramps,
nausea/vomiting

Skin and subcutaneous
tissue disorders

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)

6.3 Shelf life
3 years unopened.
Once reconstituted with sterile solvent, the suspension should be administered immediately.

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

Psychiatric disorders

4 weeks
3 weeks

6.2 Incompatibilities
Not applicable.

Tabulated list of adverse reactions
Common

2 weeks
1 week

5.3 Preclinical safety data
A teratogenic effect has been observed in rabbits but not in rats.

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

Gastrointestinal disorders

30 mins 120 mins
3 days
60 mins
1 day

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

Very common

0.01

pulmonary embolism hypertension,
hypotension (see Section 4.4)

Hepatobillary
disorders

SOC

1

visual
impairment

Cardiac disorders
Vascular
disorders

decreased
appetite, lipids
abnormal

** 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.
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 gonadotrophin releasing hormone (GnRH) which possesses
greater potency than the natural hormone. Leuprorelin acetate is a peptide and therefore unrelated to the steroids. Chronic administration results in an
inhibition of gonadotrophin production and subsequent suppression of ovarian and testicular steroid secretion. This effect is reversible on discontinuation of
therapy.
Administration of leuprorelin acetate results in an initial increase in circulating levels of gonadotrophins which leads to a transient increase in gonadal steroid
levels in both men and women. Continued administration of leuprorelin acetate results in a decrease of gonadotrophin and sex steroid levels. In men serum
testosterone levels, initially raised in response to early luteinising hormone (LH) release, fall to castrate levels in about 2-4 weeks. 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 high risk localised (T1-T2 and PSA of at least
10 ng/mL or a Gleason score of at least 7), or locally advanced (T3-T4) prostate cancer. The optimum duration of adjuvant therapy has not been established.
This US study used a higher dose of leuprorelin acetate (7.5 mg/month) which is therapeutically equivalent to the European licensed dose.
The use of a LHRH agonist may be considered after prostatectomy in selected patients considered at high risk of disease progression.
There are no disease-free survival data or survival data with leuprorelin acetate in this setting.
Neoadjuvant leuprorelin acetate prior to radiotherapy has been shown to reduce prostate volume.
In children:
Reversible suppression of pituitary gonadotropin release occurs, with a subsequent decrease in oestradiol (E2) or testosterone levels to values in the prepubertal range.
Initial gonadal stimulation (flare-up) may cause vaginal bleeding in girls who are already post-menarchal at start of treatment. Withdrawal bleeding may occur
at the start of treatment. The bleeding normally stops as treatment continues.
The following therapeutic effects can be demonstrated:
-- Suppression of basal and stimulated gonadotropin levels to pre-pubertal levels;
-- Suppression of prematurely increased sexual hormone levels to pre-pubertal levels and arrest of premature menstruation;
-- Arrest/involution of somatic pubertal development (Tanner stages);
-- Improvement/normalisation of the ratio of chronological age to bone age;
-- Prevention of progressive bone age acceleration;
-- Decrease of growth velocity and its normalization;
-- Increase in final height.
Treatment result is the suppression of the pathologically, prematurely activated hypothalamic-pituitary-gonadal axis according to pre-pubertal age.
In a long-term clinical trial in children treated with leuprorelin at doses up to 15mg monthly for > 4 years resumption of pubertal progression were observed
after cessation of treatment. Follow up of 20 female subjects to adulthood showed normal menstrual cycles in 80% and 12 pregnancies in 7 of the 20 subjects
including multiple pregnancies for 4 subjects.
5.2 Pharmacokinetic properties
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.

Ref: PSRHP/v1

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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