Skip to Content

PROSTAP SR DCS 3.75 MG POWDER AND SOLVENT FOR PROLONGED-RELEASE

Active substance(s): LEUPRORELIN ACETATE

PDF options:  View Fullscreen   Download PDF

PDF Transcript

S1785 LEAFLET Prostap 20160714



PACKAGE LEAFLET: INFORMATION FOR THE USER

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

Please tell your doctor if you have any of the following: Any
heart or blood vessel conditions, including heart rhythm
problems (arrhythmia), or are being treated with medicines for
these conditions. The risk of heart rhythm problems may be
increased when using Prostap SR.

In children:


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

In the event of a sterile abscess at the injection site (mostly
reported after injection into the muscle) your doctor will monitor
your hormone levels as there could be reduced absorption of
leuprorelin from the injection site.



Read all of this leaflet carefully before you start using this
medicine because it contains important information for you.

If the child has progressive brain tumour your doctor will decide
if treatment with leuprorelin is appropriate.

In girls with central precocious puberty:



Keep this leaflet. You may need to read it again.





If you have any further questions, ask your doctor or
pharmacist.



This medicine has been prescribed for you. Do not pass it on to
others. It may harm them, even if their signs of illness are the
same as yours.

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.





If you get any side effects, talk to your doctor or pharmacist.
This includes any possible side effects not listed in this leaflet.
See section 4.

Bone density may decrease during treatment of central
precocious puberty with Leuprorelin 1 Month Depot. However,
after treatment is stopped, subsequent bone mass growth is
preserved and peak bone mass in late adolescence does not
seem to be affected by treatment.



Often sterile abscesses at the injection site occurred when
Leuprorelin 1 Month Depot is administered in higher dosages
than recommended and when it is administered into the muscle.
Your doctor will therefore administer the medicinal product
under the skin of e.g. abdomen, bottom or thigh.



Discontinuation of treatment may lead to a slipping of the
growth plate of the thigh bone. A possible cause could be a
weakness of the growth plate due to a lower concentration of
female sexual hormones during treatment.

In this leaflet:
1. What Prostap SR is and what it is used for
2. What you need to know before you use Prostap SR
3. How to take Prostap SR
4. Possible side effects
5. How to store Prostap SR
6. Contents of the pack and other information
1. WHAT PROSTAP SR IS AND WHAT IT IS USED FOR
Prostap SR is a synthetic hormone which can be used to reduce the
levels of testosterone and estrogen circulating in the body.
Prostap SR is used to treat prostate cancer in men and
endometriosis and uterine fibroids in women. It can also be used to
reduce the thickness of the lining (endometrium) of the womb
(uterus) in preparation for surgery.
Use in children:
Prostap SR is a synthetic hormone which can be used to reduce the
levels of testosterone and estrogen circulating in the body.
Leuprorelin 1 Month Depot is used to treat premature puberty which
is caused by a release of certain hormones from the pituitary gland
(central precocious puberty) in girls under 9 years of age and boys
under 10 years of age.
2. WHAT YOU NEED TO KNOW BEFORE YOU USE PROSTAP
SR
Use in children: Your doctor will make a precise diagnosis of
central precocious puberty.
Do not take Prostap SR:

Other medicines and Prostap SR
Please tell your doctor or pharmacist if you are taking or have
recently taken any other medicines, including medicines obtained
without a prescription. Prostap SR might interfere with some
medicines used to treat heart rhythm problems (e.g. quinidine,
procainamide, amiodarone and sotalol) or might increase the risk of
heart rhythm problems when used with some other drugs (e.g.
methadone (used for pain relief and part of drug addiction
detoxification), moxifloxacin (an antibiotic), antipsychotics used for
serious mental illnesses).
Prostap SR with food and drink
Prostap SR can be taken with or without food.
Pregnancy and breastfeeding
Prostap SR must not be administered in pregnant or breast-feeding
women or girls (see also section “Do not use Prostap SR).
Driving and using machines



If you are allergic (hypersensitive) to leuprorelin acetate
(Prostap SR or Prostap 3) or any of the other ingredients of
Prostap SR (listed in section 6).

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



If you are pregnant, planning to become pregnant or are
breastfeeding.

3. HOW TO TAKE PROSTAP SR



If you have abnormal vaginal bleeding which you have not
discussed with your doctor.



In girls with central precocious puberty


if the girl to be treated is pregnant or breast-feeding.



if the girl has undiagnosed vaginal bleeding.

Warnings and precautions:
Both men and women:


If you are diabetic Prostap SR can aggravate existing diabetes
therefore diabetes patients may need more frequent monitoring
of the blood glucose levels.



If you have diabetes or suffer from heart problems you should
tell your doctor.



If you are at an increased risk of thinning of the bones
(osteoporosis) you should tell your doctor before taking Prostap
SR. Risk factors include:
o

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

o

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

o


If you take drugs for epilepsy or have taken steroids such
as hydrocortisone or prednisolone for a long time.

There have been reports of depression in patients taking
Prostap SR which may be severe. If you are taking Prostap SR
and develop depressed mood, inform your doctor.

Women only:


If you are a woman with submucous fibroids (benign tumours in
the muscle underneath the lining of the womb), Prostap SR can
cause severe bleeding when the fibroids break-down. Contact
your doctor immediately if you experience severe or unusual
bleeding or pain.



If you are a woman and continue to have periods (menstruate)
after starting treatment with Prostap SR you should tell your
doctor.



If you are a woman of child-bearing age, you should use non
hormonal contraception whilst receiving Prostap SR. Although
Prostap SR causes periods to stop, it is not itself a
contraceptive. If you are unsure about this talk to your doctor.

Men only:


In the rare event of an abscess occurring at the injection site
your doctor may measure your testosterone levels as there
could be reduced absorption of leuprorelin from the injection
site.



If you are a man with urinary obstruction or spinal cord
compression. Your doctor will supervise you closely for the first
few weeks of treatment.



If you are a man with prostate cancer, and have had injections
of a synthetic hormone in the past that has not worked, or you
have had an operation to remove your testicles you should tell
your doctor.

The doctor or nurse will give you an injection of Prostap SR. The
injection will normally be given in your arm, thigh or abdomen. The
injection site should be varied at regular intervals.
You will normally be given an injection once a month. If you are to
be given Prostap SR prior to intrauterine surgery you will receive a
single injection 5-6 weeks before your surgery.
If you have endometriosis you will be given an injection of Prostap
SR for a period of 6 months only and treatment will be initiated
during the first five days of the menstrual cycle.
If you have uterine fibroids you will be given an injection of Prostap
SR once a month usually for 3-4 months before surgery.
Use in children
Treatment of children should be under the overall supervision of the
paediatric endocrinologist.
The dosing scheme needs to be adapted individually.
The recommended starting dose is dependent on the body weight:
a) Children with a body weight 20 kg or more
Unless prescribed otherwise, 1 ml Prostap SR (3.75 mg leuprorelin
acetate) is administered once a month under the skin of e.g.
abdomen, bottom or thigh as a single injection.
b) Children with a body weight less than 20 kg
Taking into account the clinical activity of the central precocious
puberty in these rare cases, the following applies:
Unless prescribed otherwise, 0.5 ml Prostap SR (1.88 mg
leuprorelin acetate) are administered once a month under the skin
of e.g. abdomen, bottom or thigh as a single injection. The
remainder of the suspension should be discarded. Your doctor will
monitor the child’s weight gain.
Depending on the central precocious puberty activity, your doctor
may increase the dosage in the presence of inadequate
suppression (e.g. vaginal bleeding). Your doctor will determine the
minimal effective dose with the help of a blood test.
The duration of treatment depends on the clinical signs at the start
of treatment or during the course of treatment and is decided by
your doctor together with the legal guardian and, if appropriate, the
treated child. Your doctor will determine the bone age of the child in
regular intervals.
In girls with bone maturation of older than 12 years and boys with
bone maturation of older than 13 years your doctor will consider
discontinuing the treatment, depending on the clinical effects in your
child.
In girls, pregnancy should be excluded before the start of treatment.
The occurrence of pregnancy during treatment cannot be generally
excluded. In such cases, please talk to your doctor.
The therapy is a long-term treatment, adjusted individually. Please
arrange with your doctor that Prostap SR is administered as
precisely as possible in regular monthly periods. An exceptional
delay of the injection date for a few days (30 ± 2 days) does not
influence the result of the therapy.

If you miss an injection
As soon as you realise you have missed an injection, contact your
doctor who will be able to give you your next injection.

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.

Women only:

Children

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.

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):

4. POSSIBLE SIDE EFFECTS



mood swings

Like all medicines, Prostap SR can cause side effects, although not
everybody gets them.



headache

Contact your doctor immediately or go to hospital:



abdominal pain / abdominal cramps



feeling sick / vomiting



acne



vaginal bleeding

Tell your doctor:



spotting





discharge





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

 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.

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.

Not known (frequency cannot be estimated from the available
data)


In general, if vaginal bleeding (spotting) occurs with continued
treatment (after possible withdrawal bleeding in the first month of
treatment), this may be a sign of potential underdosage. Please tell
your doctor if vaginal bleeding occurs.
Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This
includes any possible side effects not listed in this leaflet. You can
also report side effects directly via the Yellow Card Scheme at:
www.mhra.gov.uk/yellowcard.
By reporting side effects you can help provide more information on
the safety of this medicine.
5. HOW TO STORE PROSTAP SR


KEEP OUT OF THE SIGHT AND REACH OF CHILDREN.



Do not store above 25°C.



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



Do not refrigerate or freeze.



Once mixed with the sterile solvent, the suspension must be
used immediately.



If the pack has been opened or damaged, return it to your
pharmacist.



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



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



Do not throw away medicines via wastewater or household
waste. Ask your pharmacist how to throw away medicines you
no longer use. These measures will help to protect the
environment.

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

Seizure

Notes:

6. CONTENTS OF THE PACK AND OTHER INFORMATION
What Prostap SR contains:


Each syringe contains 3.75mg leuprorelin acetate.



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



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

What Prostap SR looks like and contents of the pack:
Prostap SR is a dual chamber pre-filled syringe containing sterile,
white powder in the front chamber and sterile, clear solvent in the
rear chamber. The powder is mixed with the solvent before
injection.
Each pack contains


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



1 x 23 gauge syringe needle.



1 x syringe plunger and 2 x alcohol swabs.

Product Licence holder
Procured from within the EU and repackaged by the Product
Licence holder: S&M Medical Ltd, Chemilines House,
Alperton Lane, Wembley, HA0 1DX.
Manufacturer
This product is manufactured by Takeda Pharmaceutical Company
Ltd, Japan.
POM

PL: 19488/1785

Leaflet revision date: 14 July 2016
Prostap® is a registered trademark of Takeda Pharmaceutical
Company Limited.
S1785 LEAFLET Prostap 20160714

4.4 Special warnings and precautions for use

S1785 MIL LEAFLET Prostap 20160714

HEALTH PROFESSIONALS’ USER LEAFLET

Prostap®

SR DCS
3.75 mg powder and solvent for prolonged-release suspension for injection in pre-filled syringe
(leuprorelin acetate)
1. NAME OF THE MEDICINAL PRODUCT
Prostap® SR DCS 3.75 mg powder and solvent for prolonged-release suspension for injection in pre-filled syringe
2. QUALITATIVE AND QUANTITATIVE COMPOSITION

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.

PROSTAP SR Powder: Each syringe contains 3.75 mg leuprorelin acetate

Spinal fracture, paralysis and hypotension have been reported.

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

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.

When reconstituted with sterile solvent, the suspension contains 3.75 mg/ml leuprorelin acetate.

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.

For the full list of excipients, see section 6.1
3. PHARMACEUTICAL FORM

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.

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.

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.

(vii) Endometrial preparation prior to intrauterine surgical procedures including endometrial ablation or resection.

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.

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

Androgen deprivation therapy may prolong the QT interval.

(vi) Management of endometriosis, including pain relief and reduction of endometriotic lesions.

In children:
Treatment of central precocious puberty (girls under 9 years of age, boys under 10 years of age). (See Section 5.1)
4.2 Posology and method of administration
Posology
Prostate Cancer: The usual recommended dose is 3.75 mg presented as a one month depot injection and administered as a single subcutaneous or
intramuscular injection every month. The majority of patients will respond to a 3.75 mg dose. PROSTAP SR therapy should not be discontinued when
remission or improvement occurs. As with other drugs administered chronically by injection, the injection site should be varied periodically.
Response to PROSTAP SR therapy may be monitored by clinical parameters and by measuring serum levels of testosterone and acid phosphatase.
Clinical studies with leuprorelin acetate have shown that testosterone levels increased during the first 4 days of treatment in the majority of nonorchidectomised 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.

In patients with a history of or risk factors for QT prolongation and in patients receiving concomitant medicinal products that might prolong the QT
interval (see section 4.5) physicians should assess the benefit risk ratio including the potential for Torsade de pointes prior to initiating PROSTAP
SR.
Women: When considering the preoperative treatment of fibroids it is mandatory to confirm the diagnosis of fibroids and exclude an ovarian mass,
either visually by laparoscopy or by ultrasonography or other investigative technique, as appropriate, before PROSTAP SR therapy is instituted.
During the early phase of therapy, sex steroids temporarily rise above baseline because of the physiological effect of the drug. Therefore, an
increase in clinical signs and symptoms may be observed during the initial days of therapy, but these will dissipate with continued therapy. The
induced hypo-estrogenic state results in a small loss in bone density over the course of treatment, some of which may not be reversible. The extent
of bone demineralisation due to hypo-estrogenaemia is proportional to time and, consequently, is the adverse event responsible for limiting the
duration of therapy to 6 months. The generally accepted level of bone loss with LHRH analogues such as PROSTAP SR is 5%. In clinical studies
with PROSTAP SR the levels varied between 2.3% and 15.7% depending on the method of measurement. During one six-month treatment period,
this bone loss should not be important. In patients with major risk factors for decreased bone mineral content such as chronic alcohol and/or tobacco
use, strong family history of osteoporosis, or chronic use of drugs that can reduce bone mass such as anticonvulsants or corticosteroids, PROSTAP
SR therapy may pose an additional risk. In these patients, the risks and benefits must be weighed carefully before therapy with PROSTAP SR is
instituted. This is particularly important in women with uterine fibroids where age related bone loss may have already begun to occur.
Therefore, before using PROSTAP SR for the preoperative treatment of uterine fibroids, patients with major risk factors for decreased bone mineral
content (see above) should have their bone density measured and where results are below the normal (5th percentile by DEXA scan) range,
PROSTAP SR therapy should not be started.
In women with submucous fibroids there have been reports of severe bleeding following the administration of PROSTAP SR as a consequence of
the acute degeneration of the fibroids. Patients should be warned of the possibility of abnormal bleeding or pain in case earlier surgical intervention
is required.
PROSTAP SR may cause an increase in uterine cervical resistance, which may result in difficulty in dilating the cervix for intrauterine surgical
procedures.
In women receiving GnRH analogues for the treatment of endometriosis, the addition of HRT (an estrogen and progestogen) has been shown to
reduce bone mineral density loss and vasomotor symptoms.
Precautions
Men: Patients with urinary obstruction and patients with metastatic vertebral lesions should begin PROSTAP SR therapy under close supervision for
the first few weeks of treatment.

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.

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.

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).

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.

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.

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.

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:

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

The administration interval should be 30 ± 2 days in order to prevent the recurrence of precocious puberty symptoms.

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

Administration

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.

INSTRUCTIONS ON HOW TO MIX AND ADMINISTER

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
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.

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

NOTE: Pushing the plunger rod quickly or over the blue line will
cause leakage of the suspension from the needle.

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).

The following tables list adverse reactions with leuprorelin based on experience from clinical trials as well as from post-marketing experience.

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.
Tabulated list of adverse reactions
SOC

Very common

Common

Uncommon

Rare

Very rare

Not known
anaemia (reported in
medicinal products of
this class),
thrombocytopaenia,

Blood and
lymphatic
system disorders

leucopenia
4. Gently tap the syringe on the palm keeping the syringe upright to
thoroughly mix the particles to form a uniform suspension.

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

hypersensitivity
reactions

The suspension will appear milky.

(including rash, pruritus,
Immune system

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

urticaria and rarely,
wheezing

disorders

or interstitial
pneumonitis,
anaphylactic reactions)

upside

Metabolism
and nutrition

weight fluctuation

Lipids abnormal, glucose

decreased appetite

tolerance abnormal

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.
4.3 Contraindications

insomnia, depression

mood

Psychiatric

(see Section 4.4),

changes

disorders

mood changes

(short term

(long-term use)**

use)**
pituitary
apoplexy has

Nervous system

headache

dizziness,

disorders

(occasionaly severe)

parasthesiae

Hypersensitivity to the active substance, any of the excipients listed in section 6.1 or to synthetic gonadotrophin releasing homone (Gn-RH) or GnRH 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.

been reported
following initial

paralysis (see Section
4.4),

administration

seizure

in patients with
pituitary adenoma
Eye disorders

Men: There are no known contra-indications to the use of PROSTAP SR in men.

visual impairment
palpitations,

In girls with central precocious puberty:

Cardiac

electrocardiogram QT



Pregnancy and lactation

disorders



Undiagnosed vaginal bleeding.

prolonged (see Sections
4.4 and 4.5)

Vascular
disorders

hot flush

pulmonary embolism,

Reporting of suspected adverse reactions

hypertension,
hypotension

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.

(see Section 4.4)
Gastrointestinal

diarrhoea,

nausea

disorders

No case of overdose has been reported.

vomiting

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.

hepatic function
abnormal, liver

Hepatobiliary

5. PHARMACOLOGICAL PROPERTIES

function test

disorders

jaundice

5.1 Pharmacodynamic properties

abnormal (usually

Pharmacotherapeutic group: Gonadotrophin Releasing Hormone Analogues

transient)

ATC code: L02AE 02

Skin and
subcutaneous

PROSTAP SR contains leuprorelin acetate, a synthetic nonapeptide analogue of naturally occurring GnRH which possesses greater potency than
the natural hormone. Leuprorelin acetate is a peptide and therefore unrelated to the steroids. Chronic administration results in an inhibition of
gonadotrophin production and subsequent suppression of ovarian and testicular steroid secretion. This effect is reversible on discontinuation of
therapy.

hyperhydrosis

tissue disorders
Musculoskeletal,

spinal fracture (see
Section

myalgia,

connective

muscle weakness,

tissue and bone

bone pain

4.4), reduction in bone
mass

weakness

arthralgia

of lower

disorders

which may occur with
the use

extremities

of GnRH agonists
Renal and

urinary tract obstruction

urinary disorders
Reproductive
system and
breast disorders

4.9 Overdose

Libido decreased,
erectile
dysfunction,

gynaecomastia

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).

testicular atrophy
Fatigue, injection
site reaction,

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.

General

e.g., induration,

disorders and

erythema, pain,

administration

abscesses,

site conditions

swelling, nodules,

oedema peripheral

In another randomised, open-label, multi-centre comparative trial, leuprorelin acetate in combination with flutamide has been shown to significantly
improve disease-free survival and overall survival when used as an adjuvant therapy to radiotherapy in 88 patients with highrisk localised (T1-T2
and PSA of at least 10 ng/mL or a Gleason score of at least 7), or locally advanced (T3-T4) prostate cancer. The optimum duration of adjuvant
therapy has not been established. This US study used a higher dose of leuprorelin acetate (7.5mg/month) which is therapeutically equivalent to the
European licensed dose.

pyrexia

ulcers and
necrosis

The use of a LHRH agonist may be considered after prostatectomy in selected patients considered at high risk of disease progression.

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

There are no disease-free survival data or survival data with leuprorelin acetate in this setting

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.

In children:

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).

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.

Vaginal haemorrhage may occur during therapy due to acute degeneration of submucous fibroids (see Section 4.4).

The following therapeutic effects can be demonstrated:

Tabulated list of adverse reactions



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.

SOC

Very
common

Common

Uncommon

Rare

Neoadjuvant leuprorelin acetate prior to radiotherapy has been shown to reduce prostate volume.

Very rare

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

Blood and
lymphatic
system disorders

hypersensitivity reactions
(including rash, pruritus,
urticaria and rarely,

Immune system
disorders

wheezing and interstitial
pneumonitis, anaphylactic
reactions)
decreased
appetite,
lipids
abnormal

Metabolism
and nutrition

weight fluctuation

disorders
Psychiatric
disorders

Nervous system
disorders

Not known

glucose tolerance abnormal,
which may affect diabetic
control

mood altered
depression

insomnia

Treatment result is the suppression of the pathologically, prematurely activated hypothalamic-pituitary-gonadal axis according to prepubertal age.
In a long-term clinical trial in children treated with leuprorelin at doses up to 15mg monthly for > 4 years resumption of pubertal progression were
observed after cessation of treatment. Follow up of 20 female subjects to adulthood showed normal menstrual cycles in 80% and 12 pregnancies in
7 of the 20 subjects including multiple pregnancies for 4 subjects.
5.2 Pharmacokinetic properties
Studies submitted show that single intramuscular or subcutaneous doses of leuprorelin acetate over the dose range 3.75 to 15 mg results in
detectable levels of leuprorelin acetate for more than 28 days, good bioavailability, a consistent and predictable pharmacokinetic profile, and
biological efficacy at plasma levels of less than 0.5 ng/ml. The pharmacokinetic profile is similar to that seen in animal studies using the compound,
with an initial high level of drug released from the microcapsules during reconstitution and injection followed by a plateau over a 2-3 week period
before levels gradually become undetectable. There appears to be no significant difference between the routes of administration (im vs sc) in
biological effectiveness or pharmacokinetics.
The metabolism, distribution and excretion of leuprorelin acetate in humans have not been fully determined.

(see Section 4.4)

headache

pituitary

In children:

haemorrhage

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/m)l. The AUC0-672 is 105.78 ± 52.40 ng x hr/ml.

has been reported

(occasionally

Reversible suppression of pituitary gonadotropin release occurs, with a subsequent decrease in oestradiol (E2) or testosterone levels to values in
the pre-pubertal range.

parasthesiae, dizziness

following initial

severe)

paralysis (see Section 4.4),
seizure

administration
in patients with
pituitary adenoma
visual

Eye disorders

impairment

Cardiac

palpitations

disorders
Vascular
disorders

pulmonary embolism,
hypertension, hypotension
(see Section 4.4)

hot flush

Gastrointestinal

diarrhoea,

nausea

disorders

vomiting
liver function

Hepatobiliary

test abnormal

disorders

(usually
transient)

hepatic function abnormal,
jaundice

Skin and
subcutaneous

hair loss

tissue disorders
Musculoskeletal,
connective

arthralgia, muscle
weakness

tissue and bone

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

myalgia

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)

breast tenderness,

Reproductive

breast atrophy,
vulvovaginal

system and
breast disorders

vaginal haemorrhage

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

dryness

6 PHARMACEUTICAL PARTICULARS

Oedema peripheral,
General

injection site reaction

disorders and

e.g.injection site
induration, erythema,
pain, abscesses,

administration
site conditions

5.3 Preclinical safety data

6.1 List of excipients
PROSTAP SR Powder

pyrexia,

gelatin

fatigue

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

swelling, nodules, ulcers
and necrosis

mannitol
Sterile Solvent

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.

carmellose sodium

Tabulated list of adverse reactions

polysorbate 80

SOC

Very
common

Common

Very rare

Not known

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

disorders

Nervous system
disorders

Rare

6.3 Shelf life
3 years unopened.

emotional

Once reconstituted with sterile solvent, the suspension should be administered immediately.

lability
headache

6.4 Special precautions for storage
pituitary haemorrhage following initial
administration in patients with pituitary
adenoma

seizure

abdominal pain /
Gastrointestinal
disorders
Skin and
subcutaneous
tissue disorders
Reproductive
system and breast
disorders
General disorders
and administration
site conditions

water for Injections
6.2 Incompatibilities
Not applicable.

Immune system
Psychiatric
disorders

Uncommon

mannitol

abdominal cramps,

Do not store above 25°C.
Store in the original container in order to protect from light.
Do not refrigerate or freeze.
6.5 Nature and contents of container

nausea/vomiting

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.

acne

1 x 23 gauge syringe needle fitted with safety device

vaginal haemorrhage,
spotting**, vaginal

1 x syringe plunger and 2 x alcohol swabs.
6.6 Special precautions for disposal and other handling
Always ensure that the safety device to prevent needle-stick injury is deployed after injection.

discharge

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

injection site reactions

Procured from within the EU and repackaged by the Product Licence holder: S&M Medical Ltd, Chemilines House, Alperton Lane, Wembley,
HA0 1DX.
8 PRODUCT LICENCE NUMBER: PL 19488/1785

** 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.

9 DATE OF REVISION OF THE TEXT: 14 July 2016
S1785 MIL LEAFLET Prostap 20160714

+ 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.

Hide