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LUCRIN 3 DCS 11.25 MG POWDER AND SOLVENT FOR PROLONGED-RELEASE SUSPENSION FOR INJECTION IN PRE-FILLE

Active substance(s): LEUPRORELIN ACETATE

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2583
08.03.16[7]

Prostap® 3 DCS 11.25 mg Powder and
Solvent for Prolonged-release
Suspension for Injection in Pre-filled
Syringe
(leuprorelin acetate)
PATIENT INFORMATION LEAFLET
Read all of this leaflet carefully before you start using this medicine
because it contains important information for you.
- Keep this leaflet. You may need to read it again.
- If you have any further questions, ask your doctor or pharmacist.
- This medicine has been prescribed for you. Do not pass it on to others. It
may harm them, even if their signs of illness are the same as yours.
- If you get any side effects talk to your doctor or pharmacist. This includes
any possible side effects not listed in this leaflet. See section 4.
Your medicine will be referred to as PROSTAP 3 throughout the following
leaflet.
In this leaflet:
1. What PROSTAP 3 is and what it is used for
2. What you need to know before you use PROSTAP 3
3. How to take PROSTAP 3
4. Possible side effects
5. How to store PROSTAP 3
6. Contents of the pack and other information
1. WHAT PROSTAP 3 IS AND WHAT IT IS USED FOR
PROSTAP 3 is a synthetic hormone which can be used to reduce the levels
of testosterone and estrogen circulating in the body.
PROSTAP 3 is used to treat prostate cancer in men and endometriosis in
women.
Use in children:
Leuprorelin 3 Month Depot is a synthetic hormone which can be used to
reduce the levels of testosterone and estrogen circulating in the body.
Leuprorelin 3 Month Depot is used to treat premature puberty which is
caused by a release of certain hormones from the pituitary gland (central
precocious puberty) in girls under 9 years of age and boys under 10 years of
age.
2. WHAT YOU NEED TO KNOW BEFORE YOU USE PROSTAP 3
Use in children: Your doctor will make a precise diagnosis of central
precocious puberty.
Do not take PROSTAP 3:
- If you are allergic (hypersensitive) to leuprorelin acetate (PROSTAP SR or
PROSTAP 3) or any of the other ingredients of PROSTAP 3 (listed in
section 6).
- If you are pregnant, planning to become pregnant or are breastfeeding.
- If you have abnormal vaginal bleeding which you have not discussed with
your doctor.
- In girls with central precocious puberty
- if the girl to be treated is pregnant or breast-feeding.
- if the girl has undiagnosed vaginal bleeding.
Warnings and Precautions:
Both men and women:
- If you are diabetic PROSTAP 3 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 3. Risk factors include:
- If you or any of your close family have thinning of the bones.
- If you drink excessive amounts of alcohol, and/or smoke heavily.
- If you take drugs for epilepsy or have taken steroids such as
hydrocortisone or prednisolone for a long time.
- There have been reports of depression in patients taking PROSTAP 3
which may be severe. If you are taking PROSTAP 3 and develop
depressed mood, inform your doctor.

- Discontinuation of treatment may lead to a slipping of the growth plate of
the thigh bone. A possible cause could be a weakness of the growth plate
due to a lower concentration of female sexual hormones during treatment.
Other medicines and PROSTAP 3
Please tell your doctor or pharmacist if you are taking or have recently taken
any other medicines, including medicines obtained without a prescription.
PROSTAP 3 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 3 with food and drink
PROSTAP 3 can be taken with or without food.
Pregnancy and breastfeeding
PROSTAP 3 must not be administered in pregnant or breast-feeding women
or girls (see also section “Do not use PROSTAP 3’).
Driving and using machines
Do not drive or operate machinery if you experience drowsiness, dizziness
or visual disturbances whilst being treated with PROSTAP 3.
3. HOW TO TAKE PROSTAP 3
The doctor or nurse will give you an injection of PROSTAP 3. The injection
will normally be given in your arm, thigh or abdomen. The injection site
should be varied at regular intervals.
You will normally be given an injection once every 3 months.
If you have endometriosis you will be given an injection of PROSTAP 3 for a
period of 6 months only and treatment will be initiated during the first five
days of the menstrual cycle.
Use in children
Treatment of children should be under the overall supervision of the
paediatric endocrinologist.
The dosing scheme needs to be adapted individually.
The recommended starting dose is dependent on the body weight:
a) Children with a body weight 20 kg or more
Unless prescribed otherwise, 1 ml PROSTAP 3 (11,25 mg leuprorelin
acetate) is administered every 3 months under the skin of e.g. abdomen,
bottom or thigh as a single injection.
b) Children with a body weight less than 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 3 (5,625 mg leuprorelin
acetate) are administered every 3 months under the skin of e.g. abdomen,
bottom or thigh as a single injection. The remainder of the suspension
should be discarded. Your doctor will monitor the child’s weight gain.
Depending on the central precocious puberty activity, your doctor may
increase the dosage in the presence of inadequate suppression (e.g.
vaginal bleeding). Your doctor will determine the minimal effective dose with
the help of a blood test.
The duration of treatment depends on the clinical signs at the start of
treatment or during the course of treatment and is decided by your doctor
together with the legal guardian and, if appropriate, the treated child. Your
doctor will determine the bone age of the child in regular intervals.
In girls with bone maturation of older than 12 years and boys with bone
maturation of older than 13 years your doctor will consider discontinuing the
treatment, depending on the clinical effects in your child. In girls, pregnancy
should be excluded before the start of treatment. The occurrence of
pregnancy during treatment cannot be generally excluded. In such cases,
please talk to your doctor.
The therapy is a long-term treatment, adjusted individually. Please arrange
with your doctor that PROSTAP 3 is administered as precisely as possible in
regular 3-monthly periods. An exceptional delay of the injection date for a
few days (90 ± 2 days) does not influence the result of the therapy.
If you miss an injection

Women only:
- If you are a woman with submucous fibroids (benign tumours in the
muscle underneath the lining of the womb), PROSTAP 3 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 3 you should tell your doctor.

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.

- If you are a woman of child-bearing age, you should use non hormonal
contraception whilst receiving PROSTAP 3. Although PROSTAP 3 causes
periods to stop, it is not itself a contraceptive. If you are unsure about this
talk to your doctor.

4. POSSIBLE SIDE EFFECTS
Like all medicines, PROSTAP 3 can cause side effects, although not
everybody gets them.

Men only:
- In the rare event of an abscess occurring at the injection site your doctor
may measure your testosterone levels as there could be reduced
absorption of leuprorelin from the injection site.
- If you are a man with urinary obstruction or spinal cord compression. Your
doctor will supervise you closely for the first few weeks of treatment.
- If you are a man with prostate cancer, and have had injections of a
synthetic hormone in the past that has not worked, or you have had an
operation to remove your testicles you should tell your doctor.
- Please tell your doctor if you have any of the following: Any heart or blood
vessel conditions, including heart rhythm problems (arrhythmia), or are
being treated with medicines for these conditions. The risk of heart rhythm
problems may be increased when using PROSTAP 3.
In children:
- In the event of a sterile abscess at the injection site (mostly reported after
injection into the muscle) your doctor will monitor your hormone levels as
there could be reduced absorption of leuprorelin from the injection site.
- If the child has progressive brain tumour your doctor will decide if
treatment with leuprorelin is appropriate.
In girls with central precocious puberty:
- After the first injection vaginal bleeding (spotting) and discharge may
occur as a sign of hormone withdrawal. Vaginal bleeding beyond the
first/second month of treatment needs to be investigated.
- Bone density may decrease during treatment of central precocious
puberty with Leuprorelin 3 Month Depot. However, after treatment is
stopped, subsequent bone mass growth is preserved and peak bone
mass in late adolescence does not seem to be affected by treatment.
- Often sterile abscesses at the injection site occurred when Leuprorelin 3
Month Depot is administered in higher dosages than recommended and
when it is administered into the muscle. Your doctor will therefore
administer the medicinal product under the skin of e.g. abdomen, bottom
or thigh.

Women only:
If a PROSTAP 3 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 3 and contact your doctor immediately.

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 3. 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 3,
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
3 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 3,
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 longterm use), headache, nausea, abnormalities in liver function or liver blood
tests, joint pain, swelling of the breast tissue or swelling in your ankles.
Uncommon (may affect more than 1 in 100 people)
Mood changes (with short-term use), dizziness, tingling in the hands or feet,
diarrhoea, vomiting, muscle ache or weakness in the legs.
Not known (frequency cannot be estimated from the available data)
Blood tests may show anaemia (low red cell counts), low counts in white
cells or platelets, allergic reactions (may include symptoms of rash, itching,
wheals or a serious allergic reaction which causes difficulty breathing or
dizziness), changes in blood lipids (cholesterol) or blood sugar, paralysis,
seizure, altered vision, pounding heartbeats, changes in ECG (QT
prolongation), blood clots in lungs, high or low blood pressure, jaundice,
fracture of the spine, thinning of bone, difficulty passing urine, fever or chills.
Women:
- Many of the side effects of PROSTAP 3 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 3 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 3,
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 3
Keep out of the sight and reach of children
Do not store above 25oC.
Do not refrigerate or freeze.
Store in the original container in order to protect from light.
Do not use this medicine after the expiry date stated on the packaging.
The expiry date refers to the last day of that month.
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.
Medicines should not be disposed of via wastewater or household waste.
Ask your pharmacist how to dispose of medicines no longer required. These
measures will help to protect the environment.

6. CONTENTS OF THE PACK AND OTHER INFORMATION
What PROSTAP 3 contains:
The active ingredient in PROSTAP 3 Powder is leuprorelin acetate
(11.25 mg)
Leuprorelin acetate 11.25 mg equivalent to 10.72 mg leuprorelin base.
When reconstituted with the solvent, the solution contains 11.25 mg/ml of
leuprorelin acetate.
The other ingredients are:
Powder- polylactic acid, mannitol
Sterile solvent- carboxymethylcellulose sodium, mannitol, polysorbate 80,
glacial acetic acid (for pH adjustment) and water for injections.
What PROSTAP 3 looks like and contents of the pack:
One dual chamber pre-filled syringe with a needle and needle cap
containing a white powder in the front chamber and 1 ml of sterile solvent
(clear liquid) in the rear chamber, with a red end stopper.
The pack also contains 1 x syringe plunger and 1 x alcohol swab.
MANUFACTURER AND PRODUCT LICENCE HOLDER
Manufactured by
Abbott Laboratories S.A., Apartado De Correos, 967, Avenida De Burgos,
91, Madrid, E-28050, Spain.
AbbVie Logistics B.V., Meeuwenlaan 4, 8011 BZ Zwolle, The Netherlands.
Procured from within EU by Product Licence holder: Star Pharmaceuticals
Ltd., 5 Sandridge Close, Harrow, Middlesex, HA1 1XD. Repackaged by
Servipharm Ltd.
POM

PL 20636/2583

Leaflet revision and issue date (Ref): 08.03.16[7]
Prostap is a trademark of Takeda Pharmaceutical Company Limited.

2583
08.03.16[H-7]

HEALTH PROFESSIONALS’ USER LEAFLET
®

Prostap 3 DCS 11.25 mg Powder and Solvent for Prolonged-release Suspension for Injection in Pre-filled
Syringe
(leuprorelin acetate)
1. NAME OF THE MEDICINAL PRODUCT
Prostap 3 DCS 11.25 mg Powder and Solvent for Prolonged-release Suspension for Injection in Pre-filled Syringe
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
PROSTAP 3 Powder: contains 11.25 mg leuprorelin acetate (equivalent to 10.72 mg base).
Sterile Solvent: Each ml contains carboxymethylcellulose sodium 5 mg, mannitol 50 mg, polysorbate 80 1 mg in
Water for Injections.
When reconstituted with Sterile Solvent, the suspension contains 11.25 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.
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 11.25 mg presented as a three month depot injection and
administered as a single subcutaneous injection at intervals of three months. The majority of patients will respond to
this dosage. PROSTAP 3 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 3 therapy should be monitored by clinical parameters and by measuring prostate-specific
antigen (PSA) serum levels. 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 4 th 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 11.25 mg administered as a single intramuscular injection every 3 months
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 3 taking into account the risks
and benefits of each treatment.
Elderly: As for adults.
Paediatric population
The treatment of children with leuprorelin acetate should be under the overall supervision of the paediatric
endocrinologist.
The dosing scheme needs to be adapted individually.
The recommended starting dose is dependent on the body weight.
Children with a body weight ≥ 20 kg
1 ml (11.25 mg leuprorelin acetate) suspension of 130.0 mg sustained-release microcapsules in 1 ml vehicle solution
are administered every 3 months 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 (5.625 mg leuprorelin acetate) suspension of 130.0 mg sustained-release microcapsules in 1 ml vehicle
solution are administered every 3 months 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 3-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 90 ± 2 days in order to prevent the recurrenc e of precocious puberty Symptom
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 3 is contra-indicated in women who are or may become pregnant while receiving the drug.
PROSTAP 3 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 3 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 3.
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 3.
Women: During the early phase of endometriosis therapy, sex steroids temporarily rise above baseline because of
the physiological effect of the drug. Therefore, a worsening of clinical signs and symptoms may be observed during
the initial days of therapy, but these will dissipate with continued therapy.
When 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 (see ‘Posology and
Method of Administration’ section 4.2 for further information).
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 3 is 5%. In clinical studies with PROSTAP 3 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 3 therapy may pose an additional risk. In
these patients, the risks and benefits must be weighed carefully before therapy with PROSTAP 3 is instituted.
In women with submucous fibroids there have been reports of severe bleeding following administration of PROSTAP
3 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 3 may cause an increase in uterine cervical resistance, which may result in difficulty in dilating the cervix
for intrauterine surgical procedures.
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 3, 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 3 should be administered as precisely as
possible in regular 3-monthly periods.
An exceptional delay of the injection date for a few days (90 ± 2 days) does not influence the 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 3 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 3,
pregnancy must be excluded. There have been reports of foetal malformation when PROSTAP 3 has been given
during pregnancy.
PROSTAP 3 should not be used in women who are breastfeeding.
When used 3-monthly at the recommended dose, PROSTAP 3 usually inhibits ovulation and stops menstruation.
Contraception is not ensured, however, by taking PROSTAP 3 and therefore patients should use non-hormonal
methods of contraception during treatment.
Patients should be advised that if they miss successive doses of PROSTAP 3, 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 3 can influence the ability to drive and use machines due to visual disturbances and dizziness.

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.

4. Gently tap
the
syringe on the
palm keeping
the syringe
upright to
thoroughly mix
the particles to
form a unique
suspension.
The
suspension
will appear
milky.

3. Holding the syringe upright, release the
diluents by SLOWING PISHING the
plunger until the middle stopper is at 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.
5. Remove
the needle
cap and
advance
the plunger
to expel
the air from
the syringe

4.8 Undesirable effects
Adverse reactions seen with PROSTAP 3 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 3 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
Blood and
lymphatic
system
disorders

Uncommon

Rare

Very Rare

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

Immune
system
disorders

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

Metabolism
and nutrition
disorders

6. At the time of injection, check the direction as illustrated, and inject
the entire contents of the syringe subcutaneously or intramuscularly as
you would for the normal injection.
Withdraw the needle from the patient

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

Psychiatric
disorders

Nervous
system
disorders

weight
fluctuation

decreased
appetite

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

Not known

mood
changes
(short term
use)**

dizziness,
parasthesiae

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

paralysis (see
Section 4.4),
seizure

Eye
disorders
Cardiac
disorders

Vascular
disorders

hot flush

Gastrointesti
nal disorders
Hepatobiliary
disorders

Skin and
subcutaneou
s disorders
Musculoskel
etal,
connective
tissue and
bone
disorders

Renal and
urinary
disorders
Reproductiv
e system and
breast
disorders

General
disorders
and
administratio
n site
conditions

visual
impairment
palpitations,
electrocardiogra
m
QT prolonged
(see Sections
4.4 and 4.5)
pulmonary
embolism,
hypertension,
hypotension
(see Section 4.4)
nausea

diarrhoea,
vomiting

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

jaundice

hyperhydrosi
s
muscle
weakness,
bone pain

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

arthralgia

myalgia,
weakness of
lower
extremities

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

gynaecomastia

oedema
peripheral

pyrexia

** mood changes (long term use: frequency of ‘common’ and short term use: frequency of ‘uncommon’)
Women: Those adverse events occurring most frequently with PROSTAP 3 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).
Breast tenderness or change in breast size may occur occasionally. Hair loss has also been reported occasionally.
Vaginal haemorrhage may occur during therapy due to acute degeneration of submucous fibroids (see Section 4.4).
Tabulated list of adverse reactions
SOC
Very common
Common
Blood and
lymphatic
system
disorders

Uncommon

Rare

Very Rare

Immune
system
disorders

Metabolism
and
nutrition
disorders

weight
fluctuation

Psychiatric
disorders

insomnia

Nervous
system
disorders

headache
(occasionaly
severe)

Eye
disorders
Cardiac
disorders
Vascular
disorders

Gastrointes
tinal
disorders
Hepatobiliar
y disorders

Skin and
subcutaneo
us
disorders
Musculoske
letal,
connective
tissue and
bone
disorders
Reproductiv
e system
and breast
disorders

General
disorders
and
administrati
on site
conditions

hypersensitivity
reactions
(including rash,
pruritus,
urticaria and rarely,
wheezing
or interstitial
pneumonitis,
anaphylactic
reactions)
glucose
tolerance
abnormal, which
may affect diabetic
control

decreased
appetite, lipids
abnormal

mood altered
depression
(see Section
4.4)
parasthesiae,
dizziness

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

pituitary
haemorrha
ge
has been
reported
following
initial
administrati
on
in patients
with
pituitary
adenoma

paralysis (see
Section
4.4),seizure

Skin and
subcutaneo
us
disorders
Reproductiv
e system
and breast
disorders

abdominal
pain /
abdominal
cramps,
nausea/vo
miting
acne

vaginal
haemorrha
ge,
spotting**,
vaginal
discharge
injection
site
reactions

General
disorders
and
administrati
on site
conditions
** 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 3 contains leuprorelin acetate, a synthetic nonapeptide analogue of naturally occurring gonadotrophin
releasing hormone (GnRH) which possesses greater potency than the natural hormone. Leuprorelin acetate is a
peptide and therefore unrelated to the steroids. Chronic administration results in an inhibition of gonadotrophin
production and subsequent suppression of ovarian and testicular steroid secretion. This effect is reversible on
discontinuation of therapy.
Administration of leuprorelin acetate results in an initial increase in circulating levels of gonadotrophins which leads to
a transient increase in gonadal steroid levels in both men and women. Continued administration of leuprorelin acetate
results in a decrease of gonadotrophin and sex steroid levels. In men serum testosterone levels, initially raised in
response to early luteinising hormone (LH) release, fall to castrate levels in about 2-4 weeks.
Leuprorelin acetate is inactive when given orally.
A randomised, open-label, comparative multi-centre study was performed to compare the efficacy and safety of the
3.75 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 pre-pubertal range.
Initial gonadal stimulation (flare-up) may cause vaginal bleeding in girls who are already post-menarchal at start of
treatment. Withdrawal bleeding may occur at the start of treatment. The bleeding normally stops as treatment
continues.
The following therapeutic effects can be demonstrated:
- Suppression of basal and stimulated gonadotropin levels to pre-pubertal levels;
- Suppression of prematurely increased sexual hormone levels to pre-pubertal levels and arrest of premature
menstruation;
- Arrest/involution of somatic pubertal development (Tanner stages);
- Improvement/normalisation of the ratio of chronological age to bone age;
- Prevention of progressive bone age acceleration;
- Decrease of growth velocity and its normalization;
- Increase in final height.
Treatment result is the suppression of the pathologically, prematurely activated hypothalamic-pituitary-gonadal axis
according to pre-pubertal age.
In a long-term clinical trial in children treated with leuprorelin at doses up to 15mg monthly for > 4 years resumption of
pubertal progression were observed after cessation of treatment. Follow up of 20 female subjects to adulthood
showed normal menstrual cycles in 80% and 12 pregnancies in 7 of the 20 subjects including multiple pregnancies for
4 subjects.

pulmonary
embolism,
hypertension,
hypotension
(see Section 4.4)

nausea

arthralgia,
muscle
weakness

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

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

hepatic function
abnormal, jaundice

myalgia

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

emotional
lability
headache

Figure 1: Leuprorelin serum levels during the first six months of treatment with the leuprorelin acetate 3-month depot
formulation (two s.c. injections) (n=42-43)
5.3 Preclinical safety data
Animal studies have shown that leuprorelin acetate has a high acute safety factor. No major overt toxicological
problems have been seen during repeated administration. 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. No evidence of mutagenicity or teratogenicity has been shown. Animal reproductive studies showed
increased foetal mortality and decreased foetal weights reflecting the pharmacological effects of this LHRH agonist.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
The other ingredients are:
Powder- poly lactic acid, mannitol
Sterile solvent- carboxymethylcellulose sodium, mannitol, polysorbate 80, glacial acetic acid (for pH adjustment) and
water for injections.

pyrexia, fatigue

6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years unopened.
Once reconstituted with sterile solvent, the suspension should be administered immediately.
6.4 Special precautions for storage
Do not store above 25o C.
Do not refrigerate or freeze.
Store in the original container in order to protect from light.

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.
SOC
Very common
Common
Uncommon
Rare
Very Rare
Not known
Immune
hypersensitivity
system
reactions
disorders
(fever, rash,
e.g. itching,
anaphylactic
reactions)
Psychiatric
disorders
Nervous
system
disorders

Gastrointes
tinal
disorders

5.2 Pharmacokinetic properties
Leuprorelin acetate is well absorbed after subcutaneous and intramuscular injections. It binds to the LHRH receptors
and is rapidly degraded. An initially high plasma level of leuprorelin acetate peaks at around 3 hours after a
PROSTAP 3 subcutaneous injection, followed by a decrease to maintenance levels in 7 to 14 days. PROSTAP 3
provides continuous plasma levels for up to 117 days resulting in suppression of testosterone to below castration
level within 4 weeks of the first injection in the majority of patients.
The metabolism, distribution and excretion of leuprorelin acetate in humans have not been fully determined.
In children:
Figure 1 presents the leuprorelin serum levels in children during the first 6 months of treatment following s.c.
administration of Leuprorelin acetate 3-month depot (two injections).
From the first injection, the leuprorelin serum levels increase reaching maximal serum levels at month 4 (294.79 pg/ml
± 105.42) and slightly decrease until month 6 (229.02 pg/ml ± 103.33).

visual
impairement
palpitations
hot flush

pituitary
adenoma

6.5 Nature and contents of container
One dual chamber pre-filled syringe with a needle and needle cap containing a white powder in the front chamber and
1 ml of sterile solvent (clear liquid) in the rear chamber, with a red end stopper.
The pack also contains 1 x syringe plunger and 1 x alcohol swab.
6.6 Special precautions for disposal and other handling
Any unused product or waste material should be disposed of in accordance with local requirements.
7. PRODUCT LICENCE HOLDER
Procured from within EU by Product Licence holder: Star Pharmaceuticals Ltd., 5 Sandridge Close, Harrow,
Middlesex, HA1 1XD. Repackaged by Servipharm Ltd.

pituitary
haemorrhage
followinginitial
administration
in patients with

seizure
8. PRODUCT LICENCE NUMBER(S): PL 20636/2583
Leaflet revision and issue date (Ref): 08.03.16[H-7]

2583
08.03.16[7]

LUCRIN® 3 DCS 11.25 mg Powder and
Solvent for Prolonged-release
Suspension for Injection in Pre-filled
Syringe
(leuprorelin acetate)
PATIENT INFORMATION LEAFLET
Read all of this leaflet carefully before you start using this medicine
because it contains important information for you.
- Keep this leaflet. You may need to read it again.
- If you have any further questions, ask your doctor or pharmacist.
- This medicine has been prescribed for you. Do not pass it on to others. It
may harm them, even if their signs of illness are the same as yours.
- If you get any side effects talk to your doctor or pharmacist. This includes
any possible side effects not listed in this leaflet. See section 4.
Your medicine will be referred to as LUCRIN 3 throughout the following
leaflet.
In this leaflet:
1. What LUCRIN 3 is and what it is used for
2. What you need to know before you use LUCRIN 3
3. How to take LUCRIN 3
4. Possible side effects
5. How to store LUCRIN 3
6. Contents of the pack and other information
1. WHAT LUCRIN 3 IS AND WHAT IT IS USED FOR
LUCRIN 3 is a synthetic hormone which can be used to reduce the levels of
testosterone and estrogen circulating in the body.
LUCRIN 3 is used to treat prostate cancer in men and endometriosis in
women.
Use in children:
Leuprorelin 3 Month Depot is a synthetic hormone which can be used to
reduce the levels of testosterone and estrogen circulating in the body.
Leuprorelin 3 Month Depot is used to treat premature puberty which is
caused by a release of certain hormones from the pituitary gland (central
precocious puberty) in girls under 9 years of age and boys under 10 years of
age.
2. WHAT YOU NEED TO KNOW BEFORE YOU USE LUCRIN 3
Use in children: Your doctor will make a precise diagnosis of central
precocious puberty.
Do not take LUCRIN 3:
- If you are allergic (hypersensitive) to leuprorelin acetate (LUCRIN SR or
LUCRIN 3) or any of the other ingredients of LUCRIN 3 (listed in section
6).
- If you are pregnant, planning to become pregnant or are breastfeeding.
- If you have abnormal vaginal bleeding which you have not discussed with
your doctor.
- In girls with central precocious puberty
- if the girl to be treated is pregnant or breast-feeding.
- if the girl has undiagnosed vaginal bleeding.
Warnings and Precautions:
Both men and women:
- If you are diabetic LUCRIN 3 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 LUCRIN 3. Risk factors include:
- If you or any of your close family have thinning of the bones.
- If you drink excessive amounts of alcohol, and/or smoke heavily.
- If you take drugs for epilepsy or have taken steroids such as
hydrocortisone or prednisolone for a long time.
- There have been reports of depression in patients taking LUCRIN 3 which
may be severe. If you are taking LUCRIN 3 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), LUCRIN 3 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 LUCRIN 3 you should tell your doctor.
- If you are a woman of child-bearing age, you should use non hormonal
contraception whilst receiving LUCRIN 3. Although LUCRIN 3 causes
periods to stop, it is not itself a contraceptive. If you are unsure about this
talk to your doctor.
Men only:
- In the rare event of an abscess occurring at the injection site your doctor
may measure your testosterone levels as there could be reduced
absorption of leuprorelin from the injection site.
- If you are a man with urinary obstruction or spinal cord compression. Your
doctor will supervise you closely for the first few weeks of treatment.
- If you are a man with prostate cancer, and have had injections of a
synthetic hormone in the past that has not worked, or you have had an
operation to remove your testicles you should tell your doctor.
- Please tell your doctor if you have any of the following: Any heart or blood
vessel conditions, including heart rhythm problems (arrhythmia), or are
being treated with medicines for these conditions. The risk of heart rhythm
problems may be increased when using LUCRIN 3.
In children:
- In the event of a sterile abscess at the injection site (mostly reported after
injection into the muscle) your doctor will monitor your hormone levels as
there could be reduced absorption of leuprorelin from the injection site.
- If the child has progressive brain tumour your doctor will decide if
treatment with leuprorelin is appropriate.
In girls with central precocious puberty:
- After the first injection vaginal bleeding (spotting) and discharge may
occur as a sign of hormone withdrawal. Vaginal bleeding beyond the
first/second month of treatment needs to be investigated.
- Bone density may decrease during treatment of central precocious
puberty with Leuprorelin 3 Month Depot. However, after treatment is
stopped, subsequent bone mass growth is preserved and peak bone
mass in late adolescence does not seem to be affected by treatment.
- Often sterile abscesses at the injection site occurred when Leuprorelin 3
Month Depot is administered in higher dosages than recommended and
when it is administered into the muscle. Your doctor will therefore
administer the medicinal product under the skin of e.g. abdomen, bottom
or thigh.

- Discontinuation of treatment may lead to a slipping of the growth plate of
the thigh bone. A possible cause could be a weakness of the growth plate
due to a lower concentration of female sexual hormones during treatment.
Other medicines and LUCRIN 3
Please tell your doctor or pharmacist if you are taking or have recently taken
any other medicines, including medicines obtained without a prescription.
LUCRIN 3 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).
LUCRIN 3 with food and drink
LUCRIN 3 can be taken with or without food.
Pregnancy and breastfeeding
LUCRIN 3 must not be administered in pregnant or breast-feeding women
or girls (see also section “Do not use LUCRIN 3’).
Driving and using machines
Do not drive or operate machinery if you experience drowsiness, dizziness
or visual disturbances whilst being treated with LUCRIN 3.
3. HOW TO TAKE LUCRIN 3
The doctor or nurse will give you an injection of LUCRIN 3. The injection will
normally be given in your arm, thigh or abdomen. The injection site should
be varied at regular intervals.
You will normally be given an injection once every 3 months.
If you have endometriosis you will be given an injection of LUCRIN 3 for a
period of 6 months only and treatment will be initiated during the first five
days of the menstrual cycle.
Use in children
Treatment of children should be under the overall supervision of the
paediatric endocrinologist.
The dosing scheme needs to be adapted individually.
The recommended starting dose is dependent on the body weight:
a) Children with a body weight 20 kg or more
Unless prescribed otherwise, 1 ml LUCRIN 3 (11,25 mg leuprorelin acetate)
is administered every 3 months under the skin of e.g. abdomen, bottom or
thigh as a single injection.
b) Children with a body weight less than 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 LUCRIN 3 (5,625 mg leuprorelin
acetate) are administered every 3 months under the skin of e.g. abdomen,
bottom or thigh as a single injection. The remainder of the suspension
should be discarded. Your doctor will monitor the child’s weight gain.
Depending on the central precocious puberty activity, your doctor may
increase the dosage in the presence of inadequate suppression (e.g.
vaginal bleeding). Your doctor will determine the minimal effective dose with
the help of a blood test.
The duration of treatment depends on the clinical signs at the start of
treatment or during the course of treatment and is decided by your doctor
together with the legal guardian and, if appropriate, the treated child. Your
doctor will determine the bone age of the child in regular intervals.
In girls with bone maturation of older than 12 years and boys with bone
maturation of older than 13 years your doctor will consider discontinuing the
treatment, depending on the clinical effects in your child. In girls, pregnancy
should be excluded before the start of treatment. The occurrence of
pregnancy during treatment cannot be generally excluded. In such cases,
please talk to your doctor.
The therapy is a long-term treatment, adjusted individually. Please arrange
with your doctor that LUCRIN 3 is administered as precisely as possible in
regular 3-monthly periods. An exceptional delay of the injection date for a
few days (90 ± 2 days) does not influence the result of the therapy.
If you miss an injection
If you miss an injection
As soon as you realise you have missed an injection, contact your doctor
who will be able to give you your next injection.
Women only:
If a LUCRIN 3 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 LUCRIN 3 and contact your doctor immediately.
4. POSSIBLE SIDE EFFECTS
Like all medicines, LUCRIN 3 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 LUCRIN 3. 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 LUCRIN 3, 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 LUCRIN 3
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 LUCRIN 3, 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 longterm use), headache, nausea, abnormalities in liver function or liver blood
tests, joint pain, swelling of the breast tissue or swelling in your ankles.
Uncommon (may affect more than 1 in 100 people)
Mood changes (with short-term use), dizziness, tingling in the hands or feet,
diarrhoea, vomiting, muscle ache or weakness in the legs.
Not known (frequency cannot be estimated from the available data)
Blood tests may show anaemia (low red cell counts), low counts in white
cells or platelets, allergic reactions (may include symptoms of rash, itching,
wheals or a serious allergic reaction which causes difficulty breathing or
dizziness), changes in blood lipids (cholesterol) or blood sugar, paralysis,
seizure, altered vision, pounding heartbeats, changes in ECG (QT
prolongation), blood clots in lungs, high or low blood pressure, jaundice,
fracture of the spine, thinning of bone, difficulty passing urine, fever or chills.
Women:
- Many of the side effects of LUCRIN 3 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, LUCRIN 3 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 LUCRIN 3, 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 LUCRIN 3
Keep out of the sight and reach of children
Do not store above 25oC.
Do not refrigerate or freeze.
Store in the original container in order to protect from light.
Do not use this medicine after the expiry date stated on the packaging.
The expiry date refers to the last day of that month.
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.
Medicines should not be disposed of via wastewater or household waste.
Ask your pharmacist how to dispose of medicines no longer required. These
measures will help to protect the environment.

6. CONTENTS OF THE PACK AND OTHER INFORMATION
What LUCRIN 3 contains:
The active ingredient in LUCRIN 3 Powder is leuprorelin acetate
(11.25 mg)
Leuprorelin acetate 11.25 mg equivalent to 10.72 mg leuprorelin base.
When reconstituted with the solvent, the solution contains 11.25 mg/ml of
leuprorelin acetate.
The other ingredients are:
Powder- polylactic acid, mannitol
Sterile solvent- carboxymethylcellulose sodium, mannitol, polysorbate 80,
glacial acetic acid (for pH adjustment) and water for injections.
What LUCRIN 3 looks like and contents of the pack:
One dual chamber pre-filled syringe with a needle and needle cap
containing a white powder in the front chamber and 1 ml of sterile solvent
(clear liquid) in the rear chamber, with a red end stopper.
The pack also contains 1 x syringe plunger and 1 x alcohol swab.
MANUFACTURER AND PRODUCT LICENCE HOLDER
Manufactured by
Abbott Laboratories S.A., Apartado De Correos, 967, Avenida De Burgos,
91, Madrid, E-28050, Spain.
AbbVie Logistics B.V., Meeuwenlaan 4, 8011 BZ Zwolle, The Netherlands.
Procured from within EU by Product Licence holder: Star Pharmaceuticals
Ltd., 5 Sandridge Close, Harrow, Middlesex, HA1 1XD. Repackaged by
Servipharm Ltd.
POM

PL 20636/2583

Leaflet revision and issue date (Ref): 08.03.16[7]
LUCRIN is a trademark of AbbVie AG.

2583
08.03.16[H-7]

HEALTH PROFESSIONALS’ USER LEAFLET
®

LUCRIN 3 DCS 11.25 mg Powder and Solvent for Prolonged-release Suspension for Injection in Pre-filled
Syringe
(leuprorelin acetate)
1. NAME OF THE MEDICINAL PRODUCT
LUCRIN 3 DCS 11.25 mg Powder and Solvent for Prolonged-release Suspension for Injection in Pre-filled Syringe
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
LUCRIN 3 Powder: contains 11.25 mg leuprorelin acetate (equivalent to 10.72 mg base).
Sterile Solvent: Each ml contains carboxymethylcellulose sodium 5 mg, mannitol 50 mg, polysorbate 80 1 mg in
Water for Injections.
When reconstituted with Sterile Solvent, the suspension contains 11.25 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.
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 11.25 mg presented as a three month depot injection and
administered as a single subcutaneous injection at intervals of three months. The majority of patients will respond to
this dosage. LUCRIN 3 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 LUCRIN 3 therapy should be monitored by clinical parameters and by measuring prostate-specific
antigen (PSA) serum levels. 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 4 th 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 11.25 mg administered as a single intramuscular injection every 3 months
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 LUCRIN 3 taking into account the risks and
benefits of each treatment.
Elderly: As for adults.
Paediatric population
The treatment of children with leuprorelin acetate should be under the overall supervision of the paediatric
endocrinologist.
The dosing scheme needs to be adapted individually.
The recommended starting dose is dependent on the body weight.
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 (5.625 mg leuprorelin acetate) suspension of 130.0 mg sustained-release microcapsules in 1 ml vehicle
solution are administered every 3 months 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 dosag e in the
presence of inadequate suppression (clinical evidence e.g. spotting or inadequate gonadotropin suppression in the
LHRH test). The minimal effective monthly dose to be administered should then be determined by means of the
LHRH test.
Sterile abscesses at the injection site often occurred when leuprorelin acetate was administered intramuscularly at
higher than the recommended dosages. Therefore, in such cases, the medicinal product should be administered
subcutaneously (see 4.4).
It is recommended to use the lowest volumes possible for injections in children in order to decrease the
inconvenience which is associated with the intramuscular/subcutaneous injection.
The duration of treatment depends on the clinical parameters at the start of treatment or during the course of
treatment (final height prognosis, growth velocity, bone age and/or bone age acceleration) and is decided by the
treating paediatrician together with the legal guardian and, if appropriate, the treated child. The bone age should be
monitored during treatment at 6-12 month intervals.
In girls with bone maturation of older than 12 years and boys with bone maturation of older than 13 years
discontinuation of treatment should be considered taking into account the clinical parameters.
In girls, pregnancy should be excluded before the start of treatment. The occurrence of pregnancy during treatment
cannot be generally excluded. In such cases, medical advice should be sought.
Note:
The administration interval should be 30 ± 2 days in order to prevent the recurrence of precocious puberty symptoms.
Administration
INSTRUCTIONS ON HOW TO MIX AND ADMINISTER

4.3 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: LUCRIN 3 is contra-indicated in women who are or may become pregnant while receiving the drug. LUCRIN
3 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 LUCRIN 3 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 LUCRIN 3.
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 LUCRIN 3.
Women: During the early phase of endometriosis therapy, sex steroids temporarily rise above baseline because of
the physiological effect of the drug. Therefore, a worsening of clinical signs and symptoms may be observed during
the initial days of therapy, but these will dissipate with continued therapy.
When 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 (see ‘Posology and
Method of Administration’ section 4.2 for further information).
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 LUCRIN 3 is 5%. In clinical studies with LUCRIN 3 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, LUCRIN 3 therapy may pose an additional risk. In
these patients, the risks and benefits must be weighed carefully before therapy with LUCRIN 3 is instituted.
In women with submucous fibroids there have been reports of severe bleeding following administration of LUCRIN 3
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.
LUCRIN 3 may cause an increase in uterine cervical resistance, which may result in difficulty in dil ating the cervix for
intrauterine surgical procedures.
Precautions
Men: Patients with urinary obstruction and patients with metastatic vertebral lesions should begin LUCRIN 3 therapy
under close supervision for the first few weeks of treatment.
Women: Since menstruation should stop with effective doses of LUCRIN 3, 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. LUCRIN 3 should be administered as precisely as
possible in regular 3-monthly periods.
An exceptional delay of the injection date for a few days (90 ± 2 days) does not influence the 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 LUCRIN 3 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 LUCRIN 3,
pregnancy must be excluded. There have been reports of foetal malformation when LUCRIN 3 has been given during
pregnancy.
LUCRIN 3 should not be used in women who are breastfeeding.
When used 3-monthly at the recommended dose, LUCRIN 3 usually inhibits ovulation and stops menstruation.
Contraception is not ensured, however, by taking LUCRIN 3 and therefore patients should use non-hormonal
methods of contraception during treatment.
Patients should be advised that if they miss successive doses of LUCRIN 3, 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
LUCRIN 3 can influence the ability to drive and use machines due to visual disturbances and dizziness.

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
tghe diluents by SLOWING PISHING the
plunger until the middle stopper is at
blue line in the middle of the barrel.
NOTE: Pushing the plunger rod quickly
or over the blue line will cause leakage
of the suspension from the needle.

4. Gently tap
the syringe on
the palm
keeping the
syringe upright
to thoroughly
mix the
particles to
from a unique
suspension.
The suspension
will appear
milky.

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

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

4.8 Undesirable effects
Adverse reactions seen with LUCRIN 3 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 tri als 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 LUCRIN 3 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
Blood and
lymphatic
system
disorders

Psychiatric
disorders

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

Rare

Very Rare

Nervous
system
disorders

weight
fluctuation

decreased
appetite

Insomnia,
depression
(see Section
4.4),mood
changes (lingterm use)**
headache
(occasionaly
severe)

Not known
anaemia
(reported in
medicinal
products of this
class),
thrombocytopaeni
a,
leucopenia
hypersensitivity
reactions
(including rash,
pruritus,
urticaria and
rarely, wheezing
or interstitial
pneumonitis,
anaphylactic
reactions)
Lipids abnormal,
glucose
tolerance
abnormal

Immune
system
disorders

Metabolism
and nutrition
disorders
6. At the time of injection, check the direction as illustrated, and
inject the entire contents of the syringe subcutaneously or
intramuscularly as you would for the normal injection

Uncommon

Mood
changes
(short-term
use)**

dizziness,
parasthesiae

pituitary
apoplexy
has been
reported
following
initial
administration
in patients
with

paralysis (see
Section 4.4),
seizure

pituitary
adenoma
Eye
disorders

visual impairment

Cardiac
disorders

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

Vascular
disorders

hot flush

Gastrointesti
nal disorders

nausea

Hepatobiliary
disorders

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

Skin and
subcutaneou
s disorders
Musculoskel
etal,
connective
tissue and
bone
disorders
Renal and
urinary
disorders
Reproductiv
e system and
breast
disorders

General
disorders
and
administratio
n site
conditions

diarrhoea,
vomiting
jaundice

hyperhydrosis

muscle
weakness,
bone pain

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

arthralgia

myalgia,
weakness of
lower
extremities

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

oedema
peripheral

weight
fluctuation

Nervous
system
disorders

headache
(occasionaly
severe)

Eye
disorders
Cardiac
disorders
Vascular
disorders

Gastrointes
tinal
disorders
Hepatobiliar
y disorders

Skin and
subcutaneo
us
disorders
Musculoske
letal,
connective
tissue and
bone
disorders
Reproductiv
e system
and breast
disorders

General
disorders
and
administrati
on site
conditions

hypersensitivity
reactions
(including rash,
pruritus, urticaria
and rarely,
wheezing
or interstitial
pneumonitis,
anaphylactic
reactions)
glucose
tolerance
abnormal, which
may affect diabetic
control

decreased
appetite, lipids
abnormal

mood altered
depression
(see Section
4.4)
parasthesiae,
dizziness

pituitary
haemorrha
ge
has been
reported
following
initial
administrati
on
in patients
with
pituitary
adenoma

paralysis (see
Section
4.4),seizure

visual
impairment
palpitations
hot flush

pulmonary
embolism,
hypertension,
hypotension
(see Section 4.4)

nausea

Skin and
subcutaneo
us
disorders
Reproductiv
e system
and breast
disorders

vaginal
haemorrha
ge,
spotting**,
vaginal
discharge
injection
site
reactions

General
disorders
and
administrati
on site
conditions
** 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.

arthralgia,
muscle
weakness

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

emotional
lability

5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Gonadotrophin-Releasing Hormone Analogues
ATC code: L02AE 02
LUCRIN 3 contains leuprorelin acetate, a synthetic nonapeptide analogue of naturally occurring gonadotrophin
releasing hormone (GnRH) which possesses greater potency than the natural hormone. Leuprorelin acetate is a
peptide and therefore unrelated to the steroids. Chronic administration results in an inhibition of gonadotrophin
production and subsequent suppression of ovarian and testicular steroid secretion. This effect is reversible on
discontinuation of therapy.
Administration of leuprorelin acetate results in an initial increase in circulating levels of gonadotrophins which leads to
a transient increase in gonadal steroid levels in both men and women. Continued administration of leuprorelin acetate
results in a decrease of gonadotrophin and sex steroid levels. In men serum testosterone levels, initially raised in
response to early luteinising hormone (LH) release, fall to castrate levels in about 2-4 weeks.
Leuprorelin acetate is inactive when given orally.
A randomised, open-label, comparative multi-centre study was performed to compare the efficacy and safety of the
3.75 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 pre-pubertal range.
Initial gonadal stimulation (flare-up) may cause vaginal bleeding in girls who are already post-menarchal at start of
treatment. Withdrawal bleeding may occur at the start of treatment. The bleeding normally stops as treatment
continues.
The following therapeutic effects can be demonstrated:
- Suppression of basal and stimulated gonadotropin levels to pre-pubertal levels;
- Suppression of prematurely increased sexual hormone levels to pre-pubertal levels and arrest of premature
menstruation;
- Arrest/involution of somatic pubertal development (Tanner stages);
- Improvement/normalisation of the ratio of chronological age to bone age;
- Prevention of progressive bone age acceleration;
- Decrease of growth velocity and its normalization;
- Increase in final height.
Treatment result is the suppression of the pathologically, prematurely activated hypothalamic-pituitary-gonadal axis
according to pre-pubertal age.
In a long-term clinical trial in children treated with leuprorelin at doses up to 15mg monthly for > 4 years resumption of
pubertal progression were observed after cessation of treatment. Follow up of 20 female subjects to adulthood
showed normal menstrual cycles in 80% and 12 pregnancies in 7 of the 20 subjects including multiple pregnancies for
4 subjects.
5.2 Pharmacokinetic properties
Leuprorelin acetate is well absorbed after subcutaneous and intramuscular injections. It binds to the LHRH receptors
and is rapidly degraded. An initially high plasma level of leuprorelin acetate peaks at around 3 hours after a LUCRIN 3
subcutaneous injection, followed by a decrease to maintenance levels in 7 to 14 days. LUCRIN 3 provides continuous
plasma levels for up to 117 days resulting in suppression of testosterone to below castration level within 4 weeks of
the first injection in the majority of patients.
The metabolism, distribution and excretion of leuprorelin acetate in humans have not been fully determined.
In children:
Figure 1 presents the leuprorelin serum levels in children during the first 6 months of treatment following s.c.
administration of Leuprorelin acetate 3-month depot (two injections).
From the first injection, the leuprorelin serum levels increase reaching maximal serum levels at month 4 ( 294.79 pg/ml
± 105.42) and slightly decrease until month 6 (229.02 pg/ml ± 103.33).

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

hepatic function
abnormal, jaundice

myalgia

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

pyrexia, fatigue

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.
SOC
Very common
Common
Uncommon
Rare
Very Rare
Not known
Immune
Hypersensitivit
system
y reactions
disorders
(fever, rash,
e.g. itching,
anaphylactic
reactions)
Psychiatric
disorders

abdominal
pain /
abdominal
cramps,
nausea/vo
miting
acne

seizure

pyrexia

Immune
system
disorders

insomnia

Gastrointes
tinal
disorders

pituitary
haemorrhage
following initial
administration
in patients with
pituitary
adenoma

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.

Women: Those adverse events occurring most frequently with LUCRIN 3 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).
Breast tenderness or change in breast size may occur occasionally. Hair loss has also been reported occasionally.
Vaginal haemorrhage may occur during therapy due to acute degeneration of submucous fibroids (see Section 4.4).
Tabulated list of adverse reactions
SOC
Very common
Common
Uncommon
Rare
Very Rare
Not known
Blood and
anaemia (reported
lymphatic
in medicinal
system
products of this
disorders
class),
thrombocytopaenia
, leucopenia

Psychiatric
disorders

headache

gynaecomastia

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

Metabolism
and
nutrition
disorders

Nervous
system
disorders

Figure 1: Leuprorelin serum levels during the first six months of treatment with the leuprorelin acetate 3-month depot
formulation (two s.c. injections) (n=42-43)
5.3 Preclinical safety data
Animal studies have shown that leuprorelin acetate has a high acute safety factor. No major overt toxicological
problems have been seen during repeated administration. 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. No evidence of mutagenicity or teratogenicity has been shown. Animal reproductive studies showed
increased foetal mortality and decreased foetal weights reflecting the pharmacological effects of this LHRH agonist.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
The other ingredients are:
Powder- poly lactic acid, mannitol
Sterile solvent- carboxymethylcellulose sodium, mannitol, polysorbate 80, glacial acetic acid (for pH adjustment) and
water for injections.
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years unopened.
Once reconstituted with sterile solvent, the suspension should be administered immediately.
6.4 Special precautions for storage
Do not store above 25o C.
Do not refrigerate or freeze.
Store in the original container in order to protect from light.
6.5 Nature and contents of container
One dual chamber pre-filled syringe with a needle and needle cap containing a white powder in the front chamber and
1 ml of sterile solvent (clear liquid) in the rear chamber, with a red end stopper.
The pack also contains 1 x syringe plunger and 1 x alcohol swab.
6.6 Special precautions for disposal and other handling
Any unused product or waste material should be disposed of in accordance with local requirements.
7. PRODUCT LICENCE HOLDER
Procured from within EU by Product Licence holder: Star Pharmaceuticals Ltd., 5 Sandridge Close, Harrow,
Middlesex, HA1 1XD. Repackaged by Servipharm Ltd.
8. PRODUCT LICENCE NUMBER(S): PL 20636/2583
Leaflet revision and issue date (Ref): 08.03.16[H-7]

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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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