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PROSTAP 3 DCS 11.25 MG POWDER AND SOLVENT FOR PROLONGED-RELEASE SUSPENSION FOR INJECTION IN PRE-FILL

Active substance: LEUPRORELIN ACETATE

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2583
12.12.14[5]

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.
The safety and efficacy of PROSTAP 3 in children has not yet been
established.
2. WHAT YOU NEED TO KNOW BEFORE YOU USE PROSTAP 3
PROSTAP 3 is not recommended for use in children under the age of 18
years.
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.
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.
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 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.

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.
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
You should not take PROSTAP 3 if you are pregnant, planning to become
pregnant or are breastfeeding.
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.
If you miss an injection
As soon as you realise you have missed an injection, contact your doctor
who will be able to give you your next injection.
Women only:
If a PROSTAP 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.
4. POSSIBLE SIDE EFFECTS
Like all medicines, PROSTAP 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 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:
Both men and women:
- PROSTAP 3 can sometimes cause swelling in your ankles, tiredness,
nausea or headaches. The treatment may cause pain in the joints,
anaemia, fever or chills, dizziness, vomiting, loss of appetite, diarrhoea,
pounding heartbeats, tingling in the hands or feet, muscle aching or
weakness, mood changes, depression, altered vision, changes in weight,
jaundice, abnormalities in liver function, thinning of bones, increase in
blood pressure, difficulty sleeping, blood clots in the lungs, spinal
fracture, paralysis or low blood pressure. Skin reactions at the injection
site have been reported rarely following injection of leuprorelin. These
include: skin hardening, redness, pain, abscesses, swelling, nodules,
ulcers and skin damage.

- 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 an existing pituitary lesion, there may be an increased risk of
loss of blood to the area, which may cause permanent damage.
- 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.
Men only:
- 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.
- PROSTAP 3 can cause a loss of interest in sexual intercourse, hot
flushes and occasionally it may cause a reduction in size and function of
the testes or swelling of the breasts.
- Frequency unknown: changes in ECG (QT prolongation).
Women only:
- In women PROSTAP 3 may cause hot flushes and vaginal dryness. It
may cause a change in breast size or breast tenderness and can
occasionally cause hair loss. As can happen naturally when women
reach the menopause, PROSTAP 3 can cause a small amount of bone
thinning.
Additional Effects in Children:
- In children PROSTAP 3 may cause abdominal pain/abdominal cramps,
acne, vaginal bleeding, spotting, discharge or injection site reactions.
Very rarely general allergic reactions (fever, rash, itching or a serious
allergic reaction which causes difficulty in breathing or dizziness) may
occur.
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
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.
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): 12.12.14[5]
Prostap is a trademark of Takeda Pharmaceutical Company Limited.

2583
12.12.14[H-5]

HEALTH PROFESSIONALS’ USER LEAFLET

4.

®

Prostap 3 DCS 11.25 mg Powder and Solvent for Prolonged-release
Suspension for Injection in Pre-filled Syringe

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

(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.
(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.

5.

6.

At the time of injection, check the direction as illustrated,
and inject the entire contents of the syringe. Inject the entire
contents of the syringe subcutaneously or intramuscularly
as you would for a normal injection.

7.

Withdraw the needle from the patient.

Response to PROSTAP 3 therapy should be monitored by clinical parameters and by measuring prostatespecific 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 4th week of treatment.
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.

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

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.

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

Elderly: As for adults.

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.

Paediatric population
The safety and efficacy of PROSTAP 3 in children has not yet been established.
Administration
INSTRUCTIONS ON HOW TO MIX AND ADMINISTER

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.

1.

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

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.

2.

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

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.

3.

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

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.
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.
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.

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.
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.

4.8 Undesirable effects
Side effects seen with PROSTAP 3 are due mainly to the specific pharmacological action, namely increases
and decreases in certain hormone levels.
Adverse events which have been reported infrequently include peripheral oedema, pulmonary embolism,
hypertension, palpitations, fatigue, muscle weakness, diarrhoea, nausea, vomiting, anorexia, fever/chills,
headache (occasionally severe), hot flushes, arthralgia, myalgia, dizziness, insomnia, mood changes,
depression, paraesthesia, visual disturbances, weight changes, hepatic dysfunction, jaundice, and increases
in liver function test values (usually transient).
Reactions at the injection site e.g. induration, erythema, pain, abscesses, swelling, nodules, ulcers and
necrosis have been rarely reported. Changes in blood lipids and alteration of glucose tolerance have also
been reported which may affect diabetic control. Thrombocytopenia and leucopenia have been reported rarely.
Anaemia has been reported in patients receiving GnRH analogues. Hypersensitivity reactions including rash,
pruritus, urticaria, and rarely, wheezing or interstitial pneumonitis have also been reported. Anaphylactic
reactions are rare.
Spinal fracture, paralysis, hypotension and worsening of depression have been reported (see Section 4.4).

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 and water for injections.
6.2 Incompatibilities
Not applicable.

A reduction in bone mass may occur with the use of GnRH agonists.
Very rare cases of pituitary apoplexy have been reported following initial administration in patients with
pituitary adenoma.
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.
Impotence and decreased libido will be expected with PROSTAP 3 therapy.
The administration of PROSTAP 3 is often associated with hot flushes and sometimes sweating.

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

Orchiatrophy and gynaecomastia have been reported occasionally.

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.

Frequency unknown: QT prolongation (see sections 4.4 and 4.5)

The pack also contains 1 x syringe plunger and 1 x alcohol swab.

Women: Those adverse events occurring most frequently with PROSTAP 3 are associated with hypoestrogenism; the most frequently reported are hot flushes, mood swings including depression (occasionally
severe), and vaginal dryness. Estrogen levels return to normal after treatment is discontinued.

6.6 Special precautions for disposal and other handling
Any unused product or waste material should be disposed of in accordance with local requirements.

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).
In Children: Commonly reported adverse events are emotional lability, headache, abdominal pain/abdominal
cramps, nausea/vomiting, acne, vaginal bleeding, spotting, discharge and injection site reactions. General
allergic reactions (fever, rash, e.g. itching, anaphylactic reactions) are very rare. As with other medicinal
products of this class, very rare cases of pituitary apoplexy have been reported following initial administration
in patients with pituitary adenoma.
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.

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): 12.12.14[H-5]

2583
12.12.14[5]

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.
The safety and efficacy of LUCRIN 3 in children has not yet been
established.
2. WHAT YOU NEED TO KNOW BEFORE YOU USE LUCRIN 3
LUCRIN 3 is not recommended for use in children under the age of 18
years.
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.
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.
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
You should not take LUCRIN 3 if you are pregnant, planning to become
pregnant or are breastfeeding.
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.
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:
Both men and women:
- LUCRIN 3 can sometimes cause swelling in your ankles, tiredness,
nausea or headaches. The treatment may cause pain in the joints,
anaemia, fever or chills, dizziness, vomiting, loss of appetite, diarrhoea,
pounding heartbeats, tingling in the hands or feet, muscle aching or
weakness, mood changes, depression, altered vision, changes in weight,
jaundice, abnormalities in liver function, thinning of bones, increase in
blood pressure, difficulty sleeping, blood clots in the lungs, spinal
fracture, paralysis or low blood pressure. Skin reactions at the injection
site have been reported rarely following injection of leuprorelin. These
include: skin hardening, redness, pain, abscesses, swelling, nodules,
ulcers and skin damage.

- 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 an existing pituitary lesion, there may be an increased risk of
loss of blood to the area, which may cause permanent damage.
- 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.
Men only:
- 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.
- LUCRIN 3 can cause a loss of interest in sexual intercourse, hot flushes
and occasionally it may cause a reduction in size and function of the
testes or swelling of the breasts.
- Frequency unknown: changes in ECG (QT prolongation).
Women only:
- In women LUCRIN 3 may cause hot flushes and vaginal dryness. It may
cause a change in breast size or breast tenderness and can occasionally
cause hair loss. As can happen naturally when women reach the
menopause, LUCRIN 3 can cause a small amount of bone thinning.
Additional Effects in Children:
- In children LUCRIN 3 may cause abdominal pain/abdominal cramps,
acne, vaginal bleeding, spotting, discharge or injection site reactions.
Very rarely general allergic reactions (fever, rash, itching or a serious
allergic reaction which causes difficulty in breathing or dizziness) may
occur.
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
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.
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): 12.12.14[5]
LUCRIN is a trademark of AbbVie AG.

2583
12.12.14[H-5]

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)

4.

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

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.
(See Section 5.1)

5.

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

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 prostatespecific 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 4th week of treatment.
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 safety and efficacy of LUCRIN 3 in children has not yet been established.
Administration
INSTRUCTIONS ON HOW TO MIX AND ADMINISTER
1.

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

6.

At the time of injection, check the direction as illustrated,
and inject the entire contents of the syringe. Inject the entire
contents of the syringe subcutaneously or intramuscularly
as you would for a normal injection.

7.

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.
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.
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.

2.

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

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.

3.

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

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 dilating 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.
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.
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.
4.8 Undesirable effects
Side effects seen with LUCRIN 3 are due mainly to the specific pharmacological action, namely increases and
decreases in certain hormone levels.
Adverse events which have been reported infrequently include peripheral oedema, pulmonary embolism,
hypertension, palpitations, fatigue, muscle weakness, diarrhoea, nausea, vomiting, anorexia, fever/chills,
headache (occasionally severe), hot flushes, arthralgia, myalgia, dizziness, insomnia, mood changes,
depression, paraesthesia, visual disturbances, weight changes, hepatic dysfunction, jaundice, and increases
in liver function test values (usually transient).
Reactions at the injection site e.g. induration, erythema, pain, abscesses, swelling, nodules, ulcers and
necrosis have been rarely reported. Changes in blood lipids and alteration of glucose tolerance have also
been reported which may affect diabetic control. Thrombocytopenia and leucopenia have been reported rarely.
Anaemia has been reported in patients receiving GnRH analogues. Hypersensitivity reactions including rash,
pruritus, urticaria, and rarely, wheezing or interstitial pneumonitis have also been reported. Anaphylactic
reactions are rare.

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
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.
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.
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 and water for injections.

Spinal fracture, paralysis, hypotension and worsening of depression have been reported (see Section 4.4).
A reduction in bone mass may occur with the use of GnRH agonists.
Very rare cases of pituitary apoplexy have been reported following initial administration in patients with
pituitary adenoma.
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.
Impotence and decreased libido will be expected with LUCRIN 3 therapy.
The administration of LUCRIN 3 is often associated with hot flushes and sometimes sweating.
Orchiatrophy and gynaecomastia have been reported occasionally.

6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years unopened.
Once reconstituted with sterile solvent, the suspension should be administered immediately.
6.4 Special precautions for storage
Do not store above 25oC.
Do not refrigerate or freeze.
Store in the original container in order to protect from light.
6.5 Nature and contents of container
One dual chamber pre-filled syringe 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.

Frequency unknown: QT prolongation (see sections 4.4 and 4.5)
The pack also contains 1 x syringe plunger and 1 x alcohol swab.
Women: Those adverse events occurring most frequently with LUCRIN 3 are associated with hypoestrogenism; the most frequently reported are hot flushes, mood swings including depression (occasionally
severe), and vaginal dryness. Estrogen levels return to normal after treatment is discontinued.
The induced hypo-estrogenic state results in a small loss in bone density over the course of treatment, some
of which may not be reversible (see Section 4.4).
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).
In Children: Commonly reported adverse events are emotional lability, headache, abdominal pain/abdominal
cramps, nausea/vomiting, acne, vaginal bleeding, spotting, discharge and injection site reactions. General
allergic reactions (fever, rash, e.g. itching, anaphylactic reactions) are very rare. As with other medicinal
products of this class, very rare cases of pituitary apoplexy have been reported following initial administration
in patients with pituitary adenoma.
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.

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): 12.12.14[H-5]

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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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