SUMMARY OF PRODUCT CHARACTERISTICS

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 carmellose sodium 5 mg, mannitol (E421) 50 mg, polysorbate 80 1 mg, acetic acid, glacial up to 0.05 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 4th week of treatment.

In patients treated with GnRH analogues for prostate cancer, treatment is usually continued upon development of castrate-resistant prostate cancer. Reference should be made to relevant guidelines.

Endometriosis: The recommended dose is 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 minimaleffective 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 recurrence of precocious puberty symptoms.

Method of Administration

The pre-filled syringe of PROSTAP 3 microsphere powder should be reconstituted immediately prior to administration by subcutaneous or intramuscular injection.

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

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

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.

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.

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

At the time of injection, check the direction of the safety device (with round mark face up) 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

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

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

4.3 Contraindications

Hypersensitivity to the active substance, any of the excipients 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 preexisting 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 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.

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	Uncommon	Rare	Very rare	Not known
Blood and lymphatic system disorders						anaemia (reported in medicinal products of this class), thrombocytopaenia, leucopenia
Immune system disorders						hypersensitivity reactions (including rash, pruritus, urticaria and rarely, wheezing or interstitial pneumonitis, anaphylactic reactions)
Metabolism and nutrition disorders	weight fluctuation	decreased appetite				Lipids abnormal, glucose tolerance abnormal
Psychiatric disorders		insomnia, depression (see Section 4.4), mood changes (long-term use)**	mood changes (short term use)**
Nervous system disorders		headache (occasionaly severe)	dizziness, parasthesiae		pituitary apoplexy has been reported following initial administration in patients with pituitary adenoma	paralysis (see Section 4.4), seizure
Eye disorders						visual impairment
Cardiac disorders						palpitations, electrocardiogram QT prolonged (see Sections 4.4 and 4.5)
Vascular disorders	hot flush					pulmonary embolism, hypertension, hypotension (see Section 4.4)
Gastrointestinal disorders		nausea	diarrhoea, vomiting
Hepatobiliary disorders		hepatic function abnormal, liver function test abnormal (usually transient)				jaundice
Skin and subcutaneous tissue disorders	hyperhydrosis

Musculoskeletal, connective tissue and bone disorders	muscle weakness, bone pain	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
Renal and urinary disorders						urinary tract obstruction
Reproductive system and breast disorders	Libido decreased, erectile dysfunction, testicular atrophy	gynaecomastia
General disorders and administration site conditions	Fatigue, injection site reaction, e.g., induration, erythema, pain, abscesses, swelling, nodules, ulcers and necrosis	oedema peripheral				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).

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

Immune system disorders						hypersensitivity reactions (including rash, pruritus, urticaria and rarely, wheezing and interstitial pneumonitis, anaphylactic reactions)
Metabolism and nutrition disorders		weight fluctuation	decreased appetite, lipids abnormal			glucose tolerance abnormal, which may affect diabetic control
Psychiatric disorders	insomnia	mood altered depression (see Section 4.4)
Nervous system disorders	headache (occasionally severe)	parasthesiae, dizziness			pituitary haemorrhage has been reported following initial administration in patients with pituitary adenoma	paralysis (see Section 4.4), seizure
Eye disorders			visual impairment
Cardiac disorders			palpitations
Vascular disorders	hot flush					pulmonary embolism, hypertension, hypotension (see Section 4.4)
Gastrointestinal disorders		nausea	diarrhoea, vomiting
Hepatobiliary disorders			liver function test abnormal (usually transient)			hepatic function abnormal, jaundice
Skin and subcutaneous tissue disorders			hair loss
Musculoskeletal, connective tissue and bone disorders		arthralgia, muscle weakness	myalgia			spinal fracture (see section 4.4), reduction in bone mass which may occur with the use of GnRH agonists
Reproductive system and breast disorders		breast tenderness, breast atrophy, vulvovaginal dryness				vaginal haemorrhage
General disorders and administration site conditions		Oedema peripheral, injection site reaction e.g.injection site induration, erythema,	pyrexia, fatigue

pain, abscesses, swelling, nodules, ulcers and necrosis

In Children:

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

Tabulated list of adverse reactions

SOC	Very common	Common	Uncommon	Rare	Very rare	Not known
Immune system disorders					Hypersensitivity (fever, rash, e.g. itching, anaphylactic reactions)
Psychiatric disorders		emotional lability
Nervous system disorders		headache			pituitary haemorrhage following initial administration in patients with pituitary adenoma	seizure
Gastrointestinal disorders		abdominal pain / abdominal cramps, nausea/vomiting
Skin and subcutaneous tissue disorders		acne
Reproductive system and breast disorders		vaginal haemorrhage, spotting1, vaginal discharge
General disorders and administration site conditions		injection site reactions

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.

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).

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

PROSTAP 3 Powder Poly (D-L lactic acid)

Mannitol (E421)

Sterile Solvent

Carmellose sodium Mannitol (E421) Polysorbate 80 Acetic acid, glacial 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 25 ^oC.

Do not refrigerate or freeze.

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

6.5 Nature and contents of container

One dual chamber pre-filled syringe containing 11.25 mg leuprorelin acetate powder in the front chamber and 1 ml of Sterile Solvent in the rear chamber.

1 x 23 gauge syringe needle fitted with safety device.

1 x syringe plunger

Special precautions for disposal and other handling

Always ensure the safety device to prevent needle-stick injury is deployed after injection. Any unused product or waste material should be disposed of in accordance with local requirements.

7    MARKETING AUTHORISATION HOLDER

Takeda UK Limited Building 3,

Glory Park,

Glory Park Avenue,

Wooburn Green,

BUCKS,

HP10 0DF

8    MARKETING AUTHORISATION NUMBER(S)

PL 16189/0013

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

28/04/2011

10    DATE OF REVISION OF THE TEXT

16/03/2016

1

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.