Section

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2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Updated/deleted:

Powder: Each single-dose syringe contains 11.25mg leuprorelin acetate.

Solvent: Solvent contains approximately 0.4 mg (<1mmol) sodium (as carmellose sodium). 

3 PHARMACEUTICAL FORM

Solvent: A colourless, odourless, slightly viscous, aqueous sterile solvent.

4.2 Posology and method of administration

Updated:

Male Adults: The usual recommended dose is 11.25mg presented as a 3 month depot injection and administered as a single subcutaneous or intramuscular injection at intervals of 3 months.

…

Response to PROSTAP 3 therapy should be monitored by clinical parameters and by measuring prostate-specific antigen (PSA) and testosterone serum levels. Clinical studies 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 in 2-4 weeks.  Once attained, castrate levels were maintained as long as drug therapy continued.  Transient increases in PSA levels sometimes occur early in the treatment period but usually return to normal or near normal values by the 4th week of treatment.

…

Female Adults:

Treatment options for vasomotor symptoms and bone mineral density loss should be considered.

Endometriosis

The recommended dose is 11.25mg administered as a single subcutaneous or intramuscular injection every 3 months for a period of up to 6 months.  Treatment should be initiated during the first 5 days of the menstrual cycle.

Preoperative management of uterine fibroids

The recommended dose is 11.25mg administered as a single subcutaneous or intramuscular injection every 3 months for a maximum of 6 months.

4.2 Posology and method of administration

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 GnRH test). The minimal effective 3-monthly dose to be administered should then be determined by means of the LHRH GnRH test.

4.3 Contraindications

Hypersensitivity to the leuprorelin, any of the excipients (listed in section 6.1) or to other synthetic gonadotrophin releasing hormone (Gn-RH) analogues or Gn-RH derivatives.

…

In girls with central precocious puberty:

-Pregnancy and breastfeeding

-Undiagnosed vaginal bleeding.

4.4 Special warnings and precautions for use

Added:

PROSTAP 3 injectable suspension must be prepared at the time of use and, after reconstitution, used immediately.

Updated:

Depression: 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 and monitored accordingly and treated as appropriate if symptoms occur.

Seizures: 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.

Added and updated:

Adults:

Epidemiological data have shown that androgen deprivation therapy in males and estrogen deprivation therapy in females, is associated with metabolic changes (e.g. reduction in glucose tolerance or aggravation of pre-existing diabetes) as well as an increased risk for cardiovascular diseases. However, prospective data did not confirm a 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. Diabetic patients may require more frequent monitoring of blood glucose during treatment with PROSTAP 3.

Hepatic dysfunction and jaundice with elevated liver enzyme levels have been reported. Therefore, close observation should be made and appropriate measures taken if necessary.

Spinal fracture, paralysis and hypotension have been reported.

Bone mineral loss: Long-term estrogen deprivation either by bilateral oophorectomy, ovarian ablation or administration of GnRH analogues, or long-term androgen deprivation either by bilateral orchiectomy or administration of GnRH analogues is associated with increased risk of bone mineral loss which, in patients with additional risk factors, may lead to osteoporosis and an increased risk of bone fracture (see section 4.8). 

The induced hypo-estrogenic state results in a clinically significant 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. The level of bone loss seen with GnRH analogues such as PROSTAP 3 is of the order of 5%. In clinical studies the levels varied between 2.3% and 15.7% depending on the method of measurement.

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. This is particularly important in women with uterine fibroids where age related bone loss may have already begun to occur.

Treatment options for vasomotor symptoms and bone mineral density loss should be considered

In the initial stages of therapy, a transient rise in levels of testosterone, dihydro-testosterone 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. This may lead to neurological or systemic effects. For instance, in patients with vertebral metastases, neurological problems such as weakness and/or paraesthesia of the lower limbs may occur. In patients with urinary obstruction or haematuria, worsening of urinary symptoms may occur.  These symptoms usually subside on continuation of therapy.

Patients at risk of or with ureteric obstruction or spinal cord compression due to metastasis should be considered carefully and closely supervised in the first few weeks of treatment as bone pain, weakness of lower extremities and parasthesia (as neurologic symptoms) may occur.

Deleted text (updated and moved to section above):

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.

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.

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 risks and benefits including the potential for Torsade de pointes prior to initiating treatment with PROSTAP 3.

4.4

Added:

Women:  

Before starting treatment with leuprorelin acetate, pregnancy must be excluded (see section 4.3).

Since menstruation should stop with effective doses of PROSTAP 3, the patient should notify her physician if regular menstruation persists. Spotting/breakthrough bleeding may occur with PROSTAP 3 treatment.

During treatment with PROSTAP 3, patients should be instructed to prevent conception e.g. with the use of non-hormonal methods until return of menses.

Abnormal bleeding

Prior to administration of PROSTAP 3 undiagnosed abnormal vaginal bleeding must be investigated, diagnosis confirmed and relevant management initiated. 

Initial increase in sex steroids

During the early phase of therapy, sex steroids temporarily rise above baseline because of the physiological effect of the drug.  Therefore, an increase in clinical signs and symptoms may be observed during the initial days of therapy, but these will dissipate with continued therapy.

Uterine fibroids diagnosis

In the case of uterine fibroids, it is mandatory to confirm the diagnosis of fibroids and exclude ovarian mass, either visually by laparoscopy or by ultrasonography or other investigative techniques as appropriate, before PROSTAP 3 therapy is instituted.

Uterine fibroids

In women receiving GnRH analogues for the treatment of uterine fibroids, the duration of administration of PROSTAP 3 should be limited to 6 months as its use is associated with an increased risk of bone mineral loss (see Bone mineral loss, section 4.4). If it is necessary to resume administration of leuprorelin acetate changes in bone parameters should be closely followed.

In women with submucous fibroids there have been reports of severe vaginal bleeding following administration of leuprorelin 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.

Cervical resistance

PROSTAP 3 may cause an increase in uterine cervical resistance, which may result in difficulty in dilating the cervix for intrauterine surgical procedures.

Endometriosis

In women receiving GnRH analogues for the treatment of endometriosis, the duration of administration of leuprorelin acetate should be limited to 6 months, as its use is associated with an increased risk of bone mineral loss (see Bone mineral loss, section 4.4).  

Children with central precocious puberty:  Before starting the therapy, a precise diagnosis of idiopathic and/or neurogenic central precocious puberty is necessary and, in girls, pregnancy must be excluded (see section 4.3).

4.6 Fertility, pregnancy and lactation

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Contraception is not ensured, however, by taking PROSTAP 3 and therefore, patients should use non-hormonal methods of contraception during treatment and after cessation of treatment until the return of menses.

4.8 Undesirable effects

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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 follows: 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.  Adverse events, which may occur particularly at the beginning of treatment include urinary tract obstruction (as urinary symptoms).  In patients with spinal cord compression, bone pain, weakness of lower extremities and paresthesia (as neurologic symptoms) may also occur (see section 4.4). These symptoms subside on continuation of therapy.

Updated and formatting change:

In women with early breast cancer treated with a GnRH agonist, in combination with tamoxifen or an aromatase inhibitor, the following side effects have been seen:

Very common:  Nausea, fatigue, musculoskeletal disorders, osteoporosis, hot flushes, hyperhidrosis, insomnia, depression, libido decreased, vulvovaginal dryness, dyspareunia, urinary incontinence, hypertension.

Common: Diabetes mellitus, hyperglycaemia, injection site reaction, hypersensitivity fracture, embolism.

Uncommon: myocardial ischaemia, cerebral ischaemia, central nervous system haemorrhage.

Rare: QT prolongation.

** 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. Pituitary suppression should then be determined by a gonadotropin releasing hormone (GnRH) stimulation test.

5.1 Pharmacodynamic properties

Added:

Men (prostate cancer):

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), and 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 prostate-specific antigen (PSA) mirrored that of serum testosterone in both groups.

In an open-label, 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 luteinising hormone-releasing hormone (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

Updated:

PROSTAP 3 is well absorbed after subcutaneous injection.  It binds to the GnRH receptors and is rapidly degraded.

5.3 Preclinical safety data

Added:

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 GnRH agonist.

6.2 Incompatibilities

Added:

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

6.6 Special precautions for disposal and other handling

Added:

Prepare the injectable suspension at the time of use and, after reconstituting, use immediately. Always ensure the safety device to prevent needle-stick injury is deployed after injection.  For single use only. Discard any unused content. Any unused product or waste material should be disposed of in accordance with local requirements.

10 Date of revision of the text

28^th May 2020