SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Decapeptyl SR 11.25mg, powder for suspension for injection.

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Triptorelin (I.N.N.) 15mg, as triptorelin acetate.

The vial contains an overage to ensure that a dose of 11.25mg is administered to the patient.

For a full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Powder for suspension for injection, sustained release formulation.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Treatment of patients with locally advanced, non-metastatic prostate cancer, as an alternative to surgical castration (see section 5.1).

Treatment of metastatic prostate cancer.

As adjuvant treatment to radiotherapy in patients with high-risk localised or locally advanced prostate cancer.

As neoadjuvant treatment prior to radiotherapy in patients with high-risk localised or locally advanced prostate cancer.

As adjuvant treatment to radical prostatectomy in patients with locally advanced prostate cancer at high risk of disease progression.

Treatment of endometriosis.

Treatment of precocious puberty (onset before 8 years in girls and 10 years in boys).

4.2 Posology and method of administration

Prostate cancer

One intramuscular injection should be administered every 3 months.

No dosage adjustment is necessary in the elderly.

Decapeptyl is also available as a 1-month treatment (Decapeptyl SR 3 mg) and as a 6-month treatment (Decapeptyl SR 22.5 mg) for prostate cancer.

In patients treated with GnRH analogues for metastatic prostate cancer, treatment is usually continued upon development of castrate-resistant prostate cancer.

Reference should be made to relevant guidelines.

Endometriosis

One intramuscular injection should be administered every 3 months. The treatment must be initiated in the first five days of the menstrual cycle. Treatment duration depends on the initial severity of the endometriosis and the changes observed in the clinical features (functional and anatomical) during treatment. The maximum duration of treatment should be 6 months (two injections).

A further course of treatment with Decapeptyl SR 11.25 mg, or with other GnRH agonists, beyond 6 months should not be undertaken due to concerns about bone density losses.

Decapeptyl is also available as a 1-month treatment (Decapeptyl SR 3 mg) for endometriosis.

Precocious puberty (before 8 years in girls and 10 years in boys)

One intramuscular injection should be administered every 3 months.

The treatment of children with Decapeptyl SR 11.25 mg should be under the overall supervision of a paediatric endocrinologist or of a paediatrician or endocrinologist with expertise in the treatment of central precocious puberty.

Treatment should be stopped around the physiological age of puberty in boys and girls and should not be continued in girls with a bone maturation of more than 12 years. There are limited data available in boys relating to the optimum time to stop treatment based on bone age, however it is advised that treatment is stopped in boys with a bone maturation age of 13-14 years.

4.3 Contraindications

Hypersensitivity to GnRH, its analogues or to any of the excipients of the medicinal product listed in section 6.1 (see also section 4.8).

4.4 Special warnings and precautions for use

The use of GnRH agonists may cause a reduction in bone mineral density. In men, preliminary data suggest that the use of a bisphosphonate in combination with a GnRH agonist may reduce bone mineral loss. No specific data is available for patients with established osteoporosis or with risk factors for osteoporosis (e.g. chronic alcohol abuse, smokers, long-term therapy with drugs that reduce bone mineral density, e.g. anticonvulsants or corticosteroids, family history of osteoporosis, malnutrition, e.g. anorexia nervosa). Particular caution is therefore necessary since reduction in bone mineral density is likely to be more detrimental in these patients. Treatment with Decapeptyl SR 11.25mg should be considered on an individual basis and only be initiated if the benefits of treatment outweigh the risk following a very careful appraisal. Consideration should be given to additional measures in order to counteract loss of bone mineral density.

It should be confirmed that the patient is not pregnant before prescription of triptorelin.

Rarely, treatment with GnRH agonists may reveal the presence of a previously unknown gonadotroph cell pituitary adenoma. These patients may present with a pituitary apoplexy characterised by sudden headache, vomiting, visual impairment and ophthalmoplegia.

There is an increased risk of incident depression (which may be severe) in patients undergoing treatment with GnRH agonists, such as triptorelin. Patients should be informed accordingly and treated as appropriate if symptoms occur. Patients with known depression should be monitored closely during therapy.

Prostate cancer

Initially, Decapeptyl SR 11.25mg, like other GnRH agonists, causes a transient increase in serum testosterone levels. As a consequence, isolated cases of transient worsening of signs and symptoms of prostate cancer may occasionally develop during the first weeks of treatment. During the initial phase of treatment, consideration should be given to the additional administration of a suitable anti-androgen to counteract the initial rise in serum testosterone levels and the worsening of clinical symptoms.

A small number of patients may experience a temporary worsening of signs and symptoms of their prostate cancer (tumour flare) and temporary increase in cancer related pain (metastatic pain), which can be managed symptomatically.

As with other GnRH agonists, isolated cases of spinal cord compression or urethral obstruction have been observed. If spinal cord compression or renal impairment develops, standard treatment of these complications should be instituted, and in extreme cases an immediate orchidectomy (surgical castration) should be considered. Careful monitoring is indicated during the first weeks of treatment, particularly in patients suffering from vertebral metastasis, at the risk of spinal cord compression, and in patients with urinary tract obstruction.

After surgical castration, Decapeptyl SR 11.25mg does not induce any further decrease in serum testosterone levels.

Long-term androgen deprivation either by bilateral orchidectomy or administration of GnRH agonists is associated with increased risk of bone loss and may lead to osteoporosis and increased risk of bone fracture.

Long-term androgen deprivation therapy may prolong the QT interval. Physicians should consider whether the benefits of androgen deprivation therapy outweigh the potential risks in patients with congenital long QT syndrome, electrolyte abnormalities, or congestive heart failure or in patients receiving class IA or class III antiarrhythmic medications.

In addition, from epidemiological data, it has been observed that patients may experience metabolic changes (e.g. glucose intolerance), or an increased risk of cardiovascular disease during androgen deprivation therapy. However, prospective data did not confirm the link between treatment with GnRH agonists and an increase in cardiovascular mortality. Patients at high risk for metabolic or cardiovascular diseases should be carefully assessed before commencing treatment and their glucose, cholesterol and blood pressure adequately monitored during androgen deprivation therapy.

Metabolic changes may be more severe in these high risk patients. Patients at high risk of metabolic or cardiovascular disease and receiving androgen deprivation therapy should be monitored at appropriate intervals not exceeding 3 months.

Administration of triptorelin in therapeutic doses result in suppression of the pituitary gonadal system. Normal function is usually restored after treatment is discontinued. Diagnostic tests of pituitary gonadal function conducted during treatment and after discontinuation of therapy with GnRH agonists may therefore be misleading.

Endometriosis

The use of GnRH agonists is likely to cause reduction in bone mineral density averaging 1% per month during a six month treatment period. Every 10% reduction in bone mineral density is linked with about a two to three times increased fracture risk.

In the majority of women, currently available data suggest that recovery of bone loss occurs after cessation of therapy.

Used at the recommended dose, Decapeptyl SR 11.25mg causes constant hypogonadotropic amenorrhoea. If vaginal haemorrhage occurs after the first month, plasma oestradiol levels should be measured and if levels are below 50 pg/mL, possible organic lesions should be investigated.

After withdrawal of treatment, ovarian function resumes and ovulation occurs approximately 5 months after the last injection. A non-hormonal method of contraception should be used throughout treatment including for 3 months after the duration of the last injection.

Since menses should stop during Decapeptyl SR 11.25mg treatment, the patient should be instructed to notify her physician if regular menstruation persists.

Precocious puberty

Treatment of children with progressive brain tumours should follow a careful individual appraisal of the risks and benefits.

In girls, initial ovarian stimulation at treatment initiation, followed by the treatment-induced oestrogen withdrawal, may lead, in the first month, to vaginal bleeding of mild or moderate intensity.

After discontinuation of treatment the development of puberty characteristics will occur.

Information with regards to future fertility is still limited. In most girls, regular menses will start on average one year after ending the therapy.

Pseudo-precocious puberty (gonadal or adrenal tumour or hyperplasia) and gonadotropin-independent precocious puberty (testicular toxicosis, familial Leydig cell hyperplasia) should be precluded.

Bone mineral density may decrease during GnRH agonist 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 capital femoral epiphysis can be seen after withdrawal of GnRH agonist treatment. The suggested theory is that the low concentrations of oestrogen during treatment with GnRH agonists weaken 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 epiphysi

4.5 Interaction with other medicinal products and other forms of interaction

Drugs which raise prolactin levels should not be prescribed concomitantly as they reduce the level of GnRH receptors in the pituitary.

When Decapeptyl SR 22.5mg is co-administered with drugs affecting pituitary secretion of gonadotropins, caution should be exercised and it is recommended that the patient’s hormonal status be supervised.

Since androgen deprivation treatment may prolong the QT interval, the concomitant use of triptorelin 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, procainamide) or class III (e.g. amiodarone, sotalol) antiarrhythmic medicinal products should be carefully evaluated (see Section 4.4).

4.6 Pregnancy and lactation

Triptorelin should not be used during pregnancy since concurrent use of GnRH agonists is associated with a theoretical risk of abortion or foetal abnormality. Prior to treatment, potentially fertile women should be examined to exclude pregnancy. Non-hormonal methods of contraception should be employed during therapy until menses resume.

Animal studies have not revealed any teratogenic effects. During post-marketing surveillance and in a limited number of pregnant women who were exposed inadvertently to triptorelin, there were no reports of malformation or foetotoxicity attributable to the product. However, as the number of patients is too small to draw conclusions regarding the risk of foetal malformations or foetotoxicity, if a patient becomes pregnant while receiving triptorelin, therapy should be discontinued.

Triptorelin is not recommended for use during lactation.

4.7 Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed. However, the ability to drive and use machines may be impaired should the patient experience dizziness, somnolence and visual disturbances (being possible undesirable effects of treatment), or resulting from the underlying disease.

4.8 Undesirable effects

Since patients suffering from locally advanced or metastatic, hormone-dependent prostate cancer are generally old and have other diseases frequently encountered in this aged population, more than 90 % of the patients included in clinical trials reported adverse events, and often the causality is difficult to assess. As seen with other GnRH agonist therapies or after surgical castration, the most commonly observed adverse events related to triptorelin treatment were due to its expected pharmacological effects. These effects included hot flushes and decreased libido.

With the exception of immuno-allergic (rare) and injection site (< 5 %) reactions, all adverse events are known to be related to testosterone changes.

The following adverse reactions considered as at least possibly related to triptorelin treatment were reported. Most of these events are known to be related to biochemical or surgical castration.

The frequency of the adverse reactions is classified as follows: very common ( >1/10); common (>1/100, < 1/10); uncommon (>1/1000, < 1/100); rare (> 1/10000, < 1/1000).

System Organ Class	Very Common	Common	Uncommon	Rare	Additional postmarketing Frequency not known
Blood and lymphatic system disorders			Thrombocytos is
Cardiac disorders			Palpitations
Ear and labyrinth disorders			Tinnitus Vertigo
Eye disorders			Visual impairment	Abnormal sensation in eye Visual disturbance
Gastrointestinal disorders		Dry mouth Nausea	Abdominal pain Constipation Diarrhoea Vomiting	Abdominal distension Dysgeusia Flatulence
General disorders and administration site conditions	Asthenia	Injection site reaction (including erythema inflammation and pain) Oedema	Lethargy Oedema peripheral Pain Rigors Somnolence	Chest pain Dysstasia Influenza like illness Pyrexia	Malaise
Immune system disorders		Hypersensiti vity		Anaphylactic reaction	Anaphylact ic shock
Infections and infestations				Nasopharyng itis
Investigations		Weight increase	Alanine aminotransfera se increased Aspartate aminotransfera se increased, Blood creatinine	Blood alkaline phosphatase increased

			increased Blood pressure increased Blood urea increased Gamma- glutamyl transferase increased Weight decreased
Metabolism and nutrition disorders			Anorexia Diabetes mellitus Gout Hyperlipidaem ia Increased appetite
Musculoskeletal and connective tissue disorders	Back pain	Musculoskel etal pain Pain in extremity	Arthralgia Bone pain Muscle cramp Muscular weakness Myalgia	Joint stiffness Joint swelling Musculoskel etal stiffness Osteoarthritis
Nervous system disorders	Paraesthesia in lower limbs	Dizziness Headache	Paraesthesia	Memory impairment
Psychiatric disorders	Libido decreased	Loss of libido Depression* Mood changes*	Insomnia Irritability	Confusional state Decreased activity Euphoric mood	Anxiety
Renal and urinary disorders			Nocturia Urinary retention		Unrinary incontinenc e
Reproductive system and breast disorders	Erectile dysfunction (including ejaculation failure, ejaculation disorder)	Pelvic plain	Gynaecomasti a Breast pain Testicular atrophy Testicular pain
Respiratory, thoracic and mediastinal disorders			Dyspnoea Epitaxis	Orthopnoea
Skin and subcutaneous	Hyperhidros is		Acne Alopecia	Blister Purpura	Angioneuro tic oedema

tissue disorders			Erythema Pruritus Rash Urticaria
Vascular disorders	Hot flush	Hypertension		Hypotension

*This frequency is based on class-effect frequencies common for al

GnRH agonists

Triptorelin causes a transient increase in circulating testosterone levels within the first week after the initial injection of the sustained release formulation. With this initial increase in circulating testosterone levels, a small percentage of patients (< 5 %) may experience a temporary worsening of signs and symptoms of their prostate cancer (tumour flare), usually manifested by an increase in urinary symptoms (< 2%) and metastatic pain (5 %) which can be managed symptomatically. These symptoms are transient and usually disappear in one to two weeks. Isolated cases of exacerbation of disease symptoms, either urethral obstruction or spinal cord compression by metastasis have occurred. Therefore, patients with metastatic vertebral lesions and/or with upper or lower urinary tract obstruction should be closely observed during the first few weeks of therapy (see section 4.4 Special warnings and precautions for use).

The use of GnRH agonists to treat prostate cancer may be associated with increased bone loss and may lead to osteoporosis and increases the risk of bone fracture. This may also lead to an incorrect diagnosis of bone metastases.

Increased lymphocytes count has been reported with patients undergoing GnRH analogue treatment. This secondary lymphocytosis is apparently related to GnRH induced castration and seems to indicate that gonadal hormones are involved in thymic involution.

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 Y ellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9 Overdose

No case of overdose has been reported. Animal data do not predict any effects other than those on sex hormone concentration and consequent effect on the reproductive tract. If overdose occurs, symptomatic management is indicated.

5.1 Pharmacodynamic properties Pharmacotherapeutic group:

Gonadotropin-Releasing Hormone analogue L 02 A E 04: Antineoplastic and immunomodulator

Triptorelin is a synthetic decapeptide analogue of natural GnRH.

Prostate cancer

The first administration of Decapeptyl SR 11.25mg stimulates the release of pituitary gonadotropins with a transient increase in testosterone levels (“flare-up”) in men. Prolonged administration leads to a suppression of gonadotropins and a fall in plasma testosterone or oestradiol to castrate levels after approximately 20 days, which is maintained for as long as the product is administered.

The efficacy and safety of triptorelin has been determined in clinical studies involving 645 patients with locally advanced or metastatic prostate cancer.

Of these, three long term controlled studies compared the efficacy and safety of triptorelin to bilateral orchidectomy as an initial therapy in patients with locally advanced or metastatic prostate cancer (stage C or D). In one of these three long term studies, 7 patients in the triptorelin group and 7 patients in the orchidectomy group had also undergone prostatectomy. Triptorelin induced biochemical castration at least as rapidly as surgical pulpectomy and was as effective as surgical castration in the long term palliative treatment of locally advanced or metastatic prostate cancer. Both the triptorelin and orchidectomy groups showed improvements in dysuria and pain, and reduction in volume of prostate. Analysis after six and eight years in two of the studies showed that there was no significant difference in the median survival rates in the triptorelin group versus the orchidectomy group.

A study assessing the pharmacodynamic equivalence between triptorelin 3-month and 28-day prolonged release formulations in patients with locally advanced or metastatic prostate cancer, found that equivalent testosterone suppression was achieved, whether 3 doses of Decapeptyl SR 3mg (n=68) or a single dose of Decapeptyl SR 11.25mg (n=63) was given. The percentage of patients who achieved a testosterone castrate level < 0.5 ng/mL at D84 was similar in the two treatment groups (98% and 96% in the 3-month and 28-day formulation groups, respectively). The time to achieve chemical castration was not significantly different between the two groups.

In a phase III randomized clinical trial including 970 patients with locally advanced prostate cancer (mainly T2c-T4 with some T1c to T2b patients with pathological regional nodal disease) of whom 483 were assigned to short-term androgen suppression (6 months) in combination with radiation therapy and 487 to long-term therapy (3 years), a non-inferiority analysis compared the short-term to long-term concomitant and adjuvant hormonal treatment with triptorelin (62.2%) or goserelin (30.1%). The 5-year overall mortality was 19.0% and 15.2%, in the short-term and long-term groups, respectively. The observed Hazard Ratio of 1.42 with an upper one-sided 95.71% CI of 1.79 or two-sided 95.71% CI of 1.09; 1.85 (p = 0.65 for non inferiority), demonstrate that the combination of radiotherapy plus 6 months of androgen deprivation therapy provides inferior survival as compared with radiotherapy plus 3 years of androgen deprivation therapy. Overall survival at 5 years of long-term treatment and short-term treatment shows 84.8% survival and 81.0%, respectively.

Overall quality of life using QLQ-C30 did not differ significantly between the two groups (P= 0.37).

Neoadjuvant triptorelin prior to radiotherapy has been shown to significantly reduce prostate volume.

The use of a GnRH agonist may be considered after radical prostatectomy in selected patients considered at high risk of disease progression. There are no disease-free survival data or survival data with triptorelin in this setting.

Endometriosis

The first administration of Decapeptyl SR 11.25mg stimulates the release of pituitary gonadotropins with a transient increase in oestradiol levels in women. Prolonged administration leads to a suppression of gonadotropins and a fall in plasma testosterone or oestradiol to castrate levels after approximately 20 days, which is maintained for as long as the product is administered.

Continued administration of Decapeptyl SR 11.25mg induces suppression of oestrogen secretion and thus enables resting of ectopic endometrial tissue.

Precocious puberty

Inhibition of the increased hypophyseal gonadotropic activity in children with precocious puberty leads to suppression of oestradiol and testosterone secretion in girls and boys, respectively, and to lowering of the LH peak due to the GnRH stimulation test. The consequence is a regression or stabilisation of secondary sex characteristics and an improvement in median predicted adult height of 2.3 cm after one year’s treatment.

5.2 Pharmacokinetic properties

Following intramuscular injection of Decapeptyl SR 11.25mg in patients (men and women), a peak of plasma triptorelin is observed in the first 3 hours after injection. After a phase of decrease, the circulating triptorelin levels remain stable at around 0.04-0.05ng/mL in endometriosis patients and around 0.1ng/mL in prostate cancer patients until day 90.

5.3 Preclinical safety data

The compound did not demonstrate any specific toxicity in animal toxicological studies. The effects observed are related to the pharmacological properties of triptorelin on the endocrine system.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

D, L lactide-glycolide copolymer Mannitol

Carmellose sodium Polysorbate 80.

6.2 Incompatibilities

This medicinal product must not be mixed with other medicinal products except the one mentioned in 6.6.

6.3 Shelf life

2 years.

The product should be used immediately after reconstitution.

6.4 Special precautions for storage

Do not store above 25°C. Keep container in the outer carton.

6.5    Nature and contents of container

A type I, 4mL capacity glass vial with an elastomer stopper and an aluminium cap containing the powder.

A type I, 3mL capacity glass ampoule containing 2mL of the suspension vehicle.

Box containing 1 vial and 1 ampoule with 1 syringe and 2 needles.

6.6    Special precautions for disposal and other handling

The suspension for injection must be reconstituted using an aseptic technique and only using the ampoule of solvent for injection.

The instructions for reconstitution hereafter and in the leaflet must be strictly followed.

The solvent should be drawn into the syringe provided using the reconstitution needle (20 G, without safety device) and transferred to the vial containing the powder. The suspension should be reconstituted by swirling the vial gently from side to side for long enough until a homogeneous, milky suspension is formed. Do not invert the vial. It is important to check there is no unsuspended powder in the vial. The suspension obtained should then be drawn back into the syringe, without inverting the vial. The reconstitution needle should then be changed and the injection needle (20 G, with safety device) used to administer the product.

As the product is a suspension, the injection should be administered immediately after reconstitution to prevent precipitation.

For single use only.

Used needles, any unused suspension or other waste materials should be disposed of in accordance with local requirements.

7 MARKETING AUTHORISATION HOLDER

Ipsen Limited 190 Bath Road Slough Berkshire SL1 3XE United Kingdom

MARKETING AUTHORISATION NUMBER(S)

PL 34926/0003

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 16 October 2002 Date of last renewal: 16 March 2009

10    DATE OF REVISION OF THE TEXT

28/04/2016