Decapeptyl SR 11.25mg, powder for suspension for injection.

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.

Powder for suspension for injection, sustained release formulation.

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.

Treatment of endometriosis.

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

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

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 11.25mg, 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 3mg) 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 11.25mg 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.

Hypersensitivity to GnRH, its analogues or any other component of the medicinal product (see section 4.8).

Pregnancy and lactation

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.

Mood changes, including depression have been reported. 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.

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 epiphysis.

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

When Decapeptyl SR 11.25mg 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.

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.

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.

Clinical trials experience

General tolerance in men

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: Initial increase in testosterone levels, followed by almost complete suppression of testosterone. These effects included hot flushes (50%), erectile dysfunction (4%) and decreased libido (3%).

The following adverse reactions, considered as at least possibly related to triptorelin treatment, were reported. Most of these 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 to <1/10); uncommon (1/1,000 to <1/100); rare (1/10,000 to <1/1,000).

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 special warnings and special 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 in the risk of bone fracture.

General tolerance in women (see section 4.4)

As a consequence of decreased oestrogen levels, the most commonly reported adverse events (expected in 10% of women or more) were headache, decreased libido, sleep disorder, mood alterations, dyspareunia, dysmenorrhoea, genital haemorrhage, ovarian hyperstimulation syndrome, ovarian hypertrophy pelvic pain, abdominal pain, vulvovaginal dryness, hyperhidrosis, hot flushes and asthenia.

The following adverse reactions, considered as at least possibly related to triptorelin treatment, were reported. Most of these 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 to <1/10);

At the beginning of treatment, the symptoms of endometriosis including pelvic pain and dysmenorrhoea are commonly exacerbated during the initial transient increase in plasma oestradiol levels. These symptoms are transient and usually disappear in one to two weeks.

Genital haemorrhage including menorrhagia and metrorrhagia may occur in the month following the first injection.

General tolerance in children (see section 4.4)

The frequency of the adverse reactions is classified as follows: very common (1/10); common (1/100 to <1/10);

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.

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).

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 2.3cm after one year's treatment.

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.

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.

D,L lactide-glycolide copolymer

Mannitol

Carmellose sodium

Polysorbate 80.

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

2 years.

The product should be used immediately after reconstitution.

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

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.

The suspension for injection must be reconstituted using an aseptic technique and only using the ampoule of mannitol solution 0.8% for injection that is provided as the suspension vehicle for Decapeptyl SR 11.25mg.

The suspension vehicle should be drawn into the syringe provided using one of the injection needles and transferred to the vial containing the powder for injection. The vial should be shaken from side to side until a homogenous suspension is formed, and the mixture then drawn back into the syringe without inverting the vial. The injection needle should then be changed and the second needle used to administer the injection. As the product is a suspension, the injection should be administered immediately after reconstitution to prevent sedimentation. The suspension should be discarded if it is not administered immediately after reconstitution.

To ensure patients receive the correct dose, each vial of Decapeptyl contains a small overage to allow for predictable losses on reconstitution and injection.

The vial is intended for single use only and any remaining product should be discarded. Used injection needles should be disposed of in a designated sharps container.

Ipsen Limited,

190 Bath Road,

Slough,

SL1 3XE,

United Kingdom.

PL 34926/0003

Date of first authorisation: 16 October 2002

Date of last renewal: 16 March 2009

09 May 2011