Decapeptyl SR 3mg, powder for suspension for injection.

Triptorelin (I.N.N.) 4.2mg, as triptorelin acetate.

The vial contains an overage to ensure that a dose of 3mg 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 uterine fibroids prior to surgery or when surgery is not appropriate.

Prostate cancer

One intramuscular injection should be administered every 4 weeks (28 days). No dosage adjustment is necessary in the elderly.

Decapeptyl is also available as a 3-month treatment (Decapeptyl SR 11.25mg) and as a 6-month treatment (Decapeptyl SR 22.5mg) for prostate cancer.

Endometriosis and uterine fibroids

One intramuscular injection every 28 days. For the treatment of endometriosis and uterine fibroids the treatment must be initiated in the first five days of the cycle. The maximum duration of treatment should be 6 months. For patients with uterine fibroids Decapeptyl SR 3mg should be administered for a minimum of 3 months.

A further course of treatment by Decapeptyl SR 3mg or by other GnRH agonists beyond 6 months should not be undertaken due to concerns about bone density losses.

Decapeptyl is also available as a 3-month treatment (Decapeptyl SR 11.25mg) for endometriosis.

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 3mg 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 3mg, 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 3mg 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 analogues 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 results 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 and Uterine Fibromyomas

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 3mg 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 2 months after the last injection. A non-hormonal method of contraception should be used throughout treatment including for 1 month after the duration of the last injection.

Since menses should stop during Decapeptyl SR 3mg treatment, the patient should be instructed to notify her physician if regular menstruation persists.

It is recommended that during treatment of uterine fibroids, the size of the fibroid is determined regularly. There have been a few reports of bleeding in patients with submucous fibroids following GnRH agonist therapy. Typically the bleeding has occurred 6 - 10 weeks after the initiation of therapy.

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

When Decapeptyl SR 3mg 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.

Reproductive studies in primates have shown no maternal toxicity or embryotoxicity, and there was no effect on parturition. Inadvertent administration of triptorelin during human pregnancy has not demonstrated a teratogenic or other foetal risk. However, it is recommended that Decapeptyl SR 3mg should not be used during pregnancy or 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 Section 4.4 ).

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.

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, libido decreased, sleep disorder, mood altered, 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 or two weeks.

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

When used to treat infertility, the combination with gonadotropins may result in ovarian hyperstimulation syndrome. Ovarian hypertrophy, pelvic and/or abdominal pain may be observed.

There is no human experience of overdosage. Animal data do not predict any effects other than those on sex hormone concentration and consequent effect on the reproductive tract. If overdosage occurs, symptomatic management is indicated.

Pharmacotherapeutic group: Gonadotropin-Releasing Hormone analogue

L 02 A E 04: Antineoplastic and immunomodulator

Triptorelin is a decapeptide analogue of GnRH which initially stimulates release of pituitary gonadotropins.

Patients with prostate cancer

This results in an increase in peripheral circulating levels of testosterone and dihydrotestosterone. Continued administration (over 7 days) however, leads to suppression of gonadotropins and a consequent fall in plasma testosterone. In patients with prostate cancer, plasma testosterone levels fall to castrate levels after 2-3 weeks of treatment, frequently resulting in an improvement of function and objective symptoms.

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 0.5ng/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 shortterm to longterm 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).

Patients with endometriosis and uterine fibroids

Continued administration of Decapeptyl SR 3mg induces suppression of oestrogen secretion and thus enables resting of ectopic endometrial tissue. In pre-operative therapy for uterine fibroids there appears to be a beneficial effect on the blood loss at surgery. Studies have demonstrated a consistent and marked reduction in uterine and/or fibroid volume becoming maximal in a three to six month treatment period. Clinical studies have shown that 90-100% of patients with fibroids become amenorrhoeic within two months of treatment and triptorelin provides relief from the symptoms of abdominal pain, dysmenorrhoea and menorrhagia associated with uterine fibroids.

SUBCUTANEOUS FORM

In healthy volunteers

Subcutaneously administered triptorelin (100 μg) is rapidly absorbed (Tmax = 0.63 ± 0.26hr for peak plasma concentration = 1.85 ± 0.23ng/mL). Elimination is effected with a biological half-life of 7.6 ± 1.6hr, after a 3 to 4hr distribution phase. Total plasma clearance is: 161 ± 28mL/min. Distribution volume is 104.1 ± 11.7 litres.

In patients with prostate cancer

With subcutaneous administration (100μg), triptorelin blood levels oscillate between maximum values of 1.28 ± 0.24ng/mL (Cmax) obtained in general one hour after injection (Tmax) and minimum values of 0.28 ± 0.15ng/mL (Cmin) obtained 24hrs after injection.

The biological half-life is on average 11.7 ± 3.4hr but varies according to patients. Plasma clearance (118 ± 32mL/min) reflects slower elimination in patients, whilst distribution volumes are close to those of healthy volunteers (113.4 ± 21.6 litres).

SUSTAINED RELEASE FORM

In patients with prostate cancer

Following intramuscular injection of the sustained release form, an initial phase of release of the active principle present on the surface of the microspheres is observed, followed by further fairly regular release (Cmax = 0.32 ± 0.12ng/mL), with a mean rate of release of triptorelin of 46.6 ± 7.1μg/day. The bioavailability of the microparticles is approximately 53% at one month.

In patients with endometriosis and uterine fibroids

After intramuscular injection of Decapeptyl SR 3mg in patients with endometriosis and uterine fibroids the maximum blood level of triptorelin is obtained between 2 to 6 hours after injection, the peak value reached is 11ng/mL. There was no evidence of accumulation of the product following monthly injections over six months. The minimum blood level oscillates between 0.1 and 0.2ng/mL. The bioavailability of the sustained release product is approximately 50%.

Preclinical findings were only those related to the expected pharmacological activity of triptorelin, namely down-regulation of the hypothalamic-pituitary-gonadal axis. These included atrophy of the testes and genital tract, with resultant suppression of spermatogenesis, together with decreased weight of the prostate gland. These findings were largely reversible within the recovery period. In a small number of rats, in a 24 months oncogenicity study, a low incidence of benign histological changes were seen in the non-glandular part of the fore stomach. Erosions, ulcers, necrosis and inflammation were seen at varying degrees of severity. The clinical relevance of these findings is unknown. The increased incidence of adenomatous tumours in the rat pituitary observed with Decapeptyl following long-term repeated dosing is thought to be a class specific action of GnRH analogues due to a hormonally-mediated mechanism and has not been found in the mouse nor has it been described in man.

Standard mutagenicity testing revealed no mutagenic activity of triptorelin.

D,L-lactide/glycolide copolymer

Mannitol

Carmellose sodium

Polysorbate 80

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

3 years.

The product should be used immediately after reconstitution.

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

A type I, 5mL capacity glass vial with an elastomer stopper and an aluminium cap containing the powder.

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 3mg.

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 homogeneous 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.

To ensure patients receive the correct dose, each vial of Decapeptyl SR 3mg 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

Berkshire

SL1 3XE

United Kingdom

PL 34926/0002

Date of first authorisation: 29 December 1994

Date of last renewal: 13 September 2001

09 May 2011