Ipsen Pharmaceuticals Ltd

Decapeptyl SR Powder and Solvent for Supension for Injection

Each vial contains the quantity of triptorelin (as triptorelin acetate) to ensure that the minimum quantity injected is 3mg.

A 2 mL ampoule of solvent for suspension is provided in each pack.

Once reconstituted, 1 mL of the suspension contains 1.5 mg triptorelin at a minimum.

For a full list of excipients, see section 6.1.

Powder and solvent for suspension for injection.

A sterile, white to off-white, lyophilised powder which, when reconstituted as directed with the clear, colourless, sterile liquid, yields a sterile suspension for injection.

Prostatic carcinoma

In the management of advanced prostatic carcinoma

Uterine fibromyomas

Treatment of uterine fibromyomas

Endometriosis

Genital and extragenital endometriosis

Female infertility

Complementary treatment in association with the gonadotropins (hMG, FSH and hCG) in the course of ovulation induction in view of in-vitro fertilisation and embryo transfer (I.V.F.E.T.).

Prostatic cancer:

Male adults only:

One intramuscular injection of Decapeptyl SR (3 mg) every 28 days.

No special requirements are needed for the elderly.

Uterine fibromyomas:

The treatment must be initiated in the first five days of the cycle. The recommended dose is one intramuscular injection every 28 days.

Injection schedule: this depends on the change in volume of the fibromyomas, assessed by ultrasonography.

In principle, fibromyomas should be treated for at least 4 months and for a maximum of 6 months. A second course of treatment by Decapeptyl SR or by other GnRH analogues should not be undertaken.

Endometriosis:

The treatment must be initiated in the first five days of the cycle.

Injection schedule: one intramuscular injection of Decapeptyl SR every 28 days.

Duration of treatment: this depends on the initial severity of endometriosis and the change in clinical manifestations (functional and anatomical) during treatment.

In principle, endometriosis should be treated for at least 4 months and for a maximum of 6 months.

A second course of treatment by Decapeptyl SR or by other GnRH analogues should not be undertaken.

Female infertility:

One intramuscular injection of Decapeptyl SR administered on the second day of the cycle. In general, the stimulation by gonadotropins should be performed when the blood level of oestrogens are less than 50 pg/mL (usually around the 15th day of the cycle).

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 an 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 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.

Adjustment of antihypertensive therapy may be required in patients receiving such medication.

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.

This medicinal product contains less than 1mmol of sodium (23mg) per dose and is considered essentially 'sodium-free'.

Prostate cancer

Initially, Decapeptyl SR, 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 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 during androgen deprivation therapy.

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 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 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 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 analogue therapy. Typically the bleeding has occurred 6 - 10 weeks after the initiation of therapy.

Female infertility

The induction of ovulation should be monitored under rigorous medical supervision with strict and regular biological and clinical control by fast plasma oestrogen assay and ultrasonography. As with other GnRH analogues there have been reports of ovarian hyperstimulation syndrome (OHSS) associated with the use of triptorelin in combination with gonadotropins.

In cases of excessive ovarian response, interruption of the stimulation cycle by stopping the injections of gonadotropins is recommended.

The increase in the follicular retrieval induced by injection of Decapeptyl SR when associated with gonadotropins may be great in some predisposed patients and particularly in cases of polycystic ovarian disease. The ovarian response to the triptorelin-gonadotropin treatment may differ with the same doses from one patient to another, and in certain cases, from one cycle to another in the same patient.

In patients with renal or hepatic impairment, triptorelin has a mean terminal half life of 7-8 hours compared to 3-5 hours in healthy subjects. Despite this prolonged exposure, triptorelin is not expected to be present in circulation at the time of embryo transfer.

Hyperprolactinemic drugs should not be prescribed concomitantly as they reduce the level of GnRH receptors in the pituitary.

When Decapeptyl SR 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.

Pregnancy

Decapeptyl SR 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 carefully to exclude pregnancy. Non-hormonal methods of contraception should be employed during therapy until menses resume.

Pregnancy should be excluded before triptorelin is used for fertilisation treatment. When Decapeptyl SR is used in this setting, there is no clinical evidence to suggest a causal connection between Decapeptyl SR and any subsequent abnormalities of oocyte development or pregnancy or outcome.

Lactation

Decapeptyl SR should not be used during breast feeding.

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 very 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.

General

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.

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

Pharmacotherapeutic group: Hormones and related agents,

ATC code: L02A EO4

Triptorelin is a synthetic decapeptide (D-Trp6 GnRH) analogue of natural GnRH. Studies in animals and man have shown that continued administration of triptorelin exerts, after a short initial stimulation, an inhibitory effect on the gonadotropin secretion with consequent suppression of testicular and ovarian functions.

Prostatic cancer

The first administration of Decapeptyl SR stimulates the release of pituitary gonadotropins with a resultant increase in peripheral circulating levels of testosterone and dihydrotestosterone. Prolonged administration (over 7 days) leads to a suppression of gonadotropins and a fall in plasma testosterone to castrate levels after approximately 20 days and which continues for as long as the product is administered.

A transient increase in acid phosphatases may be observed in men at the beginning of treatment.

Uterine fibromyomas

The suppression of oestrogen secretion produces a significant reduction of the volume of the uterine fibromyomas.

Endometriosis

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

Female infertility

The administration of Decapeptyl SR induces an initial phase of gonadotropin stimulation (FSH and LH) followed by an inhibition phase. The treatment ensures suppression of the intercurrent LH peak enabling enhanced folliculogenesis and increased follicular retrieval and as a consequence, a better rate of pregnancy per cycle.

In men:

Following intramuscular injection an initial phase of release of the active principle present on the surface of the microspheres, is observed, followed by regular release of triptorelin at a mean rate of 46.6 ± 7.1 µg/day. The microsphere suspension bioavailability is approximately 53% at one month.

In women

After intramuscular injection of Decapeptyl in endometriosis patients the maximum blood level of triptorelin is obtained between 2 to 6 hours after injection, the peak value reached is 11 ng/mL. There was no evidence of accumulation of the product after 6 monthly injections. The minimum blood level oscillates between 0.1 and 0.2 ng/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.

Standard mutagenicity testing revealed no mutagenic activity of triptorelin.

Resorption of the microspheres is complete within 40 to 45 days following intramuscular injection in rats.

Powder

D,L-lactide/glycolide copolymer

Mannitol

Carmellose sodium

Polysorbate 80

Solvent for Suspension:

Mannitol

Water for Injections.

Not applicable

Powder: 3 years

Solvent: 5 years

The product should be used immediately after opening/reconstitution.

Do not store above 25°C.

Powder for suspension for injection:

Type I, clear, slightly tinted glass vial (4mL)

Solvent for suspension for injection:

Type I, clear glass ampoule (2mL)

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

The homogenous, milky suspension for injection is reconstituted by gentle shaking. The instructions for reconstitution hereafter and in the leaflet must be strictly followed, using exclusively the provided ampoule of mannitol 0.8% solution for injection, suspension vehicle for Decapeptyl SR.

For single use only. Any unused suspension should be discarded.

The powder is to be suspended in 2mL of mannitol solution:

Using one of the injection needles, all of the solvent (2mL) is drawn up into the injection syringe supplied and transferred to the vial containing the powder. The vial should be gently shaken to completely disperse the powder to obtain a homogenous, milky suspension. The suspension obtained is then drawn back into the injection syringe, without inverting the vial. The injection needle should be changed and the suspension should be injected immediately using the needle for injection.

The suspension should be discarded if it is not administered immediately after reconstitution. See also section 6.3.

Used injection needles should be disposed of in a designated sharps container.

Ipsen Pharmaceuticals Ltd

7 Upper Leeson Street

Dublin 4

Ireland

Trading as:

Ipsen Pharmaceuticals

PA 869/003/001

Date of first Authorisation: 05 December 1989

Date of last Renewal: 05 December 2009

June 2011