Ipsen Pharmaceuticals Ltd

Decapeptyl 3-month, 11.25mg

Powder and solvent for suspension for injection

Each vial contains the quantity of triptorelin (as triptorelin pamoate) to ensure that the minimum triptorelin quantity injected is 11.25mg.

Excipients:

Sodium < 1mmol (23mg)

For a full list of excipients, see section 6.1.

Powder for suspension for injection:

Slightly yellow lyophilised cake.

Solvent for suspension for injection:

Clear, colourless solution free of suspended particles.

Prostatic carcinoma.

In the management of advanced prostatic carcinoma.

Genital and extragenital endometriosis.

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

-see section 5.1

For intramuscular injection only.

Prostatic carcinoma:

Male Adults only: one injection every three months.

Endometriosis:

Female adults only: one injection every three months.

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

Treatment duration: this depends on the initial severity of the endometriosis and the changes observed in the clinical features (functional and anatomical) during treatment. In principle, the treatment should be administered for at least 3 months and for at most 6 months (see Section 4.8 Undesirable Effects). It is not recommended to start a second treatment course with triptorelin or another GnRH analogue.

Elderly patients:

No special requirements are needed in the elderly.

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

One intramuscular injection of Decapeptyl 3-month administered every 3 months.

The treatment of children with triptorelin should be under the overall supervision of the 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.

Patients with liver disease or renal insufficiency:

No dosage reduction is required in patients with liver disease or renal insufficiency.

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

This medication should never be used during pregnancy or the lactation period. Confirm that the patient is not pregnant or breast-feeding before starting the treatment.

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 3-month 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 3-Month, 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, triptorelin does not induce any further decrease in serum testosterone levels.

Long-term androgen deprivation either by bilateral orchidectomy or administration of GnRH analogues 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 of metabolic or cardiovascular diseases should be carefully assessed before commencing treatment and adequately monitored during androgen deprivation therapy.

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 analogues 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, triptorelin causes constant hypogonadotrophic amenorrhoea. If genital 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 triptorelin 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 (BMD) may decrease during GnRH 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 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.

When triptorelin 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

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 carefully to exclude pregnancy. Non-hormonal methods of contraception should be employed during therapy until menses resume (see section 4.4).

Data currently available concerning the effects of this type of product during pregnancy are summarised below:

- animal studies have not shown the product to have any teratogenic effects. No malformations are therefore expected in humans with this product as substances that cause malformations in humans have been found to be teratogenic in well-conducted animals studies.

- in clinical studies conducted to date, the use of GnRH analogues in a limited number of pregnant women has not resulted in any malformations or foetotoxicity. Nevertheless, further studies are required to study the consequences of exposure during pregnancy.

Lactation

Triptorelin 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 (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 very 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);

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.

ATC Classification: Gonadotropin-releasing hormone Analogue, L02AE04: antineoplasic and immunomodulator.

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 function.

The first administration of Decapeptyl 3-month stimulates the release of pituitary gonadotropins with a transient increase in testosterone levels ("flare-up"). Prolonged administration 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.

The treatment suppresses oestradiol secretion in women and thus enables resting of ectopic endometrial tissue.

One, non-comparative, open label study was undertaken in children with central precocious puberty to assess the efficacy of Decapeptyl 3-month to suppress pubertal development as defined by onset of development of sex characteristics before the age of 8 years for girls and 9 years for boys and a pubertal response of LH to luteinizing hormone releasing hormone (LHRH ) 7 IU/L.

Sixty four patients (54 girls and 10 boys) were enrolled and received the first injection, with 61 (51 girls and 10 boys) receiving all four injections and completing study visits up to month 12.

53 children (45 girls (83%) and 8 boys (80%)) had suppressed LH response (LH 3 IU/L) to LHRH challenge, three months after the injection. At 6 months the corresponding proportions were 51 girls (94%) and 9 boys (90%) and at 12 months 49 girls (91%) and 7 boys (70%).

Stabilisation of the height standard deviation score was observed in 35/51 (69%) and 7/10 (70%) boys at month 12. Stabilisation of the difference in bone age – chronological age and a decrease in the growth velocity were also observed at month 12.

Most patients (51/54 girls and 10/10 boys) achieved a regression or stabilisation of their secondary sex characteristics: all girls had stable or decreased breast development at month 12 (69% regression) and all boys had decreased or stable genital development at month 12 (70% regression).

Nine children (14%) experienced side-effects, four patients with local reaction at the injection site and five patients with withdrawal bleeding. Two patients experienced injection site pain.

Following intramuscular injection of Decapeptyl 3-month in patients (men and women), a peak in plasma triptorelin is observed approximately 3 hours after injection. After a phase of decrease, which continues during the first month, the circulating triptorelin levels remain stable until day 90.

In-vitro and animal toxicology studies have not shown any specific toxic potential for triptorelin. The observed effects are related to the pharmacological properties of triptorelin on the endocrine system.

The resorption of Decapeptyl 3-month is complete in 120 days.

D, L Lactide coglycolide polymers

Mannitol

Sodium carmellose

Polysorbate 80

Water for injections.

Not applicable. The product is not intended for admixture.

3 years.

The product should be used immediately after reconstitution. Any remaining product should be discarded.

Store below 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 3-month.

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.

Ipsen Pharmaceuticals Ltd,

7 Upper Leeson Street,

Dublin 4,

Ireland.

PA 869/003/002

Date of first Authorisation: 02 October 1998

Date of last Renewal: 02 October 2008

June 2011