Decapeptyl SR 11.25mg Powder and solvent for suspension for injection

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 central 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 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. In patients treated with GnRH analogues for endometriosis, the addition of an add-back therapy (ABT - an estrogen and progestogen) has been shown to reduce bone mineral density loss and vasomotor symptoms. Therefore, if appropriate, ABT should be co-administered with GnRH analogue taking into account the risks and benefits of each treatment.

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

Central 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 12 to 13 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 (gonadotropin releasing hormone), its analogues or to any of the excipients listed in section 6.1 (see section 4.8 Undesirable effects).

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 11.25 mg 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.

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.

In patients undergoing treatment with GnRH agonists, an increased risk of depression was reported (which may be severe and includes rare case reports of suicidal ideation from post-marketing experience, including reports of positive dechallenge and reversible symptoms, and with the majority of reports occurring in patients with a background history of depression). Patients should be informed accordingly to contact a doctor as soon as possible if worsening depression occurs, and if suicidal ideation develops and treated as appropriate if symptoms occur. Patients with known depression should be monitored closely during therapy.

Convulsions have been reported with GnRH analogues, particularly in women and children. Some of these patients had risk factors for seizures (such as a history of epilepsy, intracranial tumors or co-medication with drugs known to present a risk of seizure reactions). Convulsions have also been reported in patients in the absence of such risk factors.

This medicine contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially 'sodium-free'.

This medicine contains 2 mg of polysorbate 80 in each vial. Polysorbates may cause allergic reactions.

In men

Prostate cancer

Initially, Decapeptyl SR 11.25 mg, 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 11.25 mg 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.

Androgen deprivation therapy may prolong the QT interval.

In patients with a history of or risk factors for QT prolongation and in patients receiving concomitant medicinal products that might prolong the QT interval (see section 4.5) physicians should assess the benefit risk ratio including the potential for Torsade de pointes prior to initiating Decapeptyl SR 11.25 mg.

In addition, from epidemiological data, it has been observed that patients may experience metabolic changes (e.g. glucose intolerance, fatty liver), and 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.

Due to androgen deprivation, treatment with GnRH analogues can increase the risk of anaemia. This risk should be assessed in treated patients and monitored appropriately.

In women

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

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.

No specific data are available for patients with established osteoporosis or with risk factors for osteoporosis (e.g. chronic alcohol abusers, smokers, long-term therapy with drugs that reduce bone mineral density, e.g. anticonvulsants or corticoids, family history of osteoporosis, malnutrition, e.g. anorexia nervosa). Since reduction in bone mineral density is likely to be more detrimental in these patients, treatment with triptorelin 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.

Endometriosis

GnRH agonist is not recommended for patients under the age of 18 years. Careful attention should be given to adolescent and young women (specially less than 16 years of age) who may not have reached maximum bone density.

In patients treated with GnRH analogues for endometriosis, the addition of ABT (an estrogen and progestogen) has been shown to reduce mineral density loss and vasomotor symptoms (see 'Posology and Method of Administration' section 4.2 for further information).

Used at the recommended dose, Decapeptyl SR 11.25 mg 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 last injection.

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

In paediatric population

Central precocious puberty

In girls, it should be confirmed that the patient is not pregnant before prescribing triptorelin.

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

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

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.

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.

Idiopathic intracranial hypertension

Idiopathic intracranial hypertension (pseudotumor cerebri) has been reported in paediatric patients receiving triptorelin. Patients should be warned for signs and symptoms of idiopathic intracranial hypertension, including severe or recurrent headache, vision disturbances and tinnitus. If idiopathic intracranial hypertension occurs, discontinuation of triptorelin should be considered.

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

When Decapeptyl SR 11.25 mg 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 Decapeptyl SR 11.25 mg 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, disopyramide) or class III (e.g. amiodarone, sotalol, dofetilide, ibutilide) antiarrhythmic medicinal products, methadone, moxifloxacin, antipsychotics, etc. should be carefully evaluated (see section 4.4).

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 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.

Lactation

Triptorelin is not recommended for use during lactation.

Fertility

There is no clinical evidence to suggest a causal connection between triptorelin and any subsequent abnormalities of oocyte development or pregnancy or outcome.

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 (see section 4.4)

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 to < 1/10); uncommon (≥1/1000 to < 1/100); rare (≥1/10000 to < 1/1000); not known, (cannot be estimated from the available data).

* This frequency is based on class-effect frequencies common for all GnRH agonists

** Reported following initial administration in patients with pituitary adenoma

*** During post market experience convulsions have been reported in patients receiving GnRH analogues, including triptorelin.

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).

Patients receiving long-term treatment by GnRH analogue in combination with radiation therapy may have more side effects, mostly gastrointestinal and related to radiotherapy.

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, libido decreased, sleep disorder, mood changes, 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); uncommon (≥1/1000 to < 1/100); not known (cannot be estimated from the available data).

*Long term use: This frequency is based on class-effect frequencies common for all GnRH agonists

** Short term use: This frequency is based on class-effect frequencies common for all GnRH agonists

*** Reported following initial administration in patients with pituitary adenoma

**** During post market experience convulsions have been reported in patients receiving GnRH analogues, including triptorelin.

At the beginning of treatment, the symptoms of endometriosis may be exacerbated during the initial transient increase in plasma oestradiol levels. These symptoms are transient.

Vaginal bleeding including menorrhagia, 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); uncommon (≥1/1000 to < 1/100); not known; (cannot be estimated from the available data).

Vaginal bleeding may occur in the month following the first injection.

* During post market experience convulsions have been reported in patients receiving GnRH analogues, including triptorelin.

Long term tolerance in children population:

• The long-term clinical trial 2-54-52014-159 (NCT00909844) included 35 patients, age ranging from 4 to 10.4 years, who had received treatment (up to 4 years) with triptorelin 11.25 mg. More than half of patients (20 patients: 57.1%) reported at least one adverse event during the study, of which the most frequent were abdominal pain (17.1%), injection site pain (11.4%), headache and hot flush (each 8.6%). Overall, the safety profile was similar as seen in the other CPP studies.

General

Increased lymphocytes count has been reported with patients undergoing GnRH agonist 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 Yellow Card Scheme. Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

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 11.25 mg 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 more than 1000 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 another triptorelin 3-month formulation 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 triptorelin 28 day (n=68) or a single dose of triptorelin-3 month (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. The same pharmacodynamics equivalence has been demonstrated with Decapeptyl SR 11.25 mg and Decapeptyl SR 3 mg.

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 11.25 mg 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 11.25 mg induces suppression of oestrogen secretion and thus enables resting of ectopic endometrial tissue.

Central precocious puberty

Inhibition of the increased hypophyseal gonadotropic activity in children with central 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.

In the long-term clinical trial 2-54-52014-159 (NCT00909844), 34 girls and 1 boy with central precocious puberty (CPP) have been treated with triptorelin pamoate 11.25 mg every 3 months for a period of up to 4 years. Treatment ended when the investigator decided the patient had completed his/her treatment, that is to say at about 11 years in girls and 13 in boys, usually after 1-3 years of treatment. At that timepoint, 31/34 (91%) of girls had maintained stabilization or regression of Tanner breast pubertal stage.

Following intramuscular injection of Decapeptyl SR 11.25 mg in patients (men and women), a peak of plasma triptorelin is observed in the first 3 hours after injection. After a declining concentration phase, which continues during the first month, circulating triptorelin levels remain constant until the end of the third month following the injection.

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.

Triptorelin is not mutagenic in vitro or in vivo. In mice, no oncogenic effect has been shown with triptorelin at doses up to 6000 µg/kg after 18 months of treatment. A 23-month carcinogenicity study in rats has shown an almost 100% incidence of benign pituitary tumours at each dose level, leading to premature death. The increased incidence in pituitary tumours in rats is a common effect associated with GnRH agonist treatment. The clinical relevance of this is not known.

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.

3 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 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.