Decapeptyl SR 22.5mg powder and solvent for suspension for injection

Treatment of patients with locally advanced, non-metastatic prostate cancer, as an alternative to surgical castration.

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 central precocious puberty (CPP) in children 2 years and older with an onset of CPP before 8 years in girls and 10 years in boys).

Posology

The recommended dose of Decapeptyl SR 22.5 mg is 22.5 mg of triptorelin (1 vial) administered every six months (twenty four weeks) as a single intramuscular injection.

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.

Decapeptyl is also available as a 1-month treatment (Decapeptyl SR 3 mg) and as a 3-month treatment (Decapeptyl SR 11.25 mg).

Patients with renal or hepatic impairment

No dosage adjustment is necessary for patients with renal or hepatic impairment.

Paediatric population

Central precocious puberty (before 8 years in girls and 10 years in boys)

The treatment of children with Decapeptyl SR 22.5 mg should be under the overall supervision of a paediatric endocrinologist or of a paediatrician or an 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 12-13 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.

Method of administration

As with other medicinal products administered by injection, the injection site should be varied periodically.

Once reconstituted, the suspension of Decapeptyl SR 22.5 mg should be intramuscularly injected relatively rapidly and uninterrupted manner in order to avoid any potential blockage of the needle.

Precautions to be taken before handling or administering the medicinal product

Decapeptyl SR 22.5 mg is only intended for intramuscular use.

Since Decapeptyl SR 22.5 mg is a suspension of microparticles, inadvertent intravascular injection must be strictly avoided.

Decapeptyl SR 22.5 mg must be administered under the supervision of a physician.

For instructions on reconstitution of the medicinal product before administration, see section 6.6.

Hypersensitivity to GnRH, its analogues or to any of the excipients listed in section 6.1 (see also section 4.8).

Triptorelin is contraindicated during pregnancy and lactation (see section 4.6).

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. anti-convulsants 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.

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.

There is an increased risk of incident depression (which may be severe) in patients undergoing treatment with GnRH agonists, such as triptorelin. Patients should be informed accordingly and treated as appropriate if symptoms occur. Patients with known depression should be monitored closely during therapy.

Caution is required with intramuscular injection in patients treated with anticoagulants, due to the potential risk of haematomas at the site of injection. The efficacy and safety of Decapeptyl SR 22.5 mg has been established via intramuscular route only. The subcutaneous administration is not recommended.

Convulsions have been reported with GnRH analogues, particularly in 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 (23 mg) sodium per dose i.e it is essentially 'sodium free'.

Prostate cancer

Initially, triptorelin, 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 metastases, at 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. Once the castration levels of testosterone have been achieved by the end of the first month, serum testosterone levels are maintained for as long as the patients receive their injection every 6 months (twenty four weeks).

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 22.5 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 analogues and an increase in cardiovascular mortality. Patients at high risk of 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.

Central precocious puberty

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.

The therapy is a long-term treatment, adjusted individually. Decapeptyl SR 22.5mg should be administered as precisely as possible in regular 6 monthly periods. An exceptional delay of the injection date for a few days (169 ± 3 days) does not influence the results of the therapy.

After discontinuation of treatment the development of puberty characteristics will occur.

Information with regards to future fertility is still limited but future reproductive function and fertility appears to be unaffected by GnRH treatment. 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 due to the expected effects of oestrogen suppression. 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 22.5 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 should be supervised

Since androgen deprivation treatment may prolong the QT interval, the concomitant use of Decapeptyl SR 22.5 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).

Paediatric Population

Interaction studies have only been performed in adults.

Pregnancy

Decapeptyl SR 22.5 mg is indicated for adult men and children. There are very limited data on the use of triptorelin in pregnant women. It should be confirmed that the patient is not pregnant before prescription of Decapeptyl SR 22.5 mg.

Triptorelin must not be used during pregnancy since concurrent use of GnRH agonists is associated with a theoretical risk of abortion or fetal abnormality. Prior to treatment, potential fertile women should be examined carefully to exclude pregnancy. Non-hormonal methods of contraception should be employed during therapy until menses return.

Animal studies have shown effects on reproductive parameters (see section 5.3 Preclinical safety data).

Lactation

Decapeptyl SR 22.5 mg is not indicated in lactating women.

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.

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, < 1/10); uncommon (≥ 1/1000, < 1/100); rare (≥ 1/10 000, < 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/or 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 Special warnings and 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 increase the risk of bone fracture. This may also lead to an incorrect diagnosis of bone metastases.

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

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, < 1/100); not known (cannot be estimated from the available data).

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

General

Increased lymphocyte 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.

The pharmaceutical properties of Decapeptyl SR 22.5 mg and its mode of administration make accidental or intentional overdose unlikely. There is no experience of overdose from clinical trials. Animal tests suggest that no effect other than the intended therapeutic effects on sex hormone concentration and on the reproductive tract will be evident with higher doses of Decapeptyl SR 22.5 mg. If overdose occurs, this should be managed symptomatically.

Pharmacotherapeutic group:

Hormones and related agents, gonadotropin releasing hormone agonists.

ATC code:

L02AE04

Mechanism of action and pharmacodynamic effects

Triptorelin, a GnRH agonist, acts as a potent inhibitor of gonadotropin secretion when given continuously and in therapeutic doses. Animal and human studies show that after administration of triptorelin there is an initial and transient increase in circulating levels of luteinising hormone (LH), follicle stimulating hormone (FSH), testosterone in males and oestradiol in females.

However, chronic and continuous administration of triptorelin results in decreased LH and FSH secretion and suppression of testicular and ovarian steroidogenesis.

In men with prostate cancer

A reduction of serum testosterone levels into the range normally seen after bilateral orchidectomy occurs approximately 2 to 4 weeks after initiation of therapy. Decapeptyl SR 22.5 mg is designed to deliver 22.5 mg of triptorelin over a 6-month period. Once the castration levels of testosterone have been achieved by the end of the first month, serum testosterone levels are maintained for as long as the patients receive their injection according to the recommended posology.

This results in accessory sexual organ atrophy. These effects are generally reversible upon discontinuation of the medicinal product. The effectiveness of treatment can be monitored by measuring serum levels of testosterone and prostate specific antigen. As shown during the clinical trial programme, there was a 97% median relative reduction in PSA at Month 6 for Decapeptyl SR 22.5 mg.

In animals, administration of triptorelin resulted in the inhibition of growth of some hormone-sensitive prostate tumours in experimental models.

Clinical efficacy in prostate cancer

Administration of Decapeptyl SR 22.5 mg to patients with advanced prostate cancer as an intramuscular injection for a total of 2 doses (48 weeks) resulted in both achievement of castration levels of testosterone in 97.5% of patients after four weeks and maintenance of castration levels of testosterone in 93.0% of the patients from Month 2 through Month 12 of treatment.

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.

Clinical efficacy and safety in children with central precocious puberty

In a non-comparative clinical study, 44 children with central precocious puberty (39 girls and 5 boys) were treated with a total of two intramuscular injections of Decapeptyl SR 22.5 mg over 12 months (48 weeks). Suppression of stimulated LH concentrations to prepubertal levels was achieved in 95.5% of subjects by month 3, and in 93.2 % and 97.7% of subjects at months 6 and 12, respectively.

The consequence is a regression or stabilisation of secondary sex characteristics and slowing down of accelerated bone maturation and growth.

In girls, initial ovarian stimulation at treatment initiation, followed by the treatment-induced oestrogen increase, may lead, in the first month, to uterine 'withdrawal' bleeding of mild or moderate intensity.

Absorption:

Following a single intramuscular injection of Decapeptyl SR 22.5 mg in patients with prostate cancer, T_max was 3 (2-12) hours and C_max (0-169 days) was 40.0 (22.2-76.8)ng/mL.

In children with precocious puberty t_max was 4 (2-8) hours and C_max (0-169 days) was 39.9 (19.1-107.0) ng/ml.

Triptorelin did not accumulate over 12 months of treatment.

Distribution:

Results of pharmacokinetic investigations conducted in healthy men indicate that after intravenous bolus administration, triptorelin is distributed and eliminated according to a 3-compartment model and corresponding half-lives are approximately 6 minutes, 45 minutes, and 3 hours.

The volume of distribution at steady state of triptorelin following intravenous administration of 0.5 mg triptorelin is approximately 30L in healthy male volunteers. Since there is no evidence that triptorelin at clinically relevant concentrations binds to plasma proteins, medicinal product interactions involving binding-site displacement are unlikely.

Biotransformation:

Metabolites of triptorelin have not been determined in humans. However, human pharmacokinetic data suggest that C-terminal fragments produced by tissue degradation are either completely degraded within tissues or are rapidly further degraded in plasma, or cleared by the kidneys.

Elimination:

Triptorelin is eliminated by both the liver and the kidneys. Following intravenous administration of 0.5 mg triptorelin to healthy male volunteers, 42% of the dose was excreted in urine as intact triptorelin, which increased to 62% in subjects with hepatic impairment. Since creatinine clearance (Cl_creat) in healthy volunteers was 150mL/min and only 90mL/min in subjects with hepatic impairment, this indicates that the liver is a major site of triptorelin elimination. In these healthy volunteers, the true terminal half-life of triptorelin was 2.8 hours and total clearance of triptorelin 212mL/min, the latter being dependent on a combination of hepatic and renal elimination.

Other special populations:

Following intravenous administration of 0.5 mg triptorelin to subjects with moderate renal insufficiency (Cl_creat 40mL/min), triptorelin had an elimination half-life of 6.7 hours, 7.81 hours in subjects with severe renal insufficiency (Cl_creat 8.9mL/min) and 7.65 hours in patients with impaired hepatic function (Cl_creat 89.9 mL/min).

The effects of age and race on triptorelin pharmacokinetics have not been systematically studied. However, pharmacokinetic data obtained in young healthy male volunteers aged 20 to 22 years with an elevated creatinine clearance (approximately 150mL/min) indicated that triptorelin was eliminated twice as fast in the young population. This is related to the fact that triptorelin clearance is correlated to total creatinine clearance, which is well known to decrease with age.

Because of the large safety margin of triptorelin and since Decapeptyl SR 22.5 mg is a sustained release formulation, no dose adjustment is recommended in patients with renal or hepatic impairment.

Pharmacokinetic/pharmacodynamic relationship

The pharmacokinetics/pharmacodynamics relationship of triptorelin is not straightforward to assess, since it is non-linear and time-dependent. Thus, after acute administration in naive subjects, triptorelin induces a dose-dependent increase of LH and FSH responses.

When administered as a sustained release formulation, triptorelin stimulates LH and FSH secretion during the first days post dosing and, in consequence, testosterone secretion. As shown by the results of the different bioequivalence studies, the maximal increase in testosterone is reached after around 4 days with an equivalent C_max which is independent from the release rate of triptorelin. This initial response is not maintained despite continuous exposure to triptorelin and is followed by a progressive and equivalent decrease of testosterone levels. In this case too, the extent of triptorelin exposure can vary markedly without affecting the overall effect on testosterone serum levels.

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 µ g/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.

Powder:

poly (d,l-lactide-co-glycolide)

mannitol

carmellose sodium

polysorbate 80

Solvent:

water for injections

In the absence of compatibility studies, this medicinal product must not be reconstituted with other medicinal products.

4 years.

Do not store above 25° C. Keep the container in the outer carton. The reconstituted suspension for injection should be used immediately.

Powder vial: 6 mL septum transparent light brown vial (type I glass) with bromobutyl stopper and aluminium cap with dark green flip-off cover.

Solvent ampoule: transparent, colourless ampoule (type I glass) containing 2 mL of sterile solvent for suspension.

Box of:

1 vial, 1 ampoule and 1 blister containing 1 injection syringe and 2 injection 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.

Any unused medicinal product, needles or other waste material should be disposed of in accordance with local requirements.