Decapeptyl SR 22.5mg powder and solvent for suspension for injection.

Triptorelin (I.N.N) 28mg as triptorelin pamoate.

The vial contains an overage to ensure that a dose of 22.5mg is administered to the patient.

For a full list of excipients see section 6.1.

Powder and solvent for suspension for injection, sustained release formulation.

Powder: White to off-white powder. Solvent: Clear solution.

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.

One intramuscular injection should be administered every 6 months.

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

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

Safety and efficacy of Decapeptyl SR 22.5mg has not been established in neonates, infants, children and adolescents, therefore Decapeptyl SR 22.5mg is not indicated for use in these populations.

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

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

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.

Mood changes, including depression have been reported. Patients with known depression should be monitored closely during therapy.

Initially, Decapeptyl SR 22.5mg, 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 implemented, and in extreme cases, an immediate surgical castration 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.

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. 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.

Decapeptyl SR 22.5mg contains less than 1mmol (23mg) sodium per dose.

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

When Decapeptyl SR 22.5mg 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.

Decapeptyl SR 22.5mg is not indicated for use in females.

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

No studies of 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

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 (1/1000 to <1/100); rare (1/10000 to <1/1000).

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).

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. This may also lead to an incorrect diagnosis of bone metastases.

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.

The pharmaceutical properties of Decapeptyl SR 22.5mg and its mode of administration make accidental or intentional overdose unlikely. There is no human experience of overdose. 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 22.5mg. 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. In males, 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), and testosterone.

However, chronic and continuous administration of triptorelin results in decreased LH and FSH secretion and suppression of testicular and ovarian steroidogenesis. 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 22.5mg is designed to deliver 22.5mg 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 22.5mg.

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

Clinical efficacy

Administration of Decapeptyl SR 22.5mg 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).

Absorption:

Following a single intramuscular injection of Decapeptyl SR 22.5mg 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. 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 0.5mg 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 0.5mg 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.

Special populations:

Following intravenous administration of 0.5mg 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 22.5mg 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.

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.

3 years.

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

6mL septum vial with bromobutyl stopper and aluminium flip-off cap.

Ampoule containing 2mL 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 'water for injections' that is provided as the suspension vehicle for Decapeptyl SR 22.5mg.

The suspension vehicle should be drawn into the syringe provided using one of the injection needles and transferred to the vial containing the powder for injection. The vial should be shaken from side to side until a homogeneous suspension is formed, and the mixture then drawn back into the syringe without inverting the vial. The injection needle should then be changed and the second needle used to administer the injection. As the product is a suspension, the injection should be administered immediately after reconstitution to prevent sedimentation.

To ensure patients receive the correct dose, each vial of Decapeptyl SR 22.5mg contains a small overage to allow for predictable losses on reconstitution and injection.

The vial is intended for single use only and any remaining product should be discarded. Used injections should be disposed of in a designated sharps container.

Ipsen Limited

190 Bath Road

Slough SL1 3XE

United Kingdom

PL 34926/0013

14 Sept 2010

24 Nov 2011