Ipsen Pharmaceuticals Ltd

Decapeptyl 6-month, 22.5mg

Powder and solvent for prolonged-release suspension for injection

Each vial contains triptorelin pamoate equivalent to 22.5mg triptorelin.

After reconstitution in 2mL solvent, 1 mL of reconstituted suspension contains 11.25mg of triptorelin.

Contains sodium but less than 1mmol (23mg) sodium per vial.

For a full list of excipients see section 6.1.

Powder and solvent for prolonged-release suspension for injection

Powder: White to off-white powder.

Solvent: Clear solution.

Decapeptyl 6 Month is indicated for the treatment of locally advanced or metastatic, hormone-dependent prostate cancer.

The recommended dose of Decapeptyl 6 Month is 22.5mg triptorelin (1 vial) administered every six months (twenty four weeks) as a single intramuscular injection.

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

Since Decapeptyl 6 Month is a suspension of microgranules, inadvertent intravascular injection must be strictly avoided.

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

Decapeptyl 6 Month must be administered under the supervision of a physician. Safety and efficacy of Decapeptyl 6 Month has not been established in neonates, infants, children and adolescents, therefore Decapeptyl 6 Month is not indicated for the use in these populations.

Decapeptyl 6 Month is not indicated for use in females.

Decapeptyl 6 Month is contraindicated in patients with known hypersensitivity to triptorelin, GnRH (Gonadotropin - releasing hormone), other GnRH agonist analogues or to any of the excipients of Decapeptyl 6 Month.

The product should only be used under the supervision of an appropriate specialist having requisite facilities for regular monitoring of response.

The use of GnRH agonists may cause a reduction in bone mineral density. In men, preliminary data suggest that the use of a bisphosphonate in combination with an GnRH agonist may reduce bone mineral loss. No specific data is available for patients with established osteoporosis or with risk factors for osteoporosis (e.g. chronic alcohol abuse, smokers, long-term therapy with drugs that reduce bone mineral density, e.g. anticonvulsants or corticosteroids, family history of osteoporosis, malnutrition, e.g. anorexia nervosa). Particular caution is therefore necessary since reduction in bone mineral density is likely to be more detrimental in these patients. Treatment with Decapeptyl SR should be considered on an individual basis and only be initiated if the benefits of treatment outweigh the risk following a very careful appraisal. Consideration should be given to additional measures in order to counteract loss of bone mineral density.

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

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, 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 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 and therefore should not be used after orchidectomy.

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.

Caution is required in patients treated with anticoagulants, due to the potential risk of haematomas at the site of injection.

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.

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.

Decapeptyl 6 Month contains sodium but less than 1 mmol (23 mg) sodium per dose, ie. essentially “sodium free”.

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 should be supervised.

Decapeptyl 6 Month is not indicated for use in females.

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

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 due to dizziness, somnolence and visual disturbances being possible side 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 (1/1,000 to <1/100); rare (1/10,000 to <1/1,000).

Triptorelin causes a transient increase in circulating testosterone levels within the first week after the initial injection of the sustained release formulation. With this initial increase in circulating testosterone levels, a small percentage of patients (5%) may experience a temporary worsening of signs and symptoms of their prostate cancer (tumour flare), usually manifested by an increase in urinary symptoms (< 2%) and metastatic pain (5%), which can be managed symptomatically. These symptoms are transient and usually disappear in one to two weeks.

Isolated cases of exacerbation of disease symptoms, either urethral obstruction or spinal cord compression by metastasis have occurred. Therefore, patients with metastatic vertebral lesions and/or with upper or lower urinary tract obstruction should be closely observed during the first few weeks of therapy (see section 4.4).

The use of GnRH agonists, to treat prostate cancer may be associated with increased bone loss and may lead to osteoporosis and increases the risk of bone fracture. This may also lead to an incorrect diagnosis of bone metastases.

Hypersensitivity and anaphylactic reactions have been reported with triptorelin.

The pharmaceutical properties of Decapeptyl 6 Month and its mode of administration make accidental or intentional overdosage unlikely. There is no human experience of overdosage. 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 6 Month. If overdosage occurs, this should be managed symptomatically.

Pharmacotherapeutic group:

Hormones and related agents, Gonadotropin releasing hormone analogues.

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 luteinizing 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 in surgically castrated men occurs approximately 2 to 4 weeks after initiation of therapy. Decapeptyl 6 Month 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 every twenty four weeks.

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 6 Month.

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 6 Month to patients with advanced prostate cancer as an intramuscular injection for a total of 2 doses (12 months) 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 (Week 48) of treatment.

Absorption:

Following a single intramuscular injection of Decapeptyl 6 Month 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 acetate 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 89.9mL/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 150 mL/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 6 Month 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 toxicity of triptorelin towards extragenital organs is low.

The observed effects were mainly related to the exacerbation of the pharmacological effects of triptorelin.

In chronic toxicity studies at clinically relevant doses, triptorelin induced macro- and microscopic changes in the reproductive organs of male rats, dogs and monkeys. These were considered as a reaction to suppressed gonadal function caused by the pharmacological activity of the compound. The changes were partly reversed during recovery. After subcutaneous administration of 10µg/kg to rats on days 6 to 15 of gestation, triptorelin did not elicit any embryotoxic, teratogenic, or any other effects on the development of the offspring (F1 generation) or their reproductive performance. At 100µg/kg, a reduction in maternal weight gain and an increased number of resorptions were observed.

Triptorelin is not mutagenic in vitro or in vivo. In mice, no oncogenic effect has been shown with triptorelin at doses up to 6000µg/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 mixed with other medicinal products.

3 years.

Use immediately after reconstitution.

Do not store above 25°C.

6mL septum vial (type I glass) with bromobutyl stopper and aluminium flip-off cap.

Ampoule (type I glass) 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 powder should be suspended immediately before use and only the solvent supplied should be used. The homogenous, milky suspension for injection is reconstituted by gentle shaking. The instructions for reconstitution hereafter and in the leaflet must be strictly followed.

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

The powder is to be suspended in 2 mL water for injections:

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

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

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

Ipsen Pharmaceuticals Limited

7 Upper Leeson Street

Dublin 4

Ireland

PA 869/3/3

Date of first authorisation: 08 April 2011