Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2016 Publisher: Ipsen Limited, 190 Bath Road, Slough SL1 3XE, United Kingdom
Pharmacotherapeutic group: Hormones and related agents, gonadotropin releasing hormone agonists.
ATC code: L02AE04
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.
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.
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.
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.
Following a single intramuscular injection of Decapeptyl SR 22.5 mg in patients with prostate cancer, Tmax was 3 (2-12) hours and Cmax (0-169 days) was 40.0 (22.2-76.8)ng/mL.
In children with precocious puberty tmax was 4 (2-8) hours and Cmax (0-169 days) was 39.9 (19.1-107.0) ng/ml.
Triptorelin did not accumulate over 12 months of treatment.
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.
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.
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 (Clcreat) 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.
Following intravenous administration of 0.5 mg triptorelin to subjects with moderate renal insufficiency (Clcreat 40mL/min), triptorelin had an elimination half-life of 6.7 hours, 7.81 hours in subjects with severe renal insufficiency (Clcreat 8.9mL/min) and 7.65 hours in patients with impaired hepatic function (Clcreat 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.
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 Cmax 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.
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