Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2018 Publisher: Ipsen Limited, 190 Bath Road, Slough, Berkshire, SL1 3XE, United Kingdom
Pharmacotherapeutic group: Gonadotropin releasing hormone analogues
ATC code: L02AE04
Triptorelin, a GnRH agonist, acts as a potent inhibitor of gonadotropin secretion when given continuously and in therapeutic doses. Studies in men show that after the 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 to men results in decreased LH and FSH secretion and suppression of testicular steroidogenesis. A reduction of serum testosterone levels into the range normally seen after surgical castration occurs approximately 2 to 4 weeks after initiation of therapy. This results in accessory sexual organ atrophy. These effects are generally reversible upon discontinuation of the medicinal product.
Testosterone plays a major role in the regulation of sexuality, aggression, cognition, emotion, and personality. In particular, it is a major determinant of sexual desire, fantasies and behaviour, and basically controls the frequency, duration and magnitude of spontaneous erections. The effects of testosterone (and of its reduced metabolite 5α-dihydrotestosterone [DHT]) are mediated through their actions on the intracellular androgen receptor.
Administration of Salvacyl as an intramuscular injection for a total of 3 doses (9 months) resulted in achievement of castration levels of testosterone in 97.6% of patients with advanced prostate cancer after four weeks of treatment, which was maintained from month 2 through month 9 of treatment in 94.1% of the patients.
Following a single intramuscular injection of Salvacyl, tmax was 2 (2-6) hours and Cmax (0-85 days) was 37.1 (22.4-57.4) ng/ml. Triptorelin did not accumulate over 9 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 30 l in healthy men.
Metabolism of triptorelin has not been determined in humans.
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. In these healthy volunteers, the true terminal half-life of triptorelin was 2.8 hours and total clearance of triptorelin 212 ml/min.
Triptorelin clearance decreases with impaired renal or liver function. Following intravenous administration of 0.5 mg triptorelin to subjects with moderate renal insufficiency (Clcreat 40 ml/min), triptorelin had a clearance of 120 ml/min; 88.6 ml/min in subjects with severe renal insufficiency (Clcreat 8.9 ml/min) and 57.8 ml/min in patients with mild to moderate impaired hepatic function (Clcreat 89.9 ml/min).
Because of the large safety margin of Salvacyl, no dose adjustment is recommended in patients with renal or hepatic impairment.
The effects of age and race on triptorelin pharmacokinetics have not been systematically studied.
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 toxicity of triptorelin towards extragenital organs is low.
The observed effects were mainly related to the excessive 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 to reflect the suppressed gonadal function caused by the pharmacological activity of the compound. The changes were partly reversed during recovery. After subcutaneous administration of 10 micrograms/kg to rats on days 6 to 15 of gestation, triptorelin did not elicit any embryotoxicity, teratogenicity, or any effects on the development of the offspring (F1 generation) or their reproductive performance. At 100 micrograms/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 carcinogenic effect has been shown with triptorelin at doses up to 6000 micrograms/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.
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