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Pharmacotherapeutic group: anti-gonadotrophin-releasing hormones. ATC code: H01CC01.
Pharmacology: Pharmacodynamics: Orgalutran is a GnRH antagonist, which modulates the hypothalamic-pituitary-gonadal axis by competitive binding to the GnRH receptors in the pituitary gland. As a result a rapid, profound, reversible suppression of endogenous gonadotrophins occurs, without initial stimulation as induced by GnRH agonists. Following administration of multiple doses of 0.25 mg Orgalutran to female volunteers serum LH, FSH and E2 concentrations were maximally decreased by 74%, 32% and 25% at 4, 16 and 16 hours after injection, respectively. Serum hormone levels returned to pre-treatment values within two days after the last injection.
In patients undergoing controlled ovarian stimulation, the median duration of Orgalutran treatment was 5 days. During Orgalutran treatment the average incidence of LH rises (>10 IU/l) with concomitant progesterone rise (>1 ng/ml) was 1.2% compared to 0.8% during GnRH agonist treatment. Early LH rises, prior to the start of Orgalutran at day 6 of stimulation, did occur especially in high responders, but did not affect the clinical outcome. In these patients LH production was rapidly suppressed after the first Orgalutran administration.
In controlled studies of Orgalutran, using a long protocol of GnRH agonist as a reference, treatment with the Orgalutran regimen resulted in a faster follicular growth during the first days of stimulation but the final cohort of growing follicles was slightly smaller and produced on average less estradiol. This different pattern of follicular growth requires that FSH dose adjustments are based on the number and size of growing follicles, rather than on the amount of circulating estradiol.
Pharmacokinetics: After a single subcutaneous administration of 0.25 mg, serum levels of ganirelix rise rapidly and reach peak levels (Cmax) of approximately 15 ng/ml within 1 to 2 hours (tmax). The elimination half-life (t½) is approximately 13 hours and clearance is approximately 2.4 l/h. Excretion occurs via feces (approximately 75%) and urine (approximately 22%). The bioavailability of Orgalutran following subcutaneous administration is approximately 91%.
Pharmacokinetic parameters after multiple subcutaneous dosing of Orgalutran (once daily injection) were similar to those after a single subcutaneous dose. After repeated dosing 0.25 mg/day steady state levels of approximately 0.6 ng/ml were reached within 2 to 3 days.
Pharmacokinetic analysis indicates an inverse relationship between body weight and serum concentrations of Orgalutran.
Metabolite profile: The major circulating component in plasma is ganirelix. Ganirelix is also the main compound found in urine. Feces only contain metabolites. The metabolites are small peptide fragments formed by enzymatic hydrolysis of ganirelix at restricted sites. The metabolite profile of Orgalutran in humans was similar to that found in animals.
Toxicology: Preclinical safety data: Preclinical data reveal no special hazard for humans based on safety pharmacology, repeated dose toxicity and genotoxicity.
Reproduction studies carried out with ganirelix at doses of 0.1 to 10 μg/kg/day subcutaneously in the rat and 0.1 to 50 μg/kg/day subcutaneously in the rabbit showed increased litter resorption in the highest dose groups. No teratogenic effects were observed.
