Source: European Medicines Agency (EU) Revision Year: 2020 Publisher: Merck Sharp & Dohme B.V., Waarderweg 39, 2031 BN Haarlem, The Netherlands
Pharmacotherapeutic group: Pituitary and hypothalamic hormones and analogues, anti-gonadotrophin-releasing hormones
ATC code: H01CC01
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 0.3-1.2% compared to 0.8% during GnRH agonist treatment. There was a tendency towards an increased incidence of LH and progesterone rises in women with a higher body weight (>80 kg), but no effect on clinical outcome was observed. However, based on the small number of patients treated so far, an effect cannot be excluded. In case of a high ovarian response, either as a result of a high exposure to gonadotrophins in the early follicular phase or as a result of high ovarian responsiveness, premature LH rises may occur earlier than day 6 of stimulation. Initiation of Orgalutran treatment on day 5 can prevent these premature LH rises without compromising the clinical outcome.
In controlled studies of Orgalutran with FSH, 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 oestradiol. 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 oestradiol. Similar comparative studies with corifollitropin alfa using either a GnRH antagonist or long agonist protocol have not been performed.
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.
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 bioavailability of Orgalutran following subcutaneous administration is approximately 91%.
The major circulating component in plasma is ganirelix. Ganirelix is also the main compound found in urine. Faeces 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.
The elimination half-life (t½) is approximately 13 hours and clearance is approximately 2.4 L/h. Excretion occurs via faeces (approximately 75%) and urine (approximately 22%).
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 g/kg/day subcutaneously in the rabbit showed increased litter resorption in the highest dose groups. No teratogenic effects were observed.
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