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GnRH induces the production and release of luteinizing hormone (LH) and follicle stimulating hormone (FSH) from the gonadotrophic cells of the anterior pituitary. Due to a positive estradiol (E2) feedback at midcycle, GnRH liberation is enhanced resulting in an LH-surge. This LH-surge induces the ovulation of the dominant follicle, resumption of oocyte meiosis and subsequently luteinization as indicated by rising progesterone levels.
Cetrotide® competes with natural GnRH for binding to membrane receptors on pituitary cells and thus controls the release of LH and FSH in a dose-dependent manner. The onset of LH suppression is approximately one hour with the 3 mg dose and two hours with the 0.25 mg dose. This suppression is maintained by continuous treatment and there is a more pronounced effect on LH than on FSH. An initial release of endogenous gonadotropins has not been detected with Cetrotide®, which is consistent with an antagonist effect.
The effects of Cetrotide® on LH and FSH are reversible after discontinuation of treatment. In women, Cetrotide® delays the LH-surge, and consequently ovulation, in a dose-dependent fashion. FSH levels are not affected at the doses used during controlled ovarian stimulation. Following a single 3 mg dose of Cetrotide®, duration of action of at least 4 days has been established. A dose of Cetrotide® 0.25 mg every 24 hours has been shown to maintain the effect.
The pharmacokinetic parameters of single and multiple doses of Cetrotide® (cetrorelix acetate for injection) in adult healthy female subjects are summarized in Table 1.
Table 1: Pharmacokinetic parameters of Cetrotide®
following 3 mg single or 0.25 mg single and multiple (daily for 14 days)
subcutaneous (sc) administration.
|Single dose 3 mg||Single dose 0.25 mg||Multiple dose 0.25 mg|
|No. of subjects||12||12||12|
|tmax† [h]||1.5 (0.5-2)||1.0 (0.5-1.5)||1.0 (0.5-2)|
|t½† [h]||62.8 (38.2-108)||5.0 (2.4-48.8)||20.6 (4.1-179.3)|
|Cmax [ng/ml]||28.5 (22.5-36.2)||4.97 (4.17-5.92)||6.42 (5.18-7.96)|
|AUC [ngh/ml]||536 (451-636)||31.4 (23.4-42.0)||44.5 (36.7-54.2)|
|* CL [ml/minkg]||1.28‡|
|tmax Time to reach observed maximum plasma concentration
t½ Elimination half-life
Cmax Maximum plasma concentration; multiple dose Css, max
AUC Area under the curve; single dose AUC0-inf, multiple dose AUCt
CL Total plasma clearance
Vz Volume of distribution
Geometric mean (95% CIln),
† median (min-max)
‡ Based on iv administration (n=6, separate study 0013)
Cetrotide® is rapidly absorbed following subcutaneous injection, maximal plasma concentrations being achieved approximately one to two hours after administration. The mean absolute bioavailability of Cetrotide® following subcutaneous administration to healthy female subjects is 85%.
The volume of distribution of Cetrotide® following a single intravenous dose of 3 mg is about 1 l/kg. In vitro protein binding to human plasma is 86%.
Cetrotide® concentrations in follicular fluid and plasma were similar on the day of oocyte pick-up in patients undergoing controlled ovarian stimulation. Following subcutaneous administration of Cetrotide® 0.25 mg and 3 mg, plasma concentrations of cetrorelix were below or in the range of the lower limit of quantitation on the day of oocyte pick-up and embryo transfer.
After subcutaneous administration of 10 mg Cetrotide® to females and males, Cetrotide® and small amounts of (1-9), (1-7), (1-6), and (1-4) peptides were found in bile samples over 24 hours.
In in vitro studies, Cetrotide® was stable against phase I- and phase II-metabolism. Cetrotide® was transformed by peptidases, and the (1-4) peptide was the predominant metabolite.
Following subcutaneous administration of 10 mg cetrorelix to males and females, only unchanged cetrorelix was detected in urine. In 24 hours, cetrorelix and small amounts of the (1-9), (1-7), (1-6), and (1-4) peptides were found in bile samples. 2-4% of the dose was eliminated in the urine as unchanged cetrorelix, while 5-10% was eliminated as cetrorelix and the four metabolites in bile. Therefore, only 7-14% of the total dose was recovered as unchanged cetrorelix and metabolites in urine and bile up to 24 hours. The remaining portion of the dose may not have been recovered since bile and urine were not collected for a longer period of time.
Pharmacokinetic investigations have not been performed either in subjects with impaired renal or liver function, or in the elderly, or in children (see PRECAUTIONS).
Pharmacokinetic differences in different races have not been determined.
There is no evidence of differences in pharmacokinetic parameters for Cetrotide® between healthy subjects and patients undergoing controlled ovarian stimulation.
No formal drug-drug interaction studies have been performed with Cetrotide® (see PRECAUTIONS).
Seven hundred thirty two (732) patients were treated with Cetrotide® (cetrorelix acetate for injection) in five (two Phase 2 dose-finding and three Phase 3) clinical trials. The clinical trial population consisted of Caucasians (95.5%) and Black, Asian, Arabian and others (4.5%). Women were between 19 and 40 years of age (mean: 32). The studies excluded subjects with polycystic ovary syndrome (PCOS), subjects with low or no ovarian reserve, and subjects with stage III-IV endometriosis.
Two dose regimens were investigated in these clinical trials, either a single dose per treatment cycle or multiple dosing. In the Phase 2 studies, a single dose of 3 mg was established as the minimal effective dose for the inhibition of premature LH surges with a protection period of at least 4 days. When Cetrotide® is administered in a multidose regimen, 0.25 mg was established as the minimal effective dose. The extent and duration of LH-suppression is dose dependent.
In the Phase 3 program, efficacy of the single 3 mg dose regimen of Cetrotide® and the multiple 0.25 mg dose regimen of Cetrotide® was established separately in two adequate and well controlled clinical studies utilizing active comparators. A third non-comparative clinical study evaluated only the multiple 0.25 mg dose regimen of Cetrotide®. The ovarian stimulation treatment with recombinant FSH or human menopausal gonadotropin (hMG) was initiated on day 2 or 3 of a normal menstrual cycle. The dose of gonadotropins was administered according to the individual patient's disposition and response.
In the single dose regimen study, Cetrotide®3 mg was administered on the day of controlled ovarian stimulation when adequate estradiol levels (400 pg/mL) were obtained, usually on day 7 (range day 5-12).If hCG was not given within 4 days of the 3 mg dose of Cetrotide®, then 0.25 mg of Cetrotide® was administered daily beginning 96 hours after the 3 mg injection until and including the day of hCG administration.
In the two multiple dose regimen studies, Cetrotide®0.25 mg was started on day5 or 6 of COS. Both gonadotropins and Cetrotide® were continued daily (multiple dose regimen) until the injection of human chorionic gonadotropin (hCG).
Oocyte pick-up (OPU) followed by in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) as well as embryo transfer (ET) were subsequently performed. The results for Cetrotide® are summarized below in Table 2.
Table 2: Results of Phase 3 Clinical Studies with
Cetrotide®(cetrorelix acetate for injection) 3 mg in a single dose (sd)regimen
and 0.25 mg in a multiple dose (md) regimen
|Parameter||Cetrotide® 3 mg (sd, active comparator study)||Cetrotide® 0.25 mg (md, active comparator study)||Cetrotide® 0.25 mg (md, noncomparative study)|
|No. of subjects||115||159||303|
|hCG administered [%]||98.3||96.2||96.0|
|Oocyte pick-up [%]||98.3||94.3||93.1|
|LH-surge [%] (LH ≥ 10 U/L and P* ≥ 1 ng/mL) †||0.0||1.9||1.0|
|Serum E2 [pg/ml] at day
|Serum LH [U/L] at day hCG‡, §||1.0(0.5-2.5)||1.5 (0.5-7.6)||1.1(0.5-3.5)|
|No. of follicles ≥ 11 mm at
|11.2 ± 5.5||10.8 ± 5.2||10.4 ± 4.5|
|No. of oocytes: IVF¶||9.2 ± 5.2||7.6 ± 4.3||8.5 ± 5.1|
|ICSI¶||10.0 ± 4.2||10.1 ± 5.6||9.3 ± 5.9|
|Fertilization rate: IVF¶||0.48 ± 0.33||0.62 ± 0.26||0.60 ± 0.26|
|ICSI¶||0.66 ± 0.29||0.63 ± 0.29||0.61 ± 0.25|
|No. of embryos transferred¶||2.6 ± 0.9||2.1 ± 0.6||2.7 ± 1.0|
|Clinical pregnancy rate [%]|
|per subject with ET||26.3||24.1||23.3|
† Following initiation of Cetrotide® therapy
‡ Morning values
§ Median with 5th – 95th percentiles
Mean ± standard deviation
In addition to IVF and ICSI, one pregnancy was obtained after intrauterine insemination. In the five Phase 2 and Phase 3 clinical trials, 184 pregnancies have been reported out of a total of 732 patients (including 21 pregnancies following the replacement of frozen-thawed embryos).
In the 3 mg regimen, 9 patients received an additional dose of 0.25 mg of Cetrotide® and two other patients received two additional doses of 0.25 mg Cetrotide®. The median number of days of Cetrotide® multiple dose treatment was 5 (range 1-15) in both studies.
No drug related allergic reactions were reported from these clinical studies.
Last reviewed on RxList: 5/9/2016
This monograph has been modified to include the generic and brand name in many instances.
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