General Information

Cetrotide (cetrorelix acetate for injection) blocks the effects of a natural hormone, called gonadotropin-releasing hormone (GnRH). GnRH controls the secretion of another hormone, called luteinizing hormone (LH), which induces ovulation during the menstrual cycle. During hormone treatment for ovarian stimulation, premature ovulation may lead to eggs that are not suitable for fertilization. Cetrotide blocks such undesirable premature ovulation.

Cetrotide is specifically indicated for the inhibition of premature LH surges in women undergoing controlled ovarian stimulation.

Ovarian stimulation therapy with gonadotropins (FSH, hMG) is started on cycle Day 2 or 3. The dose of gonadotropins should be adjusted according to individual response. Cetrotide 0.25 mg may be administered subcutaneously once daily during the early- to mid-follicular phase. Cetrotide 0.25 mg is administered on either stimulation day 5 (morning or evening) or day 6 (morning) and continued daily until the day of hCG administration. When assessment by ultrasound shows a sufficient number of follicles of adequate size, hCG is administered to induce ovulation and final maturation of the oocytes. No hCG should be administered if the ovaries show an excessive response to the treatment with gonadotropins to reduce the chance of developing ovarian hyperstimulation syndrome (OHSS).

Mechanism of Action

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 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. (from FDA Label)

Clinical Trial Results

The effectiveness of Cetrotide has been examined in five clinical trials (two phase II and three phase III trials). Two dose regimens were investigated in these trials: either a single dose per treatment cycle or multiple dosing. In the phase II 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 four 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 was found to be dose dependent.

In the phase III program, efficacy of the single 3 mg dose regimen and the multiple 0.25 mg dose regimen was established separately in two controlled studies utilizing active comparitors. A third non-comparative study evaluated only the multiple 0.25 mg dose regimen of Cetrotide.

In the five phase II and phase III trials, 184 pregnancies have been reported out of a total of 732 patients (including 21 pregnancies following the replacement of frozen-thawed embryos). No drug related allergic reactions were reported from these clinical studies.