Cetrotide - Product Information
|Manufacture:||EMD Serono, Inc|
|Class:||Somatostatin and somatostatin analogs|
|Form:||Liquid solution, Subcutaneous (SC)|
Actions and Clinical Pharmacology
Cetrotide(cetrorelix for injection) is a synthetic decapeptide with gonadotropin-releasing hormone (GnRH) antagonistic activity. Cetrorelix acetate is an analog of native GnRH with substitutions of amino acids at positions 1, 2, 3, 6, and 10. The molecular formula is Acetyl-D-3-(2´-naphtyl)-alanine-D-4-chlorophenylalanine-D-3-(3´-pyridyl)-alanine-L-serine-L-tyrosine-D-citruline-L-leucine-L-arginine-L-proline-D-alanine-amide, and the molecular weight is 1431.06, calculated as the anhydrous free base.
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 (cetrorelix for injection) 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 (cetrorelix for injection), which is consistent with an antagonist effect.
The effects of Cetrotide (cetrorelix for injection) on LH and FSH are reversible after discontinuation of treatment. In women, Cetrotide (cetrorelix for injection) 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 (cetrorelix for injection), duration of action of at least 4 days has been established. A dose of Cetrotide (cetrorelix for injection) 0.25 mg every 24 hours has been shown to maintain the effect.
Seven hundred thirty two (732) patients were treated with Cetrotide (cetrorelix 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 years). 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 (cetrorelix for injection) 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 (cetrorelix for injection) and the multiple 0.25 mg dose regimen of Cetrotide (cetrorelix for injection) 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 (cetrorelix for injection). 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 (cetrorelix for injection) 3 mg was administered on the day of controlled ovarian stimulation (COS) when adequate estradiol levels (400 pg/ml) were obtained, usually on day 7 (range day 5-12). If human chorionic gonadotropin (hCG) was not given within 4 days of the 3 mg dose of Cetrotide (cetrorelix for injection), then 0.25 mg of Cetrotide (cetrorelix for injection) 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 (cetrorelix for injection) 0.25 mg was started on day 5 or 6 of COS. Both gonadotropins and Cetrotide (cetrorelix for injection) were continued daily (multiple dose regimen) until the injection of hCG.
In the two active comparative studies, results showed that on stimulation day 6/7 there were more small follicles in the Cetrotide (cetrorelix for injection) patient group than in the comparator patient groups. This was reversed on the day of hCG administration, when the number of small (11-14 mm) follicles was generally lower in the Cetrotide (cetrorelix for injection) than in the comparator groups. There was no or only a small difference with regard to the medium-size or large follicles (20 mm and over) on the day of hCG administration.
Levels of E2 increased continuously and a pronounced increase in E2 levels was seen the day before hCG administration in both groups [Cetrotide (cetrorelix for injection) and comparator]. On the day of hCG administration, E2 levels were clearly higher and the increase was faster in the comparator groups than in the Cetrotide (cetrorelix for injection) group. These higher E2 levels in the comparator groups correlate with a higher number of small follicles in this group.
The fertilization rate of Cetrotide (cetrorelix for injection) treatment versus the comparator patient groups was also similar.
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 (cetrorelix for injection) are summarized below in Table 1.
|Parameter||Cetrotide (cetrorelix for injection) 3 mg (sd, active comparative study)||Cetrotide (cetrorelix for injection) 0.25 mg (md, active comparative study)||Cetrotide (cetrorelix for injection) 0.25 mg (md, non-comparative 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 Pa ≥1 ng/mL)b||0.0||1.9||1.0|
|Serum E2 [pg/ml] at day hCGc,d||1125
(470 – 2952)
(341 – 2531)
(311 – 3676)
|Serum LH [U/L] at day hCGc,d||1.0
(0.5 – 2.5)
(0.5 – 7.6)
(0.5 – 3.5)
|No. of follicles ≥11 mm at day hCGe||11.2 ± 5.5||10.8 ± 5.2||10.4 ± 4.5|
|No. of oocytes: IVFe
9.2 ± 5.2
10.0 ± 4.2
7.6 ± 4.3
10.1 ± 5.6
8.5 ± 5.1
9.3 ± 5.9
|Fertilization rate: IVFe
0.48 ± 0.33
0.66 ± 0.29
0.62 ± 0.26
0.63 ± 0.29
0.60 ± 0.26
0.61 ± 0.25
|No. of embryos transferrede||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|
b Following initiation of Cetrotide (cetrorelix for injection) therapy
c Morning values
d Median with 5th - 95th percentiles
e 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 (cetrorelix for injection) and two other patients received two additional doses of 0.25 mg Cetrotide (cetrorelix for injection). The median number of days of Cetrotide (cetrorelix for injection) multiple dose treatment was 5 (range 1-15) in both studies.
Limited data are available in repeated administration of Cetrotide (cetrorelix for injection) in the same patient (for multiple cycles). Accordingly, it is unknown (up until now) whether the efficacy remains unchanged, or whether immunogenicity and/or sensitization has been developed with the use of Cetrotide (cetrorelix for injection) in the same patient for more than one cycle.
Indications and Clinical Use
Cetrotide (cetrorelix for injection) is indicated for the prevention of premature ovulation in patients undergoing controlled ovarian stimulation.
Cetrotide (cetrorelix for injection) is contraindicated under the following conditions:
- Hypersensitivity to cetrorelix acetate, extrinsic peptide hormones or mannitol.
- Known hypersensitivity to GnRH or any other GnRH analogs.
- Known or suspected pregnancy, and lactation (see PRECAUTIONS).
- Moderate or severe impairment of hepatic or renal function.
Cetrotide (cetrorelix for injection) should be prescribed by physicians who are experienced in fertility treatment. Before starting treatment with Cetrotide (cetrorelix for injection), pregnancy must be excluded (see CONTRAINDICATIONS and PRECAUTIONS).
Caution is advised in patients with hypersensitivity to GnRH analogs. These patients should be carefully monitored after the first injection, where treatment of possible allergic/pseudo-allergic reactions (including life-threatening anaphylaxis) is immediately available. Therefore, it is recommended that a physician supervises the first administration. Special care should be taken in women with signs and symptoms of active allergic conditions or known history of allergic predisposition. Treatment with Cetrotide (cetrorelix for injection), is not advised in women with severe allergic conditions.
Efficacy and safety (immunogenicity and/or sensitization) have not been extensively evaluated in women undergoing multiple treatment cycles with Cetrotide (cetrorelix for injection). However, hypersensitivity, antibody formation, and acute anaphylactic reaction have been reported with GnRH analogs. Therefore, special care should be taken upon using the drug in the same patient for more than one cycle.
Ovarian Hyperstimulation Syndrome (OHSS)
During or following ovarian stimulation an ovarian hyperstimulation syndrome (OHSS) can occur. This event must be considered as an intrinsic risk of the stimulation procedure with gonadotropins. Protocols combining gonadotropins and GnRH antagonist have been found to be correlated with a shorter duration of stimulation and of lower dose of gonadotropins, lower estradiol level. These findings may account for the reduction of the risk of OHSS, associated with the use of GnRH antagonists.
The prevalence of congenital anomalies after the use of assisted reproductive technologies (ART) with or without GnRH antagonists may be slightly higher than after spontaneous conceptions although it is unclear whether this is related to factors inherent to the couple's infertility or the ART procedures.
Information for Patients
Prior to therapy with Cetrotide (cetrorelix for injection), patients should be informed of the duration of treatment and monitoring procedures that will be required. The risk of possible adverse reactions should be discussed (see ADVERSE REACTIONS). Cetrotide (cetrorelix for injection) should not be prescribed if a patient is pregnant. If Cetrotide (cetrorelix for injection) is prescribed to patients for self-administration, information for proper use is given in the Patient Insert (see Information for the Consumer).
No formal drug interaction studies have been performed with Cetrotide (cetrorelix for injection). In clinical studies, no interaction between exogenous gonadotropins and Cetrotide (cetrorelix for injection) was observed.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term carcinogenicity studies in animals have not been performed with cetrorelix acetate. Cetrorelix acetate was not genotoxic invitro (Ames test, HPRT test, chromosome aberration test) or in vivo (chromosome aberration test, mouse micronucleus test). Cetrorelix acetate induced polyploidy in CHL-Chinese hamster lung fibroblasts, but not in V79-Chinese hamster lung fibroblasts, cultured peripheral human lymphocytes or in an in-vitro micronucleus test in the CHL-cell line. Treatment with 0.46 mg/kg cetrorelix acetate for 4 weeks resulted in complete infertility in female rats which was reversed 8 weeks after cessation of treatment.
Pregnancy and Lactation
Cetrotide (cetrorelix for injection) is contraindicated in pregnant women.
When administered to rats for the first seven days of pregnancy, cetrorelix acetate did not affect the development of the implanted conceptus at doses up to 38 μg/kg (approximately 1 times the recommended human therapeutic dose based on body surface area). However, a dose of 139 μg/kg (approximately 4 times the human dose) resulted in a resorption rate and a post-implantation loss of 100%.
When administered from day 6 to near term to pregnant rats and rabbits, very early resorptions and total implantation losses were seen in rats at doses from 4.6 μg /kg (0.2 times the human dose) and in rabbits at doses from 6.8 μg /kg (0.4 times the human dose). In animals that maintained their pregnancy, there was no increase in the incidence of fetal abnormalities.
The fetal resorption observed in animals is a logical consequence of the alteration in hormonal levels effected by the antigonadotrophic properties of Cetrotide (cetrorelix for injection), which could result in fetal loss in humans as well. Therefore, this drug should not be used in pregnant women.
It is not known whether Cetrotide (cetrorelix for injection) is excreted in human milk. Because many drugs are excreted in human milk, and because the effects of Cetrotide (cetrorelix for injection) on lactation and/or the breast-fed child have not been determined, Cetrotide (cetrorelix for injection) is contraindicated for nursing mothers.
The safety of Cetrotide (cetrorelix for injection) in 949 patients undergoing controlled ovarian stimulation in clinical studies was evaluated. Women were between 19 and 40 years of age (mean: 32). 94.0 % of them were Caucasian. Cetrotide (cetrorelix for injection) was given in doses ranging from 0.1 mg to 5 mg as either a single or multiple dose.
Table 2 shows systemic adverse events from the beginning of Cetrotide (cetrorelix for injection) treatment until confirmation of pregnancy by ultrasound at an incidence ≥1% in Cetrotide (cetrorelix for injection) treated subjects undergoing COS.
|Table 2: Adverse Events in ≥1%
(WHO preferred term)
|Cetrotide(cetrorelix for injection)
|Ovarian Hyperstimulation Syndrome#||3.5 (33)|
# Intensity moderate or severe, or WHO Grade II or III, respectively
Local site reactions (e.g. pain, redness, swelling pruritus, erythema, hematoma and/or irritation at the site of injection) have been commonly reported. Usually, they were of a transient nature and mild intensity. Rare cases of hypersensitivity reactions including life-threatening anaphylactoid reactions have been observed.
Two stillbirths were reported in Phase 3 studies of Cetrotide (cetrorelix for injection).
Ovarian Hyperstimulation Syndrome (OHSS)
During or following controlled ovarian stimulation an ovarian hyperstimulation syndrome can occur. This event must be considered as an intrinsic risk of the stimulation procedure with gonadotropins (refer to the relevant gonadotropin Product Monograph for warning symptoms etc.).
In this potentially serious medical event, the ovaries are massively enlarged, and intravascular fluid volume shifts into the peritoneal space, resulting in hypovolemia, oliguria, hemoconcentration, and massive ascites. The syndrome can usually be avoided by closely monitoring the patient and withholding the hCG if ovarian response becomes excessive.
Clinical follow-up studies of 316 newborns of women administered Cetrotide (cetrorelix for injection) were reviewed. One infant of a set of twin neonates was found to have anencephaly at birth and died after four days. The other twin was normal. Developmental findings from ongoing baby follow-up included a child with a ventricular septal defect and another child with bilateral congenital glaucoma.
Four pregnancies that resulted in therapeutic abortion in Phase 2 and Phase 3 controlled ovarian stimulation studies had major anomalies (diaphragmatic hernia, trisomy 21, Klinefelter syndrome, polymalformation, and trisomy 18). In three of these four cases, intracytoplasmic sperm injection (ICSI) was the fertilization method employed; in the fourth case, in-vitro fertilization (IVF) was the method employed.
The minor congenital anomalies reported include: supernumerary nipple, bilateral strabismus, imperforate hymen, congenital nevi, hemangiomata, and QT syndrome.
The causal relationship between the reported anomalies and Cetrotide (cetrorelix for injection) is unknown. Multiple factors, genetic and others (including, but not limited to ICSI, IVF, gonadotropins, and progesterone) make causal attribution difficult to study.
Symptoms and Treatment of Overdosage
There have been isolated reports of overdosage with Cetrotide (cetrorelix for injection) 0.25 mg or 3 mg in humans but no adverse events were reported. In addition, single doses up to 120 mg Cetrotide (cetrorelix for injection) have been well tolerated in patients treated for other indications without signs of overdosage.
For Management of a suspected drug overdose, contact your regional Poison Control Centre.
Dosage and Administration
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. The response should be primarily based on the number and size of the developing follicles as evidenced by ultrasound. This may be more reliable than by the amount of circulating estradiol. Cetrotide (cetrorelix for injection) may be administered subcutaneously either once daily (0.25 mg dose) as part of the multiple dose protocol or once (3 mg dose) in a single dose protocol during the early- to mid-follicular phase.
In the single dose regimen, 3 mg of Cetrotide (cetrorelix for injection) is administered when the serum estradiol level is indicative of an appropriate stimulation response, usually on stimulation day 7 (range day 5-9). If the criteria for ovulation induction are not met within four days (96 hours) of injection of Cetrotide (cetrorelix for injection) 3 mg, Cetrotide (cetrorelix for injection) 0.25 mg should be administered once daily, until the day of ovulation induction. Please note that it is not recommended to use repeated doses of Cetrotide (cetrorelix for injection) 3 mg in the same cycle.
In the multiple dose regimen, 0.25 mg of Cetrotide (cetrorelix for injection) is administered on either stimulation day 5 (morning or evening) or day 6 (morning). It is administered once daily at the same time each day at 24 hour intervals and continued daily until the day of hCG administration.
When assessment by ultrasound shows a sufficient number of follicles of adequate size ( 17 mm in diameter), 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).
The first administration of Cetrotide (cetrorelix for injection) 0.25 mg and 3 mg should be performed under the supervision of a physician and under conditions where treatment of possible allergic/pseudo-allergic reactions (including life-threatening anaphylaxis) is immediately available. The subsequent injections may be self-administered after appropriate instructions by her doctor as long as the patient is made aware of the signs and symptoms that may indicate hypersensitivity, the consequences of such a reaction and the need for immediate medical intervention.