Cetrorelix is a synthetic decapeptide with gonadotropin-releasing hormone (GnRH) antagonist activity similar to ganirelix. The drug is used to inhibit premature leuteinizing hormone (LH) surges in women undergoing controlled ovarian hyperstimulation followed by insemination or assisted reproductive technology (ART) procedures. When used for infertility, the main advantage of GnRH antagonists versus GnRH agonists (e.g., leuprolide) is a reduction in the required fertility therapy cycle from several weeks (i.e., 3 weeks) to several days. Secondarily, the onset of GnRH antagonists occurs rapidly after drug initiation, and the effects reverse rapidly, allowing pituitary function to return to baseline within 1 to 4 days after drug discontinuation. Thus, pituitary and hormonal release is essentially normalized at the time of embryo transfer or implantation. It was theorized that these properties would improve embryo viability and pregnancy success rates; however, results from meta-analyses comparing GnRH antagonists to GnRH agonists do not support this theory. One meta-analysis found that there were no differences in live births between the 2 treatment modalities (OR 0.86, 95% CI 0.72 to 1.02), and a second one found a lower rate of pregnancy by 5% in patients receiving GnRH antagonists (OR 0.75, 95% CI 0.62 to 0.97) along with a lower rate of live births (OR 0.82, 955 CI 0.69 to 0.98, P=0.03). In terms of safety, both meta-analyses found a significantly lower rate of ovarian hyperstimulation syndrome (OHSS) in protocols using GnRH antagonists; one analysis found the rate of OHSS associated with hospitalization to be lower in patients using GnRH antagonists (OR 0.46, 95% CI 0.26 to 0.82, P=0.01), and the other found a significantly lower rate of severe OHSS in the GnRH antagonist group (RR 0.61, 95% CI 0.42 to 0.89, P=0.01). Protocols utilizing GnRH antagonists versus GnRH agonists are simple and short, possibly with a lower risk of OHSS; additionally, most studies have found that gonadotropin requirements are lower. However, clinicians and patients should consider that a lower rate of pregnancy and live-birth rate has been demonstrated with the use of GnRH antagonists. Currently, two GnRH antagonists are FDA-approved for use: ganirelix and cetrorelix. Differences between cetrorelix and ganirelix are not apparent, although some data indicate that the risk of OHSS is significantly lower with cetrorelix. Additionally, both agents can be administered daily; however, cetrorelix has also been administered as a single dose. Cetrorelix has also been studied off-label for the treatment of endometriosis, benign prostatic hyperplasia (BPH), uterine fibroids, and other hormonally-sensitive conditions.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Hazardous Drugs Classification
-NIOSH 2016 List: Group 3
-NIOSH (Draft) 2020 List: Table 2
-Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
-Use double chemotherapy gloves and a protective gown. Prepare in a biological safety cabinet or compounding aseptic containment isolator with a closed system drug transfer device. Eye/face and respiratory protection may be needed during preparation and administration.
Route-Specific Administration
Injectable Administration
Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
Subcutaneous Administration
-For subcutaneous administration only.
-The 0.25 mg dose can be administered by the patient herself after appropriate instructions by her doctor.
Preparing Cetrorelix 0.25 mg injection with the enclosed needles, vial, and prefilled syringe
-Wash hands thoroughly with soap and water.
-Flip off the plastic cover of the vial and wipe the aluminum ring and the rubber stopper with an alcohol swab.
-Twist the injection needle with the yellow mark (20-gauge) on the prefilled syringe.
-Push the needle through the center of the rubber stopper of the vial and slowly inject the solvent into the vial.
-Leaving the syringe in the vial, gently swirl the vial until the solution is clear and without residues. Avoid forming bubbles.
-Draw the total contents of the vial into the syringe. If necessary, invert the vial and pull back the needle as far as needed to withdraw the entire contents of the vial.
-Replace the needle with the yellow mark by the injection needle with the grey mark (27-gauge).
-Invert the syringe and push the plunger until all air bubbles have been expelled.
Subcutaneous Administration
-Choose an injection site in the lower abdominal area, preferably around, but staying at least 1-inch away from the navel. Choose a different injection site each day to minimize local irritation.
-Use an alcohol swab to clean the skin at the injection site and allow alcohol to dry.
-Gently pinch up the skin surrounding the site of injection.
-Inject the prescribed dose subcutaneously as directed.
-Use the syringe and needles only once. Dispose of the syringe and needles properly after use.
In general, cetrorelix is well tolerated as a part of protocols for controlled ovarian hyperstimulation and assisted reproductive technology (ART). Because multiple factors, including the use of other fertility agents (i.e., FSH and HCG), influence the presence of side effects in these patients, causality to cetrorelix is not always known. In clinical studies, 949 patients receiving cetrorelix experienced headache (1.1%). In 15 women receiving cetrorelix off-label for the treatment of endometriosis, 20% reported headache after the first dose; however, the headaches did not recur after subsequent injections.
Hot flashes are estimated to occur in roughly 4-5% of female patients on cetrorelix during treatment, which is a lower rate than is reported for the use of GnRH analogs such as leuprolide. Of 13 men receiving cetrorelix off-label for the treatment of benign prostatic hyperplasia, 38% reported slight to notable hot flashes during treatment; the hot flashes disappeared after drug discontinuation.
When used in the treatment of infertility, cetrorelix may induce menstrual irregularity after failed cycles.
In clinical studies, some patients receiving cetrorelix as a part of assisted reproductive technology experienced nausea (1.3%). After the exclusion of preexisting conditions, elevated hepatic enzymes (ALT, AST, GGT, alkaline phosphatase) up to 3 times the upper limit of normal were found in 1-2% of patients receiving cetrorelix during controlled ovarian stimulation. The clinical significance of these findings was not determined. Elevated hepatic enzymes and nausea may be signs of ovarian enlargement. During clinical trials, moderate or severe ovarian hyperstimulation syndrome (OHSS) occurred in 3.5% of 949 patients receiving cetrorelix. OHSS is graded as mild, moderate, or severe; treatment is empiric and should be based on the severity and other complications that occur. Mild OHSS is usually self-limiting and characterized by mild abdominal pain, pelvic pain, or nausea; most patients will recover without sequelae within 10 to 14 days. Vomiting may occur. Patients should be closely monitored and instructed to drink at least 1 liter of fluids/day with light physical activity; a mild analgesic can be used when necessary. If the patient is pregnant, she should be closely monitored for progression to severe OHSS. Severe OHSS can be life-threatening with renal failure, adult respiratory distress syndrome, and/or thromboembolism as possible secondary complications. Patients with severe OHSS should be hospitalized and monitored for hemodynamic instability, electrolyte abnormalities, coagulation disorders, and changes in renal or hepatic function. Intravenous fluids should be administered to maintain fluid balance and adequate urine output; analgesics that are not nephrotoxic should be administered to control abdominal pain. Anticoagulants may be necessary. If the OHSS is life-threatening and the patient is pregnant, termination of the pregnancy may need to be considered.
An injection site reaction such as erythema, ecchymosis, pruritus, and swelling may occur after cetrorelix administration. The local reaction is usually transient, of mild intensity, and short lived.
In Phase 3 studies of cetrorelix, fetal death (stillbirth) occurred in two pregnancies. Ongoing clinical follow-up studies of newborns have been performed to try to assess the incidence of teratogenesis/congenital anomalies. Multiple factors including genetics and in vitro fertilization (IVF) or other ART techniques may confound neonatal outcomes. Clinical reviews of 316 newborns of women administered cetrorelix were performed. One infant of a set of twin neonates had anencephaly at birth and died after four days; the other twin was normal. Developmental findings included a child with a ventricular septal defect and another child with bilateral congenital glaucoma. Four pregnancies that resulted in therapeutic abortion in phase II and phase III controlled ovarian stimulation trials had major anomalies (diaphragmatic hernia, trisomy 21, Klinefelter syndrome, polymalformation, and trisomy 18). In 3 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 included: supernumerary nipple, bilateral strabismus, imperforate hymen, congenital nevi, hemangiomata, and QT syndrome. The causal relationship between these anomalies and cetrorelix is not known.
Cases of hypersensitivity reactions, including anaphylactoid reactions with the first cetrorelix dose, have been reported during postmarketing surveillance. One severe anaphylactic reaction associated with cough, rash (unspecified), and hypotension was observed after seven months of treatment with cetrorelix (10 mg/day) in a study for an indication unrelated to infertility. In clinical trials, antibody formation to cetrorelix was not reported. However, because cetrorelix is structurally similar to native GnRH, it is postulated that antibody formation could potentially occur.
Cetrorelix is contraindicated for use in patients with hypersensitivity to the drug, extrinsic peptide homones, or any components of the injection (e.g., immediate-type mannitol hypersensitivity). Also, use is contraindicated in patients with Gonadotropin-Releasing Hormone (GnRH) or other known Gonadotropin-Releasing Hormone (GnRH) analogs hypersensitivity. A severe anaphylactic reaction has been reported in 1 patient after 7 months of therapy with cetrorelix. In women with active allergic conditions, or those with a known predisposition to allergies (e.g., atopy), caution is advised. In women with a history of severe allergic reactions, the manufacturer recommends that cetrorelix not be used.
Cetrorelix will only be effective for assisted reproduction in women with an intact hypothalamic-pituitary axis and ovarian response. Patients who have primary ovarian failure are not candidates for infertility treatment protocols that call for ovarian hyperstimulation. The studies for cetrorelix excluded subjects with polycystic ovary syndrome (PCOS), subjects with low or no ovarian reserve (ovarian failure), and subjects with stage 3 to 4 endometriosis.
Cetrorelix is contraindicated for use after conception has occurred; pregnancy should be ruled out prior to the use of cetrorelix with each treatment course. The fetal resorption observed in animal studies is a logical consequence of the alteration in hormonal levels effected by the antigonadotrophic properties of cetrorelix, which could result in fetal loss in humans as well. When administered to rats for the first 7 days of pregnancy, cetrorelix acetate did not affect the development of the implanted conceptus at doses up to 38 mcg/kg (approximately 1 times the recommended human therapeutic dose based on body surface area). However, a dose of 139 mcg/kg (approximately 4 times the human dose) resulted in a resorption rate and a postimplantation 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 mcg/kg (0.2 times the human dose) and in rabbits at doses from 6.8 mcg/kg (0.4 times the human dose). In animals that maintained their pregnancy, there was no increase in the incidence of fetal abnormalities.
Due to GnRH suppressive activity, cetrorelix is contraindicated for use during breast-feeding. It is not known if cetrorelix is excreted in human breast milk. The effects of cetrorelix on lactation and/or the breast-fed child have not been determined.
All female patients should be instructed to immediately report symptoms of ovarian enlargement, including abdominal pain or pelvic pain; nausea; vomiting; ascites (fluid and distension in the abdomen); or weight gain. Halt the current cycle of cetrorelix if ovarian enlargement or ovarian hyperstimulation syndrome (OHSS) occurs or if an ovarian cyst develops; maximal ovarian enlargement may not be evident until several days after drug discontinuation. Do not reinstate therapy until ovary size has returned to normal. Complete pelvic exams, including pelvic ultrasounds, should be repeated in all female patients during and prior to each fertility drug cycle. Some patients with polycystic ovary syndrome (PCOS) are unusually sensitive to gonadotropins and may have an exaggerated response to ovarian hyperstimulation protocols. Other risk factors for OHSS include a history of previous OHSS, high serum estradiol concentrations prior to HCG administration, multiple follicular response, younger age, and a lean body.
Tobacco smoking is a lifestyle choice that may decrease fertility or the effectiveness of fertility treatments in some women and/or men. Patients should be encouraged to avoid tobacco consumption and pursue smoking cessation while pursuing fertility therapies such as the use of cetrorelix.
Assisted reproductive technology (ART) cycle cancellation rates are increased among overweight and obese women. One proposed mechanism for treatment failure in the presence of obesity is altered pharmacokinetics of the GnRH antagonists used in the ART procedure, including cetrorelix. The authors of one pharmacokinetic study concluded that weight-based dosing of GnRH antagonists, including cetrorelix, should be considered for obese women in order to improve ART cycle outcomes; however, no weight-based dosing recommendations were provided.
Cetrorelix is contraindicated in patients with severe renal impairment (e.g., renal failure).
Cetrorelix is not intended to be used in geriatric women 65 years and over for the treatment of infertility or for assisted reproductive technology (ART) procedures.
The safe and effective use of cetrorelix has not been established in adolescents, children, and infants less than 18 years of age.
For inhibiting premature leuteinizing hormone (LH) surges in women undergoing controlled ovarian hyperstimulation and subsequent in vitro fertilization (IVF) or other assisted reproductive technology (ART) for the treatment of infertility:
Subcutaneous dosage (multiple-dose regimen using Cetrotide 0.25 mg or generic equivalent):
Adult females: FSH is initiated on day 2 or 3 of the cycle followed by cetrorelix 0.25 mg/day subcutaneously during the early to mid follicular phase of the cycle (typically on day 5 or 6 of FSH administration). Continue cetrorelix and FSH administration (adjust FSH dose as needed) until the day of HCG administration. When a sufficient number of follicles of adequate size are present, as assessed by ultrasound, the final maturation of the follicles is induced by HCG.
For the treatment of endometriosis*:
Subcutaneous dosage:
Adults females: Limited data suggest that 3 mg subcutaneously once weekly is effective. In a pilot study of 15 women with endometriosis, cetrorelix 3 mg subcutaneously once weekly for 8 weeks caused a symptom-free period (e.g., mood changes, hot flashes, decreased libido, vaginal dryness) and a regression in disease severity in 60% (9/15) of patients (a reduction from mean stage III disease severity at study entry to a mean stage II disease severity at study end.) It should be noted that 6 of the patients had stage IV disease at study start, and only 1 of these patients demonstrated disease regression (to stage II).
Maximum Dosage Limits:
-Adults
Dosage is individualized for females according to ART protocols; a loading dose of 10 mg/day subcutaneously has been used off-label in men with BPH.
-Geriatric
Safety and efficacy have not been established; however, cetrorelix has been used off-label at a loading dose of 10 mg/day subcutaneously in men with BPH.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Cetrorelix has not been adequately studied for use in those patients with hepatic disease or hepatic impairment.
Patients with Renal Impairment Dosing
Cetrorelix has not been adequately studied for use in those patients with renal impairment.
CrCl < 30 mL/min: Contraindicated in patients with severe renal impairment (e.g., renal failure).
*non-FDA-approved indication
Aripiprazole: (Moderate) Antipsychotic-induced hyperprolactinemia results in down-regulation of the number of pituitary GnRH receptors and may interfere with the response to any of the gonadotropin-releasing hormone (GnRH) analogs including cetrorelix.
Asenapine: (Moderate) Antipsychotic-induced hyperprolactinemia results in down-regulation of the number of pituitary GnRH receptors and may interfere with the response to any of the gonadotropin-releasing hormone (GnRH) analogs including cetrorelix.
atypical antipsychotic: (Moderate) Antipsychotic-induced hyperprolactinemia results in down-regulation of the number of pituitary GnRH receptors and may interfere with the response to any of the gonadotropin-releasing hormone (GnRH) analogs including cetrorelix.
Brexpiprazole: (Moderate) Antipsychotic-induced hyperprolactinemia results in down-regulation of the number of pituitary GnRH receptors and may interfere with the response to any of the gonadotropin-releasing hormone (GnRH) analogs including cetrorelix.
Cariprazine: (Moderate) Antipsychotic-induced hyperprolactinemia results in down-regulation of the number of pituitary GnRH receptors and may interfere with the response to any of the gonadotropin-releasing hormone (GnRH) analogs including cetrorelix.
Chlorpromazine: (Moderate) Drugs that cause hyperprolactinemia, such as antipsychotics, should not be administered concomitantly with cetrorelix since hyperprolactinemia downregulates the number of pituitary GnRH receptors.
Cimetidine: (Minor) Drugs that cause hyperprolactinemia, such as cimetidine, should not be administered concomitantly with gonadotropin releasing hormone analogs since hyperprolactinemia down-regulates the number of pituitary GnRH receptors.
Clozapine: (Moderate) Antipsychotic-induced hyperprolactinemia results in down-regulation of the number of pituitary GnRH receptors and may interfere with the response to any of the gonadotropin-releasing hormone (GnRH) analogs including cetrorelix.
Codeine; Phenylephrine; Promethazine: (Moderate) Drugs that cause hyperprolactinemia, such as antipsychotics, should not be administered concomitantly with cetrorelix since hyperprolactinemia downregulates the number of pituitary GnRH receptors.
Codeine; Promethazine: (Moderate) Drugs that cause hyperprolactinemia, such as antipsychotics, should not be administered concomitantly with cetrorelix since hyperprolactinemia downregulates the number of pituitary GnRH receptors.
Fluphenazine: (Moderate) Drugs that cause hyperprolactinemia, such as antipsychotics, should not be administered concomitantly with cetrorelix since hyperprolactinemia downregulates the number of pituitary GnRH receptors.
Haloperidol: (Moderate) Antipsychotics cause hyperprolactinemia and should not be administered concomitantly with cetrorelix since hyperprolactinemia downregulates the number of pituitary GnRH receptors.
Iloperidone: (Moderate) Antipsychotic-induced hyperprolactinemia results in down-regulation of the number of pituitary GnRH receptors and may interfere with the response to any of the gonadotropin-releasing hormone (GnRH) analogs including cetrorelix.
Loxapine: (Moderate) Antipsychotics cause hyperprolactinemia and should not be administered concomitantly with cetrorelix since hyperprolactinemia downregulates the number of pituitary GnRH receptors.
Lumateperone: (Moderate) Antipsychotic-induced hyperprolactinemia results in down-regulation of the number of pituitary GnRH receptors and may interfere with the response to any of the gonadotropin-releasing hormone (GnRH) analogs including cetrorelix.
Lurasidone: (Moderate) Antipsychotic-induced hyperprolactinemia results in down-regulation of the number of pituitary GnRH receptors and may interfere with the response to any of the gonadotropin-releasing hormone (GnRH) analogs including cetrorelix.
Molindone: (Moderate) Antipsychotics cause hyperprolactinemia and should not be administered concomitantly with cetrorelix since hyperprolactinemia downregulates the number of pituitary GnRH receptors.
Olanzapine: (Moderate) Antipsychotic-induced hyperprolactinemia results in down-regulation of the number of pituitary GnRH receptors and may interfere with the response to any of the gonadotropin-releasing hormone (GnRH) analogs including cetrorelix.
Olanzapine; Fluoxetine: (Moderate) Antipsychotic-induced hyperprolactinemia results in down-regulation of the number of pituitary GnRH receptors and may interfere with the response to any of the gonadotropin-releasing hormone (GnRH) analogs including cetrorelix.
Olanzapine; Samidorphan: (Moderate) Antipsychotic-induced hyperprolactinemia results in down-regulation of the number of pituitary GnRH receptors and may interfere with the response to any of the gonadotropin-releasing hormone (GnRH) analogs including cetrorelix.
Paliperidone: (Moderate) Antipsychotic-induced hyperprolactinemia results in down-regulation of the number of pituitary GnRH receptors and may interfere with the response to any of the gonadotropin-releasing hormone (GnRH) analogs including cetrorelix.
Perphenazine: (Moderate) Drugs that cause hyperprolactinemia, such as antipsychotics, should not be administered concomitantly with cetrorelix since hyperprolactinemia downregulates the number of pituitary GnRH receptors.
Perphenazine; Amitriptyline: (Moderate) Drugs that cause hyperprolactinemia, such as antipsychotics, should not be administered concomitantly with cetrorelix since hyperprolactinemia downregulates the number of pituitary GnRH receptors.
Phenothiazines: (Moderate) Drugs that cause hyperprolactinemia, such as antipsychotics, should not be administered concomitantly with cetrorelix since hyperprolactinemia downregulates the number of pituitary GnRH receptors.
Pimozide: (Moderate) Drugs that cause hyperprolactinemia, such as pimozide, should not be administered concomitantly with gonadotropin releasing hormone since hyperprolactinemia down-regulates the number of pituitary GnRH receptors.
Prasterone, Dehydroepiandrosterone, DHEA (Dietary Supplements): (Major) Prasterone, dehydroepiandrosterone, DHEA is converted via hydrosteroid dehydrogenases and aromatase into androstenedione, testosterone, and estradiol by peripheral tissues. DHEA is a weak androgen that has complex hormonal effects. It is unclear what actions prasterone, dehydroepiandrosterone, DHEA would have on other exogenous hormonal regimens. It would seem prudent to not administer DHEA with infertility or hormonal cancer treatments such as GnRH analogs (cetrorelix, ganirelix, goserelin, histrelin, leuprolide, or triptorelin) since DHEA may theoretically interfere with these therapies.
Prasterone, Dehydroepiandrosterone, DHEA (FDA-approved): (Major) Prasterone, dehydroepiandrosterone, DHEA is converted via hydrosteroid dehydrogenases and aromatase into androstenedione, testosterone, and estradiol by peripheral tissues. DHEA is a weak androgen that has complex hormonal effects. It is unclear what actions prasterone, dehydroepiandrosterone, DHEA would have on other exogenous hormonal regimens. It would seem prudent to not administer DHEA with infertility or hormonal cancer treatments such as GnRH analogs (cetrorelix, ganirelix, goserelin, histrelin, leuprolide, or triptorelin) since DHEA may theoretically interfere with these therapies.
Prochlorperazine: (Moderate) Drugs that cause hyperprolactinemia, such as antipsychotics, should not be administered concomitantly with cetrorelix since hyperprolactinemia downregulates the number of pituitary GnRH receptors.
Promethazine: (Moderate) Drugs that cause hyperprolactinemia, such as antipsychotics, should not be administered concomitantly with cetrorelix since hyperprolactinemia downregulates the number of pituitary GnRH receptors.
Promethazine; Dextromethorphan: (Moderate) Drugs that cause hyperprolactinemia, such as antipsychotics, should not be administered concomitantly with cetrorelix since hyperprolactinemia downregulates the number of pituitary GnRH receptors.
Promethazine; Phenylephrine: (Moderate) Drugs that cause hyperprolactinemia, such as antipsychotics, should not be administered concomitantly with cetrorelix since hyperprolactinemia downregulates the number of pituitary GnRH receptors.
Quetiapine: (Moderate) Antipsychotic-induced hyperprolactinemia results in down-regulation of the number of pituitary GnRH receptors and may interfere with the response to any of the gonadotropin-releasing hormone (GnRH) analogs including cetrorelix.
Risperidone: (Moderate) Antipsychotic-induced hyperprolactinemia results in down-regulation of the number of pituitary GnRH receptors and may interfere with the response to any of the gonadotropin-releasing hormone (GnRH) analogs including cetrorelix.
Tetrabenazine: (Moderate) In the absence of relevant data and as a precaution, drugs that cause hyperprolactinemia, such as tetrabenazine, should not be administered concomitantly with gonadotropin-releasing hormone (GnRH) analogs (cetrorelix) since hyperprolactinemia down regulates the number of pituitary GnRH receptors.
Thioridazine: (Moderate) Drugs that cause hyperprolactinemia, such as antipsychotics, should not be administered concomitantly with cetrorelix since hyperprolactinemia downregulates the number of pituitary GnRH receptors.
Thiothixene: (Moderate) In the absence of relevant data and as a precaution, drugs that cause hyperprolactinemia including thiothixene should not be administered concomitantly with cetrorelix since hyperprolactinemia downregulates the number of pituitary GnRH receptors.
Trifluoperazine: (Moderate) Drugs that cause hyperprolactinemia, such as antipsychotics, should not be administered concomitantly with cetrorelix since hyperprolactinemia downregulates the number of pituitary GnRH receptors.
Ziprasidone: (Moderate) Antipsychotic-induced hyperprolactinemia results in down-regulation of the number of pituitary GnRH receptors and may interfere with the response to any of the gonadotropin-releasing hormone (GnRH) analogs including cetrorelix.
During assisted reproductive technology (ART), roughly 30% of women undergoing controlled ovarian hyperstimulation experience a marked rise in estrogen levels in response to follicle stimulating hormone (FSH), which can trigger an early surge of luteinizing hormone (LH) and premature ovulation during the menotropin or follitropin treatments. The eggs that are released prematurely typically do not lead to successful conception or implantation. By taking control of the pituitary release of LH with either gonadotropin-releasing hormone (GnRH) agonists (e.g., leuprolide) or GnRH antagonists (e.g., cetrorelix), fertility specialists can prevent the premature LH surge and improve the success rate of the fertility procedure.
In the typical protocol, cetrorelix is initiated on roughly day 5 to 9 of FSH or menotropins therapy. Cetrorelix suppresses LH production by competitively blocking the GnRH receptors directly at the pituitary level. Rapid and reversible suppression of gonadotropin secretion occurs within a few days; cetrorelix induced suppression of endogenous LH is more pronounced than the suppression of endogenous FSH. The production of the LH surge, which is required for ovulation and the initiation of the luteal phase of the cycle, is thus placed in the control of the fertility specialist. The LH surge is artificially induced by the proper timing of human chorionic gonadotropin (HCG) administration once the follicles have obtained appropriate size (e.g. 17 mm or more) as indicated by ultrasound. Following HCG administration, cetrorelix and FSH are discontinued and final maturation of the oocytes occurs. Thereafter, either ovulation can ensue for timed insemination, or oocyte retrieval can take place for ART procedures such as in vitro fertilization (IVF).
Cetrorelix is administered by subcutaneous injection. 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%. In women, 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 cetrorelix 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. The drug is not subject to hepatic metabolism. Cetrorelix is extensively metabolized via peptidases. Only 2% to 4% of the drug is eliminated unchanged in the urine, while small amounts (5 to 10%) are eliminated as unchanged cetrorelix and the four peptide metabolites in bile within 24 hours. Only 7% to 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. The half-life following multiple daily doses of 0.25 mg subcutaneously is roughly 20 hours; the half-life after a single 3 mg subcutaneous injection is roughly 62 hours.
The effects of cetrorelix on LH and FSH are reversible after discontinuation of treatment. In women, cetrorelix delays the LH-surge, and consequently ovulation, in a dose-dependent fashion. 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. FSH levels are not affected at the doses used during controlled ovarian stimulation. Following a single 3 mg dose of cetrorelix, a duration of action of at least 4 days has been established. A dose of cetrorelix 0.25 mg every 24 hours has been shown to maintain the effect.
Affected Cytochrome P450 (CYP450) isoenzymes and drug transporters: None
-Route-Specific Pharmacokinetics
Subcutaneous Route
Following subcutaneous injection, cetrorelix is rapidly absorbed; peak serum concentrations are obtained within 1 to 2 hours. The mean absolute bioavailability is 85%.
-Special Populations
Hepatic Impairment
The pharmacokinetic parameters of cetrorelix in hepatic disease have not been studied; however, the drug is not metabolized by phase I or II reactions in the liver. Some biliary excretion of small amounts of cetrorelix and the peptide metabolites occurs.
Renal Impairment
The pharmacokinetic parameters of cetrorelix in renal impairment have not been studied; the drug should not be used in severe renal impairment.
Pediatrics
The pharmacokinetic parameters of cetrorelix have not been studied in children.
Geriatric
The pharmacokinetic parameters of cetrorelix in geriatric patients have not been studied.
Ethnic Differences
Pharmacokinetic differences of cetrorelix in different races have not been determined.
Obesity
The pharmacokinetic parameters of cetrorelix may be altered in overweight and obese women, and may help explain the established increased assisted reproductive technology (ART) cycle cancellation rate in this population. In a small pharmacokinetic study, ten obese (BMI: 30 kg/m2 or greater) and ten normal-weight (BMI: 18 to 25 kg/m2), regularly menstruating women received a single 3-mg dose of cetrorelix followed by recombinant LH. Frequent blood sampling (blood drawn every 10 minutes for 6-hours) was conducted; cetrorelix was measured in serum samples at 8-, 10- and 14-hours post-dose. At the study end, a significantly decreased distributional half-life of cetrorelix was observed in obese compared to normal-weight women (8.1 +/- 1.6 hours vs. 12.7 +/- 6.2 hours, p = 0.02). A non-significantly increased clearance of cetrorelix was also observed in obese compared to normal-weight women (25.8 +/- 6.8 L/hour vs. 20.1 +/- 8.3 L/hour, p = 0.058). In addition, five of the obese women (50%) and none of the normal-weight women had a surge of LH (defined as 50% increase in LH level from nadir) over the 14-hour post-dose observation period. The authors concluded that weight-based dosing of GnRH antagonists, including cetrorelix, should be considered for obese women in order to improve ART cycle outcomes; however, no specific weight-based dosing recommendations were provided.
Other
There is no evidence of differences in pharmacokinetic parameters for cetrorelix between healthy subjects and patients undergoing controlled ovarian stimulation.