Cetrotide

Gonadotropin Releasing Hormone Receptor Antagonist

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.

Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

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.

ovarian hyperstimulation syndrome / Delayed / 3.5-3.5
teratogenesis / Delayed / Incidence not known
fetal death / Delayed / Incidence not known
anaphylactoid reactions / Rapid / Incidence not known

hot flashes / Early / 4.0-5.0
elevated hepatic enzymes / Delayed / 1.0-2.0
ovarian enlargement / Delayed / Incidence not known
erythema / Early / Incidence not known
antibody formation / Delayed / Incidence not known
hypotension / Rapid / Incidence not known

nausea / Early / 1.3-1.3
headache / Early / 1.1-1.1
menstrual irregularity / Delayed / Incidence not known
vomiting / Early / Incidence not known
pelvic pain / Delayed / Incidence not known
abdominal pain / Early / Incidence not known
pruritus / Rapid / Incidence not known
injection site reaction / Rapid / Incidence not known
ecchymosis / Delayed / Incidence not known
rash / Early / Incidence not known

Cetrotide

Rx

Injectable GnRH antagonist; actions onset and reverse rapidly; primary use is for infertility protocols
Inhibits premature LH surges in women undergoing controlled ovarian hyperstimulation for assisted reproductive technology
Pituitary and hormonal release is essentially normalized at the time of embryo transfer or implantation

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.

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).

†Indicates off-label use

Cetrorelix has not been adequately studied for use in those patients with hepatic disease or hepatic impairment.

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).

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.
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.
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.
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.
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.
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.
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.

Cetrorelix/Cetrorelix Acetate/Cetrotide Subcutaneous Inj Pwd F/Sol: 0.25mg

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.

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.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

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

Following subcutaneous injection, cetrorelix is rapidly absorbed; peak serum concentrations are obtained within 1 to 2 hours. The mean absolute bioavailability is 85%.

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.