Cetrorelix acetate

1431.04

1429.669800

1592732-453-0

OON1HFZ4BA

DTXSID7040996

C2481

H01CC02|H - Systemic hormonal preparations, excl. sex hormones and insulins

498

2.69

White powder

1.4±0.1 g/cm3

1.668

6.94e-03 g/L

Cetrotide - 3 mg: Store at 25 deg C (77 deg F); excursions permitted to 15-30 deg C (59-86 deg F) [see USP Controlled Room Temperature]. Store the packaged tray in the outer carton. Cetrotide - 0.25 mg: Store refrigerated, 2-8 deg C (36-46 deg F). Store the packaged tray in the outer carton.

Soluble in water /Acetate/

P201, P202, P281, P308+P313, P405, P501

H360

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl cetrorelix, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

|Danger|H360 (100%): May damage fertility or the unborn child [Danger Reproductive toxicity]|P201, P202, P281, P308+P313, P405, and P501|Aggregated GHS information provided by 3 companies from 3 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

68.1 mg/kg was determined as the minimal lethal dose.

86%

For the inhibition of premature LH surges in women undergoing controlled ovarian stimulation|FDA Label|Prevention of premature ovulation in patients undergoing a controlled ovarian stimulation, followed by oocyte-pick-up and assisted-reproductive techniques.In clinical trials, Cetrotide was used with human menopausal gonadotropin (HMG), however, limited experience with recombinant follicule-stimulating hormone (FSH) suggested similar efficacy.

Cetrorelix is indicated for the inhibition of premature luteinizing hormone (LH) surges in women undergoing controlled ovarian stimulation.|/EXPL THER/ This randomized, placebo-controlled, single-blind, experimental study was performed on 45 Wistar adult female rats ... . After the peritoneal implantation of endometrial tissue, rats were randomized to three equal intervention groups: (i) control group, (ii) leuprolide group, and (iii) cetrorelix group. Six weeks later, following implant volume measurements (volume-1) by performing a second laparotomy, saline (0.1 mL/rat) was administered subcutaneously to the control group once a week, leuprolide (0.075 mg/kg) subcutaneously to the leuprolide group twice at 4-week intervals and cetrorelix (0.001 mg/rat/day) subcutaneously to the cetrorelix group for 8 weeks. At the end of the treatment, by performing a third laparotomy, implant volumes were remeasured (volume-2) and implants were totally excised for histopathological examination. The volume-1 and volume-2 values within the groups, and stromal and glandular tissue scores between the groups were compared. In both the leuprolide group and the cetrorelix group, volume-2 as compared to volume-1 had significantly reduced (P < 0.01, P < 0.01 respectively), while there was no significant volume change in the control group (P > 0.05). In this group, when compared with the control group, glandular and stromal tissues had significantly lessened (P < 0.01, P < 0.01 respectively). Leuprolide and cetrorelix were found to have similar efficacy in the regression of both the size and the histological structure of experimental endometriotic implants.

Cetrorelix should be prescribed by health care providers who are experienced in fertility treatment. Before starting treatment with cetrorelix acetate, pregnancy must be excluded.|Elevations in liver function test results including ALT (SGPT), AST (SGOT), gamma-glutamyltransferase (GGT, gamma-glutamyl transpeptidase, GGTP), and alkaline phosphatase up to 3 times the upper limit of normal were reported in 1-2% of patients receiving cetrorelix during controlled ovarian stimulation.|Caution is advised in patients with hypersensitivity to GnRH. Carefully monitor these patients after the first injection. A severe anaphylactic reaction associated with cough, rash, and hypotension was observed in 1 patient after 7 months of treatment with 10 mg/day cetrorelix in a study for an indication unrelated to infertility.|Local site reactions (e.g. redness, erythema, bruising, itching, swelling and pruritus) were reported. Usually, they were of a transient nature, mild intensity and short duration.|For more Drug Warnings (Complete) data for CETRORELIX (8 total), please visit the HSDB record page.

Cetrorelix is a synthetic decapeptide with gonadotropin-releasing hormone (GnRH) antagonistic activity. 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. Cetrorelix 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.

Compounds which increase the capacity to conceive in females. (See all compounds classified as Fertility Agents, Female.)|Chemical substances which inhibit the function of the endocrine glands, the biosynthesis of their secreted hormones, or the action of hormones upon their specific sites. (See all compounds classified as Hormone Antagonists.)

Rapidly absorbed following subcutaneous injection. The mean absolute bioavailability following subcutaneous administration to healthy female subjects is 85%.|Following subcutaneous administration of 10 mg cetrorelix to males and females, only unchanged cetrorelix was detected in urine.|1.16 L/kg|1.28 ml/min·kg [adult healthy female with 3 mg single SC administration]|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.|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.|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%.|Pharmacokinetic studies were performed predominantly in rats and dogs. Absorption from the sc injection site was rapid and complete and there were no differences in absorption with regard to sex or species. A linear relationship between dose and plasma AUC was evident. Distribution of cetrorelix was rapid. Main target organs were the kidney, liver, small intestine and organs containing the luteinising hormone releasing hormone (LHRH) receptor (pituitary gland, ovaries). Plasma protein binding amounted to 86%. Elimination from most tissues was rapid and occurred predominantly within 48 hr. ... Cetrorelix crosses the placenta only to a low extent. The distribution of cetrorelix or its metabolites into milk was not investigated. Cetrorelix is excreted unchanged into urine and after metabolism by peptidases into bile. ... Studies in healthy volunteers indicate that cetrorelix is excreted in a similar manner in humans, rats and dogs.|Following subcutaneous injection, the absolute bioavailability of cetrorelix was approximately 85% in both males and females. The apparent volume of distribution was 1.16 + or - 0.29 L/kg in females and 1.02 + or - 0.33 L/kg in males. The terminal half-life was about 10 hours after iv and 30 hours after subcutaneous injection with a trend towards lower values in female. Protein binding in human plasma was around 85%. Linear pharmacokinetics were observed following both single (0.25, 0.5 and 1.00 mg) and multiple dose administration (0.25 to 1.00 mg). The pharmacokinetics were linear up to a 3 mg dose.

In in vitro studies, cetrorelix was stable against phase I- and phase II-metabolism. Cetrorelix was transformed by peptidases, and the (1-4) peptide was the predominant metabolite.|The main metabolite of cetrorelix in the rat bile was identified as being the heptapeptide (1-7). The metabolite was pharmacologically inactive in rats, in terms of testosterone suppression.|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.

~62.8 hours|In humans, the terminal half-life values after iv and sc administration were 8-9 hr and 24-40 hr, respectively.|The terminal half-lives in rats after iv and sc administration were 1-2 hr and 7-14 hr, respectively ... .|Elimination half life: Single 3 mg dose: 62.8 hr (38.2-108 hr); Single 0.25 mg dose: 5.0 hr (2.4-48.8 hr); 0.25 mg daily for 14 days: dose: 20.6 hr (4.1-179.3 hr) /From table/|Half-lives of greater than or equal to 100 hr were observed mainly in organs of elimination (liver, kidney), spleen and in the organs containing LHRH binding sites.

Cetrorelix binds to the gonadotropin releasing hormone receptor and acts as a potent inhibitor of gonadotropin secretion. It 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.|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.|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.|The mechanisms through which luteinizing hormone (LH)-releasing hormone (LHRH) antagonists suppress pituitary gonadotroph functions and LHRH-receptor (LHRH-R) expression are incompletely understood. Consequently, we investigated the direct effect of LHRH antagonist cetrorelix in vitro on the expression of the pituitary LHRH-R gene and its ability to counteract the exogenous LHRH and the agonist triptorelin in the regulation of this gene. We also compared the effects of chronic administration of cetrorelix and triptorelin on the LHRH-R mRNA level and gonadotropin secretion in ovariectomized (OVX) and normal female rats. The exposure of pituitary cells in vitro to 3-min pulses of 1 nM LHRH or 0.1 nM triptorelin for 5 hr increased the LHRH-R mRNA level by 77-88%. Continuous perfusion of the cells with 50 nM cetrorelix did not cause any significant changes, but prevented the stimulatory effect of LHRH pulses on the receptor mRNA expression. In OVX rats, 10 days after administration of a depot formulation of cetrorelix, releasing 100 microg of peptide daily, the elevated LHRH-R mRNA level was decreased by 73%, whereas daily injection of 100 microg of triptorelin caused a 41% suppression. In normal female rats, cetrorelix treatment suppressed the LHRH-R mRNA level by 33%, but triptorelin increased it by 150%. The highly elevated serum LH levels in OVX rats and the normal LH concentration of cycling rats were rapidly and completely suppressed by cetrorelix. Triptorelin decreased the serum LH in OVX rats to the precastration level, but had no effect on basal LH in normal rats. Our results confirm that LHRH antagonists, such as cetrorelix, inhibit the gene expression of pituitary LHRH-R indirectly, by counteracting the stimulatory effect of LHRH. A rapid suppression of serum LH by LHRH antagonists would be advantageous in the treatment of sex hormone-dependent tumors and other conditions.|Cetrorelix binds with high affinity to luteinising hormone releasing hormone (LHRH) receptors, and labelled LHRH was shown to be displaced from the two classes of LHRH receptors by the compound. In vitro, cetrorelix dose-dependently inhibited the LHRH-mediated LH release in perfused rat pituitary cell systems. Further, in a recently established in vitro assay, cetrorelix proved to be a high affinity antagonist at the LHRH-receptor and dose-dependently blocked the signal transduction induced by LHRH.

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/|/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/|/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

/SIGNS AND SYMPTOMS/ Cases of hypersensitivity reactions, including anaphylactoid reactions with the first dose, have been reported during post-marketing surveillance. A severe anaphylactic reaction associated with cough, rash, and hypotension, was observed in one patient after seven months of treatment with Cetrotide (10 mg/day) in a study for an indication unrelated to infertility.|/CASE REPORTS/ 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 is unknown. Multiple factors, genetic and others (including, but not limited to ICSI, IVF, gonadotropins, and progesterone) make causal attribution difficult to study.|/CASE REPORTS/ Clinical follow-up studies of 316 newborns of women administered Cetrotide 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.

cetrorelix

Parenteral: For injection, for subcutaneous use only: 0.25 mg (of cetrorelix) Cetrotide (available with prefilled disposable syringe containing 1 mL or 3 mL sterile water for injection diluent, needles, and alcohol swabs) (Serono); 3 mg (of cetrorelix) Cetrotide (available with prefilled disposable syringe containing 1 mL or 3 mL sterile water for injection diluent, needles, and alcohol swabs) (Serono).

Cetrotide (cetrorelix acetate for injection) is indicated for the inhibition of premature LH surges in women undergoing controlled ovarian stimulation. /Acetate/|Cetrorelix is a man-made hormone that blocks the effects of Gonadotropin Releasing Hormone (GnRH). GnRH controls another hormone that is called luteinizing hormone (LH), which is the hormone that starts ovulation during the menstrual cycle. When undergoing hormone treatment sometimes premature ovulation can occur, leading to eggs that are not ready for fertilization to be released. Cetrorelix does not allow the premature release of these eggs to occur.

Human drugs -> Cetrotide -> EMA Drug Category|Pituitary and hypothalamic hormones and analogues -> Human pharmacotherapeutic group|Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients