Ganirelix Acetate Injection

Overview of Ganirelix Acetate Injection

Dosage Strength of Ganirelix Acetate Injection

Commercial: 250 mcg / 0.5 mL Syringe
Compounded: 250 mcg / 0.25 mL 2 mL Vial

General Information

Ganirelix is a gonadotropin-releasing hormone (GnRH) antagonist. It is indicated for inhibiting premature leuteinizing hormone (LH) surges in women undergoing controlled ovarian hyperstimulation with FSH and HCG, followed by subsequent assisted insemination or reproductive technology (ART) procedures. The main advantage of GnRH antagonists versus GnRH agonists (e.g., leuprolide) is that they reduce the required days of fertility drug therapy per cycle from several weeks (i.e., 3 weeks) to several days, thereby increasing patient convenience. Secondarily, the onset of GnRH antagonists occurs rapidly after drug initiation, and the effects reverse rapidly, allowing pituitary function to return to baseline within about 2 days after 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 and a second meta-analysis found a lower rate of pregnancy in patients receiving GnRH antagonists along with a lower rate of live births.1 2 In terms of safety, both meta-analyses found a significantly lower rate of ovarian hyperstimulation syndrome (OHSS) in protocols using GnRH antagonists as well as a lower rate of severe OHSS, including hospitalization.1 2 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. Ganirelix was the first GnRH antagonist FDA-approved in the United States in 1999.

Mechanism of Action

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 are typically not mature enough to 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., ganirelix), fertility specialists can prevent a premature LH surge and improve the success rate of the fertility procedure.

In the typical controlled ovulation hyperstimulation protocol, ganirelix is administered on roughly day 6 of FSH therapy. Ganirelix suppresses LH production by competitively blocking the GnRH receptors directly at the pituitary level. It induces a rapid and reversible suppression of gonadotropin secretion within a few days; ganirelix induced suppression of endogenous LH is more pronounced than the suppression of endogenous FSH. Depending on the individual woman's response, the administration of ganirelix will need to occur, on average, for just 4 to 5 days. 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 specialist induces the LH surge artificially by the proper timing of the injection of human chorionic gonadotropin (HCG) once the follicles have obtained appropriate size as indicated by the diameter on ultrasound (e.g. 17 mm or larger). Following HCG administration, ganirelix and FSH are discontinued. Following HCG administration, final maturation of the oocytes occurs and either ovulation can ensue for timed insemination techniques, or oocyte retrieval can take place for ART procedures such as in vitro fertilization (IVF).3

Pharmacokinetics

Ganirelix is administered by subcutaneous injection. Steady-state concentrations are achieved within 3 days of multiple, daily doses. Ganirelix is metabolized to a 1-4-peptide metabolite and a 1-6-peptide metabolite, but the route of metabolism is uncertain. Roughly 18% of an administered dose is excreted unchanged in the urine within 24 hours; the primary metabolites (roughly 75% of the total dose) are excreted in the feces over 288 hours. The half-life at steady state is 16 hours. The pharmacokinetic parameters are dose-proportional when administered in doses ranging from 125 to 500 mcg.3

Affected cytochrome P450 (CYP450) enzymes and drug transporters: None

Subcutaneous Route: Following subcutaneous injection, ganirelix is rapidly absorbed; peak serum concentrations are obtained within 1 hour. The mean absolute bioavailability is 91% following a 250-mcg subcutaneous injection; protein binding is 81.9%. For up to 4 hours after an injection, ganirelix is the major compound found in the plasma.3

Indications

For inhibiting premature leutenizing hormone (LH) surges in women undergoing controlled ovarian hyperstimulation as part of the treatment of infertility:

Subcutaneous dosage: Adult females: FSH is initiated on day 2 or 3 of the cycle, followed by ganirelix acetate 250 mcg subcutaneously once daily during the mid to late portion follicular phase of the cycle (typically on day 6 of FSH administration). Continue ganirelix and FSH administration (adjust FSH dosage 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 the administration of HCG. In clinical studies with ganirelix, the 250 mcg/day regimen resulted in the highest vital pregnancy and implantation rates per attempt and per embryo transfer; higher and lower dosages were associated with reduced responses. Therefore, a maximum 250 mcg/day subcutaneous is recommended.4

Contraindications/Precautions

Ganirelix use requires an experienced clinician who is experienced in infertility treatment. Ganirelix is contraindicated for use in those patients with known hypersensitivity to the drug or to any of the components of the injection, including patients with a latex hypersensitivity because the needle shield of ganirelix contains natural rubber/latex. Ganirelix is also contraindicated in patients with a history of GnRH or Gonadotropin-Releasing Hormone (GnRH) analogs hypersensitivity. There is a risk for serious hypersensitivity reactions or anaphylaxis with use. Cases of hypersensitivity reactions, including anaphylactoid reactions, have been reported as early as with the first dose, during postmarketing surveillance. In the absence of clinical experience, use of ganirelix is not advised in women with severe allergic conditions.3

Ganirelix will only be effective for assisted reproduction in women with an intact hypothalamic-pituitary tract and ovarian response. Patients who are determined to have primary ovarian failure are not candidates for infertility treatment protocols that call for ovarian hyperstimulation.

Prior to receiving ganirelix treatment, patients should be informed of the duration of treatment and the monitoring procedures that will be required. 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 fertility agents (such as ganirelix) 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.3 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 (estradiol concentration more than 4000 pg/mL), multiple follicular response (more than 35), younger age, and a lean body.5

Clinical studies of ganirelix for the treatment of infertility in women did not include a sufficient number of geriatric females; ganirelix is not intended to be used in elderly women for assisted reproductive technology procedures.

Clinical and pharmacokinetic studies of ganirelix have not included patients with hepatic disease or renal impairment. Use with caution in these populations.

Ganirelix is contraindicated for use during pregnancy after conception has occurred. Therefore, pregnancy should be ruled out prior to the use of ganirelix with each treatment course. Clinical follow-up studies of 283 newborns of women administered ganirelix were reviewed; major and minor congenital anomalies were found in 3 and 18 neonates, respectively. The major anomalies included hydrocephalus/meningocele, omphalocele, and Beckwith-Wiedemann Syndrome. The minor congenital anomalies included nevus, skin tags, sacral sinus, hemangioma, torticollis/asymmetric skull, talipes, supernumerary digit finger, hip subluxation, torticollis/high palate, occiput/abnormal hand crease, hernia umbilicalis, hernia inguinalis, hydrocele, undescended testis, and hydronephrosis. A subsequent observational study analysis of over 1,000 newborns compared the incidence of congenital anomalies in newborns of women administered ganirelix to historical controls of a GnRH agonist. This analysis, which included the 283 newborns in the original studies, showed that the incidence of congenital anomalies in newborns after controlled ovarian hyperstimulation (COH) treatment in women using ganirelix was comparable with that reported after a COH treatment cycle using a GnRH agonist. The causal relationship between these congenital anomalies and ganirelix is not known. The incidence of congenital malformations after Assisted Reproductive Technology (ART) may be slightly higher than after spontaneous conceptions, and is thought to be related to differences in parental characteristics (e.g., maternal age, sperm characteristics) and to the higher incidence of multiple gestations after ART.3

Because of the GnRH suppressive activity, the manufacturer recommends that ganirelix not be used in women who are breast-feeding their infants. Alternate forms of feeding should be considered. It is not known if ganirelix is excreted into human breast milk.3

The safe and effective use of ganirelix has not been established in children.

Drinking alcoholic beverages, including ethanol intoxication, or tobacco smoking are two lifestyle choices that may decrease fertility or the effectiveness of fertility treatments (such as ganirelix) in some women and/or men. Patients should avoid excessive alcohol or tobacco consumption while pursuing fertility therapies.

Pregnancy

Ganirelix is contraindicated for use during pregnancy after conception has occurred. Therefore, pregnancy should be ruled out prior to the use of ganirelix with each treatment course. Clinical follow-up studies of 283 newborns of women administered ganirelix were reviewed; major and minor congenital anomalies were found in 3 and 18 neonates, respectively. The major anomalies included hydrocephalus/meningocele, omphalocele, and Beckwith-Wiedemann Syndrome. The minor congenital anomalies included nevus, skin tags, sacral sinus, hemangioma, torticollis/asymmetric skull, talipes, supernumerary digit finger, hip subluxation, torticollis/high palate, occiput/abnormal hand crease, hernia umbilicalis, hernia inguinalis, hydrocele, undescended testis, and hydronephrosis. A subsequent observational study analysis of over 1,000 newborns compared the incidence of congenital anomalies in newborns of women administered ganirelix to historical controls of a GnRH agonist. This analysis, which included the 283 newborns in the original studies, showed that the incidence of congenital anomalies in newborns after controlled ovarian hyperstimulation (COH) treatment in women using ganirelix was comparable with that reported after a COH treatment cycle using a GnRH agonist. The causal relationship between these congenital anomalies and ganirelix is not known. The incidence of congenital malformations after Assisted Reproductive Technology (ART) may be slightly higher than after spontaneous conceptions, and is thought to be related to differences in parental characteristics (e.g., maternal age, sperm characteristics) and to the higher incidence of multiple gestations after ART.3

Breast-Feeding

Because of the GnRH suppressive activity, the manufacturer recommends that ganirelix not be used in women who are breast-feeding their infants. Alternate forms of feeding should be considered. It is not known if ganirelix is excreted into human breast milk.3

Adverse Reactions/Side Effects

In general, ganirelix 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 ganirelix is not always known. In clinical studies, 3% of patients receiving ganirelix as a part of assisted reproductive technologies (ART) experienced headache.3

Injection site reaction including local and mild erythema, ecchymosis, or pruritus was reported in 1.1% of 794 ganirelix recipients but did not preclude patients from continuing treatments.3

Hot flashes can occur in patients receiving ganirelix treatment, but are usually reported at a lower rate than is reported with use of GnRH analogs such as leuprolide when used in assisted reproduction protocols.6 When ganirelix is used chronically, to treat uterine fibroids, a hypoestrogenic state can ensue, resulting in hot flashes and other menopause-like adverse effects.7

In clinical studies, some patients receiving ganirelix as a part of assisted reproductive technology experienced abdominal pain (1%), gynecologic/pelvic pain (4.8%), or nausea (1.1%). Abdominal, pelvic pain, and nausea may be symptoms of ovarian enlargement. During clinical trials, ovarian hyperstimulation syndrome (OHSS) occurred in 2.4% of patients receiving ganirelix.3 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 or nausea; most patients will recover without sequelae within 10 to 14 days. 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.5

Cases of hypersensitivity reactions, including anaphylactoid reactions with the first ganirelix dose, have been reported during postmarketing surveillance. In clinical trials, antibody formation to ganirelix was not reported. However, because ganirelix is structurally similar to native GnRH, it is postulated that antibody formation could potentially occur, particularly with prolonged use for indications other than fertility protocols.3

When used in the treatment of infertility, ganirelix may induce menstrual irregularity after failed cycles. In clinical studies, patients receiving ganirelix as a part of assisted reproductive technology (ART) experienced vaginal bleeding (1.8%).3

Fetal death occurred in 3.7% of 794 ganirelix recipients for ART. Additionally, ongoing clinical follow-up studies of newborns have been performed to try to assess the incidence of teratogenesis/congenital anomalies. Of 283 newborns assessed, there were 3 neonates with major anomalies (i.e., hydrocephalus/meningocele, omphalocele, and Beckwith-Wiedemann Syndrome). There were 18 neonates with minor congenital anomalies (e.g., nevus, skin tags, abnormal hand crease, sacral sinus, hemangioma, asymmetric skull, talipes, torticollis/high palate, supernumerary digits, hip subluxation, hydrocele, inguinal hernia, undescended testes, and hydronephrosis). A subsequent observational study analysis of over 1,000 newborns compared the incidence of congenital anomalies in newborns of women administered ganirelix to historical controls of a GnRH agonist. This analysis, which included the 283 newborns in the original studies, showed that the incidence of congenital anomalies in children born after controlled ovarian hyperstimulation (COH) treatment in women using ganirelix was comparable with that reported after a COH treatment cycle using a GnRH agonist. The causal relationship between these anomalies and ganirelix is not known. Multiple factors, including genetics and in vitro fertilization (IVF) or other ART techniques may confound neonatal outcomes.3

Storage

Store this medication at 68°F to 77°F (20°C to 25°C) and away from heat, moisture and light. Keep all medicine out of the reach of children. Throw away any unused medicine after the beyond use date. Do not flush unused medications or pour down a sink or drain.

  • 1. a. b. Kolibianakis EM, Collins J, Tarlatzis BC, et al. Among patients treated for IVF with gonadotrophins and GnRH analogues, is the probability of live birth dependent on the type of analogue used? A systematic review and meta-analysis. Hum Reprod Upd
  • 2. a. b. Al-Inany HG, Abou-Setta AM, Aboulghar M. Gonadotrophin-releasing hormone antagonists for assisted conception. Cochrane Database Syst Rev 2006;(3):CD001750.
  • 3. a. b. c. d. e. f. g. h. i. j. k. l. m. n. o. Ganirelix package insert. Roseland, NJ : Organon USA Inc.; 2018 May.
  • 4. Devroey P, Abyholm T, Diedrich K, et al. A double-blind, randomized, dose-finding study to assess the efficacy of the gonadotropin releasing hormone antagonist ganirelix (Org 37462) to prevent premature luteinizing hormone surges in women undergo
  • 5. a. b. Al-Shawaf T, Zosmer A, Dirnfeld M, et al. Safety of drugs used in assisted reproduction techniques. Drug Saf 2005;28:513-28.
  • 6. Fluker M, Grifo J, Leader A, et al. Efficacy and safety of ganirelix acetate versus leuprolide acetate in women undergoing controlled ovarian hyperstimulation. Fertil Steril 2001;75:38-45.
  • 7. Flierman PA, Oberye JJ, van der Hulst VP, et al. Rapid reduction of leiomyoma volume during treatment with the GnRH antagonist ganirelix. BJOG 2005;112:638-42.

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