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  • CLASSES

    Antigonadotropin-releasing Hormones

    DEA CLASS

    Rx

    DESCRIPTION

    Injectable GnRH antagonist used during infertility protocols in women
    Inhibits premature LH surges in women undergoing controlled ovarian hyperstimulation
    Actions onset and reverse rapidly; pituitary and hormonal release is essentially normalized at the time of embryo transfer or implantation

    COMMON BRAND NAMES

    Ganirelix

    HOW SUPPLIED

    Ganirelix Subcutaneous Inj Sol: 0.5mL, 250mcg

    DOSAGE & 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.

    MAXIMUM DOSAGE

    Adults

    For females, 250 mcg/day subcutaneously during the follicular phase.

    Geriatric

    Safety and efficacy have not been established.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

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

    Renal Impairment

    Ganirelix has not been adequately studied for use in those patients with renal impairment.

    ADMINISTRATION

    Injectable Administration

    For subcutaneous administration only. Do not administer intravenously, intramuscularly, or intradermally.
    No reconstitution is required prior to administration.
    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

    Subcutaneous Administration

    The most convenient sites for subcutaneous injection are either in the abdomen around the navel where there is a lot of loose skin and layers of fatty tissue or in the upper thigh.
    Rotate injection site with each subcutaneous injection.
    Wash hands prior to administration.
    Swab selected injection site with disinfectant. Clean about 2 inches around the point where the needle will be inserted and let the disinfectant dry for at least 1 minute before proceeding.
    Pinch up a large area of skin between finger and thumb; inject subcutaneously at the base of the pinched up skin at an angle of 45 to 90 degrees to the skin surface. Depress the plunger slowly and steadily. Take care not to inject intradermally. When the needle is inserted correctly, it is difficult to draw back the plunger. If blood is drawn into the syringe when pulling back the plunger, withdraw the needle slightly and reposition the needle without removing it from the skin. Or, the syringe can be completely removed and a new, sterile prefilled syringe can be used.
    The pre-filled syringe is used only once, dispose of properly after use.

    STORAGE

    Ganirelix:
    - Discard unused portion. Do not store for later use.
    - Protect from light
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Gonadotropin-Releasing Hormone (GnRH) analogs hypersensitivity, latex hypersensitivity, requires an experienced clinician, serious hypersensitivity reactions or anaphylaxis

    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.

    Ovarian failure

    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.

    Ovarian cyst, polycystic ovary syndrome

    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. 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.

    Geriatric

    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.

    Hepatic disease, renal impairment

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

    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.

    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.

    Children

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

    Ethanol intoxication, tobacco smoking

    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.

    ADVERSE REACTIONS

    Severe

    fetal death / Delayed / 3.7-3.7
    ovarian hyperstimulation syndrome (OHSS) / Delayed / 2.4-2.4
    anaphylactoid reactions / Rapid / Incidence not known
    teratogenesis / Delayed / Incidence not known

    Moderate

    vaginal bleeding / Delayed / 1.8-1.8
    hot flashes / Early / Incidence not known
    ovarian enlargement / Delayed / Incidence not known
    antibody formation / Delayed / Incidence not known

    Mild

    pelvic pain / Delayed / 4.8-4.8
    headache / Early / 3.0-3.0
    injection site reaction / Rapid / 1.1-1.1
    nausea / Early / 1.1-1.1
    abdominal pain / Early / 1.0-1.0
    pruritus / Rapid / Incidence not known
    menstrual irregularity / Delayed / Incidence not known

    DRUG INTERACTIONS

    Aripiprazole: (Moderate) Antipsychotic-induced hyperprolactinemia results in down-regulation of the number of pituitary GnRH receptors and may interfere with the response to ganirelix, a gonadotropin-releasing hormone (GnRH) analog.
    Asenapine: (Moderate) Antipsychotic-induced hyperprolactinemia results in down-regulation of the number of pituitary GnRH receptors and may interfere with the response to ganirelix, a gonadotropin-releasing hormone (GnRH) analog.
    atypical antipsychotic: (Moderate) Antipsychotic-induced hyperprolactinemia results in down-regulation of the number of pituitary GnRH receptors and may interfere with the response to ganirelix, a gonadotropin-releasing hormone (GnRH) analog.
    Black Cohosh, Cimicifuga racemosa: (Major) Due to a lack of data regarding maternal or fetal safety and efficacy, the FDA currently recommends that patients who are pregnant or who are trying to get pregnant, such as patients receiving fertility agents, should not take Black cohosh, Cimicifuga racemosa without explicit instruction to do so by their qualified health care provider, midwife, or gynecologist/obstetrician.
    Brexpiprazole: (Moderate) Antipsychotic-induced hyperprolactinemia results in down-regulation of the number of pituitary GnRH receptors and may interfere with the response to ganirelix, a gonadotropin-releasing hormone (GnRH) analog.
    Cariprazine: (Moderate) Antipsychotic-induced hyperprolactinemia results in down-regulation of the number of pituitary GnRH receptors and may interfere with the response to ganirelix, a gonadotropin-releasing hormone (GnRH) analog.
    Cimetidine: (Minor) In the absence of relevant data and as a precaution, 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 ganirelix, a gonadotropin-releasing hormone (GnRH) analog.
    Fluoxetine; Olanzapine: (Moderate) Antipsychotic-induced hyperprolactinemia results in down-regulation of the number of pituitary GnRH receptors and may interfere with the response to ganirelix, a gonadotropin-releasing hormone (GnRH) analog.
    Haloperidol: (Moderate) In the absence of relevant data and as a precaution, drugs that cause hyperprolactinemia, such as antipsychotics, should not be administered concomitantly with gonadotropin releasing hormone analogs 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 ganirelix, a gonadotropin-releasing hormone (GnRH) analog.
    Loxapine: (Moderate) In the absence of relevant data and as a precaution, drugs that cause hyperprolactinemia, such as antipsychotics, should not be administered concomitantly with gonadotropin releasing hormone analogs since hyperprolactinemia downregulates the number of pituitary GnRH receptors.
    Lurasidone: (Moderate) Antipsychotic-induced hyperprolactinemia results in down-regulation of the number of pituitary GnRH receptors and may interfere with the response to ganirelix, a gonadotropin-releasing hormone (GnRH) analog.
    Molindone: (Moderate) Antipsychotics may cause hyperprolactinemia and should not be administered concomitantly with ganirelix 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 ganirelix, a gonadotropin-releasing hormone (GnRH) analog.
    Paliperidone: (Moderate) Antipsychotic-induced hyperprolactinemia results in down-regulation of the number of pituitary GnRH receptors and may interfere with the response to ganirelix, a gonadotropin-releasing hormone (GnRH) analog.
    Phenothiazines: (Moderate) In the absence of relevant data and as a precaution, drugs that cause hyperprolactinemia, such as phenothiazines, should not be administered concomitantly with ganirelix since hyperprolactinemia downregulates the number of pituitary GnRH receptors.
    Pimozide: (Moderate) In the absence of relevant data and as a precaution, drugs that cause hyperprolactinemia, such as antipsychotics, should not be administered concomitantly with gonadotropin releasing hormone analogs 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 ganirelix, a gonadotropin-releasing hormone (GnRH) analog.
    Risperidone: (Moderate) Antipsychotic-induced hyperprolactinemia results in down-regulation of the number of pituitary GnRH receptors and may interfere with the response to ganirelix, a gonadotropin-releasing hormone (GnRH) analog.
    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 (ganirelix) 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 ganirelix 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 ganirelix, a gonadotropin-releasing hormone (GnRH) analog.

    PREGNANCY AND LACTATION

    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.

    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.

    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).

    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.
     
    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.