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  • CLASSES

    Gonadotropin-releasing Hormones

    DEA CLASS

    Rx

    DESCRIPTION

    Gonadotropin-releasing hormone (GnRH) agonist used in the palliative treatment of advanced prostate cancer or the treatment of central precocious puberty in children; histrelin implant is inserted yearly.

    COMMON BRAND NAMES

    Supprelin, Vantas

    HOW SUPPLIED

    Supprelin/Vantas Subcutaneous Imp: 50mg

    DOSAGE & INDICATIONS

    For the palliative treatment of advanced prostate cancer.
    Subcutaneous depot implant dosage (Vantas ONLY)
    Adult males, including the Geriatric

    1 implant (50 mg of histrelin acetate) inserted subcutaneously every 12 months. The implant is inserted subcutaneously in the inner aspect of the upper arm and provides continuous release of histrelin for 12 months of hormonal therapy. Histrelin implant must be removed after 12 months of therapy. At the time of implant removal, another implant may be inserted to continue therapy. Monitor prostate specific antigen (PSA), serum gonadotropin concentrations, and serum testosterone concentrations at regularly scheduled intervals. In an open-label phase III study, 138 patients with prostate cancer were treated with a single histrelin implant for a minimum of 52 weeks. At week 52, the study included the option for removal and insertion of a new implant, with evaluation for an additional 52 weeks of therapy. Following an initial increase in testosterone concentrations after implant insertion on day 2, testosterone levels decreased to below baseline by week 2, and to below the 50 ng/dL castrate threshold by week 4. Castrate testosterone concentrations were maintained in 115 (83.3%) of the 138 patients throughout the 52 week evaluation period. Serum prostate specific antigen (PSA) was monitored as a secondary endpoint and decreased to within normal limits by Week 24 of treatment in 103 (93%) of 111 evaluable patients. A phase II, dose-finding clinical trial evaluated the use of 1, 2, or 4 histrelin implants for the palliation of advanced prostate cancer. Similar decreases in serum testosterone levels were noted with each dosing level. Therefore, the insertion of more than 1 histrelin implant is not indicated.

    For the treatment of central precocious puberty (CPP) in children.
    NOTE: Prior to initiating treatment with histrelin, the diagnosis of CPP should be confirmed by measuring blood concentrations of total sex steroids, luteinizing hormone, and follicle stimulating hormone following stimulation with a GnRH analog; bone age versus chronological age should be assessed. Baseline evaluations should include height and weight measurements, diagnostic imaging of the brain to rule out an intracranial tumor, pelvic/testicular/adrenal ultrasound to rule out steroid secreting tumors, and measurement of human chorionic gonadotropin concentrations (to rule out a chorionic gonadotropin secreting tumor) and adrenal steroids (to exclude congential adrenal hyperplasia).
    Subcutaneous depot implant dosage (Supprelin LA ONLY)
    Children >= 2 years and Adolescents

    1 implant (50 mg of histrelin acetate) inserted subcutaneously in the inner aspect of the upper arm every 12 months. The implant provides continuous release of histrelin (65 mcg/day) for 12 months of hormonal therapy. The implant should be removed after 12 months, although the implant has been designed to continue to release histrelin for a few additional weeks in order to allow flexibility for medical appointments. At the time of implant removal, another implant must be inserted to continue therapy. Monitor LH, FSH, and estradiol or testosterone concentrations 1 month after the implant has been inserted and every 6 months thereafter. Additionally, height (for calculation of height velocity) and bone age should be assessed every 6—12 months. An open-label study evaluated the use of 1 or 2 histrelin implants for the treatment of precocious puberty in female children; similar efficacy was reported in patients regardless of the number of implants inserted. Therefore, the insertion of > 1 implant is not indicated. Most adolescent aged children will not require continued therapy with histrelin; discontinuation of histrelin should be considered at the discretion of the physician and at the appropriate time point for the onset of puberty (approximately 11 years for females and 12 years for males).

    MAXIMUM DOSAGE

    Adults

    No more than 1 Vantas subcutaneous implant insertion at any one time.

    Geriatric

    No more than 1 Vantas subcutaneous implant insertion at any one time.

    Adolescents

    No more than 1 Supprelin LA subcutaneous implant inserted at any one time, although most children with precocious puberty will discontinue histrelin therapy around adolescence.

    Children

     >= 2 years: No more than 1 Supprelin LA subcutaneous implant inserted at any time.
     < 2 years: Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    No clinical data are available.

    Renal Impairment

    CrCl >= 15 mL/min: No dosage adjustments are needed.
    CrCl < 15 mL/min: No clinical data are available.

    ADMINISTRATION

    Injectable Administration
    Subcutaneous Administration

    Insert implant subcutaneously in the inner aspect of the upper arm following manufacturer's directions.
    Following insertion, the insertion site should remain clean and dry for a duration of 24 hours. The patient should avoid heavy lifting and strenuous exercise for 7 days after implant insertion. The surgical strips over the site should be allowed to fall off on their own over several days.
    The implant must be removed after 12 months. At the time the implant is removed, another implant may be inserted subcutaneously to continue therapy.

    STORAGE

    Supprelin:
    - Do not freeze
    - Protect from light
    - Store implant refrigerated (36 to 46 degrees F), in unopened vial, overwrapped in amber plastic pouch and carton; excursions permitted to 77 degrees F for 7 days
    Vantas:
    - Do not freeze
    - Protect from light
    - Store implant refrigerated (36 to 46 degrees F), in unopened vial, overwrapped in amber plastic pouch and carton; excursions permitted to 77 degrees F for 7 days

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Implant insertion is a surgical procedure, and it is important that the instructions are followed to avoid complications. Both the insertion and removal of the histrelin implant should be performed under aseptic conditions. Proper surgical technique is critical in minimizing adverse events related to the insertion and removal of the implant. Occasionally, ultrasound, MRI, or CT, have been necessary to localize and/or remove the implant. In some cases the implant has been reported to break during removal and multiple pieces were recovered. Ensure that the entire implant has been removed. If the implant was not removed completely, the remaining pieces should be removed following the instructions in the product label.

    Gonadotropin-Releasing Hormone (GnRH) analogs hypersensitivity

    Histrelin is contraindicated in patients with hypersensitivity to histrelin, GnRH, or with Gonadotropin-Releasing Hormone (GnRH) analogs hypersensitivity. Anaphylactic reactions to synthetic GnRH or GnRH agonist analogs have been reported.

    Bladder obstruction, renal impairment, spinal cord compression, urinary tract obstruction

    Due to transient increases in testosterone levels, histrelin (Vantas) may cause a sudden onset or worsening of prostate cancer (flare), such as bone pain, neuropathy, hematuria, or urinary tract obstruction or bladder obstruction. Patients with urinary track obstruction or metastatic vertebral lesions should be monitored carefully for signs of renal impairment or spinal cord compression, respectively, during initial histrelin treatment.

    Females, pregnancy

    Histrelin is contraindicated during pregnancy because fetal harm is possible, including spontaneous abortion (FDA pregnancy risk category X). The Vantas implant dosage form of histrelin is contraindicated in females due to lack of clinical evaluation. The Supprelin LA dosage form is contraindicated in females who are or may become pregnant. In patients who become pregnant while receiving histrelin, the patient should be apprised of the potential hazard to the fetus. Major fetal abnormalities were observed in rabbits but not in rats after administration of histrelin acetate throughout gestation. There were increased fetal mortality and decreased fetal weights in rats and rabbits. The effects on fetal mortality are expected consequences of the alterations in hormonal levels secondary to histrelin's mechanism of action.

    Breast-feeding

    It is not known whether histrelin is excreted in human milk; therefore, breast-feeding should be avoided during treatment with histrelin, due to its pharmacologic actions and potential to effect a nursing infant.

    Pituitary insufficiency

    Therapy with histrelin results in suppression of the pituitary-gonadal system. Results of diagnostic tests for pituitary insufficiency and gonadotropic and gonadal functions conducted during and after histrelin therapy may be affected.

    Children, infants, neonates

    The Vantas implant dosage form of histrelin is contraindicated in infants and children due to lack of clinical evaluation. However, Supprelin LA is FDA-approved for use in children >= 2 years of age with central precocious puberty. Histrelin implants are not recommended for use in neonates, infants and children < 2 years of age.

    Osteoporosis

    Histrelin should be used with caution in patients with pre-existing osteoporosis. GnRH analog therapy can reduce bone mineral density. Reduced bone mineral density and osteopenia are also a concern if GnRH or LH-RH analogs are used in adolescent children.

    Cardiac disease, hypercholesterolemia, hypertension, myocardial infarction, obesity, stroke, tobacco smoking

    The use of GnRH analogs in men has been reported in association with an increased risk of myocardial infarction, sudden cardiac death, and stroke. Carefully weigh the known benefits and risks of GnRH agonists such as histrelin when determining appropriate treatment for prostate cancer. Monitor patients for signs and symptoms suggestive of the development of cardiovascular disease. The risk of myocardial infarction, sudden cardiac death, and stroke appears low but needs to be evaluated carefully along with cardiovascular risk factors like cardiac disease, tobacco smoking, hypertension, hypercholesterolemia, and obesity. Manage patients according to current clinical practice. At this time, there are no known comparable studies evaluating the risk of cardiovascular disease in women or children/adolescents taking GnRH agonists for other indications.

    Diabetes mellitus, hyperglycemia

    The use of GnRH analogs in men has been reported in association with hyperglycemia and an increased risk of developing diabetes mellitus. Carefully weigh the known benefits and risks of GnRH agonists such as histrelin when determining appropriate treatment for prostate cancer. Periodically monitor patients' blood glucose concentration and/or glycosylated hemoglobin; hyperglycemia may represent diabetes mellitus development or worsening of glycemic control in patients with the condition. Manage patients according to current clinical practice. At this time, there are no known comparable studies evaluating the risk of diabetes in women or children/adolescents taking GnRH agonists for other indications.

    Depression, suicidal ideation

    Use histrelin with caution in patients with depression and emotional instability; monitor patients for worsening of psychiatric symptoms during treatment with histrelin. During postmarketing experience, emotional lability, such as crying, irritability, impatience, anger, and aggression were reported. Depression, including rare reports of suicidal ideation and attempt, were reported in children treated for central precocious puberty. Many, but not all, of these patients had a history of psychiatric illness or other comorbidities with an increased risk of depression.

    Seizure disorder

    Use histrelin with caution in patients with a preexisting seizure disorder. Seizures have been reported during postmarketing surveillance in patients with a history of epilepsy, cerebrovascular disorders, central nervous system anomalies or tumors, and patients on concomitant medications that have been associated with seizures. Seizures have also been reported in patients without any risk factors.

    ADVERSE REACTIONS

    Severe

    hot flashes / Early / 2.3-2.3
    renal failure (unspecified) / Delayed / 0-2.0
    pituitary apoplexy / Early / Incidence not known
    visual impairment / Early / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    seizures / Delayed / Incidence not known
    suicidal ideation / Delayed / Incidence not known
    myocardial infarction / Delayed / Incidence not known
    stroke / Early / Incidence not known

    Moderate

    testicular atrophy / Delayed / 5.3-5.3
    impotence (erectile dysfunction) / Delayed / 3.5-3.5
    constipation / Delayed / 3.5-3.5
    hematuria / Delayed / 0-2.0
    urinary retention / Early / 0-2.0
    dysuria / Early / 0-2.0
    bone pain / Delayed / 0-2.0
    edema / Delayed / 0-2.0
    hypercholesterolemia / Delayed / 0-2.0
    palpitations / Early / 0-2.0
    elevated hepatic enzymes / Delayed / 0-2.0
    hyperglycemia / Delayed / 0-2.0
    neuropathic pain / Delayed / Incidence not known
    erythema / Early / Incidence not known
    osteopenia / Delayed / Incidence not known
    osteoporosis / Delayed / Incidence not known
    depression / Delayed / Incidence not known
    diabetes mellitus / Delayed / Incidence not known

    Mild

    gynecomastia / Delayed / 1.0-10.0
    fatigue / Early / 9.9-9.9
    headache / Early / 2.9-2.9
    libido decrease / Delayed / 2.3-2.3
    weight gain / Delayed / 2.3-2.3
    increased urinary frequency / Early / 0-2.0
    back pain / Delayed / 0-2.0
    diaphoresis / Early / 0-2.0
    pruritus / Rapid / 0-2.0
    night sweats / Early / 0-2.0
    malaise / Early / 0-2.0
    weakness / Early / 0-2.0
    weight loss / Delayed / 0-2.0
    nausea / Early / 0-2.0
    abdominal pain / Early / 0-2.0
    injection site reaction / Rapid / 10.0
    breast enlargement / Delayed / Incidence not known
    dysmenorrhea / Delayed / Incidence not known
    menorrhagia / Delayed / Incidence not known
    vomiting / Early / Incidence not known
    ecchymosis / Delayed / Incidence not known
    irritability / Delayed / Incidence not known
    emotional lability / Early / Incidence not known

    DRUG INTERACTIONS

    Androgens: (Major) Gonadotropin releasing hormone (GnRH) agonists (i.e.,histrelin) inhibit steroidogenesis, therefore the concomitant use of these agents with androgens may counteract this therapeutic effect. Avoid concurrent use of androgens with GnRH agonists.
    atypical antipsychotic: (Moderate) Antipsychotics may cause hyperprolactinemia and should not be administered concomitantly with GnRH analogs since hyperprolactinemia down-regulates the number of pituitary GnRH receptors.
    Chlorpromazine: (Moderate) Phenothiazines may cause hyperprolactinemia and should not be administered concomitantly with GnRH analogs since hyperprolactinemia down-regulates the number of pituitary GnRH receptors.
    Cimetidine: (Minor) Cimetidine causes hyperprolactinemia and should not be administered concomitantly with GnRH analogs, as hyperprolactinemia downregulates the number of pituitary gonadotropin-releasing hormone receptors.
    Conjugated Estrogens: (Major) Concomitant use of estrogens with GnRH analogs is relatively contraindicated, as estrogens could counteract the therapeutic effect of GnRH analogs for various hormone-sensitive conditions. In the rare cases that these drugs are used together, close clinical monitoring for the desired clinical and hormonal response is necessary.
    Conjugated Estrogens; Bazedoxifene: (Major) Concomitant use of estrogens with GnRH analogs is relatively contraindicated, as estrogens could counteract the therapeutic effect of GnRH analogs for various hormone-sensitive conditions. In the rare cases that these drugs are used together, close clinical monitoring for the desired clinical and hormonal response is necessary.
    Conjugated Estrogens; Medroxyprogesterone: (Major) Concomitant use of estrogens with GnRH analogs is relatively contraindicated, as estrogens could counteract the therapeutic effect of GnRH analogs for various hormone-sensitive conditions. In the rare cases that these drugs are used together, close clinical monitoring for the desired clinical and hormonal response is necessary.
    Danazol: (Major) Gonadotropin releasing hormone (GnRH) agonists (i.e.,histrelin) inhibit steroidogenesis, therefore the concomitant use of these agents with androgens may counteract this therapeutic effect. Avoid concurrent use of androgens with GnRH agonists.
    Dienogest; Estradiol valerate: (Major) Concomitant use of estrogens with GnRH analogs is relatively contraindicated, as estrogens could counteract the therapeutic effect of GnRH analogs for various hormone-sensitive conditions. In the rare cases that these drugs are used together, close clinical monitoring for the desired clinical and hormonal response is necessary.
    Diethylstilbestrol, DES: (Major) Concomitant use of estrogens with GnRH analogs is relatively contraindicated, as estrogens could counteract the therapeutic effect of GnRH analogs for various hormone-sensitive conditions. In the rare cases that these drugs are used together, close clinical monitoring for the desired clinical and hormonal response is necessary.
    Drospirenone; Estradiol: (Major) Concomitant use of estrogens with GnRH analogs is relatively contraindicated, as estrogens could counteract the therapeutic effect of GnRH analogs for various hormone-sensitive conditions. In the rare cases that these drugs are used together, close clinical monitoring for the desired clinical and hormonal response is necessary.
    Drospirenone; Ethinyl Estradiol: (Major) Concomitant use of estrogens with GnRH analogs is relatively contraindicated, as estrogens could counteract the therapeutic effect of GnRH analogs for various hormone-sensitive conditions. In the rare cases that these drugs are used together, close clinical monitoring for the desired clinical and hormonal response is necessary.
    Drospirenone; Ethinyl Estradiol; Levomefolate: (Major) Concomitant use of estrogens with GnRH analogs is relatively contraindicated, as estrogens could counteract the therapeutic effect of GnRH analogs for various hormone-sensitive conditions. In the rare cases that these drugs are used together, close clinical monitoring for the desired clinical and hormonal response is necessary.
    Esterified Estrogens: (Major) Concomitant use of estrogens with GnRH analogs is relatively contraindicated, as estrogens could counteract the therapeutic effect of GnRH analogs for various hormone-sensitive conditions. In the rare cases that these drugs are used together, close clinical monitoring for the desired clinical and hormonal response is necessary.
    Esterified Estrogens; Methyltestosterone: (Major) Concomitant use of estrogens with GnRH analogs is relatively contraindicated, as estrogens could counteract the therapeutic effect of GnRH analogs for various hormone-sensitive conditions. In the rare cases that these drugs are used together, close clinical monitoring for the desired clinical and hormonal response is necessary. (Major) Gonadotropin releasing hormone (GnRH) agonists (i.e.,histrelin) inhibit steroidogenesis, therefore the concomitant use of these agents with androgens may counteract this therapeutic effect. Avoid concurrent use of androgens with GnRH agonists.
    Estradiol Cypionate; Medroxyprogesterone: (Major) Concomitant use of estrogens with GnRH analogs is relatively contraindicated, as estrogens could counteract the therapeutic effect of GnRH analogs for various hormone-sensitive conditions. In the rare cases that these drugs are used together, close clinical monitoring for the desired clinical and hormonal response is necessary.
    Estradiol: (Major) Concomitant use of estrogens with GnRH analogs is relatively contraindicated, as estrogens could counteract the therapeutic effect of GnRH analogs for various hormone-sensitive conditions. In the rare cases that these drugs are used together, close clinical monitoring for the desired clinical and hormonal response is necessary.
    Estradiol; Levonorgestrel: (Major) Concomitant use of estrogens with GnRH analogs is relatively contraindicated, as estrogens could counteract the therapeutic effect of GnRH analogs for various hormone-sensitive conditions. In the rare cases that these drugs are used together, close clinical monitoring for the desired clinical and hormonal response is necessary.
    Estradiol; Norethindrone: (Major) Concomitant use of estrogens with GnRH analogs is relatively contraindicated, as estrogens could counteract the therapeutic effect of GnRH analogs for various hormone-sensitive conditions. In the rare cases that these drugs are used together, close clinical monitoring for the desired clinical and hormonal response is necessary.
    Estradiol; Norgestimate: (Major) Concomitant use of estrogens with GnRH analogs is relatively contraindicated, as estrogens could counteract the therapeutic effect of GnRH analogs for various hormone-sensitive conditions. In the rare cases that these drugs are used together, close clinical monitoring for the desired clinical and hormonal response is necessary.
    Estrogens: (Major) Concomitant use of estrogens with GnRH analogs is relatively contraindicated, as estrogens could counteract the therapeutic effect of GnRH analogs for various hormone-sensitive conditions. In the rare cases that these drugs are used together, close clinical monitoring for the desired clinical and hormonal response is necessary.
    Estropipate: (Major) Concomitant use of estrogens with GnRH analogs is relatively contraindicated, as estrogens could counteract the therapeutic effect of GnRH analogs for various hormone-sensitive conditions. In the rare cases that these drugs are used together, close clinical monitoring for the desired clinical and hormonal response is necessary.
    Ethinyl Estradiol: (Major) Concomitant use of estrogens with GnRH analogs is relatively contraindicated, as estrogens could counteract the therapeutic effect of GnRH analogs for various hormone-sensitive conditions. In the rare cases that these drugs are used together, close clinical monitoring for the desired clinical and hormonal response is necessary.
    Ethinyl Estradiol; Desogestrel: (Major) Concomitant use of estrogens with GnRH analogs is relatively contraindicated, as estrogens could counteract the therapeutic effect of GnRH analogs for various hormone-sensitive conditions. In the rare cases that these drugs are used together, close clinical monitoring for the desired clinical and hormonal response is necessary.
    Ethinyl Estradiol; Ethynodiol Diacetate: (Major) Concomitant use of estrogens with GnRH analogs is relatively contraindicated, as estrogens could counteract the therapeutic effect of GnRH analogs for various hormone-sensitive conditions. In the rare cases that these drugs are used together, close clinical monitoring for the desired clinical and hormonal response is necessary.
    Ethinyl Estradiol; Etonogestrel: (Major) Concomitant use of estrogens with GnRH analogs is relatively contraindicated, as estrogens could counteract the therapeutic effect of GnRH analogs for various hormone-sensitive conditions. In the rare cases that these drugs are used together, close clinical monitoring for the desired clinical and hormonal response is necessary.
    Ethinyl Estradiol; Levonorgestrel: (Major) Concomitant use of estrogens with GnRH analogs is relatively contraindicated, as estrogens could counteract the therapeutic effect of GnRH analogs for various hormone-sensitive conditions. In the rare cases that these drugs are used together, close clinical monitoring for the desired clinical and hormonal response is necessary.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Major) Concomitant use of estrogens with GnRH analogs is relatively contraindicated, as estrogens could counteract the therapeutic effect of GnRH analogs for various hormone-sensitive conditions. In the rare cases that these drugs are used together, close clinical monitoring for the desired clinical and hormonal response is necessary.
    Ethinyl Estradiol; Norelgestromin: (Major) Concomitant use of estrogens with GnRH analogs is relatively contraindicated, as estrogens could counteract the therapeutic effect of GnRH analogs for various hormone-sensitive conditions. In the rare cases that these drugs are used together, close clinical monitoring for the desired clinical and hormonal response is necessary.
    Ethinyl Estradiol; Norethindrone Acetate: (Major) Concomitant use of estrogens with GnRH analogs is relatively contraindicated, as estrogens could counteract the therapeutic effect of GnRH analogs for various hormone-sensitive conditions. In the rare cases that these drugs are used together, close clinical monitoring for the desired clinical and hormonal response is necessary.
    Ethinyl Estradiol; Norethindrone Acetate; Ferrous fumarate: (Major) Concomitant use of estrogens with GnRH analogs is relatively contraindicated, as estrogens could counteract the therapeutic effect of GnRH analogs for various hormone-sensitive conditions. In the rare cases that these drugs are used together, close clinical monitoring for the desired clinical and hormonal response is necessary.
    Ethinyl Estradiol; Norethindrone: (Major) Concomitant use of estrogens with GnRH analogs is relatively contraindicated, as estrogens could counteract the therapeutic effect of GnRH analogs for various hormone-sensitive conditions. In the rare cases that these drugs are used together, close clinical monitoring for the desired clinical and hormonal response is necessary.
    Ethinyl Estradiol; Norethindrone; Ferrous fumarate: (Major) Concomitant use of estrogens with GnRH analogs is relatively contraindicated, as estrogens could counteract the therapeutic effect of GnRH analogs for various hormone-sensitive conditions. In the rare cases that these drugs are used together, close clinical monitoring for the desired clinical and hormonal response is necessary.
    Ethinyl Estradiol; Norgestimate: (Major) Concomitant use of estrogens with GnRH analogs is relatively contraindicated, as estrogens could counteract the therapeutic effect of GnRH analogs for various hormone-sensitive conditions. In the rare cases that these drugs are used together, close clinical monitoring for the desired clinical and hormonal response is necessary.
    Ethinyl Estradiol; Norgestrel: (Major) Concomitant use of estrogens with GnRH analogs is relatively contraindicated, as estrogens could counteract the therapeutic effect of GnRH analogs for various hormone-sensitive conditions. In the rare cases that these drugs are used together, close clinical monitoring for the desired clinical and hormonal response is necessary.
    Fluoxymesterone: (Major) Gonadotropin releasing hormone (GnRH) agonists (i.e.,histrelin) inhibit steroidogenesis, therefore the concomitant use of these agents with androgens may counteract this therapeutic effect. Avoid concurrent use of androgens with GnRH agonists.
    Fluphenazine: (Moderate) Phenothiazines may cause hyperprolactinemia and should not be administered concomitantly with GnRH analogs since hyperprolactinemia down-regulates the number of pituitary GnRH receptors.
    Haloperidol: (Moderate) Antipsychotics may cause hyperprolactinemia and should not be administered concomitantly with GnRH analogs since hyperprolactinemia down-regulates the number of pituitary GnRH receptors.
    Hydrochlorothiazide, HCTZ; Methyldopa: (Minor) Drugs that cause hyperprolactinemia, such as methyldopa, should generally not be administered concomitantly with GnRH analogs since hyperprolactinemia downregulates the number of pituitary GnRH receptors. Monitor the patient for the proper clinical response to GnRH therapy.
    Loxapine: (Moderate) Antipsychotics may cause hyperprolactinemia and should not be administered concomitantly with GnRH analogs since hyperprolactinemia down-regulates the number of pituitary GnRH receptors.
    Mesoridazine: (Moderate) Phenothiazines may cause hyperprolactinemia and should not be administered concomitantly with GnRH analogs since hyperprolactinemia down-regulates the number of pituitary GnRH receptors.
    Mestranol; Norethindrone: (Major) Concomitant use of estrogens with GnRH analogs is relatively contraindicated, as estrogens could counteract the therapeutic effect of GnRH analogs for various hormone-sensitive conditions. In the rare cases that these drugs are used together, close clinical monitoring for the desired clinical and hormonal response is necessary.
    Methyldopa: (Minor) Drugs that cause hyperprolactinemia, such as methyldopa, should generally not be administered concomitantly with GnRH analogs since hyperprolactinemia downregulates the number of pituitary GnRH receptors. Monitor the patient for the proper clinical response to GnRH therapy.
    Methyltestosterone: (Major) Gonadotropin releasing hormone (GnRH) agonists (i.e.,histrelin) inhibit steroidogenesis, therefore the concomitant use of these agents with androgens may counteract this therapeutic effect. Avoid concurrent use of androgens with GnRH agonists.
    Metoclopramide: (Minor) Drugs that cause hyperprolactinemia, such as metoclopramide, should generally not be administered concomitantly with GnRH analogs since hyperprolactinemia downregulates the number of pituitary GnRH receptors. Monitor the patient for the proper clinical response to GnRH therapy.
    Molindone: (Moderate) Antipsychotics may cause hyperprolactinemia and should not be administered concomitantly with GnRH analogs since hyperprolactinemia down-regulates the number of pituitary GnRH receptors.
    Nandrolone Decanoate: (Major) Gonadotropin releasing hormone (GnRH) agonists (i.e.,histrelin) inhibit steroidogenesis, therefore the concomitant use of these agents with androgens may counteract this therapeutic effect. Avoid concurrent use of androgens with GnRH agonists.
    Oxandrolone: (Major) Gonadotropin releasing hormone (GnRH) agonists (i.e.,histrelin) inhibit steroidogenesis, therefore the concomitant use of these agents with androgens may counteract this therapeutic effect. Avoid concurrent use of androgens with GnRH agonists.
    Oxymetholone: (Major) Gonadotropin releasing hormone (GnRH) agonists (i.e.,histrelin) inhibit steroidogenesis, therefore the concomitant use of these agents with androgens may counteract this therapeutic effect. Avoid concurrent use of androgens with GnRH agonists.
    Perphenazine: (Moderate) Phenothiazines may cause hyperprolactinemia and should not be administered concomitantly with GnRH analogs since hyperprolactinemia down-regulates the number of pituitary GnRH receptors.
    Perphenazine; Amitriptyline: (Moderate) Phenothiazines may cause hyperprolactinemia and should not be administered concomitantly with GnRH analogs since hyperprolactinemia down-regulates the number of pituitary GnRH receptors.
    Phenothiazines: (Moderate) Phenothiazines may cause hyperprolactinemia and should not be administered concomitantly with GnRH analogs since hyperprolactinemia down-regulates the number of pituitary GnRH receptors.
    Pimozide: (Moderate) Antipsychotics may cause hyperprolactinemia and should not be administered concomitantly with GnRH analogs since hyperprolactinemia down-regulates the number of pituitary GnRH receptors.
    Prasterone, Dehydroepiandrosterone, DHEA (Dietary Supplements): (Major) Gonadotropin releasing hormone (GnRH) agonists (i.e.,histrelin) inhibit steroidogenesis, therefore the concomitant use of these agents with androgens may counteract this therapeutic effect. Avoid concurrent use of androgens with GnRH agonists.
    Prasterone, Dehydroepiandrosterone, DHEA (FDA-approved): (Major) Gonadotropin releasing hormone (GnRH) agonists (i.e.,histrelin) inhibit steroidogenesis, therefore the concomitant use of these agents with androgens may counteract this therapeutic effect. Avoid concurrent use of androgens with GnRH agonists.
    Prochlorperazine: (Moderate) Phenothiazines may cause hyperprolactinemia and should not be administered concomitantly with GnRH analogs since hyperprolactinemia down-regulates the number of pituitary GnRH receptors.
    Reserpine: (Minor) Drugs that cause hyperprolactinemia, such as reserpine, should not be administered concomitantly with GnRH analogs since hyperprolactinemia downregulates the number of pituitary GnRH receptors.
    Testolactone: (Major) Gonadotropin releasing hormone (GnRH) agonists (i.e.,histrelin) inhibit steroidogenesis, therefore the concomitant use of these agents with androgens may counteract this therapeutic effect. Avoid concurrent use of androgens with GnRH agonists.
    Testosterone: (Major) Gonadotropin releasing hormone (GnRH) agonists (i.e.,histrelin) inhibit steroidogenesis, therefore the concomitant use of these agents with androgens may counteract this therapeutic effect. Avoid concurrent use of androgens with GnRH agonists.
    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 (histrelin) since hyperprolactinemia down regulates the number of pituitary GnRH receptors.
    Thiethylperazine: (Moderate) Phenothiazines may cause hyperprolactinemia and should not be administered concomitantly with GnRH analogs since hyperprolactinemia down-regulates the number of pituitary GnRH receptors.
    Thioridazine: (Moderate) Phenothiazines may cause hyperprolactinemia and should not be administered concomitantly with GnRH analogs since hyperprolactinemia down-regulates the number of pituitary GnRH receptors.
    Trifluoperazine: (Moderate) Phenothiazines may cause hyperprolactinemia and should not be administered concomitantly with GnRH analogs since hyperprolactinemia down-regulates the number of pituitary GnRH receptors.

    PREGNANCY AND LACTATION

    Pregnancy

    Histrelin is contraindicated during pregnancy because fetal harm is possible, including spontaneous abortion (FDA pregnancy risk category X). The Vantas implant dosage form of histrelin is contraindicated in females due to lack of clinical evaluation. The Supprelin LA dosage form is contraindicated in females who are or may become pregnant. In patients who become pregnant while receiving histrelin, the patient should be apprised of the potential hazard to the fetus. Major fetal abnormalities were observed in rabbits but not in rats after administration of histrelin acetate throughout gestation. There were increased fetal mortality and decreased fetal weights in rats and rabbits. The effects on fetal mortality are expected consequences of the alterations in hormonal levels secondary to histrelin's mechanism of action.

    MECHANISM OF ACTION

    Initial or intermittent administration of histrelin stimulates the release of the gonadotropins, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) from the pituitary gland, which in turn transiently increases the production of gonadal steroids (e.g., estradiol and estrone in premenopausal females, testosterone and dihydrotestosterone in males). However, with sustained administration, histrelin continuously occupies the GnRH receptor, causing a reversible down-regulation of the GnRH receptors in the pituitary gland and desensitization of the pituitary gonadotropins. These inhibitory effects cause a significant and sustained decline in the production of LH and FSH. A decline in gonadotropin production and release causes a dramatic, reversible decrease in the synthesis of gonadal steroids.
    •Clinical activity in males: Following an initial increase in testosterone levels after histrelin implantation, testosterone levels decrease to below baseline within 2—4 weeks. Testosterone concentrations are maintained well below desired (< 50 ng/dL in males with prostate cancer and < 30 ng/dL in male children with precocious puberty) throughout the 52 week period. In male children with precocious puberty, a cessation in the progression of secondary sexual development occurs. In addition, linear growth velocity is slowed, which improves the chance of attaining predicted adult height.
    •Clinical activity in females: Long-term treatment with histrelin decreases LH concentrations to prepubertal levels within 1 month. Estradiol concentrations are maintained below prepubertal concentrations (< 20 pg/mL) throughout the 52 week period. As a result, cessation in the progression of secondary sexual development occurs. Linear growth velocity is slowed, which improves the chance of attaining predicted adult height.

    PHARMACOKINETICS

    Histrelin is administered by a subcutaneous insertion of a 50 mg implant. Histrelin is metabolized by human hepatocytes by C-terminal dealkylation. Peptide fragments resulting from hydrolysis are also likely metabolites. The clearance of histrelin is 179 ml/min and the terminal half-life is 3.92 hr in males with prostate cancer.

    Subcutaneous Route

    Continuous release of histrelin occurs over a 52-week period, with approximately 50—60 mcg/day delivered after implantation of Vantas in males with prostate cancer and approximately 65 mcg/day delivered after implantation of Supprelin LA in children with precocious puberty. Following subcutaneous insertion of a 50 mg implant in males with advanced prostate cancer, peak serum concentrations of 1.1 ng/mL are achieved within approximately 12 hours; the mean serum concentrations at the end of 52 weeks are 0.13 ng/mL. In children with central precocious puberty, after subcutaneous insertion of a 50 mg implant, the median maximum serum concentration is 0.43 ng/mL; histrelin concentrations are sustained above the limit of quantification over the study period of 12 months. After a subcutaneous bolus of 500 mcg of histrelin acetate in healthy volunteers, the volume of distribution is 58.4 L while the fraction of unbound drug in the plasma is 29.5%.