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  • CLASSES

    Gonadotropin-releasing Hormones

    DEA CLASS

    Rx

    DESCRIPTION

    A gonadotropin-releasing hormone (GnRH) agonist
    Used for the palliative treatment of advanced prostate cancer or the treatment of central precocious puberty in children
    Initial increases in hormone levels may cause temporary worsening of symptoms; implant insertion is a surgical procedure

    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

    1 implant (50 mg of histrelin acetate to deliver 41 mg histrelin) inserted subcutaneously in the upper arm every 12 months; remove the implant after 12 months of therapy. At the time of implant removal, another implant may be inserted to continue therapy. In a multicenter, open-label, phase 3 clinical trial of patients with prostate cancer (n = 138), treatment with a single histrelin implant for at least 52 weeks decreased the mean serum testosterone concentration by approximately 1.4% at the end of week 1, by 76.3% at the end of week 2, by 96.1% at the end of week 4, and by 96.3% at week 52; mean serum testosterone levels were below the 50 ng/dL castrate threshold by the end of week 4. Serum testosterone was suppressed to below the castrate level in all evaluable patients on day 28 (n = 134); all patients who were missing values at day 28 were castrate by the time of their next visit at day 56. In a subset of 17 patients, mean serum testosterone concentrations increased by approximately 40.9% on day 2, and then decreased to below baseline by week 2, and to below the 50 ng/dL castrate threshold by week 4; serum testosterone concentrations remained below the castrate level in this subset for the entire treatment period. Serum prostate specific antigen (PSA), a secondary endpoint, decreased to within normal limits by week 24 in 93% of patients. A phase 2, dose-finding clinical trial found similar decreases in serum testosterone levels with the use of 1, 2, or 4 histrelin implants for the palliation of advanced prostate cancer; the insertion of more than 1 histrelin implant is not necessary.

    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

    Children 2 years and older: No more than 1 Supprelin LA subcutaneous implant inserted at any time.
    Children younger than 2 years: Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

    Renal Impairment

    CrCL 15 mL/min or higher: No dosage adjustments are needed.
    CrCL less than 15 mL/min: Specific guidelines are not available; no dosage adjustments are recommended.

    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

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

    Gonadotropin-Releasing Hormone (GnRH) analogs hypersensitivity

    Histrelin is contraindicated in patients with hypersensitivity to histrelin, Gonadotropin-Releasing Hormone (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 prostate cancer and urinary tract obstruction or metastatic vertebral lesions should be monitored carefully for signs of renal impairment or spinal cord compression, respectively, during initial histrelin treatment.

    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.

    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.

    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.

    Cardiac disease, myocardial infarction, stroke

    The use of GnRH analogs in men has been reported in association with an increased risk of myocardial infarction, sudden cardiac death, and stroke although the risk appears to be low based on the reported odds ratios. Carefully evaluate risk factors for cardiac disease and 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 and manage 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.

    Alcoholism, bradycardia, cardiac arrhythmias, coronary artery disease, electrolyte imbalance, geriatric, heart failure, hepatic disease, hypertension, hypocalcemia, hypokalemia, hypomagnesemia, long QT syndrome, malnutrition, QT prolongation, thyroid disease

    Androgen deprivation therapy may prolong the QT/QTc interval. Use histrelin with caution in patients with cardiac disease or other conditions that may increase the risk of QT prolongation including cardiac arrhythmias, congenital long QT syndrome, heart failure, bradycardia, myocardial infarction, hypertension, coronary artery disease, hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving medications known to prolong the QT interval or cause electrolyte imbalance. Females, geriatric patients, patients with diabetes mellitus, thyroid disease, malnutrition, alcoholism, or hepatic disease may also be at increased risk for QT prolongation. Correct any electrolyte abnormalities, and consider periodic monitoring of electrocardiograms and electrolytes.

    Children, infants, neonates

    The Vantas implant dosage form of histrelin is not indicated for use in infants and children. However, Supprelin LA is FDA-approved for use in children 2 years and older of age with central precocious puberty; it is not recommended for use in neonates, infants and children younger than 2 years of age, as safety and efficacy have not been established.

    Females, pregnancy

    Histrelin is contraindicated during pregnancy because fetal harm is possible, including spontaneous abortion (FDA pregnancy risk category X). Vantas is not indicated for use in females, although Supprelin LA may be used in female children. There are no adequate and well-controlled studies in pregnant women. Women who are pregnant or who become pregnant while receiving histrelin should be apprised of the potential hazard to the fetus. In nonclinical studies, histrelin was teratogenic and fetotoxic. 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 caused by histrelin.

    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.

    ADVERSE REACTIONS

    Severe

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

    Moderate

    testicular atrophy / Delayed / 5.3-5.3
    impotence (erectile dysfunction) / Delayed / 3.5-3.5
    constipation / Delayed / 0-3.5
    erythema / Early / 0-2.8
    bone pain / Delayed / 0-2.0
    hematuria / Delayed / 0-2.0
    dysuria / Early / 0-2.0
    urinary retention / Early / 0-2.0
    hematoma / Early / 0-2.0
    depression / Delayed / 0-2.0
    palpitations / Early / 0-2.0
    dyspnea / Early / 0-2.0
    hypercholesterolemia / Delayed / 0-2.0
    edema / Delayed / 0-2.0
    elevated hepatic enzymes / Delayed / 0-2.0
    hyperglycemia / Delayed / 0-2.0
    anemia / Delayed / 0-2.0
    hypercalcemia / Delayed / 0-2.0
    amblyopia / Delayed / 0-1.0
    migraine / Early / 0-1.0
    neuropathic pain / Delayed / Incidence not known
    tumor flare / Delayed / Incidence not known
    vaginal bleeding / Delayed / Incidence not known
    osteopenia / Delayed / Incidence not known
    osteoporosis / Delayed / Incidence not known
    QT prolongation / Rapid / Incidence not known
    diabetes mellitus / Delayed / Incidence not known

    Mild

    injection site reaction / Rapid / 5.8-51.1
    menorrhagia / Delayed / 1.0-10.0
    dysmenorrhea / Delayed / 1.0-10.0
    fatigue / Early / 0-9.9
    ecchymosis / Delayed / 0-7.2
    gynecomastia / Delayed / 0-4.1
    insomnia / Early / 0-2.9
    headache / Early / 0-2.9
    libido decrease / Delayed / 2.3-2.3
    weight gain / Delayed / 0-2.3
    hyperhidrosis / Delayed / 0-2.0
    diaphoresis / Early / 0-2.0
    flushing / Rapid / 0-2.0
    night sweats / Early / 0-2.0
    back pain / Delayed / 0-2.0
    increased urinary frequency / Early / 0-2.0
    hypertrichosis / Delayed / 0-2.0
    pruritus / Rapid / 0-2.0
    irritability / Delayed / 0-2.0
    nausea / Early / 0-2.0
    abdominal pain / Early / 0-2.0
    weight loss / Delayed / 0-2.0
    dizziness / Early / 0-2.0
    tremor / Early / 0-2.0
    weakness / Early / 0-2.0
    lethargy / Early / 0-2.0
    myalgia / Early / 0-2.0
    malaise / Early / 0-2.0
    arthralgia / Delayed / 0-2.0
    infection / Delayed / 0-1.0
    influenza / Delayed / 0-1.0
    epistaxis / Delayed / 0-1.0
    breast enlargement / Delayed / Incidence not known
    vomiting / Early / Incidence not known
    emotional lability / Early / Incidence not known
    appetite stimulation / Delayed / Incidence not known

    DRUG INTERACTIONS

    Albuterol: (Minor) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and short-acting beta-agonists is necessary; correct any electrolyte abnormalities. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Albuterol; Ipratropium: (Minor) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and short-acting beta-agonists is necessary; correct any electrolyte abnormalities. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Alfuzosin: (Major) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and alfuzosin is necessary; correct any electrolyte abnormalities. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Based on electrophysiology studies performed by the manufacturer, alfuzosin may prolong the QT interval in a dose-dependent manner.
    Amiodarone: (Major) Avoid coadministration of amiodarone with histrelin if possible due to the risk of QT prolongation. If concomitant use is unavoidable, consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes; correct any electrolyte abnormalities. Amiodarone, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP), although the frequency of TdP is less with amiodarone than with other Class III agents. Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval; the risk may be increased with the concurrent use of other drugs that may prolong the QT interval. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone.
    Amitriptyline: (Minor) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and tricyclic antidepressants is necessary; correct any electrolyte abnormalities. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Amitriptyline; Chlordiazepoxide: (Minor) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and tricyclic antidepressants is necessary; correct any electrolyte abnormalities. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Amoxicillin; Clarithromycin; Lansoprazole: (Major) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and clarithromycin is necessary; correct any electrolyte abnormalities. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Clarithromycin is associated with an established risk for QT prolongation and torsade de pointes (TdP).
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and clarithromycin is necessary; correct any electrolyte abnormalities. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Clarithromycin is associated with an established risk for QT prolongation and torsade de pointes (TdP).
    Anagrelide: (Major) Do not use anagrelide with other drugs that prolong the QT interval such as histrelin. Torsade de pointes (TdP) and ventricular tachycardia have been reported with anagrelide; in addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects. Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Androgens: (Major) Avoid concurrent use of androgens with gonadotropin releasing hormone (GnRH) agonists such as histrelin. Histrelin inhibits steroidogenesis; concomitant use with androgens may counteract this therapeutic effect.
    Apomorphine: (Major) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and apomorphine is necessary; correct any electrolyte abnormalities. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Limited data indicate that QT prolongation is also possible with apomorphine administration; the change in QTc interval is not significant in most patients receiving dosages within the manufacturer's guidelines.
    Arformoterol: (Moderate) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and beta-agonists is necessary; correct any electrolyte abnormalities. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Beta-agonists may also be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Aripiprazole: (Moderate) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and aripiprazole is necessary; correct any electrolyte abnormalities. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. QT prolongation has also occurred during therapeutic use of aripiprazole and following overdose.
    Arsenic Trioxide: (Major) Avoid concomitant use of arsenic trioxide with other drugs that may cause QT interval prolongation such as histrelin; discontinue or select an alternative drug that does not prolong the QT interval prior to starting arsenic trioxide therapy. If concomitant use is unavoidable, frequently monitor electrocardiograms for QT prolongation and monitor electrolytes; correct any electrolyte abnormalities. Torsade de pointes (TdP), QT interval prolongation, and complete atrioventricular block have been reported with arsenic trioxide use. Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Artemether; Lumefantrine: (Major) Avoid coadministration of artemether with histrelin if possible due to the risk of QT prolongation. If concomitant use is unavoidable, consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes; correct any electrolyte abnormalities. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Artemether; lumefantrine is also associated with prolongation of the QT interval. (Major) Avoid coadministration of lumefantrine with histrelin if possible due to the risk of QT prolongation. If concomitant use is unavoidable, consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes; correct any electrolyte abnormalities. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Artemether; lumefantrine is also associated with prolongation of the QT interval.
    Asenapine: (Major) According to the manufacturer of asenapine, the drug should be avoided in combination with other agents also known to have this effect, such as histrelin. Asenapine has been associated with QT prolongation, and androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Atomoxetine: (Moderate) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and atomoxetine is necessary; correct any electrolyte abnormalities. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. QT prolongation has also occurred during therapeutic use of atomoxetine and following overdose.
    Azithromycin: (Major) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and azithromycin is necessary; correct any electrolyte abnormalities. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Both QT prolongation and torsade de pointes (TdP) have been spontaneously reported during azithromycin postmarketing surveillance.
    Bedaquiline: (Major) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and bedaquiline is necessary; correct any electrolyte abnormalities. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Bedaquiline has also been reported to prolong the QT interval.
    Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Moderate) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and metronidazole is necessary; correct any electrolyte abnormalities. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Potential QT prolongation has also been reported in limited case reports with metronidazole.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Moderate) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and metronidazole is necessary; correct any electrolyte abnormalities. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Potential QT prolongation has also been reported in limited case reports with metronidazole.
    Budesonide; Formoterol: (Moderate) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and beta-agonists is necessary; correct any electrolyte abnormalities. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Beta-agonists may also be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Buprenorphine: (Major) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and buprenorphine is necessary; correct any electrolyte abnormalities. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Buprenorphine has also been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval.
    Buprenorphine; Naloxone: (Major) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and buprenorphine is necessary; correct any electrolyte abnormalities. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Buprenorphine has also been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval.
    Ceritinib: (Major) Periodically monitor EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and ceritinib is necessary; correct any electrolyte abnormalities. An interruption/discontinuation of ceritinib therapy or a dosage adjustment may be necessary if QT prolongation or other serious arrhythmias occur. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Concentration-dependent QT prolongation has been reported with ceritinib.
    Chloroquine: (Major) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and chloroquine is necessary; correct any electrolyte abnormalities. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Chloroquine is also associated with an increased risk of dose-related QT prolongation and torsade de pointes (TdP); fatalities have been reported.
    Chlorpromazine: (Major) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and chlorpromazine is necessary; correct any electrolyte abnormalities. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Chlorpromazine, a phenothiazine, is also associated with an established risk of QT prolongation and torsade de pointes (TdP).
    Ciprofloxacin: (Moderate) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and ciprofloxacin is necessary; correct any electrolyte abnormalities. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Rare cases of QT prolongation and torsade de pointes (TdP) have been reported with ciprofloxacin during postmarketing surveillance.
    Cisapride: (Severe) Because of the potential for QT prolongation and torsade de pointes (TdP), the use of histrelin with cisapride is contraindicated. Prolongation of the QT interval and ventricular arrhythmias, including TdP and death, have been reported with cisapride. Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Citalopram: (Major) According to the manufacturer of citalopram, concurrent use of citalopram with other drugs that prolong the QT interval, such as histrelin, is not recommended. If concurrent therapy is considered essential, periodically monitor EGCs for QT prolongation and monitor electrolytes; correct any electrolyte abnormalities. Citalopram causes dose-dependent QT interval prolongation. Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Clarithromycin: (Major) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and clarithromycin is necessary; correct any electrolyte abnormalities. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Clarithromycin is associated with an established risk for QT prolongation and torsade de pointes (TdP).
    Clomipramine: (Minor) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and tricyclic antidepressants is necessary; correct any electrolyte abnormalities. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Clozapine: (Major) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and clozapine is necessary; correct any electrolyte abnormalities. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death.
    Codeine; Phenylephrine; Promethazine: (Moderate) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and promethazine is necessary; correct any electrolyte abnormalities. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Codeine; Promethazine: (Moderate) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and promethazine is necessary; correct any electrolyte abnormalities. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Crizotinib: (Major) Monitor EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and crizotinib is necessary; correct any electrolyte abnormalities. An interruption of crizotinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Cyclobenzaprine: (Moderate) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and cyclobenzaprine is necessary; correct any electrolyte abnormalities. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Cyclobenzaprine is also associated with a possible risk of QT prolongation and torsade de pointes (TdP), particularly in the event of acute overdose.
    Danazol: (Major) Avoid concurrent use of androgens with gonadotropin releasing hormone (GnRH) agonists such as histrelin. Histrelin inhibits steroidogenesis; concomitant use with androgens may counteract this therapeutic effect.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and ritonavir is necessary; correct any electrolyte abnormalities. Ritonavir is associated with QT prolongation. Coadministration with other drugs that prolong the QT interval may result in additive QT prolongation. Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval.
    Dasatinib: (Major) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and dasatinib is necessary; correct any electrolyte abnormalities. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. In vitro studies have shown that dasatinib also has the potential to prolong the QT interval.
    Degarelix: (Major) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and degarelix is necessary; correct any electrolyte abnormalities. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Prolongation of the QTc interval has also been reported with the use of degarelix.
    Desflurane: (Major) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and halogenated anesthetics is necessary; correct any electrolyte abnormalities. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Halogenated anesthetics can also prolong the QT interval.
    Desipramine: (Minor) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and tricyclic antidepressants is necessary; correct any electrolyte abnormalities. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Deutetrabenazine: (Moderate) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and deutetrabenazine is necessary; correct any electrolyte abnormalities. For patients taking a deutetrabenazine dosage more than 24 mg per day, assess the QTc interval before initiating concomitant therapy and after increasing the dosage of either drug. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Clinically relevant QTc prolongation may also occur with deutetrabenazine.
    Dextromethorphan; Promethazine: (Moderate) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and promethazine is necessary; correct any electrolyte abnormalities. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Dextromethorphan; Quinidine: (Major) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and quinidine is necessary; correct any electrolyte abnormalities. Quinidine administration is associated with QT prolongation and torsade de pointes (TdP). Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Disopyramide: (Major) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and disopyramide is necessary; correct any electrolyte abnormalities. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Disopyramide administration is also associated with QT prolongation and torsade de pointes (TdP).
    Dofetilide: (Severe) Because of the potential for torsade de pointes (TdP), use of histrelin with dofetilide is contraindicated. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and TdP. Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Dolasetron: (Major) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and dolasetron is necessary; correct any electrolyte abnormalities. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Dolasetron has also been associated with a dose-dependent prolongation in the QT, PR, and QRS intervals on an electrocardiogram.
    Dolutegravir; Rilpivirine: (Major) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and rilpivirine is necessary; correct any electrolyte abnormalities. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Donepezil: (Major) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and donepezil is necessary; correct any electrolyte abnormalities. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy; donepezil is considered a drug with a known risk of TdP.
    Donepezil; Memantine: (Major) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and donepezil is necessary; correct any electrolyte abnormalities. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy; donepezil is considered a drug with a known risk of TdP.
    Doxepin: (Minor) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and tricyclic antidepressants is necessary; correct any electrolyte abnormalities. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Dronedarone: (Severe) Because of the potential for torsade de pointes (TdP), use of histrelin with dronedarone is contraindicated. Dronedarone administration is associated with a dose-related increase in the QTc interval. The increase in QTc is approximately 10 milliseconds at doses of 400 mg twice daily (the FDA-approved dose) and up to 25 milliseconds at doses of 1,600 mg twice daily. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Androgen deprivation therapy (e.g., histrelin) is known to prolong the QT interval.
    Droperidol: (Major) Droperidol should not be used in combination with any drug known to have potential to prolong the QT interval, such as histrelin. If coadministration cannot be avoided, use extreme caution; initiate droperidol at a low dose and increase the dose as needed to achieve the desired effect. Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes; correct any electrolyte abnormalities. Droperidol administration is associated with an established risk for QT prolongation and torsade de pointes (TdP); some cases have occurred in patients with no known risk factors for QT prolongation and some cases have been fatal. Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Efavirenz: (Major) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and efavirenz is necessary; correct any electrolyte abnormalities. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Prolongation of the QTc interval has also been observed with the use of efavirenz.
    Efavirenz; Emtricitabine; Tenofovir: (Major) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and efavirenz is necessary; correct any electrolyte abnormalities. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Prolongation of the QTc interval has also been observed with the use of efavirenz.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and efavirenz is necessary; correct any electrolyte abnormalities. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Prolongation of the QTc interval has also been observed with the use of efavirenz.
    Eliglustat: (Major) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and eliglustat is necessary; correct any electrolyte abnormalities. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Eliglustat is predicted to cause PR, QRS, and/or QT prolongation at significantly elevated plasma concentrations.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Major) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and rilpivirine is necessary; correct any electrolyte abnormalities. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Major) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and rilpivirine is necessary; correct any electrolyte abnormalities. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Encorafenib: (Major) Avoid coadministration of encorafenib and histrelin due to QT prolongation. Consider periodic monitoring of EGCs for QT prolongation and electrolytes if coadministration of histrelin and encorafenib is necessary; correct any electrolyte abnormalities. Encorafenib is associated with dose-dependent prolongation of the QT interval. Androgen deprivation therapy (e.g.,histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Enflurane: (Major) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and halogenated anesthetics is necessary; correct any electrolyte abnormalities. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Halogenated anesthetics can also prolong the QT interval.
    Eribulin: (Major) Closely monitor EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and eribulin is necessary; correct any electrolyte abnormalities. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Eribulin has also been associated with QT prolongation.
    Erythromycin: (Major) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and erythromycin is necessary; correct any electrolyte abnormalities. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Erythromycin is also associated with QT prolongation and torsade de pointes (TdP).
    Erythromycin; Sulfisoxazole: (Major) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and erythromycin is necessary; correct any electrolyte abnormalities. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Erythromycin is also associated with QT prolongation and torsade de pointes (TdP).
    Escitalopram: (Moderate) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and escitalopram is necessary; correct any electrolyte abnormalities. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Escitalopram has also been associated with a risk of QT prolongation and torsade de pointes (TdP).
    Esterified Estrogens; Methyltestosterone: (Major) Avoid concurrent use of androgens with gonadotropin releasing hormone (GnRH) agonists such as histrelin. Histrelin inhibits steroidogenesis; concomitant use with androgens may counteract this therapeutic effect.
    Ezogabine: (Major) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and ezogabine is necessary; correct any electrolyte abnormalities. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Ezogabine has also been associated with QT prolongation.
    Fingolimod: (Major) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and fingolimod is necessary; correct any electrolyte abnormalities. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. After the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients taking QT prolonging drugs with a known risk of torsade de pointes (TdP). Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia.
    Flecainide: (Major) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and flecainide is necessary; correct any electrolyte abnormalities. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval. Flecainide is a Class IC antiarrhythmic associated with a possible risk for QT prolongation and/or torsade de pointes (TdP); flecainide increases the QT interval, but largely due to prolongation of the QRS interval. Although causality for TdP has not been established for flecainide, patients receiving concurrent drugs that have the potential for QT prolongation may have an increased risk of developing proarrhythmias.
    Fluconazole: (Major) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and fluconazole is necessary; correct any electrolyte abnormalities. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Fluconazole has also been associated with QT prolongation and rare cases of torsade de pointes (TdP).
    Fluoxetine: (Major) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and fluoxetine is necessary; correct any electrolyte abnormalities. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Prolongation of the QT interval and torsade de pointes (TdP) have been reported in patients treated with fluoxetine.
    Fluoxetine; Olanzapine: (Major) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and fluoxetine is necessary; correct any electrolyte abnormalities. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Prolongation of the QT interval and torsade de pointes (TdP) have been reported in patients treated with fluoxetine. (Moderate) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and olanzapine is necessary; correct any electrolyte abnormalities. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval.
    Fluoxymesterone: (Major) Avoid concurrent use of androgens with gonadotropin releasing hormone (GnRH) agonists such as histrelin. Histrelin inhibits steroidogenesis; concomitant use with androgens may counteract this therapeutic effect.
    Fluphenazine: (Minor) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and fluphenazine is necessary; correct any electrolyte abnormalities. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval. Fluphenazine is also associated with a possible risk for QT prolongation. Theoretically, fluphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
    Fluticasone; Salmeterol: (Moderate) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and beta-agonists is necessary; correct any electrolyte abnormalities. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Beta-agonists may also be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Fluticasone; Umeclidinium; Vilanterol: (Moderate) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and beta-agonists is necessary; correct any electrolyte abnormalities. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Beta-agonists may also be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Fluticasone; Vilanterol: (Moderate) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and beta-agonists is necessary; correct any electrolyte abnormalities. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Beta-agonists may also be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Fluvoxamine: (Moderate) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and fluvoxamine is necessary; correct any electrolyte abnormalities. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Prolongation of the QT interval and torsade de pointes (TdP) have been reported during fluvoxamine postmarketing use.
    Formoterol: (Moderate) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and beta-agonists is necessary; correct any electrolyte abnormalities. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Beta-agonists may also be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Formoterol; Mometasone: (Moderate) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and beta-agonists is necessary; correct any electrolyte abnormalities. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Beta-agonists may also be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Foscarnet: (Major) Avoid coadministration of foscarnet with histrelin due to the risk of QT prolongation. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Both QT prolongation and torsade de pointes (TdP) have been reported during postmarketing use of foscarnet.
    Gemifloxacin: (Major) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and gemifloxacin is necessary; correct any electrolyte abnormalities. Gemifloxacin may prolong the QT interval in some patients. The maximal change in the QTc interval occurs approximately 5 to 10 hours following oral administration of gemifloxacin. The likelihood of QTc prolongation may increase with increasing dose of the drug; therefore, the recommended dose should not be exceeded especially in patients with renal or hepatic impairment where the Cmax and AUC are slightly higher. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Gemtuzumab Ozogamicin: (Moderate) If coadministration of gemtuzumab ozogamicin and histrelin is necessary, obtain an ECG and serum electrolytes prior to initiation of concomitant use due to the potential for additive QT prolongation and the risk of torsade de pointes (TdP); periodically monitor ECGs and electrolytes during therapy, correcting any electrolyte abnormalities. Although QT interval prolongation has not been reported with gemtuzumab, it has been reported with other drugs that contain calicheamicin. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Glycopyrrolate; Formoterol: (Moderate) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and beta-agonists is necessary; correct any electrolyte abnormalities. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Beta-agonists may also be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Granisetron: (Major) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and granisetron is necessary; correct any electrolyte abnormalities. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Granisetron has also been associated with QT prolongation.
    Halogenated Anesthetics: (Major) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and halogenated anesthetics is necessary; correct any electrolyte abnormalities. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Halogenated anesthetics can also prolong the QT interval.
    Haloperidol: (Major) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and haloperidol is necessary; correct any electrolyte abnormalities. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Prolongation of the QT interval and torsade de pointes (TdP) have been observed during haloperidol treatment. Excessive doses (particularly in the overdose setting) or IV administration of haloperidol may be associated with a higher risk of QT prolongation.
    Halothane: (Major) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and halogenated anesthetics is necessary; correct any electrolyte abnormalities. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Halogenated anesthetics can also prolong the QT interval.
    Hydroxychloroquine: (Major) Avoid coadministration of hydroxychloroquine and histrelin due to the risk of QT prolongation. Hydroxychloroquine prolongs the QT interval. Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Hydroxyzine: (Major) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and hydroxyzine is necessary; correct any electrolyte abnormalities. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Postmarketing data indicate that hydroxyzine also causes QT prolongation and torsade de pointes (TdP).
    Ibutilide: (Major) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and ibutilide is necessary; correct any electrolyte abnormalities. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval. Ibutilide administration can cause QT prolongation and torsade de pointes (TdP); proarrhythmic events should be anticipated. The potential for proarrhythmic events with ibutilide increases with the coadministration of other drugs that prolong the QT interval.
    Iloperidone: (Major) Avoid coadministration of iloperidone with histrelin due to the risk of QT prolongation. Iloperidone has been associated with QT prolongation. Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Imipramine: (Minor) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and tricyclic antidepressants is necessary; correct any electrolyte abnormalities. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Indacaterol: (Moderate) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and beta-agonists is necessary; correct any electrolyte abnormalities. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Beta-agonists may also be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Indacaterol; Glycopyrrolate: (Moderate) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and beta-agonists is necessary; correct any electrolyte abnormalities. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Beta-agonists may also be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Inotuzumab Ozogamicin: (Major) Avoid coadministration of inotuzumab with histrelin due to the potential for additive QT prolongation and torsade de pointes (TdP). If coadministration is unavoidable, obtain ECGs and prior to the start of treatment and periodically during treatment. Additionally, periodically monitor electrolytes and correct any electrolyte abnormalities. Inotuzumab has been associated with QT interval prolongation. Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Isoflurane: (Major) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and halogenated anesthetics is necessary; correct any electrolyte abnormalities. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Halogenated anesthetics can also prolong the QT interval.
    Itraconazole: (Major) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and itraconazole is necessary; correct any electrolyte abnormalities. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Itraconazole has also been associated with prolongation of the QT interval.
    Ivosidenib: (Major) Avoid coadministration of ivosidenib with histrelin due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval.
    Ketoconazole: (Major) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and ketoconazole is necessary; correct any electrolyte abnormalities. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Ketoconazole has also been associated with prolongation of the QT interval.
    Lapatinib: (Major) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and lapatinib is necessary; correct any electrolyte abnormalities. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Lapatinib has also been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience.
    Lenvatinib: (Major) Avoid coadministration of lenvatinib with histrelin due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Androgen deprivation therapy (e.g.,histrelin) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Levalbuterol: (Minor) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and short-acting beta-agonists is necessary; correct any electrolyte abnormalities. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Levofloxacin: (Major) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and levofloxacin is necessary; correct any electrolyte abnormalities. Levofloxacin has been associated with a risk of QT prolongation; although extremely rare, torsade de pointes (TdP) has also been reported during postmarketing surveillance of levofloxacin. Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Lithium: (Moderate) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and lithium is necessary; correct any electrolyte abnormalities. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Lithium has also been associated with QT prolongation.
    Lofexidine: (Moderate) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and lofexidine is necessary; correct any electrolyte abnormalities. Lofexidine prolongs the QT interval. Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Long-acting beta-agonists: (Moderate) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and beta-agonists is necessary; correct any electrolyte abnormalities. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Beta-agonists may also be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Loperamide: (Moderate) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and loperamide is necessary; correct any electrolyte abnormalities. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. At high doses, loperamide has also been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest.
    Loperamide; Simethicone: (Moderate) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and loperamide is necessary; correct any electrolyte abnormalities. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. At high doses, loperamide has also been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest.
    Lopinavir; Ritonavir: (Major) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and lopinavir is necessary; correct any electrolyte abnormalities. Lopinavir; ritonavir is associated with QT prolongation. Coadministration of lopinavir; ritonavir with other drugs that prolong the QT interval may result in additive QT prolongation. Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval. (Major) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and ritonavir is necessary; correct any electrolyte abnormalities. Ritonavir is associated with QT prolongation. Coadministration with other drugs that prolong the QT interval may result in additive QT prolongation. Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval.
    Macimorelin: (Major) Avoid concurrent administration of macimorelin with drugs that prolong the QT interval, such as histrelin. Use of these drugs together may increase the risk of developing torsade de pointes-type ventricular tachycardia. Sufficient washout time of drugs that are known to prolong the QT interval prior to administration of macimorelin is recommended. Treatment with macimorelin has been associated with an increase in the corrected QT (QTc) interval. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Maprotiline: (Major) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and maprotiline is necessary; correct any electrolyte abnormalities. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Maprotiline has also been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and torsade de pointes (TdP) tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs.
    Mefloquine: (Major) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and mefloquine is necessary; correct any electrolyte abnormalities. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. There is evidence that the use of halofantrine after mefloquine causes a significant lengthening of the QTc interval; however, mefloquine alone has not been reported to cause QT prolongation.
    Meperidine; Promethazine: (Moderate) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and promethazine is necessary; correct any electrolyte abnormalities. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Metaproterenol: (Minor) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and short-acting beta-agonists is necessary; correct any electrolyte abnormalities. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Methadone: (Major) Coadministration of methadone with histrelin should be undertaken with extreme caution and a careful assessment of treatment risks versus benefits. Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes; correct any electrolyte abnormalities. Methadone is associated with an increased risk for QT prolongation and torsade de pointes (TdP), especially at higher doses (greater than 200 mg/day but averaging approximately 400 mg/day in adult patients). Most cases involve patients being treated for pain with large, multiple daily doses of methadone, although cases have been reported in patients receiving doses commonly used for maintenance treatment of opioid addiction. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Methyltestosterone: (Major) Avoid concurrent use of androgens with gonadotropin releasing hormone (GnRH) agonists such as histrelin. Histrelin inhibits steroidogenesis; concomitant use with androgens may counteract this therapeutic effect.
    Metronidazole: (Moderate) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and metronidazole is necessary; correct any electrolyte abnormalities. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Potential QT prolongation has also been reported in limited case reports with metronidazole.
    Midostaurin: (Major) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and midostaurin is necessary; correct any electrolyte abnormalities. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Prolongation of the QT interval was also reported in patients who received midostaurin in clinical trials.
    Mifepristone: (Moderate) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and mifepristone is necessary; correct any electrolyte abnormalities. To minimize the risk of QT prolongation, the lowest effective dose of mifepristone should always be used. Mifepristone has been associated with dose-dependent prolongation of the QT interval. Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Mirtazapine: (Moderate) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and mirtazapine is necessary; correct any electrolyte abnormalities. Mirtazapine has been associated with dose-dependent prolongation of the QT interval; torsade de pointes (TdP) has been reported postmarketing experience, primarily in overdose or in patients with other risk factors for QT prolongation. Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Moxifloxacin: (Major) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and moxifloxacin is necessary; correct any electrolyte abnormalities. Quinolones have been associated with a risk of QT prolongation; although extremely rare, torsade de pointes (TdP) has been reported during postmarketing surveillance of moxifloxacin. These reports generally involved patients with concurrent medical conditions or concomitant medications that may have been contributory. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Nandrolone Decanoate: (Major) Avoid concurrent use of androgens with gonadotropin releasing hormone (GnRH) agonists such as histrelin. Histrelin inhibits steroidogenesis; concomitant use with androgens may counteract this therapeutic effect.
    Nilotinib: (Major) Avoid administration of nilotinib with histrelin due to the risk of QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for evidence of QT prolongation during concurrent use. Additionally, monitor serum electrolytes, correcting any electrolyte abnormalities as needed. Nilotinib prolongs the QT interval. Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Nortriptyline: (Minor) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and tricyclic antidepressants is necessary; correct any electrolyte abnormalities. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Octreotide: (Moderate) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and octreotide is necessary; correct any electrolyte abnormalities. Arrhythmias, sinus bradycardia, and conduction disturbances have occurred during octreotide therapy. Since bradycardia is a risk factor for development of torsade de pointes (TdP), the potential occurrence of bradycardia during octreotide administration could theoretically increase the risk of TdP in patients receiving drugs that prolong the QT interval. Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Ofloxacin: (Major) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and ofloxacin is necessary; correct any electrolyte abnormalities. Quinolones have been associated with a risk of QT prolongation; although extremely rare, torsade de pointes (TdP) has been reported during postmarketing surveillance of ofloxacin. These reports generally involved patients with concurrent medical conditions or concomitant medications that may have been contributory. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Olanzapine: (Moderate) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and olanzapine is necessary; correct any electrolyte abnormalities. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval.
    Olodaterol: (Moderate) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and beta-agonists is necessary; correct any electrolyte abnormalities. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Beta-agonists may also be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and ritonavir is necessary; correct any electrolyte abnormalities. Ritonavir is associated with QT prolongation. Coadministration with other drugs that prolong the QT interval may result in additive QT prolongation. Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval.
    Ondansetron: (Major) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and ondansetron is necessary; correct any electrolyte abnormalities. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of torsade de pointes (TdP). Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Osimertinib: (Major) Avoid coadministration of histrelin with osimertinib if possible due to the risk of QT prolongation and torsades de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes, correcting any electrolyte abnormalities; an interruption of osimertinib therapy with dose reduction or discontinuation may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Oxaliplatin: (Major) Monitor EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and oxaliplatin is necessary; correct any electrolyte abnormalities prior to administration of oxaliplatin. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Prolongation of the QT interval and ventricular arrhythmias including fatal torsade de pointes (TdP) have been reported with oxaliplatin use in postmarketing experience.
    Oxandrolone: (Major) Avoid concurrent use of androgens with gonadotropin releasing hormone (GnRH) agonists such as histrelin. Histrelin inhibits steroidogenesis; concomitant use with androgens may counteract this therapeutic effect.
    Oxymetholone: (Major) Avoid concurrent use of androgens with gonadotropin releasing hormone (GnRH) agonists such as histrelin. Histrelin inhibits steroidogenesis; concomitant use with androgens may counteract this therapeutic effect.
    Paliperidone: (Major) Avoid coadministration of paliperidone and histrelin due to the risk of QT prolongation. If concomitant use is unavoidable, consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes; correct any electrolyte abnormalities. If the patient has known risk factors for cardiac disease or arrhythmia, close monitoring is essential. Paliperidone has been associated with QT prolongation. Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Panobinostat: (Major) Coadministration of panobinostat with histrelin is not recommended due to the risk of QT prolongation. Prolongation of the QT interval has been reported with panobinostat. Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Pasireotide: (Major) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and pasireotide is necessary; correct any electrolyte abnormalities. Prolongation of the QT interval has occurred with pasireotide at therapeutic and supra-therapeutic doses. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Pazopanib: (Major) Coadministration of pazopanib and histrelin is not advised due to the risk of QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation. Additionally, monitor electrolytes and correct any electrolyte abnormalities. Pazopanib has been reported to prolong the QT interval. Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Pentamidine: (Major) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and pentamidine is necessary; correct any electrolyte abnormalities. Systemic pentamidine has been associated with QT prolongation and torsade de pointes (TdP). Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Perphenazine: (Minor) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and perphenazine is necessary; correct any electrolyte abnormalities. Perphenazine is associated with a possible risk for QT prolongation. Theoretically, perphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation. Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Perphenazine; Amitriptyline: (Minor) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and perphenazine is necessary; correct any electrolyte abnormalities. Perphenazine is associated with a possible risk for QT prolongation. Theoretically, perphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation. Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. (Minor) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and tricyclic antidepressants is necessary; correct any electrolyte abnormalities. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Phenylephrine; Promethazine: (Moderate) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and promethazine is necessary; correct any electrolyte abnormalities. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Pimavanserin: (Major) Coadministration of pimavanserin and histrelin should generally be avoided due to the risk of QT prolongation. Prolongation of the QT interval has occurred with pimavanserin therapy. Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Pimozide: (Severe) Because of the potential for torsade de pointes (TdP), use of histrelin with pimozide is contraindicated. Pimozide is associated with a well-established risk of QT prolongation and TdP. Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Pirbuterol: (Minor) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and short-acting beta-agonists is necessary; correct any electrolyte abnormalities. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Posaconazole: (Major) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and posaconazole is necessary; correct any electrolyte abnormalities. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Posaconazole has been associated with prolongation of the QT interval as well as rare cases of torsade de pointes (TdP).
    Prasterone, Dehydroepiandrosterone, DHEA (Dietary Supplements): (Major) Avoid concurrent use of androgens with gonadotropin releasing hormone (GnRH) agonists such as histrelin. Histrelin inhibits steroidogenesis; concomitant use with androgens may counteract this therapeutic effect.
    Prasterone, Dehydroepiandrosterone, DHEA (FDA-approved): (Major) Avoid concurrent use of androgens with gonadotropin releasing hormone (GnRH) agonists such as histrelin. Histrelin inhibits steroidogenesis; concomitant use with androgens may counteract this therapeutic effect.
    Primaquine: (Major) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and primaquine is necessary; correct any electrolyte abnormalities. Primaquine has been associated with QT prolongation. Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Procainamide: (Major) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and procainamide is necessary; correct any electrolyte abnormalities. Procainamide is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Prochlorperazine: (Minor) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and prochlorperazine is necessary; correct any electrolyte abnormalities. Prochlorperazine is associated with a possible risk for QT prolongation. Theoretically, prochlorperazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation. Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Promethazine: (Moderate) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and promethazine is necessary; correct any electrolyte abnormalities. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Propafenone: (Major) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and propafenone is necessary; correct any electrolyte abnormalities. Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval. Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Protriptyline: (Minor) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and tricyclic antidepressants is necessary; correct any electrolyte abnormalities. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Quetiapine: (Major) Avoid coadministration of quetiapine and histrelin due to the risk of QT prolongation. Limited data, including some case reports, suggest that quetiapine may be associated with a significant prolongation of the QTc interval in rare instances. Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Quinidine: (Major) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and quinidine is necessary; correct any electrolyte abnormalities. Quinidine administration is associated with QT prolongation and torsade de pointes (TdP). Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Quinine: (Major) Avoid coadministration of quinine and histrelin due to the risk of QT prolongation and torsade de pointes (TdP). Quinine has been associated with QT prolongation and rare cases of TdP. Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Ranolazine: (Major) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and ranolazine is necessary; correct any electrolyte abnormalities. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
    Regadenoson: (Moderate) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and regadenoson is necessary; correct any electrolyte abnormalities. Regadenoson has been associated with QT prolongation. Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Ribociclib: (Major) Avoid coadministration of ribociclib and histrelin due to the risk of QT prolongation. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner; ribociclib-related ECG changes occurred within the first four weeks of treatment and were reversible with dose interruption. Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Ribociclib; Letrozole: (Major) Avoid coadministration of ribociclib and histrelin due to the risk of QT prolongation. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner; ribociclib-related ECG changes occurred within the first four weeks of treatment and were reversible with dose interruption. Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Rilpivirine: (Major) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and rilpivirine is necessary; correct any electrolyte abnormalities. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Risperidone: (Major) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and risperidone is necessary; correct any electrolyte abnormalities. Closely monitor patients with known risk factors for cardiac disease or arrhythmia. Risperidone has been associated with a possible risk for QT prolongation, with reports of QT prolongation and torsade de pointes (TdP) during risperidone therapy noted primarily in the overdose setting. Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Ritonavir: (Major) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and ritonavir is necessary; correct any electrolyte abnormalities. Ritonavir is associated with QT prolongation. Coadministration with other drugs that prolong the QT interval may result in additive QT prolongation. Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval.
    Romidepsin: (Major) Monitor EGCs for QT prolongation and monitor electrolytes at baseline and periodically during treatment if coadministration of histrelin and romidepsin is necessary; correct any electrolyte abnormalities. Romidepsin has been reported to prolong the QT interval. Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Salmeterol: (Moderate) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and beta-agonists is necessary; correct any electrolyte abnormalities. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Beta-agonists may also be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Saquinavir: (Major) Avoid coadministration of saquinavir boosted with ritonavir concurrently with other drugs that may prolong the QT interval such as histrelin. If no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations. Periodically monitor ECGs for QT prolongation and monitor electrolytes if coadministration of histrelin and saquinavir is necessary; correct any electrolyte abnormalities. Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as torsade de pointes (TdP). Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Sertraline: (Moderate) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and sertraline is necessary; correct any electrolyte abnormalities. There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline. Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Sevoflurane: (Major) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and halogenated anesthetics is necessary; correct any electrolyte abnormalities. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Halogenated anesthetics can also prolong the QT interval.
    Short-acting beta-agonists: (Minor) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and short-acting beta-agonists is necessary; correct any electrolyte abnormalities. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Solifenacin: (Moderate) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and solifenacin is necessary; correct any electrolyte abnormalities. Solifenacin has been associated with dose-dependent prolongation of the QT interval; torsade de pointes (TdP) has been reported with postmarketing use, although causality was not determined. Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Sorafenib: (Major) Closely monitor EGCs for QT prolongation if coadministration of histrelin and sorafenib is necessary. Periodically monitor electrolytes and correct any electrolyte abnormalities. Sorafenib has been associated with QT prolongation. Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Sotalol: (Major) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and sotalol is necessary; correct any electrolyte abnormalities. Sotalol administration is associated with QT prolongation and torsade de pointes (TdP); proarrhythmic events should be anticipated after initiation of therapy and after each upward dosage adjustment. Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Sulfamethoxazole; Trimethoprim, SMX-TMP, Cotrimoxazole: (Moderate) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and sulfamethoxazole is necessary; correct any electrolyte abnormalities. Prolongation of the QT interval resulting in ventricular tachycardia and torsade de pointes (TdP) has been reported during postmarketing use of sulfamethoxazole; trimethoprim. Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. (Moderate) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and trimethoprim is necessary; correct any electrolyte abnormalities. Prolongation of the QT interval resulting in ventricular tachycardia and torsade de pointes (TdP) has been reported during postmarketing use of sulfamethoxazole; trimethoprim. Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Sunitinib: (Major) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and sunitinib is necessary; correct any electrolyte abnormalities. Sunitinib can prolong the QT interval. Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Tacrolimus: (Major) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and tacrolimus is necessary; correct any electrolyte abnormalities. Tacrolimus causes QT prolongation. Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Tamoxifen: (Moderate) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and tamoxifen is necessary; correct any electrolyte abnormalities. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Telavancin: (Major) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and telavancin is necessary; correct any electrolyte abnormalities. Telavancin has been associated with QT prolongation. Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Telithromycin: (Major) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and telithromycin is necessary; correct any electrolyte abnormalities. Telithromycin is associated with QT prolongation and torsade de pointes (TdP). Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Terbutaline: (Minor) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and short-acting beta-agonists is necessary; correct any electrolyte abnormalities. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Testolactone: (Major) Avoid concurrent use of androgens with gonadotropin releasing hormone (GnRH) agonists such as histrelin. Histrelin inhibits steroidogenesis; concomitant use with androgens may counteract this therapeutic effect.
    Testosterone: (Major) Avoid concurrent use of androgens with gonadotropin releasing hormone (GnRH) agonists such as histrelin. Histrelin inhibits steroidogenesis; concomitant use with androgens may counteract this therapeutic effect.
    Tetrabenazine: (Major) Avoid coadministration of tetrabenazine with histrelin due to the risk of QT prolongation. Tetrabenazine causes a small increase in the corrected QT interval (QTc). Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Thioridazine: (Severe) Because of the potential for TdP, use of histrelin with thioridazine is contraindicated. Thioridazine is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Tiotropium; Olodaterol: (Moderate) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and beta-agonists is necessary; correct any electrolyte abnormalities. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Beta-agonists may also be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Tizanidine: (Moderate) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and tizanidine is necessary; correct any electrolyte abnormalities. Tizanidine administration may result in QT prolongation. Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Tolterodine: (Moderate) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and tolterodine is necessary; correct any electrolyte abnormalities. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Toremifene: (Major) Avoid coadministration of histrelin with toremifene due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes, correcting any electrolyte abnormalities. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Trazodone: (Major) Avoid coadministration of trazodone with histrelin due to the risk of QT prolongation. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are postmarketing reports of torsade de pointes (TdP). Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Tricyclic antidepressants: (Minor) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and tricyclic antidepressants is necessary; correct any electrolyte abnormalities. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Trifluoperazine: (Minor) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and trifluoperazine is necessary; correct any electrolyte abnormalities. Trifluoperazine is associated with a possible risk for QT prolongation. Theoretically, trifluoperazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation. Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Trimethoprim: (Moderate) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and trimethoprim is necessary; correct any electrolyte abnormalities. Prolongation of the QT interval resulting in ventricular tachycardia and torsade de pointes (TdP) has been reported during postmarketing use of sulfamethoxazole; trimethoprim. Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Trimipramine: (Minor) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and tricyclic antidepressants is necessary; correct any electrolyte abnormalities. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Umeclidinium; Vilanterol: (Moderate) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and beta-agonists is necessary; correct any electrolyte abnormalities. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Beta-agonists may also be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Vandetanib: (Major) Avoid coadministration of vandetanib with histrelin due to an increased risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes; correct hypocalcemia, hypomagnesemia, and/or hypomagnesemia prior to vandetanib administration. An interruption of vandetanib therapy or dose reduction may be necessary for QT prolongation. Vandetanib can prolong the QT interval in a concentration-dependent manner; TdP and sudden death have been reported in patients receiving vandetanib. Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Vardenafil: (Major) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and vardenafil is necessary; correct any electrolyte abnormalities. Vardenafil is associated with QT prolongation at both therapeutic and supratherapeutic doses. Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Vemurafenib: (Major) Closely monitor of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and vemurafenib is necessary; correct any electrolyte abnormalities. Vemurafenib has been associated with QT prolongation. Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Venlafaxine: (Major) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and venlafaxine is necessary; correct any electrolyte abnormalities. Venlafaxine administration is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has reported with postmarketing use. Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Voriconazole: (Major) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and voriconazole is necessary; correct any electrolyte abnormalities. Voriconazole has been associated with QT prolongation and rare cases of torsade de pointes. Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Vorinostat: (Moderate) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and vorinostat is necessary; correct any electrolyte abnormalities. Vorinostat therapy is associated with a risk of QT prolongation. Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Ziprasidone: (Major) Avoid concomitant use of ziprasidone and histrelin due to a potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.

    PREGNANCY AND LACTATION

    Pregnancy

    Histrelin is contraindicated during pregnancy because fetal harm is possible, including spontaneous abortion (FDA pregnancy risk category X). Vantas is not indicated for use in females, although Supprelin LA may be used in female children. There are no adequate and well-controlled studies in pregnant women. Women who are pregnant or who become pregnant while receiving histrelin should be apprised of the potential hazard to the fetus. In nonclinical studies, histrelin was teratogenic and fetotoxic. 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 caused by histrelin.

    MECHANISM OF ACTION

    Histrelin acetate is a gonadotropin releasing hormone (GnRH) agonist that is a potent inhibitor of gonadotropin secretion when given continuously in therapeutic doses. Following an initial stimulatory phase, the chronic, subcutaneous administration of histrelin acetate desensitizes responsiveness of the pituitary gonadotropin, which causes a reduction in testicular steroidogenesis. In humans, there is an initial increase in circulating levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which in turn transiently increases the production of gonadal steroids (e.g., estradiol and estrone in premenopausal females, and testosterone and dihydrotestosterone in males). However, with sustained administration, histrelin causes a reversible down-regulation of the GnRH receptors in the pituitary gland and desensitization of the pituitary gonadotropins, resulting in decreased levels of LH and FSH.
     
    Central Precocious Puberty: Long-term treatment with histrelin suppresses the LH response to GnRH, causing LH levels to decease to prepubertal levels within 1 month of treatment. As a result, serum concentrations of sex steroids (i.e., estrogen or testosterone) also decrease, ceasing progression of secondary sexual development in most patients. Additionally, linear growth velocity is slowed, which improves the chance of attaining predicted adult height.
     
    Advanced Prostate Cancer: Testosterone is reduced to castration levels within 2 to 4 weeks after initiation of treatment.

    PHARMACOKINETICS

    Histrelin is administered by a subcutaneous insertion of an implant containing histrelin acetate. The apparent volume of distribution (Vd) of histrelin following a subcutaneous bolus dose (500 mg) in healthy volunteers was 58.3 +/- 7.86 liters. In vitro, the mean fraction of unbound drug in plasma was 29.5% +/- 8.9%. Histrelin was metabolized by C-terminal dealkylation, resulting in one metabolite, in an in vitro drug metabolism study using human hepatocytes; peptide fragments resulting from hydrolysis are also likely metabolites. Following a subcutaneous bolus dose in healthy volunteers, the mean apparent clearance was 179 +/- 37.8 mL/min, and the mean terminal half-life was 3.92 +/- 1.01 hours. The mean apparent clearance following a 50 mg histrelin acetate implant in patients with prostate cancer (n = 17) was 174 +/- 56.5 mL/min. Drug excretion studies were not conducted with histrelin implants.
     
    Affected cytochrome P450 isoenzymes: None
    No pharmacokinetic-based drug interaction studies were conducted with histrelin implants.

    Oral Route

    Histrelin acetate is not active when given orally.

    Subcutaneous Route

    Mean peak serum concentrations of histrelin were 1.1 +/- 0.375 ng/mL following subcutaneous insertion of one histrelin 50 mg implant in patients with advanced prostate cancer (n = 17), occurring at a median of 12 hours. Continuous subcutaneous release was evident, as serum levels were sustained throughout the 52-week dosing period; the mean serum histrelin concentration at the end of 52 weeks was 0.13 +/- 0.065 ng/mL. Observed serum concentrations over 8 weeks following insertion of a second implant after 52 weeks were comparable to the same period following the first implant. The average rate of subcutaneous drug release from 41 implants assayed for residual drug content was 56.7 +/- 7.71 mcg/day. The relative bioavailability for the histrelin implant in prostate cancer patients with normal renal and hepatic function compared to a subcutaneous bolus dose in healthy male volunteers was 92%. Serum histrelin concentrations in prostate cancer patients were proportional to dose after insertion of 1, 2, 3, or 4 histrelin implants (n = 42).