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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

    Insertion (Vantas and Supprelin LA):
    Wear sterile gloves and use aseptic technique to minimize any chance of infection.
    Open the implant vial just before the time of insertion by removing the metal band and carefully pouring the sterile contents (implant and sterile saline) onto the sterile field drape. The implant can be handled with sterile gloves or with the sterile mosquito clamp provided. Avoid bending or pinching the implant.
    The patient should lay on his back, ideally with the arm least used positioned so that the physician has ready access to the inner aspect of the upper arm. The suggested optimum site for insertion is approximately half-way between the shoulder and elbow, in line with the crease between the biceps and triceps muscles.
    Swab insertion area with topical antiseptic, then overlay with the fenestrated sterile field drape provided so that the opening is over the insertion site.
    The method of anesthesia (i.e., local, conscious sedation, general) is at the provider's discretion. Local anesthetic is provided with the insertion kit, which may be injected into the subcutaneous tissue starting at the planned incision site, then infiltrating along the intended subcutaneous path, up to the length of the implant (slightly more than 1 inch).
    Grasp the sterile insertion tool and confirm that the cannula is fully extended by inspecting the position of the green retraction button; the button should be locked in position all the way forward, towards the cannula, farthest from the handle.
    Pick up the implant using sterile gloves or the mosquito clamp. The implant may be slightly curved and/or partially flattened after refrigerated storage; it may be rolled between the fingers and thumb a few times using a sterile glove to make it more symmetrical prior to loading into the tool.
    Insert the implant into the insertion tool; do not force the implant into the cannula. If resistance is felt, remove the implant and manually manipulate or roll as needed prior to re-insertion into the cannula. The tip of the implant should be visible at the beveled end of the cannula.
    With a sterile scalpel, make an incision transverse to the long axis of the arm, large enough to allow the bore of the cannula to be inserted into the subcutaneous tissue. Especially in pediatric patients, ensure that there is sufficient length of upper arm available to fit the implant easily within the intended insertion space.
    Visibly raise the skin at all times during pocket-making and insertion ("tenting") to ensure correct placement of the implant just under the skin.
    To ease insertion, a "pocket" for the implant may be created by blunt dissection through the incision, using the cannula of the loaded insertion tool, a sterile hemostatic clamp, or equivalent surgical tool; this tool should be inserted subcutaneously and should not enter the muscle, as this will cause difficulty with removal without improving efficacy. If using the cannula of the loaded insertion tool, insert the length of the cannula up to, but not farther than, the inscribed black ine on the cannula; DO NOT depress the green retraction button. Pull the tool back almost the beveled tip of the cannula.
    Advance the insertion tool forward again, so that the cannula completely re-enters the pocket, no farther than the inscribed black line. Be sure the insertion path is immediately subcutaneous.
    Hold the tool in place with the base against the patient's arm. Carefully depress the green retraction button to release the locking mechanism, then slide the button back toward the handle until it stops. Keep the body of the insertion tool in place and apply pressure to the skin over the implant to help ensure the implant remains in the subcutaneous pocket.
    Retracting the button causes the cannula to withdraw from the incision, leaving the implant in the subcutaneous tissue. Do not further advance the cannula once the retraction process has started, and do not withdraw the insertion tool until the button is fully retracted to avoid pulling out the implant. Thee tool may be withdrawn when retraction is complete.
    Confirm placement of the implant by palpation. The tip of the implant may not be visible through the incision.
    Close the incision with absorbable sutures and/or sterile adhesive surgical strips. Adhesion of strips may be improved by the application of benzoin tincture antiseptic, which should be allowed to dry before applying the adhesive strips.
    Cover the incision site with sterile gauze pads and secure the dressing with a bandage.
    Advise patients to avoid wetting the arm for 24 hours after implant insertion, and to avoid heavy lifting or strenuous exertion of the inserted arm for 7 days after insertion.
     
    Removal (Vantas and Supprelin LA):
    Remove the histrelin implant after 12 months of therapy. Wear sterile gloves and use aseptic technique to minimize any chance of infection.
    Most necessary supplies are provided in the implantation kit. Place the sterilized components needed for implant removal onto the non-fenestrated sterile field drape.
    The patient should lay on his back, ideally with the arm least used positioned so that the physician has ready access to the inner aspect of the upper arm. The suggested optimum site for insertion is approximately half-way between the shoulder and elbow, in line with the crease between the biceps and triceps muscles.
    Locate the implant to be removed by palpating the inner aspect of the upper arm, near the incision from the prior year. Ultrasound may be used if the implant is difficult to palpate; if ultrasound fails, other imaging techniques (e.g., CT or MRI) may be used to locate it. Plain films are not recommended as the implant is not radiopaque.
    Swab area above and around the previous implant with topical antiseptic, then overlay with the fenestrated sterile field drape provided so that the opening is over the previous insertion site.
    The method of anesthesia (i.e., local, conscious sedation, general) is at the provider's discretion. Local anesthetic is provided with the histrelin implantation kit, which may be injected into the subcutaneous tissue around the planned incision site (the site of the previous implant).
    Using a sterile scalpel, make an incision of adequate size to allow implant removal and, if a new implant will be inserted, large enough for the bore of the cannula of the insertion tool. The tip of the implant should be visible through the incision, possibly covered by a pseudocapsule of tissue. It may be necessary to palpate the head of the implant through the incision, especially if it is not visible; additionally, the distal end of the implant may need to be massaged forward toward the incision.
    Carefully nick the pseudocapsule to reveal the polymer tip of the implant. Widening the opening by inserting the mosquito clamp into the hold and opening the clamp may ease extraction.
    Gently but securely grasp the implant with the sterile mosquito clamp and extract the implant.
    If inserting a new implant, see instructions above. The new implant may be inserted into the same pocket as the removed implant, or at a new site.
    Close the incision with absorbable sutures and/or sterile adhesive surgical strips. Adhesion of strips may be improved by the application of benzoin tincture antiseptic, which should be allowed to dry before applying the adhesive strips.

    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

    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.

    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.

    Children, infants, neonates

    The safety and efficacy of the Vantas implant dosage form of histrelin has not been established in infants and children. Supprelin LA is FDA-approved for use in children 2 years of age and older 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.

    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. There are no known comparable studies evaluating the risk of diabetes in women, children, or 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. Additionally, myocardial infarction and stroke may increase the risk of histrelin prolonging the QT interval. 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. There are no known comparable studies evaluating the risk of cardiovascular disease in women, children, or adolescents taking GnRH agonists for other indications.

    Apheresis, AV block, bradycardia, cardiomyopathy, celiac disease, electrolyte imbalance, fever, geriatric, heart failure, human immunodeficiency virus (HIV) infection, hyperparathyroidism, hypocalcemia, hypokalemia, hypomagnesemia, hypothermia, hypothyroidism, long QT syndrome, pheochromocytoma, QT prolongation, rheumatoid arthritis, sickle cell disease, sleep deprivation, systemic lupus erythematosus (SLE)

    Androgen deprivation therapy may prolong the QT/QTc interval. Use histrelin with caution in patients with conditions that may increase the risk of QT prolongation including congenital long QT syndrome, bradycardia, AV block, heart failure, stress-related cardiomyopathy, myocardial infarction, stroke, hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving medications known to prolong the QT interval or cause electrolyte imbalance. Females, geriatric patients, patients with sleep deprivation, pheochromocytoma, sickle cell disease, hypothyroidism, hyperparathyroidism, hypothermia, systemic inflammation (e.g., human immunodeficiency virus (HIV) infection, fever, and some autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus (SLE), and celiac disease) and patients undergoing apheresis procedures (e.g., plasmapheresis [plasma exchange], cytapheresis) may also be at increased risk for QT prolongation.

    Laboratory test interference

    Therapy with histrelin results in suppression of the pituitary-gonadal system. Laboratory test interference may occur during and after histrelin therapy; specifically diagnostic tests of pituitary gonadotropic and gonadal functions.

    Infertility

    Based on findings in animals and its mechanism of action, histrelin may cause infertility in males of reproductive potential.

    Females, pregnancy

    While Supprelin LA (histrelin) may be used in female children, the safety and efficacy of Vantas (histrelin) have not been established in females. Although there are no adequately controlled studies in pregnant women, histrelin can cause fetal harm or death when administered during pregnancy based on its mechanism of action and animal studies. Expected hormonal changes that occur with histrelin treatment increase the risk for pregnancy loss. Advise pregnant patients and females and females of reproductive potential of the risk to the fetus. Increased fetal mortality and post-implantation loss occurred when histrelin was administered to pregnant rats during organogenesis at exposures amounting to 0.2 to 3 times the human exposure based on body surface area. These doses also reduced maternal weight gain, stimulated ovarian follicular development, increased placental weight, and caused abnormal morphology and an increase in fetal size. In pregnant rabbits, administration of histrelin during organogenesis resulted in increased fetal mortality and abortion/early termination at the 2 highest doses and caused total litter loss at all doses (exposures of approximately 8 to 31 times human exposure at the recommended dose based on body surface area). Females may also be at increased risk for histrelin prolonging the QT interval.

    Breast-feeding

    Due to the potential for serious adverse reactions in nursing infants from histrelin, advise women to discontinue breast-feeding during treatment. It is not known whether histrelin is present in human milk, although many drugs are excreted in human milk.

    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

    Aclidinium; Formoterol: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving long-acting beta-agonists. 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. Androgen deprivation therapy may also prolong the QT/QTc interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Albuterol: (Minor) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving short-acting beta-agonists. Androgen deprivation therapy may prolong the QT/QTc 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.
    Alfuzosin: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving alfuzosin. Androgen deprivation therapy may prolong the QT/QTc interval. Based on electrophysiology studies performed by the manufacturer, alfuzosin may also 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. Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks in patients receiving amiodarone. 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 also prolongs 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.
    Amisulpride: (Major) Monitor ECGs for QT prolongation when amisulpride is administered with histrelin. Amisulpride causes dose- and concentration- dependent QT prolongation. Androgen deprivation therapy (i.e., histrelin) may also prolong the QT/QTc interval.
    Amitriptyline: (Minor) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving tricyclic antidepressants (TCAs). Tricyclic antidepressants 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 may also prolong the QT/QTc interval.
    Amoxapine: (Major) Avoid coadministration of histrelin with amoxapine due to the risk of reduced efficacy of histrelin. Amoxapine can cause hyperprolactinemia, which reduces the number of pituitary gonadotropin releasing hormone (GnRH) receptors; histrelin is a GnRH analog.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving clarithromycin. Clarithromycin is associated with an established risk for QT prolongation and torsade de pointes (TdP). Androgen deprivation therapy may also prolong the QT/QTc interval.
    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: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving apomorphine since concurrent use may increase the risk of QT prolongation. Androgen deprivation therapy may prolong the QT/QTc interval. Dose-related QTc prolongation is associated with therapeutic apomorphine exposure.
    Arformoterol: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving long-acting beta-agonists. 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. Androgen deprivation therapy may also prolong the QT/QTc interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Aripiprazole: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving aripiprazole. Androgen deprivation therapy may prolong the QT/QTc interval. Prolongation of the QT interval has also occurred during therapeutic use of aripiprazole and following overdose.
    Arsenic Trioxide: (Major) Avoid concomitant use of arsenic trioxide with histrelin; discontinue or select an alternative drug that does not prolong the QT interval prior to starting arsenic trioxide therapy. If concomitant drug use is unavoidable, frequently monitor electrocardiograms. Torsade de pointes (TdP), QT interval prolongation, and complete atrioventricular block have been reported with arsenic trioxide use. Androgen deprivation therapy (i.e., histrelin) may also prolong the QT/QTc interval.
    Artemether; Lumefantrine: (Major) Avoid coadministration of artemether with histrelin if possible due to the risk of QT prolongation. Consider ECG monitoring if histrelin must be used with or after artemether; lumefantrine treatment. Artemether; lumefantrine is associated with prolongation of the QT interval. Androgen deprivation therapy (i.e., histrelin) may prolong the QT/QTc interval. (Major) Avoid coadministration of lumefantrine with histrelin if possible due to the risk of QT prolongation. Consider ECG monitoring if histrelin must be used with or after artemether; lumefantrine treatment. Artemether; lumefantrine is associated with prolongation of the QT interval. Androgen deprivation therapy (i.e., histrelin) may prolong the QT/QTc interval.
    Asenapine: (Major) Avoid coadministration of histrelin with asenapine due to the risk of reduced efficacy of histrelin as well as the risk of QT prolongation. Asenapine can cause hyperprolactinemia, which reduces the number of pituitary gonadotropin releasing hormone (GnRH) receptors; histrelin is a GnRH analog. Additionally, asenapine has been associated with QT prolongation. Androgen deprivation therapy (i.e., histrelin) may also prolong the QT/QTc interval.
    Atomoxetine: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving atomoxetine. Androgen deprivation therapy may prolong the QT/QTc interval. Prolongation of the QT interval has also occurred during therapeutic use of atomoxetine and following overdose.
    Azithromycin: (Major) Avoid coadministration of azithromycin with histrelin due to the increased risk of QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. QT prolongation and torsade de pointes (TdP) have been spontaneously reported during azithromycin postmarketing surveillance. Androgen deprivation therapy may prolong the QT/QTc interval.
    Bedaquiline: (Major) Frequently monitor ECGs for QT prolongation if coadministration of bedaquiline with histrelin is necessary. Bedaquiline has been reported to prolong the QT interval; coadministration with other QT prolonging drugs may result in additive or synergistic prolongation of the QT interval. Androgen deprivation therapy may also prolong the QT/QTc interval.
    Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Moderate) Concomitant use of metronidazole and androgen deprivation therapy (i.e. histrelin) may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Moderate) Concomitant use of metronidazole and androgen deprivation therapy (i.e. histrelin) may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
    Brexpiprazole: (Major) Avoid coadministration of histrelin with brexpiprazole due to the risk of reduced efficacy of histrelin. Brexpiprazole can cause hyperprolactinemia, which reduces the number of pituitary gonadotropin releasing hormone (GnRH) receptors; histrelin is a GnRH analog.
    Budesonide; Formoterol: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving long-acting beta-agonists. 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. Androgen deprivation therapy may also prolong the QT/QTc interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Budesonide; Glycopyrrolate; Formoterol: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving long-acting beta-agonists. 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. Androgen deprivation therapy may also prolong the QT/QTc interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Buprenorphine: (Major) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving buprenorphine. Buprenorphine has 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. Androgen deprivation therapy may also prolong the QT/QTc interval.
    Buprenorphine; Naloxone: (Major) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving buprenorphine. Buprenorphine has 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. Androgen deprivation therapy may also prolong the QT/QTc interval.
    Cabotegravir; Rilpivirine: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving rilpivirine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Androgen deprivation therapy may also prolong the QT/QTc interval.
    Cariprazine: (Major) Avoid coadministration of histrelin with cariprazine due to the risk of reduced efficacy of histrelin. Cariprazine can cause hyperprolactinemia, which reduces the number of pituitary gonadotropin releasing hormone (GnRH) receptors; histrelin is a GnRH analog.
    Ceritinib: (Major) Avoid coadministration of ceritinib with histrelin if possible due to the risk of QT prolongation. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent QT prolongation. Androgen deprivation therapy (i.e., histrelin) may prolong the QT/QTc interval.
    Chlordiazepoxide; Amitriptyline: (Minor) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving tricyclic antidepressants (TCAs). Tricyclic antidepressants 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 may also prolong the QT/QTc interval.
    Chloroquine: (Major) Avoid coadministration of chloroquine with histrelin due to the increased risk of QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Chloroquine is associated with an increased risk of QT prolongation and torsade de pointes (TdP); the risk of QT prolongation is increased with higher chloroquine doses. Androgen deprivation therapy (i.e., histrelin) may prolong the QT/QTc interval.
    Chlorpromazine: (Major) Avoid coadministration of histrelin with chlorpromazine due to the risk of reduced efficacy of histrelin; QT prolongation may also occur. Chlorpromazine can cause hyperprolactinemia, which reduces the number of pituitary gonadotropin releasing hormone (GnRH) receptors; histrelin is a GnRH analog. Additionally, chlorpromazine, a phenothiazine, is associated with an established risk of QT prolongation and torsade de pointes (TdP). Androgen deprivation therapy (i.e., histrelin) may also prolong the QT/QTc interval.
    Ciprofloxacin: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving ciprofloxacin. Androgen deprivation therapy may prolong the QT/QTc interval. Rare cases of QT prolongation and torsade de pointes (TdP) have also been reported with ciprofloxacin during postmarketing surveillance.
    Cisapride: (Contraindicated) 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) Coadministration of citalopram with histrelin is not recommended due to the risk of QT prolongation. If concurrent therapy is considered essential, ECG monitoring is recommended. Citalopram causes dose-dependent QT interval prolongation. Androgen deprivation therapy (i.e., histrelin) may prolong the QT/QTc interval.
    Clarithromycin: (Major) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving clarithromycin. Clarithromycin is associated with an established risk for QT prolongation and torsade de pointes (TdP). Androgen deprivation therapy may also prolong the QT/QTc interval.
    Clofazimine: (Major) Monitor ECGs for QT prolongation when clofazimine is administered with histrelin. Prolongation of the QT interval and torsade de pointes (TdP) have been reported in patients receiving clofazimine in combination with QT prolonging medications. Androgen deprivation therapy (i.e., histrelin) may also prolong the QT/QTc interval.
    Clomipramine: (Minor) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving tricyclic antidepressants (TCAs). Tricyclic antidepressants 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 may also prolong the QT/QTc interval.
    Clozapine: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving clozapine as concurrent use may increase the risk of QT prolongation. Androgen deprivation therapy may prolong the QT/QTc interval. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death.
    Codeine; Phenylephrine; Promethazine: (Major) Avoid coadministration of histrelin with promethazine due to the risk of reduced efficacy of histrelin; QT prolongation may also occur. Promethazine can cause hyperprolactinemia, which reduces the number of pituitary gonadotropin releasing hormone (GnRH) receptors; leuprolide is a GnRH analog. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. Androgen deprivation therapy (i.e., histrelin) may also prolong the QT/QTc interval.
    Codeine; Promethazine: (Major) Avoid coadministration of histrelin with promethazine due to the risk of reduced efficacy of histrelin; QT prolongation may also occur. Promethazine can cause hyperprolactinemia, which reduces the number of pituitary gonadotropin releasing hormone (GnRH) receptors; leuprolide is a GnRH analog. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. Androgen deprivation therapy (i.e., histrelin) may also prolong the QT/QTc interval.
    Crizotinib: (Major) Avoid coadministration of crizotinib with histrelin due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib 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.
    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.
    Dasatinib: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving dasatinib as concurrent use may increase the risk of QT prolongation. Androgen deprivation therapy may prolong the QT/QTc interval. In vitro studies have shown that dasatinib also has the potential to prolong the QT interval.
    Desflurane: (Major) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving halogenated anesthetics. Androgen deprivation therapy may prolong the QT/QTc interval. Halogenated anesthetics can also prolong the QT interval.
    Desipramine: (Minor) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving tricyclic antidepressants (TCAs). Tricyclic antidepressants 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 may also prolong the QT/QTc interval.
    Deutetrabenazine: (Major) Avoid coadministration of histrelin with deutetrabenazine due to the risk of reduced efficacy of histrelin. Deutetrabenazine can cause hyperprolactinemia, which reduces the number of pituitary gonadotropin-releasing hormone (GnRH) receptors; histrelin is a GnRH analog. Androgen deprivation therapy (i.e., histrelin) may also prolong the QT/QTc interval. Deutetrabenazine may prolong the QT interval, but the degree of QT prolongation is not clinically significant when deutetrabenazine is administered within the recommended dosage range.
    Dextromethorphan; Quinidine: (Major) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving quinidine. Quinidine administration is associated with QT prolongation and torsade de pointes (TdP). Androgen deprivation therapy may also prolong the QT/QTc interval.
    Disopyramide: (Major) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving disopyramide. Androgen deprivation therapy may prolong the QT/QTc interval. Disopyramide administration is also associated with QT prolongation and torsade de pointes (TdP).
    Dofetilide: (Major) Coadministration of dofetilide and histrelin is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Androgen deprivation therapy (i.e., histrelin) may prolong the QT/QTc interval.
    Dolasetron: (Moderate) Consider whether the benefits of androgen deprivation therapy outweigh the potential risks in patients receiving dolasetron as concurrent use may increase the risk of QT prolongation. Androgen deprivation therapy (i.e., histrelin) may prolong the QT/QTc interval. Dolasetron has been associated with a dose-dependent prolongation in the QT, PR, and QRS intervals on an electrocardiogram.
    Dolutegravir; Rilpivirine: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving rilpivirine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Androgen deprivation therapy may also prolong the QT/QTc interval.
    Donepezil: (Major) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving donepezil as concurrent use may increase the risk of QT prolongation. Androgen deprivation therapy may prolong the QT/QTc interval. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy.
    Donepezil; Memantine: (Major) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving donepezil as concurrent use may increase the risk of QT prolongation. Androgen deprivation therapy may prolong the QT/QTc interval. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy.
    Doxepin: (Minor) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving tricyclic antidepressants (TCAs). Tricyclic antidepressants 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 may also prolong the QT/QTc interval.
    Dronedarone: (Contraindicated) 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 is unavoidable, use extreme caution; initiate droperidol at a low dose and increase the dose as needed to achieve the desired effect. 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 (i.e., histrelin) may prolong the QT/QTc interval.
    Efavirenz: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving efavirenz as concurrent use may increase the risk of QT prolongation. Androgen deprivation therapy may prolong the QT/QTc interval. Prolongation of the QTc interval has also been observed with the use of efavirenz.
    Efavirenz; Emtricitabine; Tenofovir: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving efavirenz as concurrent use may increase the risk of QT prolongation. Androgen deprivation therapy may prolong the QT/QTc interval. Prolongation of the QTc interval has also been observed with the use of efavirenz.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving efavirenz as concurrent use may increase the risk of QT prolongation. Androgen deprivation therapy may prolong the QT/QTc interval. Prolongation of the QTc interval has also been observed with the use of efavirenz.
    Eliglustat: (Major) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving eliglustat. Androgen deprivation therapy may prolong the QT/QTc interval. Eliglustat is also predicted to cause PR, QRS, and/or QT prolongation at significantly elevated plasma concentrations.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving rilpivirine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Androgen deprivation therapy may also prolong the QT/QTc interval.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving rilpivirine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Androgen deprivation therapy may also prolong the QT/QTc interval.
    Encorafenib: (Major) Avoid coadministration of encorafenib and histrelin due to the risk of QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib has been associated with dose-dependent QT prolongation. Androgen deprivation therapy (i.e., histrelin) may also prolong the QT/QTc interval.
    Enflurane: (Major) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving halogenated anesthetics. Androgen deprivation therapy may prolong the QT/QTc interval. Halogenated anesthetics can also prolong the QT interval.
    Entrectinib: (Major) Avoid coadministration of entrectinib with histrelin due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Androgen deprivation therapy (i.e., histrelin) may prolong the QT/QTc interval.
    Eribulin: (Major) Closely monitor ECGs for QT prolongation if coadministration of eribulin with histrelin is necessary. Eribulin has been associated with QT prolongation. Androgen deprivation therapy (i.e., histrelin) may also prolong the QT/QTc interval.
    Erythromycin: (Major) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving erythromycin. Erythromycin is associated with QT prolongation and torsade de pointes (TdP). Androgen deprivation therapy may also prolong the QT/QTc interval.
    Erythromycin; Sulfisoxazole: (Major) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving erythromycin. Erythromycin is associated with QT prolongation and torsade de pointes (TdP). Androgen deprivation therapy may also prolong the QT/QTc interval.
    Escitalopram: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving escitalopram. Androgen deprivation therapy may prolong the QT/QTc 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: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving ezogabine as concurrent use may increase the risk of QT prolongation. Androgen deprivation therapy may prolong the QT/QTc interval. Ezogabine has also been associated with QT prolongation.
    Fingolimod: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving fingolimod as concurrent use may increase the risk of QT prolongation. Androgen deprivation therapy may prolong the QT/QTc interval. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. 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 whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving flecainide. 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. Androgen deprivation therapy may also prolong the QT/QTc 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: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving fluconazole as concurrent use may increase the risk of QT prolongation. Androgen deprivation therapy may prolong the QT/QTc interval. Fluconazole has also been associated with QT prolongation as well as rare cases of torsade de pointes (TdP).
    Fluoxetine: (Moderate) Coadministration of fluoxetine and histrelin may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation and TdP have been reported in patients treated with fluoxetine. Androgen deprivation therapy (i.e., histrelin) may prolong the QT/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: (Major) Avoid coadministration of histrelin with fluphenazine due to the risk of reduced efficacy of histrelin; QT prolongation may also occur. Fluphenazine can cause hyperprolactinemia, which reduces the number of pituitary gonadotropin releasing hormone (GnRH) receptors; histrelin is a GnRH analog. Additionally, androgen deprivation therapy (i.e., histrelin) may prolong the QT/QTc 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 whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving long-acting beta-agonists. 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. Androgen deprivation therapy may also prolong the QT/QTc 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 whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving long-acting beta-agonists. 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. Androgen deprivation therapy may also prolong the QT/QTc interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Fluticasone; Vilanterol: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving long-acting beta-agonists. 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. Androgen deprivation therapy may also prolong the QT/QTc interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Fluvoxamine: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving fluvoxamine. Androgen deprivation therapy may prolong the QT/QTc interval. Prolongation of the QT interval and torsade de pointes (TdP) has also been reported during fluvoxamine post-marketing use.
    Formoterol: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving long-acting beta-agonists. 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. Androgen deprivation therapy may also prolong the QT/QTc interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Formoterol; Mometasone: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving long-acting beta-agonists. 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. Androgen deprivation therapy may also prolong the QT/QTc 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 (i.e., histrelin) may prolong the QT/QTc interval. Both QT prolongation and torsade de pointes (TdP) have been reported during postmarketing use of foscarnet.
    Fostemsavir: (Moderate) Consider whether the benefits of androgen deprivation therapy outweigh the potential risks in patients receiving other QT prolonging agents. Androgen deprivation therapy (i.e., histrelin) may prolong the QT/QTc interval. Supratherapeutic doses of fostemsavir (2,400 mg twice daily, four times the recommended daily dose) have been shown to cause QT prolongation. Fostemsavir causes dose-dependent QT prolongation.
    Gemifloxacin: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving gemifloxacin as concurrent use may increase the risk of QT prolongation. Androgen deprivation therapy may prolong the QT/QTc interval. Gemifloxacin may also 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 may also prolong the QT/QTc interval.
    Gemtuzumab Ozogamicin: (Moderate) Obtain an ECG and serum electrolytes prior to initiation of concomitant use of gemtuzumab ozogamicin and histrelin due to the potential for additive QT prolongation and the risk of torsade de pointes (TdP); monitor ECGs and electrolytes as needed during treatment. Androgen deprivation therapy (i.e., histrelin) may prolong the QT/QTc interval. Although QT interval prolongation has not been reported with gemtuzumab, it has been reported with other drugs that contain calicheamicin.
    Gilteritinib: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and histrelin is necessary. Consider whether the benefits of androgen deprivation therapy outweigh the potential risks in patients receiving other QT prolonging agents. Androgen deprivation therapy (i.e., histrelin) may prolong the QT/QTc interval. Gilteritinib has also been associated with QT prolongation.
    Glasdegib: (Major) Avoid coadministration of glasdegib with histrelin due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Androgen deprivation therapy (i.e., histrelin) may also prolong the QT/QTc interval.
    Glycopyrrolate; Formoterol: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving long-acting beta-agonists. 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. Androgen deprivation therapy may also prolong the QT/QTc interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Granisetron: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving granisetron as concurrent use may increase the risk of QT prolongation. Androgen deprivation therapy may prolong the QT/QTc interval. Granisetron has also been associated with QT prolongation.
    Halogenated Anesthetics: (Major) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving halogenated anesthetics. Androgen deprivation therapy may prolong the QT/QTc interval. Halogenated anesthetics can also prolong the QT interval.
    Haloperidol: (Major) Avoid coadministration of histrelin with haloperidol due to the risk of reduced efficacy of histrelin; QT prolongation may also occur. Haloperidol can cause hyperprolactinemia, which reduces the number of pituitary gonadotropin releasing hormone (GnRH) receptors; histrelin is a GnRH analog. Additionally, QT prolongation and torsade de pointes (TdP) have been observed during haloperidol treatment; excessive doses (particularly in the overdose setting) or IV administration may be associated with a higher risk. Androgen deprivation therapy (i.e., histrelin) may prolong the QT/QTc interval.
    Halothane: (Major) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving halogenated anesthetics. Androgen deprivation therapy may prolong the QT/QTc interval. Halogenated anesthetics can also prolong the QT interval.
    Hydrochlorothiazide, HCTZ; Methyldopa: (Major) Avoid coadministration of histrelin with methyldopa due to the risk of reduced efficacy of histrelin. Methyldopa can cause hyperprolactinemia, which reduces the number of pituitary gonadotropin releasing hormone (GnRH) receptors; histrelin is a GnRH analog.
    Hydroxychloroquine: (Major) Avoid coadministration of histrelin and hydroxychloroquine due to the risk of increased QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Hydroxychloroquine prolongs the QT interval. Androgen deprivation therapy (e.g., histrelin) also may prolong the QT/QTc interval.
    Hydroxyzine: (Moderate) Caution is recommended if hydroxyzine is administered with histrelin due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). Postmarketing data indicate that hydroxyzine causes QT prolongation and TdP. Androgen deprivation therapy may prolong the QT/QTc interval.
    Ibutilide: (Major) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving ibutilide. 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. Androgen deprivation therapy may also prolong the QT/QTc interval.
    Iloperidone: (Major) Avoid coadministration of histrelin with iloperidone due to the risk of reduced efficacy of histrelin; QT prolongation may also occur. Iloperidone can cause hyperprolactinemia, which reduces the number of pituitary gonadotropin releasing hormone (GnRH) receptors; histrelin is a GnRH analog. Iloperidone has been associated with QT prolongation. Androgen deprivation therapy (i.e., histrelin) may prolong the QT/QTc interval.
    Imipramine: (Minor) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving tricyclic antidepressants (TCAs). Tricyclic antidepressants 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 may also prolong the QT/QTc interval.
    Indacaterol: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving long-acting beta-agonists. 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. Androgen deprivation therapy may also prolong the QT/QTc interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Indacaterol; Glycopyrrolate: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving long-acting beta-agonists. 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. Androgen deprivation therapy may also prolong the QT/QTc 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 prior to the start of treatment and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. Androgen deprivation therapy (i.e., histrelin) may prolong the QT/QTc interval.
    Ipratropium; Albuterol: (Minor) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving short-acting beta-agonists. Androgen deprivation therapy may prolong the QT/QTc 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.
    Isoflurane: (Major) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving halogenated anesthetics. Androgen deprivation therapy may prolong the QT/QTc interval. Halogenated anesthetics can also prolong the QT interval.
    Itraconazole: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving itraconazole as concurrent use may increase the risk of QT prolongation. Itraconazole has been associated with prolongation of the QT interval. Androgen deprivation therapy may also prolong the QT/QTc interval.
    Ivosidenib: (Major) Avoid coadministration of ivosidenib with histrelin if possible 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 (i.e., histrelin) also may prolong the QT/QTc interval.
    Ketoconazole: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving ketoconazole as concurrent use may increase the risk of QT prolongation. Ketoconazole has been associated with prolongation of the QT interval. Androgen deprivation therapy may also prolong the QT/QTc interval.
    Lansoprazole; Amoxicillin; Clarithromycin: (Major) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving clarithromycin. Clarithromycin is associated with an established risk for QT prolongation and torsade de pointes (TdP). Androgen deprivation therapy may also prolong the QT/QTc interval.
    Lapatinib: (Moderate) Consider whether the benefits of androgen deprivation therapy outweigh the potential risks in patients receiving lapatinib as concurrent use may increase the risk of QT prolongation. Androgen deprivation therapy (i.e., histrelin) may prolong the QT/QTc interval. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib.
    Lefamulin: (Major) Avoid coadministration of lefamulin with histrelin as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Androgen deprivation therapy (i.e., histrelin) may prolong the QT/QTc interval.
    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 (i.e., histrelin) may prolong the QT/QTc interval.
    Levalbuterol: (Minor) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving short-acting beta-agonists. Androgen deprivation therapy may prolong the QT/QTc 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.
    Levofloxacin: (Moderate) Consider whether the benefits of androgen deprivation therapy outweigh the potential risks in patients receiving other QT prolonging agents. Androgen deprivation therapy (i.e., histrelin) may prolong the QT/QTc interval. Levofloxacin has also been associated with a risk of QT prolongation and torsade de pointes (TdP). Although extremely rare, TdP has been reported during postmarketing surveillance of levofloxacin.
    Lithium: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving lithium. Lithium has been associated with QT prolongation. Androgen deprivation therapy may also prolong the QT/QTc interval.
    Lofexidine: (Moderate) Monitor ECGs for QT prolongation if coadministration of lofexidine with histrelin is necessary. Lofexidine prolongs the QT interval. Androgen deprivation therapy (i.e., histrelin) may also prolong the QT/QTc interval.
    Long-acting beta-agonists: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving long-acting beta-agonists. 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. Androgen deprivation therapy may also prolong the QT/QTc interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Loperamide: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving loperamide. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest. Androgen deprivation therapy may also prolong the QT/QTc interval.
    Loperamide; Simethicone: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving loperamide. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest. Androgen deprivation therapy may also prolong the QT/QTc interval.
    Lopinavir; Ritonavir: (Major) Avoid coadministration of lopinavir with histrelin due to the potential for additive QT prolongation. If use together is necessary, obtain a baseline ECG to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Lopinavir is associated with QT prolongation. Androgen deprivation therapy (i.e., histrelin) may prolong the QT/QTc interval.
    Lorcaserin: (Major) Avoid coadministration of histrelin with lorcaserin due to the risk of reduced efficacy of histrelin. Lorcaserin can cause hyperprolactinemia, which reduces the number of pituitary gonadotropin releasing hormone (GnRH) receptors; histrelin is a GnRH analog.
    Loxapine: (Major) Avoid coadministration of histrelin with loxapine due to the risk of reduced efficacy of histrelin. Loxapine can cause hyperprolactinemia, which reduces the number of pituitary gonadotropin releasing hormone (GnRH) receptors; histrelin is a GnRH analog.
    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 (i.e., histrelin) may also prolong the QT/QTc interval.
    Maprotiline: (Major) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving maprotiline. Maprotiline has 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. Androgen deprivation therapy may also prolong the QT/QTc interval. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs.
    Mefloquine: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving mefloquine as concurrent use may increase the risk of QT prolongation. Androgen deprivation therapy may prolong the QT/QTc interval. There is evidence that the use of halofantrine after mefloquine causes a significant lengthening of the QTc interval. Mefloquine alone has not been reported to cause QT prolongation.
    Meperidine; Promethazine: (Major) Avoid coadministration of histrelin with promethazine due to the risk of reduced efficacy of histrelin; QT prolongation may also occur. Promethazine can cause hyperprolactinemia, which reduces the number of pituitary gonadotropin releasing hormone (GnRH) receptors; leuprolide is a GnRH analog. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. Androgen deprivation therapy (i.e., histrelin) may also prolong the QT/QTc interval.
    Metaproterenol: (Minor) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving short-acting beta-agonists. Androgen deprivation therapy may prolong the QT/QTc 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.
    Methadone: (Major) Coadministration of methadone with histrelin should be undertaken with extreme caution and a careful assessment of the benefits of therapy versus the risks of QT prolongation. 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 may prolong the QT/QTc interval.
    Methyldopa: (Major) Avoid coadministration of histrelin with methyldopa due to the risk of reduced efficacy of histrelin. Methyldopa can cause hyperprolactinemia, which reduces the number of pituitary gonadotropin releasing hormone (GnRH) receptors; histrelin is a GnRH analog.
    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.
    Metoclopramide: (Major) Avoid coadministration of histrelin with metoclopramide due to the risk of reduced efficacy of histrelin. Metoclopramide can cause hyperprolactinemia, which reduces the number of pituitary gonadotropin releasing hormone (GnRH) receptors; histrelin is a GnRH analog.
    Metronidazole: (Moderate) Concomitant use of metronidazole and androgen deprivation therapy (i.e. histrelin) may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
    Midostaurin: (Major) Consider periodic monitoring of EGCs for QT prolongation if coadministration of histrelin and midostaurin is necessary. Prolongation of the QT interval was reported in patients who received midostaurin in clinical trials. Androgen deprivation therapy (i.e., histrelin) may also prolong the QT/QTc interval.
    Mifepristone: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving mifepristone. 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 may prolong the QT/QTc interval.
    Mirtazapine: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving mirtazapine. Mirtazapine has been associated with dose-dependent prolongation of the QT interval. Torsade de pointes (TdP) has been reported in postmarketing experience, primarily in overdose or in patients with other risk factors for QT prolongation. Androgen deprivation therapy may also prolong the QT/QTc interval.
    Mobocertinib: (Major) Concomitant use of mobocertinib and androgen deprivation therapy (i.e. histrelin) increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
    Molindone: (Major) Avoid coadministration of histrelin with molindone due to the risk of reduced efficacy of histrelin. Molindone can cause hyperprolactinemia, which reduces the number of pituitary gonadotropin releasing hormone (GnRH) receptors; histrelin is a GnRH analog.
    Moxifloxacin: (Major) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving moxifloxacin. 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 may also prolong the QT/QTc 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 interval prolongation. Sudden death and QT prolongation have occurred in patients who received nilotinib therapy. Androgen deprivation therapy (i.e., histrelin) may also prolong the QT/QTc interval.
    Nortriptyline: (Minor) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving tricyclic antidepressants (TCAs). Tricyclic antidepressants 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 may also prolong the QT/QTc interval.
    Octreotide: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving octreotide. 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 may prolong the QT/QTc interval.
    Ofloxacin: (Moderate) Consider whether the benefits of androgen deprivation therapy outweigh the potential risks in patients receiving ofloxacin as concurrent use may increase the risk of QT prolongation. Androgen deprivation therapy (i.e., histrelin) may prolong the QT/QTc interval. Ofloxacin has been associated with a risk of QT prolongation and torsade de pointes (TdP). Although extremely rare, TdP has been reported during postmarketing surveillance of ofloxacin.
    Olanzapine: (Major) Avoid coadministration of histrelin with olanzapine due to the risk of reduced efficacy of histrelin; QT prolongation may also occur. Olanzapine can cause hyperprolactinemia, which reduces the number of pituitary gonadotropin releasing hormone (GnRH) receptors; histrelin is a GnRH analog. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. Androgen deprivation therapy (i.e., histrelin) may also prolong the QT/QTc interval.
    Olanzapine; Fluoxetine: (Major) Avoid coadministration of histrelin with olanzapine due to the risk of reduced efficacy of histrelin; QT prolongation may also occur. Olanzapine can cause hyperprolactinemia, which reduces the number of pituitary gonadotropin releasing hormone (GnRH) receptors; histrelin is a GnRH analog. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. Androgen deprivation therapy (i.e., histrelin) may also prolong the QT/QTc interval. (Moderate) Coadministration of fluoxetine and histrelin may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation and TdP have been reported in patients treated with fluoxetine. Androgen deprivation therapy (i.e., histrelin) may prolong the QT/QTc interval.
    Olanzapine; Samidorphan: (Major) Avoid coadministration of histrelin with olanzapine due to the risk of reduced efficacy of histrelin; QT prolongation may also occur. Olanzapine can cause hyperprolactinemia, which reduces the number of pituitary gonadotropin releasing hormone (GnRH) receptors; histrelin is a GnRH analog. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. Androgen deprivation therapy (i.e., histrelin) may also prolong the QT/QTc interval.
    Olodaterol: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving long-acting beta-agonists. 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. Androgen deprivation therapy may also prolong the QT/QTc interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Ondansetron: (Major) Monitor ECGs for QT prolongation if coadministration of ondansetron with histrelin is necessary. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of torsade de pointes (TdP). Androgen deprivation therapy (i.e., histrelin) may also prolong the QT/QTc interval.
    Osilodrostat: (Moderate) Monitor ECGs in patients receiving osilodrostat with histrelin. Osilodrostat is associated with dose-dependent QT prolongation. Androgen deprivation therapy (i.e., histrelin) may also prolong the QT/QTc interval.
    Osimertinib: (Major) Avoid coadministration of histrelin with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; 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 (i.e., histrelin) may also prolong the QT/QTc interval.
    Oxaliplatin: (Major) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving oxaliplatin concomitantly with histrelin; correct electrolyte abnormalities prior to administration of oxaliplatin. Prolongation of the QT interval and ventricular arrhythmias including fatal torsade de pointes (TdP) have been reported with oxaliplatin use in postmarketing experience. Androgen deprivation therapy (i.e., histrelin) may also prolong the QT/QTc interval.
    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.
    Ozanimod: (Major) In general, do not initiate ozanimod in patients taking histrelin due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP). If treatment initiation is considered, seek advice from a cardiologist. Ozanimod initiation may result in a transient decrease in heart rate and atrioventricular conduction delays. Ozanimod has not been studied in patients taking concurrent QT prolonging drugs; however, QT prolonging drugs have been associated with TdP in patients with bradycardia. Androgen deprivation therapy (i.e., histrelin) may prolong the QT/QTc interval.
    Paliperidone: (Major) Avoid coadministration of histrelin with paliperidone due to the risk of reduced efficacy of histrelin and the risk of QT prolongation. Paliperidone can cause hyperprolactinemia, which reduces the number of pituitary gonadotropin releasing hormone (GnRH) receptors; histrelin is a GnRH analog. Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose. Androgen deprivation therapy (i.e., histrelin) may also prolong the QT/QTc 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 treatment. Androgen deprivation therapy (i.e., histrelin) may also prolong the QT/QTc interval.
    Pasireotide: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving pasireotide as concurrent use may increase the risk of QT prolongation. Prolongation of the QT interval has occurred with pasireotide at therapeutic and supra-therapeutic doses. Androgen deprivation therapy may also prolong the QT/QTc 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 interval prolongation. Pazopanib has been reported to prolong the QT interval. Androgen deprivation therapy (i.e., histrelin) may also prolong the QT/QTc interval.
    Pentamidine: (Major) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving pentamidine. Systemic pentamidine has been associated with QT prolongation. Androgen deprivation therapy may prolong the QT/QTc interval.
    Perphenazine: (Major) Avoid coadministration of histrelin with perphenazine due to the risk of reduced efficacy of histrelin; QT prolongation may also occur. Perphenazine can cause hyperprolactinemia, which reduces the number of pituitary gonadotropin releasing hormone (GnRH) receptors; histrelin is a GnRH analog. 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 (i.e., histrelin) may also prolong the QT/QTc interval.
    Perphenazine; Amitriptyline: (Major) Avoid coadministration of histrelin with perphenazine due to the risk of reduced efficacy of histrelin; QT prolongation may also occur. Perphenazine can cause hyperprolactinemia, which reduces the number of pituitary gonadotropin releasing hormone (GnRH) receptors; histrelin is a GnRH analog. 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 (i.e., histrelin) may also prolong the QT/QTc interval. (Minor) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving tricyclic antidepressants (TCAs). Tricyclic antidepressants 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 may also prolong the QT/QTc interval.
    Pimavanserin: (Major) Coadministration of pimavanserin with histrelin should generally be avoided due to the risk of QT prolongation. Pimavanserin may cause QT prolongation. Androgen deprivation therapy (i.e., histrelin) may also prolong the QT/QTc interval.
    Pimozide: (Contraindicated) Because of the potential for torsade de pointes (TdP), use of histrelin with pimozide is contraindicated; the efficacy of histrelin may also be reduced. Pimozide is associated with a well-established risk of QT prolongation and TdP. Androgen deprivation therapy (i.e., histrelin) may also prolong the QT/QTc interval. Pimozide can also cause hyperprolactinemia, which reduces the number of pituitary gonadotropin releasing hormone (GnRH) receptors; histrelin is a GnRH analog.
    Pirbuterol: (Minor) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving short-acting beta-agonists. Androgen deprivation therapy may prolong the QT/QTc 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.
    Pitolisant: (Major) Avoid coadministration of pitolisant with histrelin as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. Androgen deprivation therapy (i.e., histrelin) may prolong the QT/QTc interval.
    Ponesimod: (Major) In general, do not initiate ponesimod in patients taking histrelin due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP). If treatment initiation is considered, seek advice from a cardiologist. Ponesimod initiation may result in a transient decrease in heart rate and atrioventricular conduction delays. Ponesimod has not been studied in patients taking concurrent QT prolonging drugs; however, QT prolonging drugs have been associated with TdP in patients with bradycardia. Androgen deprivation therapy (i.e., histrelin) may prolong the QT/QTc interval.
    Posaconazole: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving posaconazole as concurrent use may increase the risk of QT prolongation. Posaconazole has been associated with prolongation of the QT interval as well as rare cases of torsade de pointes (TdP). Androgen deprivation therapy may also prolong the QT/QTc interval.
    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: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving primaquine as concurrent use may increase the risk of QT prolongation. Primaquine has the potential to cause QT prolongation. Androgen deprivation therapy may also prolong the QT/QTc interval.
    Procainamide: (Major) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving procainamide. Procainamide is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Androgen deprivation therapy may also prolong the QT/QTc interval.
    Prochlorperazine: (Major) Avoid coadministration of histrelin with prochlorperazine due to the risk of reduced efficacy of leuprolide; QT prolongation may also occur. Prochlorperazine can cause hyperprolactinemia, which reduces the number of pituitary gonadotropin releasing hormone (GnRH) receptors; histrelin is a GnRH analog. 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 (i.e., histrelin) may also prolong the QT/QTc interval.
    Promethazine: (Major) Avoid coadministration of histrelin with promethazine due to the risk of reduced efficacy of histrelin; QT prolongation may also occur. Promethazine can cause hyperprolactinemia, which reduces the number of pituitary gonadotropin releasing hormone (GnRH) receptors; leuprolide is a GnRH analog. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. Androgen deprivation therapy (i.e., histrelin) may also prolong the QT/QTc interval.
    Promethazine; Dextromethorphan: (Major) Avoid coadministration of histrelin with promethazine due to the risk of reduced efficacy of histrelin; QT prolongation may also occur. Promethazine can cause hyperprolactinemia, which reduces the number of pituitary gonadotropin releasing hormone (GnRH) receptors; leuprolide is a GnRH analog. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. Androgen deprivation therapy (i.e., histrelin) may also prolong the QT/QTc interval.
    Promethazine; Phenylephrine: (Major) Avoid coadministration of histrelin with promethazine due to the risk of reduced efficacy of histrelin; QT prolongation may also occur. Promethazine can cause hyperprolactinemia, which reduces the number of pituitary gonadotropin releasing hormone (GnRH) receptors; leuprolide is a GnRH analog. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. Androgen deprivation therapy (i.e., histrelin) may also prolong the QT/QTc interval.
    Propafenone: (Major) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving propafenone. Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval. Androgen deprivation therapy may also prolong the QT/QTc interval.
    Protriptyline: (Minor) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving tricyclic antidepressants (TCAs). Tricyclic antidepressants 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 may also prolong the QT/QTc interval.
    Quetiapine: (Major) Avoid coadministration of quetiapine with 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 (i.e., histrelin) may also prolong the QT/QTc interval.
    Quinidine: (Major) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving quinidine. Quinidine administration is associated with QT prolongation and torsade de pointes (TdP). Androgen deprivation therapy may also prolong the QT/QTc interval.
    Quinine: (Major) Avoid coadministration of quinine with 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 (i.e., histrelin) may also prolong the QT/QTc interval.
    Ramelteon: (Major) Avoid coadministration of histrelin with ramelteon due to the risk of reduced efficacy of histrelin. Ramelteon can cause hyperprolactinemia, which reduces the number of pituitary gonadotropin releasing hormone (GnRH) receptors; histrelin is a GnRH analog.
    Ranolazine: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving ranolazine as concurrent use may increase the risk of QT prolongation. Androgen deprivation therapy may prolong the QT/QTc interval. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc 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.
    Reserpine: (Major) Avoid coadministration of histrelin with reserpine due to the risk of reduced efficacy of histrelin. Reserpine can cause hyperprolactinemia, which reduces the number of pituitary gonadotropin releasing hormone (GnRH) receptors; histrelin is a GnRH analog.
    Ribociclib: (Major) Avoid coadministration of ribociclib with 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 typically occurred within the first four weeks of treatment and were reversible with dose interruption. Androgen deprivation therapy (i.e., histrelin) may also prolong the QT/QTc interval.
    Ribociclib; Letrozole: (Major) Avoid coadministration of ribociclib with 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 typically occurred within the first four weeks of treatment and were reversible with dose interruption. Androgen deprivation therapy (i.e., histrelin) may also prolong the QT/QTc interval.
    Rilpivirine: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving rilpivirine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Androgen deprivation therapy may also prolong the QT/QTc interval.
    Risperidone: (Major) Avoid coadministration of histrelin with risperidone due to the risk of reduced efficacy of histrelin; QT prolongation may also occur. Risperidone can cause hyperprolactinemia, which reduces the number of pituitary gonadotropin releasing hormone (GnRH) receptors; histrelin is a GnRH analog. Risperidone has been associated with a possible risk for QT prolongation and/or TdP, primarily in the overdose setting. Androgen deprivation therapy (i.e., histrelin) may also prolong the QT/QTc interval.
    Romidepsin: (Moderate) Monitor ECGs for QT prolongation and monitor electrolytes at baseline and periodically during treatment if coadministration of romidepsin with histrelin is necessary. Romidepsin has been reported to prolong the QT interval. Androgen deprivation therapy (i.e., histrelin) may also prolong the QT/QTc interval.
    Salmeterol: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving long-acting beta-agonists. 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. Androgen deprivation therapy may also prolong the QT/QTc 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 with histrelin if possible due to the risk of QT prolongation. If concomitant use is unavoidable, perform a baseline QCT prior to initiation of therapy and carefully follow monitoring recommendations. 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 (i.e., histrelin) may also prolong the QT/QTc interval.
    Selpercatinib: (Major) Monitor ECGs more frequently for QT prolongation if coadministration of selpercatinib with histrelin is necessary due to the risk of additive QT prolongation. Concentration-dependent QT prolongation has been observed with selpercatinib therapy. Androgen deprivation therapy (i.e., histrelin) may prolong the QT/QTc interval.
    Sertraline: (Moderate) Consider whether the benefits of histrelin therapy outweigh the potential risk of QT prolongation in patients receiving sertraline. If use together is necessary, use caution and monitor patients for QT prolongation. Androgen deprivation therapy (i.e., histrelin) may prolong the QT/QTc interval. Sertraline's FDA-approved labeling recommends avoiding concomitant use with drugs known to prolong the QTc interval; however, the risk of sertraline-induced QT prolongation is generally considered to be low in clinical practice. Its effect on QTc interval is minimal (typically less than 5 msec), and the drug has been used safely in patients with cardiac disease (e.g., recent myocardial infarction, unstable angina, chronic heart failure).
    Sevoflurane: (Major) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving halogenated anesthetics. Androgen deprivation therapy may prolong the QT/QTc interval. Halogenated anesthetics can also prolong the QT interval.
    Short-acting beta-agonists: (Minor) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving short-acting beta-agonists. Androgen deprivation therapy may prolong the QT/QTc 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.
    Siponimod: (Major) In general, do not initiate treatment with siponimod in patients receiving histrelin due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Androgen deprivation therapy (i.e., histrelin) may prolong the QT/QTc interval.
    Solifenacin: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving solifenacin. 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 may also prolong the QT/QTc interval.
    Sorafenib: (Major) Avoid coadministration of sorafenib with histrelin due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Sorafenib is associated with QTc prolongation. Androgen deprivation therapy (i.e., histrelin) may also prolong the QT/QTc interval.
    Sotalol: (Major) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving sotalol. 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 may also prolong the QT/QTc interval.
    Sunitinib: (Moderate) Consider whether the benefits of androgen deprivation therapy outweigh the potential risks in patients receiving sunitinib as concurrent use may increase the risk of QT prolongation. Androgen deprivation therapy (i.e., histrelin) may prolong the QT/QTc interval. Sunitinib can prolong the QT interval.
    Tacrolimus: (Moderate) Consider the benefits of androgen deprivation therapy and monitor ECG and electrolytes periodically during treatment if tacrolimus is administered with histrelin as concurrent use may increase the risk of QT prolongation. Tacrolimus may prolong the QT interval and cause torsade de pointes (TdP). Androgen deprivation therapy (i.e., histrelin) may prolong the QT/QTc interval.
    Tamoxifen: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving tamoxifen. 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 may prolong the QT/QTc interval.
    Telavancin: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving telavancin as concurrent use may increase the risk of QT prolongation. Androgen deprivation therapy may prolong the QT/QTc interval and telavancin has been associated with QT prolongation.
    Telithromycin: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving telithromycin as concurrent use may increase the risk of QT prolongation. Telithromycin is associated with QT prolongation and torsade de pointes (TdP). Androgen deprivation therapy may prolong the QT/QTc interval.
    Terbutaline: (Minor) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving short-acting beta-agonists. Androgen deprivation therapy may prolong the QT/QTc 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.
    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 histrelin with tetrabenazine due to the risk of reduced efficacy of histrelin; QT prolongation may also occur. Tetrabenazine can cause hyperprolactinemia, which reduces the number of pituitary gonadotropin releasing hormone (GnRH) receptors; histrelin is a GnRH analog. Tetrabenazine also causes a small increase in the corrected QT interval (QTc). Androgen deprivation therapy (i.e., histrelin) may also prolong the QT/QTc interval.
    Thioridazine: (Contraindicated) Because of the potential for torsade de pointes (TdP), use of histrelin with thioridazine is contraindicated; the efficacy of histrelin may also be reduced. Thioridazine is associated with a well-established risk of QT prolongation and TdP and is considered contraindicated for use along with agents that may prolong the QT interval and increase the risk of TdP, and/or cause orthostatic hypotension. Androgen deprivation therapy (i.e., histrelin) may also prolong the QT/QTc interval. Thioridazine can also cause hyperprolactinemia, which reduces the number of pituitary gonadotropin releasing hormone (GnRH) receptors; histrelin is a GnRH analog.
    Thiothixene: (Major) Avoid coadministration of histrelin with thiothixene due to the risk of reduced efficacy of histrelin. Thiothixene can cause hyperprolactinemia, which reduces the number of pituitary gonadotropin releasing hormone (GnRH) receptors; histrelin is a GnRH analog.
    Tiotropium; Olodaterol: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving long-acting beta-agonists. 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. Androgen deprivation therapy may also prolong the QT/QTc interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Tolterodine: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving tolterodine. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. Androgen deprivation therapy may also prolong the QT/QTc 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. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Androgen deprivation therapy (i.e., histrelin) may also prolong the QT/QTc interval.
    Trandolapril; Verapamil: (Major) Avoid coadministration of histrelin with verapamil due to the risk of reduced efficacy of histrelin. Verapamil can cause hyperprolactinemia, which reduces the number of pituitary gonadotropin releasing hormone (GnRH) receptors; histrelin is a GnRH analog.
    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 (i.e., histrelin) may prolong the QT/QTc interval.
    Triclabendazole: (Moderate) Monitor ECGs in patients receiving triclabendazole with histrelin. Transient prolongation of the mean QTc interval was noted on the ECG recordings in dogs administered triclabendazole. Androgen deprivation therapy (i.e., histrelin) may also prolong the QT/QTc interval.
    Tricyclic antidepressants: (Minor) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving tricyclic antidepressants (TCAs). Tricyclic antidepressants 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 may also prolong the QT/QTc interval.
    Trifluoperazine: (Major) Avoid coadministration of histrelin with trifluoperazine due to the risk of reduced efficacy of histrelin; QT prolongation may also occur. Trifluoperazine can cause hyperprolactinemia, which reduces the number of pituitary gonadotropin releasing hormone (GnRH) receptors; histrelin is a GnRH analog. Trifluoperazine is also 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 (i.e., histrelin) may also prolong the QT/QTc interval.
    Trimipramine: (Minor) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving tricyclic antidepressants (TCAs). Tricyclic antidepressants 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 may also prolong the QT/QTc interval.
    Umeclidinium; Vilanterol: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving long-acting beta-agonists. 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. Androgen deprivation therapy may also prolong the QT/QTc interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Valbenazine: (Major) Avoid concurrent use of histrelin with valbenazine due to the risk of reduced efficacy of histrelin. Valbenazine can cause hyperprolactinemia, which reduces the number of pituitary gonadotropin releasing hormone (GnRH) receptors; histrelin is a GnRH analog.
    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 (i.e., histrelin) may also prolong the QT/QTc interval.
    Vardenafil: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving vardenafil as concurrent use may increase the risk of QT prolongation. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval. Androgen deprivation therapy may also prolong the QT/QTc interval.
    Vemurafenib: (Major) Closely monitor ECGs for QT prolongation if coadministration of vemurafenib with histrelin is necessary. Vemurafenib has been associated with QT prolongation. Androgen deprivation therapy (i.e., histrelin) may prolong the QT/QTc interval.
    Venlafaxine: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving venlafaxine. Venlafaxine administration is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has reported with postmarketing use. Androgen deprivation therapy (i.e., histrelin) may also prolong the QT/QTc interval.
    Verapamil: (Major) Avoid coadministration of histrelin with verapamil due to the risk of reduced efficacy of histrelin. Verapamil can cause hyperprolactinemia, which reduces the number of pituitary gonadotropin releasing hormone (GnRH) receptors; histrelin is a GnRH analog.
    Voclosporin: (Moderate) Concomitant use of voclosporin and histrelin may increase the risk of QT prolongation. Consider interventions to minimize the risk of progression to torsades de pointes (TdP), such as ECG monitoring and correcting electrolyte abnormalities, particularly in patients with additional risk factors for TdP. Voclosporin has been associated with QT prolongation at supratherapeutic doses. Androgen deprivation therapy (i.e., histrelin) may prolong the QT/QTc interval.
    Voriconazole: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving voriconazole as concurrent use may increase the risk of QT prolongation. Voriconazole has been associated with QT prolongation and rare cases of torsade de pointes. Androgen deprivation therapy may also prolong the QT/QTc interval.
    Vorinostat: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving vorinostat. Vorinostat therapy is associated with a risk of QT prolongation. Androgen deprivation therapy may also prolong the QT/QTc interval.
    Ziprasidone: (Major) Concomitant use of ziprasidone and histrelin should be avoided 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 (i.e., histrelin) may prolong the QT/QTc interval.

    PREGNANCY AND LACTATION

    Pregnancy

    Due to the potential for serious adverse reactions in nursing infants from histrelin, advise women to discontinue breast-feeding during treatment. It is not known whether histrelin is present in human milk, although many drugs are excreted in human milk.

    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).