Chemical Name: 6-[1-phenylmethyl)-d-histidine]-9-(N-ethyl-l-prolinamide)-10-deglycinamide-luteinizing hormone-releasing factor (pig)
Molecular Formula: C66H86N18O12
CAS Number: 76712-82-8
Antineoplastic agent; a synthetic nonapeptide analog of gonadotropin-releasing hormone (GnRH, luteinizing hormone-releasing hormone [LHRH], gonadorelin).
Uses for Histrelin
Palliative treatment of advanced prostate cancer.
Histrelin Dosage and Administration
Administer sub-Q as an implant; insert implant in inner aspect of upper arm. Consult manufacturer’s labeling for proper methods of inserting and removing implants.
Available as histrelin acetate; dosage expressed in terms of the salt.
One 50-mg implant every 12 months; delivers 50 mcg of histrelin acetate daily.
Remove implant 12 months after insertion; the implant has been designed to allow for a few additional weeks of histrelin release to allow for flexibility in scheduling removal. At time of implant removal, may insert another implant to continue therapy. In limited clinical studies, treatment remains effective for up to 2 years.
Use of 2 or 4 implants provides no additional benefit beyond that produced by a single implant.
No dosage adjustment required. (See Special Populations under Pharmacokinetics.)
Cautions for Histrelin
Known hypersensitivity to histrelin or any ingredient in the formulation, other GnRH agonists, or GnRH.
Women who are or may become pregnant.
Fetal/Neonatal Morbidity and Mortality
Expected hormonal changes increase the risk for pregnancy loss and fetal harm when administered to a pregnant woman; teratogenic and fetotoxic in nonclinical studies. If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.
Initial Worsening of Hormone-dependent Disease
Possible worsening of signs and/or symptoms of prostate cancer and/or development of new manifestations (e.g., bone pain, neuropathy, hematuria, ureteral or bladder outlet obstruction) due to transient increase in serum testosterone concentrations during first few weeks of therapy.
Ureteral obstruction (may cause renal impairment) and spinal cord compression (may result in paralysis) reported with GnRH agonists. Observe patients with metastatic vertebral lesions and/or urinary tract obstruction closely during first few weeks of therapy.
No acute increase in serum testosterone concentration observed following removal of first implant (after 1 year of therapy) and insertion of second implant.
Possible hyperglycemia and increased risk of diabetes in patients receiving GnRH agonists for treatment of prostate cancer. Studies evaluating risk of diabetes in women and children receiving GnRH agonists not performed to date.
Evaluate patients for risk factors for diabetes and carefully weigh benefits and risks of GnRH agonist therapy before selecting treatment for prostate cancer.
Periodically monitor blood glucose and/or HbA1c in patients receiving GnRH agonists for treatment of prostate cancer. Manage hyperglycemia or diabetes according to current standards of care.
Possible increased risk of cardiovascular disease (e.g., MI, sudden cardiac death, stroke) in patients receiving GnRH agonists for treatment of prostate cancer. Studies evaluating risk of cardiovascular disease in women and children receiving GnRH agonists not performed to date.
Evaluate patients for cardiovascular risk factors and carefully weigh benefits and risks of GnRH agonist therapy before selecting treatment for prostate cancer.
Periodically monitor patients receiving GnRH agonists for manifestations of cardiovascular disease; manage cardiovascular disease according to current standards of care.
Anaphylactic reactions reported with synthetic GnRH or GnRH agonists.
Pituitary apoplexy, a clinical syndrome resulting from infarction of the pituitary gland, reported rarely. Most cases occur within 2 weeks of the first dose, sometimes within the first hour. If manifestations occur (e.g., sudden headache, vomiting, visual changes, ophthalmoplegia, altered mental status, sometimes cardiovascular collapse), immediate medical attention required. In most cases, pituitary adenoma diagnosed.
Renal impairment reported. Some patients had a single occurrence of mild impairment (Clcr of 30–59 mL/minute) that returned to normal by the next visit.
Severe liver injury reported. Hepatotoxicity reversible following removal of the implant.
To monitor response, measure serum concentrations of testosterone and PSA periodically.
Implant insertion or removal is a surgical procedure. Carefully follow recommended procedures for insertion and removal of implant to minimize potential for complications or for implant expulsion.
Implants are not radio-opaque and, therefore, will not be visible on radiographs. If implant is difficult to locate by palpation, may use ultrasound, magnetic resonance imaging (MRI), and/or computed tomography (CT) scan.
Decrease in Bone Mineral Density
Decrease in bone mineral density possible following long-term therapy with GnRH antagonists and agonists.
Category X. (See Contraindications under Cautions and also see Fetal/Neonatal Morbidity and Mortality under Warnings/Precautions: Warnings, in Cautions.)
Not indicated for use in women. (See Contraindications under Cautions.) Not known whether histrelin is distributed into milk. Discontinue nursing or the drug.
Not indicated for use in pediatric patients. (See Contraindications under Cautions.)
Studies conducted principally in patients ≥65 years of age, since prostate cancer occurs mainly in an older patient population.
Common Adverse Effects
Local or insertion site reactions (e.g., bruising, pain/soreness/tenderness, erythema), hot flushes (flashes), testicular atrophy, gynecomastia, erectile dysfunction, decreased libido, fatigue, renal impairment, constipation, headache, insomnia, weight loss.
Interactions for Histrelin
No formal drug interaction studies to date.
Following sub-Q insertion, peak serum concentrations occurred at a median of 12 hours.
Drug is delivered continuously at rate of 50–60 mcg daily over 12 months.
Serum histrelin concentrations are 50% higher in patients with mild to severe renal impairment (Clcr of 15–60 mL/minute). However, increased exposure not considered clinically relevant; dosage adjustment not required.
Plasma Protein Binding
No excretion studies to date.
Approximately 3.92 hours following sub-Q injection of a 500-mcg dose.
2–8°C in unopened glass vial, overwrapped in amber plastic pouch and carton. May be exposed to 25°C for 7 days. Do not freeze. Protect from light. Store implantation kit only at room temperature.
Antineoplastic agent; a synthetic nonapeptide analog of GnRH (LHRH, gonadorelin).
Causes a transient surge in circulating concentrations of LH, FSH, and gonadal steroids (testosterone and dihydrotestosterone in males) following initial administration. However, long-term and continuous administration (generally, 2–4 weeks after initiation of therapy) results in decreased levels of LH and FSH due to reversible down-regulation of GnRH receptors in the pituitary gland and desensitization of the pituitary gonadotropes, resulting in marked reduction in serum testosterone concentrations.
Reductions in serum testosterone concentrations following histrelin therapy comparable to those achieved after surgical castration (i.e., <50 ng/dL).
Commercially available as nonbiodegradable, diffusion-controlled implant.
Not active when given orally.
Advice to Patients
Importance of reading and understanding the manufacturer’s patient information leaflet.
Importance of protecting the affected arm following implant insertion; keep arm clean and dry (avoid bathing and swimming) for 24 hours, keep bandage in place and do not bump arm for several days, and refrain from heavy lifting or strenuous exertion with the arm for 7 days.
Importance of notifying clinician of unusual bleeding, redness, or pain at insertion site.
Importance of informing patients that serum testosterone concentrations may increase transiently following initiation of therapy. Risk of worsening symptoms of prostate cancer during initial weeks of therapy. Importance of notifying clinician immediately in case of new or worsening bone pain, weakness or loss of sensation in legs, blood in urine, or difficulty urinating or inability to urinate.
Risk of decreased bone mineral density and osteoporosis.
Risk of diabetes or loss of glycemic control in patients with preexisting diabetes. Importance of undergoing recommended monitoring of blood glucose or HbA1c concentrations.
Possibility of increased risk of MI, sudden cardiac death, and stroke in men receiving GnRH agonists for treatment of prostate cancer. Importance of being monitored for manifestations of cardiovascular disease.
Importance of promptly reporting sudden onset of headache, vomiting, or visual changes to clinicians.
Importance of notifying clinician of known or suspected implant expulsion (can occur through original incision site). This occurs infrequently. Importance of informing patients that tests (e.g., ultrasound, CT scan) may be required to locate implant prior to removal.
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.
Importance of informing patients of other important precautionary information. (See Cautions.)
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
AHFS DI Essentials™. © Copyright 2022, Selected Revisions October 16, 2017. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.
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- Drug class: gonadotropin releasing hormones