Histrelin

1323.5

1322.667236

H50H3S3W74

DTXSID50227543

C74270

L - Antineoplastic and immunomodulating agents

2937190090

449

1.79 (est)

powder

1.5±0.1 g/cm3

1800.6ºC at 760 mmHg

1042.8ºC

1.701

In water, 1.0X10+6 mg/L at 25 deg C (est) /miscible/

−20°C

0 mm Hg at 25 deg C (est)

D20 -33.9° (c = 1 in acetic acid)

Hydroxyl radical reaction rate constant = 6.67X10-10 cm/molec-sec at 25 °C (est)

NONH for all modes of transport

3

60

53-22-36/37/39-45

OK6370800

T

P201-P308 + P313

H360

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ All contaminated disposables should be contained in sealable bags for transfer to larger waste containers. /Antineoplastic agents/|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ All bottles must be discarded as contaminated waste after decontamination of the biohazard cabinet. All protective apparel (gown, gloves, goggles, and respirator) should be discarded as contaminated waste. /Antineoplastic agents/|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ The contaminated filters must be removed, bagged in thick plastic and prepared for disposal in a hazardous waste dump site or incinerator licensed by the Environmental Protection Agency (EPA). /Antineoplastic agents/|For more Disposal Methods (Complete) data for HISTRELIN (8 total), please visit the HSDB record page.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl histrelin acetate, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Histrelin acetate/

|Danger|H360 (100%): May damage fertility or the unborn child [Danger Reproductive toxicity]|P201, P202, P281, P308+P313, P405, and P501|Aggregated GHS information provided by 39 companies from 2 notifications to the ECHA C&L Inventory.

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Protective apparel: Disposable closed-front gown or coveralls, disposable utility gloves over disposable latex gloves, NIOSH-approved air-purifying half-mask respirator equipped with a high efficiency filter, and eye protection should be worn. /Antineoplastic agents/|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Class 100 clean-air work stations, both horizontal and vertical airflow (with no containment characteristics), are inappropriate engineering controls for handling hazardous drugs because they provide no personnel protection and permit environmental contamination. Although there are no engineering controls designed specifically for the safe handling of hazardous chemicals as sterile products, Class II contained vertical-flow biological safety cabinets (biohazard cabinets) have been adopted for this use. Biohazard cabinetry is, however, designed for the handling of infectious agents, not hazardous chemicals. ... Based on design, ease of use, and cost considerations, Class II contained-vertical-flow biohazard cabinetry is currently recommended for use in preparing sterile doses of hazardous drugs. Class II cabinetry design and performance specifications are defined in NSF Standard 49. Biological safety cabinets selected for use with hazardous drugs should meet NSF Standard 49 specifications to ensure the maximum protection from these engineering controls. /Antineoplastic agents/|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Workers should wear powder free, disposable surgical latex gloves of good quality when preparing hazardous drugs. Selection criteria for gloves should include thickness (especially at the fingertips where stress is the greatest), fit, length, and tactile sensation. ... The practice of double gloving is supported by research that indicates that many glove materials vary in drug permeability even within lots; therefore, double gloving is recommended. ... In general, surgical latex gloves fit better, have appropriate elasticity for double gloving and maintaining the integrity of the glove-gown interface, and have sufficient tactile sensation (even during double gloving) for stringent aseptic procedures. ... Powdered gloves should be avoided. /Antineoplastic agents/|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Workers who are not protected by the containment environment of a biohazard cabinet should use respiratory protection when handling hazardous drugs. Respiratory protection should be an adjunct to and not a substitute for engineering controls. Surgical masks of all types provide no respiratory protection against powdered or liquid aerosols of hazardous drugs. In situations where workers may be exposed to potential eye contact with hazardous drugs, an appropriate plastic face shield or splash goggles should be worn. /Antineoplastic agents/|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ During compounding of hazardous drugs (eg, crushing, dissolving, and preparing an ointment), workers should wear low permeability gowns and double gloves. Compounding should take place in a protective area such as a disposable glove box. If compounding must be done in the open, an area away from drafts and traffic must be selected, and the worker should use appropriate respiratory protection. /Antineoplastic agents/

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Spill kits containing all materials needed to clean up spills of hazardous drugs should be assembled or purchased. These kits should be readily available in all areas where hazardous drugs are routinely handled. If hazardous drugs are being prepared or administered in a nonroutine area (home setting or unusual patient-care area), a spill kit should be obtained by the drug handler. The kit should include two pairs of disposable gloves (one outer pair of utility gloves and one inner latex pair); low-permeability, disposable protective garments (coveralls or gown and shoe covers); safety glasses or splash goggles; respirator; absorbent, plastic-backed sheets or spill pads; disposable toweling; at least 2 sealable thick plastic hazardous waste disposal bags (prelabeled with an appropriate warning label); a disposable scoop for collecting glass fragments; and a puncture-resistant container for glass fragments. All individuals who routinely handle hazardous drugs must be trained in proper spill management and cleanup procedures. Spills and breakages must be cleaned up immediately according to the following procedures. If the spill is not located in a confined space, the spill area should be identified and other people should be prevented from approaching and spreading the contamination. Wearing protective apparel from the spill kit, workers should remove any broken glass fragments and place them in the puncture-resistant container. Liquids should be absorbed with a spill pad; powder should be removed with damp disposable gauze pads or soft toweling. The hazardous material should be completely removed and the area rinsed with water and then cleaned with detergent. The spill cleanup should proceed progressively from areas of lesser to greater contamination. The detergent should be thoroughly rinsed and removed. All contaminated materials should be placed in the disposal bags provided and sealed and transported to a designated containment receptacle. Spills occurring in the biohazard cabinet should be cleaned up immediately; a spill kit should be used if the volume exceeds 150 ml or the contents of one drug vial or ampule. If there is broken glass, utility gloves should be worn to remove it and place it in the puncture-resistant container located in the biohazard cabinet. The biological safety cabinet, including the drain spillage trough, should be thoroughly cleaned. If the spill is not easily and thoroughly contained, the biological safety cabinet should be decontaminated after cleanup. If the spill contaminates the high efficiency particulate air filter, use of the biological safety cabinet should be suspended until the cabinet has been decontaminated and the high efficiency particulate air filter replaced. /Antineoplastic agents/|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ If hazardous drugs are routinely prepared or administered in carpeted areas, special equipment is necessary to remove the spill. Absorbent powder should be substituted for pads or sheets and left in place on the spill for the time recommended by the manufacturer. The powder should then be picked up with a small vacuum unit reserved for hazardous drug cleanup. The carpet should then be cleaned according to usual procedures. The vacuum bag should be removed and discarded or cleaned, and the exterior of the vacuum cleaner should be washed with detergent and rinsed before being covered and stored. The contaminated powder should be discarded into a sealable plastic bag and segregated with other contaminated waste materials. Alternatively, inexpensive wet or dry vacuum units may be purchased for this express use and used with appropriate cleaners. All such units are contaminated, once used, and must be cleaned, stored, and ultimately discarded /properly/ ... The circumstances and handling of spills should be documented. Health-care personnel exposed during spill management should also complete an incident report or exposure form. /Antineoplastic agents/

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Accidental contamination of the health-care environment, resulting in exposure of personnel, patients, visitors, and family members to hazardous substances, is prevented by maintaining the physical integrity and security of packages of hazardous drugs. 1. Access to all areas where hazardous drugs are stored is limited to specified authorized staff. 2. A method should be present for identifying to personnel those drugs that require special precautions (eg, cytotoxics). One way to accomplish this is to apply appropriate warning labels to all hazardous drug containers, shelves, and bins where the drug products are stored. ... 3. A method of identifying, for patients and family members, those drugs that require special precautions in the home should be in place. This may be accomplished in the health-care setting, by providing specific labeling for discharge medications, along with written instructions. 4. Methods for identifying shipping cartons of hazardous drugs should be required from manufacturers and distributors of these drugs. 5. Written procedures for handling damaged packages of hazardous drugs should be maintained. Personnel involved in shipping and receiving hazardous drugs should be trained in these procedures, including the proper use of protective garments and equipment. Damaged shipping cartons of hazardous drugs should be received and opened in an isolated area (eg, in a laboratory fume hood, if available, not in a vertical laminar airflow biological safety cabinet used for preparing sterile products). /Antineoplastic agents/|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Facilities (eg, shelves, carts, counters, and trays) for storing hazardous drugs are designed to prevent breakage and to limit contamination in the event of leakage. Bins, shelves with barriers at the front, or other design features that reduce the chance of drug containers falling to the floor should be used. Hazardous drugs requiring refrigeration should be stored separately from nonhazardous drugs in individual bins designed to prevent breakage and to contain leakage. /Antineoplastic agents/|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Until the reproductive risks (or lack thereof) associated with handling hazardous drugs within a safety program have been substantiated, staff who are pregnant or breast-feeding should be allowed to avoid contact with these drugs. Policies should be in effect that provide these individuals with alternative tasks or responsibilities if they so desire. /Antineoplastic agents/|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ The pharmacy should provide access to information on toxicity, treatment of acute exposure (if available), chemical inactivators, solubility and stability of hazardous drugs (including investigational agents) used in the workplace. /Antineoplastic agents/|For more Preventive Measures (Complete) data for HISTRELIN (19 total), please visit the HSDB record page.

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Methods for transporting hazardous drugs to the health-care setting should be consistent with environmental protection and national or local regulations for transporting hazardous substances. When hazardous drugs are being transported to the home-care setting, appropriate containers (eg, lined cardboard boxes) and procedures should be used to prevent breakage and contain leakage. ... The drugs must be securely capped or sealed and properly packaged and protected during transport to reduce further the chance of breakage and spillage in a public area such as a corridor or elevator. /Antineoplastic agents/

Histrelin has been associated with serum enzyme elevations during therapy in rates similar to those of other GnRH analogues. The serum enzyme elevations are generally mild, asymptomatic and resolve even without dose adjustment or drug discontinuation. ALT elevations above 3 times the upper limit of normal occur in less than 1% of recipients. Histrelin has been linked to a single case of acute liver injury, but it was unclear from the report whether the episode was associated with jaundice or symptoms and other diagnoses remained possible. Thus, clinically apparent liver injury from histrelin may occur, but it is extremely rare and usually self-limited in course. There have been no episodes of acute liver failure, chronic hepatitis or vanishing bile duct syndrome associated with histrelin or other GnRH analogue therapy.

Histrelin is a gonadotropin releasing hormone (GnRH) agonist that is a potent inhibitor of production of testosterone (in men) and estrogen (in women) and is used predominantly to treat advanced prostate cancer. Histrelin is associated with a low rate of transient serum enzyme elevations during therapy, but has not been linked convincingly to cases of clinically apparent acute liver injury.

Antineoplastic Agents

Gonadotropin-Releasing Hormone agonist|/Histrelin/ is indicated in the palliative treatment of advanced prostate cancer. /Included in US product label/|/Histrelin/ is a gonadotropin releasing hormone (GnRH) agonist indicated for the treatment of children with central precocious puberty (CPP). /Included in US product label/

/Histrelin is contraindicated in patients with/ known hypersensitivity to histrelin or any ingredient in the formulation, other gonadotropin-releasing hormone (GnRH) agonists, or GnRH.|Like other GnRH agonists, histrelin causes a transient increase in serum testosterone concentrations during the first week of treatment. 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) may occur during the first few weeks of therapy.|Cases of ureteral obstruction and spinal cord compression, which may contribute to paralysis with or without fatal complications, have been reported with GnRH agonists. Patients with metastatic vertebral lesions and/or urinary tract obstruction should be closely observed during the first few weeks of therapy. If spinal cord compression or renal impairment develops, standard treatment of these complications should be instituted.|Anaphylactic reactions have been reported with synthetic gonadotropin-releasing hormone (GnRH) or GnRH agonists.|For more Drug Warnings (Complete) data for HISTRELIN (16 total), please visit the HSDB record page.

Histrelin acetate is not active when given orally.|Following subcutaneous insertion of a histrelin acetate implant in patients with advanced prostate cancer, peak serum concentrations of histrelin occurred at a median of 12 hours; the drug is delivered continuously at a rate of 50-60 ug daily over 12 months.|Following subcutaneous insertion of one Vantas (histrelin implant) 50 mg implant in advanced prostate cancer patients (n = 17), peak serum concentrations of 1.10 +/- 0.375 ng/mL (mean +/- SD) occurred at a median of 12 hours.|The average rate of subcutaneous drug release from 41 implants assayed for residual drug content was 56.7 +/- 7.71 ug/day over the 52 week dosing period.|For more Absorption, Distribution and Excretion (Complete) data for HISTRELIN (8 total), please visit the HSDB record page.

An in vitro drug metabolism study using human hepatocytes identified a single histrelin metabolite resulting from C-terminal dealkylation. Peptide fragments resulting from hydrolysis are also likely metabolites.

The mean terminal half-life of the drug following subcutaneous injection of a single 500-ug dose was approximately 3.92 hours in healthy men.

Histrelin acetate is a synthetic nonapeptide analog of gonadotropin-releasing hormone (GnRH, luteinizing hormone-releasing hormone [LHRH], gonadorelin).|Histrelin is a potent inhibitor of gonadotropin secretion when given continuously in therapeutic doses. After initial administration of histrelin, there is a transient surge in circulating concentrations of luteinizing hormone (LH), follicle-stimulating hormone (FSH), and gonadal steroids (testosterone and dihydrotestosterone in males). Following chronic and continuous administration of histrelin (generally, 2-4 weeks after initiation of therapy), a sustained decrease in LH and FSH secretion and a marked reduction in serum testosterone concentrations are observed. Reductions in serum testosterone concentrations in males receiving histrelin are comparable to those achieved after surgical castration (i.e., less than 50 ng/dL).|Histrelin acetate, an LH-RH agonist, acts as a potent inhibitor of gonadotropin secretion when given continuously in therapeutic doses. Both animal and human studies indicate that following an initial stimulatory phase, chronic, subcutaneous administration of histrelin acetate desensitizes responsiveness of the pituitary gonadotropin which, in turn, causes a reduction in testicular steroidogenesis. In humans, administration of histrelin acetate results in an initial increase in circulating levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), leading to a transient increase in concentration of gonadal steroids (testosterone and dihydrotestosterone in males). However, continuous administration of histrelin acetate results in decreased levels of LH and FSH. In males, testosterone is reduced to castrate levels. These decreases occur within 2 to 4 weeks after initiation of treatment.|The possible direct effect of gonadotropin-releasing hormone (GnRH) and a potent GnRH agonist [( imBzl )-D- His6 -Pro9-NEt]-GnRH on basal and human chorionic gonadotropin (hCG)-stimulated progesterone, androstenedione, and estradiol production by cultured human luteal cells was examined. Luteal cells from the early or midluteal phase of the menstrual cycle responded to hCG stimulation with two to fivefold increases in steroid production in both short-term (4 hours) and long-term (up to 144 hours) culture in chemically defined medium without serum. After 48 hours in this system, levels of androstenedione and estradiol were very low, and progesterone was the predominant steroid produced. The addition of GnRH or a potent GnRH agonist to the medium had no effect on either basal or hCG-stimulated steroid secretion. When luteal cells were cultured longer (for up to 10 days) in the presence of serum, GnRH agonist caused no significant alteration of either basal or hCG-stimulated progesterone production. Collectively, these results support the conclusion that GnRH and its potent agonist do not act directly on human corpora luteal cells to modulate steroidogenesis.

Maintain an open airway and assist ventilation if necessary. Treat coma, seizures, hypotension, and arrhythmias if they occur. Treat nausea and vomiting with metoclopramide and fluid loss caused by gastroenteritis with intravenous crystalloid fluids. Bone marrow depression should be treated with the assistance of an experienced hematologist or oncologist. Extravasation: Immediately stop the infusion and withdraw as much fluid as possible by negative pressure on the syringe. ... /For/ decontamination administer activated charcoal orally if conditions are appropriate. Gastric lavage is not necessary after small to moderate ingestions if activated charcoal can be given promptly. Because of the rapid intracellular incorporation of these agents, dialysis and other extracorporeal removal procedures are generally not effective. /Antineoplastic agents/|Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/|Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/|Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

/EPIDEMIOLOGY STUDIES/ Concern has been raised that children with central precocious puberty (CPP) are prone to the development of obesity. Here /investigators/ report longitudinal height, weight, and body mass index (BMI) data from 96 girls and 14 boys with CPP before, during, and after GnRH agonist (GnRHa) administration. Skinfold thickness (n = 46) and percent body fat by dual energy x-ray absorptiometry (n = 21) were determined in subsets for more accurate assessment of body composition and to validate the use of the BMI SD score as an index of body fatness in these subjects. Before the initiation of therapy (PRE), the girls with CPP had a mean BMI SD score for chronological age (CA) of 1.1+/-0.1 and for bone age (BA) of 0.1+/-0.1. By the end of the study, 12-24 months after the discontinuation of GnRHa, the mean BMI SD score was 0.9+/-0.1 for CA and 0.6+/-0.1 for BA. At the visit when GnRHa was discontinued, 41% and 22% of the girls had a BMI SD score for CA more than the 85th and 95th percentiles, respectively, indicating that obesity was present at a high rate among our subjects; the BMI SD score for CA at the PRE visit was its strongest predictor. Indeed, 86% of the girls with BMI SD score for CA above the 85th percentile when GnRHa was discontinued also had BMI SD score for CA above the 85th percentile at the PRE visit. The proportion of boys with elevated BMI SD score for CA was also high. Fifty-four percent and 31% of the SD scores were greater than the 85th and 95th percentiles after 36 months of GnRHa therapy; the BMI SD score for CA PRE had been above the 85th percentile in 71% of these overweight subjects. ...|/OTHER TOXICITY INFORMATION/ Cases of ureteral obstruction and spinal cord compression, which may contribute to paralysis with or without fatal complications, have been reported with GnRH agonists. Patients with metastatic vertebral lesions and/or urinary tract obstruction should be closely observed during the first few weeks of therapy. If spinal cord compression or renal impairment develops, standard treatment of these complications should be instituted.

((im bzl)-D-His(6), Pro(9)-NEt)LHRH

Histrelin acetate formulations: Parenteral implants, 50 mg histrelin acetate, Vanta by Valera.

Synthetic nonapeptide agonist analog of LH-RH.

Analyte: histrelin; matrix: solutions; procedure: high-performance liquid chromatography with ultraviolet detection at 210 nm and 280 nm

Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients