Leuprorelin acetate

1269.46

1268.666626

37JNS02E7V

DTXSID7049009

C1319

Fluffy solid

2937190090

466.34000

3.44730

fluffy solid

150-155°C

1720.5ºC at 760 mmHg

994.3ºC

−20°C

Specific optical rotation: -31.7 deg @ 25 °C/D (c=1 in 1% HOAc)

NONH for all modes of transport

2

22-24/25

OH6390000

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 LEUPROLIDE (8 total), please visit the HSDB record page.

Plosker GL, Brogden RN; Leuprorelin: Review of its Pharmacology and Therapeutic Use in Prostatic Cancer, Endometriosis and Other Sex Hormone-Related Disorders; Drugs 48 (Dec): 930-67 (1994)

|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 40 companies from 3 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 LEUPROLIDE (19 total), please visit the HSDB record page.

Leuprolide has been associated with mild serum enzyme elevations during therapy in 3% to 5% of patients, but values above 3 times the upper limit of normal are rare, being reported in less than 1% of recipients. The serum enzyme elevations during leuprolide therapy have generally been transient and asymptomatic, resolving even with drug continuation and rarely requiring dose modification or discontinuation. Despite use for several decades, leuprolide has not been linked to convincing cases of clinically apparent liver injury. Routine monitoring of patients for liver test abnormalities is not recommended.

OBJECTIVE: To assess the efficacy of combining sodium etidronate with low doses of the 19-nor-testosterone progestin norethindrone or using high doses of norethindrone alone as prophylaxis against the vasomotor instability and bone density loss induced by GnRH agonists alone. METHODS: Eleven patients enrolled in this randomized study received the long-acting GnRH agonist leuprolide acetate 3.75 mg intramuscularly every 4 weeks for 24 weeks. Six patients (group I) self-administered sodium etidronate 400 mg/day orally for 14 days followed by calcium carbonate 500 mg/day orally for the next 42 days during three 56-day cycles. This regimen was supplemented by norethindrone 2.5 mg/day orally. Five patients (group II) self-administered norethindrone 10 mg/day orally. Two sets of controls were used. Group III consisted of ten previously reported patients who received the same GnRH agonist only. Group IV comprised 12 regularly cycling untreated controls. Bone mineral density, vasomotor symptoms, circulating estrogens, and lipids were assessed serially. RESULTS: The significant vasomotor instability (P < .Ol) and bone mineral density loss (-4.8 +/- 0.9%; P < .05) experienced by patients in group III was prevented in those ln groups I and II despite maintenance of a persistent hypoestrogenlc state. Bone density changes ln groups I and II were similar to those in untreated controls (group IV). Persistent decreases in high-density lipoprotein (HDL) cholesterol (P = .005) and increases in the low-density lipoprotein-to-HDL ratio (P < .05) were noted only in group II patients receiving supplemental high-dose norethindrone. CONCLUSION: These preliminary data suggest that the addition of cyclic sodium etidronate in combination with low-dose norethindrone to GnRH agonists is an effective means of ameliorating the hypoestrogenic side effects induced by GnRH agonist alone.

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ The danger to health-care personnel from handling a hazardous drug stems from a combination of its inherent toxicity and the extent to which workers are exposed to the drug in the course of carrying out their duties. This exposure may be through inadvertent ingestion of the drug on foodstuffs (eg, workers' lunches), inhalation of drug dusts or droplets or direct skin contact. /Antineoplastic agents/

Drug: Leuprolideacetate

Leuprolide is a parenterally administered, gonadotropin releasing hormone (GnRH) agonist which causes an inhibition of estrogen and androgen production and is used predominantly to treat advanced prostate cancer. Leuprolide has been associated with a modest rate of serum enzyme elevations during therapy, but has not been convincingly linked to instances of clinically apparent acute liver injury.

Antineoplastic Agents

Antineoplastic Agents, Hormonal; Fertility Agents, Female|Leuprolide is indicated for the palliative treatment of advanced prostatic cancer, especially as an alternative to orchiectomy or estrogen administration. /Included in US product labeling/|Leuprolide is indicated for management of endometriosis, including pain relief and reduction of endometriotic lesions. /Included in US product labeling/|Leuprolide is about 30 times more active than natural gonadotropin-releasing hormone ... and 100 times more active than gonadorelin.|For more Therapeutic Uses (Complete) data for LEUPROLIDE (15 total), please visit the HSDB record page.

Patients sensitive to other synthetic gonadotropin-releasing hormone analogs may also be sensitive to leuprolide.|In males: Suppression of testosterone secretion results in impairment of fertility. Although it is not known whether fertility is restored after leuprolide is withdrawn, reversal of fertility suppression does occur after withdrawal of similar analogs.|Leuprolide is not recommended during pregnancy. Because the effects on fetal mortality would logically result from the hormonal effects of leuprolide, it can be concluded that there is a risk of spontaneous abortion if leuprolide is administered during pregnancy.|It is not known whether leuprolide passes into breast milk. However, because of potential adverse effects in the infant, breast-feeding is usually not recommended during treatment with leuprolide.|For more Drug Warnings (Complete) data for LEUPROLIDE (14 total), please visit the HSDB record page.

Antineoplastic agents that are used to treat hormone-sensitive tumors. Hormone-sensitive tumors may be hormone-dependent, hormone-responsive, or both. A hormone-dependent tumor regresses on removal of the hormonal stimulus, by surgery or pharmacological block. Hormone-responsive tumors may regress when pharmacologic amounts of hormones are administered regardless of whether previous signs of hormone sensitivity were observed. The major hormone-responsive cancers include carcinomas of the breast, prostate, and endometrium; lymphomas; and certain leukemias. (From AMA Drug Evaluations Annual 1994, p2079) (See all compounds classified as Antineoplastic Agents, Hormonal.)|Compounds which increase the capacity to conceive in females. (See all compounds classified as Fertility Agents, Female.)

Bioavailablity after intramuscular injection of the depot formulation is estimated to be about 90%.|The pharmacological effects of leuprolide acetate depot microspheres were studied in rats and dogs following subcutaneous and intramuscular injection. After injection the microspheres provided similar linear drug release and sustained serum drug levels for 3 months. Persistent suppression of serum luteinizing hormone, follicle stimulating hormone in rats, and testosterone in rats and dogs for over 16 wk was achieved with microspheres at a dose of 100 ug/kg/day in rats and 25.6 ug/kg/day in dogs. Responses upon periodic challenge tests revealed that a single injection of microspheres dramatically suppressed the function of the pituitary-gonadal system for 15 wks in rats. The growth of genital organs was also suppressed dose-dependently for over 3 months. It was concluded that persistent pharmacological effects are obtained with an injection of leuprolide 3-month depot microspheres.|The effect of formulation adjuvants on the absorption of leuprolide acetate after intraduodenal injection and oral administration to male castrate rats is reported. Absorption was low, approximately 0.01% and 0.08% by oral and intraduodenal administration, respectively, compared with intravenous controls. An aqueous formulation and a water-in-oil emulsion of a lipophilic salt, a decane sulfonic acid derivative of leuprolide gave intraduodenal bioavailabilities of approximately 0.2% and 1% respectively. Evaluation of formulation effects on the oral absorption of the drug showed that lipophilicity, surfactant, and vehicle properties significantly affected intraduodenal absorption of leuprolide. Absolute bioavailability of the drug in typical emulsion systems ranged from approximately 3-10% and represented an improvement of about 100-fold in gastrointestinal bioavailability of this peptide. The implications of these findings relative to the effect of formulation adjuvants on oral absorption of leuprolide and other peptides following intraduodenal administration are discussed.|The bioavailability of leuprolide acetate was studied in rats and in healthy males (ages 19-39 yr) after inhalation and intranasal administration, compared with intravenous and subcutaneous injection. Intranasal bioavailability in rats was significantly increased by alpha-cyclodextrin, eidetic acid, and solution volume. Intra-animal variability was 30-60% and absorption ranged from 8 to 46% compared with intravenous controls. In humans, the subcutaneous injection was 94% bioavailable compared with intravenous. Intranasal bioavailability averaged 2.4%, with significant intersubject variability. Plasma peak concentrations for one and 3 mg dosages were 0.24-1.6 and 0.1-11 ng/ml, respectively. Mean plasma peak concentrations of one mg aerosol and 2 mg suspension aerosols, respectively. Bioavailability of suspension aerosols was fourfold greater than that of the solution aerosol. /Leuprolide acetate/

Like naturally occurring luteinizing hormone-releasing hormone, initial or intermittent administration of leuprolide stimulates release of luteinizing hormone and follicle-stimulating hormone from the anterior pituitary.|Luteinizing hormone and follicle-stimulating hormone release from the anterior pituitary transiently increases testosterone concentration in males. However, continuous administration of leuprolide in the treatment of prostatic carcinoma suppresses secretion of gonadotropin-releasing hormone, with a resultant fall in testosterone concentrations and a "medical castration".|Initial stimulation of gonadotropins form the anterior pituitary is followed by prolonged suppression. Gonadotropin release from the anterior pituitary transiently increases estrone and estradiol concentrations in females. However, continuous administration of leuprolide in the treatment of endometriosis produces a fall in estrogens to postmenopausal levels. As a consequence of suppression of ovarian function, both normal and ectopic endometrial tissues become inactive and atrophic. As a result, amenorrhea occurs.

A case of rapid uterine enlargement and subsequent urinary retention occurring 7 days after GnRH-a administration in a 53-year-old premenopausal woman with myomas is presented. Rapid uterine enlargement was presumed to be caused by hyperestrogenism shortly after GnRH-a administration. The patient was treated with an indwelling Foley catheter for 2 weeks until the uterus decreased to near baseline dimensions. The patient's uterus continued to decrease in size during the 12 weeks she received GnRH-a and she underwent an uneventful total abdominal hysterectomy and bilateral salpingectomy/oophorectomy after donating 2 units of autologous blood. This case illustrates that adverse effects from GnRH-a treatment may be caused by the transient increase in ovarian steroid secretion shortly after drug administration.|OBJECTIVES: This is the first multicenter, double-blind randomized clinical trial that compares a depot gonadotropin-releasing hormone agonist with danazol in the treatment of endometriosis. Efficacy results have been previously reported; this report focuses on safety data. STUDY DESIGN: A total of 270 patients from 22 centers were randomly selected to receive either leuprolide acetate depot (3.75 mg injected monthly) or danazol (800 mg administered orally daily). Safety outcomes included adverse effects, clinical laboratory changes, and bone mineral density changes. RESULTS: Most patients receiving either drug reported side effects, most of which were related to the hypoestrogenism of leuprolide (e.g., vasodilatation) and relative hyperandrogenism of danazol (e.g., weight gain). Similarly small numbers of patients dropped out of the two treatment groups because of the side effects encountered. Leuprolide depot caused a greater decrease in bone density; preliminary data suggest a return to baseline on cessation of the drug. Danazol was associated with alteration of serum lipids, specifically a significant decrease ln high-density lipoprotein. CONCLUSIONS: Although side effects were commonly reported in both groups, the drugs were similarly safe in terms of the absence of serious complications and the results of cessation of therapy. Side effects were largely reversible on discontinuation of medication. More longitudinal data are necessary before the possibility of long-term risks can be excluded, especially as they pertain to bone mineral density and lipids.|The non-surgical treatment of endometriosis involves hormone therapy that either affects the lesions directly, or indirectly inhibits endometrial proliferation and induces atrophy through estrogen deprivation, or through a combination of these effects. The medications used to treat endometriosis are progestins (e.g. norethindrone, medroxyprogesterone acetate), oral contraceptives (e.g. estrogen-progesterone acetate), androgens and their derivatives (e.g., danazol, gestrinonel, and gonadotropin-releasing hormone (GnRH) agonists (e.g., buserelin, leuprolide acetate, nafarelin, goserelin, tryptorelin). Agents such as GnRH agonists that produce sustained and prolonged hypoestrogenemia, similar to the postmenopausal hypogonadal state, can have a significant negative impact on trabecular bone mass. Initial studies with dual-photon absorptiometry were unable to detect any appreciable bone loss with GnRH agonists. Later studies, however, have invariably found significant bone loss as early as 3 months after the start of treatment. Quantitated computerized tomography always shows significant trabecular bone loss of the vertebrae and hip with GnRH agonists. Depot preparations appear to produce more marked loss than daily intranasal sprays. Recovery of bone loss may take 6-12 months after the end of therapy, with considerable individual variations. /Leuprolide acetate/|The histologic features of the testes of 4 patients with disseminated prostatic carcinoma who received at least one yr of daily treatment with leuprolide (6-D-leucine-9-(N-ethyl-L-prolinamide)-10-deglycinamide-luteinizing hormone-releasing factor) and subsequently underwent bilateral orchiectomy were examined. In marked contrast to the testes from 5 control patients, the testes of these leuprolide treated patients demonstrated absence of spermatogenesis, Leydig cell hypoplasia, and Leydig cell inactivity.|For more Human Toxicity Excerpts (Complete) data for LEUPROLIDE (6 total), please visit the HSDB record page.

A 43818

Prepn: M. Fujino et al., Ger. Pat. 2,446,005 (1975 to Takeda), C.A. 83, 10895y (1975); R.L. Gendrich et al, US pat 4,005,063 (1977 to Abbott).

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