レトロゾール

Pharmaceuticals

Pharmaceuticals -> Listed in ZINC15

2.5

1.84

Freely soluble in dichloromethane; slightly soluble in ethanol; practically insoluble in water

7.99e-02 g/L

Breast Feeding; Lactation; Milk, Human; Antineoplastic Agents; Aromatase Inhibitors

FDA approved drugs -> Active ingredient

FDA approved drugs -> Active ingredient

Pharmaceuticals

Ovulation inducers

184-185 °C

181-183 °C

184 - 185 °C

Danger

H315 (29.5%): Causes skin irritation [Warning Skin corrosion/irritation]

P203, P260, P264, P264+P265, P280, P302+P352, P305+P351+P338, P318, P319, P321, P332+P317, P337+P317, P362+P364, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 44 reports by companies from 16 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

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

/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/

/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/

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

/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 LETROZOLE (19 total), please visit the HSDB record page.

/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/

Because metabolism of letrozole is mediated by cytochrome P-450 (CYP) isoenzymes 3A4 and 2A6, agents that induce or inhibit these isoenzymes may alter the metabolism of the drug. Cimetidine, which inhibits hepatic microsomal enzymes, did not alter the pharmacokinetics of letrozole. Results of an in vitro study did not show inhibition of letrozole metabolism by diazepam.

Because estrogens may diminish the pharmacologic action of aromatase inhibitors, such as letrozole, these agents should not be used concomitantly.

Concomitant use of tamoxifen 20 mg daily and letrozole 2.5 mg daily reduced letrozole plasma concentrations by an average of 38%. In a separate study, no effect of letrozole on the pharmacokinetics of tamoxifen, its principal active metabolite, N-desmethyltamoxifen, or 4-hydroxytamoxifen was observed. Analysis of blood samples from both of these studies demonstrates similar degrees of estrogen suppression for letrozole alone and in combination with tamoxifen. ... The concomitant use of letrozole and tamoxifen is not recommended.

Twelve of 17 patients completed the core period of the trial in which 2.5 mg/day letrozole was administered alone for 6 weeks and in combination with 20 mg/day tamoxifen for the subsequent 6 weeks. Patients responding to treatment continued on the combination until progression of disease or any other reason for discontinuation. ... Marked suppression of estradiol, estrone, and estrone sulfate occurred with letrozole treatment, and this was not significantly affected by the addition of tamoxifen. However, plasma levels of letrozole were reduced by a mean 37.6% during combination therapy (P<0.0001), and this reduction persisted after 4-8 months of combination therapy. Letrozole is the first drug to be described in which this pharmacokinetic interaction occurs with tamoxifen. The mechanism is likely to be a consequence of an induction of letrozole-metabolizing enzymes by tamoxifen but was not further addressed in this study. It is possible that the antitumor efficacy of letrozole may be affected. Thus, sequential therapy may be preferable with these two drugs.

Serum enzymes are reported to be elevated in up to 1% of women treated with letrozole, but these elevations are usually mild, asymptomatic and self-limited, rarely requiring dose modification. There have been few published instances of clinically apparent liver injury associated with long term letrozole therapy. More frequent have been reports of cholestatic and hepatocellular liver injury associated with anastrozole and exemestane, typically arising after 1 to 4 months of therapy and presenting with jaundice. While cases have been severe, recovery is usually prompt once the agent is stopped. There have been no cases of severe jaundice, acute liver failure, chronic hepatitis or vanishing bile duct syndrome attributed to letrozole use. Unlike tamoxifen, letrozole has not been associated with development of fatty liver disease, steatohepatitis or cirrhosis.

Letrozole is a nonsteroidal competitive inhibitor of the aromatase enzyme system; it inhibits the conversion of androgens to estrogens. In adult nontumor- and tumorbearing female animals, letrozole is as effective as ovariectomy in reducing uterine weight, elevating serum Leuteinizing hormone (LH), and causing the regression of estrogen-dependent tumors. In contrast to ovariectomy, treatment with letrozole does not lead to an increase in serum (folicile stimulating hormone (FSH). Letrozole selectively inhibits gonadal steroidogenesis but has no significant effect on adrenal mineralocorticoid or glucocorticoid synthesis. Organic nitriles decompose into cyanide ions both in vivo and in vitro. Consequently the primary mechanism of toxicity for organic nitriles is their production of toxic cyanide ions or hydrogen cyanide. Cyanide is an inhibitor of cytochrome c oxidase in the fourth complex of the electron transport chain (found in the membrane of the mitochondria of eukaryotic cells). It complexes with the ferric iron atom in this enzyme. The binding of cyanide to this cytochrome prevents transport of electrons from cytochrome c oxidase to oxygen. As a result, the electron transport chain is disrupted and the cell can no longer aerobically produce ATP for energy. Tissues that mainly depend on aerobic respiration, such as the central nervous system and the heart, are particularly affected. Cyanide is also known produce some of its toxic effects by binding to catalase, glutathione peroxidase, methemoglobin, hydroxocobalamin, phosphatase, tyrosinase, ascorbic acid oxidase, xanthine oxidase, succinic dehydrogenase, and Cu/Zn superoxide dismutase. Cyanide binds to the ferric ion of methemoglobin to form inactive cyanmethemoglobin. (L97)

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ There is no method available for routine monitoring of personnel for evidence of hazardous drug exposure. Tests for the presence of mutagens or chromosomal damage are not drug specific and are of value only in controlled studies. Chemical analysis of urine for the presence of hazardous drugs at the sensitivity level needed to detect occupational exposure is limited to a few drugs and is not yet commercially available. /Antineoplastic agents/

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ There is no method available for routine monitoring of personnel for evidence of hazardous drug exposure. Tests for the presence of mutagens or chromosomal damage are not drug specific and are of value only in controlled studies. Chemical analysis of urine for the presence of hazardous drugs at the sensitivity level needed to detect occupational exposure is limited to a few drugs and is not yet commercially available. /Antineoplastic agents/

/SIGNS AND SYMPTOMS/ Peripheral thromboembolic events (including venous thrombosis, thrombophlebitis, portal vein thrombosis, and pulmonary embolism), cardiovascular events (including angina, myocardial infarction, myocardial ischemia, and coronary heart disease), and cerebrovascular events (including transient ischemic attacks, thrombotic or hemorrhagic strokes, and development of hemiparesis) occurred in 2% or less of patients receiving letrozole as first-line therapy. Among patients receiving second-line therapy, thromboembolic events occurred less frequently in patients receiving letrozole than in those receiving megestrol acetate (0.6 versus 4.7%). Chest pain was reported in 6-8% of patients receiving letrozole.

/SIGNS AND SYMPTOMS/ In one patient, pancytopenia occurred after approximately 5 months of letrozole therapy; transfusion with packed red blood cells was administered to increase the hemoglobin level, and leukocyte and platelet counts returned to normal levels within 2 weeks following discontinuance of the drug.

/CASE REPORTS/ /The authors/ describe a case of severe hematologic toxicity secondary to oral letrozole administration. In April 2001, oral letrozole therapy (one tablet, 2.5 mg daily) was prescribed to a 64-year-old female patient for locoregional breast cancer recurrence. No other drugs were concomitantly assumed, except enalapril, 10 mg daily since 1998, for mild hypertension. Patient history is as follows: malignancy was diagnosed in February 1999 and treated with radical mastectomy (postoperative tumor-node-metastasis staging pT2, pN0 M0). Adjuvant endocrine therapy with tamoxifen, 20 mg orally, was then administered on the basis of the positive estrogen-receptor status of tumor specimens. In March 2001, routine physical examination revealed the presence of a subcutaneous lesion (1.5 cm in diameter) at the site of previous surgical approach. Local treatment consisted of surgery followed by radiation therapy (total dose received: 44 Gy). Tamoxifen administration was therefore interrupted. In August 2001, the patient presented with symptoms of severe fatigue, subjective dizziness, headache, confusion, lethargy, moderate dyspnea, anorexia, and symptomatic palpitations. General physical examination revealed mucocutaneous pallor, hypotension (90/65 mmHg), sinus tachycardia (120/min), and mild peripheral edema. Abdominal and pulmonary examination were unremarkable. Blood count showed pancytopenia, with a hemoglobin level of 6.3 g/dL, a leukocyte count of 2,000/uL-1 (granulocyte count of 800/uL-1), and a platelet count of 47,000/uL-1. Therefore, the patient was immediately hospitalized. ... After transfusion of three units of packed RBCs, hemoglobin levels (9.3 g/dL) increased and asthenia and related symptoms improved. In the hypothesis that the pancytopenia could have been related to the assumption of the aromatase inhibitor, administration of letrozole was discontinued, while maintaining antihypertensive therapy. Platelet and leukocyte counts returned to normal within 2 weeks after discontinuation of treatment with letrozole. Bone marrow biopsy performed 6 days after withdrawal of letrozole showed hyperplasia of the erythrocyte, granulocyte, and thrombocyte lineages. Subsequent blood cell counts performed every month for 3 months were substantially within the normal range.

/EPIDEMIOLOGY STUDIES/ The incidence of congenital malformations among offspring of mothers who conceived with clomiphene citrate (CC) or with letrozole treatment for infertility /was examined/. ... 911 newborns from women who conceived following CC or letrozole treatment. ... Overall, congenital malformations and chromosomal abnormalities were found in 14 of 514 newborns in the letrozole group (2.4%) and in 19 of 397 newborns in the CC group (4.8%). The major malformation rate in the letrozole group was 1.2% (6/514) and in the CC group was 3.0% (12/397). One newborn in the letrozole group was found to have a ventricular septal defect (0.2%) compared to 4 newborns in the CC group (1.0%). In addition, the rate of all congenital cardiac anomalies was significantly higher (P: 0.02) in the CC group (1.8%) compared to the letrozole group (0.2%).

Drug Induced Liver Injury Rank (DILIrank 2.0)

Letrozole

vLess-DILI-concern

2

Warnings & precautions

DOI:10.1016/j.drudis.2016.02.015

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ A study in mice given doses of 0.6 to 60 mg per kg of body weight (mg/kg) per day by oral gavage for up to 2 years found a dose-related increase in the incidence of benign ovarian stromal tumors. When the high-dose group was excluded because of low survival rates, a significant trend in the incidences of hepatocellular adenoma and carcinoma was shown in females.[Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2006., p. 1902]

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ A study in rats given oral doses of 0.1 to 10 mg/kg per day for up to 2 years found an increase in the incidence of benign ovarian stromal tumors with 10 mg/kg per day. Ovarian hyperplasia was also seen in female rats given 0.1 mg/kg or more per day.[Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2006., p. 1902]

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Studies in rabbits found fetotoxicity at doses of 0.02 mg/kg. Fetal anomalies included incomplete ossification of the skull, sternebrae, and fore- and hindlegs.[Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2006., p. 1902]

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Fertility studies in animals have not been done. However, in male and female mice, rats, and dogs receiving repeated dosing with 0.6, 0.1, and 0.03 mg/kg, respectively, letrozole caused sexual inactivity in females and atrophy of the reproductive tract in males and females.[Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2006., p. 1902]

For more Non-Human Toxicity Excerpts (Complete) data for LETROZOLE (7 total), please visit the HSDB record page.

/SRP:/ 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/

/SRP:/ 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/

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

L02BG04

L - Antineoplastic and immunomodulating agents

QL - Antineoplastic and immunomodulating agents

L02BG04

Letrozole is an aromatase inhibitor used in the treatment of breast cancer. Aromatase inhibitors work by inhibiting the action of the enzyme aromatase, which converts androgens into estrogens by a process called aromatization. As breast tissue is stimulated by estrogens, decreasing their production is a way of suppressing recurrence of the breast tumor tissue. Letrozole is a third generation type II aromatase inhibitor used to treat estrogen dependant breast cancers. It has a long duration of action as it has a half life of over 42 hours in breast cancer patients. Patients should be counselled regarding the risk of interstitial lung disease, pneumonitis, QT prolongation, elevated transaminase levels, neutropenia, and embryo-fetal toxicity.

Letrozole is a non-steroidal type II aromatase inhibitor. It blocks the active site, and therefore the electron transfer chain of CYP19A1. This competitive inhibition prevents the conversion of androgens to estrogen. This action leads to a reduction in uterine weight and elevated leuteinizing hormone. In postmenopausal women, the action of aromatase is responsible for the majority of estrogen production. With reduced availability of estrogen, estrogen-dependant tumors regress. Third generation aromatase inhibitors do not significantly affect cortisol, aldosterone, and thyroxine levels.

Letrozole is a nonsteroidal competitive inhibitor of the aromatase enzyme system; it inhibits the conversion of androgens to estrogens. In adult nontumor- and tumor-bearing female animals, letrozole is as effective as ovariectomy in reducing uterine weight, elevating serum LH, and causing the regression of estrogen-dependent tumors. In contrast to ovariectomy, treatment with letrozole does not lead to an increase in serum FSH. Letrozole selectively inhibits gonadal steroidogenesis but has no significant effect on adrenal mineralocorticoid or glucocorticoid synthesis. Letrozole inhibits the aromatase enzyme by competitively binding to the heme of the cytochrome P450 subunit of the enzyme, resulting in a reduction of estrogen biosynthesis in all tissues. Treatment of women with letrozole significantly lowers serum estrone, estradiol and estrone sulfate and has not been shown to significantly affect adrenal corticosteroid synthesis, aldosterone synthesis, or synthesis of thyroid hormones.

The terminal elimination half life of letrozole is approximately 42h in healthy volunteers, but longer in breast cancer patients.

Letrozole has a terminal elimination half-life of about 2 days.

Letrozole is metabolized by CYP2A6 to a ketone analog metabolite, which is further metabolized by CYP3A4 and CYP2A6 to 4,4'-(hydroxymethylene)dibenzonitrile. 4,4'-(hydroxymethylene)dibenzonitrile is glucuronidated by UGT2B7.

The primary elimination pathway of letrozole consists of slow metabolism in the liver to a pharmacologically inactive carbinol metabolite (4,4'-methanol-bisbenzonitrile) followed by renal excretion of the glucuronide conjugate of this metabolite. Formation of the carbinol metabolite is mediated by cytochrome P-450 (CYP) isoenzymes 3A4 and 2A6, and formation of the ketone analog of the carbinol metabolite is mediated by isoenzyme 2A6.

Primarily hepatic via CYP3A4 and CYP2A6. Letrozole inhibits the aromatase enzyme by competitively binding to the heme of the cytochrome P450 subunit of the enzyme, resulting in a reduction of estrogen biosynthesis in all tissues. It is metabolized slowly to an inactive metabolite whose glucuronide conjugate is excreted renally, representing the major clearance pathway. Half Life: 2 days

7LKK855W8I

LETROZOLE

Established Pharmacologic Class [EPC] - Aromatase Inhibitor

Mechanisms of Action [MoA] - Aromatase Inhibitors

Letrozole is an Aromatase Inhibitor. The mechanism of action of letrozole is as an Aromatase Inhibitor.

LETROZOLE

Substances that inhibit or prevent the proliferation of NEOPLASMS.

Compounds that inhibit AROMATASE in order to reduce production of estrogenic steroid hormones.

Letrozole is 99.9% orally bioavailable. A 2.5mg oral dose reaches a Cmax of 104nmol/L with a Tmax of 8.10h, and an AUC of 7387nmol\*h/L.

Letrozole is 90% eliminated in the urine. 75% of the dose is recovered as a glucuronide metabolite, 9% is in the form of the ketone and carbinol metabolites, and 6% is recovered in urine as unchanged letrozole.

The volume of distribution of letrozole is 1.87L/kg.

The average clearance after a single dose of letrozole was 1.52L/h and at steady state was 1.20L/h.

Letrozole is rapidly and completely absorbed from the GI tract following oral administration. Steady-state plasma concentrations of the drug are reached in 2-6 weeks in patients receiving letrozole 2.5 mg daily. Letrozole exhibits slightly nonlinear pharmacokinetics with repeated administration of 2.5 mg daily, with steady-state plasma concentrations 1.5-2 times higher than predicted based on plasma concentrations measured after a single dose. However, continuous accumulation of letrozole does not occur, and steady-state concentrations are maintained over extended periods of daily drug administration. Food does not affect the oral absorption of the drug.

Letrozole has a large volume of distribution of approximately 1.9 L/kg. Letrozole is weakly bound to plasma proteins.

Antineoplastic

THERAP CAT: Antineoplastic

Use (kg; approx.) in Germany (2009): >25

For the extended adjuvant treatment of early breast cancer in postmenopausal women who have received 5 years of adjuvant tamoxifen therapy. Also for first-line treatment of postmenopausal women with hormone receptor positive or hormone receptor unknown locally advanced or metastatic breast cancer. Also indicated for the treatment of advanced breast cancer in postmenopausal women with disease progression following antiestrogen therapy.