 | |
 | |
| Clinical data | |
|---|---|
| Trade names | Femara, others |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a698004 |
| License data | |
| Routes of administration | By mouth |
| Drug class | Aromatase inhibitor;Antiestrogen |
| ATC code | |
| Legal status | |
| Legal status | |
| Pharmacokinetic data | |
| Bioavailability | 99.9% |
| Protein binding | 60%, mainly to albumin |
| Metabolism | pharmacologically-inactive metabolites Bis(4-cyanophenyl)methanol and 4,4'-dicyanobenzophenone.[3] |
| Eliminationhalf-life | 2 days[3] |
| Excretion | Kidney[3] |
| Identifiers | |
| |
| CAS Number | |
| PubChemCID | |
| IUPHAR/BPS | |
| DrugBank |
|
| ChemSpider |
|
| UNII | |
| KEGG |
|
| ChEBI | |
| ChEMBL | |
| CompTox Dashboard(EPA) | |
| ECHA InfoCard | 100.200.357 |
| Chemical and physical data | |
| Formula | C17H11N5 |
| Molar mass | 285.310 g·mol−1 |
| 3D model (JSmol) | |
| |
| |
| (verify) | |
Letrozole, sold under the brand nameFemara among others, is anaromatase inhibitor medication that is used in the treatment ofbreast cancer forpost-menopausal women.[1]
It was patented in 1986 and approved for medical use in 1996.[4] In 2021, it was the 222nd most commonly prescribed medication in the United States, with more than 1 million prescriptions.[5][6] It is on theWorld Health Organization's List of Essential Medicines.[7]
Letrozole isindicated for adjuvant treatment of postmenopausal women with hormone receptor positive early breast cancer;[1] extended adjuvant treatment of postmenopausal women with early breast cancer who have received prior standard adjuvant tamoxifen therapy;[1] first and second-line treatment of postmenopausal women with hormone receptor positive or unknown advanced breast cancer.[1]
Letrozole is approved by the United StatesFood and Drug Administration (FDA) for the treatment of local or metastatic breast cancer that is hormone receptor positive or has an unknown receptor status in postmenopausal women.[8]
Tamoxifen is also used to treat hormonally-responsive breast cancer, but it does so by interfering with the estrogen receptor. However, letrozole is effective only in post-menopausal women, in whom estrogen is produced predominantly in peripheral tissues (i.e. in adipose tissue, like that of the breast) and a number of sites in the brain.[9] In pre-menopausal women, the main source of estrogen is from the ovaries not the peripheral tissues, and letrozole is ineffective.
In the BIG 1–98 Study, of post-menopausal women with hormonally-responsive breast cancer, letrozole reduced the recurrence of cancer, but did not change survival rate, compared to tamoxifen.[10][11]
Letrozole is recommended as the first-line medication for ovulation induction inpolycystic ovary syndrome. Compared toclomiphene (Clomid), it causes higher number of ovulation and live birth rates. It has the same rate of multiple pregnancies (such as twins),[12] and the same rate of miscarriages.[13] The use of letrozole is typically off-label, and some countries may not allowoff-label use.[12]
India banned the usage of letrozole in 2011, citing potential risks to infants[14] while in 2012, an Indian parliamentary committee said that their office of the drug controller had colluded with letrozole's makers to approve the drug for infertility in India. The committee also stated that letrozole's use for infertility was illegal worldwide.[15]
Studies have shown that the efficacy of first-trimestermisoprostol-only medical abortion can be improved by the addition of letrozole.[16][17][18]
Letrozole is considered aperformance enhancing drug by theWorld Antidoping Agency (WADA), as are otheraromatase inhibitors, because they may be used to counteract the side effects ofanabolic steroids. Letrozole itself is not a performance enhancer.[19]
Letrozole is contraindicated in women having a pre-menopausal hormonal status. Precautions are advised against becoming pregnant while using letrozole; on the loss of bone mineral density; on the increased level of cholesterol and fat in the blood; and on dizziness and against driving.[20] Breast feeding (lactation) is also counterindicated.[21]
The most common side effects are sweating,hot flushes,arthralgia (joint pain), andfatigue.[21]
Generally, side effects include signs and symptoms ofhypoestrogenism. There is concern that long term use may lead toosteoporosis,[22] which is why in certain patient populations such as post-menopausal women or osteoporotics,bisphosphonates may also be prescribed.[citation needed]
Letrozole inhibits the liver enzymeCYP2A6, and to a lesser extentCYP2C19,in vitro, but no relevant interactions with drugs likecimetidine andwarfarin have been observed.[21]
Letrozole is anorally active,nonsteroidal,selectivearomatase inhibitor and hence anantiestrogen. It preventsaromatase fromproducingestrogens bycompetitive,reversible binding to theheme of itscytochrome P450 unit. The action is specific, and letrozole does not reduce production ofcorticosteroids.[citation needed]
| Generation | Medication | Dosage | % inhibitiona | Classb | IC50c |
|---|---|---|---|---|---|
| First | Testolactone | 250 mg 4x/dayp.o. | ? | Type I | ? |
| 100 mg 3x/weeki.m. | ? | ||||
| Rogletimide | 200 mg 2x/dayp.o. 400 mg 2x/dayp.o. 800 mg 2x/dayp.o. | 50.6% 63.5% 73.8% | Type II | ? | |
| Aminoglutethimide | 250 mg mg 4x/dayp.o. | 90.6% | Type II | 4,500 nM | |
| Second | Formestane | 125 mg 1x/dayp.o. 125 mg 2x/dayp.o. 250 mg 1x/dayp.o. | 72.3% 70.0% 57.3% | Type I | 30 nM |
| 250 mg 1x/2 weeksi.m. 500 mg 1x/2 weeksi.m. 500 mg 1x/1 weeki.m. | 84.8% 91.9% 92.5% | ||||
| Fadrozole | 1 mg 1x/dayp.o. 2 mg 2x/dayp.o. | 82.4% 92.6% | Type II | ? | |
| Third | Exemestane | 25 mg 1x/dayp.o. | 97.9% | Type I | 15 nM |
| Anastrozole | 1 mg 1x/dayp.o. 10 mg 1x/dayp.o. | 96.7–97.3% 98.1% | Type II | 10 nM | |
| Letrozole | 0.5 mg 1x/dayp.o. 2.5 mg 1x/dayp.o. | 98.4% 98.9%–>99.1% | Type II | 2.5 nM | |
| Footnotes:a = Inpostmenopausal women.b = Type I:Steroidal,irreversible (substrate-binding site). Type II:Nonsteroidal,reversible (binding to and interference with thecytochrome P450hememoiety).c = Inbreast cancerhomogenates.Sources: See template. | |||||
The antiestrogen action of letrozole has been shown to be useful in pretreatment for termination of pregnancy, in combination withmisoprostol. It can be used in place ofmifepristone, which is expensive and unavailable in many countries.[23]
Letrozole is sometimes used as a treatment forgynecomastia, although it is probably most effective at this if caught in an early stage (such as in users ofanabolic steroids).[24][25][unreliable source?]
Some studies have shown that letrozole can be used to promote spermatogenesis in male patients with nonobstructiveazoospermia.[26]
Letrozole has also been shown to delay the fusing of thegrowth plates in mice.[27] When used in combination with growth hormone, letrozole has been shown effective in one adolescent boy with a short stature.[28]
Letrozole has also been used to treatendometriosis.[29]
Endometrial stromal sarcomas are hormonally sensitive tumors as it is represented that letrozole reduces serum estrogen levels. Letrozole is well-tolerated and is a good option for long-term management of this disease.[30] Also in a study onUterine myoma the volume was successfully reduced by use of an aromatase inhibitor. Rapid onset of action and avoidance of initial gonadotropin flare with an aromatase inhibitor.[29]
Letrozole has been documented to be safe and effective for improving height and pubertal outcomes in children living with constitutional delay in growth and puberty, and is better than testosterone with regard to improvement in testicular volume and delaying bone-age progression. This was documented in a meta-analysis published by Dutta et al. which analyzed data from 7 different randomized controlled trials.[31]
