What is letrozole

Letrozole is a nonsteroidal aromatase inhibitor which effectively blocks estrogen synthesis in postmenopausal women and is used as therapy of estrogen receptor positive breast cancer, usually after surgical resection and after failure of tamoxifen (Nolvadex, Soltamox). Letrozole is often given to women who have been taking tamoxifen for 5 years. Aromatase is the enzyme responsible for the conversion of testosterone to estrone (E1) and of androstenedione to estradiol (E2). Highest levels of aromatase are found in the ovary and placenta, which are the major sources of estrogen in premenopausal women. However, aromatase is also found in other tissues, such as liver, kidney, adrenals, brain, muscle and subcutaneous fat where it is also active in producing estrogens, although at low levels. These tissues are the major source of estrogen in postmenopausal women. Inhibitors of aromatase were developed to block the synthesis of estrogen in the peripheral tissues and, thus, as antiestrogen therapy of breast cancer in postmenopausal women. Letrozole is a nonsteroidal, specific aromatase inhibitor which has little or no effect on adrenal glucocorticoid or mineralocorticoid synthesis. Letrozole was approved for use in postmenopausal women with estrogen receptor positive breast cancer in the United States in 1997. Current indications are as adjuvant therapy in postmenopausal women with estrogen sensitive breast cancer, given in daily oral doses for up to five years. Letrozole is also indicated as a first line treatment of estrogen receptor positive (or unknown), locally advanced or metastatic breast cancer in postmenopausal women.

Letrozole lowers estrogen levels in postmenopausal women, which may slow the growth of certain types of breast tumors that need estrogen to grow in the body.

Letrozole comes as a tablet to take by mouth once a day with or without food. Letrozole is available in 2.5 mg tablets in generic forms and under the brand name Femara. The recommended dose is one tablet daily. Take letrozole at around the same time every day. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take letrozole exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

You may need to take letrozole for several years or longer. Continue to take letrozole even if you feel well. Do not stop taking letrozole without talking to your doctor.

Ask your pharmacist or doctor for a copy of the manufacturer’s information for the patient.

Letrozole common side effects include hot flashes, night sweats, fatigue, dizziness, headache, somnolence, abdominal discomfort, nausea, arthralgias, weight gain and rash. Uncommon, but potentially severe side effects include decrease in bone mineral density, increases in serum cholesterol levels and embryo-fetal toxicity.

Letrozole special precautions

Before taking letrozole:

• tell your doctor and pharmacist if you are allergic to letrozole, any other medications, or any of the ingredients in letrozole tablets. Ask your pharmacist for a list of the ingredients.
• tell your doctor and pharmacist what other prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention any of the following: medications that contain estrogen such as hormone replacement therapy (HRT) and hormonal contraceptives (birth control pills, patches, rings, and injections); raloxifene (Evista); and tamoxifen (Nolvadex).
• tell your doctor if you have high cholesterol, osteoporosis (condition in which the bones are fragile and break easily), or liver disease.
• you should know that letrozole should only be taken by women who have experienced menopause and cannot become pregnant. However, if you are pregnant or breast-feeding, you should tell your doctor before you begin taking this medication. Letrozole may harm the fetus.
• you should know that letrozole may make you dizzy, drowsy, or tired than they are normally. Do not drive a car or operate machinery until you know how this medication affects you.
• Using letrozole while you are pregnant can harm your unborn baby. Use an effective form of birth control to keep from getting pregnant during treatment with this medicine and for at least 3 weeks after your last dose. If you think you have become pregnant while using the medicine, tell your doctor right away.
• Letrozole may decrease bone mineral density when used for a long time. A low bone mineral density can cause weak bones or osteoporosis. If you have any questions about this, talk to your doctor.
• Letrozole may increase the amount of cholesterol and fat in the blood. If this happens, your doctor may give you medicine to lower the cholesterol and fat in the blood.

Letrozole and alcohol

Letrozole may make you dizzy, drowsy, or tired than they are normally. Do not drive or do anything else that could be dangerous until you know how this medicine affects you.

Letrozole uses

Letrozole is used treat early breast cancer in women who have experienced menopause (change of life; end of monthly menstrual periods) and who have had other treatments, such as radiation or surgery to remove the tumor. It is also used to treat early breast cancer in women who have experienced menopause and who have already been treated with a medication called tamoxifen (Nolvadex) for 5 years. Letrozole is also used in women who have experienced menopause as a first treatment of breast cancer that has spread within the breast or to other areas of the body or in women whose breast cancer has worsened while they were taking tamoxifen. Letrozole is in a class of medications called nonsteroidal aromatase inhibitors. It works by decreasing the amount of estrogen produced by the body. This can slow or stop the growth of some types of breast cancer cells that need estrogen to grow.

Letrozole for fertility

Letrozole is also used off label to treat infertility in women. Letrozole decreases the amount of estrogen a woman makes, stimulating her ovaries to release eggs. Based on the American College of Obstetricians and Gynecologists guidelines (ACOG) and an international guideline published by the Australian National Health and Medical Research Council (NHMRC) in partnership with the American Society of Reproductive Medicine (ASRM) and the European Society of Human Reproductions and Embryology (ESHRE), letrozole is the preferred first-line pharmacologic treatment for ovulation induction in females with polycystic ovary syndrome (PCOS) and anovulatory infertility when no other causes of infertility are present ¹.

• Patients take letrozole toward the end of their menstrual cycle for around 5 days.
• A 2015 study by researchers in the Reproductive Medicine Network found that about 19% of couples with unexplained infertility went on to have a live birth after using letrozole for 4 months. This rate was slightly lower than the live birth rate for couples using clomiphene (23%) ².
• Other studies have found that letrozole may work better than clomiphene in women with polycystic ovary syndrome (PCOS) ³.

The gonadotropin-stimulating action of letrozole has been used off-label in the treatment of patients with ovulatory dysfunction, such as polycystic ovary syndrome (PCOS) and to increase follicular recruitment in women who are already ovulatory ⁴. If prescribing letrozole, the starting dose is 2.5 mg/day for 5 days typically starting on day 3, 4, or 5 after a spontaneous menses or progestin-induced bleed. If ovulation does not occur, the dose can be increased to 5 mg/day for 5 days with a maximum dose of 7.5 mg/day. Doses higher than 7.5 mg/day have been associated with thinning of the endometrium as seen with clomiphene citrate ⁵.

For women with unexplained infertility (regular menstrual cycles, all known male or female factors excluded), a large multicenter study demonstrated that ovulation induction with letrozole resulted in lower live birth rates and multiple gestation rates compared with gonadotropins. Although letrozole and clomiphene citrate demonstrated similar live birth and multiple gestation rates, the study was not powered to detect a difference between these two medications ⁶. Further trials are needed to determine which is better for the treatment of unexplained infertility.

Letrozole also has been used for ovulation induction for women with polycystic ovary syndrome (PCOS). In an early meta-analysis of four published trials that included 662 women with PCOS, pregnancy rates were similar between women treated with clomiphene citrate and women treated with letrozole ⁷. However, in a more recent randomized controlled trial, letrozole was more effective than clomiphene citrate with a higher live birth rate (27.5% versus 10.1%), and cumulative ovulation rate (61.7% versus 48.3%) ⁸. In women with a BMI (body mass index) greater than or equal to 30.3, ovulation induction with letrozole resulted in a higher live birth rate when compared with clomiphene citrate ⁸. Therefore, for women with PCOS, and a BMI greater than 30, letrozole should be considered first-line therapy for ovulation induction because of the increased live birth rate compared with clomiphene citrate. Although ovulation induction is very effective, it is important to recognize that for obese women with PCOS, lifestyle changes that result in weight loss should be strongly encouraged. A 7% decrease in BMI may result in spontaneous ovulation and avoid the need for therapy for ovulation induction ⁹. For an obese patient, lifestyle changes should always be encouraged; weight changes as little as 5% of body weight may improve reproductive function ⁹.

A number of studies have shown that letrozole appears to have a role in the treatment of clomiphene-resistant patients; 50–80% of clomiphene nonresponders have been shown to ovulate after using letrozole ¹⁰. Some of these studies have raised concerns about this off-label use because letrozole may disrupt the normal aromatase activity in tissues during early fetal development and can be potentially teratogenic if administered inadvertently during early pregnancy. Although studies have demonstrated that newborns whose mothers achieved pregnancy by using letrozole for ovulation induction showed no significant difference in rates of congenital malformations compared with those newborns whose mothers used the clomiphene citrate treatment ¹¹, long-term data are needed to confirm this finding. It should be noted that letrozole and clomiphene citrate are pregnancy category X. When prescribing letrozole for ovulation induction, patients should be counseled that unlike clomiphene citrate, letrozole is not approved by the U.S. Food and Drug Administration (FDA) for ovulation.

How to take letrozole for fertility

It should be noted that letrozole is pregnancy FDA category X.  Pregnancy Category X means studies in animals or humans have demonstrated fetal abnormalities and/or there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience, and the risks involved in use of the drug in pregnant women clearly outweigh potential benefits.

The starting letrozole dose is 2.5 mg/day for 5 days typically starting on day 3, 4, or 5 after a spontaneous menses or progestin-induced bleed. If ovulation does not occur, the dose can be increased to 5 mg/day for 5 days with a maximum dose of 7.5 mg/day. Doses higher than 7.5 mg/day have been associated with thinning of the endometrium as seen with clomiphene citrate ⁵.

Letrozole for Endometriosis

Aromatase inhibitors are a promising therapeutic option that may help manage endometriosis-associated pain in combination therapy with progestins. The recent demonstration that aromatase is expressed at higher levels in endometriosis implants compared with normal endometrium has led to pilot studies using anastrozole co-administered with progestins in patients with endometriosis resistant to conventional medical and surgical therapies ¹². Efficacy has been demonstrated for relief of pelvic pain when aromatase inhibitors were combined with combination oral contraceptives ¹³, or when aromatase inhibitors were given concomitantly with a GnRH agonist ¹⁴. The combination of letrozole and norethisterone acetate was more effective than norethisterone acetate alone in reducing pain and deep dyspareunia in women with rectovaginal endometriosis ¹⁵. A systematic review of the use of aromatase inhibitors for the treatment of pain associated with severe endometriosis concluded that aromatase inhibitors significantly reduced pain compared with GnRH agonists alone ¹⁶. The use of aromatase inhibitors with add-back progestin or oral contraceptives does not appear to be associated with significant bone loss after 6 months of treatment and, based on the available data, may be suitable for long-term (greater than 6 months) use ¹⁷.

Letrozole dosage

Adult dose for breast cancer

Uses:

• Adjuvant treatment of postmenopausal women with hormone receptor positive early breast cancer.
• Extended adjuvant treatment of early breast cancer in postmenopausal women who have received 5 years of adjuvant tamoxifen therapy.
• First-line treatment of advanced breast cancer in postmenopausal women with hormone receptor positive or unknown locally advanced or metastatic breast cancer; second-line treatment of advanced breast cancer in postmenopausal women with disease progression following antiestrogen therapy.

Dosage: 2.5 mg orally once a day

Duration of therapy:

• Adjuvant and Extended Adjuvant Settings: Optimal duration is unknown; discontinue treatment at relapse.
• Advanced Disease: Until tumor progression is evident.

Infertility/ovulation stimulation in anovulatory females with polycystic ovarian syndrome (PCOS) (off-label use)

Off-label use:

• Infertility/ovulation stimulation in anovulatory females with polycystic ovarian syndrome (PCOS)

Oral:

• Initial dose: 2.5 mg once daily for 5 days, starting on day 3, 4, or 5 following menses or progestin induced bleed; may increase to 5 mg/day for 5 days in subsequent cycles if ovulation does not occur.
• Maximum dose: 7.5 mg/day (ACOG 194 2018; ACOG 738 2018; Legro 2014). Dosing for up to 5 cycles was used in 1 study (Legro 2014).

Renal dose adjustments

• CrCl 10 mL/min or greater: No adjustment recommended.
• CrCl less than 10 mL/min: Data not available.

Dialysis

This drug is anticipated to be dialyzable; however, no dose adjustment guidelines have been reported.

Liver dose adjustments

• Mild to Moderate Hepatic Impairment: No adjustment recommended.
• Severe Hepatic Impairment with Cirrhosis: 2.5 mg orally every other day.
• Noncirrhotic with Elevated Bilirubin: Data not available.

What should I do if I forget a dose?

Take the missed dose as soon as you remember it. However, if it is almost time for the next dose, skip the missed dose and continue your regular dosing schedule. Do not take a double dose to make up for a missed one.

Letrozole side effects

Letrozole may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:

• hot flushes
• night sweats
• nausea
• vomiting
• loss of appetite
• constipation
• diarrhea
• heartburn
• stomach pain
• changes in weight
• muscle, joint, or bone pain
• excessive tiredness
• headache
• dizziness
• weakness
• swelling of the hands, feet, ankles, or lower legs
• difficulty falling asleep or staying asleep
• vaginal bleeding or irritation
• breast pain
• hair loss
• blurry vision

Some side effects can be serious. If you experience any of these symptoms call your doctor immediately or get emergency medical treatment:

• chest pain
• rash
• hives
• itching
• difficulty breathing
• unusual bleeding or bruising
• pain in the upper right part of the stomach
• yellowing of the skin or eyes
• flu-like symptoms
• pain, warmth, or heaviness in the back of the lower leg
• severe headache
• sudden speech problems
• sudden weakness or numbness of an arm or leg

Letrozole may cause or worsen osteoporosis. It can decrease the density of your bones and increase the chance of broken bones and fractures. Talk to your doctor about the risks of taking this medication.

Letrozole may cause other side effects. Call your doctor if you have any unusual problems while taking letrozole.

References

1. ACOG Committee Opinion Number 738, June 2018. Aromatase Inhibitors in Gynecologic Practice. https://www.acog.org/Clinical-Guidance-and-Publications/Committee-Opinions/Committee-on-Gynecologic-Practice/Aromatase-Inhibitors-in-Gynecologic-Practice
2. Clomiphene more effective than letrozole for achieving pregnancy, NIH funded study finds. https://www.nichd.nih.gov/newsroom/releases/092315-treatment-infertility
3. New treatment increases pregnancy rate for women with infertility disorder. https://www.nih.gov/news-events/news-releases/new-treatment-increases-pregnancy-rate-women-infertility-disorder
4. Malloch L, Rhoton-Vlasak A. An assessment of current clinical attitudes toward letrozole use in reproductive endocrinology practices. Fertil Steril 2013;100:1740–4
5. Al-Fozan H, Al-Khadouri M, Tan SL, Tulandi T. A randomized trial of letrozole versus clomiphene citrate in women undergoing superovulation. Fertil Steril 2004;82:1561–3
6. Diamond MP, Legro RS, Coutifaris C, Alvero R, Robinson RD, Casson P, et al. Letrozole, gonadotropin, or clomiphene for unexplained infertility. NICHD Reproductive Medicine Network. N Engl J Med 2015;373:1230–40
7. Casper RF. Letrozole versus clomiphene citrate: which is better for ovulation induction? Fertil Steril 2009;92:858–9.
8. Legro RS, Brzyski RG, Diamond MP, Coutifaris C, Schlaff WD, Casson P, et al. Letrozole versus clomiphene for infertility in the polycystic ovary syndrome. NICHD Reproductive Medicine Network [published erratum appears in N Engl J Med 2014;317:1465]. N Engl J Med 2014;371:119–29
9. Huber-Buchholz MM, Carey DG, Norman RJ. Restoration of reproductive potential by lifestyle modification in obese polycystic ovary syndrome: role of insulin sensitivity and luteinizing hormone. J Clin Endocrinol Metab 1999;84:1470–4
10. Quintero RB, Urban R, Lathi RB, Westphal LM, Dahan MH. A comparison of letrozole to gonadotropins for ovulation induction, in subjects who failed to conceive with clomiphene citrate. Fertil Steril 2007;88:879–85
11. Tulandi T, Martin J, Al-Fadhli R, Kabli N, Forman R, Hitkari J, et al. Congenital malformations among 911 newborns conceived after infertility treatment with letrozole or clomiphene citrate. Fertil Steril 2006;85:1761–5
12. Ailawadi RK, Jobanputra S, Kataria M, Gurates B, Bulun SE. Treatment of endometriosis and chronic pelvic pain with letrozole and norethindrone acetate: a pilot study. Fertil Steril 2004;81:290–6
13. Amsterdam LL, Gentry W, Jobanputra S, Wolf M, Rubin SD, Bulun SE. Anastrazole and oral contraceptives: a novel treatment for endometriosis. Fertil Steril 2005;84:300–4
14. Soysal S, Soysal ME, Ozer S, Gul N, Gezgin T. The effects of post-surgical administration of goserelin plus anastrozole compared to goserelin alone in patients with severe endometriosis: a prospective randomized trial. Hum Reprod 2004;19:160–7
15. Ferrero S, Camerini G, Seracchioli R, Ragni N, Venturini PL, Remorgida V. Letrozole combined with norethisterone acetate compared with norethisterone acetate alone in the treatment of pain symptoms caused by endometriosis. Hum Reprod 2009;24:3033–41
16. Nawathe A, Patwardhan S, Yates D, Harrison GR, Khan KS. Systematic review of the effects of aromatase inhibitors on pain associated with endometriosis (published erratum appears in BJOG 2008;115:1069). BJOG 2008;115:818–22
17. Attar E, Bulun SE. Aromatase inhibitors: the next generation of therapeutics for endometriosis? Fertil Steril 2006;85:1307–18