Letrozole Tablets

Letrozole is a nonsteroidal oral aromatase inhibitor. It is used in postmenopausal women for the adjuvant treatment of early breast cancer, for extended adjuvant therapy after 5 years of tamoxifen, and for the treatment of advanced breast cancer. It is also used off-label for the treatment of infertility, idiopathic short stature in boys, and delayed puberty in boys. Unlike aminoglutethimide, an early aromatase inhibitor, letrozole does not inhibit adrenal steroid synthesis; therefore, glucocorticoid or mineralocorticoid replacement therapy is not necessary. The use of letrozole is contraindicated in pregnancy. Decreases in bone mineral density and increases in total cholesterol may occur; monitoring is recommended.

Letrozole is a highly specific nonsteroidal aromatase inhibitor, preventing the conversion of androgens to estrogens by competitively binding to the heme of the CYP450 subunit of the aromatase enzyme, resulting in a reduction of estrogen biosynthesis in all tissues. In adult nontumor- and tumor-bearing female animals, letrozole is as effective as ovariectomy in reducing uterine weight, elevating serum LH, and causing regression of estrogen-dependent tumors; however, unlike ovariectomy, letrozole treatment did not increase serum FSH. It selectively inhibits gonadal steroidogenesis but has no significant effect on adrenal mineralocorticoid or glucocorticoid synthesis. No clinically relevant changes were found in the plasma concentrations of cortisol, aldosterone, 11-deoxycortisol, 17-hydroxy-progesterone, ACTH, or in plasma renin activity among postmenopausal patients receiving a daily dose of letrozole 0.1 mg to 5 mg. An ACTH stimulation test performed after 6 and 12 weeks of treatment did not indicate any attenuation of aldosterone or cortisol production; glucocorticoid or mineralocorticoid supplementation is not necessary. Blockade of estrogen biosynthesis by letrozole did not lead to accumulation of androgenic precursors in healthy postmenopausal women. Plasma levels of LH and FSH were not affected by letrozole in patients, nor was thyroid function as evaluated by TSH, T3 uptake, and T4 levels.

In postmenopausal women, the principal source of circulating estrogens is from the conversion of adrenal and ovarian androgens (e.g., androstenedione and testosterone) to estrogens (estrone and estradiol) by aromatase. The suppression of estrogen biosynthesis in peripheral tissues and in the cancer tissue itself can thus be achieved by inhibiting the aromatase enzyme. Letrozole can reduce circulating estradiol, estrone, and estrone sulfate concentrations by 75% to 95% from baseline within 2 to 3 days.

In premenopausal women when used for ovarian stimulation, the inhibition of aromatase by letrozole may increase the release of FSH by blocking estradiol production. Normally, through negative feedback, estrogens decrease the release of FSH from the pituitary gland It is also theorized that the androgens, which would normally be converted to estrogens, may accumulate in the ovaries thereby increasing the sensitivity of ovarian follicles to FSH. Unlike clomiphene, letrozole does not deplete estrogen receptors, which may be important for inducing mono-ovulation and also for preventing the negative changes in the endometrium and cervical mucus associated with clomiphene therapy.

Letrozole is administered orally. It is weakly protein bound and has a large volume of distribution (approximately 1.9 L/kg). The major clearance pathway is slow metabolism to an inactive carbinol metabolite (4,4′-methanol-bisbenzonitrile), whose glucuronide conjugate is renally excreted. Approximately 90% of radiolabeled letrozole is recovered in urine: at least 75% as the glucuronide of the carbinol metabolite, about 9% as 2 unidentified metabolites, and 6% as unchanged drug. The terminal elimination half-life is about 2 days.

Affected cytochrome P450 isoenzymes: CYP3A4, CYP2A6

Letrozole is metabolized in human microsomes by CYP3A4 to the carbinol metabolite, while CYP2A6 formed both this metabolite and its ketone analog. In human liver microsomes, letrozole inhibited CYP2A6 and CYP2C19; however, the clinical significance of these findings is unknown.

Route-Specific Pharmacokinetics:

Oral Route: Letrozole is rapidly and completely absorbed from the gastrointestinal tract; absorption is not affected by food. Steady-state plasma concentrations are reached in 2 to 6 weeks, and are 1.5 to 2 times higher than predicted from the concentrations measured after a single dose, indicating a slight nonlinearity in the pharmacokinetics of the drug upon daily administration. These steady-state levels are maintained over extended periods, however, and continuous accumulation of letrozole does not occur. Daily doses of 0.1 mg to 5 mg of letrozole suppress plasma concentrations of estradiol, estrone, and estrone sulfate by 75% to 95% from baseline, with maximal suppression within 2 to 3 days. Suppression is dose related; estrogen suppression was maintained throughout treatment in all patients receiving greater than 0.5 mg.

Special Populations:

Hepatic Impairment: The mean AUC of letrozole was 37% higher in volunteers with moderate hepatic impairment compared to normal subjects in subjects with varying degrees of nonmetastatic liver dysfunction (e.g., cirrhosis, Child-Pugh A and B), but was still within the range seen in subjects without hepatic impairment. In a pharmacokinetic study, subjects with liver cirrhosis and severe hepatic impairment (Child Pugh C, including bilirubins 2 to 11 times the upper limit of normal with minimal to severe ascites) had a 2-fold increase in letrozole exposure (AUC) and 47% decrease in systemic clearance. The effect of hepatic impairment on letrozole exposure in noncirrhotic cancer patients with elevated bilirubin levels has not been determined.

Renal Impairment: There was no effect of renal function on the pharmacokinetics of single 2.5-mg doses of letrozole in a study of volunteers with varying renal function (24-hour CrCL, 9 to 116 mL/min). Additionally, steady-state plasma letrozole concentrations were not affected by renal impairment (CrCL 20 to 50 mL/min) in patient with advanced breast cancer (n = 347).

For adjuvant treatment of postmenopausal women with hormone receptor-positive early breast cancer

Oral dosage: Adult postmenopausal females: 2.5 mg PO once daily. The optimal duration of treatment is unknown, but the median treatment duration in clinical trials was 5 years; discontinue therapy at relapse. The Breast International Group (BIG) 1-98 study, which enrolled more than 8,000 patients, compared 4 study arms: letrozole for 5 years, tamoxifen for 5 years, letrozole for 2 years followed by tamoxifen (total 5 years of therapy), or tamoxifen for 2 years followed by letrozole (total 5 years of therapy). After a median follow-up of 25.8 months, letrozole significantly reduced the risk of recurrent disease compared with tamoxifen; the 5-year rate of disease-free survival was 87.4% versus 84.7%. The impact on overall survival was not statistically significant (91.8% vs. 90.9%).

For extended adjuvant treatment of early breast cancer in postmenopausal women who have received 5 years of adjuvant tamoxifen therapy

Oral dosage: Adult postmenopausal females: 2.5 mg PO once daily. The optimal duration of treatment in the extended adjuvant setting is not known, however the median duration of treatment in clinical trials was 5 years; discontinue treatment at tumor relapse. In a randomized, double-blind clinical trial (n = 5,100), treatment with letrozole for a median duration of 60 months significantly reduced the risk of breast cancer recurrence or contralateral breast cancer compared with placebo in postmenopausal women with receptor-positive or unknown primary breast cancer who were disease-free after 5 years of adjuvant treatment with tamoxifen. There was no significant difference in overall survival.

For first-line treatment of postmenopausal women with hormone receptor-positive or hormone receptor status unknown, locally advanced or metastatic breast cancer

Oral dosage: Adult postmenopausal females: 2.5 mg PO once daily until disease progression or unacceptable toxicity. In a large randomized, double-blind clinical trial, treatment with letrozole (n = 458) significantly improved median time to progression (9.4 months vs. 6 months) and objective response rate (32% vs. 21%) compared with tamoxifen (n = 454) in postmenopausal patients with locally advanced or metastatic breast cancer. The median duration of response was 18 months compared with 16 months, and overall survival was 35 months vs. 32 months, respectively. The improvement in median time to progression remained significant in patients who had received prior antiestrogen adjuvant therapy (8.9 months vs. 5.9 months) with an objective response rate of 26% compared with 8%, respectively.

For the treatment of advanced breast cancer in postmenopausal women with disease progression following antiestrogen therapy

Oral dosage: Adult postmenopausal females: 2.5 mg PO once daily until disease progression or unacceptable toxicity. In 6 small, noncomparative trials, 20% of advanced breast cancer patients, previously treated with at least antiestrogen therapy, who received letrozole 2.5 mg daily (n = 40) achieved an objective tumor response (complete or partial response). In a randomized controlled trial, patients with advanced breast cancer who had progressed on antiestrogen therapy and received letrozole 2.5 mg daily (n = 174) had an objective response rate (ORR) of 23.6% for a median duration not reached, compared with an ORR of 16.3% and a median duration of 561 days for megestrol acetate (n = 190); median survival was 730 days compared with 659 days, respectively. The ORR for letrozole (n = 185) was 18.4% for a median of 706 days compared with 12.3% for a median of 450 days for aminoglutethimide (n = 179) in a separate trial; median survival was 792 days versus 592 days, respectively.

Use letrozole with caution in patients with pre-existing cirrhotic hepatic disease; a dose reduction may be necessary. Exposure to letrozole was approximately doubled in subjects with biliary cirrhosis and severe hepatic impairment compared with healthy volunteers with normal liver function; the effect of hepatic impairment on letrozole exposure in noncirrhotic cancer patients with elevated bilirubin levels has not been determined.

Use letrozole with caution in patients with pre-existing osteoporosis, as use of letrozole has been associated with decreases in bone mineral density (BMD). Consider monitoring patients for signs and symptoms of osteoporosis, including decreased bone mineral density (BMD), during treatment with letrozole. Adjuvant treatment with letrozole resulted in a significantly larger decrease in lumbar spine (L2 to L4) BMD compared to tamoxifen in a safety study. The incidence of fractures and osteoporosis was also greater in the letrozole group compared with the tamoxifen group in the adjuvant treatment trial (BIG 1-98). In a separate BMD sub-study of the extended adjuvant trial (MA-17B), there was not a significant difference in the change from baseline in lumbar spine BMD in letrozole and placebo treated groups. However, the incidence of bone fractures and new osteoporosis was greater in patients treated with letrozole compared with placebo.

Use letrozole with caution in patients with pre-existing hypercholesterolemia; consider monitoring serum cholesterol levels during treatment. Hypercholesterolemia requiring lipid lowering therapy was reported more often in patients treated with letrozole compared with tamoxifen in the adjuvant therapy trial (BIG 1-98). An increase of greater than or equal to 1.5 times the upper limit of normal (ULN) in total cholesterol was also observed more often in letrozole-treated patients who had baseline total serum cholesterol within the normal range compared with those who received tamoxifen.

The safety and effectiveness of letrozole in children has not been established; however, letrozole has been used for 1 to 2 years to increase height in male children and adolescents with either idiopathic short stature or constitutional delayed puberty. In animal studies, letrozole administration for 12 weeks at exposures similar to the AUC in adult patients receiving the FDA-approved dose of 2.5 mg per day resulted in adverse skeletal / growth effects (bone maturation, bone mineral density) and neuroendocrine and reproductive developmental perturbations of the hypothalamic-pituitary axis in young (postnatal day 7) rats. Additionally, decreased fertility was accompanied by hypertrophy of the hypophysis and testicular changes that included degeneration of the seminiferous tubular epithelium and atrophy of the female reproductive tract. These changes were not reversible at clinically relevant exposures within 42 months of discontinuation.

Treatment with letrozole is contraindicated for use during pregnancy. Letrozole has been prescribed off-label as a fertility treatment because it suppresses estrogen and can promote ovulation; while the outcomes of pregnancies in one cohort study demonstrate a similar rate of miscarriage and ectopic pregnancy in women who took letrozole versus other drugs for ovarian stimulation,7 pregnancy should be avoided by females of reproductive potential during letrozole treatment and for at least 3 weeks after the last dose. Although there are no adequately controlled studies in pregnant women, letrozole can cause fetal harm or death when administered during pregnancy based on postmarketing reports, animal studies, and its mechanism of action. Women who are pregnant or who become pregnant while receiving letrozole should be apprised of the potential hazard to the fetus. In postmarketing reports, use of letrozole during pregnancy resulted in cases of spontaneous abortions and congenital birth defects; however, the data are insufficient to inform a drug-associated risk. Daily administration of letrozole to rats during organogenesis at doses approximately 0.01 times the maximum recommended human dose on a mg/m2 basis resulted in embryofetal toxicity including intrauterine mortality, increased resorptions and postimplantation loss, decreased numbers of live fetuses and fetal anomalies including absence and shortening of renal papilla, dilation of ureter, edema and incomplete ossification of frontal skull and metatarsals. Letrozole was also teratogenic to rats at the same dose, causing fetal domed head and cervical/centrum vertebral fusion. In rabbits, the same dose level resulted in intrauterine mortality, increased resorption, increased postimplantation loss, and decreased numbers of live fetuses. Fetal anomalies included incomplete ossification of the skull, sternebrae, and fore- and hind legs.

Counsel patients about the reproductive risk and contraception requirements during letrozole treatment. Letrozole can be teratogenic if taken by the mother during pregnancy. Females of reproductive potential should avoid pregnancy and use effective contraception during and for at least 3 weeks after treatment with letrozole. Females of reproductive potential should undergo pregnancy testing prior to initiation of letrozole. Women who become pregnant while receiving letrozole should be apprised of the potential hazard to the fetus. Although there are no data regarding the effect of letrozole on human fertility, male and female infertility has been observed in animal studies.

Due to the potential for serious adverse reactions in nursing infants from letrozole, advise women to discontinue breast-feeding during treatment and for 3 weeks after the final dose. It is not known whether letrozole is present in human milk, although many drugs are excreted in human milk.

Treatment with letrozole is contraindicated for use during pregnancy. Letrozole has been prescribed off-label as a fertility treatment because it suppresses estrogen and can promote ovulation; while the outcomes of pregnancies in one cohort study demonstrate a similar rate of miscarriage and ectopic pregnancy in women who took letrozole versus other drugs for ovarian stimulation, pregnancy should be avoided by females of reproductive potential during letrozole treatment and for at least 3 weeks after the last dose. Although there are no adequately controlled studies in pregnant women, letrozole can cause fetal harm or death when administered during pregnancy based on postmarketing reports, animal studies, and its mechanism of action. Women who are pregnant or who become pregnant while receiving letrozole should be apprised of the potential hazard to the fetus. In postmarketing reports, use of letrozole during pregnancy resulted in cases of spontaneous abortions and congenital birth defects; however, the data are insufficient to inform a drug-associated risk. Daily administration of letrozole to rats during organogenesis at doses approximately 0.01 times the maximum recommended human dose on a mg/m2 basis resulted in embryofetal toxicity including intrauterine mortality, increased resorptions and postimplantation loss, decreased numbers of live fetuses and fetal anomalies including absence and shortening of renal papilla, dilation of ureter, edema and incomplete ossification of frontal skull and metatarsals. Letrozole was also teratogenic to rats at the same dose, causing fetal domed head and cervical/centrum vertebral fusion. In rabbits, the same dose level resulted in intrauterine mortality, increased resorption, increased postimplantation loss, and decreased numbers of live fetuses. Fetal anomalies included incomplete ossification of the skull, sternebrae, and fore- and hind legs.

Due to the potential for serious adverse reactions in nursing infants from letrozole, advise women to discontinue breastfeeding during treatment and for 3 weeks after the final dose. It is not known whether letrozole is present in human milk, although many drugs are excreted in human milk.

Estrogens: (Severe) Estrogens, including hormonal contraceptives, could interfere competitively with the pharmacologic action of the aromatase inhibitors. The goal of aromatase inhibitor therapy is to decrease circulating estrogen concentrations and inhibit the growth of hormonally-responsive cancers. Estrogen therapy is not recommended during aromatase inhibitor treatment, due to opposing pharmacologic actions. Aromatase inhibitors (e.g., aminoglutethimide, anastrozole, exemestane, letrozole, testolactone, vorozole) exhibit their antiestrogenic effects by reducing the peripheral conversion of adrenally synthesized androgens (e.g., androstenedione) to estrogens through inhibition of the aromatase enzyme.

Prasterone, Dehydroepiandrosterone, DHEA (Dietary Supplements): (Major) Prasterone, dehydroepiandrosterone, DHEA is converted via hydrosteroid dehydrogenases and aromatase into androstenedione, testosterone, and estradiol by peripheral tissues. Prasterone or DHEA supplements should not be given concurrently with any aromatase inhibitors, as DHEA could interfere with the pharmacologic action of the aromatase inhibitor and compromise aromatase inhibitor effectiveness. Conversely, aromatase inhibitors (e.g., aminoglutethimide, anastrozole, exemestane, letrozole, testolactone, vorozole) could interfere with biotransformation of DHEA.

Prasterone, Dehydroepiandrosterone, DHEA (FDA-approved): (Major) Prasterone, dehydroepiandrosterone, DHEA is converted via hydrosteroid dehydrogenases and aromatase into androstenedione, testosterone, and estradiol by peripheral tissues. Prasterone or DHEA supplements should not be given concurrently with any aromatase inhibitors, as DHEA could interfere with the pharmacologic action of the aromatase inhibitor and compromise aromatase inhibitor effectiveness. Conversely, aromatase inhibitors (e.g., aminoglutethimide, anastrozole, exemestane, letrozole, testolactone, vorozole) could interfere with biotransformation of DHEA.

Tamoxifen: (Major) Coadministration of letrozole with tamoxifen is not recommended because the efficacy of the combination in the treatment of breast cancer has not been established. Additionally, tamoxifen reduced the plasma concentration of letrozole by 38% when the drugs were coadministered.

Cardiovascular adverse reactions have been reported with letrozole treatment. In a large randomized, double-blind clinical trial (BIG 1-98) of patients receiving adjuvant treatment for early breast cancer, myocardial infarction during treatment and within 30 days of discontinuation of therapy occurred in 1% of patients treated with letrozole (n = 2,448) compared with 0.5% of those who received tamoxifen (n = 2,447); after a median of 96 months, the incidence of myocardial infarction was 1.7% versus 1.1%, respectively. Myocardial ischemia was reported in 0.2% of letrozole-treated patients compared with 0.4% of those who received tamoxifen, while angina requiring surgery occurred in 1.4% versus 1.3% of patients, respectively; chest pain (unspecified) occurred in less than 5% of patients treated with letrozole. Other cardiovascular events occurred in 4.9% of letrozole-treated patients during therapy, and in 7% of patients after 96 months of follow-up. When used as extended adjuvant treatment after completion of 5 years of tamoxifen therapy in a separate clinical trial, the incidence of cardiovascular ischemic events was comparable between patients who received letrozole (n = 2,563) compared with placebo (n = 2,573) (6.8% vs. 6.5%); cardiovascular events during treatment or within 30 days of stopping treatment occurred in 9.8% of letrozole-treated patients compared with 7% of those who received placebo, while the rate was 14.4% versus 9.8% after 62 months of follow-up. Chest pain occurred in 6% to 8% of patients receiving letrozole for advanced breast cancer (n = 814), while cardiovascular events such as angina, myocardial infarction, myocardial ischemia, and coronary heart disease occurred in less than or equal to 2% of patients. Palpitations and sinus tachycardia were reported in a combined analysis of the first- and second-line metastatic trials and postmarketing experience.

In a large randomized, double-blind clinical trial (BIG 1-98) of patients receiving adjuvant treatment for early breast cancer, heart failure occurred in 1.1% of patients treated with letrozole (n = 2,448) compared with 0.6% of those who received tamoxifen (n = 2,447) during treatment and within 30 days of discontinuation of therapy; after a median of 96 months, the incidence of heart failure was 1.6% versus 1.4%, respectively. Edema was reported in 6.7% (grade 3 or 4, 0.1%) of patients in the letrozole arm compared with 6.5% (grade 3 or 4, less than 0.1%) of those who received tamoxifen. With extended adjuvant therapy with letrozole after completion of 5 years of tamoxifen therapy (n = 2,563), 18.4% (grade 3 or 4, 0.2%) of patients reported edema compared with 16.2% (grade 3 or 4, 0.2%) of those who received placebo. Peripheral edema occurred in 5% of patients receiving second-line therapy with letrozole for advanced breast cancer (n = 359) in another clinical trial. Heart failure was also reported in a combined analysis of the first- and second-line metastatic trials and postmarketing experiences with letrozole.

Hypertension has been reported in 5% to 8% (grade 3 or 4, 1.2% or less) of patients treated with letrozole across clinical trials.

Hypercholesterolemia has occurred in patients treated with letrozole in clinical trials. In a large randomized clinical trial (BIG 1-98), hypercholesterolemia occurred in 52.3% (grade 3 or 4, 0.4%) of patients treated with letrozole (n = 2,448) compared with 28.6% (grade 3 or 4, 0.1%) of those who received tamoxifen (n = 2,447), requiring lipid-lowering medications in 29% versus 20% of patients, respectively. An increase of greater than or equal to 1.5 times the upper limit of normal (ULN) in total cholesterol (generally nonfasting) occurred in 8.4% of letrozole-treated patients who had a normal baseline total serum cholesterol compared with 3.9% of those in the tamoxifen arm. In an adjuvant safety study (n = 263), 12% of patients receiving letrozole had at least one total cholesterol value of a higher CTCAE grade than baseline compared with 4% of those treated with tamoxifen. In an open-label adjuvant clinical trial, hypercholesterolemia occurred in 7.6% (grade 3 or 4, 0.1%) of letrozole-treated patients (n = 2,049). In the extended adjuvant setting after a median follow-up of 62 months, there was no significant difference between letrozole and placebo in total cholesterol or any lipid fraction (hypercholesterolemia: all grade, 15.6% vs. 15.5%; grade 3 or 4, less than 0.1% vs. 0.2%); general metabolic disorders including hypercholesterolemia occurred in 21.5% (grade 3 or 4, 0.9%) versus 20.9% (grade 3 or 4, 1.2%) of patients, respectively. Hypercholesterolemia occurred in 3% of patients receiving letrozole in the second-line advanced breast cancer setting in a separate clinical trial (n = 359).

Thromboembolic events have been reported with letrozole treatment. In a large randomized, double-blind clinical trial (BIG 1-98) of patients receiving adjuvant treatment for early breast cancer, cerebrovascular accident (CVA)/ transient ischemic attack (TIA) (stroke) during treatment and within 30 days of discontinuation of therapy occurred in 2.1% of patients treated with letrozole (n = 2,448) compared with 1.9% of those who received tamoxifen (n = 2,447); after a median of 96 months, the incidence of CVA/TIA was 3% versus 2.8%, respectively. A higher incidence of thromboembolic events (thromboembolism) was seen in patients treated with tamoxifen, both during study treatment (2.1% vs. 3.6%) and at a median follow-up of 96 months (3.2% vs. 4.6%). Peripheral thromboembolic events (including venous thrombosis, thrombo-phlebitis, portal vein thrombosis and pulmonary embolism) and cerebrovascular events (including TIA, thrombotic or hemorrhagic strokes and development of hemi-paresis) occurred in less than 2% of patients with advanced breast cancer who were treated with letrozole in a separate randomized trial (n = 455). Arterial thrombosis was reported in a combined analysis of the first- and second-line metastatic trials and postmarketing experiences.

Respiratory adverse reactions have been reported with letrozole therapy in clinical trials, including dyspnea (all grade, 5.5% to 18%; grade 3 or 4, 0.8%) and cough (grade 1 or 2, 5.2% to 13%). Chest wall pain occurred in 6% of patients treated with first-line letrozole for advanced breast cancer, and pleural effusion was reported in less than 5% of patients receiving second-line letrozole for advanced breast cancer.

Hyperbilirubinemia and jaundice were each identified in less than 5% of patients receiving adjuvant treatment with letrozole (n = 2,049) in a large randomized clinical trial. Additionally, elevated hepatic enzymes and hepatitis were reported in postmarketing experience with letrozole.

Gastrointestinal adverse reactions have been reported across clinical trials with letrozole, including weight gain (all grade, 2% to 12.9%; grade 3 or 4, less than or equal to 1.1%), nausea (all grade, 6.7% to 17%; grade 3 or 4, 0.1% to 0.3%), abdominal pain (less than or equal to 6%), weight loss (all grade, 5.7% to 7%; grade 3 or 4, less than or equal to 0.3%), diarrhea (all grade, 5% to 8%; grade 3 or 4, less than or equal to 0.5%), vomiting (all grade, 3.3% to 7%; grade 3 or 4, less than or equal to 0.1%), dyspepsia (less than or equal to 3%), constipation (all grade, 2% to 11.3%; grade 3 or 4, 0.1% to 0.2%), and anorexia (all grade, 0.8% to 5%; grade 3 or 4, less than 0.1%). In a combined analysis of the first- and second-line metastatic trials and postmarketing experiences, stomatitis, appetite stimulation, xerostomia, dysgeusia, and polydipsia were also reported.

Decreases in bone mineral density (BMD) have been reported with letrozole treatment. In a study evaluating the safety of letrozole in the adjuvant setting (n = 263), a median decrease in lumbar spine (L2 to L4) BMD of 4.1% occurred at 24 months in the letrozole arm compared with 0.3% in the tamoxifen arm; no patients with a normal BMD at baseline because osteoporotic over the 2 years of the safety study, and 1 patient with osteopenia at baseline (T score, -1.9) developed osteoporosis during the treatment period. The results for total hip BMD were similar, although the differences between the 2 treatments were less pronounced (4% vs. 6%, respectively). Bone fractures occurred in 10.2% of patients treated with letrozole (n = 2,448) compared with 7.2% of those who received tamoxifen (n = 2,447) during treatment and within 30 days of discontinuation of therapy in a large randomized clinical trial (BIG 1-98); after a median of 96 months, the incidence of bone fractures was 14.7% versus 11.4%, respectively. The incidence of osteoporosis in the letrozole arm was 5.1% to 10.9% (grade 3 or 4, 0.2% to 0.4%) and osteopenia was 3.6% to 9.9% (grade 3 or 4, less than or equal to 0.2%). The incidence of bone fractures at any time after randomization in an extended adjuvant treatment trial was 13.3% for letrozole and 7.8% for placebo at a median follow-up of 62 months. The incidence of new osteoporosis was 14.5% versus 7.8%, respectively. In the extended adjuvant study, clinical fractures occurred in 5.9% of patients who received letrozole (n = 2,563) compared with 5.5% of those who received placebo (n = 2,573). The overall incidence of osteoporosis was 6.9% in the letrozole arm, with 21.1% of patients treated with bisphosphonates; osteoporosis occurred in 5.5% of patients in the placebo arm, with bisphosphonates administered to 18.7%. Updated results from a BMD substudy in the extended adjuvant setting found that at 2 years, patients treated with letrozole had a median decrease from baseline of 3.8% in hip BMD compared to 2% in the placebo arm; changes from baseline in lumbar spine BMD in letrozole- and placebo-treated groups were not significantly different. In this substudy, new fractures occurred in 13.3% compared with 7.8% of patients, and new osteoporosis in 14.5% compared with 7.8% of patients, respectively. Fracture occurred in less than 5% of patients who received letrozole in the second-line advanced breast cancer setting (n = 359).

Musculoskeletal adverse reactions have been reported with letrozole therapy across clinical trials. In patients receiving letrozole as adjuvant (n = 4,497) or extended adjuvant (n = 2,563) therapy, these included arthralgia (all grade, 22% to 48.2%; grade 3 or 4, 1% to 3.9%), myalgia (all grade, 6.7% to 11.4%; grade 3 or 4, 0.3% to 0.8%), back pain (all grade, 5% to 10.3%; grade 3 or 4, 0.3% to 0.5%), bone pain (all grade, 5% to 6.7%; grade 3 or 4, 0.2% to 0.5%), pain in extremities (all grade, 4.2% to 8.2%; grade 3 or 4, 0.2% to 0.4%), arthritis (all grade, 6.7% or less; grade 3 or 4, 0.4% or less), musculoskeletal pain (all grade, 6% or less; grade 3 or 4, 0.3% or less), musculoskeletal stiffness (all grade, 5% or less; grade 3 or 4, 0.1% or less), and breast pain (all grade, 1.5% or less; grade 3 or 4, less than 0.1%). In patients receiving letrozole for advanced breast cancer (n = 814), pain (5%), bone pain (22%), musculoskeletal pain (21%), back pain (18%), arthralgia (8% to 16%), limb pain (10%), and breast pain (7%) were reported. Cancer pain was reported in a combined analysis of the first- and second-line metastatic trials and postmarketing experiences.

Psychiatric adverse reactions that have been reported with letrozole therapy in clinical trials include depression (all grade, 7.2% or less; grade 3 or 4, 0.8% or less), insomnia (all grade, 5.8% to 7.8%; grade 3 or 4, 0.3% or less), and anxiety (5% or less); psychiatric disorders in general (including insomnia) occurred in 12.5% (grade 3 or 4, 0.8%) of patients receiving extended adjuvant therapy with letrozole in a clinical trial. In a combined analysis of the first- and second-line metastatic trials and postmarketing experiences dysesthesia (including hypoesthesia/paresthesias), memory impairment, irritability, and nervousness were also reported.

Alopecia was reported in 3.4% to 6.2% (grade 3 to 4, less than or equal to 0.1%) of patients receiving adjuvant breast cancer treatment with letrozole in randomized clinical trials; radiation skin injury was also reported in less than or equal to 5.9% (grade 3 or 4, less than or equal to 0.5%) of letrozole-treated patients. In those receiving letrozole as second-line treatment for advanced breast cancer, rash (including erythematous rash (erythema), maculopapular rash, psoriaform rash, and vesicular rash) was reported in 5% and pruritus in 1% of patients; alopecia occurred in less than 5% of patients. Urticaria and xerosis were reported in a combined analysis of the first- and second-line metastatic trials and postmarketing experiences, while toxic epidermal necrolysis and erythema multiforme were both reported in postmarketing experience with letrozole.

Vaginal bleeding (all grade, 5.3% vs. 13.1%; grade 3 or 4, less than 0.1% vs. 0.3%), endometrial proliferation disorders (all grade, 0.3% to 0.6% vs. 1.8% to 3.5%; grade 3 or 4, 0% vs. 0.6%), ovarian cyst (all grade, 0.4% vs. 0.7%; grade 3 or 4, 0.2% vs. 0.2%), and other endometrial disorders (grade 1 or 2, less than 0.1% vs. 0.1%) occurred less frequently with letrozole (n = 2,448) compared with tamoxifen (n = 2,447) when administered as adjuvant therapy; there was also a higher incidence for tamoxifen regarding endometrial hyperplasia or cancer (0.3% vs. 2.9%). Vaginal irritation occurred more often in the letrozole arm (all grade, 4.6% vs. 3.1%; grade 3 or 4, less than 0.1% vs. less than 0.1%). Reproductive disorders occurred in 11.8% of patients who received extended adjuvant therapy with letrozole after completion of 5 years of tamoxifen (n = 2,563) compared with placebo (n = 2,573), including vaginal bleeding (all grade, 4.8% vs. 6.6%; grade 3 or 4, less than 0.1% vs. 0.2%) and vulvovaginal dryness (grade 1 or 2, 5.3% vs. 4.9%). A patient-reported measure that captured the impact of treatment on important symptoms associated with estrogen deficiency favored placebo for the sexual symptom domain. Vaginal discharge was also reported in a combined analysis of the first- and second-line metastatic trials and postmarketing experiences.

In a large, randomized clinical trial of patients receiving adjuvant therapy for breast cancer (BIG 1-98), a new primary malignancy occurred during treatment and within 30 days of discontinuation of therapy in 2.2% of patients treated with letrozole (n = 2,448) compared with 3.2% of those who received tamoxifen (n = 2,447); after a median of 96 months, the incidence of new primary malignancy was 5.3% versus 6.1%, respectively. Endometrial hyperplasia/cancer occurred in 0.3% versus 2.9% of patients during letrozole or tamoxifen therapy, respectively, and in 0.4% versus 2.9% of patients, respectively, after 96 months of follow-up. Lymphedema has been reported in 7% to 7.8% (grade 3 or 4, 0.2% or less) of patients treated with letrozole.

Cataracts were reported in 2% (grade 3 or 4, 0.7%) of patients receiving adjuvant therapy for early breast cancer with letrozole (n = 2,448) compared with 2.2% (grade 3 or 4, 0.7%) of those who received tamoxifen (n = 2,447) in a large randomized clinical trial (BIG 1-98). Cataracts and ocular irritation were also reported in a combined analysis of the first- and second-line metastatic trials and postmarketing experiences, while blurred vision was observed in postmarketing experience with letrozole.

Moderate decreases in lymphocyte counts (lymphopenia) of uncertain clinical significance were observed in some patients treated with letrozole 2.5 mg daily; this decrease was transient in about half of those affected. Thrombocytopenia occurred in 2 patients treated with letrozole, although the relationship to the study drug was unclear. Leukopenia was also reported in a combined analysis of the first- and second-line metastatic trials and postmarketing experiences with letrozole.

Infection was reported in 6.5% (grade 3 or 4, 1.6%) of patients receiving extended adjuvant treatment with letrozole after completion of 5 years of tamoxifen therapy (n = 2,563) compared with 6.3% (grade 3 or 4, 1.3%) of those who received placebo in a randomized clinical trial. In patients who received letrozole as first-line therapy for advanced breast cancer (n = 455), influenza was reported in 6% of patients compared with 4% of those who received tamoxifen; urinary tract infection occurred in 6% versus 3% of patients, respectively. Viral infections (not specified) were also reported in 6% of patients treated with letrozole as second-line therapy for advanced breast cancer (n = 359). Increased urinary frequency and fever were additionally reported in a combined analysis of the first- and second-line metastatic trials and postmarketing experiences with letrozole.

Spontaneous fetal abortion and congenital birth defects/teratogenesis have been reported in postmarketing experience with letrozole therapy.

Fatigue including lethargy, malaise, and asthenia occurred in 9.6% to 16.8% (grade 3 or 4, 0.2% to 0.4%) of letrozole-treated patients in 2 large randomized clinical trials of adjuvant therapy, while headache (all grade, 4.3% to 6.3%; grade 3 or 4, 0.1% to 0.3%) and dizziness (all grade, 3.4% to 4.6%; grade 3 or 4, 0.2% or less) were also reported with adjuvant letrozole therapy; less than 5% of patients treated with letrozole reported falls or vertigo. The incidence of asthenia was higher in the extended adjuvant clinical trial, occurring in 33.6% (grade 3 or 4, 0.6%) of patients treated with letrozole compared with 32.1% (grade 3 or 4, 0.3%) of those who received placebo; general disorders that included asthenia were reported in 45% (grade 3 or 4, 1.2%) and 42.4% (grade 3 or 4, 1.1%) of patients, respectively. In this trial, nervous system disorders occurred in 33.7% (grade 3 or 4, 2.5%) of patients in the letrozole arm compared with 31.8% (grade 3 or 4, 2.3%) of those who received placebo, and included headache (all grade, 20.1% vs. 19.7%; grade 3 or 4, 0.7% vs. 0.7%) and dizziness (all grade, 14.2% vs. 13.3%; grade 3 or 4, 0.4% vs. 0.2%). Fatigue/asthenia (4% to 13%), weakness (6%), headache (8% to 9%), vertigo (less than 5%), dizziness (3% or less), and somnolence (drowsiness) (3% or less) also occurred when letrozole was used to treat advanced breast cancer.

Hot flashes were reported in 33.5% of patients treated with letrozole (n = 2,448) compared with 38% of those who received tamoxifen (n = 2,447) as adjuvant therapy for early breast cancer in a large randomized clinical trial (BIG 1-98); night sweats occurred in 14.5% and 17.4% of patients, respectively. Compared to anastrozole as adjuvant therapy (all grade, 32.3%; grade 3 or 4, 0.4%), hot flashes occurred in 32.5% (grade 3 or 4, 0.8%) of those treated with letrozole. Vascular disorders occurred in 53.6% (grade 3 or 4, 2.3%) of patients receiving letrozole as extended adjuvant therapy after completion of 5 years of tamoxifen therapy compared with 47.8% (grade 3 or 4, 2.9%) of those who received placebo, including flushing (all grade, 49.7% vs. 43.3%; grade 3 or 4, 0.1% vs. 0%); hyperhidrosis was reported in 24.2% (grade 3 or 4, less than 0.1%) compared with 22.4% (grade 3 or 4, 0%), respectively. A patient-reported measure that captured the impact of letrozole treatment on important symptoms associated with estrogen deficiency favored placebo for vasomotor domains. Hot flashes also occurred in 6% to 19% of patients receiving letrozole for treatment of advanced breast cancer, while hyperhidrosis occurred in less than 5% of these patients.

Hypercalcemia was reported in less than 5% of patients treated with letrozole as second-line therapy for advanced breast cancer.

Renal disorders were reported in 5.1% of patients treated with letrozole as extended adjuvant therapy after 5 years of tamoxifen therapy (n = 2,563) compared with 3.9% of those who received placebo (n = 2,573); renal failure (unspecified), or grade 3 or 4 renal disorders, occurred in 0.5% versus 0.2% of patients, respectively.

Carpal tunnel syndrome and trigger finger have each been reported in postmarketing experience with letrozole therapy.

Anaphylactoid reactions, hypersensitivity reactions, and angioedema have all been reported in postmarketing experience with letrozole therapy.

Store this medication at 68°F to 77°F (20°C to 25°C) and away from heat, moisture and light. Keep all medicine out of the reach of children. Throw away any unused medicine after the beyond use date. Do not flush unused medications or pour down a sink or drain.

1.Femara (letrozole) package insert. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2018 April.
2.Holzer H, Casper R, Tulandi, T. A new era in ovulation induction. Fertil Steril 2006;85:277-84.
3.Jee BC, Ku SY, Suh CS, et al. Use of letrozole versus clomiphene citrate combined with gonadotropins in intrauterine insemination cycles: a pilot study. Fertil Steril 2006;85:1774-7.
4.The Breast International Group (BIG) 1-98 Collaborative Group. A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med 2005;353:2747-57.
5.Hero M, Norjavaara E, Dunkel L. Inhibition of estrogen biosynthesis with a potent aromatase inhibitor increases predicted adult height in boys with idiopathic short stature: a randomized controlled trial. J Clin Endocrinol Metab 2005;90:6396-402.
6.Hero M, Wickman S, Dunkel L. Treatment with the aromatase inhibitor letrozole during adolescence increases near-final height in boys with constitutional delay of puberty. Clin Endocrinol 2006;64:510-3.
7.Mitwally MF, Biljan MM, Casper RF. Pregnancy outcome after the use of an aromatase inhibitor for ovarian stimulation. Am J Obstet Gynecol 2005;192:381-6.
8.Teslac (testolactone) package insert. Princeton, NJ: Mead-Johnson Oncology Products, Bristol-Myers Squibb, Co.; 1998 Dec.
9.Aromasin (exemestane) tablets package insert. New York, NY: Pfizer Inc; 2018 May.
10.Arimidex (anastrozole) package insert. Baudette, MN: ANI Pharmaceuticals, Inc; 2018 Dec.
11.Kroboth PD, Slalek FS, Pittenger AL et al. DHEA and DHEA-S: a review. J Clin Pharmacol 1999;39:327-348.
12.Soltamox (tamoxifen) oral solution package insert. Raleigh, NC: Midatech Pharma US Inc.; 2018 Sept.