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letrozole 2.5 mg tablet generic femara

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Uses

Breast Cancer

Initial or Sequential Adjuvant Therapy for Early-stage Breast Cancer

Letrozole is used as adjuvant therapy in postmenopausal women with early-stage hormone receptor-positive breast cancer. Aromatase inhibitors, including letrozole, currently are considered a treatment of choice for adjuvant hormonal therapy to lower the risk of breast cancer recurrence in postmenopausal women with early-stage hormone receptor-positive breast cancer. Although tamoxifen historically has been the drug of choice for adjuvant hormonal therapy in such patients, results of large, randomized clinical studies indicate that an aromatase inhibitor-containing regimen is modestly more effective than tamoxifen alone. Longer-term follow-up of these studies is needed to further clarify lasting clinical efficacy, effects on survival, and late adverse effects of aromatase inhibitor therapy.

Clinical Trials

Efficacy of letrozole as initial or sequential adjuvant therapy in postmenopausal women with early-stage breast cancer is based principally on results of a randomized double-blind trial (Breast International Group [BIG] 1-98) in approximately 8000 postmenopausal women with early-stage hormone receptor-positive breast cancer. The study was initially designed to compare 5 years of adjuvant letrozole therapy with 5 years of adjuvant tamoxifen therapy; however, the randomization scheme subsequently was modified to include 4 regimens (2 sequential regimens in addition to the 2 single-drug regimens) to evaluate whether, in women who are disease-free approximately 2 years after initiating adjuvant therapy, switching endocrine treatments (i.e., administering tamoxifen for 2 years followed by letrozole for 3 years, or vice versa) is superior to continuing the initial agent for a total of 5 years. Letrozole was administered at a dosage of 2.5 mg daily, and tamoxifen was administered at a dosage of 20 mg daily.

At a median follow-up of 26 months, when patients had received either letrozole or tamoxifen for a median of 24 months, analysis of the data showed that patients receiving letrozole had prolonged disease-free and systemic disease-free survival and a reduced risk of distant recurrence compared with patients receiving tamoxifen. Overall survival and risk of new contralateral breast cancer did not differ significantly between letrozole- and tamoxifen-treated patients. Estimated 5-year disease-free survival was 84 or 81.4% for patients receiving letrozole or tamoxifen, respectively. Based on recommendations of an independent data monitoring board, the tamoxifen-only treatment groups were unblinded and disease-free patients in these groups were allowed to complete initial adjuvant therapy with letrozole if they had received tamoxifen for at least 2 years or to initiate extended adjuvant therapy with letrozole if they had received tamoxifen for at least 4.5 years. Approximately 25% of patients originally randomized to receive tamoxifen only for 5 years crossed over to receive letrozole, generally at 3-5 years following initiation of tamoxifen therapy. Despite the confounding effect of selective patient crossover from tamoxifen to letrozole, subsequent analysis of data for patients originally randomized to receive either letrozole only or tamoxifen only for 5 years showed that a difference in disease-free survival persisted at a median follow-up of 6.1 years. At the time of this analysis, estimated 5-year disease-free survival rates for the letrozole and tamoxifen groups were 87.4 and 84.7%, respectively; overall survival did not differ significantly between treatment groups. At a median follow-up of 8.7 years, patients originally randomized to receive letrozole only had longer overall and disease-free survival and longer breast cancer-free and distant recurrence-free intervals compared with those originally randomized to receive tamoxifen.

In the primary analysis of sequential therapy, each sequential regimen was compared with the single-drug regimen for the first drug in that sequence (e.g., letrozole followed by tamoxifen was compared with letrozole alone) from the time of the switch; no significant differences in overall survival, disease-free survival, or systemic or distant disease-free survival were observed. However, because of emerging clinical trial data and changing medical practice, additional comparisons, including comparison of each sequential regimen with letrozole alone, also were conducted. At a median follow-up of 5.9 years following randomization, neither letrozole followed by tamoxifen nor tamoxifen followed by letrozole improved disease-free survival compared with letrozole alone; estimated 5-year disease-free survival for patients receiving one of these 3 regimens was 86-88%. Similar results were observed at a median follow-up of 8 years, when disease-free and overall survival rates were 77-79 and 86-88%, respectively, for patients who received either of the sequential regimens or letrozole alone; 88-90% of these patients had no evidence of distant recurrence, and 84-86% had no evidence of breast cancer recurrence.

In this study, fracture, myocardial infarction, hypercholesterolemia, and arthralgia occurred more frequently in patients receiving letrozole, whereas thromboembolic events, vaginal bleeding, and endometrial disorders (hyperplasia, cancer, proliferation) occurred more frequently in those receiving tamoxifen.

Clinical Role

Based on data from randomized controlled trials (including BIG 1-98) demonstrating prolonged disease-free survival in patients receiving letrozole- or other aromatase inhibitor-based adjuvant regimens, the American Society of Clinical Oncology (ASCO) states that most postmenopausal women with early-stage hormone receptor-positive breast cancer should consider receiving an aromatase inhibitor (e.g., letrozole) during the course of adjuvant therapy, either as primary (initial) therapy or following 2-3 years of tamoxifen therapy (sequential therapy), to complete a total of 5 years of adjuvant endocrine therapy. Clinically meaningful differences among the currently available aromatase inhibitors (i.e., anastrozole, exemestane, letrozole) have not been demonstrated to date. Data also support switching to an aromatase inhibitor following 5 years of adjuvant tamoxifen therapy (extended therapy) (see Extended Adjuvant Therapy for Early-stage Breast Cancer under Uses: Breast Cancer). The optimal time for switching from tamoxifen to an aromatase inhibitor is not known. The duration of aromatase inhibitor therapy should not exceed 5 years, since toxicity of long-term (e.g., beyond 5 years) use of aromatase inhibitors, including letrozole, has not been determined. The optimal duration of adjuvant letrozole therapy is not known. ASCO states that clinicians should consider adverse effects, patient preference, and preexisting conditions when selecting an adjuvant regimen; during the course of adjuvant therapy, patients who are intolerant of one aromatase inhibitor may be switched to a different aromatase inhibitor or to tamoxifen.

The use of an LHRH agonist (e.g., goserelin) in combination with an aromatase inhibitor, such as letrozole, as adjuvant therapy in premenopausal women with hormone receptor-positive breast cancer is being investigated. The use of an aromatase inhibitor as a single agent for adjuvant therapy is not appropriate in premenopausal women with breast cancer because these agents alone are not likely to provide sufficient suppression of ovarian function to be of clinical benefit. Similarly, the use of monotherapy with aromatase inhibitors as adjuvant therapy for hormone receptor-positive breast cancer in premenopausal women experiencing a chemotherapy-induced disruption in ovarian function is not advised; a substantial number of such patients can expect resumption of ovarian function, and this would likely render therapy with an aromatase inhibitor ineffective.

Extended Adjuvant Therapy for Early-stage Breast Cancer

Letrozole is used as extended adjuvant therapy in postmenopausal women with early-stage breast cancer who have received 5 years of adjuvant tamoxifen therapy. Efficacy of letrozole as extended adjuvant therapy is based on analysis of disease-free survival in patients receiving the drug for a median of 5 years.

Clinical Trials

Efficacy of letrozole as extended adjuvant therapy in postmenopausal women with early-stage breast cancer who have received 5 years of adjuvant tamoxifen therapy is based principally on results of a double-blind, placebo-controlled randomized trial (National Cancer Institute of Canada Clinical Trials Group [NCIC CTC] MA.17) in postmenopausal women with mostly hormone receptor-positive breast cancer (98% hormone receptor-positive, 2% hormone receptor-unknown). In this trial, 5187 patients who had received adjuvant therapy with tamoxifen for approximately 5 years (range: 4.5-6 years) were randomized to receive letrozole 2.5 mg or placebo daily for 5 years; treatment was initiated within 3 months of discontinuance of tamoxifen therapy.

At a median follow-up of 2.4 years (based on 40% of the number of events required for the final analysis), an estimated 4-year disease-free survival rate of 93% in patients receiving letrozole and 87% in patients receiving placebo was reported. In addition, letrozole treatment was associated with reduction in the incidence of local or metastatic recurrence or new contralateral breast cancer (hazard ratio 0.57). The estimated 4-year overall survival rate was similar for patients receiving letrozole versus placebo (96 versus 94%). Based on the prolonged disease-free survival and a trend toward reduced overall mortality in patients receiving letrozole, the data and safety monitoring committee recommended early termination of the trial. The study was unblinded, all participants were informed of the findings, and letrozole therapy was offered to all women who had been receiving placebo.

After the study was unblinded, approximately 60% of patients randomized to receive placebo crossed over to receive letrozole therapy. Updated results at a median follow-up of 5.2 years (median treatment duration of 5 years) demonstrated a reduction in the incidence of breast cancer recurrence or new contralateral breast cancer in patients originally randomized to receive letrozole compared with that in patients originally randomized to receive placebo (hazard ratio 0.75). The effect of patients crossing over from placebo to letrozole therapy confounded the analysis of survival, as patients switching from placebo to letrozole accounted for 64% of the total patient-years of follow-up for the placebo group. The analysis of disease-free survival indicated that breast cancer recurrence, new contralateral breast cancer, or death from any cause occurred in 13.3% of patients originally randomized to receive letrozole compared with 15.5% of those originally randomized to receive placebo; the observed results were not statistically significant, but the treatment difference was diluted by patients crossing over from placebo to letrozole. Overall survival and distant disease-free survival of patients originally randomized to receive letrozole did not differ significantly from that of patients originally randomized to receive placebo.

An increased incidence of hot flushes (flashes), arthritis, arthralgia, and myalgia was observed in patients receiving letrozole. Patients receiving letrozole also experienced higher rates of bone fracture, newly diagnosed osteoporosis, and cardiovascular events. Because of the early stoppage of the study, long-term adverse effects associated with letrozole therapy may have been underestimated. Postmenopausal women receiving aromatase inhibitors, such as letrozole, as adjuvant therapy are at high risk for osteoporosis.(See Precautions and Contraindications and Musculoskeletal Effects sections in Cautions for further information on screening and treatment guidelines for osteoporosis in such patients.) Vaginal bleeding occurred less frequently in patients receiving letrozole than in those receiving placebo.

Clinical Role

Based on data from randomized controlled trials (including NCIC CTC MA.17) demonstrating prolonged disease-free survival in patients receiving letrozole or other aromatase inhibitors as extended adjuvant therapy following 5 years of adjuvant tamoxifen therapy, ASCO recommends extended therapy with an aromatase inhibitor (e.g., letrozole) in postmenopausal women with early-stage hormone receptor-positive breast cancer who complete 5 years of adjuvant tamoxifen therapy. Clinically meaningful differences among the currently available aromatase inhibitors (i.e., anastrozole, exemestane, letrozole) have not been demonstrated to date. Clinicians should consider adverse effects, patient preference, and preexisting conditions when selecting an adjuvant regimen. ASCO states that women who receive extended adjuvant therapy should receive a total of 8-10 years of adjuvant endocrine therapy, including 5 years of tamoxifen therapy followed by 3-5 years of aromatase inhibitor therapy. The optimal duration of letrozole as extended adjuvant therapy is not known, and the toxicity of long-term (e.g., beyond 5 years) use of aromatase inhibitors, including letrozole, in this setting has not been determined. Ongoing clinical trials are evaluating whether longer durations of aromatase inhibitor therapy are more effective. In one such trial, patients from the MA.17 trial and other patients who are disease-free after approximately 5 years of aromatase inhibitor therapy are randomized to receive 5 years of placebo or another 5 years of aromatase inhibitor therapy (i.e., letrozole).

First-Line Therapy for Advanced Breast Cancer

Letrozole is used for the first-line treatment of hormone receptor-positive or hormone receptor-unknown locally advanced or metastatic breast cancer in postmenopausal women. Data from a double-blind, randomized clinical trial indicate that letrozole is superior to tamoxifen for delaying tumor progression and producing objective tumor response in such patients. In this trial, a total of 916 postmenopausal patients (about 65% with hormone receptor-positive breast tumors and 35% with hormone receptor-unknown breast tumors) were randomized to receive letrozole 2.5 mg daily or tamoxifen 20 mg daily.

At a median follow-up of about 32 months, patients receiving letrozole had a longer median time to progression (9.4 versus 6 months), a higher overall objective response rate (32 versus 21%), and a higher complete response rate (9 versus 3%) compared with patients receiving tamoxifen. Median duration of response was 18 months in patients receiving letrozole and 16 months in those receiving tamoxifen. Among the subset of patients who had received prior antiestrogen adjuvant therapy, letrozole was associated with a higher objective response rate (26 versus 8%) and a longer median time to progression (8.9 versus 5.9 months) compared with tamoxifen. Median overall survival (35 versus 32 months) was similar in patients randomized to receive letrozole or tamoxifen, respectively. The incidence of adverse effects was similar for patients receiving letrozole or tamoxifen; common adverse effects included bone pain, hot flushes (flashes), back pain, dyspnea, nausea, and arthralgia.

The design of the study allowed patients to cross over to the opposite treatment arm upon disease progression. Approximately 50% of the patients in the study crossed over to the opposite treatment arm, with crossover occurring by 36 months in almost all cases. The median time to crossover was 17 months in patients crossing over from letrozole to tamoxifen and 13 months in patients crossing over from tamoxifen to letrozole. Among the patients who did not cross over to the opposite treatment arm, median survival was 35 months in patients receiving letrozole and 20 months in patients receiving tamoxifen.

Letrozole also is used in combination with lapatinib ditosylate for the treatment of hormone receptor-positive metastatic breast cancer that overexpresses the HER2 protein in postmenopausal women who are candidates for hormonal therapy.

Second-Line Therapy for Advanced Breast Cancer

Letrozole is used for the palliative treatment of advanced breast cancer in postmenopausal women with disease progression following antiestrogen therapy (e.g., tamoxifen). The principal goal of therapy in patients with metastatic breast cancer generally has been palliative with an emphasis on extension of survival and improvement in the quality of life.

Clinical Trials

The current labeled indication for letrozole in previously treated breast cancer is based on 2 randomized multicenter phase II trials involving postmenopausal women with locally advanced or metastatic breast cancer who had hormone receptor-positive or hormone receptor-unknown tumors; all patients had measurable or evaluable disease that had progressed following prior antiestrogen therapy. In both studies, the safety and efficacy of 2 dosages of letrozole were evaluated and the distribution of hormone receptor status was similar among the patients (about 55% with hormone receptor-positive breast tumors and 45% with hormone receptor-unknown breast tumors). In both studies, at least 60% of the patients had received therapeutic antiestrogens, and an objective response to this therapy had occurred in about one-fifth of these patients.

In a double-blind, randomized trial involving 552 postmenopausal women, patients receiving letrozole (2.5 mg daily) had a similar rate of objective response (24 versus 16%) and similar median survival (730 versus 659 days) compared with those receiving megestrol acetate (160 mg daily) at a minimum follow-up of 15 months. Responses to letrozole were observed in patients with advanced breast cancer that did not respond to first-line antiestrogen therapy. Similar objective response rate (12 versus 16%) also was observed in patients receiving the lower dosage of letrozole (0.5 mg daily) versus megestrol acetate. Adverse cardiovascular effects, principally thromboembolic events, and vaginal bleeding occurred less frequently in patients receiving either dose level of letrozole than in those receiving megestrol acetate.

In an open-label randomized trial involving 557 postmenopausal women, letrozole 2.5 mg daily was at least as effective as aminoglutethimide (250 mg twice daily) with a similar rate of objective response (about 18 versus 12%, respectively) and similar median survival (792 versus 592 days, respectively) at a minimum follow-up of 9 months; a similar rate of objective response (about 18 versus 12%, respectively) and similar median survival (636 days versus 592 days, respectively) also was observed in patients receiving the lower dosage of letrozole (0.5 mg daily) versus aminoglutethimide.

In a double-blind, randomized phase III trial comparing 2 doses of letrozole (2.5 mg or 0.5 mg) with megestrol acetate (40 mg 4 times daily) in women with advanced or metastatic breast cancer (hormone receptor-positive or hormone receptor-unknown tumors), similar rate of objective response was observed among the groups. No statistical difference in efficacy has been demonstrated between either dose level of letrozole (2.5 mg or 0.5 mg daily) and the comparison treatment (megestrol acetate or aminoglutethimide), and no statistical difference in the incidence of adverse effects has been noted for the 2 dose levels. Some clinicians question whether there is any clinically meaningful difference in efficacy and safety between these letrozole dosages; commercially available letrozole tablets are available for the 2. 5-mg dose only.

In a double-blind, randomized, crossover trial exploring the biochemical efficacy of letrozole versus anastrozole, another aromatase inhibitor, in 12 postmenopausal women with estrogen receptor-positive metastatic breast cancer, letrozole caused greater inhibition of in vivo aromatization and greater suppression of plasma concentrations of estrone and estrone sulfate than anastrozole. The clinical importance of differences in the degree of estrogen suppression between various aromatase inhibitors has not been established. In an open-label, randomized, multicenter trial involving 713 postmenopausal women with advanced or metastatic breast cancer (hormone receptor-positive tumors and hormone receptor-unknown tumors each in about half of the patients), no difference in time to progression of disease or incidence of adverse effects was observed among patients receiving letrozole or anastrozole.

Clinical Role

Letrozole is used as second-line hormonal therapy in postmenopausal women with hormone receptor-positive advanced breast cancer. In premenopausal women with hormone receptor-positive advanced breast cancer, ovarian ablation by surgery or external-beam radiation, or suppression of ovarian function with a luteinizing hormone-releasing hormone (LHRH) agonist, is advised; the use of an LHRH agonist (e.g., goserelin) in combination with an aromatase inhibitor, such as letrozole, is being investigated. The use of an aromatase inhibitor as single-agent therapy is not appropriate in premenopausal women with breast cancer because these agents alone are not likely to provide sufficient suppression of ovarian function to be of clinical benefit.

Dosage and Administration

Administration

Letrozole is administered orally. Food does not affect the absorption of letrozole, and the drug may be administered without regard to meals.

Dosage

Breast Cancer

Initial or Sequential Adjuvant Therapy for Early-stage Breast Cancer

For adjuvant treatment of early-stage hormone receptor-positive breast cancer in postmenopausal women, the recommended dosage of letrozole is 2.5 mg once daily. The optimal duration of adjuvant therapy is unknown. The planned duration of therapy in the study establishing use of letrozole as initial adjuvant therapy was 5 years; 73% of patients in this study completed adjuvant therapy. Treatment should be discontinued if relapse occurs.

The American Society of Clinical Oncology (ASCO) states that an aromatase inhibitor (e.g., letrozole) may be administered to postmenopausal women with early-stage hormone receptor-positive breast cancer as initial adjuvant therapy and continued for a total of 5 years or may be administered following initial tamoxifen therapy as part of a sequential adjuvant regimen. The optimal time to switch from tamoxifen to aromatase inhibitor therapy is not known; however, based on clinical trials conducted to date, ASCO recommends that patients who are disease-free may be switched to an aromatase inhibitor after 2-3 years of tamoxifen therapy to complete a 5-year sequential adjuvant regimen. In patients who initially receive an aromatase inhibitor but discontinue therapy prior to 5 years, ASCO states that consideration should be given to administering tamoxifen to complete the 5-year adjuvant regimen.

Extended Adjuvant Therapy for Early-stage Breast Cancer

For the extended adjuvant treatment of early-stage breast cancer in postmenopausal women who have completed 5 years of adjuvant therapy with tamoxifen, the recommended dosage of letrozole is 2.5 mg once daily. The optimal duration of therapy is unknown. The planned duration of therapy in the study establishing use of letrozole as extended adjuvant therapy was 5 years. In the final updated analysis of this study, the median treatment duration was 5 years (60 months); 71% of patients completed at least 3 years of extended adjuvant treatment, and 58% completed at least 4.5 years of such treatment. ASCO recommends that patients who receive an extended adjuvant regimen receive an aromatase inhibitor (e.g., letrozole) for 3-5 years beyond the initial 5 years of tamoxifen therapy, to complete a total of 8-10 years of adjuvant endocrine therapy. Treatment should be discontinued if relapse occurs.

First-line Therapy for Advanced Breast Cancer

For the first-line treatment of hormone receptor-positive or hormone receptor-unknown locally advanced or metastatic breast cancer in postmenopausal women, the recommended dosage of letrozole is 2.5 mg once daily. Treatment should be continued until disease progression occurs.

Second-line Therapy for Advanced Breast Cancer

For the second-line treatment of advanced or metastatic breast cancer in postmenopausal women with disease progression following antiestrogen therapy, the recommended dosage of letrozole is 2.5 mg once daily. Treatment should be continued until disease progression occurs.

Dosage in Renal and Hepatic Impairment

Although letrozole is metabolized to an inactive metabolite whose glucuronide conjugate undergoes mainly renal excretion, the manufacturer states that no dosage adjustment is necessary in patients with a creatinine clearance of at least 10 mL/minute.

Letrozole is metabolized slowly in the liver, and modest increases in serum letrozole concentrations have been observed in patients with moderate hepatic impairment secondary to cirrhosis. The manufacturer states that no dosage adjustment is required in patients with mild to moderate hepatic impairment. A 50% reduction in letrozole dosage (to 2.5 mg every other day) is recommended in patients with cirrhosis and severe hepatic impairment. The effect of hepatic impairment on letrozole pharmacokinetics in patients with cancer and elevated bilirubin concentrations who do not have cirrhosis has not been determined.

Cautions

The incidence of reported adverse effects is based on data from randomized trials of postmenopausal women receiving letrozole 2.5 mg daily for breast cancer as initial adjuvant therapy for early-stage disease (2448 patients; median duration of treatment: 5 years; median follow-up: 6.1 years), extended adjuvant therapy for early-stage disease (2563 patients; median duration of treatment: 24 months; median follow-up: 28 months), first-line therapy for advanced disease (455 patients, median duration of treatment: 11 months), or second-line therapy for advanced disease (359 patients). Rates of adverse reactions were similar among women receiving letrozole as first-line or second-line therapy for advanced disease, and unless the type of therapy is specified, incidence rates reflect the experience of all these patients receiving the drug. For an additional 380 patients receiving a lower dosage of letrozole (0.5 mg daily) as second-line therapy, the incidences of adverse effects were similar to those in the patients receiving the higher dose. The most frequent adverse effects of letrozole are hypercholesterolemia, hot flushes (flashes), and arthralgia/arthritis in patients receiving the drug as initial adjuvant therapy; flushing, asthenia, arthralgia, headache, and increased sweating in those receiving the drug as extended adjuvant therapy; and bone pain in those receiving treatment for advanced disease.

In patients receiving initial adjuvant therapy for early-stage breast cancer, fracture, myocardial infarction, hypercholesterolemia, and arthralgia occurred more frequently in those receiving letrozole, whereas thromboembolic events, vaginal bleeding, endometrial hyperplasia or cancer, and endometrial proliferation disorders occurred more frequently in those receiving tamoxifen. In patients receiving letrozole as extended adjuvant therapy following 5 years of tamoxifen therapy, hot flushes (flashes), arthralgia/arthritis, and myalgia occurred more frequently in letrozole-treated patients than in placebo recipients.

The described adverse effects occurred at a similar rate in patients receiving letrozole or tamoxifen as first-line therapy for advanced breast cancer. Discontinuance of therapy because of adverse effects other than progression of tumor was required in 2% of patients receiving letrozole and 3% of patients receiving tamoxifen.

Unless otherwise noted, the adverse effects described occurred at a similar rate in patients receiving treatments being compared with letrozole (i.e., megestrol acetate or aminoglutethimide) as second-line therapy for advanced breast cancer. Adverse effects typically were mild to moderate in severity among patients in all treatment groups; in general, it was not possible to distinguish adverse reactions secondary to treatment from the consequences of metastatic breast cancer, the effects of estrogen deprivation, or intercurrent illness. In the 2 studies comparing letrozole with either megestrol acetate or aminoglutethimide, discontinuance of therapy because of adverse effects other than progression of tumor was required as follows: megestrol acetate (7.9%), letrozole 2.5 mg (2.3%), and letrozole 0.5 mg (2.7%); aminoglutethimide (3.9%), letrozole 2.5 mg (3.8%), and letrozole 0.5 mg (3.1%).

Musculoskeletal Effects

In patients receiving letrozole as initial adjuvant therapy, arthralgia/arthritis was reported in 25% of patients and fracture was reported during treatment in 10% of patients; arthralgia/arthritis and fracture were reported less frequently in patients receiving tamoxifen (20 and 7%, respectively). The overall incidence of fractures, including those that occurred during posttreatment follow-up, was 14% in patients receiving letrozole and 10% in those receiving tamoxifen. Myalgia occurred in 9% and back pain, osteoporosis, osteopenia, bone pain, and pain in extremity each occurred in 4-5% of patients receiving letrozole as initial adjuvant therapy.

In patients receiving letrozole as extended adjuvant therapy following 5 years of adjuvant tamoxifen therapy, arthralgia was reported in 22% and arthritis, myalgia, and back pain each were reported in 5-7% of patients. At a median follow-up of 28 months, fracture was reported in 5.9% of patients receiving letrozole and 5.5% of those receiving placebo, and the incidence of self-reported osteoporosis was higher among patients receiving letrozole (6.9 versus 5.5%); about 19-21% of patients received bisphosphonate therapy. At a median follow-up of 62 months, fracture and newly diagnosed osteoporosis each were reported in 13-14% of patients receiving letrozole compared with 8% of those receiving placebo.

In patients receiving letrozole as first-line therapy for advanced disease, bone pain, back pain, and limb pain occurred in 22, 18, and 10% of patients, respectively. In patients receiving letrozole as second-line therapy for advanced disease, adverse musculoskeletal effects (including musculoskeletal, skeletal, back, arm, and leg pain) were reported in 21% and fracture was reported in less than 5% of patients. Arthralgia was reported in 16% of patients receiving letrozole as first-line therapy and in 8% of patients receiving the drug as second-line therapy. Hypercalcemia occurred in less than 5% of patients receiving letrozole as second-line therapy.

A syndrome consisting of arthralgia and other symmetrical bone and joint symptoms (e.g., pain, stiffness, achiness) that are not associated with other manifestations of rheumatologic disorders has been reported in patients receiving aromatase inhibitors. Symptoms generally resolve within 8-10 weeks following discontinuance of therapy.

Because letrozole lowers circulating estrogen concentrations, it may cause a reduction in bone mineral density (BMD). In a substudy of the controlled trial evaluating letrozole as initial adjuvant therapy, the change in lumbar spine BMD following 2 years of treatment was a median decrease of 4.1% in patients receiving letrozole compared with a median increase of 0.3% in those receiving tamoxifen (a difference of 4.4%). Results for total hip BMD were similar, although the difference between treatment groups was less pronounced. During the 2-year treatment period, osteoporosis developed in one patient with baseline osteopenia and fracture was reported in 4 or 6% of patients receiving letrozole or tamoxifen, respectively. In a substudy of the trial evaluating letrozole as extended adjuvant therapy in patients who had received 5 years of adjuvant tamoxifen therapy, the median decrease from baseline in hip BMD following 2 years of treatment was about 4% in patients receiving letrozole compared with 2% in those receiving placebo; letrozole- and placebo-treated patients had similar changes from baseline in lumbar spine BMD.

Postmenopausal women receiving an aromatase inhibitor, such as letrozole, as adjuvant therapy are at high risk for osteoporosis. All postmenopausal women initiating adjuvant therapy with an aromatase inhibitor should be evaluated for risk of osteoporotic fractures. Screening with dual energy radiographic absorptiometry (DXA) to determine the BMD of the hip and spine should be performed in conjunction with assessment of other risk factors for fracture (e.g., age, low body mass index, family history of hip fracture, prior fragility fracture, history of cigarette smoking, excessive alcohol consumption, current or prior corticosteroid use). Patients should be monitored closely for changes in risk status during therapy, and BMD should be assessed at regular intervals (e.g., every 1-2 years in those with osteopenia or osteoporosis). Other potential causes of osteoporosis (e.g., vitamin D deficiency, hyperthyroidism, hyperparathyroidism, hypercalciuria) should be considered. Appropriate therapy to prevent further bone loss should be initiated as clinically indicated. The decision to initiate therapy with an antiresorptive agent (e.g., a bisphosphonate, denosumab) should be based on overall risk of fracture and rate of bone loss. All women receiving adjuvant therapy with letrozole should be advised to adopt lifestyle changes (e.g., weight-bearing exercise, abstinence from smoking, moderation in alcohol consumption) and dietary supplementation with calcium and vitamin D to reduce the risk of osteoporosis.

GI Effects

In patients receiving letrozole as initial adjuvant therapy, nausea occurred in 12% and vomiting, constipation, and anorexia each occurred in 3% or less of patients. In patients receiving letrozole as extended adjuvant therapy, constipation, nausea, or diarrhea occurred in 11, 9, or 5%, respectively, of patients.

In patients receiving letrozole as first-line or second-line therapy for advanced disease, nausea, vomiting, and diarrhea were reported in 13-17, 7, and 6-8% of patients, respectively. Constipation and anorexia were reported in 6-10 and 4-5% of patients, respectively. Abdominal pain and dyspepsia were reported in 6 and 3%, respectively, of patients receiving the drug as second-line therapy. Stomatitis, increased appetite, dry mouth, and disturbances of taste and thirst also have been reported in patients receiving letrozole as first-line or second-line therapy.

Respiratory Effects

Dyspnea was reported in 6% of patients receiving letrozole as extended adjuvant therapy. Dyspnea also was reported in 18 or 7%, and coughing was reported in 13 or 6%, of patients receiving letrozole as first-line or second-line therapy for advanced disease, respectively. Chest wall pain was reported in 6% of patients receiving letrozole as first-line therapy. Pleural effusion occurred in less than 5% of patients receiving letrozole as second-line therapy.

Nervous System Effects

In patients receiving letrozole as initial adjuvant therapy, depression, headache, and dizziness/lightheadedness each were reported in 3-5% of patients.

In patients receiving letrozole as extended adjuvant therapy, headache, dizziness, or insomnia was reported in 20, 14, or 6% of patients.

Headache was reported in 8-9% of patients receiving letrozole as first-line or second-line therapy for advanced disease. Insomnia occurred in 7% of patients receiving letrozole as first-line therapy. In patients receiving letrozole as second-line therapy, somnolence and dizziness each occurred in 3% of patients. Depression, anxiety, and vertigo each were reported in less than 5% of patients receiving letrozole as second-line therapy. Memory impairment, irritability, nervousness, and dysesthesia (including hypoesthesia and paresthesia) also have been reported in patients receiving letrozole as first-line or second-line therapy.

Cardiovascular Effects

Thromboembolic Events and Ischemic Disease

In patients receiving letrozole as initial adjuvant therapy, myocardial infarction or ischemia, angina, cerebrovascular accident, and thromboembolic events each were reported in 3% or less of patients during treatment or posttreatment follow-up. When compared with patients receiving tamoxifen as initial adjuvant therapy, myocardial infarction occurred more frequently in patients receiving letrozole (1 versus 0.5% during treatment), whereas thromboembolic events occurred more frequently in patients receiving tamoxifen (3 versus 4.5%). Cardiovascular ischemic events were reported in 7% of patients receiving letrozole as extended adjuvant therapy following 5 years of adjuvant tamoxifen therapy.

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 for advanced disease. Among patients receiving second-line therapy for advanced disease, 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. Arterial thrombosis also has been reported in patients receiving letrozole as first-line or second-line therapy.

Vasomotor Symptoms

Hot flushes (flashes) were reported in 34% of patients receiving letrozole as initial adjuvant therapy, 19% of patients receiving letrozole as first-line therapy, and 6% of patients receiving the drug as second-line therapy for advanced disease. Flushing occurred in 50% of patients receiving letrozole as extended adjuvant therapy following 5 years of adjuvant tamoxifen therapy.

Effects on Lipoproteins

Hypercholesterolemia was reported in 52% of patients receiving letrozole as initial adjuvant therapy, 16% of patients receiving the drug as extended adjuvant therapy, and 3% of patients receiving the drug as second-line therapy for advanced disease.

In the trial evaluating letrozole as initial adjuvant therapy, hypercholesterolemia was reported more frequently in patients receiving letrozole than in those receiving tamoxifen (52 versus 29%), and a greater proportion of letrozole-treated patients received antilipemic agents (25 versus 16%). Grade 3 or 4 hypercholesterolemia was reported in 0.4 or 0.1% of patients receiving letrozole or tamoxifen, respectively. Among patients with normal baseline serum cholesterol concentrations, elevated total cholesterol concentrations were reported in 8 or 3% of those receiving letrozole or tamoxifen, respectively. In a phase 3 safety trial, 12 or 4% of postmenopausal women receiving letrozole or tamoxifen, respectively, as adjuvant therapy for breast cancer had at least one total cholesterol concentration during 2 years of treatment that was of higher adverse-event grade than the baseline concentration.

In the placebo-controlled trial evaluating letrozole as extended adjuvant therapy in patients who had received 5 years of adjuvant tamoxifen therapy, concentrations of total cholesterol and lipoprotein fractions in letrozole-treated patients were similar to those in placebo recipients throughout the 5 years of letrozole or placebo treatment. Similar proportions of letrozole- and placebo-treated patients received antilipemic agents.

Other Cardiovascular Effects

In patients receiving letrozole as initial or extended adjuvant therapy, edema occurred in 7 or 18%, respectively, of patients. In patients receiving letrozole as initial adjuvant therapy, cardiovascular events (other than myocardial infarction or ischemia, angina, cerebrovascular accident, and thromboembolic event) occurred in 13% of patients during treatment or posttreatment follow-up. Cardiovascular events were reported in 10% of patients receiving letrozole as extended adjuvant therapy.

Hypertension occurred in 5-8% and peripheral edema occurred in 5% of patients receiving letrozole as first-line or second-line therapy for advanced disease. Postmastectomy lymphedema was reported in 7% of patients receiving letrozole as first-line therapy. Palpitation, cardiac failure, and tachycardia also have been reported in patients receiving letrozole as first-line or second-line therapy.

Hematologic Effects

Moderate decreases in lymphocyte counts were observed in some patients receiving letrozole 2.5 mg daily. The decreased lymphocyte counts were transient in about half of the affected patients, and the clinical importance of this finding is uncertain. Thrombocytopenia was reported in at least 2 patients receiving letrozole. 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. Leukopenia has been reported in patients receiving letrozole as first-line or second-line therapy for advanced disease.

Infectious Complications

Infection or infestation occurred in 6% of patients receiving letrozole as extended adjuvant therapy. Influenza and urinary tract infection each were reported in 6% of patients receiving letrozole as first-line therapy for advanced disease. Viral infection was reported in 6% of patients receiving letrozole as second-line therapy for advanced disease.

Dermatologic and Sensitivity Reactions

Night sweats were reported in 15% and alopecia was reported in 3% of patients receiving letrozole as initial adjuvant therapy. Increased sweating was reported in 24% of patients receiving letrozole as extended adjuvant therapy.

In patients receiving letrozole as second-line therapy for advanced disease, rash (including rash, erythematous rash, maculopapular rash, psoriasiform rash, and vesicular rash) and pruritus were reported in 5 and 1%, respectively. Alopecia and increased sweating were reported in less than 5% of patients receiving letrozole as second-line therapy. Hair thinning also has been reported in patients receiving letrozole as first-line therapy for advanced disease. Urticaria and dryness of the skin and mucosa also have been reported in patients receiving letrozole as first-line or second-line therapy.

During postmarketing experience, angioedema, anaphylactic reaction, toxic epidermal necrolysis, and erythema multiforme have been reported in patients receiving letrozole.

Hepatic Effects

During postmarketing experience, increased hepatic enzymes and hepatitis have been reported in patients receiving letrozole.

Genitourinary Effects

Vaginal bleeding, vaginal irritation, and breast pain each were reported in 2-5% of patients receiving letrozole as initial adjuvant therapy. In patients receiving initial adjuvant therapy, endometrial hyperplasia or cancer and endometrial proliferation disorders occurred during treatment or posttreatment follow-up less frequently in patients receiving letrozole than in those receiving tamoxifen (less than 1 versus 2-4%). In patients receiving letrozole as extended adjuvant therapy, vaginal bleeding and vulvovaginal dryness each occurred in 5% of patients.

Breast pain was reported in 7% of patients receiving letrozole as first-line therapy for advanced disease. Among patients receiving second-line therapy for advanced disease, vaginal bleeding occurred less frequently in patients receiving letrozole than in those receiving megestrol acetate (0.3 versus 3.2%). Increased urinary frequency and vaginal discharge also have been reported in patients receiving letrozole as first-line or second-line therapy.

Metabolic Effects

Weight loss or gain was reported in 6 or 13%, respectively, of patients receiving letrozole as initial adjuvant therapy. In patients with advanced disease, weight loss occurred in 7% of patients receiving letrozole as first-line therapy, and weight gain occurred in 2% of patients receiving letrozole as second-line therapy.

Other Adverse Effects

Fatigue (including lethargy, malaise, and asthenia) was reported in 10% of patients receiving letrozole as initial adjuvant therapy, and asthenia was reported in 34% of patients receiving the drug as extended adjuvant therapy. Fatigue also was reported in 8-13% of patients receiving letrozole as first-line or second-line therapy for advanced disease. Weakness and pain (unspecified) were reported in 6 and 5%, respectively, of patients receiving letrozole as first-line therapy. Asthenia was reported in 4% of patients receiving letrozole as second-line therapy. Renal disorders were reported in 5% of patients receiving letrozole as extended adjuvant therapy. Cataract was reported in 2% of patients receiving letrozole as initial adjuvant therapy. Cataract, eye irritation, cancer pain, and pyrexia also have been reported in patients receiving letrozole as first-line or second-line therapy. Second malignancies occurred during treatment or posttreatment follow-up in 4% of patients receiving letrozole as initial adjuvant therapy. During postmarketing experience, blurred vision, carpal tunnel syndrome, and trigger finger also have been reported in patients receiving letrozole.

Precautions and Contraindications

Letrozole currently is indicated for use in the treatment of breast cancer in postmenopausal women only. Letrozole is not recommended for use in premenopausal women because safety and efficacy have not been established in this patient population.

Because fatigue, dizziness, and, uncommonly somnolence have been reported during letrozole therapy, patients should be advised to use caution while driving or operating machinery.

Postmenopausal women with breast cancer receiving adjuvant therapy with an aromatase inhibitor, such as letrozole, are at high risk for osteoporosis. Postmenopausal women initiating such therapy should undergo screening to determine BMD and be evaluated for other risk factors for osteoporotic fractures. Patients should be monitored closely for changes in risk status during therapy, and BMD should be assessed at regular intervals. Appropriate therapy to prevent further bone loss should be initiated as clinically indicated. All women receiving adjuvant therapy with letrozole should be advised to adopt lifestyle changes (e.g., weight-bearing exercise) and dietary supplementation with calcium and vitamin D to reduce the risk of osteoporosis.(Also see Cautions: Musculoskeletal Effects.)

The effect of letrozole on lipid metabolism has not been fully established, and serum lipid concentrations should be monitored in patients receiving long-term therapy with the drug.

Pediatric Precautions

The manufacturer states that safety and efficacy of letrozole in children have not been established.

Adverse effects on bone (bone maturation, bone mineral density) and neuroendocrine and reproductive development disorders of the hypothalamic-pituitary axis were reported following administration of letrozole 0.003-0.3 mg/kg daily in young rats (exposures less than that expected at the recommended human adult dosage) for 12 weeks beginning on postnatal day 7.

Geriatric Precautions

In the clinical trial evaluating letrozole as initial adjuvant therapy for early-stage breast cancer, 36% of patients were 65 years of age or older at enrollment, while 12% were 75 years of age or older. Adverse effects generally occurred more frequently in geriatric patients regardless of their assigned study treatment; however, no overall differences in safety and efficacy of letrozole versus tamoxifen were observed between geriatric patients and younger adults.

In the clinical trial evaluating letrozole as extended adjuvant therapy for early-stage breast cancer, 41% of patients were 65 years of age or older at enrollment, while 12% were 75 years of age or older. Although no overall differences in safety or efficacy were observed between geriatric patients and younger adults, and other clinical experience revealed no evidence of age-related differences, the possibility that some older patients may exhibit increased sensitivity to the drug cannot be ruled out.

In clinical trials evaluating letrozole as first-line or second-line therapy for advanced or metastatic breast cancer, about one-third of patients were 70 years of age or older (median age: 64-65 years). Among patients receiving letrozole as first-line therapy in a clinical trial, higher response rate and longer time to tumor progression were observed in geriatric patients (70 years or older) compared with younger patients.

Mutagenicity and Carcinogenicity

Mutagenicity

In vitro tests, including the Ames and E. coli bacterial tests, have not shown letrozole to be mutagenic. Potential clastogenicity was demonstrated by the results of 2 in vitro assays (CHO K1 and CCL 61 Chinese hamster ovary cells), but the drug was not shown to be clastogenic in the in vivo micronucleus test in rats.

Carcinogenicity

Letrozole has shown carcinogenic activity in animal models. In mice administered letrozole 0.6-60 mg/kg daily (about 1-100 times the daily maximum recommended human dosage on a mg/m basis) by oral gavage for up to 2 years, a dose-related increase in the incidence of benign ovarian stromal tumors was observed. When the high-dose group was excluded (because of low survival), an increased incidence of combined hepatocellular adenoma and carcinoma was observed in female mice. In a separate study, plasma AUC0-12h values in mice administered letrozole 60 mg/kg daily were 55 times higher than the AUC0-24h values in patients with breast cancer receiving the recommended dose of the drug.

Oral administration of letrozole 0.1-10 mg/kg daily (about 0.4-40 times the daily maximum recommended human dosage on a mg/m basis) for up to 2 years in rats resulted in an increase in the incidence of benign ovarian stromal tumors at the 10 mg/kg daily dose. Ovarian hyperplasia was observed in female rats receiving doses equal to or exceeding 0.1 mg/kg daily. Plasma AUC0-24h values in rats at 10 mg/kg daily were 80 times higher than the AUC0-24h values in breast cancer patients receiving the recommended dosage of the drug.

Pregnancy, Fertility, and Lactation

Pregnancy

Letrozole is contraindicated in women who are or may become pregnant (i.e., premenopausal women) since the drug can cause fetal toxicity when administered to pregnant women and clinical benefits of letrozole therapy in premenopausal women with breast cancer have not been established. Perimenopausal women and women who recently have become postmenopausal should be advised of the need to use adequate methods of contraception until the postmenopausal state is clinically well established. If letrozole is administered during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be informed of the potential hazard to the fetus.

Adequate, well-controlled studies of letrozole in pregnant women have not been conducted. In rats receiving doses equal to or exceeding 0.003 mg/kg (about 1/100 the daily maximum recommended human dose on a mg/m basis) during the period of organogenesis, letrozole was embryotoxic and fetotoxic, causing intrauterine mortality, increased resorption, increased 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 shown to be teratogenic in rats; administration of 0.03 mg/kg letrozole (about 1/10 the daily maximum recommended human dose on a mg/m basis) resulted in fetal domed head and cervical/centrum vertebral fusion. In rabbits, letrozole was embryotoxic at doses equal to or exceeding 0.002 mg/kg (about 1/100,000 the daily maximum recommended human dose on a mg/m basis) and fetotoxic at a dose of 0.02 mg/kg (about 1/10,000 the daily maximum recommended human dose on a mg/m basis); fetal anomalies included incomplete ossification of the skull, sternebrae, forelegs, and hindlegs.

Fertility

Studies have not been conducted to date to determine whether letrozole affects fertility in males or females. However, repeated administration of letrozole 0.6, 0.1, and 0.03 mg/kg in mice, rats, and dogs, respectively (about 1, 0.4, and 0.4 times the daily maximum recommended human dose on a mg/m basis, respectively) caused sexual inactivity in females and atrophy of the reproductive tract in males and females. In young rats receiving doses of 0.003-0.3 mg/kg daily (exposures less than that expected at the recommended human dosage) for 12 weeks beginning on postnatal day 7, letrozole resulted in neuroendocrine and reproductive developmental disturbances of the hypothalamic-pituitary axis; decreased fertility was accompanied by pituitary gland hypertrophy, testicular changes including degeneration of the seminiferous tubular epithelium in males, and atrophy of the reproductive tract in females.

Lactation

It is not known whether letrozole is distributed into milk. Because many drugs are distributed into milk and because of the potential for serious adverse reactions to letrozole in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.

Drug Interactions

Selective Estrogen Receptor Modulators

The concomitant use of selective estrogen receptor modulators (e.g., tamoxifen, raloxifene) and aromatase inhibitors, such as letrozole, is not recommended.

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. Although the clinical importance of this pharmacokinetic interaction is uncertain, the concomitant use of letrozole and tamoxifen is not recommended. Clinical experience in patients with previously treated advanced breast cancer indicates that administration of letrozole immediately after tamoxifen does not reduce the therapeutic effect of letrozole.

Because this pharmacokinetic interaction may occur with similar agents and reduce plasma concentrations of letrozole, the concomitant use of other selective estrogen receptor modulators (e.g., raloxifene) is not recommended. Among women receiving letrozole who require drug therapy for osteoporosis, the use of an oral bisphosphonate agent, rather than raloxifene, is advised.

Estrogens

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

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

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.

In human liver microsomes, letrozole has been shown to strongly inhibit in vitro metabolic reactions catalyzed by CYP2A6 and to moderately inhibit reactions catalyzed by CYP2C19; thus, concomitant use of letrozole may result in decreased metabolism and increased plasma concentrations of agents metabolized by these hepatic microsomal enzymes. An interaction study did not show a clinically important effect of letrozole on the pharmacokinetics of warfarin.

Pharmacokinetics

Absorption

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.

Distribution

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

It is not known whether letrozole is distributed into milk in humans.

Elimination

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

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.

Following oral administration of radiolabeled letrozole, 90% of the administered dose was excreted in the urine. Of the radiolabeled drug recovered in urine, at least 75% was the glucuronide of the carbinol metabolite, about 9% consisted of 2 unidentified metabolites, and 6% was unchanged drug.

Age-related differences in pharmacokinetics over the range of 35 years of age to greater than 80 years of age have not been observed in patients receiving letrozole in clinical trials. Age-related differences between adults and children or race-related differences in the pharmacokinetics of letrozole have not been evaluated.

Liver function influences serum concentrations of letrozole, and the need for dosage adjustment is determined by the extent of hepatic dysfunction. In individuals with liver cirrhosis and severe hepatic impairment (Child-Pugh classification C, which included serum bilirubin concentrations of about 2-11 times the upper limit of normal with minimal to severe ascites), a twofold increase in mean area under the plasma concentration-time curve (AUC) and a 47% reduction in systemic clearance of letrozole have been reported. Patients with severe hepatic impairment are exposed to higher concentrations of letrozole, and dosage reduction is necessary.(See Dosage and Administration: Dosage in Renal and Hepatic Impairment.) In individuals with moderate hepatic impairment unrelated to liver metastases (e.g., cirrhosis, Child-Pugh classification A and B), the mean AUC values for letrozole were increased by 37% but were still within the range observed for control subjects with normal hepatic function. The effect of hepatic impairment on letrozole pharmacokinetics in patients with cancer and elevated bilirubin concentrations who do not have cirrhosis has not been determined.

Letrozole pharmacokinetics were not altered in individuals with varying renal function (24-hour creatinine clearance 9-116 mL/minute) receiving single doses of 2.5 mg or in patients with advanced breast cancer and renal impairment (calculated creatinine clearance 20-50 mL/minute) receiving multiple doses of 0.5 or 2.5 mg daily.

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