VA Class:AN900

AHFS Class:

• Antiestrogens 68:16.08

Generic Name(s):

• Letrozole

Chemical Name:

• 4,4'-(1 H -1,2,4-triazol-1-ylmethylene)bis-benzonitrile

Molecular Formula:

• C₁₇H₁₁N₅

Letrozole, an aromatase inhibitor, is an antineoplastic agent.1

Breast Cancer

Initial, Sequential, or Extended Adjuvant Therapy for Postmenopausal Women with Early-Stage Hormone Receptor-Positive Breast Cancer

Letrozole is used as adjuvant therapy in postmenopausal women with early-stage hormone receptor-positive breast cancer.1,  39,  40,  41 Letrozole is also used as extended adjuvant therapy in postmenopausal women with early-stage breast cancer who have received 5 years of adjuvant tamoxifen therapy.1 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.1

Clinical Experience as Initial or Sequential Adjuvant Therapy

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.1,  39,  40 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.1,  39,  40 Letrozole was administered at a dosage of 2.5 mg daily, and tamoxifen was administered at a dosage of 20 mg daily.39,  40

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.1,  40 Overall survival and risk of new contralateral breast cancer did not differ significantly between letrozole- and tamoxifen-treated patients.1,  40 Estimated 5-year disease-free survival was 84 or 81.4% for patients receiving letrozole or tamoxifen, respectively.40 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.1,  39 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.52 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.1 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.1 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.52 At a median follow-up of 12.6 years, patients originally randomized to receive letrozole did not have significantly longer disease-free survival, overall survival, breast cancer-free intervals, or distant recurrence-free intervals compared with those originally randomized to receive tamoxifen.82

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.1 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.1,  39 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%.39 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.52

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.1,  39,  40

The efficacy of letrozole and other aromatase inhibitors as sequential therapy following tamoxifen or as initial therapy was further evaluated in a multicenter, open-label, randomized trial (FATA-GIM30).10053 Postmenopausal women with surgically-resected hormone receptor-positive breast cancer were randomly assigned to treatment with either anastrozole 1 mg once daily, exemestane 25 mg once daily, or letrozole 2.5 mg once daily; these treatments were given as initial therapy for 5 years or as sequential therapy for 3 years following 2 years of treatment with tamoxifen 20 mg once daily.10053 A total of 3697 patients were enrolled and followed for a median of 60 months.10053 The primary outcome was disease-free survival.10053 At 5 years, disease-free survival was similar between the initial and sequential regimens (89.8 versus 88.5%, respectively).10053 The secondary outcome of overall survival was also similar between the initial and sequential regimens (96.8 versus 95.3%, respectively).10053 Comparisons between the 3 aromatase inhibitors found 5-year disease-free survival rates of 90.0, 88.0, and 89.4% with anastrozole, exemestane, and letrozole, respectively.10053

An additional trial compared letrozole to anastrozole for initial adjuvant therapy in postmenopausal women with hormone receptor-positive early breast cancer and found no significant differences in survival outcomes.10029

Clinical Experience as Extended Adjuvant Therapy

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).1,  25,  50 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.25

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.25 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).25 The estimated 4-year overall survival rate was similar for patients receiving letrozole versus placebo (96 versus 94%).25 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.25 The study was unblinded, all participants were informed of the findings, and letrozole therapy was offered to all women who had been receiving placebo.25

After the study was unblinded, approximately 60% of patients randomized to receive placebo crossed over to receive letrozole therapy.1 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).1 The effect of patients crossing over from placebo to letrozole therapy confounded the analysis of survival,1,  27 as patients switching from placebo to letrozole accounted for 64% of the total patient-years of follow-up for the placebo group.1 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.1 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.1

An increased incidence of hot flushes (flashes), arthritis, arthralgia, and myalgia was observed in patients receiving letrozole.1,  25 Patients receiving letrozole also experienced higher rates of bone fracture, newly diagnosed osteoporosis, and cardiovascular events.1,  25 Because of the early stoppage of the study, long-term adverse effects associated with letrozole therapy may have been underestimated.27 Postmenopausal women receiving aromatase inhibitors, such as letrozole, as adjuvant therapy are at high risk for osteoporosis.29 (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.1,  25

Clinical Perspective

In the 2010 American Society of Clinical Oncology (ASCO) guidelines on use of adjuvant endocrine therapy for hormone receptor-positive breast cancer, aromatase inhibitors were recommended either as initial therapy or as sequential therapy following 2-3 years of tamoxifen, for a total of 5 years of adjuvant endocrine therapy.10075 Choice of adjuvant endocrine therapy strategy should be based on individual adverse effect profiles of each agent, patient preferences, and pre-existing patient conditions.10075

Focused updates have been published by ASCO since 2010 with some revision to the recommendations for adjuvant endocrine therapy.10019 The updated document states that postmenopausal women with node-positive hormone receptor-positive breast cancer should be offered extended adjuvant endocrine therapy with one of the following: aromatase inhibitor therapy for up to a total of 10 years; tamoxifen for 10 years; tamoxifen for 5 years, then an aromatase inhibitor for 5 years; or tamoxifen for 2-3 years, then an aromatase inhibitor for 7-8 years.10019

Women with node-negative breast cancer may also be offered extended adjuvant endocrine therapy for up to a total of 10 years, although benefits are likely narrower due to the lower risk for recurrence.10019 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 treatment may be switched to a different treatment.10075 Consult the ASCO guidelines for additional information.10019,  10075

Adjuvant Therapy for Early-stage Breast Cancer in Premenopausal Women

Endocrine therapy (i.e., anastrozole, exemestane, letrozole, tamoxifen) has been used in combination with ovarian suppression† as adjuvant therapy in premenopausal women† with early-stage hormone receptor-positive breast cancer.10010,  10011,  10013,  10023,  10026

Clinical Trials

Efficacy and safety of endocrine therapy in combination with ovarian suppression as adjuvant therapy in premenopausal women with early-stage hormone receptor-positive breast cancer have been studied in several open-label, randomized, phase 3 studies.10010,  10011,  10013,  10026

In the Suppression of Ovarian Function Trial (SOFT), 3066 premenopausal women with early-stage hormone receptor-positive breast cancer were randomized to receive 5 years of treatment with tamoxifen 20 mg daily, tamoxifen 20 mg daily and ovarian suppression, or exemestane 25 mg daily and ovarian suppression.10010 Ovarian suppression could be achieved with triptorelin 3.75 mg administered by IM injection every 28 days, bilateral oophorectomy, or bilateral ovarian irradiation.10010 Approximately one-half (53%) of patients enrolled in the study had received prior adjuvant chemotherapy.10010 The primary analysis involved comparison of tamoxifen and ovarian suppression with tamoxifen alone.10010 At a median follow-up of 8 years, disease-free survival and overall survival were prolonged, without a reduction in distant recurrences, in women receiving tamoxifen and ovarian suppression compared with those receiving tamoxifen alone; a disease-free survival benefit and a reduction in distant recurrences were observed, without an overall survival benefit, in women receiving exemestane and ovarian suppression compared with those receiving tamoxifen alone.10012 (See Table 1.)

Subgroup analysis in the SOFT study suggested that the relative clinical benefits of the 3 treatments generally were similar regardless of prior use of adjuvant chemotherapy; however, no difference in disease-free survival was observed with the addition of ovarian suppression to tamoxifen therapy in patients at lower risk of breast cancer recurrence (i.e., older age, node-negative disease, low-grade tumor, smaller tumor size) who had not required prior adjuvant chemotherapy.10010,  10012,  10017 The absolute benefit of combined endocrine and ovarian suppression therapy was greater in higher-risk patients who had received adjuvant chemotherapy.10012 The absolute difference in 8-year disease-free survival rates between women receiving exemestane and ovarian suppression and those receiving tamoxifen alone was greater in women at higher risk of breast cancer recurrence (i.e., younger age, larger or high-grade tumor, lymph node involvement10010,  10012 ) who had received prior adjuvant chemotherapy (9%) compared with those in the lower-risk cohort (5.2%).10012 The absolute difference in 8-year disease-free survival rates between women receiving tamoxifen and ovarian suppression and those receiving tamoxifen alone also was greater in women in the higher-risk cohort (5.3%) compared with those in the lower-risk cohort (3.2%).10012

A combined analysis of the SOFT study and the Tamoxifen and Exemestane Trial (TEXT) included data for 4690 premenopausal women with hormone receptor-positive operable breast cancer who were randomized to receive ovarian suppression and either exemestane 25 mg daily or tamoxifen 20 mg daily for 5 years.10011 Ovarian suppression could be achieved with triptorelin 3.75 mg administered by IM injection every 28 days, bilateral oophorectomy, or bilateral ovarian irradiation.10011 In patients who received adjuvant chemotherapy in the TEXT study, triptorelin was initiated concomitantly with chemotherapy.10011 Approximately one-half (57.4%) of patients in the combined analysis received adjuvant chemotherapy.10011 A 5-year disease-free survival benefit and higher 5-year rates of freedom from breast cancer and freedom from distant recurrence were observed in women receiving exemestane and ovarian suppression compared with those receiving tamoxifen and ovarian suppression.10011 Beneficial effects of combined exemestane and ovarian suppression therapy on disease-free survival and distant recurrences were maintained at 8 years.10012 (See Table 2.) Musculoskeletal symptoms (89.9 versus 77.8%) and osteoporosis (42.2 versus 27.9%) occurred more frequently in exemestane-treated patients compared with tamoxifen-treated patients.10012

In the HOBOE study, 1065 premenopausal women with early-stage hormone receptor-positive breast cancer were randomized to receive 5 years of treatment with tamoxifen 20 mg daily, letrozole 2.5 mg daily, or letrozole 2.5 mg daily in combination with zoledronic acid 4 mg IV every 6 months; all patients received ovarian suppression with triptorelin 3.75 mg by IM injection every 4 weeks for 5 years or until the age of 55 years.10026 The majority (62.6%) of patients had received prior neoadjuvant or adjuvant chemotherapy.10026 At a median follow-up of approximately 5.3 years, a substantial disease-free survival benefit was observed in women receiving letrozole in combination with zoledronic acid and ovarian suppression (hazard ratio of 0.52, which corresponded to an absolute improvement in disease-free survival of 7.9%) but not in those receiving letrozole and ovarian suppression (hazard ratio of 0.72 with a 95% confidence interval of 0.48-1.07), compared with women receiving tamoxifen and ovarian suppression.10026 No difference in overall survival was observed among the 3 treatment groups.10026 However, at the time of the analysis, only 81% of the number of events required for final analysis had occurred.10026 Among patients receiving either letrozole or tamoxifen in combination with ovarian suppression, hypercholesterolemia (30.4 versus 20.3%), arthralgia (44.5 versus 22%), bone pain (29 versus 15.3%), insomnia (8.1 versus 4.2%), sensory neuropathy (13 versus 7.7%), and vaginal dryness ( 20.8 versus 11.7%) occurred more frequently in those receiving letrozole, while endometrial abnormalities (3 versus 6.8%) occurred more frequently in those receiving tamoxifen.10026

In the E-3193/INT-0142 study, 345 premenopausal women with early-stage hormone receptor-positive breast cancer were randomized to receive tamoxifen 20 mg daily with or without ovarian suppression for 5 years.10013 Ovarian suppression therapy could be achieved with goserelin 3.6 mg implanted subcutaneously every 4 weeks, leuprolide acetate 3.75 mg by IM injection every 4 weeks, bilateral oophorectomy, or bilateral ovarian irradiation.10013 Patients enrolled in the study had baseline characteristics associated with lower risk of breast cancer recurrence (i.e., node-negative disease, tumor size of 3 cm or less, no prior adjuvant chemotherapy, median age 45 years).10013,  10017 At a median follow-up of approximately 9.9 years, results of this study were consistent with those of the SOFT study, demonstrating no difference in disease-free or overall survival between lower-risk women receiving tamoxifen and ovarian suppression and those receiving tamoxifen alone; however, interpretation of the results is limited by failure to meet the accrual goal of 1600 patients for superiority testing.10013,  10017 In this study, the addition of ovarian suppression to tamoxifen therapy was associated with increased menopausal symptoms, decreased sexual function, increased breast cancer-specific symptoms, and lower quality of life during the first 3 years of therapy.10013

Clinical Role

Use of adjuvant exemestane or tamoxifen therapy in combination with ovarian suppression improved disease-free survival rates compared with tamoxifen alone in premenopausal women with early-stage hormone receptor-positive breast cancer in the SOFT study;10012 however, more deaths occurred despite fewer distant recurrences in women receiving exemestane and ovarian suppression compared with those receiving tamoxifen and ovarian suppression.10012,  10016 Factors contributing to the discordance between distant recurrence rates and overall survival in women receiving exemestane and ovarian suppression have not been elucidated; however, some clinicians suggest that incomplete and/or intermittent estrogen suppression with gonadotropin-releasing hormone (GnRH) agonists used to achieve ovarian suppression may be a potential mechanism.10016,  10025,  10027 In the combined analysis of the SOFT and TEXT studies, clinical benefits (i.e., disease-free survival, freedom from distant recurrence) were observed in women receiving exemestane and ovarian suppression compared with those receiving tamoxifen and ovarian suppression;10012 however, in the HOBOE study, no difference in disease-free survival was observed between women receiving letrozole and ovarian suppression and those receiving tamoxifen and ovarian suppression.10026

The role of adding ovarian suppression to adjuvant endocrine therapy has not been fully elucidated; however, no discernible benefit from the addition of ovarian suppression to tamoxifen therapy has been observed in premenopausal women at lower risk of disease recurrence (i.e., older age, node-negative disease, low-grade tumor, smaller tumor size) in the SOFT and E-3193/INT-0142 studies, whereas a disease-free survival advantage was observed in a cohort of women at higher risk of disease recurrence (i.e., younger age, high-grade tumor, increased risk of lymph node involvement) receiving ovarian suppression in addition to exemestane or tamoxifen therapy in the SOFT study.10012,  10017

Based on evidence from clinical trials,10010,  10011,  10012,  10013,  10023,  10026 use of endocrine therapy (i.e., anastrozole, exemestane, letrozole, tamoxifen) in combination with ovarian suppression as adjuvant therapy may be considered a reasonable choice (accepted) in premenopausal women with early-stage hormone receptor-positive breast cancer at higher risk of disease recurrence (i.e., younger age, larger or high-grade tumor, increased risk of lymph node involvement) and those who received prior adjuvant chemotherapy.10028 ASCO states that the duration of adjuvant GnRH agonist therapy should not exceed 5 years, since the toxicity of long-term (e.g., beyond 5 years) use of GnRH agonist-induced ovarian suppression has not been determined and comparative data for alternative treatment durations are lacking.10017,  10019 Although inconsistent estrogen suppression may occur in premenopausal women receiving combined ovarian suppression and endocrine therapy, routine monitoring of serum estradiol concentrations is not recommended since there is insufficient evidence to support specific monitoring guidelines and validated estradiol assays are not widely available;10016,  10017,  10020,  10025 however, ASCO recommends monitoring for physiologic changes that would suggest recovery of ovarian function.10017 ASCO states that clinicians should consider recurrence risk, adverse effects, patient preference, quality of life, consequences for childbearing, and the potential for ambiguity regarding the status of ovarian function (e.g., in women with chemotherapy-induced amenorrhea, hysterectomy-induced amenorrhea, incomplete ovarian suppression, or noncompliance with ovarian suppression therapy) when considering the addition of ovarian suppression therapy to adjuvant endocrine therapy.10017,  10019

Advanced Breast Cancer in Postmenopausal Women

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.1 Letrozole is also used for the treatment of advanced breast cancer in postmenopausal women with disease progression following antiestrogen therapy.1

Letrozole is used in combination with ribociclib for the initial treatment of hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer in adults, including postmenopausal women.75,  76,  78,  81

Letrozole also is used in combination with lapatinib ditosylate for the treatment of hormone receptor-positive metastatic breast cancer that overexpresses HER2 in postmenopausal women who are candidates for hormonal therapy.44,  49,  53

Clinical Experience as First-Line Therapy

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 postmenopausal women with hormone receptor-positive or hormone receptor-unknown locally advanced or metastatic breast cancer.1,  20 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.1,  20

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.1,  21 The median duration of response was 18 months in patients receiving letrozole and 16 months in those receiving tamoxifen.1 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.1 Median overall survival (35 versus 32 months) was similar in patients randomized to receive letrozole or tamoxifen, respectively.1 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.1

The design of the study allowed patients to cross over to the opposite treatment arm upon disease progression.1 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.1 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.1 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.1

Clinical Experience as Second-Line Therapy After Tamoxifen

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.1,  7,  8,  19 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).1,  7,  8 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.1

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.1,  19 Responses to letrozole were observed in patients with advanced breast cancer that did not respond to first-line antiestrogen therapy.7 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.1 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.1

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.1,  19

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.22 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.1,  7,  8,  22 Some clinicians question whether there is any clinically meaningful difference in efficacy and safety between these letrozole dosages;30,  31,  37 commercially available letrozole tablets are available for the 2. 5-mg dose only.1,  14

One open-label randomized controlled trial compared anastrozole to letrozole for the treatment of postmenopausal women with advanced breast cancer whose disease had progressed following treatment with tamoxifen or another antiestrogen treatment.84 In this trial, the overall response rate was higher in the letrozole group (19.1 versus 12.3% with anastrozole), but no significant differences in time to progression, clinical benefit, median duration of response, duration of clinical benefit, time to treatment failure, or overall survival were observed between groups.84

For further information on agents used in combination with letrozole for advanced breast cancer, please refer to the Ribociclib and Lapatinib monographs.

Clinical Perspective

Updated guidelines from the ASCO provide recommendations for treatment of women and men with hormone receptor-positive, HER2-negative advanced or metastatic breast cancer.4000 According to ASCO, combination therapy with a nonsteroidal aromatase inhibitor (e.g., letrozole, anastrozole) and a cyclin-dependent kinase (CDK) 4/6 inhibitor should be offered first line to postmenopausal patients with treatment-naive hormone receptor-positive metastatic breast cancer.4000 Although most postmenopausal patients appear to benefit from combination therapy, endocrine monotherapy with an aromatase inhibitor may be the best choice for first-line therapy in some patients; the choice between monotherapy and combination therapy should be based on factors such as disease burden, disease-free interval, patient age, patient choice, and treatment tolerance.4000

Choice of second-line hormonal therapy should take into account prior treatment exposure and response to previous endocrine therapy; options for second-line therapy include tamoxifen, an aromatase inhibitor, or fulvestrant with or without everolimus.4000 Patients with progressive disease during treatment with aromatase inhibitors and patients who develop recurrence within 1 year of adjuvant aromatase inhibitor therapy should be offered fulvestrant and a CDK4/6 inhibitor.4000 Treatment with exemestane and everolimus may be offered, either before or after treatment with fulvestrant, to postmenopausal patients with hormone receptor-positive metastatic disease that progressed during treatment with a nonsteroidal aromatase inhibitor; this combination should not be offered as first-line therapy for patients who relapse more than 12 months from prior nonsteroidal aromatase inhibitor therapy or for those who are naive to hormonal therapy.4000 Consult the ASCO guideline for additional information.4000

Advanced Breast Cancer in Pre-/Perimenopausal Women and Men

Letrozole is used in combination with ribociclib and a GnRH agonist for the initial treatment of hormone receptor-positive, HER2-negative advanced or metastatic breast cancer in adult patients, including pre-/perimenopausal women and men.76,  80

Clinical Perspective

In premenopausal women with treatment-naive, hormone receptor-positive metastatic breast cancer, ASCO recommends combination therapy with a nonsteroidal aromatase inhibitor (e.g., letrozole, anastrozole) and a CDK 4/6 inhibitor, in conjunction with chemical ovarian function suppression.4000 In most patients, these combination regimens are the preferred first-line treatment, based on data demonstrating improvements in progression-free and overall survival.4000 Ovarian suppression (e.g., with goserelin) or ablation in combination with hormonal therapy should be offered to premenopausal women with metastatic hormone receptor-positive breast cancer; patients without prior exposure to hormonal therapy may be treated with tamoxifen or ovarian suppression/ablation alone, but combination therapy is preferred.4000

In men with advanced or metastatic hormone receptor-positive, HER2-negative breast cancer, ASCO recommends endocrine therapy first line except in cases of visceral crisis or rapidly progressing disease.10056 Options for endocrine therapy include tamoxifen, an aromatase inhibitor combined with a GnRH agonist, and fulvestrant.10056 As in women, CDK 4/6 inhibitors may be used in combination with endocrine therapy.10056

General

Pretreatment Screening

• Perform pregnancy testing in females of reproductive potential prior to starting letrozole.1

Patient Monitoring

• Consider bone density and serum cholesterol monitoring during therapy.1

Dispensing and Administration Precautions

• To avoid medication errors, the Institute for Safe Medication Practices (ISMP) recommends that prescribers communicate both the brand and generic names for letrozole on the prescription order form.222

Administration

Letrozole is administered orally.1 Food does not affect the absorption of letrozole, and the drug may be administered without regard to meals.1

Commercially available letrozole tablets should be stored at a controlled room temperature of 20-25°C (excursions permitted between 15-30°C).1

Dosage

Breast Cancer

Initial, Sequential, or Extended Adjuvant Therapy for Postmenopausal Women with Early-Stage Hormone Receptor-Positive 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.1 The optimal duration of adjuvant therapy is unknown.1 The median duration of therapy in the study establishing use of letrozole as initial adjuvant therapy was 5 years.1 Treatment should be discontinued if relapse occurs.1

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.1,  25 The optimal duration of therapy is unknown.1,  25 The planned duration of therapy in the study establishing use of letrozole as extended adjuvant therapy was 5 years.1,  25 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.1 Treatment should be discontinued if relapse occurs.1,  25

The American Society of Clinical Oncology (ASCO) states that postmenopausal women with node-positive hormone receptor-positive early breast cancer should be offered extended adjuvant endocrine therapy with one of the following: aromatase inhibitor therapy for up to a total of 10 years; tamoxifen for 10 years; tamoxifen for 5 years, then an aromatase inhibitor for 5 years; or tamoxifen for 2-3 years, then an aromatase inhibitor for 7-8 years.10019 Women with node-negative breast cancer may also be offered extended adjuvant endocrine therapy for up to a total of 10 years, although benefits are likely narrower due to the lower risk for recurrence.10019

Adjuvant Therapy for Early-stage Breast Cancer in Premenopausal Women in Combination with Ovarian Suppression

When used in combination with ovarian suppression† as adjuvant therapy in premenopausal women† with early-stage hormone receptor-positive breast cancer, letrozole has been administered at a dosage of 2.5 mg once daily for 5 years.10026

Advanced Breast Cancer in Postmenopausal Women

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.1 Treatment should be continued until disease progression occurs.1

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.1 Treatment should be continued until disease progression occurs.1

Advanced Breast Cancer in Pre-/Perimenopausal Women and Men

For the initial treatment of hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer in pre-/perimenopausal women and men, the recommended dosage of letrozole is 2.5 mg once daily, taken in combination with ribociclib.76 These patients also should receive therapy with a luteinizing hormone-releasing hormone (LHRH) agonist according to current clinical practice standards.76

Special Populations

Hepatic Impairment

The manufacturer states that no dosage adjustment is required in patients with mild to moderate hepatic impairment.1 A 50% reduction in letrozole dosage (to 2.5 mg every other day) is recommended in patients with cirrhosis and severe hepatic impairment.1

Renal 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.1

Geriatric Patients

The manufacturer makes no specific dosage recommendations for geriatric patients.1

Contraindications

• Pregnancy.1
• Known hypersensitivity to letrozole or any ingredient in the formulation.1

Warnings/Precautions

Bone Effects

Because letrozole lowers circulating estrogen concentrations, it may cause a reduction in bone mineral density (BMD).1,  14,  43 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%).1 Results for total hip BMD were similar, although the difference between treatment groups was less pronounced.1 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.1 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 3.8% in patients receiving letrozole compared with 2% in those receiving placebo;1 letrozole- and placebo-treated patients had similar changes from baseline in lumbar spine BMD.1

In the trial evaluating letrozole as initial or sequential adjuvant therapy (BIG 1-98), bone fractures occurred in 14.7 and 11.4% of patients treated with letrozole and tamoxifen, respectively, at a median follow-up of 96 months.1 Osteoporosis occurred in 5.1 and 2.7% of patients in the letrozole and tamoxifen groups, respectively.1 In the trial evaluating letrozole as extended adjuvant therapy, bone fractures occurred in 13.3 and 7.8% of patients receiving letrozole and placebo, respectively, at a median follow-up of 62 months.1 Osteoporosis occurred in 14.5 and 7.8% of patients receiving letrozole and placebo, respectively.1

Consider BMD monitoring in patients receiving letrozole.1

Cholesterol

In the BIG 1-98 trial, hypercholesterolemia was reported in 52.3 and 28.6% of patients receiving letrozole and tamoxifen, respectively; hypercholesterolemia was grade 3 or 4 in 0.4% of letrozole-treated patients and 0.1% of tamoxifen-treated patients.1 Among patients with normal serum cholesterol at baseline (defined as less than 1.5 times the upper limit of normal [ULN]), increases to 1.5 times the ULN or greater occurred in 8.4 and 3.9% of patients in the letrozole and tamoxifen groups, respectively.1 Lipid-lowering medications were required in 29% of letrozole-treated patients and 20% of tamoxifen-treated patients.1

Consider cholesterol monitoring in patients receiving letrozole.1

Hepatic Impairment

Patients with cirrhosis and severe hepatic impairment experienced twice the exposure to letrozole as healthy volunteers with normal liver function.1 Dosage reduction is recommended in this population.1 The effect of hepatic impairment on letrozole exposure in cancer patients with elevated bilirubin levels has not been determined.1

Fatigue and Dizziness

Because fatigue, dizziness, and, uncommonly, somnolence have been reported during letrozole therapy, patients should be advised to use caution while driving or operating machinery.1

Laboratory Test Abnormalities

No dose-related effects on hematologic or clinical chemistry parameters were identified in clinical trials.1 Some patients receiving letrozole 2.5 mg experienced moderate decreases in lymphocyte counts that were of uncertain clinical significance; these decreases were transient in approximately half of the affected patients.1 Thrombocytopenia occurred in 2 patients receiving letrozole, but the relationship to letrozole was unclear.1 Patient withdrawal due to laboratory abnormalities occurred infrequently.1

Fetal/Neonatal Morbidity and Mortality

Based on postmarketing reports, findings from animal studies, and the mechanism of action, letrozole can cause fetal toxicity and is contraindicated during pregnancy.1 Advise females of reproductive potential to use effective contraceptive methods while receiving the drug and for at least 3 weeks after discontinuance of the drug.1 Perform pregnancy testing prior to the initiation of letrozole.1 If letrozole is administered during pregnancy or if the patient becomes pregnant while receiving the drug, inform the patient of the potential hazard to the fetus.1

Specific Populations

Pregnancy

Letrozole is contraindicated in women who are pregnant since the drug can cause fetal toxicity when administered to pregnant women.1 The manufacturer states that a pregnancy test should be performed prior to initiation of letrozole therapy in females of reproductive potential and that such women should be advised to use effective contraceptive methods while receiving the drug and for at least 3 weeks after discontinuance of the drug.1 If letrozole is administered during pregnancy or if the patient becomes pregnant while receiving the drug, inform the patient of the potential hazard to the fetus.1

Spontaneous abortion and congenital birth defects have been reported during postmarketing experience when the drug was used in pregnant women; however, postmarketing reports on letrozole use during pregnancy are insufficient to inform a drug-associated risk of adverse pregnancy-related outcomes.1 In animal reproduction studies, letrozole administered to pregnant rats and rabbits during organogenesis was associated with increased pregnancy loss (increased postimplantation loss, increased resorption, and decreased number of live fetuses) and teratogenicity (skeletal and renal malformations) at dosages approximately 0.1 times the maximum recommended human dosage on a mg/m² basis.1

Lactation

It is not known whether letrozole is distributed into human milk or if the drug has any effects on nursing infants or on milk production.1 Because many drugs are distributed into milk and because impaired reproductive performance has been observed in male offspring of lactating rats and letrozole has the potential to cause serious adverse reactions in nursing infants, women should be advised to discontinue breast-feeding during letrozole therapy and for at least 3 weeks after discontinuance of the drug.1

Females and Males of Reproductive Potential

Based on animal studies, letrozole may cause fetal harm; use of letrozole is contraindicated during pregnancy.1 Perform pregnancy testing in all females of reproductive potential prior to starting treatment with letrozole.1 Advise females of reproductive potential to use effective contraceptive methods while receiving the drug and for at least 3 weeks after discontinuance of the drug.1

Results of animal studies suggest that letrozole may impair male and female fertility.1 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/m² basis, respectively) caused sexual inactivity in females and atrophy of the reproductive tract in males and females.1

Pediatric Use

The manufacturer states that safety and efficacy of letrozole in pediatric patients have not been established.1

Adverse effects on bone (bone maturation, BMD) 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 7.1

Geriatric Use

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.1 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.1

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.1 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.1

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).1 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.1

Hepatic Impairment

Letrozole is metabolized slowly in the liver.1 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.1 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 AUC and a 47% reduction in systemic clearance of letrozole have been reported.1 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.1 The manufacturer states that no dosage adjustment is required in patients with mild to moderate hepatic impairment.1 Patients with severe hepatic impairment are exposed to higher concentrations of letrozole, and dosage reduction is necessary.1 A 50% reduction in letrozole dosage (to 2.5 mg every other day) is recommended in patients with cirrhosis and severe hepatic impairment.1

Renal Impairment

Although letrozole is metabolized to an inactive metabolite whose glucuronide conjugate undergoes mainly renal excretion, 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.1

The manufacturer states that no dosage adjustment is necessary in patients with a creatinine clearance of at least 10 mL/minute.1

Common Adverse Effects

The most common adverse effects (occurring in greater than 20% of patients) are hot flashes, arthralgia, flushing, asthenia, edema, headache, dizziness, hypercholesterolemia, increased sweating, bone pain, and musculoskeletal effects.1

Letrozole is a substrate of cytochrome P-450 (CYP) 3A4 and CYP2A6.1 Letrozole has been shown to inhibit CYP2A6 and CYP2C19 in human liver microsomes, but the clinical significance of this is not known.1

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.1,  14 Cimetidine, which inhibits hepatic microsomal enzymes, did not alter the pharmacokinetics of letrozole.1,  14

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.1,  14 An interaction study did not show a clinically important effect of letrozole on the pharmacokinetics of warfarin.1,  14

Estrogens

Because estrogens may diminish the pharmacologic action of aromatase inhibitors, such as letrozole, these agents should not be used concomitantly.14,  37

Tamoxifen

Concomitant use of tamoxifen 20 mg daily and letrozole 2.5 mg daily reduced letrozole plasma concentrations by an average of 38%.1,  23 In a separate study, no effect of letrozole on the pharmacokinetics of tamoxifen, its principal active metabolite, N -desmethyltamoxifen, or 4-hydroxytamoxifen was observed.24 Analysis of blood samples from both of these studies demonstrates similar degrees of estrogen suppression for letrozole alone and in combination with tamoxifen.23,  24 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.1

Description

Letrozole, a benzyltriazole derivative, is a selective, nonsteroidal aromatase inhibitor.1,  13 Letrozole differs structurally from aminoglutethimide but shares the pharmacologic activity of competitive aromatase inhibition; although both drugs are selective nonsteroidal inhibitors, letrozole is more potent and selective on a molar basis.12,  13 Competitive aromatase inhibitors also have been referred to as type II inhibitors of the enzyme.13 Like anastrozole, letrozole is a triazole derivative.13 The N -4 nitrogen of the triazole ring, which coordinates with the heme iron atom of the aromatase enzyme complex, is thought to be responsible for the high affinity of the drug for the estrogen synthetase enzyme.4

The growth of some breast cancers is stimulated or maintained by estrogens; in these cancers, decreasing estrogen levels or inhibiting estrogen effects can lead to decreased tumor mass or delayed cancer progression.1 In postmenopausal women, estrogens are primarily produced through the action of aromatase enzymes, which convert adrenal androgens (e.g., androstenedione, testosterone) to estrone and estradiol.1 Letrozole selectively inhibits synthesis of estrogens via inhibition of the aromatase enzyme; it does not affect synthesis of adrenal corticosteroid, aldosterone, or thyroid hormone.1,  6 Suppression of plasma concentrations of estradiol, estrone, and estrone sulfate by 75-95% from baseline, with maximal suppression achieved within 2-3 days, has been observed in postmenopausal women with advanced breast cancer receiving daily letrozole doses of 0.1-5 mg.1 Suppression was dose-related, and letrozole doses equal to or exceeding 0.5 mg resulted in suppression to estrone and estrone sulfate concentrations below the lower limit of detection in many cases.1 Suppression of serum estrogen concentrations was maintained throughout treatment in all patients receiving daily letrozole doses equal to or exceeding 0.5 mg.1

Letrozole is rapidly and completely absorbed from the GI tract following oral administration.1 Steady-state plasma concentrations of the drug are reached in 2-6 weeks in patients receiving letrozole 2.5 mg daily.1 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.1 However, continuous accumulation of letrozole does not occur, and steady-state concentrations are maintained over extended periods of daily drug administration.1 Food does not affect the oral absorption of the drug.1

Letrozole is weakly bound to plasma proteins.1 It has a terminal elimination half-life of about 2 days.1 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.1 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 2A6.1

Following oral administration of radiolabeled letrozole, 90% of the administered dose was excreted in the urine.1 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.1

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.1 Age-related differences between adults and children or race-related differences in the pharmacokinetics of letrozole have not been evaluated.1

Advice to Patients

• Risk of dizziness, fatigue, or somnolence; use caution when driving or operating machinery.1
• Risk of osteoporosis.1,  29 Monitor bone mineral density (BMD).1
• Risk of fetal harm and pregnancy loss.1 Advise females of reproductive potential to use effective contraception during letrozole therapy and for ≥3 weeks after the last dose.1 Importance of women informing clinicians immediately if they become pregnant or if pregnancy is suspected during therapy.1 If pregnancy occurs, advise pregnant women of potential risk to the fetus.1
• Advise women to avoid breast-feeding while receiving letrozole and for ≥3 weeks following discontinuance of therapy.1
• Risk of male or female infertility.1
• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1
• Importance of informing patients of other important precautionary information.1 (See Cautions.)

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

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