Femara 2.500 mg

Food slightly decreases the rate of absorption (median t_max 1 hour fasted vs. 2 hours fed and mean C_max 129±20.3 nmol/L fasted vs. 98.7±18.6 nmol/L fed), but the extent of absorption (area under the curve (AUC)) remains unchanged. This minor effect on absorption rate is not considered to be of clinical relevance and therefore letrozole may be taken with or without food.

Clinical trials of interaction with FEMARA (letrozole) and cimetidine or warfarin indicate that coadministration does not result in clinically significant drug interactions.

A review of the clinical trial database indicated no evidence of other clinically relevant interactions with other commonly prescribed drugs.

In vitro, letrozole inhibits the cytochrome P450 isoenzymes 2A6 and moderately 2C19. CYP2A6 does not play a major role in drug metabolism. In in vitro experiments letrozole was not able to substantially inhibit the metabolism of diazepam (a substrate of CYP2C19) at concentrations approximately 100-fold higher than those observed in plasma at steady-state. Thus clinically relevant interactions with CYP2C19 are unlikely to occur. However, caution should be used in the concomitant administration of drugs whose disposition is mainly dependent on these isoenzymes and whose therapeutic index is narrow.

No clinically significant changes in the results of clinical laboratory tests have been observed.

Co-administration of FEMARA and tamoxifen 20 mg daily resulted in a reduction of letrozole plasma levels by 38% on average. The clinical significance of this finding has not been explored in prospective clinical trials.

There is no clinical experience to date on the use of FEMARA in combination with other anti-cancer agents.

No dosage adjustment is required for patients with renal impairment (creatinine clearance ≥10 mL/min) or moderate hepatic impairment. Insufficient data are available to recommend a dose adjustment in breast cancer patients with severe non-metastatic hepatic impairment. Therefore, patients with severe hepatic impairment (Child-Pugh score C) should be kept under close supervision for adverse events (see Warnings and Precautions).

Insufficient data available to recommend dose adjustment in patients with severe hepatic impairment (see Patients with Hepatic and/or Renal Impairment).

The recommended dose is one 2.5 mg tablet once daily. No dose adjustment is required for elderly patients.

In the adjuvant setting, the intended duration of treatment is 5 years, although data are limited to a median follow-up of 26 months.

In the extended adjuvant setting, treatment with FEMARA (letrozole) is intended for 5 years, although scientific evidence collected to date covers a median follow-up of 49 months.

In the first- and second-line advanced breast cancer settings, FEMARA (letrozole) treatment should continue until further tumour progression is evident.

The missed dose should be taken as soon as the patient remembers. However, if it is almost time for the next dose, the missed dose should be skipped, and the patient should go back to her regular dosage schedule. Do not double doses.

cataract, eye irritation, blurred vision.

The most frequent adverse events irrespective of drug relationship (cut-off frequency of at least 2%) reported in the 604/2566 (23.5%) patients randomized to the FEMARA arm who had actually completed 5 years of treatment were: flushing (384, 64%), asthenia (288, 47.4%), increased sweating (241, 40%), headache (221, 37%), arthralgia (220, 36%), hypercholesterolemia (187, 31%), edema NOS (160, 26.5%) and dizziness (145, 24%).

In contrast to general self-reported adverse events presented in Table 3, dates of onset were recorded for serious adverse events (SAE) and for targeted adverse events of fracture, osteoporosis and cardiovascular events. The comparison between the FEMARA randomized arm to placebo until switch is therefore more meaningful for these events.

cough.

memory impairment, dysesthesia{*Including paresthesia, hypoesthesia.}, taste disturbance, cerebrovascular accident.

rash{‡Including erythematous, maculopapular, psoriaform and vesicular rash.}, pruritus, dry skin, urticaria, angioedema, erythema multiforme, toxic epidermal necrolysis.

myalgia, osteoporosis, bone fractures.

urinary tract infection.

thrombophlebitis{§Including superficial and deep thrombophlebitis.}, hypertension, pulmonary embolism, arterial thrombosis, cerebrovascular infarction, ischemic cardiac events.

weight increase, weight loss, increase in aminotransferases.

leukopenia.

anxiety{†Including nervousness, irritability.}.

dyspepsia, abdominal pain, stomatitis, dry mouth.

The most frequent cause of non-cancer death during study treatment or within 30 days of stopping treatment (regardless of treatment arm) was cardiovascular. (See Warnings and Precautions, Cardiovascular.)

The incidence of serious adverse events (all grades 1-5) regardless of study drug relationship was 0.5% in the FEMARA group, 1.3% in the placebo not switched arm and 0.3% in FEMARA after switch arm. Breast cancer related death reported during treatment or within 30 days of stopping treatment occurred in 0.5% of patients in the FEMARA arm, 0.8% in the placebo not switched arm and 0.3% in the FEMARA after switch arm. Non-breast cancer related death reported during treatment or within 30 days of stopping treatment occurred in 1.7% of patients in the FEMARA arm, 2.6% in the placebo not switched arm and 0.5% in the FEMARA after switch arm.

vaginal discharge.

Spontaneously reported adverse drug reactions are presented below. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or clearly establish a causal relationship to FEMARA exposure.

tumour pain.

palpitations, tachycardia, atrial fibrillation, atrial flutter, cardiac failure.

pyrexia, mucosal dryness, thirst.

FEMARA (letrozole) was generally well tolerated across all studies as first-line and second-line treatment for advanced breast cancer. Approximately one third of patients treated with FEMARA can be expected to experience adverse reactions. The most frequently reported adverse reactions in the clinical trials were hot flushes, nausea and fatigue. Many adverse reactions can be attributed to the normal physiological consequences of estrogen deprivation (e.g., hot flushes, alopecia and vaginal bleeding). The adverse drug reactions reported from clinical trials are summarized for first-line and second-line treatment with FEMARA.

increased urinary frequency.

Updated results (median follow-up was approximately 50 months) from the lipid sub-study showed no significant differences between the FEMARA and placebo groups at any time.

The MA-17 study is ongoing. The final study results are pending.

There were no differences in the incidence and severity of adverse reactions in patients ≤55 years, 55-69 years and ≥70 years.

The Data and Safety Monitoring Committee, after review of the primary analysis results of the BIG 1-98 study, observed a difference in incidence in grade 5 myocardial infarctions (9 vs. 2 in the letrozole and tamoxifen arms, respectively) and recommended that these cardiac events and certain other safety data be reviewed. As a result, a blinded medical review of more than 2000 patients with pre-specified adverse events (cardiovascular events, fractures, arthritis/arthralgia, myalgia, any adverse event leading to discontinuation) or death without a prior cancer event was conducted following the primary analysis of the adjuvant trial BIG 1-98. This medical review resulted in a change in the cause of death for 25 patients, 19 of which were reclassified from a cardiac cause to either “sudden death, cause unknown” (9 cases in letrozole arm, 7 cases in tamoxifen arm) or to “other” (3 cases in letrozole arm). Some adverse events (such as arthritis/arthralgia and edema) reported in the primary analysis did not meet the definition of a treatment-emergent adverse event as they were present at baseline and did not worsen in severity during treatment. The BIG 1-98 study is currently ongoing, and the medical review is being conducted on an ongoing basis; the updated efficacy and safety results from the study will be made available at the 5-year median treatment duration. It is important to note that these updated safety data will not be comparable with those of the primary analysis. Extrapolation of the absolute risk of these pre-specified events as a function of time cannot be reasonably established.

FEMARA was generally well tolerated as adjuvant treatment of early breast cancer. In the adjuvant setting (26 months median follow-up) approximately 91% vs. 86% of the patients allocated to FEMARA or tamoxifen, respectively, experienced adverse events. Generally, the observed adverse events were mainly mild or moderate in nature, and most were associated with estrogen deprivation. The most frequently reported adverse events in the adjuvant setting were hot flushes (letrozole: 33.7%, tamoxifen: 38.0%), arthralgia/arthritis (letrozole: 21.2%, tamoxifen 13.5%), and night sweats (letrozole: 14.1%, tamoxifen: 16.4%).

increased hepatic enzymes, hepatitis.

Adverse events discussed below were analyzed irrespective of relationship to study treatment.

FEMARA was generally well tolerated as extended adjuvant treatment in women who have received prior standard adjuvant tamoxifen treatment. In the phase III trial for extended adjuvant therapy, after a median follow-up of 28 months 87.2% vs. 84.5% of the patients on FEMARA or placebo experienced adverse events. The most frequent events were: hot flushes (FEMARA 49.7% vs. placebo 43.3%), fatigue (lethargy, asthenia, malaise) (FEMARA 33.8% vs. placebo 32.2%), arthralgia/arthritis (FEMARA 27.7% vs. placebo 22.2%); and sweating (diaphoresis) (24.3% vs. placebo 22.5%).

After the study unblinding, patients randomized to placebo arm were offered to switch to FEMARA. The placebo results beyond 28 months median follow-up are confounded by the fact that 56% of patients randomised placebo opted to switch to FEMARA and that dates of onset for general adverse events (based on self-report) were not recorded. In most cases, therefore, it cannot be determined if the adverse events in the placebo group occurred before switch to FEMARA or after switch to FEMARA. General adverse event data after unblinding of the study should therefore be interpreted with caution.

In the extended adjuvant study after study unblinding at a median follow-up of approximately 49 months the overall incidence of adverse events reported during study treatment or within 30 days irrespective of causality was 94.2% in FEMARA, 91.1% in placebo not switched and 94.1% in placebo patients switched to FEMARA. The most frequent adverse events were: hot flushes (60.3% in FEMARA vs. 52.6% in placebo not switched), fatigue (lethargy, malaise, asthenia) (45.0% in FEMARA vs. 44.8% in placebo not switched), arthralgia/arthritis (37.9% in FEMARA vs. 26.8% in placebo not switched), sweating (diaphoresis) (34.0% in FEMARA vs. 29.8% in placebo not switched).

Most frequently reported adverse events from the clinical trials in adjuvant and extended adjuvant are summarized in Table 1, Table 2 and Table 3.

anaphylactic reaction.

After the study unblinding, patients randomized to the placebo arm were offered to switch to FEMARA or discontinue treatment.

The updated results from the MA-17 core safety population obtained after unblinding, showed that at a median follow-up of 49 months, the incidence of osteoporosis any time after randomization was higher in patients originally randomized in the FEMARA arm than for patients in the placebo until switch arm [12.3% in FEMARA arm vs. 7.4% in placebo until switch arm (P<0.001)].

The incidence of bone fractures, any time after randomization, was significantly higher in patients who received FEMARA than for placebo until switch (10.9% vs. 7.2%, respectively). In the placebo patients who switched to FEMARA, newly diagnosed osteoporosis, any time after switching, was reported in 3.6% while fractures were reported in 5.1% any time after switching.

In the randomized FEMARA arm, 1.9% of patients experienced more than one fracture, compared with 1.1% in the placebo until switch group and 1.0% in the FEMARA after switch from placebo group. Of the 74/1448 patients who experienced a fracture after switching to FEMARA from placebo, 12 patients had previously experienced a fracture on placebo (and 3 of these patients had experienced more than one fracture on placebo).

The interpretation of the updated results in the core study is confounded by the fact that after study unblinding, 56% of patients randomized placebo opted to switch to FEMARA, resulting in different median exposure to treatment (47 months for FEMARA, 28 months for placebo until switch and 20 months for FEMARA after switch from placebo).

Updated results (median follow-up was 40 months) from the bone mineral density (BMD) sub-study conducted in a subset of 219 patients (117 on FEMARA and 102 on placebo, including 77 placebo/FEMARA switchers), demonstrated that, at 2 years, compared to baseline, patients receiving FEMARA had a median decrease of 3.8% in hip BMD compared to 2.0% in the placebo until switch group (P=0.018). There were no statistically significant differences in median % changes from baseline in hip BMD at any other measured time-points other than at 2 years. There were no statistically significant changes in lumbar spine BMD at any time between FEMARA and placebo until switch groups. In the 77 placebo patients who switched to FEMARA, BMD in the hip and lumbar spine showed a median decrease from baseline of approximately 1-2% at each of the first, second and third annual visits after switching to FEMARA. The treatment duration in each group was median 38 months for FEMARA, 22 months for placebo until switch and 22 months for FEMARA after switch from placebo respectively. (See also Warnings and Precautions, Musculoskeletal and Special Populations, Geriatrics.)

There have been no age-related effects observed on the pharmacokinetics of letrozole.

In the adjuvant setting, more than 8000 postmenopausal women were enrolled in the clinical study. In total, 36% of patients were aged 65 years or older at enrolment, while 12% were 75 or older. Although more adverse events were generally reported in elderly patients irrespective of study treatment allocation, the differences between the two treatment groups were similar to those of younger patients.

In a 5-year, phase III trial for extended adjuvant therapy, after a median follow-up of 28 months, fracture rates recorded any time after randomization in patients 65 years and older were 7.1% (77/1090) in the FEMARA arm compared to 7.5 % (77/1033) in the placebo arm; the difference is not statistically significant (P=0.738). These results were obtained prior to study unblinding.

After the study unblinding, patients randomized to the placebo arm were offered to switch to FEMARA or discontinue treatment.

The updated results obtained from this phase III trial after unblinding at a median follow-up of approximately 49 months, showed that the fracture rates any time after randomization in patients 65 years and older were 12.2% (133/1090) in FEMARA arm compared to 10.2% (105/1032) in placebo until switch arm and 6.9% (34/495) in FEMARA after switch arm.

The interpretation of the updated results is confounded by the fact that after study unblinding, 56% of patients randomized placebo opted to switch to FEMARA, resulting in different median exposure to treatment (47 months for FEMARA, 28 months for placebo until switch and 20 months for FEMARA after switch). (See also Adverse Reactions, Clinical Trial Adverse Drug Reactions.) The study is ongoing.

Letrozole was evaluated for maternal toxicity as well as embryotoxic, fetotoxic and teratogenic potential in female rats following oral administration of daily doses of 0.003, 0.01 or 0.03 mg/kg on gestation days 6 through 17. Oral administration of letrozole to pregnant rats resulted in teratogenicity and maternal toxicity at 0.03 mg/kg. Embryotoxicity and fetotoxicity were seen at doses of ≥0.003 mg/kg and there was an increase in the incidence of fetal malformation among the animals treated. However it is not known whether this was an indirect consequence of the pharmacological activity of FEMARA (inhibition of estrogen biosynthesis) or a direct drug effect.

Clinical trial evidence (median follow-up duration of 26 months in the adjuvant setting, 49 months in the extended adjuvant setting) is insufficient to assess adverse effects associated with long term use of letrozole for five years.

In the adjuvant setting, the use of aromatase inhibitors, including FEMARA, may increase lipid levels (see Adverse Reactions, Clinical Trial Adverse Drug Reactions). Women should have their cholesterol levels assessed and managed according to current clinical practice and guidelines.

Since fatigue and dizziness have been observed with the use of FEMARA, and somnolence has been reported uncommonly, caution is advised when driving or using machines.

In a single dose trial with 2.5 mg letrozole in volunteers with hepatic impairment, mean AUC values of the volunteers with moderate hepatic impairment was 37% higher than in normal subjects, but still within the range seen in subjects with normal hepatic function. In a study comparing the pharmacokinetics of letrozole after a single oral dose of 2.5 mg in eight subjects with liver cirrhosis and severe non-metastatic hepatic impairment (Child-Pugh score C) to those in healthy volunteers (N=8), AUC and t_½ increased by 95 % and 187%, respectively. Breast cancer patients with severe hepatic impairment are thus expected to be exposed to higher levels of letrozole than patients without severe hepatic dysfunction. Long term effects of this increased exposure have not been studied.

These results indicate that no dosage adjustment is necessary for breast cancer patients with mild to moderate hepatic dysfunction. However, since letrozole elimination depends mainly on intrinsic metabolic clearance, caution is recommended. Insufficient data are available to recommend a dose adjustment in breast cancer patients with severe non-metastatic hepatic impairment. Therefore, such patients should be kept under close supervision for adverse events.

There have been post-market reports of spontaneous abortions and congenital anomalies in infants of mothers who have taken FEMARA. Letrozole should not be given to women with premenopausal endocrine status (see Contraindications). Women who are not premenopausal but have the potential to become pregnant, including women who are perimenopausal or who recently became postmenopausal, should use appropriate contraception while being treated with FEMARA (see also Sexual Function/Reproduction, Reproductive Toxicology).

Letrozole should not be given to pregnant women (see Contraindications).

Letrozole should not be administered to nursing mothers (see Contraindications).

Pharmacokinetics of a single 2.5 mg letrozole dose were unchanged in a study in postmenopausal women with varying degrees of renal function (24-hour creatinine clearance=9-116 mL/min.). In a study in 364 patients with advanced breast cancer there was no significant association between letrozole plasma levels and calculated CL_cr (range 22.9-211.9 mL/min). No dosage adjustment is required in patients with CL_cr ≥10 mL/min. No data are available for patients with CL_cr ≤9 mL/min. The potential risks and benefits to such patients should be considered carefully before prescribing letrozole.

In the adjuvant setting, the use of some aromatase inhibitors, including FEMARA, may increase the risk of cardiovascular events compared to tamoxifen. The overall incidence of cardiovascular events in the BIG 1-98 study for FEMARA and tamoxifen arms was 9.7 vs. 10.5%, respectively. However, a higher incidence of events was seen for FEMARA vs. tamoxifen, including cardiac failure (0.9 vs. 0.4%, respectively), myocardial infarction (0.8 vs. 0.4%, respectively), fatal cardiac events (0.6 vs. 0.3%, respectively) and numerically higher fatal stroke (0.15%, 6 cases vs. 0.03%, 1 case, respectively), and a lower incidence was seen for thromboembolic events (1.4% vs. 3.0%, respectively). Patients with non-malignant systemic diseases (cardiovascular, renal, hepatic, lung embolism etc.) which would prevent prolonged follow-up were ineligible from enrolment in the BIG 1-98 trial (see Adverse Reactions, Clinical Trial Adverse Drug Reactions).

In the extended adjuvant setting, in a 5-year, phase III trial, after a median follow-up of 28 months, the incidence of cardiovascular events any time after randomization was comparable between treatment arms; 6.8% in the FEMARA arm compared to 6.5% in the placebo arm. The most frequent cardiovascular events were: new or worsening angina (1.4% in the FEMARA arm vs. 1.0% in the placebo arm), myocardial infarction (0.6% in the FEMARA arm vs. 0.7% in the placebo arm), and stroke/transient ischemic attack (0.9% in the FEMARA arm vs. 0.9% in the placebo arm). These results were obtained prior to unblinding the study.

After the study unblinding, patients randomized to the placebo arm were offered to switch to FEMARA or discontinue treatment.

The updated results obtained from this Phase III study after study unblinding showed that after a median follow-up of approximately 49 months, the frequency of cardiovascular events any time after randomization was higher in the FEMARA arm than in placebo arm until the switch (11.1% vs. 8.6%, respectively). The most frequent cardiovascular events included arrhythmia (4.0% in the FEMARA arm vs. 3.3% in the placebo arm until switch), new or worsening angina (1.7% on FEMARA vs. 1.2% on placebo until switch), and stroke/transient ischemic attack (1.7% on FEMARA vs. 1.3% on placebo until the switch).

At a median follow-up of approximately 49 months, the number of deaths attributed to a cardiovascular cause during treatment or within 30 days of stopping treatment was slightly higher in the placebo arm [16/2577 (0.6%)] than in the FEMARA arm [10/2566 (0.4%)], but the difference was not statistically significant. Of the 16 deaths attributed to a cardiovascular cause in the placebo arm, 12 occurred in the group of 1129 patients who did not switch to FEMARA after study unblinding, and 4 occurred in the group of 1448 patients who did switch to FEMARA. There was a statistically significant higher incidence of fatal stroke in the FEMARA arm [5/2566 (0.2%)] than in the placebo arm (0/2577) (P<0.0001)). (See also Adverse Reactions, Clinical Trial Adverse Drug Reactions).

FEMARA reduces circulating estrogen levels. The use of estrogen lowering agents, including FEMARA, may cause a reduction in bone mineral density (BMD) with a possible consequent increased risk of osteoporosis and fracture. Osteoporosis and/or bone fractures have been reported with the use of FEMARA (see also Special Populations, Geriatrics and Adverse Reactions, Clinical Trial Adverse Drug Reactions). Therefore, monitoring of overall bone health is recommended during treatment with FEMARA. Women should have their osteoporosis risk assessed and managed according to local clinical practice and guidelines.

In the 5-year, phase III trial for extended adjuvant therapy, after a median follow-up of 28 months, the incidence of self-reported osteoporosis any time after randomization was higher in patients who received FEMARA (6.9%) than in patients who received placebo (5.5%) (P=0.042). The incidence of clinical fractures any time after randomization was slightly higher in patients who received FEMARA than who received placebo (5.9% vs. 5.5% respectively; P=0.548, not statistically significant). Fracture rates any time after randomization in patients with a history of osteoporosis were 10.6% in the FEMARA arm compared to 7.3% in the placebo arm; the difference is not statistically significant (P=0.161). In patients with a previous history of fractures, fracture rates were 12.2% in the FEMARA arm compared to 8.7% in the placebo arm; the difference is not statistically significant (P=0.177). These results were obtained prior to the study unblinding.

After the study unblinding, patients randomized to the placebo arm were offered to switch to FEMARA or discontinue treatment.

The updated results obtained from this phase III trial after unblinding showed that at a median follow-up of approximately 49 months, the incidence of osteoporosis, any time after randomization, was higher in the FEMARA arm (12.3%) than in the placebo until switch arm (7.4%) and the FEMARA after switch arm (3.6%).

Fracture rates any time after randomization in patients with a history of osteoporosis were 17.7% (55/311) in FEMARA arm compared to 10.9% (33/304) in placebo until switch arm and 5.6% (9/162) in the FEMARA after switch arm. In patients with a previous history of fractures, fracture rates any time after randomization were 18.1% (52/287) in the FEMARA arm compared to 12.2% (37/304) in the placebo arm until switch, and 10.2% (17/167) in the FEMARA after switch arm.

The interpretation of the updated results is confounded by the fact that after study unblinding, 56% of patients randomized placebo opted to switch to FEMARA, resulting in different median exposure to treatment (47 months for FEMARA, 28 months for placebo until switch and 20 months for FEMARA after switch). (See also Adverse Reactions, Clinical Trial Adverse Drug Reactions.) The study is ongoing.

Letrozole is rapidly and extensively distributed into tissues (Vd_SS=1.87±0.47 L/kg). Plasma protein binding is approximately 60%, mainly to albumin. The letrozole concentration in erythrocytes is about 80% of that in plasma. After administration of 2.5 mg ¹⁴C-labelled letrozole, approximately 82% of the radioactivity in plasma was unchanged compound. Systemic exposure to metabolites is therefore low.

Letrozole is rapidly and completely absorbed from the gastrointestinal tract (absolute bioavailability=99.9%). Food slightly decreases the rate of absorption (median t_max 1 hour fasted vs. 2 hours fed and mean C_max 129±20.3 nmol/L fasted vs. 98.7±18.6 nmol/L fed), but the extent of absorption (area under the curve (AUC)) remains unchanged. This minor effect on absorption rate is not considered to be of clinical relevance and therefore letrozole may be taken with or without food.

FEMARA (letrozole) is a potent and highly specific non-steroidal aromatase inhibitor. It inhibits the aromatase enzyme by competitively binding to the heme of the cytochrome P450 subunit of the enzyme, resulting in a reduction of estrogen biosynthesis in all tissues.

FEMARA exerts its antitumour effect by depriving estrogen-dependent breast cancer cells of one of their growth stimuli. In postmenopausal women, estrogens are derived mainly from the action of the aromatase enzyme, which converts adrenal androgens—primarily androstenedione and testosterone—to estrone (E1) and estradiol (E2). The suppression of estrogen biosynthesis in peripheral tissues and the malignant tissue can be achieved by specifically inhibiting the aromatase enzyme.

In healthy postmenopausal women, single oral doses of 0.1, 0.5 and 2.5 mg letrozole suppressed serum estrone by 75-78% and estradiol by 78% from baseline. Maximum suppression is achieved in 48-78 hours.

In postmenopausal women with advanced breast cancer, daily letrozole doses of 0.1 to 5 mg suppress estradiol, estrone and estrone sulphate plasma levels by 75-95% from baseline in all patients treated. With 0.5 mg doses and higher, many plasma levels of estrone and estrone sulphate are below the limit of detection of the assays, indicating that higher estrogen suppression is achieved with these doses. Estrogen suppression was maintained throughout treatment in all patients.

Letrozole is highly specific in inhibiting aromatase activity. Impairment of adrenal steroidogenesis has not been observed. No clinically relevant changes in the plasma levels of cortisol, aldosterone, 11-deoxycortisol, 17-hydroxy-progesterone, ACTH (adrenocorticotropic hormone) or in plasma renin activity were found in postmenopausal patients treated with 0.1 to 5 mg letrozole daily. The ACTH stimulation test performed after 6 and 12 weeks of treatment with daily doses of 0.1 to 5 mg letrozole did not indicate any attenuation of aldosterone or cortisol production. Thus, glucocorticoid or mineralocorticoid supplementation is not required.

Letrozole had no effect on plasma androgen concentrations (androstenedione and testosterone) among healthy postmenopausal women after single doses of 0.1, 0.5 and 2.5 mg, or on plasma androstenedione concentrations among postmenopausal patients treated with daily doses of 0.1 to 5 mg. These results indicate that accumulation of androgenic precursors does not occur. Plasma levels of LH and FSH are not affected by letrozole in patients, nor is thyroid function as evaluated by TSH, T₄ and T₃ uptake.

The apparent terminal elimination half-life in plasma is about 2 days. After daily administration of 2.5 mg steady-state levels are reached within 2 to 6 weeks. Plasma concentrations at steady-state are approximately 7 times higher than concentrations measured after a single dose of 2.5 mg, while they are 1.5 to 2 times higher than steady-state values predicted from the concentrations measured after a single dose, indicating a slight non-linearity in the pharmacokinetics of letrozole upon daily administration of 2.5 mg. Since steady state levels are maintained over time, it can be concluded that no continuous accumulation of letrozole occurs.

Metabolic clearance to a pharmacologically inactive carbinol metabolite, CGP 44645, is the major elimination pathway of letrozole (Cl_m=2.1 L/h), but it is relatively slow when compared to hepatic blood flow (about 90 L/h). The cytochrome P450 isoenzymes 3A4 and 2A6 were found to be capable of converting letrozole to this metabolite. Formation of minor unidentified metabolites and direct renal and fecal excretion play only a minor role in the overall elimination of letrozole. Within 2 weeks after administration of 2.5 mg ¹⁴C-labelled letrozole to healthy postmenopausal volunteers, 88.2±7.6% of the radioactivity was recovered in urine and 3.8±0.9% in feces. At least 75% of the radioactivity recovered in urine up to 216 hours (84.7±7.8% of the dose) was attributed to the glucuronide of the carbinol metabolite, about 9% to two unidentified metabolites, and 6% to unchanged letrozole.