Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Endocrine therapy. Hormone antagonist and related agents: aromatase inhibitor, ATC code: L02BG04.

Pharmacodynamic effects
The elimination of oestrogen-mediated growth stimulation is a prerequisite for tumour response in cases where the growth of tumour tissue depends on the presence of oestrogens and endocrine therapy is used.
In postmenopausal women, oestrogens are mainly derived from the action of the aromatase enzyme, which converts adrenal androgens - primarily androstenedione and testosterone - to oestrone and oestradiol. The suppression of oestrogen biosynthesis in peripheral tissues and the cancer tissue itself can therefore be achieved by specifically inhibiting the aromatase enzyme.

Letrozole is a non-steroidal aromatase inhibitor. It inhibits the aromatase enzyme by competitively binding to the haem of the aromatase cytochrome P450, resulting in a reduction of oestrogen biosynthesis in all tissues where present.

In healthy postmenopausal women, single doses of 0.1 mg, 0.5 mg, and 2.5 mg letrozole suppress serum oestrone and oestradiol by 75%, 78% and 78% from baseline respectively. Maximum suppression is achieved in 48-78 hours.

In postmenopausal patients with advanced breast cancer, daily doses of 0.1 mg to 5 mg suppressed plasma concentration of oestradiol, oestrone, and oestrone sulphate by 75-95% from baseline in all patients treated. With doses of 0.5 mg and higher, many values of oestrone and oestrone sulphate were below the limit of detection in the assays, indicating that higher oestrogen suppression is achieved with these doses.
Oestrogen suppression was maintained throughout treatment in all these patients.


FEM API OCT20 V1                                                               REF UK SMPC APR 2020 Letrozole is highly specific in inhibiting aromatase activity. Impairment of adrenal steroidogenesis has not been observed. No clinically relevant changes were found in the plasma concentrations of cortisol, aldosterone, 11-deoxycortisol, 17-hydroxyprogesterone, and ACTH or in plasma renin activity among postmenopausal patients treated with a daily dose of letrozole 0.1 to 5 mg. The ACTH stimulation test performed after 6 and 12 weeks of treatment with daily doses of 0.1 mg, 0.25 mg, 0.5 mg, 1 mg, 2.5 mg, and 5 mg did not indicate any attenuation of aldosterone or cortisol production. Thus, glucocorticoid and mineralocorticoid supplementation is not necessary.

No changes were noted in plasma concentrations of androgens (androstenedione and testosterone) among healthy postmenopausal women after 0.1 mg, 0.5 mg, and 2.5 mg single doses of letrozole or in plasma concentrations of androstenedione among postmenopausal patients treated with daily doses of 0.1 mg to 5 mg, indicating that the blockade of oestrogen biosynthesis does not lead to accumulation of androgenic precursors. 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 test.

Adjuvant treatment
Study BIG 1-98
BIG 1-98 was a multicentre, double-blind study in which over 8,000 postmenopausal women with hormone receptor-positive early breast cancer were randomised to one of the following treatments: A. tamoxifen for 5 years; B. Femara for 5 years; C. tamoxifen for 2 years followed by Femara for 3 years; D. Femara for 2 years followed by tamoxifen for 3 years.

The primary endpoint was disease-free survival (DFS); secondary efficacy endpoints were time to distant metastasis (TDM), distant disease-free survival (DDFS), overall survival (OS), systemic disease-free survival (SDFS), invasive contralateral breast cancer and time to breast cancer recurrence.

Efficacy results at a median follow-up of 26 and 60 months
Data in Table 4 reflect the results of the Primary Core Analysis (PCA) based on data from the monotherapy arms (A and B) and from the two switching arms (C and D) at a median treatment duration of 24 months and a median follow-up of 26 months and at a median treatment duration of 32 months and a median follow-up of 60 months.

The 5-year DFS rates were 84% for Femara and 81.4% for tamoxifen.

Table 4    Primary Core Analysis: Disease-free and overall survival, at a median follow-up of 26 months and at median follow-up of 60 months (ITT population)

Primary Core Analysis
Median follow-up 26 months    Median follow-up 60 months
1
Femara Tamoxifen       HR    Femara Tamoxifen         HR1
N=4003     N=4007 (95% CI) N=4003        N=4007    (95% CI)
P                             P

Disease-free survival (primary)      351          428          0.81         585         664           0.86 - events (protocol definition2)                            (0.70, 0.93)                           (0.77, 0.96) 0.003                                  0.008
Overall survival (secondary)          166         192          0.86       330         374             0.87 Number of deaths                                           (0.70, 1.06)                           (0.75, 1.01) HR = Hazard ratio; CI = Confidence interval
1
Log rank test, stratified by randomisation option and use of chemotherapy (yes/no) 2
DFS events: loco-regional recurrence, distant metastasis, invasive contralateral breast cancer, second (non-breast) primary malignancy, death from any cause without a prior cancer event.


FEM API OCT20 V1                                                            REF UK SMPC APR 2020 Results at a median follow-up of 96 months (monotherapy arms only)
The Monotherapy Arms Analysis (MAA) long-term update of the efficacy of Femara monotherapy compared to tamoxifen monotherapy (median duration of adjuvant treatment: 5 years) is presented in Table 5.

Table 5     Monotherapy Arms Analysis: Disease-free and overall survival at a median follow-up of 96 months (ITT population)

Femara Tamoxifen          Hazard Ratio1       P Value
N=2463  N=2459              (95% CI)

Disease-free survival events (primary) 2       626         698        0.87 (0.78, 0.97)       0.01 Time to distant metastasis (secondary)         301         342        0.86 (0.74, 1.01)       0.06 Overall survival (secondary) - deaths          393         436        0.89 (0.77, 1.02)       0.08 3
Censored analysis of DFS                       626         649        0.83 (0.74, 0.92) 3
Censored analysis of OS                        393         419        0.81 (0.70, 0.93) 1
Log rank test, stratified by randomisation option and use of chemotherapy (yes/no) 2
DFS events: loco-regional recurrence, distant metastasis, invasive contralateral breast cancer, second (non-breast) primary malignancy, death from any cause without a prior cancer event.
3
Observations in the tamoxifen arm censored at the date of selectively switching to letrozole 
Sequential Treatments Analysis (STA)
The Sequential Treatments Analysis (STA) addresses the second primary question of BIG 1-98, namely whether sequencing of tamoxifen and letrozole would be superior to monotherapy. There were no significant differences in DFS, OS, SDFS, or DDFS from switch with respect to monotherapy (Table 6).

Table 6     Sequential treatments analysis of disease-free survival with letrozole as initial endocrine agent (STA switch population)

Number of        Hazard      (97.5% confidence        Cox model
N events1          ratio2          interval)            P-value
[Letrozole→]Tamoxifen
1460           254           1.03           (0.84, 1.26)              0.72 Letrozole
1464           249
1 Protocol definition, including second non-breast primary malignancies, after switch / beyond two years 2 Adjusted by chemotherapy use

There were no significant differences in DFS, OS, SDFS or DDFS in any of the STA from randomisation pairwise comparisons (Table 7).

Table 7     Sequential Treatments Analyses from randomisation (STA-R) of disease-free survival (ITT STA-R population)

Letrozole→Tamoxifen             Letrozole
Number of patients                                            1540                     1546 Number of patients with DFS events (protocol                   330                      319 definition)
Hazard ratio1 (99% CI)                                             1.04 (0.85, 1.27) Letrozole→Tamoxifen           Tamoxifen2
Number of patients                                            1540                   1548 Number of patients with DFS events (protocol                   330                    353 FEM API OCT20 V1                                                          REF UK SMPC APR 2020 definition)
Hazard ratio1 (99% CI)                                              0.92 (0.75, 1.12) 1
Adjusted by chemotherapy use (yes/no)
2
626 (40%) patients selectively crossed to letrozole after tamoxifen arm unblinded in 2005 
Study D2407
Study D2407 is an open-label, randomised, multicentre post approval safety study designed to compare the effects of adjuvant treatment with letrozole and tamoxifen on bone mineral density (BMD) and serum lipid profiles. A total of 262 patients were assigned either letrozole for 5 years or tamoxifen for 2 years followed by letrozole for 3 years.

At 24 months there was a statistically significant difference in the primary end-point; the lumbar spine BMD (L2-L4) showed a median decrease of 4.1% for letrozole compared to a median increase of 0.3% for tamoxifen.

No patient with a normal BMD at baseline became osteoporotic during 2 years of treatment and only 1 patient with osteopenia at baseline (T score of -1.9) developed osteoporosis during the treatment period (assessment by central review).

The results for total hip BMD were similar to those for lumbar spine but less pronounced.

There was no significant difference between treatments in the rate of fractures – 15% in the letrozole arm, 17% in the tamoxifen arm.
Median total cholesterol levels in the tamoxifen arm were decreased by 16% after 6 months compared to baseline and this decrease was maintained at subsequent visits up to 24 months. In the letrozole arm, total cholesterol levels were relatively stable over time, giving a statistically significant difference in favour of tamoxifen at each time point.

Extended adjuvant treatment (MA-17)
In a multicentre, double-blind, randomised, placebo-controlled study (MA-17), over 5,100 postmenopausal women with receptor-positive or unknown primary breast cancer who had completed adjuvant treatment with tamoxifen (4.5 to 6 years) were randomised to either Femara or placebo for 5 years.

The primary endpoint was disease-free survival, defined as the interval between randomisation and the earliest occurrence of loco-regional recurrence, distant metastasis, or contralateral breast cancer.

The first planned interim analysis at a median follow-up of around 28 months (25% of patients being followed up for at least 38 months), showed that Femara significantly reduced the risk of breast cancer recurrence by 42% compared with placebo (HR 0.58; 95% CI 0.45, 0.76; P=0.00003). The benefit in favour of letrozole was observed regardless of nodal status. There was no significant difference in overall survival: (Femara 51 deaths; placebo 62; HR 0.82; 95% CI 0.56, 1.19).

Consequently, after the first interim analysis the study was unblinded and continued in an open-label fashion and patients in the placebo arm were allowed to switch to Femara for up to 5 years. Over 60% of eligible patients (disease-free at unblinding) opted to switch to Femara. The final analysis included 1,551 women who switched from placebo to Femara at a median of 31 months (range 12 to 106 months) after completion of tamoxifen adjuvant therapy. Median duration for Femara after switch was 40 months.

The final analysis conducted at a median follow-up of 62 months confirmed the significant reduction in the risk of breast cancer recurrence with Femara.


FEM API OCT20 V1                                                              REF UK SMPC APR 2020 Table 8 Disease-free and overall survival (Modified ITT population)

Median follow-up 28 months1                Median follow-up 62 months Letrozole   Placebo    HR (95% CI)2        Letrozole Placebo       HR (95% N=2582      N=2586       P value           N=2582      N=2586        CI)2 P value
Disease-free survival3
Events                 92 (3.6%) 155 (6.0%)              0.58           209         286           0.75 (0.45, 0.76)     (8.1%)      (11.1%)     (0.63, 0.89)
0.00003
4-year DFS rate           94.4%       89.8%                           94.4%        91.4%
Disease-free survival3, including deaths from any cause
Events                   122 (4.7%) 193 (7.5%)          0.62            344         402           0.89 (0.49, 0.78)     (13.3%)     (15.5%)     (0.77, 1.03)
5 year DFS rate             90.5%        80.8%                         88.8%       86.7% Distant metastases
Events                    57 (2.2%)    93 (3.6%)         0.61           142          169          0.88 (0.44, 0.84)     (5.5%)       (6.5%)     (0.70, 1.10)

Overall survival
Deaths                    51 (2.0%)    62 (2.4%)         0.82       236 (9.1%) 232 (9.0%)         1.13 (0.56, 1.19)                             (0.95, 1.36)
Deaths4                       --           --             --           2365         1706          0.78 (9.1%)       (6.6%)     (0.64, 0.96)
HR = Hazard ratio; CI = Confidence Interval
1
When the study was unblinded in 2003, 1551 patients in the randomised placebo arm (60% of those eligible to switch – i.e. who were disease-free) switched to letrozole at a median 31 months after randomisation. The analyses presented here ignore the selective crossover.
2
Stratified by receptor status, nodal status and prior adjuvant chemotherapy.
3
Protocol definition of disease-free survival events: loco-regional recurrence, distant metastasis or contralateral breast cancer.
4
Exploratory analysis, censoring follow-up times at the date of switch (if it occurred) in the placebo arm.
5
Median follow-up 62 months.
6
Median follow-up until switch (if it occurred) 37 months.

In the MA-17 bone substudy in which concomitant calcium and vitamin D were given, greater decreases in BMD compared to baseline occurred with Femara compared with placebo. The only statistically significant difference occurred at 2 years and was in total hip BMD (letrozole median decrease of 3.8% vs placebo median decrease of 2.0%).

In the MA-17 lipid substudy there were no significant differences between letrozole and placebo in total cholesterol or in any lipid fraction.

In the updated quality of life substudy there were no significant differences between treatments in physical component summary score or mental component summary score, or in any domain score in the SF-36 scale. In the MENQOL scale, significantly more women in the Femara arm than in the placebo arm were most bothered (generally in the first year of treatment) by those symptoms deriving from oestrogen deprivation – hot flushes and vaginal dryness. The symptom that bothered most patients in both treatment arms was aching muscles, with a statistically significant difference in favour of placebo.


FEM API OCT20 V1                                                          REF UK SMPC APR 2020 First-line treatment
One controlled double-blind trial was conducted comparing Femara (letrozole) 2.5 mg to tamoxifen 20 mg as first-line therapy in postmenopausal women with advanced breast cancer. In 907 women,
letrozole was superior to tamoxifen in time to progression (primary endpoint) and in overall objective response, time to treatment failure and clinical benefit.
The results are summarised in Table 9:

Table 9 Results at a median follow-up of 32 months

Variable                           Statistic                   Femara                   Tamoxifen N=453                       N=454
Time to progression               Median                     9.4 months                 6.0 months (95% CI for median)          (8.9, 11.6 months)          (5.4, 6.3 months) Hazard ratio (HR)                                 0.72
(95% CI for HR)                              (0.62, 0.83)
P<0.0001
Objective response                 CR+PR                       145 (32%)                  95 (21%) rate (ORR)
(95% CI for rate)                (28, 36%)                  (17, 25%) Odds ratio                                    1.78
(95% CI for odds ratio)                         (1.32, 2.40)
P=0.0002

Time to progression was significantly longer, and response rate significantly higher for letrozole irrespective of whether adjuvant anti-oestrogen therapy had been given or not. Time to progression was significantly longer for letrozole irrespective of dominant site of disease. Median time to progression was 12.1 months for Femara and 6.4 months for tamoxifen in patients with soft tissue disease only and median 8.3 months for Femara and 4.6 months for tamoxifen in patients with visceral metastases.

Study design allowed patients to cross over upon progression to the other therapy or discontinue from the study. Approximately 50% of patients crossed over to the opposite treatment arm and crossover was virtually completed by 36 months. The median time to crossover was 17 months (Femara to tamoxifen) and 13 months (tamoxifen to Femara).

Femara treatment in the first-line therapy of advanced breast cancer resulted in a median overall survival of 34 months compared with 30 months for tamoxifen (logrank test P=0.53, not significant). The absence of an advantage for Femara on overall survival could be explained by the crossover design of the study.

Second-line treatment
Two well-controlled clinical trials were conducted comparing two letrozole doses (0.5 mg and 2.5 mg) to megestrol acetate and to aminoglutethimide, respectively, in postmenopausal women with advanced breast cancer previously treated with anti-oestrogens.

Time to progression was not significantly different between letrozole 2.5 mg and megestrol acetate (P=0.07). Statistically significant differences were observed in favour of letrozole 2.5 mg compared to megestrol acetate in overall objective tumour response rate (24% vs 16%, P=0.04), and in time to treatment failure (P=0.04). Overall survival was not significantly different between the 2 arms (P=0.2).


FEM API OCT20 V1                                                            REF UK SMPC APR 2020 In the second study, the response rate was not significantly different between letrozole 2.5 mg and aminoglutethimide (P=0.06). Letrozole 2.5 mg was statistically superior to aminoglutethimide for time to progression (P=0.008), time to treatment failure (P=0.003) and overall survival (P=0.002).

Male breast cancer
Use of Femara in men with breast cancer has not been studied.

Pharmacokinetic Properties

5.2 Pharmacokinetic properties
Absorption
Letrozole is rapidly and completely absorbed from the gastrointestinal tract (mean absolute bioavailability: 99.9%). Food slightly decreases the rate of absorption (median tmax 1 hour fasted versus 2 hours fed; and mean Cmax 129 ± 20.3 nmol/litre fasted versus 98.7 ± 18.6 nmol/litre fed) but the extent of absorption (AUC) is not changed. The minor effect on the absorption rate is not considered to be of clinical relevance, and therefore letrozole may be taken without regard to mealtimes.

Distribution
Plasma protein binding of letrozole is approximately 60%, mainly to albumin (55%). The concentration of letrozole 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 extensively distributed to tissues. Its apparent volume of distribution at steady state is about 1.87 ± 0.47 l/kg.

Biotransformation
Metabolic clearance to a pharmacologically inactive carbinol metabolite is the major elimination pathway of letrozole (CLm = 2.1 l/h) but 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 faecal 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 faeces. 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.

Elimination
The apparent terminal elimination half-life in plasma is about 2 to 4 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 the 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.

Linearity/non-linearity
The pharmacokinetics of letrozole were dose proportional after single oral doses up to 10 mg (dose range: 0.01 to 30 mg) and after daily doses up to 1.0 mg (dose range: 0.1 to 5mg). After a 30 mg single oral dose there was a slightly dose over-proportional increase in AUC value. The dose over-proportionality is likely to be the result of a saturation of metabolic elimination processes. Steady levels were reached after 1 to 2 months at all dosage regimens tested (0.1-5.0 mg daily).

Special populations
Elderly
Age had no effect on the pharmacokinetics of letrozole.

FEM API OCT20 V1                                                            REF UK SMPC APR 2020 Renal impairment
In a study involving 19 volunteers with varying degrees of renal function (24-hour creatinine clearance 9- 116 ml/min) no effect on the pharmacokinetics of letrozole was found after a single dose of 2.5 mg. In addition to the above study assessing the influence of renal impairment on letrozole, a covariate analysis was performed on the data of two pivotal studies (Study AR/BC2 and Study AR/BC3). Calculated creatinine clearance (CLcr) [Study AR/BC2 range: 19 to 187 mL/min; Study AR/BC3 range: 10 to 180 mL/min] showed no statistically significant association between letrozole plasma trough levels at steady- state (Cmin). Futhermore, data of Study AR/BC2 and Study AR/BC3 in second-line metastatic breast cancer showed no evidence of an adverse effect of letrozole on CLcr or an impairment of renal function.
Therefore, no dose adjustment is required for patients with renal impairment (CLcr ≥10 mL/min). Little information is available in patients with severe impairment of renal function (CLcr <10 mL/min).

Hepatic impairment
In a similar study involving subjects with varying degrees of hepatic function, the mean AUC values of the volunteers with moderate hepatic impairment (Child-Pugh B) was 37% higher than in normal subjects, but still within the range seen in subjects without impaired function. In a study comparing the pharmacokinetics of letrozole after a single oral dose in eight male subjects with liver cirrhosis and severe hepatic impairment (Child-Pugh C) to those in healthy volunteers (N=8), AUC and t½ increased by 95 and 187%, respectively. Thus, Femara should be administered with caution to patients with severe hepatic impairment and after consideration of the risk/benefit in the individual patient.