Femara^®, Letrozole 2.5mg Tablets

Active substance: 4, 4'-[(1H-1, 2, 4-triazol-1-yl)-methylene]bis-benzonitrile (INN/USAN= letrozole).

Each film-coated tablet contains 2.5 mg letrozole.

For a full list of excipients, see section 6.1 List of excipients.

Film-coated tablets.

Coated tablet, dark yellow, round, slightly biconvex with bevelled edges. One side bears the imprint FV, the other CG.

Adjuvant treatment of postmenopausal women with hormone receptor positive invasive early breast cancer.

Treatment of early invasive breast cancer in postmenopausal women who have received prior standard adjuvant tamoxifen therapy.

First-line treatment in postmenopausal women with advanced breast cancer.

Advanced breast cancer in postmenopausal women in whom tamoxifen or other anti-oestrogen therapy has failed.

Pre-operative therapy in postmenopausal women with localised hormone receptor positive breast cancer, to allow subsequent breast-conserving surgery in women not originally considered candidates for breast-conserving surgery. Subsequent treatment after surgery should be in accordance with standard of care.

Adult and elderly patients

The recommended dose of Femara is 2.5 mg once daily. In the adjuvant setting, treatment with Femara should continue for 5 years or until tumour relapse occurs, whichever comes first. Following standard adjuvant tamoxifen therapy, treatment with Femara should continue for 5 years or until tumour relapse occurs, whichever comes first. In patients with metastatic disease, treatment with Femara should continue until tumour progression is evident. Regular monitoring to observe progression during the pre-operative treatment period is recommended (see Section 5.1 “Pharmacodynamic properties”). No dose adjustment is required for elderly patients.

Children

Not recommended for use in children.

Patients with hepatic and/or renal impairment

No dosage adjustment is required for patients with mild to moderate hepatic impairment (Child-Pugh grade A and B) or renal impairment (creatinine clearance 10 mL/min.), (see section 5.2 "Pharmacokinetic properties").

Known hypersensitivity to the active substance or to any of the excipients.

Premenopausal, pregnant or lactating women (see section 4.6 Pregnancy and Lactation).

Patients with severe hepatic impairment (Child-Pugh grade C).

Pre-operative use of letrozole is contraindicated if the receptor status is negative or unknown.

Femara is not recommended for use in children as efficacy and safety in this patient group have not been assessed in clinical studies. There are no efficacy data to support the use of Femara in men with breast cancer.

Femara has not been investigated in patients with creatinine clearance < 10 mL/min. The potential risk/benefit to such patients should be carefully considered before administration of Femara.

As Femara is a potent oestrogen lowering agent, reductions in bone mineral density can be anticipated. During adjuvant treatment with Femara, women with osteoporosis or at risk of osteoporosis should have their bone mineral density formally assessed by bone densitometry e.g. DEXA scanning at the commencement of treatment. Treatment for osteoporosis should be initiated as appropriate and patients treated with Femara should be carefully monitored (see sections 4.8 Undesirable effects and 5.1 Pharmacodynamic properties).

Clinical interaction studies with cimetidine and warfarin indicated that the coadministration of Femara with these drugs does not result in clinically significant drug interactions, even though cimetidine is a known inhibitor of one of the cytochrome P450 isoenzymes capable of metabolising letrozole in vitro (see also section 5.2, "Metabolism and elimination").

There was no evidence of other clinically relevant interaction in patients receiving other commonly prescribed drugs (e.g. benzodiazepines; barbiturates; NSAIDs such as diclofenac sodium, ibuprofen; paracetamol; furosemide; omeprazole).

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

Letrozole inhibits in vitro the cytochrome P450-isoenzymes 2A6 and moderately 2C19, however, 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. Nevertheless, caution should be used in the concomitant administration of drugs whose disposition is mainly dependent on these isoenzymes and whose therapeutic index is narrow.

Pregnancy

Femara is contraindicated during pregnancy (see section 4.3 Contraindications).

Isolated cases of birth defects (labial fusion, ambiguous genitalia) have been reported in pregnant women exposed to Femara.

Lactation

Femara is contraindicated during lactation (see section 4.3 Contraindications).

Women of child-bearing potential

The physician needs to discuss the necessity of adequate contraception with women who have the potential to become pregnant including women who are perimenopausal or who have recently become postmenopausal, until their postmenopausal status is fully established.

There are no adequate data from the use of Femara in pregnant women.

Studies in animals have shown reproductive toxicity (see section 5.3).

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.

Femara was generally well tolerated across all studies as first-line and second-line treatment for advanced breast cancer, as adjuvant treatment of early breast cancer as well as in the treatment of women who have received prior standard tamoxifen therapy. Approximately one third of the patients treated with Femara in the metastatic and neoadjuvant settings, and approximately 80% of the patients in the adjuvant setting (both Femara and tamoxifen arms, at a median treatment duration of 60 months), and approximately 80% of the patients treated following standard adjuvant tamoxifen (both Femara and placebo arms, at a median treatment duration of 60 months) experienced adverse reactions. Generally, the observed adverse reactions are mainly mild or moderate in nature, and most are associated with oestrogen deprivation.

The most frequently reported adverse reactions in the clinical studies were hot flushes, arthralgia, nausea and fatigue. Many adverse reactions can be attributed to the normal pharmacological consequences of oestrogen deprivation (e.g. hot flushes, alopecia and vaginal bleeding).

After standard adjuvant tamoxifen, the following adverse events irrespective of causality were reported significantly more often with Femara than with placebo – hot flushes (Femara, 61% versus placebo, 51%), arthralgia/arthritis (41% versus 27%), sweating (35% versus 30%), hypercholesterolaemia (24% versus 15%) and myalgia (18% versus 9.4%). The majority of these adverse events were observed during the first year of treatment. In the 60% of patients in the placebo arm who switched to Femara following a median duration of 31 months after completion of tamoxifen following unblinding of the study in 2003, a similar pattern of general adverse events was observed. The incidence of osteoporosis during treatment was significantly higher for Femara than for placebo (12.2% versus 6.4%). The incidence of clinical fractures during treatment was significantly higher for Femara than for placebo patients (10.4% versus 5.8%). In patients who switched to Femara, newly diagnosed osteoporosis during treatment with Femara was reported in 5.4% of patients while fractures were reported in 7.7% of patients. Irrespective of treatment, patients 65 years experienced more bone fractures and more osteoporosis.

The following adverse drug reactions, listed in Table 1, were reported from clinical studies and from post marketing experience with Femara.

Table 1

Adverse reactions are ranked under headings of frequency, the most frequent first, using the following convention: very common 10%; common 1% to <10%; uncommon 0.1% to <1%; rare 0.01% to < 0.1%; very rare <0.01%, not known (cannot be estimated from the available data).

*Including:

(1) including nervousness, irritability

(2) including paraesthesia, hypoaesthesia

(3) including superficial and deep thrombophlebitis

(4) including erythematous, maculopapular, psoriaform and vesicular rash

(5) including aesthenia and malaise

(6) in metastatic/neoadjuvant setting only

(7) in the adjuvant setting, irrespective of causality, the following adverse events occurred in the Femara and tamoxifen groups respectively: thromboembolic events (2.1% vs. 3.6%), angina pectoris (1.1% vs. 1.0%), myocardial infarction (1.0% vs. 0.5%), cardiac failure (0.8% vs. 0.5%) (see section 5.1 Pharmacodynamic properties, adjuvant treatment)

(8) After standard adjuvant tamoxifen, at a median treatment duration of 60 months for Femara and 37 months for placebo, the following AEs were reported for Femara and placebo (excluding all switches to Femara) respectively: new or worsening angina (1.4% vs. 1.0%); angina requiring surgery (0.8% vs. 0.6%); myocardial infarction (1.0% vs. 0.7%); thromboembolic event (0.9% vs. 0.3%); stroke/TIA (1.5% vs. 0.8%) (see section 5.1 Pharmacodynamic properties, treatment after standard tamoxifen)

Table 2 presents the frequency of specific target adverse events, CTC grades 1-4 in the BIG 1-98 study, irrespective of causality, reported in patients receiving letrozole or tamoxifen monotherapy, at a median treatment duration of 60 months. The reporting period includes 30 days after cessation of trial therapy.

Table 2

There is no clinical experience of overdosage. In animal studies, Femara exhibits only a slight degree of acute toxicity. In clinical trials, the highest single and multiple dose tested in healthy volunteers was 30 mg and 5 mg, respectively, the latter also being the highest dose tested in postmenopausal breast cancer patients. Each of these doses was well tolerated. There is no clinical evidence for a particular dose of Femara resulting in life-threatening symptoms.

There is no specific antidote to Femara. In general, supportive care, symptomatic treatment and frequent monitoring of vital signs is appropriate.

Pharmacotherapeutic group

ATC Code: L02B G04

Non-steroidal aromatase inhibitor (inhibitor of oestrogen biosynthesis); antineoplastic agent.

Pharmacodynamic effects

The elimination of oestrogen-mediated stimulatory effects is a prerequisite for tumour response in cases where the growth of tumour tissue depends on the presence of oestrogens. In postmenopausal women, oestrogens are mainly derived from the action of the aromatase enzyme, which converts adrenal androgens - primarily androstenedione and testosterone - to oestrone (E1) and oestradiol (E2). 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 cytochrome P450 subunit of the enzyme, resulting in a reduction of oestrogen biosynthesis in all tissues.

In healthy postmenopausal women, single doses of 0.1, 0.5, 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 h.

In postmenopausal patients with advanced breast cancer, daily doses of 0.1 to 5 mg suppress 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 are 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.

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-hydroxy-progesterone, 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, 0.25, 0.5, 1, 2.5, 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, 0.5, and 2.5 mg single doses of letrozole or in plasma concentrations of androstenedione among postmenopausal patients treated with daily doses of 0.1 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.

Adjuvant treatment, study BIG 1-98

BIG 1-98 is a multicentre, double-blind study randomised over 8000 postmenopausal women with resected receptor-positive early breast cancer, to one of the following arms:

• 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

This study was designed to investigate two primary questions: whether Femara for 5 years was superior to tamoxifen for 5 years (Primary Core Analysis and Monotherapy Arms Analysis) and whether switching endocrine treatments at 2 years was superior to continuing the same agent for a total of 5 years (Sequential Treatments Analysis).

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

Femara was approved for the adjuvant treatment of early breast cancer on the basis of the Primary Core Analysis (PCA) results at a median follow-up of only 26 months (see Table 3). The updated analysis, using all data from the monotherapy arms (Monotherapy Arms Analysis, MAA) at a median follow-up of 73 months confirmed the superiority of Femara over tamoxifen in reducing the risk of a disease-free survival event, including the risk of distant metastasis (Table 3).

The independent Data Monitoring Committee recommended unblinding the tamoxifen arms (other treatment arms remained blinded) and, in accordance with a formal protocol amendment, patients in the tamoxifen arms were allowed to cross over to letrozole to complete their adjuvant therapy (if they had received tamoxifen for 2 to 4.5 years) or to start further adjuvant therapy (if they had received tamoxifen for at least 4.5 years). Approximately 26% of patients (632 in total) in the tamoxifen monotherapy arms selectively crossed to letrozole or another aromatase inhibitor (12 patients), mostly to complete adjuvant therapy.

Table 3 Comparison of letrozole and tamoxifen monotherapy at a median follow-up of 26 months and of 73 months

The Sequential Treatments Analyses from switch (STA-S) address the second primary question in BIG 1-98, namely for a new patient, whether it was better to switch endocrine agents after approximately 2 years, or to continue with the same endocrine agent for a total of 5 years. Table 4 shows that there was no statistically significant difference between treatments. The safety profile of the sequential treatments should be considered in reviewing the efficacy results.

Table 4 Summary of sequential treatment analyses from switch (STA-S) (ITT population)

Adjuvant Therapy in Early Breast Cancer, study D2407

Study D2407 is a phase III, open-label, randomised, multicentre study designed to compare the effects of adjuvant treatment with letrozole to tamoxifen on bone mineral density (BMD), bone markers and fasting serum lipid profiles. A total of 262 postmenopausal women with hormone sensitive resected primary breast cancer were randomly assigned to either letrozole 2.5 mg daily for 5 years or tamoxifen 20 mg daily for 2 years followed by 3 years of letrozole 2.5 mg daily.

The primary objective was to compare the effects on lumbar spine (L2-L4) BMD of letrozole versus tamoxifen, evaluated as percent change from baseline lumbar spine BMD at 2 years.

At 24 months, the lumbar spine (L2-L4) BMD showed a median decrease of 4.1% in the letrozole arm compared to a median increase of 0.3% in the tamoxifen arm (difference = 4.4%). At 2 years, overall the median difference in lumbar spine BMD change between letrozole and tamoxifen was statistically significant in favour of tamoxifen (P<0.0001). The current data indicates that no patient with a normal BMD at baseline became osteoporotic at year 2 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 BMD. The differences, however, were less pronounced. At 2 years, a significant difference in favour of tamoxifen was observed in the overall BMD safety population and all stratification categories (P<0.0001). During the 2 year period, fractures were reported by 20 patients (15%) in the letrozole arm, and 22 patients (17%) in the tamoxifen arm.

In the tamoxifen arm, the median total cholesterol levels decreased by 16% after 6 months compared to baseline; a similar decrease was also observed at subsequent visits up to 24 months. In the letrozole arm, the median total cholesterol levels were relatively stable over time, with no significant increase at a single visit. The differences between the 2 arms were statistically significant in favour of tamoxifen at each time point (P<0.0001).

Treatment after standard adjuvant tamoxifen, study CFEM345G MA-17

In a multicentre, double-blind, randomised, placebo-controlled study, performed in over 5100 postmenopausal patients with receptor-positive or unknown primary breast cancer patients who had remained disease-free after completion of adjuvant treatment with tamoxifen (4.5 to 6 years) were randomly assigned either Femara or placebo.

The primary analysis conducted at a median follow-up of around 28 months (25% of the patients being followed-up for up to 38 months) showed that Femara significantly reduced the risk of recurrence by 42% compared with placebo (hazard ratio 0.58; P=0.00003), an absolute reduction of 2.4%. This statistically significant benefit in DFS in favour of letrozole was observed regardless of nodal status or prior chemotherapy.

The independent Data and Safety Monitoring Committee recommended that women who were disease-free in the placebo arm be allowed to switch to Femara for up to 5 years when the study was unblinded in 2003. In the updated, final analysis conducted in 2008, 1551 women (60% of those eligible to switch) switched from placebo to Femara at a median 31 months after completion of adjuvant tamoxifen therapy. Median duration of Femara after switch was 40 months.

The updated final analysis conducted at a median follow-up of 62 months confirmed the significant reduction in the risk of breast cancer recurrence with Femara compared with placebo, despite 60% of eligible patients in the placebo arm switching to Femara after the study was unblinded. In the Femara arm, median duration of treatment was 60 months; in the placebo arm, median duration of treatment was 37 months. The protocol-specified 4-year DFS rate was identical in the Femara arm for both the 2004 and the 2008 analyses, confirming the stability of the data and robust effectiveness of Femara long-term. In the placebo arm, the increase in 4-year DFS rate at the updated analysis clearly reflects the impact of 60% of the patients having switched to Femara. This switching also accounts for the apparent dilution in treatment difference.

In the original analysis, for the secondary endpoint overall survival (OS) a total 113 deaths were reported (51 Femara, 62 placebo). Overall, there was no significant difference between treatments in OS (hazard ratio 0.82; P=0.29). Table 5 summarises the results:

Table 5 Summary of results of study MA-17 after completion of adjuvant therapy with tamoxifen (Modified ITT population)

HR = Hazards ratio; CI = Confidence interval

P values are given for the primary endpoint only, in view of multiple endpoints and multiple analyses. If both bounds of the 95% confidence interval are 1.00, the treatment difference may be regarded as “significant” at the 5% level at face value; values < 1.00 favour letrozole; values > 1.00 favour placebo

¹ When the study was unblinded after the first interim analysis, 1551 patients in the randomised placebo arm (60% of those eligible to switch – i.e. who were disease-free) switched to Femara at a median 31 months after randomisation. The analyses presented here ignore the switching under the ITT principle

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 switching (if a switch occurred) – see footnote 1.⁵ Median follow-up 62 months

⁶ Median follow-up until switch (if it occurred) 37 months

⁷ Odds ratio and 95% CI for the odds ratio

According to the study protocol, patients who completed standard adjuvant treatment with tamoxifen not more than 3 months previously could enter the study. In the updated analysis of MA-17, however, analysis included data from patients who switched from placebo to Femara (60% of eligible patients) at a median 31 months after completing tamoxifen.In the updated analysis, as shown in Table 5, there was a significant reduction in the odds of an invasive contralateral breast cancer with Femara compared with placebo, despite 60% of the patients in the placebo arm having switched to Femara. There was no significant difference in overall survival.

An exploratory analysis censoring follow-up times at the date of switch (if it occurred) showed a significant reduction in the risk of all-cause mortality with Femara compared with placebo (Table 5).

There was no difference in efficacy or safety between patients aged < 65 versus 65 years.

The updated safety profile of Femara did not reveal any new adverse event and was entirely consistent with the profile reported in 2004.

Updated results (median follow-up was 61 months) from the bone sub-study (n=226) demonstrated that, at 2 years, compared to baseline, patients receiving Femara had a median decrease of 3.8 % in hip bone mineral density (BMD) compared to 2.0 % in the placebo group (P=0.022). There was no significant difference between treatments in changes in lumbar spine BMD at any time. Concomitant calcium and vitamin D supplementation was mandatory in the BMD substudy. Updated results (median follow-up was approximately 62 months) from the lipid sub-study (n=347) showed for any of the lipid measurements no significant difference between the Femara and placebo groups at any time. In the updated analysis the incidence of cardiovascular events (including cerebrovascular and thromboembolic events) during treatment with Femara versus placebo until switch was 9.8% vs. 7.0%, a statistically significant difference.

Amongst the pre-printed, check-listed terms during study treatment, the most frequently reported events were: stroke/transient ischemic attack (letrozole, 1.5%; placebo until switch, 0.8%); new or worsening angina (letrozole, 1.4%; placebo until switch, 1.0%); myocardial infarction (letrozole, 1.0%; placebo until switch, 0.7%); thromboembolic events (letrozole, 0.9%; placebo until switch, 0.3%).

The reported frequency of thromboembolic events as well as of stroke/transient ischaemic attack was significantly higher for Femara than placebo until switch. The interpretation of safety results should consider that there was an imbalance in the median duration of treatment with letrozole (60 months) compared with placebo (37 months) due to the switch from placebo to Femara which occurred in approximately 60% of the patients.

First-line treatment

One large well-controlled double-blind trial was conducted comparing Femara 2.5 mg to tamoxifen 20 mg daily as first-line therapy in postmenopausal women with locally advanced or metastatic breast cancer. In this trial of 907 women, Femara was superior to tamoxifen in time to progression (primary endpoint) and in overall objective response, time to treatment failure and clinical benefit (CR+PR+NC>24 weeks).

Femara treatment in the first line therapy of advanced breast cancer patients is associated with an early survival advantage over tamoxifen. A significantly greater number of patients were alive on Femara versus tamoxifen throughout the first 24 months of the study. As the study design allowed patients to cross-over upon progression to the other therapy the long-term survival could not be evaluated.

Pre-operative treatment

A double blind trial was conducted in 337 postmenopausal breast cancer patients randomly allocated either Femara 2.5mg for 4 months or tamoxifen for 4 months. At baseline all patients had tumours stage T2-T4c, N0-2, M0, ER and/or PgR positive and none of the patients would have qualified for breast-conserving surgery. There were 55% objective responses in the Femara treated patients versus 36% for the tamoxifen treated patients (p<0.001) based on clinical assessment. This finding was consistently confirmed by ultrasound (p=0.042) and mammography (p<0.001) giving the most conservative assessment of response. This response was reflected in a statistically significantly higher number of patients in the Femara group who became suitable for and underwent breast-conserving therapy (45% of patients in the Femara group versus 35% of patients in the tamoxifen group, p=0.022). During the 4 month pre-operative treatment period, 12% of patients treated with Femara and 17% of patients treated with tamoxifen had disease progression on clinical assessment.

Absorption

Letrozole is rapidly and completely absorbed from the gastrointestinal tract (mean absolute bioavailability: 99.9%). Food slightly decreases the rate of absorption (median t_max: 1 hour fasted versus 2 hours fed; and mean C_max: 129 ± 20.3 nmol/L fasted versus 98.7 ± 18.6 nmol/L 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.

Metabolism and elimination

Metabolic clearance to a pharmacologically inactive carbinol metabolite is the major elimination pathway of letrozole (CL_m= 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 in vitro, but their individual contributions to letrozole clearance in vivo have not been established. In an interaction study co-administration with cimetidine, which is known to inhibit only the 3A4 isoenzyme, did not result in a decrease in letrozole clearance suggesting that in vivo the 2A6 isoenzyme plays an important part in total clearance. In this study a slight decrease in AUC and increase in C_max were observed.

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.

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 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.

Age had no effect on the pharmacokinetics of letrozole.

Special populations

In a study involving volunteers with varying degrees of renal function (24 hour creatinine clearance 9-116 mL/min) no effect on the pharmacokinetics of letrozole or the urinary excretion of the glucoronide of its carbinol metabolite was found after a single dose of 2.5 mg. The C_max, AUC and half-life of the metabolite have not been determined. In a similar study involving subjects with varying degrees of hepatic function, the 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 without impaired function.

Femara showed a low degree of acute toxicity in rodents exposed up to 2000 mg/kg. In dogs Femara caused signs of moderate toxicity at 100 mg/kg.

In repeated-dose toxicity studies in rats and dogs up to 12 months, the main findings can be attributed to the pharmacological action of the compound. Effects on the liver (increased weight, hepatocellular hypertrophy, fatty changes) were observed, mainly at high dose levels. Increased incidences of hepatic vacuolation (both sexes, high dose) and necrosis (intermediate and high dose females) were also noted in rats treated for 104 weeks in a carcinogenicity study. They may have been associated with the endocrine effects and hepatic enzyme-inducing properties of Femara. However, a direct drug effect cannot be ruled out.

In a 104-week mouse carcinogenicity study, dermal and systemic inflammation occurred, particularly at the highest dose of 60 mg/kg, leading to increased mortality at this dose level. Again it is not known whether these findings were an indirect consequence of the pharmacological activity of Femara (i.e. linked to long-term oestrogen deprivation) or a direct drug effect.

The pharmacological effects of letrozole resulted in skeletal, neuroendocrine and reproductive findings in a juvenile rat study at doses between 0.003 mg/kg/day and 0.3 mg/kg/day. Bone growth and maturation were decreased from the lowest dose (0.003 mg/kg/day) in males and increased from the lowest dose (0.003 mg/kg) in females. In addition, bone mineral density (BMD) was decreased at that dose in females. In the same study, decreased fertility at all doses was accompanied by hypertrophy of the hypophysis, testicular changes which included a degeneration of the seminiferous tubular epithelium, ovarian cysts and atrophy of the female reproductive tract. Effects on bone size in females at 0.3 mg/kg/day and males at 0.03 mg/kg/day and morphological changes in the testes were not reversible. All other effects were at least partially reversible at 0.003 and 0.03 mg/kg/day.

Both in vitro and in vivo investigations on Femara's mutagenic potential revealed no indication of any genotoxicity.

In the carcinogenicity studies no treatment-related tumours were noted in male animals. In female animals, treatment-related changes in genital tract tumours (a reduced incidence of benign and malignant mammary tumours in rats, an increased incidence of benign ovarian stromal tumours in mice) were secondary to the pharmacological effect of the compound.

Letrozole was embryotoxic and fetotoxic in pregnant rats and rabbits following oral administration at clinically relevant doses. In rats that had live fetuses, there was an increase in the incidence of fetal malformations including domed head and cervical/centrum vertebral fusion. These teratogenic effects were not seen in the rabbit. It is not known whether this was an indirect consequence of the pharmacological activity of letrozole (inhibition of oestrogen biosynthesis) or a direct drug effect (see sections 4.3 Contraindications and 4.6 Pregnancy and lactation).

Silica aerogel, cellulose, lactose, magnesium stearate, maize starch, sodium carboxymethyl starch, hydroxypropyl methylcellulose, polyethylene glycol, talc, titanium dioxide, iron oxide yellow.

None known

Five years

Do not store above 30°C. Store in the original package.

PVC/PE/PVDC blister packs of 14, 28 or 30 tablets.

No specific instructions for use/handling.

Novartis Pharmaceuticals UK Limited

Trading as Ciba Laboratories

Frimley Business Park

Frimley

Camberley

Surrey

GU16 7SR

PL 00101/0493

8 August 2006

16 March 2012

POM