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.

Embryotoxicity and foetotoxicity were seen in pregnant rats following oral administration of Femara, and there was an increase in the incidence of foetal malformation among the animals treated. However, it is not known whether this was an indirect consequence of the pharmacological activity of Femara (inhibition of oestrogen biosynthesis) or a direct drug effect.

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

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).

Due to addition of Sandoz Limited as own label supplier, Section 1 has been updated and now states  the name Letrozole

Paragraph 1 in Section 4.2 Posology and method of administration now reads as follows:

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.

Paragraph 1 in Section 4.8 Undesirable effects now reads as follows:

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

Paragraph 3 in Section 4.8 Undesirable effects now reads as follows:

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 point has been added to the bottom of Table 1

(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)

Information for Table 2 now reads as follows:

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. 

Section  5.1, Pharmacodynamic properties now states the following under Adjuvant treatment, study BIG 1-98

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).

Paragraph 3  and 4 in  section 5.1 under Treatment after standard adjuvant tamoxifen, study CFEM345G MA-17 now read as follows:

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.

Update Section 5.3 as below (underlined text is new):

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.

In section 4.8 (undesirable effects),  the paragraph above Table 1 now reads as follows:

Adverse reactions are ranked under headings of frequency, the most frequent first, using the following convention: very common ³ 10%; common ³ 1% to <10%; uncommon ³ 0.1% to <1%; rare ³ 0.01% to < 0.1%; very rare <0.01%, not known (cannot be estimated from the available data..

The following have been added to Table 1 in section 4.8 (undesirable effects);

Hepatitis

Toxic epidermal necrolysis, erythema multiforme 

SECTION 1

Product name changed from

Femara

to

Femara 2.5 mg Tablets

SECTION 2

The following text has been added:

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

SECTION 3

The following has been added:

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

SECTION 4.3

Changed from

Hypersensitivity to the active substances…..

to

Known hypersensitivity to the active substances…..

SECTION 4.8

The following has been deleted:

Skin and subcutaneous tissue disorders
Very rare: angioedema, anaphylactic reaction

and replaced by:

 Immune system disorders
Not known: Angioedema, anaphylactic reactions

SECTION 10

Date of revision has been changed from 6 March 2008 to 15 August 2008

•     "(See section 4.3 Contraindications") added

SECTION 4.8

The following changes have been made:

After standard adjuvant tamoxifen, the following adverse events irrespective of causality were reported significantly more often with Femara than with placebo – hot flushes (49.7 % vs. 43.3 %60.3 % vs. 52.6 %), arthralgia/arthritis (27.7 % vs. 22.2 %37.9 % vs. 26.8 %) and myalgia (9.5 % vs. 6.7 %15.8 % vs. 8.9 %). The majority of these adverse events were observed during the first year of treatment. In the patients in the placebo arm who switched to Femara, a similar pattern of general adverse events was observed. The incidence of self-reported osteoporosis, any time after randomisation was higher in patients who received Femara than in patients who received placebo (6.9 % vs. 5.5 %12.3 % vs. 7.4 %). The incidence of clinical fractures, at any time after randomisation, was only slightly higher in patients who received Femara than in for placebo patients (5.9 % vs. 5.5 %10.9 % vs. 7.2 %).  In patients who switched to Femara, newly diagnosed osteoporosis, any time after switching, was reported in 3.6 % of patients while fractures were reported in 5.1 % of patients any time after switching. The fracture rate per 1000-women years in the letrozole group (24.6) is in the range of aged-matched postmenopausal healthy women. 


SECTION 5.1

The following paragraph has been added:

Updated analyses were conducted at a median follow-up of 49 months. In the Femara arm at least 30% of the patients had completed 5 years and 59% had completed at least 4 years of follow-up. After the unblinding of the study, 56% of the patients in the placebo arm opted to switch to Femara.

In this analysis of DFS, Femara significantly reduced the risk of breast cancer recurrence compared with placebo (HR 0.68; 95% CI 0.55, 0.83; P=0.0001). Femara also significantly reduced the odds of a new invasive contralateral cancer by 41% compared with placebo (OR 0.59; 95% CI 0.36, 0.96; P=0.03). There was no significant difference in distant disease-free survival or overall survival.

The clinical interpretation of these updated analyses should take into account that over half of the patients in the placebo arm switched to Femara. Therefore, analyses were conducted to evaluate the effect of the switch. In one exploratory analysis comparing Femara with placebo until switch, Femara reduced the risk of breast cancer recurrence (HR 0.55; 95% CI 0.45,0.68, p<0.001).

After unblinding, patients who switched to Femara from placebo had been off adjuvant tamoxifen for a median 31 months (range 14 to 79 months). Other analyses were performed within the placebo arm taking account of the switch to Femara. Acknowledging the varying times of the switch after the completion of prior tamoxifen therapy and the known limitations of non-randomised comparison, results suggested a consistent reduction in the risk of breast cancer recurrence in those patients who switched to Femara (HR 0.31; 95% CI 0.20, 0.49, p<0.001).

In addition, the following changes have also been made:

Preliminary Updated results (median duration of follow-up was 2040 months) from the bone mineral density (BMD) sub-study (n=2226) demonstrated that, at 2 years, compared to baseline, patients receiving letrozole Femara had a mean median decrease of 3.8 % in hip BMD compared to 0.42.0 % in the placebo group (P=0.048018). There was no significant difference in terms of changes in lumbar spine BMD at any time.  Concomitant calcium and vitamin D supplementation was mandatory in the BMD substudy. Preliminary Updated results (median duration of follow-up was 29approximately 50  months) from the lipid sub-study (n=310347) showed no significant difference between the Femara and placebo groups at any time. In the core study the incidence of cardiovascular ischemic events for Femara versus placebo until switch was 11.1 % vs. 8.6 % comparable between treatment arms (6.8%  vs. 6.5%).