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LETROZOLE FAIR-MED 2.5 MG FILM-COATED TABLETS

Active substance(s): LETROZOLE

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT

Letrozole Fair-Med Healthcare 2.5 mg film coated tablets

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

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.
Excipient with known effect: Sunset yellow FCF (E110). May cause allergic
reactions.
For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Film-coated tablet.
Yellow, round, biconvex, film-coated, tablets. Debossed "2.5" on one side, plain on
reverse.

4.1






Therapeutic indications
Adjuvant treatment of postmenopausal women with hormone receptor positive
invasive early breast cancer.
Extended adjuvant treatment of hormone-dependent invasive breast cancer in
postmenopausal women who have received prior standard adjuvant tamoxifen
therapy for 5 years.
First-line treatment in postmenopausal women with hormone-dependent advanced
breast cancer.
Advanced breast cancer after relapse or disease progression, in women with
natural or artificially induced postmenopausal endocrine status, who have
previously been treated with anti-oestrogens.
Neo-adjuvant treatment of postmenopausal women with hormone receptor
positive, HER-2 negative breast cancer where chemotherapy is not suitable and
immediate surgery not indicated.

Efficacy has not been demonstrated in patients with hormone receptor negative breast
cancer.

4.2

Posology and method of administration

Adult and elderly patients

Posology
The recommended dose of Letrozole is 2.5 mg once daily. No dose adjustment is required for
elderly patients.
In patients with advanced or metastatic breast cancer, treatment with Letrozole should
continue until tumour progression is evident.
In the adjuvant and extended adjuvant setting, treatment with Letrozole should continue for 5
years or until tumour relapse occurs, whichever is first.
In the adjuvant setting a sequential treatment schedule (letrozole 2 years followed by
tamoxifen 3 years) could also be considered (see sections 4.4 and 5.1).
In the neoadjuvant setting, treatment with could be continued for 4 to 8 months in order to
establish optimal tumour reduction. If the response is not adequate, treatment with Letrozole
should be discontinued and surgery scheduled and/or further treatment options discussed with
the patient.
Paediatric population
Letrozole is not recommended for use in children and adolescents. The safety and efficacy of
Letrozole in children and adolescents aged up to 17 years have not been established. Limited
data are available and no recommendation on a posology can be made.
Renal impairment
No dosage adjustment of Letrozole is required for patients with renal insufficiency with
creatinine clearance ≥10 ml/min.
Insufficient data are available in cases of renal insufficiency with creatinine clearance lower
than 10 ml/min (see sections 4.4 and 5.2).
Hepatic impairment
No dose adjustment of Letrozole is required for patients with mild to moderate hepatic
insufficiency (Child-Pugh A or B).
Insufficient data are available for patients with severe hepatic impairment. Patients with
severe hepatic impairment (Child-Pugh C) require close supervision (see sections 4.4 and
5.2).
Method of administration
Letrozole should be taken orally and can be taken with or without food.

4.3





4.4

Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Premenopausal endocrine status
Pregnancy (see section 4.6)
Breast-feeding (see section 4.6)
Special warnings and precautions for use

Menopausal status
In patients whose menopausal status is unclear, luteinising hormone (LH), follicle-stimulating
hormone (FSH) and/or oestradiol levels should be measured before initiating treatment with
Letrozole. Only women of postmenopausal endocrine status should receive Letrozole.
Renal Impairment
Letrozole has not been investigated in a sufficient number of patients with a creatinine
clearance lower than 10 ml/min. The potential risk/benefit to such patients should be carefully
considered before administration of Letrozole.
Hepatic Impairment

In patients with severe hepatic impairment (Child-Pugh C), systemic exposure and terminal
half-life were approximately doubled compared to healthy volunteers. Such patients should
therefore be kept under close supervision (see section 5.2).
Bone effects
Letrozole is a potent oestrogen-lowering agent. Women with a history of osteoporosis and/or
fractures, or who are at increased risk of osteoporosis, should have their bone mineral density
formally assessed prior to the commencement of adjuvant and extended adjuvant treatment
and monitored during and following treatment with letrozole. Treatment or prophylaxis for
osteoporosis should be initiated as appropriate and carefully monitored. In the adjuvant
setting a sequential treatment schedule (letrozole 2 years followed by tamoxifen 3 years)
could also be considered depending on the patient`s safety profile (see sections 4.2, 4.8 and
5.1).
Other warnings
Co-administration of Letrozole with tamoxifen, other anti-oestrogens or oestrogen-containing
therapies should be avoided as these substances may diminish the pharmacological action of
letrozole (see section 4.5).
Letrozole film-coated tablets contain Sunset yellow FCF (E110). May cause allergic
reactions.

4.5

Interaction with other medicinal products and other forms of interaction

Metabolism of letrozole is partly mediated via CYP2A6 and CYP3A4. Cimetidine, a weak,
unspecific inhibitor of CYP450 enzymes, did not affect the plasma concentrations of
letrozole. The effect of potent CYP450 inhibitors is unknown.
There is no clinical experience to date on the use of letrozole in combination with oestrogens
or other anticancer agents, other than tamoxifen. Tamoxifen, other anti-oestrogens or
oestrogen-containing therapies may diminish the pharmacological action of letrozole. In
addition, co-administration of tamoxifen with letrozole has been shown to substantially
decrease plasma concentrations of letrozole. Co-administration of letrozole with tamoxifen,
other anti-oestrogens or oestrogens should be avoided.
In vitro, letrozole inhibits the cytochrome P450 isoenzymes 2A6 and, moderately, 2C19, but
the clinical relevance is unknown. Caution is therefore indicated when giving letrozole
concomitantly with medicinal products whose elimination is mainly dependent on these
isoenzymes and whose therapeutic index is narrow (e.g. phenytoin, clopidrogel).

4.6

Fertility, pregnancy and lactation

Women of perimenopausal status or child-bearing potential
Letrozole should only be used in women with a clearly established postmenopausal status (see
section 4.4). As there are reports of women regaining ovarian function during treatment with
Letrozole despite a clear postmenopausal status at start of therapy, the physician needs to
discuss adequate contraception when necessary.
Pregnancy
Based on human experience in which there have been isolated cases of birth defects (labial
fusion, ambiguous genitalia), Letrozole may cause congenital malformations when
administered during pregnancy. Studies in animals have shown reproductive toxicity (see
section 5.3).
Letrozole is contraindicated during pregnancy (see section 4.3 and 5.3).

Breastfeeding
It is unknown whether letrozole and its metabolites are excreted in human milk. A risk to the
newborns/infants cannot be excluded.
Letrozole is contraindicated during breastfeeding (see section 4.3).

Fertility
The pharmacological action of letrozole is to reduce oestrogen production by
aromatase inhibition. In premenopausal women, the inhibition of oestrogen synthesis
leads to feedback increases in gonadotropin (LH, FSH) levels. Increased FSH levels
in turn stimulate follicular growth, and can induce ovulation.
4.7
Effects on ability to drive and use machines
Letrozole has minor influence on the ability to drive and use machines. Since fatigue and
dizziness have been observed with the use of letrozole and somnolence has been reported
uncommonly, caution is advised when driving or using machines.

4.8

Undesirable effects

Summary of the safety profile
The frequencies of adverse reactions for letrozole are mainly based on data collected from
clinical trials.
Up to approximately one third of the patients treated with letrozole in the metastatic setting
and approximately 80% of the patients in the adjuvant setting as well as in the extended
adjuvant setting experienced adverse reactions. The majority of the adverse reactions occurred
during the first few weeks of treatment.
The most frequently reported adverse reactions in clinical studies were hot flushes,
hypercholesterolaemia, arthralgia, fatigue, increased sweating and nausea.
Important additional adverse reactions that may occur with letrozole are: skeletal events such
as osteoporosis and/or bone fractures and cardiovascular events (including cerebrovascular
and thromboembolic events). The frequency category for these adverse reactions is described
in Table 1.
Tabulated listing of adverse reactions
The frequencies of adverse reactions for letrozole are mainly based on data collected from
clinical trials.
The following adverse drug reactions, listed in Table 1, were reported from clinical studies
and from post marketing experience with letrozole:
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).

Infections and infestations
Uncommon:

Urinary tract infection

Neoplasms, benign, malignant and unspecified (including cysts and polyps)

Uncommon:

Tumour pain1

Blood and the lymphatic system disorders
Uncommon:

Leukopenia

Immune system disorders
Not known:

Anaphylactic reaction

Metabolism and nutrition disorders
Very common:

Hypercholesterolaemia

Common:

Anorexia, appetite increase

Psychiatric disorders
Common:

Depression

Uncommon:

Anxiety (including nervousness), irritability

Nervous system disorders
Common:

Headache, dizziness

Uncommon:

Somnolence, insomnia, memory impairment, dysaesthesia (including
paraesthesia, hypoaesthesia), taste disturbance, cerebrovascular
accident

Eye disorders
Uncommon

Cataract, eye irritation, blurred vision

Cardiac disorders

Uncommon:

Palpitations1, tachycardia, ischaemic cardiac events (including
new or worsening angina, angina requiring surgery, myocardial
infarction and myocardial ischaemia)

Vascular disorders
Very common:

Hot flushes

Common:

Hypertension

Uncommon:

Thrombophlebitis (including superficial and deep vein
thrombophlebitis)

Rare:

Pulmonary embolism, arterial thrombosis, cerebrovascular infarction

Respiratory, thoracic and mediastinal disorders
Uncommon:

Dyspnoea, cough

Gastrointestinal disorders
Common:

Nausea, dyspepsia1, constipation, abdominal pain, diarrhoea, vomiting

Uncommon:

Dry mouth, stomatitis1

Hepatobiliary disorders
Uncommon:

Increased hepatic enzymes

Not known:

Hepatitis

Skin and subcutaneous tissue disorders
Very common:

Increased sweating

Common:

Alopecia, rash (including erythematous, maculopapular, psoriaform,
and vesicular rash), dry skin

Uncommon:

Pruritus, urticaria

Not known:

Angioedema, toxic epidermal necrolysis, erythema multiforme

Musculoskeletal and connective tissue disorders
Very common:

Arthralgia

Common:

Myalgia, bone pain1, osteoporosis, bone fractures

Uncommon:

Arthritis

Renal and urinary disorders
Uncommon:

Increased urinary frequency

Reproductive system and breast disorders
Common:

Vaginal bleeding

Uncommon:

Vaginal discharge, vaginal dryness, breast pain

General disorders and administration site conditions
Very common:

Fatigue (including asthenia, malaise)

Common:

Peripheral oedema

Uncommon:

General oedema, mucosal dryness, thirst, pyrexia

Investigations
Common:

Weight increase

Uncommon:

Weight loss

1

Adverse drug reactions reported only in the metastatic setting

Some adverse reactions have been reported with notably different frequencies in the
adjuvant treatment setting. The following tables provide information on significant
differences in letrozole versus tamoxifen monotherapy and in the letrozole-tamoxifen
sequential treatment therapy:
Table 2 Adjuvant letrozole monotherapy versus tamoxifen monotherapy –
adverse events with significant differences

Bone fracture

Letrozole, incidence rate Tamoxifen, incidence
rate
10.1% (13.8%)
7.1% (10.5%)

Osteoporosis

5.1% (5.1%)

2.7% (2.7%)

Thromboembolic events

2.1% (2.9%)

3.6% (4.5%)

Myocardial infarction

1.0% (1.5%)

0.5% (1.0%)

Endometrial hyperplasia /
endometrial cancer

0.2% (0.4%)

2.3% (2.9%)

Note: Median duration of treatment 60 months. Reporting period includes
treatment period plus 30 days after stopping treatment.
Percentages in parentheses indicate event frequencies any time after randomisation,
including post study treatment period. Median follow-up was 73 months.
Table 3 Sequential treatment versus letrozole monotherapy – adverse events with
significant differences

Bone fractures

Letrozole
monotherapy

Letrozole ->
Tamoxifen

Tamoxifen->
Letrozole

9.9%

7.6%*

9.6%

Endometrial
proliferative

0.7%

3.4%**

1.7%**

Hypercholesterolaemi 52.5%
a
37.7%
Hot flushes

44.2%*

40.8%*

41.7%**

43.9%**

Vaginal bleeding

9.6%**

12.7%**

6.3%

* Significantly less than with letrozole monotherapy
**Significantly more than with letrozole monotherapy
Note : Reporting period is during treatment or within 30 days of stopping treatment

Description of selected adverse reactions
Cardiac adverse reactions
In the adjuvant setting, in addition to the data presented in Table 2, the following
adverse events were reported for letrozole and tamoxifen, respectively (at median
treatment duration of 60 months plus 30 days): angina requiring surgery (1.0% vs.
1.0%); cardiac failure (1.1% vs. 0.6%); hypertension (5.6% vs. 5.7%);
cerebrovascular accident/transient ischaemic attack (2.1% vs. 1.9%).
In the extended adjuvant setting for letrozole (median duration of treatment 5 years)
and placebo (median duration of treatment 3 years), respectively: angina requiring
surgery (0.8% vs. 0.6%); new or worsening angina (1.4% vs. 1.0%); myocardial
infarction (1.0% vs. 0.7%); thromboembolic event* (0.9% vs. 0.3%); stroke/transient
ischaemic attack* (1.5% vs. 0.8%) were reported.
Events marked * were statistically significantly different in the two treatment arms.
Skeletal adverse reactions
For skeletal safety data from the adjuvant setting, please refer to Table 2.
In the extended adjuvant setting, significantly more patients treated with letrozole
experienced bone fractures or osteoporosis (bone fractures, 10.4% and osteoporosis,
12.2%) than patients in the placebo arm (5.8% and 6.4%, respectively). Median
duration of treatment was 5 years for letrozole, compared with 3 years for placebo.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is
important. It allows continued monitoring of the benefit/risk balance of the medicinal
product. Healthcare professionals are asked to report any suspected adverse reactions
via
Yellow Card Scheme
Website: www.mhra.gov.uk/yellowcard.
4.9
Overdose
Isolated cases of overdose with letrozole have been reported.

No specific treatment for overdose is known; treatment should be symptomatic and
supportive.

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 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.
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. letrozole for 5 years; C. tamoxifen for 2 years followed by
letrozole for 3 years; D. letrozole 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 letrozole 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

Letrozole
N=4003

Tamoxifen
N=4007

HR1
(95% CI)
P

Disease-free
survival (primary)
- events (protocol
definition2)

351

428

Overall survival
(secondary)
Number of deaths

166

192

Median follow-up 60 months

Tamoxifen
N=4007

HR1
(95% CI)
P

0.81
585
(0.70, 0.93)
0.003

664

0.86
(0.77, 0.96)
0.008

0.86
330
(0.70, 1.06)

374

0.87
(0.75, 1.01)

Letrozole
N=4003

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.
Results at a median follow-up of 73 months (monotherapy arms only)
The Monotherapy Arms Analysis (MAA) long-term update of the efficacy of letrozole
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 73 months (ITT population)

Letrozole

Tamoxifen

Hazard Ratio1 P Value

N=2463

N=2459

(95% CI)

Disease-free survival
509
events
2
Time to distant metastasis 257
(secondary)

565

0.88 (0.78, 0.99) 0.03

298

0.85 (0.72, 1.00) 0.045

303

343

0.87 (0.75, 1.02) 0.08

509
Censored analysis of
DFS3
Censored analysis of OS3 303

543

0.85 (0.75, 0.96)

338

0.82 (0.70, 0.96)

Overall survival
(secondary) - deaths

1

Log rank test, stratified by randomisation option and use of chemotherapy (yes/no)
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
2

Sequential Treatments Analysis (STA)
The Sequential Treatments Analysis (STA) addresses the second primary question of BIG 198, 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)

N

Number of Hazard
ratio2
events1

Cox model
(97.5%
confidence P-value
interval)

[Letrozole→]Tamoxif 1460
en

160

(0.72, 1.17) 0.42

1463

178

Letrozole

0.92

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
definition)

236

248

Hazard ratio1 (99% CI)

0.96 (0.76, 1.21)
Letrozole →
Tamoxifen

Tamoxifen2

Number of patients

1540

1548

Number of patients with DFS events (protocol
definition)

236

269

Hazard ratio1 (99% CI)

0.87 (0.69, 1.09)

1
2

Adjusted by chemotherapy use (yes/no)
624 (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 favor 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
letrozole 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 letrozole 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: (letrozole 51 deaths; placebo 62; HR
0.82; 95% CI 0.56, 1.19).
Consequently, after the 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 letrozole for up
to 5 years. Over 60% of eligible patients (disease-free at unblinding) opted to switch to
letrozole. The final analysis included 1,551 women who switched from placebo to letrozole at
a median of 31 months (range 12 to 106 months) after completion of tamoxifen adjuvant
therapy. Median duration for letrozole 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 letrozole.
Table 8 Disease-free and overall survival (Modified ITT population)

Median follow-up 28 months

Median follow-up 62 months1

Letrozole

Placebo

Letrozole Placebo

N=2582

N=2586

HR (95%
CI)2

N=2582

N=2586

P value

HR (95%
CI)2
P value

Disease-free survival3
Events

92 (3.6%)

155 (6.0%) 0.58

209 (8.1%) 286 (11.1%) 0.75

(0.45, 0.76)

(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
(0.49, 0.78)

5 year DFS rate

344
(13.3%)

402 (15.5%) 0.89
(0.77, 1.03)

90.5%

80.8%

88.8%

86.7%

57 (2.2%)

93 (3.6%) 0.61

142

169

0.88

(6.5%

(0.70, 1.10)

Distant metastases
Events

(0.44, 0.84) (5.5%)
Overall survival
Deaths

51 (2.0%)

62 (2.4%) 0.82
(0.56, 1.19)

236 (9.1%) 232 (9.0%) 1.13
(0.95, 1.36)

Deaths4

--

--

--

2365
(9.1%)

1706 (6.6%) 0.78
(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 letrozole 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
letrozole 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.
Neoadjuvant treatment
A double blind trial (P024) was conducted in 337 postmenopausal breast cancer patients
randomly allocated either letrozole 2.5 mg 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. Based on clinical
assessment there were 55% objective responses in the letrozole arm versus 36% for the
tamoxifen arm (P<0.001). This finding was consistently confirmed by ultrasound (letrozole
35% vs tamoxifen 25%, P=0.04) and mammography (letrozole 34% vs tamoxifen 16%,
P<0.001). In total 45% of patients in the letrozole group versus 35% of patients in the
tamoxifen group (P=0.02) underwent breast-conserving therapy). During the 4-month preoperative treatment period, 12% of patients treated with letrozole and 17% of patients treated
with tamoxifen had disease progression on clinical assessment.
First-line treatment

One controlled double-blind trial was conducted comparing 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

Time to
progression

Statistic

Median

Letrozole

Tamoxifen

N =453

N =454

9.4 months

6.0 months

(95% CI for median) (8.9, 11.6 months)
Hazard ratio (HR)

0.72

(95% CI for HR)

(0.62, 0.83)

P

<0.0001

Objective response CR+PR
rate

(5.4, 6.3 months)

145 (32%)

95 (21%)

(95% CI for rate)

(28, 36%)

(17, 25%)

Odds ratio

1.78

(95% CI for odds
ratio)
P

(1.32, 2.40)
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 letrozole and 6.4 months for tamoxifen in
patients with soft tissue disease only and median 8.3 months for letrozole 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 (letrozole to tamoxifen) and 13 months (tamoxifen to letrozole).
Letrozole 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 letrozole 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).
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 letrozole in men with breast cancer has not been studied.

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/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.
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.
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 nonlinearity 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.
Special populations
Elderly
Age had no effect on the pharmacokinetics of letrozole.
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.
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 t1/2 increased by 95 and 187%, respectively. Thus, letrozole
should be administered with caution to patients with severe hepatic impairment and after
consideration of the risk/benefit in the individual patient.

5.3

Preclinical safety data

In a variety of preclinical safety studies conducted in standard animal species, there was no
evidence of systemic or target organ toxicity.
Letrozole showed a low degree of acute toxicity in rodents exposed up to 2000 mg/kg. In
dogs letrozole 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 observed
can be attributed to the pharmacological action of the compound. The no-adverse-effect level
was 0.3 mg/kg in both species.
Both in vitro and in vivo investigations of letrozole's mutagenic potential revealed no
indications of any genotoxicity.
In a 104-week rat carcinogenicity study, no treatment-related tumours were noted in male
rats. In female rats, a reduced incidence of benign and malignant mammary tumours at all the
doses of letrozole was found.
Letrozole was embryotoxic and foetotoxic in pregnant rats and rabbits following oral
administration at clinically relevant doses. In rats that had live foetuses, there was an increase
in the incidence of foetal malformations including domed head and cervical/centrum vertebral
fusion. An increased incidence of foetal malformations was not seen in the rabbit. It is not
known whether this was an indirect consequence of the pharmacological properties (inhibition
of oestrogen biosynthesis) or a direct drug effect (see sections 4.3 and 4.6).
Preclinical observations were confined to those associated with the recognised
pharmacological action, which is the only safety concern for human use derived from animal
studies.

6.1

List of excipients

Tablet core

Silicified microcrystalline cellulose, contains microcrystalline cellulose and silica
colloidal, anhydrous
Sodium starch glycolate (Type A)
Magnesium stearate
Tablet coating
Polyvinyl Alcohol
Polyethylene glycol
Titanium Dioxide (E171)
Talc
Yellow Iron Oxide (E172)
Sunset yellow FCF aluminium lake (E110)
6.2

Incompatibilities
Not applicable.

6.3

Shelf life
4 years

6.4

Special precautions for storage
This medicinal product does not require any special storage conditions.

6.5

Nature and contents of container

Letrozole 2.5 mg film-coated tablets are packed in blisters composed of
Aluminium/PVC/PVdC.
Cartons of: 10, 14, 28, 30, 100 tablets.
Not all pack sizes may be marketed.
6.6

Special precautions for disposal and other handling

No specific instructions for use/handling.
Any unused medicinal product or waste material should be disposed of in accordance
with local requirements.

7

MARKETING AUTHORISATION HOLDER
Fair-Med Healthcare GmbH
Planckstrasse 13
22765 Hamburg
Germany

8

MARKETING AUTHORISATION NUMBER(S)
PL 20242/0015

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
20/03/2012

10

DATE OF REVISION OF THE TEXT
10/01/2014

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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