• 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 cance
r

Posology
Adult and elderly patients
The recommended dose of Marlet is 2.5 mg once daily. No dose adjustment is required for elderly patients.
In patients with advanced or metastatic breast cancer, treatment with Marlet should continue until tumour
progression is evident.
In the adjuvant and extended adjuvant setting, treatment with Marlet 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 Marlet could be continued for 4 to 8 months in order to establish
optimal tumour reduction. If the response is not adequate, treatment with Marlet should be discontinued
and surgery scheduled and/or further treatment options discussed with the patient.
Paediatric population
Marlet is not recommended for use in children and adolescents. The safety and efficacy of Marlet 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 Marlet 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 Marlet is required for patients with mild to moderate hepatic insufficiency (ChildPugh 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
Marlet should be taken orally and can be taken with or without food.
A missed dose should be taken as soon as the patient remembers. However, if it is almost time for the next
dose (within 2 or 3 hours), the missed dose should be skipped, and the patient should go back to her
regular dosage schedule. Doses should not be doubled because with daily doses over the 2.5 mg
recommended dose, over-proportionality in systemic exposure was observed (see section 5.2)
 

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 Marlet. Only women of
postmenopausal endocrine status should receive Marlet.
Renal impairment
Marlet 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
Marlet.
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
Marlet 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 Marlet 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).
As the tablets contain lactose, Marlet is not recommended for patients with rare hereditary problems
of galactose intolerance, of severe lactase deficiency or of glucose-galactose malabsorption
 

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 Marlet 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. Coadministration 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)
 

Pregnancy Category: X
Women of premenopausal status or child-bearing potential
Marlet 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 Marlet 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), Marlet may cause congenital malformations when administered during pregnancy.
Studies in animals have shown reproductive toxicity (see section 5.3).
Marlet is contraindicated during pregnancy (see sections 4.3 and 5.3).
Breast-feeding
It is unknown whether letrozole and its metabolites are excreted in human milk. A risk to the
newborns/infants cannot be excluded.
Marlet is contraindicated during breast-feeding (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
 

Marlet has minor influence on the ability to drive and use machines. Since fatigue and dizziness have been
observed with the use of Marlet and somnolence has been reported uncommonly, caution is advised when
driving or using machines
 

a. Summary of the safety profile
The frequencies of adverse reactions for Marlet are mainly based on data collected from clinical trials.
Up to approximately one third of the patients treated with Marlet 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 Marlet 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.
b. Tabulated listing of adverse reactions
The frequencies of adverse reactions for Marlet 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 postmarketing experience with Marlet:

c. 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 Marlet 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 Marlet (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 Marlet 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 Marlet, compared with 3 years for
placebo.
d. Pediatric Population:
Marlet is not recommended for use in children and adolescents. The safety and efficacy of Marlet 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.
e. Special Population:
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. In
addition to the above study assessing the influence of renal impairment on letrozole, a covariate analysis
was performed on the data of two pivotal studies (Study AR/BC2 and Study AR/BC3). Calculated creatinine
clearance (CLcr) [Study AR/BC2 range: 19 to 187 mL/min; Study AR/BC3 range: 10 to 180 mL/min]
showed no statistically significant association between letrozole plasma trough levels at steady-state
(Cmin). Futhermore, data of Study AR/BC2 and Study AR/BC3 in second-line metastatic breast cancer
showed no evidence of an adverse effect of letrozole on CLcr or an impairment of renal function.
Therefore, no dose adjustment is required for patients with renal impairment (CLcr ≥10 mL/min). Little
information is available in patients with severe impairment of renal function (CLcr <10 mL/min).
Hepatic impairment
In a similar study involving subjects with varying degrees of hepatic function, the mean AUC values of the
volunteers with moderate hepatic impairment (Child-Pugh B) was 37% higher than in normal subjects, but
still within the range seen in subjects without impaired function. In a study comparing the pharmacokinetics
of letrozole after a single oral dose in eight male subjects with liver cirrhosis and severe hepatic impairment
(Child-Pugh C) to those in healthy volunteers (N=8), AUC and t½ increased by 95 and 187%, respectively.
Thus, Marlet should be administered with caution to patients with severe hepatic impairment and after
consideration of the risk/benefit in the individual patient

Isolated cases of overdose with Marlet have been reported.
No specific treatment for overdose is known; treatment should be symptomatic and supportive
 

Pharmacotherapeutic group: Endocrine therapy. Hormone antagonist and related agents: aromatase
inhibitor, ATC code: L02BG04.
Pharmacodynamic effects
The elimination of oestrogen-mediated growth stimulation is a prerequisite for tumour response in cases
where the growth of tumour tissue depends on the presence of oestrogens and endocrine therapy is used.
In postmenopausal women, oestrogens are mainly derived from the action of the aromatase enzyme, which
converts adrenal androgens - primarily androstenedione and testosterone - to oestrone and oestradiol. The
suppression of oestrogen biosynthesis in peripheral tissues and the cancer tissue itself can therefore be
achieved by specifically inhibiting the aromatase enzyme.
Letrozole is a non-steroidal aromatase inhibitor. It inhibits the aromatase enzyme by competitively binding
to the haem of the aromatase cytochrome P450, resulting in a reduction of oestrogen biosynthesis in all
tissues where present.
In healthy postmenopausal women, single doses of 0.1 mg, 0.5 mg, and 2.5 mg letrozole suppress serum
oestrone and oestradiol by 75%, 78% and 78% from baseline respectively. Maximum suppression is
achieved in 48-78 hours.
In postmenopausal patients with advanced breast cancer, daily doses of 0.1 mg to 5 mg suppressed
plasma concentration of oestradiol, oestrone, and oestrone sulphate by 75-95% from baseline in all patients
treated. With doses of 0.5 mg and higher, many values of oestrone and oestrone sulphate were below the
limit of detection in the assays, indicating that higher oestrogen suppression is achieved with these doses.
Oestrogen suppression was maintained throughout treatment in all these patients.
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. Marlet for 5 years; C. tamoxifen for 2 years followed by Marlet for 3 years; D. Marlet 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 Marlet and 81.4% for tamoxifen

Absorption
Letrozole is rapidly and completely absorbed from the gastrointestinal tract (mean absolute bioavailability:
99.9%). Food slightly decreases the rate of absorption (median tmax 1 hour fasted versus 2 hours fed; and
mean Cmax 129 ± 20.3 nmol/litre fasted versus 98.7 ± 18.6 nmol/litre fed) but the extent of absorption (AUC)
is not changed. The minor effect on the absorption rate is not considered to be of clinical relevance, and
therefore letrozole may be taken without regard to mealtimes.
Distribution
Plasma protein binding of letrozole is approximately 60%, mainly to albumin (55%). The concentration of
letrozole in erythrocytes is about 80% of that in plasma. After administration of 2.5 mg 14C-labelled
letrozole, approximately 82% of the radioactivity in plasma was unchanged compound. Systemic exposure
to metabolites is therefore low. Letrozole is rapidly and extensively distributed to tissues. Its apparent
volume of distribution at steady state is about 1.87 ± 0.47 l/kg.
Biotransformation
Metabolic clearance to a pharmacologically inactive carbinol metabolite is the major elimination pathway of
letrozole (CLm = 2.1 l/h) but is relatively slow when compared to hepatic blood flow (about 90 l/h). The
cytochrome P450 isoenzymes 3A4 and 2A6 were found to be capable of converting letrozole to this
metabolite. Formation of minor unidentified metabolites and direct renal and faecal excretion play only a
minor role in the overall elimination of letrozole. Within 2 weeks after administration of 2.5 mg 14C-labelled
letrozole to healthy postmenopausal volunteers, 88.2 ± 7.6% of the radioactivity was recovered in urine and
3.8 ± 0.9% in faeces. At least 75% of the radioactivity recovered in urine up to 216 hours (84.7 ± 7.8% of
the dose) was attributed to the glucuronide of the carbinol metabolite, about 9% to two unidentified
metabolites, and 6% to unchanged letrozole.
Elimination
The apparent terminal elimination half-life in plasma is about 2 to 4 days. After daily administration of 2.5
mg steady-state levels are reached within 2 to 6 weeks. Plasma concentrations at steady state are
approximately 7 times higher than concentrations measured after a single dose of 2.5 mg, while they are
1.5 to 2 times higher than the steady-state values predicted from the concentrations measured after a
single dose, indicating a slight non-linearity in the pharmacokinetics of letrozole upon daily administration of
2.5 mg. Since steady-state levels are maintained over time, it can be concluded that no continuous
accumulation of letrozole occurs.
Linearity/non-linearity
The pharmacokinetics of letrozole were dose proportional after single oral doses up to 10 mg (dose range:
0.01 to 30 mg) and after daily doses up to 1.0 mg (dose range: 0.1 to 5mg). After a 30 mg single oral dose
there was a slightly dose over-proportional increase in AUC value. The dose over-proportionality is likely to
be the result of a saturation of metabolic elimination processes. Steady levels were reached after 1 to 2
months at all dosage regimens tested (0.1-5.0 mg daily).
Special populations
Elderly
Age had no effect on the pharmacokinetics of letrozole.
Renal impairment
In a study involving 19 volunteers with varying degrees of renal function (24-hour creatinine clearance 9-
116 ml/min) no effect on the pharmacokinetics of letrozole was found after a single dose of 2.5 mg. In
addition to the above study assessing the influence of renal impairment on letrozole, a covariate analysis
was performed on the data of two pivotal studies (Study AR/BC2 and Study AR/BC3). Calculated creatinine
clearance (CLcr) [Study AR/BC2 range: 19 to 187 mL/min; Study AR/BC3 range: 10 to 180 mL/min]
showed no statistically significant association between letrozole plasma trough levels at steady-state
(Cmin). Futhermore, data of Study AR/BC2 and Study AR/BC3 in second-line metastatic breast cancer
showed no evidence of an adverse effect of letrozole on CLcr or an impairment of renal function.
Therefore, no dose adjustment is required for patients with renal impairment (CLcr ≥10 mL/min). Little
information is available in patients with severe impairment of renal function (CLcr <10 mL/min).
Hepatic impairment
In a similar study involving subjects with varying degrees of hepatic function, the mean AUC values of the
volunteers with moderate hepatic impairment (Child-Pugh B) was 37% higher than in normal subjects, but
still within the range seen in subjects without impaired function. In a study comparing the pharmacokinetics
of letrozole after a single oral dose in eight male subjects with liver cirrhosis and severe hepatic impairment
(Child-Pugh C) to those in healthy volunteers (N=8), AUC and t½ increased by 95 and 187%, respectively.
Thus, Marlet should be administered with caution to patients with severe hepatic impairment and after
consideration of the risk/benefit in the individual patient
 

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.
Oral administration of letrozole to female rats resulted in decreases in mating and pregnancy ratios and
increases in pre-implantation loss.
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.
In a 104-week mouse carcinogenicity study, no treatment-related tumors were noted in male mice. In
female mice, a generally dose-related increase in the incidence of benign ovarian granulosa theca cell
tumors was observed at all doses of letrozole tested. These tumors were considered to be related to the
pharmacological inhibition of estrogen synthesis and may be due to increased LH resulting from the
decrease in circulating estrogen.
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
 

Core Tablet:
• Magnesium Stearate
• Sodium Starch Glycolate
• Microcrystalline Cellulose
• Corn Starch
• Lactose monohydrate
• Talc
Film Coating (Aquapolish Yellow):
• Talc
• Hypromellose
• Hydroxypropylcellulose
• Cotton seed oil, hydrogenated
• Iron oxide yellow
• Iron oxide red
• Titanium dioxide
 

Not Applicable
 

Store below 30 ○C
 

Marlet 2.5 mg are packed in PVC.PVDC/ Aluminum blisters in pack of 30 tablets
 

Any unused medicinal product or waste material should be disposed of in accordance with local requirements