Letrozole is indicated for the following conditions:
 Adjuvant treatment of postmenopausal women with hormone receptor (estrogen (ER) and/or
progesterone (PR) receptor) positive early breast cancer,
 Extended adjuvant treatment of early breast cancer in postmenopausal women with hormone
receptor (ER and/or PR receptor) positive, who have received prior standard tamoxifen therapy
(for 5 years).
 First-line treatment of postmenopausal women with hormone receptor (ER and/or PR) positive,
locally advanced and metastatic breast cancer.
 Treatment of breast cancer in postmenopausal women with relapse or disease progression
following anti-estrogen therapy.
 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.

Posology/Frequency and duration of administration
The recommended dose of LETRASAN for adults is 2.5 mg once daily.
In the adjuvant and extended adjuvant setting, treatment with LETRASAN should continue for 5
years or until tumor relapse occurs (whichever comes first).
In the adjuvant setting a sequential treatment schedule (letrozole 2 years followed by tamoxifen 3
years) could also be considered.
In the neoadjuvant setting, treatment with letrozole could be continued for 4 to 8 months in order to
establish optimal tumor 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.

Method of administration
LETRASAN should be taken orally and can be taken with or without food because food has no
effect on the extent of absorption.
LETRASAN should be used once daily and preferably at the same time of each day.
The missed dose should be taken as soon as the patient remembers. However, if it is almost time for
the next dose, 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

Renal impairment
LETRASAN 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
LETRASAN.
Hepatic impairment
In patients with severe hepatic impairment (Child-Pugh score C), systemic exposure and terminal
half-life were approximately doubled compared to healthy volunteers. Such patients should
therefore be kept under close supervision

Bone effects
LETRASAN significantly decreases estrogen levels; osteoporosis and/or bone fractures have been
reported with the use of LETRASAN. Therefore, monitoring of overall bone health is
recommended during treatment (see sections 4.8 and 5.1).
Letrozole is a potent estrogen-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”
Menopausal status
In patients whose menopausal status is unclear, luteinizing hormone (LH), follicle-stimulating
hormone (FSH) and/or estradiol levels should be measured before initiating treatment with
LETRASAN. Only women of postmenopausal endocrine status receive LETRASAN.
Fertility
The pharmacological actionof letrozole is to reduce estrogen production by aromatase inhibition.

General recommendation
Pregnancy category is X

Breast-feeding
LETRASAN is contraindicated during lactation (see section 4.3). It is unknown whether
LETRASAN is excreted in human milk.
Fertility
The pharmacological action of letrozole is to reduce estrogen production by aromatase inhibition. In
premenopausal women, the inhibition of estrogen synthesis leads to feedback increases in
gonadotropin (LH, FSH) levels. Increased FSH levels in turn stimulate follicular growth, and can
induce ovulation.

Since fatigue and dizziness have been observed with the use of LETRASAN and somnolence has
been reported uncommonly, caution is advised when driving or using machines.

Letrozole 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 and as extended adjuvant
treatment in women who have received prior standard tamoxifen therapy.
Approximately one third of the patients treated with letrozole in the metastatic and neoadjuvant
settings, approximately 80% of the patients in the adjuvant setting (both letrozole and tamoxifen
arms, at a median treatment duration of 60 months), and approximately 80% of the patients in the
extended adjuvant setting (both letrozole 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 estrogen deprivation. The majority of the
adverse reactions occurred during the first few weeks of treatment.
The most frequently reported adverse reactions in the clinical studies were hot flushes, arthralgia,
nausea, sweating, hypercholesterolemia and fatigue. 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). Many adverse
reactions can be attributed to the normal pharmacological consequences of estrogen deprivation
(e.g. hot flushes, alopecia and vaginal bleeding).The following adverse drug reactions, listed below,
were reported from clinical studies and from post marketing experience with letrozole.
Adverse reactions are ranked under headings of frequency, the most frequent first. Within each
frequency grouping, adverse reactions are presented in the order of decreasing seriousness.

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

In healthy postmenopausal women, single doses of 0.1 mg, 0.5 mg, and 2.5 mg letrozole suppress
serum estrone and estradiol 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 suppress plasma concentration of estradiol, estrone, and estrone sulphate by 75 to 95%
from baseline in all patients treated. With doses of 0.5 mg and higher, many values of estrone and
estrone sulphate are below the limit of detection in the assays, indicating that higher estrogen
suppression is achieved with these doses. Estrogen 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 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 androgen (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 to 5 mg, indicating that the blockade of estrogen 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.

LETRASAN (letrozole) is a non-steroidal aromatase inhibitor and antineoplastic agent. Letrozole is
white-yellowish crystal powder. Letrozole is freely soluble in dichloromethane and slightly soluble
in ethanol. Letrozole is practically insoluble in water.
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/liter fasted versus 98.7 ±18.6 nmol/liter fed).
But the extent of absorption [AUC (area under the curve)] 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%). Letrozole is
rapidly and extensively distributed to tissues. Its apparent volume of distribution at steady state is
about 1.87 ±0.47 L/kg.
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 steadystate
levels are maintained over time, it can be concluded that no continuous accumulation of
letrozole occurs.
Biotransformation
The concentration of letrozole in erythrocytes is about 80% of that in plasma. After administration
of 2.5 mg 14C-labeled letrozole, approximately 82% of the radioactivity in plasma was unchanged
compound. Systemic exposure to metabolites is therefore low.
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 (CYP) isoenzymes CYP3A4 and CYP2A6 were found to be capable of converting letrozole to this metabolite.
Elimination
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. Formation of minor unidentified
metabolites and direct renal and fecal excretion play only a minor role in the overall elimination of
letrozole. Within 2 weeks after administration of 2.5 mg 14C-labeled letrozole to healthy
postmenopausal volunteers, 88.2 ±7.6% of the radioactivity was recovered in urine and 3.8 ±0.9%
in feces. 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.
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 5 mg). After a 30 mg
single oral dose there was a slightly dose over-proportional increase in AUC value. With daily
doses of 2.5 and 5 mg the AUC values increased about 3.8 and 12 fold instead of 2.5 and 5 fold,
respectively, when compared to the 1.0 mg/day dose. The recommended dose of 2.5 mg/day may
thus be a borderline dose at which an onset of over-proportionality becomes apparent, whereas at 5
mg/day the over-proportionality is more pronounced. 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).

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.
The pharmacological effects of letrozole resulted in skeletal, neuroendocrine and reproductive
findings in a juvenile rat study. 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. Bone
mineral density (BMD) was also 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 and atrophy of the female
reproductive tract. With the exception of bone size in females and morphological changes in the
testes, all effects were at least partially reversible.
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 tumors were noted in male rats. In
female rats, a reduced incidence of benign and malignant mammary tumors 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 tumours 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.
Oral administration of letrozole to gravid Sprague-Dawley rats resulted in a slight increase in the
incidence of fetal malformation (domed head and fused centrum/vertebrae) among the animals
treated. Similar malformations were not seen in New Zealand White rabbits However, it was not
possible to show whether this was an indirect consequence of the pharmacological properties
(inhibition of estrogen biosynthesis), or a direct effect of letrozole in its own right (see sections 4.3
and 4.6).
Preclinical observations were confined to those associated with the recognized pharmacological
action, which is the only safety concern for human use derived from animal studies.

Maize starch
Lactose monohydrate
Sodium starch glycolate
Microcrystalline cellulose PH 102
Magnesium stearate
Film-coating material: Opadry II Yellow
Polyvinyl alcohol
Polyethylene glycol
Titanium dioxide
Talc
Yellow iron oxide
Red iron oxide

No sufficient data are available

Store at room temperature below 30°C.

PVC/PE/PVDC blisters
Blister package containing 30 film coated tablets

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