• Adjuvant treatment of postmenopausal women with hormone receptor positive early breast cancer.
•  Extended adjuvant treatment of early breast cancer in post menopausal women who have received ≥4.5 and ≤6.0 years prior standard adjuvant tamoxifen therapy.
•  First-line treatment in postmenopausal women with advanced breast cancer.
• Treatment of advanced breast cancer in women with natural or artificially induced postmenopausal status, who have previously been treated with antioestrogens.

LETARA should be administered once daily. Do not halve tablet. Dose equivalence when the tablet is divided has not been established.
 

Adult and elderly patients

The recommended dose of LETARA is 2.5 mg once daily. In the adjuvant and extended adjuvant setting, treatment with LETARA should continue for 5 years or until tumour relapse occurs, whichever comes first. In patients with metastatic disease, treatment with LETARA should continue until tumour progression is evident. No dose adjustment is required for elderly patients.
 

Children
Not applicable.
 

Patients with hepatic and/or renal impairment
No dosage adjustment is required for patients with mild hepatic impairment or renal impairment (creatinine clearance ≥ 30 mL/min.). Insufficinet data are available to justify a dose advice in cases of renal insufficiency with a creatinine clearance less than 30 mL/min or in patients with severe hepatic insufficiency. Patients with severe hepatic impairment (Child-Pugh score C) should be kept under close supervision (see Pharmacokinetics).

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 to up to 2,000 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 on 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.

Oral administration of letrozole to gravid rats resulted in a slight increase in the incidence of fetal malformation among the animals treated. However, it was not possible to show whether this was an indirect consequence of the pharmacological properties (inhibition of oestrogen biosynthesis), or a direct effect of letrozole in its own right (see recommendations in Contraindications and Pregnancy and lactation).

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.

Renal impairment
Letrozole has not been investigated in patients with creatinine clearance <10 mL/min nor in a sufficient number of patients with a creatinine clearance less than 30 mL/min. The potential risk/benefit to such patients should be carefully considered before administration of Letrozole. As letrozole is weakly bound to plasma proteins (see Pharmacokinetics), it is anticipated that it could be removed from circulation by dialysis. Similar caution should be exercised in patients with severe hepatic insufficiency.
 

Hepatic impairment
In patients with severe hepatic cirrhosis 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 (see Pharmacokinetics).
 

Bone effects
Osteoporosis and/or bone fractures have been reported with the use of Letrozole. Therefore monitoring of overall bone health is recommended during treatment (see Adverse effects).

Pregnancy (Category D) and lactation
Pregnancy
Letrozole is contraindicated during pregnancy (see Contraindications and Preclinical safety data).

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 recently became postmenopausal, until their postmenopausal status is fully established (see Preclinical safety data).

Lactation
Letrozole is contraindicated during lactation (see Contraindications).
 

Effects on 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.
 

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.
As the tablets contain lactose, Letrozole is not recommended for patients with rare hereditary problems of galactose intolerance, of severe lactase deficiency or of glucose-galactose malabsorption.

Clinical interaction studies with cimetidine and warfarin indicated that the coadministration of letrozole with these drugs does not result in clinically significant drug interactions.
A review of the clinical trial database indicated no evidence of other clinically relevant interaction with other commonly prescribed drugs.
There is no clinical experience to date on the use of letrozole in combination with other anti-cancer agents.
Letrozole inhibits in vitro the cytochrome P450-isozymes 2A6, and moderately 2C19. CYP2A6 does not play a major role in drug metabolism. In in vitro experiments letrozole, was not able to substantially inhibit the metabolism of diazepam (a substrate of CYP2C19) at concentrations approximately 100-fold higher than those observed in plasma at steady state. Thus, clinically relevant interactions with CYP2C19 are unlikely to occur. However, caution should be used in the concomitant administration of drugs whose disposition is mainly dependent on these isoenzymes and whose therapeutic index is narrow.

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.

Pregnancy (Category D) and lactation
Pregnancy
Letrozole is contraindicated during pregnancy (see Contraindications and Preclinical safety data).
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 recently became postmenopausal, until their postmenopausal status is fully established (see Preclinical safety data).
Lactation
Letrozole is contraindicated during lactation (see Contraindications).

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

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 70 to 75% of the patients in the adjuvant setting (both Letrozole and tamoxifen arms), and approximately 40% of the patients in the extended adjuvant setting (both Letrozole and placebo arms) experienced adverse reactions. Generally, the observed adverse reactions are mainly mild or moderate in nature, and most are associated with oestrogen deprivation.

The most frequently reported adverse reactions in the clinical studies were hot flushes, hypercholesterolaemia, arthralgia, fatigue, increased sweating and nausea. Many adverse reactions can be attributed to the normal pharmacological consequences of oestrogen deprivation (e.g. hot flushes, alopecia and vaginal bleeding).The following adverse drug reactions, listed in Table 1, were reported from clinical studies and from post marketing experience with Letrozole.

In the adjuvant settings there was a significant difference in incidence of osteoporosis and bone fractures in patients who received Letrozole compared to patients who received tamoxifen (osteoporosis 2.0% vs 1.1%, P=0.001 and bone fractures 6.4% vs 4.8%, P=0.003 at any time after randomization, respectively).

In the extended adjuvant setting there was a higher but non significant incidence of osteoporosis and bone fractures in patients who received Letrozole than in patients who received placebo (6.9% vs 5.5% and 5.9% vs 5.5% respectively) (see Further information – Clinical trial results - Extended adjuvant treatment)

Table 1

Adverse reactions are ranked under headings of frequency, the most frequent first, using the following convention: very common (≥1/10); common (≥1/100, <1/10); uncommon ≥1/1000, <1/100); rare (≥1/10,000, <1/1000); very rare (<1/10,000), including isolated report.

1. including nervousness, irritability

2. including paraesthesia, hypoaesthesia

3. including superficial and deep thrombophlebitis

4. including erythematous, maculopapular, psoriaform and vesicular rash

5. including asthenia and malaise

6. in metastatic/neoadjuvant setting only

7. in the adjuvant setting, irrespective of causality, the following adverse events occurred in the Letrozole and tamoxifen groups respectively: thromboembolic events (1.2% vs. 2.8%), angina pectoris (0.7% vs. 0.6%), myocardial infarction (0.6% vs. 0.4% ) and cardiac failure (0.9% vs. 0.4%).

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

The elimination of oestrogen-mediated stimulatory effects is a prerequisite for tumour response in cases where the growth of tumour tissue depends on the presence of oestrogens. In postmenopausal women, oestrogens are mainly derived from the action of the aromatase enzyme, which converts adrenal androgens - primarily androstenedione and testosterone - to oestrone (E1) and oestradiol (E2). The suppression of oestrogen biosynthesis in peripheral tissues and the cancer tissue itself can therefore be achieved by specifically inhibiting the aromatase enzyme.
Letrozole is a non-steroidal aromatase inhibitor. It inhibits the aromatase enzyme by competitively binding to the haem of the cytochrome P450 subunit of the enzyme, resulting in a reduction of oestrogen biosynthesis in all tissues.

In healthy postmenopausal women, single doses of 0.1 mg, 0.5 mg and 2.5 mg letrozole suppress serum oestrone and oestradiol by 75 to 78% and 78% from baseline, respectively. Maximum suppression is achieved in 48 to 78 hours.

In postmenopausal patients with advanced breast cancer, daily doses of 0.1 to 5 mg suppress plasma concentration of oestradiol, oestrone, and oestrone sulphate by 75 to 95% from baseline in all patients treated. With doses of 0.5 mg and higher, many values of oestrone and oestrone sulphate are below the limit of detection in the assays, indicating that higher oestrogen suppression is achieved with these doses. Oestrogen suppression was maintained throughout treatment in all these patients.

Letrozole is highly specific in inhibiting aromatase activity. Impairment of adrenal steroidogenesis has not been observed. No clinically relevant changes were found in the plasma concentrations of cortisol, aldosterone, 11-deoxycortisol, 17-hydroxy-progesterone, and ACTH, or in plasma renin activity among postmenopausal patients treated with a daily dose of letrozole 0.1 to 5 mg. The ACTH stimulation test performed after 6 and 12 weeks of treatment with daily doses of 0.1 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 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.

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 meal times.
Distribution
Plasma protein binding of letrozole is approximately 60%, mainly to albumin (55%). The concentration of letrozole in erythrocytes is about 80% of that in plasma. After administration of 2.5 mg 14C-labelled letrozole, approximately 82% of the radioactivity in plasma was unchanged compound. Systemic exposure to metabolites is therefore low. Letrozole is rapidly and extensively distributed to tissues. Its apparent volume of distribution at steady state is about 1.87 ± 0.47 L/kg.
Metabolism and elimination
Metabolic clearance to a pharmacologically inactive carbinol metabolite is the major elimination pathway of letrozole (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 non-linearity in the pharmacokinetics of letrozole upon daily administration of 2.5 mg. Since steady-state levels are maintained over time, it can be concluded that no continuous accumulation of letrozole occurs.

Age had no effect on the pharmacokinetics of letrozole.
 

Special populations
In a study involving volunteers with varying degrees of renal function (24-hour creatinine clearance 9 to 116 mL/min), no effect on the pharmacokinetics of letrozole was found after a single dose of 2.5 mg. 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 score 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 subjects with liver cirrhosis and severe hepatic impairment (Child-Pugh score C) to those in healthy volunteers (n=8), AUC and t½ increased by 95 and 187%, respectively. Breast-cancer patients with severe hepatic impairment are thus expected to be exposed to higher levels of letrozole than patients without severe hepatic dysfunction. However, since in patients dosed at 5 or 10 mg/day no increase in toxicity was observed, a dose reduction in patients with severe hepatic impairment appears not to be warranted, although such patients should be kept under close supervision. In addition, in two well-controlled studies involving 359 patients with advanced breast cancer, no effect of renal impairment (calculated creatinine clearance: 20 to 50 mL/min) or hepatic dysfunction was found on the letrozole concentration.

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 to up to 2,000 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 on 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.

Oral administration of letrozole to gravid rats resulted in a slight increase in the incidence of fetal malformation among the animals treated. However, it was not possible to show whether this was an indirect consequence of the pharmacological properties (inhibition of oestrogen biosynthesis), or a direct effect of letrozole in its own right (see recommendations in Contraindications and Pregnancy and lactation).

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.

Colloidal anhydrous silica, microcrystalline cellulose, lactose monohydrate, magnesium stearate, maize starch, sodium starch glycollate, hypromellose, macrogol 400, titanium dioxide (E 171), iron oxide yellow (E 172).

NOt applicable

Do not store above 30°C, protect from moisture.
LETARA should be kept out of the reach and sight of children.

PVC/PVDC blister packs containing 30 tablets.

No specific instructions for use/handling