1. Name Of The Medicinal Product
Letrozole 2.5 mg film coated tablets
2. Qualitative And Quantitative Composition
Each tablet contains: 2.5 mg letrozole. Also contains Sunset Yellow FCF (E110).
For a 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. Clinical Particulars
4.1 Therapeutic Indications
• Adjuvant treatment of postmenopausal women with hormone receptor positive early breast cancer.
• Extended adjuvant treatment of hormone-dependent early 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 in women with natural or artificially induced postmenopausal status after relapse or disease progression, who have previously been treated with anti-oestrogens.
Efficacy has not been demonstrated in patients with hormone receptor negative breast cancer.
4.2 Posology And Method Of Administration
Oral use
Adult and elderly patients
The recommended dose of Letrozole 2.5 mg film coated tablets is 2.5 mg once daily. No dose adjustment is required for elderly patients.
In the adjuvant setting, it is recommended to treat for 5 years or until tumour relapse occurs. In the adjuvant setting, clinical experience is available for 2 years (median duration of treatment was 25 months).
In the extended adjuvant setting, clinical experience is available for 4 years (median duration of treatment).
In patients with advanced or metastatic disease, treatment with Letrozole 2.5 mg film coated tablets should continue until tumour progression is evident.
Children
Not applicable.
Patients with hepatic and/or renal impairment
No dosage adjustment is required for patients with renal insufficiency with creatinine clearance greater than 30 ml/min.
Insufficient data are available in cases of renal insufficiency with creatinine clearance lower than 30 ml/min or in patients with severe hepatic insufficiency (see sections 4.4 and 5.2).
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients.
Premenopausal endocrine status; pregnancy; lactation (see sections 4.6 Pregnancy and lactation and 5.3 Preclinical safety data).
4.4 Special Warnings And Precautions For Use
In patients whose postmenopausal status seems unclear, LH, FSH and/or oestradiol levels must be assessed before initiating treatment in order to clearly establish menopausal status.
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
Letrozole has only been studied in a limited number of non-metastatic patients with varying degrees of hepatic function: mild to moderate, and severe hepatic insufficiency. In non-cancer male volunteers with severe hepatic impairment (liver cirrhosis and Child-Pugh score C), systemic exposure and terminal half-life were increased 2-3-fold compared to healthy volunteers. Thus, letrozole should be administered with caution and after careful consideration of the potential risk/benefit to such patients (see section 5.2 Pharmacokinetic properties).
Bone Effects
Letrozole is a potent oestrogen-lowering agent. In the adjuvant and extended adjuvant setting the median follow-up duration of 30 and 49 months respectively is insufficient to fully assess fracture risk associated with long term use of letrozole. 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 by bone densitometry prior to the commencement of adjuvant and extended adjuvant treatment and be monitored for development of osteoporosis during and following treatment with letrozole. Treatment or prophylaxis for osteoporosis should be initiated as appropriate and carefully monitored (see section 4.8 Undesirable effects).
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Clinical interaction studies with cimetidine and warfarin indicated that the coadministration of letrozole with these drugs does not result in clinically significant drug interactions.
Additionally, a review of the clinical trial database indicated no evidence of clinically relevant interactions with other commonly prescribed drugs.
There is no clinical experience to date on the use of letrozole in combination with other anticancer agents.
In vitro, letrozole inhibits the cytochrome P450 isoenzymes 2A6 and, moderately, 2C19. Thus, caution should be used in the concomitant administration of drugs whose disposition is mainly dependent on these isoenzymes and whose therapeutic index is narrow.
4.6 Pregnancy And Lactation
Women of perimenopausal status or child-bearing potential
The physician needs to discuss the necessity of a pregnancy test before initiating Letrozole 2.5 mg film coated tablets and of adequate contraception with women who have the potential to become pregnant (i.e. women who are perimenopausal or who recently became postmenopausal) until their postmenopausal status is fully established (see sections 4.4 Special warnings and precautions for use and 5.3 Preclinical safety data).
Pregnancy:
Letrozole 2.5 mg film-coated tablets are contraindicated during pregnancy (see Section 4.3 – Contraindications).
Lactation
Letrozole 2.5 mg film-coated tablets are contraindicated during lactation (see Section 4.3 – Contraindications).
4.7 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.
4.8 Undesirable Effects
Letrozole is generally well tolerated across all studies as first-line and second-line treatment for advanced breast cancer and as adjuvant treatment of early breast cancer. Up to approximately one third of the patients treated with letrozole in the metastatic setting, up to approximately 70-75% of the patients in the adjuvant setting (both letrozole and tamoxifen arms), and up to approximately 40% of the patients treated 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. Most adverse reactions can be attributed to normal pharmacological consequences of oestrogen deprivation (e.g. hot flushes).
The most frequently reported adverse reactions in the clinical studies were hot flushes, arthralgia, nausea and fatigue. Many adverse reactions can be attributed to the normal pharmacological consequences of oestrogen deprivation (e.g. hot flushes, alopecia and vaginal bleeding).
After standard adjuvant tamoxifen, based on median follow-up of 28 months, the following adverse events irrespective of causality were reported significantly more often with letrozole than with placebo- hot flushes (50.7% vs. 44.3%), arthralgia/arthritis (28.5% vs. 23.2%) and myalgia (10.2% vs. 7.0%). The majority of these adverse events were observed during the first year of treatment. There was a higher but non significant incidence of osteoporosis and bone fractures in patients who received letrozole than in patients who received placebo (7.5% vs. 6.3% and 6.7% vs. 5.9%, respectively).
In an updated analysis in the extended adjuvant setting conducted at a median treatment duration of 47 months for letrozole and 28 months for placebo, the following adverse events irrespective of causality were reported significantly more often with letrozole than with placebo – hot flushes (60.3% vs. 52.6%), arthralgia/arthritis (37.9% vs. 26.8%) and myalgia (15.8% vs. 8.9%). The majority of these adverse events were observed during the first year of treatment. In the patients in placebo arm who switched to letrozole a similar pattern of general events was observed. There was a higher incidence of osteoporosis and bone fractures, any time after randomisation, in patients who received letrozole than in patients who received placebo (12.3% vs. 7.4% and 10.9% vs. 7.2%, respectively). In patients who switched to letrozole, newly diagnosed osteoporosis, any time after switching, was reported in 3.6% of patients while fracture were reported in 5.1% of patients any time after switching.
In the adjuvant setting, irrespective of causality, the following adverse events occurred any time after randomization in the letrozole and tamoxifen groups respectively: thromboembolic events (1.5% vs. 3.2%, P<0.001), angina pectoris (0.8% vs. 0.8%,), myocardial infarction (0.7% vs. 0.4%) and cardiac failure (0.9% vs. 0.4%, P=0.006).
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
common
uncommon
rare
very rare < 0.01%, including isolated reports.
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4.9 Overdose
Isolated cases of overdosage with letrozole has been reported.
No specific treatment for overdosage is known; treatment should be symptomatic and supportive.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group: Enzyme inhibitor. Non-steroidal aromatase inhibitor (inhibitor of oestrogen biosynthesis); antineoplastic agent, ATC code: L02B G04
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, 0.5, 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 h.
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 75-95% 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-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, 0.25, 0.5, 1, 2.5, 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, 0.5, 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 test.
Adjuvant treatment
A multi-centre, double-blind study randomised over 8000 postmenopausal women with resected receptor-positive early breast cancer, to one of the following options:
Option 1:
A. tamoxifen for 5 years
B. letrozole for 5 years
C. tamoxifen for 2 years followed by Letrozole 2.5 mg film coated tablets for 3 years
D. letrozole for 2 years followed by tamoxifen for 3 years
Option 2:
A. tamoxifen for 5 years
B. letrozole for 5 years
Data in Table 2 reflect results based on data from the monotherapy arms in each randomization option and data from the two switching arms up to 30 days after the date of switch. The analysis of monotherapy vs. sequencing of endocrine treatments will be conducted when the necessary number of events has been achieved.
Patients have been followed for a median of 26 months, 76% of the patients for more than 2 years, and 16% (1252 patients) for 5 years or longer.
The primary endpoint of the trial was disease-free survival (DFS) which was assessed as the time from randomization to the earliest event of loco-regional or distant recurrence (metastases) of the primary disease, development of invasive contralateral breast cancer, appearance of a second non-breast primary tumor or death from any cause without a prior cancer event. Letrozole reduced the risk of recurrence by 19% compared with tamoxifen (hazard ratio 0.81; P=0.003). The 5-year DFS rates were 84.0% for letrozole and 81.4% for tamoxifen. The improvement in DFS with letrozole is seen as early as 12 months and is maintained beyond 5 years. Letrozole also significantly reduced the risk of recurrence compared with tamoxifen whether prior adjuvant chemotherapy was given (hazard ratio 0.72 ; P=0.018) or not (hazard ratio 0.84 ; P=0.044).
For the secondary endpoint overall survival a total of 358 deaths were reported (166 on letrozole and 192 on tamoxifen). There was no significant difference between treatments in overall survival (hazard ratio 0.86; P=0.15). Distant disease-free survival (distant metastases), a surrogate for overall survival, differed significantly overall (hazard ratio 0.73; P=0.001) and in pre-specified stratification subsets. Letrozole significantly reduced the risk of systemic failure by 17% compared with tamoxifen (hazard ratio 0.83; P=0.02)
However, although in favour of letrozole non significant difference was obtained in the contralateral breast cancer (hazard ratio 0.61; P=0.09). An exploratory analysis of DFS by nodal status showed that letrozole was significantly superior to tamoxifen in reducing the risk of recurrence in patients with node positive disease (HR 0.71; 95% CI 0.59, 0.85; P=0.0002) while no significant difference between treatments was apparent in patients with node negative disease (HR 0.98; 95% CI 0.77, 1.25; P=0.89). This reduced benefit in node negative patients was confirmed by an exploratory interaction analysis (p=0.03).
Patients receiving letrozole, compared to tamoxifen, had fewer second malignancies (1.9% vs. 2.4%). Particularly the incidence of endometrial cancer was lower with letrozole compared to tamoxifen (0.2% vs. 0.4%).
See Tables 2 and 3 that summarize the results. The analyses summarized in Table 4 omit the 2 sequential arms from randomization option 1, i.e. take account only of the monotherapy arms:
Table 2 Disease-free and overall survival (ITT population)
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Table 3 Disease-free and overall survival by nodal status and prior adjuvant chemotherapy (ITT population)
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Table 4 Primary Core Analysis: Efficacy endpoints according to randomization option monotherapy arms (ITT population)
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The median duration of treatment (safety population) was 25 months, 73% of the patients were treated for more than 2 years, 22% of the patients for more than 4 years. The median duration of follow-up was 30 months for both letrozole and tamoxifen.
Adverse events suspected of being related to study drug were reported for 78% of the patients treated with letrozole compared with 73% of those treated with tamoxifen. The most common adverse events experienced with letrozole we
