POM: Prescription only medicine
This information is intended for use by health professionals
Adult and elderly patientsThe 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 letrozole 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 populationLetrozole 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 impairmentNo dosage adjustment of letrozole is required for patients with renal insufficiency with creatinine clearance ≥10ml/min.Insufficient data are available in cases of renal insufficiency with creatinine clearance lower than 10ml/min (see sections 4.4 and 5.2).
Hepatic impairmentNo 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 administrationLetrozole should be taken orally and can be taken with or without food.
Menopausal statusIn patients whose menopausal status is unclear, luteinising harmone (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 impairmentLetrozole 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 impairmentIn 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 effectsLetrozole 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 patient's safety profile (see sections 4.2, 4.8 and 5.1). Other warningsCo-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 tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Women of perimenopausal status or child-bearing potentialLetrozole 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.
PregnancyBased 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 sections 4.3 and 5.3).
Breast-feedingIt 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 breast-feeding (see section 4.3).FertilityThe 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.
Summary of the safety profileThe 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, hypercholesterolemia, 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.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 (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data).Table 1: Adverse Reactions
|MedDRA SOC||Adverse reactions|
|Infections and infestations|
|Uncommon:||Urinary tract infection|
|Neoplasms, benign, malignant and unspecified (including cysts and polyps)|
|Blood and the lymphatic system disorders|
|Immune system disorders|
|Not known:||Anaphylactic reaction|
|Metabolism and nutrition disorders|
|Common:||Anorexia, appetite increase|
|Uncommon:||Anxiety (including nervousness), irritability|
|Nervous system disorders|
|Uncommon:||Somnolence, insomnia, memory impairment, dysaesthesia (including paraesthesia, hypoesthesia), taste disturbance, cerebrovascular accident|
|Uncommon:||Cataract, eye irritation, blurred vision|
|Uncommon:||Palpitations1, tachycardia, ischaemic cardiac events (including new or worsening angina, angina requiring surgery, myocardial infarction and myocardial ischaemia)|
|Very common:||Hot flushes|
|Uncommon:||Thrombophlebitis (including superficial and deep vein thrombophlebitis)|
|Rare:||Pulmonary embolism, arterial thrombosis, cerebrovascular infarction|
|Respiratory, thoracic and mediastinal disorders|
|Common:||Nausea, dyspepsia1, constipation, abdominal pain, diarrhoea, vomiting|
|Uncommon:||Stomatitis1, dry mouth|
|Uncommon:||Increased hepatic enzymes|
|Skin and subcutaneous tissue disorders|
|Very common:||Increased sweating|
|Common:||Alopecia, rash (including erythematous, maculopapular, psoriaform, and vesicular rash), dry skin|
|Not known:||Angioedema, toxic epidermal necrolysis, erythema multiforme|
|Musculoskeletal and connective tissue disorders|
|Common:||Myalgia, bone pain1, osteoporosis, bone fractures|
|Renal and urinary disorders|
|Uncommon:||Increased urinary frequency|
|Reproductive system and breast disorders|
|Uncommon:||Vaginal discharge, vaginal dryness, breast pain|
|General disorders and administration site conditions|
|Very common:||Fatigue (including asthenia, malaise)|
|Uncommon:||General oedema, mucosal dryness, thirst, pyrexia|
Table 2: Adjuvant letrozole monotherapy versus tamoxifen monotherapy adverse events with significant differences
|Letrozole, incidence rate||Tamoxifen, incidence rate|
|Bone fracture||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
|Letrozole monotherapy||Letrozole → >tamoxifen||Tamoxifen → >letrozole|
|Endometrial proliferative disorders||0.7%||3.4%**||1.7%**|
|* 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 reactionsIn 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 reactionsFor 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.
Pharmacodynamic effectsThe 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 - primary 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 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 0.1mg, 0.5mg and 2.5mg letrozole suppresses 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 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 were below the limit of detection in the assays, indicating that higher oestrogene 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 0.1mg, 0.25mg, 0.5mg, 1mg, 2.5mg, 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 0.1mg, 0.5mg 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.
Study BIG 1-98BIG 1-98 was a multicenter, double-blind study in which over 8000 postmenopausal women with hormone receptor-positive early breast cancer were randomised 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 monthsData in Table 4 reflect results of the Primary Core Analysis (PCA) based on data from the monotherapy arms (A and B) and data 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||Median follow-up 60 months|
|Letrozole||Tamoxifen||HR1 (95% CI)||letrozole||Tamoxifen||HR1 (95% CI)|
|Disease-free survival (primary) - events (protocol definition2)||351||428||0.81 (0.70, 0.93) 0.003||585||664||0.86 (0.77, 0.96) 0.008|
|Overall survival (secondary) Number of deaths||166||192||0.86 (0.70, 1.06)||330||374||0.87 (0.75, 1.01)|
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 N=2459||Hazard Ratio 1 (95%CI)||P Value|
|Disease-free survival events (primary)2||509||565||0.88 (0.78, 0.99)||0.03|
|Time to distant metastasis (secondary)||257||298||0.85 (0.72, 1.00)||0.045|
|Overall survival (secondary) - deaths||303||343||0.87 (0.75, 1.02)||0.08|
|Censored analysis of DFS3||509||543||0.85 (0.75, 0.96)|
|Censored analysis of OS3||303||338||0.82 (0.70, 0.96)|
Sequential Treatments Analysis (STA)The Sequential Treatments Analysis (STA) addresses the second primary question of BIG 1-98 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 events1||Hazard ratio2||(97.5% confidence interval)||Cox model P-value|
|Letrozole → tamoxifen||1460||160||0.92||(0.72, 1.17)||0.42|
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 randomization (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)|
Study D2407Study D2407 is an open-label, randomized, multicenter 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 endpoint; 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 favour 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 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 1551 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 months|
|Letrozole N=2582||Placebo N=2586||HR (95% CI)2 P value||Letrozole N=2582||Placebo N=2586||HR (95% CI)2 P value|
|Disease-free survival3 Events||92 (3.6%)||155 (6.0%)||0.58 (0.45, 0.76) 0.00003||209 (8.1%)||286 (11.1%)||0.75 (0.63, 0.89)|
|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)||344 (13.3%)||402 (15.5%)||0.89 (0.77, 1.03)|
|5-year DFS rate||90.5%||80.8%||88.8%||86.7%|
|Distant metastases Events||57 (2.2%)||93 (3.6%)||0.61 (0.44, 0.84)||142 (5.5%)||169 (6.5%)||0.88 (0.70, 1.10)|
|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)|
First-line treatmentOne 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 summarized in Table 9.
Table 9: Results at a median follow-up of 32 months
|Variable||Statistic||Letrozole N=453||Tamoxifen N=454|
|Time to progression||Median||9.4 months||6.0 months|
|(95% CI for median)||(8.9, 11.6 months)||(5.4, 6.3 months)|
|Hazard ratio (HR)||0.72|
|(95% CI for HR)||(0.62, 0.83)|
|Objective response rate (ORR)||CR+PR||145 (32%)||95 (21%)|
|(95% CI for rate)||(28, 36%)||(17, 25%)|
|(95% CI for odds ratio)||(1.32, 2.40)|
Second-line treatmentTwo 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 cancerUse of letrozole in men with breast cancer has not been studied.
AbsorptionLetrozole 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.
DistributionPlasma 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.
BiotransformationMetabolic 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 predicated 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.
ElderyAge had no effect on the pharmacokinetics of letrozole.
Renal impairmentIn 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 impairmentIn 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.
Tablet coreLactose monohydrateCellulose, microcrystalline (E460)Maize starch, pregelatinisedSodium starch glycolate, type AMagnesium stearate (E572)Silica, colloidal anhydrous (E551)Film-coatingMacrogol 8000Talc (E553b)Hypromellose (E464)Titanium dioxide (E171)Iron oxide yellow (E172)