This information is intended for use by health professionals

1. Name of the medicinal product

Letrozole 2.5 mg film-coated tablets

2. Qualitative and quantitative composition

Each film-coated tablet contains 2.5 mg letrozole.

Excipient with known effect

Each film-coated tablet contains 45 mg of lactose monohydrate.

Each film-coated tablet contains 0.546 mg of sodium.

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Film-coated tablet.

Yellow, circular, biconvex film-coated tablets, plain on both sides.

4. Clinical particulars
4.1 Therapeutic indications

Adjuvant treatment of postmenopausal women with hormone receptor positive invasive early breast cancer.

Extended adjuvant treatment of hormone-dependent early 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 antioestrogens.

Neoadjuvant 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 cancer.

4.2 Posology and method of administration

Posology

Adult and elderly patients

The recommended dose of Letrozole tablet is 2.5 mg once daily.

In patients with advanced or metastatic breast cancer, treatment with letrozole tablets should continue until tumour progression is evident.

In the adjuvant and extended adjuvant setting, treatment with Letrozole tablets should continue for 5 years or until tumour relapse occurs, whichever is first.

In the neoadjuvant setting, treatment with letrozole tablets could be continued for 4 to 8 months in order to establish optimal tumour reduction. If the response is not adequate, treatment with letrozole tablets should be discontinued and surgery scheduled and/or further treatment options discussed with the patient.

Following standard adjuvant tamoxifen therapy, treatment with letrozole tablets should continue for 5 years or until tumour relapse occurs, whichever comes first. In patients with metastatic disease, treatment with letrozole tablets should continue until tumour progression is evident. Regular monitoring to observe progression during the pre-operative treatment period is recommended (see section 5.1). No dose adjustment is required for elderly patients.

Paediatric population

Letrozole tablets is not recommended for use in children and adolescents. The safety and efficacy of letrozole tablets 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 letrozole tablets 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 dosage adjustment of letrozole tablets is required for patients with mild to moderate hepatic insufficiency (Child-Pugh grade 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

Letrozole tablets 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).

4.3 Contraindications

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1

• Premenopausal endocrine status

• Premenopausal, pregnant or lactating women (see section 4.6).

4.4 Special warnings and precautions for use

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 letrozole. Only women of postmenopausal endocrine status should receive letrozole.

Paediatric population

Letrozole tablets are not recommended for use in children as efficacy and safety in this patient group have not been assessed in clinical studies.

Male breast cancer

There are no efficacy data to support the use of letrozole in men with breast cancer.

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

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

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. 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).

As letrozole is a potent oestrogen lowering agent, reductions in bone mineral density can be anticipated. During adjuvant treatment with letrozole, women with osteoporosis or at risk of osteoporosis should have their bone mineral density formally assessed by bone densitometry e.g. DEXA scanning at the commencement of treatment. Treatment or prophylaxis for osteoporosis should be initiated as appropriate and patients treated with letrozole tablets should be carefully monitored (see sections 4.8 and 5.1).

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 (see section 4.5).

Lactose

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Sodium

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free'.

4.5 Interaction with other medicinal products and other forms of interaction

Metabolism of letrozole is partly mediated via CYP2A6 and CYP3A4. Clinical interaction studies with cimetidine and warfarin indicated that the co-administration of letrozole with these drugs does not result in clinically significant drug interactions, even though cimetidine is a known weak inhibitor of one of the cytochrome P450 isoenzymes capable of metabolising letrozole in vitro (See section 5.2 Metabolism and elimination).

There was no evidence of other clinically relevant interaction in patients receiving other commonly prescribed drugs (e.g. benzodiazepines; barbiturates; NSAIDs such as diclofenac sodium, ibuprofen; paracetamol; furosemide; omeprazole).

There is no clinical experience to date on the use of letrozole 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. Co-administration of letrozole with tamoxifen, other anti-oestrogens or oestrogens should be avoided.

Letrozole inhibits in vitro the cytochrome P450-isoenzymes 2A6 and moderately 2C19, however, 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. Nevertheless, caution should be used in the concomitant administration of drugs whose disposition is mainly dependent on these isoenzymes and whose therapeutic index is narrow (e.g phenytoin, clopidrogel).

4.6 Fertility, pregnancy and lactation

Women of perimenopausal status or child-bearing potential

Letrozole 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.

Pregnancy

Based 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 section 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.

Letrozole 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.

4.7 Effects on ability to drive and use machines

Letrozole has minor influence on the 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 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 as well as in the treatment of women who have received prior standard tamoxifen therapy. Approximately, one third of the patients treated with letrozole in the metastatic and neoadjuvant settings, and 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 treated following standard adjuvant tamoxifen (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 oestrogen deprivation.

The most frequently reported adverse reactions in 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).

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.

Tabulated listing of adverse reactions

The frequencies of adverse reactions for letrozole 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 post marketing experience with letrozole tablets.

Table 1

Adverse reactions are ranked under headings of frequency, the most frequent first, using the following convention: very common ≥ 10%; common ≥ 1% to < 10%; uncommon ≥ 0.1% to < 1%; rare ≥ 0.01% to < 0.1%; very rare < 0.01%, not known (cannot be estimated from the available data).

Frequency

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)

Organ System

Infections and infestations

Urinary tract infection

Neoplasms benign, malignant and unspecified (including cysts and polyps)

Tumour pain6

Blood and lymphatic system disorders

Leucopenia

Immune system disorders

Angioedema

Anaphylactic reactions

Metabolism and nutrition disorders

Hypercholesterolaemia

Anorexia, appetite increase,

General oedema

Psychiatric disorders

Depression

Anxiety1, irritability

Nervous system disorders

Headache, dizziness

Somnolence, insomnia, memory impairment, dysaesthesia2, taste disturbance, cerebrovascular accident, carpal tunnel syndrome

Eye disorders

Cataract, eye irritation, blurred vision

Cardiac disorders

Palpitations6

Tachycardia, ischaemic cardiac events (including new or worsening angina, angina requiring surgery, myocardial infarction and myocardial ischaemia)

Vascular disorders

Hot flushes

Hypertension

Thrombophlebitis3, ischemic cardiac events7, 8

Pulmonary embolism, arterial thrombosis, cerebrovascu-lar infarction

Respiratory, thoracic and mediastinal disorders

Dyspnoea, cough

Gastrointestinal disorders

Nausea, dyspepsia 6, constipation, abdominal pain, diarrhoea, vomiting

Dry mouth, stomatitis6

Hepatobiliary disorders

Increased hepatic enzymes, hyperbilirubinemia, jaundice.

Hepatitis

Skin and subcutaneous tissue disorders

Increased sweating

Alopecia, rash4, dry skin

Pruritus, urticaria

Toxic epidermal necrolysis, erythema multiforme

Musculoskeletal and connective tissue disorders

Arthralgia

Myalgia, bone pain6, osteoporosis, bone fractures, arthritis.

Trigger finger

Renal and urinary disorders

Increased urinary frequency

Reproductive system and breast disorders

Vaginal bleeding

Vaginal discharge, vaginal dryness, breast pain

General disorders and administration site conditions

Fatigue5, hot flushes

Peripheral oedema, chest pain.

General oedema, pyrexia, mucosal dryness, thirst

Investigations

Weight increase

Weight loss

Including:

(1) nervousness, irritability

(2) paraesthesia, hypoaesthesia

(3) superficial and deep thrombophlebitis

(4) erythematous, maculopapular, psoriaform and vesicular rash

(5) aesthenia 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 (2.1% vs. 3.6%), angina pectoris (1.1% vs. 1.0%), myocardial infarction (1.0% vs. 0.5%), cardiac failure (0.8% vs. 0.5%) (see section 5.1).

(8) After standard adjuvant tamoxifen, at a median treatment duration of 60 months for letrozole and 37 months for placebo, the following AEs were reported for letrozole and placebo (excluding all switches to letrozole) respectively: new or worsening angina (1.4% vs. 1.0%); angina requiring surgery (0.8% vs. 0.6%); myocardial infarction (1.0% vs. 0.7%); thromboembolic event (0.9% vs. 0.3%); stroke/TIA (1.5% vs. 0.8%) (see section 5.1)

Table 2 presents the frequency of specific target adverse events, CTC grades 1-4 in the BIG 1-98 study, irrespective of causality, reported in patients receiving letrozole or tamoxifen monotherapy, at a median treatment duration of 60 months. The reporting period includes 30 days after cessation of trial therapy.

Table 2:

CTC grades 1-4

CTC grades 3-4

Pre-specified event

Letrozole

N = 2448

Tamoxifen

N - 2447

Letrozole

N = 2448

Tamoxifen

N = 2447

n

(%)

n

(%)

n

(%)

n

(%)

Hypercholesterolaemia

1280

(52.3)

700

(28.6)

11

(0.4)

6

(0.2)

Hot flashes / hot flushes

821

(33.5)

929

(38.0)

0

-

0

-

Arthralgia / arthritis

617

(25.2)

500

(20.4)

84

(3.4)

49

(2.0)

Night sweats

357

(14.6)

426

(17.4)

0

-

0

-

Nausea

283

(11.6)

277

(11.3)

6

(0.2)

9

(0.4)

Bone fractures

245

(10.0)

170

(6.9)

83

(3.4)

43

(1.8)

Fatigue (lethargy, malaise, asthenia)

235

(9.6)

250

(10.2)

6

(0.2)

7

(0.3)

Myalgia

217

(8.9)

212

(8.7)

18

(0.7)

14

(0.6)

Vaginal bleeding

128

(5.2)

320

(13.2)

1

(<0.1)

8

(0.3)

Oedema

164

(6.7)

160

(6.5)

3

(0.1)

1

(<0.1)

Headache

105

(4.3)

94

(3.8)

9

(0.4)

5

(0.2)

Osteoporosis

124

(5.1)

66

(2.7)

10

(0.4)

5

(0.2)

Vaginal irritation

111

(4.5)

77

(3.1)

2

(<0.1)

2

(<0.1)

Osteopaenia

87

(3.6)

74

(3.0)

0

-

2

(<0.1)

Dizziness / light-headedness

84

(3.4)

84

(3.4)

1

(<0.1)

6

(0.2)

Vomiting

80

(3.3)

80

(3.3)

3

(0.1)

5

(0.2)

Total serum cholesterol>1.5*ULN1

151/1843

(8.2)

57/1840

(3.1)

-

-

-

-

Thromboembolic event2

51

(2.1)

89

(3.6)

-

-

-

-

Constipation

49

(2.0)

71

(2.9)

3

(0.1)

1

(<0.1)

Cerebrovascular accident/ Transient ischaemic attack2, 3

52

(2.1)

46

(1.9)

-

-

-

-

Endometrial proliferation disorders

14

(0.6)

86

(3.5)

0

-

14

(0.6)

Cataract

49

(2.0)

54

(2.2)

16

(0.7)

17

(0.7)

Breast pain

37

(1.5)

43

(1.8)

1

(<0.1)

0

-

Endometrial hyperplasia or cancer4

6/1909

(0.3)

57/1943

(2.3)

-

-

-

-

Anorexia

20

(0.8)

20

(0.8)

1

(<0.1)

1

(<0.1)

Angina pectoris (new worsening, or requiring surgical intervention) 2

26

(1.1)

24

(1.0)

-

-

-

-

Cardiac failure 2

30

(1.2)

24

(1.0)

-

-

-

-

Myocardial infarction2

24

(1.0)

12

(0.5)

-

-

-

-

Ovarian cyst

11

(0.4)

18

(0.7)

4

(0.2)

4

(0.2)

1 Based on number of patients with normal serum cholesterol levels at baseline, and developing at least one value greater than 1.5 times the upper limit of normal in the laboratory measuring total serum cholesterol. Approximately 90% of the measured values were non-fasting measurements

2 All cardiovascular events (including cerebrovascular and thromboembolic events) assumed to be grades 3-5

3 Pre-printed term “CVA/TIA” without distinguishing between terms

4 Denominator is number of patients not having undergone hysterectomy at baseline

After standard adjuvant tamoxifen, the following adverse events irrespective of causality were reported significantly more often with letrozole than with placebo – hot flushes (letrozole, 61% versus placebo, 51%), arthralgia/arthritis (41% versus 27%), sweating (35% versus 30%), hypercholesterolaemia (24% versus 15%) and myalgia (18 % versus 9.4%). The majority of these adverse events were observed during the first year of treatment. In the 60% of patients in the placebo arm who switched to letrozole following a median duration of 31 months after completion of tamoxifen following unblinding of the study in 2003, a similar pattern of general adverse events was observed. The incidence of osteoporosis during treatment was significantly higher for letrozole than for placebo (12.2% versus 6.4%). The incidence of clinical fractures during treatment was significantly higher for letrozole than for placebo patients (10.4% versus 5.8%). In patients who switched to letrozole, newly diagnosed osteoporosis during treatment with letrozole was reported in 5.4% of patients while fractures were reported in 7.7% of patients. Irrespective of treatment, patients ≥ 65 years experienced more bone fractures and more osteoporosis.

Some adverse reactions have been reported with notably different frequencies in the adjuvant treatment setting. The following tables provide information on significant differences in letrozole versus tamoxifen monotherapy and in the letrozole-tamoxifen sequential treatment therapy:

Table 3 Adjuvant letrozole monotherapy versus tamoxifen monotherapy – adverse events with significant differences

Letrozole, incidence rate

Tamoxifen, incidence rate

N=2448

N=2447

During treatment (Median 5y)

Any time after randomization (Median 8y)

During treatment (Median 5y)

Any time after randomization (Median 8y)

Bone fracture

10.2%

14.7%

7.2%

11.4%

Osteoporosis

5.1%

5.1%

2.7%

2.7%

Thromboembolic events

2.1%

3.2%

3.6%

4.6%

Myocardial infarction

1.0%

1.7%

0.5%

1.1%

Endometrial hyperplasia/endometrial cancer

0.2%

0.4%

2.3%

2.9%

Note: “During treatment” includes 30 days after last dose. “Any time” includes follow-up period after completion or discontinuation of study treatment.

Differences were based on risk ratios and 95% confidence intervals.

Table 4 Sequential treatment versus letrozole monotherapy – adverse events with significant differences

Letrozole monotherapy

Letrozole->tamoxifen

Tamoxifen->Letrozole

N=1535

N=1527

N=1541

5 years

2 yrs-> 3y

2 yrs-> 3y

Bone fractures

10.0%

7.7%*

9.7%

Endometrial proliferative disorders

0.7%

3.4%**

1.7%*

Hypercholesterolaemia

52.5%

44.2%*

40.8%*

Hot flushes

37.6%

41.7%**

43.9%**

Vaginal bleeding

6.3%

9.6%**

12.7%**

* 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 reactions

In 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 reactions

For 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.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

There is no clinical experience of overdosage only isolated cases of overdose with letrozole have been reported. In animal studies, letrozole exhibits only a slight degree of acute toxicity. In clinical trials, the highest single and multiple dose tested in healthy volunteers was 30 mg and 5 mg, respectively, the latter also being the highest dose tested in postmenopausal breast cancer patients. Each of these doses was well tolerated. There is no clinical evidence for a particular dose of letrozole resulting in life-threatening symptoms.

There is no specific antidote to letrozole. In general, supportive care, symptomatic treatment and frequent monitoring of vital signs are appropriate.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Endocrine therapy. Hormone antagonist and related agents: aromatase inhibitor; ATC Code: L02BG04.

Letrozole is a Non-steroidal aromatase inhibitor (inhibitor of oestrogen biosynthesis); antineoplastic agent.

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. 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.

This study was designed to investigate two primary questions: whether letrozole for 5 years was superior to tamoxifen for 5 years (Primary Core Analysis and Monotherapy Arms Analysis) and whether switching endocrine treatments at 2 years was superior to continuing the same agent for a total of 5 years (Sequential Treatments Analysis).

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 5 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 letrozole and 81.4% for tamoxifen.

Table 5 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

N=4003

Tamoxifen

N=4007

HR1

(95% CI) P

Letrozole

N=4003

Tamoxifen

N=4007

HR1

(95% CI) P

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)

HR = Hazard ratio; CI = Confidence interval

1 Log rank test, stratified by randomisation option and use of chemotherapy (yes/no)

2 DFS events: loco-regional recurrence, distant metastasis, invasive contralateral breast cancer, second (non-breast) primary malignancy, death from any cause without a prior cancer event.

Results at a median follow-up of 96 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 6.

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 6.

Table 6 Monotherapy Arms Analysis: Disease-free and overall survival at a median follow-up of 96 months (ITT population)

Letrozole

N=2463

Tamoxifen

N=2459

Hazard Ratio1 (95% CI)

P Value

Disease-free survival events (primary) 2

626

698

0.87 (0.78, 0.97)

0.01

Time to distant metastasis (secondary)

301

342

0.86 (0.74, 1.01)

0.06

Overall survival (secondary) deaths

393

436

0.89 (0.77, 1.02)

0.08

Censored analysis of DFS3

626

649

0.83 (0.74, 0.92)

Censored analysis of OS3

393

419

0.81 (0.70, 0.93)

1 Log rank test, stratified by randomisation option and use of chemotherapy (yes/no)

2 DFS events: loco-regional recurrence, distant metastasis, invasive contralateral breast cancer, second (non-breast) primary malignancy, death from any cause without a prior cancer event.

3 Observations in the tamoxifen arm censored at the date of selectively switching to letrozole

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 7).

Table 7 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

254

1.03

(0.84, 1.26)

0.72

Letrozole

1464

249

1 Protocol definition, including second non-breast primary malignancies, after switch / beyond two years

2 Adjusted by chemotherapy use

There were no significant differences in DFS, OS, SDFS or DDFS in any of the STA from randomisation pairwise comparisons (Table 7).

Table 8 Sequential Treatments Analyses from randomisation (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)

330

319

Hazard ratio1 (99% CI)

1.04 (0.85, 1.27)

Letrozole→Tamoxifen

Tamoxifen2

Number of patients

1540

1548

Number of patients with DFS events (protocol definition)

330

353

Hazard ratio1 (99% CI)

0.92 (0.75, 1.12)

1 Adjusted by chemotherapy use (yes/no)

2 626 (40%) patients selectively crossed to letrozole after tamoxifen arm unblinded in 2005

Letrozole was approved for the adjuvant treatment of early breast cancer on the basis of the Primary Core Analysis (PCA) results at a median follow-up of only 26 months (see Table 9). The updated analysis, using all data from the monotherapy arms (Monotherapy Arms Analysis, MAA) at a median follow-up of 73 months confirmed the superiority of letrozole over tamoxifen in reducing the risk of a disease-free survival event, including the risk of distant metastasis (Table 9).

The independent Data Monitoring Committee recommended unblinding the tamoxifen arms (other treatment arms remained blinded) and, in accordance with a formal protocol amendment, patients in the tamoxifen arms were allowed to cross over to letrozole to complete their adjuvant therapy (if they had received tamoxifen for 2 to 4.5 years) or to start further adjuvant therapy (if they had received tamoxifen for at least 4.5 years). Approximately 26% of patients (632 in total) in the tamoxifen monotherapy arms selectively crossed to letrozole or another aromatase inhibitor (12 patients), mostly to complete adjuvant therapy.

Table 9: Comparison of letrozole and tamoxifen monotherapy at a median follow-up of 26 months and of 73 months

PCA (median follow-up 26 months)

(PCA ITT population)

MAA (median follow-up 73 months)

(MAA ITT population)

Letrozole

Tamoxifen

HR (95% CI) 1

Letrozole

Tamoxifen

HR (95% CI) 1

N=4003

N=4007

P value

N=4003

N=4007

P value

Disease-free survival (DFS) (protocol definition)2 (primary endpoint)

Events

351

428

0.81

(0.70, 0.93)

0.003

509

565

0.88

(0.78, 0.99)

0.03

5-year DFS rate

84.0%

81.4%

---

85.6%

82.6%

---

Time to distant metastases (TDM) (secondary endpoint)3

Events

184

249

0.73

(0.60, 0.88)

257

298

0.85

(0.72, 1.00)

Distant disease-free survival (DDFS) (secondary endpoint)4

Events

265

318

0.82

(0.70, 0.97)

385

432

0.87

(0.76, 1.00)

Overall survival (OS) (secondary endpoint)

Events

166

192

0.86

(0.70, 1.06)

303

343

0.87

(0.75, 1.02)

5-year OS rate

91.1%

89.7%

---

89.3%

88.1%

---

Censored analysis of DFS (protocol definition)5

Events

---

---

---

509

543

0.85

(0.75, 0.96)

Censored analysis of OS5

Events

---

---

---

303

338

0.82

(0.70, 0.96)

PCA = Primary Core Analysis; MAA = Monotherapy Arms Analysis; HR = Hazard ratio; CI = Confidence interval

1 Adjusted by stratification factors of randomisation option and use of adjuvant chemotherapy

2 Protocol definition of DFS events: loco-regional recurrence, distant metastasis, invasive contralateral breast cancer, second non-breast primary cancer, death from any cause without a prior cancer event

3 Time to distant metastasis. Note: In original analysis, this endpoint was erroneously labelled “distant disease-free survival” (DDFS)

4 DDFS events: Earlier event of either distant metastasis or death from any cause

5 Follow-up times censored at date of selectively crossing from tamoxifen to letrozole, after tamoxifen arm was unblinded following the PCA results

Note: P values are provided only for the primary endpoint; if the 95% CI does not include 1.0, the result may be regarded as “statistically significant” at face value

The Sequential Treatments Analyses from switch (STA-S) address the second primary question in BIG 1- 98, namely for a new patient, whether it was better to switch endocrine agents after approximately 2 years, or to continue with the same endocrine agent for a total of 5 years. Table 10 shows that there was no statistically significant difference between treatments. The safety profile of the sequential treatments should be considered in reviewing the efficacy results.

Table 10: Summary of sequential treatment analyses from switch (STA-S) (ITT population)

[Letrozole 2y -] Tamoxifen vs Letrozole 5y beyond 2 years 1

[Tamoxifen 2y -] Letrozole vs Tamoxifen 5y beyond 2 years 1

Tmaoxifen

Letrozole

Letrozole

Tamoxifen 2

N=1460

N=1463

N=1446

N=1459

Disease-free survival (protocol definition) (primary endpoint)

Events

160

178

160

186

HR (97.5% CI) 3

0.92 (0.72, 1.17)

0.85 (0.67, 1.09)

P value

0.42

0.14

DFS censoring follow-up times at date of selective crossover in tamoxifen arm 2

Events

---

---

160

165

HR (97.5% CI) 3

---

0.76 (0.59, 0.97)

Overall survival (secondary endpoint)

Events

72

86

85

94

HR (97.5% CI) 3

0.85 (0.59, 1.22)

0.92 (0.66, 1.28)

OS censoring follow-up times at date of selective crossover in tamoxifen arm 2

Events

---

---

85

89

HR (97.5% CI) 3

---

0.73 (0.52, 1.02)

HR = Hazard ratio; CI = Confidence interval

1 Median follow-up beyond switch approximately 43 months

2 Approximately 43% of patients (624) in the tamoxifen 5 years arm selectively crossed to an aromatase inhibitor after the switch, mostly to complete adjuvant therapy

3 Adjusted by stratification factor of use of adjuvant chemotherapy

Adjuvant Therapy in Early Breast Cancer, Study D2407

Study D2407 is an open-label, randomised, multicentre 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 end-point; the lumbar spine BMD (L2-L4) showed a median decrease of 4.1% for letrozole compared to a median increase of 0.3% in the 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.

Treatment after standard adjuvant tamoxifen, study CFEM345G MA-17

In a multicentre, double-blind, randomised, placebo-controlled study (MA-17), performed in over 5100 postmenopausal patients with receptor-positive or unknown primary breast cancer patients who had remained disease-free after completion of adjuvant treatment with tamoxifen (4.5 to 6 years) were randomly assigned 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 primary analysis conducted at a median follow-up of around 28 months (25% of the patients being followed-up for up to 38 months) showed that letrozole reduced the risk of recurrence by 42% compared with placebo (hazard ratio 0.58; P = 0.00003), an absolute reduction of 2.4%. This statistically significant benefit in DFS in favour of letrozole was observed regardless of nodal status or prior chemotherapy.

There was no significant difference in overall survival: (letrozole 51 deaths; placebo 62; HR 0.82; 95% CI 0.56, 1.19).

The independent Data and Safety Monitoring Committee recommended that women who were disease free in the placebo arm be allowed to switch to letrozole for up to 5 years when the study was unblinded in 2003. In the updated, final analysis conducted in 2008, 1551 women (60% of those eligible to switch) switched from placebo to letrozole at a median 31 months after completion of adjuvant tamoxifen therapy. Median duration of letrozole after switch was 40 months.

The updated final analysis conducted at a median follow-up of 62 months confirmed the significant reduction in the risk of breast cancer recurrence with letrozole compared with placebo, despite 60% of eligible patients in the placebo arm switching to letrozole after the study was unblinded. In the letrozole arm, median duration of treatment was 60 months; in the placebo arm, median duration of treatment was 37 months. The protocol-specified 4-year DFS rate was identical in the letrozole arm for both the 2004 and the 2008 analyses, confirming the stability of the data and robust effectiveness of letrozole long-term. In the placebo arm, the increase in 4-year DFS rate at the updated analysis clearly reflects the impact of 60% of the patients having switched to letrozole. This switching also accounts for the apparent dilution in treatment difference.

In the original analysis, for the secondary endpoint overall survival (OS) a total 113 deaths were reported (51 letrozole, 62 placebo). Overall, there was no significant difference between treatments in OS (hazard ratio 0.82; P = 0.29). Table 11 summarises the results:

Table 11: Summary of results of study MA-17 after completion of adjuvant therapy with tamoxifen (Modified ITT population)

Initial analysis

Median follow-up 28 months

Updated analysis 1

Median follow-up 62 months

Letrozole

Placebo

HR2 (95% CI)

Letrozole

Placebo

HR2 (95% CI)

N = 2582

n (%)

N = 2586

n (%)

P value

N = 2582

n (%)

N = 2586

n (%)

P value

Disease-free survival (protocol definition)3

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)

0.001

4-year DFS rate

94.4%

89.8%

94.4%

91.4%

Disease-free survival 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)

Deaths 4

---

---

---

236 (9.1) 5

170 (6.6) 6

0.78 (0.64, 0.96)

Contralateral breast cancer (invasive)

Events

15 (0.6)

25 (1.0)

0.60 7 (0.31, 1.14)

33 (1.3)

51 (2.0)

0.64 7 (0.41, 1.00)

HR = Hazards ratio; CI = Confidence interval

P values are given for the primary endpoint only, in view of multiple endpoints and multiple analyses. If both bounds of the 95% confidence interval are ≤ 1.00, the treatment difference may be regarded as “significant” at the 5% level at face value; values < 1.00 favour letrozole; values > 1.00 favour placebo

1 When the study was unblinded after the first interim analysis, 1551 patients in the randomised placebo arm (60% of those eligible to switch – i.e. who were disease-free) switched to letrozole at a median 31 months after randomisation. The analyses presented here ignore the switching under the ITT principle

2 Stratified by receptor status, nodal status and prior adjuvant chemotherapy

3 Protocol definition of disease-free survival events: loco-regional recurrence, distant metastasis or contralateral breast cancer

4 Exploratory analysis, censoring follow-up times at the date of switching (if a switch occurred) – see footnote 1.

5 Median follow-up 62 months

6 Median follow-up until switch (if it occurred) 37 months

7 Odds ratio and 95% CI for the odds ratio

In the updated quality of life substudy there were no significant differences between treatments in physical component summary score or mental component summary score, or in any domain score in the SF36 scale. In the MENQOL scale, significantly more women in the letrozole arm than in the placebo arm were most bothered (generally in the first year of treatment) by those symptoms deriving from oestrogen deprivation – hot flushes and vaginal dryness. The symptom that bothered most patients in both treatment arms was aching muscles, with a statistically significant difference in favour of placebo. According to the study protocol, patients who completed standard adjuvant treatment with tamoxifen not more than 3 months previously could enter the study. In the updated analysis of MA-17, however, analysis included data from patients who switched from placebo to letrozole (60% of eligible patients) at a median 31 months after completing tamoxifen. In the updated analysis, as shown in Table 11, there was a significant reduction in the odds of an invasive contralateral breast cancer with letrozole compared with placebo, despite 60% of the patients in the placebo arm having switched to letrozole. There was no significant difference in overall survival.

An exploratory analysis censoring follow-up times at the date of switch (if it occurred) showed a significant reduction in the risk of all-cause mortality with letrozole compared with placebo (Table 11).

There was no difference in safety and efficacy between patients aged < 65 versus ≥ 65 years.

The updated safety profile of letrozole did not reveal any new adverse event and was entirely consistent with the profile reported in 2004.

Updated results (median follow-up was 61 months) from the bone sub-study (n=226) demonstrated that, at 2 years, compared to baseline, patients receiving letrozole had a median decrease of 3.8 % in hip bone mineral density (BMD) compared to 2.0 % in the placebo group (P = 0.022). There was no significant difference between treatments in changes in lumbar spine BMD at any time. Concomitant calcium and vitamin D supplementation was mandatory in the BMD substudy. Updated results (median follow-up was approximately 62 months) from the lipid sub-study (n=347) showed for any of the lipid measurements no significant difference between the letrozole and placebo groups at any time. In the updated analysis, the incidence of cardiovascular events (including cerebrovascular and thromboembolic events) during treatment with letrozole versus placebo until switch was 9.8% vs. 7.0%, a statistically significant difference.

Amongst the pre-printed, check-listed terms during study treatment, the most frequently reported events were: stroke/transient ischemic attack (letrozole, 1.5%; placebo until switch, 0.8%); new or worsening angina (letrozole, 1.4%; placebo until switch, 1.0%); myocardial infarction (letrozole, 1.0%; placebo until switch, 0.7%); thromboembolic events (letrozole, 0.9%; placebo until switch, 0.3%).

The reported frequency of thromboembolic events as well as of stroke/transient ischaemic attack was significantly higher for letrozole than placebo until switch. The interpretation of safety results should consider that there was an imbalance in the median duration of treatment with letrozole (60 months) compared with placebo (37 months) due to the switch from placebo to letrozole which occurred in approximately 60% of the patients.

Neoadjuvant treatment

A double blind trial (P024) was conducted in 337 postmenopausal breast cancer patients randomly allocated either letrozole 2.5 mg for 4 months or tamoxifen for 4 months. At baseline all patients had tumours stage T2T4c, N02, M0, ER and/or PgR positive and none of the patients would have qualified for breast-conserving surgery. Based on clinical assessment there were 55% objective responses in the letrozole arm versus 36% for the tamoxifen arm (P<0.001). This finding was consistently confirmed by ultrasound (letrozole 35% vs tamoxifen 25%, P=0.04) and mammography (letrozole 34% vs tamoxifen 16%, P<0.001). In total 45% of patients in the letrozole group versus 35% of patients in the tamoxifen group (P=0.02) underwent breast-conserving therapy). During the 4month preoperative treatment period, 12% of patients treated with letrozole and 17% of patients treated with tamoxifen had disease progression on clinical assessment.

First-line treatment

One large well-controlled double-blind trial was conducted comparing letrozole 2.5 mg to tamoxifen 20 mg daily as first-line therapy in postmenopausal women with locally advanced or metastatic breast cancer. In this trial of 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 (CR+PR+NC ≥ 24 weeks).

The results are summarised in Table 12:

Table 12 Results at a median follow-up of 32 months

Variable

Statis ic

Letrozole

N=453

Tamoxifen

N=454

Time of 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)

P <0.0001

Objective response rate (ORR)

CR+PR

145 (32%)

95 (21%)

(95% CI for rate)

(28, 36%)

(17, 25%)

Odds ratio

1.78

(95% CI for oddsrate)

(1.32, 2.40)

P=0.0002

Time to progression was significantly longer, and response rate significantly higher for letrozole irrespective of whether adjuvant anti-oestrogen therapy had been given or not. Time to progression was significantly longer for letrozole irrespective of dominant site of disease. Median time to progression was 12.1 months for letrozole and 6.4 months for tamoxifen in patients with soft tissue disease only and median 8.3 months for letrozole an 4.6 months for tamoxifen in patients with visceral metastases.

Study design allowed patients to cross over upon progression to the other therapy or discontinue from the study. Approximately 50% of patients crossed over to the opposite treatment arm and crossover was virtually completed by 36 months. The median time to crossover was 17 months (letrozole to tamoxifen) and 13 months (tamoxifen to letrozole).

Letrozole treatment in the firstline therapy of advanced breast cancer resulted in a median overall survival of 34 months compared with 30 months for tamoxifen (logrank test P=0.53, not significant). The absence of an advantage for letrozole on overall survival could be explained by the crossover design of the study. As the study design allowed patients to cross-over upon progression to the other therapy the long-term survival could not be evaluated.

Pre-operative treatment

A double blind trial (P024) was conducted in 337 postmenopausal breast cancer patients randomly allocated either letrozole 2.5 mg for 4 months or tamoxifen for 4 months. At baseline all patients had tumours stage T2-T4c, N0-2, M0, ER and/or PgR positive and none of the patients would have qualified for breast-conserving surgery. There were 55% objective responses in the letrozole treated patients versus 36% for the tamoxifen treated patients (p < 0.001) based on clinical assessment. This finding was consistently confirmed by ultrasound (p = 0.042) and mammography (p < 0.001) giving the most conservative assessment of response. This response was reflected in a statistically significantly higher number of patients in the letrozole group who became suitable for and underwent breast-conserving therapy (45% of patients in the letrozole group versus 35% of patients in the tamoxifen group, p = 0.022). During the 4 month pre-operative treatment period, 12% of patients treated with letrozole and 17% of patients treated with tamoxifen had disease progression on clinical assessment.

Second-line treatment

Two 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 cancer

Use of letrozole in men with breast cancer has not been studied.

5.2 Pharmacokinetic properties

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. in vitro, but their individual contributions to letrozole clearance in vivo have not been established. In an interaction study co-administration with cimetidine, which is known to inhibit only the 3A4 isoenzyme, did not result in a decrease in letrozole clearance suggesting that in vivo the 2A6 isoenzyme plays an important part in total clearance. In this study a slight decrease in AUC and increase in Cmax were observed.

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.

Special populations

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 or the urinary excretion of the glucoronide of its carbinol metabolite 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 secondline 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

The Cmax, AUC and half-life of the metabolite have not been determined. 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, letrozole should be administered with caution to patients with severe hepatic impairment and after consideration of the risk/benefit in the individual patient.

5.3 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 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.

Effects on the liver (increased weight, hepatocellular hypertrophy, fatty changes) were observed, mainly at high dose levels. Increased incidences of hepatic vacuolation (both sexes, high dose) and necrosis (intermediate and high dose females) were also noted in rats treated for 104 weeks in a carcinogenicity study. They may have been associated with the endocrine effects and hepatic enzyme-inducing properties of letrozole. However, a direct drug effect cannot be ruled out.

In a 104-week mouse carcinogenicity study, dermal and systemic inflammation occurred, particularly at the highest dose of 60 mg/kg, leading to increased mortality at this dose level. Again it is not known whether these findings were an indirect consequence of the pharmacological activity of letrozole (i.e. linked to long-term oestrogen deprivation) or a direct drug effect.

The pharmacological effects of letrozole resulted in skeletal, neuroendocrine and reproductive findings in a juvenile rat study at doses between 0.003 mg/kg/day and 0.3 mg/kg/day. 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. In addition, bone mineral density (BMD) was 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, ovarian cysts and atrophy of the female reproductive tract. Effects on bone size in females at 0.3 mg/kg/day and males at 0.03 mg/kg/day and morphological changes in the testes were not reversible. All other effects were at least partially reversible at 0.003 and 0.03 mg/kg/day. Both in vitro and in vivo investigations on letrozole's mutagenic potential revealed no indication of any genotoxicity.

In the carcinogenicity studies no treatment-related tumours were noted in male animals. In female animals, treatment-related changes in genital tract tumours (a reduced incidence of benign and malignant mammary tumours in rats, an increased incidence of benign ovarian stromal tumours in mice) were secondary to the pharmacological effect of the compound.

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.

6. Pharmaceutical particulars
6.1 List of excipients

Tablet core:

Lactose monohydrate,

Sodium starch glycolate,

Microcrystalline cellulose,

Hypromellose 6 cP,

Colloidal anhydrous silica,

Magnesium stearate (E572).

Film coat (Opadry 04F52158 Yellow):

Hypromellose 15 cP (E464),

PEG 6000.

Titanium dioxide, (E171),

Iron oxide yellow E172 (iii),

Iron oxide red, E172 (ii),

FD&C yellow #5 Aluminium lake, (E102).

6.2 Incompatibilities

None known.

6.3 Shelf life

2 years

6.4 Special precautions for storage

Store in in the original package

6.5 Nature and contents of container

PVC/PE/PVDC Aliminium blister packs of 14 or 28 tablets.

6.6 Special precautions for disposal and other handling

No specific instructions for use/handling.

7. Marketing authorisation holder

Cipla (EU) Limited,

Dixcart House, Addlestone Road,

Bourne Business Park, Addlestone,

Surrey, KT15 2LE,

United Kingdom

8. Marketing authorisation number(s)

PL 36390/0103

9. Date of first authorisation/renewal of the authorisation

18/02/2010

10. Date of revision of the text

14/08/2018