Letrozole 2.5mg Film-Coated Tablets

Document: spc-doc_PL 36390-0103 change

SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Letrozole 2.5mg film-coated tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 2.5 mg letrozole.

Excipient with known effects:

Each tablet contains 45 mg of lactose monohydrate (see section 4.4) 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.

4.1 Therapeutic indications

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

• Extended adjusted treatment of hormone-dependent 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 artificial induced postmenopausal endocrine status, who have previously been treated with anti-oestrogen .

• Neo-adjuvant treatment of postmenopausal women with hormone receptor positive, HER-2 negative breast cancer where chemotherapy is not suitable and immediate surgery not indicated

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. No dose adjusted 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 population

Letrozole 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 impairment

No dosage adjustment of letrozole 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 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

Method of administration

Letrozole tablet should be taken orally and can be taken with or without food.

4.3 Contraindications

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

• Premenopausal endocrine status.

• Pregnancy (see section 4.6).

• Breast-feeding (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.

Renal impairment

Letrozole has not been investigated in a sufficient number of patients with 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).

Letrozole 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 the patient's safety profile (see sections 4.2, 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).

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

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 coadministration 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

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 ).

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.

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 the clinical studies were hot flushes, hypercholesterolaemia, arthralgia, nausea, increased sweating and fatigue. 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).

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.

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 Organ System \	Very Commo n (>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)
Infections and infestations			Urinary tract infection
Neoplasms benign, malignant and unspecified (including cysts and p°iyp^s)			Tumour pain ⁽⁶⁾
Blood and lymphatic system disorders			Leucopenia
Immune system disorders					Angioedema	Anaphylactic reactions

Frequency Organ System \	Very Commo n (>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)
Metabolism and nutrition disorders	Hyperch olesterol aemia	Anorexia, appetite increase,	General oedema
Psychiatric disorders		Depression	Anxiety ⁽¹⁾, irritability
Nervous system disorders		Headache, dizziness	Somnolence, insomnia, memory impairment, dysaesthesia ⁽²⁾, 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	hypertensio n	Thrombophlebitis ⁽³⁾, , ischemic cardiac events (7)(8)	Pulmonary embolism, arterial thrombosis, cerebrovascular infarction
Respiratory, thoracic and mediastinal disorders			Dyspnoea, cough
Gastrointestinal disorders		Nausea, vomiting, dyspepsia⁶, constipation, diarrhoea, Abdominal pain	stomatitis⁶, dry mouth
Hepatobiliary disorders			Increased hepatic enzymes			Hepatitis
Skin and subcutaneous tissue disorders	increased sweating	Alopecia, , rash ⁽⁴⁾, dry skin	Pruritus, , urticaria			Angioedema ,toxic epidermal necrolysis,

Frequency Organ System \	Very Commo n (>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)
						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	Fatigue ⁽⁵⁾Hot flushes	, Peripheral oedema	General oedema, pyrexia, mucosal dryness, thirst
Investigations		Weight increase	Weight loss

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 Pharmacodynamic properties, treatment after standard tamoxifen)

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	Letrozol N = 2448	e j	Tamox N - 244	ifen 17	Letrozo N = 244	le 8	Tamoxifen N = 2447
	n	(%)	n	(%)	n	(%)	n	(%)
Hypercholesterol aemia	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	(18)
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 / lightheadedness	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>1.5¹ ULN¹	151/18 43	(8.2)	57/18 40	(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 attack^{2, 3}	52	(2.1)	46	(19)
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	(15)	43	(18)	1	(<0.1 )	0	-
Endometrial hyperplasia or 4 cancer	6/1909	(0.3)	57/19 43	(2.3)
Anorexia	20	(0.8)	20	(0.8)	1	(<0.1 )	1	(<0.1)
Angina pectoris (new worsening, or requiring surgical ₂ intervention)	26	(11)	24	(10)
Cardiac failure ²	30	(1.2)	24	(1.0)	-	-	-	-
Myocardial infarction²	24	(10)	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 developing at least one value greater than 1.5 times the upper limit of r laboratory measuring total serum cholesterol. Approximately 90% of t values were non-fasting measurements ₂ All cardiovascular events (including cerebrovascular and thromboem 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 hysterecton							baseline, and ormal in the he measured bolic events) iy at baseline

4.9 Overdose

Isolated cases of overdose with letrozole have been reported.

No specific treatment for overdose is known; treatment should be symptomatic and supportive.

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Endocrine therapy. Hormone antagonist and related agents: aromatase inhibitor; ATC Code: L02B G04

Pharmacodynamic effects

The elimination of oestrogen-mediated 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 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 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 are below the limit of detection in the assays, indicating that higher oestrogen suppression is achieved with these doses. Oestrogen suppression was maintained throughout treatment in all these patients.

Letrozole is highly specific in inhibiting aromatase activity. Impairment of adrenal steroidogenesis has not been observed. No clinically relevant changes were found in the plasma concentrations of cortisol, aldosterone, 11-deoxycortisol, 17-hydroxy-progesterone and ACTH or in plasma renin activity among postmenopausal patients treated with a daily dose of letrozole 0.1 to 5 mg. The ACTH stimulation test performed after 6 and 12 weeks of treatment with daily doses of 0.1 mg, 0.25 mg, 0.5 mg, 1 mg, 2.5 mg and 5 mg did not indicate any attenuation of aldosterone or cortisol production. Thus, glucocorticoid and mineralocorticoid supplementation is not necessary.

No changes were noted in plasma concentrations of androgens (androstenedione and testosterone) among healthy postmenopausal women after 0.1 mg, 0.5 mg and 2.5 mg single doses of letrozole or in plasma concentrations of androstenedione among postmenopausal patients treated with daily doses of 0.1 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 are 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 8000 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

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 4 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 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

N=4003

Tamoxifen

HR¹

Letrozole

N=4003

Tamoxifen

HR¹

		N=4007	(95% CI)		N=4007	(95% CI)
			P			P
Disease-free	351	428	0.81	585	664	0.86
survival (primary) -events (protocol definition )			(0.70, 0.93)			(0.77, 0.96)
			0.003			0.008
Overall survival (secondary)	166	192	0.86	330	374	0.87
Number of deaths			(0.70, 1.06)			(0.75, 1.01)

HR = Hazard ratio; CI = Confidence interval

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

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 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 N=2463	Tamoxifen N=2459	Hazard Ratio¹(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)

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

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.

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 6).

Table 6 Sequential treatments analysis of disease-free survival with letrozole as initial endocrine agent (STA switch population)

Number

events¹

Hazard

ratio²

(97.5%

confidence

interval)

Cox

model P-value

[Letrozole^]Tamoxifen

1460

160

0.92

(0.72,

1.17)

0.42

Letrozole

1463

178

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 pair wise comparisons (Table 7).

Table 7 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)	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

¹ Adjusted by chemotherapy use (yes/no)

624 (40%) patients selectively crossed to letrozole after tamoxifen arm unblinded in 2005

Study D2407

Study D2407 is an open-label, randomised, multicentre post approval safety study designed to compare the effects of adjuvant treatment with letrozole to tamoxifen on bone mineral density (BMD) and serum lipid profiles. A total of 262 patients were assigned either for 5 years or tamoxifen 2 years followed by letrozole 3 years.

At 24 months there was a statistically significant difference in the primary end-point; the lumbar spine (L2-L4) BMD showed a median decrease of 4.1% in the 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 treatment in the rate of fractures -15% in the Letrozole arm, 17% in the tamoxifen arm.

Median total cholesterol levels in tamoxifen arm were decreased by 16% after 6 months compared to baseline and 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 patients with receptor-positive or unknown primary breast cancer patients who had completed 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 first planned interim analysis at a median follow-up of around 28 months (25% of the 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 be 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 included 1,551 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 of 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 months¹
	Letrozole N = 2582	Placebo N = 2586	HR (95% CI)²P value	Letrozole N = 2582	Placebo N = 2586	HR (95% CI)²P value
Disease-free survival
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 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%)

(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%)

(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)

HR = Hazards ratio; CI = Confidence interval

¹ When the study was unblinded in 2003, 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 selective crossover.

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 switch(if it occurred) in the placebo arm.

⁵ Median follow-up 62 months

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

In the MA-17 bone substudy in which concomitant calcium and vitamin D were given, greater decreases in BMD compared to baseline occurred with letrozole compared with placebo. The only statistically significant difference occurred at 2 years and was in total hip BMD (letrozole median decrease of 3.8% vs placebo median decrease of 2.0%).

In the MA-17 lipid substudy there were no significant differences between letrozole and placebo in total cholesterol or in any lipid fraction.

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 SF-36 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.

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 T2-T4c, N0-2, 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 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.

First-line treatment

One controlled double-blind trial was conducted comparing letrozole 2.5 mg to tamoxifen 20 mg as first-line therapy in postmenopausal women with locally 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 summarised 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)
	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 odds ratio)	(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 and 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 first-line 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.

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 t_max: 1 hour fasted versus 2 hours fed; and mean C_max: 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.

Metabolism and elimination

Metabolic clearance to a pharmacologically inactive carbinol metabolite is the major elimination pathway of letrozole (CL_m= 2.1 l/h) but is relatively slow when compared to hepatic blood flow (about 90 l/h). The cytochrome P450 isoenzymes 3A4 and 2A6 were found to be capable of converting letrozole to this metabolite. Formation of minor unidentified metabolites and direct renal and faecal excretion play only a minor role in the overall elimination of letrozole. Within 2 weeks after administration of 2.5 mg ¹⁴C-labelled letrozole to healthy postmenopausal volunteers, 88.2 ± 7.6% of the radioactivity was recovered in urine and 3.8 ± 0.9% in faeces. At least 75% of the radioactivity recovered in urine up to 216 hours (84.7 ± 7.8% of the dose) was attributed to the glucuronide of the carbinol metabolite, about 9% to two unidentified metabolites, and 6% to unchanged letrozole.

The apparent terminal elimination half-life in plasma is about 2 days. After daily administration of 2.5 mg steady-state levels are reached within 2 to 6 weeks. Plasma concentrations at steady state are approximately 7 times higher than concentrations measured after a single dose of 2.5 mg, while they are 1.5 to 2 times higher than the steady-state values predicted from the concentrations measured after a single dose, indicating a slight non-linearity in the pharmacokinetics of letrozole upon daily administration of 2.5 mg. Since steady-state levels are maintained over time, it can be concluded that no continuous accumulation of letrozole occurs.

Special populations

Elderly

Age had no effect on the pharmacokinetics of letrozole.

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 was found after a single dose of 2.5 mg.

Hepatic impairment

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 t_/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.

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.

Both in vitro and in vivo investigations of letrozole's mutagenic potential revealed no indications of any genotoxicity.

In a 104-week rat carcinogenicity study, no treatment-related tumours were noted in male rata. In female rats, a reduced incidence of benign and malignant mammary tumours at all the doses of letrozole was found. .

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 section 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 the original package

6.5 Nature and contents of container

PVC/PE/PVDC Aluminium blister packs of 14 or 28 tablets

6.6 Special precautions for disposal

No specific instructions for use/handling

7 MARKETING AUTHORISATION HOLDER

CIPLA (EU) Limited,

Hillbrow House,

Hillbrow Road,

Esher,

Surrey, KT10 9NW

MARKETING AUTHORISATION NUMBER(S)

PL 36390/0103

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

18/02/2010

DATE OF REVISION OF THE TEXT

05/03/2015

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 Pharmacodynamic properties, adjuvant treatment).

(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%);