Document: spc-doc_PL 40378-0145 change

• spc-doc_PL 01656-0183
• spc-doc_PL 04569-1026
• spc-doc_PL 14048-0072
• spc-doc_PL 14894-0660
• spc-doc_PL 15413-0013
• spc-doc_PL 17907-0496
• spc-doc_PL 20416-0414
• spc-doc_PL 25258-0198
• spc-doc_PL 30306-0051
• spc-doc_PL 30306-0052
• spc-doc_PL 34760-0001
• spc-doc_PL 37222-0013
• spc-doc_PL 40378-0145

---

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.

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

For the full list of excipients, see section 6.1 List of excipients

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.

Treatment of early invasive breast cancer in postmenopausal women who have received prior standard adjuvant tamoxifen therapy.

First-line treatment in postmenopausal women with advanced breast cancer.

Advanced breast cancer in postmenopausal women in whom tamoxifen or other antioestrogen therapy has failed.

Pre-operative therapy in postmenopausal women with localised hormone receptor positive breast cancer, to allow subsequent breast-conserving surgery in women not originally considered candidates for breast-conserving surgery. Subsequent treatment after surgery should be in accordance with standard of care.

4.2 Posology and method of administration

Adult and elderly patients

The recommended dose of Letrozole tablet is 2.5 mg once daily. In the adjuvant setting, treatment with Letrozole tablet should continue for 5 years or until tumour relapse occurs, whichever comes first. Following standard adjuvant tamoxifen therapy, treatment with Letrozole should continue for 5 years or until tumour relapse occurs, whichever comes first. In patients with metastatic disease, treatment with Letrozole should continue until tumour progression is evident. Regular monitoring to observe progression during the pre-operative treatment period is recommended (see section 5.1 Pharmacodynamic properties). No dose adjustment is required for elderly patients.

Paediatric population

Not recommended for use in children.

Patients with hepatic and/or renal impairment

No dosage adjustment is required for patients with mild to moderate hepatic impairment (Child-Pugh grade A and B) or renal impairment (creatinine clearance > 10 mL/min.), (see section 5.2 Pharmacokinetic properties).

4.3 Contraindications

Known hypersensitivity to the active substance or to any of the excipients.

Premenopausal, pregnant or lactating women (see section 4.6 Pregnancy and Lactation).

Patients with severe hepatic impairment (Child-Pugh grade C).

Pre-operative use of Letrozole is contraindicated if the receptor status is negative or unknown.

4.4 Special warnings and precautions for use

Letrozole tablet is not recommended for use in children as efficacy and safety in this patient group have not been assessed in clinical studies. There are no efficacy data to support the use of Letrozole in men with breast cancer.

Letrozole has not been investigated in patients with creatinine clearance < 10 mL/min. The potential risk/benefit to such patients should be carefully considered before administration of Letrozole.

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 for osteoporosis should be initiated as appropriate and patients treated with Letrozole should be carefully monitored (see sections 4.8 Undesirable effects and 5.1 Pharmacodynamic properties).

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

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 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 other anti-cancer agents.

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.

4.6 Fertility, pregnancy and lactation

Pregnancy

Letrozole is contraindicated during pregnancy (see section 4.3 Contraindications). Lactation

Letrozole is contraindicated during lactation (see section 4.3 Contraindications). Women of child-bearing potential

The physician needs to discuss the necessity of adequate contraception with women who have the potential to become pregnant including women who are perimenopausal or who have recently become postmenopausal, until their postmenopausal status is fully established.

There are no adequate data from the use of Letrozole in pregnant women.

Embryotoxicity and foetotoxicity were seen in pregnant rats following oral administration of Letrozole, and there was an increase in the incidence of foetal malformation among the animals treated. However, it is not known whether this was an indirect consequence of the pharmacological activity of Letrozole (inhibition of oestrogen biosynthesis) or a direct drug effect.

4.7 Effects on ability to drive and use machines

Since fatigue and dizziness have been observed with the use of Letrozole and somnolence has been reported uncommonly, caution is advised when driving or using machines.

4.8 Undesirable effects

Letrozole 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, arthralgia, nausea and fatigue. Many adverse reactions can be attributed to the normal pharmacological consequences of oestrogen deprivation (e.g. hot flushes, alopecia and vaginal bleeding).

After standard adjuvant tamoxifen, 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).

Organ\ System \	Commo n (>1/10)	(>1/100 to <1/10)	(>1/1,000 to <1/100)	(>1/10,000 to <1/1,000)	(<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°!yps)			Tumour pain (6)
Blood and lymphatic system disorders			Leucopenia
Immune system disorders					Angioedema 5 anaphylactic reactions
Metabolism and nutrition disorders		Anorexia, appetite increase, raised serum cholesterol	General oedema
Psychiatric disorders		Depression	Anxiety (1)
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			Palpitations, tachycardia
Vascular disorders			Thrombophlebitis (3), hypertension, ischemic cardiac events (7)(8)	Pulmonary embolism, arterial thrombosis, cerebrovascular infarction

\ 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)
Respiratory, thoracic and mediastinal disorders			Dyspnoea, cough
Gastrointestinal disorders		Nausea, vomiting, dyspepsia, constipation, diarrhoea	Abdominal pain, stomatitis, dry mouth
Hepatobiliary disorders			Increased hepatic enzymes		Hepatitis
Skin and subcutaneous tissue disorders		Alopecia, increased sweating, rash (4)	Pruritus, dry skin, urticaria		Toxic epidermal necrolysis, erythema multiforme
Musculoskeletal and connective tissue disorders	Arthralgia	Myalgia, bone pain, 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	Hot flushes	Fatigue (5), peripheral 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 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%); 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>1.5* 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 attack2, 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)

4.9 Overdose

There is no clinical experience of overdosage. 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 30mg and 5mg, 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: Enzyme inhibitors; ATC Code: L02B G04

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

Pharmacodynamic effects

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

Letrozole is a non-steroidal aromatase inhibitor. It inhibits the aromatase enzyme by competitively binding to the haem of the cytochrome P450 subunit of the enzyme, resulting in a reduction of oestrogen biosynthesis in all tissues.

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

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

Letrozole is highly specific in inhibiting aromatase activity. Impairment of adrenal steroidogenesis has not been observed. No clinically relevant changes were found in the plasma concentrations of cortisol, aldosterone, 11-deoxycortisol, 17-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, 0.25, 0.5, 1, 2.5 and 5 mg did not indicate any attenuation of aldosterone or cortisol production. Thus, glucocorticoid and mineralocorticoid supplementation is not necessary.

No changes were noted in plasma concentrations of androgens (androstenedione and testosterone) among healthy postmenopausal women after 0.1, 0.5 and 2.5 mg single doses of Letrozole or in plasma concentrations of androstenedione among postmenopausal patients treated with daily doses of 0.1 to 5 mg, indicating that the blockade of oestrogen biosynthesis does not lead to accumulation of androgenic precursors. Plasma levels of LH and FSH are not affected by Letrozole in patients, nor are thyroid function as evaluated by TSH, T4 and T3 uptake.

Adjuvant treatment, study BIG 1-98

BIG 1-98 is a multicentre, double-blind study randomised over 8000 postmenopausal women with resected receptor-positive early breast cancer, to one of the following arms:

•    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 endpoints were overall survival (OS), distant disease free survival (DDFS), systemic disease-free survival (SDFS), invasive contralateral breast cancer, and time to distant metastasis (TDM).

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 3). 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 3).

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.

months and of 73 months

Table 3: Comparison of Letrozole and tamoxifen monotherapy at a median follow-up of 26

	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

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 4 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 4: 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 a phase III, open-label, randomised, multicentre study designed to compare the effects of adjuvant treatment with Letrozole to tamoxifen on bone mineral density (BMD), bone markers and fasting serum lipid profiles. A total of 262 postmenopausal women with hormone sensitive resected primary breast cancer were randomly assigned to either Letrozole 2.5 mg daily for 5 years or tamoxifen 20 mg daily for 2 years followed by 3 years of Letrozole 2.5 mg daily.

The primary objective was to compare the effects on lumbar spine (L2-L4) BMD of Letrozole versus tamoxifen, evaluated as percent change from baseline lumbar spine BMD at 2 years.

At 24 months, the lumbar spine (L2-L4) BMD showed a median decrease of 4.1% in the Letrozole arm compared to a median increase of 0.3% in the tamoxifen arm (difference = 4.4%). At 2 years, overall the median difference in lumbar spine BMD change between Letrozole and tamoxifen was statistically significant in favour of tamoxifen (P < 0.0001). The current data indicates that no patient with a normal BMD at baseline became osteoporotic at year 2 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 BMD. The differences, however, were less pronounced. At 2 years, a significant difference in favour of tamoxifen was observed in the overall BMD safety population and all stratification categories (P < 0.0001). During the 2 year period, fractures were reported by 20 patients (15%) in the Letrozole arm, and 22 patients (17%) in the tamoxifen arm.

In the tamoxifen arm, the median total cholesterol levels decreased by 16% after 6 months compared to baseline; a similar decrease was also observed at subsequent visits up to 24 months. In the Letrozole arm, the median total cholesterol levels were relatively stable over time, with no significant increase at a single visit. The differences between the 2 arms were statistically significant in favour of tamoxifen at each time point (P < 0.0001).

Treatment after standard adjuvant tamoxifen, study CFEM345G MA-17

In a multicentre, double-blind, randomised, placebo-controlled study, 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.

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.

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 5 summarises the results:

Table 5: 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)

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 5, 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 5).

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.

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).

Letrozole treatment in the first line therapy of advanced breast cancer patients is associated with an early survival advantage over tamoxifen. A significantly greater number of patients were alive on Letrozole versus tamoxifen throughout the first 24 months 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 was conducted in 337 postmenopausal breast cancer patients randomly allocated either Letrozole 2.5mg 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.

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/L fasted versus 98.7 ± 18.6 nmol/L fed) but the extent of absorption (AUC) is not changed. The minor effect on the absorption rate is not considered to be of clinical relevance and therefore Letrozole may be taken without regard to 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 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 C_max 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.

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

Age had no effect on the pharmacokinetics of Letrozole.

Special populations

In a study involving volunteers with varying degrees of renal function (24 hour creatinine clearance 9-116 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. The C_max, 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 was 37% higher than in normal subjects, but still within the range seen in subjects without impaired function.

5.3 Preclinical safety data

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 can be attributed to the pharmacological action of the compound. 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.

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

APTIL Pharma Limited 9th Floor, CP House 97 - 107 Uxbridge Road Ealing, London W5 5TL

8    MARKETING AUTHORISATION NUMBER(S)

PL 40378/0145

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

03/10/2012

10    DATE OF REVISION OF THE TEXT

03/10/2012