4.1. Therapeutic indications

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

• Extended adjuvant 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 artificially induced postmenopausal endocrine status, who have previously been treated with anti-oestrogens.

• 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 is 2.5 mg once daily. No dose adjustment is required for elderly patients.

In patients with advanced or metastatic breast cancer, treatment with Letrozole 2.5 mg Film-coated tablets should continue until tumour progression is evident.

In the adjuvant and extended adjuvant setting, treatment with Letrozole 2.5 mg Film- coated tablets 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 2.5 mg Film-coated 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 2.5 mg Film-coated tablets should be discontinued and surgery scheduled and/or further treatment options discussed with the patient.

Paediatric Population

Letrozole 2.5 mg Film-coated tablets 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 2.5 mg Film-coated 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 dose adjustment of Letrozole 2.5 mg Film-coated tablets is required for patients with mild to moderate hepatic insufficiency (Child-Pugh A or B). Insufficient data are available for patients with severe hepatic impairment. Patients with severe hepatic impairment (Child-Pugh C) require close supervision (see sections 4.4 and 5.2).

Method of administration

Letrozole 2.5 mg Film-coated 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

• Pregnancy(see section 4.6)

• Breast-feeding (see sections 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 2.5 mg Film-coated tablets. Only women of postmenopausal endocrine status should receive Letrozole 2.5 mg Film-coated tablets.

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 2.5 mg Film-coated tablets.

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

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).

Tendonitis and tendon rupture

Tendonitis and tendon ruptures (rare) may occur. Close monitoring of the patients and appropriate measures (e.g. immobilisation) must be initiated for the affected tendon (see section 4.8).

Other warnings

Co-administration of Letrozole 2.5 mg Film-coated tablets 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).

This product contains lactose and sodium

Patients with rare hereditary problems of galactose intolerance, total 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. Cimetidine, a weak, unspecific inhibitor of CYP450 enzymes, did not affect the plasma concentrations of letrozole. The effect of potent CYP450 inhibitors is unknown.

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.

In vitro, letrozole inhibits the cytochrome P450 isoenzymes 2A6 and, moderately, 2C19 but the clinical relevance is unknown. Caution is therefore indicated when giving letrozole concomitantly with medicinal products whose elimination 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 2.5 mg Film-coated tablets 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 2.5 mg Film-coated tablets is contraindicated during pregnancy (see sections 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 2.5 mg Film-coated tablets 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

Summary of the safety profile

The frequencies of adverse reactions for letrozole are mainly based on data collected from clinical trials.

Up to approximately one third of the patients treated with letrozole in the metastatic setting and approximately 80% of the patients in the adjuvant setting as well as in the extended adjuvant setting experienced adverse reactions. The majority of the adverse reactions occurred during the first few weeks of treatment.

The most frequently reported adverse reactions in clinical studies were hot flushes, hypercholesterolemia, arthralgia, fatigue, increased sweating and nausea.

Important additional adverse reactions that may occur with letrozole are: skeletal events such as osteoporosis and/or bone fractures and cardiovascular events (including cerebrovascular and thromboembolic events). The frequency category for these adverse reactions is described in Table 1.

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:

Table 1

Adverse reactions are ranked under headings of frequency, the most frequent first, using the following convention: very common (≥ 1/10), common (≥ 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

Uncommon:

Urinary tract infection

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

Uncommon:

Tumour pain1

Blood and lymphatic system disorders

Uncommon:

Leukopenia

Immune system disorders

Not known:

Anaphylactic reaction

Metabolism and nutrition disorders

Very common:

Hypercholesterolemia

Common:

Decreased appetite, increased appetite

Psychiatric disorders

Common:

Depression

Uncommon:

Anxiety (including nervousness), irritability

Nervous system disorders

Common:

Headache, dizziness

Uncommon:

Somnolence, insomnia, memory impairment, dysaesthesia (including paresthesia, hypoesthesia), dysgeusia, cerebrovascular accident, carpal tunnel syndrome

Eye disorders

Uncommon:

Cataract, eye irritation, blurred vision

Cardiac disorders

Common:

Palpitations1

Uncommon:

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

Vascular disorders

Very common:

Hot flushes

Common:

Hypertension

Uncommon:

Thrombophlebitis (including superficial and deep vein thrombophlebitis)

Rare:

Pulmonary embolism, arterial thrombosis, cerebral infarction

Respiratory, thoracic and mediastinal disorders

Uncommon:

Dyspnoea, cough

Gastrointestinal disorders

Common:

Nausea, dyspepsia1, constipation, abdominal pain, diarrhoea, vomiting

Uncommon:

Dry mouth, stomatitis1

Hepatobiliary disorders

Uncommon:

Increased hepatic enzymes, hyperbilirubinemia, jaundice

Not known:

Hepatitis

Skin and subcutaneous tissue disorders

Very common:

Hyperhidrosis

Common:

Alopecia, rash (including erythematous, maculopapular, psoriaform, and vesicular rash), dry skin

Uncommon:

Pruritus, urticaria

Not known:

Angioedema, toxic epidermal necrolysis, erythema multiforme

Musculoskeletal and connective tissue disorders

Very common:

Arthralgia

Common:

Myalgia, bone pain1, osteoporosis, bone fractures, arthritis

Uncommon:

Tendonitis

Rare:

Tendon rupture

Not known:

Trigger finger

Renal and urinary disorders

Uncommon:

Pollakiuria

Reproductive system and breast disorders

Common:

Vaginal haemorrhage

Uncommon:

Vaginal discharge, vulvovaginal dryness, breast pain

General disorders and administration site conditions

Very common:

Fatigue (including asthenia, malaise)

Common:

Peripheral oedema, chest pain

Uncommon:

General oedema, mucosal dryness, thirst, pyrexia

Investigations

Common:

Weight increased

Uncommon:

Weight decreased

1Adverse drug reactions reported only in the metastatic setting

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 2 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 rations and 95% confidence intervals.

Table 3 Sequential treatment versus letrozole monotherpay – adverse events with significant differences

Letrozole monotherapy

Letrozole->tamoxifen

Tamoxifen- >letrozole

N=1535

N=1527

N=1541

5 years

2 yrs -> 3 yrs

2 yrs -> 3 yrs

Bone fracture

10.0%

7.7%*

9.7%

Endometrial proliferative disorder

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 Yellow Card Scheme; www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

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.