Letrozol Orion 2,5 mg Filmdragerad tablett

Sverige - svenska - Läkemedelsverket (Medical Products Agency)

Bipacksedel Bipacksedel (PIL)

25-02-2020

Produktens egenskaper Produktens egenskaper (SPC)

21-04-2018

Aktiva substanser:
letrozol
Tillgänglig från:
Orion Corporation
ATC-kod:
L02BG04
INN (International namn):
letrozole
Dos:
2,5 mg
Läkemedelsform:
Filmdragerad tablett
Sammansättning:
letrozol 2,5 mg Aktiv substans; tartrazin aluminiumlack Hjälpämne; laktosmonohydrat Hjälpämne
Receptbelagda typ:
Receptbelagt
Produktsammanfattning:
Förpacknings: Blister, 30 tabletter; Blister, 100 tabletter
Bemyndigande status:
Godkänd
Godkännandenummer:
53166
Tillstånd datum:
2016-06-09

Dokument på andra språk

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12-04-2021

Produktens egenskaper Produktens egenskaper - engelska

12-04-2021

Offentlig bedömningsrapport Offentlig bedömningsrapport - engelska

19-10-2020

Läs hela dokumentet

Package leaflet: Information for the user

Letrozol Orion 2.5 mg film-coated tablets

letrozole

Read all of this leaflet carefully before you start taking this medicine because it contains

important information for you.

Keep this leaflet. You may need to read it again.

If you have any further questions, ask your doctor or pharmacist.

This medicine has been prescribed for you only. Do not pass it on to others. It may harm them,

even if their signs of illness are the same as yours.

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side

effects not listed in this leaflet. See section 4.

What is in this leaflet

What Letrozol Orion is and what it is used for

What you need to know before you take Letrozol Orion

How to take Letrozol Orion

Possible side effects

How to store Letrozol Orion

Contents of the pack and other information

1.

What Letrozol Orion is and what it is used for

What Letrozol Orion is and how it works

Letrozol Orion contains an active substance called letrozole. It belongs to a group of medicines called

aromatase inhibitors. It is a hormonal (or “endocrine”) breast cancer treatment. Growth of breast

cancer is frequently stimulated by oestrogens which are female sex hormones. Letrozol Orion reduces

the amount of oestrogen by blocking an enzyme (“aromatase”) involved in the production of

oestrogens and therefore may block the growth of breast cancer that needs oestrogens to grow. As a

consequence tumour cells slow or stop growing and/or spreading to other parts of the body.

What Letrozol Orion is used for

Letrozol Orion is used to treat breast cancer in women who have gone through menopause i.e.

cessation of periods.

It is used to prevent cancer from happening again. It can be used as first treatment before breast

cancer surgery in case immediate surgery is not suitable or it can be used as first treatment after breast

cancer surgery or following five years treatment with tamixofen. Letrozol Orion is also used to

prevent breast tumour spreading to other parts of the body in patients with advanced breast cancer.

If you have any questions about how Letrozol Orion works or why this medicine has been prescribed

for you, ask your doctor.

2.

What you need to know before you take Letrozol Orion

Follow all the doctor’s instructions carefully. They may differ from the general information in this

leaflet.

Do not take Letrozol Orion

if you are allergic to letrozole or to any of the other ingredients of this medicine (listed in

section 6)

if you still have periods, i.e. if you have not yet gone through the menopause

if you are pregnant

if you are breast-feeding.

If any of these conditions apply to you,

do not take this medicine and talk to your doctor

Warnings and precautions

Talk to your doctor or pharmacist before taking Letrozol Orion

if you have a severe kidney disease

if you have a severe liver disease

if you have a history of osteoporosis or bone fractures (see also “Follow-up during Letrozol

Orion treatment” in section 3).

If any of these conditions apply to you,

tell your doctor

. Your doctor will take this into account

during your treatment with Letrozol Orion.

Letrozole may cause inflammation in tendons or tendon injury (see section 4). At any sign of tendon

pain or swelling – rest the painful area and contact your doctor.

Children and adolescents (below 18 years)

Children and adolescents should not use this medicine.

Older people (age 65 years and over)

People aged 65 years and over can use this medicine at the same dose as for other adults.

Other medicines and Letrozol Orion

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other

medicines, including medicines obtained without a prescription.

Pregnancy, breast-feeding and fertility

You should only take Letrozol Orion when you have gone through the menopause. However,

your doctor should discuss with you about using effective contraceptive, as you may still have

the potential to become pregnant during treatment with Letrozol Orion.

You must not take Letrozol Orion if you are pregnant or breast feeding as it may harm your

baby.

Driving and using machines

If you feel dizzy, tired, drowsy or generally unwell, do not drive or operate any tools or machines until

you feel normal again.

Letrozol Orion contains lactose and tartrazine (E102)

This medicine contains 42.8 mg lactose (as monohydrate) in each tablet. If you have been told by your

doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine.

This medicine contains tartrazine which may cause allergic reactions.

Other excipients

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

free’.

3.

How to take Letrozol Orion

Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor

or pharmacist if you are not sure.

The usual dose is one tablet of Letrozol Orion to be taken once a day. Taking Letrozol Orion at the

same time each day will help you remember when to take your tablet.

The tablet can be taken with or without food and should be swallowed whole with a glass of water or

another liquid.

How long to take Letrozol Orion

Continue taking Letrozol Orion every day for as long as your doctor tells you. You may need to take it

for months or even years. If you have any questions about how long to keep taking Letrozol Orion,

talk to your doctor.

Follow-up during Letrozol Orion treatment

You should only take this medicine under strict medical supervision. Your doctor will regularly

monitor your condition to check whether the treatment is having the right effect.

Letrozol Orion may cause thinning or wasting of your bones (osteoporosis) due to the reduction of

oestrogens in your body. Your doctor may decide to measure your bone density (a way of monitoring

for osteoporosis) before, during and after treatment.

If you take more Letrozol Orion than you should

If you have taken too much Letrozol Orion, or if someone else accidentally takes your tablets, contact

a doctor or hospital for advice immediately. Show them the pack of tablets. Medical treatment may be

necessary.

If you forget to take Letrozol Orion

If it is almost time for your next dose (e.g. within 2 or 3 hours), skip the dose you missed and

take your next dose when you are meant to.

Otherwise, take the dose as soon as your remember, and then take the next tablet as you would

normally.

Do not take a double dose to make up for the one that you missed.

If you stop taking Letrozol Orion

Do not stop taking Letrozol Orion unless your doctor tells you to. See also the section above “How

long to take Letrozol Orion”.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4.

Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Most of the side effects are mild to moderate and will generally disappear after a few days to a few

weeks of treatment.

Some of these side effects, such as hot flushes, hair loss or vaginal bleeding, may be due to the lack of

oestrogens in your body.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

Some side effects could be serious:

Rare or uncommon side effects (may affect between 1 to 100 in every 10,000 patients):

weakness, paralysis or loss of feeling in any part of the body (particularly arm or leg), loss of

coordination, nausea, or difficulty speaking or breathing (sign of a brain disorder, e.g. stroke)

sudden oppressive chest pain (sign of a heart disorder)

difficulty breathing, chest pain, fainting, rapid heart rate, bluish skin discoloration, or sudden

arm, leg or foot pain (signs that a blood clot may have formed)

swelling and redness along a vein which is extremely tender and possibly painful when touched

severe fever, chills or mouth ulcers due to infections (lack of white blood cells)

severe persistent blurred vision.

If any of the above occurs, tell your doctor straight away.

You should also inform the doctor straight away if you experience any of the following symptoms

during treatment with Letrozol Orion:

swelling mainly of the face and throat (signs of allergic reaction)

yellow skin and eyes, nausea, loss of appetite, dark-coloured urine (signs of hepatitis)

rash, red skin, blistering of the lips, eyes or mouth, skin peeling, fever (signs of skin disorder).

Very common side effects (

may affect more than 1 in 10 people

hot flushes

increased level of cholesterol (hypercholesterolaemia)

fatigue

increased sweating

pain in bones and joints (arthralgia).

Common side effects

may affect up to 1 in 10 people

skin rash

headache

dizziness

malaise (generally feeling unwell)

gastrointestinal disorders such as nausea, vomiting, indigestion, constipation, diarrhoea

increase in or loss of appetite

pain in muscles

thinning or wasting of your bones (osteoporosis), leading to bone fractures in some cases (see

also “Follow-up during Letrozol Orion treatment” in section 3)

swelling of arms, hands, feet, ankles (oedema)

depression

weight increase

hair loss

raised blood pressure (hypertension)

palpitations, rapid heart rate

chest pain

abdominal pain

dry skin

joint stiffness (arthritis)

vaginal bleeding.

Uncommon side effects (

may affect up to 1 in 100 people

nervous disorders such as anxiety, nervousness, irritability, drowsiness, memory problems,

somnolence, insomnia

pain or burning sensation in the hands or wrist (carpal tunnel syndrome)

impairment of sensation, especially that of touch

eye disorders such as blurred vision, eye irritation

skin disorders such as itching (urticaria)

vaginal discharge or dryness

breast pain

fever

thirst, taste disorder, dry mouth

dryness of mucous membranes

weight decrease

urinary tract infection, increased frequency of urination

cough

yellowing of the skin and eyes

high blood levels of bilirubin (a breakdown product of red blood cells)

increased level of enzymes

inflammation of a tendon or tendonitis (connective tissues that connect muscles to bones)

Rare side effects (

may affect up to 1 in 1,000 people

rupture of a tendon (connective tissues that connect muscles to bones)

Not known (

frequency cannot be estimated from the available data

trigger finger, a condition in which your finger or thumb catches in a bent position.

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects

not listed in this leaflet.

You can also report side effects directly via the national reporting system

listed in Appendix V. By reporting side effects you can help provide more information on the safety

of this medicine.

5.

How to store Letrozol Orion

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the carton and blister after EXP. The

expiry date refers to the last day of that month.

This medicine does not require any special storage conditions.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to

throw away of medicines you no longer use. These measures will help protect the environment.

6.

Contents of the pack and other information

What Letrozol Orion contains

The active substance is letrozole. Each film-coated tablet contains 2.5 mg letrozole.

The other ingredients are:

Tablet core: lactose monohydrate, microcrystalline cellulose, sodium starch glycolate,

hypromellose, colloidal anhydrous silica and magnesium stearate.

Film-coating (Opadry Yellow): hypromellose, titanium dioxide (E171), macrogols, iron

oxide yellow (E172), iron oxide red (E172) and tartrazine aluminium lake (E102).

What Letrozol Orion looks like and contents of the pack

Letrozol Orion 2.5 mg tablets are yellow, circular, biconvex film-coated tablets plain on both sides.

Diameter of the tablet is 6.1 ± 0.20 mm.

Letrozol Orion 2.5 mg film-coated tablets are available in blister packs with 30 and 100 tablets.

Not all pack sizes may be marketed.

Marketing Authorisation Holder

<To be completed nationally>

Manufacturer

Orion Corporation Orion Pharma

Orionintie 1

FI-02200 Espoo

Finland

This leaflet was last revised in 2021-04-09.

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SUMMARY OF PRODUCT CHARACTERISTICS

NAME OF THE MEDICINAL PRODUCT

Letrozol Orion 2.5 mg film-coated tablets

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 2.5 mg letrozole.

Excipients with known effect:

Each film-coated tablet contains 42.8 mg lactose (as monohydrate) and 0.0024 mg tartrazine

aluminium lake.

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.

Diameter of the tablet is

6.1 ± 0.20 mm.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Adjuvant treatment of postmenopausal women with hormone receptor positive invasive early

breast cancer.

Extended adjuvant treatment of hormone-dependent-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 Letrozol Orion is 2.5 mg once daily. No dose adjustment is required for

elderly patients.

In patients with advanced or metastatic breast cancer, treatment with letrozole should continue until

tumour progression is evident.

In the adjuvant and extended adjuvant setting, treatment with letrozole should continue for 5 years or

until tumour relapse occurs, whichever is first.

In the adjuvant setting a sequential treatment schedule (letrozole 2 years followed by tamoxifen

3 years) could also be considered (see sections 4.4 and 5.1).

In the neoadjuvant setting, treatment with letrozole could be continued for 4 to 8 months in order to

establish optimal tumour reduction. If the response is not adequate, treatment with letrozole should be

discontinued and surgery scheduled and/or further treatment options discussed with the patient.

Paediatric population

Letrozol Orion 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 5.2).

Method of administration

Letrozol Orion 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 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

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 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).

Excipients

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-

galactose malabsorption should not take this medicinal product.

This medicinal product contains less than 1 mmol (23 mg) sodium per tablet, that is to say essentially

‘sodium-free’.

This medicinal product contains tartrazine which may cause allergic reactions.

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 unkown. Caution is therefore indicated when giving letrozole contomitantly with

medicinal products whose elimination is mainly dependent on these isoenzymes and whose

therapeutic index is narrow (e.g. phenytoin, clopidogrel).

4.6

Fertility, pregnancy and lactation

Women of perimenopausal status or child-bearing potential

Letrozole should only be used in women with a clearly established postmenopausal status (see section

4.4). As there are reports of women regaining ovarian function during treatment with letrozole despite

a clear postmenopausal status at start of therapy, the physician needs to discuss adequate

contraception when necessary.

Pregnancy

Based on human experience in which there have been isolated cases of birth defects (labial fusion,

ambiguous genitalia), letrozole is suspected to cause congenital malformations when administered

during pregnancy. Studies in animals have shown reproductive toxicity (see section 5.3).

Letrozole is contraindicated during pregnancy (see sections 4.3 and 5.3).

Breast-feeding

It is unknown whether letrozole and its metabolites are excreted in human milk. A risk to the

newborns/infants cannot be excluded.

Letrozole is contraindicated during breast-feeding (see section 4.3).

Fertility

The pharmacological action of letrozole is to reduce oestrogen production by aromatase inhibition. In

premenopausal women, the inhibition of oestrogen synthesis leads to feedback increases in

gonadotropin (LH, FSH) levels. Increased FSH levels in turn stimulate follicular growth, and can

induce ovulation.

4.7

Effects on ability to drive and use machines

Letrozol Orion 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.

most

frequently

reported

adverse

reactions

clinical

studies

were

flushes,

hypercholesterolaemia, 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

cardiovascular

events

(including

cerebrovascular

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.

The frequencies of undesirable effects are following:

Very common

1/10

Common

1/100 to <1/10

Uncommon

1/1,000 to <1/100

Rare

1/10,000 to <1/1,000

Not known

cannot be estimated from the available data

System organ class

Frequency

Adverse reaction

Infections and

infestations

Uncommon

Urinary tract infection

Neoplasms benign,

malignant and

unspecified

(including cysts and

polyps)

Uncommon

Tumour pain

Blood and lymphatic

system disorders

Uncommon

Leukopenia

Immune system

disorders

Not known

Anaphylactic reaction

Very common

Hypercholesterolaemia

Metabolism and

nutrition disorders

Common

Anorexia, appetite increase

Common

Depression

Psychiatric disorders

Uncommon

Anxiety (including nervousness), irritability

Common

Headache, dizziness

Nervous system

disorders

Uncommon

Somnolence, insomnia, memory impairment,

dysaesthesia (including paresthesia, hypoesthesia),

taste disturbance, cerebrovascular accident, carpal

tunnel syndrome

Eye disorders

Uncommon

Cataract, eye irritation, blurred vision

Common

Palpitations

Cardiac disorders

Uncommon

Tachycardia, ischaemic cardiac events (including

new or worsening angina, angina requiring surgery,

myocardial infarction and myocardial ischaemia)

Very common

Hot flushes

Common

Hypertension

Uncommon

Thrombophlebitis (including superficial and deep

vein thrombophlebitis)

Vascular disorders

Rare

Pulmonary embolism, arterial thrombosis,

cerebrovascular infarction

Respiratory, thoracic

and mediastinal

disorders

Uncommon

Dyspnoea, cough

Common

Nausea, dyspepsia

, constipation, abdominal pain,

diarrhoea, vomiting

Gastrointestinal

disorders

Uncommon

Dry mouth, stomatitis

Uncommon

Increased hepatic enzymes, hyperbilirubinemia,

jaundice

Hepatobiliary disorders

Not known

Hepatitis

Very common

Increased sweating

Common

Alopecia, rash

(including erythematous,

maculopapular, psoriaform, and vesicular rash

dry skin

Uncommon

Pruritus, urticaria

Skin and subcutaneous

tissue disorders

Not known

Angioedema, toxic epidermal necrolysis, erythema

multiforme

Very common

Arthralgia

Common

Myalgia, bone pain

, osteoporosis, bone fractures,

arthritis

Uncommon

Tendonitis

Musculoskeletal and

connective tissue

disorders

Rare

Tendon rupture

System organ class

Frequency

Adverse reaction

Not known

Trigger finger

Renal and urinary

disorders

Uncommon

Increased urinary frequency

Common

Vaginal bleeding

Reproductive system

and breast disorders

Uncommon

Vaginal discharge, vaginal dryness, breast pain

Very common

Fatigue (including asthenia, malaise)

Common

Peripheral oedema, chest pain

General disorders and

administration site

conditions

Uncommon

General oedema, mucosal dryness, thirst, pyrexia

Common

Weight increase

Investigations

Uncommon

Weight loss

1

Adverse 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 ratios and 95% confidence intervals.

Table 3. Sequential treatment versus letrozole monotherapy – adverse events with significant

differences

Letrozole

monotherapy

Letrozole ->

tamoxifen

Tamoxifen ->

Letrozole

N=1535

N=1527

N=1541

5 years

2 yrs-> 3 yrs

2 yrs-> 3 yrs

Bone fractures

10.0%

7.7%*

9.7%

Endometrial

proliferative disorders

0.7%

3.4%**

1.7%**

Hypercholesterolaemia

52.5%

44.2%*

40.8%*

Hot flushes

37.6%

41.7%**

43.9%**

Vaginal bleeding

6.3%

9.6%**

12.7%**

* Significantly less than with letrozole monotherapy

** Significantly more than with letrozole monotherapy

Note : Reporting period is during treatment or within 30 days of stopping treatment

Description of selected adverse reactions

Cardiac adverse reactions

In the adjuvant setting, in addition to the data presented in Table 2, the following adverse events were

reported for letrozole and tamoxifen, respectively (at median treatment duration of 60 months plus

30 days): angina requiring surgery (1.0% vs. 1.0%); cardiac failure (1.1% vs. 0.6%); hypertension

(5.6% vs. 5.7%); cerebrovascular accident/transient ischaemic attack (2.1% vs. 1.9%).

In the extended adjuvant setting for letrozole (median duration of treatment 5 years) and placebo

(median duration of treatment 3 years), respectively: angina requiring surgery (0.8% vs. 0.6%); new

or worsening angina (1.4% vs. 1.0%); myocardial infarction (1.0% vs. 0.7%); thromboembolic event*

(0.9% vs. 0.3%); stroke/transient ischaemic attack* (1.5% vs. 0.8%) were reported.

Events marked * were statistically significantly different in the two treatment arms.

Skeletal adverse reactions

For skeletal safety data from the adjuvant setting, please refer to Table 2.

In the extended adjuvant setting, significantly more patients treated with letrozole experienced bone

fractures or osteoporosis (bone fractures, 10.4% and osteoporosis, 12.2%) than patients in the placebo

arm (5.8% and 6.4%, respectively). Median duration of treatment was 5 years for letrozole, compared

with 3 years for placebo.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It

allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare

professionals are asked to report any suspected adverse reactions via the national reporting system

listed in Appendix V.

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.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: Endocrine therapy. Hormone antagonist and related agents: aromatase

inhibitor, ATC code: L02BG04.

Pharmacodynamic effects

The elimination of oestrogen-mediated growth stimulation is a prerequisite for tumour response in

cases where the growth of tumour tissue depends on the presence of oestrogens and endocrine therapy

is used. In postmenopausal women, oestrogens are mainly derived from the action of the aromatase

enzyme, which converts adrenal androgens - primarily androstenedione and testosterone - to oestrone

and oestradiol. The suppression of oestrogen biosynthesis in peripheral tissues and the cancer tissue

itself can therefore be achieved by specifically inhibiting the aromatase enzyme.

Letrozole is a non-steroidal aromatase inhibitor. It inhibits the aromatase enzyme by competitively

binding to the haem of the aromatase cytochrome P450, resulting in a reduction of oestrogen

biosynthesis in all tissues where present.

In healthy postmenopausal women, single doses of 0.1 mg, 0.5 mg, and 2.5 mg letrozole suppress

serum oestrone and oestradiol by 75%, 78% and 78% from baseline respectively. Maximum

suppression is achieved in 48-78 hours.

In postmenopausal patients with advanced breast cancer, daily doses of 0.1 mg to 5 mg suppressed

plasma concentration of oestradiol, oestrone, and oestrone sulphate by 75-95% from baseline in all

patients treated. With doses of 0.5 mg and higher, many values of oestrone and oestrone sulphate were

below the limit of detection in the assays, indicating that higher oestrogen suppression is achieved

with these doses. Oestrogen suppression was maintained throughout treatment in all these patients.

Letrozole is highly specific in inhibiting aromatase activity. Impairment of adrenal steroidogenesis

has not been observed. No clinically relevant changes were found in the plasma concentrations of

cortisol, aldosterone, 11-deoxycortisol, 17-hydroxyprogesterone, and ACTH or in plasma renin

activity among postmenopausal patients treated with a daily dose of letrozole 0.1 mg to 5 mg. The

ACTH stimulation test performed after 6 and 12 weeks of treatment with daily doses of 0.1 mg, 0.25

mg, 0.5 mg, 1 mg, 2.5 mg, and 5 mg did not indicate any attenuation of aldosterone or cortisol

production. Thus, glucocorticoid and mineralocorticoid supplementation is not necessary.

No changes were noted in plasma concentrations of androgens (androstenedione and testosterone)

among healthy postmenopausal women after 0.1 mg, 0.5 mg, and 2.5 mg single doses of letrozole or

in plasma concentrations of androstenedione among postmenopausal patients treated with daily doses

of 0.1 mg to 5 mg, indicating that the blockade of oestrogen biosynthesis does not lead to

accumulation of androgenic precursors. Plasma levels of LH and FSH are not affected by letrozole in

patients, nor is thyroid function as evaluated by TSH, T4 and T3 uptake test.

Adjuvant treatment

Study BIG 1-98

BIG 1-98 was a multicentre, double-blind study in which over 8,000 postmenopausal women with

hormone receptor-positive early breast cancer were randomised to one of the following treatments: A.

tamoxifen for 5 years; B. Letrozole for 5 years; C. tamoxifen for 2 years followed by letrozole for

3 years; D. Letrozole for 2 years followed by tamoxifen for 3 years.

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

Tamoxife

n

HR

1

(95% CI)

Letrozole

N=4003

Tamoxife

n

HR

1

(95% CI)

N=4007

P value

N=4007

P value

Disease-free

survival

(primary) - events

(protocol

definition

2

)

0.81(0.70,

0.93)

0.003

0.86

(0.77,

0.96)

0.008

Overall survival

(secondary)

Number of deaths

0.86

(0.70,

1.06)

0.87

(0.75,

1.01)

HR = Hazard ratio; CI = Confidence interval

1

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

2

DFS events: loco-regional recurrence, distant metastasis, invasive contralateral breast cancer, second

(non-breast) primary malignancy, death from any cause without a prior cancer event.

Results at a median follow-up of 96 months (monotherapy arms only)

The Monotherapy Arms Analysis (MAA) long-term update of the efficacy of letrozole monotherapy

compared to tamoxifen monotherapy (median duration of adjuvant treatment: 5 years) is presented in

Table 5.

Table 5. Monotherapy Arms Analysis: Disease-free and overall survival at a median follow-up

of 96 months (ITT population)

Letrozole

N=2463

Tamoxifen

N=2459

Hazard Ratio

1

(95% CI)

P value

Disease-free survival events

(primary)

2

0.87 (0.78, 0.97)

0.01

Time to distant metastasis

(secondary)

0.86 (0.74, 1.01)

0.06

Overall survival

(secondary) - deaths

0.89 (0.77, 1.02)

0.08

Censored analysis of DFS

3

0.83 (0.74, 0.92)

Censored analysis of OS

3

0.81 (0.70, 0.93)

1

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

2

DFS events: loco-regional recurrence, distant metastasis, invasive contralateral breast cancer, second

(non-breast) primary malignancy, death from any cause without a prior cancer event.

3

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

Sequential Treatments Analysis (STA)

The Sequential Treatments Analysis (STA) addresses the second primary question of BIG 1-98,

namely whether sequencing of tamoxifen and letrozole would be superior to monotherapy. There were

no significant differences in DFS, OS, SDFS, or DDFS from switch with respect to monotherapy

(Table 6).

Table 6. Sequential treatments analysis of disease-free survival with letrozole as initial

endocrine agent (STA switch population)

N

Number

of events

1

Hazard

ratio

2

(97.5% confidence

interval)

Cox

model P

value

[Letrozole →]

Tamoxifen

1460

1.03

(0.84, 1.26)

0.72

Letrozole

1464

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

years

Adjusted by chemotherapy use

There were no significant differences in DFS, OS, SDFS or DDFS in any of the STA from

randomisation pairwise comparisons (Table 7).

Table 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)

Hazard ratio

1

(99% CI)

1.04 (0.85, 1.27)

Letrozole → Tamoxifen

Tamoxifen

2

Number of patients

1540

1548

Number of patients with DFS events

(protocol definition)

Hazard ratio

1

(99% CI)

0.92 (0.75, 1.12)

1

Adjusted by chemotherapy use (yes/no)

2

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

Study D2407

Study D2407 is an open-label, randomised, multicentre post approval safety study designed to

compare the effects of adjuvant treatment with letrozole and tamoxifen on bone mineral density

(BMD) and serum lipid profiles. A total of 262 patients were assigned either letrozole for 5 years or

tamoxifen for 2 years followed by letrozole for 3 years.

At 24 months there was a statistically significant difference in the primary end-point; the lumbar spine

BMD (L2-L4) showed a median decrease of 4.1% for letrozole compared to a median increase of

0.3% for tamoxifen.

No patient with a normal BMD at baseline became osteoporotic during 2 years of treatment and only

1 patient with osteopenia at baseline (T score of -1.9) developed osteoporosis during the treatment

period (assessment by central review).

The results for total hip BMD were similar to those for lumbar spine but less pronounced.

There was no significant difference between treatments in the rate of fractures – 15% in the letrozole

arm, 17% in the tamoxifen arm.

Median total cholesterol levels in the tamoxifen arm were decreased by 16% after 6 months compared

to baseline and this decrease was maintained at subsequent visits up to 24 months. In the letrozole

arm, total cholesterol levels were relatively stable over time, giving a statistically significant

difference in favor of tamoxifen at each time point.

Extended adjuvant treatment (MA-17)

In a multicentre, double-blind, randomised, placebo-controlled study (MA-17), over

5,100 postmenopausal women with receptor-positive or unknown primary breast cancer who had

completed adjuvant treatment with tamoxifen (4.5 to 6 years) were randomised to either letrozole or

placebo for 5 years.

The primary endpoint was disease-free survival, defined as the interval between randomisation and

the earliest occurrence of loco-regional recurrence, distant metastasis, or contralateral breast cancer.

The first planned interim analysis at a median follow-up of around 28 months (25% of patients being

followed up for at least 38 months), showed that letrozole significantly reduced the risk of breast

cancer recurrence by 42% compared with placebo (HR 0.58; 95% CI 0.45, 0.76;

P

=0.00003). The

benefit in favour of letrozole was observed regardless of nodal status. There was no significant

difference in overall survival: (letrozole 51 deaths; placebo 62; HR 0.82; 95% CI 0.56, 1.19).

Consequently, after the first interim analysis the study was unblinded and continued in an open-label

fashion and patients in the placebo arm were allowed to switch to letrozole for up to 5 years. Over

60% of eligible patients (disease-free at unblinding) opted to switch to letrozole. The final analysis

included 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 for letrozole after

switch was 40 months.

The final analysis conducted at a median follow-up of 62 months confirmed the significant reduction

in the risk of breast cancer recurrence with letrozole.

Table 8. Disease-free and overall survival (Modified ITT population)

Median follow-up 28 months

Median follow-up 62 months

Letrozole

N=2582

Placebo

N=2586

(95% CI)

P

value

Letrozole

N=2582

Placebo

N=2586

(95% CI)

P

value

Disease-free survival

3

Events

92 (3.6%)

155 (6.0%)

0.58

(0.45, 0.76)

0.00003

(8.1%)

(11.1%)

0.75

(0.63, 0.89)

4-year DFS

rate

94.4%

89.8%

94.4%

91.4%

Disease-free survival

3

, including deaths from any cause

Events

122 (4.7%)

193 (7.5%)

0.62

(0.49, 0.78)

(13.3%)

(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)

(5.5%)

(6.5%)

0.88

(0.70, 1.10)

Overall survival

Deaths

51 (2.0%)

62 (2.4%)

0.82

(0.56, 1.19)

236 (9.1%)

232 (9.0%)

1.13

(0.95, 1.36)

Deaths

(9.1%)

(6.6%)

0.78

(0.64, 0.96)

HR = Hazard 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.

2

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

3

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

contralateral breast cancer.

4

Exploratory analysis, censoring follow-up times at the date of 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 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

: 1 hour fasted

versus 2 hours fed; and mean C

: 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

C-labelled letrozole, approximately 82% of the radioactivity in plasma was unchanged

compound. Systemic exposure to metabolites is therefore low. Letrozole is rapidly and extensively

distributed to tissues. Its apparent volume of distribution at steady state is about 1.87 ± 0.47 l/kg.

Biotransformation

Metabolic clearance to a pharmacologically inactive carbinol metabolite is the major elimination

pathway of letrozole (CL

= 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

C-labelled letrozole to healthy postmenopausal volunteers, 88.2 ±

7.6% of the radioactivity was recovered in urine and 3.8 ± 0.9% in faeces. At least 75% of the

radioactivity recovered in urine up to 216 hours (84.7 ± 7.8% of the dose) was attributed to the

glucuronide of the carbinol metabolite, about 9% to two unidentified metabolites, and 6% to

unchanged letrozole.

Elimination

The apparent terminal elimination half-life in plasma is about 2 to 4 days. After daily administration

of 2.5 mg steady-state levels are reached within 2 to 6 weeks. Plasma concentrations at steady state

are approximately 7 times higher than concentrations measured after a single dose of 2.5 mg, while

they are 1.5 to 2 times higher than the steady-state values predicted from the concentrations measured

after a single dose, indicating a slight non-linearity in the pharmacokinetics of letrozole upon daily

administration of 2.5 mg. Since steady-state levels are maintained over time, it can be concluded that

no continuous accumulation of letrozole occurs.

Linearity/non-linearity

The pharmacokinetics of letrozole were dose proportional after single oral doses up to 10 mg (dose

range: 0.01 to 30 mg) and after daily doses up to 1.0 mg (dose range: 0.1 to 5 mg). After a 30 mg

single oral dose there was a slightly dose over-proportional increase in AUC value. The dose over-

proportionality is likely to be the result of a saturation of metabolic elimination processes. Steady

levels were reached after 1 to 2 months at all dosage regimens tested (0.1-5.0 mg daily).

Special populations

Elderly

Age had no effect on the pharmacokinetics of letrozole.

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. In addition to the above study assessing the influence of renal impairment on letrozole, a

covariate analysis was performed on the data of two pivotal studies (Study AR/BC2 and Study

AR/BC3). Calculated creatinine clearance (CLcr) [Study AR/BC2 range: 19 to 187 mL/min; Study

AR/BC3 range: 10 to 180 mL/min] showed no statistically significant association between letrozole

plasma trough levels at steady-state (C

). Futhermore, data of Study AR/BC2 and Study AR/BC3 in

second-line metastatic breast cancer showed no evidence of an adverse effect of letrozole on CLcr or

an impairment of renal function.

Therefore, no dose adjustment is required for patients with renal impairment (CLcr ≥10 mL/min).

Little information is available in patients with severe impairment of renal function (CLcr

<10 mL/min).

Hepatic impairment

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

increased by 95 and 187%, respectively.

Thus, letrozole should be administered with caution to patients with severe hepatic impairment and

after consideration of the risk/benefit in the individual patient.

5.3

Preclinical safety data

In a variety of preclinical safety studies conducted in standard animal species, there was no evidence

of systemic or target organ toxicity.

Letrozole showed a low degree of acute toxicity in rodents exposed up to 2000 mg/kg. In dogs

letrozole caused signs of moderate toxicity at 100 mg/kg.

In repeated-dose toxicity studies in rats and dogs up to 12 months, the main findings observed can be

attributed to the pharmacological action of the compound. The no-adverse-effect level was 0.3 mg/kg

in both species.

Oral administration of letrozole to female rats resulted in decreases in mating and pregnancy ratios

and increases in pre-implantation loss.

Both

in vitro

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 rats. In

female rats, a reduced incidence of benign and malignant mammary tumours at all the doses of

letrozole was found.

In a 104-week mouse carcinogenicity study, no treatment-related tumors were noted in male mice. In

female mice, a generally dose-related increase in the incidence of benign ovarian granulosa theca cell

tumors was observed at all doses of letrozole tested. These tumors were considered to be related to the

pharmacological inhibition of estrogen synthesis and may be due to increased LH resulting from the

decrease in circulating estrogen.

Letrozole was embryotoxic and foetotoxic in pregnant rats and rabbits following oral administration

at clinically relevant doses. In rats that had live foetuses, there was an increase in the incidence of

foetal malformations including domed head and cervical/centrum vertebral fusion. An increased

incidence of foetal malformations was not seen in the rabbit. It is not known whether this was an

indirect consequence of the pharmacological properties (inhibition of oestrogen biosynthesis) or a

direct drug effect (see sections 4.3 and 4.6).

Preclinical observations were confined to those associated with the recognised pharmacological

action, which is the only safety concern for human use derived from animal studies.

6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Tablet core:

Lactose monohydrate

Cellulose, microcrystalline

Sodium starch glycolate

Hypromellose

Silica, colloidal anhydrous

Magnesium stearate

Film-coating:

Hypromellose

Titanium dioxide (E171)

Macrogols

Iron oxide yellow (E172)

Iron oxide red (E172)

Tartrazine aluminium lake (E102)

6.2

Incompatibilities

Not applicable.

6.3

Shelf life

3 years.

6.4

Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5

Nature and contents of container

PVC/PE/PVDC

/Alu foil blisters.

30 and 100 film-coated tablets.

Not all pack sizes may be marketed.

6.6

Special precautions for disposal

Any unused medicinal product or waste material should be disposed of in accordance with local

requirements.

7.

MARKETING AUTHORISATION HOLDER

< To be completed nationally>

8.

MARKETING AUTHORISATION NUMBER(S)

<To be completed nationally>

9.

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

<To be completed nationally>

10.

DATE OF REVISION OF THE TEXT

2021-04-09

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