Active ingredients: Letrozole
Femara 2.5 mg film-coated tablets
Why is Femara used? What is it for?
What is Femara and how does it work
Femara contains an active substance called letrozole. It belongs to a group of medicines called aromatase inhibitors. It is a hormonal (or 'endocrine') treatment for breast cancer. Breast cancer growth is frequently stimulated by estrogen which is a female sex hormone. Femara reduces the amount of estrogen by blocking an enzyme ('aromatase') which is involved in the production of estrogen and therefore can block the growth of breast tumors that need estrogen to grow. As a result, the growth of cancer cells and / or their spread to other parts of the body is slowed down or stopped.
What Femara is used for
Femara is used to treat breast cancer in postmenopausal women who are no longer menstruating.
It is used to prevent breast cancer from coming back. It can be used as a first treatment before breast surgery if immediate surgery is not possible or as a first treatment after breast surgery or after five years of tamixofen treatment. Femara is also used to prevent the spread of breast cancer to other parts of the body in patients with advanced breast cancer.
If you have any questions about how Femara works or why this medicine has been prescribed for you, ask your doctor.
Contraindications When Femara should not be used
Follow your doctor's instructions carefully. They may differ from the general information given in this leaflet.
Do not take Femara
- if you are allergic to letrozole or any of the other ingredients of this medicine
- if you are still menstruating, i.e. if you are not yet in menopause,
- if you are pregnant,
- if you are breastfeeding.
If any of these apply to you, do not take this medicine and tell your doctor.
Precautions for use What you need to know before taking Femara
Talk to your doctor or pharmacist before taking Femara
- if you have severe kidney disease,
- if you have severe liver disease,
- if you have a history of osteoporosis or bone fractures (see also "Monitoring treatment with Femara" in section).
If any of these apply to you, tell your doctor. This will be taken into consideration by your doctor during treatment with Femara.
Children and adolescents (under 18 years of age)
Children and adolescents should not use this medicine.
Elderly (65 years of age or older)
Women aged 65 and over can use this medicine at the same dose as for adult women.
Interactions What medications or foods can change the effect of Femara
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines, including medicines obtained without a prescription.
Warnings It is important to know that:
Pregnancy, breastfeeding and fertility
- She should only take Femara when she has entered menopause. However, your doctor will discuss with you the need to use an effective contraceptive system as you could potentially become pregnant while being treated with Femara.
- You should not take Femara if you are pregnant or breastfeeding as it may harm the baby.
Driving and using machines
If you feel dizzy, tired, drowsy or generally unwell, do not drive or operate machinery until you feel normal again.
Femara contains lactose
Femara contains lactose (milk sugar). If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product.
For those who carry out sporting activities: the use of the drug without therapeutic necessity constitutes doping and can in any case determine positive anti-doping tests.
Dose, Method and Time of Administration How to use Femara: Posology
Always take this medicine exactly as your doctor or pharmacist has told you.
If in doubt, consult your doctor or pharmacist. The usual dose is one Femara tablet to be taken once a day. Taking Femara at the same time each day will help you remember when to take your tablet.
The tablet should be taken with or without food and should be swallowed whole with a glass of water or other beverage.
How long to take Femara
Continue to take Femara every day for as long as your doctor has told you. He may need to take it for months or even years. If you have any questions about how long to take Femara, talk to your doctor.
Monitoring during Femara treatment
You must take this medicine under strict supervision of your doctor. Your doctor will check your health regularly to make sure that the treatment is having the right effect.
Femara can cause brittleness or loss of bone mass (osteoporosis) due to a decrease in estrogen in the body. Your doctor may decide to have your bone density measured (a way to check for osteoporosis) before, during and after treatment.
Overdose What to do if you have taken too much Femara
If you take more Femara than you should
If you have taken too much Femara, or if someone else accidentally takes your tablets, contact your doctor or hospital immediately for advice. Show them the pack of tablets. You may need medical treatment.
If you forget to take Femara
- If it is near time for your next dose (for example within 2 or 3 hours), skip the missed dose and take your next dose when you are supposed to.
- Otherwise, take the missed dose as soon as you remember and then take the next tablet as you normally would.
- Do not take a double dose to make up for a forgotten dose.
If you stop taking Femara
Do not stop taking Femara unless your doctor tells you to. See also above under "How long to take Femara".
Side Effects What are the side effects of Femara
Like all medicines, this medicine can cause side effects, although not everybody gets them.
Most side effects are mild to moderate and will usually disappear after a treatment period of between a few days and a few weeks.
Some of these side effects, such as hot flashes, hair loss, or vaginal bleeding, can be caused by a lack of estrogen in the body.
Don't worry about this list of possible side effects. It may not be subject to it.
Some side effects can be serious:
Rare or uncommon effects (i.e. may affect between 1 and 100 patients in 10,000):
- Weakness, paralysis or loss of sensation in any other part of the body (especially arm or leg), loss of coordination, nausea, or difficulty in speaking or breathing (symptom of a brain disorder such as stroke).
- Sudden tightening chest pain (symptom of heart disease).
- Difficulty breathing, chest pain, fainting, rapid heartbeat, blue discoloration of the skin, or sudden pain in the arm, leg or foot (symptoms of a possible blood clot formation).
- Swelling and redness in correspondence of a vein that is extremely sensitive and also painful to the touch.
- High fever, chills or mouth ulceration caused by infections (lack of white blood cells).
- Severe and persistent blurred vision.
If any of these occur, tell your doctor immediately.
You should tell your doctor immediately if you experience any of the following symptoms while being treated with Femara:
- Swelling mainly of the face and throat (signs of an allergic reaction).
- Yellowish skin and eyes, nausea, loss of appetite, dark urine (signs of hepatitis).
- Rash, red skin, blistering of the lips, eyes or lips, peeling of the skin, fever (signs of skin disease).
Some side effects are very common. These side effects may affect more than 10 in every 100 patients.
- Hot flashes
- Increased cholesterol levels (hypercholesterolemia)
- Fatigue
- Increased sweating
- Pain in the bones and joints (arthralgia)
If any of these affects you severely, tell your doctor.
Some side effects are common. These side effects may affect between 1 and 10 in every 100 patients.
- Rash
- Headache
- Dizziness
- Malaise (usually feeling unwell)
- Gastrointestinal disorders such as nausea, vomiting, indigestion, constipation, diarrhea
- Increase or loss of appetite
- Muscular pain
- Fragility or loss of bone mass (osteoporosis), which in some cases leads to bone fractures (see also "Monitoring during treatment with Femara in section)
- Swelling of the arms, hands, feet, ankles (edema)
- Depression
- Weight gain
- Hair loss
- Increased blood pressure (hypertension)
- Abdominal pain
- Dryness of the skin
- Vaginal bleeding
- If any of these affects you severely, tell your doctor.
Other side effects are uncommon. These side effects may affect between 1 and 10 in every 1,000 patients.
- Nervous system disorders such as anxiety, nervousness, irritability, drowsiness, memory problems, sleepiness, insomnia
- Pain or burning sensation in the hands or wrist (carpal tunnel syndrome)
- Impaired sensitivity, especially to touch
- Eye disorders such as blurred vision, eye irritation
- Palpitations, fast heartbeat
- Skin disorders such as itching (hives)
- Vaginal discharge or dryness
- Joint stiffness (arthritis)
- Breast pain
- Fever
- Thirst, taste disturbances, dry mouth
- Dryness of the mucous membranes
- Weight loss
- Urinary tract infections, increased urinary frequency
- Cough
- Increased levels of enzymes in the liver
Undesirable effects with frequency not known
Snap finger, a condition in which one of the fingers of the hand gets stuck in a bent position.
If any of these affects you severely, tell your doctor.
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet
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 at https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse. By reporting side effects you can help provide more information on safety of this medicine.
Expiry and Retention
- Keep out of the reach and sight of children.
- Do not use Femara after the expiry date which is stated on the carton after EXP. The expiry date refers to the last day of the month.
- Do not store above 30 ° C.
- Store in the original package to protect the medicine from moisture.
- Do not use packaging that is damaged or shows signs of tampering.
What Femara contains
- The active ingredient is letrozole. Each film-coated tablet contains 2.5 mg of letrozole.
- The other ingredients are lactose monohydrate, microcrystalline cellulose, maize starch, sodium carboxymethyl starch, magnesium stearate and anhydrous colloidal silica. The coating consists of hypromellose, talc, macrogol 8000, titanium dioxide (E 171) and yellow iron oxide (E 172).
What Femara looks like and contents of the pack
- Femara is supplied in the form of film-coated tablets. The film-coated tablets are dark yellow in color and round in shape. They are marked on one side with "FV" and with "CG" on the other side.
- Each blister contains 10, 14, 28, 30 or 100 tablets. Not all pack sizes may be available in your country.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
FEMARA 2.5 MG TABLETS COATED WITH FILM
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Active ingredient: letrozole.
Each film-coated tablet contains 2.5 mg of letrozole.
Each tablet contains 61.5 mg of lactose. For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Film-coated tablet.
Dark yellow, round, slightly biconvex film-coated tablet with beveled edges. One part bears the inscription "FV", the other "CG".
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Adjuvant treatment of early invasive breast cancer in postmenopausal women with hormone receptor positive status.
Adjuvant treatment of invasive hormone-sensitive breast cancer in postmenopausal women after standard adjuvant treatment with tamoxifen lasting 5 years.
First-line treatment of hormone-sensitive advanced breast cancer in postmenopausal women.
Treatment of advanced breast cancer in naturally or artificially induced postmenopausal women after disease recurrence or progression who have previously been treated with antiestrogens.
Neoadjuvant treatment in postmenopausal women with hormone receptor positive, HER-2 negative breast cancer where chemotherapy is not possible and immediate surgery is not indicated.
Efficacy has not been demonstrated in patients with negative hormone receptor status.
04.2 Posology and method of administration
Dosage
Adult and elderly patients
The recommended dose of Femara is 2.5 mg once a day. No dose modification is required in elderly patients.
In patients with advanced or metastatic breast cancer, treatment with Femara should be continued until tumor progression is evident.
In adjuvant treatment and adjuvant treatment after standard tamoxifen therapy, Femara treatment should be continued for 5 years or until tumor recurrence occurs, whichever comes first.
A sequential treatment regimen (letrozole for 2 years followed by tamoxifen for 3 years) may also be considered in adjuvant treatment (see sections 4.4 and 5.1).
In neoadjuvant treatment, Femara treatment should be continued for 4 to 8 months to establish optimal tumor shrinkage. If the response is inadequate, Femara treatment should be stopped
and surgery should be planned and / or additional therapeutic alternatives should be discussed with the patient.
Pediatric population
Femara is not recommended for use in children and adolescents. The safety and efficacy of Femara in children and adolescents over 17 years of age have not yet been established. Limited data are available and no recommendation on a posology can be made.
Renal impairment
No dose modification of Femara is required for patients with renal impairment with creatinine clearance ≥ 10 ml / min. Insufficient data are available in cases of renal insufficiency with creatinine clearance below 10 ml / min (see sections 4.4 and 5.2).
Hepatic impairment
No dose modification of Femara is required for patients with mild to moderate hepatic impairment (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 monitoring (see sections 4.4 and 5.2).
Method of administration
Femara must be taken orally and can be taken with or without food.
The missed dose should be taken as soon as the patient remembers it. However, if it is almost time for the next dose (within 2 to 3 hours), the missed dose should not be taken and the patient should return to his or her regular intake schedule. Doses should not be doubled because with daily doses above the recommended dose of 2.5 mg, over-proportional systemic exposure was observed (see section 5.2).
04.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1
Premenopausal hormonal status
Pregnancy (see section 4.6)
Breastfeeding (see section 4.6)
04.4 Special warnings and appropriate precautions for use
Menopausal state
In patients where menopausal status is unclear, luteinizing hormone (LH), follicle stimulating hormone (FSH) and / or estradiol should be measured prior to initiating treatment with Femara. Only women with postmenopausal hormone status can receive Femara.
Renal impairment
Femara has not been studied in a sufficient number of patients with a creatinine clearance of less than 10 ml / min. In such patients the potential benefit / risk ratio should be carefully considered before administration of Femara.
Hepatic impairment
In patients with severe hepatic impairment (Child-Pugh C), the systemic exposure and terminal half-life are approximately double that of healthy volunteers. These patients should therefore be monitored closely (see section 5.2).
Effects on the bone
Femara is a powerful estrogen reducing agent. Patients with a history of osteoporosis and / or fractures, or at increased risk of osteoporosis, should undergo bone mineral density assessment prior to initiation of adjuvant and adjuvant treatment after standard tamoxifen therapy and should be monitored during and after treatment with letrozole Treatment or prophylaxis
osteoporosis should be initiated appropriately and monitored closely. A sequential treatment regimen (letrozole for 2 years followed by tamoxifen for 3 years) could also be considered in adjuvant treatment based on the patient's safety profile (see sections 4.2, 4.8 and 5.1).
Other warnings
Concomitant administration of Femara with tamoxifen, other anti-estrogens or estrogen-containing therapies should be avoided as these substances may decrease the pharmacological action of letrozole (see section 4.5).
As the tablets contain lactose, Femara is not recommended for patients with rare hereditary problems of galactose intolerance, severe lactase deficiency or glucose-galactose malabsorption.
04.5 Interactions with other medicinal products and other forms of interaction
The metabolism of letrozole is mediated in part by CYP2A6 and CYP3A4. Cimetidine, a weak nonspecific inhibitor of CYP450 enzymes, did not affect the plasma concentrations of letrozole. The effect of potent CYP450 inhibitors is unknown.
To date, there is no clinical experience on the use of Femara in combination with estrogen or other antineoplastic agents, other than tamoxifen. Tamoxifen, other anti-estrogens or estrogen-containing therapies may decrease the pharmacological action of letrozole. In addition, concomitant administration of tamoxifen with letrozole has been shown to substantially reduce the plasma concentrations of letrozole. Concomitant administration of letrozole with tamoxifen, other anti-estrogen agents or estrogens should be avoided.
In vitro, letrozole inhibits cytochrome P450 isoenzymes 2A6 and, moderately, 2C19, but the clinical relevance is unknown. Therefore, caution should be used if it is necessary to administer letrozole concomitantly with medicinal products whose elimination depends mainly on these isoenzymes and whose therapeutic index is narrow (e.g. phenytoin, clopidrogel).
04.6 Pregnancy and lactation
Women in perimenopausal state or of childbearing age
Femara should only be used in women with a clearly defined postmenopausal status (see section 4.4). As there are reports of women who have recovered ovarian function during treatment with Femara despite a clear postmenopausal status at the start of therapy, the physician should discuss adequate contraception if necessary.
Pregnancy
Based on human data in which there have been isolated cases of birth defects (lip fusion, ambiguous genitalia), Femara can cause congenital malformations when administered during pregnancy. Animal studies have shown reproductive toxicity (see section 5.3 ).
Femara is contraindicated during pregnancy (see sections 4.3 and 5.3).
Feeding time
It is unknown whether letrozole / metabolites are excreted in human milk. A risk to the newborns / infants cannot be excluded.
Femara is contraindicated during lactation (see section 4.3).
Fertility
The pharmacological action of letrozole is to reduce the production of estrogen through the inhibition of aromatase. In premenopausal women, the inhibition of estrogen synthesis leads to increases in the levels of gonadotropins (LH, FSH). The increased levels of FSH in turn stimulate follicular growth and can induce ovulation.
04.7 Effects on ability to drive and use machines
Femara has minor effects on the ability to drive or use machines. Caution should be used when driving or operating machinery as fatigue and dizziness and uncommonly somnolence have been reported with the use of Femara.
04.8 Undesirable effects
Summary of the safety profile
The frequencies of adverse reactions for Femara are mainly based on data collected from clinical studies.
Up to about one third of patients treated with Femara in the metastatic phase and about 80% of patients in adjuvant treatment, as well as in adjuvant treatment after standard tamoxifen therapy, experienced adverse reactions. Most adverse reactions occurred. manifested during the first weeks of treatment.
The most frequently reported adverse reactions in clinical trials were flushing, hypercholesterolaemia, arthralgia, fatigue, increased sweating and nausea.
Additional important adverse reactions that may occur with Femara 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 list of adverse reactions
The frequencies of adverse reactions for Femara are mainly based on data collected from clinical studies.
The following adverse reactions, listed in Table 1, were reported from clinical studies and from post-marketing experience with Femara:
Table 1
Adverse reactions are classified within each frequency class, in order of decreasing frequency, 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 (frequency cannot be estimated from the available data).
Infections and infestations
Uncommon: urinary tract infection
Neoplasms benign, malignant and unspecified (including cysts and polyps)
Uncommon: Tumor pain 1
Disorders of the blood and lymphatic system
Uncommon: Leukopenia
Disorders of the immune system
Not known: Anaphylactic reactions
Metabolism and nutrition disorders
Very common: Hypercholesterolaemia
Common: Anorexia, increased appetite
Psychiatric disorders
Common: Depression
Uncommon: Anxiety (including nervousness), irritability
Nervous system disorders
Common: Headache, dizziness
Uncommon: Somnolence, insomnia, memory impairment, dysesthesia
(including paraesthesia, hypoesthesia), taste perversion, accident
cerebrovascular, carpal tunnel syndrome
Eye disorders
Uncommon Cataract, eye irritation, vision blurred
Cardiac pathologies
Uncommon: Palpitations1, tachycardia, cardiac ischemic events (including
new onset angina or aggravation of angina, angina che
requires surgery, myocardial infarction and ischemia
myocardial)
Vascular pathologies
Very common: Flushing
Common: Hypertension
Uncommon: Thrombophlebitis (including superficial vein thrombophlebitis and
deep)
Rare: Pulmonary embolism, arterial thrombosis, cerebrovascular infarction
Respiratory, thoracic and mediastinal disorders
Uncommon: Dyspnoea, cough
Gastrointestinal disorders
Common: Nausea, dyspepsia1, constipation, abdominal pain, diarrhea,
He retched
Uncommon: Dry mouth, stomatitis 1
Hepatobiliary disorders
Uncommon: Elevation of liver enzymes
Not known: Hepatitis
Skin and subcutaneous tissue disorders
Very common: Increased sweating
Common: Alopecia, rash (including erythematous rash,
maculopapular, similar to psoriasis, and vesicular erythema),
dryness of the skin
Uncommon: Pruritus, urticaria
Not known: Angioedema, toxic epidermal necrolysis, erythema multiforme
Musculoskeletal and connective tissue disorders
Very common: Arthralgia
Common:
Uncommon:
Myalgia, bone pain1, osteoporosis, bone fractures
Arthritis
Not known: Snap finger
Renal and urinary disorders
Uncommon: Increased urinary frequency
Diseases of the reproductive system and breast
Common: Vaginal bleeding
Uncommon: Vaginal discharge, vaginal dryness, breast pain
General disorders and administration site conditions
Very common: Fatigue (including asthenia, malaise)
Common: Peripheral edema
Uncommon: General edema, dry mucous membranes, thirst, pyrexia
Diagnostic tests
Common: Weight gain
Uncommon: Weight loss
1 Adverse drug reactions reported only in the treatment of the metastatic phase
Some adverse reactions have been reported with considerable frequency differences in adjuvant treatment. The following tables provide information on the significant differences between Femara versus tamoxifen alone and between Femara-tamoxifen in sequential treatment:
Table 2 Adjuvant Femara Monotherapy versus Tamoxifen Monotherapy - Adverse Events with
Significant differences
Table 3 Sequential treatment versus Femara monotherapy - adverse events with differences
Significant
Description of selected adverse reactions
Cardiac adverse reactions
In adjuvant treatment, in addition to the data presented in Table 2, the following adverse reactions were reported for Femara and tamoxifen, respectively (at the median duration of treatment of 60 months plus 30 days): angina requiring surgery (1.0 % vs. 1.0%); heart failure (1.1% vs. 0.6%); hypertension (5.6% vs. 5.7%); cerebrovascular accident / transient ischemic attack (2.1% vs. 1.9%).
In adjuvant treatment following standard tamoxifen therapy, angina requiring surgery (0.8% vs. 0, respectively) was reported for Femara (median treatment duration of 5 years) and placebo (median treatment duration 3 years), respectively. 6%); new onset angina or angina aggravation (1.4% vs. 1.0%); myocardial infarction (1.0% vs. 0.7%); thromboembolic events * (0.9% vs. 0.3%); stroke / transient ischemic attack * (1.5% vs. 0.8%).
Events marked with * had statistically significant differences in the two treatment groups.
Skeletal adverse reactions
For safety data on skeletal events in adjuvant treatment, please refer to Table 2.
In adjuvant treatment following standard tamoxifen therapy, significantly more patients treated with Femara reported bone fractures or osteoporosis (bone fractures, 10.4% and osteoporosis 12.2%) than patients in the group (5.8% and 6, respectively, 4%). The median duration of treatment was 5 years for Femara, compared with 3 years for placebo.
Reporting of suspected adverse reactions
The reporting of suspected adverse reactions that occur after the authorization of the medicinal product is important, as it allows continuous monitoring of the benefit / risk ratio of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Italian Medicines Agency. , website: https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse
04.9 Overdose
There have been isolated reports of overdose with Femara.
No specific treatment for overdose is known; treatment should be symptomatic and supportive.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: Endocrine therapies. Hormone antagonist and related agents: aromatase inhibitor, ATC code: L02BG04.
Pharmacodynamic effects
"Inhibition of estrogen-mediated stimulation of cell growth is a prerequisite for tumor response in cases where tumor growth is dependent on the presence of estrogen and endocrine therapy is used. In postmenopausal women, estrogen is primarily derived from" action of the aromatase enzyme, which converts adrenal estrogens - mainly androstenedione and testosterone - into estrone and estradiol. The suppression of estrogen biosynthesis in peripheral tissues and in neoplastic tissue itself can therefore be achieved by specific inhibition of the aromatase enzyme.
Letrozole is a non-steroidal aromatase inhibitor. It inhibits the aromatase enzyme by binding completely to the heme of cytochrome P450, resulting in a reduction in estrogen biosynthesis in all tissues where it is present.
In healthy postmenopausal women, administration of single doses of 0.1 mg, 0.5 mg, and 2.5 mg of letrozole suppresses the serum levels of estrone and estradiol by 75% -78% and 78% respectively compared to baseline values. Maximum suppression is achieved within 48-78 hours.
In postmenopausal patients with advanced breast cancer, daily doses of 0.1-5 mg suppress plasma concentrations of estradiol, oestrone and oestrone sulfate by 75-95% of baseline in all treated patients. At doses of 0.5 mg and above, many values of oestrone and oestrone sulfate are below the sensitivity threshold of the assay; which means that, at these doses, greater suppression of estrogen production is achieved. This suppression was maintained throughout the duration of treatment in all patients.
Inhibition of aromatase activity by letrozole is highly specific. No impairment of adrenal steroidogenesis has been detected. No clinically relevant changes in plasma concentrations of cortisol, aldosterone, 11-deoxycortisol, 17-hydroxy were detected. progesterone and ACTH, as well as plasma renin activity in postmenopausal patients treated with a daily dose of 0.1-5 mg of letrozole. The ACTH stimulation test, performed after 6 and 12 weeks of treatment with daily administrations of 0.1 mg, 0.25 mg, 0.5 mg, 1 mg, 2.5 mg and 5 mg, did not indicate any reduction of aldosterone or cortisol production. Consequently, it was not necessary to administer
supplements based on glucocorticoids and mineralocorticoids.
No changes in plasma concentrations of androgens (androstenedione and testosterone) were observed among healthy postmenopausal women after single doses of 0.1 mg, 0.5 mg, and 2.5 mg of letrozole or in plasma concentrations of androstenedione among patients in postmenopausal treated with daily doses from
0.1 mg to 5 mg, indicating that blocking estrogen biosynthesis does not result in accumulation of androgenic precursors. Neither plasma LH and FSH levels nor thyroid function, as assessed by TSH and T3 and T4 uptake test, are affected by letrozole.
Adjuvant treatment
Study BIG 1-98
BIG 1-98 is a multicenter, double-blind study in which more than 8,000 postmenopausal women with hormone receptor-positive early stage breast cancer were randomized to one of the following treatments: A. tamoxifen for 5 years; B. Femara for 5 years; C. tamoxifen for 2 years followed by Femara for
3 years; D. Femara 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), rate of invasive contralateral breast cancer and time to breast cancer recurrence.
Efficacy results at median follow-up of 26 and 60 months
The data in Table 4 reflect the Primary Core Analysis (PCA) results based on data from the monotherapy groups
(A and B) and on the data of the two groups in which the switch was expected (C and D) to a treatment with a median duration of 24 months and a median follow-up of 26 months and to a treatment with a median duration of 32 months and a median follow-up of 60 months.
The rates for 5-year DFS were 84% for Femara and 81.4% for tamoxifen.
Table 4 Primary Core Analysis: Disease-free and overall survival, at a median follow-up of 26 months and a median follow-up of 60 months (ITT population)
HR = Hazard ratio; CI = confidence interval
1 Log rank test, stratified by randomization and use of chemotherapy (yes / no)
2 DFS events: loco-regional recurrence, distant metastasis, invasive contralateral breast cancer, second primary (non-breast) malignancy, death from any cause without a previous tumor event.
Results at a median follow-up of 96 months (monotherapy groups only)
The analysis of the monotherapy groups (MAA) with long-term update of the efficacy of Femara monotherapy compared to tamoxifen monotherapy (median duration of adjuvant treatment: 5 years) is presented in Table 5.
Table 5 Analysis of Monotherapy Groups: Disease-Free Survival and Overall Survival
at a median follow-up of 96 months (ITT population)
1 Log rank test, stratified by randomization and use of chemotherapy (yes / no)
2 DFS events: loco-regional recurrence, distant metastasis, invasive breast cancer
contralateral, second primary (non-breast) malignancy, death from any cause without a previous cancer event.
3 Observations in the tamoxifen treatment group at the time of the selective switch to letrozole
Sequential Treatment Analysis (STA)
Sequential Treatment Analysis (STA) addresses the second primary question of study BIG 1-98, aimed at determining whether the letrozole and tamoxifen sequence is superior to letrozole monotherapy. No significant differences were observed in DFS, OS, SDFS , or DDFS between switch and monotherapy (Table 6).
Table 6 Analysis of Sequential Treatments for Disease-Free Survival with Letrozole as Initial Endogenous Agent (STA for the Switched Population)
1 Protocol definition, including second primary non-breast malignancies after switch / over two years
2 Adjusted for use of chemotherapy
There were no significant differences in DFS, OS, SDFS, or DDFS in any of the STAs from the randomized pairwise comparisons (Table 7).
Table 7 Sequential Treatments Analysis from Randomization (STA-R) of Disease-Free Survival (ITT STA-R Population)
1 Adjusted for use of chemotherapy (yes / no)
2 626 (40%) patients selectively switched to letrozole after opening the tamoxifen treatment group in 2005
Study D2407
Study D2407 is an open-label, randomized, multicenter 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 were assigned either to letrozole treatment for 5 years or to tamoxifen for 2 years followed by letrozole for 3 years.
At 24 months there was a statistically significant difference in the primary endpoint; bone mineral density (BMD) at the level of the lumbar spine (L2-L4) showed a median decrease of 4.1% in the letrozole treatment group compared to a median increase of 0.3% in the tamoxifen treatment group.
No patient with normal baseline BMD became osteoporotic during 2 years of treatment and only 1 patient with baseline osteopenia (T score of -1.9) developed osteoporosis during the treatment period (centralized review assessment).
Results for total hip BMD were similar to lumbar spine but less pronounced. There were no significant differences in fracture rate - 15% in the letrozole treatment group, 17% in the tamoxifen treatment group .
Median total cholesterol levels in the tamoxifen treatment group decreased by 16% after 6 months from baseline and this decrease was maintained on subsequent visits for up to 24 months. In the letrozole treatment group, total cholesterol levels were relatively stable over time, showing a statistically significant difference in favor of tamoxifen at each time point.
Adjuvant treatment after standard tamoxifen therapy (MA-17)
In a multicenter, double-blind, randomized, placebo-controlled (MA-17) study involving more than 5,100 postmenopausal women with receptor-positive or unknown primary breast cancer who had completed adjuvant tamoxifen treatment (from 4.5 at 6 years) were randomized to either Femara or placebo treatment for 5 years.
The primary endpoint was disease-free survival, defined as the interval between randomization and the first event of loco-regional recurrence, distant metastasis, or contralateral breast cancer.
The first interim analysis scheduled at a median follow-up of approximately 28 months (25% of patients were followed for at least 38 months), showed that Femara significantly reduced the risk of breast cancer recurrence by 42% compared to placebo. (HR 0.58; 95% CI 0.45, 0.76; P.= 0.00003). The benefit in favor of letrozole was observed regardless of lymph node status. There were no significant differences in overall survival: Femara 51 deaths; placebo 62; HR 0.82; 95% CI 0.56, 1.19).
Consequently, after the first interim analysis the study continued open label and, patients in the placebo treatment group were allowed to switch to Femara for 5 years. Over 60% of eligible patients (disease free at study opening) chose to switch to Femara. The final analysis included 1,551 women who switched from placebo to Femara in a median of 31 months (range 12 months). at 106 months) after completion of adjuvant tamoxifen therapy. The median duration of Femara treatment was 40 months.
Final analyzes conducted at a median follow-up of 62 months confirmed the significant reduction in the risk of breast cancer recurrence with Femara.
Table 8 Disease Free Period and Overall Survival (Modified ITT Population)
HR = Hazard ratio; CI = Confidence Interval
1 When the study opened in 2003, 1,551 patients in the randomized placebo treatment group (60% of these were eligible for the switch, i.e. they were disease-free) switched to letrozole treatment at a median time of 31 months after randomization. The analyzes presented here ignore the selective crossover.
2 Stratified by receptor status, lymph node status and previous adjuvant chemotherapy.
3 Protocol definition of disease-free survival events: loco-regional recurrence,
distant metastases or contralateral breast cancer.
4 Exploratory analyzes of follow-up times at the date of switch (if any) in the placebo treatment group.
5 Median follow-up of 62 months.
6 Median follow-up until transition (if any) 37 months.
In the MA-17 bone substudy where calcium and vitamin D were administered concomitantly, there was a greater reduction in bone mineral density (BMD) from baseline with Femara compared with placebo. The only difference statistically. occurring at 2 years was in total hip BMD (median decrease with letrozole of 3.8% versus median decrease with placebo of
2,0%).
In the MA-17 lipid substudy there were no statistically significant differences between letrozole and placebo in total cholesterol or any lipid fraction.
In the updated quality of life substudy there were no significant differences between treatments with respect to the summary score of the physical or mental component, or in any scoring domain on the SF-36 scale. On the MENQOL scale, a significant majority of women in the Femara treatment group compared to those who received placebo were more disturbed (usually in the first year of treatment) by those symptoms resulting from estrogen deprivation - flushing and vaginal dryness. The most disturbing symptom in most patients in both treatment groups was muscle pain, with a statistically significant difference in favor of placebo.
Neoadjuvant treatment
A double-blind study (P024) was conducted in 337 postmenopausal breast cancer patients randomized to each receive Femara 2.5 mg for 4 months or Tamoxifen for 4 months. At baseline all patients had stage T2-T4c, N0-2, M0, ER and / or PgR positive cancers and none of the patients could be eligible for breast-conserving surgery. Based on clinical evaluation, objective responses were recorded in 55% of the Femara treatment group versus 36% of the tamoxifen treatment group (P.Femara ultrasound 35% versus tamoxifen 25%, P.= 0.04) and from mammography Femara 34% versus tamoxifen 16%, P.P = 0.02) underwent breast-conserving surgery. During the 4-month preoperative treatment period, 12% of patients treated with Femara and 17% of patients treated with tamoxifen had disease progression at clinical evaluation.
First-line treatment
A double-blind controlled study was conducted to compare Femara (letrozole) 2.5 mg and tamoxifen 20 mg as first-line therapy in postmenopausal women with advanced breast cancer. In 907 women, letrozole was superior to tamoxifen for time to progression (primary endpoint) and objective response rate, time to treatment failure and clinical benefit.
The results obtained are summarized in Table 9:
Table 9 Results at a median follow-up of 32 months
Time to progression was significantly longer and the response rate significantly higher for letrozole regardless of whether adjuvant anti-estrogen therapy was administered or not. Time to progression was significantly longer for letrozole regardless of the dominant site of disease.Median time to progression was 12.1 months for Femara and 6.4 months for tamoxifen in patients with disease site only in soft tissue and a median of 8.3 months for Femara and 4.6 months for tamoxifen. in patients with visceral metastases.
The study design allowed patients to cross over to alternative therapy or discontinue the study upon disease progression. Approximately 50% of patients cross over to the opposite treatment group and the cross over was in fact completed within 36 months Median time to crossover was 17 months (Femara to tamoxifen) and 13 months (tamoxifen to Femara).
First-line treatment of advanced breast cancer resulted in a median overall survival for Femara 34 months versus 30 months for tamoxifen (log rank test P = 0.53, not significant). The lack of an advantage for Femara on overall survival can be explained by the crossover design of the study.
Second-line treatment
In postmenopausal women with advanced breast cancer, previously treated with anti-estrogens, two well-controlled clinical trials were conducted comparing two doses of letrozole (0.5 mg and 2.5 mg) and megestrol, respectively. acetate and aminoglutethimide.
Time to progression was not significantly different between 2.5 mg letrozole and megestrol acetate (P.= 0.07). There were statistically significant differences in favor of letrozole 2.5 mg versus megestrol acetate with regard to the overall objective tumor response rate (24% versus 16%, P.= 0.04), and the time to treatment failure (P.= 0.04). Overall survival was not significantly different between the 2 groups (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 in time to progression (P.= 0.008), time to treatment failure (P.= 0.003) and overall survival (P.=0,002).
Male breast cancer
The use of Femara in men with breast cancer has not been studied.
05.2 Pharmacokinetic properties
Absorption
Letrozole is rapidly and completely absorbed from the gastrointestinal tract (mean absolute bioavailability: 99.9%). Food slightly reduces the rate of absorption (median Tmax 1 hour fasting versus 2 hours post-meal; and mean Cmax 129 ± 20.3 nmol / liter fasting versus 98.7 ± 18.6 nmol / liter post-meal) but the extent of absorption (AUC) does not vary. This modest effect on the rate of absorption is considered to be of no clinical relevance and therefore letrozole can be taken with or without meals.
Distribution
Plasma protein binding of letrozole is approximately 60%, of which the majority (55%) is albumin bound. The letrozole concentration in erythrocytes is approximately 80% of the plasma level. After administration of 2.5 mg of 14C-labeled letrozole, approximately 82% of the plasma radioactivity is the parent compound. Systemic exposure to metabolites is low. Letrozole is rapidly and widely distributed in tissues. Its apparent volume of distribution at steady state is approximately 1.87 ± 0.47 L / kg.
Biotransformation
The main route of elimination of letrozole is represented by metabolic clearance with the formation of a pharmacologically inactive metabolite, carbinol CLm = 2.1 l / h but is relatively slow compared to the hepatic blood flow (about 90 l / h). Cytochrome P450 isoenzymes 3A4 and 2A6 are capable of converting letrozole to this metabolite. Formation of these unidentified minor metabolites and direct renal and faecal excretion play a minor role in the overall elimination of letrozole. After administration of 2.5 mg of 14C-labeled letrozole to healthy volunteers in postmenopause, 88.2 ± 7.6% of the radioactivity was recovered in the urine and 3.8 ± 0.9% in the faeces within 2 weeks. At least 75% of the radioactivity recovered in urine up to 216 hours (84.7 ± 7.8% of dose) was attributed to the glucuronide of the metabolite carbinol, approximately 9% to two unidentified metabolites and 6% to unchanged letrozole. .
Elimination
The apparent terminal elimination half-life is approximately 2 to 4 days. After daily administration of 2.5 mg steady-state was achieved within 2-6 weeks. Plasma concentrations at steady-state are approximately 7-fold. higher than the concentrations detected after a single dose of 2.5 mg, while they are 1.5 to 2 times higher than the expected steady-state values based on the concentrations detected after a single dose, this suggests that there is a slight lack of linearity of the pharmacokinetics of letrozole after daily administration of 2.5 mg Since steady-state levels are maintained over time, it can be concluded that there is no continuous accumulation of letrozole.
Linearity / non-linearity
The pharmacokinetics of letrozole were dose proportional after single oral doses up to 10 mg (dose range: 0.01-30 mg) and after daily doses up to 1.0 mg (dose range: 0.1 - 5 mg). . After a single oral dose of 30 mg there was a small dose-proportional increase in the AUC value. The over-proportionality is likely to be the result of a saturation of metabolic processes of elimination. Steady levels were reached after 1-2 months at all tested dosing regimens (0.1-5.0 mg per day).
Special populations
Elderly patients
Age has 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 of 9-116 mL / min), no effect on the pharmacokinetics of letrozole was found after a single 2.5 mg dose. In addition to this study evaluating the influence of renal impairment on letrozole, a covariate analysis was performed on data from two pivotal studies (Study AR / BC2 and Study AR / BC3).
Calculated creatinine clearance (CLcr) [Study AR / BC2: range: 19 - 187 mL / min; AR / BC3 study: range: 10 -180 mL / min] did not demonstrate a statistically significant association between steady-state trough plasma letrozole levels (Cmin). In addition, data from Study AR / BC2 and Study AR / BC3 in second-line metastatic breast cancer showed no evidence of a negative effect of letrozole on CLcr or impaired renal function.
Therefore, no dosage adjustment is necessary in patients with renal impairment (CLcr ≥ 10 ml / min). Little information is available in patients with severe renal impairment (CLcr
Hepatic impairment
In a similar study in subjects with varying degrees of hepatic function, the mean AUC values in volunteers with moderate hepatic impairment (Child-Pugh class B) were 37% higher than in normal subjects. but still within the limits observed in subjects without impaired liver function. The pharmacokinetics of letrozole were evaluated in a comparator study in which, following administration of a single oral dose in eight male subjects with hepatic cirrhosis and severe hepatic insufficiency (Child-Pugh class C) and in healthy volunteers ( N = 8), the area under the AUC curve and the half-life t½ increased by 95 and 187%, respectively. Therefore, Femara should be administered in these patients with caution and after careful consideration of the potential risk / benefit ratio.
05.3 Preclinical safety data
There was no evidence of systemic or target organ toxicity in a number of preclinical toxicology studies conducted with standard animal species.
The acute toxicity of letrozole was low in rodents exposed to doses up to 2000 mg / kg. In dogs, letrozole induced signs of moderate toxicity at doses up to 100 mg / kg.
In the context of toxicological studies for repeated administration in rats and dogs, lasting up to 12 months, the main results observed can be attributed to the pharmacological activity of the compound. The no adverse event dose was 0.3 mg / kg in both species.
Oral administration of letrozole to female rats resulted in a reduction in the mating-pregnancy ratio and an increase in pre-implantation losses.
Studies on the mutagenic potential of letrozole conducted both in vitro that in vivo did not document any evidence of genotoxicity.
In a 104-week carcinogenicity study in male rats, no treatment-related tumors were detected. In female rats, a reduction in the incidence of both benign and malignant mammary tumors was found at all doses of letrozole used.
In a 104-week mouse carcinogenicity study, no treatment-related tumors were detected in male mice. In female mice, a generally dose-related increase in the incidence of benign tumors of theca granulosa ovarian cells was observed with all doses of letrozole tested. These tumors were considered to be related to pharmacological inhibition of estrogen synthesis and they can be caused by an increase in LH resulting from a decrease in circulating estrogen.
In pregnant rats and rabbits, letrozole was shown to be embryotoxic and foetotoxic following oral administration at clinically relevant doses. In rats that gave birth to live fetuses, there was an increased incidence of fetal malformations including domed head and cervical / central vertebral fusion. No increase in fetal malformations was observed in rabbits. It is not known whether these malformations were an indirect consequence of pharmacological properties (inhibition of estrogen biosynthesis) or a direct effect of the drug (see sections 4.3 and 4.6).
The observations emerging from the preclinical studies are limited to those associated with the known pharmacological activity, which represents the only area of concern in terms of safety for use in humans deriving from extrapolation from studies conducted in animals.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Tablet contents: lactose monohydrate, microcrystalline cellulose, corn starch, sodium carboxymethyl starch, magnesium stearate and anhydrous colloidal silica.
Coating: hypromellose, talc, macrogol 8000, titanium dioxide (E171) and yellow iron oxide (E172).
06.2 Incompatibility
Not relevant
06.3 Period of validity
5 years
06.4 Special precautions for storage
Do not store above 30 ° C.
Store in the original package to protect the medicine from moisture.
06.5 Nature of the immediate packaging and contents of the package
PVC / PE / PVDC / aluminum blisters.
Packs of 10 (1 x 10), 14 (1 x 14), 28 (2 x 14), 30 (3 x 10), 100 (10 x 10) tablets
Not all pack sizes may be marketed.
06.6 Instructions for use and handling
No special instructions
07.0 MARKETING AUTHORIZATION HOLDER
Novartis Europharm Limited
Wimblehurst Road
Horsham
West Sussex, RH12 5AB United Kingdom
08.0 MARKETING AUTHORIZATION NUMBER
30 tablets: 033242013
100 tablets: 033242025
10 tablets 033242037
14 tablets 033242049
28 tablets 033242052
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: 21.03.1997
Renewal date: 24.07.2006
