Indications for use
adjuvant therapy of breast cancer in postmenopausal women with hormone-positive early invasive breast cancer
Continuation of adjuvant therapy in postmenopausal women with hormone-positive early invasive breast cancer who have previously received standard adjuvant tamoxifen therapy for 5 years
First-line therapy in postmenopausal women with hormone-positive breast cancer
advanced breast cancer after recurrence or progression in postmenopausal women (natural or induced) who have received prior anti-estrogen therapy
Neoadjuvant therapy in postmenopausal women with hormone-positive, HER-2-negative breast cancer when chemotherapy is not an appropriate therapy and immediate surgical intervention is not indicated.
List of information required prior to administration
Contraindications
hypersensitivity to the active substance or to any of the excipients
Persons with hereditary galactose intolerance, Lapp (LAPP)-lactase enzyme deficiency, glucose-galactose malabsorption
premenopausal endocrine status
Pregnancy and lactation
Children and adolescents under 18 years of age

Necessary precautions for use
Menopause
In patients whose menopausal status is unclear, levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), and/or estradiol should be measured prior to initiation of treatment with letrozole. Only postmenopausal women of endocrine endocrine status should receive treatment with letrozole.
Renal impairment
Letrozole has not been studied in a sufficient number of patients with creatinine clearance less than 10 mL/min. The potential risk/benefit for such patients should be carefully considered before using letrozole.
Hepatic impairment
In patients with severe hepatic impairment (Child-Pugh C), systemic exposure and terminal half-life were approximately twice as great compared to healthy volunteers. Therefore, such patients should be closely monitored.
Effects on bone
Letrozole is a substance that lowers estrogen levels. Women with a history of osteoporosis and/or fractures, or who are at increased risk for osteoporosis, should have a formal bone mineral density evaluation before starting adjuvant and extended adjuvant therapy, and be monitored during and after treatment with letrozole. Treatment or prophylaxis for osteoporosis should be initiated when appropriate and closely monitored. In adjuvant therapy, a sequential treatment schedule (letrozole for 2 years followed by tamoxifen for 3 years) may also be considered depending on the patient's safety profile.
Tendinitis and tendon rupture
In rare cases, there have been reports of the development of tendonitis and rupture of the
tendon rupture. Patients should be monitored and appropriate measures (e.g., immobilization) should be taken if tendon involvement occurs.
Other indications
The use of letrozole with tamoxifen and other anti-estrogen or estrogen-containing therapies should be avoided, as these substances may reduce the pharmacological effect of letrozole.
Special notes regarding excipients
Lactose
As an excipient the preparation contains lactose, therefore the preparation is contraindicated in persons with hereditary galactose intolerance, Lapp (LAPP)-lactase enzyme deficiency, glucose-galactose malabsorption.
Sodium
This medication contains less than 1 mmol of sodium (23 mg) in one tablet, that is, virtually no sodium.

Interactions with other medicinal products
Letrozole is metabolized in part by cytochromes P2A6 and P3A4. Cimetidine, a weak, nonspecific inhibitor of cytochrome P450 enzymes, does not affect plasma concentrations of letrozole. The effects of potent cytochrome P450 inhibitors are unknown.
There are currently no clinical data on the use of letrozole in combination with estrogens or anticancer agents other than tamoxifen. Tamoxifen and other anti-estrogen or estrogen-containing therapies may reduce the pharmacologic effects of letrozole. In addition, co-administration of tamoxifen with letrozole has shown a significant decrease in plasma concentrations of letrozole. Co-administration of letrozole with tamoxifen and other anti-estrogens or estrogens should be avoided.
In vitro, letrozole inhibits cytochrome P450 isoenzymes 2A6 and, moderately, 2C19, but the clinical relevance is unknown. Consequently, caution is indicated when concomitantly administering letrozole with drugs whose excretion depends mainly on these isoenzymes and whose therapeutic index is narrow (e.g., phenytoin, clopidogrel).

Special Warnings
Women of perimenopausal or reproductive age
Letrozole should be used only in women with a clearly defined postmenopausal period. Since there are reports of women who have had recovery of ovarian function during treatment with letrozole despite their clearly established postmenopausal status at the start of therapy, the physician should discuss adequate contraception, if necessary.
Reproductive function
The pharmacologic action of letrozole is manifested by decreasing estrogen synthesis through aromatase inhibition. In premenopause, inhibition of estrogen synthesis leads to a reciprocal increase in gonadotropin (LH, FSH) levels. The increase in FSH levels, in turn, stimulates follicle growth and can induce ovulation.
Pregnancy
Based on experience in people who have had isolated cases of birth defects (labial fusion, intermediate genitalia), letrozole may cause birth defects when taken during pregnancy. There are reports of reproductive toxicity.
Letrozole is contraindicated during pregnancy.
Breastfeeding
Whether letrozole and its metabolites penetrate into maternal milk has not been established. A risk to neonates/infants cannot be excluded.
Letrozole is contraindicated during breastfeeding.
Peculiarities of the drug effect on the ability to drive a vehicle or potentially dangerous mechanisms
Since general fatigue, weakness, dizziness, drowsiness were observed during treatment with the drug, caution should be exercised when driving a vehicle or potentially dangerous mechanisms.

Directions for use
Dosing regimen
Adults
The recommended dose of the drug is 2.5 mg once a day.
It is not recommended to exceed the daily dose of 2.5 mg.
Special groups of patients
Patients with renal impairment
In patients with renal impairment (creatinine clearance ³ 10 ml/min), the drug dose adjustment is not required. There is insufficient data regarding patients with creatinine clearance <10 ml/min.
Patients with hepatic impairment
In patients with mild and moderate degree of hepatic impairment (class A and B on the Child-Pugh scale) dose adjustment is not required. There is insufficient data regarding patients with severe hepatic impairment, but patients with severe hepatic impairment of Child-Pugh class C should be under close medical supervision.
Children
Use of the drug in children and adolescents is not recommended.
Elderly patients (≥ 65 years)
The recommended dose of the drug is 2.5 mg once a day.
In elderly patients there is no need to adjust the drug dose.
It is not recommended to exceed the daily dose of 2.5 mg.
Method and route of administration
Perorally.
Frequency of administration with indication of time of administration
The drug LETERO can be taken with or without food, as food does not affect the absorption of the drug.
Duration of treatment
In adjuvant and extended adjuvant therapy treatment with the drug should be continued for 5 years or until relapse occurs. In patients with metastases, therapy with the drug should be continued until signs of disease progression appear.
In neoadjuvant (preoperative) therapy it is recommended to administer the drug for 4-8 months to achieve optimal tumor reduction. In case this therapy is ineffective, it is recommended to cancel the drug, prescribe surgical intervention and/or discuss further treatment with the patient.
In patients with advanced breast cancer, treatment should be continued until tumor progression.
Measures to be taken in case of overdose
There are no reports of letrozole overdose to date.
Symptoms: in case of overdose it is possible to increase the side effects of the drug.
Treatment: carrying out symptomatic therapy.
Measures required in case of missing one or more doses of the medicinal product
The missed dose should be taken as soon as the patient remembers it. However, if the patient recalls it shortly before the next dose (within 2 or 3 hours), the missed dose should be skipped and the next dose should be taken as scheduled. A double dose should not be taken, as disproportionate systemic effects have been observed with a daily dose higher than the recommended 2.5 mg.
Recommendations for seeking the advice of a health care professional for clarification of how to use the medicinal product
Seek medical advice before taking the medicinal product.

Description of adverse reactions that occur during the standard use of medicinal products and measures to be taken in this case

Very common (≥10%), common (≥ 1% to < 10%), uncommon (≥ 0.1% to < 1%), rare (≥ 0.01% to < 0.1%) , very rare (< 0.01%), frequency unknown (cannot be calculated from available data)

Very common
hypercholesterolemia
hot flashes
profuse sweating
joint pain
Fatigue (including asthenia, malaise)

Common
arterial hypertension
nausea, vomiting, dyspepsia, constipation, diarrhea, abdominal pain
anorexia, increased appetite, weight gain
headache, dizziness
alopecia, dry skin, rash (including erythematous, patchy-papular, psoriasis-like and vesicular rash)
myalgia, bone pain, osteoporosis, bone fractures, arthritis, chest pain
palpitations
depression
peripheral edema
vaginal bleeding

Uncommon
leukopenia
tachycardia, ischemic cardiovascular complications (including onset or worsening of angina attacks, angina requiring surgery, myocardial infarction, myocardial ischemia)
thrombophlebitis (including superficial and deep veins)
pain in tumor foci (patients with metastases)
anxiety (including nervousness), irritability
drowsiness, insomnia, memory impairment, dysesthesia (including paresthesia, hypoesthesia), taste disturbance, acute cerebral circulation disorder, carpal tunnel syndrome
shortness of breath, cough
dry mouth, stomatitis
elevation of liver enzymes,
urinary tract infections, urinary frequency.
vaginal discharge, vaginal dryness, breast pain
cataracts, eye irritation, blurred vision
itching, hives
generalized edema, fever, dry mucous membranes, thirst
weight loss
tendonitis

Rarely
pulmonary embolism
arterial thrombosis
cerebral vascular infarction
tendon rupture

Very rare
Hepatitis
Frequency unknown
anaphylactic reactions
Quincke’s edema, toxic epidermal necrolysis, erythema multiforme
snapping finger syndrome
If adverse drug reactions occur, contact your health care provider, pharmacist, or directly to the Adverse Drug Reactions (Actions) Information Database, including reports of drug ineffectiveness
Republican State enterprise on the Right of Economic Management National Center for Expertise of Medicines and Medical Devices of the Committee for Medical and Pharmaceutical Control of the Ministry of Healthcare of the Republic of Kazakhstan
http://www.ndda.kz

Additional information
Composition of the medicinal product
One tablet contains
active substance - letrozole 2.5 mg,
excipients: lactose monohydrate, croscarmellose sodium, povidone, anhydrous colloidal silicon dioxide, magnesium stearate.
film coating composition: Opadray yellow 03B82 401 (hydroxypropyl methylcellulose 2910/hypromellose 6CP, titanium dioxide (E 171), iron (III) oxide yellow (E172), macrogol/PEG 400, talc), purified water.
Description of appearance, odor, taste
Round tablets, slightly biconvex, with beveled edges, covered with a film coating of dark yellow color, engraved ʻ5ʼ on one side and ʻHʼ on the other side.

Form of release and packaging
10 tablets each in blister package made of aluminum-triplex (aluminum foil with thermolac coating on the light side with triple lamination of PVC/PE/PVDH (polyvinyl chloride/polyethylene/polyvinylidene chloride) film).
3 or 6 blister packages together with instructions for medical use in Kazakh and Russian languages are placed in a carton pack.
Shelf life
3 years
Do not use after expiration date.
Storage conditions
Store at a temperature not exceeding 25 °C.
Keep out of reach of children!

Conditions of release from pharmacies
By prescription