Expiration date: 02/2027

Composition and form of issue:

Tablets, film-coated 1 tab.

letrozole (in terms of 100% substance) 2, 5 mg

excipients: lactose monohydrate, corn starch, hypromellose, MC carboxymethyl starch sodium silicon dioxide colloidal magnesium stearate Opadry yellow 03V82927 (hypromellose, titanium dioxide E171, iron dye oxide yellow E172, macrogol-400, talc)

in packages contour bezyazykov 10 or 14 PCs. in cardboard pack of 3 or 2 packs.

Description of dosage form:

Round biconvex tablets, film-coated, yellow.

Pharmacokinetics:

Letrozole is rapidly and completely absorbed from the gastrointestinal tract, the average bioavailability is 99, 9%. Eating slightly reduces the rate of absorption. The average time Tmax is 1 h when taking letrozole on an empty stomach and 2 h-when taken with food, the average Cmax is (129±20, 3) nmol/l when taking on an empty stomach and (98, 7±18, 6) nmol/l — when taken with food, but the degree of absorption of letrozole (when evaluated by the value of AUC) does not change.

Small changes in the rate of absorption are regarded as not having clinical significance, so letrozole can be taken regardless of food intake. The relationship of letrozole with plasma proteins is approximately 60% (mainly with albumin — 55%). The concentration of letrozole in red blood cells is about 80% of that in plasma. The apparent volume of distribution in the equilibrium state is about (1, 87±0, 47) l / kg. the Equilibrium concentration is achieved within 2-6 weeks of daily intake of a daily dose of 2, 5 mg. Pharmacokinetics is nonlinear. Cumulation with long-term use is not noted. Letrozole largely metabolized by the action of isozymes CYP3A4 and CYP2A6 cytochrome P450 with the formation of pharmacologically inactive carbonlook connection.

It is excreted mainly by the kidneys in the form of metabolites, to a lesser extent-through the intestine. The final T1/2 is 48 h. the Pharmacokinetic parameters of letrozole does not depend on the age of the patient. In renal failure pharmacokinetic parameters are not changed. In moderately expressed violation of liver function (Child-Pugh B), the average values of AUC, although higher by 37%, but remain within the range of values that are observed in persons without liver function disorders. In patients with cirrhosis and severe impairment of its function (Child-Pugh C), AUC increases by 95% and T1/2 — by 187%. However, given the good tolerability of high doses of the drug (5-10 mg/day), in these cases, there is no need to change the dose of letrozole.

Description of pharmacological action:

Letrozole has an antiestrogenic effect, selectively inhibits aromatase (estrogen synthesis enzyme) by highly specific competitive binding to the subunit of this enzyme — cytochrome P450 heme. Blocks the synthesis of estrogens in both peripheral and tumor tissues.

In postmenopausal women, estrogens are formed mainly with the participation of the aromatase enzyme, which converts androgens synthesized in the adrenal glands (primarily Androstenedione and testosterone) into estrone and estradiol.

Daily intake of letrozole at a daily dose of 0, 1-5 mg leads to a decrease in the concentration of estradiol, estron and estron sulfate in plasma by 75-95% of the initial content. Suppression of estrogen synthesis is maintained throughout the treatment period.

With the use of letrozole in the dose range of 0, 1 to 5 mg of a violation of the synthesis of steroid hormones in the adrenal glands is not observed, the ACTH test does not detect violations of the synthesis of aldosterone or cortisol. Additional appointment of glucocorticoids and mineralocorticoids is not required.

Blockade of estrogen biosynthesis does not lead to the accumulation of androgens, which are precursors of estrogen. Against the background of taking letrozole, changes in the concentrations of luteinizing and follicle stimulating hormones in the blood plasma, changes in thyroid function, changes in the lipid profile, an increase in the frequency of myocardial infarctions and strokes were not observed.

Against the background of treatment with letrozole, the incidence of osteoporosis is slightly increased (6, 9% compared to 5, 5% on placebo). However, the frequency of bone fractures in patients receiving letrozole does not differ from that in healthy people of the same age.

Adjuvant therapy with letrozole early stages of breast cancer reduces the risk of recurrence, increases survival without signs of disease for 5 years, reduces the risk of secondary tumors.

Prolonged adjuvant therapy with letrozole reduces the risk of recurrence by 42%. A significant advantage in survival without signs of the disease in the letrozole group was noted regardless of the involvement of lymph nodes. Treatment with letrozole reduces the mortality of patients with involvement of lymph nodes by 40%.

Indications:

• early stages of breast cancer, whose cells have hormone receptors, in postmenopausal women as adjuvant therapy
  
• early stages of breast cancer in postmenopausal women after completion of standard adjuvant therapy with tamoxifen as an extended adjuvant therapy
  
• common hormone-dependent forms of breast cancer in postmenopausal women (first-line therapy)
  
• common forms of breast cancer in postmenopausal women (natural or induced artificially) receiving prior therapy with antiestrogens.
  

Contraindications:

• hypersensitivity to letrozole or any other component of the drug
  
• endocrine status characteristic of the reproductive period
  
• pregnancy
  
• lactation
  
• child age (efficacy and safety for children has not been established).
  

Caution: there are no data on the use of letrozole in patients with Cl creatinine less than 10 ml/min Before the appointment of letrozole so patients should carefully weigh the ratio between potential risk and expected effect of treatment.

Side effect:

As a rule, adverse reactions were mild or moderate and are mainly associated with the suppression of estrogen synthesis.

The frequency of adverse reactions is estimated as follows: occurring very often ->, 10%, often-1-10%, sometimes-0, 1-1%, rarely-0, 01-0, 1%, very rarely -<, 0, 01%, p="">,

From the digestive system: often-nausea, vomiting, dyspepsia, constipation, diarrhea sometimes — abdominal pain, stomatitis, dry mouth, increased activity of liver enzymes.

From the nervous system: often-headache, dizziness, depression sometimes — anxiety, nervousness, irritability, drowsiness, insomnia, memory impairment, dysesthesia, paresthesia, hypesthesia, impaired taste perception, episodes of cerebral circulation.

On the part of the blood: sometimes — leukopenia.

From the cardiovascular system: sometimes-a feeling of heartbeat, tachycardia, thrombophlebitis of superficial and deep veins, increased blood PRESSURE, coronary artery disease (angina, myocardial infarction, heart failure), thromboembolism rarely — pulmonary embolism, arterial thrombosis, stroke.

From the respiratory system: sometimes-shortness of breath, cough.

From the skin and skin appendages: often-alopecia, excessive sweating, skin rash (including erythematous, maculopapular, vesicular rash, psoriasis — like rashes) sometimes — itching, dry skin, urticaria very rarely-angioedema, anaphylactic reactions.

From the musculoskeletal system: very often — arthralgia often-myalgia, bone pain, osteoporosis, bone fractures, sometimes — arthritis.

From the senses: sometimes-cataract, eye irritation, blurred vision, violation of taste sensations.

From the urinary system: sometimes-frequent urination, urinary tract infections.

From the reproductive system: sometimes-vaginal bleeding, vaginal discharge, vaginal dryness, pain in the mammary glands.

Other: very often — paroxysmal sensation of heat (hot flashes) often — increased fatigue, asthenia, malaise, peripheral edema, weight gain, hypercholesterolemia, anorexia, increased appetite sometimes — weight loss, thirst, hyperthermia (pyrexia), dry mucous membranes, generalized edema, pain in tumor foci.

Drug interaction:

While the appointment of letrozole with cimetidine and warfarin clinically significant interactions are not observed.

Clinical experience in the use of letrozole in combination with other anticancer agents is currently not available.

According to in vitro studies, letrozole inhibits the activity of cytochrome P450 — CYP2A6 and CYP2C19 isoenzymes (the latter — moderately). When deciding on the significance of these data for the clinic, it should be taken into account that the CYP2A6 isoenzyme does not play a significant role in the metabolism of drugs. In experiments in vitro, it was shown that letrozole in concentrations 100 times higher than the equilibrium values in plasma does not have the ability to significantly suppress the metabolism of diazepam (substrate for CYP2C19). Thus, clinically significant interactions with CYP2C19 are unlikely. However, caution should be exercised when combining the use of letrozole and drugs, metabolized mainly with the participation of the above-mentioned isoenzymes and having a narrow therapeutic index.

Dosage and administration:

Inside, regardless of the meal.

Adults the recommended dose of Letrozole Teva is 2, 5 mg of 1 times a day, every day, for a long time.

As an extended adjuvant therapy, treatment should last for 5 years (no longer).

If signs of disease progression appear, Letrozole-Teva should be discontinued.

In elderly patients, correction of the dose of Letrozole-Teva is not required.

Patients with impaired liver and/or kidney function: in liver or kidney function disorders (creatinine Cl >,10 ml/min) dose adjustment is not required. However, in severe liver dysfunction (Child-Pugh C) patients should be under constant surveillance.

Overdose:

Symptoms: there are separate reports of cases of letrozole overdose.

Treatment: symptomatic and supportive care. Any specific treatments for overdose are unknown. Letrozole is excreted from the plasma by hemodialysis.

Special instruction:

Patients with severe hepatic impairment should be under constant supervision.

During therapy with letrozole, given the potential for pregnancy, women in the perimenopausal and early postmenopausal periods should use reliable methods of contraception to establish a stable postmenopausal hormonal level.

Influence on the ability to drive and control mechanisms. Some side effects of the drug, such as General weakness and dizziness, may affect the ability to perform potentially hazardous activities that require concentration and rapid reactions. In this regard, care should be taken when driving vehicles and machinery.