Pharmacological properties of the drug Femara
Letrozole is a highly specific inhibitor of aromatase activity. In cases of estrogen-dependent tumors, elimination of indirect stimulatory effects is a prerequisite for suppressing tumor growth. In postmenopausal women, estrogens are formed mainly with the participation of the enzyme aromatase, which converts androgens synthesized in the adrenal glands (primarily androstenedione and testosterone) into estrone and estradiol. Therefore, by specifically inhibiting the aromatase enzyme, suppression of estrogen biosynthesis in peripheral tissues and tumor tissue can be achieved. Letrozole inhibits aromatase by competitively binding to the cytochrome P450 heme subunit of this enzyme, which ultimately reduces estrogen biosynthesis in all tissues. In healthy postmenopausal women, a single dose of letrozole of 0.1; 0.5 and 2.5 mg, reduces serum estrone and estradiol levels (compared to baseline) by 75, 78 and 78%, respectively. The maximum reduction is achieved after 48–78 hours. In postmenopausal women with advanced breast cancer, daily use of letrozole at a dose of 0.1–5.0 mg leads to a decrease in the levels of estradiol, estrone and estrone sulfate in the blood plasma by 75–95 % of the initial level. When using the drug in a dose of ≥0.5 mg, in many cases the concentrations of estrone and estrone sulfate are below the sensitivity threshold of the hormone determination method used. This indicates that with these doses of the drug a more pronounced suppression of estrogen synthesis is achieved. Estrogen suppression was maintained throughout treatment in all patients. Letrozole is a highly specific inhibitor of aromatase activity. No disturbances in the synthesis of steroid hormones in the adrenal glands were detected. In postmenopausal patients who were treated with letrozole at a daily dose of 0.1–5.0 mg, clinically significant changes in plasma concentrations of cortisol, aldosterone, 11-deoxycortisol, 17-hydroxyprogesterone, ACTH, and renin activity were not detected. Carrying out a stimulation test with ACTH after 6 and 12 weeks of treatment with letrozole at a daily dose of 0.1; 0.25; 0.5; 1; 2.5 and 5 mg did not show any significant decrease in aldosterone or cortisol synthesis. Thus, there is no need to supplement glucocorticoids and mineralocorticoids. In healthy postmenopausal women, after a single use of letrozole in doses of 0.1; 0.5 and 2.5 mg changes in the concentration of androgens (androstenedione and testosterone) in the blood plasma were not detected. In postmenopausal patients receiving letrozole at a daily dose of 0.1–5.0 mg, no changes in the level of androstenedione in the blood plasma were also noted. All this indicates that blockade of estrogen biosynthesis does not lead to the accumulation of androgens, which are estrogen precursors. In patients receiving letrozole, there were no changes in the concentrations of luteinizing and follicle-stimulating hormones in the blood plasma, and no changes in thyroid function, which was assessed by the levels of TG, T4 and T3. Suction. Letrozole is quickly and completely absorbed from the gastrointestinal tract (average bioavailability is 99.9%). Food slightly reduces the rate of absorption (the average time to reach the maximum concentration of letrozole in the blood is 1 hour when taking the drug on an empty stomach and 2 hours when taking the drug with food; the average value of the maximum concentration of letrozole in the blood is 129±20.3 nmol/l when taken on an empty stomach and 98.7±18.6 nmol/l when taken with food), however, the degree of absorption of letrozole (as assessed by AUC) does not change. Minor changes in the rate of absorption are considered to be of no clinical significance, so letrozole can be taken with or without food. Distribution. The binding of letrozole to plasma proteins is approximately 60% (mainly with albumin - 55%). The concentration of letrozole in erythrocytes is approximately 80% of its plasma level. After administration of 2.5 mg of 14C-labeled letrozole, approximately 82% of the radioactivity in the blood plasma was due to unchanged active substance. Consequently, systemic exposure to letrozole metabolites is small. Letrozole is rapidly and widely distributed in tissues. The apparent volume of distribution during the steady state period is about 1.87 ± 0.47 l/kg body weight. Metabolism and excretion. Letrozole is extensively metabolized to form a pharmacologically inactive carbinol compound. The metabolic clearance of letrozole is 2.1 l/h, which is less than the hepatic blood flow (about 90 l/h). It was revealed that the transformation of letrozole into its metabolite is carried out under the influence of isoenzymes 3A4 and 2A6 of cytochrome P450. Other metabolites formed, as well as excretion of unchanged drug in urine and feces, are not of great importance in the overall elimination of letrozole. Within 2 weeks after administration of 2.5 mg of 14C-labeled letrozole to healthy postmenopausal volunteers, 88.2 ± 7.6% of radioactivity was detected in urine, and 3.8 ± 0.9% in feces. At least 75% of the radioactivity detected in urine over a period of up to 216 hours (84.7 ± 7.8% of the letrozole dose value) was from the glucuronide conjugates of the carbinol metabolite, about 9% from two other unidentified metabolites, and 6% from to unchanged letrozole. The apparent terminal half-life from plasma is about 2 days. After daily use of 2.5 mg of the drug, the equilibrium concentration of letrozole is achieved within 2-6 weeks, while it is approximately 7 times higher than after a single dose of the drug at the same dose. At the same time, the value of the equilibrium concentration is 1.5–2 times higher than predicted based on calculations based on the values registered after taking a single dose of the drug. This indicates that with daily use of letrozole at a dose of 2.5 mg, its pharmacokinetics are non-linear. Since the steady-state concentration of letrozole is maintained during treatment over a long period of time, it can be concluded that there is no accumulation of letrozole. In studies conducted in volunteers with varying levels of renal function (24-hour creatinine clearance varied from 9 to 116 ml/min), it was noted that after a single dose of letrozole at a dose of 2.5 mg, its pharmacokinetics did not change. In a similar study conducted in volunteers with varying levels of liver function, it was found that in those with moderately severe liver dysfunction, mean AUC values were 37% higher than in healthy controls, but remained within the range of values noted in those without impairment. liver functions. In addition, there was no effect of renal impairment (estimated creatinine clearance of 20–50 ml/min) or liver impairment on letrozole plasma concentrations in 359 patients with advanced breast cancer. The pharmacokinetics of letrozole does not depend on age.
Instructions for use FEMARA
Suction
Letrozole is quickly and completely absorbed from the gastrointestinal tract (average bioavailability is 99.9%). Food slightly reduces the rate of absorption (the average time to reach Cmax of letrozole in the blood is 1 hour when taking Femara on an empty stomach and 2 hours when taken with food; the average Cmax of letrozole in the blood is 129±20.3 nmol/l when taken on an empty stomach and 98.7±18.6 nmol/l - when taken with food), however, the degree of absorption of letrozole (as assessed by AUC) does not change. Minor changes in the rate of absorption are considered to be of no clinical significance, so letrozole can be taken with or without food.
Distribution
Letrozole binding to plasma proteins is approximately 60% (mainly with albumin - 55%). The concentration of letrozole in erythrocytes is about 80% of its level in blood plasma. After administration of 2.5 mg of 14C-labeled letrozole, approximately 82% of the radioactivity in the blood plasma was due to unchanged active substance. Consequently, systemic exposure to letrozole metabolites is low. Letrozole is rapidly and widely distributed in tissues. The apparent Vd during the equilibrium period is about 1.87±0.47 l/kg.
Metabolism and excretion
Letrozole is extensively metabolized to form a pharmacologically inactive carbinol compound. The metabolic clearance of letrozole is 2.1 l/h, which is less than the hepatic blood flow (about 90 l/h). It was found that the transformation of letrozole into its metabolite is carried out under the influence of isoenzymes 3A4 and 2A6 of cytochrome P450. The formation of a small number of other, as yet unidentified metabolites, as well as unchanged excretion in urine and feces, play only a small role in the overall elimination of letrozole. Within 2 weeks after the administration of 2.5 mg of 14C-labeled letrozole to healthy postmenopausal volunteers, 88.2 ± 7.6% of radioactivity was detected in urine, and 3.8 ± 0.9% in feces. At least 75% of the radioactivity detected in urine up to 216 hours (84.7 ± 7.8% of the letrozole dose) was from the glucuronide conjugates of the carbinol metabolite, about 9% from two other unidentified metabolites, and 6% from unchanged letrozole.
The apparent final T1/2 from blood plasma is about 2 days. After daily use of 2.5 mg of the drug, letrozole Css is achieved within 2 to 6 weeks, while it is approximately 7 times higher than after a single dose of the same dose. At the same time, the Css value is 1.5-2 times higher than the equilibrium concentration that could be predicted based on calculations based on the values registered after a single dose of the drug. This indicates that with daily use of letrozole at a dose of 2.5 mg, its pharmacokinetics are nonlinear. Since the steady state is maintained during therapy for a long time, it can be concluded that there is no ongoing accumulation of letrozole.
Pharmacokinetics in special clinical situations
In studies conducted in volunteers with different states of nocturnal function (24-hour creatinine clearance varied from 9 to 116 ml/min), it was noted that after a single dose of letrozole at a dose of 2.5 mg, its pharmacokinetics did not change. In a similar study conducted in volunteers with varying levels of liver function, it was found that in subjects with moderate hepatic impairment, mean AUC values were 37% higher than in healthy subjects, but remained within the range of values observed in persons without liver dysfunction. In addition, there was no effect of renal impairment (calculated creatinine clearance 20-50 ml/min) or liver impairment on letrozole plasma concentrations in 359 patients with advanced breast cancer.
The pharmacokinetics of letrozole does not depend on age.
Indications for use of the drug Femara
Adjuvant therapy for hormone-dependent breast cancer in the early stages in postmenopausal women; extended adjuvant therapy for early-stage breast cancer in postmenopausal women who have received standard adjuvant therapy with tamoxifen; as a first-line drug for the treatment of common forms of breast cancer in postmenopausal women; treatment of common forms of breast cancer in postmenopausal women who have previously received antiestrogens therapy; neoadjuvant therapy of localized forms of breast cancer with positive estrogen receptors in postmenopausal women, followed by breast-conserving surgery in cases where such surgery was not initially considered indicated. After the operation, the issue of subsequent administration of Femara should be decided taking into account generally accepted treatment regimens.
After surgical treatment, radiation therapy and chemotherapy for breast cancer, the risk of relapse of this disease remains. Since the growth of breast cancer depends on the action of estrogens, long-term reduction in the risk of tumor recurrence can be achieved by adjuvant endocrine therapy aimed at suppressing estrogen activity.
Currently, the standard of adjuvant endocrine therapy after surgical treatment of breast cancer with positive estrogen and/or progesterone receptors in postmenopausal patients is the administration of the estrogen receptor modulator tamoxifen for 5 years. This reportedly reduces the risk of disease relapse by 47% and associated mortality by 26% [1].
It is important to note that increasing the duration of treatment with tamoxifen for more than 5 years is associated with an increased risk of complications (uterine cancer, thromboembolism, etc.) and is even associated with worsening treatment results [2,3]. This is because tamoxifen is not only an antagonist, but also a partial agonist of estrogen receptors. Under certain circumstances, it may stimulate the effects of estrogens, thereby reducing the potential antitumor activity of this drug. In addition, there is the problem of the development of resistance to tamoxifen with its long-term use. Given all these data, the US National Cancer Institute recommends limiting the use of the drug to 5 years (with the exception of clinical trials).
In recent years, aromatase (estrogen synthetase) inhibitors, in particular Femara (letrozole) have attracted increasing attention from researchers [4,5]. Possessing high antitumor activity and minor side effects, Femara gradually replaced megestrol acetate from the second line of endocrine therapy for metastatic breast cancer; it was subsequently found that when used in the first line of endocrine therapy, Femara provides therapeutic results similar to tamoxifen, but is superior to the latter in terms of tolerability.
At the same time, the superiority of Femara over tamoxifen in neoadjuvant endocrine therapy was established (in terms of the frequency of the effect and the time of its onset).
All these data suggested that in women undergoing surgery for breast cancer, the use of Femara can solve the problems associated with the impossibility of adjuvant therapy with tamoxifen for more than 5 years. A large randomized, double-blind, placebo-controlled study was devoted to this issue (Goss P. et al), the results of which were published on November 6, 2003 in the New England Journal of Medicine [6].
In this study, letrozole (Femara) was administered to postmenopausal women undergoing surgery for early-stage breast cancer who had completed 5 years of standard adjuvant endocrine therapy with tamoxifen 20 mg.
The study included 5187 patients (mean age 62.2 years) randomized to receive Femara 2.5 mg daily (n = 2593) or placebo (n = 2594) for the next 5 years.
At the start of the study, patients included in the Femara and placebo groups practically did not differ in age (62.4 and 60.0 years; 33% and 34% aged 50-59 years; 58% each >=60 years) and time onset of menopause (76% at age >=50 years). Adjuvant chemotherapy in both groups was previously performed in 46% of women, adjuvant radiation therapy in 60% and 59%. Metastases to regional lymph nodes during surgery were found in 46% of patients in both groups. Positive estrogen and/or progesterone receptors were detected in 98% of women in the Femara and placebo groups.
Thus, there were no differences in patient characteristics between groups.
The first interim analysis of the study results, conducted at a mean follow-up of 2.4 years, showed that 132 women in the placebo group had recurrence or recurrence of cancer in the second breast, but only 75 had recurrence in the Femara group ( risk ratio 0.57; p = 0.00008).
Relapse of the disease was observed in 106 (4.1%) patients in the placebo group and in 61 (2.4%) during treatment with Femara, i.e. the risk of relapse was reduced by 43%. The frequency of bone metastases decreased especially significantly under the influence of this aromatase inhibitor.
A new primary tumor in the second breast developed in 26 (1%) patients in the placebo group and in 14 (0.5%) in the Femara group, i.e. When using Femara, the risk of developing a new tumor was reduced by 46%.
The 4-year survival rate was 93% with Femara and 87% with placebo. The number of deaths from breast cancer in the Femara group was almost 2 times less than in the placebo group (9 and 17, respectively).
Side effects were rarely observed during treatment with Femara: minor hot flashes, arthritis, arthralgia, myalgia. There was no increase in osteoporosis or bone fractures.
Thus, in patients with hormone receptor-positive breast cancer who received adjuvant endocrine therapy with tamoxifen for 5 years after surgical treatment, the administration of Femara at a dose of 2.5 mg daily increases survival and significantly reduces the risk of relapse of the disease or the development of cancer of the second breast. The study results indicate the safety of this treatment.
These data, together with the results of other studies, suggest that current standards of endocrine therapy for breast cancer in postmenopausal patients will be changed in the near future. It is obvious that the results of the study by Goss R. et al. will be of paramount importance in shaping these standards. There is no doubt that new data on the use of Femara obtained by practical oncologists will help improve the results of treatment of patients with breast cancer.
Use of the drug Femara
Adults and elderly patients. The recommended dose of Femara is 2.5 mg once a day every day. In adjuvant and extended adjuvant therapy, treatment with Femara should continue for 5 years or until disease relapse occurs. In patients with metastases, Femara therapy is continued until signs of disease progression appear. In elderly patients, no dose adjustment of Femara is required. The drug is not used in children. In patients with liver or kidney damage (with creatinine clearance ≥10 ml/min), no dose adjustment is required.
Side effects of Femara
The drug was well tolerated in all studies as stage I and II therapy in the treatment of advanced breast cancer, adjuvant therapy for early stage breast cancer, and extended adjuvant therapy for breast cancer in patients who had previously received standard adjuvant therapy with tamoxifen. Adverse reactions were reported in approximately 1/3 of patients treated with Femara in the metastatic and neoadjuvant setting, approximately 70% to 75% of patients treated in the adjuvant setting (Femara and tamoxifen), and approximately 40% in the extended adjuvant setting (Femara and placebo). Adverse reactions were predominantly mild or moderate in nature and in most cases were associated with estrogen deficiency. When assessing the frequency of occurrence of various adverse reactions, the following gradations were used: very often - ≥10, often - from ≥1% to ≤10%, sometimes - from ≥0.1% to ≤1%, rarely - from ≥0.01% to ≤0.1%, very rarely - ≤0.01%. Infections: sometimes - infections of the urinary system. From the side of the tumor: sometimes - pain (only with metastatic/neoadjuvant therapy). From the circulatory and lymphatic systems: sometimes - leukopenia. Metabolic disorders: often - anorexia, increased appetite, hypercholesterolemia, weight gain; sometimes - weight loss. From the mental side: often - depression; sometimes - excitement, including nervousness, irritability. From the nervous system: often - headache, dizziness; sometimes - drowsiness, insomnia, memory impairment, dysentesia, including paresthesia, hypoesthesia; taste disturbance, cerebrovascular disorders. On the part of the organ of vision: sometimes - cataracts, eye irritation, blurred vision. From the cardiovascular system: very often - flushing; sometimes - a feeling of palpitations, tachycardia, thrombophlebitis, including superficial and deep, hypertension (arterial hypertension), peripheral edema, cases of cardiac ischemia (with adjuvant therapy, regardless of the causal relationship). In the groups where patients took Femara and tamoxifen, the following adverse reactions were noted: thromboembolic reactions (1.2% compared to 2.8%), angina pectoris (0.7% compared to 0.6%), myocardial infarction (0 .6% versus 0.4%) and heart failure (0.9% versus 0.4%); rarely - pulmonary embolism, arterial thrombosis, heart attack. From the respiratory system: rarely - shortness of breath. From the gastrointestinal tract: often - nausea, vomiting, dyspepsia, constipation, diarrhea; sometimes - pain in the abdomen, stomatitis, dry mucous membranes, thirst, increased liver enzymes. Dermatological reactions: often - baldness, increased sweating, rashes, including erythematous, maculopapular, psoriasis-like and vesicular; sometimes - itching, dry skin, urticaria. From the musculoskeletal system: very often - arthralgia; often - myalgia, bone pain, osteoporosis, bone cracks; sometimes - arthritis. From the urinary system: sometimes - increased frequency of urination. From the reproductive system: sometimes - vaginal bleeding, discharge, vaginal dryness, pain in the mammary glands. General disorders: often - fatigue, including asthenia and malaise; sometimes - increased body temperature.
Femara 2.5 mg 30 pcs. film-coated tablets
pharmachologic effect
Antitumor agent, estrogen synthesis inhibitor.
Composition and release form Femara 2.5 mg 30 pcs. film-coated tablets
Tablets - 1 tablet:
- active ingredient: letrozole 2.5 mg;
- excipients: lactose monohydrate 61.500 mg, microcrystalline cellulose 20.000 mg, corn starch 9.500 mg, sodium carboxymethyl starch 5.000 mg, colloidal silicon dioxide 0.500 mg, magnesium stearate 1.000 mg;
- tablet shell: hypromellose 1.838 mg, talc 1.331 mg, macrogol 8000 0.333 mg, iron dye yellow oxide (17268) 0.249 mg, titanium dioxide 0.249 mg.
10 tablets in a blister. 3 blisters along with instructions for use in a cardboard box.
Description of the dosage form
Round, slightly biconvex, with beveled edges, dark yellow tablets. “FV” is printed on one side of the tablet and “CG” on the other.
Directions for use and doses
Inside, regardless of food intake.
If a dose is missed, it should be taken as soon as possible, but avoiding duplication (if it is almost time for the next dose).
Exceeding the daily dose >2.5 mg may increase the systemic effects of the drug.
Adults. The recommended dose of Femara® is 2.5 mg once a day, daily, for a long time.
As extended adjuvant therapy, treatment should continue for 5 years (not longer than 5 years).
If signs of disease progression appear, Femara® should be discontinued.
In the neoadjuvant (preoperative period) regimen, treatment with Femara® should be continued for 4-8 months to achieve optimal tumor shrinkage. If an adequate tumor response to treatment is not achieved, the use of Femara® should be discontinued, and the issue of surgical or other types of treatment must be considered.
Patients with liver dysfunction
For mild to moderate liver dysfunction, no dose adjustment of Femara® is required (class A or B on the Child-Pugh scale). There is insufficient data on use in patients with severely impaired liver function (class C on the Child-Pugh scale), and therefore the use of the drug in such patients should be under constant medical supervision.
Patients with impaired renal function
In case of impaired renal function (creatinine clearance >10 ml/min), no dose adjustment is required. Data on use in patients with creatinine clearance
Patients aged > 65 years
In elderly patients, no dose adjustment of Femara® is required.
Pharmacodynamics
Letrozole has an antiestrogenic effect, selectively inhibits aromatase (an enzyme in estrogen synthesis) through highly specific competitive binding to the subunit of this enzyme, the cytochrome P450 heme. Blocks estrogen synthesis in both peripheral and tumor tissues.
In postmenopausal women, estrogens are formed mainly with the participation of the enzyme aromatase, which converts androgens synthesized in the adrenal glands (primarily androstenedione and testosterone) into estrone and estradiol.
Daily intake of letrozole in a daily dose of 0.1-5 mg leads to a decrease in the concentration of estradiol, estrone and estrone sulfate in the blood plasma by 75-95% of the initial content. Suppression of estrogen synthesis is maintained throughout the entire treatment period.
When using letrozole in a dose range from 0.1 to 5 mg, no disruption of the synthesis of steroid hormones in the adrenal glands is observed; an adenocorticotropic hormone (ACTH) test does not reveal disturbances in the synthesis of aldosterone or cortisol. Additional administration of glucocorticosteroids and mineralocorticosteroids is not required. Blockade of estrogen biosynthesis does not lead to the accumulation of androgens, which are estrogen precursors. While taking letrozole, there were no changes in the concentrations of luteinizing and follicle-stimulating hormones in the blood plasma, changes in thyroid function, changes in the lipid profile, or an increase in the frequency of myocardial infarction and strokes.
During treatment with letrozole, the incidence of osteoporosis slightly increased (6.9% compared with 5.5% on placebo). However, the incidence of bone fractures in patients receiving letrozole does not differ from that in healthy people of the same age. Adjuvant therapy with letrozole for early stages of breast cancer reduces the risk of relapses, increases disease-free survival for 5 years, and reduces the risk of developing secondary tumors. Extended adjuvant therapy with letrozole reduces the risk of relapse by 42%. A significant advantage in disease-free survival in the letrozole group was observed regardless of lymph node involvement.
Treatment with letrozole reduces mortality in patients with lymph node involvement by 40%. Extended adjuvant therapy with letrozole after completion of 5 years of tamoxifen therapy led to a significant reduction in the risk of progression and development of contralateral breast cancer compared with placebo.
Pharmacokinetics
Letrozole is quickly and completely absorbed from the gastrointestinal tract (GIT), the average bioavailability is 99.9%. Eating slightly reduces the rate of absorption. The average time to reach the maximum concentration of letrozole in the blood (Tmax) is 1 hour when taking letrozole on an empty stomach and 2 hours when taking it with food; the average maximum concentration (Cmax) is 129 ± 20.3 nmol/l when taken on an empty stomach and 98.7 ± 18.6 nmol/l when taken with food, but the degree of absorption of letrozole (assessed by the area under the concentration-time curve (AUC)) does not change. Minor changes in the rate of absorption are considered to be of no clinical significance, so letrozole can be taken with or without food. The binding of letrozole to plasma proteins is approximately 60% (mainly with albumin - 55%). The concentration of letrozole in erythrocytes is about 80% of that in blood plasma. The apparent volume of distribution at steady state is about 1.87±0.47 l/kg. Steady-state concentrations are achieved within 2-6 weeks of daily administration of a daily dose of 2.5 mg. Pharmacokinetics is nonlinear. No accumulation was observed with long-term use. Letrozole is extensively metabolized by the cytochrome P450 isoenzymes CYP3A4 and CYP2A6 to form a pharmacologically inactive carbinol compound. It is excreted primarily by the kidneys in the form of metabolites, and to a lesser extent through the intestines. The terminal half-life (T1/2) is 48 hours.
The pharmacokinetic parameters of letrozole do not depend on the age of the patient.
In renal failure, pharmacokinetic parameters do not change.
With moderate liver dysfunction (Child-Pugh B), the average AUC values, although 37% higher, remain within the range of values observed in individuals without liver dysfunction. In patients with cirrhosis of the liver and severe impairment of its function (Child-Pugh C), AUC increases by 95% and T1/2 by 187%. However, given the good tolerance of high doses of the drug (5-10 mg/day), in these cases there is no need to change the dose of letrozole.
Indications for use Femara 2.5 mg 30 pcs. film-coated tablets
Early stages of invasive breast cancer, the cells of which have hormone receptors, in postmenopausal women, as adjuvant therapy.
Early stage invasive breast cancer in postmenopausal women after completion of standard adjuvant therapy with tamoxifen for 5 years as extended adjuvant therapy.
Common hormone-dependent forms of breast cancer in postmenopausal women (first-line therapy).
Common forms of breast cancer with the development of relapse or progression of the disease in postmenopausal women (natural or artificially induced) who received previous antiestrogens therapy.
Hormone-dependent HER-2 negative breast cancer in postmenopausal women as neoadjuvant therapy when chemotherapy is contraindicated and there is no need for emergency surgery.
Contraindications
Hypersensitivity to letrozole or any other component of the drug.
Endocrine status characteristic of the reproductive period.
Pregnancy, breastfeeding period.
Age up to 18 years.
Caution should be exercised when using Femara® in patients with severe hepatic impairment (class C on the Child-Pugh scale), severe renal impairment (creatinine clearance less than 10 ml/min).
Application of Femara 2.5 mg 30 pcs. film-coated tablets during pregnancy and breastfeeding
Femara is contraindicated during pregnancy and lactation. Breastfeeding should be stopped during treatment with Femara.
special instructions
Patients with severely impaired liver function should be under constant supervision.
There is no data on the use of Femara® in patients with creatinine clearance less than 10 ml/min. Before starting the use of Femara® in such patients, the balance between the potential risk and the expected effect of treatment should be carefully assessed.
Since Femara® is used only in postmenopausal patients, in case of unclear status of hormonal regulation of the reproductive system, it is recommended to determine the concentration of luteinizing hormone (LH), follicle-stimulating hormone (FSH) and/or estradiol before starting treatment.
An increase in the level of FSH in the blood serum leads to stimulation of follicular growth and can cause ovulation, and therefore, during therapy with Femara®, there is a potential for pregnancy in women in the perimenopausal and early postmenopausal period. In such cases, reliable methods of contraception should be used until stable postmenopausal hormonal levels are established in this category of patients.
There is evidence of the development of osteoporosis and/or the occurrence of bone fractures during the use of Femara® (see “Adverse reactions from the musculoskeletal system and connective tissue”), and therefore careful monitoring of the condition of bone tissue is recommended throughout the entire period of use drug.
It is recommended to avoid the simultaneous use of Femara® with tamoxifen, other antiestrogenic and estrogen-containing drugs, since these drugs may weaken the pharmacological effect of letrozole. The mechanism of this interaction has not been studied. The drug is not indicated for the treatment of breast cancer that does not contain receptors for steroid hormones (estrogen or progesterone).
Impact on the ability to drive vehicles and operate machinery
Some side effects of the drug, such as general weakness, dizziness and drowsiness, may affect the ability to perform potentially dangerous activities that require concentration and quick reactions. In this regard, care should be taken when operating vehicles and machinery. If the described adverse events occur, you should refrain from performing these activities.
Overdose
There are isolated reports of cases of overdose with Femara®.
Any specific treatment methods for overdose are unknown. Symptomatic and supportive therapy is indicated. Letrozole is eliminated from plasma by hemodialysis.
Side effects of Femara 2.5 mg 30 pcs. film-coated tablets
As a rule, adverse reactions were mild or moderate and were mainly associated with suppression of estrogen synthesis.
The incidence of adverse reactions is estimated as follows: occurring “very often” - >10%, “often” - >1 - 0.1% - 0.01 -
Infectious and parasitic diseases: uncommon - urinary tract infections.
Benign, malignant and unspecified neoplasms (including cysts and polyps): uncommon - pain in the area of the tumor.
Blood and lymphatic system disorders: uncommon: leukopenia.
Immune system disorders: frequency unknown - anaphylactic reactions.
Metabolic and nutritional disorders: very often - hypercholesterolemia; often - anorexia, increased appetite.
Mental disorders: often - depression; infrequently - anxiety (including nervousness), irritability.
Nervous system disorders: often - headache, dizziness; uncommon - drowsiness, insomnia, memory impairment, sensory disturbances (including paresthesia, hypoesthesia), taste disturbances, episodes of cerebrovascular accidents, carpal tunnel syndrome.
Visual disorders: uncommon - cataracts, eye irritation, blurred vision.
Cardiac disorders: uncommon - palpitations*, tachycardia, coronary heart disease (including newly diagnosed or worsening existing angina, angina requiring surgical intervention, myocardial infarction, myocardial ischemia).
Vascular disorders: very often - paroxysmal sensations of heat (“hot flashes”); often - increased blood pressure (BP); uncommon - thrombophlebitis (including thrombophlebitis of superficial and deep veins); rarely - pulmonary embolism, arterial thrombosis, stroke.
Disorders of the respiratory system, chest and mediastinal organs: infrequently - dyspnea, cough.
Gastrointestinal disorders: often - nausea*, vomiting, dyspepsia, constipation, diarrhea, abdominal pain; infrequently - stomatitis, dry mouth. Disorders of the liver and biliary tract: infrequently, increased activity of liver enzymes; very rarely - hepatitis.
Disorders of the skin and subcutaneous tissues: very often - increased sweating; often - alopecia, dry skin, rash (including erythematous, maculopapular, psoriasiform and vesicular); infrequently - skin itching, urticaria; frequency unknown - angioedema, Lyell's syndrome (toxic epidermal necrolysis), Stevens-Johnson syndrome (malignant polymorphic exudative erythema).
Musculoskeletal and connective tissue disorders: very often - arthralgia; often - myalgia, bone pain*, osteoporosis, bone fractures; infrequently - arthritis; frequency unknown - trigger finger syndrome.
Renal and urinary tract disorders: infrequently - frequent urination.
Disorders of the genital organs and mammary glands: often - vaginal bleeding; uncommon - vaginal discharge, vaginal dryness, pain in the mammary glands.
General disorders and disorders at the injection site: very often - increased fatigue (including asthenia and discomfort); often - peripheral edema; infrequently generalized edema, dry mucous membranes, thirst, fever.
Laboratory and instrumental data: often - increase in body weight; infrequently - weight loss.
* - adverse reactions detected in the metastatic period.
Selected adverse reactions
Adverse reactions from the heart
During adjuvant therapy with Femara® for 5 years, compared with placebo therapy for 3 years, the following adverse reactions were observed: angina pectoris requiring surgical intervention occurred in 0.8% of cases and in 0.6% of cases, respectively; coronary heart disease (including newly diagnosed or worsening existing angina) - in 1.4% and 1.0% of cases, respectively; myocardial infarction - in 1.0% and 0.7% of cases, respectively; thromboembolic events - in 0.9% and 0.3% of cases, respectively; stroke/transient ischemic attack - in 1.5% and 0.8% of cases, respectively.
Adverse reactions from the musculoskeletal system and connective tissue
During adjuvant therapy with Femara® for 5 years compared to placebo therapy for 3 years, the following adverse reactions were observed: bone fractures - in 10.4% and 5.8% of cases, respectively; osteoporosis - in 12.2% and 6.4% of cases, respectively.
If any of the side effects indicated in the instructions get worse, or you notice any other side effects not listed in the instructions, tell your doctor.
Drug interactions
Letrozole is metabolized primarily in the liver with the participation of the cytochrome P 450 isoenzymes CYP3A4 and CYP2A6. The systemic elimination of letrozole may be influenced by drugs that affect these isoenzymes.
The metabolism of letrozole shows low affinity for the CYP3A4 isoenzyme, since this isoenzyme in normal clinical situations at concentrations 150 times higher than the equilibrium values of letrozole in blood plasma does not have the ability to suppress the metabolism of letrozole.
Drugs that increase letrozole serum concentrations
Inhibitors of the CYP3A4 and CYP2A6 isoenzymes can reduce the metabolism of letrozole, thereby increasing its concentration in the blood serum. Concomitant use of potent inhibitors of these isoenzymes (for the CYP3A4 isoenzyme, these include, for example, ketoconazole, itraconazole, voriconazole, ritonavir, clarithromycin and telithromycin; for the CYP2A6 isoenzyme, methoxsalene) may lead to increased exposure to letrozole. Caution must be exercised when using letrozole and potent inhibitors of CYP3A4 and CYP2A6 isoenzymes.
Drugs that lead to a decrease in letrozole serum concentrations
Inducers of the CYP3A4 and CYP2A6 isoenzymes can increase the metabolism of letrozole, thereby reducing its concentration in the blood serum. The simultaneous use of inducers of these isoenzymes (for the CYP3A4 isoenzyme, these are, for example, phenytoin, rifampicin, carbamazepine, phenobarbital, St. John's wort) may lead to a decrease in letrozole exposure; for the CYP2A6 isoenzyme, no inducers are known.
The simultaneous use of Femara® (at a dose of 2.5 mg) and tamoxifen at a dose of 20 mg/day leads to a decrease in the concentration of letrozole in the blood serum by an average of 38%. There are no clinical data on the effect on the effectiveness and safety of the use of Femara® after the appointment of tamoxifen.
Drugs whose serum concentrations are affected by letrozole
In vitro, letrozole inhibits the CYP2A6 isoenzyme of cytochrome P 450 and slightly the CYP2C19 isoenzyme; the clinical significance of this phenomenon has not been established. Caution must be exercised during the simultaneous use of letrozole and drugs with a narrow therapeutic index, the elimination of which depends primarily on the CYP2C19 isoenzyme (for example, phenytoin, clopidogrel).
There are currently no known drugs with a narrow therapeutic index for the CYP2A6 isoenzyme.
When letrozole is co-administered with cimetidine (a known non-specific inhibitor of the CYP2C19 and CYP3A4 isoenzymes) and warfarin (a sensitive substrate of the CYP2C9 isoenzyme with a narrow therapeutic index, which is often prescribed as concomitant therapy to patients taking Femara®), no clinically significant interactions are observed.
Special instructions for the use of Femara
There is no data on the use of Femara in patients with creatinine clearance ≤10 ml/min. Before prescribing Femara, such patients should carefully weigh the risk/benefit ratio of treatment. In patients with severe hepatic impairment, the half-life of letrozole is approximately 2 times longer than in patients with normal liver function. Such patients require more careful monitoring. The drug is contraindicated during pregnancy and breastfeeding. The ability to drive vehicles and operate hazardous machinery is unlikely to be affected. But since general weakness and dizziness were noted during treatment with the drug, patients should be warned about this.
Femara drug interactions
Clinical studies have shown that with simultaneous use of Femara with cimetidine and warfarin, no clinically significant interactions are detected. No clinically significant interaction of Femara with other commonly used drugs has been established. There is currently no clinical experience with the use of Femara in combination with other antitumor agents. in vitro studies , letrozole suppresses the activity of cytochrome P450 isoenzymes 2A6 and 2C19 (the latter moderately). The CYP 2A6 isoenzyme does not play a significant role in drug metabolism. In vitro experiments have shown that letrozole, used in concentrations 100 times higher than equilibrium values in blood plasma, does not have the ability to significantly suppress the metabolism of diazepam (a substrate for CYP 2C19). Thus, clinically significant interactions with the CYP2C19 isoenzyme are unlikely. However, caution should be exercised when concomitantly using letrozole and drugs that are metabolized predominantly by the above-mentioned isoenzymes and with a small range of therapeutic concentrations.
