Description
Latin name
LETROZOLE
Release form
Film-coated tablets.
Packaging
In a blister pack of 10 tablets. In a cardboard box 3 blisters.
Pharmacological action of
Pharmacodynamics
Antitumor drug, an inhibitor of estrogen synthesis. Letrozole has an antiestrogenic effect, selectively inhibits aromatase (an enzyme for the synthesis of estrogens) by highly specific competitive binding to the subunit of this enzyme – the cytochrome P450 heme. It blocks the synthesis of estrogen in both peripheral and tumor tissues.
In postmenopausal women, estrogens are formed mainly with the participation of the aromatase enzyme, which converts the 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 blood plasma by 75-95% of the initial content. Suppression of estrogen synthesis is maintained throughout the treatment period.
When using Letrozole in the dose range from 0.1 to 5 mg, there is no violation of the synthesis of steroid hormones in the adrenal glands, the ACTH test does not reveal violations of the synthesis of aldosterone or cortisol. Additional prescription of glucocorticoids and mineralocorticoids is not required.
Blockade of estrogen biosynthesis does not lead to the accumulation of androgens, which are the precursors of estrogens.
No changes in LH and FSH concentrations in blood plasma, changes in thyroid function, changes in lipid profile, increase in the incidence of myocardial infarction and stroke were observed with Letrozole. During treatment with Letrozole, the incidence of osteoporosis is slightly increased (6.9% compared to 5.5% with 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 in the early stages of breast cancer reduces the risk of relapse, increases survival without signs of disease for 5 years, and reduces the risk of secondary tumors.
Extended adjuvant therapy with letrozole reduces the risk of relapse by 42%. A significant advantage in survival without signs of disease in the letrozole group was observed regardless of the involvement of lymph nodes. Treatment with Letrozole reduces mortality in patients with lymph node involvement by 40%.
Pharmacokinetics
Absorption
After oral administration, letrozole is rapidly and completely absorbed from the gastrointestinal tract. Bioavailability averages 99.9%. Eating slightly reduces the rate of absorption. The average value of Tmax is 1 hour when taking letrozole on an empty stomach and 2 hours when taken with food, the average value of Cmax in blood plasma 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 (when assessed by the AUC value) does not change.
Small changes in the rate of absorption are regarded as not having clinical significance, therefore Letrozole can be taken regardless of food intake.
Pharmacokinetics is not linear.
Distribution of
The binding of letrozole to plasma proteins is approximately 60% (predominantly with albumin – 55%). The concentration of letrozole in red blood cells is about 80% of that in blood plasma. The apparent Vd in equilibrium is about 1.87 ± 0.47 L / kg. Css is achieved within 2-6 weeks of daily use of the drug in a daily dose of 2.5 mg. Cumulation with prolonged use is not noted.
Metabolism
Letrozole is significantly metabolized by the isoenzymes CYP3A4 and CYP2A6 to form a pharmacologically inactive carbinol compound.
Excretion
It is excreted mainly by the kidneys in the form of metabolites, to a lesser extent through the intestines. The final T1 / 2 is 48 hours.
Pharmacokinetics in special clinical cases
The pharmacokinetic parameters of letrozole are independent of the patient’s age.
With renal failure, the pharmacokinetic parameters do not change.
With moderate hepatic impairment (class B on the Child-Pugh scale), the average AUC values, although higher by 37%, remain within the range of values observed in individuals without impaired liver function. In patients with cirrhosis of the liver and severely impaired function (class C on the Child-Pugh scale), AUC increases by 95%, T1 / 2 – by 187%. However, given the good tolerability of the drug in high doses (5-10 mg / day), in these cases, there is no need to change the dose of Letrozole.
Indications
Early stages of breast cancer expressing estrogen receptors in postmenopausal women as adjuvant therapy for
early stages of breast cancer in postmenopausal women after standard adjuvant tamoxifen therapy is completed as an extended adjuvant breast cancer in postmenopausal women – first-line therapy
common forms of breast cancer in postmenopausal women (natural or artificially constant), previously treated with antiestrogens.
Contraindications
Endocrine status characteristic of the reproductive period
pregnancy
lactation (breastfeeding)
childhood (efficacy and safety for children not established)
hypersensitivity to the components of the drug.
Caution: the drug should be used for lactase deficiency, lactase intolerance, glucose-galactose malabsorption. There is no data on the use of Letrozole in patients with CC < 30 ml / min (before prescribing the drug, such patients should carefully weigh the ratio between the potential risk and the expected treatment effect). Use during pregnancy and lactation Use in pregnancy and during lactation (breastfeeding) is contraindicated. Composition 1 tablet contains: Active substances: capecitabine 150 mg. Excipients: lactose – 15.6 mg, microcrystalline cellulose – 7.2 mg, croscarmellose sodium – 6 mg, hypromellose (3 mPa.s) – 4.5 mg, magnesium stearate – 2.7 mg. Shell composition: pink opaque 03A14309 (hypromellose (6 mPa.s), talc, titanium dioxide (E171), yellow iron oxide dye (E172), red iron oxide dye (E172) – 8.5 mg. Composition 1 tablet contains: Active substances: letrozole 2.5 mg. Excipients: lactose monohydrate 50 mg, sodium carboxymethyl starch 2.5 mg, colloidal silicon dioxide 500 μg, microcrystalline cellulose 28 mg, crospovidone 4 mg, pregelatinized corn starch 11.5 mg, magnesium stearate 1 mg. Film composition: Opadry Y 1-7000 (hypromellose, titanium dioxide, macrogol (polyethylene glycol)) 3.73 mg, iron dye yellow oxide 270 μg. Dosage and administration The drug is taken orally, regardless of food intake. The recommended dose of Letrozole is 2.5 mg 1 time / day, daily, for a long time (for 5 years or until relapse). As an extended adjuvant therapy, treatment should be continued for 4 years (no longer than 5 let). If signs of disease progression appear, taking Letrozole should be discontinued. In patients with advanced disease or a metastatic tumor, treatment with Letrozole should be continued until tumor progression is expressed. In elderly patients, dose adjustment of the drug Letrozole is not required. In case of impaired liver or kidney function (CC> 10 ml / min), dose adjustment is not required. However, in severely impaired liver function (Child-Pugh class C), patients require ongoing medical supervision.
Side effects
As a rule, adverse reactions were mild or moderate and were mainly associated with suppression of estrogen synthesis.
Determination of the frequency of adverse reactions: very often (> 10%)
often (1-10%)
sometimes (0.1-1%)
rare (0.01-0.1%)
very rare (<0.01% ), including individual messages. 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, episodes of cerebrovascular accident. From the hemopoietic system: sometimes – leukopenia. From the cardiovascular system: sometimes – a feeling of palpitations, tachycardia, thrombophlebitis of superficial and deep veins, increased blood pressure, coronary heart disease (angina pectoris, myocardial infarction, heart failure), rarely thromboembolism – pulmonary embolism, arterial thrombosis, stroke. From the respiratory system: sometimes – shortness of breath, cough. Dermatological reactions: often – alopecia, excessive sweating, skin rash (including erythematous, maculopapular rash, vesicular rash, psoriasis-like rash) sometimes – itching, dry skin, urticaria, very rarely – angioedema, anaphylactic reaction. From the musculoskeletal system: very often – arthralgia often – myalgia, bone pain, osteoporosis, bone fractures, sometimes arthritis. On the part of the sensory organs: sometimes – cataracts, eye irritation, blurred vision, impaired 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. From the side of metabolism: often – weight gain, hypercholesterolemia, anorexia, increased appetite, sometimes – weight loss, thirst. Other: very often – paroxysmal sensations of heat (hot flashes) often – increased fatigue, asthenia, malaise, sometimes peripheral edema – hyperthermia (pyrexia), dry mucous membranes, generalized edema, pain in the tumor foci. Drug Interaction No clinically relevant interaction was observed with the co-administration of Letrozole with cimetidine and warfarin. There is currently no clinical experience with the use of Letrozole in combination with other antitumor agents. According to in vitro studies, letrozole suppresses the activity of CYP2A6 and CYP2C19 isoenzymes (the latter being moderately). When deciding whether these data are relevant to the clinic, it should be borne in mind that the CYP2A6 isoenzyme does not play a significant role in drug metabolism. In vitro experimental studies have shown that letrozole at concentrations 100 times higher than plasma Css does not have the ability to significantly suppress the metabolism of diazepam (CYP2C19 isoenzyme substrate). Thus, a clinically relevant interaction due to the effect on CYP2C19 isoenzyme activity is unlikely. However, caution should be exercised when co-administering Letrozole and medicines metabolised predominantly with the participation of these isoenzymes and having a narrow therapeutic index. overdose There are some reports of letrozole overdoses. Treatment: symptomatic and supportive therapy is indicated. No specific treatment for overdose is known. Letrozole is excreted from the plasma by hemodialysis. Storage conditions Keep out of the reach of children, in a dry, dark place at a temperature not exceeding 25 ° C. Expiration 2 years. pharmacy terms for prescription Dosage form dosage form tablets Kern Pharma, Spain
