Letrozole

Brand Sinton Spain S.L.

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Available since: 2019-09-19

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Clinical Pharmacology

Antitumor drug, estrogen synthesis inhibitor. Letrozole has an anti-estrogenic effect, selectively inhibits aromatase (an estrogen synthesis enzyme) by highly specific competitive binding to the subunit of this enzyme - the heme of cytochrome P450. Blocks the synthesis of estrogen in both peripheral and tumor tissues.

In women in the postmenopausal period, estrogens are formed mainly with the participation of the aromatase enzyme, which turns 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 the blood plasma by 75-95% of the initial content. Suppression of estrogen synthesis is maintained throughout the entire period of treatment.

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 any impairment in the synthesis of aldosterone or cortisol. Additional administration of glucocorticoids and mineralocorticoids is not required.

The blockade of estrogen biosynthesis does not lead to the accumulation of androgens, which are precursors of estrogen.

While receiving Letrozole, there were no changes in the concentrations of LH and FSH in the blood plasma, changes in thyroid function, changes in the lipid profile, an increase in the incidence of myocardial infarction and stroke. During treatment with letrozole, the incidence of osteoporosis increases to a small extent (6.9% compared with 5.5% against 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 in early stages of breast cancer reduces the risk of recurrence, increases survival without signs of disease for 5 years, reduces the risk of developing secondary tumors.

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

Pharmacokinetics

Suction

After oral administration, letrozole is rapidly and completely absorbed from the digestive tract. Bioavailability averages 99.9%. Food intake slightly reduces the rate of absorption. Average t_max is 1 hour when taking letrozole on an empty stomach and 2 hours when taken with food; mean C_max 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, but the degree of absorption of letrozole (as measured by AUC) does not change.

Small changes in the rate of absorption are regarded as having no clinical significance, therefore Letrozole can be taken regardless of the meal.

Pharmacokinetics is nonlinear.

Distribution

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 plasma. Seeming v_d in equilibrium state is about 1.87 ± 0.47 l / kg. Css is achieved within 2-6 weeks of daily administration of the drug in a daily dose of 2.5 mg. Cumulation with prolonged use is not marked.

Metabolism

Letrozole is largely metabolized with the participation of CYP3A4 and CYP2A6 isoenzymes with the formation of a pharmacologically inactive carbinol compound.

Removal

Excreted mainly by the kidneys in the form of metabolites, to a lesser extent - through the intestines. Final t_1/2 is 48 hours

Pharmacokinetics in special clinical situations

The pharmacokinetic parameters of letrozole do not depend on the patient's age.

In renal failure, the pharmacokinetic parameters do not change.

In moderately severe liver dysfunction (Child-Pugh class 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 severely impaired function (class C on the Child-Pugh scale), the AUC increases by 95%, T_1/2 - 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

The early stages of breast cancer expressing estrogen receptors, in postmenopausal women, as an adjuvant therapy;
early stages of breast cancer in postmenopausal women after the 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 artificially induced) who received prior anti-estrogen therapy.

Letrozole is marketed under different brands and generic names, and comes in different dosage forms:

Brand name	Manufacturer	Country	Dosage form
Loreta	Sinton Spain S.L	Spain	pills
Estrolet	Native/Pharmstandard	Russia	pills
Letrozole	Kern Pharma	Spain	pills
Extra	Veropharm	Russia	pills
Femara	Novartis	Switzerland	pills

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Dosage and Administration

The drug is taken orally, regardless of the meal.

The recommended dose of Letrozole is 2.5 mg 1 time / day, daily, long-term (for 5 years or until relapse).

As extended adjuvant therapy, treatment should continue for 4 years (not longer than 5 years).

If there is evidence of disease progression, the administration of the drug Letrozole should be discontinued.

In patients with late-stage disease or a metastatic tumor, Lethrozole treatment should be continued until tumor progression is expressed.

Elderly patients do not require dose adjustment of the drug Letrozole.

At dysfunction of a liver or kidneys (KK> 10 ml / min.) dose adjustment is not required. However, in patients with severely impaired liver function (class C on the Child-Pugh scale), patients need constant medical supervision.

Adverse reactions

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

Determination of the frequency of adverse reactions:

very often (> 10%);
often (1-10%);
sometimes (0.1-1%);
rarely (0.01–0.1%);
very rarely (<0.01%), including individual messages.

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

From the nervous system: often - headache, dizziness, depression; sometimes - anxiety, nervousness, irritability, drowsiness, insomnia, memory impairment, dysesthesia, paresthesia, hypoesthesia, episodes of cerebral circulation.

From the hemopoietic system: sometimes leukopenia.

Since the cardiovascular system: sometimes - palpitations, tachycardia, superficial and deep vein thrombophlebitis, increased blood pressure, coronary artery disease (angina, myocardial infarction, heart failure), thromboembolism; rarely - pulmonary embolism, arterial thrombosis, stroke.

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

Dermatological reactions: often - alopecia, excessive sweating, skin rash (including erythematous, maculo-papular, vesicular rash, psoriasis-like rash); sometimes - itchy skin, dry skin, urticaria; very rarely - angioedema, anaphylactic reactions.

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

From the senses: sometimes - cataract, eye irritation, blurred vision, impaired taste.

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.

Metabolism: often - weight gain, hypercholesterolemia, anorexia, increased appetite; sometimes - weight loss, thirst.

Other: very often - hot flashes (hot flashes); often - increased fatigue, asthenia, malaise, peripheral edema; sometimes - hyperthermia (pyrexia), dry mucous membranes, generalized edema, pain in the tumor foci.

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Drug interactions

With simultaneous use of letrozole with cimetidine and warfarin, there is no clinically significant interaction.

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

According to the results of in vitro studies, letrozole suppresses the activity of CYP2A6 and CYP2C19 isoenzymes (the latter is moderate). When deciding on the significance of this data for the clinic, it is necessary to take into account that CYP2A6 isoenzyme does not play a significant role in drug metabolism. In experimental studies in vitro, it was shown that letrozole in concentrations 100 times higher than Css in plasma does not have the ability to significantly inhibit the metabolism of diazepam (substrate CYP2C19 isoenzyme). Thus, clinically significant interaction due to the effect on the activity of the CYP2C19 isoenzyme is unlikely. Nevertheless, caution should be exercised in the combined use of Letrozole and drugs that are metabolized mainly with the participation of these isoenzymes and have a narrow therapeutic index.

Pregnancy and Lactation

Contraindicated use during pregnancy and lactation (breastfeeding).

Special instructions

Patients with severely impaired liver function should be under constant supervision.

During therapy with Letrozole, taking into account the possibility of pregnancy, women in the perimenopausal and early postmenopausal period should use reliable methods of contraception until stable postmenopausal hormonal status is established.

Impact on the ability to drive vehicles and other mechanisms that require high concentration of attention

Some side effects of the drug, such as general weakness and dizziness, may affect the ability to perform potentially hazardous activities that require increased concentration and psychomotor speed. Therefore, patients should be careful when driving and working with mechanisms.

Overdosage

There are separate reports of cases of overdose of Letrozole.

Treatment: symptomatic and supportive therapy is indicated. No specific treatment for overdose is known. Letrozole is excreted from the plasma through hemodialysis.