Letromara

Letromara is an antitumor drug; it contains the non-steroidal substance letrozole, which slows down the activity of aromatase (slowing down the processes of estrogen biosynthesis).

When tumor tissues grow depending on the amount of estrogens, the elimination of the stimulating effect associated with their activity is a prerequisite for suppressing tumor growth. In postmenopause, the formation of estrogens develops mainly with the help of the aromatase enzyme, which converts androgens synthesized by the adrenal glands (primarily testosterone with androstenedione) into estradiol with estrone. Because of this, specific inhibition of the aromatase enzyme allows suppressing estrogen biosynthesis within tumor and peripheral tissues. [ 1 ]

Indications Letromara

It is used in the following situations:

• adjuvant treatment of hormone-positive invasive breast carcinoma (early stage) in postmenopause (also for extended adjuvant treatment of the above-described disease in women who have received standard adjuvant use of tamoxifen for 5 years);
• first-line treatment for hormone-dependent breast carcinoma (of widespread nature) during postmenopause;
• therapy in case of widespread types of breast carcinoma in postmenopause (natural or artificially induced), in case of relapse or progression of the disease (with preliminary use of antiestrogens);
• neoadjuvant treatment during postmenopause for hormone-positive HER-2-negative breast carcinoma - in cases where chemotherapy is not suitable and emergency surgery is not required.

Release form

The drug is produced in tablet form - 10 pieces inside a cell plate. Inside the box - 3 such plates.

Pharmacodynamics

Letrozole inhibits the action of aromatase in competitive synthesis with a subunit of this enzyme, the heme of hemoprotein P 450; as a result, estrogen biosynthesis in all tissues is weakened.

In healthy postmenopausal women, a single dose of letrozole equal to 0.1, 0.5, or 2.5 mg reduces serum estrone and estradiol values (compared to baseline values) by 75-78% and 78%, respectively. The maximum reduction is observed after 48-78 hours. [ 2 ]

In a common form of breast carcinoma during postmenopause, daily administration of 0.1-0.5 mg of letrozole reduces the values of estrone with estradiol, as well as estrone sulfate in the blood plasma by 75-95% of the initial values. The introduction of doses of 0.5+ mg often leads to values of estrone with estrone sulfate that are below the lower limits of the sensitivity limit of the method used to detect hormones. This indicates that with the use of such doses, there is a more intense suppression of estrogen binding. Estrogen suppression is maintained during therapy in all women using the drug.

Pharmacokinetics

Absorption.

Letrozole is fully absorbed in the gastrointestinal tract at a high rate (average bioavailability is 99.9%). Food slightly reduces the absorption rate (the average period for reaching the blood level Tmax of letrozole is 60 minutes when administered on an empty stomach and 120 minutes when taken with food). The average blood Cmax of the substance is 129±20.3 nmol/l after administration on an empty stomach, and 98.7±18.6 nmol/l after administration with food. At the same time, the degree of absorption of the drug does not change.

Small variations in the rate of absorption are considered to be of no clinical significance, allowing letrozole to be taken without regard to food intake.

Distribution processes.

Protein synthesis of letrozole is approximately 60% (mostly with albumin (55%)). The substance levels inside red blood cells are approximately 80% of the plasma values.

When 2.5 mg of 14C-labeled letrozole is administered, about 82% of the radioactivity in the blood plasma is due to the unchanged active component. Because of this, the systemic effect of the metabolic elements of the substance is quite weak.

The drug is distributed extensively and rapidly within tissues. The estimated distribution volume at steady state concentrations is approximately 1.87±0.47 L/kg.

Metabolic processes and excretion.

A significant portion of letrozole is involved in metabolic processes with the formation of a non-medicinal carbinol metabolic element - this is the main mechanism of elimination.

The metabolic clearance of the drug is 2.1 l/hour, which is lower than the intrahepatic circulation (about 90 l/hour). It is noted that the transformation of the active substance into a metabolic component is realized with the help of isoenzymes CYP3A4 with CYP2A6 of hemoprotein P450. The formation of a small amount of other, not yet defined metabolic elements, and in addition, the excretion of unchanged substance with feces and urine have little effect on the overall elimination of Letromara.

The expected terminal half-life from blood plasma is approximately 2-4 days. With daily administration of 2.5 mg of the drug, its steady-state values appear over a period of 0.5-1.5 months (they are approximately seven times higher than the level observed with a single administration of a similar portion). In this case, the steady-state indicator is 1.5-2 times higher than those steady-state marks that were assumed by calculations based on the values observed after administration of a single portion of the drug. From this it can be concluded that with daily administration of the substance in a portion of 2.5 mg, its pharmacokinetic parameters become slightly nonlinear. Given that the steady-state level of the drug is maintained during therapy for a long time, it can be assumed that letrozole accumulation will not occur.

Linearity/nonlinearity indicators.

The pharmacokinetic properties of letrozole correspond to those after administration of a single oral dose of up to 10 mg (within portions of 0.01-30 mg), and also after daily doses of up to 1.0 mg (within the range of 0.1-5 mg).

Oral administration of a single 30 mg dose resulted in a slight but proportional increase in AUC. Daily doses of 2.5 and 5 mg resulted in approximately 3.8- and 12-fold increases in AUC (compared to 2.5- and 5-fold increases with daily administration of a 1.0 mg dose).

This allows us to conclude that the recommended daily dose of 2.5 mg may be a borderline dose, at which the disproportionality can be determined; however, in the case of using a daily dose of 5 mg, the disproportionality becomes more noticeable. The dosage disproportionality is most likely associated with the saturation of metabolic excretion processes.

Equilibrium values are observed after 1-2 months in the case of using any of the studied dosage regimens (in the range of 0.1-5.0 mg daily).

Dosing and administration

The drug should be taken in a daily dose of 2.5 mg. In the case of adjuvant (also extended) treatment, the therapeutic cycle should last 5 years or until the pathology relapses. In patients with metastases, treatment is continued until the symptoms of disease progression become noticeably pronounced. In adjuvant therapy, it is also necessary to consider options using a sequential treatment regimen (administration of letrozole for a period of 2 years, followed by a transition to 3-year use of tamoxifen).

In neoadjuvant therapy, the drug is administered for 4-8 months to optimally reduce the size of the tumor. If the response to treatment is poor, Letromara should be discontinued and a planned operation should be performed or options for subsequent therapy should be discussed with the patient.

Use in women with renal/hepatic dysfunction.

No dosage changes are required for individuals with mild to moderate liver impairment or renal impairment (creatinine clearance values greater than 10 ml per minute).

Experience with the use of drugs in patients with CC values <10 ml per minute or severe liver dysfunction is very limited. The condition of such patients should be closely monitored during therapy.

The medication is taken orally, regardless of food intake, since it does not change the degree of absorption of the drug.

The missed dose should be taken as soon as it is remembered. However, if this happened shortly before the use of a new dose (for example, 2-3 hours), the previous dose should be skipped, taking the new one according to the prescribed regimen. It is prohibited to take a double dose, because in the case of the introduction of a daily dose exceeding 2.5 mg, an excess of the proportional norm of total exposure was noted.

• Application for children

The drug is not prescribed in pediatrics, since there is no information regarding its effectiveness and therapeutic safety in this age group. The available information on use is very limited, which is why it is impossible to select dosage portions.

Use Letromara during pregnancy

Patients in perimenopause or of childbearing age.

Letrozole should only be used in women who have been reliably diagnosed as postmenopausal. There have been reports of spontaneous abortions or congenital malformations in newborns when letrozole was used during pregnancy.

Given the information regarding the reactivation of ovarian function with letrozole, even in patients with established postmenopause at the time of treatment initiation, the physician should, if necessary, advise the patient on reliable contraception.

Pregnancy.

Taking into account the experience of using the drug, which demonstrates individual situations with the appearance of congenital anomalies (external genitalia of an intermediate shape, as well as fusion of the lips), it can be stated that the drug can lead to congenital disorders if administered during pregnancy. Animal tests have demonstrated its reproductive toxicity. Therefore, the drug is not prescribed to pregnant women.

Breastfeeding period.

There is no information on whether letrozole with its metabolic components can be excreted in breast milk, so a risk to the child cannot be excluded. In this regard, Letromar is not used during breastfeeding.

Contraindications

Main contraindications:

• severe sensitivity to the active ingredient or other elements of the medication;
• endocrine status that corresponds to the premenopausal period;
• patients of childbearing age.

Side effects Letromara

Side effects include:

• Invasions and infections: urinary tract lesions;
• tumors, malignant or benign, as well as of an unknown type (including polyps and cysts): pain in the area of the tumor1;
• problems with blood and lymph function: leukopenia;
• immune disorders: anaphylactic reactions;
• disorders of nutritional regime and metabolic processes: anorexia, hypercholesterolemia and increased appetite;
• mental health problems: anxiety (also feeling nervous), depression and irritability;
• manifestations associated with NS: drowsiness, stroke, headaches, memory loss and taste disorders, as well as dizziness, insomnia, dysesthesia (including hypoesthesia with paresthesia) and carpal tunnel syndrome;
• visual impairment: irritation in the eye area, cataracts and blurred vision;
• disorders of the heart: tachycardia, palpitations1 and cases of myocardial ischemia (including worsening of angina or its development, ischemia and myocardial infarction, as well as angina requiring surgery);
• vascular system lesions: pulmonary embolism, hot flashes, thrombophlebitis (also affecting deep and superficial veins), increased blood pressure, cerebrovascular infarction and thrombosis in the arteries;
• problems of thoracic, respiratory and mediastinal nature: cough or dyspnea;
• gastrointestinal dysfunction: pain in the abdominal area, xerostomia, nausea, constipation, stomatitis1, vomiting, diarrhea and dyspepsia1;
• disorders of hepatobiliary function: hepatitis and increased liver enzyme levels;
• lesions of subcutaneous tissues and epidermis: itching, alopecia, TEN, hyperhidrosis, urticaria, epidermal dryness, rash (also maculopapular, erythematous, vesicular and psoriatic), Quincke's edema and erythema multiforme;
• problems with the functioning of connective tissues and musculoskeletal structure: osteoporosis, muscle pain, arthritis or arthralgia, bone fractures or pain in the bone area1 and stenosing ligamentitis;
• renal and urinary dysfunction: increased frequency of urination;
• symptoms related to the mammary glands and reproductive activity: vaginal discharge or bleeding and vaginal dryness, as well as pain in the mammary glands;
• systemic disorders: peripheral or generalized edema, thirst, increased fatigue (this includes malaise and asthenia), dryness in the mucous membranes and increased temperature;
• test results: weight gain or loss.

1exclusively in the case of therapy of metastatic lesions.

Overdose

There are isolated data on the development of poisoning with Letromara.

There is no specific treatment regimen for overdose. Symptomatic and supportive measures are taken.

Interactions with other drugs

The metabolism of the drug is partially mediated by CYP2A6 and CYP3A4. Therefore, the total excretion of letrozole may be affected by drugs that have an effect on the above enzymes. Apparently, the metabolism of letrozole has a low affinity for CYP3A4, because this enzyme is not saturated at values 150 times higher than the level of letrozole observed in the blood plasma at steady state in the case of a typical clinical picture.

Tamoxifen, as well as other antiestrogenic substances or drugs containing estrogen, are capable of neutralizing the therapeutic activity of letrozole. At the same time, it has been established that when combining the drug with tamoxifen, the plasma indices of the former are significantly reduced. It is necessary to refuse to use letrozole together with tamoxifen, estrogens or other estrogen antagonists.

Medicines that may increase serum letrozole levels.

Agents that inhibit the action of CYP3A4 with CYP2A6 can weaken the metabolism of letrozole, which increases its plasma values. Administration together with drugs that strongly inhibit the said enzymes (among the substances that strongly inhibit CYP3A4 are itraconazole and ritonavir with ketoconazole, telithromycin, voriconazole and clarithromycin; among the elements that act on CYP2A6 is methoxsalen) can increase the exposure of Letromar. For this reason, women using these drugs should use them with extreme caution.

Drugs that can reduce serum letrozole levels.

Substances that induce the effect of CYP3A4 can enhance the metabolic processes of drugs, which leads to a decrease in the plasma level of letrozole. Concomitant use with drugs that stimulate the action of CYP3A4 (including carbamazepine with phenytoin, phenobarbital and St. John's wort) can cause a decrease in the exposure of letrozole. For this reason, people using strong inducers of the CYP3A4 component should be very careful when combining them with Letromara. There is no data on which drugs induce CYP2A6 activity.

The use of 2.5 mg of the drug together with tamoxifen (20 mg once a day) caused an average decrease in the plasma letrozole level by 38%.

Clinical data from trials of second-line treatment for breast carcinoma indicate that the drug effects of letrozole and the incidence of adverse events were not increased when the drug was used immediately after tamoxifen. The mechanism of this interaction has not yet been determined.

Substances whose systemic and serum levels may be altered by letrozole exposure.

In vitro, the drug inhibits hemoprotein P 450 isoenzymes – elements of CYP2A6, as well as CYP2C19 (moderately), but the clinical significance of such a reaction is unknown. It is necessary to combine the drug very carefully with substances whose excretion depends on CYP2C19 activity, which also have a narrow drug range (including clopidogrel and phenytoin).

Storage conditions

Letromara should be stored in a place out of reach of small children. Temperature values are within the 25°C mark.

Shelf life

Letromara can be used for a period of 4 years from the date of sale of the therapeutic substance.

Analogues

Analogues of the drug are Letero, Femara with Araletom, Letrozole with Lesroy, Letrotera with Etrusil and Letoraip.