Letromara

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

With the growth of neoplasm tissues, depending on the amount of estrogens, the elimination of the stimulating effect associated with their activity is a precondition for suppressing tumor growth. In postmenopausal women, 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, a specific slowdown of the aromatase enzyme allows you to suppress estrogenic biosynthesis inside tumor, and also peripheral tissues. [1]

Indications Letromara

It is used in such situations:

• adjuvant treatment of hormone-positive invasive breast carcinoma (at an early stage) in postmenopausal women (also for extended adjuvant treatment of the above-described disease in women who have undergone standard adjuvant use of tamoxifen for 5 years);
• 1st-line treatment for hormone - dependent breast carcinoma (common) during postmenopause;
• therapy in the case of common types of breast carcinoma in postmenopausal women (natural or artificially induced), in case of relapse or progression of the disease (with prior use of antiestrogens);
• neoadjuvant treatment for postmenopausal hormone-positive HER-2-negative breast carcinoma - in cases where chemotherapy is not suitable and urgent surgery is not required.

Release form

The drug is produced in tablet form - 10 pieces inside the cell plate. There are 3 such records inside the box.

Pharmacodynamics

Letrozole inhibits the effect of aromatase during competitive synthesis with a subunit of the specified enzyme - heme of hemoprotein P 450; as a result, estrogenic biosynthesis within all tissues is weakened.

In healthy postmenopausal women, 1-fold portion of letrozole, equal to 0.1, 0.5, or 2.5 mg, reduces the serum values of estrone with estradiol (when compared with the initial numbers), respectively, by 75-78%, and also 78%. The maximum decrease is noted after 48-78 hours. [2]

With a common type of breast carcinoma during postmenopause, daily intake of 0.1-0.5 mg letrozole reduces the values of estrone with estradiol, as well as estrone sulfate inside the blood plasma by 75-95% of the starting values. The administration of dosages of 0.5+ mg often leads to rates of estrone with estrone sulfate, which are outside the lower limits of the sensitivity of the method used to detect hormones. This shows that when using such portions, there is a more intense suppression of estrogen binding. Estrogen suppression during therapy is supported in all women using the drug.

Pharmacokinetics

Absorption.

Letrozole is fully absorbed inside the gastrointestinal tract at high speed (average bioavailability is 99.9%). Food weakly reduces the rate of absorption (the average period of reaching the blood level Tmax of letrozole is 60 minutes when administered on an empty stomach and 120 minutes when consumed with food). The average values of the blood substance Cmax are 129 ± 20.3 nmol / l after administration on an empty stomach, as well as 98.7 ± 18.6 nmol / l after administration with food. In this case, the degree of absorption of drugs does not change.

Slight fluctuations in the rate of absorption are considered to be of no clinical significance, which allows letrozole to be taken without reference to food intake.

Distribution processes.

The protein synthesis of letrozole is approximately 60% (most of it is with albumin (55%)). Indicators of the substance inside the erythrocytes are about 80% of the plasma values.

With the introduction of 2.5 mg of letrozole, marked with 14C, about 82% of the radioactivity inside the blood plasma belongs to the unchanged active ingredient. Because of this, the systemic effect of the metabolic elements of the substance is rather weak.

The medicine is extensive and is distributed at high speed within the tissues. The assumed indicators of the distribution volume at equilibrium concentrations are approximately 1.87 ± 0.47 l / kg.

Metabolic processes and excretion.

A significant part 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 indicators of the exchange clearance of the drug are 2.1 l / h, which is lower than the values of the intrahepatic circulation (about 90 l / h). It is noted that the transformation of the active substance into the 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 to this, the excretion of unchanged substances with feces and urine has little effect on the total elimination of Letromara.

The estimated terminal half-life from blood plasma is approximately 2-4 days. With daily administration of 2.5 mg of drugs, its equilibrium values appear over a period of 0.5-1.5 months (they are approximately seven times higher than the level observed with 1-time use of a similar portion). At the same time, the equilibrium indicator is 1.5-2 times higher than those equilibrium marks that were assumed by calculations based on the values noted after the introduction of 1-fold portion of the drug. From this it can be inferred that with daily use of the substance in a 2.5 mg portion, its pharmacokinetic parameters become slightly non-linear. Given that the equilibrium drug level is maintained during therapy for a long time, it can be assumed that the cumulation of letrozole will not occur.

Linearity / nonlinearity indicators.

The pharmacokinetic properties of letrozole correspond to those after the introduction of a 1-fold oral dosage up to 10 mg (within 0.01-30 mg portions), and in addition, after daily portions up to 1.0 mg (within 0.1-5 mg).

Oral administration of a 1-fold portion of 30 mg resulted in a slight but proportional increase in the AUC level. The use of daily dosages of 2.5 and 5 mg causes an increase in the AUC indicator by about 3.8, as well as 12 times (for comparison, when a 1.0 mg portion was administered per day, these values were 2.5 and 5 times).

This allows us to conclude that the recommended daily portion of 2.5 mg may be borderline, with the introduction of which disproportion can be determined; in the case of using a daily dosage of 5 mg, the disproportion becomes more noticeable. Dosage disproportion is most likely associated with 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 medication should be taken in a daily dosage of 2.5 mg. In the case of adjuvant (also extended) treatment, the therapeutic cycle should continue for 5 years or until the onset of a relapse of the pathology. For people with metastases, treatment continues until the symptoms of disease progression become noticeable. In adjuvant therapy, it is also necessary to consider options using a sequential treatment regimen (administration of letrozole over a period of 2 years, followed by a transition to 3-year use of tamoxifen).

With neoadjuvant therapy, the administration of the drug continues for a period of 4-8 months - to optimally reduce the size of the neoplasm. In case of a poor response to treatment, the reception of Letromara should be canceled and a planned operation should be performed or the options for subsequent therapy should be discussed with the patient.

Use in women with renal / hepatic dysfunction.

Persons with mild or moderate hepatic impairment or renal impairment (CC values greater than 10 ml per minute) do not need dosage changes.

Experience with the use of drugs in people with CC values <10 ml per minute or severe hepatic dysfunction is very limited. It is necessary to carefully monitor the condition of such patients during therapy.

The medication is used orally, without reference to food intake, because it does not change the degree of absorption of the drug.

The missed portion must be taken immediately after it is remembered. But if this happened shortly before applying a new dosage (for example, 2-3 hours), the previous portion should be skipped, taking a new one according to the prescribed regimen. It is forbidden to use a double dosage, because in the case of a daily dose exceeding 2.5 mg, a total exposure exceeding the proportional norm was noted.

• Application for children

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

Use Letromara during pregnancy

Patients with perimenopause or childbearing age.

Letromar can only be used in women whose postmenopause has been reliably diagnosed. There is information about cases of spontaneous abortions or congenital malformations in newborns when using letrozole during pregnancy.

Taking into account the information regarding the renewal of ovarian activity when using letrozole, even with established postmenopause at the time of the start of treatment, the doctor, if necessary, needs to consult the patient about reliable contraception.

Pregnancy.

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

Breastfeeding period.

There is no information as to whether letrozole, with its metabolic elements, can be excreted in breast milk, so a risk to the baby cannot be excluded. In this regard, Letromar is not used for HS.

Contraindications

The main contraindications:

• severe sensitivity to the active ingredient or other elements of the drug;
• endocrine status, which corresponds to the premenopausal period;
• patients who are of childbearing age.

Side effects Letromara

Among the side signs:

• invasions and infections: lesions of the urinary tract;
• tumors, malignant or benign, as well as of an unknown type (including polyps and cysts): pain in the area of the tumor1;
• problems with the function of blood and lymph: leukopenia;
• immune disorders: anaphylactic manifestations;
• disorders of the nutritional regime and metabolic processes: anorexia, hypercholesterolemia and increased appetite;
• mental problems: anxiety (also a feeling of nervousness), depression and irritability;
• manifestations associated with NS: drowsiness, stroke, headaches, memory impairment and taste disturbances, as well as dizziness, insomnia, dysesthesia (this includes hypesthesia with paresthesia) and carpal tunnel syndrome;
• visual impairment: irritation in the eye area, cataracts and blurred vision;
• disorders in the work of the heart: tachycardia, palpitations1 and cases of myocardial ischemia (among these are worsening of the course of angina pectoris or its development, ischemia and myocardial infarction, as well as angina pectoris, which requires surgery);
• lesions of the vascular system: pulmonary embolism, hot flashes, thrombophlebitis (also affecting deep and superficial veins), increased blood pressure, cerebrovascular type infarction and thrombosis in the arterial region;
• problems of a thoracic, respiratory and mediastinal nature: cough or dyspnea;
• dysfunction of the gastrointestinal tract: pain in the abdominal area, xerostomia, nausea, constipation, stomatitis1, vomiting, diarrhea and dyspepsia1;
• disorders of hepatobiliary activity: hepatitis and an increase in liver enzymes;
• 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 region1 and stenosing ligamentitis;
• impaired renal and urinary function: increased urination;
• symptoms associated with the breasts and reproductive activity: discharge or bleeding from the vagina and vaginal dryness, as well as pain in the breast area;
• systemic disorders: peripheral or generalized edema, thirst, increased fatigue (this includes malaise and asthenia), dryness in the mucous membranes and an increase in temperature;
• test indications: increase or decrease in weight.

 1 exclusively in the case of the treatment of metastatic lesions.

Overdose

There are sporadic data on the development of Letromara poisoning.

There is no specific treatment regimen for overdose. Symptomatic and supportive actions are performed.

Interactions with other drugs

The metabolic processes of the drug are partially realized with the help of CYP2A6 elements with CYP3A4. Therefore, the total excretion of letrozole can be affected by medications that have an effect on the above enzymes. Obviously, the metabolic processes of letrozole have a low affinity for CYP3A4, because this enzyme does not undergo saturation at values 150 times higher than the level of letrozole observed inside the blood plasma at equilibrium in the case of a typical clinical picture.

Tamoxifen, as well as other antiestrogenic substances or drugs containing estrogen, are able to neutralize the therapeutic activity of letrozole. At the same time, it was found that when the drug is combined with tamoxifen, the plasma parameters of the former are significantly reduced. It is necessary to stop using letrozole together with tamoxifen, estrogens or other estrogenic antagonists.

Medicines that can increase the serum levels of letrozole.

Drugs that slow down the action of CYP3A4 with CYP2A6 are able to weaken the metabolic processes of letrozole, which increases its plasma values. Administration together with drugs that strongly suppress these enzymes (among substances that strongly inhibit CYP3A4, itraconazole and ritonavir with ketoconazole, telithromycin, voriconazole and clarithromycin; among the elements acting against CYP2A6, methoxalen) may increase the exposure of Letromara. Because of this, women using these drugs need to use them with extreme caution.

Drugs that can reduce serum letrozole levels.

Substances inducing the effect of CYP3A4 are capable of enhancing 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 (this includes carbamazepine with phenytoin, phenobarbital, and St. John's wort) may cause a decrease in letrozole exposure. Because of this, persons using strong inducers of the CYP3A4 component must be very careful when combining them with Letromara. There is no data on which agents induce CYP2A6 activity.

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

Clinical evidence obtained from testing the treatment of 2nd line breast carcinoma demonstrates that the drug effect from the use of letrozole, as well as the incidence of negative signs, did not increase when the drug was used immediately after tamoxifen. It has not yet been possible to determine the mechanism of the described interaction.

Substances whose systemic intra-serum values may change due to exposure to letrozole.

In vitro, the drug suppresses the isoenzymes of hemoprotein P 450 - elements of CYP2A6, as well as CYP2C19 (moderately), but the clinical significance of this reaction is not known. It is necessary to very carefully combine the drug with substances whose excretion depends on the activity of CYP2C19, which also have a narrow drug range (among them clopidogrel and phenytoin).

Storage conditions

Letromara should be kept out of the reach of small children. Temperature values are within the 25 ° C mark.

Shelf life

Letromara can be used for a 4-year term from the moment the therapeutic substance is marketed.

Analogs

Analogs of the drug are Letero, Femara with Aralet, Letrozole with Lezra, Letrotera with Etruzil and Letorayp.