Exemplary

Exemesine is an inhibitor of enzymes, is included in the category of hormone antagonists, as well as similar drugs.

Indications Exemplary

It is shown as a means of adjuvant therapy in the early stages of breast cancer development (with an unspecified or positive test for estrogen receptors) in postmenopausal patients - to reduce the risk of contralateral, locoregional, and distant metastases.

As a first-line drug in the treatment of a common form of breast cancer (with a positive sample on hormone receptors) in women in the stage of induced or natural postmenopausal.

As second-line drugs in the treatment of a common form of breast cancer in women in the period of induced or natural postmenopause, which also showed a progression of the pathology after using monotherapy with anti-estrogens.

As a third-line agent in the treatment of a common form of breast cancer in postmenopausal women, who also showed the progression of the disease after polyhormonal treatment.

[1], [2], [3], [4], [5]

Release form

Produced in tablet form. One blister contains 10 tablets, in one package - 3 blister plates.

[6], [7], [8], [9]

Pharmacodynamics

Exemestane is a steroid-type aromatase inhibitor substance (irreversible form) that resembles the natural component of androstenedione. During postmenopause, estrogens in the female body are mainly produced by the conversion of androgens into them - under the influence of the aromatase enzyme inside the peripheral tissues.

The implementation of estrogen blocking due to aromatase suppression is an effective selective hormonal method for eliminating breast cancer that develops in postmenopausal women.

Oral administration of the medication at the postmenopausal stage largely reduces the estrogen levels inside the serum, already at a dosage of 5 mg. Peak suppression (> 90%) of the drug reached when using dosages of 10-25 mg. As a result of application of a daily dosage of 25 mg of the drug in patients with breast cancer, the total activity of the aromatase substance decreased by 98% during the postmenopause.

Exemestane does not have an estrogenic or progestogenic effect. A weak androgenic effect is most likely due to 17-hydro-derivatives, and is observed, mainly, when using drugs in large doses.

As a result of the study of the effect of the drug on the body with its long-term use, there was no significant effect of the adrenal glands on the process of the biosynthesis of aldosterone or cortisol. Their level was measured before or after taking a sample with ACTH - this demonstrates the selectivity of the drug relative to other enzymes involved in steroidogenic metabolism. This allows us to abandon HRT using mineralocorticoids and GCS.

A slight increase in the level of FSH, as well as LH inside the serum, was observed even with the administration of small dosages. But this effect is expected for this pharmacological category, and probably is a consequence of feedback on the pituitary level. It is caused by a decrease in the estrogenic level, as a result of which stimulation of gonadotropin release through the pituitary gland (during postmenopause, including) occurs.

[10], [11], [12]

Pharmacokinetics

After internal use of drugs, it is rapidly absorbed. Most of the dose is absorbed from the digestive tract. Bioavailability in humans is unknown, but there are suggestions that it is limited to a significant effect of the 1st passage inside the liver. In animals this indicator is equal to 5%.

When taking a single dose of the drug, the peak plasma concentration (18 ng / ml) reaches 2 hours later. It was found that taking with food accelerates absorption, and plasma index increases by 40% in comparison with the same level after fasting drug use on an empty stomach.

The distribution volume of drugs (without correction with respect to the oral bioavailability index) is 20,000 liters. Pharmacokinetics is linear, and the terminal half-life is 24 hours. Synthesis with a plasma protein is 90% regardless of the concentration of drugs. The active component, together with the decay products, is synthesized with erythrocytes.

The repeated use of exemestane does not lead to an unexpected accumulation of substance in the body.

The metabolism of the active substance is carried out in the process of oxidation of the methyl radical in the 6th position by means of isoenzyme CYP 3A4, or by reduction of the 17-keto group under the action of aldoketoreductase with subsequent conjugation. The coefficient of clearance of exemestane is about 500 l / h (without possible corrections with respect to oral bioavailability).

Concerning the inhibition of aromatase, decondition products of exemestane are either generally inactive or less active than the parent compound. The use of a single dose of a substance labeled with a 14C radionuclide showed that the excretion of the drug and its decay products mainly lasted about the 1st week. Dosage was excreted in equal parts (40% each) together with feces, as well as urine. Approximately 0.1-1% of the radioactive dosage was eliminated by unchanged (radioactively labeled substance) along with urine.

[13], [14], [15], [16]

Dosing and administration

The recommended daily dosage is 25 mg (1 tablet). Drink 1 time per day, preferably after eating.

In the early stage of breast cancer treatment should last until the end of 5-year sequential combination therapy with hormones (tamoxifen, and later - exemestane) or less - with the appearance of distant or local metastases, or contralateral neoplasm.

Patients with a common form of breast cancer should take the medicine until the progression of the cancerous tumor becomes noticeable.

For patients suffering from liver or kidney failure, dosage adjustment is not needed.

[26], [27], [28], [29]

Use Exemplary during pregnancy

There are no clinical data on the use of Exemesin in pregnant women. Animal studies have shown that the drug has reproductive toxicity, which is why its use during pregnancy is prohibited.

Contraindications

Among the contraindications: intolerance of the active component or auxiliary elements of drugs, but also the period of premenopause.

[17], [18], [19], [20], [21], [22], [23]

Side effects Exemplary

In general, the drug was well tolerated during clinical trials (use in the recommended daily dosage of 25 mg), and adverse reactions were generally mild or weak:

• metabolic and metabolic processes: anorexia often developed;
• mental disorders: mostly insomnia, also quite often the development of depression;
• organs of the National Assembly: often - headaches, quite often also - the appearance of dizziness or carpal tunnel syndrome, rarely - a feeling of drowsiness;
• organs of the cardiovascular system: hot flushes (very often);
• organs of the digestive system: nausea is most often observed, but abdominal pains, dyspeptic manifestations, diarrhea, constipation and vomiting can often develop;
• subcutaneous tissue and skin: very often sweating is increased, quite often also there is an alopecia and a rash on the skin;
• skeleton and bone system: very often pains in the muscles of the skeleton, as well as joints (the development of arthralgia and, more rarely, osteoarthritis, arthritis, muscle pains, limbs or back, and in addition a fetching sensation in the joints), often there are fractures or osteoporosis;
• systemic disorders: mainly there is the development of fatigue, less often - there are peripheral puffiness or pain, asthenia rarely develops.

[24], [25]

Overdose

Clinical studies have shown good tolerability of drugs after receiving a single dose of healthy volunteers to 800 mg, and after use by patients with a common form of breast cancer (during the menopause) dosages of up to 600 mg. The size of a single dose of the drug is not known, which can lead to the development of symptoms that are dangerous for health and life. Death in animals occurred after a single dose, in 2000 and 4000 times, respectively, exceeding the recommended value for a person (in terms of dose per mg / m ² ).

The medicine does not have a specific antidote, in case of an overdose, symptomatic therapy is necessary. Also, supportive measures are required - constant monitoring of the patient, as well as careful monitoring of all vital signs.

[30], [31], [32], [33], [34]

Interactions with other drugs

In vitro tests have shown that the metabolism of drugs is carried out with the help of hemoprotein 450 (CYP) 3A4, and also aldoketoreductase. The drug is not a blocker of any of the major isoenzymes of CYP. The specific inhibition of the element CYP 3A4 by the substance ketoconazole does not have a noticeable effect on the pharmacokinetic properties of Exemesin.

When studying the interaction with the substance rifampicin (a pronounced inhibitor of the CYP 450 element), it was found that its combination (in a daily dosage of 600 mg) with a single dose of Exemesin reduced the AUC level of the latter by 54% and the peak concentration index by 41%. It is believed that the combination with anticonvulsants (for example, carbamazepine or phenytoin) rifampicin, as well as herbal medicines containing St. John's wort (it induces the element CYP3A4) can reduce the effectiveness of the drug.

Exemestane should be carefully combined with drugs that have a small drug range, which also metabolize the element CYP3A4. There are data on the clinical experience of the combined use of Exemesin and other antitumor drugs.

The drug should not be combined with medications containing estrogens, since their combination causes a negative pharmacological effect.

[35], [36], [37]

Storage conditions

Contained under standard conditions for medications not available to young children. The temperature is a maximum of 25 ° C.

[38], [39], [40], [41],

Shelf life

Exemesin is suitable for use within 3 years from the date of manufacture of the medicine.

[42]