Exemestane

Package leaflet (information for patients)

Tradename
Exemestane

Dosage form
Tablets 40 mg.

Description
Round, flat, beveled to the edge white tablets with an imprint in the form of the brand name "V" on one side.

Structure
Active ingredient: Exemestane 40 mg.
Excipients: microcrystalline cellulose 102, calcium stearate, aerosil ® 200 (hydrophilic pyrogenic silicon dioxide).

Pharmacotherapeutic group
Antiestrogens

Pharmacological properties
Pharmacodynamics. Exemestane is an irreversible steroidal aromatase inhibitor, similar in structure to the natural substance androstenedione. In postmenopausal women, estrogens are produced primarily by the conversion of androgens to estrogens under the action of the aromatase enzyme in peripheral tissues. Blocking estrogen production by inhibiting aromatase is an effective and selective treatment for hormone-dependent breast cancer in postmenopausal women. The mechanism of action of Exemestan- TL is due to the fact that it irreversibly binds to the active fragment of the enzyme, causing its inactivation. In postmenopausal women, exemestane significantly reduces the concentration of estrogens in the blood serum starting from a dose of 5 mg, and the maximum decrease (> 90%) is achieved with doses of 10-25 mg. In postmenopausal women with breast cancer who received 25 mg of the drug daily, the total level of the aromatase enzyme in the body decreased by 98%. Exemestane has no progestogenic and estrogenic activity. Only a slight androgenic activity is detected, mainly when using high doses. Exemestane has no effect on the biosynthesis of cortisol and aldosterone in the adrenal glands, which confirms the selectivity of the drug. In this regard, there is no need for replacement therapy with glucocorticoids and mineralocorticoids. When using the drug, even in low doses, there is a slight increase in the content of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in the blood serum, which probably develops according to the principle of feedback at the pituitary level: a decrease in estrogen concentration stimulates the secretion of gonadotropins in the pituitary gland also in postmenopausal women. Pharmacokinetics. After oral administration, exemestane is rapidly absorbed, mainly from the gastrointestinal tract. The absolute bioavailability of the drug has not been established. It is believed to be limited by the first pass effect through the liver. With a single dose of 25 mg, the maximum plasma concentration of the drug, equal to 17 mg / ml, is reached after two hours. Simultaneous food intake increases the bioavailability of the drug by 40%. Pharmacokinetic parameters are linear. The final half-life is approximately 24 hours. Plasma protein binding is approximately 90%. Exemestane and its metabolites do not bind to erythrocytes. With repeated intake of unpredictable cumulation of exemestane is not observed. The process of biotransformation of exemestane is carried out by oxidation of the methylene group in the 6th position under the action of the isoenzyme CYP3A4 and / or reduction of the 17-keto group under the action of aldoketo reductase, followed by conjugation. The metabolic products of exemestane are either inactive or less active in inhibiting aromatase than the parent compound. Approximately equal amounts of exemestane (about 40%) are excreted in urine and feces within a week. From 0.1 to 1.0% is excreted in the urine unchanged. A pronounced relationship between systemic exposure to the drug and age has not been established. In patients with severe renal impairment (creatinine clearance <30 ml / min), the systemic exposure of exemestane is twice as high, but dose adjustment is not required. In patients with moderate or severe hepatic impairment, the systemic exposure of exemestane is 2-3 times higher, however, dose adjustment is not required.

Indications for use
Widespread breast cancer in women in natural or induced postmenopausal women, including with the progression of the disease against the background of antiestrogen therapy, as well as with the progression of the disease after repeated use of various types of hormonal therapy. Adjuvant therapy for early breast cancer in postmenopausal women with estrogen-positive receptors or with unknown receptor status after completion of 2-3 years of initial adjuvant therapy with tamoxifen in order to reduce the risk of relapse (distant or regional), as well as contralateral breast cancer.

Method of administration and dosage
Adults and elderly patients. The recommended dose is 25 mg once a day, preferably after meals. In patients with early breast cancer, it is recommended to continue treatment with the drug until the total duration of consecutive adjuvant hormonal therapy reaches five years. Treatment of patients with advanced breast cancer is long-term. If signs of tumor progression or contralateral breast cancer appear, exemestane treatment should be discontinued. Hepatic or renal impairment: No dose adjustment is required. Children: Not recommended for use in children.

Side effects
Adverse effects distributed by system organ classes and frequency: very common (1/10); often (1/100, <1/10); infrequently (1/1000, <1/100); rarely (1/10 000, <1/1000); very rare (<1/10 000). Metabolic and eating disorders: often - anorexia. Disturbances from the gastrointestinal tract: very often - pain in the abdomen, nausea; often - vomiting, diarrhea, constipation, dyspepsia, increased appetite; infrequently - gastric ulcer (Most patients had a history of stomach ulcers or were receiving nonsteroidal anti-inflammatory drugs therapy). Mental disorders: very often - depression, insomnia. Nervous system disorders: very often - headache, dizziness; often - anxiety, confusion, carpal tunnel syndrome, paresthesia, hypesthesia, asthenia; infrequently - neuropathy. Heart disorders: often - heart failure; infrequently - myocardial infarction. Violations of the skin and subcutaneous tissues: very often - increased sweating; often - alopecia, rash, pruritus, dermatitis. Musculoskeletal and bone disorders: very often - joint and musculoskeletal pain (including arthralgia, pain in the extremities, back pain, arthritis, myalgia); often - fracture, osteoporosis. Violations of the organ of vision: often - visual impairment. Vascular disorders: very often - increased blood pressure, "hot flashes". Disorders from the liver and biliary tract: very often - an increase in the activity of hepatic enzymes, an increase in the concentration of bilirubin in the blood, an increase in the activity of alkaline phosphatase in the blood. Disturbances from the respiratory system, chest and mediastinal organs: often - shortness of breath, cough, bronchitis, sinusitis, pharyngitis, rhinitis, chest pain, upper respiratory tract infections. Kidney and urinary tract disorders: often - urinary tract infections. Disorders of the blood and lymphatic system: often - lymphedema. General disorders and disorders at the injection site: very often - pain, increased fatigue; often - peripheral edema, flu-like syndrome, fever, general weakness, infections. Approximately 20% of patients (especially those with initial lymphopenia) experienced a periodic decrease in the number of lymphocytes. However, the average number of lymphocytes in these patients did not change significantly over time, and no concomitant increase in the incidence of viral infections was observed. Post-marketing research. Immune system disorders: infrequently - hypersensitivity reactions. Liver and biliary tract disorders: rarely - hepatitis, cholestatic hepatitis. Skin and subcutaneous tissue disorders: often - urticaria; rarely - acute generalized exanthematous pustulosis.

Contraindication
Hypersensitivity to the active or any auxiliary substance of the drug; premenopausal endocrine status; pregnancy and lactation; children under 18 years of age. Use with caution in case of impaired liver or kidney function. The use of exemestane during pregnancy is prohibited due to the potential risk to the fetus. The drug should also not be administered during breastfeeding. The physician should warn women of premenopausal status or of childbearing age about the need for adequate contraception until the postmenopausal status is fully established.

Overdose
A single dose of the drug that could cause life-threatening symptoms has not been established. The use of exemestane in a single dose of up to 800 mg in healthy women and in a daily dose of up to 600 mg in postmenopausal women with advanced breast cancer was well tolerated. There are no specific antidotes. Treatment is symptomatic, under regular monitoring of vital functions and close supervision.

Precautions
Should not be prescribed to women with premenopausal endocrine status (the efficacy and safety of the drug in this group of patients has not been studied). No dose adjustment is required in patients with hepatic or renal impairment. Not recommended for use in children. During treatment, one should refrain from activities that require concentration of attention and speed of psychomotor reactions (when using the drug, symptoms such as drowsiness, asthenia and dizziness were noted).

Interaction with others and drugs
Exemestane is metabolized under the influence of the CYP3A4 isoenzyme of the cytochrome P450 system and aldoketoreductases and does not inhibit any of the main isoenzymes of the P450 system. Specific inhibition of the CYP3A4 isoenzyme by ketoconazole does not significantly affect the pharmacokinetics of exemestane. Interaction studies of exemestane at a dose of 25 mg with rifampicin at a dose of 600 mg daily showed a decrease in the area under the concentration-time curve (AUC) of exemestane by 54% and a decrease in the maximum concentration (Cmax) by 41%. The clinical significance of this interaction has not been studied. Combined use with anticonvulsants (phenytoin, carbamazepine), herbal preparations containing St. John's wort, rifampicin can reduce the effectiveness of exemestane. Exemestane should be used with caution with drugs that are metabolized by the CYP3A4 isoenzyme and have a narrow therapeutic index.

Special instructions
Exemestane should not be given to women with premenopausal endocrine status, therefore, in cases where this is clinically justified, postmenopausal status should be confirmed by determining the levels of LH, FSH and estradiol. Exemestane should not be administered concurrently with drugs containing estrogens. Due to the powerful estrogen - lowering effect of exemestane, a decrease in bone mineral density is possible. Prior to initiating adjuvant exemestane therapy, densitometry is recommended to assess bone mineral density in women with osteoporosis or an increased risk of osteoporosis. During treatment with exemestane, special monitoring of women with osteoporosis with the appointment of appropriate therapy is necessary. Due to the high prevalence of severe vitamin D deficiency in patients with early breast cancer, the concentration of vitamin D in blood plasma should be determined before starting therapy with an aromatase inhibitor. If vitamin D deficiency is detected, preparations containing this vitamin should be prescribed. Patients should be warned about the possibility of drowsiness, asthenia and dizziness during treatment with exemestane. When these symptoms occur, patients are advised to refrain from driving and engaging in other potentially hazardous activities that require increased concentration and psychomotor speed.

Pregnancy and elbowing
Etc. otivopokazano during pregnancy.
Category action tions on the fetus by FDA - D.
During treatment, breastfeeding should be discontinued.

Influence on the ability to drive vehicles and work with mechanisms
Does not affect.

Storage conditions
Store in a dry, dark place at a temperature not exceeding 25 ° C, out of the reach of children.

Shelf life
3 years. Do not use after the expiration date printed on the package.

Vacation conditions
On prescription.

Packaging
Exemestane Tablets. There are 25 tablets in a blister. 2 blisters are packed in a cardboard box together with an enclosed leaflet.