Exemestane has no progestogenic and estrogenic activity. Minor androgenic activity, probably associated with a 17-gidroderivativom, observed mainly in the application of the drug at high doses. Studies with long exemestane daily administration had no effect on synthesis of hormones such as cortisol and aldosterone levels are changed before and after the test with ACTH; selectivity has been demonstrated that relative to the other enzymes involved in hormone metabolism. In this regard, there is no need to appoint a replacement therapy of corticosteroids and mineralocorticoids. The slight increase in levels of luteinizing hormone and follicle-stimulating hormone in serum note even when applied at low doses of the drug. This effect, however, is expected for the formulations of this pharmacological group; probably it develops on the basis of feedback at the pituitary level: reduction of the concentration of estrogen stimulates the secretion of the pituitary gonadotropins (including in postmenopausal women).
Pharmacokinetics. Absorption . After receiving exemestane is rapidly absorbed. The aromasin for sale dose is absorbed from the gastrointestinal tract, high. Absolute bioavailability is not revealed, but should be limited to distribution of the first passage effect. For a single administration of a dose of 25 mg of the average level in blood plasma reaches its maximum after 2 hours and at 18 ng / ml. Simultaneous use of the drug with food increases its bioavailability is 40%.
Distribution. The volume of distribution of exemestane without correction on the oral bioavailability of 20 000 liters. Pharmacokinetics exemestane and is a linear finite time T ½ of 24 hours. Binding to plasma proteins is 90% and is independent of concentration. Exemestane and its metabolites bind to red blood cells. Exemestane is not accumulated by unforeseen after application of repeated doses.
Metabolism and excretion. Exemestane is metabolized by oxidation of the methylene group (6) with participation of CYP isoenzyme ZA4 and / or by reducing the 17-keto group with aldoketoreduktazy and further conjugation. Clearance exemestane is 500 l / h, without the correction with respect to oral bioavailability. With respect to inhibition of aromatase, or of these metabolites are inactive, or less active than the parent compound. The amount of drug in an unmodified form, excreted in the urine, is 1% of the dose. Equal volume (40%) exemestane, isotope-labeled 14 C, excreted in the urine and feces within a week.
Age . Significant correlation between the systemic exposure of the drug Aromasin and the age of the patient is not revealed.
Patients with impaired renal function and liver – see SPECIFIC NOTES..
Treatment of advanced breast cancer in women with natural or induced postmenopausal status, who have disease progression revealed after antiestrogen therapy. Not demonstrated efficacy in patients with negative test on estrogen receptors.
AROMASIN is recommended to take 25 mg 1 time a day, every day, preferably after meals.
In patients with breast cancer in the early stages of the treatment of Aromasin should continue until completion of 5 years of adjuvant hormonal therapy (continued therapy with Aromasin after tamoxifen) or to the recurrence of the tumor.
In patients with advanced breast cancer treatment AROMASIN should continue until such time until tumor progression is evident.
Patients with liver failure or kidney dose adjustment is required.
The frequency of discontinuation due to side effects was 7.4% in patients with breast cancer at an early stage, are treated AROMASIN after initial adjuvant tamoxifen therapy. The most common side effects were flushing (22%), arthralgia (18%) and fatigue (16%).
The frequency of discontinuation due to side effects was 2.8% in the general population of patients with advanced breast cancer. The most common side effects were flushing (14%) and nausea (12%).
Most of the side effects may be due to normal pharmacological effects of the blocking estrogen (e.g. hot flushes).
Below are the side-effects of various organs and body systems, grouped by frequency of occurrence (very often (> 10%), frequent (> 1% but ≤10%), rare (> 0.1% but ≤1%) rarely (> 0.01%, but the error ≤ 0.1%).
Violations of substances metabolism and metabolism: often – anorexia.
Violations of the psyche: very often – insomnia, depression.
Neurological disorders: very often – headache, dizziness; often – carpal tunnel syndrome, rarely – drowsiness.
Vascular disorders: very common – hot flushes.
disorders of the gastrointestinal tract: oche s often – nausea, stomach pain, often – vomiting, constipation, dyspepsia, diarrhea.
On the part of the hepatobiliary system : very often – increased liver enzymes, increased bilirubin, alkaline phosphatase in the blood.
The disorder of the skin and subcutaneous tissue: very often – increased sweating, often – rash, alopecia.
disorders from musculoskeletal system: very often – pain in joints and muscles (arthralgia, to a lesser extent – pain in limbs, back, osteoarthritis, arthritis, myalgia, stiffness in the joints), often – osteoporosis, fracture s.
General disorders: often – fatigue; often – peripheral edema, rarely – fatigue.
From the blood system and lymphatic system: patients with advanced breast cancer are rarely reported thrombocytopenia and leukopenia.
Episodes of reducing the number of lymphocytes observed in approximately 20% of patients treated with Aromasin, particularly in patients with pre-existing lymphopenia, but the average number of lymphocytes over a prolonged period in these patients were not significantly changed; also reported no increase in the incidence of viral infections. These effects were not detected in patients with breast cancer in the early stages.
In the study, the initial stage of breast cancer incidence of cardiac ischemic complications in the treatment groups exemestane and tamoxifen was 4.5 and 4.2%, respectively. Significant differences were found for any of the individual cardiovascular complications, including arterial hypertension (9.9% compared with 8.4%), myocardial infarction (0.6% compared with 0.2%) and cardiac failure (1.1% compared with 0.7%). There have also been vaginal hemorrhage (4% compared with 5.3%), cancer of other organs at an early stage (3.6% compared with 5.3%), thromboembolism (0.7% compared to 0.8% ).
Exemestane was associated with high incidence of hypercholesterolemia compared with tamoxifen (3.7% compared with 2.1%).
In the study, the initial stage of breast cancer of the stomach ulcer was observed a slightly higher frequency in the band exemestane compared to tamoxifen (0.7% compared to <0.1%). The majority of patients with stomach ulcer simultaneously with exemestane therapy received concomitant treatment with NSAIDs and / or had a history of ulcer.
Immune system : Infrequent – increased sensitivity.
From the nervous system : often – paresthesia.
On the part of the hepatobiliary system : rarely – hepatitis, cholestatic hepatitis.
Skin and subcutaneous tissue : often – urticaria, pruritus; rarely – acute generalized exanthematous pustulosis.
Given the mechanism of action, Aromasin should not be administered to women with premenopausal endocrine status. Therefore within acceptable clinical cases postmenopausal must install status by evaluating the levels of LH, FSH and estradiol.
Given that Aromasin is a drug that greatly reduces the level of estrogen, you can expect a decrease in bone mineral density. During adjuvant drug therapy in patients with osteoporosis or at risk of its occurrence, at the beginning of treatment should be to evaluate the parameters of bone mineral density by densitometry. Patients receiving AROMASIN should be supervised, they should appoint a treatment for osteoporosis, if necessary.
AROMASIN Tablets contain sucrose and should not be administered to patients with rare congenital defects of metabolism of fructose, glucose and galactose malabsorption or sucrose isomaltase deficiency.
Tablets contain AROMASIN metilparagidrooksibenzoat which can cause allergic reactions (possibly delayed).
Patients with renal insufficiency . Patients with severe renal impairment (CLsr <30 ml / min) exemestane exposure level was twice as high as compared with healthy volunteers. No dose adjustment is required.
Patients with hepatic insufficiency . Patients with liver disease moderate or severe exemestane exposure levels 2-3 times higher as compared with healthy volunteers. No dose adjustment is required.
Use during pregnancy and lactation:
Pregnancy. Animal studies showed reproductive toxicity, so Aromazin is contraindicated for use in pregnant women.
Lactation. Aromazin also not be used in women during lactation.
Women in the perimenopausal period, or of childbearing age. With women who have the potential to become pregnant, your doctor should discuss the need for appropriate contraception, the same applies to women who are perimenopausal or have recently moved into the postmenopausal, until their postmenopausal status will not be fully understood.
Children. The drug is not recommended for use in children.
Ability to influence the reaction rate when driving or operating other machines. During the drug reported drowsiness, somnolence, asthenia and dizziness, so patients should refrain from driving vehicles or working with other mechanisms.
Although pharmacokinetic studies of interaction with rifampicin, a potent inhibitor of CYP 3A4, observed pharmacokinetic effects, pharmacological activity of the drug (i.e., inhibition of estrogen) was not broken and correction dose is not required.
Aromazin not applicable to medicinal preparations containing estrogen, because while the application they have negative pharmacological effects.