Pharmacological properties of the drug Aromasin
Antineoplastic agent, irreversible steroidal aromatase inhibitor, similar in chemical structure to natural androstenedione. In postmenopausal women, estrogens are produced primarily by the conversion of androgens to estrogens by the enzyme aromatase in peripheral tissues. Blocking estrogen production by aromatase inhibition is an effective and selective treatment for hormone-dependent breast cancer in postmenopausal women. In postmenopausal women, exemestane significantly reduces the concentration of estrogen in the blood serum, starting with a dose of 5 mg; the maximum reduction (90%) is achieved when used at a dose of 10–25 mg. In postmenopausal patients with breast cancer who received the drug at a dose of 25 mg/day, the level of aromatase activity decreased by 98%. Exemestane does not have progestogenic or estrogenic activity. Minor androgenic activity, probably associated with the 17-hydro derivative, was noted mainly when using the drug in high doses. In studies with long-term daily dosing, exemestane did not affect the synthesis of hormones such as cortisol and aldosterone, the level of which changed before or after the ACTH test, which confirms the selectivity of the drug. In this regard, there is no need to prescribe replacement therapy with GCS and mineralocorticoids. A slight increase in the levels of LH and FSH in the blood serum is noted even when using the drug in low doses. This effect, however, is expected for drugs of this pharmacological group; it probably develops according to the feedback principle: a decrease in the concentration of estrogen in the blood stimulates the secretion of gonadotropins in the pituitary gland, including in postmenopausal women. After oral administration, exemestane is rapidly absorbed. The percentage of absorption in the gastrointestinal tract is high. Absolute bioavailability has not been established, although distribution of the drug may be limited by the first pass effect. With a single dose of 25 mg after meals, the average level in blood plasma is reached after 2 hours and averages 17 ng/ml. The pharmacokinetics of exemestane is linear and does not depend on time; no accumulation has been detected with long-term use. The final half-life of the drug is about 24 hours. It has been established that taking it with food improves the absorption of the drug: the level in the blood plasma is 40% higher than in patients who took the drug on an empty stomach. The volume of distribution of exemestane is large. The binding of the drug to plasma proteins is about 90%; in this case, the degree of binding does not depend on the total concentration. Exemestane and its metabolites do not bind to red blood cells. Exemestane is metabolized by oxidation of the methylene group (6) with the participation of the CYP 3A4 isoenzyme and/or by reduction of the 17-keto group with the participation of aldokereductase and further conjugation. The clearance of exemestane is 500 l/h. With respect to aromatase inhibition, these metabolites are either inactive or less active than the parent compound. After a single oral dose of radiolabeled exemestane C, it was found that elimination of the drug and its metabolites was largely completed within a week, with equal parts of the dose excreted in urine and feces (40%). About 0.1–1% of the dose was excreted in the urine as unchanged radiolabeled exemestane. There was no significant correlation between systemic exemestane exposure and age. In patients with deteriorating renal function (creatinine clearance less than 30 ml/min), systemic exposure to exemestane was twice as high as in healthy volunteers. Given the safety data for exemestane, no dose adjustment is required. In patients with moderate to severe hepatic impairment, systemic exposure to exemestane was two to three times higher than in healthy volunteers. Given the safety data for exemestane, no dose adjustment is required.
Aromasin, 30 pcs., 25 mg, film-coated tablets
INSTRUCTIONS for use
APPROVED by the FC Ministry of Health of the Russian Federation 03/16/2000, pr. No. 1b
Description.
Round, biconvex tablets, white with a slightly grayish tint, sugar-coated, about 6 mm in diameter, inscribed with the number 7663 in black printing ink on one side.
Compound.
Each tablet contains:
active substance:
exemestane 25 mg;
Excipients:
mannitol, hypromellose, polysorbate 80, crospovidone, silicon dioxide, colloidal, hydrated, MCC, sodium starch glycolic acid, magnesium stearate; shell: hypromellose, simethicone, macrogol 6000, sucrose, magnesium carbonate, titanium dioxide, methyl n-hydroxybenzoate, polyvinyl alcohol.
Pharmacological properties.
Aromasin is an irreversible steroidal aromatase inhibitor, similar in structure to the natural substance androstenedione.
Pharmacodynamics.
In postmenopausal women, estrogens are produced primarily by the conversion of androgens to estrogens by the enzyme aromatase in peripheral tissues. Blocking estrogen production by aromatase inhibition is an effective and selective treatment for hormone-dependent breast cancer in postmenopausal women. The mechanism of action of the drug Aromasin is due to the fact that it irreversibly binds to the active fragment of the enzyme, causing its inactivation. In postmenopausal women, Aromasin significantly reduces the concentration of estrogen in the serum, already starting with a dose of 5 mg; maximum reduction (>90%) is achieved at a dose of 10–25 mg. In postmenopausal patients diagnosed with breast cancer who received 25 mg of the drug daily, the total level of the aromatase enzyme in the body decreased by 98%.
Aromasin does not have progestogenic or estrogenic activity. Only minor androgenic activity is detected, mainly when using high doses. In tests with repeated doses throughout the day, Aromasin had no effect on the biosynthesis of cortisol and aldosterone in the adrenal glands, which confirms the selectivity of the action of this drug.
In this regard, there is no need for replacement therapy with glucocorticoids and mineralocorticoids. Slight increases in serum LH and FSH levels are observed even at low doses; this effect, however, is expected for drugs of this pharmacological group; it probably develops according to the feedback principle at the level of the pituitary gland: a decrease in the concentration of estrogen stimulates the secretion of gonadotropins in the pituitary gland also in postmenopausal women.
Pharmacokinetics.
Suction.
After oral administration, Aromasin is rapidly and extensively absorbed. With a single dose of 25 mg after a meal, the average maximum plasma level of 18 ng/ml is achieved within 2 hours. It has been established that food improves absorption, the plasma level achieved is 40% higher than in patients taking drug on an empty stomach.
Distribution.
After reaching a maximum, the plasma level of Aromasin decreases, with a final T1/2 of approximately 24 hours. Aromasin is widely distributed in tissues, as indicated by a large volume of distribution. The binding of the drug Aromasin to plasma proteins is approximately 90%, and the degree of binding does not depend on the total concentration.
Metabolism and excretion.
After repeated doses of 25 mg/day, plasma concentrations of unchanged drug were similar to those measured after a single dose. After oral administration of a single dose of the radiolabeled drug Aromasin, it was found that the elimination of the drug and its metabolites was largely completed within 1 week, with approximately equal parts of the dose being excreted in the urine and feces. The amount of drug excreted unchanged in the urine is less than 1% of the administered dose. Aromasin is characterized by high clearance, mainly due to metabolism. The biotransformation process is carried out by oxidation of the methylene group at position 6 with the participation of the CYP 3A4 isoenzyme and/or by reduction of the 17-keto group with the participation of aldokereductases. As a result, numerous secondary metabolites are formed, but the amount of each of them is very small compared to the administered dose. With respect to aromatase inhibition, these metabolites are either inactive or less active than the parent compound.
Indications for use.
Aromasin is indicated for the treatment of advanced breast cancer in women in natural or induced postmenopause in whom disease progression has been detected during anti-estrogen therapy.
Aromasin is also indicated as third-line hormonal therapy for advanced breast cancer in women in natural or induced postmenopause whose disease has progressed on anti-estrogen therapy, as well as therapy with either non-steroidal aromatase inhibitors or progestins.
Dosage and method of application.
Adults and elderly patients
are recommended to take Aromasin 25 mg daily, 1 time per day, preferably after meals. Treatment should be continued until signs of tumor progression appear.
In patients with hepatic or renal insufficiency, no dose adjustment is required.
Children.
Not recommended for use in children.
Side effect.
During clinical trials of the drug Aromasin, side effects were observed to be minor or moderate. The most common side effects, both drug-related and unspecified, were hot flushes, nausea, fatigue, sweating, and dizziness. Less frequently observed were headache, insomnia, skin rash, abdominal pain, anorexia, depression, alopecia, peripheral edema (swelling of the feet, legs), constipation or dyspepsia.
Episodes of decreased lymphocyte levels were observed in approximately 20% of patients receiving Aromasin, especially in patients with baseline lymphopenia; however, the average level of lymphocytes did not change significantly in these patients over a fairly long period of time, and there was no concomitant increase in the incidence of viral infections.
Thrombocytopenia and leukopenia have also been detected in rare cases.
Increases in serum liver function tests as well as increases in alkaline phosphatase levels have been reported occasionally. Such an increase in enzyme levels was observed mainly in patients with metastases to the liver and bones, as well as in the presence of other liver lesions. These changes may or may not be related to the drug Aromasin.
Contraindications.
Aromasin is contraindicated in patients with hypersensitivity to the drug or any of the excipients, as well as during pregnancy and while breastfeeding a child.
Interactions with other drugs and other forms of interactions.
Preparations containing estrogens, when used simultaneously with Aromasin, completely neutralize the pharmacological effect of the latter.
To date, there have been no studies of interactions with other drugs. In vitro results
showed that this drug is metabolized by cytochrome P450 (CYP) 3A4 and aldokereductases, and does not inhibit any of the major CYP isoenzymes. During a clinical pharmacokinetic study, it was found that specific inhibition of CYP 3A4 by ketoconazole does not have a significant effect on the pharmacokinetics of Aromasin. However, a possible decrease in the concentration of the drug Aromasin in plasma cannot be excluded under the influence of substances known as inducers of CYP 3A4.
Overdose.
Data on the use of Aromasin in single doses of 600–800 mg indicate good tolerability of these doses. A single dose of Aromasin that can cause life-threatening symptoms has not been established. There are no specific antidotes for overdose; symptomatic treatment should be carried out. General supportive therapy is indicated, as well as regular monitoring of vital functions and careful monitoring.
Special warnings and precautions for use.
Aromasin should not be prescribed to women with premenopausal endocrine status, since the effectiveness and safety of the drug in this group of patients have not been assessed. Therefore, in cases where it is clinically justified, postmenopausal status should be confirmed by determining the levels of LH, FSH and estradiol.
It is unlikely that Aromasin impairs the ability of patients to drive a car or operate moving or precision machinery. However, when using this drug, symptoms such as drowsiness, asthenia and dizziness were observed. Patients should be warned that when these phenomena occur, their physical and/or mental capabilities necessary for work requiring special attention and quick reactions may be impaired.
Release form.
Tablets of 25 mg, sugar-coated, in blister packs of 15 pcs., in a cardboard box 1, 2 or 6 packs.
Storage conditions.
Store at a temperature not exceeding 30 °C, out of the reach of children.
Best before date.
3 years.
Conditions for dispensing from pharmacies.
Dispensed with a doctor's prescription.
Manufacturer.
Pharmacia & Upjohn, Italy.
Indications for use of the drug Aromasin
Adjuvant therapy for early-stage breast cancer with a positive or unspecified test for estrogen receptors in postmenopausal women to reduce the risk of developing distant, local regional or contralateral metastases. As a first-line drug for the treatment of advanced hormone receptor-positive breast cancer in women with natural or induced postmenopausal status. As a second-line drug for the treatment of advanced breast cancer in women with natural or induced postmenopausal status in whom disease progression has been detected during antiestrogens monotherapy. As a third-line drug for the treatment of advanced breast cancer in postmenopausal women whose disease has progressed during polyhormonal therapy.
Aromasin
Answers to frequently asked questions. This document is not a substitute for instructions for the drug. The drug cannot be prescribed independently. This drug is prescribed only by a doctor.
What is aromasin?
Aromasin (exemestane) is a drug for hormone therapy for breast cancer from the group of aromatase inhibitors.
What is aromatase and how does aromasin work?
Aromatase is an enzyme that synthesizes female sex hormones in women after the end of the menstrual cycle (menopause). It is known that after the end of the menstrual cycle, female sex hormones, although in smaller quantities, are produced in the adrenal glands and tissues. Synthesis occurs due to the enzyme aromatase.
Why is it necessary to reduce estrogen levels during hormone therapy?
It is known that estrogens are stimulants for the growth of tumor cells, so the goal of hormone therapy is to reduce estrogen levels (in women before menopause, ovarian function is switched off using Zoladex).
Are all tumors sensitive to hormone therapy?
No. Sensitive to hormone therapy are tumors on the surface of which there are receptors for estrogen and progesterone (protein substances). The sensitivity of a tumor to hormone therapy can be determined using an analysis (immunohistochemical study).
Indications for the use of aromazin
- treatment of advanced breast cancer in women in natural or induced postmenopause who have progressed during anti-estrogen therapy (during treatment with tamoxifen).
- as a third line of hormone therapy in patients receiving antiestrogens (tamoxifen, toremifene) and progestins.
Contraindications
- pregnancy
- breast-feeding
- increased sensitivity of the tumor to the components of the drug
Side effects
From the central nervous system: fatigue, dizziness, headache, insomnia, depression, asthenia.
Digestive system: nausea, abdominal pain, loss of appetite, constipation, rarely increased levels of liver enzymes.
From the endocrine system: paroxysmal sensations of heat (hot flashes).
Dermatological reactions: skin rash, rarely - alopecia.
From the side of hematopoiesis: rarely - a decrease in the level of lymphocytes and platelets.
Increased sweating.
Does aromasin have advantages over other representatives from the group of aromatase inhibitors (arimidex, femara)?
There are no real medical advantages of aromazin over other drugs from this group (Femara, Arimidex, Extrasa).
However, there are significant social advantages - the cost of aromazine is half that of Arimidex and Femara. On average, the cost of aromazine is 5–6 thousand for 1 month. treatment rubles, while the cost of Arimidex and Femara for 1 month. treatment costs 8–9 thousand rubles.
Does aromasin have any advantages over tamoxifen?
Yes. The main advantage of aromazin (as well as arimidex, femara) is a significantly lower number of side effects. Aromasin does not affect the uterus and does not cause endometrial hyperplasia and, accordingly, does not increase the risk of developing uterine cancer or increase the risk of blood clots.
Dmitry Andreevich Krasnozhon, especially for the site “All about breast cancer” (www.breast-cancer.ru). Last revised December 24, 2014
Use of the drug Aromasin
adult patients, including the elderly, are prescribed 25 mg orally once a day, preferably after meals. In patients with early-stage breast cancer, treatment with Aromasin should be continued until completion of 5 years of adjuvant hormonal therapy or until local or distant metastases or a new contralateral tumor occurs. In patients with advanced breast cancer, treatment with Aromasin should be continued until tumor progression becomes apparent. Patients with insufficiency of liver or kidney function do not require dose adjustment. Children The drug is not recommended for use in children.
Side effects of the drug Aromasin
The observed side effects of the drug were mild or moderate. Due to side effects, the drug was discontinued in 6.3% of patients with early breast cancer who were treated with Aromasin after initial tamoxifen therapy, and in 2.8% of patients with advanced breast cancer who received the standard dose of 25 mg. In patients with early stage cancer, the most common drug-related or unknown side effects were flushing (21%), arthralgia (18%), and fatigue (16%). In patients with advanced breast cancer, the most common side effects were flushing (14%) and nausea (12%). Most adverse reactions may be due to pharmacological consequences of blocking the effects of estrogens. Below are side effects from various organs and systems of the body, grouped by frequency of occurrence (very common (10%), common (1%, but ≤10%), uncommon (0.1%, but ≤1%), rare ( 0.01%, but ≤0.1%). Metabolic and metabolic disorders: often - anorexia. Mental disorders: very often - insomnia; often - depression. Neurological disorders: very often - headache; often - dizziness, carpal tunnel syndrome. Vascular disorders: very often - flushing. Digestive disorders: very often - nausea; often - abdominal pain, vomiting, constipation, dyspepsia, diarrhea. Disorders of the skin and subcutaneous tissue: very often - increased sweating; often - rash, alopecia. Disorders of the musculoskeletal system: very often - pain in the joints and muscles (arthralgia, to a lesser extent - pain in the limbs, back, osteoarthritis, arthritis, myalgia, stiffness in the joints), often - osteoporosis, fractures bones General disorders: very often - fatigue; often - pain, peripheral edema, including swelling of the legs. A decrease in the number of lymphocytes was noted in approximately 20% of patients taking Aromasin, especially in patients with initial lymphopenia, but the average number of lymphocytes did not change significantly in these patients for quite a long time; There was also no increase in the incidence of viral infections. In studies comparing therapy with Aromasin and tamoxifen in patients with early stages of breast cancer, there were no differences in the incidence of myocardial ischemia, cardiovascular events, including hypertension (arterial hypertension), myocardial infarction, and heart failure. The incidence of peptic ulcers with Aromasin is slightly increased compared with tamoxifen (0.7 versus ≤0.1). The majority of patients who reported peptic ulcers were taking concomitant NSAID treatment concomitantly with exemestane therapy and/or had a history of peptic ulcers. An increase in liver function tests was detected, which included determining the activity of liver enzymes, bilirubin and alkaline phosphatase levels.
Aromasin®
In general, Aromasin® is well tolerated; Undesirable effects when using the drug at a dose of 25 mg/day are mostly minor or moderate.
The following are the undesirable reactions, distributed by system-organ classes and frequency: very often (≥1/10), often (≥1/100, but <1/10), infrequently (≥1/1000, but <1/100) , rare (≥ 1/10,000, but < 1/1000).
Metabolic and eating disorders
: often - anorexia.
Gastrointestinal disorders
: very often - abdominal pain, nausea; often - vomiting, diarrhea, constipation, dyspepsia, increased appetite; infrequently - stomach ulcer*.
Mental disorders
: very often - depression, insomnia.
Nervous system disorders
: very often - headache, dizziness; often - anxiety, confusion, carpal tunnel syndrome, paresthesia, hypoesthesia, asthenia; infrequently - neuropathy.
Heart disorders
: often - heart failure; infrequently - myocardial infarction.
Skin and subcutaneous tissue disorders
: very often - increased sweating; often alopecia, rash, itching, dermatitis.
Musculoskeletal and bone disorders
: very often - joint and musculoskeletal pain (including arthralgia, pain in the extremities, back pain, arthritis, myalgia); often - fracture, osteoporosis.
Visual disorders
: often - visual impairment.
Vascular disorders
: very often - increased blood pressure, hot flashes.
Liver and biliary tract disorders
: very often - increased activity of liver enzymes, increased concentration of bilirubin in the blood, increased activity of alkaline phosphatase in the blood.
Respiratory, thoracic and mediastinal disorders
: often - shortness of breath, cough, bronchitis, sinusitis, pharyngitis, rhinitis, chest pain, upper respiratory tract infections.
Renal and urinary tract disorders
: often - urinary tract infections.
Blood and lymphatic system disorders
: often lymphedema.
General and administration site disorders
: very often - pain, increased fatigue; often - peripheral edema, flu-like syndrome, fever, general weakness, infections.
In approximately 20% of patients (especially in patients with initial lymphopenia), a periodic decrease in the number of lymphocytes was observed. However, the mean lymphocyte count in these patients did not change significantly over time, and there was no concomitant increase in the incidence of viral infections.
* most patients had a history of gastric ulcer or were treated with non-steroidal anti-inflammatory drugs.
Post-marketing studies
:
Immune system disorders
: uncommon - hypersensitivity reactions.
Disorders of the liver and biliary tract
: rarely - hepatitis, cholestatic hepatitis.
Skin and subcutaneous tissue disorders
: often - urticaria; rarely - acute generalized exanthematous pustulosis.
Special instructions for the use of the drug Aromasin
Aromasin should not be prescribed to women with premenopausal endocrine status. Aromasin should be used with caution in patients with impaired liver and kidney function. Considering that Aromasin is a drug that strongly reduces estrogen levels, a decrease in bone mineral density can be expected. During adjuvant therapy with the drug in patients with osteoporosis or at risk of its occurrence, bone mineral density parameters should be assessed using densitometry at the beginning of treatment. Patients taking Aromasin should be monitored and, if necessary, treated for osteoporosis. Animal studies have revealed reproductive toxicity of the drug, therefore Aromasin is contraindicated for use in pregnant women. Aromasin should not be used during breastfeeding. The effect of exemestane on the ability to drive a car and operate machinery has not been studied in detail. It is unlikely that Aromasin impairs the ability to drive vehicles or operate machinery.
Drug interactions Aromasin
in vitro studies demonstrated that exemestane is metabolized by cytochrome P450 (CYP) 3A4 and aldoketoreductases and does not block any of the major CYP isoenzymes. In a clinical pharmacokinetic study, it was found that specific inhibition of CYP 3A4 by ketoconazole did not affect the pharmacokinetics of exemestane. When studying the interaction of rifampicin, a potent P450 inducer, at a dose of 600 mg per day, and exemestane at a single dose of 25 mg, the AUC value of exemestane decreased by 54% and the maximum plasma concentration by 41%. Since the clinical significance of this effect has not been studied, concomitant use of drugs such as rifampicin, anticonvulsants (for example, phenytoin and carbamazepine) and herbal remedies containing St. John's wort, which is a CYP3A4 inducer, may reduce the effectiveness of Aromasin. There is no clinical experience regarding the simultaneous use of Aromasin with other anticancer drugs. Aromasin should not be used with medications containing estrogens, since when used simultaneously they have a negative pharmacological effect.
