Aromasin^® (Tablets) Instructions for Use

Marketing Authorization Holder

Pfizer, Inc. (USA)

Manufactured By

Pfizer Italia, S.r.L. (Italy)

Contact Information

PFIZER INNOVATIONS LLC (Russia)

ATC Code

L02BG06 (Exemestane)

Active Substance

Exemestane (Rec.INN registered by WHO)

Dosage Form

Aromasin®

Coated tablets 25 mg: 15, 30 or 90 pcs.

Dosage Form, Packaging, and Composition

Coated tablets white or white with a grayish tint, round, biconvex, with the marking “7663” on one side, printed in black ink.

Excipients: mannitol – 26 mg, hypromellose – 1.5 mg, polysorbate 80 – 0.125 mg, crospovidone – 2.125 mg, colloidal silicon dioxide – 0.125 mg, microcrystalline cellulose (PH 101) – 4.625 mg, sodium carboxymethyl starch, type A – 2.375 mg, magnesium stearate – 0.625 mg.

Coating composition hypromellose – 1.81 mg, simethicone emulsion – 0.009 mg, macrogol 6000 – 0.181 mg, light magnesium carbonate – 1.157 mg, titanium dioxide – 3.453 mg, methylparaben – 0.003 mg, polyvinyl alcohol – 0.697 mg, sucrose – 30.19 mg.
Polishing components cetyl ester wax – 0.0175 mg, talc – 0.01 mg, carnauba wax – 0.0225 mg.
Ink composition shellac, ethanol, isobutanol, iron oxide dye (E171), titanium dioxide (E171).

15 pcs. – blisters (1) – cardboard packs with first opening control.
15 pcs. – blisters (2) – cardboard packs with first opening control.
15 pcs. – blisters (6) – cardboard packs with first opening control.

Clinical-Pharmacological Group

Antitumor drug. Aromatase inhibitor

Pharmacotherapeutic Group

Antineoplastic agent, estrogen synthesis inhibitor

Pharmacological Action

An irreversible steroidal aromatase inhibitor, structurally similar 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 the formation of estrogens by inhibiting aromatase is an effective and selective method of treating hormone-dependent breast cancer in postmenopausal women. The mechanism of action of the drug Aromasin^® is due to its irreversible binding to the active site of the enzyme, causing its inactivation. In postmenopausal women, Aromasin^® reliably reduces serum estrogen concentrations, starting from a dose of 5 mg, with the maximum reduction (>90%) achieved with doses of 10-25 mg. In postmenopausal patients diagnosed with breast cancer who received 25 mg of the drug daily, the overall level of aromatase enzyme in the body decreased by 98%.

Exemestane has no progestogenic or estrogenic activity. Only slight androgenic activity is detected, mainly when used in high doses.

Aromasin^® does not affect the biosynthesis of cortisol and aldosterone in the adrenal glands, which confirms the selectivity of the drug’s action. Therefore, there is no need for replacement therapy with glucocorticoids and mineralocorticoids.

When using the drug even in low doses, a slight increase in the content of LH and FSH in the blood serum is observed, which is characteristic of drugs in this pharmacological group and probably develops through a feedback principle at the level of the pituitary gland: a decrease in estrogen concentration stimulates the secretion of gonadotropins in the pituitary gland even in postmenopausal women.

Pharmacokinetics

Absorption

After oral administration, Exemestane is rapidly absorbed, mainly from the gastrointestinal tract. The absolute bioavailability of the drug has not been established. It is assumed to be limited by an extensive first-pass effect through the liver. After a single dose of the drug at 25 mg, C_max in plasma is 17 ng/ml and is reached within 2 hours. Concurrent food intake increases the bioavailability of the drug by 40%.

The pharmacokinetic parameters of exemestane are linear.

Distribution

Plasma protein binding is approximately 90%. Exemestane and its metabolites do not bind to red blood cells. No unpredictable accumulation of exemestane is observed upon repeated administration.

Metabolism

The biotransformation process of exemestane is carried out by oxidation of the methylene group in the 6-position under the action of the isoenzyme CYP3A4 and/or reduction of the 17-keto group under the action of aldoketoreductase, followed by conjugation. The metabolites of exemestane are either inactive or less active in inhibiting aromatase than the parent compound.

Excretion

The terminal T_1/2 is approximately 24 hours. Approximately equal amounts of exemestane (about 40%) are excreted in urine and feces within a week. From 0.1% to 1% is excreted unchanged in the urine.

Pharmacokinetics in special clinical cases

No pronounced relationship between the systemic exposure of the drug and age has been established.

In patients with severe renal failure (CrCl < 30 ml/min), the systemic exposure of exemestane is 2 times higher, but no dose adjustment is required.

In patients with moderate or severe hepatic impairment, the systemic exposure of exemestane is 2-3 times higher, but no dose adjustment is required.

Indications

• Advanced breast cancer in women in natural or induced postmenopause with disease progression during antiestrogen therapy, as well as with disease progression after repeated use of various types of hormonal therapy;
• Adjuvant therapy of early breast cancer in postmenopausal women with estrogen receptor-positive status or with unknown receptor status, after completion of 2-3 years of initial adjuvant therapy with tamoxifen, in order to reduce the risk of recurrence (distant or regional), as well as contralateral breast cancer.

ICD codes

Dosage Regimen

Administered orally. For adults and elderly patients the recommended dose is 25 mg once daily, preferably after a meal.

For early breast cancer, treatment with the drug is recommended to continue until the total duration of sequential adjuvant hormonal therapy reaches 5 years. Treatment of patients with advanced breast cancer is long-term. If signs of tumor disease progression or contralateral breast cancer appear, treatment with Aromasin^® should be discontinued.

In hepatic or renal impairment no dose adjustment is required.

Not recommended for use in children.

Adverse Reactions

Adverse effects when using the drug at a dose of 25 mg/day are mild or moderate.

The following are adverse reactions distributed by body system and frequency: very common (>10%), common (>1%, <10%), uncommon (>0.1%, <1%), rare (>0.01%, <0.1%).

From the digestive system very common – nausea; common – anorexia, abdominal pain, vomiting, constipation, dyspepsia, diarrhea.

From the central and peripheral nervous system: very common – insomnia, headache; common – depression, dizziness, carpal tunnel syndrome.

From the cardiovascular system: very common – hot flashes.

Dermatological reactions: very common – sweating; common – rash, alopecia.

From the musculoskeletal system: very common – joint and skeletal muscle pain.

Other: very common – increased fatigue; common – pain of unspecified localization, peripheral edema or leg edema.

Approximately 20% of patients (especially patients with initial lymphopenia) experienced a periodic decrease in lymphocyte count. However, the average lymphocyte count in these patients did not change significantly over time, and no concomitant increase in the incidence of viral infections was observed.

An increase in the activity of liver enzymes and alkaline phosphatase was sometimes observed, mainly in patients with liver and bone metastases, as well as in the presence of other liver lesions (it has not been established whether these changes are associated with taking the drug or not).

Contraindications

• Premenopausal endocrine status;
• Pregnancy;
• Lactation period (breastfeeding);
• Hypersensitivity to exemestane or any other component of the drug.

Use with caution in patients with impaired liver or kidney function.

Use in Pregnancy and Lactation

Aromasin^® is contraindicated for use during pregnancy and lactation.

Use in Hepatic Impairment

In hepatic impairment no dose adjustment is required.

Use with caution in patients with impaired liver function.

Use in Renal Impairment

In renal impairment no dose adjustment is required.

Use with caution in patients with impaired kidney function.

Pediatric Use

Not recommended for use in children.

Geriatric Use

For elderly patients the recommended dose is 25 mg once daily, preferably after a meal.

Special Precautions

Aromasin^® should not be prescribed to women with premenopausal endocrine status, therefore, when clinically justified, postmenopausal status should be confirmed by determining the levels of LH, FSH and estradiol.

Aromasin^® should not be prescribed concomitantly with drugs containing estrogens.

Effect on ability to drive vehicles and operate machinery

Patients should be warned about the possibility of drowsiness, asthenia and dizziness during treatment with Aromasin^®. If these symptoms occur, patients are advised to refrain from driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

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.

Treatment there are no specific antidotes. If necessary, symptomatic therapy should be carried out, as well as regular monitoring of vital functions and careful observation.

Drug Interactions

Drugs containing estrogens, when used concomitantly with Aromasin^®, completely negate its pharmacological action.

Exemestane is metabolized under the influence of CYP3A4 and aldoketoreductases and does not inhibit any of the major CYP isoenzymes. Specific inhibition of CYP3A4 by ketoconazole does not have a significant effect on the pharmacokinetics of exemestane. Despite the established pharmacokinetic interaction of exemestane with rifampicin, a strong inducer of CYP3A4, the pharmacological activity of Aromasin^® (estrogen suppression) remains unchanged, so no dose adjustment is required.

Storage Conditions

The drug should be stored at a temperature not exceeding 30°C (86°F) in a place inaccessible to children.

Shelf Life

The shelf life is 3 years. The drug should not be used after the expiration date printed on the package.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.