Letrosun (Tablets) Instructions for Use

Marketing Authorization Holder

Sun Pharmaceutical Industries, Ltd. (India)

ATC Code

L02BG04 (Letrozole)

Active Substance

Letrozole (Rec.INN WHO registered)

Dosage Form

Letrosun

Film-coated tablets, 2.5 mg: 30 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets yellow, round, biconvex.

Excipients: lactose monohydrate – 84.7 mg, microcrystalline cellulose – 19 mg, corn starch – 20.9 mg, povidone K30 (polyvinylpyrrolidone-K30) – 2 mg, colloidal silicon dioxide – 1.5 mg, talc – 2.8 mg, magnesium stearate – 1.4 mg, sodium carboxymethyl starch – 6.4 mg, yellow iron oxide dye – 0.7 mg.

Film coating composition: talc – 0.12 mg, hypromellose-E5 – 1.75 mg, macrogol-6000 – 0.35 mg, titanium dioxide – 0.5 mg, yellow iron oxide dye – 0.09 mg.

10 pcs. – blisters (3) – cardboard packs.

Clinical-Pharmacological Group

Antitumor drug. Aromatase inhibitor

Pharmacotherapeutic Group

Antineoplastic agent, estrogen synthesis inhibitor

Pharmacological Action

Letrozole has an antiestrogenic effect, selectively inhibits aromatase (the enzyme of estrogen synthesis) by highly specific competitive binding to the heme subunit of this enzyme – cytochrome P450. It blocks the synthesis of estrogens both in peripheral and tumor tissues.

In postmenopausal women, estrogens are formed mainly with the participation of the aromatase enzyme, which converts androgens synthesized in the adrenal glands (primarily androstenedione and testosterone) into estrone and estradiol. Daily intake of letrozole at a daily dose of 0.1-5 mg leads to a decrease in the concentration of estradiol, estrone and estrone sulfate in blood plasma by 75-95% from the initial content. Suppression of estrogen synthesis is maintained throughout the entire treatment period.

When using letrozole in the dose range from 0.1 to 5 mg, no disturbances in the synthesis of steroid hormones in the adrenal glands are observed, the ACTH test does not reveal disturbances in the synthesis of aldosterone or cortisol. Additional prescription of glucocorticoids and mineralocorticoids is not required.

Blockade of estrogen biosynthesis does not lead to the accumulation of androgens, which are precursors of estrogens. Against the background of letrozole intake, no changes in the concentration of luteinizing and follicle-stimulating hormones in blood plasma, changes in thyroid function, changes in lipid profile, increased frequency of myocardial infarctions and strokes were noted.

Against the background of treatment with letrozole, the frequency of osteoporosis slightly increases (6.9% compared with 5.5% with placebo). However, the frequency of bone fractures in patients receiving Letrozole does not differ from that in healthy people of the same age.

Adjuvant therapy with letrozole for early stages of breast cancer reduces the risk of relapse, increases disease-free survival for 5 years, and reduces the risk of secondary tumors.

Extended adjuvant therapy with letrozole reduces the risk of relapse by 42%. A significant advantage in disease-free survival in the letrozole group was noted regardless of lymph node involvement. Treatment with letrozole reduces mortality in patients with lymph node involvement by 40%.

Pharmacokinetics

Letrozole is rapidly and completely absorbed from the gastrointestinal tract, the average bioavailability is 99.9%. Food intake slightly reduces the rate of absorption. The average time to reach C_max of letrozole in the blood is 1 hour when taking letrozole on an empty stomach and 2 hours when taking with food; the average C_max is 129±20.3 nmol/L when taken on an empty stomach and 98.7±18.6 nmol/L when taken with food, however, the degree of absorption of letrozole (when assessed by AUC) does not change.

Minor changes in the rate of absorption are considered to be of no clinical significance, so Letrozole can be taken regardless of food intake. The binding of letrozole to plasma proteins is approximately 60% (mainly to albumin – 55%). The concentration of letrozole in erythrocytes is about 80% of that in plasma. The apparent V_d at steady state is about 1.87±0.47 L/kg. The equilibrium concentration is reached within 2-6 weeks of daily intake of a daily dose of 2.5 mg. The pharmacokinetics are non-linear. No accumulation was noted with long-term use. Letrozole is largely metabolized by the action of cytochrome P450 isoenzymes CYP3A4 and CYP2A6 to form a pharmacologically inactive carbinol compound.

It is excreted mainly by the kidneys in the form of metabolites, to a lesser extent – through the intestines. The final T_1/2 is 48 hours.

The pharmacokinetic parameters of letrozole do not depend on the patient’s age.

In renal failure, the pharmacokinetic parameters do not change.

In moderate hepatic impairment (class B according to the Child-Pugh scale), the average AUC values, although 37% higher, remain within the range of values observed in individuals without hepatic impairment. In patients with liver cirrhosis and severe hepatic impairment (class C according to the Child-Pugh scale), AUC increases by 95% and T_1/2 by 187%. However, given the good tolerability of high doses of the drug (5-10 mg/day) in these cases, there is no need to change the dose of letrozole.

Indications

• Early stages of breast cancer, the cells of which have hormone receptors, in postmenopausal women, as adjuvant therapy;
• Early stages of breast cancer in postmenopausal women after completion of standard adjuvant therapy with tamoxifen as extended adjuvant therapy;
• Advanced hormone-dependent forms of breast cancer in postmenopausal women (first-line therapy);
• Advanced forms of breast cancer in postmenopausal women (natural or artificially induced) who have received prior antiestrogen therapy.

ICD codes

Dosage Regimen

Orally, regardless of meals.

Adults: the recommended dose of Letrosun is 2.5 mg once/day, daily, for a long time.

As extended adjuvant therapy, treatment should continue for 5 years (no longer than 5 years).

If signs of disease progression appear, Letrosun should be discontinued.

In elderly patients, no dose adjustment of Letrosun is required.

Patients with impaired liver and/or kidney function with impaired liver or kidney function (creatinine clearance >10 ml/min) no dose adjustment of the drug is required. Nevertheless, in case of severe hepatic impairment (class C according to the Child-Pugh scale), patients should be under constant supervision.

Adverse Reactions

As a rule, adverse reactions were mild or moderate and mainly associated with the suppression of estrogen synthesis.

The frequency of adverse reactions is estimated as follows: occurring “very often” – >10%, “often” – 1-10%, “sometimes” – 0.1-1%, “rarely” – 0.01-0.1%, “very rarely” – <0.01%, including individual reports.

From the digestive system often – nausea, vomiting, dyspepsia, constipation, diarrhea; sometimes – abdominal pain, stomatitis, dry mouth, increased activity of liver enzymes.

From the nervous system often – headache, dizziness, depression; sometimes – anxiety, nervousness, irritability, drowsiness, insomnia, memory impairment, dysesthesia, paresthesia, hypesthesia, taste perception disorders, episodes of cerebrovascular accident.

From the hematopoietic organs sometimes – leukopenia.

From the cardiovascular system sometimes – palpitations, tachycardia, thrombophlebitis of superficial and deep veins, increased blood pressure, coronary heart disease (angina pectoris, myocardial infarction, heart failure), thromboembolism; rarely – pulmonary embolism, arterial thrombosis, stroke.

From the respiratory system sometimes – shortness of breath, cough.

From the skin often – alopecia, increased sweating, skin rash (including erythematous, maculopapular, vesicular rash, psoriasis-like rashes); sometimes – skin itching, dry skin, urticaria; very rarely – angioedema, anaphylactic reactions.

From the musculoskeletal system very often – arthralgia; often – myalgia, bone pain, osteoporosis, bone fractures, sometimes – arthritis.

From the sensory organs sometimes – cataract, eye irritation, “blurred” vision, taste disturbance.

From the urinary system sometimes – frequent urination, urinary tract infections.

From the reproductive system sometimes – vaginal bleeding, vaginal discharge, vaginal dryness, breast pain.

Other very often – paroxysmal sensations of heat (“hot flashes”); often – increased fatigue, asthenia, malaise, peripheral edema, weight gain, hypercholesterolemia, anorexia, increased appetite; sometimes – weight loss, thirst, hyperthermia (pyrexia), dryness of mucous membranes, generalized edema, pain in tumor foci.

Contraindications

• Endocrine status characteristic of the reproductive period;
• Pregnancy;
• Lactation period;
• Childhood (efficacy and safety for children have not been established);
• Hypersensitivity to letrozole or any other component of the drug.

With caution: there are no data on the use of letrozole in patients with creatinine clearance less than 10 ml/min. Before prescribing letrozole to such patients, the ratio between the potential risk and the expected effect of treatment should be carefully weighed.

Use in Pregnancy and Lactation

Contraindicated.

Use in Hepatic Impairment

In case of impaired liver function no dose adjustment of the drug is required. Nevertheless, in case of severe hepatic impairment (class C according to the Child-Pugh scale), patients should be under constant supervision.

Use in Renal Impairment

In case of impaired renal function (creatinine clearance >10 ml/min) no dose adjustment of the drug is required.

With caution: there are no data on the use of letrozole in patients with creatinine clearance less than 10 ml/min. Before prescribing letrozole to such patients, the ratio between the potential risk and the expected effect of treatment should be carefully weighed.

Geriatric Use

In elderly patients, no dose adjustment of Letrosun is required.

Special Precautions

Patients with severe hepatic impairment should be under constant supervision.

During therapy with letrozole, given the potential possibility of pregnancy, women in the perimenopausal and early postmenopausal period should use reliable methods of contraception until a stable postmenopausal hormonal level is established.

Effect on the ability to drive vehicles and mechanisms

Some side effects of the drug, such as general weakness and dizziness, may affect the ability to perform potentially hazardous activities that require concentration and quick reactions. In this regard, caution should be exercised when driving vehicles and mechanisms.

Overdose

There are isolated reports of cases of letrozole overdose. No specific methods of treating overdose are known. Symptomatic and supportive therapy is indicated. Letrozole is removed from plasma by hemodialysis.

Drug Interactions

When letrozole is co-administered with cimetidine and warfarin, no clinically significant interactions are observed.

There is currently no clinical experience with the use of letrozole in combination with other antitumor agents.

According to the results of in vitro studies, Letrozole inhibits the activity of cytochrome P450 isoenzymes – CYP2A6 and CYP2C19 (the latter – moderately). When deciding on the significance of these data for the clinic, it should be taken into account that the CYP2A6 isoenzyme does not play a significant role in the metabolism of drugs.

In vitro experiments have shown that Letrozole at concentrations 100 times higher than the equilibrium values in plasma does not have the ability to significantly suppress the metabolism of diazepam (a substrate for CYP2C19). Thus, clinically significant interactions with the CYP2C19 isoenzyme are unlikely. Nevertheless, caution should be exercised when using letrozole concomitantly with drugs that are metabolized mainly with the participation of the above-mentioned isoenzymes and have a narrow therapeutic index.

Storage Conditions

Store the drug in a dry, light-protected place at a temperature not exceeding 25°C (77°F). Keep out of reach of children.

Shelf Life

Shelf life – 3 years.

Do not use after the expiration date indicated 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.