Androgel^® (Gel) Instructions for Use

Marketing Authorization Holder

Besins Healthcare, SA (Belgium)

Manufactured By

Laboratoires Besins International, SAS (France)

Or

Besins Manufacturing Belgium, SA (Belgium)

Contact Information

BESINS HEALTHCARE RUS LLC (Russia)

ATC Code

G03BA03 (Testosterone)

Active Substance

Testosterone (Rec.INN registered by WHO)

Dosage Form

Androgel®

Gel for external use 50 mg/5 g: sachets 30 pcs.

Dosage Form, Packaging, and Composition

Gel for external use transparent or slightly opalescent, colorless, with a characteristic odor of alcohol.

Excipients : isopropyl myristate – 5 mg, carbomer 980 – 9 mg, sodium hydroxide – 47.2 mg, ethanol 96% – 0.714 g, purified water – up to 1 g.

* Excipients : isopropyl myristate – 25 mg, carbomer 980 – 45 mg, sodium hydroxide – 236 mg, ethanol 96% – 3.570 g, purified water – up to 5 g.

5 g – single-dose sachets (30) – cardboard packages.

Clinical-Pharmacological Group

Androgenic drug

Pharmacotherapeutic Group

Sex hormones and modulators of the genital system; androgens; derivatives of 3-oxoandrost-4-ene

Pharmacological Action

Endogenous androgens (mainly Testosterone), secreted by the testes, and their main metabolite dihydrotestosterone are responsible for the development of external and internal genital organs and for the development and maintenance of secondary sexual characteristics (stimulation of hair growth, deepening of the voice), libido.

They have a general effect on protein anabolism, on the development of skeletal muscles and the distribution of subcutaneous fat, reduce the excretion of nitrogen, sodium, potassium, chlorides, phosphates and water in the urine.

Testosterone does not cause the development of testes: it reduces the pituitary secretion of gonadotropins.

The effects of testosterone on some target organs are manifested after the peripheral conversion of testosterone to estradiol, which then binds to estrogen receptors in the nuclei of target organ cells (such as the pituitary gland, adipose tissue, brain, bones, etc.).

Pharmacokinetics

Absorption

The degree of testosterone absorption through the skin varies within approximately 9% to 14% of the applied dose. After absorption through the skin, Testosterone enters the systemic circulation in relatively constant concentrations over 24 hours.

Distribution

The concentration of testosterone in blood plasma increases from the first hour after the application of Androgel^®, reaching a constant value from the second day of therapy.

The daily fluctuations in testosterone concentrations have the same amplitude as those observed in the circadian rhythms of changes in endogenous testosterone content.

With the external route of administration, there are no supraphysiological peaks of testosterone concentration in the blood that occur with the injection method of application.

In contrast to oral androgen therapy, external application of the drug does not cause an increase in the concentration of sex hormones in the liver above physiological norms.

Application of 5 g of Androgel^® causes an average increase in plasma testosterone concentration of approximately 2.5 ng/ml (8.7 nmol/l).

After discontinuation of treatment, the testosterone concentration begins to decrease approximately 24 hours after the last application.

The concentration returns to the baseline level approximately 72-96 hours after the application of the last dose.

Metabolism

The main active metabolites of testosterone are dihydrotestosterone and estradiol.

Excretion

The drug is excreted mainly in the urine and feces in the form of conjugated metabolites of testosterone.

Indications

• Testosterone replacement therapy for hypogonadism in men, when testosterone deficiency is confirmed by clinical symptoms and laboratory tests.

ICD codes

Dosage Regimen

The recommended daily dose is 5 g of gel (i.e., 50 mg of testosterone).

The drug is used once a day at approximately the same time of day, preferably in the morning.

The individual daily dose may be adjusted by the doctor depending on the clinical and laboratory parameters of the patients, but should not exceed 10 g of gel/day (100 mg of testosterone).

Testosterone dose adjustment should be carried out in steps of 2.5 g of gel/day.

A constant concentration of testosterone in blood plasma is achieved approximately on the 2nd day of using Androgel^®.

To adjust the dose of Androgel^®, it is necessary to determine the concentration of testosterone in blood plasma in the morning, before applying the gel to the skin, from the 3rd day after the start of treatment (within one week).

The dose of the drug can be reduced if the plasma testosterone concentration increases.

If the plasma testosterone concentration decreases, the dose of Androgel^® can be increased, but not more than 10 g of gel/day.

Children

Androgel^® is not used in children and adolescents under 18 years of age.

Safety and efficacy of the drug have not been established.

Data are not available.

Method of Application

Applied transdermally.

Patients should be informed that other persons (including children and adults) should not come into contact with the area of the body where the gel was applied (see section “Special Precautions”).

The gel application is performed by the patient himself on clean, dry, intact skin of the shoulder, forearms, or abdomen.

The gel should not be applied to the area of the external genitalia, as the high content of ethyl alcohol in the drug may cause local irritation.

After extracting the gel from the sachet onto the palm, it should be immediately applied to the skin.

The gel is applied carefully in a thin layer.

It is not necessary to rub the gel into the skin.

The gel should be allowed to dry for 3-5 minutes before putting on clothes.

• After applying the gel to the skin, wash hands thoroughly with soap.
• After the gel has dried, cover the application site with clean clothing (e.g., a T-shirt).
• After using this medicinal product, patients should wait at least 1 hour before showering or bathing.

Physical Contact

Before close physical contact with another person (adult or child), it is necessary to wash the application site with water and soap after the recommended period of time (at least 1 hour) and cover the application area again with clean clothing.

Additional information on washing after application of the drug is provided in the “Special Precautions” section (“Potential Testosterone Transfer”).

Adverse Reactions

The most frequently occurring adverse reactions (AR) when using Androgel^® at the recommended daily dose were: skin reactions at the application site, erythema, acne, dry skin.

Clinical Trial Data

ARs registered in clinical trials in less than 10% of patients receiving therapy with Androgel^® are presented in the table below and distributed by system-organ classes with an indication of their frequency of occurrence according to WHO recommendations.

ARs were classified according to the following frequency categories: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10000, <1/1000), very rare (<1/10000), frequency unknown (cannot be estimated from the available data).

Post-Marketing Experience

The table below presents ARs identified during the post-marketing period of all dosage forms of testosterone.

Since adverse events are reported voluntarily from a population of uncertain size, it is not always possible to reliably confirm their frequency or establish a definite causal relationship with drug exposure.

ARs were classified according to the following frequency categories: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10000, <1/1000), very rare (<1/10000), frequency unknown (cannot be estimated from the available data).

Adverse reactions based on post-marketing frequency reporting data for testosterone preparations

¹ Data on the risk of prostate cancer in combination with testosterone therapy are inconclusive.
² May develop and persist in patients treated for hypogonadism with testosterone.
³ Retention of sodium, chlorides, potassium, calcium, inorganic phosphates and water.

Contraindications

• Hypersensitivity to testosterone and/or any excipient in the drug;
• Diagnosed prostate cancer (or suspicion of its presence);
• Diagnosed breast cancer (or suspicion of its presence);
• Age under 18 years (due to lack of data on the efficacy and safety of testosterone use in this age population).

Androgel^® is not indicated for use in women.

With caution in patients with malignant neoplasms (due to the risk of hypercalcemia and hypercalciuria); with severe cardiac, renal or hepatic insufficiency; with coronary heart disease; diabetes mellitus; benign prostatic hyperplasia; arterial hypertension; epilepsy; migraine; history of sleep apnea; over 65 years of age; in the presence of thrombophilic conditions or risk factors for venous thromboembolism (VTE); in patients receiving oral anticoagulants.

Use in Pregnancy and Lactation

Pregnancy

Androgel^® is not indicated for use in women during pregnancy.

Clinical studies in women have not been conducted.

Pregnant women should avoid any contact with the drug (see section “Special Precautions”), as this drug may have an adverse virilizing effect on the fetus.

In case of accidental contact of the gel on the skin, the contact area should be washed thoroughly with water and soap as soon as possible.

Breastfeeding period

Androgel^® is not indicated for use in women during breastfeeding.

Fertility

Androgel^® may reversibly suppress spermatogenesis.

Use in Hepatic Impairment

The drug should be prescribed with caution in severe hepatic insufficiency.

Use in Renal Impairment

The drug should be prescribed with caution in severe renal insufficiency.

Pediatric Use

Androgel^® is not used in children and adolescents under 18 years of age.

Safety and efficacy of the drug have not been established.

Special Precautions

Androgel^® should be used only in cases of confirmed hypogonadism (hyper- and hypogonadotropic) and after excluding other causes underlying the clinical symptoms.

Testosterone deficiency must clearly correlate with clinical manifestations, such as: underdevelopment or regression of secondary sexual characteristics, change in body structure, increased fatigue, decreased libido, erectile dysfunction, etc. and be confirmed by the results of two independent examinations to determine testosterone concentration.

Due to the variability of laboratory values, the determination of testosterone concentration in each specific patient should be carried out in the same laboratory.

Before starting testosterone therapy, all patients should undergo a thorough examination to exclude the presence of subclinical prostate cancer.

Androgens may accelerate the progression of subclinical prostate cancer and benign prostatic hyperplasia.

During testosterone therapy, careful and regular monitoring of the prostate condition (digital rectal examination of the prostate and determination of prostate-specific antigen (PSA) in blood plasma) and breasts should be carried out – at least once a year in all patients; in elderly patients and patients at risk (with the presence of clinical or family factors) – at least 2 times a year.

Testosterone preparations should be used with caution in patients with malignant neoplasms due to the risk of hypercalcemia (and concomitant hypercalciuria), due to bone metastases.

In these patients, it is recommended to monitor the serum calcium concentration.

Due to the increased risk of edema, precautions should be taken when using testosterone concomitantly with ACTH or corticosteroids in patients with heart, liver or kidney diseases.

In patients with severe cardiac, hepatic or renal insufficiency or severe coronary heart disease, testosterone treatment may cause serious complications characterized by edema with or without chronic heart failure.

In such a case, treatment should be discontinued immediately.

In addition, diuretic therapy may be required.

Testosterone may cause an increase in blood pressure, therefore Androgel^® should be used with caution in men with arterial hypertension.

Testosterone should be used with caution in patients with a hereditary or acquired predisposition to thrombosis and thromboembolism or risk factors for venous thromboembolism (VTE), as cases of thromboembolic and thrombotic complications (such as deep vein thrombosis, pulmonary embolism, ocular vessel thrombosis) have been reported in such patients during testosterone therapy.

In patients with thrombophilic conditions, cases of VTE have been reported even against the background of anticoagulant therapy, so after the first thrombotic event or thrombotic complication, a thorough assessment of the advisability of further testosterone therapy should be carried out.

If treatment is continued, further measures must be taken to minimize the individual risk of developing VTE.

In patients receiving long-term androgen treatment, in addition to determining the blood testosterone concentration, the hemoglobin content, hematocrit (to detect polycythemia), lipid profile and liver function test parameters should be periodically monitored in blood plasma.

Determination of blood testosterone concentration should be carried out before starting treatment and at regular intervals during treatment.

The doctor should monitor the dose of the drug in each specific patient to ensure that the testosterone level is maintained within the normal range.

Currently, there is no consensus regarding clear age norms for testosterone concentration.

However, it should be taken into account that physiological concentrations of testosterone in blood plasma decrease in men with age.

Androgel^® should be used with caution in patients with epilepsy and migraine.

Scientific literature contains data on an increased risk of sleep apnea development in patients with hypogonadism receiving treatment with testosterone esters, especially in those with risk factors such as obesity and chronic respiratory diseases.

In patients with diabetes mellitus receiving androgens, achieving a normal plasma testosterone concentration may lead to an increase in insulin sensitivity, which may require a reduction in the dose of hypoglycemic drugs. Patients receiving androgen therapy are recommended to monitor blood glucose and HbA_1C concentrations.

Certain clinical symptoms: irritability, nervousness, weight gain, prolonged or frequent erections may indicate an excessively strong pharmacological effect of the androgen, requiring correction of the testosterone dose.

If a severe local reaction develops at the application site in a patient, the treatment should be reviewed and, if necessary, discontinued.

Athletes should be informed that the drug contains Testosterone as the active substance, which may yield a positive result in doping control.

Potential Testosterone Transfer

In the absence of precautions, transfer of testosterone to another person after drug application can occur at the moment of physical contact at any time after application, leading to an increase in serum testosterone concentration and the possible occurrence of adverse effects (increased facial and/or body hair growth, voice deepening, menstrual cycle disturbances in women, and premature sexual maturation and genital enlargement in children) upon repeated contact (unintentional androgenization).

When prescribing the drug Androgel^®, the physician must inform the patient about the risk of testosterone transfer, for example, during physical contact between individuals, including children, and about safety measures.

Transfer via Skin-to-Skin Contact – Pregnant Women and Children

Additional caution should be exercised when using this medicinal product and during close physical contact with children, as secondary transfer of testosterone through clothing cannot be excluded. During physical contact with children, it is important to follow the application technique (see section “Dosage Regimen”), including covering the application sites with clean clothing after the gel has dried. Furthermore, it is necessary to wash the application site with soap after the recommended period of time (at least 1 hour) and cover it again with clean clothing before physical contact with children.

In case of contact, the child’s skin should be washed with soap and water as soon as possible. A doctor should be consulted if signs and symptoms (secondary sexual changes) appear in a child who may have been accidentally exposed to the testosterone gel.

Patients are advised to observe the following precautions

• After applying the gel, wash hands with soap and water;
• After the gel has dried, cover the gel application area with clothing;
• Take a shower and thoroughly wash the gel application area(s) with soap and water to remove testosterone residue before any situation involving close contact;
• The patient should be advised to thoroughly wash the gel application area with soap during a shower before sexual intercourse or, if this is not possible, to remain clothed, for example, in a shirt with sleeves covering the application site during contact.

For individuals not using the drug Androgel^®:

• In case of accidental contact of a partner with this drug, the affected person should immediately wash the affected area with soap and water;
• It is necessary to inform a doctor about the appearance and development of such signs of hyperandrogenization as acne or changes in usual hair growth.

After application of this medicinal product, patients must wait at least 1 hour before taking a shower or bath.

Pregnant women should avoid any contact with the application sites of this medicinal product. In case of the partner’s pregnancy, the patient must increase his attention to the precautions for using the drug (see section “Pregnancy and Lactation”).

The drug Androgel^® should not be prescribed to patients who are unable to comply with the safety instructions (for example, severe chronic alcoholism, drug abuse, severe mental disorders).

The drug Androgel^® contains 96% alcohol (ethanol) – 3.6 g in a 5 g sachet.

Use of the drug may cause a burning sensation on damaged skin.

This medicinal product contains ethanol, which facilitates transdermal delivery, and is flammable. Caution should be exercised during the first application of the drug, avoiding heat sources/open flame until the gel has dried on the skin.

Effect on Ability to Drive and Operate Machinery

The drug does not affect the ability to drive vehicles or engage in other potentially hazardous activities requiring increased concentration and speed of psychomotor reactions.

Overdose

Symptoms

Plasma testosterone concentration should be determined in the presence of clinical signs and symptoms indicating excessive androgen exposure.

Cases of rashes at the gel application site have been reported with overdose of the drug Androgel^®.

Treatment

The gel application site should be washed immediately and therapy discontinued as recommended by the treating physician.

Drug Interactions

Oral Anticoagulants

Change in anticoagulant activity (possible enhancement of the effect of the oral anticoagulant by modifying the synthesis of hepatic coagulation factors and competitive inhibition of plasma protein binding). This has not been reported for new-generation anticoagulants such as apixaban and rivaroxaban. Careful monitoring of prothrombin time and INR in the patient should be performed, especially at the beginning and/or end of the testosterone therapy course.

Adrenocorticotropic hormone (ACTH) and glucocorticosteroids (GCS)

Concomitant use of testosterone with ACTH or GCS may increase the risk of edema.

Effect on Laboratory Data

Androgens may decrease the concentration of thyroxine-binding globulin, leading to decreased serum T₄ concentrations and increased sensitivity to T₃ and T₄. However, concentrations of free thyroid hormones remain unchanged, and there are no clinical manifestations of hypothyroidism.

Effect on Glycemic Control

Changes in insulin sensitivity and glucose tolerance, glycemic control, blood glucose concentration, and glycated hemoglobin (HbA_1C) content have been recorded during androgen therapy.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 3 years. Do not use after the expiration date.

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.