Instructions Androgel gel 1.62% 88 g No. 1
Composition
active ingredient: testosterone;
1 g of gel contains 16.2 mg of testosterone;
excipients: isopropyl myristate, ethanol 96%, carbomer (carbopol 980), sodium hydroxide 0.1 N, purified water.
Dosage form
Gel for external use.
Main physicochemical properties: transparent or slightly opalescent colorless gel with an alcohol odor.
Pharmacotherapeutic group
Androgens. 3-oxoandrostene derivatives. ATX code G0ZV A03.
Pharmacological properties
Pharmacodynamics
Endogenous androgens, mainly testosterone, which is secreted by the testes, and its main metabolite dihydrotestosterone, are responsible for the development of external and internal genitalia, as well as secondary sexual characteristics in men (stimulation of hair growth, deepening of the voice, development of libido). Androgens also stimulate protein anabolism, skeletal muscle development and adipose tissue distribution, reduce fluid excretion and the level of nitrogen, sodium, potassium, chloride and phosphorus in the urine. Testosterone reduces pituitary secretion of gonadotropins.
In some target organs, testosterone exerts its effects after peripheral conversion to estradiol, which then binds to estrogen receptors in the nuclei of target organ cells, such as the pituitary gland, adipose tissue, brain, bone, and Leydig cells in the testes.
Pharmacokinetics
From 1 to 8.5% of the applied dose of testosterone is absorbed through the skin.
After absorption through the skin, testosterone diffuses into the systemic circulation at a relatively constant concentration over a 24-hour cycle.
The concentration of testosterone in the blood increases from the first hour of application, reaching an equilibrium concentration already from the 2nd day. After that, daily changes in testosterone concentration have a similar amplitude to changes characteristic of the circadian rhythm of endogenous testosterone secretion. Thus, the transdermal route of administration allows you to avoid peak increases in the concentration of the drug in the blood, which occur after injections, and supraphysiological concentrations of this steroid in the liver with oral administration of androgens.
The use of 5 g of the drug provides an increase in the concentration of testosterone in the blood plasma by an average of approximately 2.3 ng/ml (8.0 nmol/l).
After discontinuation of treatment, testosterone concentrations begin to decline approximately 24 hours after the last dose. Concentrations return to baseline approximately 72-96 hours after the last dose.
The main active metabolites of testosterone are dihydrotestosterone and estradiol. Testosterone is excreted mainly in the urine, and also in small amounts in the feces in the form of conjugated metabolites.
In a double-blind phase III study, at the end of a 112-day treatment period during which the dose of Androgel could be increased based on total testosterone levels, 81.6% (CI 75.1–87.0%) of men had total testosterone levels within the normal range for eugonadal young men (300–1000 ng/dL). In patients receiving daily Androgel, the mean (± SD) daily testosterone concentration on day 112 (Cav) was 561 (± 259) ng/dL, the mean Cmax was 845 (± 480) ng/dL, and the mean Cmin was 334 (± 155) ng/dL. Corresponding concentrations on day 184 (double-blind period) were: Cav – 536 (± 236) ng/dL, mean Cmax – 810 (± 497) ng/dL and mean Cmin – 330 (± 147) ng/dL.
In an open-label phase III study, at the end of a 264-day treatment period, during which the dose of Androgel could be increased based on total testosterone levels, 77% (CI 69.8-83.2%) of men had total testosterone levels within the normal range for eugonadal young men (300-1000 ng/dL).
In patients receiving daily Androgel, the mean (± SD) daily testosterone concentration on day 266 (Cav) was 459 (± 218) ng/dL, the mean Cmax was 689 (± 414) ng/dL, and the mean Cmin was 305 (± 121) ng/dL. The corresponding concentrations on day 364 (extension of the open-label period) were: Cav - 454 (± 193) ng/dL, the mean Cmax was 698 (± 382) ng/dL, and the mean Cmin was 302 (± 126) ng/dL.
Preclinical safety data
Testosterone has been shown to be nonmutagenic in in vitro studies using the reverse mutation model (Ames test) or Chinese hamster ovary cells. Studies in laboratory animals have shown a relationship between androgen treatment and certain types of cancer. Experimental data from a study in rats have shown an increased incidence of prostate cancer after testosterone treatment.
Sex hormones are known to promote the development of some tumors caused by known carcinogens. The significance of these findings and the actual risk to humans remain unknown.
Exogenous testosterone has been reported to inhibit spermatogenesis in rats, dogs, and nonhuman primates. The changes were reversible upon cessation of treatment.
Indication
Testosterone hormone replacement therapy in adult men with hypogonadism, if its deficiency is confirmed by clinical course and laboratory tests.
Contraindication
Diagnosed or suspected prostate cancer or breast cancer.
Hypersensitivity to testosterone or to any other component of the drug.
Interaction with other medicinal products and other types of interactions
Because of changes in anticoagulant activity (enhanced effect of oral anticoagulants is possible due to modification of hepatic coagulation factor synthesis and competitive inhibition of plasma protein binding), careful monitoring of prothrombin time and determination of international normalized ratio (INR) is recommended. Patients receiving oral anticoagulants require close supervision, especially when starting androgen therapy or after its withdrawal.
The concomitant administration of testosterone with adrenocorticotropic hormone (ACTH) or corticosteroids may increase the risk of edema. Therefore, these drugs should be used with caution in combination, especially in patients with heart, kidney, or liver disease.
Laboratory Test Effects: Androgens may decrease thyroxine-binding globulin levels, resulting in decreased serum T4 concentrations and increased T3 and T4 absorption. Free thyroid hormone levels remain unchanged and there are no clinical signs of thyroid insufficiency.
Changes in insulin sensitivity, glucose tolerance, glycemic control, blood glucose levels, and glycosylated hemoglobin have been reported with androgen use. Patients with diabetes may require a reduction in the dosage of antidiabetic agents.
Using a suntan cream or lotion does not reduce effectiveness.
Washing off 2 hours after application does not have a significant effect on testosterone levels in the blood.
Application features
Androgel should only be used if hypogonadism (hyper- and hypogonadotropic) is confirmed and other possible etiologies of symptoms have been excluded before treatment. It is necessary that testosterone deficiency be clearly demonstrated by clinical manifestations (regression of secondary sexual characteristics, changes in body composition, asthenia, decreased libido, erectile dysfunction, etc.) and confirmed by two separate blood tests for testosterone content. There is still no consensus on changes in testosterone concentration depending on age, but it should be borne in mind that physiological levels of testosterone in the blood decrease with age.
Due to possible fluctuations in laboratory values, all testosterone measurements should be performed in the same laboratory.
Androgel is not a drug for the treatment of male infertility or impotence.
Before starting testosterone therapy, all patients should undergo a complete examination to exclude prostate cancer. Patients receiving testosterone should have their prostate and breast examined regularly and thoroughly using recommended methods (digital rectal examination, serum PSA measurement) at least once a year, and in elderly patients and patients with risk factors (clinical and familial) twice a year.
Androgens can accelerate the progression of subclinical prostate cancer and benign prostatic hyperplasia.
Androgel should be used with caution in patients with malignant neoplasms due to the risk of developing hypercalcemia (and associated hypercalciuria) due to bone metastases. In such patients, regular monitoring of blood calcium levels is recommended.
In patients with severe cardiac, hepatic or renal insufficiency or ischemic heart disease, testosterone treatment may cause severe complications characterized by edema with or without congestive heart failure. In such cases, treatment should be discontinued immediately. In addition, diuretics should be administered if necessary.
Androgel should be used with caution in patients with coronary heart disease.
Testosterone may cause an increase in blood pressure, therefore, Androgel should be prescribed with caution to patients with arterial hypertension.
Testosterone should be used with caution in patients with thrombophilia, as there have been post-marketing reports of thrombotic complications in such patients during testosterone treatment.
Testosterone levels should be checked at the start of treatment and regularly during treatment. The physician should adjust the dose individually to ensure that testosterone levels are maintained at eugonadal levels.
In patients taking androgens for a long time, in addition to determining the level of testosterone in the blood, it is necessary to periodically check the following laboratory parameters: hemoglobin level, hematocrit (to detect polycythemia), liver function tests, and lipid profile.
The available data on the safety and efficacy of Androgel in patients aged 65 years and older are limited. There is currently no consensus on age-specific reference values for testosterone levels. However, the physiological decline in testosterone levels in the blood with age should be taken into account.
Patients with epilepsy and migraine should use Androgel with caution, as the course of these conditions may worsen.
Improvement in insulin sensitivity may occur in patients who have used androgens, which may require a reduction in the dose of antidiabetic agents.
Some clinical signs – irritability, nervousness, weight gain, frequent or prolonged erections – may indicate excessive androgen effects, which requires dose adjustment.
If a patient develops a severe local reaction, continued therapy should be reconsidered.
The use of high doses of exogenous androgens can suppress spermatogenesis through feedback inhibition of pituitary follicle-stimulating hormone (FSH), which can lead to abnormal values of sperm parameters, including sperm count.
Patients receiving androgen treatment for hypogonadism sometimes develop gynecomastia, which is rarely persistent.
Androgel should not be used in women due to a possible virilizing effect.
Attention athletes: This medicine contains an active substance (testosterone) that may give a positive reaction in anti-doping tests.
It is possible for the gel to get on another person's skin.
If care is not taken, testosterone gel may come into contact with another person's skin during close contact, which may cause an increase in serum testosterone levels and side effects (excessive facial and/or body hair growth, deepening of the voice, menstrual irregularities in women, and premature sexual development and enlargement of the genitals in children) in the event of repeated contact (unintentional androgenization). If virilization occurs, testosterone should be discontinued immediately until the cause is determined.
The physician should inform the patient of this risk and the need to comply with safety precautions (see below). Androgel should not be prescribed to patients who have a significant risk of non-compliance with safety precautions (severe alcoholism, drug addiction, severe mental illness).
The potential risk of the gel getting on another person's skin can be prevented (but not eliminated) by wearing clothing that covers the area where the gel is applied (e.g., a shirt with sleeves). Most of the testosterone remaining on the skin can be removed by washing with soap and water before contact.
When using the drug, it is recommended to observe the following safety measures:
for patients:
wash your hands with soap and water after applying the gel;
cover the area where the drug is applied with clothing (for example, a shirt with sleeves) after the gel dries;
take a shower and wash the application site with soap and water to remove any testosterone residue before any situation where close contact with another person is possible;
for people not treated with Androgel:
in case of contact with the gel application site that has not been washed or has not been covered with clothing, immediately wash the area of skin that may have been exposed to testosterone with soap and water;
Consult a doctor if you develop signs of hyperandrogenism, such as acne or changes in normal hair growth.
Based on in vitro data on testosterone absorption from Androgel, patients should wait at least 2 hours between application of the gel and bathing or showering. Occasional bathing or showering between 2 and 6 hours after application of the gel will not significantly affect the outcome of the treatment.
To ensure the safety of the partner, the patient should be advised, for example, to wash the gel application site with soap during showering before sexual intercourse or, if this is not possible, to wear a shirt or T-shirt to cover the gel application site during contact.
In addition, it is recommended to wear clothing that covers the gel application site (e.g., a shirt with sleeves) when in contact with children to prevent the gel from getting on their skin.
Pregnant women should avoid any contact with the application sites of Androgel. If the woman with whom the patient is in contact is pregnant, he should pay increased attention to the safety precautions during use as described above (see also section "Use during pregnancy or lactation").
Use during pregnancy or breastfeeding
Androgel is intended for the treatment of men only.
Androgel should not be used during pregnancy or breastfeeding due to possible virilization of the fetus. Clinical studies of this treatment in women have not been conducted.
Pregnant women should avoid any contact with the application sites of Androgel (see section "Special instructions for use"). In case of contact, wash the affected areas immediately with soap and water.
Androgel can reversibly inhibit spermatogenesis.
Ability to influence reaction speed when driving vehicles or other mechanisms
Androgel has no or negligible influence on the ability to drive or operate machinery.
Method of administration and doses
For external use (on the skin).
The recommended dose is 2 actuations of the dosing device (40.5 mg of testosterone) once a day, preferably at the same time in the morning. The daily dose can be adjusted by the doctor individually for each patient depending on the clinical effect and the results of laboratory monitoring, but should not exceed 4 actuations of the dosing device (81 mg of testosterone) per day. Dose correction should be carried out by adding one actuation of the dosing device.
The dose should be increased gradually, taking into account the testosterone level in the blood the morning before applying the gel. Steady-state testosterone concentration in the blood is usually achieved on the second day of treatment with Androgel. To adjust the testosterone dose, the testosterone concentration in the blood should be measured in the morning before applying the gel after reaching a steady state. Testosterone levels in the blood should be assessed periodically. The dose can be reduced if the testosterone concentration in the blood is found to be elevated. If the concentration is low, the dose can be gradually increased, but it should not exceed 81 mg of gel per day (4 presses on the dosing device).
Therapy should be discontinued if blood testosterone levels consistently exceed the normal range at the lowest daily dose of 20.25 mg (1.25 g of gel, equivalent to one actuation of the dosing device) or if blood testosterone levels do not reach the normal range at the highest dose of 81 mg of testosterone (5 g of gel, equivalent to four actuations of the dosing device).
Patients with severe renal or hepatic impairment
See the section "Application features".
Method of application
The gel should be applied by patients themselves to clean, dry, healthy skin on both shoulders and upper arms.
The gel should be applied with light movements, spreading it over the skin in a thin layer. The gel should not be rubbed into the skin. Allow to dry for at least 3-5 minutes before getting dressed. After applying the gel, wash your hands with soap and water and cover the application site with clothing after the gel has dried. In any situation where close contact with another person is expected, the application site should be thoroughly washed with soap and water. For additional information on washing after applying the medicine, see the section "Special instructions for use".
The gel should not be applied to the genitals, as alcohol in high concentrations can cause local irritation.
To obtain the first dose, the dosing device must be filled. To do this, holding the bottle in an upright position, it is necessary to make three slow and full presses on the dosing device. After the first three presses, the gel should be safely disposed of. The dosing device should only be filled before the first use.
After the filling procedure, one full press on the dosing device should be made to release 1.25 g of Androgel into the palm of your hand and then applied to the shoulders and upper arms (see figure).
Children
The safety and efficacy of Androgel in children (under 18 years of age) have not been established. Data are lacking.
Overdose
Only one case of acute overdose of testosterone after injection has been described in the literature. This involved cerebral blood flow in a patient with a high plasma testosterone concentration of 114 ng/mL (395 nmol/L). It is unlikely that such high testosterone levels could be achieved by transdermal administration.
Treatment of overdose should include discontinuation of Androgel and appropriate symptomatic and supportive therapy.
Side effects
Most often, when using the recommended dose of Androgel, side effects such as mental disorders and skin reactions at the site of gel application may occur.
The table below lists the adverse reactions reported in the 182-day double-blind period of the Phase III clinical trial of Androgel and which were observed more frequently in the Androgel group (n=234) than in the placebo group (n=40).
Table 1
Frequency of adverse reactions with the use of the drug Androgel in a phase III study
| MedDRA system organ classes | Adverse reactions (terms of preferred use) |
|---|
Often (≥ 1/100 to < 1/10) | Infrequently (≥ 1/1000 to < 1/100) |
|---|
| Mental disorders | Symptoms of emotional disturbances* (mood swings, affective disorder, anger, aggression, impatience, insomnia, unusual dreams, increased libido) | |
| Vascular disorders | Malignant hypertension, hot flashes, phlebitis | |
| Digestive system disorders | Diarrhea, bloating, mouth pain | |
| Skin and subcutaneous tissue disorders | Skin reactions * (acne, alopecia, dry skin, skin lesions, contact dermatitis, hair color change, rash, hypersensitivity at the application site, itching at the application site) | |
| Reproductive system and mammary gland disorders | Gynecomastia, nipple disorder, testicular pain, increased erection | |
| Mild swelling | |
| Research results | Elevated PSA, elevated hematocrit, or elevated hemoglobin | |
* Adverse reactions are grouped.
Due to the presence of alcohol, frequent application to the skin may cause irritation and dryness.
The following adverse reactions have been identified during post-marketing use of Androgel. Because adverse reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Table 2
Adverse reactions to the use of the drug Androgel according to spontaneous reports
| MedDRA system organ classes | Adverse reactions (terms of preferred use) |
| Blood and lymphatic system disorders | Polycythemia, anemia |
| Mental disorders | Insomnia, depression, anxiety, aggression |
| Nervous system disorders | Headache, dizziness, paresthesia |
| Vascular disorders | Vasodilation (hot flashes), deep vein thrombosis |
| Respiratory, thoracic and mediastinal disorders | Dyspnea |
| Digestive system disorders | Nausea |
| Skin and subcutaneous tissue disorders | Application site reaction, acne, alopecia, increased sweating, hypertrichosis |
| Musculoskeletal and connective tissue disorders | Musculoskeletal pain |
| Renal and urinary disorders | Urination disorders |
| Reproductive system and mammary gland disorders | Gynecomastia, testicular disorder, prostate enlargement, oligospermia, benign prostatic hyperplasia |
| General disorders and administration site conditions | Asthenia, edema, malaise |
| Research results | Weight gain, elevated PSA, elevated hematocrit, or elevated hemoglobin |
The following adverse reactions have been identified during post-marketing use of testosterone preparations.
Table 3
Adverse reactions to testosterone drugs
| MedDRA system organ classes | Adverse reactions (terms of preferred use) |
|---|
Often (≥ 1/100 to < 1/10) |
|---|
| Blood and lymphatic system disorders | Increased hematocrit, increased red blood cell count, increased hemoglobin level |
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after a medicinal product has been authorised is important. This allows for continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system.
Expiration date
3 years.
After first opening the package – 30 days.
Storage conditions
Does not require special storage conditions.
Keep out of reach of children.
Packaging
88 g of gel in a bottle with a dosing device, one bottle in a cardboard box.
Vacation category
According to the recipe.
Producer
Bezen Manufacturing Belgium.
Bezen International Laboratories.
Location of manufacturers and addresses of their place of business
Grote-Bigardenstraat 128, 1620 Drogenbos, Belgium.
13 rue Perrier, Montrouge, 92120, France.
