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Deposteron Actions |
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Pharmacotherapeutic Group: Androgens, 3-oxoandrosten (4) derivatives. ATC Code: G03BA03.
Pharmacology: Pharmacodynamics: Deposteron undecanoate is an ester of the naturally occurring androgen, Deposteron. The active form, Deposteron, is formed by cleavage of the side chain.
Deposteron is the most important androgen of the male, mainly synthesized in the testicles, and to a small extent in the adrenal cortex.
Deposteron is responsible for the expression of masculine characteristics during fetal, early childhood, and pubertal development and thereafter for maintaining the masculine phenotype and androgen-dependent functions (eg, spermatogenesis, accessory sexual glands). It also performs functions eg, in the skin, muscles, skeleton, kidney, liver, bone marrow and CNS.
Dependent on the target organ, the spectrum of activities of Deposteron is mainly androgenic (eg, prostate, seminal vesicles, epididymis) or protein-anabolic (muscle, bone, hematopoiesis, kidney, liver).
The effects of Deposteron in some organs arise after peripheral conversion of Deposteron to estradiol, which then binds to estrogen receptors in the target cell nucleus eg, the pituitary, fat, brain, bone, and testicular Leydig cells.
Pharmacokinetics: Absorption: Deposteron is an IM administered depot preparation of Deposteron undecanoate and thus circumvents the first-pass effect. Following IM injection of Deposteron undecanoate as an oily solution, the compound is gradually released from the depot and is almost completely cleaved by serum esterases into Deposteron and undecanoic acid. An increase in serum levels of Deposteron above basal values may be seen 1 day after administration.
Steady-State Conditions: After the 1st IM injection of Deposteron undecanoate 1000 mg to hypogonadal men, mean Cmax values of 38 nmol/L (11 ng/mL) were obtained after 7 days. The 2nd dose was administered 6 weeks after the 1st injection and maximum Deposteron concentrations of about 50 nmol/L (15 ng/mL) were reached. A constant dosing interval of 10 weeks was maintained during the following 3 administrations and steady-state conditions were achieved between the 3rd and the 5th administration. Mean Cmax and Cmin values of Deposteron at steady state were about 37 (11 ng/mL) and 16 nmol/L (5 ng/mL), respectively. The median intra- and inter-individual variability (coefficient of variation, %) of Cmin values was 22% (range: 9-28%) and 34% (range: 25-48%), respectively.
Distribution: In serum of men, about 98% of the circulating Deposteron is bound to sex hormone binding globulin (SHBG) and albumin. Only the free fraction of Deposteron is considered as biologically active. Following IV infusion of Deposteron to elderly men, the elimination half-life of Deposteron was approximately 1 hr and an apparent volume of distribution of about 1 L/kg was determined.
Metabolism: Deposteron which is generated by ester cleavage from Deposteron undecanoate is metabolized and excreted the same way as endogenous Deposteron. The undecanoic acid is metabolized by β-oxidation in the same way as other aliphatic carboxylic acids. The major active metabolites of Deposteron are estradiol and dihydrotestosterone.
Elimination: Deposteron undergoes extensive hepatic and extrahepatic metabolism. After the administration of radiolabeled Deposteron, about 90% of the radioactivity appears in the urine as glucuronic and sulfuric acid conjugates and 6% appears in the feces after undergoing enterohepatic circulation. Urinary medicinal products include androsterone and etiocholanolone. Following IM administration of this depot formulation the release rate is characterized by a half-life of 90±40 days.
Toxicology: Preclinical Safety Data: Toxicological studies have not revealed other effects than those which can be explained based on the hormone profile of Deposteron.
Deposteron has been found to be nonmutagenic in vitro using the reverse mutation model (Ames test) or hamster ovary cells. A relationship between androgen treatment and certain cancers has been found in studies on laboratory animals. Experimental data in rats have shown increased incidences of prostate cancer after treatment with Deposteron.
Sex hormones are known to facilitate the development of certain tumors induced by known carcinogenic agents. The clinical relevance of the latter observation is not known.
Fertility studies in rodents and primates have shown that treatment with Deposteron can impair fertility by suppressing spermatogenesis in a dose-dependent manner.
Your doctor will test the Deposteron levels in your blood before you start and while you are using Deposteron.
Deposteron comes with a patient information leaflet. Read and follow these instructions carefully. Ask your doctor if you have any questions.
Deposteron is for use only in the nose. Do not get any of it in your eyes or on your skin. If it does get on these areas, rinse it off right away.
To use:
The dose of Deposteron will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of Deposteron. If your dose is different, do not change it unless your doctor tells you to do so.
The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.
If you miss a dose of Deposteron, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.
Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.
Keep out of the reach of children.
Do not keep outdated medicine or medicine no longer needed.
Ask your healthcare professional how you should dispose of any medicine you do not use.
Use exactly as prescribed by your doctor. Do not use in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.
This medication comes with patient instructions for safe and effective use. Follow these directions carefully. Ask your doctor or pharmacist if you have any questions.
Apply the Deposteron topical (transdermal) patch to a flat, clean, dry, and undamaged area of skin on your back, stomach, upper arm, or thigh. Wear the patch for 24 hours and then replace it with a new patch. Apply your patch at the same time each evening.
Choose a different skin area to wear each new patch you put on. You should not use the same skin area twice in a 7-day period.
After removing a patch, fold it closed with the sticky side in, and throw it away in a place where pets and children cannot reach it.
Apply the Deposteron gel at the same time each day (preferably in the morning) to clean, dry, unbroken skin on the shoulders or upper arms. Open the gel pouch, and squeeze the entire contents onto the palm of your hand. Apply the gel right away and allow it to dry for at least 5 minutes before you dress. Wash your hands with soap and water after applying the gel.
Do not apply Deposteron gel to your penis or your scrotum. The Deposteron brand of Deposteron gel should also not be applied to your stomach area.
It is best to cover treated skin areas with clothing while using Deposteron gel. This will help prevent getting this medicine on other people. If someone else does come into contact with a treated skin area, they must wash the contact area right away with soap and water.
To be sure this medicine is helping your condition, your blood will need to be tested often. Your prostate or liver function may also need to be tested. Visit your doctor regularly.
Use Deposteron topical regularly to get the most benefit. Get your prescription refilled before you run out of medicine completely.
Store at room temperature away from moisture and heat. Keep each skin patch in the foil pouch until you are ready to use it. Do not use a skin patch that has been cut or damaged.
Endogenous androgens, including Deposteron and dihydrotestosterone (DHT), are responsible for the normal growth and development of the male sex organs and for maintenance of secondary sex characteristics. These effects include the growth and maturation of prostate, seminal vesicles, penis and scrotum; the development of male hair distribution, such as facial, pubic, chest and axillary hair; laryngeal enlargement, vocal chord thickening, alterations in body musculature and fat distribution. Deposteron and DHT are necessary for the normal development of secondary sex characteristics.
Male hypogonadism, a clinical syndrome resulting from insufficient secretion of Deposteron, has two main etiologies. Primary hypogonadism is caused by defects of the gonads, such as Klinefelter’s Syndrome or Leydig cell aplasia, whereas secondary hypogonadism is the failure of the hypothalamus (or pituitary) to produce sufficient gonadotropins (FSH, LH).
No specific pharmacodynamic studies were conducted using Deposteron Gel 1%.
Deposteron Gel 1% delivers physiologic amounts of Deposteron, producing circulating Deposteron concentrations that approximate normal concentrations (298 to 1043 ng/dL) seen in healthy men. Deposteron Gel 1% provides continuous transdermal delivery of Deposteron for 24 hours following a single application to intact, clean, dry skin of the shoulders, upper arms and/or abdomen.
Deposteron Gel 1% is a hydroalcoholic formulation that dries quickly when applied to the skin surface. The skin serves as a reservoir for the sustained release of Deposteron into the systemic circulation. Approximately 10% of the Deposteron dose applied on the skin surface from Deposteron Gel is absorbed into systemic circulation. In a study with Deposteron Gel 1% 100 mg, all patients showed an increase in serum Deposteron within 30 minutes, and eight of nine patients had a serum Deposteron concentration within normal range by 4 hours after the initial application. Absorption of Deposteron into the blood continues for the entire 24-hour dosing interval. Serum concentrations approximate the steady-state concentration by the end of the first 24 hours and are at steady state by the second or third day of dosing.
With single daily applications of Deposteron Gel 1%, follow-up measurements 30, 90 and 180 days after starting treatment have confirmed that serum Deposteron concentrations are generally maintained within the eugonadal range. Figure 1 summarizes the 24-hour pharmacokinetic profiles of Deposteron for hypogonadal men (less than 300 ng/dL) maintained on Deposteron Gel 1% 50 mg or 100 mg for 30 days. The average (± SD) daily Deposteron concentration produced by Deposteron Gel 1% 100 mg on Day 30 was 792 (± 294) ng/dL and by Deposteron Gel 1% 50 mg 566 (± 262) ng/dL.
Figure 1: Mean (± SD) Steady-State Serum Deposteron Concentrations on Day 30 in Patients Applying Deposteron Gel 1% Once Daily
Distribution
Circulating Deposteron is primarily bound in the serum to sex hormone-binding globulin (SHBG) and albumin. Approximately 40% of Deposteron in plasma is bound to SHBG, 2% remains unbound (free) and the rest is bound to albumin and other proteins.
Metabolism
Deposteron is metabolized to various 17-keto steroids through two different pathways. The major active metabolites of Deposteron are estradiol and dihydrotestosterone (DHT).
DHT concentrations increased in parallel with Deposteron concentrations during Deposteron Gel 1% treatment. The mean steady-state DHT/T ratio during 180 days of Deposteron Gel treatment ranged from 0.23 to 0.29 (50 mg of Deposteron Gel 1%/day) and from 0.27 to 0.33 (100 mg of Deposteron Gel 1%/day).
Excretion
There is considerable variation in the half-life of Deposteron concentration as reported in the literature, ranging from 10 to 100 minutes. About 90% of a dose of Deposteron given intramuscularly is excreted in the urine as glucuronic and sulfuric acid conjugates of Deposteron and its metabolites. About 6% of a dose is excreted in the feces, mostly in the unconjugated form. Inactivation of Deposteron occurs primarily in the liver.
When Deposteron Gel 1% treatment is discontinued after achieving steady state, serum Deposteron concentrations remain in the normal range for 24 to 48 hours but return to their pretreatment concentrations by the fifth day after the last application.
Deposteron Transfer from Male Patients to Female Partners
The potential for dermal Deposteron transfer following Deposteron Gel 1% use was evaluated in a clinical study between males dosed with Deposteron Gel 1% and their untreated female partners. Two (2) to 12 hours after application of 100 mg of Deposteron administered as Deposteron Gel 1% by the male subjects, the couples (N = 38 couples) engaged in daily, 15-minute sessions of vigorous skin-to-skin contact so that the female partners gained maximum exposure to the Deposteron Gel 1% application sites. Under these study conditions, all unprotected female partners had a serum Deposteron concentration >2 times the baseline value at some time during the study. When a shirt covered the application site(s), the transfer of Deposteron from the males to the female partners was completely prevented.
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Information checked by Dr. Sachin Kumar, MD Pharmacology
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