Malerone Actions

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Actions of Malerone in details

infoThe action of the drug on the human body is called Pharmacodynamics in Medical terminology. To produce its effect and to change the pathological process that is happening the body and to reduce the symptom or cure the disease, the medicine has to function in a specific way. The changes it does to the body at cellular level gives the desired result of treating a disease. Drugs act by stimulating or inhibiting a receptor or an enzyme or a protein most of the times. Medications are produced in such a way that the ingredients target the specific site and bring about chemical changes in the body that can stop or reverse the chemical reaction which is causing the disease.
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Pharmacotherapeutic Group: Androgens, 3-oxoandrosten (4) derivatives. ATC Code: G03BA03.

Pharmacology: Pharmacodynamics: Malerone undecanoate is an ester of the naturally occurring androgen, Malerone. The active form, Malerone, is formed by cleavage of the side chain.

Malerone is the most important androgen of the male, mainly synthesized in the testicles, and to a small extent in the adrenal cortex.

Malerone 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 Malerone is mainly androgenic (eg, prostate, seminal vesicles, epididymis) or protein-anabolic (muscle, bone, hematopoiesis, kidney, liver).

The effects of Malerone in some organs arise after peripheral conversion of Malerone 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: Malerone is an IM administered depot preparation of Malerone undecanoate and thus circumvents the first-pass effect. Following IM injection of Malerone undecanoate as an oily solution, the compound is gradually released from the depot and is almost completely cleaved by serum esterases into Malerone and undecanoic acid. An increase in serum levels of Malerone above basal values may be seen 1 day after administration.

Steady-State Conditions: After the 1st IM injection of Malerone 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 Malerone 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 Malerone 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 Malerone is bound to sex hormone binding globulin (SHBG) and albumin. Only the free fraction of Malerone is considered as biologically active. Following IV infusion of Malerone to elderly men, the elimination half-life of Malerone was approximately 1 hr and an apparent volume of distribution of about 1 L/kg was determined.

Metabolism: Malerone which is generated by ester cleavage from Malerone undecanoate is metabolized and excreted the same way as endogenous Malerone. The undecanoic acid is metabolized by β-oxidation in the same way as other aliphatic carboxylic acids. The major active metabolites of Malerone are estradiol and dihydrotestosterone.

Elimination: Malerone undergoes extensive hepatic and extrahepatic metabolism. After the administration of radiolabeled Malerone, 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 Malerone.

Malerone 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 Malerone.

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 Malerone can impair fertility by suppressing spermatogenesis in a dose-dependent manner.

How should I take Malerone?

This section provides information on the proper use of a number of products that contain Malerone. It may not be specific to Malerone. Please read with care.

This medicine comes with a Medication Guide and patient instructions. Read and follow these instructions carefully. Ask your doctor if you have any questions.

Malerone® or Fortesta® is available in two forms: individual packets or multi-dose pump. Vogelxo™ is available in three forms: individual packets, multi-dose pump, or tube. If you are using the pump gel for the first time, prime the pump before measuring out your first dose. Hold the pump over a sink and press the pump all the way down at least 3 times (Malerone® or Vogelxo™) or 8 times (Fortesta®) or until the gel begins to flow freely. Rinse the medicine discarded into the sink down the drain. Place the palm of your hand under the pump and press the pump the proper number of times to measure out your correct dose.

If you are using the gel in foil packets, tear the packet completely open along the perforation. Squeeze the entire contents directly onto the skin where you will apply the gel. You may also empty the packet into the palm of your hand and then apply the medicine. Throw away the empty foil packet in a place where children and pets cannot reach it.

Malerone® is available in two dosage strengths: Malerone® 1% and Malerone® 1.62%. Malerone® 1% is used differently than Malerone® 1.62%, even though they are both applied to the skin. Do not change your dose unless your doctor tells you to.

To use the gel:

  • Make sure that you wash your hands with soap and water before and after applying the gel.
  • Apply Malerone® 1% to a clean, dry, intact skin of the shoulders, upper arms, or abdomen (stomach), unless your doctor tells you to use it on another part of your body. Malerone® 1.62% should only be applied to a clean, dry intact skin of the shoulders and upper arms. Fortesta® should be applied to a clean, dry, intact skin of the front or inner thighs. Vogelxo™ should be applied to a clean, dry, intact skin of the shoulders or upper arms. Do not apply Vogelxo™ to your abdomen or stomach. Do not apply this medicine to your scrotum or your penis. Do not use the medicine on skin that has a cut, scrape, or other type of injury.
  • Allow the gel to dry on your skin before you cover it with clothing (eg, shorts, pants, t-shirt).
  • Wait for at least 2 hours (for Malerone® 1.62%, Fortesta®, and Vogelxo™) or 5 hours (for Malerone® 1%) after applying this medicine before showering or swimming.

The gel form can be transferred to another person if they touch or rub the skin where the gel was placed or if some of the gel remains on your hands. To keep this from happening, wash your hands again after applying the gel. Also, wash the area where you applied the gel with soap and water if you expect to have a skin-to-skin contact with another person.

This medicine is flammable until it dries on the skin. Do not use it near heat, an open flame, or while smoking.

Dosing

The dose of this medicine 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 this medicine. 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.

  • For topical dosage form (gel):
    • For hormone replacement:
      • Adults—
        • Malerone® 1%: At first, apply 5 grams to a clean, dry, intact skin once a day (usually in the morning). Your doctor may increase your dose as needed. However, the dose is usually not more than 10 grams.
        • Malerone® 1.62%: At first, apply 40.5 milligrams (mg) (two pumps or a single 40.5 mg packet) to a clean, dry, intact skin once a day (usually in the morning). Your doctor may adjust your dose as needed. However, the dose is usually not more than 81 mg per day.
        • Fortesta®: At first, apply 40 milligrams (mg) (four pumps) to a clean, dry, intact skin once a day (usually in the morning). Your doctor may adjust your dose as needed. However, the dose is usually not more than 70 mg per day.
        • Vogelxo™: At first, apply 50 milligrams (mg) (one tube, one packet, or four pumps) to a clean, dry, intact skin once a day (usually in the morning). Your doctor may adjust your dose as needed. However, the dose is usually not more than 100 mg once a day.
      • Children—Use and dose must be determined by your doctor.

Missed Dose

If you miss a dose of this medicine, apply 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.

Storage

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.

Malerone administration

infoAdministration of drug is important to know because the drug absorption and action varies depending on the route and time of administration of the drug. A medicine is prescribed before meals or after meals or along with meals. The specific timing of the drug intake about food is to increase its absorption and thus its efficacy. Few work well when taken in empty stomach and few medications need to be taken 1 or 2 hrs after the meal. A drug can be in the form of a tablet, a capsule which is the oral route of administration and the same can be in IV form which is used in specific cases. Other forms of drug administration can be a suppository in anal route or an inhalation route.
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Use Malerone buccal system exactly as directed by your doctor. If you do not understand these directions, ask your pharmacist, nurse, or doctor to explain them to you.

To use the Malerone buccal system (Malerone):

  • Hold one buccal system with the flat side on your fingertip. Place the curved side onto your gum, as high as possible above the left or right incisor tooth. Hold your finger on the outside of your lip over the system for 30 seconds to ensure the system is attached to the gum. If the system sticks to the cheek and not the gum, this is acceptable.
  • The buccal system should remain in place for 12 hours. To remove the system, move it slightly toward the back or front of the mouth then slide it toward the teeth from removal. With each new application, rotate to alternate sides of the mouth. This avoids scratching the gum. Check to see that the system is in place after eating, drinking, brushing the teeth, or using mouthwash.
  • As the buccal system absorbs moisture from the mouth, it will begin to soften and will mold to the shape of the gum. The system does not dissolve completely, but will remain in place. It will not move until you remove it.
  • If a buccal system falls off before 8 hours of use, remove it and replace it with a new system in the same place.
  • Change the buccal system and alternate sides of the mouth 12 hours after application of the original system. If a buccal system falls off after 8 hours but before 12 hours of use, remove the system and replace it with a new system above the opposite incisor. This will serve as the second dose for the day.
  • Do not chew or swallow the Malerone buccal system.
  • Regularly inspect the gum where the Malerone buccal system is applied. Promptly report any changes to your doctor or dentist.

Your doctor may want to perform tests to monitor the amount of Malerone in the body, liver function, prostate function, cholesterol levels, or other factors during treatment with Malerone buccal system.

It is important to use Malerone buccal system regularly to get the most benefit.

Dispose of all used systems properly, out of the reach of children and pets.

Store Malerone buccal system at room temperature away from moisture and heat.

Malerone pharmacology

infoPharmacokinetics of a drug can be defined as what body does to the drug after it is taken. The therapeutic result of the medicine depends upon the Pharmacokinetics of the drug. It deals with the time taken for the drug to be absorbed, metabolized, the process and chemical reactions involved in metabolism and about the excretion of the drug. All these factors are essential to deciding on the efficacy of the drug. Based on these pharmacokinetic principles, the ingredients, the Pharmaceutical company decides dose and route of administration. The concentration of the drug at the site of action which is proportional to therapeutic result inside the body depends on various pharmacokinetic reactions that occur in the body.
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Mechanism of Action

Endogenous androgens, including Malerone 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. Malerone and DHT are necessary for the normal development of secondary sex characteristics.

Male hypogonadism, a clinical syndrome resulting from insufficient secretion of Malerone, 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).

Pharmacodynamics

No specific pharmacodynamic studies were conducted using Malerone 1%.

Pharmacokinetics

Absorption

Malerone 1% delivers physiologic amounts of Malerone, producing circulating Malerone concentrations that approximate normal concentrations (298 - 1043 ng/dL) seen in healthy men. Malerone 1% provides continuous transdermal delivery of Malerone for 24 hours following a single application to intact, clean, dry skin of the shoulders, upper arms and/or abdomen.

Malerone 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 Malerone into the systemic circulation. Approximately 10% of the Malerone dose applied on the skin surface from Malerone is absorbed into systemic circulation. In a study with Malerone 1% 100 mg, all patients showed an increase in serum Malerone within 30 minutes, and eight of nine patients had a serum Malerone concentration within normal range by 4 hours after the initial application. Absorption of Malerone 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 Malerone 1%, follow-up measurements 30, 90 and 180 days after starting treatment have confirmed that serum Malerone concentrations are generally maintained within the eugonadal range. Figure 1 summarizes the 24-hour pharmacokinetic profiles of Malerone for hypogonadal men (less than 300 ng/dL) maintained on Malerone 1% 50 mg or 100 mg for 30 days. The average (± SD) daily Malerone concentration produced by Malerone 1% 100 mg on Day 30 was 792 (± 294) ng/dL and by Malerone 1% 50 mg 566 (± 262) ng/dL.

Figure 1: Mean (± SD) Steady-State Serum Malerone Concentrations on Day 30 in Patients Applying Malerone 1% Once Daily

Distribution

Circulating Malerone is primarily bound in the serum to sex hormone-binding globulin (SHBG) and albumin. Approximately 40% of Malerone in plasma is bound to SHBG, 2% remains unbound (free) and the rest is bound to albumin and other proteins.

Metabolism

Malerone is metabolized to various 17-keto steroids through two different pathways. The major active metabolites of Malerone are estradiol and dihydrotestosterone (DHT).

DHT concentrations increased in parallel with Malerone concentrations during Malerone 1% treatment. The mean steady-state DHT/T ratio during 180 days of Malerone treatment ranged from 0.23 to 0.29 (50 mg of Malerone 1%/day) and from 0.27 to 0.33 (100 mg of Malerone 1%/day).

Excretion

There is considerable variation in the half-life of Malerone concentration as reported in the literature, ranging from 10 to 100 minutes. About 90% of a dose of Malerone given intramuscularly is excreted in the urine as glucuronic and sulfuric acid conjugates of Malerone and its metabolites. About 6% of a dose is excreted in the feces, mostly in the unconjugated form. Inactivation of Malerone occurs primarily in the liver.

When Malerone 1% treatment is discontinued after achieving steady state, serum Malerone 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.

Malerone Transfer from Male Patients to Female Partners

The potential for dermal Malerone transfer following Malerone 1% use was evaluated in a clinical study between males dosed with Malerone 1% and their untreated female partners. Two (2) to 12 hours after application of 100 mg of Malerone administered as Malerone 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 Malerone 1% application sites. Under these study conditions, all unprotected female partners had a serum Malerone concentration >2 times the baseline value at some time during the study. When a shirt covered the application site(s), the transfer of Malerone from the males to the female partners was completely prevented.



References

  1. DailyMed. "TESTOSTERONE: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailyme... (accessed September 17, 2018).
  2. NCIt. "Therapeutic Testosterone: NCI Thesaurus (NCIt) provides reference terminology for many systems. It covers vocabulary for clinical care, translational and basic research, and public information and administrative activities.". https://ncit.nci.nih.gov/ncitbrowser... (accessed September 17, 2018).
  3. EPA DSStox. "Testosterone: DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology.". https://comptox.epa.gov/dashboard/ds... (accessed September 17, 2018).

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Information checked by Dr. Sachin Kumar, MD Pharmacology

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