Leuprolide Acetate - Hormone Dependent Conditions

Overview

A synthetic 9-residue peptide counterpart of the gonadotropin-releasing hormone is called Leuprolide. Leuprolide has a single D-amino acid (D-leucyl) residue, unlike the endogenous decapeptide GnRH (gonadotropin-releasing hormone), which contributes to an increase in its circulation half-life from three to four minutes to roughly three hours. Leuprolide, a GnRH mimic, has the ability to bind to the gonadotropin-releasing hormone receptor (GnRHR) and cause downstream regulation of the levels of both gonadotropin hormone and sex steroids. Leuprolide's clinical effectiveness in a variety of illnesses, including advanced prostate cancer, central precocious puberty, and endometriosis, is mostly attributable to the prolonged activation of gonadotropin-releasing hormone receptor (GnRHR), which causes a considerable downregulation of sex steroid levels.

Agonist of gonadotropin-releasing hormone (GnRH), Leuprolide, alters how the pituitary gland functions and produces fewer hormones, such as estrogen and testosterone. Leuprolide was initially created by scientists as a medication to combat prostate cancer. The drug induces a menopausal-like state in endometriosis patients' bodies. Menstruation stops, and symptoms of estrogen withdrawal, like hot flashes, commonly appear. Some endometriosis symptoms may get better or go away with these adjustments because the condition is estrogen dependent. For instance, endometriosis-related excessive bleeding and pain during periods may stop as well as the period itself.

AbbVie, an American biopharmaceutical company, received the initial approval for Leuprolide in 1985 as a daily subcutaneous injection. Numerous long-acting subcutaneous and intramuscular medicines have been created since this first approval, allowing patients to get a dosage once every six months. Leuprolide continues to be the first line of treatment for all disorders for which it is approved.

Indications of the Drug:

The drug Leuprolide acetate is indicated in:

1. The treatment of endometriosis and includes the easing of pain and the reduction of endometriotic lesions.

2. The treatment of uterine fibroids.

3. The treatment of advanced prostate cancer.

4. The treatment of kids with central precocious puberty (CPP).

What Is Leuprolide Acetate's Mechanism of Action?

Endometriosis is treated with Leuprolide injection, either alone or in combination with another drug (norethindrone). Anemia (a lower-than-usual amount of red blood cells) brought on by uterine fibroids (noncancerous growths in the uterus) can also be treated with Leuprolide injection in combination with other medications. Leuprolide injection belongs to a group of drugs known as GnRH (gonadotropin-releasing hormone) agonists. It functions by lowering the body's levels of specific hormones. This medicine lowers the body's level of estrogen, one of the hormones that trigger periods, by turning off the hormones the ovaries produce. The estrogen level will increase after the first injection or shot of the drug before it declines. "Estrogen surge" is the term used for this. One can have an increase in their symptoms for a few weeks as a result of this surge in estrogen. The estrogen levels will drop after this estrogen rise. Periods will temporarily be stopped by this. Usually, endometriosis symptoms go away after one stops having periods.

Contraindications:

• Patients known to be hypersensitive to the gonadotropin-releasing hormone, gonadotropin-releasing hormone agonist analogs, or any of the excipients of the drug Leuprolide injection are contraindicated for Leuprolide acetate.

• Leuprolide acetate should not be used by pregnant females or who may conceive while taking the medication. When given to a pregnant woman, the drug may harm the fetus. Therefore, if the medication is given during pregnancy, it is possible that a spontaneous abortion will take place. The patient should be informed of the potential risk to the fetus if this medication is given during pregnancy or if the patient gets pregnant while taking any formulation of the medication.

Dosage of Leuprolide:

The suggested dosage is once the daily subcutaneous injection of 1 mg (0.2 mL, or 20 unit mark). The injection site should be changed sporadically, just like with other medications given chronically via subcutaneous injection. Each 0.2 mL includes 1 mg of Leuprolide acetate, 1.8 mg of benzyl alcohol as a preservative, sodium chloride for adjusting tonicity, and water for injection. It is possible that acetic acid or sodium hydroxide was used to change the pH.

Overdosage:

According to body weight, subcutaneous treatment of 250 to 500 times the advised human dose in rats caused dyspnea, impaired function, and localized irritation at the site of injection. There is currently no proof that this phenomenon has a clinical counterpart. Initial clinical trials with Leuprolide acetate showed no side effects different from those seen with the 1 mg per day dose at doses as strong as 20 mg per day for up to two years.

Warnings and Precautions:

• Like other luteinizing hormone-releasing hormone (LH-RH) agonists, Leuprolide first raises the levels of testosterone in the serum. Occasionally, during the first few weeks of Leuprolide treatment, symptoms may temporarily worsen, or new signs and symptoms may appear.

• A small percentage of patients might have an increase in their bone pain that passes quickly and can be treated symptomatically. The spinal cord compression and isolated occurrences of ureteral obstruction that have been reported with other LH-RH agonists may cause paralysis with or without fatal side effects.

• Leuprolide acetate has not been clinically proven safe for usage during pregnancy. Pregnancy must be ruled out before beginning the medication.

• It is advised to routinely check the levels of blood testosterone and prostate-specific antigen (PSA), particularly if the anticipated biochemical or clinical response to treatment has not yet been realized. It should be mentioned that the assay methodology affects the findings of testosterone measurements. To make the best clinical and therapeutic decisions, it is necessary to be informed of the type and precision of the test methodology.

• During the first few weeks of treatment, patients with metastatic vertebral lesions and urinary tract obstruction should be thoroughly monitored.

• Patients with documented benzyl alcohol allergies may exhibit hypersensitive symptoms, which are often localized and manifest as erythema and induration at the injection site.

For Patients:

What Is Endometriosis?

Endometriosis is a condition in which endometrium, the tissue that usually lines the interior of the uterus, grows outside of the uterus. The tissue lining the pelvic region, fallopian tubes, and ovaries are all frequently affected by endometriosis. Rarely, tissue resembling endometrium may be seen outside the region around the pelvic organs.

Endometrial-like tissue behaves like endometrial tissue and swells, breaks down, and bleeds out with each menstrual period if the individual is affected by endometriosis. However, this tissue becomes imprisoned since it has nowhere to go but inside the body. Endometriomas, or endometrial cysts, can develop when endometriosis affects the ovaries. Scar tissue and adhesions, bands of fibrous tissue that can enable pelvic organs and tissues to adhere to surrounding tissue, can form when the tissue becomes irritated. Pain from endometriosis, which can occasionally be severe, is common, especially during menstruation. Additionally, fertility issues could arise.

What Are the Symptoms Observed During Endometriosis?

The main sign of endometriosis is pelvic pain, which is frequently related to menstruation. Although many women suffer cramps throughout their periods, individuals who have endometriosis frequently have significantly more severe menstrual pain than usual. Over time, pain may potentially get worse.

The Following Are Typical Endometriosis Symptoms and Signs:

• Before and for a few days after a period, pelvic pain and cramps are common.

• Dysmenorrhea or painful menstruation cycle.

• Lower back and stomach ache.

• Discomfort when urinating.

• Pain during or after sex.

• Heavy periods or intermenstrual bleeding.

• Infertility.

Additional symptoms and indicators which are observed are; during menstrual periods, one can have lethargy, diarrhea, constipation, bloating, or nausea. An individual's condition's severity may not always be accurately predicted by how much pain they are in. Endometriosis can be moderate and cause considerable pain, or it can be advanced and cause little to no pain.

How to Diagnose Endometriosis?

The physician will ask patients to describe their symptoms, along with the site of the pain and when it happens, in order to identify endometriosis and other disorders that can cause pelvic discomfort.

Tests to Look For Endometriosis Physical Signs Include:

1. Pelvic Exam - The doctor will physically feel (palpate) various parts of the pelvis during a pelvic exam to check for any abnormalities.

2. Ultrasound - High-frequency sound waves are employed in this examination to produce images of the interior of the body. A tool known as a transducer is either placed against the abdomen or introduced into the vagina to acquire the images (transvaginal ultrasound).

3. Magnetic Resonance Imaging - An MRI is a test that produces finely detailed images of the body's organs and tissues using a magnetic field and radio waves. Some people find that an MRI aids in surgical planning by providing the surgeon with specific details regarding the size and location of endometrial implants.

4. Laparoscopy - The doctor may occasionally recommend that one sees a surgeon for a procedure that will enable the surgeon to see within the abdomen. Under general anesthesia, the doctor makes a small incision close to the navel and inserts a laparoscope to check for evidence of endometrial tissue outside the uterus.

How to Treat Endometriosis?

Medication or surgery is typically used to treat endometriosis. The course of action the patient and their doctor take will depend on the severity of their symptoms and whether or not the patient wants to get pregnant. Doctors often advise trying conservative treatment methods first and only resorting to surgery if such methods fail.

• Painkillers:

If patients suffer from unpleasant menstrual cramps, the doctor may advise them to take an over-the-counter pain medicine, such as Ibuprofen. If they are not attempting to conceive, the doctor may advise hormone therapy in addition to painkillers.

• Hormone Therapy:

Endometriosis discomfort can occasionally be lessened or completely eliminated with the help of additional hormones. Endometrial implants thicken, disintegrate, and bleed as a result of the hormonal fluctuations that occur during the menstrual cycle. Hormone therapy may reduce endometrial tissue growth and stop new endometrial tissue implants. Endometriosis cannot be permanently treated with hormone therapy. Following the end of the treatment, the symptoms can come back.

Endometriosis Is Treated With the Following Methods:

• Hormonal Contraceptives: Birth control pills, patches, and vaginal rings assist in regulating the hormones that cause the monthly accumulation of endometrial tissue.

When using a hormonal contraceptive, many women experience lighter and shorter menstrual cycles. In some circumstances, using hormonal contraceptives, particularly continuous-cycle regimens, may lessen or completely eliminate pain.

• Gonadotropin-releasing Hormones: These medications suppress estrogen levels and stop menstruation by blocking the synthesis of ovarian-stimulating hormones. Endometrial tissue contracts as a result.

• Anti-aromatase Drugs: A group of medications known as aromatase inhibitors works to lower the estrogen level in the body. In order to manage endometriosis, the doctor may advise using a combination hormonal contraception that combines an aromatase inhibitor with a progestin.

• Progestin Therapy: Numerous progestin treatments, such as an intrauterine device, a contraceptive implant, an intravenous contraceptive, or a progestin pill, can stop menstruation and the development of endometrial implants, which may alleviate the signs and symptoms of endometriosis.

How Should This Medicine Be Given?

A doctor or nurse will typically administer Leuprolide injection intramuscularly (into a muscle) once a month or every three, four, or six months. Leuprolide injection is available as a long-acting suspension, which is administered by a physician or nurse in a hospital or clinic on a regular basis subcutaneously (just beneath the skin). How long the Leuprolide injectable treatment will last will be determined by the doctor. When the patient initially gets Leuprolide long-acting suspension by subcutaneous injection, they can experience a little bump where the injection was administered. This bump ought to disappear gradually. In the first few weeks following injection, Leuprolide may boost levels of several hormones. Throughout this period, the doctor will keep a close eye on the patient for any new or worsening symptoms.

How Is the Drug Supplied and Stored?

Leuprolide acetate is a sterile injection that comes in 2.8 mL multiple-dose vials. Following is how the vial is packaged: The 14-Day Patient Administration Kit includes 14 single-use syringes, 28 alcohol swabs, and a six-vial carton. The drug should be kept below 77° Fahrenheit (25° Celsius). The drug should not be frozen. When not in use, the vial should be kept in a carton and shielded from light.

For Doctors:

Clinical Pharmacology:

When administered continuously and in therapeutic quantities, the LH-RH agonist Leuprolide acetate exerts a significant inhibitory effect on the release of gonadotropins. Studies on animals and people show that persistent administration of Leuprolide acetate suppresses ovarian and testicular steroidogenesis after initially stimulating gonadotropins. Upon stopping medication therapy, this effect can be reversed. Leuprolide acetate administration has been shown to cause atrophy of the reproductive organs as well as a suppression of the growth of several hormone-dependent malignancies.

In humans, a single daily dose of Leuprolide acetate causes a transient rise in the levels of the gonadal steroids, dihydrotestosterone, and testosterone, in men and estrone and estradiol, in premenopausal women. This rise is caused by an initial rise in the levels of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) in the blood. LH and FSH levels fall with a continued daily dose of Leuprolide acetate, though. Castrate levels of testosterone are reached in males. Estrogen levels drop to post-menopausal levels in premenopausal females.

Pharmacodynamics:

An analog of gonadotropin-releasing hormone (GnRH), Leuprolide acts as a superagonist for the GnRH receptor. In keeping with other types of androgen-deprivation therapy, chronic administration causes a considerable decline in circulating steroid levels after an initial surge in GnRH-mediated steroid synthesis, including testosterone and estradiol. The associated hormonal and steroid alterations cause particular negative effects in certain patient populations.

It is recommended that pregnant women who are receiving treatment for uterine leiomyomata or endometriosis give their pregnancy status significant thought. Estradiol levels may initially rise, which could make symptoms like discomfort and bleed worse. A decrease in bone mineral density is a side effect of long-term Leuprolide use. Patients who use norethisterone and other drugs concurrently run the risk of sudden vision loss, diplopia, proptosis, migraines, thrombophlebitis, pulmonary embolism, and cardiovascular disease. Patients who have previously battled depression may face a serious relapse.

Short-term increases in testosterone levels may promote tumor flare and accompanying symptoms such as hematuria, bone pain, neuropathy, bladder and ureteral blockage, and spinal cord compression in men receiving palliative care for advanced or metastatic prostate cancer. The risk of developing hyperglycemia and cardiovascular problems is also elevated in individuals. These conditions can appear as stroke, myocardial infarction, cardiac mortality, or a prolonged QT/QTc interval. Leuprolide can also harm developing fetuses and cause convulsions.

Within 2-4 weeks after starting treatment, the initial steroidal rise may be linked to an increase in the clinical indicators of puberty in pediatric patients being treated for central precocious puberty (CPP). Leuprolide may also result in convulsions and mental symptoms such as sobbing, frustration, hostility, and wrath.

Mechanism of Action of the Drug:

The hypothalamic-pituitary-gonadal (HPG) axis is modulated by the naturally occurring decapeptide gonadotropin-releasing hormone (GnRH). The release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH), which in turn affect the production and distribution of the sex hormones testosterone, dihydrotestosterone, estrone, and estradiol, is influenced by the binding of GnRH to the corresponding receptors on the anterior pituitary gonadotropes.

Despite the wide range of illnesses that Leuprolide is prescribed to treat, its efficacy is always supported by the same mechanism of action. Leuprolide is a GnRH agonist that binds to downstream FSH and LH release, activating it initially. This initial rise in gonadotropin levels is the cause of some of the side effects related to treatment. After two to four weeks of therapy, persistently stimulating GnRHR causes feedback inhibition, a considerable downregulation of LH and FSH, and their associated downstream effects, providing therapeutic benefit. In the event that the treatment is stopped, these symptoms will disappear.

Absorption:

The most common way to deliver Leuprolide is as a single dosage of a long-acting formulation that uses either biodegradable or microsphere solid depot technology. The Cmax is normally reached by four to five hours after injection, regardless of the precise formulation and the strength of the initial dose, and it varies greatly between 4.6 and 212 ng/mL. A smaller range of 0.1 - 2 ng/mL is often reached at the end of four weeks for eventual steady-state kinetics. No research has been done on how food affects absorption.

Distribution:

Following intravenous bolus delivery of Leuprolide to healthy males, there is an apparent 27 L steady-state volume of distribution for the drug. It is unknown what the distribution volume is for the recommended intramuscular or subcutaneous injection routes.

Metabolism:

A 1 mg bolus of Leuprolide given intravenously to healthy male volunteers exhibited a mean systemic clearance of 7.6 L/h with a terminal elimination half-life of roughly three hours based on a two-compartment model. Leuprolide, which had been 14C-labeled, was administered to rats and dogs, and it was discovered that it was broken down into smaller, inactive peptides, including a pentapeptide, tripeptides, and a dipeptide. These pieces might undergo more catabolization.

The primary metabolite (M-I) plasma concentrations were 6% of the peak parent drug concentration and reached their greatest concentration two to six hours after the dose in 5 prostate cancer patients. Mean plasma M-I concentrations were 20% of mean leuprolide concentrations a week after dosing.

Elimination:

Less than 5% of the first dosage of 3.75 mg of Leuprolide depot suspension that was given to three patients was retrieved as an unaltered or pentapeptide metabolite in the urine.

Half-Life of the Drug:

The terminal elimination half-life of Leuprolide is about three hours.

Clearance:

The mean systemic clearance of Leuprolide in healthy males delivered as a 1 mg intravenous bolus ranges from 7.6 to 8.3 L/h.

Toxicity:

Leuprolide is thought to be very safe, with minimal dose-related toxicity and relatively minor side effects. Compared to those getting 1 mg/day, individuals with prostate cancer receiving Leuprolide at a high dose of 20 mg/day for a two-year period had no additional side effects.

Interaction With Other Drugs:

Leuprolide acetate has not been the subject of any drug-drug interaction investigations based on pharmacokinetics. Drug interactions, however, would not be anticipated because Leuprolide acetate is a peptide that is predominantly broken down by peptidase and not by cytochrome P-450 enzymes, as indicated in certain investigations, and the drug is only around 46 % bound to plasma proteins.

Results From Clinical Studies:

After two years of treatment, the survival rates for the two groups in controlled research comparing LUPRON (Leuprolide acetate) 1 mg/day administered subcutaneously to DES (diethylstilbestrol) 3 mg/day were comparable. Both groups' objective responses to the treatment were comparable.

Carcinogenesis:

Studies on the carcinogenicity of rats and mice were done over a two-year period. When the medication was given subcutaneously at high daily dosages (0.6 to 4 mg/kg) to rats, a dose-related rise in benign pituitary adenomas and benign pituitary hyperplasia was observed at 24 months. Both female pancreatic islet-cell adenomas and male testicular interstitial cell adenomas increased significantly but not in a dose-related manner. When given to mice for two years at a level of up to 60 mg/kg, no alterations of the pituitary were seen. Leuprolide acetate has been administered to patients for up to three years at a high dose of 10 mg/day and for two years at a dose of 20 mg/day without obvious pituitary abnormality.

Mutagenesis:

Leuprolide acetate has been the subject of mutagenicity tests employing bacterial and mammalian systems. There was no proof of a mutagenic potential in this research.

Impairment of Fertility:

Leuprolide acetate and related analogs show full reversibility of fertility suppression when the drug is withdrawn after a continuous administration for a period of up to 24 weeks in clinical and pharmacologic investigations in adults (18 years). Leuprolide acetate has not been the subject of any clinical research evaluating the reversibility of fertility suppression, nevertheless.

How to Use the Drug?

1. With soap and water, thoroughly wash the hands.

2. Flip off the plastic cover on a brand-new bottle to reveal the gray rubber stopper before using it. Each time one uses Leuprolide, the metal ring should be cleaned, and the rubber stopper should be wiped clean with an alcohol wipe. Verify the liquid content of the bottle. Do not use it if it has impurities or is not clear.

3. Take one syringe's outer covering off. The plunger should be pulled back until the tip is at the 0.2 mL or 20 unit mark.

4. Remove the needle's cover. Insert the needle into the medicine bottle's rubber stopper in the middle.

5. To inject, fully engage the plunger.

6. Keep the needle inside the bottle and tip it on its side. Verify that the needle's tip is in the fluid by looking. Pull the plunger back gradually until the syringe has filled to the 0.2 mL or 20 unit level.

7. There would not be much medication in the bottle by the end of the two-week term. When drawing back on the plunger, take extra care to hold the bottle straight and maintain the needle tip submerged in liquid.

8. Examine the syringe for air bubbles while keeping the syringe in the bottle, and the bottle is turned upside down. Whenever one spot one, gently press the plunger in to force the air bubble into the bottle again. Pull the plunger back once more to fill to the 0.2 mL or 20 unit mark while keeping the needle's tip in the liquid.

9. Repeat this process to get rid of air bubbles if necessary.

10. Inject each dose every day at a separate body location to protect the skin.

11. Decide where to inject. Use a second alcohol wipe to clean the injection site.

12. Use one hand to hold the syringe. Hold the skin taut or, when directed, use the other hand to draw up a small amount of flesh.

13. The needle should be inserted at a 90-degree angle into the skin while holding the syringe like a pencil.

14. To give the injection, press the plunger.

15. Retract the needle at the same angle it was inserted and place an alcohol swab on the skin where the needle was inserted.

16. Only use the disposable syringe once, and then dispose of it as directed. Needles placed in a trash bag run the risk of accidentally sticking someone.