Degarelix

Degarelix is an antineoplastic agent belonging to the pharmacological class of Gonadotropin-releasing hormone (GnRH) antagonists.

Degarelix has been approved by the FDA for treating Advanced Prostate Carcinoma (Stage D).

When administered subcutaneously, degarelix develops a depot that releases slowly into the bloodstream. It binds to plasma proteins significantly and distributes widely, with a volume of distribution of 1 L/kg. Peptide hydrolysis occurs during metabolism, but CYP450 is not involved. Urine (20–30%) and faeces (70–80%) are the primary routes of elimination.

The most common side effects of Degarelix include injection site reactions (pain, swelling, redness), weight gain, hot flashes, increased liver enzymes, and low sexual desire.

Degarelix is available as a powder for injection.

The molecule is available in Germany, the United States, Canada, France, Italy, the United Kingdom, Australia, and Japan.

Degarelix is an antineoplastic agent belonging to the pharmacological class of Gonadotropin-releasing hormone (GnRH) antagonists.

By competitively inhibiting GnRH receptors in the pituitary gland, degarelix stops the release of follicle-stimulating and luteinizing hormones (LH). Decreased LH inhibits the release of testosterone, which slows the growth and shrinks the size of prostate cancers.

Degarelix exhibits its onset of action within three days.

Degarelix reaches its peak plasma concentration within two days, particularly with the loading dose.

Injectable solutions: To be administered parenterally as applicable.

The physician recommends the frequency, and the course duration, it can be taken with or without food.

Prostate cancer: In males, the prostate gland, a small walnut-sized organ, produces seminal fluid that nourishes and transports sperm. Degarelix rapidly suppresses testosterone production, an essential hormone driving the growth of prostate cancer, and so effectively treats hormone-dependent advanced prostate carcinoma (Stage D). It quickly lowers testosterone levels, providing immediate symptom relief and delaying the course of the illness.

Degarelix is indicated in the following health conditions:

• For treatment of advanced hormone-dependent prostate cancer in adult male patients.
• In combination with radiotherapy for treatment of hormone-dependent prostate cancer that is both locally advanced and at high risk.
• In those patients with high-risk localized or locally advanced hormone-dependent prostate cancer, as a neoadjuvant treatment before radiotherapy.

Parenterally: Administer Degarelix by injecting subcutaneously into the abdominal wall. The initiation pack contains six millilitres of sterile water for the injection diluent and two vials, each holding 120 mg. Take 3 mL of the diluent, pour it into a vial, and stir to combine. Give the reconstituted solution within an hour, and then administer the second injection at a different site, following the same procedure. The maintenance pack contains one vial containing 80 mg and 4.2 millilitres of diluent. To achieve an 80 mg dose, reconstitute with 4.2 mL and remove 4 mL. Adhere to aseptic procedures to ensure correct drug integrity and avoid contamination. To prevent reactions, rotate the injection sites.

The dosage and duration of treatment should be as per the treating physician's clinical judgment.

Degarelix is available as a powder for injection.

Dose Adjustment in Adult Patients:

Hormone-dependent Advanced Prostate Carcinoma (Stage D)

In two separate injections of 120 mg each, the loading dose is 240 mg as a 40 mg/mL solution.

28 days following the first dose, maintenance should begin with 80 mg once every 28 days as a 20 mg/mL solution.

Follow the dietary guidelines while taking Degarelix; Avoid smoking and alcohol consumption for optimal results. Additionally, refrain from consuming fast food, fried items, processed meats, refined carbs, and added sugars to support your overall well-being.

The dietary restriction should be individualized as per patient requirements.

• Hypersensitivity to Degarelix or any of its excipients
• Pregnancy

• It is advised to exercise caution in case of severe liver impairment.
• The use of androgen deprivation therapy may lengthen the QT interval; evaluate risks in individuals with heart failure, long QT syndrome, electrolyte imbalances, or who are taking drugs that prolong the QT period; resolve electrolyte imbalances; and consider routine electrocardiogram and electrolyte monitoring.
• Bone mineral density may be reduced by androgen deprivation therapy.
• Insulin resistance and obesity are outcomes of androgen deprivation's increased risk of diabetes.
• Hypersensitivity reactions (anaphylaxis, urticaria, angioedema) have been reported; if a significant reaction happens during injection, stop the medication immediately; treat it as a doctor recommends, and don't follow up.

It is not indicated for use during pregnancy.

The clinically relevant drug interactions of Degarelix are briefly summarized here.

QT prolongation is more likely to occur when using class IA (disopyramide) or class III (amiodarone) antiarrhythmics, antipsychotics, methadone, and moxifloxacin.

The common side effects of Degarelix include

Hot flushes

Reactions at the injection site (pain, redness, swelling)

Weight gain

Fatigue

Increased liver enzymes

Low sexual desire

Erectile dysfunction

Nausea

Diarrhoea

Dizziness

Headache

• Pregnancy

Pregnancy Category X (FDA): When pregnant, avoid using. The risks outweigh the potential benefits. There are safer alternatives available.

Not proven to be safe or effective in women

Animal data

The mechanism of action and results from animal studies suggest that a drug may harm fetuses and cause pregnancy loss when given to pregnant women. Human data on drug use in pregnancy is lacking, making it difficult to determine the risks associated with drug use. Oral administration of degarelix during organogenesis caused abortion and embryo-fetal lethality in rats and rabbits, increased post-implantation loss, and decreased number of live fetuses in animals at doses lower than clinical loading dose based on body surface area; pregnant patients and females with reproductive potential should be advised of the potential risk to the fetus.

According to research on animals and their mode of action, degarelix may reduce fertility in both males and females capable of reproduction.

• Nursing Mothers

There is no information on the presence of drugs in human milk, their effects on breastfed children, or their effects on milk production. Since many drugs are present in human milk and there is a chance that a breastfed child may experience serious adverse reactions from therapy, it is up to the mother to decide whether to stop nursing or to stop taking Degarelix. All of these factors should be taken into consideration.

• Pediatric Use

As per the FDA, Degarelix has not been indicated in pediatric patients.

• Geriatric Use

82% of the subjects in TRADENAME clinical trials were 65 years of age or older, and 42% were 75 years of age or older. Although there were no overall differences in safety or effectiveness between these subjects and younger subjects, some older people may be more sensitive than others.

Dose Adjustment in Kidney Impairment Patients:

≥50 mL/min: No need to adjust the dosage.

<50 mL/min: Continue with caution.

Dose Adjustment in Hepatic Impairment Patients:

Mild to moderate: No need to change dosage.

Severe: Use caution as safety and efficacy have not been established.

Pharmacodynamic

The ligand of the GnRH receptor, GnRH decapeptide, is synthesized to produce degarelix. When endogenous GnRH binds to the GnRH receptor, androgen and gonadotropin are produced. Degarelix inhibits the release of LH and FSH from the pituitary by antagonistically interacting with the GnRH receptor. A concentration-dependent decline is observed in both LF and FSH. Testicular release of testosterone decreases in response to a decrease in LH.

Pharmacokinetics

• Absorption: A depot forms at the injection site when degarelix is injected subcutaneously. With a time-to-peak plasma concentration of two days for the loading dose, the medication is progressively released into circulation.
• Distribution: Degarelix diffuses throughout the body's tissues with an estimated volume of distribution of approximately 1 L/kg and a plasma protein binding of about 90%.
• Metabolism: Between 70% and 80% of degarelix is impacted by peptide hydrolysis, which takes place during the hepatic passage. Without the involvement of CYP450 isozymes or the production of active or inactive metabolites, this process leads to the faecal elimination of peptide fragments.
• Excretion: About 70–80% of degarelix is eliminated through faeces, primarily as peptide fragments, and the remaining 20–30% is eliminated through urine. For the loading dose, the terminal elimination half-life is roughly 43–53 days, and for the maintenance dose, it is approximately 28 days.

• Klotz L, Boccon-Gibod L, Shore ND, Andreou C, Persson BE, Cantor P, Jensen JK, Olesen TK, Schröder FH. The efficacy and safety of degarelix: a 12-month, comparative, randomized, open-label, parallel-group phase III study in patients with prostate cancer. BJU Int. 2008 Dec;102(11):1531-8. doi: 10.1111/j.1464-410X.2008.08183.x. PMID: 19035858.
• Zengerling F, Jakob JJ, Schmidt S, Meerpohl JJ, Blümle A, Schmucker C, Mayer B, Kunath F. Degarelix for treating advanced hormone-sensitive prostate cancer. Cochrane Database Syst Rev. 2021 Aug 5;8(8):CD012548. doi: 10.1002/14651858.CD012548.pub2. PMID: 34350976; PMCID: PMC8407409.
• Ozono S, Tsukamoto T, Naito S, Ohashi Y, Ueda T, Nishiyama T, Maeda H, Kusuoka H, Akazawa R, Ito M, Akaza H. Efficacy and safety of a 3-month dosing regimen of degarelix in Japanese patients with prostate cancer: a phase II maintenance-dose-finding study. Jpn J Clin Oncol. 2017 May 1;47(5):438-446. doi: 10.1093/jjco/hyx011. PMID: 28334771; PMCID: PMC5421626.
• Uttley L, Whyte S, Gomersall T, Ren S, Wong R, Chambers D, Tappenden P. Degarelix for Treating Advanced Hormone-Dependent Prostate Cancer: An Evidence Review Group Perspective of a NICE Single Technology Appraisal. Pharmacoeconomics. 2017 Jul;35(7):717-726. doi: 10.1007/s40273-016-0481-1. PMID: 27943135.
• Crawford ED, Shore ND, Moul JW, Tombal B, Schröder FH, Miller K, Boccon-Gibod L, Malmberg A, Olesen TK, Persson BE, Klotz L. Long-term tolerability and efficacy of degarelix: 5-year results from a phase III extension trial with a 1-arm crossover from leuprolide to degarelix. Urology. 2014 May;83(5):1122-8. doi: 10.1016/j.urology.2014.01.013. Epub 2014 Mar 22. PMID: 24661333.

• US Food and Drug Administration (FDA) [Internet]. Maryland. USA; Package leaflet information for the user; Tradename® (degarelix)
• https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/022201lbl.pdf
• April Hazard Vallerand, Cynthia A. Sanoski. [link]. Sixteenth Edition. Philadelphia, China: F. A. Davis Company; 2019: Page No 408-410
• https://www.ncbi.nlm.nih.gov/books/NBK548578/