Degarelix Acetate

1632.28

1630.748779

1312995-182-4

SX0XJI3A11

C48385

L02BX02|L - Antineoplastic and immunomodulating agents

513

4.45

1.3±0.1 g/cm3

1.620

White to off-white amorphous powder /Degarelix, acetate anhydrate/

P201, P202, P281, P308+P313, P405, P501

H360

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.|SRP: At the time of review, regulatory criteria for small quantity disposal are subject to significant revision, however, household quantities of waste pharmaceuticals may be managed as follows: Mix with wet cat litter or coffee grounds, double bag in plastic, discard in trash.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, including degarelix acetate, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Degarelix acetate/

Gloves should be worn during preparation and administration

The most commonly observed adverse reactions (> 10%) during degarelix therapy included injection site reactions (e.g., pain, erythema, swelling, or induration), hot flashes, increased weight, and increases in serum levels of transaminases and gamma-glutamyltransferase (GGT).

Degarelix therapy has been associated with serum enzyme elevations in up to one-third of patients. The elevations, however, are generally mild and self-limited, resolving even without dose adjustment. ALT values above 3 times the ULN occur in less than 1% of patients. Occasional patients require drug discontinuation because of serum enzyme elevations, but no instances of liver injury with jaundice or clinically apparent acute liver injury were reported in the initial clinical trials of degarelix. Since its approval and more widescale use, there have been no published reports of clinically apparent liver injury attributed to degarelix, although its general use has been limited.

Since androgen deprivation treatment may prolong the QTc interval, the concomitant use of degarelix with medicinal products known to prolong the QTc interval or medicinal products able to induce torsades de pointes such as class IA (e.g. quinidine, disopyramide) or class III (e.g. amiodarone, sotalol, dofetilide, ibutilide) antiarrhythmic medicinal products, methadone, cisapride, moxifloxacine, antipsychotics, etc. should be carefully evaluated.

A reduction in glucose tolerance has been observed in men who have had orchiectomy or who have been treated with a GnRH agonist. Development or aggravation of diabetes may occur; therefore diabetic patients may require more frequent monitoring of blood glucose when receiving androgen deprivation therapy. The effect of degarelix on insulin and glucose levels has not been studied.|Long-term androgen deprivation therapy prolongs the QT interval. Physicians should consider whether the benefits of androgen deprivation therapy outweigh the potential risks in patients with congenital long QT syndrome, electrolyte abnormalities, or congestive heart failure and in patients taking Class IA (e.g. quinidine, procainamide) or Class III (e.g. amiodarone, sotalol) antiarrhythmic medications. In the randomized, active-controlled trial comparing Firmagon to leuprolide, periodic electrocardiograms were performed. Seven patients, three (<1%) in the pooled degarelix group and four (2%) patients in the leuprolide 7.5 mg group, had a QTcF > or + 500 ms. From baseline to end of study the median change for Firmagon was 12.3 msec and for leuprolide was 16.7 msec.

90% of the drug is bound to plasma proteins.

Degaralix is used for the management of advanced prostate cancer.|FDA Label|Firmagon is a gonadotrophin-releasing-hormone (GnRH) antagonist indicated for treatment of adult male patients with advanced hormone-dependent prostate cancer.|Drug: Degarelix

Degarelix is a parenterally administered, gonadotropin releasing hormone (GnRH) antagonist that effectively blocks androgen production and is used to treat advanced prostate cancer. Degarelix therapy is associated with serum enzyme elevations during therapy, but has yet to be linked to instances of clinically apparent acute liver injury.

Antineoplastic Agents

Degarelix is used for the treatment of advanced prostate cancer. /Use included in US product label/

Degarelix is contraindicated in women who are or may become pregnant. Degarelix can cause fetal harm when administered to a pregnant woman.|FDA Pregnancy Risk Category: X /CONTRAINDICATED IN PREGNANCY. Studies in animals or humans, or investigational or post-marketing reports, have demonstrated positive evidence of fetal abnormalities or risk which clearly outweights any possible benefit to the patient./|The most frequently reported adverse reactions at the injection sites were pain (28%), erythema (17%), swelling (6%), induration (4%) and nodule (3%). These adverse reactions were mostly transient, of mild to moderate intensity, occurred primarily with the starting dose and led to few discontinuations (<1%). Grade 3 injection site reactions occurred in 2% or less of patients receiving degarelix.|A total of 1325 patients with prostate cancer received Firmagon either as a monthly treatment (60-160 mg) or as a single dose (up to 320 mg). A total of 1032 patients (78%) were treated for at least 6 months and 853 patients (64%) were treated for one year or more. The most commonly observed adverse reactions during Firmagon therapy included injection site reactions (e.g. pain, erythema, swelling or induration), hot flashes, increased weight, fatigue, and increases in serum levels of transaminases and gammaglutamyltransferase (GGT). The majority of the adverse reactions were Grade 1 or 2, with Grade 3/4 adverse reaction incidences of 1% or less.|For more Drug Warnings (Complete) data for Degarelix (15 total), please visit the HSDB record page.

Degarelix is a synthetic derivative of GnRH decapeptide, the ligand of the GnRH receptor. Gonadotropin and androgen production result from the binding of endogenous GnRH to the GnRH receptor. Degarelix antagonizes the GnRH receptor which in turn blocks the release of LH and FSH from the pituitary. LF and FSH decreases in a concentration-dependent manner. The reduction in LH leads to a decrease in testosterone release from the testes.

Degarelix forms a depot at the site of injection after subcutaneous administration from which the drug slowly released into circulation. After a single bolus dose of 2mg/kg, peak plasma concentrations of degarelix occured within 6 hours at a concentration of 330 ng/mL. Ki = 0.082 ng/mL and 93% of receptors were fully suppressed; MRT = 4.5 days.|Fecal (70% to 80%) and renal (20%-30% of unchanged drug)|Central compartment: 8.88 - 11.4 L; Peripheral compartment: 40.9 L|Following subcutaneous administration of degarelix to prostate cancer patients the clearance is approximately 9 L/hr.|The protein binding in plasma of mouse, rat, dog, monkey, and humans was measured using the (3)H-degarelix and the ultracentrifugation technique. The plasma binding was approximately 90% in animals and humans. Distribution of radioactivity following administration of (3)H-degarelix was studied in rats, dogs and monkeys, doses were respectively 0.03 mg/kg, 0.003 mg/kg and 0.0082 mg/kg. Radioactivity of tissues was measured after sacrifice and necropsy of the animals. High concentrations were mainly seen at the s.c. injection site and in organs of excretion. Lower concentrations, but still higher than those in plasma were generally seen in some organs of the endocrine and reproductive systems most of which contain specific receptors for LHRH, and organs rich in reticuloendothelial cells during the elimination phase. There was no indication of tissue retention.|Balance of the radioactivity following SC administration of (3)H-degarelix was studied in rats, dogs and monkeys. Degarelix was mainly excreted unchanged via the urine and was subject to sequential peptidic degradation during its elimination via the hepato-biliary pathway in both animals and man.|After subcutaneous administration, degarelix forms a local depot at the injection site, leading to retarded and extended release of the active drug. The release from the depot is dependent on the concentration in the dose formulation and the dose volume. Furthermore, in repeat dose studies, increasing concentrations in the dose formulation resulted in sub-proportional increases in maximum plasma concentration (Cmax) and area under plasma concentration vs time in the dosing interval (AUC), an increase in trough plasma concentration (Ctrough), an increase in terminal half-life (t1/2), thus increasing the time to reach steady state, and a tendency of increase in time to maximum plasma concentration (Tmax).|Degarelix forms a depot at the injection site following subcutaneous administration from which the drug is very slowly released into circulation. Peak plasma concentrations of degarelix generally occur within 2 days following subcutaneous administration of a single 240 mg dose at a concentration of 40 mg/mL.. The pharmacokinetic behavior of degarelix is strongly influenced by its concentration in the injection solution. Approximately 90% of the drug is bound to plasma proteins. No quantitatively substantial metabolites have been detected in plasma following subcutaneous adminstration. Degarelix does not appear to be a substrate, inducer, or inhibitor of the cytochrome P-450 (CYP) enzyme or P-glycoprotein transport systems based on in vitro studies. Degarelix is eliminated in a biphasic manner, with a median terminal half-life of about 53 days following subcutaneous administration of a 240 mg dose at a concentration of 40 mg/mL in prostate cancer patients. Degarelix is subject to peptide hydrolysis during its passage through the hepatobiliary system and is mainly excreted as peptide fragments in feces. Approximately 20-30% of a given dose of degarelix is renally eliminated, suggesting that approximately 70-80% is excreted via the hepatobiliary system.|For more Absorption, Distribution and Excretion (Complete) data for Degarelix (6 total), please visit the HSDB record page.

70% - 80% of degarelix is subject to peptide hydrolysis during its passage through the hepatobiliary system and then fecally eliminated. No active or inactive metabolites or involvement of CYP450 isozymes.|The stability of degarelix was studied in liver microsomes from males in rat, guinea pig, rabbit, dog, monkey, and human, for up to 60 min. No degradation of degarelix was detected in liver microsomes from rabbit, dog, monkey, and human. Tendency to minor degradation of degarelix was seen in liver microsomes from guinea pig and rat. The in vitro metabolism of degarelix was further investigated in human liver microsomes for up to 60 min. The metabolism pattern of degarelix was reported to be similar in humans and animals. Degarelix was virtually no substrate for oxidative metabolism, but was degraded by peptidases with generation of various truncated peptides. Only low concentration of one metabolite was seen in human plasma, and this metabolite was also seen in rats, dogs and monkeys.

Terminal half-life: 41.5 - 70.2 days; Absorption half-life: 32.9 hours; Half-life from injection site: 1.17 days.|Degarelix is eliminated in a biphasic manner, with a median terminal half-life of about 53 days following subcutaneous administration of a 240 mg dose at a concentration of 40 mg/mL in prostate cancer patients.

Degarelix competitively inhibits GnRH receptors in the pituitary gland, preventing the release of luteinizing hormone (LH) and follicle stimulating hormone. Reduced LH suppresses testosterone release, which slows the growth and reduces the size of prostate cancers.|Degarelix is a selective gonadotrophin releasing-hormone (GnRH) antagonist that competitively and reversibly binds to the pituitary GnRH receptors, thereby rapidly reducing the release of the gonadotrophins, luteinizing hormone (LH) and follicle stimulating hormone (FSH), and thereby reducing the secretion of testosterone (T) by the testes. Prostatic carcinoma is known to be androgen sensitive and responds to treatment that removes the source of androgen. Unlike GnRH agonists, GnRH antagonists do not induce a LH surge with subsequent testosterone surge/tumour stimulation and potential symptomatic flare after the initiation of treatment.|Degarelix, a synthetic decapeptide, is a gonadotropin-releasing hormone (GnRH, luteinizing hormone-releasing hormone, gonadorelin) antagonist. The drug immediately, competitively, and reversibly binds to and blocks GnRH receptors in the pituitary, thereby reducing the release of gonadotropins (i.e., luteinizing hormone [LH], follicle stimulating hormone [FSH]) and, consequently, testosterone without initial stimulation of the hypothalamic-pituitary-gonadal axis and the associated testosterone surge. Degarelix appears to have low histamine-releasing potential compared with other GnRH antagonists; there have been no signs of immediate- or late-onset systemic allergic reactions with degarelix.

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/|/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/|/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

Ac-2Nal-4Cpa-3Pal-Ser-4Aph(hydroorotyl)-4Aph(carbamoyl)-Leu-ILys-pro-Ala-NH2

Table: Degarelix Acetate Preparations [Table#7523]

Gonadotropin-releasing hormone (GnRH) antagonist; decapeptide amide with seven unnatural amino acids, five of which are D-amino acids.

Human drugs -> Firmagon -> EMA Drug Category|Endocrine therapy -> Human pharmacotherapeutic group|Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients