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{{Short description|Chemical compound}}
{{Use dmy dates|date=November 2023}}
{{cs1 config |name-list-style=vanc |display-authors=6}}
{{Drugbox {{Drugbox
| Verifiedfields = changed
| verifiedrevid = 405800371
| Watchedfields = changed
| IUPAC_name =
| verifiedrevid = 417553629
| image = Degarelix.svg
| image = Degarelix.svg
| CAS_number = 214766-78-6
| width = 250
| ATC_prefix = L02
| alt =
| ATC_suffix = BX02

| PubChem = 16186010
<!--Clinical data-->
| DrugBank =
| tradename = Firmagon, others
| Drugs.com = {{drugs.com|monograph|degarelix-acetate}}
| MedlinePlus = a609022
| DailyMedID = Degarelix
| licence_EU = yes
| licence_US = Degarelix
| pregnancy_AU = D
| pregnancy_AU_comment = <ref name="Drugs.com pregnancy">{{cite web | title=Degarelix (Firmagon) Use During Pregnancy | website=Drugs.com | date=3 February 2020 | url=https://www.drugs.com/pregnancy/degarelix.html | access-date=25 February 2020 | archive-date=26 February 2020 | archive-url=https://web.archive.org/web/20200226002541/https://www.drugs.com/pregnancy/degarelix.html | url-status=live }}</ref>
| pregnancy_category = Contraindicated<ref name="Drugs.com pregnancy" />
| routes_of_administration = ]
| class = ]; ]; ]
| ATC_prefix = L02
| ATC_suffix = BX02

<!-- Legal status -->
| legal_AU = S4
| legal_AU_comment =
| legal_BR = <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F-->
| legal_BR_comment =
| legal_CA = <!-- OTC, Rx-only, Schedule I, II, III, IV, V, VI, VII, VIII -->
| legal_CA_comment =
| legal_DE = <!-- Anlage I, II, III or Unscheduled-->
| legal_DE_comment =
| legal_NZ = <!-- Class A, B, C -->
| legal_NZ_comment =
| legal_UK = POM
| legal_UK_comment = <ref>{{cite web | title=Firmagon 120mg Injection - Summary of Product Characteristics (SmPC) | website=(emc) | date=15 January 2020 | url=https://www.medicines.org.uk/emc/medicine/21701/SPC/Firmagon+120mg+Injection/ | access-date=25 February 2020 | archive-date=26 February 2020 | archive-url=https://web.archive.org/web/20200226002543/https://www.medicines.org.uk/emc/medicine/21701/SPC/Firmagon%2B120mg%2BInjection/ | url-status=live }}</ref>
| legal_US = Rx-only
| legal_US_comment = <ref name="Firmagon FDA label" />
| legal_EU = Rx-only
| legal_EU_comment = <ref name="Firmagon EPAR" />
| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV-->
| legal_UN_comment =
| legal_status = Rx-only

<!--Pharmacokinetic data-->
| bioavailability = 30–40%
| protein_bound = ~90%
| metabolism = Subject to common peptidic degradation during passage through the hepato-biliary system; not a substrate for the human CYP450 system
| elimination_half-life = 23–61 days
| excretion = ]: 70–80%<br />]: 20–30%

<!--Identifiers-->
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 214766-78-6
| PubChem = 16136245
| IUPHAR_ligand = 5585
| DrugBank_Ref = {{drugbankcite|changed|drugbank}}
| DrugBank = DB06699
| UNII_Ref = {{fdacite|changed|FDA}}
| UNII = SX0XJI3A11
| KEGG_Ref = {{keggcite|correct|kegg}} | KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D08901 | KEGG = D08901
| KEGG2_Ref = {{keggcite|correct|kegg}}
| C=84|H=107|Cl=1|N=18|O=18
| KEGG2 = D09400
| molecular_weight = 1692.311180 g/mol
| ChEMBL_Ref = {{ebicite|changed|EBI}}
| smiles =
| ChEMBL = 264089
| bioavailability = 30-40%
| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}
| protein_bound = ~90%
| ChemSpiderID = 17292756
| metabolism = Subject to common peptidic degradation during passage through the hepato-biliary system; not a substrate for the human CYP450 system
| synonyms = FE-200486
| elimination_half-life = 23-61 days

| excretion = ~20-30% in the urine, ~70-80% in the faeces
<!--Chemical data-->
| pregnancy_AU =
| pregnancy_US = | IUPAC_name =
| C=82 | H=103 | Cl=1 | N=18 | O=16
| pregnancy_category= N/A
| SMILES = C(C(=O)N)NC(=O)1CCCN1C(=O)(CCCCNC(C)C)NC(=O)(CC(C)C)NC(=O)(Cc2ccc(cc2)NC(=O)N)NC(=O)(Cc3ccc(cc3)NC(=O)4CC(=O)NC(=O)N4)NC(=O)(CO)NC(=O)(Cc5cccnc5)NC(=O)(Cc6ccc(cc6)Cl)NC(=O)(Cc7ccc8ccccc8c7)NC(=O)C
| licence_EU = Firmagon
| StdInChI_Ref = {{stdinchicite|changed|chemspider}}
| licence_US = Degarelix
| StdInChI = 1S/C82H103ClN18O16/c1-45(2)35-60(72(107)92-59(16-9-10-33-87-46(3)4)80(115)101-34-12-17-68(101)79(114)88-47(5)70(84)105)93-74(109)63(38-51-23-30-58(31-24-51)91-81(85)116)95-76(111)64(39-50-21-28-57(29-22-50)90-71(106)66-42-69(104)100-82(117)99-66)97-78(113)67(44-102)98-77(112)65(41-53-13-11-32-86-43-53)96-75(110)62(37-49-19-26-56(83)27-20-49)94-73(108)61(89-48(6)103)40-52-18-25-54-14-7-8-15-55(54)36-52/h7-8,11,13-15,18-32,36,43,45-47,59-68,87,102H,9-10,12,16-17,33-35,37-42,44H2,1-6H3,(H2,84,105)(H,88,114)(H,89,103)(H,90,106)(H,92,107)(H,93,109)(H,94,108)(H,95,111)(H,96,110)(H,97,113)(H,98,112)(H3,85,91,116)(H2,99,100,104,117)/t47-,59+,60+,61-,62-,63-,64+,65-,66+,67+,68+/m1/s1
| legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled-->
| StdInChIKey_Ref = {{stdinchicite|changed|chemspider}}
| legal_CA = <!-- Schedule I, II, III, IV, V, VI, VII, VIII -->
| StdInChIKey = MEUCPCLKGZSHTA-XYAYPHGZSA-N
| legal_UK = <!-- GSL, P, POM, CD, or Class A, B, C -->
| legal_US = Rx-only
| legal_status = Prescription only
| routes_of_administration = ]
}} }}
'''Degarelix''' (]) or '''degarelix acetate''' (]) (tradename ''Firmagon'') is a ] used in the treatment of ]. During development it was known as '''FE200486'''.


'''Degarelix''', sold under the brand name '''Firmagon''' among others, is a ] used in the treatment of ].<ref name="Firmagon FDA label">{{cite web | title=Firmagon- degarelix kit | website=DailyMed | date=18 September 2019 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ab11dd8a-0fd9-4013-89ab-e114557c7e4b | access-date=26 February 2020 | archive-date=12 August 2020 | archive-url=https://web.archive.org/web/20200812190646/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ab11dd8a-0fd9-4013-89ab-e114557c7e4b | url-status=live }}</ref><ref>{{cite web | title=Degarelix Acetate Monograph for Professionals | website=Drugs.com | date=7 October 2019 | url=https://www.drugs.com/monograph/degarelix-acetate.html | access-date=25 February 2020 | archive-date=26 February 2020 | archive-url=https://web.archive.org/web/20200226002542/https://www.drugs.com/monograph/degarelix-acetate.html | url-status=live }}</ref>
] is a male ] that promotes growth of many prostate ] and therefore reducing circulating testosterone to very low (]) levels is often the treatment goal in the management of men with advanced prostate cancer. Degarelix has an immediate onset of action, binding to ] (GnRH) receptors in the ] and blocking their interaction with GnRH. This induces a fast and profound reduction in ] (LH), ] (FSH) and in turn, testosterone suppression.<ref>Princivalle M, Broqua P, White R, et al (March 2007). Rapid suppression of plasma testosterone levels and tumor growth in the dunning rat model treated with degarelix, a new gonadotropin-releasing hormone antagonist. J. Pharmacol. Exp. Ther. '''320''': 1113-8.</ref>


] is a male ] that promotes growth of many prostate ] and therefore reducing circulating testosterone to very low (]) levels is often the treatment goal in the management of advanced prostate cancer. Degarelix has an immediate onset of action, binding to ] (GnRH) receptors in the ] and blocking their interaction with GnRH. This induces a fast and profound reduction in ] (LH), ] (FSH) and in turn, testosterone suppression.<ref name="PrincivalleBroqua2007">{{cite journal | vauthors = Princivalle M, Broqua P, White R, Meyer J, Mayer G, Elliott L, Bjarnason K, Haigh R, Yea C | title = Rapid suppression of plasma testosterone levels and tumor growth in the dunning rat model treated with degarelix, a new gonadotropin-releasing hormone antagonist | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 320 | issue = 3 | pages = 1113–8 | date = March 2007 | pmid = 17179469 | doi = 10.1124/jpet.106.112326 | s2cid = 2892725 }}</ref>
==Status==
On 24 December 2008, the ] (FDA) approved degarelix for the treatment of patients with advanced prostate cancer in the USA.<ref>PR Newswire. FDA approves Ferring Pharmaceuticals' Degarelix (generic name) for the treatment of advanced prostate cancer. PR Newswire, Europe Ltd 2008 ; Available from </ref> It was subsequently approved by the European Commission at the recommendation of the ] (EMEA) on February 17, 2009 for use in adult male patients with advanced, hormone-dependent prostate cancer. ] markets the drug under the name ''Firmagon''.


==Mode of action== ==Medical uses==
GnRH antagonists (] blockers) such as degarelix are a new type of hormonal therapy for prostate cancer. These agents are synthetic ] derivatives of the natural GnRH decapeptide – a hormone that is made by ] in the ]. GnRH antagonists compete with natural GnRH for binding to ] ] in the pituitary gland. This reversible blinding blocks the release of LH and FSH from the pituitary. The reduction in LH subsequently leads to a rapid and sustained suppression of testosterone release from the ] and subsequently reduces the size and growth of the prostate cancer. This in turn results in a reduction in ] (PSA) levels in the patient's blood. Measuring PSA levels is a way to monitor how patients with prostate cancer are responding to treatment.


The GnRH antagonist degarelix, through its ability to reduce serum testosterone, is used to treat hormone-sensitive prostate cancer.<ref name="Clinton_2017">{{cite journal | vauthors = Clinton TN, Woldu SL, Raj GV | title = Degarelix versus luteinizing hormone-releasing hormone agonists for the treatment of prostate cancer | journal = Expert Opinion on Pharmacotherapy | volume = 18 | issue = 8 | pages = 825–832 | date = June 2017 | pmid = 28480768 | pmc = 7171911 | doi = 10.1080/14656566.2017.1328056 }}</ref>
Unlike the GnRH agonists, which cause an initial stimulation of the ] (HPGA), leading to a surge in testosterone levels, and under certain circumstances, a flare-up of the tumour, GnRH antagonists do not cause a surge in testosterone or clinical flare.<ref>Van Poppel H, Nilsson S (June 2008). Testosterone surge: rationale for gonadotropin-releasing hormone blockers? Urology '''71''': 1001-6.</ref> Clinical flare is a phenomenon that occurs in patients with advanced disease, which can precipitate a range of clinical symptoms such as ], ] obstruction, and ]. Drug agencies have issued boxed warnings regarding this phenomenon in the prescribing information for GnRH agonists. As testosterone surge does not occur with GnRH antagonists, there is no need for patients to receive an ] as flare protection during prostate cancer treatment. GnRH agonists also induce an increase in testosterone levels after each reinjection of the drug – a phenomenon that does not occur with GnRH antagonists such as degarelix.


==Side effects==
GnRH antagonists have an immediate onset of action leading to a fast and profound suppression of testosterone and are therefore especially valuable in the treatment of patients with prostate cancer, where fast control of disease is needed.
Degarelix is commonly associated with hormonal side effects such as ] and ].<ref name="Clinton_2017"/><ref name="GittelmanPommerville2008">{{cite journal | vauthors = Gittelman M, Pommerville PJ, Persson BE, Jensen JK, Olesen TK | title = A 1-year, open label, randomized phase II dose finding study of degarelix for the treatment of prostate cancer in North America | journal = The Journal of Urology | volume = 180 | issue = 5 | pages = 1986–92 | date = November 2008 | pmid = 18801505 | doi = 10.1016/j.juro.2008.07.033 }}</ref><ref name="Van PoppelTombal2008">{{cite journal | vauthors = Van Poppel H, Tombal B, de la Rosette JJ, Persson BE, Jensen JK, Kold Olesen T | title = Degarelix: a novel gonadotropin-releasing hormone (GnRH) receptor blocker--results from a 1-yr, multicentre, randomised, phase 2 dosage-finding study in the treatment of prostate cancer | journal = European Urology | volume = 54 | issue = 4 | pages = 805–13 | date = October 2008 | pmid = 18538469 | doi = 10.1016/j.eururo.2008.04.065 }}</ref> Due to its mode of administration (]), degarelix is also associated with injection-site reactions such as injection-site pain, ] or swelling. Injection-site reactions are usually mild or moderate in intensity and occur predominantly after the first dose, decreasing in frequency thereafter.<ref name="Clinton_2017"/> Less common: Anemia. Diarrhea, nausea. Hyperhidrosis including night sweats, rash. ], testicular atrophy, erectile dysfunction. Increased transaminases. Musculoskeletal pain and discomfort. Dizziness, headache. Insomnia. Weight gain. Chills, fever, fatigue, flu-like illness.<ref>{{Cite web|title=Firmagon "Ferring Pharmaceuticals A/S" - Felleskatalogen|url=https://www.felleskatalogen.no/medisin/firmagon-ferring-pharmaceuticals-a-s-559100|website=www.felleskatalogen.no|access-date=5 May 2020|archive-date=28 November 2020|archive-url=https://web.archive.org/web/20201128114154/https://www.felleskatalogen.no/medisin/firmagon-ferring-pharmaceuticals-a-s-559100|url-status=live}}</ref>


==Pharmacology==
==Clinical effectiveness==
] levels during the first month of ] in men with ] treated with ]s of the GnRH antagonist degarelix (240 then 80{{nbsp}}mg/month or the ] ] (7.5{{nbsp}}mg/month).<ref name="pmid19035858">{{cite journal | vauthors = Klotz L, Boccon-Gibod L, Shore ND, Andreou C, Persson BE, Cantor P, Jensen JK, Olesen TK, Schröder FH | title = The efficacy and safety of degarelix: a 12-month, comparative, randomized, open-label, parallel-group phase III study in patients with prostate cancer | journal = BJU Int | volume = 102 | issue = 11 | pages = 1531–8 | date = December 2008 | pmid = 19035858 | doi = 10.1111/j.1464-410X.2008.08183.x | s2cid = 8280692 | url = }}</ref>]]
The effectiveness of degarelix was recently{{when|date=March 2011}} evaluated in a ], randomised, 12 month ] (CS21) in 610 patients with prostate cancer, for whom ] therapy was indicated.<ref name="Klotz">Klotz L, Boccon-Gibod L, Shore ND, et al (December 2008). 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. '''102''': 1531-8.</ref> Patients were randomised to receive treatment with one of two doses of degarelix or the GnRH agonist, ]. Both degarelix doses were at least as effective as leuprolide at suppressing testosterone to ] levels (≤0.5&nbsp;ng/mL) from Day 28 to study end (Day 364). Testosterone levels were suppressed significantly faster with degarelix than with leuprolide, with nearly all of the degarelix patients achieving castration levels by Day 3 of treatment compared with none in the leuprolide group. No patients receiving degarelix experienced a testosterone surge compared with 81% of those patients receiving leuprolide. Furthermore, degarelix resulted in a significantly faster reduction in PSA levels compared with leuprolide indicating faster control of the prostate cancer. Recent results also suggest that degarelix therapy may result in longer control of prostate cancer compared with leuprolide.<ref>Schröder FH, Boccon-Gibod L, Tombal B, et al (March 2009) Degarelix versus leuprolide in patients with prostate cancer: effect in metastatic patients as assessed by serum alkaline phosphatase. ] (EAU) Annual congress 17–21 March 2009, Stockholm, Sweden. Abstract 40.</ref>


GnRH antagonists (] blockers) such as degarelix are synthetic ] derivatives of the natural GnRH decapeptide – a hormone that is made by ]s in the ]. GnRH antagonists compete with natural GnRH for binding to ] receptors in the ]. This reversible binding blocks the release of LH and FSH from the pituitary. The reduction in LH subsequently leads to a rapid and sustained suppression of testosterone release from the ] and subsequently reduces the size and growth of the prostate cancer. This in turn results in a reduction in ] (PSA) levels in the patient's blood. Measuring PSA levels helps to monitor how patients with prostate cancer are responding to treatment.{{medcn|date=February 2020}}
==Side effects==
As with all hormonal therapies, degarelix is commonly associated with hormonal side effects such as ] and ].<ref name="Klotz"/><ref>Gittelman M, Pommerville PJ, Persson BE, et al (November 2008). A 1-year, open label, randomized phase II dose finding study of degarelix for the treatment of prostate cancer in North America. J. Urol. '''180''': 1986-92.</ref><ref>Van Poppel H, Tombal B, de la Rosette JJ, et al (October 2008). Degarelix: a novel gonadotropin-releasing hormone (GnRH) receptor blocker--results from a 1-yr, multicentre, randomised, phase 2 dosage-finding study in the treatment of prostate cancer. Eur. Urol. '''54''': 805-13.</ref> Due to its mode of administration (]), degarelix is also associated with injection-site reactions such as injection-site pain, ] or swelling. Injection-site reactions are usually mild or moderate in intensity and occur predominantly after the first dose, decreasing in frequency thereafter.<ref name="Klotz"/>


Unlike GnRH agonists, which cause an initial stimulation of the ] (HPGA), leading to a surge in testosterone levels, and under certain circumstances, a flare-up of the tumour, GnRH antagonists do not cause a surge in testosterone or clinical flare.<ref name="van PoppelNilsson2008">{{cite journal | vauthors = van Poppel H, Nilsson S | title = Testosterone surge: rationale for gonadotropin-releasing hormone blockers? | journal = Urology | volume = 71 | issue = 6 | pages = 1001–6 | date = June 2008 | pmid = 18407326 | doi = 10.1016/j.urology.2007.12.070 }}</ref> Clinical flare is a phenomenon that occurs in patients with advanced disease, which can precipitate a range of clinical symptoms such as ], ] obstruction, and ]. Drug agencies have issued boxed warnings regarding this phenomenon in the prescribing information for GnRH agonists. As testosterone surge does not occur with GnRH antagonists, there is no need for patients to receive an ] as flare protection during prostate cancer treatment. GnRH agonists also induce an increase in testosterone levels after each reinjection of the drug – a phenomenon that does not occur with GnRH antagonists such as degarelix.{{medcn|date=February 2020}}
==Potential future role in suppression of FSH for antiangiogenesis effect on wide range of solid tumors ==


GnRH antagonists have an immediate onset of action leading to a fast and profound suppression of testosterone and are therefore especially valuable in the treatment of patients with prostate cancer where fast control of disease is needed.{{medcn|date=February 2020}}
A recent NEJM article (Oct 2010) found substantially elevated FSH levels in the
endothelia of the tumor vasculature of a wide range of solid tumors.
FSH suppression may serve an anti tumor angiogenesis effect via two distinct
mechanisms (one independent of ]). This work is still in early stages.


==History==
http://www.nejm.org/doi/pdf/10.1056/NEJMoa1001283
In December 2008, the US ] (FDA) approved degarelix for the treatment of people with advanced prostate cancer.<ref>{{cite web | title=Drug Approval Package: Degarelix NDA #022201 | website=U.S. ] (FDA) | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2008/022201s000_TOC.cfm | access-date=29 September 2020 | archive-date=9 August 2020 | archive-url=https://web.archive.org/web/20200809212239/https://www.accessdata.fda.gov/drugsatfda_docs/nda/2008/022201s000_TOC.cfm | url-status=live }}</ref><ref>{{cite press release | via=PR Newswire | title=FDA Approves Ferring Pharmaceuticals' Degarelix (Generic Name) for Treatment of Advanced Prostate Cancer | publisher=] | date=24 December 2008 | url=https://www.prnewswire.co.uk/cgi/news/release?id=245656 | archive-url=https://web.archive.org/web/20110608193757/https://www.prnewswire.co.uk/cgi/news/release?id=245656 | archive-date=8 June 2011 | url-status=dead | access-date=25 February 2020}}</ref> It was subsequently approved by the European Commission at the recommendation of the ] (EMA) in February 2009, for use in adult males with advanced, hormone-dependent prostate cancer.<ref name="Firmagon EPAR">{{cite web | title=Firmagon EPAR | website=] (EMA) | date=10 January 2020 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/firmagon | access-date=25 February 2020 | archive-date=26 February 2020 | archive-url=https://web.archive.org/web/20200226002538/https://www.ema.europa.eu/en/medicines/human/EPAR/firmagon | url-status=live }}</ref> ] markets the drug under the name Firmagon.<ref name="Firmagon EPAR" />


==References== ==Research==
Degarelix is studied for use as a ] agent on men with pedophilia in ].<ref>{{cite news|title=Pedofiler ska stoppas – med kemisk kastrering|url=http://www.expressen.se/nyheter/pedofiler-ska-stoppas--med-kemisk-kastrering/|website=Expressen|access-date=4 August 2016|archive-date=26 February 2021|archive-url=https://web.archive.org/web/20210226142944/https://www.expressen.se/nyheter/pedofiler-ska-stoppas--med-kemisk-kastrering/|url-status=live}}</ref> A study demonstrated a reduced the risk score for committing child sexual abuse in men with pedophilic disorder two weeks after initial injection.<ref>{{cite journal | vauthors = Landgren V, Malki K, Bottai M, Arver S, Rahm C | title = Effect of Gonadotropin-Releasing Hormone Antagonist on Risk of Committing Child Sexual Abuse in Men With Pedophilic Disorder: A Randomized Clinical Trial | journal = JAMA Psychiatry | date = April 2020 | volume = 77 | issue = 9 | pages = 897–905 | pmid = 32347899 | pmc = 7191435 | doi = 10.1001/jamapsychiatry.2020.0440 }}</ref>
{{reflist}}


==External links== == See also ==
* ]
*


== References ==
{{Gonadotropins and GnRH}}
{{Reflist}}


{{GnRH and gonadotropins}}
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{{GnRH and gonadotropin receptor modulators}}
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