Degarelix
JFDA label: Firmagon 80mg
Mechanism of Action
Gonadotropin-releasing hormone (GnRH) antagonist which reversibly binds to GnRH receptors in the anterior pituitary gland, blocking the receptor and decreasing secretion of luteinizing hormone (LH) and follicle stimulation hormone (FSH), resulting in rapid androgen deprivation by decreasing testosterone production, thereby decreasing testosterone levels. Testosterone levels do not exhibit an initial surge, or flare, as is typical with GnRH agonists (Crawford 2011).
Indications
Approved
- Prostate cancer, advanced
Contraindications
Source: Lexicomp
- Known hypersensitivity to degarelix or any component of the formulation Absolute
- women who are or may become pregnant. Documentation of allergenic cross-reactivity for drugs in this class is limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity can not be ruled out with certainty Absolute
Adverse Reactions
Cardiac disorders (1)
Common Hypertension
Nervous system disorders (5)
Very Common Fatigue
Common Chills · dizziness · headache · insomnia
Hepatobiliary disorders (2)
Very Common Increased serum transaminases
Common Increased serum ALT
Renal and urinary disorders (3)
Common erectile dysfunction · testicular atrophy · Urinary tract infection
Metabolism and nutrition disorders (6)
Very Common Hot flash · increased gamma-glutamyl transferase · weight gain · weight loss
Common gynecomastia · Hypercholesterolemia
Gastrointestinal disorders (3)
Common Constipation · diarrhea · nausea
Skin and subcutaneous tissue disorders (1)
Common Diaphoresis
Musculoskeletal and connective tissue disorders (3)
Common arthralgia · Back pain · weakness
General disorders and administration site conditions (3)
Very Common Fever · Injection site reactions
Common Night sweats
Dosing
Source: Lexicomp
Warnings & Precautions
Source: Lexicomp
Anemia
Testosterone suppression is associated with the development of anemia.
Decreased bone mineral density
Androgen deprivation therapy is associated with decreased bone mineral density.
Hypersensitivity
Hypersensitivity reactions (including anaphylaxis, urticaria, and angioedema) have been reported. Discontinue for serious hypersensitivity reaction (immediately if dose not fully injected); manage hypersensitivity as clinically indicated. Do not rechallenge after serious hypersensitivity reaction.
QT prolongation
Androgen deprivation therapy may prolong the QT interval. Use with caution in patients with congenital long QT syndrome, known history of QT prolongation, or other risk factors for QT prolongation (eg, concomitant use of medications known to prolong QT interval, heart failure, and/or electrolyte abnormalities). Consider periodic electrolyte and ECG monitoring. Disease-related concerns:
Cardiovascular disease
Androgen-deprivation therapy may increase the risk for cardiovascular disease (Levine 2010).
Diabetes
Androgen deprivation therapy may be associated with an increased risk for insulin resistance and diabetes (Keating 2006).
Hepatic impairment
Degarelix exposure is decreased in patients with hepatic impairment, dosage adjustment is not recommended in patients with mild to moderate hepatic impairment, although testosterone levels should be monitored. Has not been studied in patients with severe hepatic impairment; use with caution. Mild transient increases in transaminases have been observed; monitor liver function in patients with known or suspected hepatic disorder.
Renal impairment
Data for use in patients with moderate to severe renal impairment (CrCl Concurrent drug therapy issues:
Drug-drug interactions
Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.
Pregnancy & Lactation
Pregnancy
Use is contraindicated in women who are or may become pregnant. Adverse events were observed in animal reproduction studies.
Lactation
It is not known if degarelix is excreted in breast milk. This product is not indicated for use in women.
Monitoring
| Clinical pearl | Prostate-specific antigen (PSA) periodically, serum testosterone levels (if PSA increases; in patients with hepatic impairment: monitor testosterone levels monthly until achieve castration levels, then consider monitoring every other month), liver function tests (at baseline); consider baseline and periodic monitoring of serum electrolytes (calcium, magnesium, potassium, sodium); bone mineral density; consider baseline and periodic ECG monitoring. Screen for diabetes and cardiovascular risk (blood pressure, lipid profile, serum glucose) prior to initiating treatment and 3 to 6 months after initiation (Levine 2010). |
|---|
Chemistry & Properties
| Formula | C82H103ClN18O16 |
|---|---|
| Molecular weight | 1632.29 g/mol |
| IUPAC name | (4S)-N-[4-[(2S)-2-[[(2S)-2-[[(2R)-2-[[(2R)-2-[[(2R)-2-acetamido-3-naphthalen-2-ylpropanoyl]amino]-3-(4-chlorophenyl)propanoyl]amino]-3-pyridin-3-ylpropanoyl]amino]-3-hydroxypropanoyl]amino]-3-[[(2R)-1-[[(2S)-1-[[(2S)-1-[(2S)-2-[[(2R)-1-amino-1-oxopropan-2-yl]carbamoyl]pyrrolidin-1-yl]-1-oxo-6-(propan-2-ylamino)hexan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-[4-(carbamoylamino)phenyl]-1-oxopropan-2-yl]amino]-3-oxopropyl]phenyl]-2,6-dioxo-1,3-diazinane-4-carboxamide |
| CAS | 214766-78-6 |
| PubChem CID | 16136245 |
| InChIKey | MEUCPCLKGZSHTA-XYAYPHGZSA-N |
SMILES
CC(=O)N[C@H](Cc1ccc2ccccc2c1)C(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N[C@H](Cc1cccnc1)C(=O)N[C@@H](CO)C(=O)N[C@@H](Cc1ccc(NC(=O)[C@@H]2CC(=O)NC(=O)N2)cc1)C(=O)N[C@H](Cc1ccc(NC(N)=O)cc1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCNC(C)C)C(=O)N1CCC[C@H]1C(=O)N[C@H](C)C(N)=OBiology & Pharmacokinetics
Pharmacokinetics predicted
| Bioavailability | 70.0% |
|---|---|
| Half-life | 1.229 h |
| Volume of distribution | 0.565 L/kg |
| Protein binding | 76.4% |
| BBB penetrant | No |
Enzyme interactions
| Enzyme | Role | Detail |
|---|---|---|
| CYP2B6 | Inhibitor | — |
| CYP3A4 | Inhibitor | — |
Receptor binding (top 1)
| Target | Action | Affinity |
|---|---|---|
| GnRH1 receptor (GNRHR) | Antagonist | pKi 8.8 |
Transporters
BCRP (Inhibitor)BCRP (Inhibitor)BSEP (Inhibitor)MDR1 (Inhibitor)MRP1 (Inhibitor)MRP2 (Inhibitor)OATP1B1 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)OATP1B3 (Inhibitor)OATP2B1 (Inhibitor)P-gp (Inhibitor)MDR1 (Substrate)P-gp (Substrate)
Drug–drug interactions (100+, DDInter)
| Interacting drug | Severity | Management |
|---|---|---|
| Amiodarone | major | |
| Amisulpride | major | |
| Anagrelide | major | |
| Arsenic trioxide | major | |
| Bedaquiline | major | |
| Bepridil | major | |
| Cabozantinib | major | |
| Ceritinib | major | |
| Cisapride | major | |
| Citalopram | major | |
| Clozapine | major | |
| Crizotinib | major | |
| Disopyramide | major | |
| Dofetilide | major | |
| Dolasetron | major | |
| Dronedarone | major | |
| Droperidol | major | |
| Efavirenz | major | |
| Escitalopram | major | |
| Fingolimod | major | |
| Gatifloxacin | major | |
| Grepafloxacin | major | |
| Halofantrine | major | |
| Haloperidol | major | |
| Ibutilide | major | |
| Iloperidone | major | |
| Ivabradine | major | |
| Ivosidenib | major | |
| Lefamulin | major | |
| Levacetylmethadol | major | |
| Lumefantrine | major | |
| Macimorelin | major | |
| Mesoridazine | major | |
| Methadone | major | |
| Mifepristone | major | |
| Moxifloxacin | major | |
| Nilotinib | major | |
| Osimertinib | major | |
| Ozanimod | major | |
| Panobinostat | major |
Showing 40 of 100+.
Registered Products (2)
| Brand | Form / strength | Pack | Agent | Citizen (JOD) |
|---|---|---|---|---|
| Firmagon | Vial 80 mg | 1 vial | Petra Drug Store | — |
| Firmagon | Vial 120 mg | 2 vial | Petra Drug Store | — |