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degarelix
Degarelix, a synthetic decapeptide is a gonadotropin-releasing hormone (GnRH) receptor antagonist and reduces the release of LH/FSH. Unlike earlier compounds, degarelix has only weak histamine releasing activity.
Marketing approval was based on testosterone suppression to castrate levels over a 1 year treatment period. Evidence of palliation of improved survival has not been demonstrated.
Linear pharmacokinetics with no accumulation. Pharmacokinetics dependent upon concentration at injection site (↓ exposure with ↑ concentration).
Distributed throughout total body water
| Cross blood brain barrier? |
No information found. |
| PPB |
90% (alpha-glycoprotein and albumin) |
Undergoes hydrolysis by peptidases and proteases in the hepatobiliary system. Not a substrate, inducer, nor inhibitor of CYP 450 or p-glycoprotein.
| Active metabolites |
No |
| Inactive metabolites |
Peptide fragments |
Biphasic elimination
| Half-life |
43 days(starting dose); 31 days (maintenance dose) |
| Urine |
20-30% (unchanged) |
| Clearance |
Hepatobiliary: 70-80% |
| Clearance | 35-50 mL/h/kg |
Testosterone suppression in patients with advanced prostate cancer in whom androgen deprivation is warranted.
Emetogenic Potential:
Extravasation Potential: None
The following table contains adverse effects reported mainly in the controlled study at the recommended dose.
| ORGAN SITE | SIDE EFFECT* (%) | ONSET** | |||
|---|---|---|---|---|---|
| Cardiovascular | Arterial thromboembolism (1%) | E | |||
| Atrioventricular block (rare) | E | ||||
| Hypertension (6%) | E | ||||
| QT interval prolonged (20%) | E | ||||
| Gastrointestinal | Constipation (5%) | E | |||
| Diarrhea | I E | ||||
| Nausea (4%) | I | ||||
| Weight gain (9%) | E | ||||
| General | Fatigue (3%) | E | |||
| Flu-like symptoms (5%) | I | ||||
| Hematological | Anemia (3%) | E | |||
| Hepatobiliary | ↑ LFTs (10%) ( <1% Grade 3) | E | |||
| Hypersensitivity | Hypersensitivity (rare) | I | |||
| Immune | Antibody response (46%) | D | |||
| Injection site | Injection site reaction (35%) (2% severe) | I | |||
| Metabolic / Endocrine | Abnormal electrolyte(s) | E | |||
| ↑ Cholesterol (3%) | E | ||||
| Hyperglycemia | E | ||||
| Musculoskeletal | Muscle weakness (less common) | E | |||
| Musculoskeletal pain (6%) | E | ||||
| Osteoporosis (3%) | D | ||||
| Nervous System | Dizziness (<5%) | E | |||
| Headache (<5%) | E | ||||
| Insomnia (<5%) | E | ||||
| Renal | Creatinine increased (2%) | E | |||
| Reproductive and breast disorders | Androgen deprivation symptoms (26%) (hot flashes, erectile dysfunction, gynecomastia) | E | |||
| Urinary | Urinary symptoms (5%) (including infection) | E | |||
* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare"
may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal
reports.
Dose-limiting side effects are underlined.
** I = immediate (onset in hours to days)
E = early (days to weeks)
D = delayed (weeks to months)
L = late (months to years)
The most common side effects for degarelix include injection site reaction, androgen deprivation symptoms, QT interval prolonged, ↑ LFTs, weight gain, hypertension, musculoskeletal pain, constipation and flu-like symptoms.
Pain, erythema, swelling, nodule and induration were the most common injection site reactions and primarily occurred with the first dose. These reactions were mostly transient and usually resolved after a few days. Reported serious injection site reactions include injection site infection, abscess and necrosis that could require surgical treatment/drainage.
Mild, transient increases in LFTs have been observed, and were not accompanied by a rise in bilirubin or clinical symptoms.
Men treated with androgen deprivation (including orchiectomy, GnRH agonists and antiandrogens) are at increased risk of developing heart disease, QTc prolongation, poor glucose tolerance and osteoporosis. However, degarelix has no intrinsic effect on the QTc.
Refer to protocol by which patient is being treated.
Starting dose: 240 mg subcut once (given as 2 x 120 mg injections at 40 mg/mL)
One month later, start:
Maintenance: 80 mg subcut (1 injection at 20 mg/mL) monthly
Although drug exposure is 10-18% lower in mild to moderate hepatic impairment, no dosage adjustment is required in these patients. Exercise caution in patients with severe hepatic impairment as no studies have been conducted in this population.
Drug clearance decreases by 23% in patients with moderate renal impairment (< 50 mL/min); however, no dosage adjustment is required in mild to moderate renal impairment. Exercise caution in patients with severe renal impairment as there is insufficient data available in this population.
No dose adjustment required.
Not indicated for use in patients < 18 years of age.
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Outpatient prescription for administration at Cancer Centre or at physician’s office.
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For subcutaneous injection in the abdomen.
-
Dosage strength and concentration of injection differ between starting and maintenance doses. The concentrations recommended in the dosing section should be used, since the pharmacokinetics of degarelix are strongly concentration-dependent.
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Gloves should be worn during preparation and administration.
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Reconstitute using sterile water for injection (SWI) as directed in the product monograph. Reconstitution procedure may take up to 15 minutes.
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Do not shake the vial(s). Swirl gently during reconstitution.
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Resulting solution should be clear and free of undissolved powder or particles.
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Reconstituted product must be administered within 2 hours after addition of SWI.
-
Ensure injection site is free of pressure from belts, waistbands, other clothing, or ribs. Rotate injection sites.
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For further details regarding proper reconstitution of degarelix, refer to the most updated Product Monograph.
- Patients who have hypersensitivity to degarelix or to any of its excipients.
-
Fatigue and dizziness are common adverse reactions with degarelix and caution must be exercised with driving and operating machines.
-
Long-term androgen deprivation prolongs the QT interval. Although a thorough QT study showed that there was no intrinsic effect of degarelix on heart rate, QT/QTc, PR intervals, QRS duration, or T or U wave morphology in healthy men, caution should be exercised in patients with congenital long QT syndrome, electrolyte abnormalities, congestive heart failure, and in patients taking antiarrhythmic medications.
Other Drug Properties:
-
Carcinogenicity:
Yes
-
Embryotoxicity:
Yes
-
Fertility effects:
Documented in animals
Reversible infertility has been observed in animal studies. -
Fetotoxicity:
Yes
Degarelix is contraindicated in pregnancy and in women of child-bearing potential. Adequate contraception should be used during treatment, and for at least 6 months after the last dose.
-
Genotoxicity:
No information available
-
Mutagenicity:
No
-
Excretion into breast milk:
Unknown
Breastfeeding is not recommended.
Clinically significant drug-drug interactions are unlikely other than those listed below.
Degarelix suppresses the pituitary-gonadal axis. Results of diagnostic tests for pituitary or gonadal functions may be affected.
| AGENT | EFFECT | MECHANISM | MANAGEMENT |
|---|---|---|---|
| Drugs that may prolong QT (i.e. Amiodarone, procainamide, sotalol, venlafaxine, amitriptyline, sunitinib, methadone, chloroquine, clarithromycin, haloperidol, fluconazole, moxifloxacin, domperidone, ondansetron, etc) | ↑ risk of QT interval prolongation | Additive | Caution; monitor closely. |
| Monitor Type | Monitor Frequency |
|---|---|
Creatinine |
Baseline and as clinically indicated. |
Electrolytes, including calcium, magnesium, potassium, sodium |
Baseline and as clinically indicated. |
Liver function tests |
Baseline and as clinically indicated. |
Blood glucose |
Baseline and as clinically indicated. |
ECG |
Baseline and as clinically indicated. |
Testosterone concentrations |
In patients with hepatic impairment: monthly until medical castration is achieved then every 2 months. |
Clinical assessment for local reactions, diabetes, osteoporosis, cardiovascular changes, hot flashes |
Baseline and as clinically indicated. |
Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version
Degarelix acetate: e-AHFS. Accessed December 30, 2009.
Frampton JE and Lyseng-Williamson KA. Degarelix. Drugs 2009; 69(14): 1967-76.
Prescribing Information: Firmagon® (degarelix acetate). Ferring Pharmaceuticals Inc. (US), Feb 2009.
Product Monograph: Firmagon® (degarelix acetate). Ferring Pharmaceuticals, March 18, 2016.
August 2018 Updated adverse effects (severe injection site reactions, hypersensitivity, antibody formation), and warnings.
Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.
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