Degarelix

Degarelix is a synthetic derivative of the GnRH decapeptide and a selective GnRH receptor antagonist. Prostate cancer is androgen-sensitive and responds to treatment that removes the source of androgen. By blocking the pituitary signal that drives testosterone production, degarelix lowers testosterone to the level defined as medical castration.

Mechanism of Action

• Receptor blockade: degarelix binds competitively and reversibly to GnRH receptors in the pituitary gland. This rapidly reduces the release of luteinising hormone (LH) and follicle-stimulating hormone (FSH) and, in turn, the secretion of testosterone by the testes.
• No testosterone surge: unlike GnRH agonists, a GnRH antagonist does not cause an LH surge followed by a testosterone surge, tumour stimulation and a possible symptomatic flare at the start of treatment. An anti-androgen is therefore not needed as surge protection.
• Hormone response: a single 240 mg dose followed by monthly 80 mg doses quickly lowers LH, FSH and then testosterone. Dihydrotestosterone falls in a similar way.
• Castration level: in clinical studies, 96% of patients reached serum testosterone at or below the medical castration level of 0.5 ng/mL after three days and 100% after one month. With monthly 80 mg maintenance doses, 97% kept testosterone suppressed for at least one year. No testosterone microsurges were seen after re-injection, and the median testosterone level after one year was 0.087 ng/mL.
• Cardiac electrophysiology: a thorough QT study found no intrinsic effect of degarelix on the QT/QTc interval, although long-term androgen deprivation therapy in general may prolong it.

Pharmacokinetics

• Absorption: after subcutaneous injection, degarelix forms a depot at the injection site and is released into the circulation very slowly. In the pivotal study, a 240 mg starting dose given at 40 mg/mL reached a peak concentration (Cmax) of 66.0 ng/mL about 40 hours after injection, with an AUC over 28 days of 635 day·ng/mL. Mean trough levels were about 11–12 ng/mL after the starting dose and 11–16 ng/mL after 80 mg maintenance doses given at 20 mg/mL.
• Dependence on concentration: Cmax and bioavailability tend to fall, and half-life rises, as the concentration of the injected solution increases. Only the recommended concentrations should therefore be used.
• Distribution: the volume of distribution in healthy elderly men is about 1 L/kg, and about 90% of degarelix is bound to plasma proteins.
• Metabolism: degarelix undergoes ordinary peptide degradation as it passes through the liver and bile and is excreted mainly as peptide fragments in the faeces. No significant metabolites were found in plasma after subcutaneous injection, and it is not a substrate of the CYP450 system in vitro.
• Elimination: after a subcutaneous maintenance dose, the plasma concentration falls in two phases, with a mean terminal half-life of about 29 days. The long half-life reflects the slow release from the depot. In healthy men, 20–30% of an intravenous dose is excreted in the urine and 70–80% by the hepatobiliary route. Clearance after single intravenous doses in healthy elderly men was 35–50 mL/h/kg.
• Special populations: no pharmacokinetic study has been done in renal impairment. A population analysis found clearance about 23% lower in mild to moderate renal impairment, and no dose adjustment is recommended.

Degarelix is a GnRH antagonist indicated:

• Advanced hormone-dependent prostate cancer: treatment of adult male patients with advanced hormone-dependent prostate cancer.
• High-risk localised and locally advanced hormone-dependent prostate cancer: treatment in combination with radiotherapy.
• Neo-adjuvant use: neo-adjuvant treatment before radiotherapy in patients with high-risk localised or locally advanced hormone-dependent prostate cancer.

• Hypersensitivity to degarelix or to any of the excipients (mannitol).

The most common side effects in the confirmatory phase III study (409 patients) were the expected physiological effects of testosterone suppression, such as hot flushes (25% of patients treated for one year) and weight increase (7%), together with injection site reactions. The frequencies below come from 1,259 patients treated for a total of 1,781 patient-years in phase II and III studies, plus post-marketing reports.

Very common (≥1/10): hot flushes, injection site reactions (mainly pain and redness).

Common (≥1/100 to <1/10): anaemia, weight increase, insomnia, dizziness, headache, diarrhoea, nausea, increased liver transaminases, excessive sweating (including night sweats), rash, musculoskeletal pain and discomfort, gynaecomastia, testicular atrophy, erectile dysfunction, chills, fever, fatigue, influenza-like illness.

Uncommon (≥1/1,000 to <1/100): hypersensitivity, hyperglycaemia or diabetes mellitus, increased cholesterol, weight decrease, decreased appetite, changes in blood calcium, depression, decreased libido, mental impairment, hypoaesthesia, blurred vision, cardiac arrhythmia (including atrial fibrillation), palpitations, QT prolongation, hypertension, vasovagal reaction (including hypotension), dyspnoea, constipation, vomiting, abdominal pain, abdominal discomfort, dry mouth, increased bilirubin, increased alkaline phosphatase, urticaria, skin nodule, alopecia, pruritus, erythema, osteoporosis or osteopenia, joint pain, muscle weakness, muscle spasms, joint swelling or stiffness, frequent urination, urgency, painful urination, nocturia, renal failure, incontinence, testicular pain, breast pain, pelvic pain, genital irritation, ejaculation failure, malaise, peripheral oedema.

Rare (≥1/10,000 to <1/1,000): febrile neutropenia, anaphylactic reactions, myocardial infarction, cardiac failure, rhabdomyolysis.

Several of these reactions are physiological consequences of testosterone suppression: hot flushes, weight increase, anaemia, decreased libido, QT prolongation, excessive sweating, gynaecomastia, testicular atrophy, erectile dysfunction and fatigue.

Injection site reactions were mainly pain (28% of patients) and redness (17%), less often swelling (6%), induration (4%) and nodule (3%). They occurred mostly after the starting dose; with the 80 mg maintenance dose the incidence per 100 injections was 3 for pain and under 1 for redness, swelling, nodule and induration. They were mostly transient, mild to moderate and led to very few discontinuations (under 1%). Serious injection site reactions such as infection, abscess or necrosis that could need surgical treatment or drainage were reported very rarely. Transient chills, fever or influenza-like illness can appear a few hours after dosing (3%, 2% and 1% of patients).

No formal drug interaction studies have been done with degarelix.

• QT-prolonging medicines: because androgen deprivation therapy may prolong the QTc interval, using degarelix with medicines known to prolong the QTc interval or to cause torsades de pointes should be carefully evaluated. The SmPC names class IA antiarrhythmics (for example quinidine, disopyramide), class III antiarrhythmics (for example amiodarone, sotalol, dofetilide, ibutilide), methadone, moxifloxacin and antipsychotics.
• CYP450 enzymes: degarelix is not a substrate of the human CYP450 system and, in vitro, has not been shown to induce or inhibit CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A4/5 to any great extent. Clinically significant pharmacokinetic interactions through these enzymes are therefore unlikely.

Degarelix is a prescription medicine for subcutaneous injection only. The powder must be reconstituted with the solvent before use (instructions are in the SmPC). The effect of treatment is followed with clinical parameters and serum prostate-specific antigen (PSA) levels.

Recommended Dose

• Starting dose: 240 mg, given as two consecutive subcutaneous injections of 120 mg each.
• Maintenance dose: 80 mg as one subcutaneous injection every month. The first maintenance dose is given one month after the starting dose.
• With radiotherapy: degarelix may be used as neo-adjuvant or adjuvant therapy together with radiotherapy in high-risk localised and locally advanced prostate cancer.

Monitoring and Response

• Testosterone suppression begins right after the starting dose. In clinical studies, 96% of patients had testosterone at or below 0.5 ng/mL after three days and 100% after one month. During maintenance treatment for up to one year, 97% kept it suppressed.
• If the clinical response seems sub-optimal, it should be confirmed that serum testosterone remains sufficiently suppressed.
• Because degarelix does not cause a testosterone surge, an anti-androgen is not needed as surge protection at the start of treatment.

Method of Administration

• Subcutaneous use only: degarelix must not be given intravenously. Intramuscular use is not recommended because it has not been studied.
• Site: injected in the abdominal region. The injection site should be varied from time to time and placed where the patient will not be exposed to pressure, for example not close to a waistband or belt and not close to the ribs.
• Concentration: the pharmacokinetics depend on the concentration of the injected solution, so only the recommended concentrations (20 mg/mL for the 80 mg vial and 40 mg/mL for the 120 mg vial) should be used.

Special Populations

• Elderly: no dose adjustment.
• Renal and hepatic impairment: no dose adjustment in mild or moderate liver or kidney impairment. Patients with severe liver or kidney impairment have not been studied, so caution is needed.
• Children and adolescents: there is no relevant use of degarelix in children and adolescents for the treatment of advanced hormone-dependent prostate cancer in adult men.

Missed or Late Injection

The SmPC gives no separate rule for a missed or late monthly injection; the treating doctor decides when to give it. If the clinical response seems sub-optimal, serum testosterone should be checked to confirm that it remains sufficiently suppressed.

QT Interval

Long-term androgen deprivation therapy may prolong the QT interval. In the confirmatory study against leuprorelin, regular electrocardiograms showed QT/QTc intervals above 450 msec in about 20% of patients on either treatment and above 500 msec in 1% of patients on degarelix and 2% on leuprorelin. Degarelix has not been studied in patients with a history of a corrected QT interval above 450 msec, in those with a history of or risk factors for torsades de pointes, or in those taking medicines that might prolong the QT interval. In these patients the benefit and risk must be thoroughly weighed. A thorough QT study showed no intrinsic effect of degarelix on the QT/QTc interval.

Liver Function

Patients with a known or suspected liver disorder were not included in long-term clinical trials. Mild, transient rises in ALT and AST have been seen without a rise in bilirubin or clinical symptoms. Liver function should be monitored during treatment in patients with a known or suspected hepatic disorder. Patients with severe liver impairment have not been studied, so caution is needed.

Kidney Function

Degarelix has not been studied in patients with severe renal impairment, so caution is needed.

Hypersensitivity

Degarelix has not been studied in patients with a history of severe untreated asthma, anaphylactic reactions, or severe urticaria or angioedema.

Bone Density

Reduced bone density has been reported in men who have had an orchiectomy or been treated with a GnRH agonist, and long periods of testosterone suppression can be expected to affect bone density. Bone density has not been measured during degarelix treatment.

Glucose Tolerance

Reduced glucose tolerance has been seen in men after orchiectomy or on a GnRH agonist, and diabetes may develop or worsen. Diabetic patients may need their blood glucose checked more often during androgen deprivation therapy. The effect of degarelix on insulin and glucose levels has not been studied.

Cardiovascular Disease

Stroke and myocardial infarction have been reported in the medical literature in patients on androgen deprivation therapy, so all cardiovascular risk factors should be taken into account.

Pregnancy, Breastfeeding and Fertility

• Women: there is no relevant indication for degarelix in women.
• Fertility: degarelix may inhibit male fertility for as long as testosterone is suppressed.

Effect on Driving

Degarelix has no or negligible influence on the ability to drive and use machines. Fatigue and dizziness are common side effects and might affect it.

Firmagon does not require any special storage conditions, so no cold chain is needed. After reconstitution, the solution should be used at once (see Shelf Life). Each pack also holds the solvent in a pre-filled syringe, a plunger rod, a vial adapter and an injection needle. Keep out of the sight and reach of children.

• Unopened pack: 3 years.
• After reconstitution: chemical and physical in-use stability has been shown for 2 hours at 25 °C. From a microbiological point of view, the product should be used immediately unless the method of reconstitution rules out the risk of microbial contamination. If it is not used immediately, in-use times and conditions are the responsibility of the user.

Prescription only (Rx): the EU marketing authorisation classes Firmagon as a medicinal product subject to medical prescription. Degarelix is reconstituted before use and given as a subcutaneous injection in the abdominal region, so it is supplied to the clinic or hospital that administers it. No cold-chain delivery is needed.