Source: European Medicines Agency (EU) Revision Year: 2020 Publisher: Ferring Pharmaceuticals A/S, Kay Fiskers Plads 11, DK-2300, Copenhagen S, Denmark, Tel: +45 88 33 88 34
Hypersensitivity to the active substance or to any of the excipients listed in section 6.
Long-term androgen deprivation therapy may prolong the QT interval. In the confirmatory study comparing FIRMAGON to leuprorelin periodic (monthly) electrocardiograms (ECGs) were performed; both therapies showed QT/QTc intervals exceeding 450 msec in approximately 20% of the patients, and 500 msec in 1% and 2% of the degarelix and leuprorelin patients, respectively (see section 5.1). FIRMAGON has not been studied in patients with a history of a corrected QT interval over 450 msec, in patients with a history of or risk factors for torsades de pointes and in patients receiving concomitant medicinal products that might prolong the QT interval. Therefore in such patients, the benefit/risk ratio of FIRMAGON must be thoroughly appraised (see sections 4.5 and 4.8). A thorough QT study showed that there was no intrinsic effect of degarelix on QT/QTc interval (see section 4.8).
Patients with known or suspected hepatic disorder have not been included in long-term clinical trials with degarelix. Mild, transient increases in ALT and AST have been seen, these were not accompanied by a rise in bilirubin or clinical symptoms. Monitoring of liver function in patients with known or suspected hepatic disorder is advised during treatment. The pharmacokinetics of degarelix has been investigated after single intravenous administration in subjects with mild to moderate hepatic impairment (see section 5.2).
Degarelix has not been studied in patients with severe renal impairment and caution is therefore warranted.
Degarelix has not been studied in patients with a history of severe untreated asthma, anaphylactic reactions or severe urticaria or angioedema.
Decreased bone density has been reported in the medical literature in men who have had orchiectomy or who have been treated with a GnRH agonist. It can be anticipated that long periods of testosterone suppression in men will have effects on bone density. Bone density has not been measured during treatment with degarelix.
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.
Cardiovascular disease such as stroke and myocardial infarction has been reported in the medical literature in patients with androgen deprivation therapy. Therefore, all cardiovascular risk factors should be taken into account.
No formal drug-drug interaction studies have been performed.
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, moxifloxacin, antipsychotics, etc. should be carefully evaluated (see section 4.4).
Degarelix is not a substrate for the human CYP450 system and has not been shown to induce or inhibit CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4/5 to any great extent in vitro. Therefore, clinically significant pharmacokinetic drug-drug interactions in metabolism related to these isoenzymes are unlikely.
There is no relevant indication for use of FIRMAGON in women.
FIRMAGON may inhibit male fertility as long as the testosterone is suppressed.
FIRMAGON has no or negligible influence on the ability to drive and use machines. Fatigue and dizziness are common adverse reactions that might influence the ability to drive and use machines.
The most commonly observed adverse reactions during degarelix therapy in the confirmatory phase III study (N=409) were due to the expected physiological effects of testosterone suppression, including hot flushes and weight increase (reported in 25% and 7%, respectively, of patients receiving treatment for one year), or injection site adverse reactions. Transient chills, fever or influenza like illness were reported to occur hours after dosing (in 3%, 2% and 1% of patients, respectively).
The injection site adverse reactions reported were mainly pain and erythema, reported in 28% and 17% of patients, respectively, less frequently reported were swelling (6%), induration (4%) and nodule (3%). These events occurred primarily with the starting dose whereas during maintenance therapy with the 80 mg dose, the incidence of these events pr 100 injections was: 3 for pain and <1 for erythema, swelling, nodule and induration. The reported events were mostly transient, of mild to moderate intensity and led to very few discontinuations (<1%). Serious injection site reactions were very rarely reported such as injection site infection, injection site abscess or injection site necrosis that could require surgical treatment/drainage.
The frequency of undesirable effects listed below is defined using the following convention: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000) and very rare (<1/10,000). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Table 1. Frequency of adverse drug reactions reported in 1,259 patients treated for a total of 1781 patient years (phase II and III studies) and from post-marketing reports:
Common: Anaemia*
Rare: Neutropenic fever
Uncommon: Hypersensitivity Anaphylactic reactions
Common: Weight increase*
Uncommon: Hyperglycemia/Diabetes mellitus, cholesterol increased, weight decreased, appetite decreased, changes in blood calcium
Common: Insomnia
Uncommon: Depression, libido decreased*
Common: Dizziness, headache
Uncommon: Mental impairment, hypoaesthesia
Uncommon: Vision blurred
Uncommon: Cardiac arrhythmia (incl. atrial fibrillation), palpitations, QT prolongation*(see sections 4.4 and 4.5)
Rare: Myocardial infarction, cardiac failure
Very common: Hot flush*
Uncommon: Hypertension, vasovagal reaction (incl. hypotension)
Uncommon: Dyspnoea
Common: Diarrhoea, nausea
Uncommon: Constipation, vomiting, abdominal pain, abdominal discomfort, dry mouth
Common: Liver transaminases increased
Uncommon: Bilirubin increased, alkaline phosphatase increased
Common: Hyperhidrosis (incl. night sweats)*, rash
Uncommon: Urticaria, skin nodule, alopecia, pruritus, erythema
Common: Musculoskeletal pain and discomfort
Uncommon: Osteoporosis/osteopenia, arthralgia muscular weakness, muscle spasms, joint swelling/stiffness
Rare: Rhabdomyolysis
Uncommon: Pollakiuria, micturition urgency, dysuria, nocturia, renal impairment, incontinence
Common: Gynaecomastia*, testicular atrophy*, erectile dysfunction*
Uncommon: Testicular pain, breast pain, pelvic pain, genital irritation, ejaculation failure
Very common: Injection site adverse reactions
Common: Chills, pyrexia, fatigue*, Influenzalike illness
Uncommon: Malaise, peripheral oedema
* Known physiological consequence of testosterone suppression
Changes in laboratory values seen during one year of treatment in the confirmatory phase III study (N=409) were in the same range for degarelix and a GnRH-agonist (leuprorelin) used as comparator. Markedly abnormal (>3*ULN) liver transaminase values (ALT, AST and GGT) were seen in 2-6% of patients with normal values prior to treatment, following treatment with both medicinal products. Marked decrease in haematological values, hematocrit (≤0.37) and hemoglobin (≤115 g/l) were seen in 40% and 13-15%, respectively, of patients with normal values prior to treatment, following treatment with both medicinal products. It is unknown to what extent this decrease in haematological values was caused by the underlying prostate cancer and to what extent it was a consequence of androgen deprivation therapy. Markedly abnormal values of potassium (≥5.8 mmol/l), creatinine (≥177 μmol/l) and BUN (≥10.7 mmol/l) in patients with normal values prior to treatment, were seen in 6%, 2% and 15% of degarelix treated patients and 3%, 2% and 14% of leuprorelin treated patients, respectively.
Changes in ECG measurements seen during one year of treatment in the confirmatory phase III study (N=409) were in the same range for degarelix and a GnRH-agonist (leuprorelin) used as comparator. Three (<1%) out of 409 patients in the degarelix group and four (2%) out of 201 patients in the leuprorelin 7.5 mg group, had a QTcF≥500 msec. From baseline to end of study the median change in QTcF for degarelix was 12.0 msec and for leuprorelin was 16.7 msec. The lack of intrinsic effect of degarelix on cardiac repolarisation (QTcF), heart rate, AV conduction, cardiac depolarisation, or T or U wave morphology was confirmed in a thorough QT study in healthy subjects (N=80) receiving an i.v. infusion of degarelix over 60 min, reaching a mean Cmax of 222 ng/mL, approx. 3-4-fold the Cmax obtained during prostate cancer treatment.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
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