Clinical Trial Experience
The safety of all ELIGARD® formulations was evaluated in clinical trials involving patients with advanced prostate cancer. In addition, the safety of ELIGARD® 7.5 mg was evaluated in 8 surgically castrated males (Table 4). ELIGARD® , like other GnRH analogs, caused a transient increase in serum testosterone concentrations during the first one to two weeks of treatment. Therefore, potential exacerbations of signs and symptoms of the disease during the first weeks of treatment are of concern in patients with vertebral metastases and/or urinary obstruction or hematuria. If these conditions are aggravated, it may lead to neurological problems such as weakness and/or paresthesia of the lower limbs or worsening of urinary symptoms [see WARNINGS AND PRECAUTIONS].
During the clinical trials, injection sites were closely monitored. Refer to Table 3 for a summary of reported injection site events.
Table 3: Reported Injection Site Adverse Events
|7.5 mg||22.5 mg||30 mg||45 mg|
|Number of patients||120||117||90||111|
|Treatment||1 injection every month up to 6 months||1 injection every 3 months up to 6 months||1 injection every 4 months up to 8 months||1 injection every 6 months up to 12 months|
|Number of injections||716||230||175||217|
|Transient burning/ stinging||248 (34.6%) injections;84% reported as mild||50 (21.7%) injections; 86% reported as mild||35 (20%) injections; 100% reported as mild||35 (16%) injections; 91.4% reported as mild3|
|Pain (generally brief and mild)||4.3% of injections (18.3% of patients)||3.5% of injections (6.0% of patients)||2.3% of injections2 (3.3% of patients)||4.6% of injections4|
|Erythema (generally brief and mild)||2.6% of injections (12.5% of patients)||0.9% of injections1 (1.7% of patients)||1.1% of injections (2.2% of patients)|
|Bruising (Mild)||2.5% of injections (11.7% of patients)||1.7% of injections (3.4% of patients)||2.3% of injections5|
|Pruritis||1.4% of injections (9.2% of patients)||0.4% of injections (0.9% of patients)|
|Induration||0.4% of injections (2.5% of patients)|
|Ulceration||0.1% of injections ( > 0.8% of patients)|
|1 Erythema was reported following 2 injections of ELIGARD® 22.5 mg. One report characterized the erythema as mild and it resolved within 7 days. The other report characterized the erythema as moderate and it resolved within 15 days. Neither patient experienced erythema at multiple injections.
2 A single event reported as moderate pain resolved within two minutes and all 3 mild pain events resolved within several days following injection of ELIGARD® 30 mg.
3 Following injection of ELIGARD® 30 mg, three of the 35 burning/stinging events were reported as moderate.
4 Transient pain was reported as mild in intensity in nine of ten (90%) events and moderate in intensity in one of ten (10%) events following injection of ELIGARD® 45 mg.
5 Mild bruising was reported following 5 (2.3%) study injections and moderate bruising was reported following 2 ( < 1%) study injections of ELIGARD® 45 mg.
These localized adverse events were non-recurrent over time. No patient discontinued therapy due to an injection site adverse event.
The following possibly or probably related systemic adverse events occurred during clinical trials with ELIGARD® , and were reported in > 2% of patients (Table 7). Often, causality is difficult to assess in patients with metastatic prostate cancer. Reactions considered not drug-related are excluded.
Table 4: Summary of Possible or Probably Related Systemic Adverse Events Reported by > 2% of Patients treated with ELIGARD®
|7.5 mg||7.5 mg||22.5 mg||30 mg||45 mg|
|Number of patients||120||8||117||90||111|
|Treatment||1 injection every month up to 6 months||1 injection (surgically castrated patients)||1 injection every 3 months up to 6 months||1 injection every 4 months up to 8 months||1 injection every 6 months up to 12 months|
|Body System||Adverse Event||Number (Percent)|
|Body as a Whole||Malaise and Fatigue||21 (17.5 %)||7 (6.0%)||12 (13.3%)||13 (11.7%)|
|Nervous System||Dizziness||4 (3.3%)||4 (4.4%)|
|Vascular||Hot flashes/sweats||68 (56.7%)*||2 (25.0%)*||66 (56.4%)*||66 (73.3%)*||64 (57.7%)*|
|Renal/Urinary||Urinary frequency||3 (2.6%)||2 (2.2%)|
|Gastrointestinal||Nausea||4 (3.4%)||2 (2.2%)|
|Night sweats||3 (3.3%)*||3 (2.7%)*|
|Myalgia||2 (2.2%)||5 (4.5%)|
|Pain in limb||3 (2.7%)|
|Reproductive||Testicular atrophy||6 (5.0%)||4 (4.4%)*||8 (7.2%)*|
|Gynecomastia||2 (2.2%)*||4 (3.6%)*|
|Testicular pain||2 (2.2%)|
|Psychiatric||Decreased libido||3 (3.3%)*|
|*Expected pharmacological consequences of testosterone suppression.
In the patient populations studied with ELIGARD® 7.5 mg, a total of 86 hot flashes/sweats adverse events were reported in 70 patients. Of these, 71 events (83%) were mild; 14 (16%) were moderate; 1 (1%) was severe.
In the patient population studied with ELIGARD® 22.5 mg, a total of 84 hot flashes/sweats adverse events were reported in 66 patients. Of these, 73 events (87%) were mild; 11 (13%) were moderate; none were severe.
In the patient population studied with ELIGARD® 30 mg, a total of 75 hot flash adverse events were reported in 66 patients. Of these, 57 events (76%) were mild; 16 (21%) were moderate; 2 (3%) were severe.
In the patient population studied with ELIGARD® 45 mg, a total of 89 hot flash adverse events were reported in 64 patients. Of these, 62 events (70%) were mild; 27 (30%) were moderate; none were severe.
In addition, the following possibly or probably related systemic adverse events were reported by < 2% of the patients treated with ELIGARD® in these clinical studies.
Body System :Adverse Event
General : Sweating, insomnia, syncope, rigors, weakness, lethargy
Gastrointestinal : Flatulence, constipation, dyspepsia
Hematologic : Decreased red blood cell count, hematocrit and hemoglobin
Metabolic : Weight gain
Musculoskeletal : Tremor, backache, joint pain, muscle atrophy, limb pain
Nervous : Disturbance of smell and taste, depression, vertigo
Psychiatric : Insomnia, depression, loss of libido*
Renal/Urinary: Difficulties with urination, pain on urination, scanty urination, bladder spasm, blood in urine, urinary retention, urinary urgency, incontinence, nocturia, nocturia aggravated
Reproductive/ Urogenital: Testicular soreness/pain, impotence*, decreased libido*, gynecomastia*, breast soreness/tenderness*, testicular atrophy*, erectile dysfunction, penile disorder*, reduced penis size
Skin : Alopecia, clamminess, night sweats*, sweating increased*
Vascular : Hypertension, hypotension
* Expected pharmacological consequences of testosterone suppression.
Changes in Bone Density
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 analog. It can be anticipated that long periods of medical castration in men will have effects on bone density.
During post-marketing surveillance, rare cases of pituitary apoplexy (a clinical syndrome secondary to infarction of the pituitary gland) have been reported after the administration of gonadotropin-releasing hormone agonists. In a majority of these cases, a pituitary adenoma was diagnosed with a majority of pituitary apoplexy cases occurring within 2 weeks of the first dose, and some within the first hour. In these cases, pituitary apoplexy has presented as sudden headache, vomiting, visual changes, ophthalmoplegia, altered mental status, and sometimes cardiovascular collapse. Immediate medical attention has been required.
Convulsions have also been reported in the postmarketing setting.