Adverse Reactions
Adverse Reactions
ELIGARD® has a well-established safety profile. [1]
Most common adverse reactions in clinical studies (incidence ≥ 5%): Malaise, fatigue, hot flashes/sweats, and testicular atrophy.
As with other GnRH agonists, other adverse reactions, including decreased bone density and rare cases of pituitary apoplexy have been reported.
Often, causality is difficult to assess in patients with metastatic prostate cancer. Reactions considered not drug-related are excluded.
Localized adverse events were non-recurrent over time. No patient discontinued therapy due to an injection site adverse event.
Clinical trials
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 eight (8) surgically castrated males (see Table 2).
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 2 for a full summary of reported injection site events.
| ELIGARD® | 7.5 mg | 22.5 mg | 30 mg | 45 mg |
| Study number | AGL9904 | AGL9909 | AGL0001 | AGL0205 |
| 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) | — | — | — |
- 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 injection times.
- 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.
- Following injection of ELIGARD 30 mg, three of the 35 burning/stinging events were reported as moderate.
- 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.
- 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 3). Often, causality is difficult to assess in patients with metastatic prostate cancer. Reactions considered not drug-related are excluded.
| ELIGARD® | 7.5 mg | 7.5 mg | 22.5 mg | 30 mg | 45 mg | |
| Study number | AGL9904 | AGL9802 | AGL9909 | AGL0001 | AGL0205 | |
| 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%) |
| Weakness | — | — | — | — | 4 (3.6%) | |
| 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%) | — |
| Nocturia | — | — | — | 2 (2.2%) | — | |
| Gastrointestinal | Nausea | — | — | 4 (3.4%) | 2 (2.2%) | — |
| Gastroenteritis/ colitis | 3 (2.5%) | — | — | — | — | |
| Skin | Pruritis | — | — | 3 (2.6%) | — | — |
| Clamminess | — | — | — | 4 (4.4%)* | — | |
| Night sweats | — | — | — | 3 (3.3%)* | 3 (2.7%)* | |
| Alopecia | — | — | — | 2 (2.2%) | — | |
| Musculoskeletal | Arthralgia | — | — | 4 (3.4%) | — | — |
| 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 bilateral 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.
Post-marketing Experience
Pituitary apoplexy
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
- Sometimes cardiovascular collapse
Immediate medical attention has been required.
Nervous system
Convulsions
Respiratory system
Interstitial lung disease
References
- ELIGARD® (leuprolide acetate) for injectable suspension, 7.5 mg, 22.5 mg, 30 mg, 45 mg prescribing information. Fort Collins, CO: Tolmar Therapeutics, Inc.; 2019