Eligard
(Leuprolide Acetate)Eligard Prescribing Information
ELIGARD is indicated for the treatment of advanced prostate cancer.
ELIGARD is an injectable suspension of leuprolide acetate available in a pre-connected syringe system and packaged with a sterile safety needle and cap (Table 2), a desiccant, prescribing information and instructions for use. The pre-connected syringe system consists of syringe A and syringe B connected using a coupling device. Syringe A contains the in situ polymeric extended release technology and the syringe B contains leuprolide acetate powder. When reconstituted, ELIGARD is administered as a single dose. Refer to Table 10 for details of the description of the dosage form before and after mixing
ELIGARD is supplied as a single-dose, two syringe-mixing system with a sterile safety needle and cap. ELIGARD is available as follows (Table 10):
ELIGARD strength | NDC number | Description of Syringe A with the delivery system | Description of Syringe B with leuprolide acetate | Description of the suspension after mixing |
| 7.5 mg | 62935-756-80 | Light tan to tan, clear, viscous solution | White to off white powder | Light tan to tan |
| 22.5 mg | 62935-227-10 | Colorless to pale yellow, clear viscous solution | White to off white powder | Colorless to pale yellow |
| 30 mg | 62935-306-40 | Colorless to pale yellow, clear viscous solution | White to off white powder | Colorless to pale yellow |
| 45 mg | 62935-461-50 | Colorless to pale yellow, clear viscous solution | White to off white powder | Colorless to pale yellow |
Store at 2°C to 8°C (36°F to 46°F)
Once outside the refrigerator this product may be stored in its original packaging at room temperature 15°C to 30°C (59°F to 86°F) for up to eight weeks prior to mixing and administration.
ELIGARD strength | Gauge | Length |
| 7.5 mg | 20-gauge | 5/8-inch |
| 22.5 mg | 20-gauge | 5/8-inch |
| 30 mg | 20-gauge | 5/8-inch |
| 45 mg | 18-gauge | 5/8-inch |
ELIGARD is contraindicated in patients with hypersensitivity to GnRH, GnRH agonist analogs or any of the components of ELIGARD. Anaphylactic reactions to synthetic GnRH or GnRH agonist analogs have been reported in the literature.
The following clinically significant adverse reactions are described elsewhere in the labeling:
- Tumor Flare[see Warnings and Precautions ()]5.1 Tumor Flare
ELIGARD 7.5 mg, 22.5 mg, and 30 mg like other GnRH agonists, causes a transient increase in serum concentrations of testosterone during the first week of treatment. ELIGARD 45 mg causes a transient increase in serum concentrations of testosterone during the first two weeks of treatment. Patients may experience worsening of symptoms or onset of new signs and symptoms during the first few weeks of treatment, including bone pain, neuropathy, hematuria, or bladder outlet obstruction.
Cases of ureteral obstruction and/or spinal cord compression, which may contribute to paralysis with or without fatal complications, have been observed in the treatment of advanced prostate cancer using GnRH agonists.
Patients with metastatic vertebral lesions and/or with urinary tract obstruction should be closely observed during the first few weeks of therapy. If spinal cord compression or ureteral obstruction develops, standard treatment of these complications should be instituted.
- Hyperglycemia and Diabetes [see Warnings and Precautions ()]5.2 Hyperglycemia and Diabetes
Hyperglycemia and an increased risk of developing diabetes have been reported in men receiving GnRH agonists. Hyperglycemia may represent development of diabetes mellitus or worsening of glycemic control in patients with diabetes. Monitor blood glucose and/or glycosylated hemoglobin (HbA1c) periodically in patients receiving a GnRH agonist and manage with current practice for treatment of hyperglycemia or diabetes.
- Cardiovascular Disease [see Warnings and Precautions (5.3 Cardiovascular Diseases
Increased risk of developing myocardial infarction, sudden cardiac death and stroke has been reported in association with use of GnRH agonists in men. The risk appears low based on the reported odds ratios, and should be evaluated carefully along with cardiovascular risk factors when determining a treatment for patients with prostate cancer. Patients receiving a GnRH agonist should be monitored for symptoms and signs suggestive of development of cardiovascular disease and be managed according to current clinical practice.
)] - Effect on QT/QTc Interval [see Warnings and Precautions (5.4 Effect on QT/QTc Interval
Androgen deprivation therapy may prolong the QT/QTc interval. Providers should consider whether the benefits of androgen deprivation therapy outweigh the potential risks in patients with congenital long QT syndrome, congestive heart failure, frequent electrolyte abnormalities, and in patients taking drugs known to prolong the QT interval. Electrolyte abnormalities should be corrected. Consider periodic monitoring of electrocardiograms and electrolytes.
)] - Convulsions [see Warnings and Precautions (5.5 Convulsions
Postmarketing reports of convulsions have been observed in patients on leuprolide acetate therapy. These included patients with a history of seizures, epilepsy, cerebrovascular disorders, central nervous system anomalies or tumors, and in patients on concomitant medications that have been associated with convulsions such as bupropion and SSRIs. Convulsions have also been reported in patients in the absence of any of the conditions mentioned above. Patients receiving a GnRH agonist who experience convulsion should be managed according to current clinical practice.
)] - Severe Cutaneous Adverse Reactions [see Warnings and Precautions (5.6 Severe Cutaneous
Adverse ReactionsSevere cutaneous adverse reactions (SCARs), including Steve-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), and erythema multiforme, occurred in patients receiving ELIGARD
[see Adverse Reactions ].Monitor patients for the development of SCARs. Advise patients of the signs and symptoms of SCARs (e.g., a prodrome of fever, flu-like symptoms, mucosal lesions, progressive skin rash, or lymphadenopathy).
If a SCAR is suspected, interrupt ELIGARD until the etiology of the reaction has been determined. Consultation with a dermatologist is recommended. If a SCAR is confirmed, or for other grade 4 skin reactions, permanently discontinue ELIGARD.
5.6 Severe Cutaneous
Adverse ReactionsSevere cutaneous adverse reactions (SCARs), including Steve-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), and erythema multiforme, occurred in patients receiving ELIGARD
[see Adverse Reactions ].Monitor patients for the development of SCARs. Advise patients of the signs and symptoms of SCARs (e.g., a prodrome of fever, flu-like symptoms, mucosal lesions, progressive skin rash, or lymphadenopathy).
If a SCAR is suspected, interrupt ELIGARD until the etiology of the reaction has been determined. Consultation with a dermatologist is recommended. If a SCAR is confirmed, or for other grade 4 skin reactions, permanently discontinue ELIGARD.
)]
ELIGARD is a sterile polymeric matrix formulation of leuprolide acetate, a GnRH agonist, for subcutaneous injection. It is designed to deliver leuprolide acetate at a controlled rate over a one-, three-, four, or six-month therapeutic period.
Leuprolide acetate is a synthetic nonapeptide analog of naturally occurring gonadotropin releasing hormone (GnRH) that, when given continuously, inhibits pituitary gonadotropin secretion and suppresses testicular and ovarian steroidogenesis. The analog possesses greater potency than the natural hormone. The chemical name is 5-oxo-L-prolyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-D-leucyl-L-leucyl-L-arginyl-N-ethyl-L-prolinamide acetate (salt) with the following structural formula:
ELIGARD is supplied as a pre-connected syringe system comprised of two prefilled syringes (syringe A and syringe B) connected using a coupling device. Immediately prior to administration, the contents of the pre-connected syringe system are mixed until homogenous. ELIGARD is administered subcutaneously, where it forms a solid drug delivery depot.
Syringe A contains the in situ polymeric extended release technology consisting of a biodegradable poly (DL-lactide-co-glycolide) (PLGH or PLG) polymer formulation dissolved in a biocompatible solvent,
Refer to Table 5 for the delivery system composition and reconstituted product formulation for each ELIGARD product.
ELIGARD | 7.5 mg | 22.5 mg | 30 mg | 45 mg | |
In situ polymeric extended release technology | Polymer | PLGH | PLG | PLG | PLG |
Polymer description | Copolymer containing carboxyl endgroups | Copolymer with hexanediol | Copolymer with hexanediol | Copolymer with hexanediol | |
Polymer DL-lactide to glycolide | 50:50 | 75:25 | 75:25 | 85:15 | |
Reconstituted product | Polymer delivered | 82.5 mg | 158.6 mg | 211.5 mg | 165 mg |
NMP delivered | 160.0 mg | 193.9 mg | 258.5 mg | 165 mg | |
Leuprolide acetate delivered | 7.5 mg | 22.5 mg | 30 mg | 45 mg | |
Approximate Leuprolide free | 7.0 mg | 21 mg | 28 mg | 42 mg | |
Approximate administered formulation weight | 250 mg | 375 mg | 500 mg | 375 mg | |
Approximate injection volume | 0.25 mL | 0.375 mL | 0.5 mL | 0.375 mL | |
One open-label, multicenter study was conducted with each ELIGARD formulation (7.5 mg, 22.5 mg, 30 mg, and 45 mg) in patients with Jewett stage A though D prostate cancer who were treated with at least a single injection of study drug (Table 7). The efficacy outcome measure was medical castration rate, defined as achieving and maintaining serum testosterone suppression to ≤ 50 ng/dL (Figures 1-4).
During the AGL9904 study using ELIGARD 7.5 mg, once testosterone suppression below 50 ng/dL was achieved, no patients (0%) demonstrated breakthrough (concentration > 50 ng/dL) at any time in the study.
During the AGL9909 study using ELIGARD 22.5 mg, once testosterone suppression below 50 ng/dL was achieved, one patient (< 1%) demonstrated breakthrough following the initial injection; that patient remained below 50 ng/dL following the second injection.
During the AGL0001 study using ELIGARD 30 mg, once testosterone suppression below 50 ng/dL was achieved, three patients (3%) demonstrated breakthrough. In the first of these patients, a single serum testosterone concentration of 53 ng/dL was reported on the day after the second injection. In this patient, suppression below 50 ng/dL was reported for all other time points. In the second patient, a serum testosterone concentration of 66 ng/dL was reported immediately prior to the second injection. This rose to a maximum concentration of 147 ng/dL on the second day after the second injection. In this patient, suppression below 50 ng/dL was again reached on the seventh day after the second injection and was maintained thereafter. In the final patient, serum testosterone concentrations > 50 ng/dL were reported at 2 and at 8 hours after the second injection. Serum testosterone concentration rose to a maximum of 110 ng/dL on the third day after the second injection. In this patient, suppression below 50 ng/dL was again reached eighteen days after the second injection and was maintained until the final day of the study, when a single serum testosterone concentration of 55 ng/dL was reported.
During the AGL0205 study using ELIGARD 45 mg, once testosterone suppression below 50 ng/dL was achieved, one patient (<1%) demonstrated breakthrough. This patient reached castrate suppression below 50 ng/dL at Day 21 and remained suppressed until Day 308 when his testosterone level rose to 112 ng/dL. At Month 12 (Day 336), his testosterone was 210 ng/dL.
ELIGARD | 7.5 mg | 22.5 mg | 30 mg | 45 mg | ||
Study number | AGL9904 | AGL9909 | AGL0001 | AGL0205 | ||
Total number of patients | 120 (117 completed) | 1172 (111 completed3) | 90 (82 completed4) | 111 (103 completed5) | ||
Jewett stages | Stage A | ‑ | 2 | 2 | 5 | |
Stage B | ‑ | 19 | 38 | 43 | ||
Stage C | 89 | 60 | 16 | 19 | ||
Stage D | 31 | 36 | 34 | 44 | ||
Treatment | 6 monthly injections | 1 injection (4 patients) | 1 injection (5 patients) | 1 injection (5 patients) | ||
2 injections, one every three months (113 patients) | 2 injections, one every four months (85 patients) | 2 injections, one every six months (106 patients) | ||||
Duration of therapy | 6 months | 6 months | 8 months | 12 months | ||
Mean testosterone concentration (ng/dL) | Baseline | 361.3 | 367.1 | 385.5 | 367.7 | |
Day 2 | 574.6 (Day 3) | 588.0 | 610.0 | 588.6 | ||
Day 14 | Below Baseline (Day 10) | Below Baseline | Below Baseline | Below Baseline | ||
Day 28 | 21.8 | 27.7 (Day 21) | 17.2 | 16.7 | ||
Conclusion | 6.1 | 10.1 | 12.4 | 12.6 | ||
Number of patients with testosterone ≤ 50 ng/dL | Day 28 | 112 of 119 (94.1%) | 115 of 116 (99%) | 85 of 89 (96%) | 108 of 109 (99.1%) | |
Day 35 | ‑ | 116 (100%) | ‑ | - | ||
Day 42 | 118 (100%) | ‑ | 89 (100%) | - | ||
Conclusion | 1171 (100%) | 111 (100%) | 81 (99%) | 102 (99%) | ||
Number of patients with testosterone ≤ 20 ng/dL | Day 28 | 90 of 119 (76%) | 94 of 116 (81%) | 60 of 89 (67%) | 87 of 109 (80%) | |
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Serum PSA decreased in all patients in all studies whose Baseline values were elevated above the normal limit. Refer to Table 8 for a summary of the effectiveness of ELIGARD in reducing serum PSA values.
ELIGARD | 7.5 mg | 22.5 mg | 30 mg | 45 mg |
Mean PSA reduction at study conclusion | 94% | 98% | 86% | 97% |
Patients with normal PSA at study conclusion* | 94% | 91% | 93% | 95% |
*Among patients who presented with elevated levels at Baseline | ||||
Other secondary efficacy endpoints evaluated included WHO performance status, bone pain, urinary pain and urinary signs and symptoms. Refer to Table 9 for a summary of these endpoints.
ELIGARD | 7.5 mg | 22.5 mg | 30 mg | 45 mg | |
Baseline | WHO Status = 01 | 88% | 94% | 90% | 90% |
| WHO Status = 12 | 11% | 6% | 10% | 7% | |
| WHO Status = 23 | - | - | - | 3% | |
Mean bone pain4 | 1.22 (1-9) | 1.20 (1-9) | 1.20 (1-7) | 1.38 (1-7) | |
Mean urinary pain (range) | 1.12 (1-5) | 1.02 (1-2) | 1.01 (1-2) | 1.22 (1-8) | |
Mean urinary signs and symptoms (range) | Low | 1.09 (1-4) | Low | Low | |
Number of patients with prostate abnormalities | 102 (85%) | 96 (82%) | 66 (73%) | 89 (80%) | |
Month 6 | Month 6 | Month 8 | Month 12 | ||
Follow-up | WHO status = 0 | Unchanged | 96% | 87% | 94% |
WHO status = 1 | Unchanged | 4% | 12% | 5% | |
WHO status = 2 | - | - | 1% | 1% | |
Mean bone pain (range) | 1.26 (1-7) | 1.22 (1-5) | 1.19 (1-8) | 1.31 (1-8) | |
Mean urinary pain (range) | 1.07 (1-8) | 1.10 (1-8) | 1.00 (1-1) | 1.07 (1-5) | |
Mean urinary signs and symptoms (range) | Modestly decreased | 1.18 (1-7) | Modestly decreased | Modestly decreased | |
Number of patients with prostate abnormalities | 77 (64%) | 76 (65%) | 54 (60%) | 60 (58%) | |
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