Prescription Drugs

CLINICAL PHARMACOLOGY Mechanism Of Action Leuprolide acetate, a gonadotropin releasing hormone (GnRH) agonist, acts as a potent inhibitor of gonadotropin secretion when given continuously in therapeutic doses. Animal and human studies indicate that after an initial stimulation, chronic administration of leuprolide acetate results in suppression of testicular and ovarian steroidogenesis. This effect is reversible upon discontinuation of drug therapy. In humans, administration of leuprolide acetate results in an initial increase in circulating levels of luteinizing hormone (LH) and follicle stimulating hormone (FSH), leading to a transient increase in levels of the gonadal steroids (testosterone and dihydrotestosterone in males, and estrone and estradiol in premenopausal females). However, continuous administration of leuprolide acetate results in decreased levels of LH and FSH. In males, testosterone is reduced to below castrate threshold ( ≤ 50 ng/dL). These decreases occur within two to four weeks after initiation of treatment. Long-term studies have shown that continuation of therapy with leuprolide acetate maintains testosterone below the castrate level for up to seven years. Pharmacodynamics Following the first dose of ELIGARD®  , mean serum testosterone concentrations transiently increased, then fell to below castrate threshold ( ≤ 50 ng/dL) within three weeks for all ELIGARD®  concentrations. Continued monthly treatment with ELIGARD®  7.5 mg maintained castrate testosterone suppression throughout the study. No breakthrough of testosterone concentrations above castrate threshold ( > 50 ng/dL) occurred at any time during the study once castrate suppression was achieved (Figure 18). One patient received less than a full dose of ELIGARD®  22.5 mg at baseline, never suppressed and withdrew from the study at Day 73. Of the 116 patients remaining in the study, 115 (99%) had serum testosterone levels below the castrate threshold by Month 1 (Day 28). By Day 35, 116 (100%) had serum testosterone levels below the castrate threshold. Once testosterone suppression was achieved, one patient ( < 1%) demonstrated breakthrough (concentrations > 50 ng/dL after achieving castrate levels) following the initial injection; that patient remained below the castrate threshold following the second injection (Figure 19). One patient withdrew from the ELIGARD®  30 mg study at Day 14. Of the 89 patients remaining in the study, 85 (96%) had serum testosterone levels below the castrate threshold by Month 1 (Day 28). By Day 42, 89 (100%) of patients attained castrate testosterone suppression. Once castrate testosterone suppression was achieved, three patients (3%) demonstrated breakthrough (concentrations > 50 ng/dL after achieving castrate levels) (Figure 20). One patient at Day 1 and another patient at Day 29 were withdrawn from the ELIGARD®  45 mg study. Of the 109 patients remaining in the study, 108 (99.1%) had serum testosterone levels below the castrate threshold by Month 1 (Day 28). One patient did not achieve castrate suppression and was withdrawn from the study at Day 85. Once castrate testosterone suppression was achieved, one patient ( < 1%) demonstrated breakthrough (concentrations > 50 ng/dL after achieving castrate levels) (Figure 21). Leuprolide acetate is not active when given orally. Pharmacokinetics Absorption ELIGARD®  7.5 mg The pharmacokinetics/pharmacodynamics observed during three once-monthly injections in 20 patients with advanced prostate cancer is shown in Figure 18. Mean serum leuprolide concentrations following the initial injection rose to 25.3 ng/mL (Cmax ) at approximately 5 hours after injection. After the initial increase following each injection, serum concentrations remained relatively constant (0.28 – 2.00 ng/mL). Figure 18: Pharmacokinetic/Pharmacodynamic Response (N=20) to ELIGARD®  7.5 mg – Patients Dosed Initially and at Months 1 and 2 A reduced number of sampling time points resulted in the apparent decrease in Cmax values with the second and third doses of ELIGARD®  7.5 mg (Figure 18). ELIGARD®  22.5 mg The pharmacokinetics/pharmacodynamics observed during two injections every three months (ELIGARD®  22.5 mg) in 22 patients with advanced prostate cancer is shown in Figure 19. Mean serum leuprolide concentrations rose to 127 ng/mL and 107 ng/mL at approximately 5 hours following the initial and second injections, respectively. After the initial increase following each injection, serum concentrations remained relatively constant (0.2 – 2.0 ng/mL). Figure 19: Pharmacokinetic/Pharmacodynamic Res ponse (N=22) to ELIGARD®  22.5 mg – Patients Dosed Initially and at Month 3 ELIGARD®  30 mg The pharmacokinetics/pharmacodynamics observed during injections administered initially and at four months (ELIGARD®  30 mg) in 24 patients with advanced prostate cancer is shown in Figure 20. Mean serum leuprolide concentrations following the initial injection rose rapidly to 150 ng/mL (Cmax ) at approximately 3.3 hours after injection. After the initial increase following each injection, mean serum concentrations remained relatively constant (0.1 – 1.0 ng/mL). Figure 20: Pharmacokinetic/Pharmacodynamic Response (N=24) to ELIGARD®  30 mg - Patients Dosed Initially and at Month 4 ELIGARD®  45 mg The pharmacokinetics/pharmacodynamics observed during injections administered initially and at six months (ELIGARD®  45 mg) in 27 patients with advanced prostate cancer is shown in Figure 21. Mean serum leuprolide concentrations rose to 82 ng/mL and 102 ng/mL (C ) at approximately 4.5 hours following the initial and second injections, respectively. After the initial increase following each injection, mean serum concentrations remained relatively constant (0.2 – 2.0 ng/mL). Figure 21: Pharmacokinetic/Pharmacodynamic Response (N=27) to ELIGARD®  45 mg - Patients Dosed Initially and at Month 6 There was no evidence of significant accumulation during repeated dosing. Non-detectable leuprolide plasma concentrations have been occasionally observed during ELIGARD®  administration, but testosterone levels were maintained at castrate levels. Distribution The mean steady-state volume of distribution of leuprolide following intravenous bolus administration to healthy male volunteers was 27 L. In vitro binding to human plasma proteins ranged from 43% to 49%. Metabolism In healthy male volunteers, a 1-mg bolus of leuprolide administered intravenously revealed that the mean systemic clearance was 8.34 L/h, with a terminal elimination half-life of approximately 3 hours based on a two compartment model. No drug metabolism study was conducted with ELIGARD® . Upon administration with different leuprolide acetate formulations, the major metabolite of leuprolide acetate is a pentapeptide (M-1) metabolite. Excretion No drug excretion study was conducted with ELIGARD® . Geriatrics [see Use In Special Populations] Race In patients studied, mean serum leuprolide concentrations were similar regardless of race. Refer to Table 6 for distribution of study patients by race. Table 6: Race Characterization of ELIGARD®  Study Patients Race ELIGARD® 7.5 mg ELIGARD® 22.5 mg ELIGARD® 30 mg ELIGARD® 45 mg White 26 19 18 17 Black - 4 4 7 Hispanic 2 2 2 3 Renal and Hepatic Insufficiency The pharmacokinetics of ELIGARD®  in hepatically and renally impaired patients have not been determined. Clinical Studies 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). These studies evaluated the achievement and maintenance of castrate serum testosterone suppression over the duration of therapy (Figures 22-25). During the AGL9904 study using ELIGARD®  7.5 mg, once testosterone suppression 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 was achieved, only one patient ( < 1%) demonstrated breakthrough following the initial injection; that patient remained below the castrate threshold following the second injection. During the AGL0001 study using ELIGARD®  30 mg, once testosterone suppression 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, castrate suppression 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, castrate suppression 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, castrate suppression 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 was achieved, one patient ( < 1%) demonstrated breakthrough. This patient reached castrate suppression 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. Table 7: Summary of ELIGARD®  Clinical Studies 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, o ne 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 below castrate threshold ( ≤ 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 42 119 (100%) 89 (100%) Conclusion 1171 (100%) 111 (100%) 81 (99%) 102 (99%) 1. Two patients withdrew for reasons unrelated to drug. 2. One patient received less than a full dose at Baseline, never suppressed, and was withdrawn at Day 73 and given an alternate treatment. 3. All non-evaluable patients who attained castration by Day 28 maintained castration at each time point up to and including the time of withdrawal. 4. One patient withdrew on Day 14. All 7 non-evaluable patients who had achieved castration by Day 28 maintained castration at each time point, up to and including the time of withdrawal. 5. Two patients were withdrawn prior to the Month 1 blood draw. One patient did not achieve castration and was withdrawn on Day 85. All 5 non-evaluable patients who attained castration by Day 28, maintained castration at each time point up to and including the time of withdrawal. Figure 22: ELIGARD®  7.5 mg Mean Serum Testosterone Concentrations (n=117) Figure 23: ELIGARD®  22.5 mg Mean Serum Testosterone Concentrations (n=111) Figure 24: ELIGARD®  30 mg Mean Serum Testosterone Concentrations (n=90) Figure 25: ELIGARD®  45 mg Mean Serum Testosterone Concentrations (n=103) 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. Table 8: Effect of ELIGARD®  on Patient 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. Table 9: Secondary Efficacy 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 (range) 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%) 1. WHO status = 0 classified as “fully active.” 2. WHO status = 1 classified as “restricted in strenuous activity but ambulatory and able to carry out work of a light or sedentary nature.” 3. WHO status = 2 classified as “ambulatory but unable to carry out work activities.” 4. Pain score scale: 1 (no pain) to 10 (worst pain possible). REFERENCES 1. “OSHA Hazardous Drugs.” OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html

Find Lowest Prices on ELIGARD® (leuprolide acetate) Suspension for Subcutaneous Injection DESCRIPTION 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-Dleucyl- L-leucyl-L-arginyl-N-ethyl-L-prolinamide acetate (salt) with the following structural formula: ELIGARD®  is prefilled and supplied in two separate, sterile syringes whose contents are mixed immediately prior to administration. The two syringes are joined and the single dose product is mixed until it is homogenous. ELIGARD®  is administered subcutaneously, where it forms a solid drug delivery depot. One syringe contains the ATRIGEL Delivery System and the other contains leuprolide acetate. ATRIGEL is a polymeric (non-gelatin containing) delivery system consisting of a biodegradable poly (DL-lactide-co-glycolide) (PLGH or PLG) polymer formulation dissolved in a biocompatible solvent, N-methyl-2-pyrrolidone (NMP). Refer to Table 5 for the delivery system composition and constituted product formulation for each ELIGARD®  product. Table 5: ELIGARD®  Delivery System Composition and Constituted Product Formulation ELIGARD® 7.5 mg 22.5 mg 30 mg 45 mg ATRIGEL® Delivery System syringe 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 molar ratio 50:50 75:25 75:25 85:15 Constituted 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 base equivalent 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

INDICATIONS ELIGARD® is indicated for the palliative treatment of advanced prostate cancer. DOSAGE AND ADMINISTRATION As with other similar agents, the use of gloves is recommended during mixing and administration. ELIGARD®  is administered s ubcutaneous ly and provides continuous release of leuprolide acetate over a one-, three-, four-, or six-month treatment period (Table 1). The injection delivers the dose of leuprolide acetate incorporated in a polymer formulation. Table 1: ELIGARD®  Recommended Dosing Dosage 7.5 mg 22.5 mg 30 mg 45 mg Recommended dose 1 injection every month 1 injection every 3 months 1 injection every 4 months 1 injection every 6 months As with other drugs administered by subcutaneous injection, the injection site should vary periodically. The specific injection location chosen should be an area with sufficient soft or loose subcutaneous tissue. In clinical trials, the injection was administered in the upper- or mid-abdominal area. Avoid areas with brawny or fibrous subcutaneous tissue or locations that could be rubbed or compressed (i.e., with a belt or clothing waistband). Mixing Procedure IMPORTANT: Allow the product to reach room temperature before mixing. Once mixed, the product must be administered within 30 minutes or it should be discarded. Follow the detailed instructions below to ensure proper preparation of ELIGARD®  prior to administration: ELIGARD®  is packaged in two thermoformed trays. Each carton contains: One sterile syringe (Syringe A) pre-filled with the ATRIGEL Delivery System One sterile syringe (Syringe B) pre-filled with leuprolide acetate powder One long white plunger rod for use with Syringe B One sterile needle or One sterile safety needle Desiccant pack(s) 1. On a clean field, open all of the packages and remove the contents. Discard the desiccant pack(s). Figure 1 and 2 2. Pull out the short blue plunger rod with attached grey s topper from Syringe B and discard (Figure 1). Twist the long, white replacement plunger rod into the gray primary stopper remaining in Syringe B (Figure 2). Figure 3 and 4 3. Unscrew and discard the clear cap from Syringe A (Figure 3). Remove and discard the gray rubber cap from Syringe B (Figure 4). Figure 5 4. Join the two syringes together by pushing and twisting until secure (Figure 5). Figure 6 5. Inject the liquid contents of Syringe A into Syringe B that contains the leuprolide acetate powder. Thoroughly mix the product for approximately 45 seconds by pushing the contents back and forth between both syringes to obtain a uniform suspension (Figure 6). When thoroughly mixed, the suspension will appear light tan to tan (ELIGARD®  7.5 mg) or colorless to pale yellow (ELIGARD®  22.5 mg, 30 mg and 45 mg). Pleas e Note: Product must be mixed as described; shaking will NOT provide adequate mixing of the product. Figure 7 6. After mixing, hold the syringes vertically with Syringe B on the bottom. The syringes should remain securely coupled. Draw the entire mixed product into Syringe B (short, wide syringe) by depressing the Syringe A plunger and slightly withdrawing the Syringe B plunger. Unscrew Syringe A to decouple the syringes while continuing to push down on the Syringe A plunger (Figure 7). Note: Small air bubbles will remain in the formulation – this is acceptable. Figure 8,9 and 10 [Applies to ELIGARD®  single use kit of a two syringe-mixing system with sterile needle] 7. Hold Syringe B vertically. Remove and discard the cap on the bottom of the sterile needle cartridge by twisting it (Figure 8). Attach the needle cartridge to the end of Syringe B (Figure 9) by pushing in and turning the needle until it is firmly seated. Do not overtwist the needle onto the syringe because the thread may become stripped. Pull off the clear needle cartridge cover prior to administration (Figure 10). Figure 11,12 and 13 [Applies to ELIGARD®  single use kit of a two syringe-mixing system with sterile safety needle] 8. Hold Syringe B vertically. Open the sterile safety needle package by peeling back the paper tab and remove the safety needle (Figure 11). Secure the needle to the end of Syringe B by holding the protective needle sheath and twisting the syringe clockwise to fully seat the needle (Figure 12). Do not over twist the needle onto the syringe because the thread may become stripped. Remove the protective needle sheath prior to administration (Figure 13). Administration Procedure IMPORTANT: Allow the product to reach room temperature before mixing. Once mixed, the product must be administered within 30 minutes or it should be discarded. 1. Choose an injection site on the abdomen, upper buttocks, or another location with adequate amounts of subcutaneous tissue that does not have excessive pigment, nodules, lesions, or hair. Since you can vary the injection site for subcutaneous injections, choose an area that hasn't recently been used. 2. Cleanse the injection-site area with an alcohol swab. 3. Using the thumb and forefinger of your non-dominant hand, grab and bunch the area of skin around the injection site. Figure 13a 4. Using your dominant hand, insert the needle quickly at a 90° angle to the skin surface. The depth of penetration will depend on the amount and fullness of the subcutaneous tissue and the length of the needle. After the needle is inserted, release the skin with your nondominant hand. Figure 13b 5. Inject the drug using a slow, steady push. Press down on the plunger until the syringe is empty. 6. Withdraw the needle quickly at the same 90° angle used for insertion. Figure 14, 15, 16 and 17 [Step 7 only applies to ELIGARD®  single use kit of a two syringe-mixing system with sterile safety needle] 7. Immediately following the withdrawal of the needle, activate the safety shield on the needle by using a thumb (Figure 14) or finger (Figure 15) or a flat surface (Figure 16) to push the safety shield forward until it completely covers the needle tip and locks into place. An audible and tactile “click” verifies a locked position for the safety shield (Figure 17). 8. Discard all components safely in an appropriate biohazard container. HOW SUPPLIED Dosage Forms And Strengths ELIGARD®  is an injectable suspension of leuprolide acetate available in a single use kit. The kit consists of a two-syringe mixing system, a sterile needle or a sterile safety needle (Table 2), a silica gel desiccant pouch to control moisture uptake, and a package insert for constitution and administration procedures. Each syringe is individually packaged. One contains the ATRIGEL Delivery System and the other contains leuprolide acetate powder. When constituted, ELIGARD®  is administered as a single dose. Table 2: ELIGARD®  Needle specifications ELIGARD® formulation Sterile needle Sterile safety needle Gauge Length Gauge Length 7.5 mg 20-gauge ½-inch 20- gauge 5/8-inch 22.5 mg 20-gauge ½-inch gauge 5/8-inch 30 mg 20-gauge 5/8-inch 20- gauge 5/8-inch 45 mg 18-gauge 5/8-inch 18- gauge 5/8-inch Storage And Handling ELIGARD®  is available in a single use kit of a two syringe-mixing system with a sterile needle in the following strengths: ELIGARD®  7.5 mg – NDC 62935-752-75 ELIGARD®  22.5 mg – NDC 62935-222-05 ELIGARD®  30 mg – NDC 62935-302-30 ELIGARD®  45 mg – NDC 62935-452-45 ELIGARD®  is available in a single use kit of a two syringe-mixing system with a sterile safety needle in the following strengths: ELIGARD®  7.5 mg – NDC 62935-753-75 ELIGARD®  22.5 mg – NDC 62935-223-05 ELIGARD®  30 mg – NDC 62935-303-30 ELIGARD®  45 mg – NDC 62935-453-45 Storage Store at 2 - 8 °C (35.6 - 46.4 °F) Once outside the refrigerator this product may be stored in its original packaging at room temperature 15 – 30 °C (59 – 86 °F) for up to eight weeks prior to mixing and administration. Manufactured by: TOLMAR Inc., Fort Collins, CO 80526. for: TOLMAR Therapeutics, Inc. Fort Collins, CO 80526. Distributed by: TOLMAR Pharmaceuticals, Inc., Fort Collins, CO 80526. Revised: Feb 2016

PATIENT INFORMATION As with other GnRH agonists, patients may experience hot flashes. During the first few weeks of treatment, patients may also experience increased bone pain, increased difficulty in urinating, and the onset or aggravation of weakness or paralysis. Patients should notify their doctor if they develop new or worsened symptoms after beginning ELIGARD®  treatment. Patients should be told about the injection site related adverse reactions, such as transient burning/stinging, pain, bruising, and redness. These injection site reactions are usually mild and reversible. If they do not resolve, patients should tell their doctor. If the patient experiences an allergic reaction, they should contact their doctor immediately.

SIDE EFFECTS 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 Advers e 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/s tinging 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) Druisuig (mild) 2.5% of injections (11.7%of patients) 1.7% of injections(3.4% of patients) 2.3% of injections5 Pruritus 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 4). 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® 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 mo nths 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 mo nths up to 12 mo nths 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 Nervous system Dizziness 4 (3.3%) 4 (4.4%) 4 (3.6%) 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%) Pruritus 3 (2.6%) Skin Clamminess 4 (4.4%)* Night sweats 3 (3.3%)* 3 (2.7%)* Alopecia 2 (2.2%) Arthralgia 4 (3.4%) Musculoskeletal 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. Postmarketing Experience 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. DRUG INTERACTIONS No pharmacokinetic drug-drug interaction studies were conducted with ELIGARD® .

WARNINGS Included as part of the PRECAUTIONS section. PRECAUTIONS Tumor Flare ELIGARD® 7.5 mg 22.5 mg 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 palliative 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. Laboratory Tests Response to ELIGARD® should be monitored by periodic measurement of serum concentrations of testosterone and prostate specific antigen. In the majority of patients, testosterone levels increased above Baseline during the first week, declining thereafter to Baseline levels or below by the end of the second or third week. Castrate levels were generally reached within two to four weeks. Castrate testosterone levels were maintained for the duration of the treatment with ELIGARD® 7.5 mg. No increases to above the castrate level occurred in any of the patients. Castrate levels were generally maintained for the duration of treatment with ELIGARD® 22.5 mg. Once castrate levels were achieved with ELIGARD® 30 mg, most (86/89) patients remained suppressed throughout the study. Once castrate levels were achieved with ELIGARD® 45 mg, only one patient ( < 1%) experienced a breakthrough, with testosterone levels > 50 ng/dL. Results of testosterone determinations are dependent on assay methodology. It is advisable to be aware of the type and precision of the assay methodology to make appropriate clinical and therapeutic decisions. Drug/Laboratory Test Interactions Therapy with leuprolide acetate results in suppression of the pituitary-gonadal system. Results of diagnostic tests of pituitary gonadotropic and gonadal functions conducted during and after leuprolide therapy may be affected. 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 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 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. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility Two-year carcinogenicity studies were conducted with leuprolide acetate in rats and mice. In rats, a dose-related increase of benign pituitary hyperplasia and benign pituitary adenomas was noted at 24 months when the drug was administered subcutaneously at high daily doses (0.6 to 4 mg/kg). There was a significant but not dose-related increase of pancreatic islet-cell adenomas in females and of testicular interstitial cell adenomas in males (highest incidence in the low dose group). In mice, no leuprolide acetate-induced tumors or pituitary abnormalities were observed at a dose as high as 60 mg/kg for two years. Patients have been treated with leuprolide acetate for up to three years with doses as high as 10 mg/day and for two years with doses as high as 20 mg/day without demonstrable pituitary abnormalities. No carcinogenicity studies have been conducted with ELIGARD® . Mutagenicity studies have been performed with leuprolide acetate using bacterial and mammalian systems and with ELIGARD® 7.5 mg in bacterial systems. These studies provided no evidence of a mutagenic potential. Use In Specific Populations Pregnancy Pregnancy category X. [See 'CONTRAINDICATIONS' section] ELIGARD® is contraindicated in women who are or may become pregnant while receiving the drug. Expected hormonal changes that occur with ELIGARD® treatment increase the risk for pregnancy loss. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be informed of the potential hazard to the fetus and the potential risk for pregnancy loss. In non-clinical studies in rats, major fetal abnormalities were observed after administration of leuprolide acetate throughout gestation. There were increased fetal mortality and decreased fetal weights in rats and rabbits. The effects of fetal mortality are expected consequences of the alterations in hormonal levels brought about by this drug. The possibility exists that spontaneous abortion may occur. Nursing Mothers ELIGARD® is not indicated for use in women [see INDICATIONS AND USAGE]. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from ELIGARD® , a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use The safety and effectiveness of ELIGARD® in pediatric patients have not been established. Geriatric Use The majority of the patients (approximately 70%) studied in the clinical trials were age 70 and older.