INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. HypersensitivityInform patients that if they have experienced hypersensitivity with other GnRH agonist drugs like ELIGARD, ELIGARD is contraindicated [see Contraindications (4)]. Tumor FlareInform patients that ELIGARD can cause tumor flare during the first weeks of treatment. Inform patients that the increase in testosterone can cause an increase in urinary symptoms or pain. Advise patients to contact their healthcare provider if uretral obstruction, spinal cord compression, paralysis, or new or worsened symptoms occur after beginning ELIGARD treatment [see Warnings and Precautions (5.1)]. Hyperglycemia and DiabetesAdvise patients that there is an increased risk of hyperglycemia and diabetes with ELIGARD therapy. Inform patients that periodic monitoring for hyperglycemia and diabetes is required when being treated with ELIGARD [see Warnings and Precautions (5.3)]. Cardiovascular DiseaseInform patients that there is an increased risk of myocardial infarction, sudden cardiac death, and stroke with ELIGARD treatment. Advise patients to immediately report signs and symptoms associated with these events to their healthcare provider for evaluation [see Warnings and Precautions (5.4)]. Injection Site ReactionsInform patients that injection site related adverse reactions may occur such as transient burning/stinging, pain, bruising, and redness. Advise patients to contact their healthcare provider if they experience rash or severe injection site reactions [see Adverse Reactions (6.1)]. Urogenital DisordersAdvise patients that ELIGARD may cause impotence. InfertilityInform patients that ELIGARD may cause infertility [see Use In Specific Populations (8.3)]. Rx onlyRevised xx/xxxxManufactured by: Tolmar, Fort Collins, CO 80526(C)2023 Tolmar 04006171 Rev. xx/xx. Inform patients that if they have experienced hypersensitivity with other GnRH agonist drugs like ELIGARD, ELIGARD is contraindicated [see Contraindications (4)]. Inform patients that ELIGARD can cause tumor flare during the first weeks of treatment. Inform patients that the increase in testosterone can cause an increase in urinary symptoms or pain. Advise patients to contact their healthcare provider if uretral obstruction, spinal cord compression, paralysis, or new or worsened symptoms occur after beginning ELIGARD treatment [see Warnings and Precautions (5.1)]. Advise patients that there is an increased risk of hyperglycemia and diabetes with ELIGARD therapy. Inform patients that periodic monitoring for hyperglycemia and diabetes is required when being treated with ELIGARD [see Warnings and Precautions (5.3)]. Inform patients that there is an increased risk of myocardial infarction, sudden cardiac death, and stroke with ELIGARD treatment. Advise patients to immediately report signs and symptoms associated with these events to their healthcare provider for evaluation [see Warnings and Precautions (5.4)]. Inform patients that injection site related adverse reactions may occur such as transient burning/stinging, pain, bruising, and redness. Advise patients to contact their healthcare provider if they experience rash or severe injection site reactions [see Adverse Reactions (6.1)]. Advise patients that ELIGARD may cause impotence. Inform patients that ELIGARD may cause infertility [see Use In Specific Populations (8.3)].

INSTRUCTIONS FOR USE SECTION.

INSTRUCTIONS FOR USE. Follow the detailed instructions below to ensure correct preparation of ELIGARD prior to administration:Step 1Use aseptic technique throughout the procedure. Gloves are recommended during mixing and administration. Allow the product to reach room temperature before mixing. Once mixed, the product must be administered within 30 minutes or it should be discarded.On clean field open the tray by tearing off the foil from the corner and remove the contents. Discard the desiccant pack. Remove the pre-connected syringe system from the tray. Open the sterile safety needle package by peeling back the paper tab. Note: Syringe and Syringe should not be lined-up yet. The product should only be administered with the co-packaged, sterile safety needle.Step 2Grasp the latching button on the coupling device with your finger and thumb and press until you hear snapping sound. The two syringes will be aligned. Do not bend the pre-connected syringe system.Step 3Holding the syringes in horizontal position, transfer the liquid contents of Syringe into the leuprolide acetate powder contained in Syringe B. Thoroughly mix the product for 60 cycles by pushing the contents back and forth between both syringes to obtain uniform suspension. cycle is one push of the Syringe plunger and one push of the Syringe plunger.When thoroughly mixed, the suspension will appear light tan to tan (ELIGARD 7.5 mg) or colorless to pale yellow (ELIGARD 22.5 mg, and 30 mg).Note: Product must be mixed as described; shaking will NOT provide adequate mixing. Do not bend.Step 4After mixing, hold the syringes vertically (upright) with Syringe (wide syringe) on the bottom. The syringes should remain securely coupled. Transfer all of the mixed product into Syringe by depressing the Syringe plunger and slightly withdrawing the Syringe plunger.Step 5While ensuring the Syringe plunger is fully pushed down, hold the coupling device and unscrew Syringe B. This will disconnect Syringe from the coupling device. Syringe will remain attached to the coupling device.Note: Small air bubbles will remain in the formulation this is acceptable.Do not purge the air bubbles from Syringe as product may be lostStep 6Continue to hold Syringe upright with the open end at the top. Hold back the white plunger on Syringe to prevent loss of the product and attach the safety needle and cap. Gently screw clockwise with approximately three-quarter turn until the safety needle and cap are secure.Do not overtighten, as the needle hub may become damaged which could result in leakage of the product during injection. The safety shield may also be damaged if the safety needle and cap are screwed with too much force.Step 7Move the safety shield away from the needle and towards the syringe.Pull off the cap immediately prior to administration. Note: Should the needle hub appear to be damaged, or leak, the product should NOT be used. The damaged safety needle and cap should NOT be replaced and the product should NOT be injected. In the event of damage to the needle hub, use new replacement ELIGARD carton. Follow the detailed instructions below to ensure correct administration of ELIGARD:1. Select 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 and hasnt recently been used.2. Cleanse the injection-site area with an alcohol swab (not enclosed).3. Using the thumb and forefinger, grab and bunch the area of skin around the injection site. 4. Using your dominant hand, insert the needle quickly at 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.5. Inject the drug using slow, steady push and press down on the plunger until the syringe is empty. Make sure all the drug has been injected before removing the needle. 6. Withdraw the needle quickly at the same 90 angle used for insertion. 7. Immediately following the withdrawal of the needle, activate the safety shield using finger/thumb or flat surface and push until it completely covers the needle tip and locks into place.8. An audible and tactile click verifies locked position.9. Check to confirm the safety shield is fully engaged. Discard all components safely in an appropriate biohazard container.(C)2023 Tolmar Manufactured by: Tolmar, Fort Collins, CO 80526 04006171 Rev. XX/XX. cycle is one push of the Syringe plunger and one push of the Syringe plunger.. When thoroughly mixed, the suspension will appear light tan to tan (ELIGARD 7.5 mg) or colorless to pale yellow (ELIGARD 22.5 mg, and 30 mg).. mixing. step 2. step 3. step 4. step 5. step 6. step 7. admin 1. admin. admin.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS . Most common adverse reactions in clinical studies (incidence >= 5%): Malaise, fatigue, hot flashes/sweats, and testicular atrophy. (6.1) As with other GnRH agonists, other adverse reactions, including decreased bone density and rare cases of pituitary apoplexy have been reported. (6.1, 6.2)To report SUSPECTED ADVERSE REACTIONS, contact Tolmar Pharmaceuticals, Inc. at 1-888-354-4273 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. Most common adverse reactions in clinical studies (incidence >= 5%): Malaise, fatigue, hot flashes/sweats, and testicular atrophy. (6.1). As with other GnRH agonists, other adverse reactions, including decreased bone density and rare cases of pituitary apoplexy have been reported. (6.1, 6.2). 6.1 Clinical Trial Experience The safety of all ELIGARD formulations was evaluated in clinical trials involving patients with advanced prostate cancer (Table 3). In addition, the safety of ELIGARD 7.5 mg was evaluated in surgically castrated males (Table 4). ELIGARD, like other GnRH analogs, caused 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 (5.2)].During the clinical trials, injection sites were closely monitored. Refer to Table for summary of reported injection site adverse reactions.Table 3. Reported Injection Site Adverse ReactionsELIGARD7.5 mg 22.5 mg 30 mg Study numberAGL9904AGL9909AGL0001Number of patients120117 90Treatment1 injection every month up to months injection every months up to months1 injection every months up to monthsNumber of injections716230175Transient burning/stinging248 (34.6%) injections; 84% reported as mild50 (21.7%) injections; 86% reported as mild35 (20%) injections; 100% reported as mild2 Pain (generally brief and mild)4.3% of injections (18.3% of patients)3.5% of injections(6.0% of patients)2.3% of injections3 (3.3% of patients)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) -Pruritus1.4% of injections (9.2% of patients)0.4% of injections (0.9% of patients) -Induration0.4% of injections (2.5% of patients) -Ulceration0.1% of injections(> 0.8% of patients) -Erythema was reported following injections of ELIGARD 22.5 mg. One report characterized the erythema as mild and it resolved within days. The other report characterized the erythema as moderate and it resolved within 15 days. Neither patient experienced erythema at multiple injection times. Following injection of ELIGARD 30 mg, three of the 35 burning/stinging reactions were reported as moderate.A single reaction reported as moderate pain resolved within two minutes and all mild pain reactions resolved within several days following injection of ELIGARD 30 mg.These localized adverse reactions were non-recurrent over time. No patient discontinued therapy due to an injection site adverse reaction.The following possibly or probably related systemic adverse reactions 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 Reactions Reported by 2% of Patients Treated with ELIGARDELIGARD7.5 mg7.5 mg 22.5 mg 30 mg Study numberAGL9904AGL9802AGL9909AGL0001Number of patients120 117 90Treatment1 injection every month up to months1 injection(surgically castratedpatients) injection every months up to months1 injectionevery months up to 8monthsBody systemAdverse reaction Number (percent) Body as wholeMalaise and fatigue21 (17.5%) 7 (6.0%)12 (13.3%)Nervous systemDizziness4 (3.3%) -4 (4.4%) VascularHot flashes/sweats68 (56.7%) (25.0%)66 (56.4%) 66 (73.3%) Renal/urinary Urinary frequency --3 (2.6%) (2.2%) Nocturia -- -2 (2.2%) GastrointestinalNausea --4 (3.4%) (2.2%) Gastroenteritis/colitis3 (2.5%)- -Skin Pruritus --3 (2.6%) -Clamminess -- -4 (4.4%) Night sweats -- -3 (3.3%) Alopecia -- -2 (2.2%) Musculoskeletal Arthralgia --4 (3.4%) Myalgia --- (2.2%) Reproductive Testicular atrophy6 (5.0%)--4 (4.4%) Gynecomastia ---2 (2.2%) Testicular pain -- (2.2%) Psychiatric Decreased libido -- (3.3%) Expected pharmacological consequences of testosterone suppression.In the patient populations studied with ELIGARD 7.5 mg, total of 86 hot flashes/sweats adverse reactions were reported in 70 patients. Of these, 71 reactions (83%) were mild; 14 (16%) were moderate; (1%) was severe. In the patient population studied with ELIGARD 22.5 mg, total of 84 hot flashes/sweats adverse reactions were reported in 66 patients. Of these, 73 reactions (87%) were mild; 11 (13%) were moderate; none were severe. In the patient population studied with ELIGARD 30 mg, total of 75 hot flash adverse reactions were reported in 66 patients. Of these, 57 reactions (76%) were mild; 16 (21%) were moderate; (3%) were severe. In addition, the following possibly or probably related systemic adverse reactions were reported by 2% of the patients treated with ELIGARD in these clinical studies.Body systemAdverse ReactionsGeneralSweating, insomnia, syncope, rigors, weakness, lethargyGastrointestinalFlatulence, constipation, dyspepsiaHematologicDecreased red blood cell count, hematocrit and hemoglobinMetabolicWeight gainMusculoskeletalTremor, backache, joint pain, muscle atrophy, limb painNervousDisturbance of smell and taste, depression, vertigoPsychiatricInsomnia, depression, loss of libidoRenal/urinaryDifficulties with urination, pain on urination, scanty urination, bladder spasm, blood in urine, urinary retention, urinary urgency, incontinence, nocturia, nocturia aggravatedReproductive/ UrogenitalTesticular soreness/pain, impotence, decreased libido, gynecomastia, breast soreness/tenderness, testicular atrophy, erectile dysfunction, penile disorder, reduced penis sizeSkinAlopecia, clamminess, night sweats, sweating increasedVascularHypertension, 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 GnRH agonist analog. It can be anticipated that long periods of medical castration in men will have effects on bone density. Erythema was reported following injections of ELIGARD 22.5 mg. One report characterized the erythema as mild and it resolved within days. The other report characterized the erythema as moderate and it resolved within 15 days. Neither patient experienced erythema at multiple injection times. Following injection of ELIGARD 30 mg, three of the 35 burning/stinging reactions were reported as moderate.. single reaction reported as moderate pain resolved within two minutes and all mild pain reactions resolved within several days following injection of ELIGARD 30 mg.. 6.2 Postmarketing Experience Pituitary apoplexy-During postmarketing 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 majority of these cases, pituitary adenoma was diagnosed with majority of pituitary apoplexy cases occurring within 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. Nervous System-ConvulsionsRespiratory System-Interstitial lung disease.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Leuprolide acetate, gonadotropin releasing hormone (GnRH) agonist, acts as 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 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.. 12.2 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 1). One patient received less than 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 (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 2). 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 (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 3). Leuprolide acetate is not active when given orally. 12.3 Pharmacokinetics AbsorptionELIGARD 7.5 mg The pharmacokinetics/pharmacodynamics observed during three once-monthly injections in 20 patients with advanced prostate cancer is shown in Figure 1. Mean serum leuprolide concentrations following the initial injection rose to 25.3 ng/mL (Cmax) at approximately hours after injection. After the initial increase following each injection, serum concentrations remained relatively constant (0.28 2.00 ng/mL).Figure 1. Pharmacokinetic/Pharmacodynamic Response (N=20) to ELIGARD 7.5 mg Patients Dosed Initially and at Months and 2A 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 1). 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 2. Mean serum leuprolide concentrations rose to 127 ng/mL and 107 ng/mL at approximately 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 2. Pharmacokinetic/Pharmacodynamic Response (N=22) to ELIGARD 22.5 mg Patients Dosed Initially and at Month 3ELIGARD 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 3. 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 3. Pharmacokinetic/Pharmacodynamic Response (N=24) to ELIGARD 30 mg Patients Dosed Initially and at Month 4There 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.DistributionThe 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%.Elimination In healthy male volunteers, 1-mg bolus of leuprolide administered intravenously revealed that the mean systemic clearance was 8.34 L/h, with terminal elimination half-life of approximately hours based on two compartment model.Metabolism Upon administration with different leuprolide acetate formulations, the major metabolite of leuprolide acetate is pentapeptide (M-1) metabolite.Specific Populations Geriatrics. [see USE IN SPECIAL POPULATIONS (8.5)] Race In patients studied, mean serum leuprolide concentrations were similar regardless of race. Refer to Table for distribution of study patients by race.Table 6. Race Characterization of ELIGARD Study PatientsRaceELIGARD7.5 mgELIGARD22.5 mg ELIGARD30 mgWhite261918Black-44Hispanic222Renal and Hepatic Impairment The pharmacokinetics of ELIGARD in hepatically and renally impaired patients have not been determined. fig 1. fig 2. fig 3.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES One open-label, multicenter study was conducted with each ELIGARD formulation (7.5 mg, 22.5 mg and 30 mg) in patients with Jewett stage though prostate cancer who were treated with at least 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 4-6).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, 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, serum testosterone concentration of 66 ng/dL was reported immediately prior to the second injection. This rose to 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 and at hours after the second injection. Serum testosterone concentration rose to 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 single serum testosterone concentration of 55 ng/dL was reported.Table 7. Summary of Patients in ELIGARD Clinical StudiesELIGARD7.5 mg 22.5 mg 30 mg Study numberAGL9904AGL9909AGL0001Total number of patients120 (117 completed)1172 (111 completed3)90 (82 completed4)Jewett stagesStage A-22Stage B-1938Stage C896016Stage D313634Treatment6 monthly injections1 injection (4 patients)1 injection (5 patients)2 injections, one every three months (113 patients)2 injections, one every four months (85 patients)Duration of therapy6 months6 months8 monthsMean testosterone concentration (ng/dL)Baseline361.3367.1385.5Day 2574.6 (Day 3)588.0610.0Day 14Below Baseline (Day 10)Below BaselineBelow BaselineDay 2821.827.7 (Day 21)17.2Conclusion6.110.112.4Number of patients below castrate threshold (<= 50 ng/dL) Day 28112 of 119 (94.1%)115 of 116 (99%)85 of 89 (96%)Day 35-116 (100%)-Day 42119 (100%)-89 (100%)Conclusion1171 (100%)111 (100%)81 (99%)Two patients withdrew for reasons unrelated to drug.One patient received less than full dose at Baseline, never suppressed, and was withdrawn at Day 73 and given an alternate treatment.All non-evaluable patients who attained castration by Day 28 maintained castration at each time point up to and including the time of withdrawal. One patient withdrew on Day 14. All non-evaluable patients who had achieved castration by Day 28 maintained castration at each time point, up to and including the time of withdrawal. Figure 4. ELIGARD 7.5 mg Mean Serum Testosterone Concentrations (n=117)Figure 5. ELIGARD 22.5 mg Mean Serum Testosterone Concentrations (n=111)Figure 6. ELIGARD 30 mg Mean Serum Testosterone Concentrations (n=90)Serum PSA decreased in all patients in all studies whose Baseline values were elevated above the normal limit. Refer to Table for summary of the effectiveness of ELIGARD in reducing serum PSA values.Table 8. Effect of ELIGARD on Patient Serum PSA ValuesELIGARD7.5 mg22.5 mg30 mgMean PSA reduction at study conclusion94%98%86%Patients with normal PSA at study conclusion94%91%93%Among patients who presented with elevated levels at BaselineOther secondary efficacy endpoints evaluated included WHO performance status, bone pain, urinary pain and urinary signs and symptoms. Refer to Table for summary of these endpoints.Table 9. Secondary Efficacy EndpointsELIGARD 7.5 mg 22.5 mg 30 mg BaselineWHO Status 01 88%94%90%WHO Status 12 11%6%10%WHO Status 23 ---Mean bone pain4 (range)1.22 (1-9)1.20 (1-9)1.20 (1-7)Mean urinary pain (range)1.12 (1-5)1.02 (1-2)1.01 (1-2) Mean urinary signs and symptoms (range)Low1.09 (1-4)LowNumber of patients with prostate abnormalities102 (85%)96 (82%)66 (73%)Month 6Month 6Month 8Follow-upWHO status 0Unchanged96%87%WHO status 1Unchanged4%12% WHO status 2--1%Mean bone pain (range)1.26 (1-7)1.22 (1-5)1.19 (1-8) Mean urinary pain (range)1.07 (1-8)1.10 (1-8)1.00 (1-1)Mean urinary signs and symptoms (range)Modestly decreased1.18 (1-7)Modestly decreasedNumber of patients with prostate abnormalities77 (64%)76 (65%)54 (60%)WHO status 0 classified as fully active. WHO status 1 classified as restricted in strenuous activity but ambulatory and able to carry out work of light or sedentary nature. WHO status 2 classified as ambulatory but unable to carry out work activities. Pain score scale: (no pain) to 10 (worst pain possible).. Two patients withdrew for reasons unrelated to drug.. One patient received less than full dose at Baseline, never suppressed, and was withdrawn at Day 73 and given an alternate treatment.. All non-evaluable patients who attained castration by Day 28 maintained castration at each time point up to and including the time of withdrawal. One patient withdrew on Day 14. All non-evaluable patients who had achieved castration by Day 28 maintained castration at each time point, up to and including the time of withdrawal. WHO status 0 classified as fully active. WHO status 1 classified as restricted in strenuous activity but ambulatory and able to carry out work of light or sedentary nature. WHO status 2 classified as ambulatory but unable to carry out work activities. Pain score scale: (no pain) to 10 (worst pain possible).. Figure 4. figure 5. figure 6.

DESCRIPTION SECTION.

11 DESCRIPTION ELIGARD is sterile polymeric matrix formulation of leuprolide acetate, GnRH agonist, for subcutaneous injection. It is designed to deliver leuprolide acetate at controlled rate over one-, three-, or four-month therapeutic period.Leuprolide acetate is 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 pre-connected syringe system comprised of two prefilled syringes (syringe and syringe B) connected using 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 solid drug delivery depot.Syringe contains the in situ polymeric extended release technology consisting of biodegradable poly (DL-lactide-co-glycolide) (PLG) polymer formulation dissolved in biocompatible solvent, N-methyl-2-pyrrolidone (NMP) and syringe contains leuprolide acetate. Refer to Table for the delivery system composition and reconstituted product formulation for each ELIGARD product. Table 5. ELIGARD Delivery System Composition and Reconstituted Product FormulationELIGARD7.5 mg22.5 mg30 mgIn situ polymeric extended release technologyPolymerPLGHPLGPLGPolymer descriptionCopolymer containing carboxyl endgroupsCopolymer with hexanediolCopolymer with hexanediolPolymer DL-lactide to glycolidemolar ratio50:5075:2575:25Reconstituted productPolymer delivered82.5 mg158.6 mg211.5 mgNMP delivered160.0 mg193.9 mg258.5 mgLeuprolide acetate delivered7.5 mg22.5 mg30 mgApproximate Leuprolide freebase equivalent7.0 mg21 mg28 mgApproximate administered formulation weight250 mg375 mg500 mgApproximate injection volume0.25 mL0.375 mL0.5 mL structure.

DOSAGE & ADMINISTRATION SECTION.

DOSAGE AND ADMINISTRATION . 7.5 mg subcutaneously every month (2.1) 22.5 mg subcutaneously every months (2.1)30 mg subcutaneously every months (2.1) 7.5 mg subcutaneously every month (2.1) 22.5 mg subcutaneously every months (2.1). 30 mg subcutaneously every months (2.1) 2.1 Recommended Dosage. ELIGARD is administered subcutaneously and provides continuous release of leuprolide acetate over one-, three-, or four-month treatment period (Table 1). ELIGARD must be administered by healthcare provider. The injection delivers the dose of leuprolide acetate incorporated in polymer formulation. Table 1. ELIGARD Recommended DosingDosage7.5 mg22.5 mg30 mgRecommended dose1 injection everymonth1 injection every3 months1 injection every4 monthsAs with other drugs administered by subcutaneous injection, the injection site should vary periodically. The specific injection location should be an area with sufficient soft or loose subcutaneous tissue. In clinical trials, the injections were 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 belt or clothing waistband). 2.2 Mixing Procedure. Use aseptic technique throughout the procedure. As with other similar agents, the use of gloves is recommended during mixing and administration.1 Allow the product to reach room temperature before mixing. Once mixed, the product must be administered within 30 minutes or it should be discarded.ELIGARD is packaged in carton containing: Tray containing pre-connected syringe system and desiccant pack Prescribing informationSterile safety needle and cap (located under the tray in carton)Follow the detailed instructions below to ensure correct preparation of ELIGARD prior to administration:Step On clean field open the tray by tearing off the foil from the corner and remove the contents. Discard the desiccant pack. Remove the pre-connected syringe system from the tray. Open the sterile safety needle package by peeling back the paper tab. Note: Syringe and Syringe should not be lined-up yet. The product should only be administered with the co-packaged, sterile safety needle. Step Grasp the latching button on the coupling device with your finger and thumb and press until you hear snapping sound. The two syringes will be aligned. Do not bend the pre-connected syringe system. Step Holding the syringes in horizontal position, transfer the liquid contents of Syringe into the leuprolide acetate powder contained in Syringe B. Thoroughly mix the product for 60 cycles by pushing the contents back and forth between both syringes to obtain uniform suspension. cycle is one push of the Syringe plunger and one push of the Syringe plunger.When thoroughly mixed, the suspension will appear light tan to tan (ELIGARD 7.5 mg) or colorless to pale yellow (ELIGARD 22.5 mg, and 30 mg). Note: Product must be mixed as described; shaking will NOT provide adequate mixing. Do not bend. Step After mixing, hold the syringes vertically (upright) with Syringe (wide syringe) on the bottom. The syringes should remain securely coupled. Transfer all of the mixed product into Syringe by depressing the Syringe plunger and slightly withdrawing the Syringe plunger. Step While ensuring the Syringe plunger is fully pushed down, hold the coupling device and unscrew Syringe B. This will disconnect Syringe from the coupling device. Syringe will remain attached to the coupling device. Note: Small air bubbles will remain in the formulation this is acceptable. Do not purge the air bubbles from Syringe as product may be lost Step Continue to hold Syringe upright with the open end at the top. Hold back the white plunger on Syringe to prevent loss of the product and attach the safety needle and cap. Gently screw clockwise with approximately three-quarter turn until the safety needle and cap are secure. Do not overtighten, as the needle hub may become damaged which could result in leakage of the product during injection. The safety shield may also be damaged if the safety needle and cap are screwed with too much force. Step Move the safety shield away from the needle and towards the syringe. Pull off the cap immediately prior to administration. Note: Should the needle hub appear to be damaged, or leak, the product should NOT be used. The damaged safety needle and cap should NOT be replaced and the product should NOT be injected. In the event of damage to the needle hub, use new replacement ELIGARD carton.. Tray containing pre-connected syringe system and desiccant pack Prescribing information. Sterile safety needle and cap (located under the tray in carton). cycle is one push of the Syringe plunger and one push of the Syringe plunger.. When thoroughly mixed, the suspension will appear light tan to tan (ELIGARD 7.5 mg) or colorless to pale yellow (ELIGARD 22.5 mg, and 30 mg).. mixing. step2. step3. step4. step5. step6. step7. 2.3 Administration Procedure. 1. Select 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 and hasnt recently been used.2. Cleanse the injection-site area with an alcohol swab (not enclosed).3. Using the thumb and forefinger, grab and bunch the area of skin around the injection site. 4. Using your dominant hand, insert the needle quickly at 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.5. Inject the drug using slow, steady push and press down on the plunger until the syringe is empty. Make sure all the drug has been injected before removing the needle. 6. Withdraw the needle quickly at the same 90 angle used for insertion. 7. Immediately following the withdrawal of the needle, activate the safety shield using finger/thumb or flat surface and push until it completely covers the needle tip and locks into place.8. An audible and tactile click verifies locked position.9. Check to confirm the safety shield is fully engaged. Discard all components safely in an appropriate biohazard container. admin1. admin. admin.

PHARMACODYNAMICS SECTION.

12.2 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 1). One patient received less than 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 (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 2). 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 (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 3). Leuprolide acetate is not active when given orally.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS . Females and males of reproductive potential: ELIGARD may impair fertility. (8.3)Safety and effectiveness in pediatric patients have not been established. (8.4). Females and males of reproductive potential: ELIGARD may impair fertility. (8.3). Safety and effectiveness in pediatric patients have not been established. (8.4). 8.1 Pregnancy Risk Summary Based on findings in animal studies and mechanism of action, ELIGARD may cause fetal harm when administered to pregnant woman [see Clinical Pharmacology (12.1)]. There are no available data in pregnant women to inform the drug-associated risk. Expected hormonal changes that occur with ELIGARD treatment increase the risk for pregnancy loss. In animal developmental and reproductive studies, major fetal abnormalities were observed after administration of leuprolide acetate throughout gestation in rats. Advise pregnant patients and females of reproductive potential of the potential risk to the fetus (see Data). Animal Data In animal developmental and reproductive studies, 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.. 8.2 Lactation. The safety and efficacy of ELIGARD have not been established in females. There is no information regarding the presence of ELIGARD in human milk, the effects on the breastfed child, or the effects on milk production. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in breastfed child from ELIGARD, decision should be made to discontinue breastfeeding or discontinue the drug, taking into account the importance of the drug to the mother.. 8.3 Females and Males ofReproductive Potential Infertility Males Based on mechanism of action, ELIGARD may impair fertility in males of reproductive potential [see Clinical Pharmacology (12.1)]. 8.4 Pediatric Use The safety and effectiveness of ELIGARD in pediatric patients have not been established.. 8.5 Geriatric Use The majority of the patients (approximately 70%) studied in the clinical trials were age 70 and older.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS . Tumor Flare: Transient increase in serum levels of testosterone during treatment may result in worsening of symptoms or onset of new signs and symptoms during the first few weeks of treatment, including bone pain, neuropathy, hematuria, bladder outlet obstruction, ureteral obstruction, or spinal cord compression. Monitor patients at risk closely and manage as appropriate. (5.1, 5.2) Hyperglycemia and diabetes: Hyperglycemia and an increased risk of developing diabetes have been reported in men receiving GnRH analogs. Monitor blood glucose level and manage according to current clinical practice. (5.3) Cardiovascular diseases: Increased risk of myocardial infarction, sudden cardiac death and stroke has been reported in men. Monitor for cardiovascular disease and manage according to current clinical practice. (5.4) Effect on QT/QTc Interval: Androgen deprivation therapy may prolong the QT interval. Consider risks and benefits. (5.5)Embryo-Fetal Toxicity: May cause fetal harm. (5.6, 8.1)Convulsions have been observed in patients with or without history of predisposing factors. Manage convulsions according to the current clinical practice. (5.7) Tumor Flare: Transient increase in serum levels of testosterone during treatment may result in worsening of symptoms or onset of new signs and symptoms during the first few weeks of treatment, including bone pain, neuropathy, hematuria, bladder outlet obstruction, ureteral obstruction, or spinal cord compression. Monitor patients at risk closely and manage as appropriate. (5.1, 5.2). Hyperglycemia and diabetes: Hyperglycemia and an increased risk of developing diabetes have been reported in men receiving GnRH analogs. Monitor blood glucose level and manage according to current clinical practice. (5.3). Cardiovascular diseases: Increased risk of myocardial infarction, sudden cardiac death and stroke has been reported in men. Monitor for cardiovascular disease and manage according to current clinical practice. (5.4). Effect on QT/QTc Interval: Androgen deprivation therapy may prolong the QT interval. Consider risks and benefits. (5.5). Embryo-Fetal Toxicity: May cause fetal harm. (5.6, 8.1). Convulsions have been observed in patients with or without history of predisposing factors. Manage convulsions according to the current clinical practice. (5.7) 5.1 Tumor Flare. ELIGARD 7.5 mg, 22.5 mg, and 30 mg like other GnRH agonists, causes transient increase in serum concentrations of testosterone during the first week 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. 5.2 Laboratory Tests. Monitor ELIGARD response 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.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.. 5.3 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 GnRH agonist and manage with current practice for treatment of hyperglycemia or diabetes.. 5.4 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 treatment for patients with prostate cancer. Patients receiving GnRH agonist should be monitored for symptoms and signs suggestive of development of cardiovascular disease and be managed according to current clinical practice.. 5.5 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.. 5.6 Embryo-Fetal Toxicity. Based on findings in animal studies and mechanism of action, leuprolide acetate may cause fetal harm when administered to pregnant woman. In animal developmental and reproductive studies, major fetal abnormalities were observed after administration of leuprolide acetate throughout gestation in rats. Advise pregnant patients and females of reproductive potential of the potential risk to the fetus [see Use in Specific Populations (8.1), Clinical Pharmacology (12.1)].. 5.7 Convulsions. Postmarketing reports of convulsions have been observed in patients on leuprolide acetate therapy. These included patients with 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 GnRH agonist who experience convulsion should be managed according to current clinical practice.