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 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 6 for the delivery system composition and reconstituted product formulation for each ELIGARD ® product. Table 6. ELIGARD ® Delivery System Composition and Reconstituted 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 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 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 153d1272-figure-12

ELIGARD ® is indicated for the palliative treatment of advanced prostate cancer. ELIGARD ® is a gonadotropin releasing hormone (GnRH) agonist indicated for the palliative treatment of advanced prostate cancer

ELIGARD ® is an injectable suspension of leuprolide acetate available in a single-dose kit. The kit consists of a two-syringe mixing system, a sterile safety needle (Table 3), a desiccant, and a package insert for reconstitution and administration procedures. The syringes are packaged separately: Syringe A contains the ATRIGEL ® Delivery System and the Syringe B contains leuprolide acetate powder. When reconstituted, ELIGARD ® is administered as a single dose. Table 3. Specifications for ELIGARD ® Sterile Safety Needle 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 Injectable suspension: 7.5 mg Injectable suspension: 22.5 mg Injectable suspension: 30 mg Injectable suspension: 45 mg

ELIGARD ® is administered subcutaneously 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 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 a belt or clothing waistband)

mg subcutaneously every month 22.5 mg subcutaneously every 3 months 30 mg subcutaneously every 4 months 45 mg subcutaneously every 6 months 2.1 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 a carton containing two thermoformed trays and this package insert: Table 2: Contents of the Two Trays in the ELIGARD ® Carton Syringe A Tray Syringe B Tray Syringe A pre-filled with the ATRIGEL ® Delivery System Syringe B pre-filled with the leuprolide acetate powder Long white plunger rod Safety needle Desiccant pack Desiccant pack Follow the detailed instructions below to ensure correct preparation of ELIGARD ® prior to administration: 1. On a clean field, open both trays by tearing off the foil from the corners and removing the contents. Discard the desiccant pack(s). Open the safety needle package by peeling back the paper tab. 2. Pull out (do not unscrew) the short blue plunger rod with attached gray stopper from Syringe B and discard. 3. Gently screw the white plunger rod into the remaining gray stopper in Syringe B. 4. Unscrew and discard the clear cap from Syringe A. 5. Remove and discard the gray rubber cap from Syringe B. 6. Join the two syringes together by pushing and gently screwing until secure. 7. Inject the liquid contents of Syringe A into the leuprolide acetate powder contained in Syringe B. Thoroughly mix the product for approximately 45 seconds by pushing the contents back and forth between both syringes to obtain a uniform suspension. 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). Note: Product must be mixed as described; shaking will NOT provide adequate mixing. 8. After mixing, hold the syringes vertically (upright) with Syringe B (short, wide syringe) on the bottom. The syringes should remain securely coupled. Draw all of the mixed product into Syringe B by depressing the Syringe A plunger and slightly withdrawing the Syringe B plunger. 9. Unscrew Syringe A to decouple the syringes while continuing to push down on the Syringe A plunger. Note: Small air bubbles will remain in the formulation – this is acceptable. 10. Continue to hold Syringe B upright with the open end at the top. Hold back the white plunger on Syringe B to prevent loss of the product and attach the safety needle cartridge. Gently screw clockwise with approximately a three-quarter turn until the needle is secure. Do not overtighten, as the hub may become damaged resulting in leakage of the product during injection . The safety sheath may also be damaged if the needle is screwed with too much force. 11. Move the safety sheath away from the needle and towards the syringe and pull off the clear needle cartridge cover immediately prior to administration. Note: Should the needle hub appear to be damaged, or leak, the product should NOT be used. The damaged needle should NOT be replaced and the product should NOT be injected. In the event of damage to the needle hub, use a new replacement ELIGARD ® carton. Figure 1-1 Figure 1-2 Figure 2 Figure 3 Figure 4 Figure-5 Figure-6 Figure-7 Figure-8 Figure-9 step 10 Figure11 2.2 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 hasn’t 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 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. 5. Inject the drug using a slow, steady push and press down on the plunger until the syringe is empty. 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 a 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 a locked position. 9. Check to confirm the safety sheath is fully engaged. Discard all components safely in an appropriate biohazard container. Figure 2-2-1 Figure 2-2-2 Figure-7 Figure 7-2 Figure-2-8-8 Figure 2-8-9

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. 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. 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. Effect on QT/QTc Interval: Androgen deprivation therapy may prolong the QT interval. Consider risks and benefits. Embryo-Fetal Toxicity: May cause fetal harm. (5.6, 8.1) Convulsions have been observed in patients with or without a history of predisposing factors. Manage convulsions according to the current clinical practice. 5.1 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

Embryo-Fetal Toxicity Based on findings in animal studies and mechanism of action, leuprolide acetate may cause fetal harm when administered to a 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

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.

No pharmacokinetic drug-drug interaction studies were conducted with ELIGARD ® .