ELIGARD

RECENT MAJOR CHANGES Dosage and Administration, Administration Procedure (2.2) 04/2019 Warnings and Precautions, Embryo-Fetal Toxicity ( 5.6 ) 02/2019

1 INDICATIONS AND USAGE 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 ( 1 )

2 DOSAGE AND ADMINISTRATION 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). 7.5 mg subcutaneously every month ( 2 ) 22.5 mg subcutaneously every 3 months ( 2 ) 30 mg subcutaneously every 4 months ( 2 ) 45 mg subcutaneously every 6 months ( 2 ) 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. (1) Move the safety sheath away from the needle and towards the syringe and (2) pull off the clear needle cartridge cover immediat …

3 DOSAGE FORMS AND STRENGTHS 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 ( 3 ) Injectable suspension: 22.5 mg ( 3 ) Injectable suspension: 30 mg ( 3 ) Injectable suspension: 45 mg ( 3 )

4 CONTRAINDICATIONS Hypersensitivity ELIGARD ® is contraindicated in patients with hypersensitivity to GnRH, GnRH agonist analogs or any of the components of ELIGARD ® . Anaphylactic reactions to synthetic GnRH or GnRH agonist analogs have been reported in the literature. Known hypersensitivity to GnRH, GnRH agonist analogs or any of the components of ELIGARD ® ( 4.1 )

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. 6.1 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 5). 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 ( 5.2 )] . During the clinical trials, injection sites were closely monitored. Refer to Table 4 for a summary of reported injection site events. Table 4. Reported Injection Site Adverse Events ELIGARD ® 7.5 mg 22.5 mg 30 mg 45 mg Study number AGL9904 AGL9909 AGL0001 AGL0205 Number of patients 120 117 90 111 Treatment 1 injection every month up to 6 months 1 injection every 3 months up to 6 months 1 injection every 4 months up to 8 months 1 injection every 6 months up to 12 months Number of injections 716 230 175 217 Transient burning/ stinging 248 (34.6%) injections; 84% reported as mild 50 (21.7%) injections; 86% reported as mild 35 (20%) injections; 100% reported as mild 35 (16%) injections; 91.4% reported as mild 3 Pain (generally brief and mild) 4.3% of injections (18.3% of patients) 3.5% of injections (6.0% of patients) 2.3% of injections 2 (3.3% of patients) 4.6% of injections 4 Erythema (generally brief and mild) 2.6% of injections (12.5% of patients) 0.9% of injections 1 (1.7% of patients) 1.1% of injections (2.2% of patients) - Bruising (mild) 2.5% of injections (11.7% of patients) 1.7% of injections (3.4% of patients) - 2.3% of injections 5 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) - - - Erythema was reported following 2 injections of ELIGARD ® 22.5 mg. One report characterized the erythema as mild and it resolved within 7 days. The other report characterized the erythema as moderate and it resolved within 15 days. Neither patient experienced erythema at multiple injection times. A single event reported as moderate pain resolved within two minutes and all 3 mild pain events resolved within several days following injection of ELIGARD ® 30 mg. Following injection of ELIGARD ® 30 mg, three of the 35 burning/stinging events were reported as moderate. Transient pain was reported as mild in intensity in nine of ten (90%) events and moderate in intensity in one of ten (10%) events following injection of ELIGARD ® 45 mg. Mild bruising was reported following 5 (2.3%) study injections and moderate bruising was reported following 2 ( 2% of patients (Table 5). Often, causality is difficult to assess in patients with metastatic prostate cancer. Reactions considered not drug-related are excluded. Table 5. 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 months 1 injection (surgically castrated patients) 1 inje …

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

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 ) 8.1 Pregnancy Risk Summary Based on findings in animal studies and mechanism of action, ELIGARD ® may cause fetal harm when administered to a 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 a breastfed child from ELIGARD ® , a 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 of Reproductive 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.

12.1 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.

11 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-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

10 OVERDOSAGE In clinical trials using daily subcutaneous injections of leuprolide acetate in patients with prostate cancer, doses as high as 20 mg/day for up to two years caused no adverse effects differing from those observed with the 1 mg/day dose.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied ELIGARD ® is available in a single-dose 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 16.2 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.