Eligard

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 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

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 )

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 a 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 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. 5.2 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. 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 a 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 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. 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 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 [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 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.

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

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 (<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 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 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 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 - - - - 4 (3.6%) Nervous system Dizziness 4 (3.3%) - - 4 (4.4%) - 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%) - - - - Skin Pruritus - - 3 (2.6%) - - Clamminess - - - 4 (4.4%) * - Night sweats - - - 3 (3.3%) * 3 (2.7%) * Alopecia - - - 2 (2.2%) - Musculoskeletal Arthralgia - - 4 (3.4%) - - 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. 6.2 Postmarketing Experience Pituitary apoplexy-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. Nervous System-Convulsions Respiratory System-Interstitial lung disease

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.