ELIGARD

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.

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

<table width="100%" cellspacing="0" cellpadding="0"><col width="1px"/><col width="1px"/><col width="1px"/><col width="1px"/><col width="1px"/><tbody><tr><td styleCode=" Botrule Toprule Rrule"><paragraph><content styleCode="bold">ELIGARD^&#xAE;</content></paragraph></td><td styleCode=" Botrule Toprule Rrule"><paragraph><content styleCode="bold">7.5 mg </content></paragraph></td><td styleCode=" Botrule Toprule Rrule"><paragraph><content styleCode="bold">22.5 mg </content></paragraph></td><td styleCode=" Botrule Toprule Rrule"><paragraph><content styleCode="bold">30 mg </content></paragraph></td><td styleCode=" Botrule Toprule"><paragraph><content styleCode="bold">45 mg </content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Rrule"><paragraph><content styleCode="bold">Study number</content></paragraph></td><td styleCode=" Botrule Toprule Rrule"><paragraph>AGL9904</paragraph></td><td styleCode=" Botrule Toprule Rrule"><paragraph>AGL9909</paragraph></td><td styleCode=" Botrule Toprule Rrule"><paragraph>AGL0001</paragraph></td><td styleCode=" Botrule Toprule"><paragraph>AGL0205</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Rrule"><paragraph><content styleCode="bold">Number of patients</content></paragraph></td><td styleCode=" Botrule Toprule Rrule"><paragraph>120</paragraph></td><td styleCode=" Botrule Toprule Rrule"><paragraph>117 </paragraph></td><td styleCode=" Botrule Toprule Rrule"><paragraph>90</paragraph></td><td styleCode=" Botrule Toprule"><paragraph>111</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Rrule"><paragraph><content styleCode="bold">Treatment</content></paragraph></td><td styleCode=" Botrule Toprule Rrule"><paragraph>1 injection every month up to 6 months </paragraph></td><td styleCode=" Botrule Toprule Rrule"><paragraph>1 injection every 3 months up to 6 months</paragraph></td><td styleCode=" Botrule Toprule Rrule"><paragraph>1 injection every 4 months up to 8 months</paragraph></td><td styleCode=" Botrule Toprule"><paragraph>1 injection every 6 months up to 12 months</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Rrule"><paragraph><content styleCode="bold">Number of injections</content></paragraph></td><td styleCode=" Botrule Toprule Rrule"><paragraph>716</paragraph></td><td styleCode=" Botrule Toprule Rrule"><paragraph>230</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>175</paragraph></td><td styleCode=" Botrule Toprule"><paragraph>217</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Rrule"><paragraph><content styleCode="bold">Transient burning/ stinging</content></paragraph></td><td styleCode=" Botrule Toprule Rrule"><paragraph>248 (34.6%) injections; 84% reported as mild</paragraph></td><td styleCode=" Botrule Toprule Rrule"><paragraph>50 (21.7%) injections; 86% reported as mild</paragraph></td><td styleCode=" Botrule Toprule Rrule"><paragraph>35 (20%) injections; 100% reported as mild</paragraph></td><td styleCode=" Botrule Toprule"><paragraph>35 (16%) injections; 91.4% reported as mild³</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Rrule"><paragraph><content styleCode="bold">Pain (generally brief and mild)</content></paragraph></td><td styleCode=" Botrule Toprule Rrule"><paragraph>4.3% of injections (18.3% of patients)</paragraph></td><td styleCode=" Botrule Toprule Rrule"><paragraph>3.5% of injections (6.0% of patients)</paragraph></td><td styleCode=" Botrule Toprule Rrule"><paragraph>2.3% of injections² (3.3% of patients)</paragraph></td><td styleCode=" Botrule Toprule"><paragraph>4.6% of injections⁴</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Rrule"><content styleCode="bold">Erythema (generally brief and mild)</content></td><td styleCode=" Botrule Toprule Rrule">2.6% of injections (12.5% of patients) </td><td styleCode=" Botrule Toprule Rrule">0.9% of injections¹ (1.7% of patients)</td><td styleCode=" Botrule Toprule Rrule">1.1% of injections (2.2% of patients)</td><td styleCode=" Botrule Toprule"> -</td></tr><tr><td styleCode=" Botrule Toprule Rrule"><content styleCode="bold">Bruising (mild)</content></td><td styleCode=" Botrule Toprule Rrule">2.5% of injections (11.7% of patients)</td><td styleCode=" Botrule Toprule Rrule">1.7% of injections (3.4% of patients)</td><td styleCode=" Botrule Toprule Rrule"> -</td><td styleCode=" Botrule Toprule">2.3% of injections⁵</td></tr><tr><td styleCode=" Botrule Toprule Rrule"><content styleCode="bold">Pruritus</content></td><td styleCode=" Botrule Toprule Rrule">1.4% of injections (9.2% of patients)</td><td styleCode=" Botrule Toprule Rrule">0.4% of injections (0.9% of patients)</td><td styleCode=" Botrule Toprule Rrule"> -</td><td styleCode=" Botrule Toprule"> -</td></tr><tr><td styleCode=" Botrule Toprule Rrule"><content styleCode="bold">Induration</content></td><td styleCode=" Botrule Toprule Rrule">0.4% of injections (2.5% of patients)</td><td styleCode=" Botrule Toprule Rrule"> -</td><td styleCode=" Botrule Toprule Rrule"> -</td><td styleCode=" Botrule Toprule"> -</td></tr><tr><td styleCode=" Botrule Toprule Rrule"><content styleCode="bold">Ulceration</content></td><td styleCode=" Botrule Toprule Rrule">0.1% of injections (&gt; 0.8% of patients)</td><td styleCode=" Botrule Toprule Rrule"> -</td><td styleCode=" Botrule Toprule Rrule"> -</td><td styleCode=" Botrule Toprule"> -</td></tr><tr><td colspan="5" styleCode=" Botrule Toprule"><list listType="ordered" styleCode="Arabic"><item>Erythema was reported following 2 injections of ELIGARD^&#xAE; 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. </item><item>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^&#xAE; 30 mg. </item><item>Following injection of ELIGARD^&#xAE; 30 mg, three of the 35 burning/stinging events were reported as moderate. </item><item>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^&#xAE; 45 mg. </item><item>Mild bruising was reported following 5 (2.3%) study injections and moderate bruising was reported following 2 (&lt;1%) study injections of ELIGARD^&#xAE; 45 mg.</item></list></td></tr></tbody></table>

<table width="80%" cellspacing="0" cellpadding="0"><col width="1px"/><col width="58.35pt"/><col width="53.9pt"/><col width="58.35pt"/><col width="58.35pt"/><col width="1px"/><col/><col/><col/><tbody><tr><td colspan="4" styleCode=" Botrule Toprule Rrule"><paragraph><content styleCode="bold">ELIGARD^&#xAE;</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">7.5 mg</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">7.5 mg </content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">22.5 mg </content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">30 mg </content></paragraph></td><td styleCode=" Botrule Toprule Lrule"><paragraph><content styleCode="bold">45 mg </content></paragraph></td></tr><tr><td colspan="4" styleCode=" Botrule Toprule Rrule"><paragraph><content styleCode="bold">Study number</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>AGL9904</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>AGL9802</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>AGL9909</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>AGL0001</paragraph></td><td styleCode=" Botrule Toprule Lrule"><paragraph>AGL0205</paragraph></td></tr><tr><td colspan="4" styleCode=" Botrule Toprule Rrule"><paragraph><content styleCode="bold">Number of patients</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>120 </paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>8 </paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>117 </paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>90</paragraph></td><td styleCode=" Botrule Toprule Lrule"><paragraph>111</paragraph></td></tr><tr><td colspan="4" styleCode=" Botrule Toprule Rrule"><paragraph><content styleCode="bold">Treatment</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1 injection every month up to 6 months</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1 injection (surgically castrated patients) </paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1 injection every 3 months up to 6 months</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1 injection every 4 months up to 8 months</paragraph></td><td styleCode=" Botrule Toprule Lrule"><paragraph>1 injection every 6 months up to 12 months</paragraph></td></tr><tr><td colspan="3" styleCode=" Botrule Toprule Rrule"><content styleCode="bold">Body system</content></td><td styleCode=" Botrule Toprule Lrule Rrule"><content styleCode="bold">Adverse event</content></td><td align="center" colspan="5" styleCode=" Botrule Toprule Lrule"> <content styleCode="bold">Number (percent)</content></td></tr><tr><td colspan="3" rowspan="2" styleCode=" Botrule Toprule Rrule"><content styleCode="bold">Body as a whole</content></td><td styleCode=" Botrule Toprule Lrule Rrule">Malaise and fatigue</td><td styleCode=" Botrule Toprule Lrule Rrule">21 (17.5%) </td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> -</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> 7 (6.0%)</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule">12 (13.3%)</td><td align="center" styleCode=" Botrule Toprule Lrule">13 (11.7%)</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule">Weakness</td><td styleCode=" Botrule Toprule Lrule Rrule"> -</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> -</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> -</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule">- </td><td align="center" styleCode=" Botrule Toprule Lrule">4 (3.6%)</td></tr><tr><td colspan="3" styleCode=" Botrule Toprule Rrule"><content styleCode="bold">Nervous system</content></td><td styleCode=" Botrule Toprule Lrule Rrule">Dizziness</td><td styleCode=" Botrule Toprule Lrule Rrule">4 (3.3%)</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> -</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> -</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule">4 (4.4%) </td><td align="center" styleCode=" Botrule Toprule Lrule">-</td></tr><tr><td colspan="3" styleCode=" Botrule Toprule Rrule"><content styleCode="bold">Vascular</content></td><td styleCode=" Botrule Toprule Lrule Rrule">Hot flashes/sweats</td><td styleCode=" Botrule Toprule Lrule Rrule">68 (56.7%)^*</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule">2 (25.0%)*</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule">66 (56.4%)^*</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>66 (73.3%)^*</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule">64 (57.7%)^*</td></tr><tr><td colspan="3" rowspan="2" styleCode=" Botrule Toprule Rrule"><content styleCode="bold">Renal/urinary</content> </td><td styleCode=" Botrule Toprule Lrule Rrule">Urinary frequency</td><td styleCode=" Botrule Toprule Lrule Rrule"> -</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule">-</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule">3 (2.6%) </td><td align="center" styleCode=" Botrule Toprule Lrule Rrule">2 (2.2%) </td><td align="center" styleCode=" Botrule Toprule Lrule">- </td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule">Nocturia</td><td styleCode=" Botrule Toprule Lrule Rrule"> -</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule">-</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> -</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule">2 (2.2%) </td><td align="center" styleCode=" Botrule Toprule Lrule">- </td></tr><tr><td colspan="3" rowspan="2" styleCode=" Botrule Toprule Rrule"><content styleCode="bold">Gastrointestinal</content></td><td styleCode=" Botrule Toprule Lrule Rrule">Nausea</td><td styleCode=" Botrule Toprule Lrule Rrule"> -</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule">-</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule">4 (3.4%) </td><td align="center" styleCode=" Botrule Toprule Lrule Rrule">2 (2.2%) </td><td align="center" styleCode=" Botrule Toprule Lrule">- </td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule">Gastroenteritis/colitis</td><td styleCode=" Botrule Toprule Lrule Rrule">3 (2.5%)</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule">-</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> -</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> -</td><td align="center" styleCode=" Botrule Toprule Lrule">- </td></tr><tr><td colspan="3" rowspan="4" styleCode=" Botrule Toprule Rrule"><content styleCode="bold">Skin </content></td><td styleCode=" Botrule Toprule Lrule Rrule">Pruritus</td><td styleCode=" Botrule Toprule Lrule Rrule"> -</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule">-</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule">3 (2.6%)</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> -</td><td align="center" styleCode=" Botrule Toprule Lrule">-</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule">Clamminess</td><td styleCode=" Botrule Toprule Lrule Rrule"> -</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule">-</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> -</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule">4 (4.4%)^*</td><td align="center" styleCode=" Botrule Toprule Lrule">-</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule">Night sweats</td><td styleCode=" Botrule Toprule Lrule Rrule"> -</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule">-</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> -</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule">3 (3.3%)^*</td><td align="center" styleCode=" Botrule Toprule Lrule">3 (2.7%)^*</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule">Alopecia</td><td styleCode=" Botrule Toprule Lrule Rrule"> -</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule">-</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> -</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule">2 (2.2%) </td><td align="center" styleCode=" Botrule Toprule Lrule">- </td></tr><tr><td colspan="3" rowspan="3" styleCode=" Botrule Toprule Rrule"> <content styleCode="bold">Musculoskeletal</content></td><td styleCode=" Botrule Toprule Lrule Rrule">Arthralgia</td><td styleCode=" Botrule Toprule Lrule Rrule"> -</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule">-</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule">4 (3.4%) </td><td align="center" styleCode=" Botrule Toprule Lrule Rrule">- </td><td align="center" styleCode=" Botrule Toprule Lrule">- </td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule">Myalgia</td><td styleCode=" Botrule Toprule Lrule Rrule"> -</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule">-</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule">- </td><td align="center" styleCode=" Botrule Toprule Lrule Rrule">2 (2.2%) </td><td align="center" styleCode=" Botrule Toprule Lrule">5 (4.5%) </td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule">Pain in limb</td><td styleCode=" Botrule Toprule Lrule Rrule"> -</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule">-</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule">- </td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> -</td><td align="center" styleCode=" Botrule Toprule Lrule">3 (2.7%) </td></tr><tr><td colspan="3" rowspan="3" styleCode=" Botrule Toprule Rrule"> <content styleCode="bold">Reproductive</content></td><td styleCode=" Botrule Toprule Lrule Rrule">Testicular atrophy</td><td styleCode=" Botrule Toprule Lrule Rrule">6 (5.0%)</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule">-</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule">-</td><td align="center">4 (4.4%)^* </td><td align="center" styleCode=" Botrule Toprule Lrule">8 (7.2%)^* </td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule">Gynecomastia</td><td styleCode=" Botrule Toprule Lrule Rrule"> -</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule">-</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule">-</td><td align="center" styleCode=" Toprule Lrule Rrule">2 (2.2%)^* </td><td align="center" styleCode=" Botrule Toprule Lrule">4 (3.6%)^* </td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule">Testicular pain </td><td styleCode=" Botrule Toprule Lrule Rrule"> -</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> -</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule">- </td><td align="center" styleCode=" Botrule Toprule Lrule Rrule">2 (2.2%) </td><td align="center" styleCode=" Botrule Toprule Lrule"> -</td></tr><tr><td colspan="3" styleCode=" Botrule Toprule Rrule"> <content styleCode="bold">Psychiatric</content></td><td styleCode=" Botrule Toprule Lrule Rrule">Decreased libido</td><td styleCode=" Botrule Toprule Lrule Rrule"> -</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> -</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule">- </td><td align="center" styleCode=" Botrule Toprule Lrule Rrule">3 (3.3%)^*</td><td align="center" styleCode=" Botrule Toprule Lrule"> -</td></tr><tr><td colspan="9"> </td></tr><tr><td colspan="9"><paragraph>*Expected pharmacological consequences of testosterone suppression.</paragraph><paragraph>In the patient populations studied with ELIGARD^&#xAE; 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^&#xAE; 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^&#xAE; 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^&#xAE; 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.</paragraph></td></tr></tbody></table>

<table width="100%" cellspacing="0" cellpadding="0"><col width="1px"/><col width="1px"/><tbody><tr><td styleCode=" Botrule Toprule Rrule"><paragraph><content styleCode="bold">Body system</content></paragraph></td><td styleCode=" Botrule Toprule"><paragraph><content styleCode="bold">Adverse event</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Rrule"><paragraph>General</paragraph></td><td styleCode=" Botrule Toprule"><paragraph>Sweating, insomnia, syncope, rigors, weakness, lethargy</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Rrule"><paragraph>Gastrointestinal</paragraph></td><td styleCode=" Botrule Toprule"><paragraph>Flatulence, constipation, dyspepsia</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Rrule"><paragraph>Hematologic</paragraph></td><td styleCode=" Botrule Toprule"><paragraph>Decreased red blood cell count, hematocrit and hemoglobin</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Rrule"><paragraph>Metabolic</paragraph></td><td styleCode=" Botrule Toprule"><paragraph>Weight gain</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Rrule"><paragraph>Musculoskeletal</paragraph></td><td styleCode=" Botrule Toprule"><paragraph>Tremor, backache, joint pain, muscle atrophy, limb pain</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Rrule"><paragraph>Nervous</paragraph></td><td styleCode=" Botrule Toprule"><paragraph>Disturbance of smell and taste, depression, vertigo</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Rrule"><paragraph>Psychiatric</paragraph></td><td styleCode=" Botrule Toprule"><paragraph>Insomnia, depression, loss of libido*</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Rrule"><paragraph>Renal/urinary</paragraph></td><td styleCode=" Botrule Toprule"><paragraph>Difficulties with urination, pain on urination, scanty urination, bladder spasm, blood in urine, urinary retention, urinary urgency, incontinence, nocturia, nocturia aggravated</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Rrule"><paragraph>Reproductive/ Urogenital</paragraph></td><td styleCode=" Botrule Toprule"><paragraph>Testicular soreness/pain, impotence*, decreased libido*, gynecomastia*, breast soreness/tenderness*, testicular atrophy*, erectile dysfunction, penile disorder*, reduced penis size</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Rrule"><paragraph>Skin</paragraph></td><td styleCode=" Botrule Toprule"><paragraph>Alopecia, clamminess, night sweats*, sweating increased*</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Rrule"><paragraph>Vascular</paragraph></td><td styleCode=" Botrule Toprule"><paragraph>Hypertension, hypotension</paragraph></td></tr><tr><td colspan="2" styleCode=" Botrule Toprule"><paragraph>* Expected pharmacological consequences of testosterone suppression.</paragraph></td></tr></tbody></table>