FDA label bda391c0-97ad-44c4-8487-1b6724c64bc5

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 ) 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 measuring serum concentrations of testosterone and prostate specific antigen periodically. 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.

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 agonist, 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 sanofi-aventis U.S. LLC at 1-800-633-1610 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 4). 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 3 for a summary of reported injection site events. Table 3. Reported Injection Site Adverse Events 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 Following injection of ELIGARD® 30 mg, three of the 35 burning/stinging events were reported as moderate. 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 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. (3.3% of patients) 4.6% of injections 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. Erythema (generally brief and mild) 2.6% of injections (12.5% of patients) 0.9% of injections 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 injections. (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 Mild bruising was reported following 5 (2.3%) study injections and moderate bruising was reported following 2 (<1%) study injections of ELIGARD® 45 mg. Pruritis 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) 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 7). 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 Events Reported by > 2% of Patients treated with 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%) 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. 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 Pruritis 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%) 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 Expected pharmacological consequences of testosterone suppression. 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 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 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. Convulsions have also been reported in the postmarketing setting.

<table> <caption>Table 3. Reported Injection Site Adverse Events</caption> <col/> <col/> <col/> <col/> <col/> <thead> <tr> <th valign="top" styleCode=" Lrule "/> <th valign="top" styleCode=" Lrule "> 7.5 mg </th> <th valign="top" styleCode=" Lrule "> 22.5 mg </th> <th valign="top" styleCode=" Lrule "> 30 mg </th> <th valign="top" styleCode=" Lrule Rrule "> 45 mg </th> </tr> </thead> <tbody> <tr> <td valign="top" styleCode=" Lrule "> Study Number</td> <td valign="top" styleCode=" Lrule "> AGL9904</td> <td valign="top" styleCode=" Lrule "> AGL9909</td> <td valign="top" styleCode=" Lrule "> AGL0001</td> <td valign="top" styleCode=" Lrule Rrule "> AGL0205</td> </tr> <tr> <td valign="top" styleCode=" Lrule "> Number of patients</td> <td valign="top" styleCode=" Lrule "> 120</td> <td valign="top" styleCode=" Lrule "> 117</td> <td valign="top" styleCode=" Lrule "> 90</td> <td valign="top" styleCode=" Lrule Rrule "> 111</td> </tr> <tr> <td valign="top" styleCode=" Lrule "> Treatment</td> <td valign="top" styleCode=" Lrule "> 1 injection every month up to 6 months</td> <td valign="top" styleCode=" Lrule "> 1 injection every 3 months up to 6 months</td> <td valign="top" styleCode=" Lrule "> 1 injection every 4 months up to 8 months</td> <td valign="top" styleCode=" Lrule Rrule "> 1 injection every 6 months up to 12 months</td> </tr> <tr> <td valign="top" styleCode=" Lrule "> Number of injections</td> <td valign="top" styleCode=" Lrule "> 716</td> <td valign="top" styleCode=" Lrule "> 230</td> <td valign="top" styleCode=" Lrule "> 175</td> <td valign="top" styleCode=" Lrule Rrule "> 217</td> </tr> <tr> <td valign="top" styleCode=" Lrule "> </td> <td valign="top" styleCode=" Botrule "> </td> <td valign="top" styleCode=" Botrule "> </td> <td valign="top" styleCode=" Botrule "> </td> <td valign="top" styleCode=" Rrule "> </td> </tr> <tr> <td valign="top" styleCode=" Lrule "> Transient burning/stinging</td> <td valign="top" styleCode=" Lrule "> 248 (34.6%) injections;84% reported as mild</td> <td valign="top" styleCode=" Lrule "> 50 (21.7%) injections; 86% reported as mild</td> <td valign="top" styleCode=" Lrule "> 35 (20%) injections; 100% reported as mild</td> <td valign="top" styleCode=" Lrule Rrule "> 35 (16%) injections; 91.4% reported as mild<footnote ID="FOOT_9184">Following injection of ELIGARD&#xAE; 30 mg, three of the 35 burning/stinging events were reported as moderate.</footnote> </td> </tr> <tr> <td valign="top" styleCode=" Lrule "> Pain (generally brief and mild)</td> <td valign="top" styleCode=" Lrule "> 4.3% of injections (18.3% of patients)</td> <td valign="top" styleCode=" Lrule "> 3.5% of injections (6.0% of patients)</td> <td valign="top" styleCode=" Lrule "> 2.3% of injections<footnote ID="FOOT_9185">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.</footnote> (3.3% of patients)</td> <td valign="top" styleCode=" Lrule Rrule "> 4.6% of injections<footnote ID="FOOT_9186">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.</footnote> </td> </tr> <tr> <td valign="top" styleCode=" Lrule "> Erythema (generally brief and mild)</td> <td valign="top" styleCode=" Lrule "> 2.6% of injections (12.5% of patients)</td> <td valign="top" styleCode=" Lrule "> 0.9% of injections<footnote ID="FOOT_9187">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 injections.</footnote> (1.7% of patients)</td> <td valign="top" styleCode=" Lrule "> 1.1% of injections (2.2% of patients)</td> <td valign="top" styleCode=" Lrule Rrule "> </td> </tr> <tr> <td valign="top" styleCode=" Lrule "> Bruising (Mild)</td> <td valign="top" styleCode=" Lrule "> 2.5% of injections (11.7% of patients)</td> <td valign="top" styleCode=" Lrule "> 1.7% of injections (3.4% of patients)</td> <td valign="top" styleCode=" Lrule "> </td> <td valign="top" styleCode=" Lrule Rrule "> 2.3% of injections<footnote ID="FOOT_9188">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.</footnote> </td> </tr> <tr> <td valign="top" styleCode=" Lrule "> Pruritis</td> <td valign="top" styleCode=" Lrule "> 1.4% of injections (9.2% of patients)</td> <td valign="top" styleCode=" Lrule "> 0.4% of injections (0.9% of patients)</td> <td valign="top" styleCode=" Lrule "> </td> <td valign="top" styleCode=" Lrule Rrule "> </td> </tr> <tr> <td valign="top" styleCode=" Lrule "> Induration</td> <td valign="top" styleCode=" Lrule "> 0.4% of injections (2.5% of patients)</td> <td valign="top" styleCode=" Lrule "> </td> <td valign="top" styleCode=" Lrule "> </td> <td valign="top" styleCode=" Lrule Rrule "> </td> </tr> <tr> <td valign="top" styleCode=" Lrule "> Ulceration</td> <td valign="top" styleCode=" Lrule "> 0.1% of injections (&gt; 0.8% of patients)</td> <td valign="top" styleCode=" Lrule "> </td> <td valign="top" styleCode=" Lrule "> </td> <td valign="top" styleCode=" Lrule Rrule "> </td> </tr> </tbody> </table>

<table> <caption>Table 4. Summary of Possible or Probably Related Systemic Adverse Events Reported by &gt; 2% of Patients treated with ELIGARD&#xAE;</caption> <col width="25%"/> <col width="25%"/> <col width="10%"/> <col width="10%"/> <col width="10%"/> <col width="10%"/> <col width="10%"/> <thead> <tr> <th valign="top" colspan="2" styleCode=" Lrule "/> <th valign="top" styleCode=" Lrule "> 7.5 mg </th> <th valign="top" styleCode=" Lrule "> 7.5 mg </th> <th valign="top" styleCode=" Lrule "> 22.5 mg </th> <th valign="top" styleCode=" Lrule "> 30 mg </th> <th valign="top" styleCode=" Lrule Rrule "> 45 mg </th> </tr> </thead> <tbody> <tr> <td valign="top" colspan="2" styleCode=" Lrule "> Study Number</td> <td valign="top" styleCode=" Lrule "> AGL9904</td> <td valign="top" styleCode=" Lrule "> AGL9802</td> <td valign="top" styleCode=" Lrule "> AGL9909</td> <td valign="top" styleCode=" Lrule "> AGL0001</td> <td valign="top" styleCode=" Lrule Rrule "> AGL0205</td> </tr> <tr> <td valign="top" colspan="2" styleCode=" Lrule "> Number of patients</td> <td valign="top" styleCode=" Lrule "> 120</td> <td valign="top" styleCode=" Lrule "> 8</td> <td valign="top" styleCode=" Lrule "> 117</td> <td valign="top" styleCode=" Lrule "> 90</td> <td valign="top" styleCode=" Lrule Rrule "> 111</td> </tr> <tr> <td valign="top" colspan="2" styleCode=" Lrule "> Treatment</td> <td valign="top" styleCode=" Lrule "> 1 injection every month up to 6 months</td> <td valign="top" styleCode=" Lrule "> 1 injection (surgically castrated patients)</td> <td valign="top" styleCode=" Lrule "> 1 injection every 3 months up to 6 months</td> <td valign="top" styleCode=" Lrule "> 1 injection every 4 months up to 8 months</td> <td valign="top" styleCode=" Lrule Rrule "> 1 injection every 6 months up to 12 months</td> </tr> <tr> <td valign="top" styleCode=" Lrule "> Body System</td> <td valign="top" styleCode=" Lrule "> Adverse Event</td> <td align="center" valign="top" colspan="5" styleCode=" Lrule Rrule "> Number (Percent)</td> </tr> <tr> <td valign="top" rowspan="2" styleCode=" Botrule Lrule "> Body as a Whole</td> <td valign="top" styleCode=" Botrule Lrule "> Malaise and Fatigue</td> <td valign="top" styleCode=" Botrule Lrule "> 21 (17.5 %)</td> <td valign="top" styleCode=" Botrule Lrule "> </td> <td valign="top" styleCode=" Botrule Lrule "> 7 (6.0%)</td> <td valign="top" styleCode=" Botrule Lrule "> 12 (13.3%)</td> <td valign="top" styleCode=" Botrule Lrule Rrule "> 13 (11.7%)</td> </tr> <tr> <td valign="top" styleCode=" Lrule "> Weakness</td> <td valign="top" styleCode=" Lrule "> </td> <td valign="top" styleCode=" Lrule "> </td> <td valign="top" styleCode=" Lrule "> </td> <td valign="top" styleCode=" Lrule "> </td> <td valign="top" styleCode=" Lrule Rrule "> 4 (3.6%)</td> </tr> <tr> <td valign="top" styleCode=" Lrule "> Nervous System</td> <td valign="top" styleCode=" Lrule "> Dizziness</td> <td valign="top" styleCode=" Lrule "> 4 (3.3%)</td> <td valign="top" styleCode=" Lrule "> </td> <td valign="top" styleCode=" Lrule "> </td> <td valign="top" styleCode=" Lrule "> 4 (4.4%)</td> <td valign="top" styleCode=" Lrule Rrule "> </td> </tr> <tr> <td valign="top" styleCode=" Lrule "> Vascular</td> <td valign="top" styleCode=" Lrule "> Hot flashes/sweats</td> <td valign="top" styleCode=" Lrule "> 68 (56.7%)<footnote ID="FOOT_9189">Expected pharmacological consequences of testosterone suppression. 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.</footnote> </td> <td valign="top" styleCode=" Lrule "> 2 (25.0%)<footnoteRef IDREF="FOOT_9189"/> </td> <td valign="top" styleCode=" Lrule "> 66 (56.4%)<footnoteRef IDREF="FOOT_9189"/> </td> <td valign="top" styleCode=" Lrule "> 66 (73.3%)<footnoteRef IDREF="FOOT_9189"/> </td> <td valign="top" styleCode=" Lrule Rrule "> 64 (57.7%)<footnoteRef IDREF="FOOT_9189"/> </td> </tr> <tr> <td valign="top" rowspan="2" styleCode=" Botrule Lrule "> Renal/Urinary</td> <td valign="top" styleCode=" Botrule Lrule "> Urinary frequency</td> <td valign="top" styleCode=" Botrule Lrule "> </td> <td valign="top" styleCode=" Botrule Lrule "> </td> <td valign="top" styleCode=" Botrule Lrule "> 3 (2.6%)</td> <td valign="top" styleCode=" Botrule Lrule "> 2 (2.2%)</td> <td valign="top" styleCode=" Botrule Lrule Rrule "> </td> </tr> <tr> <td valign="top" styleCode=" Lrule "> Nocturia</td> <td valign="top" styleCode=" Lrule "> </td> <td valign="top" styleCode=" Lrule "> </td> <td valign="top" styleCode=" Lrule "> </td> <td valign="top" styleCode=" Lrule "> 2 (2.2%)</td> <td valign="top" styleCode=" Lrule Rrule "> </td> </tr> <tr> <td valign="top" rowspan="2" styleCode=" Botrule Lrule "> Gastrointestinal</td> <td valign="top" styleCode=" Botrule Lrule "> Nausea</td> <td valign="top" styleCode=" Botrule Lrule "> </td> <td valign="top" styleCode=" Botrule Lrule "> </td> <td valign="top" styleCode=" Botrule Lrule "> 4 (3.4%)</td> <td valign="top" styleCode=" Botrule Lrule "> 2 (2.2%)</td> <td valign="top" styleCode=" Botrule Lrule Rrule "> </td> </tr> <tr> <td valign="top" styleCode=" Lrule "> Gastroenteritis/colitis</td> <td valign="top" styleCode=" Lrule "> 3 (2.5%)</td> <td valign="top" styleCode=" Lrule "> </td> <td valign="top" styleCode=" Lrule "> </td> <td valign="top" styleCode=" Lrule "> </td> <td valign="top" styleCode=" Lrule Rrule "> </td> </tr> <tr> <td valign="top" rowspan="4" styleCode=" Botrule Lrule "> Skin </td> <td valign="top" styleCode=" Botrule Lrule "> Pruritis</td> <td valign="top" styleCode=" Botrule Lrule "> </td> <td valign="top" styleCode=" Botrule Lrule "> </td> <td valign="top" styleCode=" Botrule Lrule "> 3 (2.6%)</td> <td valign="top" styleCode=" Botrule Lrule "> </td> <td valign="top" styleCode=" Botrule Lrule Rrule "> </td> </tr> <tr> <td valign="top" styleCode=" Lrule "> Clamminess</td> <td valign="top" styleCode=" Lrule "> </td> <td valign="top" styleCode=" Lrule "> </td> <td valign="top" styleCode=" Lrule "> </td> <td valign="top" styleCode=" Lrule "> 4 (4.4%)<footnoteRef IDREF="FOOT_9189"/> </td> <td valign="top" styleCode=" Lrule Rrule "> </td> </tr> <tr> <td valign="top" styleCode=" Lrule "> Night sweats</td> <td valign="top" styleCode=" Lrule "> </td> <td valign="top" styleCode=" Lrule "> </td> <td valign="top" styleCode=" Lrule "> </td> <td valign="top" styleCode=" Lrule "> 3 (3.3%)<footnoteRef IDREF="FOOT_9189"/> </td> <td valign="top" styleCode=" Lrule Rrule "> 3 (2.7%)<footnoteRef IDREF="FOOT_9189"/> </td> </tr> <tr> <td valign="top" styleCode=" Lrule "> Alopecia</td> <td valign="top" styleCode=" Lrule "> </td> <td valign="top" styleCode=" Lrule "> </td> <td valign="top" styleCode=" Lrule "> </td> <td valign="top" styleCode=" Lrule "> 2 (2.2%)</td> <td valign="top" styleCode=" Lrule Rrule "> </td> </tr> <tr> <td valign="top" rowspan="3" styleCode=" Botrule Lrule "> Musculoskeletal</td> <td valign="top" styleCode=" Botrule Lrule "> Arthralgia</td> <td valign="top" styleCode=" Botrule Lrule "> </td> <td valign="top" styleCode=" Botrule Lrule "> </td> <td valign="top" styleCode=" Botrule Lrule "> 4 (3.4%)</td> <td valign="top" styleCode=" Botrule Lrule "> </td> <td valign="top" styleCode=" Botrule Lrule Rrule "> </td> </tr> <tr> <td valign="top" styleCode=" Lrule "> Myalgia</td> <td valign="top" styleCode=" Lrule "> </td> <td valign="top" styleCode=" Lrule "> </td> <td valign="top" styleCode=" Lrule "> </td> <td valign="top" styleCode=" Lrule "> 2 (2.2%)</td> <td valign="top" styleCode=" Lrule Rrule "> 5 (4.5%)</td> </tr> <tr> <td valign="top" styleCode=" Lrule "> Pain in limb</td> <td valign="top" styleCode=" Lrule "> </td> <td valign="top" styleCode=" Lrule "> </td> <td valign="top" styleCode=" Lrule "> </td> <td valign="top" styleCode=" Lrule "> </td> <td valign="top" styleCode=" Lrule Rrule "> 3 (2.7%)</td> </tr> <tr> <td valign="top" rowspan="3" styleCode=" Botrule Lrule "> Reproductive</td> <td valign="top" styleCode=" Botrule Lrule "> Testicular atrophy</td> <td valign="top" styleCode=" Botrule Lrule "> 6 (5.0%)</td> <td valign="top" styleCode=" Botrule Lrule "> </td> <td valign="top" styleCode=" Botrule Lrule "> </td> <td valign="top" styleCode=" Botrule Lrule "> 4 (4.4%)<footnoteRef IDREF="FOOT_9189"/> </td> <td valign="top" styleCode=" Botrule Lrule Rrule "> 8 (7.2%)<footnoteRef IDREF="FOOT_9189"/> </td> </tr> <tr> <td valign="top" styleCode=" Lrule "> Gynecomastia</td> <td valign="top" styleCode=" Lrule "> </td> <td valign="top" styleCode=" Lrule "> </td> <td valign="top" styleCode=" Lrule "> </td> <td valign="top" styleCode=" Lrule "> 2 (2.2%)<footnoteRef IDREF="FOOT_9189"/> </td> <td valign="top" styleCode=" Lrule Rrule "> 4 (3.6%)<footnoteRef IDREF="FOOT_9189"/> </td> </tr> <tr> <td valign="top" styleCode=" Lrule "> Testicular pain</td> <td valign="top" styleCode=" Lrule "> </td> <td valign="top" styleCode=" Lrule "> </td> <td valign="top" styleCode=" Lrule "> </td> <td valign="top" styleCode=" Lrule "> 2 (2.2%)</td> <td valign="top" styleCode=" Lrule Rrule "> </td> </tr> <tr> <td valign="top" styleCode=" Lrule "> Psychiatric</td> <td valign="top" styleCode=" Lrule "> Decreased libido</td> <td valign="top" styleCode=" Lrule "> </td> <td valign="top" styleCode=" Lrule "> </td> <td valign="top" styleCode=" Lrule "> </td> <td valign="top" styleCode=" Lrule "> 3 (3.3%)<footnoteRef IDREF="FOOT_9189"/> </td> <td valign="top" styleCode=" Lrule Rrule "> </td> </tr> </tbody> </table>

<table> <col/> <col/> <thead> <tr> <th valign="top"> Body System</th> <th valign="top"> Adverse Event</th> </tr> </thead> <tbody> <tr> <td valign="top"> General</td> <td valign="top"> Sweating, insomnia, syncope, rigors, weakness, lethargy</td> </tr> <tr> <td valign="top"> Gastrointestinal</td> <td valign="top"> Flatulence, constipation, dyspepsia</td> </tr> <tr> <td valign="top"> Hematologic</td> <td valign="top"> Decreased red blood cell count, hematocrit and hemoglobin</td> </tr> <tr> <td valign="top"> Metabolic</td> <td valign="top"> Weight gain</td> </tr> <tr> <td valign="top"> Musculoskeletal</td> <td valign="top"> Tremor, backache, joint pain, muscle atrophy, limb pain</td> </tr> <tr> <td valign="top"> Nervous</td> <td valign="top"> Disturbance of smell and taste, depression, vertigo</td> </tr> <tr> <td valign="top"> Psychiatric</td> <td valign="top"> Insomnia, depression, loss of libido<footnote ID="FOOT_9190">Expected pharmacological consequences of testosterone suppression.</footnote> </td> </tr> <tr> <td valign="top"> Renal/Urinary</td> <td valign="top"> Difficulties with urination, pain on urination, scanty urination, bladder spasm, blood in urine, urinary retention, urinary urgency, incontinence, nocturia, nocturia aggravated</td> </tr> <tr> <td valign="top"> Reproductive/ Urogenital:</td> <td valign="top"> Testicular soreness/pain, impotence<footnoteRef IDREF="FOOT_9190"/>, decreased libido<footnoteRef IDREF="FOOT_9190"/>, gynecomastia<footnoteRef IDREF="FOOT_9190"/>, breast soreness/tenderness<footnoteRef IDREF="FOOT_9190"/>, testicular atrophy<footnoteRef IDREF="FOOT_9190"/>, erectile dysfunction, penile disorder<footnoteRef IDREF="FOOT_9190"/>, reduced penis size</td> </tr> <tr> <td valign="top"> Skin</td> <td valign="top"> Alopecia, clamminess, night sweats<footnoteRef IDREF="FOOT_9190"/>, sweating increased<footnoteRef IDREF="FOOT_9190"/> </td> </tr> <tr> <td valign="top"> Vascular</td> <td valign="top"> Hypertension, hypotension</td> </tr> </tbody> </table>