FDA label f22212f4-3bbb-4201-801b-2667f90610d2

5 WARNINGS AND PRECAUTIONS Transient Increase in Serum Testosterone: Detected during the first week of treatment and may result in worsening of tumor symptoms. ( 5.1 ) Spinal Cord Compression and Urinary Tract Obstruction: May cause paralysis or renal impairment. Monitor patients at risk closely during therapy. ( 5.2 ) Difficulty Locating or Removing Implant: Loss of or inability to locate or remove an inserted implant has been reported. Caution is recommended. ( 5.3 ) 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. ( 5.4 ) 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. ( 5.5 ) Effect on QT/QTc Interval: Androgen deprivation therapy may prolong the QT interval. Consider risks and benefits. ( 5.7 ) Embryo-Fetal Toxicity: Can cause fetal harm. ( 5.8 , 8.1 ) 5.1 Transient Increase in Serum Testosterone VANTAS causes a transient increase in serum concentrations of testosterone during the first week of treatment. Patients may experience worsening of symptoms or onset of new symptoms, including bone pain, neuropathy, hematuria, or ureteral or bladder outlet obstruction. 5.2 Spinal Cord Compression and Urinary Tract Obstruction Cases of spinal cord compression, which may result in paralysis, and ureteral obstruction, which may cause renal impairment, have been reported with GnRH agonists. Patients with metastatic vertebral lesions and/or with urinary tract obstruction should be closely observed during the first few weeks of therapy. 5.3 Difficulty Locating or Removing Implant In all clinical trials combined, an implant was not recovered in 8 patients. For two of these [see Clinical Studies ( 14 )] , serum testosterone rose above castrate level and the implant was neither palpable nor visualized with ultrasound. These two implants were believed to have been extruded without appreciation by the patients. In the other six, serum testosterone remained below the castrate level, but the implant was not palpable. No further diagnostic tests were conducted. One of these patients underwent in-clinic surgical exploration that did not locate the implant. Implant insertion is a surgical procedure. Careful adherence to the Recommended Procedure for Implant Insertion and Removal [see Dosage and Administration ( 2.2 )] is advised to minimize the potential for complications and for implant expulsion. In addition, patients should be instructed to refrain from wetting the arm for 24 hours and from heavy lifting or strenuous exertion of the inserted arm for 7 days after implant insertion. 5.4 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. 5.5 Cardiovascular Disease 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. 5.6 Laboratory Tests Response to VANTAS should be monitored by measuring serum concentrations of testosterone and prostate-specific antigen periodically, especially if the anticipated clinical or biochemical response to treatment has not been achieved. 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. 5.7 Effect on QT/QTc Interva l 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. 5.8 Embryo-Fetal Toxicity The safety and efficacy of VANTAS have not been established in females. Based on findings from animal studies and its mechanism of action, VANTAS can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology ( 12.1 )] . In animal reproduction studies, administration of VANTAS to pregnant rats and rabbits during the period of organogenesis caused an increase in fetal loss at clinically relevant exposures. Advise pregnant patients and females of reproductive potential of the potential risk to the fetus [see Use in Specific Populations ( 8.1 )] .

6 ADVERSE REACTIONS The most common adverse reactions observed in >5% of men: hot flashes, fatigue, implant site reaction, testicular atrophy. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Endo Pharmaceuticals Solutions Inc. at 1-800-462-3636 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of VANTAS was evaluated in 171 patients with prostate cancer treated for up to 36 months in two clinical trials. The pivotal study (Study 1) consisted of 138 patients, while a separate supportive study (Study 2) consisted of 33 patients. VANTAS, like other GnRH analogs, caused a transient increase in serum testosterone concentrations during the first week of treatment. Therefore, potential exacerbations of signs and symptoms of the disease during the first few 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 ( 5.1 )] . In the first 12 months after initial insertion of the implant(s), an implant extruded through the incision site in eight of 171 patients in the clinical trials (see the Recommended Procedure for correct implant placement). In the pivotal study (Study 1) a detailed evaluation for implant site reactions was conducted. Out of the 138 patients in the study, 19 patients (13.8%) experienced local or insertion site reactions. All these local site reactions were reported as mild in severity. The majority were associated with initial insertion or removal and insertion of a new implant, and began and resolved within the first two weeks following implant insertion. Reactions persisted in 4 (2.8%) patients. An additional 4 (2.8%) patients developed application-site reactions after the first two weeks following insertion. Local reactions after implant insertion included bruising (7.2% of patients) and pain/soreness/tenderness (3.6% of patients). Other, less frequently reported, reactions included erythema (2.8% of patients) and swelling (0.7% of patients). In this study, two patients had events described as local infections/inflammations, one that resolved after treatment with oral antibiotics and the other without treatment. Local reactions following insertion of a subsequent implant were comparable to those seen after initial insertion. The following possibly or probably related systemic adverse events occurred during clinical trials of up to 24 months of treatment with VANTAS, and were reported in ≥ 2% of patients (Table 1). Table 1: Incidence (%) of Possibly or Probably Related Systemic Adverse Events Reported by ≥ 2% of Patients Treated with VANTAS for up to 24 Months * Expected pharmacological consequences of testosterone suppression. ** 5 of the 8 patients had a single occurrence of mild renal impairment (defined as creatinine clearance ≥30 <60 mL/min), which returned to a normal range by the next visit. Body System Adverse Event Number (%) Vascular Disorders Hot flashes* 112 (65.5%) General Disorders Fatigue Weight increased 17 (9.9%) 4 (2.3%) Skin and Appendage Disorders Implant site reaction 10 (5.8%) Reproductive System and Breast Disorders Erectile dysfunction* Gynecomastia* Testicular atrophy* 6 (3.5%) 7 (4.1%) 9 (5.3%) Psychiatric Disorders Insomnia Libido decreased* 5 (2.9%) 4 (2.3%) Renal and Urinary Disorders Renal impairment** 8 (4.7%) Gastrointestinal Disorders Constipation 6 (3.5%) Nervous System Disorders Headache 5 (2.9%) Hot flashes were the most common adverse event reported (65.5% of patients). In terms of severity, 2.3% of patients reported severe hot flashes, 25.4% of patients reported moderate hot flashes and 37.7% reported mild hot flashes. In addition, the following possibly or probably related systemic adverse events were reported by < 2% of patients using VANTAS in clinical studies. Blood and Lymphatic System Disorders: Anemia Cardiac Disorders: Palpitations, ventricular extrasystoles Gastrointestinal Disorders: Abdominal discomfort, nausea General Disorders: Feeling cold, lethargy, malaise, edema peripheral, pain, pain exacerbated, weakness, weight decreased Hepatobiliary Disorders: Hepatic disorder Injury, Poisoning and Procedural Complications: Stent occlusion Laboratory Investigations: Aspartate aminotransferase increased, blood glucose increased, blood lactate dehydrogenase increased, blood testosterone increased, creatinine clearance decreased, prostatic acid phosphatase increased Metabolism and Nutrition Disorders: Appetite increased, fluid retention, food craving, hypercalcaemia, hypercholesterolemia Musculoskeletal and Connective Tissue Disorders: Arthralgia, back pain, back pain aggravated, bone pain, muscle twitching, myalgia, neck pain, pain in limb Nervous System Disorders: Dizziness, tremor Psychiatric Disorders: Depression, irritability Renal and Urinary Disorders: Calculus renal, dysuria, hematuria aggravated, renal failure aggravated, urinary frequency, urinary frequency aggravated, urinary retention Reproductive System and Breast Disorders: Breast pain, breast tenderness, genital pruritus male, gynecomastia aggravated, sexual dysfunction Respiratory, Thoracic and Mediastinal Disorders: Dyspnea exertional Skin and Subcutaneous Tissue Disorders: Contusion, hypotrichosis, night sweats, pruritus, sweating increased Vascular Disorders: Flushing, hematoma 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 The following adverse reactions have been identified during post approval use of VANTAS. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Pituitary Apoplexy: 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 final dose, and some within the first hour. In these cases, pituitary apoplexy has presented as sudden headache, vomiting, visual changes, opthalmoplegia, altered mental status, and sometimes cardiovascular collapse. Immediate medical attention has been required. Drug-Induced Liver Injury: Severe liver injury has been reported in association with VANTAS. The toxicity was reversible with the removal of the VANTAS implant. Nervous System Disorders : Convulsions

<table><caption>Table 1: Incidence (%) of Possibly or Probably Related Systemic Adverse Events Reported by &#x2265; 2% of Patients Treated with VANTAS for up to 24 Months</caption><col/><col/><col/><tfoot><tr><td> * Expected pharmacological consequences of testosterone suppression. ** 5 of the 8 patients had a single occurrence of mild renal impairment (defined as creatinine clearance &#x2265;30 &lt;60 mL/min), which returned to a normal range by the next visit.</td></tr></tfoot><tbody><tr><th>Body System</th><th>Adverse Event</th><th>Number (%)</th></tr><tr><td> Vascular Disorders</td><td> Hot flashes*</td><td align="right">112 (65.5%)</td></tr><tr><td> General Disorders</td><td> Fatigue Weight increased</td><td align="right"> 17 (9.9%) 4 (2.3%)</td></tr><tr><td> Skin and Appendage Disorders</td><td> Implant site reaction</td><td align="right"> 10 (5.8%)</td></tr><tr><td> Reproductive System and Breast Disorders</td><td> Erectile dysfunction* Gynecomastia* Testicular atrophy*</td><td align="right"> 6 (3.5%) 7 (4.1%) 9 (5.3%)</td></tr><tr><td> Psychiatric Disorders</td><td> Insomnia Libido decreased*</td><td align="right"> 5 (2.9%) 4 (2.3%)</td></tr><tr><td> Renal and Urinary Disorders</td><td> Renal impairment**</td><td align="right"> 8 (4.7%)</td></tr><tr><td> Gastrointestinal Disorders</td><td> Constipation</td><td align="right"> 6 (3.5%)</td></tr><tr><td> Nervous System Disorders</td><td> Headache</td><td align="right"> 5 (2.9%)</td></tr></tbody></table>