Lupron Depot

1 INDICATIONS AND USAGE LUPRON DEPOT 7.5 mg for 1-month administration, 22.5 mg for 3-month administration, 30 mg for 4-month administration, and 45 mg for 6-month administration (leuprolide acetate) are indicated for the treatment of advanced prostate cancer. LUPRON DEPOT is a gonadotropin releasing hormone (GnRH) agonist indicated for: treatment of advanced prostate cancer. ( 1 )

2 DOSAGE AND ADMINISTRATION LUPRON DEPOT must be administered by a healthcare provider. In patients treated with GnRH analogues for prostate cancer, treatment is usually continued upon development of non-metastatic and metastatic castration-resistant prostate cancer. Table 1. LUPRON DEPOT Recommended Dosing Dosage 7.5 mg for 1-Month Administration 22.5 mg for 3-Month Administration 30 mg for 4-Month Administration 45 mg for 6-Month Administration Recommended dose 1 injection every 4 weeks 1 injection every 12 weeks 1 injection every 16 weeks 1 injection every 24 weeks LUPRON DEPOT must be administered under the supervision of a physician. Due to different release characteristics, the dosage strengths are not additive and must be selected based upon the desired dosing schedule. ( 2 ) LUPRON DEPOT 7.5 mg for 1-month administration, given as a single intramuscular injection every 4 weeks. ( 2.1 ) LUPRON DEPOT 22.5 mg for 3-month administration, given as a single intramuscular injection every 12 weeks. ( 2.2 ) LUPRON DEPOT 30 mg for 4-month administration, given as a single intramuscular injection every 16 weeks. ( 2.3 ) LUPRON DEPOT 45 mg for 6-month administration, given as a single intramuscular injection every 24 weeks. ( 2.4 ) Figure 1 Figure 2 Figure 3 figure 4 figure 5 Figure 6 Figure 7 2.1 LUPRON DEPOT 7.5 mg for 1-Month Administration The recommended dose of LUPRON DEPOT 7.5 mg for 1-month administration is one injection every 4 weeks. Do not use concurrently a fractional dose, or a combination of doses of this or any depot formulation due to different release characteristics. Incorporated in a depot formulation, the lyophilized microspheres must be reconstituted and should be administered every 4 weeks as a single intramuscular injection. For optimal performance of the prefilled dual chamber syringe (PDS), read and follow the instructions in Section 2.5 . 2.2 LUPRON DEPOT 22.5 mg for 3-Month Administration The recommended dose of LUPRON DEPOT 22.5 mg for 3-month administration is one injection every 12 weeks. Do not use concurrently a fractional dose, or a combination of doses of this or any depot formulation due to different release characteristics. Incorporated in a depot formulation, the lyophilized microspheres must be reconstituted and should be administered every 12 weeks as a single intramuscular injection. For optimal performance of the prefilled dual chamber syringe (PDS), read and follow the instructions in Section 2.5 . 2.3 LUPRON DEPOT 30 mg for 4-Month Administration The recommended dose of LUPRON DEPOT 30 mg for 4-month administration is one injection every 16 weeks. Do not use concurrently a fractional dose, or a combination of doses of this or any depot formulation due to different release characteristics. Incorporated in a depot formulation, the lyophilized microspheres must be reconstituted and should be administered every 16 weeks as a single intramuscular injection. For optimal performance of the prefilled dual chamber syringe (PDS), read and follow the instructions in Section 2.5 . 2.4 LUPRON DEPOT 45 mg for 6-Month Administration The recommended dose of LUPRON DEPOT 45 mg for 6-month administration is one injection every 24 weeks. Do not use concurrently a fractional dose, or a combination of doses of this or any depot formulation due to different release characteristics. Incorporated in a depot formulation, the lyophilized microspheres must be reconstituted and should be administered every 24 weeks as a single intramuscular injection. For optimal performance of the prefilled dual chamber syringe (PDS), read and follow the instructions in Section 2.5 . 2.5 Reconstitution and Administration for Injection of LUPRON DEPOT Reconstitute and administer the lyophilized microspheres as a single intramuscular injection. Inject the suspension immediately or discard if not used within two hours, because LUPRON DEPOT does not contain a preservative. 1. Visually inspect the LUPRON DEPOT powder. DO NOT USE the sy…

5 WARNINGS AND PRECAUTIONS Tumor Flare: Increased serum testosterone (~ 50% above baseline) may occur when initiating treatment with LUPRON DEPOT. Monitor for worsening of prostate cancer symptoms during the first few weeks of treatment. Monitor patients for increased bone pain, neuropathy, hematuria, ureteral obstruction, and spinal cord compression. Spinal cord compressions may contribute to paralysis with or without fatal complications. ( 5.1 ) Metabolic Syndrome: The use of GnRH agonists may lead to an increased risk of metabolic changes such as hyperglycemia, diabetes, hyperlipidemia, and non-alcoholic fatty liver disease. Monitor for signs and symptoms of metabolic syndrome including lipids, blood glucose level and/or HbA1c and manage according to current treatment guidelines. ( 5.2 ) Cardiovascular Diseases: Increased risk of myocardial infarction, sudden cardiac death and stroke has been reported in association with use of GnRH analogs in men. Monitor for cardiovascular disease and manage according to institutional guidelines. ( 5.3 ) Effect on QT/QTc Interval: Androgen deprivation therapy may prolong the QT interval. Consider risks and benefits. ( 5.4 ) Convulsions have been observed in patients with or without a history of predisposing factors. Manage convulsions according to institutional guidelines. ( 5.5 ) Severe Cutaneous Adverse Reactions (SCARs), including Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), occurred in patients treated with LUPRON DEPOT. Interrupt LUPRON DEPOT if signs or symptoms of SCARs develop. Permanently discontinue if SCARs are confirmed. ( 5.6 ) Embryo-Fetal Toxicity: LUPRON DEPOT may cause fetal harm. ( 5.8 , 8.1 ) 5.1 Tumor Flare Initially, LUPRON DEPOT, like other GnRH agonists, causes increases in serum levels of testosterone to approximately 50% above baseline during the first 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. Spinal cord compression may contribute to paralysis with or without fatal complications. Monitor patients for tumor flare symptoms during the first few weeks of treatment with LUPRON DEPOT. Closely monitor patients with metastatic vertebral lesions and/or with urinary tract obstruction for new or worsening symptoms. 5.2 Metabolic Syndrome The use of GnRH agonists may lead to metabolic changes such as hyperglycemia, diabetes mellitus, and hyperlipidemia. Non-alcoholic fatty liver disease, including cirrhosis, occurred in the post-marketing setting. Hyperglycemia may represent new-onset diabetes mellitus or worsening of glycemic control in patients with pre-existing diabetes. Monitor for changes in serum lipids, blood glucose and/or glycosylated hemoglobin (HbA1c) in patients receiving a GnRH agonist, and manage according to current treatment guidelines. 5.3 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 institutional guidelines. 5.4 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. 5.5 Convuls…

4 CONTRAINDICATIONS LUPRON DEPOT is contraindicated in: Hypersensitivity LUPRON DEPOT is contraindicated in individuals with known hypersensitivity to GnRH agonists or any of the excipients in LUPRON DEPOT. Reports of anaphylactic reactions to GnRH agonists have been reported in the medical literature. Hypersensitivity to GnRH, GnRH agonist or any of the excipients in LUPRON DEPOT. ( 4 )

7 DRUG INTERACTIONS 7.1 Drug/Laboratory Test Interactions Administration of LUPRON DEPOT in therapeutic doses results in suppression of the pituitary-gonadal system. Normal function is usually restored within three months after treatment is discontinued. Due to the suppression of the pituitary-gonadal system by LUPRON DEPOT, diagnostic tests of pituitary gonadotropic and gonadal functions conducted during treatment and up to three months after discontinuation of LUPRON DEPOT may be affected.

8.1 Pregnancy Risk Summary Based on findings in animal studies and mechanism of action, LUPRON DEPOT 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. In animal developmental and reproductive toxicology studies, administration of a monthly formulation of leuprolide acetate on day 6 of pregnancy (sustained exposure was expected throughout the period of organogenesis) caused adverse embryo-fetal toxicity in animals at doses less than the human dose based on body surface area using an estimated daily dose (see data) . Advise pregnant patients and females of reproductive potential of the potential risk to the fetus. Data Animal Data Major fetal malformations were observed in developmental and reproductive toxicology studies in rabbits after a single administration of the monthly formulation of leuprolide acetate on day 6 of pregnancy at doses of 0.00024, 0.0024, and 0.024 mg/kg (approximately 1/1600 to 1/16 the human dose based on body surface area using an estimated daily dose in animals and humans). Since a depot formulation was utilized in the study, a sustained exposure to leuprolide was expected throughout the period of organogenesis and to the end of gestation. Similar studies in rats did not demonstrate an increase in fetal malformations, however, there was increased fetal mortality and decreased fetal weights with the two higher doses of the monthly formulation of leuprolide acetate in rabbits and with the highest dose (0.024 mg/kg) in rats.

6 ADVERSE REACTIONS The following is discussed in more detail in other sections of the labeling: Tumor Flare [see Warnings and Precautions ( 5.1 )] Metabolic Syndrome [see Warnings and Precautions ( 5.2 )] Cardiovascular Disease [see Warnings and Precautions ( 5.3 )] Effect on QT/QTc Interval [see Warnings and Precautions ( 5.4 )] Convulsions [see Warnings and Precautions ( 5.5 )] Severe Cutaneous Adverse Reactions [see Warnings and Precautions ( 5.6 )] 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. LUPRON DEPOT 7.5 mg for 1-month administration: The most common adverse reactions (>10%) were general pain, hot flashes/sweats, GI disorders, edema, respiratory disorder, urinary disorder. ( 6.1 ) LUPRON DEPOT 22.5 mg for 3-month administration: The most common adverse reactions (>10%) were general pain, injection site reaction, hot flashes/sweats, GI disorders, joint disorders, testicular atrophy, urinary disorders. ( 6.2 ) LUPRON DEPOT 30 mg for 4-month administration: The most common adverse reactions (>10%) were asthenia, flu syndrome, general pain, headache, injection site reaction, hot flashes/sweats, GI disorders, edema, skin reaction, urinary disorders. ( 6.3 ) LUPRON DEPOT 45 mg for 6-month administration: The most common adverse reactions (>10%) were hot flush, injection site pain, upper respiratory infection, and fatigue. ( 6.4 ) In postmarketing experience, mood swings, depression, rare reports of suicidal ideation and attempt, rare reports of pituitary apoplexy, and rare reports of serious drug-induced liver injury have been reported. ( 6.5 ) To report SUSPECTED ADVERSE REACTIONS, contact AbbVie Inc.at 1-800-633-9110 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 LUPRON DEPOT 7.5 mg for 1-Month Administration 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 week of treatment. Potential exacerbations of signs and symptoms during the first few weeks of treatment is a concern in patients with vertebral metastases and/or urinary obstruction or hematuria which, if aggravated, may lead to neurological problems such as temporary weakness and/or paresthesia of the lower limbs or worsening of urinary symptoms [see Warnings and Precautions ( 5.1 )] . In a clinical trial of LUPRON DEPOT 7.5 mg for 1-month administration, the following adverse reactions were reported in 5% or more of the patients during the initial 24-week treatment period. Table 2. Adverse Reactions Reported in ≥ 5% of Patients LUPRON DEPOT 7.5 mg for 1-Month Administration (N=56) N (%) Body As A Whole General pain 13 (23.2) Infection 3 (5.4) Cardiovascular System Hot flashes/sweats* 32 (57.1) Digestive System GI disorders 8 (14.3) Metabolic and Nutritional Disorders Edema 8 (14.3) Nervous System Libido decreased* 3 (5.4) Respiratory System Respiratory disorder 6 (10.7) Urogenital System Urinary disorder 7 (12.5) Impotence* 3 (5.4) Testicular atrophy* 3 (5.4) * Due to the expected physiologic effect of decreased testosterone levels. In this same study, the following adverse reactions were reported in less than 5% of the patients on LUPRON DEPOT 7.5 mg for 1-month administration. Body As A Whole - asthenia, cellulitis, fever, headache, injection site reaction, neoplasm Cardiovascular System - angina, congestive heart failure Digestive System - anorexia, dysphagia, eructation, peptic ulcer Blood and Lymphatic System - ecchymosis Musculoskeletal System - myalgia Nervous System - agitation, insomnia/sleep disorders, neuromuscular disorders Respiratory System - emphysema, hemoptysis, lung edema, sputum increased Skin and Appendages - hair disorder, skin reaction Urogenital System - balanitis, breast enlargement, urinary tract infe…