Lupron Depot

1 INDICATIONS AND USAGE LUPRON DEPOT 3.75 mg is a gonadotropin-releasing hormone (GnRH) agonist indicated for: Endometriosis Management of endometriosis, including pain relief and reduction of endometriotic lesions. ( 1.1 ) In combination with a norethindrone acetate for initial management of the painful symptoms of endometriosis and for management of recurrence of symptoms. ( 1.1 ) Limitations of Use: The total duration of therapy with LUPRON DEPOT 3.75 mg plus add-back therapy should not exceed 12 months due to concerns about adverse impact on bone mineral density. ( 1.1 , 2.1 , 5.1 ) Uterine Leiomyomata (Fibroids) Concomitant use with iron therapy for preoperative hematologic improvement of women with anemia caused by fibroids for whom three months of hormonal suppression is deemed necessary. ( 1.2 ) Limitations of Use: LUPRON DEPOT 3.75 mg is not indicated for combination use with norethindrone acetate add-back therapy for the preoperative hematologic improvement of women with anemia caused by heavy menstrual bleeding due to fibroids. ( 1.2 ) 1.1 Endometriosis Monotherapy LUPRON DEPOT 3.75 mg is indicated for management of endometriosis, including pain relief and reduction of endometriotic lesions. In Combination with Norethindrone Acetate LUPRON DEPOT 3.75 mg in combination with norethindrone acetate is indicated for initial management of the painful symptoms of endometriosis and for management of recurrence of symptoms. Use of norethindrone acetate in combination with LUPRON DEPOT 3.75 mg is referred to as add-back therapy, and is intended to reduce the loss of bone mineral density (BMD) and reduce vasomotor symptoms associated with use of LUPRON DEPOT 3.75 mg. Limitations of Use : The total duration of therapy with LUPRON DEPOT 3.75 mg plus add-back therapy should not exceed 12 months due to concerns about adverse impact on bone mineral density [see Dosage and Administration ( 2.1 ) and Warnings and Precautions ( 5.1 ) ] . 1.2 Uterine Leiomyomata (Fibroids) LUPRON DEPOT 3.75 mg, used concomitantly with iron therapy, is indicated for the preoperative hematologic improvement of women with anemia caused by fibroids for whom three months of hormonal suppression is deemed necessary. Consider a one-month trial period on iron alone, as some women will respond to iron alone [see Clinical Studies ( 14.2 )] . LUPRON DEPOT 3.75 mg may be added if the response to iron alone is considered inadequate. Limitations of Use : LUPRON DEPOT 3.75 mg is not indicated for combination use with norethindrone acetate add-back therapy for the preoperative hematologic improvement of women with anemia caused by heavy menstrual bleeding due to fibroids [see Dosage and Administration ( 2.1 )] .

2 DOSAGE AND ADMINISTRATION LUPRON DEPOT 3.75 mg for 1-month administration, given by a healthcare provider as a single intramuscular injection. LUPRON DEPOT 3.75 mg has different release characteristics than LUPRON 11.25 mg and is dosed differently. ( 2.1 ) Do not substitute LUPRON DEPOT 3.75 mg for LUPRON DEPOT 11.25 mg. Do not administer LUPRON DEPOT 3.75 mg more frequently than once a month. Do not give a fractional dose of the LUPRON DEPOT 11.25 mg 3-month formulation, as it is not equivalent to a single dose of the LUPRON DEPOT 3.75 mg. Do not give a triple dose of the LUPRON DEPOT 3.75 mg, as it is not equivalent to a single dose of the LUPRON DEPOT 11.25 mg 3- month formulation. Reconstitute LUPRON DEPOT 3.75 mg prior to use. ( 2.2 ) Endometriosis: LUPRON DEPOT 3.75 mg administered as a single intramuscular (IM) injection once every month for up to six injections (6 months of therapy). LUPRON DEPOT may be administered alone or in combination with daily 5 mg tablet of norethindrone acetate (add-back). ( 2.1 ) If endometriosis symptoms recur after initial course of therapy, retreatment for no more than six months may be considered but only with the addition of norethindrone acetate add-back therapy. Do not re-treat with LUPRON DEPOT 3.75 mg alone. ( 2.1 ) Fibroids: Recommended dose of LUPRON DEPOT 3.75 mg is one IM injection every month for up to three months. ( 2.1 ) Figure A Figure B Figure C Figure D Figure E Figure F Figure G 2.1 Important Use Information LUPRON DEPOT 3.75 mg must be administered by a healthcare professional. LUPRON DEPOT 3.75 mg for 1-month administration has different release characteristics than LUPRON 11.25 mg for 3-month administration and is dosed differently. Do not substitute LUPRON DEPOT 3.75 mg for LUPRON DEPOT 11.25 mg. Do not administer LUPRON DEPOT 3.75 mg more frequently than once a month. Do not give a fractional dose of the LUPRON DEPOT 11.25 mg 3-month formulation as it is not equivalent to a single dose of the LUPRON DEPOT 3.75 mg. Do not give a triple dose of the LUPRON DEPOT 3.75 mg, as it is not equivalent to a single dose of the LUPRON DEPOT 11.25 mg 3-month formulation. Endometriosis The initial and retreatment dosage regimens for LUPRON DEPOT 3.75 mg for the management of women with endometriosis are outlined in Table 1. Table 1. LUPRON DEPOT 3.75 mg, Management of Endometriosis Treatment Phase LUPRON DEPOT 3.75 mg Dosing Maximum Treatment Duration Initial Treatment 1 3.75 mg IM every 1 month for 1 to 6 doses 6 months Retreatment 2 3.75 mg IM every 1 month for 1 to 6 doses 6 months 12 MONTHS 3 TOTAL TREATMENT DURATION 1 May use LUPRON DEPOT 3.75 mg with or without norethindrone acetate 5 mg tablet taken daily. 2 Use LUPRON DEPOT 3.75 mg with norethindrone acetate for retreatment 5 mg tablet taken daily [see Warnings and Precautions ( 5.1 ) ] and assess bone mineral density (BMD) prior to retreatment. 3 Treatment should not exceed 12 months due to concerns about adverse impact on bone mineral density. Fibroids The recommended dosage of LUPRON DEPOT 3.75 mg is one IM injection every month for up to three months. 2.2 Reconstitution and Administration for Injection of LUPRON DEPOT Reconstitute and administer the lyophilized microsphere as a single IM injection as directed below. Visually inspect the drug product for particulate matter and discoloration prior to administration, whenever solution and container permit. Inject the LUPRON DEPOT 3.75 mg suspension immediately or discard if not used within two hours as the suspension does not contain a preservative. 1. Visually inspect the LUPRON DEPOT 3.75 mg powder. Do not use the syringe if clumping or caking is evident. A thin layer of powder on the wall of the syringe is considered normal prior to mixing with the diluent. The diluent should appear clear. 2. To prepare for injection, screw the white plunger into the end stopper until the stopper begins to turn (see Figure A and Figure B ). Figure A: Figure B: 3. Hold the syringe UPRIGHT. Release the diluent by SLOWLY PUSHING the plunger for 6 to 8 seconds until the first middle stopper is at the blue line in the middle of the barrel (see Figure C ). Figure C: 4. Keep the syringe upright . Mix the microsphere powder thoroughly by gently shaking the syringe until the powder forms a uniform suspension. The suspension will appear milky. If the powder adheres to the stopper or caking/clumping is present, tap the syringe with your finger to disperse. Do not use if any of the powder has not gone into suspension (see Figure D ). Figure D: 5. Keep the syringe upright . With the opposite hand pull the needle cap upward without twisting. 6. Keep the syringe upright. Advance the plunger to expel the air from the syringe. The syringe is now ready for injection. 7. After cleaning the injection site with an alcohol swab, administer the IM injection by inserting the needle at a 90-degree angle into the gluteal area, anterior thigh, or deltoid. Injection sites should be alternated (see Figure E ). Figure E: Note : If a blood vessel is accidentally penetrated, aspirated blood will be visible just below the luer lock (see Figure F ) and can be seen through the transparent LuproLoc ® safety device. If blood is present, remove the needle immediately. Do not inject the medication. Figure F: 8. Inject the entire contents of the syringe intramuscularly. 9. Withdraw the needle. Once the syringe has been withdrawn, immediately activate the LuproLoc ® safety device by pushing the arrow on the lock upward towards the needle tip with the thumb or finger, as illustrated, until the needle cover of the safety device over the needle is fully extended and a click is heard or felt (see Figure G ). Figure G: 10. Dispose of the syringe according to local regulations/procedures.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Loss of Bone Mineral Density [see Warnings and Precautions ( 5.1 )] Severe Cutaneous Adverse Reactions [see Warnings and Precautions ( 5.3 )] Hypersensitivity Reactions [see Warnings and Precautions ( 5.4 ) ] Initial Flare of Symptoms with Management of Endometriosis [see Warnings and Precautions ( 5.5 ) ] Convulsions [see Warnings and Precautions ( 5.6 ) ] Clinical Depression [see Warnings and Precautions ( 5.7 ) ] Most common adverse reactions (>10%) in clinical trials were hot flashes/sweats, headache/migraine, vaginitis, depression/emotional lability, general pain, weight gain/loss, nausea/vomiting, decreased libido, and dizziness. ( 6.1 ) 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 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 clinical practice. LUPRON DEPOT 3.75 mg (Monotherapy) The safety of LUPRON DEPOT 3.75 mg for the endometriosis and fibroids indications was established based on adequate and well-controlled adult studies. The safety of LUPRON DEPOT 3.75 mg was evaluated in six clinical studies in which a total of 332 women were treated for up to six months. Women were treated with monthly IM injections of LUPRON DEPOT 3.75 mg. The population age range was 18 to 53 years old. Adverse Reactions (>1%) Leading to Study Discontinuation In the six studies 1.8% of women treated with LUPRON DEPOT 3.75 mg discontinued prematurely due to hot flashes. Common Adverse Reactions The safety of LUPRON DEPOT 3.75 mg was evaluated in controlled clinical trials in 166 women with endometriosis and 166 women with uterine fibroids. Adverse reactions reported in ≥ 5% of women in either of these populations are noted in Tables 2 and 3 , below. Table 2. Adverse Reactions Reported in ≥ 5% of Women with Endometriosis Taking LUPRON DEPOT 3.75 mg - 2 Studies LUPRON DEPOT 3.75 mg N=166 Danazol N=136 Placebo N=31 % % % Hot flashes/sweats* 84 57 29 Headache* 32 22 6 Vaginitis* 28 17 0 Depression/emotional lability* 22 20 3 General pain 19 16 3 Weight gain/loss 13 26 0 Nausea/vomiting 13 13 3 Decreased libido* 11 4 0 Dizziness 11 3 0 Acne 10 20 0 Skin reactions 10 15 3 Joint disorder* 8 8 0 Edema 7 13 3 Paresthesias 7 8 0 GI disturbances* 7 6 3 Neuromuscular disorders* 7 13 0 Breast changes/tenderness/pain* 6 9 0 Nervousness* 5 8 0 In these same studies, symptoms reported in 1%) Leading to Study Discontinuation In the controlled study, 18% of women treated monthly with LUPRON DEPOT 3.75 mg and 18% of women treated monthly with LUPRON DEPOT 3.75 mg plus norethindrone acetate discontinued therapy due to adverse reactions, most commonly hot flashes (6%) and insomnia (4%) in the LUPRON DEPOT 3.75 mg alone group and hot flashes and emotional lability (4% each) in the LUPRON DEPOT 3.75 mg plus norethindrone group. In the open-label study, 13% of women treated monthly with LUPRON DEPOT 3.75 mg plus norethindrone acetate discontinued therapy due to adverse reactions, most commonly depression (4%) and acne (2%). Common Adverse Reactions Table 4 lists the adverse reactions observed in at least 5% of women in any treatment group, during the first 6 months of treatment in the two add-back clinical studies, in which women were treated with monthly LUPRON DEPOT 3.75 mg with or without norethindrone acetate 5 mg daily co-treatment. The most frequently-occurring adverse reactions observed in these studies were hot flashes and headaches. Table 4. Adverse Reactions Occurring in the First Six Months of Treatment in ≥ 5% of Women with Endometriosis Controlled Study Open Label Study LD-Only* LD/N† LD/N† N=51 N=55 N=136 Adverse Reactions % % % Any Adverse Reaction 98 96 93 Hot flashes/Sweats 98 87 57 Headache/Migraine 65 51 46 Depression/Emotional Lability 31 27 34 Insomnia/Sleep Disorder 31 13 15 Nausea/Vomiting 25 29 13 Pain 24 29 21 Vaginitis 20 15 8 Asthenia 18 18 11 Dizziness/Vertigo 16 11 7 Altered Bowel Function (constipation, diarrhea) 14 15 10 Weight Gain 12 13 4 Decreased Libido 10 4 7 Nervousness/Anxiety 8 4 11 Breast Changes/Pain/Tenderness 6 13 8 Memory Disorder 6 2 4 Skin/Mucous Membrane Reaction 4 9 11 GI Disturbance (dyspepsia, flatulence) 4 7 4 Androgen-Like Effects (acne, alopecia) 4 5 18 Changes in Appetite 4 0 6 Injection Site Reaction 2 9 3 Neuromuscular Disorder (leg cramps, paresthesia) 2 9 3 Menstrual Disorders 2 0 5 Edema 0 9 7 * LD-Only = LUPRON DEPOT 3.75 mg † LD/N = LUPRON DEPOT 3.75 mg plus norethindrone acetate 5 mg In the controlled clinical trial, 50 of 51 (98%) women in the LUPRON DEPOT 3.75 mg arm and 48 of 55 (87%) women in the LUPRON DEPOT 3.75 mg plus norethindrone acetate arm reported experiencing hot flashes on one or more occasions during treatment. Table 5 presents hot flash data in the last month of treatment. Table 5. Hot Flashes in the Month Prior to the Assessment Visit (Controlled Study) Assessment Visit Treatment Group Number of Women Reporting Hot Flashes Number of Days with Hot Flashes Maximum Number Hot Flashes in 24 Hours N (%) N 2 Mean N 2 Mean Week 24 LD-Only* 32/37 86 37 19 36 5.8 LD/N† 22/38 58 1 38 7 1 38 1.9 1 * LD-Only = LUPRON DEPOT 3.75 mg. † LD/N = LUPRON DEPOT 3.75 mg plus norethindrone acetate 5 mg. 1 Statistically significantly less than the LD-Only group (p240 mg/dL) 15% 23% 15% 20% 6% 7% HDL Cholesterol (160 mg/dL) 0% 8% 5% 7% 9% 11% LDL/HDL Ratio (>4.0) 0% 3% 2% 15% 7% 21% Triglycerides (>200 mg/dL) 13% 13% 12% 10% 5% 9% * Includes all women regardless of baseline value. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of LUPRON DEPOT monotherapy or LUPRON DEPOT with norethindrone acetate add-back therapy. 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. During postmarketing surveillance which includes other dosage forms and other populations, the following adverse reactions were reported: Skin and Subcutaneous Tissue : rash, urticaria, photosensitivity, erythema multiforme, bullous dermatitis, dermatitis exfoliative, drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), and acute generalized exanthematous pustulosis (AGEP) Body as a whole: Hypersensitivity reactions including anaphylaxis Nervous/Psychiatric System: Mood swings, including depression; suicidal ideation and attempt; convulsion, peripheral neuropathy, paralysis Hepato-biliary system: Serious liver injury General disorders and administration site conditions : Injection site reactions including induration, abscess, and necrosis Injury, poisoning and procedural complications: Spinal fracture Investigations: Decreased white blood count Musculoskeletal and connective tissue system: Tenosynovitis-like symptoms Vascular system: Hypotension, hypertension, deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke, transient ischemic attack Respiratory system: Symptoms consistent with an asthmatic process Multi-system disorders: Symptoms consistent with fibromyalgia (e.g., joint and muscle pain, headaches, sleep disorders, gastrointestinal distress, and shortness of breath), individually and collectively. Pituitary apoplexy During postmarketing surveillance, cases of pituitary apoplexy (a clinical syndrome secondary to infarction of the pituitary gland) have been reported after the administration of leuprolide acetate and other GnRH 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.

7 DRUG INTERACTIONS No drug-drug interaction studies have been conducted with LUPRON DEPOT 3.75 mg.

16 HOW SUPPLIED/STORAGE AND HANDLING Each LUPRON DEPOT 3.75 mg kit (NDC 0074-3641-03) contains: one prefilled dual-chamber syringe one plunger two alcohol swabs Each single-dose dual chamber syringe contains sterile white lyophilized microsphere powder of 3.75 mg of leuprolide acetate incorporated in a biodegradable polymer in one chamber and a colorless diluent (1 mL) in the other chamber. When mixed with the diluent, LUPRON DEPOT 3.75 mg for injection, is administered as a single IM injection. Store between 20° to 25°C (68° to 77°F). Excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature] .