Lupron Depot

5 WARNINGS AND PRECAUTIONS Loss of bone mineral density (BMD): Duration of treatment is limited by risk of bone mineral density. When using for management of endometriosis: combination use with norethindrone acetate is effective in reducing loss of BMD; do not retreat without combination norethindrone acetate. Assess BMD before retreatment. ( 1.1 , 1.2 , 5.1 ) Embryo-Fetal Toxicity: May cause fetal harm. Exclude pregnancy before initiating treatment if clinically indicated and discontinue use if pregnancy occurs. Use non-hormonal methods of contraception only. ( 5.2 ) Severe Cutaneous Adverse Reactions (SCARs), including Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), occurred in patients treated with LUPRON DEPOT. Discontinue LUPRON DEPOT 11.25 mg if signs or symptoms of SCARs develop. Permanently discontinue if SCARs are confirmed. ( 5.3 ) Hypersensitivity reactions including anaphylaxis, have been reported with LUPRON DEPOT 11.25 mg. ( 5.4 ) If LUPRON is administered with norethindrone acetate, the warnings and precautions for norethindrone acetate apply to the combination regimen. ( 5.8 ) 5.1 Loss of Bone Mineral Density LUPRON DEPOT 11.25 mg induces a hypoestrogenic state that results in loss of bone mineral density (BMD), some of which may not be reversible after stopping treatment. In women with major risk factors for decreased BMD such as chronic alcohol use (> 3 units per day), tobacco use, strong family history of osteoporosis, or chronic use of drugs that can decrease BMD, such as anticonvulsants or corticosteroids, use of LUPRON DEPOT 11.25 mg may pose an additional risk. Carefully weigh the risks and benefits of LUPRON DEPOT 11.25 mg use in these populations. The duration of LUPRON DEPOT 11.25 mg treatment is limited by the risk of loss of bone mineral density [see Dosage and Administration ( 2.1 )] . When using LUPRON DEPOT 11.25 mg for the management of endometriosis, combination use of norethindrone acetate (add-back therapy) is effective in reducing the loss of BMD that occurs with leuprolide acetate [see Clinical Studies ( 14.2 )] . Do not retreat with LUPRON DEPOT 11.25 mg without combination norethindrone acetate. Assess BMD before retreatment. 5.2 Embryo-Fetal Toxicity Based on animal reproduction studies and the drug’s mechanism of action, LUPRON DEPOT 11.25 mg may cause fetal harm if administered to a pregnant woman and is contraindicated in pregnant women. Exclude pregnancy prior to initiating treatment with LUPRON DEPOT 11.25 mg if clinically indicated. Discontinue LUPRON DEPOT 11.25 mg if the woman becomes pregnant during treatment and inform the woman of potential risk to the fetus [see Contraindications ( 4 ) and Use in Specific Populations ( 8.1 ) ] . Advise women to notify their healthcare provider if they believe they may be pregnant. When used at the recommended dose and dosing interval, LUPRON DEPOT 11.25 mg usually inhibits ovulation and stops menstruation. Contraception, however, is not ensured by taking LUPRON DEPOT 11.25 mg. If contraception is indicated, advise women to use non-hormonal methods of contraception while on treatment with LUPRON DEPOT 11.25 mg. 5.3 Severe Cutaneous Adverse Reactions Severe cutaneous adverse reactions (SCARs) have been reported in patients receiving GnRH agonists, including LUPRON DEPOT. These reactions include Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP), including cases with visceral involvement and/or requiring skin grafts [see Adverse Reactions ( 6.2 )]. Monitor patients for the signs and symptoms of SCARs such as fever, flu-like symptoms, mucosal lesions, progressive skin rash, or lymphadenopathy. Advise patients of the signs and symptoms of SCARs. If a SCAR is suspected, discontinue LUPRON DEPOT 11.25 mg. Consult with a healthcare provider with expertise in the diagnosis and management of SCARs. If a diagnosis of SCAR is confirmed, permanently discontinue LUPRON DEPOT 11.25 mg. 5. 4 Hypersensitivity Reactions Hypersensitivity reactions, including anaphylaxis, have been reported with LUPRON DEPOT use. LUPRON DEPOT 11.25 mg is contraindicated in women with a history of hypersensitivity to gonadotropin-releasing hormone (GnRH) or GnRH agonist analogs [see Adverse Reactions ( 6.2 )] . In clinical trials of LUPRON DEPOT 11.25 mg, adverse events of asthma were reported in women with pre-existing histories of asthma, sinusitis, and environmental or drug allergies. Symptoms consistent with an anaphylactoid or asthmatic process have been reported postmarketing. 5. 5 Initial Flare of Symptoms Following the first dose of LUPRON DEPOT 11.25 mg, sex steroids temporarily rise above baseline because of the physiologic effect of the drug. Therefore, an increase in symptoms may be observed during the initial days of therapy, but these should dissipate with continued therapy. 5. 6 Convulsions There have been postmarketing reports of convulsions in women on GnRH agonists, including leuprolide acetate. These included women with and without concurrent medications and comorbid conditions. 5. 7 Clinical Depression Depression may occur or worsen during treatment with GnRH agonists including LUPRON DEPOT 11.25 mg [see Adverse Reactions ( 6.1 )] . Carefully observe women for depression, especially those with a history of depression and consider whether the risks of continuing LUPRON DEPOT 11.25 mg outweigh the benefits. Women with new or worsening depression should be referred to a mental health professional, as appropriate. 5. 8 Risks Associated with Norethindrone Combination Treatment If LUPRON DEPOT 11.25 mg is administered with norethindrone acetate, the warnings and precautions for norethindrone acetate apply to this regimen. Refer to the norethindrone acetate prescribing information for a full list of the warnings and precautions for norethindrone acetate.

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 11.25 mg (Monotherapy) The safety of LUPRON DEPOT 11.25 mg for the endometriosis and fibroids indications was established based on adequate and well-controlled adult studies of LUPRON DEPOT 3.75 mg for 1-month administration and on a single trial of LUPRON DEPOT 11.25 mg. 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 < 5% of women included: Body as a Whole - Injection site reactions Cardiovascular System - Palpitations, syncope, tachycardia Digestive System - Appetite changes, dry mouth, thirst Endocrine System - Androgen-like effects, lactation Blood and Lymphatic System - Ecchymosis Nervous/Psychiatric System - Anxiety*, insomnia/sleep disorders*, delusions, memory disorder, personality disorder Dermal System - Alopecia, hair disorder Ocular system - Ophthalmologic disorders* Urogenital System - Dysuria*. * = Possible effect of decreased estrogen. Table 3. Adverse Reactions Reported in ≥ 5% of Women with Uterine Fibroids (4 Studies) Taking LUPRON DEPOT 3.75 mg LUPRON DEPOT 3.75 mg N=166 Placebo N=163 % % Hot flashes/sweats* 73 18 Headache* 26 18 Vaginitis* 11 2 Depression/emotional lability* 11 4 Asthenia 8 5 General pain 8 6 Joint disorder* 8 3 Edema 5 1 Nausea/vomiting 5 4 Nervousness* 5 1 In these same studies, symptoms reported in < 5% of women included: Body as a Whole - Body odor, flu syndrome, injection site reactions Cardiovascular System - Tachycardia Digestive System - Appetite changes, dry mouth, taste perversion Endocrine System - Androgen-like effects, menstrual disorders Nervous/Psychiatric System - Anxiety*, insomnia/sleep disorders* Respiratory System - Rhinitis Dermal System - Nail disorder Ocular system - Conjunctivitis * = Possible effect of decreased estrogen. In one controlled clinical trial utilizing the monthly formulation of LUPRON DEPOT 3.75 mg and LUPRON DEPOT 7.5 mg in women diagnosed with uterine fibroids received one injection every 4 weeks for a duration of 12 weeks. Adverse reactions of galactorrhea, pyelonephritis, and urinary incontinence were reported in the 7.5 mg dose group but not in the 3.75 mg dose group. Generally, a higher incidence of hypoestrogenic effects was observed at the higher dose. In a pharmacokinetic trial involving 20 healthy female subjects receiving LUPRON DEPOT 11.25 mg, a few adverse reactions were reported with this formulation that were not reported previously, including face edema. In a phase 4 study involving women with endometriosis who received LUPRON DEPOT 3.75 mg (N=20) administered monthly or LUPRON DEPOT 11.25 mg (N=21) administered every 3 months, similar adverse reactions were reported by the two groups of women. In general, the safety profiles of the two formulations were comparable in this study. LUPRON DEPOT 3.75 mg in combination with Norethindrone Acetate 5 mg The safety of co-administering LUPRON DEPOT 3.75 mg and norethindrone acetate was evaluated in two clinical studies in which a total of 242 women with endometriosis were treated for up to one year. Women were treated with monthly IM injections of LUPRON DEPOT 3.75 mg (13 injections) alone or monthly IM injections of LUPRON DEPOT 3.75 mg (13 injections) plus norethindrone acetate 5 mg daily. The population age range was 17 to 43 years old. The majority of women were Caucasian (87%). In one study, 106 women were randomized to one year of treatment with LUPRON DEPOT 3.75 mg alone or with LUPRON DEPOT 3.75 mg and norethindrone acetate. The other study was an open-label, single arm clinical study in 136 women on one year of treatment with LUPRON DEPOT 3.75 mg plus norethindrone acetate, with follow-up for up to 12 months after completing treatment. Adverse Reactions (>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 5mg 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 (p<0.01). 2 Number of women assessed. Serious Adverse Reactions Urinary tract infection (1.9%), renal calculus (0.7%), depression (0.7%) Changes in Laboratory Values during Treatment Liver Enzymes Three percent of women with uterine fibroids treated with LUPRON DEPOT 3.75 mg for 1-month administration, manifested post-treatment transaminase values that were at least twice the baseline value and above the upper limit of the normal range. In the two clinical trials of women with endometriosis, 2% (4 of 191) women receiving leuprolide acetate plus norethindrone acetate for up to 12 months developed an elevated (at least twice the upper limit of normal) SGPT and 1% (2 of 136) developed an elevated GGT. Among these six women with increased liver tests, the increases in five were observed beyond 6 months of treatment. None were associated with an elevated bilirubin concentration. Lipids Triglycerides were increased above the upper limit of normal in 12% of the women with endometriosis who received LUPRON DEPOT 3.75 mg and in 32% of the women receiving LUPRON DEPOT 11.25 mg. Of those endometriosis and women with uterine fibroid whose pretreatment cholesterol values were in the normal range, mean change following therapy was +16 mg/dL to +17 mg/dL in women with endometriosis and +11 mg/dL to +29 mg/dL in women with uterine fibroids. In the women with endometriosis, increases from the pretreatment values were statistically significant (p<0.03). There was essentially no increase in the LDL/HDL ratio in women from either population receiving LUPRON DEPOT 3.75 mg. Percent changes from baseline for serum lipids and percentages of women with serum lipid values outside of the normal range in the two studies of LUPRON DEPOT 3.75 mg and norethindrone acetate are summarized in Table 6 and Table 7 below. The major impact of adding norethindrone acetate to treatment with LUPRON DEPOT 3.75 mg was a decrease in serum HDL cholesterol and an increase in the LDL/HDL ratio. Table 6. Serum Lipids: Mean Percent Changes from Baseline Values at Treatment Week 24 LUPRON DEPOT 3.75 mg LUPRON DEPOT 3.75 mg plus norethindrone acetate 5 mg daily Controlled Study (n=39) Controlled Study (n=41) Open Label Study (n=117) Baseline Value* Week 24 % Change Baseline Value* Week 24 % Change Baseline Value* Week 24 % Change Total Cholesterol 170.5 9.2% 179.3 0.2% 181.2 2.8% HDL Cholesterol 52.4 7.4% 51.8 -18.8% 51.0 -14.6% LDL Cholesterol 96.6 10.9% 101.5 14.1% 109.1 13.1% LDL/HDL Ratio 2.0† 5.0% 2.1† 43.4% 2.3† 39.4% Triglycerides 107.8 17.5% 130.2 9.5% 105.4 13.8% * mg/dL † ratio Changes from baseline tended to be greater at Week 52. After treatment, mean serum lipid levels from women with follow-up data returned to pretreatment values. Table 7. Percentage of Women with Serum Lipids Values Outside of the Normal Range LUPRON DEPOT 3.75 mg LUPRON DEPOT 3.75 mg plus norethindrone acetate 5 mg daily Controlled Study (n=39) Controlled Study (n=41) Open Label Study (n=117) Week 0 Week 24* Week 0 Week 24* Week 0 Week 24* Total Cholesterol (>240 mg/dL) 15% 23% 15% 20% 6% 7% HDL Cholesterol (<40 mg/dL) 15% 10% 15% 44% 15% 41% LDL 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.

<table ID="Table2"><caption>Table 2. Adverse Reactions Reported in &#x2265; 5% of Women with Endometriosis Taking LUPRON DEPOT 3.75 mg - 2 Studies</caption><col width="302"/><col width="161"/><col width="83"/><col width="79"/><tbody><tr><td styleCode="Toprule Lrule Rrule "> </td><td styleCode="Toprule Lrule Rrule " valign="bottom" align="center"><content styleCode="bold">LUPRON DEPOT</content><content styleCode="bold"> 3.75 mg</content><content styleCode="bold"> N=166</content></td><td styleCode="Toprule Lrule Rrule " valign="bottom" align="center"><content styleCode="bold">Danazol</content><content styleCode="bold"> N=136</content></td><td styleCode="Toprule Lrule Rrule " valign="bottom" align="center"><content styleCode="bold">Placebo</content><content styleCode="bold"> N=31</content></td></tr><tr><td styleCode="Toprule Lrule Rrule "> </td><td styleCode="Toprule Lrule Rrule " align="center"><content styleCode="bold">%</content></td><td styleCode="Toprule Lrule Rrule " align="center"><content styleCode="bold">%</content></td><td styleCode="Toprule Lrule Rrule " align="center"><content styleCode="bold">%</content></td></tr><tr><td styleCode="Toprule Lrule Rrule ">Hot flashes/sweats* </td><td styleCode="Toprule Lrule Rrule " align="center">84</td><td styleCode="Toprule Lrule Rrule " align="center">57</td><td styleCode="Toprule Lrule Rrule " align="center">29</td></tr><tr><td styleCode="Toprule Lrule Rrule ">Headache*</td><td styleCode="Toprule Lrule Rrule " align="center">32</td><td styleCode="Toprule Lrule Rrule " align="center">22</td><td styleCode="Toprule Lrule Rrule " align="center">6</td></tr><tr><td styleCode="Toprule Lrule Rrule ">Vaginitis*</td><td styleCode="Toprule Lrule Rrule " align="center">28</td><td styleCode="Toprule Lrule Rrule " align="center">17</td><td styleCode="Toprule Lrule Rrule " align="center">0</td></tr><tr><td styleCode="Toprule Lrule Rrule ">Depression/emotional lability*</td><td styleCode="Toprule Lrule Rrule " align="center">22</td><td styleCode="Toprule Lrule Rrule " align="center">20</td><td styleCode="Toprule Lrule Rrule " align="center">3</td></tr><tr><td styleCode="Toprule Lrule Rrule ">General pain </td><td styleCode="Toprule Lrule Rrule " align="center">19</td><td styleCode="Toprule Lrule Rrule " align="center">16</td><td styleCode="Toprule Lrule Rrule " align="center">3</td></tr><tr><td styleCode="Toprule Lrule Rrule ">Weight gain/loss</td><td styleCode="Toprule Lrule Rrule " align="center">13</td><td styleCode="Toprule Lrule Rrule " align="center">26</td><td styleCode="Toprule Lrule Rrule " align="center">0</td></tr><tr><td styleCode="Toprule Lrule Rrule ">Nausea/vomiting</td><td styleCode="Toprule Lrule Rrule " align="center">13</td><td styleCode="Toprule Lrule Rrule " align="center">13</td><td styleCode="Toprule Lrule Rrule " align="center">3</td></tr><tr><td styleCode="Toprule Lrule Rrule ">Decreased libido*</td><td styleCode="Toprule Lrule Rrule " align="center">11</td><td styleCode="Toprule Lrule Rrule " align="center">4</td><td styleCode="Toprule Lrule Rrule " align="center">0</td></tr><tr><td styleCode="Toprule Lrule Rrule ">Dizziness</td><td styleCode="Toprule Lrule Rrule " align="center">11</td><td styleCode="Toprule Lrule Rrule " align="center">3</td><td styleCode="Toprule Lrule Rrule " align="center">0</td></tr><tr><td styleCode="Toprule Lrule Rrule ">Acne</td><td styleCode="Toprule Lrule Rrule " align="center">10</td><td styleCode="Toprule Lrule Rrule " align="center">20</td><td styleCode="Toprule Lrule Rrule " align="center">0</td></tr><tr><td styleCode="Toprule Lrule Rrule ">Skin reactions</td><td styleCode="Toprule Lrule Rrule " align="center">10</td><td styleCode="Toprule Lrule Rrule " align="center">15</td><td styleCode="Toprule Lrule Rrule " align="center">3</td></tr><tr><td styleCode="Toprule Lrule Rrule ">Joint disorder*</td><td styleCode="Toprule Lrule Rrule " align="center">8</td><td styleCode="Toprule Lrule Rrule " align="center">8</td><td styleCode="Toprule Lrule Rrule " align="center">0</td></tr><tr><td styleCode="Toprule Lrule Rrule ">Edema</td><td styleCode="Toprule Lrule Rrule " align="center">7</td><td styleCode="Toprule Lrule Rrule " align="center">13</td><td styleCode="Toprule Lrule Rrule " align="center">3</td></tr><tr><td styleCode="Toprule Lrule Rrule ">Paresthesias</td><td styleCode="Toprule Lrule Rrule " align="center">7</td><td styleCode="Toprule Lrule Rrule " align="center">8</td><td styleCode="Toprule Lrule Rrule " align="center">0</td></tr><tr><td styleCode="Toprule Lrule Rrule ">GI disturbances*</td><td styleCode="Toprule Lrule Rrule " align="center">7</td><td styleCode="Toprule Lrule Rrule " align="center">6</td><td styleCode="Toprule Lrule Rrule " align="center">3</td></tr><tr><td styleCode="Toprule Lrule Rrule ">Neuromuscular disorders*</td><td styleCode="Toprule Lrule Rrule " align="center">7</td><td styleCode="Toprule Lrule Rrule " align="center">13</td><td styleCode="Toprule Lrule Rrule " align="center">0</td></tr><tr><td styleCode="Toprule Lrule Rrule ">Breast changes/tenderness/pain*</td><td styleCode="Toprule Lrule Rrule " align="center">6</td><td styleCode="Toprule Lrule Rrule " align="center">9</td><td styleCode="Toprule Lrule Rrule " align="center">0</td></tr><tr><td styleCode="Toprule Lrule Rrule ">Nervousness*</td><td styleCode="Toprule Lrule Rrule " align="center">5</td><td styleCode="Toprule Lrule Rrule " align="center">8</td><td styleCode="Toprule Lrule Rrule " align="center">0</td></tr><tr><td styleCode="Toprule Lrule Rrule " colspan="4">In these same studies, symptoms reported in &lt; 5% of women included: <list><item><content styleCode="italics">Body as a Whole -</content> Injection site reactions </item><item><content styleCode="italics">Cardiovascular System -</content> Palpitations, syncope, tachycardia </item><item><content styleCode="italics">Digestive System -</content> Appetite changes, dry mouth, thirst </item><item><content styleCode="italics">Endocrine System -</content> Androgen-like effects, lactation </item><item><content styleCode="italics">Blood and Lymphatic System -</content> Ecchymosis </item><item><content styleCode="italics">Nervous/Psychiatric System -</content> Anxiety*, insomnia/sleep disorders*, delusions, memory disorder, personality disorder </item><item><content styleCode="italics">Dermal System -</content> Alopecia, hair disorder </item><item><content styleCode="italics">Ocular system -</content> Ophthalmologic disorders* </item><item><content styleCode="italics">Urogenital System -</content> Dysuria*. * = Possible effect of decreased estrogen. </item></list></td></tr></tbody></table>

<table ID="Table3"><caption>Table 3. Adverse Reactions Reported in &#x2265; 5% of Women with Uterine Fibroids (4 Studies) Taking LUPRON DEPOT 3.75 mg</caption><col width="284"/><col width="264"/><col width="79"/><tbody><tr><td styleCode="Toprule Lrule Rrule "> </td><td styleCode="Toprule Lrule Rrule " align="center"><content styleCode="bold">LUPRON DEPOT 3.75 mg</content><content styleCode="bold"> N=166</content></td><td styleCode="Toprule Lrule Rrule " align="center"><content styleCode="bold">Placebo</content><content styleCode="bold"> N=163</content></td></tr><tr><td styleCode="Lrule Rrule "/><td styleCode="Toprule Lrule Rrule " align="center"><content styleCode="bold">%</content></td><td styleCode="Toprule Lrule Rrule " align="center"><content styleCode="bold">%</content></td></tr><tr><td styleCode="Toprule Lrule Rrule ">Hot flashes/sweats*</td><td styleCode="Toprule Lrule Rrule " align="center">73</td><td styleCode="Toprule Lrule Rrule " align="center">18</td></tr><tr><td styleCode="Toprule Lrule Rrule ">Headache*</td><td styleCode="Toprule Lrule Rrule " align="center">26</td><td styleCode="Toprule Lrule Rrule " align="center">18</td></tr><tr><td styleCode="Toprule Lrule Rrule ">Vaginitis*</td><td styleCode="Toprule Lrule Rrule " align="center">11</td><td styleCode="Toprule Lrule Rrule " align="center">2</td></tr><tr><td styleCode="Toprule Lrule Rrule ">Depression/emotional lability*</td><td styleCode="Toprule Lrule Rrule " align="center">11</td><td styleCode="Toprule Lrule Rrule " align="center">4</td></tr><tr><td styleCode="Toprule Lrule Rrule ">Asthenia</td><td styleCode="Toprule Lrule Rrule " align="center">8</td><td styleCode="Toprule Lrule Rrule " align="center">5</td></tr><tr><td styleCode="Toprule Lrule Rrule ">General pain</td><td styleCode="Toprule Lrule Rrule " align="center">8</td><td styleCode="Toprule Lrule Rrule " align="center">6</td></tr><tr><td styleCode="Toprule Lrule Rrule ">Joint disorder*</td><td styleCode="Toprule Lrule Rrule " align="center">8</td><td styleCode="Toprule Lrule Rrule " align="center">3</td></tr><tr><td styleCode="Toprule Lrule Rrule ">Edema</td><td styleCode="Toprule Lrule Rrule " align="center">5</td><td styleCode="Toprule Lrule Rrule " align="center">1</td></tr><tr><td styleCode="Toprule Lrule Rrule ">Nausea/vomiting</td><td styleCode="Toprule Lrule Rrule " align="center">5</td><td styleCode="Toprule Lrule Rrule " align="center">4</td></tr><tr><td styleCode="Toprule Lrule Rrule ">Nervousness*</td><td styleCode="Toprule Lrule Rrule " align="center">5</td><td styleCode="Toprule Lrule Rrule " align="center">1</td></tr><tr><td styleCode="Toprule Lrule Rrule " colspan="3">In these same studies, symptoms reported in &lt; 5% of women included:<list><item><content styleCode="italics">Body as a Whole</content> - Body odor, flu syndrome, injection site reactions </item><item><content styleCode="italics">Cardiovascular System</content> - Tachycardia </item><item><content styleCode="italics">Digestive System</content> - Appetite changes, dry mouth, taste perversion </item><item><content styleCode="italics">Endocrine System</content> - Androgen-like effects, menstrual disorders </item><item><content styleCode="italics">Nervous/Psychiatric System</content> - Anxiety*, insomnia/sleep disorders* </item><item><content styleCode="italics">Respiratory System</content> - Rhinitis </item><item><content styleCode="italics">Dermal System </content>- Nail disorder </item><item><content styleCode="italics">Ocular system </content>- Conjunctivitis * = Possible effect of decreased estrogen. </item></list></td></tr></tbody></table>

<table ID="Table4"><caption>Table 4. Adverse Reactions Occurring in the First Six Months of Treatment in &#x2265; 5% of Women with Endometriosis</caption><col width="389"/><col width="84"/><col width="57"/><col width="97"/><tbody><tr><td styleCode="Toprule Lrule Rrule "> </td><td styleCode="Toprule Lrule Rrule " colspan="2" align="center"><content styleCode="bold">Controlled</content><content styleCode="bold"> Study</content></td><td styleCode="Toprule Lrule Rrule " align="center"><content styleCode="bold">Open Label</content><content styleCode="bold"> Study</content></td></tr><tr><td styleCode="Lrule Rrule "/><td styleCode="Toprule Lrule Rrule " align="center"><content styleCode="bold">LD-Only*</content></td><td styleCode="Toprule Lrule Rrule " align="center"><content styleCode="bold">LD/N&#x2020;</content></td><td styleCode="Toprule Lrule Rrule " align="center"><content styleCode="bold">LD/N&#x2020;</content></td></tr><tr><td styleCode="Lrule Rrule "/><td styleCode="Toprule Lrule Rrule " align="center"><content styleCode="bold">N=51</content></td><td styleCode="Toprule Lrule Rrule " align="center"><content styleCode="bold">N=55</content></td><td styleCode="Toprule Lrule Rrule " align="center"><content styleCode="bold">N=136</content></td></tr><tr><td styleCode="Toprule Lrule Rrule "><content styleCode="bold">Adverse Reactions</content></td><td styleCode="Toprule Lrule Rrule " align="center"><content styleCode="bold">%</content></td><td styleCode="Toprule Lrule Rrule " align="center"><content styleCode="bold">%</content></td><td styleCode="Toprule Lrule Rrule " align="center"><content styleCode="bold">%</content></td></tr><tr><td styleCode="Toprule Lrule Rrule "><content styleCode="bold">Any Adverse Reaction</content></td><td styleCode="Toprule Lrule Rrule " align="center">98</td><td styleCode="Toprule Lrule Rrule " align="center">96</td><td styleCode="Toprule Lrule Rrule " align="center">93</td></tr><tr><td styleCode="Toprule Lrule Rrule "> Hot flashes/Sweats</td><td styleCode="Toprule Lrule Rrule " align="center">98</td><td styleCode="Toprule Lrule Rrule " align="center">87</td><td styleCode="Toprule Lrule Rrule " align="center">57</td></tr><tr><td styleCode="Toprule Lrule Rrule "> Headache/Migraine</td><td styleCode="Toprule Lrule Rrule " align="center">65</td><td styleCode="Toprule Lrule Rrule " align="center">51</td><td styleCode="Toprule Lrule Rrule " align="center">46</td></tr><tr><td styleCode="Toprule Lrule Rrule "> Depression/Emotional Lability</td><td styleCode="Toprule Lrule Rrule " align="center">31</td><td styleCode="Toprule Lrule Rrule " align="center">27</td><td styleCode="Toprule Lrule Rrule " align="center">34</td></tr><tr><td styleCode="Toprule Lrule Rrule "> Insomnia/Sleep Disorder</td><td styleCode="Toprule Lrule Rrule " align="center">31</td><td styleCode="Toprule Lrule Rrule " align="center">13</td><td styleCode="Toprule Lrule Rrule " align="center">15</td></tr><tr><td styleCode="Toprule Lrule Rrule "> Nausea/Vomiting</td><td styleCode="Toprule Lrule Rrule " align="center">25</td><td styleCode="Toprule Lrule Rrule " align="center">29</td><td styleCode="Toprule Lrule Rrule " align="center">13</td></tr><tr><td styleCode="Toprule Lrule Rrule "> Pain</td><td styleCode="Toprule Lrule Rrule " align="center">24</td><td styleCode="Toprule Lrule Rrule " align="center">29</td><td styleCode="Toprule Lrule Rrule " align="center">21</td></tr><tr><td styleCode="Toprule Lrule Rrule "> Vaginitis</td><td styleCode="Toprule Lrule Rrule " align="center">20</td><td styleCode="Toprule Lrule Rrule " align="center">15</td><td styleCode="Toprule Lrule Rrule " align="center">8</td></tr><tr><td styleCode="Toprule Lrule Rrule "> Asthenia</td><td styleCode="Toprule Lrule Rrule " align="center">18</td><td styleCode="Toprule Lrule Rrule " align="center">18</td><td styleCode="Toprule Lrule Rrule " align="center">11</td></tr><tr><td styleCode="Toprule Lrule Rrule "> Dizziness/Vertigo</td><td styleCode="Toprule Lrule Rrule " align="center">16</td><td styleCode="Toprule Lrule Rrule " align="center">11</td><td styleCode="Toprule Lrule Rrule " align="center">7</td></tr><tr><td styleCode="Toprule Lrule Rrule "> Altered Bowel Function (constipation, diarrhea)</td><td styleCode="Toprule Lrule Rrule " align="center">14</td><td styleCode="Toprule Lrule Rrule " align="center">15</td><td styleCode="Toprule Lrule Rrule " align="center">10</td></tr><tr><td styleCode="Toprule Lrule Rrule "> Weight Gain</td><td styleCode="Toprule Lrule Rrule " align="center">12</td><td styleCode="Toprule Lrule Rrule " align="center">13</td><td styleCode="Toprule Lrule Rrule " align="center">4</td></tr><tr><td styleCode="Toprule Lrule Rrule "> Decreased Libido</td><td styleCode="Toprule Lrule Rrule " align="center">10</td><td styleCode="Toprule Lrule Rrule " align="center">4</td><td styleCode="Toprule Lrule Rrule " align="center">7</td></tr><tr><td styleCode="Toprule Lrule Rrule "> Nervousness/Anxiety</td><td styleCode="Toprule Lrule Rrule " align="center">8</td><td styleCode="Toprule Lrule Rrule " align="center">4</td><td styleCode="Toprule Lrule Rrule " align="center">11</td></tr><tr><td styleCode="Toprule Lrule Rrule "> Breast Changes/Pain/Tenderness</td><td styleCode="Toprule Lrule Rrule " align="center">6</td><td styleCode="Toprule Lrule Rrule " align="center">13</td><td styleCode="Toprule Lrule Rrule " align="center">8</td></tr><tr><td styleCode="Toprule Lrule Rrule "> Memory Disorder</td><td styleCode="Toprule Lrule Rrule " align="center">6</td><td styleCode="Toprule Lrule Rrule " align="center">2</td><td styleCode="Toprule Lrule Rrule " align="center">4</td></tr><tr><td styleCode="Toprule Lrule Rrule "> Skin/Mucous Membrane Reaction</td><td styleCode="Toprule Lrule Rrule " align="center">4</td><td styleCode="Toprule Lrule Rrule " align="center">9</td><td styleCode="Toprule Lrule Rrule " align="center">11</td></tr><tr><td styleCode="Toprule Lrule Rrule "> GI Disturbance (dyspepsia, flatulence)</td><td styleCode="Toprule Lrule Rrule " align="center">4</td><td styleCode="Toprule Lrule Rrule " align="center">7</td><td styleCode="Toprule Lrule Rrule " align="center">4</td></tr><tr><td styleCode="Toprule Lrule Rrule "> Androgen-Like Effects (acne, alopecia)</td><td styleCode="Toprule Lrule Rrule " align="center">4</td><td styleCode="Toprule Lrule Rrule " align="center">5</td><td styleCode="Toprule Lrule Rrule " align="center">18</td></tr><tr><td styleCode="Toprule Lrule Rrule "> Changes in Appetite</td><td styleCode="Toprule Lrule Rrule " align="center">4</td><td styleCode="Toprule Lrule Rrule " align="center">0</td><td styleCode="Toprule Lrule Rrule " align="center">6</td></tr><tr><td styleCode="Toprule Lrule Rrule "> Injection Site Reaction</td><td styleCode="Toprule Lrule Rrule " align="center">2</td><td styleCode="Toprule Lrule Rrule " align="center">9</td><td styleCode="Toprule Lrule Rrule " align="center">3</td></tr><tr><td styleCode="Toprule Lrule Rrule "> Neuromuscular Disorder (leg cramps, paresthesia)</td><td styleCode="Toprule Lrule Rrule " align="center">2</td><td styleCode="Toprule Lrule Rrule " align="center">9</td><td styleCode="Toprule Lrule Rrule " align="center">3</td></tr><tr><td styleCode="Toprule Lrule Rrule "> Menstrual Disorders</td><td styleCode="Toprule Lrule Rrule " align="center">2</td><td styleCode="Toprule Lrule Rrule " align="center">0</td><td styleCode="Toprule Lrule Rrule " align="center">5</td></tr><tr><td styleCode="Toprule Lrule Rrule "> Edema</td><td styleCode="Toprule Lrule Rrule " align="center">0</td><td styleCode="Toprule Lrule Rrule " align="center">9</td><td styleCode="Toprule Lrule Rrule " align="center">7</td></tr><tr><td styleCode="Toprule Lrule Rrule " colspan="4">* LD-Only = LUPRON DEPOT 3.75 mg &#x2020; LD/N = LUPRON DEPOT 3.75 mg plus norethindrone acetate 5 mg </td></tr></tbody></table>