FDA label 7f949be4-97ca-4a25-9350-dd7cb4693f2f

5 WARNINGS AND PRECAUTIONS Loss of bone mineral density (BMD): Duration of treatment is limited by risk of bone mineral density loss. When using LUPANETA PACK for the management of endometriosis, the norethindrone acetate component of the LUPANETA PACK reduces the BMD loss. Do not retreat with leuprolide acetate for depot suspension alone. Assess BMD after 6 months of treatment before retreatment. Do not use for more than 12 months due to concerns about adverse impact on BMD. ( 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 ) Hypersensitivity Reactions: Acute hypersensitivity, including anaphylaxis, have been reported. Delayed hypersensitivity has been very rarely reported in association with leuprolide-containing therapy. Discontinue future leuprolide therapy at first signs or symptoms of a delayed hypersensitivity reaction, and treat patients according to current treatment guidelines. ( 5.3 ) Cardiovascular and Metabolic Disorders: Assess and manage risk factors before starting LUPANETA PACK. ( 5.4 ) Clinical Depression: Carefully observe women for depression and refer to a mental health professional, as appropriate. ( 5.7 ) Visual Abnormalities: Discontinue norethindrone acetate in case of sudden loss of vision or onset of proptosis, diplopia, or migraine pending visual examination. Discontinue LUPANETA PACK if examination reveals papilledema or retinal vascular lesions. ( 5.8 ) 5.1 Loss of Bone Mineral Density Leuprolide acetate for depot suspension 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 LUPANETA PACK may pose an additional risk. Carefully weigh the risks and benefits of LUPANETA PACK use in these populations. Total treatment duration with LUPANETA PACK should not exceed 12 months. The duration of LUPANETA PACK treatment is limited by the risk of loss of bone mineral density [see Dosage and Administration ( 2.1 )] . When using LUPANETA PACK for the management of endometriosis, the norethindrone acetate component of the LUPANETA PACK reduces the BMD loss that occurs with leuprolide acetate use alone [see Clinical Studies ( 14 )]. Do not retreat with leuprolide acetate for depot suspension alone. Assess BMD after 6 months of treatment before retreatment. 5.2 Embryo-Fetal Toxicity Based on animal reproduction studies and the drug’s mechanism of action, leuprolide acetate for depot suspension may cause fetal harm if administered to a pregnant woman and is contraindicated in pregnant women. Exclude pregnancy prior to initiating treatment with LUPANETA PACK if clinically indicated. Discontinue LUPANETA PACK 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, leuprolide acetate for depot suspension usually inhibits ovulation and stops menstruation. Contraception, however, is not ensured by taking leuprolide acetate for depot suspension. If contraception is indicated, advise women to use nonhormonal methods of contraception while on treatment with LUPANETA PACK. 5.3 Hypersensitivity Reactions Acute Hypersensivity Acute hypersensitivity reactions, including anaphylaxis, have been reported with LUPANETA PACK use. LUPANETA PACK is contraindicated in women with a history of hypersensitivity to gonadotropin-releasing hormone (GnRH), GnRH agonist analogs, or norethindrone acetate [see Adverse Reactions ( 6.2 )] . In clinical trials for LUPANETA PACK, 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. Delayed Hypersensitivity Delayed hypersensitivity reactions including the severe cutaneous adverse reactions (SCAR) of Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) have been very rarely reported post-marketing in association with leuprolide-containing therapy [see Adverse Reactions ( 6.2 )]. Discontinue future leuprolide therapy at first signs or symptoms of a delayed hypersensitivity reaction, and treat patients according to current treatment guidelines. 5. 4 Cardiovascular and Metabolic Disorders Assess and manage risk factors for cardiovascular disease before starting LUPANETA PACK. Closely monitor women on norethindrone acetate who have risk factors for arterial vascular disease (e.g., hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or venous thromboembolism (e.g., family history of VTE, obesity, and smoking) when using LUPANETA PACK [see Contraindications ( 4 ) ] . 5. 5 Initial Flare of Symptoms Following the first dose of leuprolide acetate component of LUPANETA PACK, 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 taking GnRH agonists such as the leuprolide acetate component of LUPANETA PACK. 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 LUPANETA PACK [see Adverse Reactions ( 6.1 )] . Carefully observe women for depression, especially those with a history of depression and consider whether the risks of continuing LUPANETA PACK outweigh the benefits. Women with new or worsening depression should be referred to a mental health professional, as appropriate. 5.8 Visual Abnormalities Discontinue norethindrone acetate tablets in the LUPANETA PACK pending examination if there is a sudden partial or complete loss of vision or if there is sudden onset of proptosis, diplopia, or migraine. Discontinue LUPANETA PACK if examination reveals papilledema or retinal vascular lesions. 5. 9 Fluid Retention Because norethindrone acetate, a component of LUPANETA PACK, may cause some degree of fluid retention, carefully observe women with conditions that might be influenced by this effect, such as epilepsy, migraine, cardiac or renal dysfunctions.

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 )] Hypersensitivity Reactions [see Warnings and Precautions ( 5.3 ) ] Initial Flare of Symptoms [see Warnings and Precautions ( 5.5 )] Convulsions [see Warnings and Precautions ( 5.6 ) ] Clinical Depression [see Warnings and Precautions ( 5.7 ) ] Leuprolide acetate for depot suspension co-administered with norethindrone acetate : Most common related adverse reactions (>10%) were hot flashes/sweats, headache/migraine, nausea/vomiting, pain, depression/emotional lability, asthenia, constipation/diarrhea, vaginitis, insomnia/sleep disorder, breast changes/pain/tenderness, weight gain, dizziness/vertigo. ( 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. The safety of co-administering leuprolide acetate for depot suspension and norethindrone acetate was evaluated in two clinical studies in which a total of 242 women were treated for up to one year. Women were treated with monthly IM injections of leuprolide acetate 3.75 mg (13 injections) alone or monthly IM injections of leuprolide acetate 3.75 mg (13 injections) and norethindrone acetate 5 mg orally once daily. The population age range was 17-43 years old. The majority of women were Caucasian (87%). In the first study, 106 women were randomized to one year of treatment with leuprolide acetate for depot suspension alone or with leuprolide acetate for depot suspension and norethindrone acetate. The second study was an open-label, single arm clinical study in 136 women who received one year of leuprolide acetate for depot suspension and norethindrone acetate; these women were followed 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 leuprolide acetate for depot suspension 3.75 mg alone and 18% of women treated concomitantly monthly with leuprolide acetate for depot suspension 3.75 mg and norethindrone acetate 5 mg discontinued therapy due to adverse reactions. The most common adverse reactions leading to discontinuation were hot flashes (6%) and insomnia (4%) in the leuprolide acetate for depot suspension 3.75 mg alone group and hot flashes and emotional lability (4% each) in the leuprolide acetate for depot suspension 3.75 mg and norethindrone acetate 5 mg group. In the open-label study, 13% of women treated monthly with leuprolide acetate for depot suspension 3.75 mg plus norethindrone acetate 5 mg discontinued therapy due to adverse reactions, most commonly depression (4%) and acne (2%). Common Adverse Reactions: Table 2 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 clinical studies. The most common adverse reactions observed in these studies were hot flashes and headaches. Table 2. Adverse Reactions Occurring in the First Six Months of Treatment in ≥ 5% of Women with Endometriosis Controlled Study Open Label Study LA-Only* LA/N† LA/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 * LA-Only = leuprolide acetate for depot suspension 3.75 mg † LA/N = leuprolide acetate for depot suspension 3.75 mg and norethindrone acetate 5 mg In the controlled clinical trial, 50 of 51 (98%) women in the leuprolide acetate for depot suspension and 48 of 55 (87%) women in the leuprolide acetate for depot suspension and norethindrone acetate arm reported experiencing hot flashes on one or more occasions during treatment. Table 3 presents hot flash data in the sixth month of treatment. Table 3. 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 of Hot Flashes in 24 Hours N (%) N 2 Mean N 2 Mean Week 24 LA-Only* 32/37 86 37 19 36 5.8 LA/N† 22/38 58 1 38 7 1 38 1.9 1 * LA-Only = leuprolide acetate for depot suspension 3.75 mg † LA/N = leuprolide acetate for depot suspension 3.75 mg plus norethindrone acetate 5 mg 1 Statistically significantly less than the LA-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 In the two clinical trials of women with endometriosis, 2% (4 of 191) women receiving leuprolide acetate for depot suspension and norethindrone acetate for up to 12 months developed an elevated (at least twice the upper limit of normal) serum glutamic pyruvic transaminase (SGPT) and 1% (2 of 136) developed an elevated gamma glutamyl transferase (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 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 leuprolide acetate for depot suspension 3.75 mg and norethindrone acetate 5 mg daily are summarized in Tables 4 and 5 below. The major impact of adding norethindrone acetate to treatment with leuprolide acetate for depot suspension was a decrease in serum HDL cholesterol and an increase in the LDL/HDL ratio. Table 4. Serum Lipids: Mean Percent Changes from Baseline Values at Treatment Week 24 leuprolide acetate for depot suspension 3.75 mg leuprolide acetate for depot suspension 3.75 mg and 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 (105 of 158 women) returned to pretreatment values. Table 5. Percent of Women with Serum Lipid Values Outside of the Normal Range leuprolide acetate for depot suspension 3.75 mg plus norethindrone acetate 5 mg daily Controlled Study (n=41) Open Label Study (n=117) Week 0 Week 24* Week 0 Week 24* Total Cholesterol (>240 mg/dL) 15% 20% 6% 7% HDL Cholesterol (<40 mg/dL) 15% 44% 15% 41% LDL Cholesterol (>160 mg/dL) 5% 7% 9% 11% LDL/HDL Ratio (>4.0) 2% 15% 7% 21% Triglycerides (>200 mg/dL) 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 leuprolide acetate for depot suspension or norethindrone acetate. 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: Body as a whole: Hypersensitivity reactions including anaphylaxis, localized reactions including induration and abscess at the site of injection Nervous/Psychiatric System: Mood swings, including depression; suicidal ideation and attempt; convulsion, peripheral neuropathy, paralysis Hepato-biliary system: Serious liver injury Skin reactions: erythema multiforme, dermatitis bullous, dermatitis exfoliative, Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) 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 post-marketing 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><col width="445"/><col width="97"/><col width="68"/><col width="112"/><tbody><tr><td styleCode="Toprule Lrule Rrule " colspan="4" align="center"><content styleCode="bold">Table 2. Adverse Reactions Occurring in the First Six Months of Treatment in &#x2265; 5% of Women with Endometriosis</content></td></tr><tr><td styleCode="Toprule Lrule Rrule "/><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">LA-Only*</content></td><td styleCode="Toprule Lrule Rrule " align="center"><content styleCode="bold">LA/N&#x2020;</content></td><td styleCode="Toprule Lrule Rrule " align="center"><content styleCode="bold">LA/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">* LA-Only = leuprolide acetate for depot suspension 3.75 mg &#x2020; LA/N = leuprolide acetate for depot suspension 3.75 mg and norethindrone acetate 5 mg </td></tr></tbody></table>

<table><col width="106"/><col width="125"/><col width="102"/><col width="68"/><col width="45"/><col width="92"/><col width="61"/><col width="123"/><tbody><tr><td styleCode="Toprule Lrule Rrule " colspan="8" align="center"><content styleCode="bold">Table 3. Hot Flashes in the Month Prior to the Assessment Visit (Controlled Study)</content></td></tr><tr><td styleCode="Toprule Lrule Rrule " align="center"><content styleCode="bold">Assessment Visit</content></td><td styleCode="Toprule Lrule Rrule " align="center"><content styleCode="bold">Treatment Group</content></td><td styleCode="Toprule Lrule Rrule " colspan="2" align="center"><content styleCode="bold">Number of </content><content styleCode="bold">Women</content><content styleCode="bold"> Reporting Hot Flashes</content></td><td styleCode="Toprule Lrule Rrule " colspan="2" align="center"><content styleCode="bold">Number of Days with Hot Flashes</content></td><td styleCode="Toprule Lrule Rrule " colspan="2" align="center"><content styleCode="bold">Maximum Number of Hot Flashes in 24 Hours</content></td></tr><tr><td styleCode="Toprule Lrule Rrule " colspan="2"> </td><td styleCode="Toprule Lrule Rrule " align="center">N</td><td styleCode="Toprule Lrule Rrule " align="center">(%)</td><td styleCode="Toprule Lrule Rrule " align="center">N²</td><td styleCode="Toprule Lrule Rrule " align="center">Mean</td><td styleCode="Toprule Lrule Rrule " align="center">N²</td><td styleCode="Toprule Lrule Rrule " align="center">Mean</td></tr><tr><td styleCode="Toprule Lrule Rrule " align="center">Week 24</td><td styleCode="Toprule Lrule Rrule " align="center">LA-Only*</td><td styleCode="Toprule Lrule Rrule " align="center">32/37</td><td styleCode="Toprule Lrule Rrule " align="center">86</td><td styleCode="Toprule Lrule Rrule " align="center">37</td><td styleCode="Toprule Lrule Rrule " align="center">19</td><td styleCode="Toprule Lrule Rrule " align="center">36</td><td styleCode="Toprule Lrule Rrule " align="center">5.8</td></tr><tr><td styleCode="Toprule Lrule Rrule "> </td><td styleCode="Toprule Lrule Rrule " align="center">LA/N&#x2020;</td><td styleCode="Toprule Lrule Rrule " align="center">22/38</td><td styleCode="Toprule Lrule Rrule " align="center">58¹</td><td styleCode="Toprule Lrule Rrule " align="center">38</td><td styleCode="Toprule Lrule Rrule " align="center">7¹</td><td styleCode="Toprule Lrule Rrule " align="center">38</td><td styleCode="Toprule Lrule Rrule " align="center">1.9¹</td></tr><tr><td styleCode="Toprule Lrule Rrule " colspan="8">* LA-Only = leuprolide acetate for depot suspension 3.75 mg &#x2020; LA/N = leuprolide acetate for depot suspension 3.75 mg plus norethindrone acetate 5 mg ¹Statistically significantly less than the LA-Only group (p&lt;0.01) ²Number of women assessed. </td></tr></tbody></table>

<table><col width="133"/><col width="116"/><col width="107"/><col width="85"/><col width="107"/><col width="85"/><col width="123"/><tbody><tr><td styleCode="Toprule Lrule Rrule " colspan="7" align="center"><content styleCode="bold">Table 4. Serum Lipids: Mean Percent Changes from Baseline Values at Treatment Week 24</content></td></tr><tr><td styleCode="Toprule Lrule Rrule "> </td><td styleCode="Toprule Lrule Rrule " colspan="2" align="center"><content styleCode="bold">leuprolide acetate for depot suspension 3.75 mg</content></td><td styleCode="Toprule Lrule Rrule " colspan="4" align="center"><content styleCode="bold">leuprolide acetate for depot suspension 3.75 mg and</content><content styleCode="bold"> norethindrone acetate 5 mg daily</content></td></tr><tr><td styleCode="Lrule Rrule "/><td styleCode="Toprule Lrule Rrule " colspan="2" align="center"><content styleCode="bold">Controlled Study</content><content styleCode="bold"> (n=39)</content></td><td styleCode="Toprule Lrule Rrule " colspan="2" align="center"><content styleCode="bold">Controlled Study</content><content styleCode="bold"> (n=41)</content></td><td styleCode="Toprule Lrule Rrule " colspan="2" align="center"><content styleCode="bold">Open Label Study</content><content styleCode="bold"> (n=117)</content></td></tr><tr><td styleCode="Lrule Rrule "/><td styleCode="Toprule Lrule Rrule " align="center"><content styleCode="bold">Baseline</content><content styleCode="bold"> Value*</content></td><td styleCode="Toprule Lrule Rrule " align="center"><content styleCode="bold">Week 24</content><content styleCode="bold"> % Change</content></td><td styleCode="Toprule Lrule Rrule " align="center"><content styleCode="bold">Baseline</content><content styleCode="bold"> Value*</content></td><td styleCode="Toprule Lrule Rrule " align="center"><content styleCode="bold">Week 24</content><content styleCode="bold"> % Change</content></td><td styleCode="Toprule Lrule Rrule " align="center"><content styleCode="bold">Baseline</content><content styleCode="bold"> Value*</content></td><td styleCode="Toprule Lrule Rrule " align="center"><content styleCode="bold">Week 24</content><content styleCode="bold"> % Change</content></td></tr><tr><td styleCode="Toprule Lrule Rrule ">Total Cholesterol</td><td styleCode="Toprule Lrule Rrule " align="center">170.5</td><td styleCode="Toprule Lrule Rrule " align="center">9.2%</td><td styleCode="Toprule Lrule Rrule " align="center">179.3</td><td styleCode="Toprule Lrule Rrule " align="center">0.2%</td><td styleCode="Toprule Lrule Rrule " align="center">181.2</td><td styleCode="Toprule Lrule Rrule " align="center">2.8%</td></tr><tr><td styleCode="Toprule Lrule Rrule ">HDL Cholesterol</td><td styleCode="Toprule Lrule Rrule " align="center">52.4</td><td styleCode="Toprule Lrule Rrule " align="center">7.4%</td><td styleCode="Toprule Lrule Rrule " align="center">51.8</td><td styleCode="Toprule Lrule Rrule " align="center">-18.8%</td><td styleCode="Toprule Lrule Rrule " align="center">51.0</td><td styleCode="Toprule Lrule Rrule " align="center">-14.6%</td></tr><tr><td styleCode="Toprule Lrule Rrule ">LDL Cholesterol</td><td styleCode="Toprule Lrule Rrule " align="center">96.6</td><td styleCode="Toprule Lrule Rrule " align="center">10.9%</td><td styleCode="Toprule Lrule Rrule " align="center">101.5</td><td styleCode="Toprule Lrule Rrule " align="center">14.1%</td><td styleCode="Toprule Lrule Rrule " align="center">109.1</td><td styleCode="Toprule Lrule Rrule " align="center">13.1%</td></tr><tr><td styleCode="Toprule Lrule Rrule ">LDL/HDL Ratio</td><td styleCode="Toprule Lrule Rrule " align="center">2.0&#x2020;</td><td styleCode="Toprule Lrule Rrule " align="center">5.0%</td><td styleCode="Toprule Lrule Rrule " align="center">2.1&#x2020;</td><td styleCode="Toprule Lrule Rrule " align="center">43.4%</td><td styleCode="Toprule Lrule Rrule " align="center">2.3&#x2020;</td><td styleCode="Toprule Lrule Rrule " align="center">39.4%</td></tr><tr><td styleCode="Toprule Lrule Rrule ">Triglycerides</td><td styleCode="Toprule Lrule Rrule " align="center">107.8</td><td styleCode="Toprule Lrule Rrule " align="center">17.5%</td><td styleCode="Toprule Lrule Rrule " align="center">130.2</td><td styleCode="Toprule Lrule Rrule " align="center">9.5%</td><td styleCode="Toprule Lrule Rrule " align="center">105.4</td><td styleCode="Toprule Lrule Rrule " align="center">13.8%</td></tr><tr><td styleCode="Toprule Lrule Rrule " colspan="7">* mg/dL &#x2020; ratio </td></tr></tbody></table>