Lupron Depot Drug Information

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 < 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. 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 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

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, 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. Of those women with 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.

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.

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

Pregnancy Risk Summary LUPRON DEPOT 3.75 mg is contraindicated in pregnancy . LUPRON DEPOT 3.75 mg may cause fetal harm based on findings from animal studies and the drug’s mechanism of action . There are limited human data on the use of LUPRON DEPOT in pregnant women. Based on animal reproduction studies, LUPRON DEPOT 3.75 mg may be associated with an increased risk of pregnancy complications, including early pregnancy loss and fetal harm. In animal reproduction studies, subcutaneous administration of leuprolide acetate to rabbits during the period of organogenesis caused embryo-fetal toxicity, decreased fetal weights and a dose-dependent increase in major fetal abnormalities in animals at doses less than the recommended human dose based on body surface area using an estimated daily dose.

A similar rat study also showed increased fetal mortality and decreased fetal weights but no major fetal abnormalities at doses less than the recommended human dose based on body surface area using an estimated daily dose . Data Animal Data When administered on day 6 of pregnancy at test dosages of 0.00024 mg/kg, 0.0024 mg/kg, and 0.024 mg/kg (1/300 to 1/3 of the human dose) to rabbits, leuprolide acetate produced a dose-related increase in major fetal abnormalities. Similar studies in rats failed to demonstrate an increase in fetal malformations. There was increased fetal mortality and decreased fetal weights with the two higher doses of LUPRON DEPOT in rabbits and with the highest dose (0.024 mg/kg) in rats.

Pediatric Use Safety and effectiveness of LUPRON DEPOT 3.75 mg for management of endometriosis and the preoperative hematologic improvement of women with anemia caused by fibroids have been established in females of reproductive age. Efficacy is expected to be the same for postpubertal adolescents under the age of 18 as for users 18 years and older. The safety and effectiveness of LUPRON DEPOT 3.75 mg for these indications have not been established in premenarcheal pediatric patients.

3.75 mg is contraindicated in women with the following: Hypersensitivity to gonadotropin-releasing hormone (GnRH), GnRH agonist analogs, including leuprolide acetate, or any of the excipients in LUPRON DEPOT 3.75 mg Undiagnosed abnormal uterine bleeding Pregnancy When norethindrone acetate is administered with LUPRON DEPOT 3.75 mg, the contraindications to the use of norethindrone acetate also apply to this combination regimen. Refer to the norethindrone acetate prescribing information for a list of contraindications for norethindrone acetate. Hypersensitivity to GnRH, GnRH agonist analogs, including leuprolide acetate, or any of the excipients in LUPRON DEPOT 3.75 mg.

Undiagnosed abnormal uterine bleeding. Pregnancy. If LUPRON DEPOT 3.75 mg is administered with norethindrone acetate, the contraindications for norethindrone acetate also apply.