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 with Management of Endometriosis [see Warnings and Precautions (5.4)]
Convulsions [see Warnings and Precautions (5.5)]
Clinical Depression [see Warnings and Precautions (5.6)]

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	(%)	N2	Mean	N2	Mean
Week 24	LD-Only*	32/37	86	37	19	36	5.8
	LD/N†	22/38	581	38	71	38	1.91
* LD-Only = LUPRON DEPOT 3.75 mg. † LD/N = LUPRON DEPOT 3.75 mg plus norethindrone acetate 5 mg. 1Statistically significantly less than the LD-Only group (p<0.01). 2Number 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 reactions: Erythema multiforme, dermatitis bullous, dermatitis exfoliative, and severe cutaneous adverse reactions (SCAR) including Stevens-Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN).
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
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.