Lupron Depot

1 INDICATIONS AND USAGE LUPRON DEPOT 11.25 mg is a gonadotropin-releasing hormone (GnRH) agonist indicated for: Endometriosis Management of endometriosis, including pain relief and reduction of endometriotic lesions. ( 1.1 ) In combination with a norethindrone acetate for initial management of the painful symptoms of endometriosis and for management of recurrence of symptoms. ( 1.1 ) Limitations of Use: The total duration of therapy with LUPRON DEPOT 11.25 mg plus add-back therapy should not exceed 12 months due to concerns about adverse impact on bone mineral density. ( 1.1 , 2.1 , 5.1 ) Uterine Leiomyomata (Fibroids) Concomitant use with iron therapy for preoperative hematologic improvement of women with anemia caused by fibroids for whom three months of hormonal suppression is deemed necessary. ( 1.2 ) Limitations of Use: LUPRON DEPOT 11.25 mg is not indicated for combination use with norethindrone acetate add-back therapy for the preoperative hematologic improvement of women with anemia caused by heavy menstrual bleeding due to fibroids. ( 1.2 ) 1.1 Endometriosis Monotherapy LUPRON DEPOT 11.25 mg is indicated for management of endometriosis, including pain relief and reduction of endometriotic lesions. In Combination with Norethindrone Acetate LUPRON DEPOT 11.25 mg in combination with norethindrone acetate is indicated for initial management of the painful symptoms of endometriosis and for management of recurrence of symptoms. Use of norethindrone acetate in combination with LUPRON DEPOT 11.25 mg is referred to as add-back therapy, and is intended to reduce the loss of bone mineral density (BMD) and reduce vasomotor symptoms associated with use of LUPRON DEPOT 11.25 mg. Limitations of Use : The total duration of therapy with LUPRON DEPOT 11.25 mg plus add-back therapy should not exceed 12 months due to concerns about adverse impact on bone mineral density [see Dosage and Administration ( 2.1 ) and Warnings and Precautions ( 5.1 ) ] . 1.2 Uterine Leiomyomata (Fibroids) LUPRON DEPOT 11.25 mg, used concomitantly with iron therapy, is indicated for the preoperative hematologic improvement of women with anemia caused by fibroids for whom three months of hormonal suppression is deemed necessary. Consider a one-month trial period on iron alone, as some women will respond to iron alone [see Clinical Studies ( 14.2 )]. LUPRON DEPOT 11.25 mg may be added if the response to iron alone is considered inadequate. Limitations of Use : LUPRON DEPOT 11.25 mg is not indicated for combination use with norethindrone acetate add-back therapy for the preoperative hematologic improvement of women with anemia caused by heavy menstrual bleeding due to fibroids [see Dosage and Administration ( 2.1 )].

2 DOSAGE AND ADMINISTRATION LUPRON DEPOT 11.25mg for 3-month administration, given by a healthcare provider as a single intramuscular injection. LUPRON DEPOT 11.25 mg has different release characteristics than LUPRON 3.75 mg and is dosed differently. ( 2.1 ) Do not substitute LUPRON DEPOT 11.25 mg for LUPRON DEPOT 3.75 mg. Do not administer LUPRON DEPOT 11.25 mg more frequently than every 3 months. Do not give a fractional dose of the LUPRON DEPOT 11.25 mg, as it is not equivalent to the same dose of the LUPRON DEPOT 3.75 mg monthly formulation. Reconstitute LUPRON DEPOT 11.25 mg prior to use. ( 2.2 ) Endometriosis: LUPRON DEPOT 11.25 mg administered as a single intramuscular (IM) injection once every three months for up to two injections (6 months of therapy). LUPRON DEPOT may be administered alone or in combination with daily 5 mg tablet of norethindrone acetate (add-back). ( 2.1 ) If endometriosis symptoms recur after initial course of therapy, retreatment for no more than six months may be considered but only with the addition of norethindrone acetate add-back therapy. Do not re-treat with LUPRON DEPOT 11.25 mg alone. ( 2.1 ) Fibroids: Recommended dose of LUPRON DEPOT 11.25 mg is one IM injection. ( 2.1 ) Figure A img-128 plunger img-129 blue line img-0184 shake Injection site Figure F Figure G 2.1 Important Use Information LUPRON DEPOT 11.25 mg must be administered by a healthcare professional. LUPRON DEPOT 11.25 mg for 3-month administration has different release characteristics than LUPRON 3.75 mg for 1-month administration and is dosed differently. Do not substitute LUPRON DEPOT 11.25 mg for LUPRON DEPOT 3.75 mg. Do not administer LUPRON DEPOT 11.25 mg more frequently than every 3 months. Do not give a fractional dose of the LUPRON DEPOT 11.25 mg, as it is not equivalent to the same dose of the LUPRON DEPOT 3.75 mg monthly formulation. Endometriosis The initial and retreatment dosage regimens for LUPRON DEPOT 11.25 mg for the management of women with endometriosis are outlined in Table 1 . Table 1. LUPRON DEPOT 11.25 mg, Management of Endometriosis Treatment Phase LUPRON DEPOT 11.25 mg Dosing Maximum Treatment Duration Initial Treatment 1 11.25 mg IM every 3 months for 1 to 2 doses 6 months Retreatment 2 11.25 mg IM every 3 months for 1 to 2 doses 6 months 12 MONTHS 3 TOTAL TREATMENT DURATION 1 May use LUPRON DEPOT 11.25 mg with or without norethindrone acetate 5 mg tablet taken daily. 2 Use LUPRON DEPOT 11.25 mg with norethindrone acetate for retreatment 5 mg tablet taken daily [see Warnings and Precautions ( 5.1 ) ] and assess bone mineral density (BMD) prior to retreatment. 3 Treatment should not exceed 12 months due to concerns about adverse impact on bone mineral density. Fibroids The recommended dosage of LUPRON DEPOT 11.25 mg is one IM injection of 11.25 mg which provides a three-month treatment course. 2.2 Reconstitution and Administration for Injection of LUPRON DEPOT Reconstitute and administer the lyophilized microsphere as a single IM injection as directed below. Visually inspect the drug product for particulate matter and discoloration prior to administration, whenever solution and container permit. Inject the LUPRON DEPOT 11.25 mg suspension immediately or discard if not used within two hours as the suspension does not contain a preservative. 1. Visually inspect the LUPRON DEPOT 11.25 mg powder. Do not use the syringe if clumping or caking is evident. A thin layer of powder on the wall of the syringe is considered normal prior to mixing with the diluent. The diluent should appear clear. 2. To prepare for injection, screw the white plunger into the end stopper until the stopper begins to turn (see Figure A and Figure B ). Figure A: Figure B: 3. Hold the syringe UPRIGHT. Release the diluent by SLOWLY PUSHING the plunger for 6 to 8 seconds until the first middle stopper is at the blue line in the middle of the barrel (see Figure C ). Figure C: 4. Keep the syringe upright . Mix the microsphere powder thorough…

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 diagnos…

4 CONTRAINDICATIONS LUPRON DEPOT 11.25 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 11.25 mg [see Warnings and Precautions ( 5.4 ) and Adverse Reactions ( 6.2 ) ] Undiagnosed abnormal uterine bleeding Pregnancy [see Warnings and Precautions ( 5.2 ) and Use in Specific Populations ( 8.1 ) ] When norethindrone acetate is administered with LUPRON DEPOT 11.25 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 11.25 mg. ( 4 , 5.4 ) Undiagnosed abnormal uterine bleeding. ( 4 ) Pregnancy. ( 4 , 8.1 ) If LUPRON DEPOT 11.25 mg is administered with norethindrone acetate, the contraindications for norethindrone acetate also apply. ( 4 )

7 DRUG INTERACTIONS No drug-drug interaction studies have been conducted with LUPRON DEPOT 11.25 mg.

8.1 Pregnancy Risk Summary LUPRON DEPOT 11.25 mg is contraindicated in pregnancy [see Contraindications ( 4 ) ] . LUPRON DEPOT 11.25 mg may cause fetal harm based on findings from animal studies and the drug’s mechanism of action [see Clinical Pharmacology ( 12.1 ) ] . There are limited human data on the use of LUPRON DEPOT in pregnant women. Based on animal reproduction studies, LUPRON DEPOT 11.25 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 [see Data ] . 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.

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, …