Lupron Depot

Dosage and Administration ( 2 ) 8/2025 Dosage Forms and Strengths ( 3 ) 8/2025

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 must be administered by a healthcare provider. In patients treated with GnRH analogues for prostate cancer, treatment is usually continued upon development of non-metastatic and metastatic castration-resistant prostate cancer. Table 1. LUPRON DEPOT Recommended Dosing Dosage 7.5 mg for 1-Month Administration 22.5 mg for 3-Month Administration 30 mg for 4-Month Administration 45 mg for 6-Month Administration Recommended dose 1 injection every 4 weeks 1 injection every 12 weeks 1 injection every 16 weeks 1 injection every 24 weeks LUPRON DEPOT must be administered under the supervision of a physician. Due to different release characteristics, the dosage strengths are not additive and must be selected based upon the desired dosing schedule. ( 2 ) LUPRON DEPOT 7.5 mg for 1-month administration, given as a single intramuscular injection every 4 weeks. ( 2.1 ) LUPRON DEPOT 22.5 mg for 3-month administration, given as a single intramuscular injection every 12 weeks. ( 2.2 ) LUPRON DEPOT 30 mg for 4-month administration, given as a single intramuscular injection every 16 weeks. ( 2.3 ) LUPRON DEPOT 45 mg for 6-month administration, given as a single intramuscular injection every 24 weeks. ( 2.4 ) Figure 1 Figure 2 Figure 3 figure 4 figure 5 Figure 6 Figure 7 2.1 LUPRON DEPOT 7.5 mg for 1-Month Administration The recommended dose of LUPRON DEPOT 7.5 mg for 1-month administration is one injection every 4 weeks. Do not use concurrently a fractional dose, or a combination of doses of this or any depot formulation due to different release characteristics. Incorporated in a depot formulation, the lyophilized microspheres must be reconstituted and should be administered every 4 weeks as a single intramuscular injection. For optimal performance of the prefilled dual chamber syringe (PDS), read and follow the instructions in Section 2.5 . 2.2 LUPRON DEPOT 22.5 mg for 3-Month Administration The recommended dose of LUPRON DEPOT 22.5 mg for 3-month administration is one injection every 12 weeks. Do not use concurrently a fractional dose, or a combination of doses of this or any depot formulation due to different release characteristics. Incorporated in a depot formulation, the lyophilized microspheres must be reconstituted and should be administered every 12 weeks as a single intramuscular injection. For optimal performance of the prefilled dual chamber syringe (PDS), read and follow the instructions in Section 2.5 . 2.3 LUPRON DEPOT 30 mg for 4-Month Administration The recommended dose of LUPRON DEPOT 30 mg for 4-month administration is one injection every 16 weeks. Do not use concurrently a fractional dose, or a combination of doses of this or any depot formulation due to different release characteristics. Incorporated in a depot formulation, the lyophilized microspheres must be reconstituted and should be administered every 16 weeks as a single intramuscular injection. For optimal performance of the prefilled dual chamber syringe (PDS), read and follow the instructions in Section 2.5 . 2.4 LUPRON DEPOT 45 mg for 6-Month Administration The recommended dose of LUPRON DEPOT 45 mg for 6-month administration is one injection every 24 weeks. Do not use concurrently a fractional dose, or a combination of doses of this or any depot formulation due to different release characteristics. Incorporated in a depot formulation, the lyophilized microspheres must be reconstituted and should be administered every 24 weeks as a single intramuscular injection. For optimal performance of the prefilled dual chamber syringe (PDS), read and follow the instructions in Section 2.5 . 2.5 Reconstitution and Administration for Injection of LUPRON DEPOT Reconstitute and administer the lyophilized microspheres as a single intramuscular injection. Inject the suspension immediately or discard if not used within two hours, because LUPRON DEPOT does not contain a preservative. 1. Visually inspect the LUPRON DEPOT powder. DO NOT USE the sy …

3 DOSAGE FORMS AND STRENGTHS LUPRON DEPOT 7.5 mg for 1-month administration, 22.5 mg for 3-month administration, 30 mg for 4-month administration, and 45 mg for 6-month administration are each supplied as a kit with a prefilled single-dose dual chamber syringe containing white lyophilized microsphere powder in one chamber and a clear, colorless diluent for reconstitution in the other chamber. 7.5 mg, 22.5 mg, 30 mg, and 45 mg injections in a kit with prefilled dual chamber syringe. ( 3 )

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 )

6 ADVERSE REACTIONS The following is discussed in more detail in other sections of the labeling: Tumor Flare [see Warnings and Precautions ( 5.1 )] Metabolic Syndrome [see Warnings and Precautions ( 5.2 )] Cardiovascular Disease [see Warnings and Precautions ( 5.3 )] Effect on QT/QTc Interval [see Warnings and Precautions ( 5.4 )] Convulsions [see Warnings and Precautions ( 5.5 )] Severe Cutaneous Adverse Reactions [see Warnings and Precautions ( 5.6 )] 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 practice. LUPRON DEPOT 7.5 mg for 1-month administration: The most common adverse reactions (>10%) were general pain, hot flashes/sweats, GI disorders, edema, respiratory disorder, urinary disorder. ( 6.1 ) LUPRON DEPOT 22.5 mg for 3-month administration: The most common adverse reactions (>10%) were general pain, injection site reaction, hot flashes/sweats, GI disorders, joint disorders, testicular atrophy, urinary disorders. ( 6.2 ) LUPRON DEPOT 30 mg for 4-month administration: The most common adverse reactions (>10%) were asthenia, flu syndrome, general pain, headache, injection site reaction, hot flashes/sweats, GI disorders, edema, skin reaction, urinary disorders. ( 6.3 ) LUPRON DEPOT 45 mg for 6-month administration: The most common adverse reactions (>10%) were hot flush, injection site pain, upper respiratory infection, and fatigue. ( 6.4 ) In postmarketing experience, mood swings, depression, rare reports of suicidal ideation and attempt, rare reports of pituitary apoplexy, and rare reports of serious drug-induced liver injury have been reported. ( 6.5 ) 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 LUPRON DEPOT 7.5 mg for 1-Month Administration In the majority of patients testosterone levels increased above baseline during the first week, declining thereafter to baseline levels or below by the end of the second week of treatment. Potential exacerbations of signs and symptoms during the first few weeks of treatment is a concern in patients with vertebral metastases and/or urinary obstruction or hematuria which, if aggravated, may lead to neurological problems such as temporary weakness and/or paresthesia of the lower limbs or worsening of urinary symptoms [see Warnings and Precautions ( 5.1 )] . In a clinical trial of LUPRON DEPOT 7.5 mg for 1-month administration, the following adverse reactions were reported in 5% or more of the patients during the initial 24-week treatment period. Table 2. Adverse Reactions Reported in ≥ 5% of Patients LUPRON DEPOT 7.5 mg for 1-Month Administration (N=56) N (%) Body As A Whole General pain 13 (23.2) Infection 3 (5.4) Cardiovascular System Hot flashes/sweats* 32 (57.1) Digestive System GI disorders 8 (14.3) Metabolic and Nutritional Disorders Edema 8 (14.3) Nervous System Libido decreased* 3 (5.4) Respiratory System Respiratory disorder 6 (10.7) Urogenital System Urinary disorder 7 (12.5) Impotence* 3 (5.4) Testicular atrophy* 3 (5.4) * Due to the expected physiologic effect of decreased testosterone levels. In this same study, the following adverse reactions were reported in less than 5% of the patients on LUPRON DEPOT 7.5 mg for 1-month administration. Body As A Whole - asthenia, cellulitis, fever, headache, injection site reaction, neoplasm Cardiovascular System - angina, congestive heart failure Digestive System - anorexia, dysphagia, eructation, peptic ulcer Blood and Lymphatic System - ecchymosis Musculoskeletal System - myalgia Nervous System - agitation, insomnia/sleep disorders, neuromuscular disorders Respiratory System - emphysema, hemoptysis, lung edema, sputum increased Skin and Appendages - hair disorder, skin reaction Urogenital System - balanitis, breast enlargement, urinary tract infe …

7 DRUG INTERACTIONS 7.1 Drug/Laboratory Test Interactions Administration of LUPRON DEPOT in therapeutic doses results in suppression of the pituitary-gonadal system. Normal function is usually restored within three months after treatment is discontinued. Due to the suppression of the pituitary-gonadal system by LUPRON DEPOT, diagnostic tests of pituitary gonadotropic and gonadal functions conducted during treatment and up to three months after discontinuation of LUPRON DEPOT may be affected.

8 USE IN SPECIFIC POPULATIONS 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. 8.2 Lactation Risk Summary There are no data on the presence of leuprolide acetate in either animal or human milk, the effects on the breastfed infants, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for LUPRON DEPOT 11.25 mg and any potential adverse effects on the breastfed infant from LUPRON DEPOT 11.25 mg or from the underlying maternal condition. 8.3 Females and Males of Reproductive Potential Pregnancy Testing Exclude pregnancy in women of reproductive potential prior to initiating LUPRON DEPOT 11.25 mg if clinically indicated [see Warnings and Precautions ( 5.2 ) ] . Contraception Females LUPRON DEPOT 11.25 mg may cause embryo-fetal harm when administered during pregnancy. LUPRON DEPOT 11.25 mg is not a contraceptive. If contraception is indicated, advise females of reproductive potential to use a non-hormonal method of contraception during treatment with LUPRON DEPOT 11.25 mg [see Warnings and Precautions ( 5.2 ) ] . Infertility Based on its pharmacodynamic effects of decreasing secretion of gonadal steroids, fertility is expected to be decreased while on treatment with LUPRON DEPOT 11.25 mg. Clinical and pharmacologic studies in adults (>18 years) with leuprolide acetate and similar analogs have shown reversibility of fertility suppression when the drug is discontinued after continuous administration for periods of up to 24 weeks [see Clinical Pharmacology ( 12.1 ) ] . There is no evidence that pregnancy rates are affected following discontinuation of LUPRON DEPOT 11.25 mg. Animal studies (prepubertal and adult rats and monkeys) with leuprolide acetate and other GnRH analogs have shown functional recovery of fertility suppression. 8.4 Pediatric Use Safety and effectiveness of LUPRON DEPOT 11.25 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 11.25 mg for these indications have not been established in premenarcheal pediatric patients. 8.5 Geriatric Use LUPRON DEPOT 11.25 mg is not indicated in postmenopausal women and has not be …

12.1 Mechanism of Action Leuprolide acetate, a GnRH agonist, acts as an inhibitor of gonadotropin secretion. Animal studies indicate that following an initial stimulation, continuous administration of leuprolide acetate results in suppression of ovarian and testicular steroidogenesis. This effect was reversible upon discontinuation of drug therapy. Administration of leuprolide acetate has resulted in inhibition of the growth of certain hormone dependent tumors (prostatic tumors in Noble and Dunning male rats and DMBA-induced mammary tumors in female rats) as well as atrophy of the reproductive organs.

11 DESCRIPTION Leuprolide acetate is a synthetic nonapeptide analog of naturally occurring gonadotropin-releasing hormone (GnRH). The analog possesses greater potency than the natural hormone. The chemical name is 5-oxo-L-prolyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-D-leucyl-L-leucyl-L-arginyl-N-ethyl-L-prolinamide acetate (salt) with the following structural formula: LUPRON DEPOT 7.5 mg for 1-month administration is available in a prefilled dual-chamber syringe containing sterile lyophilized microspheres which, when mixed with diluent, becomes a suspension intended as a monthly intramuscular injection. The front chamber of LUPRON DEPOT 7.5 mg for 1-month administration prefilled dual-chamber syringe contains leuprolide acetate (7.5 mg), purified gelatin (1.3 mg), DL-lactic and glycolic acids copolymer (66.2 mg), and D-mannitol (13.2 mg). The second chamber of diluent contains carboxymethylcellulose sodium (5 mg), D-mannitol (50 mg), polysorbate 80 (1 mg), water for injection, USP, and glacial acetic acid, USP to control pH. LUPRON DEPOT 22.5 mg for 3-month administration is available in a prefilled dual-chamber syringe containing sterile lyophilized microspheres which, when mixed with diluent, become a suspension intended as an intramuscular injection to be given ONCE EVERY 12 WEEKS . The front chamber of LUPRON DEPOT 22.5 mg for 3-month administration prefilled dual-chamber syringe contains leuprolide acetate (22.5 mg), polylactic acid (198.6 mg) and D-mannitol (38.9 mg). The second chamber of diluent contains carboxymethylcellulose sodium (7.5 mg), D-mannitol (75.0 mg), polysorbate 80 (1.5 mg), water for injection, USP, and glacial acetic acid, USP to control pH. LUPRON DEPOT 30 mg for 4-month administration is available in a prefilled dual-chamber syringe containing sterile lyophilized microspheres which, when mixed with diluent, become a suspension intended as an intramuscular injection to be given ONCE EVERY 16 WEEKS . The front chamber of LUPRON DEPOT 30 mg for 4-month administration prefilled dual-chamber syringe contains leuprolide acetate (30 mg), polylactic acid (264.8 mg) and D-mannitol (51.9 mg). The second chamber of diluent contains carboxymethylcellulose sodium (7.5 mg), D-mannitol (75.0 mg), polysorbate 80 (1.5 mg), water for injection, USP, and glacial acetic acid, USP to control pH. LUPRON DEPOT 45 mg for 6-month administration is available in a prefilled dual-chamber syringe containing sterile lyophilized microspheres which, when mixed with diluent, become a suspension intended as an intramuscular injection to be given ONCE EVERY 24 WEEKS . The front chamber of LUPRON DEPOT 45 mg for 6-month administration prefilled dual-chamber syringe contains leuprolide acetate (45 mg), polylactic acid (169.9 mg), D-mannitol (39.7 mg), and stearic acid (10.1 mg). The second chamber of diluent contains carboxymethylcellulose sodium (7.5 mg), D-mannitol (75.0 mg), polysorbate 80 (1.5 mg), water for injection, USP, and glacial acetic acid, USP to control pH. Chemical structure of leuprolide acetate

10 OVERDOSAGE There is no experience of overdosage in clinical trials. In rats, a single subcutaneous dose of 100 mg/kg (approximately 4,000 times the estimated daily human dose based on body surface area), resulted in dyspnea, decreased activity, and excessive scratching. In early clinical trials with daily subcutaneous leuprolide acetate, doses as high as 20 mg/day for up to two years caused no adverse effects differing from those observed with the 1 mg/day dose.

16 HOW SUPPLIED/STORAGE AND HANDLING Each LUPRON DEPOT kit contains: one prefilled dual-chamber syringe containing needle with LuproLoc® safety device one plunger two alcohol swabs a complete prescribing information enclosure Strength Frequency of Administration Description NDC Number 7.5 mg Every month Single-dose prefilled dual-chamber syringe containing sterile white lyophilized microspheres of leuprolide acetate incorporated in a biodegradable lactic acid/glycolic acid copolymer to be mixed with 1 mL of accompanying clear, colorless diluent. 0074-3642-03 0074-3642-55 22.5 mg Every 3 months Single-dose prefilled dual-chamber syringe containing sterile white lyophilized microspheres of leuprolide acetate incorporated in a biodegradable lactic acid polymer to be mixed with 1.5 mL of accompanying clear, colorless diluent. 0074-3346-03 0074-3346-55 30 mg Every 4 months Single-dose prefilled dual-chamber syringe containing sterile white lyophilized microspheres of leuprolide acetate incorporated in a biodegradable lactic acid polymer to be mixed with 1.5 mL of accompanying clear, colorless diluent. 0074-3683-03 0074-3683-55 45 mg Every 6 months Single-dose prefilled dual-chamber syringe containing sterile white lyophilized microspheres of leuprolide acetate incorporated in a biodegradable lactic acid polymer to be mixed with 1.5 mL of accompanying clear, colorless diluent. 0074-3473-03 0074-3473-55 Store between 20° to 25°C (68° to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature].