Generic Name
Leuprolide Acetate
Brand Names
Lupron, Fensolvi, Vabrinty, Lutrate, Eligard, Lupron Depot-PED
FDA approval date: January 26, 1989
Classification: Gonadotropin Releasing Hormone Receptor Agonist
Form: Injection, Kit
What is Lupron (Leuprolide Acetate)?
VABRINTY is indicated for the treatment of advanced prostate cancer. VABRINTY is a gonadotropin releasing hormone agonist indicated for the treatment of advanced prostate cancer.
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Brand Information
Lupron Depot (leuprolide acetate)
1DOSAGE FORMS AND STRENGTHS
For Injection: 3.75 mg of leuprolide acetate as a white lyophilized microsphere powder for reconstitution in a single dose prefilled dual chamber syringe; with one chamber containing the lyophilized powder and the other chamber containing the clear diluent.
2CONTRAINDICATIONS
LUPRON DEPOT 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.
3ADVERSE REACTIONS
The following clinically significant adverse reactions are described elsewhere in the labeling:
- Loss of Bone Mineral Density
- Severe Cutaneous Adverse Reactions
- Hypersensitivity Reactions
- Initial Flare of Symptoms with Management of Endometriosis
- Convulsions
- Clinical Depression
3.1Clinical 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
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
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
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
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.
3.2Postmarketing 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.
4DRUG INTERACTIONS
No drug-drug interaction studies have been conducted with LUPRON DEPOT 3.75 mg.
5DESCRIPTION
Leuprolide acetate is a synthetic nonapeptide analog of gonadotropin-releasing hormone [GnRH or luteinizing hormone releasing hormone (LH-RH)], a GnRH agonist. 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 3.75 mg (leuprolide acetate for depot suspension for injection) is available in a prefilled dual-chamber syringe containing sterile lyophilized microspheres powder which, when mixed with diluent, become a suspension intended as an IM injection.
The front chamber of LUPRON DEPOT 3.75 mg prefilled dual-chamber syringe contains leuprolide acetate for depot suspension (3.75 mg), purified gelatin (0.65 mg), DL-lactic and glycolic acids copolymer (33.1 mg) and D-mannitol (6.6 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.
During the manufacture of LUPRON DEPOT 3.75 mg, acetic acid is lost, leaving the peptide.
6CLINICAL STUDIES
The safety and efficacy of LUPRON DEPOT 3.75 mg for the indicated populations has been established based on adequate and well-controlled studies in adults (See Table
6.1Endometriosis
LUPRON DEPOT 3.75 mg Monotherapy
In controlled clinical studies, LUPRON DEPOT 3.75 mg monthly for six months was shown to be comparable to danazol 800 mg/day in relieving the clinical sign/symptoms of endometriosis (pelvic pain, dysmenorrhea, dyspareunia, pelvic tenderness, and induration) and in reducing the size of endometrial implants as evidenced by laparoscopy.
The clinical significance of a decrease in endometriotic lesions is not known, and laparoscopic staging of endometriosis does not necessarily correlate with the severity of symptoms.
LUPRON DEPOT 3.75 mg monthly induced amenorrhea in 74% and 98% of the women after the first and second month of treatment, respectively. Most of the remaining women reported episodes of only light bleeding or spotting. In the first, second and third post-treatment months, normal menstrual cycles resumed in 7%, 71% and 95% of women, respectively, excluding those who became pregnant.
Figure
Figure 1. Percent of Women with Signs/Symptoms of Endometriosis at Baseline, Final Treatment Visit, and After 6 and 12 Months of Follow-Up, LUPRON DEPOT 3.75 mg Monthly for Six Months
LUPRON DEPOT with Norethindrone Acetate Add-Back Therapy
Two clinical studies with treatment duration of 12 months were conducted to evaluate the effect of co-administration of LUPRON DEPOT 3.75 mg and norethindrone acetate on the loss of bone mineral density (BMD) associated with LUPRON DEPOT 3.75 mg and on the efficacy of LUPRON DEPOT in relieving symptoms of endometriosis. All women in these studies received calcium supplementation with 1000 mg elemental calcium. A total of 242 women were treated with monthly administration of LUPRON DEPOT 3.75 mg (13 injections) and 191 of them were co-administered 5 mg norethindrone acetate taken daily. The population age range was 17-43 years old. The majority of women were Caucasian (87%).
One co-administration study was a controlled, randomized and double-blind study included 51 women treated monthly with LUPRON DEPOT 3.75 mg alone and 55 women treated monthly with LUPRON DEPOT 3.75 mg plus norethindrone acetate daily. Women in this trial were followed for up to 24 months after completing one year of treatment. The other study was an open-label single arm clinical study in 136 women of one year of treatment with LUPRON DEPOT 3.75 mg monthly and daily norethindrone acetate 5 mg, with follow-up for up to 12 months after completing treatment. See Table
The assessment of efficacy was based on the investigator’s or the woman’s monthly assessment of five signs or symptoms of endometriosis (dysmenorrhea, pelvic pain, deep dyspareunia, pelvic tenderness and pelvic induration).
Table
Suppression of menses (menses was defined as three or more consecutive days of menstrual bleeding) was maintained throughout treatment in 84% and 73% of women receiving leuprolide acetate and norethindrone acetate, in the controlled study and open label study, respectively. The median time for menses resumption after treatment with leuprolide acetate and norethindrone acetate was 8 weeks.
Changes in Bone Density
The effect of LUPRON DEPOT 3.75 mg and norethindrone acetate on bone mineral density was evaluated by dual energy x-ray absorptiometry (DEXA) scan in the two clinical trials. For the open-label study, success in mitigating BMD loss was defined as the lower bound of the 95% confidence interval around the change from baseline at one year of treatment not to exceed -2.2%. The bone mineral density data of the lumbar spine from these two studies are presented in Table
The change in BMD following discontinuation of treatment is shown in Table
These clinical studies demonstrated that co-administration of leuprolide acetate and norethindrone acetate 5 mg daily is effective in significantly reducing the loss of bone mineral density that occurs with LUPRON DEPOT 3.75 mg and in relieving symptoms of endometriosis.
6.2Fibroids
LUPRON DEPOT 3.75 mg monthly for a period of three to six months was studied in four controlled clinical trials.
In one of these clinical studies, enrollment was based on hematocrit ≤ 30% and/or hemoglobin ≤ 10.2 g/dL. Administration of LUPRON DEPOT 3.75 mg monthly, concomitantly with iron, produced an increase of ≥ 6% hematocrit and ≥ 2 g/dL hemoglobin in 77% of women at three months of therapy. The mean change in hematocrit was 10.1% and the mean change in hemoglobin was 4.2 g/dL. Clinical response was judged to be a hematocrit of ≥ 36% and hemoglobin of ≥ 12 g/dL, thus allowing for autologous blood donation prior to surgery. At two and three months, respectively, 71% and 75% of women met this criterion (Table
Excessive vaginal bleeding (menorrhagia or menometrorrhagia) decreased in 80% of women at three months. Episodes of spotting and menstrual-like bleeding were noted in 16% of women at final visit.
In this same study, a decrease in uterine volume and myoma volume of ≥25% was seen in 60% and 54% of women, respectively. The mean fibroid diameter was 6.3 cm at pretreatment and decreased to 5.6 cm at the end of treatment. LUPRON DEPOT 3.75 mg was found to relieve symptoms of bloating, pelvic pain, and pressure.
In three other controlled clinical trials, enrollment was not based on hematologic status. Mean uterine volume decreased by 41% and myoma volume decreased by 37% at final visit as evidenced by ultrasound or MRI. The mean fibroid diameter was 5.6 cm at pretreatment and decreased to 4.7 cm at the end of treatment. These women also experienced a decrease in symptoms including excessive vaginal bleeding and pelvic discomfort. Ninety-five percent of these women became amenorrheic with 61%, 25%, and 4% experiencing amenorrhea during the first, second, and third treatment months respectively.
In addition, post-treatment follow-up was carried out in one clinical trial for a small percentage of women on LUPRON DEPOT 3.75 mg (N=46) among the 77% who demonstrated a ≥ 25% decrease in uterine volume while on therapy. Menses usually returned within two months of cessation of therapy. Mean time to return to pretreatment uterine size was 8.3 months. Regrowth did not appear to be related to pretreatment uterine volume.
Changes in Bone Density
In one of the studies for fibroids described above, when LUPRON DEPOT 3.75 mg was administered for three months in women with uterine fibroids, vertebral trabecular bone mineral density, as assessed by quantitative digital radiography (QDR), revealed a mean decrease of 2.7% compared with baseline. Six months after discontinuation of therapy, a trend toward recovery was observed.
7HOW SUPPLIED/STORAGE AND HANDLING
Each LUPRON DEPOT 3.75 mg kit (NDC 0074-3641-03) contains:
- one prefilled dual-chamber syringe
- one plunger
- two alcohol swabs
Each single-dose dual chamber syringe contains sterile white lyophilized microsphere powder of 3.75 mg of leuprolide acetate incorporated in a biodegradable polymer in one chamber and a colorless diluent (1 mL) in the other chamber. When mixed with the diluent, LUPRON DEPOT 3.75 mg for injection, is administered as a single IM injection.
Store between 20° to 25°C (68° to 77°F). Excursions permitted to 15° to 30°C (59° to 86°F)
8PATIENT COUNSELING INFORMATION
Loss of Bone Density
Advise patients about the risk of loss of bone mineral density and that treatment is limited
Embryo-Fetal Toxicity
- Advise females of reproductive potential of the possible risk to a fetus. Advise patients to inform healthcare provider of a known or suspected pregnancy
- If contraception is indicated, advise females of reproductive potential to use non-hormonal contraception during treatment with LUPRON DEPOT 3.75 mg
Severe Cutaneous Adverse Reactions
Inform patients that severe cutaneous adverse reactions (SCARs) may occur during treatment with LUPRON DEPOT 3.75 mg. Advise patients to discontinue LUPRON DEPOT 3.75 mg and immediately contact their healthcare provider if they experience signs or symptoms of SCARs
Hypersensitivity Reactions
Inform patients that hypersensitivity reactions, including anaphylaxis, have been reported with LUPRON DEPOT. Advise patients to seek appropriate medical care if symptoms of hypersensitivity reactions occur
Initial Flare of Symptoms
Advise patients that they may experience an increase in symptoms during the initial days of therapy. Advise patients that these symptoms should dissipate with continued therapy
Convulsions
Inform patients that convulsions have been reported in patients who have received LUPRON DEPOT. Advise patients to seek medical attention in the event of a convulsion
Clinical Depression
Inform patients that depression may occur or worsen during treatment with GnRH agonists, including LUPRON DEPOT 3.75 mg, especially in patients with a history of depression. Advise patients to immediately report thoughts and behaviors of concern to healthcare providers
Manufactured for
Revised 09/2025
20085416
9PRINCIPAL DISPLAY PANEL
NDC 0074-3641-03
FOR ADULT USE 3.75 mg for 1 - Month administration
Single Dose Administration Kit with prefilled dual-chamber syringe.
LupronDepot
(leuprolide acetate for depot suspension)
3.75 mg for 1 - Month administration
FOR INTRAMUSCULAR INJECTION
The front chamber contains: leuprolide acetate 3.75 mg, purified gelatin 0.65 mg, DL-lactic & glycolic acids copolymer 33.1 mg, D-mannitol 6.6 mg
The second chamber contains: D-mannitol 50 mg, carboxymethylcellulose sodium 5 mg, polysorbate 80 1 mg, water for injection, USP, and glacial acetic acid, USP to control pH
Rx only
