May 28, 2017
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Lupron Depot 3.75

"Using sophisticated computer-based technology to analyze genetic data obtained from uterine tissue, researchers have identified patterns of genetic activity that can be used to diagnose endometriosis, an often-painful condition that occurs wh"...


Lupron Depot 3.75 mg


Leuprolide acetate is a long-acting GnRH analog. A single monthly injection of LUPRON DEPOT 3.75 mg results in an initial stimulation followed by a prolonged suppression of pituitary gonadotropins.

Repeated dosing at monthly intervals results in decreased secretion of gonadal steroids; consequently, tissues and functions that depend on gonadal steroids for their maintenance become quiescent. This effect is reversible on discontinuation of drug therapy.

Leuprolide acetate is not active when given orally. Intramuscular injection of the depot formulation provides plasma concentrations of leuprolide over a period of one month.



A single dose of LUPRON DEPOT 3.75 mg was administered by intramuscular injection to healthy female volunteers. The absorption of leuprolide was characterized by an initial increase in plasma concentration, with peak concentration ranging from 4.6 to 10.2 ng/mL at four hours postdosing. However, intact leuprolide and an inactive metabolite could not be distinguished by the assay used in the study. Following the initial rise, leuprolide concentrations started to plateau within two days after dosing and remained relatively stable for about four to five weeks with plasma concentrations of about 0.30 ng/mL.


The mean steady-state volume of distribution of leuprolide following intravenous bolus administration to healthy male volunteers was 27 L. In vitro binding to human plasma proteins ranged from 43% to 49%.


In healthy male volunteers, a 1 mg bolus of leuprolide administered intravenously revealed that the mean systemic clearance was 7.6 L/h, with a terminal elimination half-life of approximately 3 hours based on a two compartment model.

In rats and dogs, administration of 14C-labeled leuprolide was shown to be metabolized to smaller inactive peptides, a pentapeptide (Metabolite I), tripeptides (Metabolites II and III) and a dipeptide (Metabolite IV). These fragments may be further catabolized.

The major metabolite (M-I) plasma concentrations measured in 5 prostate cancer patients reached maximum concentration 2 to 6 hours after dosing and were approximately 6% of the peak parent drug concentration. One week after dosing, mean plasma M-I concentrations were approximately 20% of mean leuprolide concentrations.


Following administration of LUPRON DEPOT 3.75 mg to 3 patients, less than 5% of the dose was recovered as parent and M-I metabolite in the urine.

Special Populations

The pharmacokinetics of the drug in hepatically and renally impaired patients have not been determined.

Drug Interactions

No pharmacokinetic-based drug-drug interaction studies have been conducted with LUPRON DEPOT. However, because leuprolide acetate is a peptide that is primarily degraded by peptidase and not by cytochrome P-450 enzymes as noted in specific studies, and the drug is only about 46% bound to plasma proteins, drug interactions would not be expected to occur.

Clinical Studies


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 at this time, and in addition 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 patients after the first and second treatment months respectively. Most of the remaining patients 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 patients, respectively, excluding those who became pregnant.

Figure 1 illustrates the percent of patients with symptoms at baseline, final treatment visit and sustained relief at 6 and 12 months following discontinuation of treatment for the various symptoms evaluated during two controlled clinical studies. This included all patients at end of treatment and those who elected to participate in the follow-up period. This might provide a slight bias in the results at follow-up as 75% of the original patients entered the follow-up study, and 36% were evaluated at 6 months and 26% at 12 months.

Figure 1

percent of patients with symptoms at baseline, final treatment visit and sustained relief at 6 and 12 months - Illustration

Hormonal Replacement Therapy

Two clinical studies with a treatment duration of 12 months indicate that concurrent hormonal therapy (norethindrone acetate 5 mg daily) is effective in significantly reducing the loss of bone mineral density associated with LUPRON, without compromising the efficacy of LUPRON in relieving symptoms of endometriosis. (All patients in these studies received calcium supplementation with 1000 mg elemental calcium). One controlled, randomized and double-blind study included 51 women treated with LUPRON DEPOT alone and 55 women treated with LUPRON plus norethindrone acetate 5 mg daily. The second study was an open label study in which 136 women were treated with LUPRON plus norethindrone acetate 5 mg daily. This study confirmed the reduction in loss of bone mineral density that was observed in the controlled study. Suppression of menses was maintained throughout treatment in 84% and 73% of patients receiving LD/N in the controlled study and open label study, respectively. The median time for menses resumption after treatment with LD/N was 8 weeks.

Figure 2 illustrates the mean pain scores for the LD/N group from the controlled study.

Figure 2

Mean pain scores for the LD/N group - Illustration

Uterine Leiomyomata (Fibroids)

In controlled clinical trials, administration of LUPRON DEPOT 3.75 mg for a period of three or six months was shown to decrease uterine and fibroid volume, thus allowing for relief of clinical symptoms (abdominal bloating, pelvic pain, and pressure). Excessive vaginal bleeding (menorrhagia and menometrorrhagia) decreased, resulting in improvement in hematologic parameters.

In three 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. These patients also experienced a decrease in symptoms including excessive vaginal bleeding and pelvic discomfort. Benefit occurred by three months of therapy, but additional gain was observed with an additional three months of LUPRON DEPOT 3.75 mg. Ninety-five percent of these patients became amenorrheic with 61%, 25%, and 4% experiencing amenorrhea during the first, second, and third treatment months respectively.

Post-treatment follow-up was carried out for a small percentage of LUPRON DEPOT 3.75 mg patients 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.

In another controlled clinical study, enrollment was based on hematocrit ≤ 30% and/or hemoglobin ≤ 10.2 g/dL. Administration of LUPRON DEPOT 3.75 mg, concomitantly with iron, produced an increase of ≥ 6% hematocrit and ≥ 2 g/dL hemoglobin in 77% of patients 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 three months, 75% of patients met this criterion.

At three months, 80% of patients experienced relief from either menorrhagia or menometrorrhagia. As with the previous studies, episodes of spotting and menstrual-like bleeding were noted in some patients.

In this same study, a decrease of ≥ 25% was seen in uterine and myoma volumes in 60% and 54% of patients respectively. LUPRON DEPOT 3.75 mg was found to relieve symptoms of bloating, pelvic pain, and pressure.

There is no evidence that pregnancy rates are enhanced or adversely affected by the use of LUPRON DEPOT 3.75 mg.

Last reviewed on RxList: 10/17/2016
This monograph has been modified to include the generic and brand name in many instances.

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