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Lupron Depot (Leuprolide Acetate) - Description and Clinical Pharmacology


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Leuprolide acetate is a synthetic nonapeptide analog of naturally occurring gonadotropin-releasing hormone (GnRH or LH-RH). 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–3 Month 11.25 mg 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 THREE MONTHS.

The front chamber of LUPRON DEPOT–3 Month 11.25 mg prefilled dual-chamber syringe contains leuprolide acetate (11.25 mg), polylactic acid (99.3 mg) and D-mannitol (19.45 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.

During the manufacture of LUPRON DEPOT–3 Month 11.25 mg, acetic acid is lost, leaving the peptide.


Leuprolide acetate is a long-acting GnRH analog.  A single injection of LUPRON DEPOT–3 Month 11.25 mg will result in an initial stimulation followed by a prolonged suppression of pituitary gonadotropins. Repeated dosing at quarterly (LUPRON DEPOT–3 Month 11.25 mg) 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.



Following a single injection of the three month formulation of LUPRON DEPOT–3 Month 11.25 mg in female subjects, a mean plasma leuprolide concentration of 36.3 ng/mL was observed at 4 hours.  Leuprolide appeared to be released at a constant rate following the onset of steady-state levels during the third week after dosing and mean levels then declined gradually to near the lower limit of detection by 12 weeks.  The mean (± standard deviation) leuprolide concentration from 3 to 12 weeks was 0.23 ± 0.09 ng/mL. However, intact leuprolide and an inactive major metabolite could not be distinguished by the assay which was employed in the study. The initial burst, followed by the rapid decline to a steady-state level, was similar to the release pattern seen with the monthly formulation.


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.

In a pharmacokinetic/pharmacodynamic study of endometriosis patients, intramuscular 11.25 mg LUPRON DEPOT (n=19) every 12 weeks or intramuscular 3.75 mg LUPRON DEPOT (n=15) every 4 weeks was administered for 24 weeks.  There was no statistically significant difference in changes of serum estradiol concentration from baseline between the 2 treatment groups.

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.


In a pharmacokinetic/pharmacodynamic study of healthy female subjects (N=20), the onset of estradiol suppression was observed for individual subjects between day 4 and week 4 after dosing.  By the third week following the injection, the mean estradiol concentration (8 pg/mL) was in the menopausal range.  Throughout the remainder of the dosing period, mean serum estradiol levels ranged from the menopausal to the early follicular range.

Serum estradiol was suppressed to ≤20 pg/mL in all subjects within four weeks and remained suppressed (≤40 pg/mL) in 80% of subjects until the end of the 12‑week dosing interval, at which time two of these subjects had a value between 40 and 50 pg/mL.  Four additional subjects had at least two consecutive elevations of estradiol (range 43-240 pg/mL) levels during the 12-week dosing interval, but there was no indication of luteal function for any of the subjects during this period.

LUPRON DEPOT–3 Month 11.25 mg induced amenorrhea in 85% (N=17) of subjects during the initial month and 100% during the second month following the injection. All subjects remained amenorrheic through the remainder of the 12‑week dosing interval.  Episodes of light bleeding and spotting were reported by a majority of subjects during the first month after the injection and in a few subjects at later time-points.  Menses resumed on average 12 weeks (range 2.9 to 20.4 weeks) following the end of the 12‑week dosing interval.

LUPRON DEPOT–3 Month 11.25 mg produced similar pharmacodynamic effects in terms of hormonal and menstrual suppression to those achieved with monthly injections of LUPRON DEPOT 3.75 mg during the controlled clinical trials for the management of endometriosis and the anemia caused by uterine fibroids.


In a Phase IV pharmacokinetic/pharmacodynamic study of patients, LUPRON DEPOT–3 Month 11.25 mg (N=21) was shown to be comparable to monthly LUPRON DEPOT 3.75 mg (N=20) in relieving the clinical signs/symptoms of endometriosis (dysmenorrhea, non-menstrual pelvic pain, pelvic tenderness and pelvic induration).  In both treatment groups, suppression of menses was achieved in 100% of the patients who remained in the study for at least 60 days.  Suppression is defined as no new menses for at least 60 consecutive days.

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 the two controlled clinical studies.  A total of 166 patients received LUPRON DEPOT 3.75 mg.  Seventy-five percent (N=125) of these elected to participate in the follow-up period.  Of these patients, 36% and 24% are included in the 6 month and 12 month follow-up analysis, respectively.  All the patients who had a pain evaluation at baseline and at a minimum of one treatment visit, are included in the Baseline (B) and final treatment visit (F) analysis.

Hormonal add-back 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 3.75 mg alone and 55 women treated with LUPRON DEPOT 3.75 mg plus norethindrone acetate 5 mg (LD/N) daily.  The second study was an open label study in which 136 women were treated with monthly LUPRON DEPOT 3.75 mg 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.

Uterine Leiomyomata (Fibroids)

LUPRON DEPOT 3.75 mg 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, 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 two and three months respectively, 71% and 75% of patients met this criterion (Table 1).  These data suggest however, that some patients may benefit from iron alone or 1 to 2 months of LUPRON DEPOT 3.75 mg.

Treatment Group Week 4 Week 8 Week 12
LUPRON DEPOT 3.75 mg with Iron (N=104) 40* 71† 75*
Iron Alone (N=98) 17 39 49
* P-Value < 0.01
† P-Value < 0.001

Excessive vaginal bleeding (menorrhagia or menometrorrhagia) decreased in 80% of patients at three months.  Episodes of spotting and menstrual-like bleeding were noted in 16% of patients at final visit.

In this same study, a decrease of ≥25% was seen in uterine and myoma volumes in 60% and 54% of patients 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 patients also experienced a decrease in symptoms including excessive vaginal bleeding and pelvic discomfort. Ninety-five percent of these patients became amenorrheic with 61%, 25%, and 4% experiencing amenorrhea during the first, second, and third treatment months respectively.

In addition, posttreatment follow-up was carried out in one clinical trial for a small percentage of LUPRON DEPOT 3.75 mg patients (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.

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

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