LUPRON DEPOT Powder for solution for injection Ref.[109539] Active ingredients: Leuprorelin

Administration of LUPRON DEPOT 3.75 mg in therapeutic doses results in suppression of the pituitary-gonadal system. Normal function is usually restored within three months after treatment is discontinued. Therefore, diagnostic tests of pituitary gonadotropic and gonadal functions conducted during treatment and for up to three months after discontinuation of LUPRON DEPOT 3.75 mg may be affected.

Absorption

Following a single IM injection of LUPRON DEPOT 3.75 mg in healthy female volunteers, 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.

Distribution

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%.

Metabolism

Leuprolide acetate is a peptide that is primarily degraded by peptidase. 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.

The major metabolite (M-I, a pentapeptide) 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.

Excretion

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.

Use in Specific Populations

The pharmacokinetics of LUPRON DEPOT have not been evaluated in patients with hepatic and renal impairment.

Drug Interactions

No pharmacokinetic drug-drug interaction studies have been conducted with LUPRON DEPOT 3.75 mg. However, leuprolide acetate is a peptide that is not degraded by cytochrome P-450 enzymes; hence, drug interactions associated with cytochrome P-450 enzymes would not be expected to occur.

A two-year carcinogenicity study was conducted in rats and mice. In rats, a dose-related increase of benign pituitary hyperplasia and benign pituitary adenomas was noted at 24 months when the drug was administered subcutaneously at high daily doses (0.6 to 4 mg/kg). There was a significant but not dose-related increase of pancreatic islet-cell adenomas in females and of testicular interstitial cell adenomas in males (highest incidence in the low dose group). In mice, no leuprolide acetate-induced tumors or pituitary abnormalities were observed at a dose as high as 60 mg/kg for two years. Patients have been treated with leuprolide acetate for up to three years with doses as high as 10 mg/day and for two years with doses as high as 20 mg/day without demonstrable pituitary abnormalities.

Mutagenicity studies have been performed with leuprolide acetate using bacterial and mammalian systems. These studies provided no evidence of a mutagenic potential.

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 8) of LUPRON DEPOT 3.75 mg [see Indications and Usage (1)].

14.1 Endometriosis

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

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:

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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 8.

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 8 below provides detailed efficacy data regarding relief of symptoms of endometriosis based on the two studies of co-administration of LUPRON DEPOT 3.75 mg monthly and norethindrone acetate 5 mg daily.

Table 8. Effect of LUPRON DEPOT and Norethindrone Acetate on the Symptoms of Endometriosis and Mean Clinical Severity Scores:

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 9.

Table 9. Mean Percent Change from Baseline in Bone Mineral Density of Lumbar Spine:

The change in BMD following discontinuation of treatment is shown in Table 10.

Table 10. Mean Percent Change from Baseline in BMD of Lumbar Spine in Post-Treatment Follow-up Period¹:

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.

14.2 Fibroids

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 11). These data suggest however, that some women may benefit from iron alone or 1 to 2 months of LUPRON DEPOT 3.75 mg.

Table 11. Percent of Women Achieving Hematocrit ≥ 36% and Hemoglobin ≥ 12 g/dL:

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.