LUPRON DEPOT 11.25 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

In a pharmacokinetic/pharmacodynamic study of healthy female subjects (N=20) LUPRON DEPOT 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 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 [see Clinical Pharmacology (12.2)]. 

A six-month pharmacokinetic/pharmacodynamic post-marketing study in 41 women that included both the LUPRON DEPOT 3.75 mg dose (N=20) administered once monthly and the LUPRON DEPOT 11.25 mg dose (N=21) administered once every three months did not reveal clinically significant differences in terms of efficacy in reducing painful symptoms of endometriosis or magnitude of the decrease in bone mineral density (BMD) associated with use of LUPRON DEPOT 3.75 mg and LUPRON DEPOT 11.25 mg. In both treatment groups, suppression of menses (defined as no new menses for at least 60 consecutive days) was achieved in 100% of the women who remained in the study for at least 60 days. Vertebral bone density measured by dual energy x-ray absorptiometry (DEXA) decreased compared with baseline by an average of 3.0% and 2.8% at six months for the two groups, respectively. 

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. 

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.

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

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 both LUPRON DEPOT 3.75 mg and 11.25 mg treatments, and in relieving symptoms of endometriosis.