14.1 Endometriosis
LUPRON DEPOT 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 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 8 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.
Figure 1. Percent of Patients with Signs/Symptoms of Endometriosis at Baseline, Final Treatment Visit, and After 6 and 12 Months of Follow-Up
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 also Clinical Pharmacology (12.2).
A six-month pharmacokinetic/pharmacodynamic post-marketing study in 41 women that included both the 3.75 mg dose (N=20) administered once monthly and the 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 leuprolide acetate. In both treatment groups, suppression of menses (defined as no new menses for at least 60 consecutive days) was achieved in 100% of the patients 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 and norethindrone acetate on the loss of bone mineral density (BMD) associated with LUPRON DEPOT and on the efficacy of LUPRON DEPOT in relieving symptoms of endometriosis. (All patients in these studies received calcium supplementation with 1000 mg elemental calcium). A total of 242 women were treated with monthly administration of leuprolide acetate 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 patients were Caucasian (87%).
One co-administration study was a controlled, randomized and double-blind study included 51 women treated monthly with LUPRON DEPOT alone (See Table 8) and 55 women treated monthly with LUPRON DEPOT 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 and daily norethindrone acetate 5 mg, with follow-up for up to 12 months after completing treatment.
The assessment of efficacy was based on the investigator s or the patient 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 leuprolide acetate and norethindrone acetate.
Table 8. Percentages of Patients with Symptoms of Endometriosis and Mean Clinical Severity Scores | | Percent of Patients
with Symptoms | Clinical Pain
Severity Score |
| Baseline | Final | Baseline | Final |
| Variable | Study | Group | N1 | (%)2 | (%) | N1 | Value3 | Change |
| Dysmenorrhea | Controlled Study | LD*4 | 51 | (100) | (4) | 50 | 3.2 | -2.0 |
| | LD/N | 55 | (100) | (4) | 54 | 3.1 | -2.0 |
| Open Label Study | LD/N5 | 136 | (99) | (9) | 134 | 3.3 | -2.1 |
| Pelvic Pain | Controlled Study | LD4 | 51 | (100) | (66) | 50 | 2.9 | -1.1 |
| | LD/N | 55 | (96) | (56) | 54 | 3.1 | -1.1 |
| Open Label Study | LD/N5 | 136 | (99) | (63) | 134 | 3.2 | -1.2 |
| Deep Dyspareunia | Controlled Study | LD | 42 | (83) | (37) | 25 | 2.4 | -1.0 |
| | LD/N | 43 | (84) | (45) | 30 | 2.7 | -0.8 |
| Open Label Study | LD/N | 102 | (91) | (53) | 94 | 2.7 | -1.0 |
| Pelvic Tenderness | Controlled Study | LD4 | 51 | (94) | (34) | 50 | 2.5 | -1.0 |
| | LD/N | 54 | (91) | (34) | 52 | 2.6 | -0.9 |
| Open Label Study | LD/N5 | 136 | (99) | (39) | 134 | 2.9 | -1.4 |
| Pelvic Induration | Controlled Study | LD4 | 51 | (51) | (12) | 50 | 1.9 | -0.4 |
| | LD/N | 54 | (46) | (17) | 52 | 1.6 | -0.4 |
| Open Label Study | LD/N5 | 136 | (75) | (21) | 134 | 2.2 | -0.9 |
* LD = LUPRON DEPOT 3.75 mg assessment
LD/N = LUPRON DEPOT 3.75 mg plus norethindrone acetate 5 mg
1 Number of patients that were included in the assessment
2 Percentage of patients with the symptom/sign
3 Value description: 1=none; 2= mild; 3= moderate; 4= severe
4 6-month study duration of treatment
5 12months study duration of treatment with 12 months follow up |
Suppression of menses (menses was defined as three or more consecutive days of menstrual bleeding) was maintained throughout treatment in 84% and 73% of patients 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 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 | | LUPRON DEPOT
3.75 mg | LUPRON DEPOT 3.75 mg
plus norethindrone acetate 5 mg daily |
| | Controlled Study | Controlled Study | Open Label Study |
| | N | Change (Mean, 95% CI)# | N | Change (Mean, 95% CI)# | N | Change (Mean, 95% CI)# |
| Week 24* | 41 | -3.2% (-3.8, -2.6) | 42 | -0.3% (-0.8, 0.3) | 115 | -0.2% (-0.6, 0.2) |
| Week 52 | 29 | -6.3% (-7.1, -5.4) | 32 | -1.0% (-1.9, -0.1) | 84 | -1.1% (-1.6, -0.5) |
* Includes on-treatment measurements that fell within 2-252 days after the first day of treatment.
Includes on-treatment measurements >252 days after the first day of treatment.
# 95% CI: 95% Confidence Interval |
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 Period Post Treatment
Measurement | Controlled Study | Open Label Study |
| LD-Only | LD/N | LD/N |
| N | Mean
%
Change | 95% CI
(%) | N | Mean
%
Change | 95% CI
(%) | N | Mean
%
Change | 95% CI
(%)2 |
| Month 8 | 19 | -3.3 | (-4.9, -1.8) | 23 | -0.9 | (-2.1, 0.4) | 89 | -0.6 | (-1.2, 0.0) |
| Month 12 | 16 | -2.2 | (-3.3, -1.1) | 12 | -0.7 | (-2.1, 0.6) | 65 | 0.1 | (-0.6, 0.7) |
1 Patients with post treatment measurements
2 95% CI (2-sided) of percent change in BMD values from baseline |
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.
14.2 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 11). These data suggest however, that some patients may benefit from iron alone or 1 to 2 months of LUPRON DEPOT 3.75 mg.
Table 11. Percent of Patients Achieving Hematocrit 36% and Hemoglobin 12 GM/DL | 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, post-treatment 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.
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 uterine fibroid patients, 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.
There is no evidence that pregnancy rates are enhanced or adversely affected following discontinuation of LUPRON DEPOT 11.25 mg.
