Lupron Depot GYN-ENDO
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Lupron Depot GYN-ENDO - Scientific Information

Manufacture: AbbVie
Country: Canada
Condition: Endometriosis, Hirsutism, Prostate Cancer, Uterine Fibroids
Class: Gonadotropin releasing hormones, Hormones/antineoplastics
Form: Liquid solution, Intramuscular (IM)
Ingredients: leuprolide acetate, carboxymethylcellulose sodium, DL-lactic and glycolic acids copolymer, D-mannitol, gelatin, glacial acetic acid, polysorbate 80 and water for injection

Pharmaceutical information

Proper name: leuprolide acetate
Chemical name: 5-oxo-L-prolyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-D-Leucyl-L-leucyl-L-arginyl-N-ethyl-L-prolinamide acetate.

or: des-Glycine10, [D-Leucine6) LH-RH ethylamide acetate.

or: [D-Leu6, des-Gly-NH210, Proethylamide9] GnRH.
Molecular formula and molecular mass: C59H84N16O12∙C2H4O2       1209.41 as free base

Structural formula:

Physicochemical
properties:
Leuprolide acetate is a fine or fluffy, white to off-white powder, very soluble in water, ethanol and propylene glycol; pKa = 9.6.

Clinical trials

Study Demographics and Trial Design

LUPRON DEPOT 3.75 mg (1-Month SR)

The first two studies conducted were Phase III, randomized, double-blind, multi-centre studies of the effects of LUPRON DEPOT 3.75 mg (1-Month SR) in endometriosis. Study I was placebo- controlled, while Study II used danazol as an active control. The studies were conducted at a total of 23 investigative sites, with 11 investigators participating in both studies. Study I had a planned sample size of 60 (30 LUPRON DEPOT, 30 placebo), and Study II had a planned sample size of 250 (125 LUPRON DEPOT, 125 danazol).

A total of 333 patients for the two studies were enrolled at 23 investigative centres.

Sixty-three patients entered the Study I and 270 patients entered Study II.

The number of patients enrolled into each study and the number of evaluable (for efficacy) is summarized in Table 1.

Table 1 Number of Patients Enrolled in Two Phase III, Randomized, Double-Blind, Multicentre Studies Evaluating the Effects of LUPRON DEPOT 3.75 mg (1-Month SR) in Endometriosis (Studies I and II)
Study Number of
Investigators
Number of Patients Entered Number of Evaluable Patients
LUPRON
DEPOT
Placebo Danazol LUPRON
DEPOT
Placebo Danazol
I 12 32 31 -- 28 24 --
II 22 134 -- 136 128 -- 125
Total 23* 166 31 136 156 24 125
* Eleven investigators entered patients in both studies.

A total of 166 patients were exposed to LUPRON DEPOT in Studies I and II. Of the 166 patients, 153 were treated for the full 6-month study period and 13 prematurely terminated from the study and were treated for periods ranging from one to six months. The patients were treated with LUPRON DEPOT for a total of 79 accumulated patient-years experience in these two studies (assuming each injection is equivalent to four weeks treatment).

A summary of the trial design and patient demographics is shown in Table 2.

Table 2 Summary of Patient Demographics for Clinical Trials in Endometriosis
Study# Trial design Dosage, route of
administration and duration
Study
subjects (n)
Mean age
(Range)
Gender
I Phase III, parallel
randomized,
double-blind,
multicenter study
3.75 mg LUPRON DEPOT
vs.
placebo
Intramuscular
24 weeks
63 30
(19 to 44)
Females
only
II Phase III, parallel
randomized,
double-blind,
multicenter study
3.75 mg LUPRON DEPOT
plus danazol placebo
vs.
LUPRON DEPOT placebo plu
200 mg danazol b.i.d.
Intramuscular
24 weeks
270 Not
available
Females
only
III Phase III, 4-arm,
parallel,
randomized,
double-blind,
multicenter study
3.75 mg LUPRON DEPOT
alone vs. LUPRON DEPOT
plus norethindrone acetate 5 mg
52 weeks
106 28.6
(18 to 43)
Females
only
IV Phase IV, open-
label, single-arm,
multicenter
extension of
Study III
LUPRON DEPOT plus
norethindrone acetate 5 mg
52 weeks
136 28.8
(17 to 41)
Females
only
Definitions: b.i.d. = twice daily; n = number.

Two other clinical studies were conducted with LUPRON DEPOT 3.75 mg (1-Month SR) in patients with endometriosis. Study III was a double-blind, randomized, parallel-group, multi- center study, conducted at 26 investigative sites, with planned sample sizes of 200 (4 groups of 50 patients; LUPRON DEPOT alone or in combination with estrogen and/or the progestin norethindrone acetate as add-back regimens). Study IV was an open-label, single-arm, multi- center extension of Study III, conducted at 24 investigative sites, with a planned sample size of 135. Both studies had a 52-week Treatment Period with either 24 months (Study III) or 12 months (Study IV) of follow-up after the completion of treatment.

The primary efficacy objective of studies III and IV was to compare the efficacy of continuous, combined administration of oral norethindrone acetate 5 mg and LUPRON DEPOT to the efficacy of administration of LUPRON DEPOT alone, in the management of endometriosis.

A total of 242 patients were enrolled in studies III and IV to receive either LUPRON DEPOT alone (51 patients) or in combination with norethindrone acetate 5 mg (191 patients). The number of patients enrolled into each study and the number of evaluable (for efficacy) is summarized in Table 3.

Table 3. Number of Patients Enrolled in Studies III and IV
Study Number of
Investigators
Number of Patients Randomized Number of Patients Completing
Treatment
LUPRON
DEPOT 3.75 mg
LUPRON
DEPOT 3.75 mg
+ norethindrone
acetate 5 mg
LUPRON
DEPOT 3.75 mg
LUPRON
DEPOT 3.75 mg
+ norethindrone
acetate 5 mg
III 26 51 55 32 31
IV 24 -- 136 -- 82
Total 44* 51 191 32 113
* Six investigators entered patients in both studies.

Of the 51 patients randomized to receive LUPRON DEPOT only, 32 completed the 52-week study period while 19 terminated prematurely. Of the 191 patients who received LUPRON DEPOT with norethindrone acetate, 113 completed the 52-week study period and 78 terminated prematurely.

A summary of the trial design and patient demographics is shown in Table 2.

Study Results

LUPRON DEPOT 3.75 mg (1-Month SR)

The results of the studies were as follows:

Clinical Evaluation in Studies I and II

At each study visit, an assessment was made of dysmenorrhea, non-menstrual pelvic pain, and dyspareunia (by patient interview). Symptoms were graded as absent, mild, moderate, or severe. Degree of analgesic use was utilized by the investigators to help assess pelvic pain. Pelvic tenderness, induration, and ovarian enlargement (by pelvic examination) were evaluated at every monthly visit for patients in the placebo-controlled pain study and every 12 weeks for patients in the active-controlled study. Pelvic tenderness and induration were also graded as absent, mild, moderate, or severe; ovarian size was assessed to be normal, two times normal, or greater than or equal to three times normal.

At each visit, a patient was considered improved if her evaluation at that visit had a less severe classification than did her baseline evaluation. A change to a more severe classification was counted as worse. Patients with a baseline classification of absent could not improve and patients with a baseline classification of severe could not get worse. Therefore, the percentages of patients with treatment changes of "worse", "no change", and "improved" do not add to 100%.

Forty-nine patients (28 LUPRON DEPOT, 21 placebo) in the placebo-controlled study and 251 patients (127 LUPRON DEPOT, 124 danazol) in the active-controlled study were evaluable for one or more of the clinical valuation variables.

Dysmenorrhea

LUPRON DEPOT patients showed reductions in dysmenorrhea compared to baseline at every visit in both studies. Table 4 summarizes changes in clinical evaluation of dysmenorrhea at the Final Visit against baseline for patients included in the efficacy analysis.

Table 4 Summary of Changes in Clinical Evaluation of Dysmenorrhea at the Final Visit Against Baseline for Patients Included in the Efficacy Analysis
LUPRON DEPOT Danazol Placebo
Worse 1/121 = 1% 3/11 = 3% 7/12 = 58%
No change 20/155 = 13% 14/124 = 11% 6/21 = 29%
Improved 134/136 = 99% 107/112 = 96% 8/21 = 30%
Pelvic pain

LUPRON DEPOT patients showed decreases in pelvic pain severity levels at each visit. Table 5 summarizes the changes in clinical evaluation of pelvic pain at the Final Visit compared to baseline for patients included in the efficacy analysis.

Table 5 Summary Changes in Clinical Evaluation of Pelvic Pain at the Final Visit Compared to Baseline for Patients Included in the Efficacy Analysis
LUPRON DEPOT Danazol Placebo
Worse 13/145 = 9% 5/116 = 4% 2/13 = 15%
No change 56/155 = 36% 56/124 = 45% 10/21 = 48%
Improved 86/118 = 73% 63/86 = 73% 9/21 = 43%
Dyspareunia

LUPRON DEPOT patients in both studies showed slight decreases or no change when compared to baseline at all visits. Table 6 summarizes the changes in clinical evaluation of dyspareunia at the Final Visit compared to baseline for patients included in the efficacy evaluation.

Table 6 Summary of the Changes in Clinical Evaluation of Dyspareunia at the Final Visit Compared to Baseline for Patients Included in the Efficacy Analysis
LUPRON DEPOT Danazol Placebo
Worse 22/126 = 17% 7/105 = 7% 4/13 = 31%
No change 65/139 = 47% 62/110 = 56% 6/13 = 46%
Improved 42/72 = 58% 41/58 = 71% 3/10 = 30%
Pelvic Tenderness

Decreases in severity levels of pelvic tenderness occurred at every visit for the combined LUPRON DEPOT group. Pelvic tenderness changes from baseline to the Final Visit for both studies are summarized in Table 7.

Table 7 Pelvic Tenderness Changes from Baseline to the Final Visit for the Placebo- and Active-Controlled Studies
LUPRON DEPOT Danazol Placebo
Worse 8/150= 5% 6/120 = 5% 3/20 = 15%
No change 55/152 = 36% 61/122 = 50% 11/21 = 52%
Improved 89/117 = 76% 55/70 = 79% 7/21 = 33%
Induration

At baseline in each study, treatment groups were similar. In the placebo-controlled study, LUPRON DEPOT patients showed similar or better results (less induration) than the placebo group at all visits. At the Final Visit, induration was significantly less for the LUPRON DEPOT group (p=0.023). In active-controlled study, LUPRON DEPOT patients showed similar results compared to the danazol group at all visits. No significant differences were seen between groups.

Ovarian Enlargement

For both studies, ovarian enlargement had a relatively low prevalence rate at baseline. Ovarian enlargement for most LUPRON DEPOT patients and danazol patients either improved over time or did not change. Only two placebo patients had ovarian enlargement at baseline.

Menses

Menses were considered suppressed if no menstrual-like bleeding occurred for more than

60 days (day of first injection or first day of one episode of menstrual-like bleeding to the first day of the subsequent episode of menstrual-like bleeding or end-of-study).

In the placebo-controlled study menses were suppressed in all of the LUPRON DEPOT patients (100%) and one of the placebo patients (4%). Once suppressed, menses remained suppressed through the study for all except three LUPRON DEPOT patients.

In the active-controlled study menses were suppressed in 99% of the LUPRON DEPOT patients and 96% of the danazol patients. However, suppression did not occur in one LUPRON DEPOT and five danazol patients. Menses were completely suppressed from the initiation of treatment for 77% of the LUPRON DEPOT and 63% of the danazol patients. The number of episodes of menstrual-like bleeding before suppression are presented in Table 8.

Table 8 Number of Episodes of Menstrual-Like Bleeding Before Suppression in the Active-Controlled Study
Number of Episodes Number of Patients
LUPRON DEPOT
Number of Patients
Danazol
0 98 79
1 29 26
2 0 10
3 0 4

Once suppressed, menses remained suppressed through the study for all except eight LUPRON DEPOT and 23 danazol patients.

Hormone Determinations

In each study, mean estradiol decreases were significantly greater for LUPRON DEPOT patients compared to each of the control groups (p < 0.05). Most estradiol values for LUPRON DEPOT patients were at or near the post-menopausal range (< 1.5 ng/dL). Progesterone decreased significantly within each treatment group in each study at every visit

where hormonal determinations were made (p < 0.05); however, between group significance was seen only in the placebo-controlled study.

Analgesic Usage

Analgesic usage for each patient was surveyed at each visit to assist the investigator in the evaluation of pain. In the placebo-controlled pain study, 98% of the patients took analgesics for pain; in the active-controlled study, 78% of the patients took analgesics for pain. The most common pain medications used were mild analgesics or non-narcotic analgesics.

Clinical Evaluation in Studies III and IV

Clinical assessment of pain parameters (dysmenorrhea, pelvic pain, deep dyspareunia, pelvic tenderness, and pelvic induration) was evaluated on the 4-point Biberoglu and Berhman scale completed by the study staff. Return to baseline pain levels during follow-up was also assessed using this scale. Improvement in pain was also evaluated via patient evaluations of dysmenorrhea, pelvic pain and deep dyspareunia using analog scales (0 = none; 10 = intolerable). Pain evaluations were collected at each visit during treatment and the first year of follow-up. Improvement in ovarian enlargement was assessed by comparing ovarian size determined at each visit during treatment and the first year of the Follow-Up period to baseline measurements. Estradiol level was assessed at each Treatment period visit beginning with Day 0 (baseline) and once at the first Follow-Up period visit after resumption of menses. Menses frequency and duration were collected on patient diaries. Suppression of estradiol (E2) and menses are used as efficacy markers.

Pain Parameters

Statistically significant mean decreases from baseline in all pain scores were seen in patients taking either LUPRON DEPOT alone or in combination with norethindrone acetate 5 mg (p < 0.001). The improvements were generally statistically significant by Week 4 and were maintained throughout the 52-week Treatment Period. Table 9 summarizes the prevalence in clinical pain variables at the Final Visits against baseline for patients included in the efficacy analysis.

Table 9 Prevalence of Clinical Pain Variables at Baseline and the Final Treatment Visit (Integrated Results from Study III and Study IV)
Variable Treatment Group Baseline
n/N (%)
Final Treatment Visit
n/N (%)
Dysmenorrhea LUPRON DEPOT
LUPRON DEPOT + norethindrone acetate
51/51 (100)
190/191 (99)
2/50 (4)
14/188 (7)
Pelvic Pain LUPRON DEPOT
LUPRON DEPOT + norethindrone acetate
51/51 (100)
188/191 (98)
33/50 (66)
115/188 (61)
Deep Dyspareunia LUPRON DEPOT
LUPRON DEPOT + norethindrone acetate
35/42 (83)
129/145 (89)
17/46 (37)
78/153 (51)
Pelvic Tenderness LUPRON DEPOT
LUPRON DEPOT + norethindrone acetate
48/51 (94)
184/190 (97)
17/50 (34)
70/187 (37)
Pelvic Induration LUPRON DEPOT
LUPRON DEPOT + norethindrone acetate
26/51 (51)
127/190 (67)
6/50 (12)
37/187 (20)
Serum Estradiol Levels

Statistically significant within-group mean decreases from baseline were noted for both groups at all visits starting at Week 4 (p < 0.001) and were generally constant throughout the Treatment Period. For the majority of visits, the mean decrease for the LUPRON DEPOT plus norethindrone acetate group was statistically significantly greater than that of the LUPRON DEPOT-Only group (p < 0.01). The mean of serum estradiol levels averaged over the Treatment Period was within or near the menopausal range (< 15 pg/mL) for both treatment groups: 8.40 pg/mL for Integrated LUPRON DEPOT plus norethindrone acetate and 15.59 pg/mL for LUPRON DEPOT-Only.

Menstrual Suppression

Menses were considered suppressed if no menstrual-like bleeding occurred for more than 60 days (day of first injection or first day of one episode of menstrual-like bleeding to the first day of the subsequent episode of menstrual-like bleeding or end-of-study). A summary of menstrual data for patients who were in the Treatment Period for at least 60 days is presented in Table 10.

Table 10 Menses Suppression During the Treatment Period
Parameter LUPRON DEPOT LUPRON DEPOT +
norethindrone acetate 5mg
Suppression n/N (%) 47/47 (100) 174/177 (98)*
Suppression Maintained to End of Treatment n/N (%) 41/47 (87) 132/174 (76)*
* Values are integrated from Studies III and IV.

Efficacy

The placebo- and active-controlled studies have proven that LUPRON DEPOT is safe and effective in reducing not only the symptoms of endometriosis but also the extent of disease. It is at least as effective in this regard as is danazol and shows less of the androgenic adverse events which commonly accompany danazol treatments.

Based on results from studies III and IV, norethindrone acetate 5 mg daily is an effective add- back regimen combined with LUPRON DEPOT and does not have any relevant negative impact on endometriosis symptoms when compared with LUPRON DEPOT alone. Duration of initial treatment or retreatment should be limited to a period of six months.

Conclusion

LUPRON DEPOT, alone or in combination with norethindrone acetate 5 mg add-back, was effective in producing a transient, therapeutic menopausal state in patients with endometriosis facilitating statistically and medically significant improvement in disease signs and symptoms, and reduction in the extent of disease.

Safety

Adverse Events in Studies I and II

All 333 patients enrolled in the two studies were included in the adverse event analysis.

Adverse events reported by 95% (n=158) of the 166 LUPRON DEPOT patients, by 93% (n=127) of the 136 danazol patients, and by 45% (n=14) of the 31 placebo patients. The most frequently reported adverse event in all treatment groups was vasodilatation (hot flashes) with 83% (n=138) of the LUPRON DEPOT patients, 54% (n=74) of the danazol patients, and 29% (n=9) of the placebo patients reporting it.

Eighty-seven percent of those reporting vasodilatation rated it mild or moderate with 32 LUPRON DEPOT, 9 danazol, and 1 placebo patient reporting it as severe. The mean onset of vasodilatation was 29 days after the initiation of treatment for the LUPRON DEPOT group and 35 days for the danazol group. Generally, vasodilatation continued intermittently throughout the study. The difference between treatment groups in the proportion of patients reporting it was statistically significant (p < 0.05) in each study.

Other than vasodilatation, the adverse events having the highest prevalence (>10%) among LUPRON DEPOT patients were headache (35%), vaginitis (27%), insomnia (17%), emotional lability (15%), nausea (13%), nervousness (12%), weight gain (11%), dizziness (11%), decreased libido (11%), and depression (11%). The severity of these events was predominantly mild or moderate.

The most prevalent events in the danazol group were vasodilatation (54%), weight gain (27%), headache (26%), acne (20%), vaginitis (19%), edema (18%), nervousness (16%), nausea (13%), depression (12%), and emotional lability (11%). In the placebo group, the most prevalent event was vasodilatation (29%). The only other adverse events to occur in more than 5% of the placebo patients were headache (10%) and insomnia (7%).

In the placebo-controlled study, the difference in prevalence between the treatment groups was significant for vasodilatation and headache. In the active-controlled study, the LUPRON DEPOT group had significantly higher prevalence of vasodilatation, pelvic pain, insomnia, and decreased libido than did the danazol patients. Danazol patients had significantly more edema and weight gain than did the LUPRON DEPOT patients.

Many of the adverse events occurring in more than 5% of the LUPRON DEPOT group had onset within the first two months of treatment. Forty-nine percent (n=262) of the 530 total initial occurrences of these events had onset within the first month of treatment and 72% within the first two months.

Most of the events occurring in at least 5% of the LUPRON DEPOT group are symptoms that occur frequently in the post-menopausal population and are generally considered to be related to the hypoestrogenic state. Other symptoms such as weight gain, acne, and hypertonia occurred with much greater frequency in the active-controlled study where LUPRON DEPOT was compared with danazol which is known to have androgenic effects.

Other symptoms, such as pain, have no apparent explanation. Most of the adverse events reported in the studies were considered by the investigator to be probably or possibly related to treatment.

Eight patients in the LUPRON DEPOT group terminated prematurely from the studies due to adverse events. Overall, 19 patients (8 LUPRON DEPOT, 10 danazol, and 1 placebo) prematurely terminated the studies due to adverse events.

The length of treatment received by these patients who terminated prematurely is summarized in Table 11.

Table 11 Treatment Length for Patients Who Prematurely Terminated in the Placebo- and Active-Controlled Studies
Treatment (months) LUPRON DEPOT Danazol Placebo
1 1 5 0
2 3 1 1
3 0 2 0
4 3 0 0
5 0 1 0
6 1 1 0
Total 8 10 1
Adverse Events in Studies III and IV

Almost 100% of patients (190 of 191) in the Integrated LUPRON DEPOT plus norethindrone acetate group reported one or more adverse events during the Treatment Period. The most prevalent adverse events were vasodilatation (hot flashes) and headache, which were reported by 68% and 60% of patients, respectively.

When the Integrated LUPRON DEPOT plus norethindrone acetate group was compared with the LUPRON DEPOT-Only group from Study III, statistically significant differences (p < 0.05) were noted between the groups in the prevalence of hot flashes and sweating. The prevalence of hot flashes was greater for the LUPRON DEPOT-Only group, while the prevalence of sweating was greater for the LUPRON DEPOT plus norethindrone acetate group. Potentially study drug-related adverse events for which there was a difference between the Integrated LUPRON DEPOT plus norethindrone acetate and LUPRON DEPOT-Only groups of 10% or more are summarized in Table 12.

Table 12 Adverse Events Attributed to Study Drug with ≥ 10% Difference Between Groups in Prevalence During the Treatment Period
COSTART Term Study III
LUPRON DEPOT
N=51
Integrated Studies III and IV
LUPRON DEPOT + norethindrone
acetate 5mg
N=191
N % N %
Hot Flashes/
Sweats
50 98 136 71*
Headache/Migraine 34 67 98 51
Nausea/Vomiting 15 29 37 19
Edema 0 0 21 11
+
Insomnia/Sleep
Disorders
16 31 38 20
Androgen-Like
Effects
2 4 29 15
+
Vaginitis 12 24 24 13
* Statistically significantly less than the LUPRON DEPOT-Only group (p < 0.05).
+ Statistically significantly greater than the LUPRON DEPOT-Only group (p < 0.05).

There is minimal overall risk to treatment with the combination of LUPRON DEPOT and norethindrone acetate. The adverse event pattern characteristically seen in patients treated with LUPRON DEPOT or other GnRH agonists and norethindrone acetate largely reflects the menopausal symptom profile seen with GnRH agonist treatment. Although much reduced in incidence compared to the administration of LUPRON DEPOT alone, hot flashes remains the most prevalent of these events.

Bone Mineral Density in Studies I and II

Bone density measurements were performed pre-study and at the end of the treatment period.

An analysis of percent changes in bone mineral density from baseline to the end of treatment for the combined LUPRON DEPOT patients from both studies shows that one hundred fifteen patients had a mean decrease of 4.2% in bone mineral density. This decrease was significant within the LUPRON DEPOT treatment group (p < 0.001) and is consistent with data published on the effect of other GnRH agonists on bone mineral density.

When LUPRON DEPOT was compared to danazol, moderate mean decreases were observed in the LUPRON DEPOT group, and slight to moderate mean increases were observed in the danazol group. Treatment with LUPRON DEPOT produces a hypoestrogenic environment which can result in increased bone turnover, and treatment with danazol can result in androgenic effects such as increased bone mass.

Bone Mineral Density in Studies III and IV

The mean changes from baseline in BMD during the Treatment Period experienced by the Integrated LUPRON DEPOT plus norethindrone acetate group were compared to those of the Study III LUPRON DEPOT-Only group. There was no statistically significant difference in mean BMD between the 2 groups at baseline. Statistically significant (p < 0.001) mean decreases in BMD from baseline were noted for the Integrated LUPRON DEPOT plus norethindrone acetate group at Week 52, and at all evaluations for the LUPRON DEPOT-Only group.

Comparisons of the mean percent changes from baseline between the two groups showed that the LUPRON DEPOT plus norethindrone acetate group experienced a statistically significantly (p < 0.001) smaller decrease in BMD than the LUPRON DEPOT-Only group at all evaluations. The results of the analyses of percent change in BMD from baseline to the Week 24 and Week 52 visits for the comparison of the Integrated LUPRON DEPOT plus norethindrone acetate (with calcium supplementation) and Study III LUPRON DEPOT-Only treatment groups are presented in Table 13.

Table 13. Mean Percent Change from Baseline in Lumbar Spine Bone Mineral Density
Treatment Group N Week 24 N Week 52
LUPRON DEPOT 41 -3.2%* 29 -6.3%*
LUPRON DEPOT + norethindrone
acetate 5 mg daily
157 -0.2%+ 116 -1.0%*+
* Statistically significant within-group change (p < 0.001).
+ Statistically significant difference between groups (p < 0.001), combined and in each study separately.

Overall, changes in safety parameters as a result of LUPRON DEPOT administration did not exceed expected limits. Adverse events experienced by patients in the four studies were primarily those symptoms characteristically experienced in the post-menopausal population and reflect the hormonal suppression which forms the basis of the therapeutic effect. In Studies III and IV, bone mineral density was minimally decreased from baseline after 12 months of treatment with LUPRON DEPOT when used in conjunction with norethindrone acetate and calcium supplementation. This decrease was considerably less than that seen with LUPRON DEPOT alone. The concurrent use of LUPRON DEPOT with norethindrone acetate 5 mg daily is effective in reducing loss of bone mineral density that occurs with LUPRON DEPOT alone.

Hot Flashes in Studies III and IV

The incidence of the menopausal symptoms of vasodilatation (hot flashes) and sweating was significantly less than that seen in patients who received treatment with leuprolide acetate alone.

Conclusion

The primary consequence of treatment with LUPRON DEPOT is the predictable, yet substantially reversible, bone turnover consequent to hypoestrogenism. After six months of treatment, the risks attending this decrease in bone mineral density are minimal in women who began treatment with normal bone density. Concomitant administration of norethindrone acetate 5 mg in combination with LUPRON DEPOT resulted in a decreased prevalence and severity of adverse events attributable to the chronic hypoestrogenic state induced by LUPRON DEPOT and greatly attenuated the loss of bone mineral density and the incidence of hot flashes.

LUPRON DEPOT 11.25 mg (3-Month SR)

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) reached 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/mLin 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 to 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 11.25 mg (3-Month SR) 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 a 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 (3-Month SR) produced similar pharmacodynamic effects in terms of hormonal and menstrual suppression to those achieved with monthly injections of LUPRON DEPOT 3.75 mg (1-Month SR) during the controlled clinical trials for the management of endometriosis. Similar clinical outcome to that with LUPRON DEPOT 3.75 mg (1-Month SR) administered monthly is predicted with LUPRON DEPOT 11.25 mg (3-Month SR) administered every 3 months.

Detailed pharmacology

Leuprolide is an analog of gonadotropin-releasing hormone (GnRH). It was found to have antireproductive properties on chronic administration at high doses, interfering with gonadal steroidogenesis. It produces a reversible regression of steroid-dependent reproductive tissues in both male and female, in a manner analogous to that produced by gonadectomy or by antiandrogenic and antiestrogenic drugs.

Animal Pharmacology

Pharmacodynamics

LUPRON

Several studies in rats were conducted to determine the effects of prolonged administration of leuprolide.

In two non-tumor studies, leuprolide showed in male rats a marked reduction of LH and FSH, accompanied by decreased plasma testosterone at 20 mcg/twice a day for 106 days in the first study and at 20 and 100 mcg/twice a day for 160 days in the second study.

In a tumor study, in male rats implanted with R3327-G prostatic carcinoma, a daily dose of leuprolide at 1, 50 or 1000 mcg/kg for 20 days showed a significant reduction in the tumor growth rate, and enhanced the survival of the animals.

Leuprolide has also been tested in female rats having mammary tumors induced by the administration of 7-12-dimethylbenz[α]-anthracene (DMBA). Doses of leuprolide used ranged from 0.01 mcg to 10 mcg twice a day, up to 31 days. Except for 0.01 mcg which was a "no- effect-dose", leuprolide produced regression of tumor growth similar to the effects seen in the castrate control.

Pharmacokinetics

LUPRON DEPOT

Pharmacokinetic behaviors of leuprolide acetate for depot suspension were studied in rats and dogs.

  • In rats, release kinetics after subcutaneous and intramuscular injections, exhibited a pseudo-zero-order kinetics for one month in a dose ranging from 3 to 30 mg/kg; the release rate at a dose of 3 mg/kg was 2.8% of dose/day. Serum levels for leuprolide showed a sharp increase immediately after injection, result of an initial burst of the drug, accompanied by an initial flare up of testosterone level. Serum level for leuprolide and testosterone decreased to below normal level, and were sustained at a suppressed level for over 6 weeks.
  • In dogs, serum level profiles showed essentially the same pattern.
  • In a series of experiments with multiple administration (once every 4 weeks), serum testosterone levels in rats at a dose of 3 mg/kg and those in dogs at 1.5 mg/kg did not show any flare-up at the second and third injection, and continued to be maintained at the suppressed levels. This study demonstrates that leuprolide acetate for depot suspension releases the drug at a constant rate for one month and has a long acting potency.
  • In another study, the effects of leuprolide acetate for depot suspension on accessory sex organ weights and hormone levels in adult male rats were compared to those produced by leuprolide acetate solution with subcutaneous administration. One group of rats were given 0.2, 1.0 and 5.0 mg/kg/day leuprolide acetate solution for 4 weeks; the other group received 0.6, 3.0 and 15 mg/kg leuprolide acetate for depot suspension once a week for 4 weeks. The reduction of organ weights and hormone levels was found more significant with the depot formulation than with the solution.
  • In a third study with rats, the effects of a single administration of leuprolide acetate for depot suspension at doses of 0.03, 0.3 and 3 mg/kg intramuscular, and 3 mg/kg subcutaneously on genital organ weights, were compared to those of the subcutaneous daily injection of 100 mcg/kg/day of solution for two weeks. Results showed that at the beginning of treatment, there was a slight increase, but over the remaining two-week treatment period, the organ weights decreased in dose-related fashion.
  • Sustained serum drug level, inhibition of steroidogenesis, drastic suppression of the growth of the reproductive organs were observed over a 3-Month period when LUPRON DEPOT (3-Month SR) formulation was studied in rats and dogs.

Human Pharmacology

Pharmacodynamics

With chronic administration, leuprolide had demonstrated a reduction in gonadotropins and sex steroids.

After an initial transient increase in testosterone or estradiol level, leuprolide produces a marked suppression of these levels as well as an inhibition of mammary and prostate tumor growth, and atrophy of the reproductive organs.

This decrease is maintained at castrate levels, as long as treatment continues.

There was no evidence of a dose-response relationship in the testosterone level with doses of 1 mg or 10 mg/day.

Pharmacokinetics

The absorption, metabolism, distribution, and excretion of leuprolide acetate in humans have not been fully established. See ACTION AND CLINICAL PHARMACOLOGY.

Absorption

LUPRON

The pharmacokinetics profile of leuprolide has been characterized in a single-dose, randomized, two-period, cross-over bioavailability study after administration of 1 mg doses by subcutaneous and by intravenous route in healthy male volunteers. Mean leuprolide plasma level curves were characteristic for each route. Mean levels during earlier sampling times were generally higher after the intravenous regimen, while levels during the later sampling times were generally higher after the subcutaneous regimen. The absolute bioavailability based on the ratio of the mean area under the curve (AUC) for subcutaneous/intravenous was 0.94 with a range of 0.70 to 1.24.

The mean plasma half-life was 2.9 hours. The study demonstrates that the bioavailability of leuprolide after subcutaneous administration was comparable to that of intravenous administration.

LUPRON DEPOT

The pharmacokinetic profile of LUPRON DEPOT has been characterized in an open, single- dose study in 10 orchierectomized prostatic cancer patients given 7.5 mg (1-Month SR) intramuscularly. Blood plasma levels were measured over an 8-week period.

After an initial burst, mean plasma leuprolide acetate concentrations declined to approximately 0.8 ng/mL within four days after the injection and remained basically stable for 2.5 weeks. Prolonged plasma concentrations were achieved with all but one patient with detectable plasma levels up to 4 weeks. Approximately 85 to 100% of the observed 8-week AUC was obtained for each patient after the first four weeks. After 8 weeks, plasma levels were essentially undetectable in all patients.

An estimate of the absolute bioavailability from this dosage form was approximately 90% when compared to an equivalent intravenous solution dose used in another study.

Toxicology

Acute Toxicity

LUPRON

Acute studies were conducted in rats and mice at 100 mg/kg/day. Only signs of decreased motor activity, dyspnea, and excessive scratching were reported; the LD50 is greater than 100 mg/kg/day in rats and mice.

LUPRON DEPOT

Mice and rats were given leuprolide acetate for depot suspension with different routes of administration: oral, intraperitoneal and subcutaneous (doses of 5 g/kg) and intramuscular (doses of 2 g/kg). No death occurred. The LD50 was concluded to be greater than 5 g/kg for intraperitoneal and subcutaneous routes and 2 g/kg for the intramuscular route.

Long-Term Toxicity

LUPRON

A series of subchronic and chronic toxicity studies conducted in mice, rats, and monkeys with daily subcutaneous injections of leuprolide acetate resulted in atrophy of the sex organs in both male and female animals. Reduced serum levels of gonadotropin hormones were observed in rats and monkeys following administration of leuprolide for 90 days.

Mouse

Maximum tolerated dose studies (prelude to carcinogenicity studies) were conducted in mice. The mice were dosed subcutaneously with 0, 20, 60, 200 and 600 mg/kg/day. Marked skin irritation at injection sites was observed in mice dosed with 200 and 600 mg/kg/day. Hypertrophy of anterior pituitary cells were observed in female mice dosed with 200 mg/kg/day but not at 600 mg/kg/day. Sex organ atrophy, secondary to the drug pharmacologic effects, were observed in all treated male and female mice. The maximum tolerated dose in mice was 60 mg/kg/day.

Rat

Marked pharmacologic effects consisting of atrophy of primary and secondary sex organs in both sexes were observed in rats dosed with 1 to 4 mg/kg/day of leuprolide for 90 days. No overt toxic effects were observed. The "no-toxic-effect" dosage was 4 mg/kg/day.

Maximum tolerated dose studies (prelude to carcinogenicity studies) were conducted in rats. Rats were dosed subcutaneously with 0, 10, 30, 100 and 300 mg/kg/day for 90 days. Drug related pituitary hyperplasia and hypertrophy, atrophy of sex organs (both sexes) and marked skin irritation at the injection sites were observed in rats. As a result, no maximum tolerated dose was established by the study.

Monkey

Rhesus monkeys dosed subcutaneously with 0, 1, 2 and 4 mg/kg/day for 90 days exhibited marked atrophy of the primary and secondary sex organs of both sexes. The reproductive effects were consistent with the pharmacologic action of the drug. The "no-toxic-effect" dosage was 4 mg/kg/day as no overt toxicity was observed.

Leuprolide was administered subcutaneously to cynomolgus monkeys once daily at dosages of 0, 0.6, 4.0 and 10 mg/kg/day for one year. Atrophy of sex organs of both sexes was the principal finding. These changes were ascribed to the pharmacologic activity of the drug. The "no-toxic- effect" dose was 10 mg/kg/day.

LUPRON DEPOT

Rat

Leuprolide acetate for depot suspension was administered intramuscularly to three groups of male rats at doses from 10, 30 and 100 mg/kg/week (corresponding to 0.8, 2.4 and 8.0 mg/kg/week of leuprolide acetate injection) once a week for 13 weeks. Rats dosed at 100 mg/kg/week showed atrophy of testes; in addition white spots were noted at the injection sites. The atrophy of the testes was reported to be due to the hormonal action of leuprolide acetate injection; the "no-toxic-effect" dose was considered to be 100 mg/kg/week.

In another toxicity study, male rats were given leuprolide acetate for depot suspension subcutaneously once a week for 3 weeks, at doses of 30 mg/kg/week (corresponding to 2.4 mg/kg/week of leuprolide acetate injection). Atrophy of the testes, and a slight induration were noted. The "no-toxic effect" dose was considered to be 30 mg/kg/week.

In a third study, leuprolide acetate for depot suspension was given subcutaneously to groups of male and female rats, at doses of 0, 10, 30 and 100 mg/kg/week once a week for 13 weeks (corresponding to 0, 0.8, 2.4 and 8 mg/kg/week of leuprolide acetate injection). Atrophy of the testes was noted, with induration at injection site; in female rats, the vagina failed to open throughout the dosing period. Leuprolide acetate for depot suspension produced changes related to the expected pharmacologic effects. The "no-toxic-effect" dose was considered to be 100 mg/kg/week.

Dog

In two different studies, female and male beagle dogs were given leuprolide acetate for depot suspension subcutaneously for 13 weeks, once a week at doses of 10, 30, 100 mg/kg/week, corresponding to 0.8, 2.4 and 8 mg/kg/week leuprolide acetate injection. No death was reported. Signs and symptoms include inflammatory lesions at the injection sites, and atrophic changes of the primary and accessory sex glands. The injection site change, seen in both control and test groups, was induced by the microcapsule, not leuprolide, and was reversible.

Special Studies

LUPRON DEPOT

Rabbits

In a preliminary study, male rabbits were given single injections (1 mL/animal) of a 15% suspension of leuprolide acetate for depot suspension into the subcutaneous tissue of the abdomen to assess local irritation.

Deposition of the test drug at site of injection was noted at 2 and 14 days after the injection, along with slight hemorrhage and dilatation of capillaries at 50 days after the injection. Leuprolide acetate for depot suspension was reported not to produce significant subcutaneous irritation in rabbits in this study.

In a second irritation study, male rabbits were injected once or 4 successive times with leuprolide acetate for depot suspension (15% suspension) by intramuscular administration. Results were compared to those obtained with placebo-microcapsule or a 0.75% solution of acetic acid as the positive control. Deposition at injection sites, and slight irritation changes (hemorrhage, edema, inflammation) were noted: leuprolide acetate for depot suspension produced the same effects with same the degree as the placebo-microcapsule, but these are less than those of the positive control (0.75% acetic acid), and their severity were not potentiated by 4 repeated injections.

The injection-site toxicity and irritation effects of LUPRON DEPOT (3-Month SR) were studied in rabbits. The rabbits were administered with intramuscular and subcutaneous injections at doses of 11.25 mg/mL for intramuscular injection and 5.64 mg/mL for subcutaneous injection. Intramuscular injection was in the left vastus lateralis muscle, and subcutaneous injection was in the abdominal region. Only mild irritative changes such as mild hemorrhage and degeneration of the muscle fiber were seen 2 days after the injection. Moreover, granulation tissue composed of macrophages and multinucleated giant cells was observed. The size of granulation tissue observed was decreased 13 weeks after the injection. Therefore, these changes were characterized mainly by foreign body reactions caused by the persistence of the microcapsule formulation.

Guinea Pigs

Two studies were performed to evaluate the potential of leuprolide acetate for depot suspension to produce either systemic anaphylaxis or delayed hypersensitivity reactions in guinea pigs.

Preliminary antigenicity study. Leuprolide acetate for depot suspension was given to guinea pigs at a dose of 123 mg/kg every 2 weeks by intramuscular route 4 times, and once by subcutaneous route 2 weeks after the last intramuscular dose. Results were compared to controls treated with placebo-microcapsule 122 mg/kg intraperitoneally, or with ovalbumin 5 mg/animal intravenously. No systemic anaphylactic reactions were observed with animals treated with leuprolide acetate for depot suspension and placebo-microcapsule, but some induced equivocal weak antibody production was noted.

In a second study, the sensitization potential of leuprolide acetate for depot suspension at doses of 50 mg/animal/dosing by intramuscular (systemic anaphylaxis) or at doses of approximately 7.2 mg/animal/dosing (0.05 mL of a 144.23 mg/mL of suspension) intradermal (delayed hypersensitivity), were compared to those seen with gelatin, egg albumin or captan. No signs of anaphylactic reactions nor delayed hypersensitivity were observed for leuprolide acetate for depot suspension, while signs of anaphylactic reactions (such as nose scratching, sneezing, dyspnea or local irritation) were noted with other compounds.

Mutagenicity and Carcinogenicity

Mutagenicity

LUPRON

Leuprolide has been studied in vitro and in vivo, using bacterial and mammalian systems.

In vitro assays using Salmonella and Saccharomyces with and without the presence of liver microsomal enzyme from Aroclor-1254 induced rats, no signs of mutagenicity have been observed.

Leuprolide was non-mutagenic in vivo cytogenic assay in rats or in the Mouse Dominant Lethal assay at doses of 0, 1, 2 and 4 mg/kg administered subcutaneously.

Both in vitro and in vivo studies have provided no evidence of a mutagenic potential of leuprolide.

LUPRON DEPOT

In the Ames Test, using S. typhimurium, strains TA 98, TA 100, TA 1535 and TA 1537, and E. coli strain WP2hcr, leuprolide acetate for depot suspension was found not mutagenic at dosing ranging from 0.03 to 10 mg/plate, irrespective of treatment with mammalian metabolic activation system (S-9 mix).

Carcinogenicity

LUPRON DEPOT

Two rodent carcinogenicity studies were conducted for two years with daily doses of 0.6, 1.5, and 4 mg/kg/day in the rat, and with 0.6, 6, and 60 mg/kg/day in the mouse.

In rats, a dose-related incidence of pituitary hyperplasia, hypertrophy and benign pituitary adenomas were noted at 12 month necropsy, while a statistically significant dose-related incidence of benign pituitary adenomas was observed in both male and female rats after 24 months when the drug was administered subcutaneously at high daily doses (0.6 to 4 mg/kg).

In mice, no drug-induced neoplastic changes or pituitary abnormalities were observed at doses as high as 60 mg/kg for two years.

Patients have been treated with leuprolide 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. Clinical signs of pituitary abnormalities have not been observed in any of these patients.

Reproduction and Teratology

Fertility and Reproduction

LUPRON DEPOT

Fertility and reproductive performance studies cannot be conducted with leuprolide, because the compound affects the pituitary-gonadal axis and influences endocrine reproductive organs. As a result, there would be a decrease in fertility and reproduction.

Clinical and pharmacologic studies with leuprolide acetate and similar analogs have shown full reversibility of fertility suppression when the drug is discontinued after continuous administration for periods of up to 24 weeks.

Although no clinical studies have been completed in children to assess the full reversibility of fertility suppression, animal studies (prepubertal and adult rats and monkeys) with leuprolide acetate and other GnRH analogs have shown functional recovery. However, following a study with leuprolide acetate, immature male rats demonstrated tubular degeneration in the testes even after a recovery period. In spite of the failure to recover histologically, the treated males proved to be as fertile as the controls. Also, no histologic changes were observed in the female rats following the same protocol. In both sexes, the offspring of the treated animals appeared normal. The effect of the treatment of the parents on the reproductive performance of the F1 generation was not tested. The clinical significance of these findings is unknown.

LUPRON DEPOT Product Monograph

Teratology

LUPRON DEPOT

Leuprolide administered to pregnant rats at dosages of 0, 1, 3 and 10 mcg/kg/day from gestational day 6 to gestational day 15 (major period of organogenesis) was not teratogenic. At 10 mcg/kg/day, leuprolide increased the incidence of resorptions; surviving fetuses showed no abnormalities. The "no-toxic-effect" dosage was 3 mcg/kg/day.

Leuprolide increased the incidence of embryonic resorptions in pregnant rabbits when dosed with 0, 0.1, 0.3 or 1.0 mcg/kg/day during the period of major organogenesis, i.e., gestational day 6 through gestational day 18. Surviving fetuses showed no abnormalities.