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DESCRIPTION
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-PED 7.5 mg, 11.25 mg, or 15 mg for 1-month administration
LUPRON DEPOT-PED is available in a prefilled dual-chamber syringe containing sterile lyophilized microspheres which, when mixed with diluent, become a suspension intended as a single intramuscular injection.
The front chamber of LUPRON DEPOT-PED 7.5 mg, 11.25 mg, and 15 mg prefilled dual-chamber syringe contains leuprolide acetate (7.5/11.25/15 mg), purified gelatin (1.3/1.95/2.6 mg), DL-lactic and glycolic acids copolymer (66.2/99.3/132.4 mg), and D-mannitol (13.2/19.8/26.4 mg). The second chamber of diluent contains carboxymethylcellulose sodium (5 mg), D-mannitol (50 mg), polysorbate 80 (1 mg), water for injection, USP, and glacial acetic acid, USP to control pH.
LUPRON DEPOT-PED 11.25 mg or 30 mg for 3-month administration
LUPRON DEPOT-PED 11.25 mg or 30 mg for 3-month administration 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-PED 11.25 mg for 3-month administration 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.
The front chamber of LUPRON DEPOT-PED 30 mg for 3-month administration prefilled dual-chamber syringe contains leuprolide acetate (30 mg), polylactic acid (264.8 mg) and D-mannitol (51.9 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.
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CLINICAL PHARMACOLOGY
Mechanism of Action
Leuprolide acetate, a GnRH agonist, acts as a potent inhibitor of gonadotropin secretion when given continuously and in therapeutic doses. Human studies indicate that following an initial stimulation of gonadotropins, chronic stimulation with leuprolide acetate results in suppression or "downregulation" of these hormones and consequent suppression of ovarian and testicular steroidogenesis. These effects are reversible on discontinuation of drug therapy.
Leuprolide acetate is not active when given orally.
Pharmacokinetics
Absorption
LUPRON DEPOT-PED 7.5 mg, 11.25 mg, or 15 mg for 1-month administration
Following a single LUPRON DEPOT-PED 7.5 mg for 1-month administration to adult patients, mean peak leuprolide plasma concentration was almost 20 ng/mL at 4 hours and then declined to 0.36 ng/mL at 4 weeks. However, intact leuprolide and an inactive major metabolite could not be distinguished by the assay which was employed in the study. Nondetectable leuprolide plasma concentrations have been observed during chronic LUPRON DEPOT-PED 7.5 mg administration, but testosterone levels appear to be maintained at castrate levels.
In a study of 55 children with central precocious puberty, doses of 7.5 mg, 11.25 mg and 15.0 mg of LUPRON DEPOT-PED were given every 4 weeks and in a subset of 22 children, trough leuprolide plasma levels were determined according to weight categories as summarized below:
| * Group average values determined at Week 4 immediately prior to leuprolide injection. Drug levels at 12 and 24 weeks were similar to respective 4 week levels. |
Patient Weight
Range (kg)
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Group Weight
Average (kg)
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Dose (mg)
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Trough Plasma Leuprolide Level
Mean ±SD (ng/mL)*
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| 20.2 - 27.0 |
22.7 |
7.5 |
0.77±0.033 |
| 28.4 - 36.8 |
32.5 |
11.25 |
1.25±1.06 |
| 39.3 - 57.5 |
44.2 |
15.0 |
1.59±0.65 |
LUPRON DEPOT-PED 11.25 mg or 30 mg for 3-month administration
Following a single LUPRON DEPOT-PED 11.25 mg or 30 mg for 3-month administration to children with CPP, leuprolide concentrations increased with increasing dose with mean peak leuprolide plasma concentration of 19.1 and 52.5 ng/mL at 1 hour for the 11.25 and 30 mg dose levels, respectively. The concentrations then declined to 0.08 and 0.25 ng/mL at 2 weeks after dosing for the 11.25 and 30 mg dose levels. Mean leuprolide plasma concentration remained constant from month 1 to month 3 for both 11.25 and 30 mg doses. The mean leuprolide concentrations 3 months after the first and second injections were similar indicating no accumulation of leuprolide from repeated administration.
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
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.
The major metabolite (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.
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.
Specific Populations
The pharmacokinetics of LUPRON DEPOT-PED has not been determined in patients with hepatic or renal impairment.
Drug-Drug Interactions
No pharmacokinetic-based drug-drug interaction studies have been conducted with LUPRON DEPOT-PED. 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 are not expected to occur.
NONCLINICAL TOXICOLOGY
Carcinogenesis, Mutagenesis, Impairment of Fertility
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. Adult 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.
Following subcutaneous administration of LUPRON DEPOT to male and female rats before mating there was atrophy of the reproductive organs and suppression of reproductive performance.
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 has been evaluated using LUPRON DEPOT formulation to groups of rats as one-time subcutaneous dose of 0.024 mg/kg (1/19 of the pediatric dose) on Day 15 of gestation or dosing on parturition day at doses up to 8 mg/kg (18 fold of the pediatric dose). There was no effect on growth, morphological development and reproductive performance of F1 generation.
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CLINICAL STUDIES
LUPRON DEPOT-PED 7.5 mg, 11.25 mg, or 15 mg for 1-month administration
In children with central precocious puberty (CPP), therapeutic doses of LUPRON DEPOT-PED reduce stimulated and basal gonadotropins to prepubertal levels. Testosterone and estradiol are also reduced to prepubertal levels in males and females respectively. Reduction of gonadotropins and sex steroids allow a return to age-appropriate physical and psychological growth and development. The following effects have been noted with the chronic administration of leuprolide: cessation of menses (in girls), normalization and stabilization of linear growth and bone age advancement, stabilization of clinical signs and symptoms of puberty.
55 CPP subjects (49 females and 6 males, naïve to previous GnRHa treatment), were treated with LUPRON DEPOT-PED 1-month formulations until age appropriate for entry into puberty (see treatment period data below) and a subset of 40 subjects were then followed post-treatment (see follow-up period data below).
Treatment Period Data:
During the treatment period, LUPRON DEPOT-PED suppressed gonadotropins and sex steroids to prepubertal levels. Suppression of peak stimulated LH concentrations to < 1.75 mIU/mL was achieved in 96% of subjects by month 1. Five subjects required increased doses of study drug to achieve or retain LH suppression. The number and percentage of subjects with suppression of peak stimulated LH < 1.75 mIU/mL and mean ± SD peak stimulated LH over time is shown in Table 4. The mean ± SD age at the start of treatment was 7 ± 2 years and the duration of treatment was 4 ± 2 years. Six months after the treatment period was finished, the mean peak stimulated LH was 20.6 ± SD 13.7 mIU/mL (n=30).
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Table 4. The number and percentage of patients with peak stimulated LH < 1.75 mIU/mL and Mean (SD) peak LH at each clinic visit
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Weeks on Study
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n with peak stimulated LH < 1.75 mIU/mL/
N with a LH measurement for that week
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Mean (SD) peak LH
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n/N
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%
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| Baseline |
0/55 |
0% |
35.0 (21.32) |
| Week 4 |
53/55 |
96.4% |
0.8 (0.57) |
| Week 12 |
48/54 |
88.9% |
1.1 (1.77) |
| Week 24 |
48/53 |
90.6% |
0.8 (0.79) |
| Week 36 |
51/54 |
94.4% |
0.6 (0.43) |
| Week 48 |
51/54 |
94.4% |
0.6 (0.47) |
| Week 72 |
52/52 |
100% |
0.5 (0.30) |
| Week 96 |
46/46 |
100% |
0.4 (0.33) |
| Week 120 |
40/40 |
100% |
0.4 (0.27) |
| Week 144 |
36/36 |
100% |
0.4 (0.24) |
| Week 168 |
27/28 |
96.4% |
1.2 (4.58) |
| Week 216 |
18/19 |
94.7% |
0.5 (0.90) |
| Week 240 |
16/17 |
94.1% |
0.4 (0.62) |
| Week 264 |
14/15 |
95.3% |
0.4 (0.41) |
| Week 288 |
11/11 |
100% |
0.3 (0.22) |
| Week 312 |
9/9 |
100% |
0.4 (0.20) |
| Week 336 |
6/6 |
100% |
0.3 (0.10) |
| Week 360 |
6/6 |
100% |
0.3 (0.13) |
| Week 384 |
5/5 |
100% |
0.2 (0.10) |
| Week 408 |
3/3 |
100% |
0.2 (0.09) |
| Week 432 |
2/2 |
100% |
0.3 (0.04) |
| Week 456 |
2/2 |
100% |
0.2 (0.04) |
| Week 480 |
1/1 |
100% |
0.2 (NA) |
| Week 504 |
1/1 |
100% |
0.2 (NA) |
Suppression (defined as regression or no change) of the clinical/physical signs of puberty was achieved in most patients. In females, suppression of breast development ranged from 66.7 to 90.6% of subjects during the first 5 years of treatment. The mean stimulated estradiol was 15.1 pg/mL at baseline, decreased to the lower level of detection (5.0 pg/mL) by Week 4 and was maintained there during the first 5 years of treatment. In males, suppression of genitalia development ranged from 60% to 100% of subjects during the first 5 years of treatment. The mean stimulated testosterone was 347.7 ng/dL at baseline and was maintained at levels no greater than 25.3 ng/dL during the first 5 years of treatment.
A “flare effect” of transient bleeding or spotting during the first 4 weeks of treatment was observed in 19.4% (7/36) females who had not reached menarche at baseline. After the first 4 weeks and for the remainder of the treatment period, no subject reported menstrual-like bleeding, and only rare spotting was noted.
In many subjects, growth rate decreased on treatment, as did bone age: chronological age ratio. Through year 5, the mean growth rate ranged between 3.4 and 5.6 cm/yr. The mean ratio of bone age to chronological age decreased from 1.5 at baseline to 1.1 by end of treatment. The mean height standard deviation score changed from 1.6 at baseline to 0.7 at the end of the treatment phase.
Follow-up Period Data:
35 females and 5 males participated in a post-treatment follow-up period to assess reproductive function (in females) and final height. At 6 months post-treatment, most subjects reverted to pubertal levels of LH (87.9%) and clinical signs of resumption of pubertal progression were evident with increase in breast development in girls (66.7%) and increase in genitalia development in boys (80%).
Of the 40 patients evaluated in the follow-up, 33 were observed until they reached final or near-final adult height. These patients had a mean increase in final adult height compared to baseline predicted adult height. The mean final adult height standard deviation score was -0.2.
After stopping treatment, regular menses were reported for all female subjects who reached 12 years of age during follow-up; mean time to menses was approximately 1.5 years; mean age of onset of menstruation after stopping treatment was 12.9 years. Data to assess reproductive function was collected in a post-study survey of 20 girls who reached adulthood (ages 18-26): menstrual cycles were reported to be normal in 80% of women; 12 pregnancies were reported for a total of 7 of the 20 subjects, including multiple pregnancies for 4 subjects.
LUPRON DEPOT-PED 11.25 mg or 30 mg for 3-month administration
In a randomized, open-label clinical study of LUPRON DEPOT-PED 3-Month formulations, 84 subjects (76 female, 8 male) between 1 and 11 years of age received the LUPRON DEPOT-PED 11.25 mg or 30 mg for 3-month administration formulation. Each dose group had an equal number of treatment-naïve patients who had pubertal LH levels and patients previously treated with GnRHa therapies who had prepubertal LH levels at the time of study entry. The percentage of subjects with suppression of peak-stimulated LH to < 4.0 mIU/mL, as determined by assessments at months 2, 3 and 6 is 78.6% in the 11.25 mg dose and 95.2% in the 30 mg dose as shown in Table 5.
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Table 5. Suppression of Peak-Stimulated LH from Month 2 Through Month 6
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LUPRON DEPOT-PED
11.25 mg every 3 Months
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LUPRON DEPOT-PED
30 mg every 3 Months
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Parameter
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Naïve
N = 21
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Prev Trta
N = 21
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Total
N = 42
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Naïve
N = 21
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Prev Trta
N = 21
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Total
N = 42
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| Percent with Suppression |
76.2 |
81.0 |
78.6 |
90.5 |
100 |
95.2 |
| 2-sided 95% CI |
52.8, 91.8 |
58.1, 94.6 |
63.2, 89.7 |
69.6, 98.8 |
83.9, 100 |
83.8, 99.4 |
| a. Previously treated with GnRHa for at least 6 months prior to enrollment in pivotal Study L-CP07-167. |
The mean peak stimulated LH levels for all visits are shown by dose and subgroup (naïve vs. previously treated subjects) in Figures 1 and 2.
Figure 1. Mean Peak Stimulated LH for LUPRON DEPOT-PED 11.25 mg for 3-month administration
Figure 2. Mean Peak Stimulated LH for LUPRON DEPOT-PED 30 mg for 3-month administration
For the LUPRON DEPOT-PED 11.25 mg dose for 3-month administration, 93% (39/42) of subjects and for LUPRON DEPOT-PED 30 mg dose for 3-month administration 100% (42/42) of subjects had sex steroid (estradiol or testosterone) suppressed to prepubertal levels at all visits. Clinical suppression of puberty in female patients was observed in 29 of 32 (90.6%) and 28 of 34 (82.4%) of patients in the 11.25 mg and 30 mg groups, respectively, at month 6. Clinical suppression of puberty in males was observed in 1 of 2 (50.0%) and 2 of 5 (40.0%) patients in the 11.25 mg and 30 mg groups, respectively, at month 6. In subjects with complete data for bone age, 29 of 33 (87.9 %) in the 11.25 mg group and 30 of 40 in the 30 mg group (75.0%) had a decrease in the ratio of bone age to chronological age at month 6 compared to screening.
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