Lupron Depot Pediatric

Lupron Depot Pediatric

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

Following a single LUPRON DEPOT-PED–1 Month 7.5 mg injection 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:

Patient Weight Range (kg) Group Weight Average (kg) Dose (mg) Trough Plasma Leuprolide Level Mean ±SD (ng/mL)*
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
* 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.

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 the drug has not been determined in patients with hepatic and renal impairment.

Drug-Drug Interactions

No pharmacokinetic-based drug-drug interaction studies have been conducted with LUPRON DEPOT-PED–1 Month. 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.

Clinical Studies

Lupron Depot Ped–1 Month

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, na´ve 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. 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 3. 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).

Table 3: The number and percentage of patients with peak stimulated LH < 1.75 mIU/mL and Mean (SD) peak LH at each clinic visit

Weeks on Study n with peak stimulated LH 1.75 mIU/mL / N with a LH measurement for that week n/N % Mean (SD) peak LH
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.

Last reviewed on RxList: 10/21/2011
This monograph has been modified to include the generic and brand name in many instances.

A A A

Report Problems to the Food and Drug Administration

 

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.


Women's Health

Find out what women really need.

Related Drugs
Health Resources
Related Supplements
advertisement
advertisement
Use Pill Finder Find it Now See Interactions

Pill Identifier on RxList

  • quick, easy,
    pill identification

Find a Local Pharmacy

  • including 24 hour, pharmacies

Interaction Checker

  • Check potential drug interactions
Search the Medical Dictionary for Health Definitions & Medical Abbreviations