Lupron CPP
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Lupron CPP - Scientific Information

Manufacture: AbbVie
Country: Canada
Condition: Endometriosis, Hirsutism, Prostate Cancer, Uterine Fibroids
Class: Gonadotropin-releasing hormone antagonists, Hormones/antineoplastics
Form: Liquid solution, Subcutaneous (SC)
Ingredients: leuprolide acetate, benzyl alcohol, sodium chloride, sterile 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

Table 1. Summary of Patient Demographics for Clinical Trials in Patients with Central Precocious Puberty
Study # Trial design Dosage, route of administration and duration Study
subjects
(n=number)
Mean age
(Range)
Gender
I Phase 3,
open,
multicenter
study
LUPRON DEPOT 7.5, 11.25 or 15 mg based on body weight Intramuscular Drug is discontinued when an age appropriate for puberty is attained 22 6.9 years
(1.1 - 8.9 years)
2 M, 20 F
Definitions: M = male, F = female.

Study Results

In an open, multicenter study, LUPRON DEPOT (leuprolide acetate for depot suspension) was shown to be safe and effective in the therapeutic management of children with central precocious puberty (CPP). Successful suppression of gonadotropins and sex steroids to prepubertal levels was achieved in 95% of the children by Week 4. In addition, the majority of these children demonstrated decreases or stabilization in Tanner staging of breast, pubic hair, and genitalia compared with baseline. Menses ceased in all females by the end of the second therapeutic month, and growth rates were reduced.

Table 2. Results of Study I in Patients with Central Precocious Puberty
Primary Endpoints Associated value and statistical
significance for LUPRON DEPOT
The criteria for effectiveness include:
  1. Height, weight, growth rate
  2. Bone age and predicted height
  3. Tanner Staging (Breast, Pubic Hair, Genitalia)
  4. Menses
  5. Hormone Determinations (Gonadotropins, Sex Steroids)
Successful suppression of gonadotropins
and sex steroids to prepubertal levels was
achieved in 95% of the children by week 4.

In an open, non-comparative, multi-centre study involving LUPRON (leuprolide acetate injection) and LUPRON DEPOT (leuprolide acetate for depot suspension), once adequate suppression of the pituitary-gonadal axis was achieved, the children demonstrated both physical and psychological regression of sexual maturation, slowing of linear growth velocity, and a decrease in the ratio of bone age to chronological age.

LUPRON/LUPRON DEPOT

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.

Detailed pharmacology

Leuprolide acetate is an analog of gonadotropin-releasing hormone (Gn-RH). 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 another 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

General

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.

Central Precocious Puberty

With chronic administration, LUPRON and LUPRON DEPOT demonstrated a reduction of gonadotropins and sex steroids to prepubertal levels, and a slowing of linear growth velocity, as long as treatment continued at therapeutic doses.

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 pharmacokinetic 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 orchiectomized 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 than100 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.

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 the same degree as the placebo-microcapsule, but these were 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

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.

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.

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.

Maximum tolerated dose studies (prelude to carcinogenicity studies) were conducted in rats and mice. Rats were dosed subcutaneously with 0, 10, 30, 100 and 300 mg/kg/day for 90 days while mice received 0, 20, 60, 200 and 600 mg/kg/day.

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.

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.

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 included 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.

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.

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.