Lupaneta Pack 3.75 mg - Pharmaceutical Information, Clinical Trials, Detailed Pharmacology, Toxicology
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Lupaneta Pack 3.75 mg - Scientific Information

Manufacture: AbbVie
Country: United States
Condition: Endometriosis
Class: Sex hormone combinations
Form: Intramuscular (IM), Tablets, Powder
Ingredients: leuprolide acetate, gelatin, DL-lactic and glycolic acids copolymer, D-mannitol, carboxymethylcellulose sodium, polysorbate 80, water for injection, USP, glacial acetic acid, norethindrone acetate USP, colloidal silicon dioxide, lactose monohydrate, magnesium stearate, microcrystalline cellulose, talc.

Description

LUPANETA PACK (leuprolide acetate for depot suspension; norethindrone acetate tablets) 1-month contains one dual chamber syringe with leuprolide acetate for depot suspension 3.75 mg and norethindrone acetate tablets USP: 5 mg (bottle of 30 tablets).

Leuprolide Acetate for Depot Suspension

Leuprolide acetate for depot suspension is a synthetic nonapeptide analog of gonadotropin-releasing hormone (GnRH or LH-RH), a GnRH agonist. 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:

Leuprolide acetate for depot suspension 3.75 mg 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.

The front chamber of leuprolide acetate for depot suspension 3.75 mg prefilled dual-chamber syringe contains leuprolide acetate for depot suspension (3.75 mg), gelatin (0.65 mg), DL-lactic and glycolic acids copolymer (33.1 mg), and D-mannitol (6.6 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.

During the manufacture of leuprolide acetate for depot suspension, acetic acid is lost, leaving the peptide.

Norethindrone Acetate

Norethindrone acetate tablets USP — 5 mg oral tablets.

Norethindrone acetate USP, (17-hydroxy-19-nor-17α-pregn-4-en-20-yn-3-one acetate), a synthetic, orally active progestin, is the acetic acid ester of norethindrone. It is a white, or creamy white, crystalline powder.

neta chemical structure

Norethindrone acetate tablets USP, 5 mg contain the following inactive ingredients: colloidal silicon dioxide, lactose monohydrate, magnesium stearate, microcrystalline cellulose and talc.

Clinical Pharmacology

Mechanism of Action

Leuprolide Acetate for Depot Suspension

Leuprolide acetate for depot suspension is a long-acting GnRH analog. A single injection of leuprolide acetate for depot suspension results in an initial elevation followed by a prolonged suppression of pituitary gonadotropins. Repeated dosing at quarterly intervals results in decreased secretion of gonadal steroids; consequently, tissues and functions that depend on gonadal steroids for their maintenance become quiescent. This effect is reversible on discontinuation of drug therapy.

Leuprolide acetate is not active when given orally.

Norethindrone Acetate

Norethindrone acetate induces secretory changes in an estrogen-primed endometrium.

Pharmacodynamics

In a pharmacokinetic/pharmacodynamic study of leuprolide acetate 11.25 mg for 3-month administration in 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) was in 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/mL in 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 43-240 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.

Pharmacokinetics

Absorption

Leuprolide Acetate for Depot Suspension

Following a single injection of the three month formulation of leuprolide acetate for depot suspension (11.25 mg) in female subjects, a mean plasma leuprolide concentration of 36.3 ng/mL was observed at 4 hours. Leuprolide appeared to be released at a constant rate following the onset of steady-state levels during the third week after dosing and mean levels then declined gradually to near the lower limit of detection by 12 weeks. The mean (± standard deviation) leuprolide concentration from 3 to 12 weeks was 0.23 ± 0.09 ng/mL. However, intact leuprolide and an inactive major metabolite could not be distinguished by the assay which was employed in the study. The initial burst, followed by the rapid decline to a steady-state level, was similar to the release pattern seen with the monthly formulation.

Norethindrone Acetate

Norethindrone acetate is deacetylated to norethindrone after oral administration, and the disposition of norethindrone acetate is indistinguishable from that of orally administered norethindrone. Norethindrone acetate is absorbed from norethindrone acetate tablets, with maximum plasma concentration of norethindrone generally occurring at about 2 hours post-dose (see Figure 1). The pharmacokinetic parameters of norethindrone following single oral administration of 5 mg norethindrone acetate under fasting conditions in 29 healthy female volunteers are summarized in Table 1.

Table 1. Pharmacokinetic Parameters after a Single Dose of Norethindrone Acetate in Healthy Women
Norethindrone Acetate (n=29) Arithmetic Mean ± SD
Norethindrone
AUC (0-inf) (ng/ml*h) 166.90 ± 56.28
Cmax (ng/ml) 26.19 ± 6.19
tmax (h) 1.83 ± 0.58
t1/2 (h) 8.51 ± 2.19

AUC = area under the curve,

Cmax = maximum plasma concentration,

tmax = time at maximum plasma concentration,

t1/2 = half-life

SD = standard deviation

Figure 1. Mean Norethindrone Plasma Concentration Profile after a Single Dose of 5 mg Norethindrone Acetate Administered to 29 Healthy Female Volunteers under Fasting Conditions

Effect of Food:

The effect of food administration on the pharmacokinetics of norethindrone acetate has not been studied.

Distribution

Leuprolide Acetate for Depot Suspension

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%.

Norethindrone Acetate

Norethindrone is 36% bound to sex hormone-binding globulin (SHBG) and 61% bound to albumin. Volume of distribution of norethindrone is about 4 L/kg.

Metabolism

Leuprolide Acetate for Depot Suspension

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 14 C-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.

In a pharmacokinetic/pharmacodynamic study of endometriosis patients, intramuscular 11.25 mg leuprolide acetate for depot suspension (n=19) every 12 weeks or intramuscular 3.75 mg leuprolide acetate for depot suspension (n=15) every 4 weeks was administered for 24 weeks. There was no statistically significant difference in changes of serum estradiol concentration from baseline between the 2 treatment groups.

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.

Norethindrone Acetate

Norethindrone undergoes extensive biotransformation, primarily via reduction, followed by sulfate and glucuronide conjugation. The majority of metabolites in the circulation are sulfates, with glucuronides accounting for most of the urinary metabolites.

Excretion

Leuprolide Acetate for Depot Suspension

Following administration of leuprolide acetate for depot suspension 3.75 mg for 1-month administration to 3 patients, less than 5% of the dose was recovered as parent and M-I metabolite in the urine.

Norethindrone Acetate

Plasma clearance value for norethindrone is approximately 0.4 L/hr/kg. Norethindrone is excreted in both urine and feces, primarily as metabolites. The mean terminal elimination half-life of norethindrone following a single dose administration of norethindrone acetate is approximately 9 hours.

Specific Populations

Hepatic Impairment

The effect of hepatic disease on the disposition of norethindrone after norethindrone acetate administration has not been evaluated. However, norethindrone acetate is contraindicated in markedly impaired liver function or liver disease [see Contraindications].

The pharmacokinetics of the leuprolide acetate for depot suspension in hepatically impaired patients has not been determined.

Renal Impairment

The effect of renal disease on the disposition of norethindrone after norethindrone acetate administration has not been evaluated. In pre-menopausal women with chronic renal failure undergoing peritoneal dialysis who received multiple doses of an oral contraceptive containing ethinyl estradiol and norethindrone, plasma norethindrone concentration was unchanged compared to concentrations in pre-menopausal women with normal renal function.

The pharmacokinetics of the leuprolide acetate for depot suspension in renally impaired patients has not been determined.

Race

The effect of race on the disposition of norethindrone after norethindrone acetate administration has not been evaluated.

Drug Interactions

Leuprolide Acetate for Depot Suspension

Leuprolide acetate for depot suspension 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 would not be expected to occur.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Leuprolide Acetate for Depot Suspension

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. 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.

Mutagenicity studies have been performed with leuprolide acetate using bacterial and mammalian systems. These studies provided no evidence of a mutagenic potential.

Clinical and pharmacologic studies in adults (>18 years) with leuprolide acetate and similar analogs have shown 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.

Clinical Studies

Leuprolide Acetate for Depot Suspension

Initial endometriosis efficacy data for leuprolide acetate for depot suspension were based on the 3.75 mg dose administered once monthly.

A pharmacokinetic/pharmacodynamic study in 41 women that included both the 3.75 mg dose administered once monthly and the 11.25 mg dose administered once every three months did not reveal clinically significant differences in terms of efficacy in reducing painful symptoms of endometriosis or magnitude of the decrease in bone mineral density (BMD) associated with use of leuprolide acetate.

Leuprolide Acetate for Depot Suspension Plus Norethindrone Acetate

Two clinical studies with treatment duration of 12 months were conducted to evaluate the effect of coadministration of leuprolide acetate for depot suspension and norethindrone acetate on the loss of bone mineral density (BMD) associated with leuprolide acetate for depot suspension and on the efficacy of leuprolide acetate for depot suspension in relieving symptoms of endometriosis. (All patients in these studies received calcium supplementation with 1000 mg elemental calcium). A total of 242 women were treated with monthly administration of leuprolide acetate 3.75 mg (13 injections) and with 5 mg norethindrone acetate taken daily. The population age range was 17-43 years old. The majority of patients were Caucasian (87%).

One coadministration study was a controlled, randomized and double-blind study included 51 women treated monthly with leuprolide acetate for depot suspension alone and 55 women treated monthly with leuprolide acetate for depot suspension plus norethindrone acetate daily. Women in this trial were followed for up to 24 months after completing one year of treatment. The other study was an open-label single arm clinical study in 136 women of one year of treatment with leuprolide acetate for depot suspension and norethindrone acetate, with follow-up for up to 12 months after completing treatment.

The second study was an open label, single arm study in which 136 women were treated monthly with leuprolide acetate for depot suspension plus norethindrone acetate daily, with follow-up for up to 12 months after completing treatment.

The assessment of efficacy was based on the investigator’s or the patient’s monthly assessment of five signs or symptoms of endometriosis (dysmenorrhea, pelvic pain, deep dyspareunia, pelvic tenderness and pelvic induration).

Table 2 below provides detailed efficacy data regarding relief of symptoms of endometriosis based on the two studies of coadministration of leuprolide acetate and norethindrone acetate.

Table 2. Percentages of Patients with Symptoms of Endometriosis and Mean Clinical Severity Scores
  Percent of Patients with Symptom Clinical Pain Severity Score
Baseline Final Baseline Final
Variable Study Group N1 (%)2 (%) N1 Value3 Change
Dysmenorrhea Controlled Study LA* 51 (100) (4) 50 3.2 -2.0
  LA/N 55 (100) (4) 54 3.1 -2.0
Open Label Study LA/N 136 (99) (9) 134 3.3 -2.1
Pelvic Pain Controlled Study LA 51 (100) (66) 50 2.9 -1.1
  LA/N 55 (96) (56) 54 3.1 -1.1
Open Label Study LA/N 136 (99) (63) 134 3.2 -1.2
Deep Dyspareunia Controlled Study LA 42 (83) (37) 25 2.4 -1.0
  LA/N 43 (84) (45) 30 2.7 -0.8
Open Label Study LA/N 102 (91) (53) 94 2.7 -1.0
Pelvic Tenderness Controlled Study LA 51 (94) (34) 50 2.5 -1.0
  LA/N 54 (91) (34) 52 2.6 -0.9
Open Label Study LA/N 136 (99) (39) 134 2.9 -1.4
Pelvic Induration Controlled Study LA 51 (51) (12) 50 1.9 -0.4
  LA/N 54 (46) (17) 52 1.6 -0.4
Open Label Study LA/N 136 (75) (21) 134 2.2 -0.9

* LA = leuprolide acetate 3.75 mg

LA/N = leuprolide acetate 3.75 mg plus norethindrone acetate 5 mg

1Number of patients that were included in the assessment

2 Percentage of patients with the symptom/sign

3Value description: 1=none; 2= mild; 3= moderate; 4= severe

Suppression of menses (menses was defined as three or more consecutive days of menstrual bleeding) was maintained throughout treatment in 84% and 73% of patients receiving leuprolide acetate and norethindrone acetate, in the controlled study and open label study, respectively. The median time for menses resumption after treatment with leuprolide acetate and norethindrone acetate was 8 weeks.

Changes in Bone Density

The effect of leuprolide acetate for depot suspension and norethindrone acetate on bone mineral density was evaluated by dual energy x-ray absorptiometry (DXA) scan in the two clinical trials. For the open-label study, success in mitigating BMD loss was defined as the lower bound of the 95% confidence interval around the change from baseline at one year of treatment not to exceed –2.2%. The bone mineral density data of the lumbar spine from these two studies are presented in Table 3.

Table 3. Mean Percent Change from Baseline in BMD of Lumbar Spine
  leuprolide acetate for depot suspension 3.75 mg leuprolide acetate for depot suspension 3.75 mg plus norethindrone acetate 5 mg daily
Controlled Study Controlled Study Open Label Study
N Change
(Mean, 95% CI)#
N Change
(Mean, 95% CI)#
N Change
(Mean, 95% CI)#
Week 24* 41 -3.2% (-3.8, -2.6) 42 -0.3% (-0.8, 0.3) 115 -0.2% (-0.6, 0.2)
Week 52 29 -6.3% (-7.1, -5.4) 32 -1.0% (-1.9, -0.1) 84 -1.1% (-1.6, -0.5)

* Includes on-treatment measurements that fell within 2-252 days after the first day of treatment.

Includes on-treatment measurements >252 days after the first day of treatment.

# 95% CI: 95% Confidence Interval

The change in BMD following discontinuation of treatment is shown in Table 4.

Table 4. Mean Percent Change from Baseline in BMD of Lumbar Spine in Post-Treatment Follow-up Period
Post Treatment Measurement Controlled Study Open Label Study
LA-Only LA/N LA/N
N Mean % Change 95% CI (%) N Mean % Change 95% CI (%) N Mean % Change 95% CI (%)2
Month 8 19 -3.3 (-4.9, -1.8) 23 -0.9 (-2.1, 0.4) 89 -0.6 (-1.2, 0.0)
Month 12 16 -2.2 (-3.3, -1.1) 12 -0.7 (-2.1, 0.6) 65 0.1 (-0.6, 0.7)

1 Patients with post treatment measurements

2 95% CI (2-sided) of percent change in BMD values from baseline

These clinical studies demonstrated that coadministration of leuprolide acetate and norethindrone acetate 5 mg daily is effective in significantly reducing the loss of bone mineral density that occurs with leuprolide acetate for depot suspension treatment, and in relieving symptoms of endometriosis.