Lupaneta Pack Leuprolide Acetate for Depot Suspension; Norethindrone Acetate Tablets

LUPANETA PACK (leuprolide acetate for depot suspension and norethindrone acetate tablets) is indicated for initial management of the painful symptoms of endometriosis and for management of recurrence of symptoms.

Limitation of Use

Duration of use is limited due to concerns about adverse impact on bone mineral density [see WARNINGS AND PRECAUTIONS]. The initial treatment course of LUPANETA PACK is limited to six months. A single retreatment course of not more than six months may be administered after the initial course of treatment if symptoms recur. Use of LUPANETA PACK for longer than a total of 12 months is not recommended.

Included as part of the PRECAUTIONS section.

No information provided.

Mechanism Of Action

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 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

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 8). 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 5.

Table 5: Pharmacokinetic Parameters after a Single Dose of Norethindrone Acetate in Healthy Women

Figure 8: 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.

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.

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 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.

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.

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 halflife of norethindrone following a single dose administration of norethindrone acetate is approximately 9 hours.

Specific Populations

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.

The effect of renal disease on the disposition of norethindrone after norethindrone acetateadministration 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.

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

Drug Interactions

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.

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 6 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 6: Percentages of Patients with Symptoms of Endometriosis and Mean Clinical Severity Scores

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.

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 7.

Table 7: Mean Percent Change from Baseline in BMD of Lumbar Spine

The change in BMD following discontinuation of treatment is shown in Table 8.

Table 8: Mean Percent Change from Baseline in BMD of Lumbar Spine in Post-Treatment Follow-up Period

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.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The safety of co-administering leuprolide acetate for depot suspension and norethindrone acetate was evaluated in two clinical studies in which a total of 242 women were treated for up to one year. Women were treated with monthly IM injections of leuprolide acetate 3.75 mg (13 injections) alone or monthly IM injections of leuprolide acetate 3.75 mg (13 injections) and 5 mg norethindrone acetate daily. The population age range was 17-43 years old. The majority of patients were Caucasian (87%).

One study was a controlled clinical trial in which 106 women were randomized to one year of treatment with leuprolide acetate for depot suspension alone or with leuprolide acetate for depot suspension and norethindrone acetate. 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.

In the controlled study, 18% of patients treated monthly with leuprolide acetate and 18% of patients treated monthly with leuprolide acetate plus norethindrone acetate discontinued therapy due to adverse reactions, most commonly hot flashes (6%) and insomnia (4%) in the leuprolide acetate alone group and hot flashes and emotional lability (4% each) in the leuprolide acetate and norethindrone group.

In the open label study, 13% of patients treated monthly with leuprolide acetate plus norethindrone acetate discontinued therapy due to adverse reactions, most commonly depression (4%) and acne (2%).

Table 1 lists the adverse reactions observed in at least 5% of patients in any treatment group, during the first 6 months of treatment in the add-back clinical studies, in which patients were treated with monthly leuprolide acetate for depot suspension 3.75 mg with or without norethindrone acetate co-treatment. The most frequently-occurring adverse reactions observed in these studies were hot flashes and headaches.

Table 1: Adverse Reactions Occurring in the First Six Months of Treatment in ≥ 5% of Patients with Endometriosis

In the controlled clinical trial, 50 of 51 (98%) patients in the leuprolide acetate alone group and 48 of 55 (87%) patients in the leuprolide acetate and norethindrone group reported experiencing hot flashes on one or more occasions during treatment. Table 2 presents hot flash data in the sixth month of treatment.

Table 2: Hot Flashes in the Month Prior to the Assessment Visit (Controlled Study)

Urinary tract infection, renal calculus, depression

Changes in Laboratory Values during Treatment

In the two clinical trials of women with endometriosis, 4 of 191 patients receiving leuprolide acetate and norethindrone acetate for up to 12 months developed an elevated (at least twice the upper limit of normal) SGPT and 2 of 136 developed an elevated GGT. Five of the 6 increases were observed beyond 6 months of treatment. None was associated with an elevated bilirubin concentration.

Percent changes from baseline for serum lipids and percentages of patients with serum lipid values outside of the normal range in the two studies of leuprolide acetate and norethindrone acetate are summarized in the tables below. The major impact of adding norethindrone acetate to treatment with leuprolide acetate for depot suspension was a decrease in serum HDL cholesterol and an increase in the LDL/HDL ratio.

Table 3: Serum Lipids: Mean Percent Changes from Baseline Values at Treatment Week 24

Changes from baseline tended to be greater at Week 52. After treatment, mean serum lipid levels from patients with follow up data (105 of 158 patients) returned to pretreatment values.

Table 4: Percent of Patients with Serum Lipid Values Outside of the Normal Range

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of leuprolide acetate for depot suspension or norethindrone acetate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

During postmarketing surveillance with other dosage forms and in the same or different populations, the following adverse reactions were reported:

• Allergic reactions (anaphylactic, rash, urticaria, and photosensitivity reactions)
• Mood swings, including depression
• Suicidal ideation and attempt
• Symptoms consistent with an anaphylactoid or asthmatic process
• Localized reactions including induration and abscess at the site of injection
• Symptoms consistent with fibromyalgia (e.g., joint and muscle pain, headaches, sleep disorders, gastrointestinal distress, and shortness of breath), individually and collectively

Other adverse reactions reported are:

Hepato-biliary disorder - Serious liver injury

Injury, poisoning and procedural complications - Spinal fracture

Investigations - Decreased white blood count

Musculoskeletal and connective tissue disorder - Tenosynovitis-like symptoms

Nervous System disorder - Convulsion, peripheral neuropathy, paralysis

Vascular disorder - Hypotension, Hypertension

Serious venous and arterial thrombotic and thromboembolic events, including deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke, and transient ischemic attack

During post-marketing surveillance, cases of pituitary apoplexy (a clinical syndrome secondary to infarction of the pituitary gland) have been reported after the administration of leuprolide acetate and other GnRH agonists. In a majority of these cases, a pituitary adenoma was diagnosed, with a majority of pituitary apoplexy cases occurring within 2 weeks of the first dose, and some within the first hour. In these cases, pituitary apoplexy has presented as sudden headache, vomiting, visual changes, ophthalmoplegia, altered mental status, and sometimes cardiovascular collapse. Immediate medical attention has been required.

Read the entire FDA prescribing information for Lupaneta Pack (Lupaneta Pack Leuprolide Acetate for Depot Suspension; Norethindrone Acetate Tablets)