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Overview
Leuprorelin is a gonadatropin releasing hormone (GnRH) agonist that is FDA approved for the {{{indicationType}}} of advanced prostate cancer - palliative. Common adverse reactions include Malaise, fatigue, hot flashes/sweats, and testicular atrophy.
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
Palliative Treatment Of Advanced Prostate Cancer
ELIGARD® is administered subcutaneously and provides continuous release of leuprolide acetate over a one-, three-, four-, or six-month treatment period (TABLE 1). The injection delivers the dose of leuprolide acetate incorporated in a polymer formulation.
T1
Once mixed, ELIGARD® should be discarded if not administered within 30 minutes.
As with other drugs administered by subcutaneous injection, the injection site should vary periodically. The specific injection location chosen should be an area with sufficient soft or loose subcutaneous tissue. In clinical trials, the injection was administered in the upper- or mid-abdominal area. Avoid areas with brawny or fibrous subcutaneous tissue or locations that could be rubbed or compressed (i.e., with a belt or clothing waistband).
T
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
Condition1
Developed by:
Class of Recommendation:
Strength of Evidence:
Dosing Information
Dosage
Condition2
There is limited information regarding Off-Label Guideline-Supported Use of Leuprorelin in adult patients.
Non–Guideline-Supported Use
Condition1
Dosing Information
Dosage
Condition2
There is limited information regarding Off-Label Non–Guideline-Supported Use of Leuprorelin in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
Condition1
Dosing Information
Dosage
Condition2
There is limited information regarding FDA-Labeled Use of Leuprorelin in pediatric patients.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
Condition1
Developed by:
Class of Recommendation:
Strength of Evidence:
Dosing Information
Dosage
Condition2
There is limited information regarding Off-Label Guideline-Supported Use of Leuprorelin in pediatric patients.
Non–Guideline-Supported Use
Condition1
Dosing Information
Dosage
Condition2
There is limited information regarding Off-Label Non–Guideline-Supported Use of Leuprorelin in pediatric patients.
Contraindications
Hypersensitivity
ELIGARD® is contraindicated in patients with hypersensitivity to GnRH, GnRH agonist analogs or any of the components of ELIGARD®. Anaphylactic reactions to synthetic GnRH or GnRH agonist analogs have been reported in the literature.
Pregnancy
ELIGARD may cause fetal harm when administered to a pregnant woman. Expected hormonal changes that occur with ELIGARD treatment increase the risk for pregnancy loss and fetal harm when administered to a pregnant women. ELIGARD is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
Warnings
Precautions
Tumor Flare
ELIGARD® 7.5 mg 22.5 mg 30 mg, like other GnRH agonists, causes a transient increase in serum concentrations of testosterone during the first week of treatment. ELIGARD® 45 mg causes a transient increase in serum concentrations of testosterone during the first two weeks of treatment. Patients may experience worsening of symptoms or onset of new signs and symptoms during the first few weeks of treatment, including bone pain, neuropathy, hematuria, or bladder outlet obstruction.
Cases of ureteral obstruction and/or spinal cord compression, which may contribute to paralysis with or without fatal complications, have been observed in the palliative treatment of advanced prostate cancer using GnRH agonists.
Patients with metastatic vertebral lesions and/or with urinary tract obstruction should be closely observed during the first few weeks of therapy. If spinal cord compression or ureteral obstruction develops, standard treatment of these complications should be instituted.
Laboratory Tests
Response to ELIGARD® should be monitored by measuring serum concentrations of testosterone and prostate specific antigen periodically.
In the majority of patients, testosterone levels increased above Baseline during the first week, declining thereafter to Baseline levels or below by the end of the second or third week. Castrate levels were generally reached within two to four weeks.
Castrate testosterone levels were maintained for the duration of the treatment with ELIGARD® 7.5 mg. No increases to above the castrate level occurred in any of the patients.
Castrate levels were generally maintained for the duration of treatment with ELIGARD® 22.5 mg.
Once castrate levels were achieved with ELIGARD® 30 mg, most (86/89) patients remained suppressed throughout the study.
Once castrate levels were achieved with ELIGARD® 45 mg, only one patient (< 1%) experienced a breakthrough, with testosterone levels > 50 ng/dL.
Results of testosterone determinations are dependent on assay methodology. It is advisable to be aware of the type and precision of the assay methodology to make appropriate clinical and therapeutic decisions.
Drug/Laboratory Test Interactions: Therapy with leuprolide acetate results in suppression of the pituitary-gonadal system. Results of diagnostic tests of pituitary gonadotropic and gonadal functions conducted during and after leuprolide therapy may be affected.
Hyperglycemia and Diabetes
Hyperglycemia and an increased risk of developing diabetes have been reported in men receiving GnRH agonists. Hyperglycemia may represent development of diabetes mellitus or worsening of glycemic control in patients with diabetes. Monitor blood glucose and/or glycosylated hemoglobin (HbA1c) periodically in patients receiving a GnRH agonist and manage with current practice for treatment of hyperglycemia or diabetes.
Cardiovascular Diseases
Increased risk of developing myocardial infarction, sudden cardiac death and stroke has been reported in association with use of GnRH agonists in men. The risk appears low based on the reported odds ratios, and should be evaluated carefully along with cardiovascular risk factors when determining a treatment for patients with prostate cancer. Patients receiving a GnRH agonist should be monitored for symptoms and signs suggestive of development of cardiovascular disease and be managed according to current clinical practice.
Adverse Reactions
Clinical Trials Experience
The safety of all ELIGARD® formulations was evaluated in clinical trials involving patients with advanced prostate cancer. In addition, the safety of ELIGARD® 7.5 mg was evaluated in 8 surgically castrated males (TABLE 4). ELIGARD®, like other GnRH analogs, caused a transient increase in serum testosterone concentrations during the first one to two weeks of treatment. Therefore, potential exacerbations of signs and symptoms of the disease during the first weeks of treatment are of concern in patients with vertebral metastases and/or urinary obstruction or hematuria. If these conditions are aggravated, it may lead to neurological problems such as weakness and/or paresthesia of the lower limbs or worsening of urinary symptoms [see WARNINGS AND PRECAUTIONS (5.2)].
During the clinical trials, injection sites were closely monitored. Refer to TABLE 3 for a summary of reported injection site events.
T3
These localized adverse events were non-recurrent over time. No patient discontinued therapy due to an injection site adverse event.
The following possibly or probably related systemic adverse events occurred during clinical trials with ELIGARD®, and were reported in > 2% of patients (TABLE 7). Often, causality is difficult to assess in patients with metastatic prostate cancer. Reactions considered not drug-related are excluded.
T4
In addition, the following possibly or probably related systemic adverse events were reported by < 2% of the patients treated with ELIGARD® in these clinical studies.
Alopecia, clamminess, night sweats*, sweating increased*
Vascular
Hypertension, hypotension
-*Expected pharmacological consequences of testosterone suppression.
Changes in Bone Density
Decreased bone density has been reported in the medical literature in men who have had orchiectomy or who have been treated with a GnRH agonist analog. It can be anticipated that long periods of medical castration in men will have effects on bone density.
Postmarketing Experience
During post-marketing surveillance, rare cases of pituitary apoplexy (a clinical syndrome secondary to infarction of the pituitary gland) have been reported after the administration of gonadotropin-releasing hormone 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.
Convulsions have also been reported in the postmarketing setting.
Drug Interactions
No pharmacokinetic drug-drug interaction studies were conducted with ELIGARD®.
ELIGARD® is contraindicated in women who are or may become pregnant while receiving the drug. Expected hormonal changes that occur with ELIGARD® treatment increase the risk for pregnancy loss. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus and the potential risk for pregnancy loss.
In non-clinical studies in rats, major fetal abnormalities were observed after administration of leuprolide acetate throughout gestation. There were increased fetal mortality and decreased fetal weights in rats and rabbits. The effects of fetal mortality are expected consequences of the alterations in hormonal levels brought about by this drug. The possibility exists that spontaneous abortion may occur.
Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Leuprorelin in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of Leuprorelin during labor and delivery.
Nursing Mothers
ELIGARD® is not indicated for use in women [see INDICATIONS AND USAGE (1)]. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Eligard, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric Use
The safety and effectiveness of ELIGARD® in pediatric patients have not been established.
Geriatic Use
The majority of the patients (approximately 70%) studied in the clinical trials were age 70 and older.
Gender
There is no FDA guidance on the use of Leuprorelin with respect to specific gender populations.
Race
There is no FDA guidance on the use of Leuprorelin with respect to specific racial populations.
Renal Impairment
There is no FDA guidance on the use of Leuprorelin in patients with renal impairment.
Hepatic Impairment
There is no FDA guidance on the use of Leuprorelin in patients with hepatic impairment.
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Leuprorelin in women of reproductive potentials and males.
Immunocompromised Patients
There is no FDA guidance one the use of Leuprorelin in patients who are immunocompromised.
Administration and Monitoring
Administration
Subcutaneous
Monitoring
There is limited information regarding Monitoring of Leuprorelin in the drug label.
IV Compatibility
There is limited information regarding IV Compatibility of Leuprorelin in the drug label.
Overdosage
In clinical trials using daily subcutaneous injections of leuprolide acetate in patients with prostate cancer, doses as high as 20 mg/day for up to two years caused no adverse effects differing from those observed with the 1 mg/day dose.
Leuprolide acetate, a gonadotropin releasing hormone (GnRH) agonist, acts as a potent inhibitor of gonadotropin secretion when given continuously in therapeutic doses. Animal and human studies indicate that after an initial stimulation, chronic administration of leuprolide acetate results in suppression of testicular and ovarian steroidogenesis. This effect is reversible upon discontinuation of drug therapy.
In humans, administration of leuprolide acetate results in an initial increase in circulating levels of luteinizing hormone (LH) and follicle stimulating hormone (FSH), leading to a transient increase in levels of the gonadal steroids (testosterone and dihydrotestosterone in males, and estrone and estradiol in premenopausal females). However, continuous administration of leuprolide acetate results in decreased levels of LH and FSH. In males, testosterone is reduced to below castrate threshold (≤ 50 ng/dL). These decreases occur within two to four weeks after initiation of treatment. Long-term studies have shown that continuation of therapy with leuprolide acetate maintains testosterone below the castrate level for up to seven years.
Structure
ELIGARD® is a sterile polymeric matrix formulation of leuprolide acetate, a GnRH agonist, for subcutaneous injection. It is designed to deliver leuprolide acetate at a controlled rate over a one-, three-, four- or six-month therapeutic period.
Leuprolide acetate is a synthetic nonapeptide analog of naturally occurring gonadotropin releasing hormone (GnRH) that, when given continuously, inhibits pituitary gonadotropin secretion and suppresses testicular and ovarian steroidogenesis. 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:
ELIGARD® is prefilled and supplied in two separate, sterile syringes whose contents are mixed immediately prior to administration. The two syringes are joined and the single dose product is mixed until it is homogenous. ELIGARD® is administered subcutaneously, where it forms a solid drug delivery depot.
One syringe contains the ATRIGEL® Delivery System and the other contains leuprolide acetate. ATRIGEL® is a polymeric (non-gelatin containing) delivery system consisting of a biodegradable poly (DL-lactide-co-glycolide) (PLGH or PLG) polymer formulation dissolved in a biocompatible solvent, N-methyl-2-pyrrolidone (NMP).
Refer to TABLE 5 for the delivery system composition and constituted product formulation for each ELIGARD® product.
T5
Pharmacodynamics
Following the first dose of ELIGARD®, mean serum testosterone concentrations transiently increased, then fell to below castrate threshold (≤ 50 ng/dL) within three weeks for all ELIGARD® concentrations.
Continued monthly treatment with ELIGARD® 7.5 mg maintained castrate testosterone suppression throughout the study. No breakthrough of testosterone concentrations above castrate threshold (> 50 ng/dL) occurred at any time during the study once castrate suppression was achieved (FIGURE 11).
One patient received less than a full dose of ELIGARD® 22.5 mg at baseline, never suppressed and withdrew from the study at Day 73. Of the 116 patients remaining in the study, 115 (99%) had serum testosterone levels below the castrate threshold by Month 1 (Day 28). By Day 35, 116 (100%) had serum testosterone levels below the castrate threshold. Once testosterone suppression was achieved, one patient (< 1%) demonstrated breakthrough (concentrations > 50 ng/dL after achieving castrate levels) following the initial injection; that patient remained below the castrate threshold following the second injection (FIGURE 12).
One patient withdrew from the ELIGARD® 30 mg study at Day 14. Of the 89 patients remaining in the study, 85 (96%) had serum testosterone levels below the castrate threshold by Month 1 (Day 28). By Day 42, 89 (100%) of patients attained castrate testosterone suppression. Once castrate testosterone suppression was achieved, three patients (3%) demonstrated breakthrough (concentrations > 50 ng/dL after achieving castrate levels) (FIGURE 13).
One patient at Day 1 and another patient at Day 29 were withdrawn from the ELIGARD® 45 mg study. Of the 109 patients remaining in the study, 108 (99.1%) had serum testosterone levels below the castrate threshold by Month 1 (Day 28). One patient did not achieve castrate suppression and was withdrawn from the study at Day 85. Once castrate testosterone suppression was achieved, one patient (< 1%) demonstrated breakthrough (concentrations > 50 ng/dL after achieving castrate levels) (FIGURE 14).
Leuprolide acetate is not active when given orally.
Pharmacokinetics
Absorption
ELIGARD® 7.5 mg
The pharmacokinetics/pharmacodynamics observed during three once-monthly injections in 20 patients with advanced prostate cancer is shown in Figure 11. Mean serum leuprolide concentrations following the initial injection rose to 25.3 ng/mL (Cmax) at approximately 5 hours after injection. After the initial increase following each injection, serum concentrations remained relatively constant (0.28 – 2.00 ng/mL).
F1
ELIGARD® 22.5 mg
The pharmacokinetics/pharmacodynamics observed during two injections every three months (ELIGARD® 22.5 mg) in 22 patients with advanced prostate cancer is shown in Figure 12. Mean serum leuprolide concentrations rose to 127 ng/mL and 107 ng/mL at approximately 5 hours following the initial and second injections, respectively. After the initial increase following each injection, serum concentrations remained relatively constant (0.2 – 2.0 ng/mL).
F2
ELIGARD® 30 mg
The pharmacokinetics/pharmacodynamics observed during injections administered initially and at four months (ELIGARD® 30 mg ) in 24 patients with advanced prostate cancer is shown in Figure 13. Mean serum leuprolide concentrations following the initial injection rose rapidly to 150 ng/mL (Cmax) at approximately 3.3 hours after injection. After the initial increase following each injection, mean serum concentrations remained relatively constant (0.1 – 1.0 ng/mL).
F3
ELIGARD® 45 mg
The pharmacokinetics/pharmacodynamics observed during injections administered initially and at six months (ELIGARD® 45 mg) in 27 patients with advanced prostate cancer is shown in Figure 14. Mean serum leuprolide concentrations rose to 82 ng/mL and 102 ng/mL (Cmax) at approximately 4.5 hours following the initial and second injections, respectively. After the initial increase following each injection, mean serum concentrations remained relatively constant (0.2 – 2.0 ng/mL).
F4
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 8.34 L/h, with a terminal elimination half-life of approximately 3 hours based on a two compartment model.
No drug metabolism study was conducted with ELIGARD®. Upon administration with different leuprolide acetate formulations, the major metabolite of leuprolide acetate is a pentapeptide (M-1) metabolite.
Excretion
No drug excretion study was conducted with ELIGARD®.
Race
In patients studied, mean serum leuprolide concentrations were similar regardless of race. Refer to TABLE 6 for distribution of study patients by race.
T6
Renal and Hepatic Insufficiency
The pharmacokinetics of ELIGARD® in hepatically and renally impaired patients have not been determined.
Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Leuprorelin in the drug label.
Clinical Studies
There is limited information regarding Clinical Studies of Leuprorelin in the drug label.
How Supplied
Storage
There is limited information regarding Leuprorelin Storage in the drug label.
Images
Drug Images
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