Leuprolide acetate is a synthetic nonapeptide analog of naturally occurring gonadotropin-releasing hormone (GnRH or LH-RH). 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:
LUPRON DEPOT is available in a prefilled dual-chamber syringe containing sterile lyophilized microspheres which, when mixed with diluent, become a suspension intended as a monthly intramuscular injection.
The front chamber of LUPRON DEPOT 3.75 mg prefilled dual-chamber syringe contains leuprolide acetate (3.75 mg), purified 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 LUPRON DEPOT 3.75 mg, acetic acid is lost, leaving the peptide.
Leuprolide acetate is a long-acting GnRH analog. A single monthly injection of LUPRON DEPOT 3.75 mg results in an initial stimulation followed by a prolonged suppression of pituitary gonadotropins. Repeated dosing at monthly 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. Intramuscular injection of the depot formulation provides plasma concentrations of leuprolide over a period of one month.
Absorption A single dose of LUPRON DEPOT 3.75 mg was administered by intramuscular injection to healthy female volunteers. The absorption of leuprolide was characterized by an initial increase in plasma concentration, with peak concentration ranging from 4.6 to 10.2 ng/mL at four hours postdosing. However, intact leuprolide and an inactive metabolite could not be distinguished by the assay used in the study. Following the initial rise, leuprolide concentrations started to plateau within two days after dosing and remained relatively stable for about four to five weeks with plasma concentrations of about 0.30 ng/mL.
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 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.
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.
Special Populations The pharmacokinetics of the drug in hepatically and renally impaired patients have not been determined.
Endometriosis In controlled clinical studies, LUPRON DEPOT 3.75 mg monthly for six months was shown to be comparable to danazol 800 mg/day in relieving the clinical sign/symptoms of endometriosis (pelvic pain, dysmenorrhea, dyspareunia, pelvic tenderness, and induration) and in reducing the size of endometrial implants as evidenced by laparoscopy. The clinical significance of a decrease in endometriotic lesions is not known at this time, and in addition laparoscopic staging of endometriosis does not necessarily correlate with the severity of symptoms.
LUPRON DEPOT 3.75 mg monthly induced amenorrhea in 74% and 98% of the patients after the first and second treatment months respectively. Most of the remaining patients reported episodes of only light bleeding or spotting. In the first, second and third post-treatment months, normal menstrual cycles resumed in 7%, 71% and 95% respectively, of those patients who did not become pregnant.
Figure 1 illustrates the percent of patients with symptoms at baseline, final treatment visit and sustained relief at 6 and 12 months following discontinuation of treatment for the various symptoms evaluated during the study. This included all patients at end of treatment and those who elected to participate at the follow-up periods. This might provide a slight bias in the results at follow-up as 75% of the original patients entered the follow-up study, and 36% were evaluated at 6 months and 26% at 12 months respectively.
Hormonal replacement therapy: Clinical studies suggest that the addition of hormonal replacement therapy (estrogen and/or progestin) to LUPRON is effective in reducing loss of bone mineral density which occurs with LUPRON, without compromising the efficacy of LUPRON in relieving symptoms of endometriosis. The optimal drug/dose is not established.
Uterine Leiomyomata (Fibroids): In controlled clinical trials, administration of LUPRON DEPOT 3.75 mg for a period of three or six months was shown to decrease uterine and fibroid volume, thus allowing for relief of clinical symptoms (abdominal bloating, pelvic pain, and pressure). Excessive vaginal bleeding (menorrhagia and menometrorrhagia) decreased, resulting in improvement in hematologic parameters.
In three clinical trials, enrollment was not based on hematologic status. Mean uterine volume decreased by 41% and myoma volume decreased by 37% at final visit as evidenced by ultrasound or MRI. These patients also experienced a decrease in symptoms including excessive vaginal bleeding and pelvic discomfort. Benefit occurred by three months of therapy, but additional gain was observed with an additional three months of LUPRON DEPOT 3.75 mg. Ninety-five percent of these patients became amenorrheic with 61%, 25%, and 4% experiencing amenorrhea during the first, second, and third treatment months respectively.
Post-treatment follow-up was carried out for a small percentage of LUPRON DEPOT 3.75 mg patients among the 77% who demonstrated a >/= 25% decrease in uterine volume while on therapy. Menses usually returned within two months of cessation of therapy. Mean time to return to pretreatment uterine size was 8.3 months. Regrowth did not appear to be related to pretreatment uterine volume.
In another controlled clinical study, enrollment was based on hematocrit </= 30% and/or hemoglobin </= 10.2 g/dL. Administration of LUPRON DEPOT 3.75 mg, concomitantly with iron, produced an increase of >/= 6% hematocrit and >/= 2 g/dL hemoglobin in 77% of patients at three months of therapy. The mean change in hematocrit was 10.1% and the mean change in hemoglobin was 4.2 g/dL. Clinical response was judged to be a hematocrit of >/= 36% and hemoglobin of >/= 12 g/dL, thus allowing for autologous blood donation prior to surgery. At three months, 75% of patients met this criterion.
At three months, 80% of patients experienced relief from either menorrhagia or menometrorrhagia. As with the previous studies, episodes of spotting and menstrual-like bleeding were noted in some patients.
In this same study, a decrease of >/= 25% was seen in uterine and myoma volumes in 60% and 54% of patients respectively. LUPRON DEPOT 3.75 mg was found to relieve symptoms of bloating, pelvic pain, and pressure.
There is no evidence that pregnancy rates are enhanced or adversely affected by the use of LUPRON DEPOT 3.75 mg.
LUPRON DEPOT 3.75 mg is indicated for management of endometriosis, including pain relief and reduction of endometriotic lesions.
Experience with LUPRON DEPOT 3.75 mg in females has been limited to women 18 years of age and older treated for 6 months.
LUPRON DEPOT 3.75 mg concomitantly with iron therapy is indicated for the preoperative hematologic improvement of patients with anemia caused by uterine leiomyomata. The clinician may wish to consider a one-month trial period on iron alone inasmuch as some of the patients will respond to iron alone. (See clinical trial results below.) LUPRON may be added if the response to iron alone is considered inadequate. Recommended duration of therapy with LUPRON DEPOT 3.75 mg is up to three months.
Experience with LUPRON DEPOT in females has been limited to women 18 years of age and older.
Safe use of leuprolide acetate in pregnancy has not been established clinically. Before starting treatment with LUPRON DEPOT, pregnancy must be excluded.
When used monthly at the recommended dose, LUPRON DEPOT usually inhibits ovulation and stops menstruation. Contraception is not insured, however, by taking LUPRON DEPOT. Therefore, patients should use non-hormonal methods of contraception. Patients should be advised to see their physician if they believe they may be pregnant. If a patient becomes pregnant during treatment, the drug must be discontinued and the patient must be apprised of the potential risk to the fetus.
During the early phase of therapy, sex steroids temporarily rise above baseline because of the physiologic effect of the drug. Therefore, an increase in clinical signs and symptoms may be observed during the initial days of therapy, but these will dissipate with continued therapy.
Information for Patients An information pamphlet for patients is included with the product. Patients should be aware of the following information:
Laboratory Tests See ADVERSE REACTIONS section.
Drug Interactions No pharmacokinetic-based drug-drug interaction studies have been conducted with LUPRON DEPOT. 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 would not be expected to occur.
Drug/Laboratory Test Interactions Administration of LUPRON DEPOT in therapeutic doses results in suppression of the pituitary-gonadal system. Normal function is usually restored within three months after treatment is discontinued. Therefore, diagnostic tests of pituitary gonadotropic and gonadal functions conducted during treatment and for up to three months after discontinuation of LUPRON DEPOT may be misleading.
Carcinogenesis, Mutagenesis, Impairment of Fertility 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.
Pregnancy, Teratogenic Effects Pregnancy Category X. (See CONTRAINDICATIONS section.) When administered on day 6 of pregnancy at test dosages of 0.00024, 0.0024, and 0.024 mg/kg (1/300 to 1/3 of the human dose) to rabbits, LUPRON DEPOT produced a dose-related increase in major fetal abnormalities. Similar studies in rats failed to demonstrate an increase in fetal malformations. There was increased fetal mortality and decreased fetal weights with the two higher doses of LUPRON DEPOT in rabbits and with the highest dose (0.024 mg/kg) in rats.
Nursing Mothers It is not known whether LUPRON DEPOT is excreted in human milk. Because many drugs are excreted in human milk, and because the effects of LUPRON DEPOT on lactation and/or the breast-fed child have not been determined, LUPRON DEPOT should not be used by nursing mothers.
Pediatric Use See LUPRON DEPOT-PED ® (leuprolide acetate for depot suspension) labeling for the safety and effectiveness in children with central precocious puberty.
Estradiol levels may increase during the first weeks following the initial injection, but then decline to menopausal levels. This transient increase in estradiol can be associated with a temporary worsening of signs and symptoms. (See section.)
As would be expected with a drug that lowers serum estradiol levels, the most frequently reported adverse reactions were those related to hypoestrogenism.
Endometriosis : In controlled studies comparing LUPRON DEPOT 3.75 mg monthly and danazol (800 mg/day) or placebo, adverse reactions most frequently reported and thought to be possibly or probably drug-related are shown in Figure 2.
Cardiovascular System - Palpitations, Syncope, Tachycardia; Gastrointestinal System - Appetite changes, Dry mouth, Thirst; Central/Peripheral Nervous System - Anxiety,* Delusions, Memory Disorder, Personality disorder; Integumentary System - Alopecia, Ecchymosis, Hair disorder; Urogenital System - Dysuria,* Lactation; Miscellaneous - Lymphadenopathy, Ophthalmologic disorders.*
Uterine Leiomyomata (Fibroids): In controlled clinical trials comparing LUPRON DEPOT 3.75 mg and placebo, adverse events reported in >5% of patients and thought to be potentially related to drug are noted in the following table.
In one controlled clinical trial, patients received a higher dose (7.5 mg) of LUPRON DEPOT. Events seen with this dose that were thought to be potentially related to drug and were not seen at the lower dose included palpitations, syncope, glossitis, ecchymosis, hypesthesia, confusion, lactation, pyelonephritis, and urinary disorders. Generally, a higher incidence of hypoestrogenic effects was observed at the higher dose.
In controlled clinical studies, patients with endometriosis (six months of therapy) or uterine fibroids (three months of therapy) were treated with LUPRON DEPOT 3.75 mg. In endometriosis patients, vertebral bone density as measured by dual energy x-ray absorptiometry (DEXA) decreased by an average of 3.2% at six months compared with the pretreatment value. In this same study, LUPRON DEPOT 3.75 mg alone and LUPRON DEPOT 3.75 mg plus three different hormonal add-back regimens were compared for one year. All add-back groups demonstrated mean changes in bone mineral density of </=1% from baseline and showed statistically significantly (P-value <0.001) less loss of bone density than the group treated with LUPRON DEPOT 3.75 mg alone, at all time points. Clinical studies suggest that the addition of hormonal replacement therapy (estrogen and/or progestin) to LUPRON is effective in reducing loss of bone mineral density which occurs with LUPRON, without compromising the efficacy of LUPRON in relieving symptoms of endometriosis. The optimal drug/dose is not established.
When LUPRON DEPOT 3.75 mg was administered for three months in uterine fibroid patients, vertebral trabecular bone mineral density as assessed by quantitative digital radiography (QDR) revealed a mean decrease of 2.7% compared with baseline. Six months after discontinuation of therapy, a trend toward recovery was observed. Use of LUPRON DEPOT for longer than three months (uterine fibroids) or six months (endometriosis) or in the presence of other known risk factors for decreased bone mineral content may cause additional bone loss and is not recommended.
Endometriosis: During clinical trials with LUPRON DEPOT 3.75 mg, regular laboratory monitoring revealed that AST levels were more than twice the upper limit of normal in only one patient. There was no clinical or other laboratory evidence of abnormal liver function.
Uterine Leiomyomata (Fibroids): In clinical trials with LUPRON DEPOT 3.75 mg, five (3%) patients had a post-treatment transaminase value that was at least twice the baseline value and above the upper limit of the normal range. None of the laboratory increases were associated with clinical symptoms.
Endometriosis At enrollment, 4% of the LUPRON DEPOT 3.75 mg patients and 1% of the danazol patients had total cholesterol values above the normal range. These patients also had cholesterol values above the normal range at the end of treatment.
Of those patients whose pretreatment cholesterol values were in the normal range, 7% of the LUPRON DEPOT 3.75 mg patients and 9% of the danazol patients had post-treatment values above the normal range.
The mean (±SEM) pretreatment values for total cholesterol from all patients were 178.8 (2.9) mg/dL in the LUPRON DEPOT 3.75 mg groups and 175.3 (3.0) mg/dL in the danazol group. At the end of treatment, the mean values for total cholesterol from all patients were 193.3 mg/dL in the LUPRON DEPOT 3.75 mg group and 194.4 mg/dL in the danazol group. These increases from the pretreatment values were statistically significant (p<0.03) in both groups.
Triglycerides were increased above the upper limit of normal in 12% of the patients who received LUPRON DEPOT 3.75 mg and in 6% of the patients who received danazol.
At the end of treatment, HDL cholesterol fractions decreased below the lower limit of the normal range in 2% of the LUPRON DEPOT 3.75 mg patients compared with 54% of those receiving danazol. LDL cholesterol fractions increased above the upper limit of the normal range in 6% of the patients receiving LUPRON DEPOT 3.75 mg compared with 23% of those receiving danazol. There was no increase in the LDL/HDL ratio in patients receiving LUPRON DEPOT 3.75 mg but there was approximately a two-fold increase in the LDL/HDL ratio in patients receiving danazol.
Uterine Leiomyomata (Fibroids): In patients receiving LUPRON DEPOT 3.75 mg, mean changes in cholesterol (+11 mg/dL to +29 mg/dL), LDL cholesterol (+8 mg/dL to +22 mg/dL), HDL cholesterol (0 to +6 mg/dL), and the LDL/HDL ratio (-0.1 to +0.5) were observed across studies. In the one study in which triglycerides were determined, the mean increase from baseline was 32 mg/dL.
Endometriosis In comparative studies, the following changes were seen in approximately 5% to 8% of patients. LUPRON DEPOT 3.75 mg was associated with elevations of LDH and phosphorus, and decreases in WBC counts. Danazol therapy was associated with increases in hematocrit, platelet count, and LDH.
Hematology: (See CLINICAL STUDIES section.) In LUPRON DEPOT 3.75 mg treated patients, although there were statistically significant mean decreases in platelet counts from baseline to final visit, the last mean platelet counts were within the normal range. Decreases in total WBC count and neutrophils were observed, but were not clinically significant.
Chemistry: Slight to moderate mean increases were noted for glucose, uric acid, BUN, creatinine, total protein, albumin, bilirubin, alkaline phosphatase, LDH, calcium, and phosphorus. None of these increases were clinically significant.
During postmarketing surveillance, the following adverse events were reported. Like other drugs in this class, mood swings, including depression, have been reported as a physiologic effect of decreased sex steroids. There have been very rare reports of suicidal ideation and attempt. Many, but not all, of these patients had a history of depression or other psychiatric illness. Patients should be counseled on the possibility of worsening of depression.
Symptoms consistent with an anaphylactoid or asthmatic process have been rarely reported. Rash, urticaria, and photosensitivity reactions have also been reported.
Localized reactions including induration and abscess have been reported at the site of injection.
Cardiovascular System - Hypotension; Hemic and Lymphatic System - Decreased WBC; Central/Peripheral Nervous System - Peripheral neuropathy, Spinal fracture/paralysis; Musculoskeletal System - Tenosynovitis-like symptoms; Urogenital System - Prostate pain.
See other LUPRON DEPOT and LUPRON Injection package inserts for other events reported in different patient populations.
In rats subcutaneous administration of 250 to 500 times the recommended human dose, expressed on a per body weight basis, resulted in dyspnea, decreased activity, and local irritation at the injection site. There is no evidence that there is a clinical counterpart of this phenomenon. In early clinical trials using daily subcutaneous 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.
LUPRON DEPOT Must Be Administered Under The Supervision Of A Physician.
The recommended dose of LUPRON DEPOT is 3.75 mg, incorporated in a depot formulation. The lyophilized microspheres are to be reconstituted and administered monthly as a single intramuscular injection, in accord with the following directions:
Since the product does not contain a preservative, the suspension should be discarded if not used immediately.
Endometriosis The recommended duration of administration is six months. Retreatment cannot be recommended since safety data for retreatment are not available. If the symptoms of endometriosis recur after a course of therapy, and further treatment with LUPRON DEPOT 3.75 mg is contemplated, it is recommended that bone density be assessed before retreatment begins to ensure that values are within normal limits.
Uterine Leiomyomata (Fibroids): Recommended duration of therapy with LUPRON DEPOT 3.75 mg is up to 3 months. The symptoms associated with uterine leiomyomata will recur following discontinuation of therapy. If additional treatment with LUPRON DEPOT 3.75 mg is contemplated, bone density should be assessed prior to initiation of therapy to ensure that values are within normal limits.
As with other drugs administered by injection, the injection site should be varied periodically.
LUPRON DEPOT 3.75 mg is packaged as follows:
Kit with prefilled dual-chamber
syringe NDC 0300-3641-01
Each syringe contains sterile lyophilized microspheres which is leuprolide incorporated in a biodegradable copolymer of lactic and glycolic acids. When mixed with diluent, LUPRON DEPOT 3.75 mg is administered as a single monthly IM injection.
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [See USP Controlled Room Temperature]
1.MacLeod TL, et al. Anaphylactic reaction to synthetic luteinizing hormone-releasing hormone. Fertil Steril 1987 Sept;48(3):500-502.
U.S. Patent Nos. 4,652,441; 4,677,191; 4,728,721; 4,849,228; 4,917,893; 4,954,298; 5,330,767; 5,476,663; 5,575,987; 5,631,020; 5,631,021; and 5,716,640.
TAP Pharmaceuticals Inc.
Lake Forest, IL 60045, U.S.A.
by Takeda Chemical Industries, Ltd. Osaka, JAPAN 541
03-5043-R12; Revised: April 2000
© 1990-2000, TAP Pharmaceutical Products Inc.