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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:
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LUPRON Injection is a sterile, aqueous solution intended for daily subcutaneous injection.
Leuprolide acetate, a GnRH agonist, acts as a potent inhibitor of gonadotropin secretion when given continuously and in therapeutic doses. Human studies indicate that following an initial stimulation of gonadotropins, chronic stimulation with leuprolide acetate results in suppression or "downregulation" of these hormones and consequent suppression of ovarian and testicular steroidogenesis. These effects are reversible on discontinuation of drug therapy.
Leuprolide acetate is not active when given orally. In adults, bioavailability by subcutaneous administration is comparable to that by intravenous administration; and leuprolide acetate has a plasma half-life of approximately three hours. The metabolism, distribution and excretion of leuprolide acetate in humans have not been determined. A pharmacokinetic study of leuprolide acetate in children has not been performed.
In children with central precocious puberty (CPP), stimulated and basal gonadotropins are reduced to prepubertal levels. Testosterone and estradiol are reduced to prepubertal levels in males and females respectively. Reduction of gonadotropins will allow for normal physical and psychological growth and development. Natural maturation occurs when gonadotropins return to pubertal levels following discontinuation of leuprolide acetate.
The following physiologic effects have been noted with the chronic administration of leuprolide acetate in this patient population.
LUPRON Injection is indicated in the treatment of children with central precocious puberty. Children should be selected using the following criteria:
LUPRON Injection is contraindicated in women who are or may become pregnant while receiving the drug. When administered on day 6 of pregnancy at test dosages of 0.00024, 0.0024, and 0.024 mg/kg (1/1200 to 1/12 the human pediatric dose) to rabbits, LUPRON 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 in rabbits and with the highest dose in rats. The effects on fetal mortality are logical consequences of the alterations in hormonal levels brought about by this drug. Therefore, the possibility exists that spontaneous abortion may occur if the drug is administered during pregnancy.
Leuprolide acetate is contraindicated in children demonstrating hypersensitivity to GnRH, GnRH agonist analogs, or any of the excipients.
A report of an anaphylactic reaction to synthetic GnRH (Factrel) has been reported in the medical literature. 1
During the early phase of therapy, gonadotropins and sex steroids rise above baseline because of the natural stimulatory effect of the drug. Therefore, an increase in clinical signs and symptoms may be observed (see " CLINICAL PHARMACOLOGY " section).
Noncompliance with drug regimen or inadequate dosing may result in inadequate control of the pubertal process. The consequences of poor control include the return of pubertal signs such as menses, breast development, and testicular growth. The long-term consequences of inadequate control of gonadal steroid secretion are unknown, but may include a further compromise of adult stature.
Patients with known allergies to benzyl alcohol, an ingredient of the vehicle of Lupron Injection, may present symptoms of hypersensitivity, usually local, in the form of erythema and induration at the injection site.
Laboratory Tests: Response to leuprolide acetate should be monitored 1-2 months after the start of therapy with a GnRH stimulation test and sex steroid levels. Measurement of bone age for advancement should be done every 6-12 months.
Sex steroids may increase or rise above prepubertal levels if the dose is inadequate (see " " section). Once a therapeutic dose has been established, gonadotropin and sex steroid levels will decline to prepubertal levels.
Drug Interactions: No pharmacokinetic-based drug-drug interaction studies have been conducted. 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 leuprolide acetate in therapeutic doses results in suppression of the pituitary-gonadal system. Normal function is usually restored within 4 to 12 weeks after treatment is discontinued.
Information for Parents: Prior to starting therapy with LUPRON Injection, the parent or guardian must be aware of the importance of continuous therapy. Adherence to daily drug administration schedules must be accepted if therapy is to be successful.
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 testes 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. Adult 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.
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.
Pregnancy Category X. See " CONTRAINDICATIONS " section.
Nursing Mothers: It is not known whether leuprolide acetate is excreted in human milk. LUPRON should not be used by nursing mothers.
Potential exacerbation of signs and symptoms during the first few weeks of treatment (See " PRECAUTIONS " section) is a concern in patients with rapidly advancing central precocious puberty.
In two studies of children with central precocious puberty, in 2% or more of the patients receiving the drug, the following adverse reactions were reported to have a possible or probable relationship to drug as ascribed by the treating physician. Reactions considered not drug related are excluded.
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In those same studies, the following adverse reactions were reported in less than 2% of the patients.
Body as a Whole --Body Odor, Fever, Headache, Infection; Cardiovascular System --Syncope, Vasodilation; Digestive System --Dysphagia, Gingivitis, Nausea/Vomiting; Endocrine System --Accelerated Sexual Maturity; Metabolic and Nutritional Disorders --Peripheral Edema, Weight Gain; Nervous System --Nervousness, Personality Disorder, Somnolence, Emotional Lability; Respiratory System --Epistaxis; Integumentary System --Alopecia, Skin Striae; Urogenital System --Cervix Disorder, Gynecomastia/Breast Disorders, Urinary Incontinence.
See other package inserts for adverse events reported in other patient populations.
In rats, subcutaneous administration of 125 to 250 times the recommended human pediatric dose, expressed on a per body weight basis, resulted in dyspnea, decreased activity, and local irritation at the injection site. There is no evidence at present that there is a clinical counterpart of this phenomenon. In early clinical trials using leuprolide acetate in adult patients, 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 INJECTION can be administered by a patient/parent or health care professional.
The dose of LUPRON Injection must be individualized for each child. The dose is based on a mg/kg ratio of drug to body weight. Younger children require higher doses on a mg/kg ratio.
For either dosage form, after 1-2 months of initiating therapy or changing doses, the child must be monitored with a GnRH stimulation test, sex steroids, and Tanner staging to confirm downregulation. Measurements of bone age for advancement should be monitored every 6-12 months. The dose should be titrated upward until no progression of the condition is noted either clinically and/or by laboratory parameters.
The first dose found to result in adequate downregulation can probably be maintained for the duration of therapy in most children. However, there are insufficient data to guide dosage adjustment as patients move into higher weight categories after beginning therapy at very young ages and low dosages. It is recommended that adequate downregulation be verified in such patients whose weight has increased significantly while on therapy.
As with other drugs administered by injection, the injection site should be varied periodically.
Discontinuation of LUPRON Injection should be considered before age 11 for females and age 12 for males.
The recommended starting dose is 50 mcg/kg/day administered as a single subcutaneous injection. If total downregulation is not achieved, the dose should be titrated upward by 10 mcg/kg/day. This dose will be considered the maintenance dose.
NOTE: As with other parenteral products, inspect container's solution for discoloration and particulate matter before each use.
LUPRON (leuprolide acetate) Injection is a sterile solution.
Rx ONLY
U.S. Patent Nos. 4,005,063; 4,005,194.
TAP Pharmaceuticals Inc.
Deerfield, IL 60015, U.S.A.
Lupron Injection manufactured by Abbott Laboratories, North Chicago, IL 60064
®-Registered
Ref. 03-4881-R1 Revised: July, 1998