Lupron Information
Lupron (Leuprolide)
Lupron (Leuprolide) Description
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 (Leuprolide) INJECTION is a sterile, aqueous solution intended for subcutaneous injection. It is available in a 2.8 mL multiple-dose vial containing leuprolide acetate (5 mg/mL), sodium chloride, USP (6.3 mg/mL) for tonicity adjustment, benzyl alcohol, NF as a preservative (9 mg/mL), and water for injection, USP. The pH may have been adjusted with sodium hydroxide, NF and/or acetic acid, NF.
Lupron (Leuprolide) Clinical Pharmacology
Leuprolide acetate, an LH-RH agonist, acts as a potent inhibitor of gonadotropin secretion when given continuously and in therapeutic doses. Animal and human studies indicate that following an initial stimulation of gonadotropins, chronic administration of leuprolide acetate results in suppression of ovarian and testicular steroidogenesis. This effect is reversible upon discontinuation of drug therapy. Administration of leuprolide acetate has resulted in inhibition of the growth of certain hormone dependent tumors (prostatic tumors in Noble and Dunning male rats and DMBA-induced mammary tumors in female rats) as well as atrophy of the reproductive organs.
In humans, subcutaneous administration of single daily doses 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 pre-menopausal females). However, continuous daily administration of leuprolide acetate results in decreased levels of LH and FSH. In males, testosterone is reduced to castrate levels. In pre-menopausal females, estrogens are reduced to post-menopausal levels. These decreases occur within two to four weeks after initiation of treatment, and castrate levels of testosterone in prostatic cancer patients have been demonstrated for periods of up to five years.
Leuprolide acetate is not active when given orally.
Lupron (Leuprolide) Clinical Studies
In a controlled study comparing Lupron (Leuprolide) 1 mg/day given subcutaneously to DES (diethylstilbestrol), 3 mg/day, the survival rate for the two groups was comparable after two years of treatment. The objective response to treatment was also similar for the two groups.
Lupron (Leuprolide) Indications And Usage
Lupron (Leuprolide) INJECTION (leuprolide acetate) is indicated in the palliative treatment of advanced prostatic cancer.
Lupron (Leuprolide) Warnings
Initially, Lupron (Leuprolide) , like other LH-RH agonists, causes increases in serum levels of testosterone. Transient worsening of symptoms, or the occurrence of additional signs and symptoms of prostate cancer, may occasionally develop during the first few weeks of Lupron (Leuprolide) treatment. A small number of patients may experience a temporary increase in bone pain, which can be managed symptomatically. As with other LH-RH agonists, isolated cases of ureteral obstruction and spinal cord compression have been observed, which may contribute to paralysis with or without fatal complications.
Safe use of leuprolide acetate in pregnancy has not been established clinically. Before starting treatment with Lupron (Leuprolide) , pregnancy must be excluded (see section).
Periodic monitoring of serum testosterone and prostate-specific antigen (PSA) levels is recommended, especially if the anticipated clinical or biochemical response to treatment has not been achieved. It should be noted that 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.
Lupron (Leuprolide) Precautions
Patients with metastatic vertebral lesions and/or with urinary tract obstruction should be closely observed during the first few weeks of therapy (see and sections).
Patients with known allergies to benzyl alcohol, an ingredient of the drug's vehicle, may present symptoms of hypersensitivity, usually local, in the form of erythema and induration at the injection site.
Lupron (Leuprolide) Adverse Reactions
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 week of treatment. This transient increase was occasionally associated with a temporary worsening of signs and symptoms, usually manifested by an increase in bone pain (see section). In a few cases a temporary worsening of existing hematuria and urinary tract obstruction occurred during the first week. Temporary weakness and paresthesia of the lower limbs have been reported in a few cases.
Potential exacerbations of signs and symptoms during the first few weeks of treatment is a concern in patients with vertebral metastases and/or urinary obstruction which, if aggravated, may lead to neurological problems or increase the obstruction.
In a comparative trial of Lupron (Leuprolide) INJECTION (leuprolide acetate) versus DES, in 5% or more of the patients receiving either drug, the following adverse reactions were reported to have a possible or probable relationship to drug as ascribed by the treating physician. Often, causality is difficult to assess in patients with metastatic prostate cancer. Reactions considered not drug related are excluded.
In this same study, the following adverse reactions were reported in less than 5% of the patients on Lupron (Leuprolide) .
In an additional clinical trial and from long-term observation of both studies, the following additional adverse events (excluding those considered not drug related) were reported for patients receiving Lupron (Leuprolide) .
During postmarketing surveillance which includes other dosage forms and other patient populations, the following adverse events were reported.
Symptoms consistent with an anaphylactoid or asthmatic process have been rarely (incidence rate of about 0.002%) reported. Rash, urticaria, and photosensitivity reactions have also been reported.
Localized reactions including induration and abscess have been reported at the site of injection.
Symptoms consistent with fibromyalgia (e.g., joint and muscle pain, headaches, sleep disorders, gastrointestinal distress, and shortness of breath) have been reported individually and collectively.
Lupron (Leuprolide) Overdosage
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 at present that there is a clinical counterpart of this phenomenon. In early clinical trials with leuprolide acetate 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 (Leuprolide) Dosage And Administration
The recommended dose is 1 mg (0.2 mL or 20 unit mark) administered as a single daily subcutaneous injection. As with other drugs administered chronically by subcutaneous injection, the injection site should be varied periodically. Each 0.2 mL contains 1 mg of leuprolide acetate, sodium chloride for tonicity adjustment, 1.8 mg of benzyl alcohol as preservative and water for injection. The pH may have been adjusted with sodium hydroxide and/or acetic acid.
Follow the pictorial directions on the reverse side of this package insert for administration.
NOTE: As with all parenteral products, inspect the solution for discoloration and particulate matter before each use.
Lupron (Leuprolide) How Supplied
Lupron (Leuprolide) INJECTION (leuprolide acetate) is a sterile solution supplied in a 2.8 mL multiple-dose vial. The vial is packaged as follows: 14 Day Patient Administration Kit with 14 disposable syringes and 28 alcohol swabs, NDC 0300-3612-28 and six-vial carton, NDC 0300-3612-24.
Store below 77°F (25°C). Do not freeze. Protect from light; store vial in carton until use.
U.S. Patent Nos. 4,005,063 and 4,005,194.
Lupron (Leuprolide)
Lupron (Leuprolide) Description
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 (Leuprolide) INJECTION is a sterile, aqueous solution intended for daily subcutaneous injection.
It is available in a 2.8 mL multiple dose vial containing leuprolide acetate (5 mg/mL), sodium chloride, USP (6.3 mg/mL) for tonicity adjustment, benzyl alcohol, NF as a preservative (9 mg/mL), and water for injection, USP. The pH may have been adjusted with sodium hydroxide, NF and/or acetic acid, NF.
Lupron (Leuprolide) Clinical Pharmacology
Leuprolide acetate, a GnRH agonist, acts as a potent inhibitor of gonadotropin secretion when given continuously and in therapeutic doses. Animal and human studies indicate that following an initial stimulation of gonadotropins, chronic administration of leuprolide acetate results in suppression of ovarian and testicular steroidogenesis. This effect is reversible upon discontinuation of drug therapy.
Leuprolide acetate is not active when given orally.
Lupron (Leuprolide) Clinical Studies
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 (Leuprolide) Indications And Usage
Lupron (Leuprolide) INJECTION is indicated in the treatment of children with central precocious puberty. Children should be selected using the following criteria:
Lupron (Leuprolide) Warnings
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 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.
Lupron (Leuprolide) Precautions
Patients with known allergies to benzyl alcohol, an ingredient of the vehicle of Lupron (Leuprolide) INJECTION, may present symptoms of hypersensitivity, usually local, in the form of erythema and induration at the injection site.
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.
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 of 0.6 to 4 mg/kg (>100 times the clinical doses of 7.5 to 15 mg/month based on body surface area). 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 daily dose as high as 60 mg/kg (>5000 times the clinical doses based on body surface area). 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.
Lupron (Leuprolide) Adverse Reactions
Potential exacerbation of signs and symptoms during the first few weeks of treatment (see 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.
In those same studies, the following adverse reactions were reported in less than 2% of the patients.
During postmarketing surveillance, which includes other dosage forms and other patient populations, the following adverse events were reported.
Symptoms consistent with an anaphylactoid or asthmatic process have been rarely (incidence rate of about 0.002%) reported. Rash, urticaria, and photosensitivity reactions have also been reported. Localized reactions including induration and abscess have been reported at the site of injection. Symptoms consistent with fibromyalgia (e.g., joint and muscle pain, headaches, sleep disorders, gastrointestinal distress, and shortness of breath) have been reported individually and collectively.
Lupron (Leuprolide) Overdosage
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 (Leuprolide) Dosage And Administration
Lupron (Leuprolide) INJECTION can be administered by a patient/parent or health care professional.
The dose of Lupron (Leuprolide) 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.
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 (Leuprolide) 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.
Follow the pictorial directions on the reverse side of this package insert for administration.
NOTE: As with other parenteral products, inspect the solution for discoloration and particulate matter before each use.
Lupron (Leuprolide) How Supplied
Lupron (Leuprolide) INJECTION (leuprolide acetate) is a sterile solution supplied in a 2.8 mL multiple-dose vial. The vial is packaged as follows:
U.S. Patent Nos. 4,005,063; 4,005,194.
Lupron (Leuprolide)
Lupron (Leuprolide) Administering The Injection
Read this booklet before injecting the medication. Read the complete instructions for injection.
Lupron (Leuprolide)
Lupron (Leuprolide)
