Lupron depot--3 month 22.5 mg

Absorption   Following a single injection of the three month formulation of LUPRON DEPOT-3 Month 22.5 mg in patients, mean peak plasma leuprolide concentration of 48.9 ng/mL was observed at 4 hours and then declined to 0.67 ng/mL at 12 weeks. Leuprolide appeared to be released at a constant rate following the onset of steady-state levels during the third week after dosing, providing steady plasma concentrations through the 12-week dosing interval. However, intact leuprolide and an inactive major metabolite could not be distinguished by the assay which was employed in the study. Detectable levels of leuprolide were present at all measurement points in all patients. The initial burst, followed by the rapid decline to a steady-state level, was similar to the release pattern seen with the monthly formulation.

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.

LUPRON DEPOT-3 Month 22.5 mg is indicated in the palliative treatment of advanced prostatic cancer. It offers an alternative treatment of prostatic cancer when orchiectomy or estrogen administration are either not indicated or unacceptable to the patient. In clinical trials, the safety and efficacy of LUPRON DEPOT-3 Month 22.5 mg were similar to that of the original daily subcutaneous injection and the monthly depot formulation.

Isolated cases of worsening of signs and symptoms during the first weeks of treatment have been reported with LH-RH analogs. Worsening of symptoms may contribute to paralysis with or without fatal complications. For patients at risk, the physician may consider initiating therapy with daily LUPRON (leuprolide acetate) Injection for the first two weeks to facilitate withdrawal of treatment if that is considered necessary.

General   Patients with metastatic vertebral lesions and/or with urinary tract obstruction should be closely observed during the first few weeks of therapy. (See WARNINGS section.)

Laboratory Tests   Response to LUPRON DEPOT-3 Month 22.5 mg should be monitored by measuring serum levels of testosterone, as well as prostate-specific antigen and prostatic acid phosphatase. 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. Castrate levels were reached within two to four weeks and once achieved were maintained for as long as the patients received their injections.

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 3.75 mg in women results in suppression of the pituitary-gonadal system. Normal function is usually restored within one to three months after treatment is discontinued. Therefore, diagnostic tests of pituitary gonadotropic and gonadal functions conducted during treatment and up to three months after discontinuation of LUPRON DEPOT 3.75 mg therapy may be misleading.

Carcinogenesis, Mutagenesis, Impairment of Fertility Two-year carcinogenicity studies were 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 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.

Pregnancy, Teratogenic Effects   Pregnancy Category X. (See CONTRAINDICATIONS section.)

Pediatric Use   See LUPRON DEPOT-PED (leuprolide acetate for depot suspension) labeling for the safety and effectiveness of the monthly formulation in children with central precocious puberty.

Geriatric Use   In the clinical trials for LUPRON DEPOT-3 Month 22.5 mg, the majority (80%) of the subjects studied were at least 65 years of age. Therefore, the labeling reflects the pharmacokinetics, efficacy and safety of LUPRON DEPOT in this population.

Clinical Trials

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.

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 or hematuria which, if aggravated, may lead to neurological problems such as temporary weakness and/or paresthesia of the lower limbs or worsening of urinary symptoms. (See WARNINGS section.)

In two clinical trials of LUPRON DEPOT-3 Month 22.5 mg, the following adverse reactions were reported to have a possible or probable relationship to drug as ascribed by the treating physician in 5% or more of the patients receiving the drug. Often, causality is difficult to assess in patients with metastatic prostate cancer. Reactions considered not drug-related are excluded.

In these same studies, the following adverse reactions were reported in less than 5% of the patients on LUPRON DEPOT-3 Month 22.5 mg.

Body As A Whole - Enlarged abdomen, Fever; Cardiovascular System - Arrhythmia, Bradycardia, Heart failure, Hypertension, Hypotension, Varicose vein; Digestive System - Anorexia, Duodenal ulcer, Increased appetite, Thirst/dry mouth; Hemic and Lymphatic System - Anemia, Lymphedema; Metabolic and Nutritional Disorders - Dehydration, Edema; Central/Peripheral Nervous System - Anxiety, Delusions, Depression, Hypesthesia, Libido decreased * , Nervousness, Paresthesia; Respiratory System - Epistaxis, Pharyngitis, Pleural effusion, Pneumonia; Special Senses - Abnormal vision, Amblyopia, Dry eyes, Tinnitus; Urogenital System - Gynecomastia, Impotence * , Penis disorders, Testis disorders.

Laboratory:   Abnormalities of certain parameters were observed, but are difficult to assess in this population. The following were recorded in >/= 5% of patients: Increased BUN, Hyperglycemia, Hyperlipidemia (total cholesterol, LDL-cholesterol, triglycerides), Hyperphosphatemia, Abnormal liver function tests, Increased PT, Increased PTT. Additional laboratory abnormalities reported were: Decreased platelets, Decreased potassium and Increased WBC.

Postmarketing

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 (eg, joint and muscle pain, headaches, sleep disorders, gastrointestinal distress, and shortness of breath) have been reported individually and collectively.

Cardiovascular System - Hypotension, Pulmonary embolism; Hemic and Lymphatic System - Decreased WBC; Central/Peripheral Nervous System - Peripheral neuropathy, Spinal fracture/paralysis; Musculoskeletal System - Tenosynovitis-like symptoms; Urogenital System - Prostate pain.

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 an LH-RH agonist analog. In a clinical trial, 25 men with prostate cancer, 12 of whom had been treated previously with leuprolide acetate for at least six months, underwent bone density studies as a result of pain. The leuprolide-treated group had lower bone density scores than the nontreated control group. It can be anticipated that long periods of medical castration in men will have effects on bone density.

See other LUPRON DEPOT and LUPRON Injection package inserts for other events reported in women and pediatric populations.

LUPRON DEPOT-3 Month 22.5 mg is packaged as follows:

Kit with prefilled dual-chamber syringeNDC 0300-3346-01

Each syringe contains sterile lyophilized microspheres which is leuprolide acetate incorporated in a biodegradable polymer of polylactic acid. When mixed with 1.5 mL of accompanying diluent, LUPRON DEPOT-3 Month 22.5 mg is administered as a single IM injection EVERY THREE MONTHS (84 days).

An information pamphlet for patients is included with the kit.

Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [See USP Controlled Room Temperature]

REFERENCE

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. 4,728,721; 4,849,228; 5,330,767; 5,476,663; 5,480,656; 5,575,987; 5,631,020; 5,631,021; 5,643,607; 5,716,640; 5,814,342; 5,823,997; 5,980,488 and 6,036,976. Other patents pending.

Manufactured for

TAP Pharmaceuticals Inc.

Lake Forest, IL 60045, U.S.A.

by Takeda Chemical Industries, Ltd.

Osaka, JAPAN 541

™-Trademark

- Registered trademark

(No. 3346)

03-5307-R9; Revised September 2003

©1995-2003 TAP Pharmaceutical Products Inc.

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