2.1 Mixing Procedure

IMPORTANT: Allow the product to reach room temperature before using. Once mixed, the product must be administered within 30 minutes.

Follow the instructions as directed to ensure proper preparation of ELIGARD® prior to administration:

ELIGARD® is packaged in either thermoformed trays or pouches. Each carton contains:

• One sterile Syringe A pre-filled with the ATRIGEL® Delivery System
• One Syringe B pre-filled with leuprolide acetate powder
• One long white plunger rod for use with Syringe B
• One sterile needle
• Desiccant pack(s)

• On a clean field, open all of the packages and remove the contents. Discard the desiccant pack(s).
  
  
• Pull out the blue-tipped short plunger rod and attached stopper from Syringe B and discard (Figure 1). Gently insert the long, white replacement plunger rod into the gray primary stopper remaining in Syringe B by twisting it in place (Figure 2).
  
  
• Unscrew the clear cap from Syringe A (Figure 3). Remove the gray rubber cap from Syringe B (Figure 4).
  
  
• Join the two syringes together by pushing in and twisting until secure (Figure 5).
  
  
• Inject the liquid contents of Syringe A into Syringe B containing the leuprolide acetate. Thoroughly mix the product by pushing the contents of both syringes back and forth between syringes (approximately 45 seconds) to obtain a uniform suspension (Figure 6). When thoroughly mixed, the suspension will appear light tan to tan (ELIGARD® 7.5 mg) or colorless to pale yellow (ELIGARD®, 22.5 mg, 30 mg and 45 mg) in color. Please Note: Product must be mixed as described; shaking will not provide adequate mixing of the product.
  
  
• Hold the syringes vertically with Syringe B on the bottom. The syringes should remain securely coupled. Draw the entire mixed product into Syringe B (short, wide syringe) by depressing the Syringe A plunger and slightly withdrawing the Syringe B plunger. Uncouple Syringe A while continuing to push down on the Syringe A plunger (Figure 7). Note: Small air bubbles will remain in the formulation – this is acceptable.
  
• Hold Syringe B upright. Remove the cap on the bottom of the sterile needle cartridge by twisting it (Figure 8). Attach the needle cartridge to the end of Syringe B (Figure 9) by pushing in and turning the needle until it is firmly seated. Do not twist the needle onto the syringe until it is stripped. Pull off the clear needle cartridge cover prior to administration (Figure 10).

2.2 Administration Procedure

IMPORTANT: Allow the product to reach room temperature before using. Once mixed, the product must be administered within 30 minutes.

• Choose an injection site on the abdomen, upper buttocks, or anywhere with adequate amounts of subcutaneous tissue that does not have excessive pigment, nodules, lesions, or hair. Since you can vary the injection site with a subcutaneous injection, choose an area that hasn't recently been used.
• Cleanse the injection-site area with an alcohol swab.
• Using the thumb and forefinger of your non-dominant hand, grab and bunch the area of skin around the injection site.
  
• Using your dominant hand, insert the needle quickly at a 90° angle. The approximate angle you use will depend on the amount and fullness of the subcutaneous tissue and the length of the needle. After the needle is inserted, release the skin with your nondominant hand.
  
• Inject the drug using a slow, steady push. Press down on the plunger until the syringe is empty.
• Withdraw the needle quickly at the same angle used for insertion.
• Discard all components safely in an appropriate biohazard container.

4.1 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.

4.2. 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 [see Use in Specific Populations (8.1)]. 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.

5.1 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.

5.2 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.

5.3 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.

5.4 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.

6.1 Clinical trial 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.

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.

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.

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.

6.2 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.

8.1 Pregnancy

8.3 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.

8.4 Pediatric Use

The safety and effectiveness of ELIGARD® in pediatric patients have not been established.

8.5 Geriatric Use

The majority of the patients (approximately 70%) studied in the clinical trials were age 70 and older.

12.1 Mechanism of Action

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.

12.2 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.

12.3 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).

Figure 11. Pharmacokinetic/Pharmacodynamic Response (N=20) to ELIGARD® 7.5 mg – Patients Dosed Initially and at Months 1 and 2

A reduced number of sampling timepoints resulted in the apparent decrease in Cmax values with the second and third doses of ELIGARD® 7.5 mg (Figure 11).

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).

Figure 12. Pharmacokinetic/Pharmacodynamic Response (N=22) to ELIGARD® 22.5 mg – Patients Dosed Initially and at Month 3

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).

Figure 13. Pharmacokinetic/Pharmacodynamic Response (N=24) to ELIGARD® 30 mg – Patients Dosed Initially and at Month 4

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).

Figure 14. Pharmacokinetic/Pharmacodynamic Response (N=27) to ELIGARD® 45 mg - Patients Dosed Initially and at Month 6

There was no evidence of significant accumulation during repeated dosing. Non-detectable leuprolide plasma concentrations have been occasionally observed during ELIGARD® administration, but testosterone levels were maintained at castrate levels.

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®.

Geriatrics. [see USE IN SPECIAL POPULATIONS (8.5)]

Race. In patients studied, mean serum leuprolide concentrations were similar regardless of race. Refer to Table 6 for distribution of study patients by race.

Renal and Hepatic Insufficiency. The pharmacokinetics of ELIGARD® in hepatically and renally impaired patients have not been determined.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Two-year carcinogenicity studies were conducted with leuprolide acetate 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. No carcinogenicity studies have been conducted with ELIGARD®.

Mutagenicity studies have been performed with leuprolide acetate using bacterial and mammalian systems and with ELIGARD® 7.5 mg in bacterial systems. These studies provided no evidence of a mutagenic potential.

16.1 How supplied

ELIGARD® is available in a single use kit of a two syringe-mixing system in the following strengths:

ELIGARD® 7.5 mg – NDC 0024-0793-75
ELIGARD® 22.5 mg – NDC 0024-0222-05
ELIGARD® 30 mg – NDC 0024-0610-30
ELIGARD® 45 mg – NDC 0024-0605-45

16.2 Storage:

Store at 2 – 8 °C (35.6 – 46.4 °F)