These highlights do not include all the information needed to use ELIGARD ® safely and effectively. See full prescribing information for ELIGARD. ELIGARD (leuprolide acetate) for injectable suspension, for subcutaneous use Initial U.S. Approval: 2002

Eligard by

Drug Labeling and Warnings

Eligard by is a Prescription medication manufactured, distributed, or labeled by TOLMAR Inc.. Drug facts, warnings, and ingredients follow.

Drug Details [pdf]

ELIGARD- leuprolide acetate injection, suspension, extended release 
TOLMAR Inc.

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FULL PRESCRIBING INFORMATION

1.  INDICATIONS AND USAGE

ELIGARD® is indicated for the treatment of advanced prostate cancer.

2.  DOSAGE AND ADMINISTRATION

2.1 Recommended Dosage

ELIGARD 45 mg is administered subcutaneously every 6 months and provides continuous release of leuprolide acetate over a six-month treatment period.  ELIGARD must be administered by a healthcare provider.  The injection delivers the dose of leuprolide acetate incorporated in a polymer formulation.

As with other drugs administered by subcutaneous injection, the injection site should vary periodically.  The specific injection location should be an area with sufficient soft or loose subcutaneous tissue.  In clinical trials, the injections were administered in the upper- or mid-abdominal area.  Avoid areas with brawny or fibrous subcutaneous tissue or locations that could be rubbed or compressed (i.e., with a belt or clothing waistband).

2.2 Mixing Procedure

Use aseptic technique throughout the procedure.  As with other similar agents, the use of gloves is recommended during mixing and administration.1  Allow the product to reach room temperature before mixing.  Once mixed, the product must be administered within 30 minutes or it should be discarded.

ELIGARD is packaged in a carton containing:

• Tray containing pre-connected syringe system and desiccant pack
• Prescribing information
• Sterile safety needle and cap (located under the tray in carton)

Follow the detailed instructions below to ensure correct preparation of ELIGARD prior to administration:

Step 1 On a clean field open the tray by tearing off the foil from the corner and remove the contents. Discard the desiccant pack. Remove the pre-connected syringe system from the tray. Open the sterile safety needle package by peeling back the paper tab. Note: Syringe A and Syringe B should not be lined-up yet. The product should only be administered with the co-packaged, sterile safety needle.
Step 2 Grasp the latching button on the coupling device with your finger and thumb and press until you hear a snapping sound. The two syringes will be aligned. ; Do not bend the pre-connected syringe system.
Step 3 Holding the syringes in a horizontal position, transfer the liquid contents of Syringe A into the leuprolide acetate powder contained in Syringe B. Thoroughly mix the product for 60 cycles by pushing the contents back and forth between both syringes to obtain a uniform suspension. A cycle is one push of the Syringe A plunger and one push of the Syringe B plunger. When thoroughly mixed, the suspension will appear colorless to pale yellow.; Note: Product must be mixed as described; shaking will NOT provide adequate mixing. Do not bend.
Step 4 After mixing, hold the syringes vertically (upright) with Syringe B (wide syringe) on the bottom. The syringes should remain securely coupled. Transfer all of the mixed product into Syringe B by depressing the Syringe A plunger and slightly withdrawing the Syringe B plunger.
Step 5 While ensuring the Syringe A plunger is fully pushed down, hold the coupling device and unscrew Syringe B. This will disconnect Syringe B from the coupling device. Syringe A will remain attached to the coupling device.   Note: Small air bubbles will remain in the formulation – this is acceptable.   Do not purge the air bubbles from Syringe B as product may be lost!
Step 6 Continue to hold Syringe B upright with the open end at the top. Hold back the white plunger on Syringe B to prevent loss of the product and attach the safety needle and cap. Gently screw clockwise with approximately a three-quarter turn until the safety needle and cap are secure.   Do not overtighten, as the needle hub may become damaged which could result in leakage of the product during injection. The safety shield may also be damaged if the safety needle and cap are screwed with too much force.
Step 7 Move the safety shield away from the needle and towards the syringe. Pull off the cap immediately prior to administration.

Note: Should the needle hub appear to be damaged, or leak, the product should NOT be used. The damaged safety needle and cap should NOT be replaced and the product should NOT be injected. In the event of damage to the needle hub, use a new replacement ELIGARD carton.

2.3 Administration Procedure

3.  DOSAGE FORMS AND STRENGTHS

ELIGARD is an injectable suspension of leuprolide acetate available in a pre-connected syringe system and packaged with a sterile safety needle and cap (Table 1), a desiccant, prescribing information and instructions for use. The pre-connected syringe system consists of syringe A and syringe B connected using a coupling device.  Syringe A contains the in situ polymeric extended release technology and the syringe B contains leuprolide acetate powder.  When reconstituted, ELIGARD is administered as a single dose.

Table 1. Specifications for ELIGARD Sterile Safety Needle and Cap

ELIGARD® strength	Gauge	Length
45 mg	18-gauge	5/8-inch

4.  CONTRAINDICATIONS

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.

5.  WARNINGS AND PRECAUTIONS

5.1 Tumor Flare

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

Monitor ELIGARD response  by periodic measurement of serum concentrations of testosterone and prostate specific antigen.

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.

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.

Drug/Laboratory Test Interactions: Therapy with leuprolide acetate results in suppression of the pituitary-gonadal system.  Results of diagnostic tests of pituitary gonadotropic and gonadal functions conducted during and after leuprolide therapy may be affected.

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.

5.5 Effect on QT/QTc Interval

Androgen deprivation therapy may prolong the QT/QTc interval. Providers should consider whether the benefits of androgen deprivation therapy outweigh the potential risks in patients with congenital long QT syndrome, congestive heart failure, frequent electrolyte abnormalities, and in patients taking drugs known to prolong the QT interval. Electrolyte abnormalities should be corrected. Consider periodic monitoring of electrocardiograms and electrolytes.

5.6 Embryo-Fetal Toxicity

Based on findings in animal studies and mechanism of action, leuprolide acetate may cause fetal harm when administered to a pregnant woman. In animal developmental and reproductive studies, major fetal abnormalities were observed after administration of leuprolide acetate throughout gestation in rats. Advise pregnant patients and females of reproductive potential of the potential risk to the fetus [see Use in Specific Populations (8.1), Clinical Pharmacology (12.1)].

5.7 Convulsions

Postmarketing reports of convulsions have been observed in patients on leuprolide acetate therapy. These included patients with a history of seizures, epilepsy, cerebrovascular disorders, central nervous system anomalies or tumors, and in patients on concomitant medications that have been associated with convulsions such as bupropion and SSRIs. Convulsions have also been reported in patients in the absence of any of the conditions mentioned above. Patients receiving a GnRH agonist who experience convulsion should be managed according to current clinical practice.

6.  ADVERSE REACTIONS

6.1 Clinical Trial Experience

The safety of ELIGARD was evaluated in clinical trials involving patients with advanced prostate cancer (Table 3). 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 2 for a summary of reported injection site adverse reactions.

Table 2. Reported Injection Site Adverse Reactions

ELIGARD 45 mg
Study number	AGL0205
Number of patients	111
Treatment	1 injection every 6 months up to 12 months
Number of injections	217
Transient burning/stinging	35 (16%) injections; 91.4% reported as mild
Pain (generally brief and mild)	4.6% of injections1
Bruising (mild)	2.3% of injections2
Transient pain was reported as mild in intensity in nine of ten (90%) adverse reactions and moderate in intensity in one of ten (10%) events following injection of ELIGARD 45 mg. Mild bruising was reported following 5 (2.3%) study injections and moderate bruising was reported following 2 (<1%) study injections of ELIGARD 45 mg.

These localized adverse reactions were non-recurrent over time.  No patient discontinued therapy due to an injection site adverse reaction.

The following possibly or probably related systemic adverse reactions occurred during clinical trials with ELIGARD, and were reported in > 2% of patients (Table 3).  Often, causality is difficult to assess in patients with metastatic prostate cancer.  Reactions considered not drug-related are excluded.

Table 3. Summary of Possible or Probably Related Systemic Adverse Reactions Reported by > 2% of Patients Treated with ELIGARD

ELIGARD 45 mg
Study number				AGL0205
Number of patients				111
Treatment				1 injection every 6 months up to 12 months
Body system			Adverse Reaction
Body as a whole			Malaise and fatigue	13 (11.7%)
			Weakness	4 (3.6%)
Vascular			Hot flashes/sweats	64 (57.7%)*
Skin			Night sweats	3 (2.7%)*
Musculoskeletal			Myalgia	5 (4.5%)
			Pain in limb	3 (2.7%)
Reproductive			Testicular atrophy	8 (7.2%)*
			Gynecomastia	4 (3.6%)*
*Expected pharmacological consequences of testosterone suppression. In the patient population studied with ELIGARD 45 mg, a total of 89 hot flash adverse reactions were reported in 64 patients. Of these, 62 adverse reactions (70%) were mild; 27 (30%) were moderate; none were severe.

In addition, the following possibly or probably related systemic adverse reactions were reported by < 2% of the patients treated with ELIGARD in clinical studies.

Body system	Adverse Reactions
General	Sweating, insomnia, syncope, rigors, weakness, lethargy
Gastrointestinal	Flatulence, constipation, dyspepsia
Hematologic	Decreased red blood cell count, hematocrit and hemoglobin
Metabolic	Weight gain
Musculoskeletal	Tremor, backache, joint pain, muscle atrophy, limb pain
Nervous	Disturbance of smell and taste, depression, vertigo
Psychiatric	Insomnia, depression, loss of libido*
Renal/urinary	Difficulties with urination, pain on urination, scanty urination, bladder spasm, blood in urine, urinary retention, urinary urgency, incontinence, nocturia, nocturia aggravated
Reproductive/; Urogenital	Testicular soreness/pain, impotence*, decreased libido*, gynecomastia*, breast soreness/tenderness*, testicular atrophy*, erectile dysfunction, penile disorder*, reduced penis size
Skin	Alopecia, clamminess, night sweats*, sweating increased*
Vascular	Hypertension, hypotension
* Expected pharmacological consequences of testosterone suppression.

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

Pituitary apoplexy-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.

Nervous System-Convulsions

Respiratory System-Interstitial lung disease

8.  USE IN SPECIFIC POPULATIONS

8.1  Pregnancy

Risk Summary
Based on findings in animal studies and mechanism of action, ELIGARD may cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available data in pregnant women to inform the drug-associated risk. Expected hormonal changes that occur with ELIGARD treatment increase the risk for pregnancy loss. In animal developmental and reproductive studies, major fetal abnormalities were observed after administration of leuprolide acetate throughout gestation in rats. Advise pregnant patients and females of reproductive potential of the potential risk to the fetus (see Data).

Animal Data
In animal developmental and reproductive studies, major fetal abnormalities were observed after administration of leuprolide acetate throughout gestation.  There were increased fetal mortality and decreased fetal weights in rats and rabbits.  The effects of fetal mortality are expected consequences of the alterations in hormonal levels brought about by this drug.

8.2 Lactation

The safety and efficacy of ELIGARD have not been established in females. There is no information regarding the presence of ELIGARD in human milk, the effects on the breastfed child, or the effects on milk production. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in a breastfed child from ELIGARD, a decision should be made to discontinue breastfeeding or discontinue the drug, taking into account the importance of the drug to the mother.

8.3  Females and Males of Reproductive Potential 

Infertility
Males
Based on mechanism of action, ELIGARD may impair fertility in males of reproductive potential [see Clinical Pharmacology (12.1)].

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.

10.  OVERDOSAGE

In clinical trials using daily subcutaneous injections of 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.

11.  DESCRIPTION

ELIGARD 45 mg is a sterile polymeric matrix formulation of leuprolide acetate, a GnRH agonist, for subcutaneous injection.  It is designed to deliver leuprolide acetate at a controlled rate over a six-month therapeutic period.

Leuprolide acetate is a synthetic nonapeptide analog of naturally occurring gonadotropin releasing hormone (GnRH) that, when given continuously, inhibits pituitary gonadotropin secretion and suppresses testicular and ovarian steroidogenesis.  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:

ELIGARD is supplied as a pre-connected syringe system comprised of two prefilled syringes (syringe A and syringe B) connected using a coupling device.  Immediately prior to administration, the contents of the pre-connected syringe system are mixed until homogenous.  ELIGARD is administered subcutaneously, where it forms a solid drug delivery depot.

Syringe A contains the in situ polymeric extended release technology consisting of a biodegradable poly (DL-lactide-co-glycolide) (PLG) polymer formulation dissolved in a biocompatible solvent, N-methyl-2-pyrrolidone (NMP) and syringe B contains leuprolide acetate.

Refer to Table 4 for the delivery system composition and reconstituted product formulation for the ELIGARD product.

Table 4.  ELIGARD Delivery System Composition and Reconstituted Product Formulation

ELIGARD 45 mg
In situ polymeric extended release technology	Polymer	PLG
	Polymer description	Copolymer with hexanediol
	Polymer DL-lactide to glycolide; molar ratio	85:15
Reconstituted product	Polymer delivered	165 mg
	NMP delivered	165 mg
	Leuprolide acetate delivered	45 mg
	Approximate leuprolide free base equivalent	42 mg
	Approximate administered formulation weight	375 mg
	Approximate injection volume	0.375 mL

12.  CLINICAL PHARMACOLOGY

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.

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 1).

Leuprolide acetate is not active when given orally.

12.3  Pharmacokinetics   

Absorption

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 1.  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 1. 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%.

Elimination
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.

Metabolism
Upon administration with different leuprolide acetate formulations, the major metabolite of leuprolide acetate is a pentapeptide (M-1) metabolite.

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

Race
In patients studied, mean serum leuprolide concentrations were similar regardless of race [White (n = 80), Black (n = 15)] and ethnicity [Hispanic (n=9)]. 

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

13.  NONCLINICAL TOXICOLOGY

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.

14.  CLINICAL STUDIES

One open-label, multicenter study (AGL0205) was conducted in patients with Jewett stage A though D prostate cancer who were treated with at least a single injection of 45 mg of ELIGARD (Table 5).  This study evaluated the achievement and maintenance of castrate serum testosterone suppression over the duration of therapy (Figure 2).

During the AGL0205 study using ELIGARD 45 mg, once testosterone suppression was achieved, one patient (<1%) demonstrated breakthrough.  This patient reached castrate suppression at Day 21 and remained suppressed until Day 308 when his testosterone level rose to 112 ng/dL.  At Month 12 (Day 336), his testosterone was 210 ng/dL.

Table 5.  Summary of Patients in Study AGL0205

ELIGARD 45 mg
Study number			AGL0205
Total number of patients			111 (103 completed1)
Jewett stages	Stage A		5
	Stage B		43
	Stage C		19
	Stage D		44
Treatment			1 injection (5 patients)
			2 injections, one every six months (106 patients)
Duration of therapy			12 months
Mean testosterone concentration (ng/dL)		Baseline	367.7
		Day 2	588.6
		Day 14	Below Baseline
		Day 28	16.7
		Conclusion	12.6
Number of patients below castrate threshold; (≤ 50 ng/dL)		Day 28	108 of 109 (99.1%)
		Conclusion	102 (99%)
Two patients were withdrawn prior to the Month 1 blood draw. One patient did not achieve castration and was withdrawn on Day 85. All 5 non-evaluable patients who attained castration by Day 28, maintained castration at each time point up to and including the time of withdrawal.

Figure 2.  ELIGARD 45 mg Mean Serum Testosterone Concentrations (n=103)

Serum PSA decreased in all patients whose Baseline values were elevated above the normal limit.  Refer to Table 6 for a summary of the effectiveness of ELIGARD in reducing serum PSA values.

Table 6. Effect of ELIGARD on Patient Serum PSA Values

ELIGARD 45 mg
Mean PSA reduction at study conclusion	97%
Patients with normal PSA at study conclusion*	95%
*Among patients who presented with elevated levels at Baseline

Other secondary efficacy endpoints evaluated included WHO performance status, bone pain, urinary pain and urinary signs and symptoms.  Refer to Table 7 for a summary of these endpoints.

Table 7. Secondary Efficacy Endpoints

Secondary Efficacy Endpoint	Baseline	Month 12
WHO Status = 01	90%	94%
WHO Status = 12	7%	5%
WHO Status = 23	3%	1%
Mean bone pain4; (range)	1.38 (1-7)	1.31 (1-8)
Mean urinary pain (range)	1.22 (1-8)	1.07 (1-5)
Mean urinary signs and symptoms (range)	Low	Modestly decreased
Number of patients with prostate abnormalities	89 (80%)	60 (58%)
WHO status = 0 classified as “fully active.”  WHO status = 1 classified as “restricted in strenuous activity but ambulatory and able to carry out work of a light or sedentary nature.”  WHO status = 2 classified as “ambulatory but unable to carry out work activities.”  Pain score scale: 1 (no pain) to 10 (worst pain possible).

15.  REFERENCES

1. "OSHA Hazardous Drugs."  OSHA.  http://www.osha.gov/SLTC/hazardousdrugs/index.html

16.  HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

ELIGARD is available in a single-dose, two syringe-mixing system with a sterile safety needle and cap in the following strength:

ELIGARD 45 mg – NDC: 62935-461-50

16.2 Storage

Store at 2°C to 8°C (36°F to 46°F)

Once outside the refrigerator this product may be stored in its original packaging at room temperature 15°C to 30°C (59°F to 86°F) for up to eight weeks prior to mixing and administration.

17.  PATIENT COUNSELING INFORMATION

Hypersensitivity

• Inform patients that if they have experienced hypersensitivity with other GnRH agonist drugs like ELIGARD, ELIGARD is contraindicated [see Contraindications (4)].

Tumor Flare

• Inform patients that ELIGARD can cause tumor flare during the first weeks of treatment. Inform patients that the increase in testosterone can cause an increase in urinary symptoms or pain. Advise patients to contact their healthcare provider if uretral obstruction, spinal cord compression, paralysis, or new or worsened symptoms occur after beginning ELIGARD treatment [see Warnings and Precautions (5.1)].

Hyperglycemia and Diabetes

• Advise patients that there is an increased risk of hyperglycemia and diabetes with ELIGARD therapy.  Inform patients that periodic monitoring for hyperglycemia and diabetes is required when being treated with ELIGARD [see Warnings and Precautions (5.3)].

Cardiovascular Disease

• Inform patients that there is an increased risk of myocardial infarction, sudden cardiac death, and stroke with ELIGARD treatment. Advise patients to immediately report signs and symptoms associated with these events to their healthcare provider for evaluation [see Warnings and Precautions (5.4)].

Injection Site Reactions

• Inform patients that injection site related adverse reactions may occur such as transient burning/stinging, pain, bruising, and redness.  Advise patients to contact their healthcare provider if they experience rash or severe injection site reactions [see Adverse Reactions (6.1)].

Urogenital Disorders

• Advise patients that ELIGARD may cause impotence.

Infertility

• Inform patients that ELIGARD may cause infertility [see Use In Specific Populations (8.3)].

Rx only

Revised 04/23

Manufactured by: Tolmar, Fort Collins, CO 80526
©2022 Tolmar

04006171 Rev. 2 04/23

INSTRUCTIONS FOR USE

Follow the detailed instructions below to ensure correct preparation of ELIGARD prior to administration:

Step 1 Use aseptic technique throughout the procedure.  Gloves are recommended during mixing and administration. Allow the product to reach room temperature before mixing.  Once mixed, the product must be administered within 30 minutes or it should be discarded. On a clean field open the tray by tearing off the foil from the corner and remove the contents. Discard the desiccant pack. Remove the pre-connected syringe system from the tray. Open the sterile safety needle package by peeling back the paper tab. Note: Syringe A and Syringe B should not be lined-up yet. The product should only be administered with the co-packaged, sterile safety needle.
Step 2 Grasp the latching button on the coupling device with your finger and thumb and press until you hear a snapping sound. The two syringes will be aligned.; Do not bend the pre-connected syringe system.
Step 3 Holding the syringes in a horizontal position, transfer the liquid contents of Syringe A into the leuprolide acetate powder contained in Syringe B. Thoroughly mix the product for 60 cycles by pushing the contents back and forth between both syringes to obtain a uniform suspension. A cycle is one push of the Syringe A plunger and one push of the Syringe B plunger. When thoroughly mixed, the suspension will appear colorless to pale yellow.   Note: Product must be mixed as described; shaking will NOT provide adequate mixing. Do not bend.
Step 4 After mixing, hold the syringes vertically (upright) with Syringe B (wide syringe) on the bottom. The syringes should remain securely coupled. Transfer all of the mixed product into Syringe B by depressing the Syringe A plunger and slightly withdrawing the Syringe B plunger.
Step 5 While ensuring the Syringe A plunger is fully pushed down, hold the coupling device and unscrew Syringe B. This will disconnect Syringe B from the coupling device. Syringe A will remain attached to the coupling device.   Note: Small air bubbles will remain in the formulation – this is acceptable.   Do not purge the air bubbles from Syringe B as product may be lost!
Step 6 Continue to hold Syringe B upright with the open end at the top. Hold back the white plunger on Syringe B to prevent loss of the product and attach the safety needle and cap. Gently screw clockwise with approximately a three-quarter turn until the safety needle and cap are secure.   Do not overtighten, as the needle hub may become damaged which could result in leakage of the product during injection. The safety shield may also be damaged if the safety needle and cap are screwed with too much force.
Step 7 Move the safety shield away from the needle and towards the syringe. Pull off the cap immediately prior to administration.

Note: Should the needle hub appear to be damaged, or leak, the product should NOT be used. The damaged safety needle and cap should NOT be replaced and the product should NOT be injected. In the event of damage to the needle hub, use a new replacement ELIGARD carton.

Follow the detailed instructions below to ensure correct administration of ELIGARD:

©2022 Tolmar

Manufactured by: Tolmar, Fort Collins, CO 80526     04006171 Rev. 2 04/23

PRINCIPAL DISPLAY PANEL

45 mg carton

ELIGARD 
leuprolide acetate injection, suspension, extended release

Product Information
Product Type	HUMAN PRESCRIPTION DRUG	Item Code (Source)	NDC: 62935-461
Route of Administration	SUBCUTANEOUS

Active Ingredient/Active Moiety
Ingredient Name	Basis of Strength	Strength
LEUPROLIDE ACETATE (UNII: 37JNS02E7V) (LEUPROLIDE - UNII:EFY6W0M8TG)	LEUPROLIDE ACETATE	45 mg  in 0.375 mL

Inactive Ingredients
Ingredient Name	Strength
METHYL PYRROLIDONE (UNII: JR9CE63FPM)	165  mg  in 0.375 mL
POLY(DL-LACTIC-CO-GLYCOLIC ACID), (85:15; 23000 MW) (UNII: 93PPD1S477)	165 mg  in 0.375 mL

Packaging
#	Item Code	Package Description	Marketing Start Date	Marketing End Date
1	NDC: 62935-461-50	1 in 1 CARTON	03/06/2023
1		0.375 mL in 1 SYRINGE; Type 2: Prefilled Drug Delivery Device/System (syringe, patch, etc.)

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
NDA	NDA021731	03/06/2023

Labeler - TOLMAR Inc. (791156578)

Revised: 9/2023

Document Id: bc1570f9-f7f2-4210-b893-10e2ca7bf094

34391-3

Set id: 0f03a91d-37eb-4e91-bf00-7fe097a4bead

Version: 15

Effective Time: 20230914