Eligard (Page 2 of 6)

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 2), 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. Refer to Table 10 for details of the description of the dosage form before and after mixing [see How Supplied/Storage and Handling (16)].

Table 2. Specifications for ELIGARD Sterile Safety Needle and Cap

ELIGARD strength Gauge Length
7.5 mg 20-gauge 5/8-inch
22.5 mg 20-gauge 5/8-inch
30 mg 20-gauge 5/8-inch
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 7.5 mg, 22.5 mg, and 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 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.

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, 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 ELIGARD results in suppression of the pituitary-gonadal system. Results of diagnostic tests of pituitary gonadotropic and gonadal functions conducted during and after ELIGARD 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 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.

5.7 Embryo-Fetal Toxicity

Based on findings in animal studies and mechanism of action, ELIGARD 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)].

6 ADVERSE REACTIONS

The following clinically significant adverse reactions are described elsewhere in the labeling:

  • Tumor Flare [see Warnings and Precautions (5.1)]
  • Hyperglycemia and Diabetes [see Warnings and Precautions ( 5.3)]
  • Cardiovascular Disease [see Warnings and Precautions ( 5.4)]
  • Effect on QT/QTc Interval [see Warnings and Precautions ( 5.5)]
  • Convulsions [see Warnings and Precautions ( 5.6)]

6.1 Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

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 adverse reactions.

Table 3. Reported Injection Site Adverse Reactions

ELIGARD

7.5 mg

22.5 mg

30 mg

45 mg

Study number

AGL9904

AGL9909

AGL0001

AGL0205

Number of patients

120

117

90

111

Treatment

1 injection every month up to 6 months

1 injection every 3 months up to 6 months

1 injection every 4 months up to 8 months

1 injection every 6 months up to 12 months

Number of injections

716

230

175

217

Transient burning/ stinging

248 (34.6%) injections; 84% reported as mild

50 (21.7%) injections; 86% reported as mild

35 (20%) injections; 100% reported as mild3

35 (16%) injections; 91.4% reported as mild

Pain (generally brief and mild)

4.3% of injections (18.3% of patients)

3.5% of injections (6.0% of patients)

2.3% of injections2 (3.3% of patients)

4.6% of injections4

Erythema (generally brief and mild) 2.6% of injections (12.5% of patients) 0.9% of injections1 (1.7% of patients) 1.1% of injections (2.2% of patients)
Bruising (mild) 2.5% of injections (11.7% of patients) 1.7% of injections (3.4% of patients)

2.3% of injections5

Pruritus 1.4% of injections (9.2% of patients) 0.4% of injections (0.9% of patients)
Induration 0.4% of injections (2.5% of patients)
Ulceration 0.1% of injections (> 0.8% of patients)
  1. Erythema was reported following 2 injections of ELIGARD 22.5 mg. One report characterized the erythema as mild and it resolved within 7 days. The other report characterized the erythema as moderate and it resolved within 15 days. Neither patient experienced erythema at multiple injection times.
  2. A single reaction reported as moderate pain resolved within two minutes and all 3 mild pain reactions resolved within several days following injection of ELIGARD 30 mg.
  3. Following injection of ELIGARD 30 mg, three of the 35 burning/stinging reactions were reported as moderate.
  4. Transient pain was reported as mild in intensity in nine of ten (90%) events and moderate in intensity in one of ten (10%) events following injection of ELIGARD 45 mg.
  5. 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 4). Reactions considered not drug-related are excluded.

Table 4. Summary of Possible or Probably Related Systemic Adverse Reactions Reported by > 2% of Patients Treated with ELIGARD

ELIGARD

7.5 mg

7.5 mg

22.5 mg

30 mg

45 mg

Study number

AGL9904

AGL9802

AGL9909

AGL0001

AGL0205

Number of patients

120

8

117

90

111

Treatment

1 injection every month up to 6 months

1 injection (surgically castrated patients)

1 injection every 3 months up to 6 months

1 injection every 4 months up to 8 months

1 injection every 6 months up to 12 months
Body system Adverse Reaction Number (percent)
Body as a whole Malaise and fatigue 21 (17.5%) 7 (6.0%) 12 (13.3%) 13 (11.7%)
Weakness 4 (3.6%)
Nervous system Dizziness 4 (3.3%) 4 (4.4%)
Vascular Hot flashes/sweats 68 (56.7%)* 2 (25.0%)* 66 (56.4%)*

66 (73.3%)*

64 (57.7%)*
Renal/urinary Urinary frequency 3 (2.6%) 2 (2.2%)
Nocturia 2 (2.2%)
Gastrointestinal Nausea 4 (3.4%) 2 (2.2%)
Gastroenteritis/colitis 3 (2.5%)
Skin Pruritus 3 (2.6%)
Clamminess 4 (4.4%)*
Night sweats 3 (3.3%)* 3 (2.7%)*
Alopecia 2 (2.2%)
Musculoskeletal Arthralgia 4 (3.4%)
Pain in limb 2 (2.2%) 5 (4.5%)
Myalgia 3 (2.7%)
Reproductive Testicular atrophy 6 (5.0%)* 4 (4.4%)* 8 (7.2%)*
Gynecomastia 2 (2.2%)* 4 (3.6%)*
Testicular pain 2 (2.2%)
Psychiatric Decreased libido 3 (3.3%)*

*Expected pharmacological consequences of testosterone suppression.

In the patient populations studied with ELIGARD 7.5 mg, a total of 86 hot flashes/sweats adverse reactions were reported in 70 patients. Of these, 71 reactions (83%) were mild; 14 (16%) were moderate; 1 (1%) was severe. In the patient population studied with ELIGARD 22.5 mg, a total of 84 hot flashes/sweats adverse reactions were reported in 66 patients. Of these, 73 reactions (87%) were mild; 11 (13%) were moderate; none were severe. In the patient population studied with ELIGARD 30 mg, a total of 75 hot flash adverse reactions were reported in 66 patients. Of these, 57 reactions (76%) were mild; 16 (21%) were moderate; 2 (3%) were severe. 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 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 these 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.

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