Lupron Depot GYN-ENDO: Indications, Dosage, Precautions, Adverse Effects
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Lupron Depot GYN-ENDO - Product Information

Manufacture: AbbVie
Country: Canada
Condition: Endometriosis, Hirsutism, Prostate Cancer, Uterine Fibroids
Class: Gonadotropin releasing hormones, Hormones/antineoplastics
Form: Liquid solution, Intramuscular (IM)
Ingredients: leuprolide acetate, carboxymethylcellulose sodium, DL-lactic and glycolic acids copolymer, D-mannitol, gelatin, glacial acetic acid, polysorbate 80 and water for injection

LUPRON DEPOT

leuprolide acetate for depot suspension

Summary product information

Route of Administration Dosage Form/Strength Clinically Relevant Non-medicinal Ingredients
intramuscular pre-filled dual chamber syringe containing sterile lyophilized microspheres / 3.75 mg (1-month slow release)

pre-filled dual chamber syringe containing sterile lyophilized microspheres / 11.25 mg (3-month slow release)
carboxymethylcellulose sodium, DL-lactic and glycolic acids copolymer, D-mannitol, gelatin, glacial acetic acid, polysorbate 80

carboxymethylcellulose sodium, D-mannitol, glacial acetic acid, polylactic acid, polysorbate 80

For a complete listing see DOSAGE FORMS, COMPOSITION AND PACKAGING section.

Indications and clinical use

Both LUPRON DEPOT (leuprolide acetate for depot suspension) 3.75 mg (1-Month SR) and 11.25 mg (3-Month SR) are indicated for:

  • the treatment of endometriosis, including pain relief and reduction of endometriosis lesions, for a period of six months.

LUPRON DEPOT with norethindrone acetate 5 mg daily is indicated for the initial management of endometriosis and for management of recurrence of symptoms.

LUPRON DEPOT can be used as sole therapy where it may provide symptomatic relief for women close to menopause who do not desire surgery, or as an adjunct to surgery.

Experience with LUPRON DEPOT for the management of endometriosis has been limited to women 18 years of age and older.

LUPRON DEPOT must be administered under the supervision of a physician.

Geriatrics (> 65 years of age):

LUPRON DEPOT 3.75 mg (1-Month SR) and 11.25 mg (3-Month SR) are not indicated for women over 65 years of age.

Pediatrics (< 18 years of age):

LUPRON DEPOT 11.25 mg (3-Month SR) is not indicated for pediatric use. LUPRON DEPOT treatment of children is covered in the LUPRON DEPOT 3.75 mg and 7.5 mg “Central Precocious Puberty” Product Monograph.

Contraindications

  • LUPRON DEPOT (leuprolide acetate for depot suspension) is contraindicated in patients with hypersensitivity to the drug or its components or similar nonapeptides or components of the container. Isolated cases of anaphylaxis have been reported. For a complete listing, see the DOSAGE FORMS, COMPOSITION AND PACKAGING section of the Product Monograph.
  • LUPRON DEPOT is contraindicated in women who are or may become pregnant. When administered on day 6 of pregnancy at test dosages of 0.00024, 0.0024, and 0.024 mg/kg (1/300 to 1/3* the 3.75 mg LUPRON DEPOT human dose) to rabbits, LUPRON DEPOT produced a dose-related increase in major fetal abnormalities. Similar studies in rats failed to demonstrate an increase in fetal malformations. There was increased fetal mortality and decreased fetal weights with the two higher doses of LUPRON DEPOT in rabbits and with the highest dose (0.024 mg/kg) in rats. The effects on fetal mortality are logical consequences of the alterations in hormonal levels brought about by this drug. Therefore, the possibility exists that spontaneous abortion may occur if the drug is administered during pregnancy.

    Patients treated with LUPRON DEPOT should use nonhormonal methods of contraception.
  • LUPRON DEPOT is also contraindicated in patients with undiagnosed abnormal vaginal bleeding.
  • It is not known whether leuprolide acetate is excreted in human milk; therefore, LUPRON DEPOT is contraindicated in patients who are breast-feeding.
  • Refer to the Norlutate Product Monograph for contraindications specific to norethindrone acetate.

Warnings and precautions

General

Postmarketing reports of convulsions have been observed in patients on leuprolide acetate therapy. These included patients in the female and pediatric populations, 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.

Isolated cases of short-term worsening of signs and symptoms have been reported during initiation of leuprolide therapy. They are sometimes, but not necessarily, associated with a stimulation of the pituitary gland and an initial increase in the levels of circulating gonadal hormones.

During the early phase of therapy, sex steroids temporarily rise above baseline because of the physiologic effect of the drug. Therefore, an increase in clinical signs and symptoms may be observed during the initial days of therapy, but these will dissipate with continued therapy at adequate doses.

Worsening of the clinical condition may occasionally require discontinuation of therapy and/or surgical intervention.

Before initiating treatment with LUPRON DEPOT (leuprolide acetate for depot suspension), pregnancy must be ruled out. See WARNINGS AND PRECAUTIONS, Special Populations, Pregnant Women.

Patients on leuprolide therapy should be assessed on a regular basis by their attending physician.

Refer to the Norlutate Product Monograph for information on the WARNINGS and PRECAUTIONS related to norethindrone acetate.

Carcinogenesis and Mutagenesis

Two-year carcinogenicity studies were conducted in rats and mice. In rats, a dose-related increase of benign pituitary hyperplasia and benign 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. See TOXICOLOGY.

Dependence/Tolerance

No drug-dependence has been reported with the use of leuprolide acetate.

Endocrine and Metabolism

Changes in Bone Density

Since bone loss can be anticipated as part of natural menopause, it may also be expected to occur during the medically induced hypoestrogenic state caused by the long-term use of LUPRON DEPOT. For a period of up to six months, this bone loss should not be important.

Clinical studies indicate that concurrent hormonal replacement therapy (add-back therapy) with norethindrone acetate 5 mg daily and calcium supplementation is effective in reducing the loss of bone mineral density which occurs with LUPRON DEPOT. See CLINICAL TRIALS, Study Results, LUPRON DEPOT 3.75 mg, Safety, Bone Mineral Density in Studies III and IV.

If the symptoms of endometriosis recur after a course of therapy, and further treatment with LUPRON DEPOT is contemplated, it is recommended that bone density be assessed before retreatment begins to ensure that values are within normal limits. Retreatment with a six-month course of LUPRON DEPOT and norethindrone acetate 5 mg daily may be considered. Retreatment with LUPRON DEPOT alone is not recommended.

In patients with significant risk factors for decreased bone mineral content and/or bone mass such as family history of osteoporosis, chronic use of corticosteroids or anticonvulsants or chronic abuse of alcohol or tobacco, leuprolide may pose additional risk. In these patients, risk versus benefit must be weighed carefully before initiation of leuprolide therapy, and concomitant treatment with norethindrone acetate 5 mg daily should be considered. Retreatment with gonadotropin-releasing hormones analogs, including LUPRON DEPOT is not advisable in patients with major risk factors for loss in bone mineral content.

A controlled study in endometriosis patients showed that vertebral bone density, as measured by dual energy X-ray absorptiometry (DEXA), decreased by an average of 4.1% at six months compared with the pretreatment value.

For those patients who were tested at six or twelve months after discontinuation of therapy, the mean bone density returned to -2.6% of pretreatment.

Earlier studies in endometriosis patients, utilizing quantitative computed tomography (QCT), demonstrated that in the few patients who were retested at six and twelve months, partial to complete recovery of bone density was recorded in the posttreatment period. Use of

LUPRON DEPOT for longer than six months or in the presence of other known risk factors for decreased bone mineral content may cause additional bone loss.

Two clinical studies demonstrated that concurrent hormonal therapy with norethindrone acetate 5 mg daily and calcium supplementation significantly reduced the loss of bone mineral density that occurs with LUPRON DEPOT treatment, without compromising the efficacy of LUPRON DEPOT in relieving symptoms of endometriosis. The bone mineral density data from these two studies, evaluated after 6 months and 1 year of treatment at the lumbar spine, are presented in Table 1.

Table 1. Mean Percent Change from Baseline in Bone Mineral Density of Lumbar Spine in the Add- Back Studies
LUPRON DEPOT 3.75 mg LUPRON DEPOT 3.75 mg + norethindrone acetate 5 mg daily
Controlled Study (Study III) Controlled Study (Study III) Open Label Study (Study IV)
N Change N Change N Change
Week 24* 41 -3.2% 42 -0.3% 115 -0.2%
Week 52** 29 -6.3% 32 -1.0% 84 -1.1%
*   Includes on-treatment measurements that fell within 2 to 252 days after the first day of treatment.
**     Includes on-treatment measurements >252 days after the first day of treatment.

The safety of retreatment as well as treatment beyond 6 months with LUPRON DEPOT has not been established.

Adverse events occurring in clinical studies with LUPRON DEPOT that are associated with hypoestrogenism include hot flashes, headaches, emotional lability, decreased libido, acne, myalgia, reduction in breast size, and vaginal dryness. Estrogen levels returned to normal after treatment was discontinued.

Hepatic/Biliary/Pancreatic

The pharmacokinetics of the drug in patients with hepatic, biliary or pancreatic impairment have not been determined.

Renal

The pharmacokinetics of the drug in patients with renal impairment have not been determined.

Special Populations

Pregnant Women

Safe use of the drug in pregnancy has not been established; therefore, a nonhormonal method of contraception should be used during treatment. Patients should be advised that if they miss or postpone a dose of LUPRON DEPOT, ovulation may occur with the potential for conception. If a patient becomes pregnant during treatment, she should discontinue treatment and consult her physician.

Since menstruation should stop with effective doses of LUPRON DEPOT, the patient should notify her physician if regular menstruation persists. Patients missing successive doses of LUPRON DEPOT may experience breakthrough bleeding.

Before initiating treatment with LUPRON DEPOT, pregnancy must be ruled out.

Nursing Women

It is not known whether leuprolide is excreted in human milk; therefore, LUPRON DEPOT is contraindicated in patients who are breast-feeding.

Pediatrics (< 18 years of age)

Safety and effectiveness of LUPRON DEPOT 11.25 mg (3-Month SR) have not been established in pediatric patients. Refer to the “Central Precocious Puberty” Product Monograph for the safety and effectiveness of LUPRON DEPOT 3.75 mg (1-Month SR) in children with central precocious puberty.

Geriatrics (> 65 years of age)

LUPRON DEPOT 3.75 mg (1-Month SR) and 11.25 mg (3-Month SR) have not been studied in women over 65 years of age and are not indicated in this population.

Monitoring and Laboratory Tests

Changes in Laboratory Values During Treatment

Plasma Enzymes

During clinical trials with LUPRON DEPOT alone, regular laboratory monitoring revealed that serum glutamic oxaloacetic transaminase (SGOT) levels were more than twice the upper limit of normal in only one patient. There was no other clinical or laboratory evidence of abnormal liver function.

In two other clinical trials, 6 of 191 patients receiving LUPRON DEPOT 3.75 mg plus norethindrone acetate 5 mg daily for up to 12 months developed an elevated (at least twice the upper limit of normal) serum glutamic pyruvic transaminase (SGPT) or γ-glutamyltransferase (GGT). Five of the 6 increases were observed beyond 6 months of treatment. None were associated with elevated bilirubin concentration.

Hematology

Slight decreases in hemoglobin and hematocrit values to below normal were noted with receipt of LUPRON DEPOT 11.25 mg (3-Month SR), but none were considered clinically significant.

Lipids

At enrolment, 4% of LUPRON DEPOT 3.75 mg (1-Month SR) patients and 1% of the danazol patients had total cholesterol values above the normal range. These patients also had cholesterol values above the normal range at the end of treatment. Of those patients whose pretreatment cholesterol values were in the normal range, 7% of the LUPRON DEPOT patients and 9% of the danazol patients had posttreatment values above the normal range.

The mean (± SEM) pretreatment values for total cholesterol from all patients were 4.63 (0.08) mmol/L in the LUPRON DEPOT 3.75 mg (1-Month SR) group and 4.54 (0.08) mmol/L in the danazol group. At the end of treatment, the mean values for total cholesterol from all patients were 5.01 mmol/L in the LUPRON DEPOT group and 5.03 mmol/L in the danazol group. These increases from the pretreatment values were statistically significant (p < 0.03) in both groups.

Triglycerides were increased above the upper limit of normal in 12% of the patients who received LUPRON DEPOT 3.75 mg (1-Month SR) and in 6% of the patients who received danazol.

At the end of treatment, high-density lipoprotein (HDL) cholesterol fractions decreased below the lower limit of the normal range in 2% of the LUPRON DEPOT 3.75 mg (1-Month SR) patients compared with 54% of those receiving danazol. Low-density lipoprotein (LDL) cholesterol fractions increased above the upper limit of the normal range in 6% of the patients receiving LUPRON DEPOT 3.75 mg (1-Month SR) compared with 23% of those receiving danazol. There was no increase in the LDL/HDL ratio in patients receiving LUPRON DEPOT 3.75 mg (1-Month SR), but there was approximately a two-fold increase in the LDL/HDL ratio in patients receiving danazol. The clinical implication of these changes in this patient population for a restricted therapeutic period is unclear.

Isolated elevations of SGOT were observed in leuprolide acetate- and danazol-treated patients.

In subjects receiving LUPRON DEPOT 11.25 mg (3-Month SR), triglycerides were slightly elevated (range 142 to 210 mg/dL) in 32% of the subjects who had demonstrated normal baseline values.

In two other clinical trials, LUPRON DEPOT 3.75 mg plus norethindrone acetate 5 mg daily were evaluated for 12 months of treatment. LURON DEPOT 3.75 mg was used as a control group in one study. Percent changes from baseline for serum lipids and percentages of patients with serum lipid values outside of the normal range in the two studies are summarized in Table 2 and Table 3, below.

Table 2. Serum Lipids: Mean Percent Changes From Baseline Values at Treatment Week 24 in the Add-Back Studies
Controlled Study (Study III) Open Label Study (Study IV)
LUPRON DEPOT 3.75 mg
N=39
LUPRON DEPOT 3.75 mg +
norethindrone acetate 5 mg
N=41
LUPRON DEPOT 3.75 mg
+ norethindrone acetate 5 mg
N=117
Baseline
Value
(mg/dL)
Week 24
% Change       
Baseline
Value
(mg/dL)
Week 24
% Change
Baseline   
Value
(mg/dL)
Week 24
% Change
Total
Cholesterol
170.5 9.2% 179.3 0.2% 181.2 2.8%
HDL
Cholesterol
52.4 7.4% 51.8 -18.8% 51.0 -14.6%
LDL
Cholesterol
96.6 10.9% 101.5 14.1% 109.1 13.1%
LDL/HDL
Ratio1
2.0 5.0% 2.1 43.4% 2.3 39.4%
Triglycerides 107.8 17.5% 130.2 9.5% 105.4 13.8%
1. Values expressed as ratio

Changes from baseline tended to be greater at Week 52. After treatment, mean serum lipid levels from patients with follow up data returned to pretreatment values.

Table 3. Percentage of Patients with Serum Lipid Values Outside of the Normal Range in the Add-Back Studies
Controlled Study (Study III) Open Label Study (Study IV)
LUPRON DEPOT 3.75 mg
N=39        
LUPRON DEPOT 3.75 mg
+ norethindrone acetate 5 mg
N=41
LUPRON DEPOT 3.75 mg
+ norethindrone acetate 5 mg
N=117
Week 0 Week 241 Week 0 Week 241 Week 0 Week 241
Total Cholesterol
(>240 mg/dL)
15% 23% 15% 20% 6% 7%
HDL Cholesterol
(<40 mg/dL)
15% 10% 15% 44% 15% 41%
LDL Cholesterol
(>160 mg/dL)
0% 8% 5% 7% 9% 11%
LDL/HDL Ratio
(>4.0)
0% 3% 2% 15% 7% 21%
Triglycerides
(>200 mg/dL)
13% 13% 12% 10% 5% 9%
1. Includes all patients regardless of baseline values.

Low HDL-cholesterol (<40 mg/dL) and elevated LDL-cholesterol (>160 mg/dL) are recognized risk factors for cardiovascular disease. The long-term significance of the observed treatment- related changes in serum lipids in women with endometriosis is unknown. Therefore assessment of cardiovascular risk factors should be considered prior to initiation of concurrent treatment with LUPRON DEPOT and norethindrone acetate.

Other Changes

In comparative studies, the following changes were seen in approximately 5 to 8% of patients. LUPRON DEPOT was associated with elevations of lactate dehydrogenase (LDH) and phosphorus, and decreases in white blood cell (WBC) counts, and danazol therapy was associated with increases in hematocrit, platelet count, and LDH.

Adverse reactions

Adverse Drug Reaction Overview

Estradiol levels may increase during the first weeks following the initial injection, but then decline to basal levels. This transient increase in estradiol can be associated with a temporary worsening of signs and symptoms. See WARNINGS AND PRECAUTIONS.

Refer to the Norlutate Product Monograph for information on the adverse reactions related to norethindrone acetate.

Interstitial lung disease has been reported with a variable time to onset in the post-marketing reports of patients treated with leuprolide acetate. Although a direct causal relationship between leuprolide acetate therapy and interstitial lung disease has not been established on the basis of the underlined disease (i.e., endometriosis), discontinuation of leuprolide acetate to allow for a potential resolution of the interstitial lung disease should be considered.

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

LUPRON DEPOT 3.75 mg (1-Month SR)

In two controlled clinical trials treating endometriosis, one comparing LUPRON DEPOT 3.75 mg (1-Month SR) with danazol (800 mg/day) and the other with placebo, the following adverse reactions were reported to have a possible or probable relationship to study drugs as ascribed by the treating physician in 5% or more of the patients receiving the drug (Table 4).

Table 4. Adverse Reactions Reported Having a Possible or Probable Relationship to Study Drugs in 5% or More of Patients Receiving LUPRON DEPOT 3.75 mg (1-Month SR) versus Danazol (800 mg/day) and LUPRON DEPOT 3.75 mg (1-Month SR) versus Placebo
LUPRON DEPOT
3.75 mg (1-Month SR)
N=166 (%)
Danazol
800 mg/day
N=136 (%)
Placebo
N=31 (%)
Number of Reports (%)
Cardiovascular System
Edema 12 (7) 17 (13) 1 (3)
Gastrointestinal System
Nausea/vomiting 21 (13) 17 (13) 1 (3)
GI disturbances* 11 (7) 8 (6) 1 (3)
Endocrine System
Hot flashes/sweats* 139 (84) 77 (57) 9 (29)
Breast changes, tenderness/pain* 10 (6) 12 (9) 0 (0)
Decreased libido* 19 (11) 6 (4) 0 (0)
Androgen-like effects 22 (13) 44 (32)** 1 (3)
Virilism 0 (0) 1 (1) 0 (0)
Acne 17 (10) 27 (20) 0 (0)
Seborrhea 2 (1) 5 (4) 0 (0)
Hirsutism 2 (1) 9 (7) 1 (3)
Voice alteration 1 (1) 2 (1) 0 (0)
Musculoskeletal System
Myalgia* 1 (1) 7 (5) 0 (0)
Joint disorder* 14 (8) 11 (8) 0 (0)
Central/Peripheral Nervous System
Depression/emotional lability* 36 (22) 27 (20) 1 (3)
Headaches* 53 (32) 30 (22) 2 (6)
Dizziness 19 (11) 4 (3) 0 (0)
Insomnia/sleep disorders* 2 (1) 4 (3) 0 (0)
General pain 31 (19) 22 (16) 1 (3)
Neuromuscular disorders* 11 (7) 17 (13) 0 (0)
Nervousness* 8 (5) 11 (8) 0 (0)
Paresthesias 12 (7) 11 (8) 0 (0)
Integumentary System
Skin reactions 17 (10) 20 (15) 1 (3)
Urogenital System
Vaginitis* 46 (28) 23 (17) 0 (0)
Miscellaneous
Asthenia 5 (3) 9 (7) 0 (0)
Weight gain/loss 22 (13) 36 (26) 0 (0)
* Physiologic effect of decreased estrogen.
** Individual percentages equal 33% due to rounding.
Reactions considered not drug-related are excluded.

LUPRON DEPOT 11.25 mg (3-Month SR)

In a pharmacokinetic trial involving 20 healthy female subjects receiving LUPRON DEPOT 11.25 mg (3-Month SR), a few adverse events were reported with this formulation that were not reported previously. These included face edema, agitation, laryngitis and ear pain, and are noted in Table 5.

Table 5. Adverse Events Reported by 20 Healthy Female Subjects Receiving LUPRON DEPOT 11.25 mg (3-Month SR) in a Pharmacokinetic Trial
LUPRON DEPOT 11.25 mg (3-Month SR)
N=20 (%)
Body as a Whole
Asthenia 1 (5.0)
Face edema 1 (5.0)
General pain 4 (20.0)
Headache/migraine* 16 (80.0)
Cardiovascular System
Hot flashes/sweats 13 (65.0)
Digestive System
GI disturbance* 2 (10.0)
Liver function test abnormal 1 (5.0)
Nausea/vomiting 2 (10.0)
Metabolic and Nutritional Disorders
Edema 1 (5.0)
Musculoskeletal System В 
Myalgia* 2 (10.0)
Nervous System
Agitation 1 (5.0)
Depression/emotional lability* 1 (5.0)
Dizziness/vertigo 1 (5.0)
Insomnia/sleep disorders* 2 (10.0)
Neuromuscular disorders* 1 (5.0)
Respiratory System
Laryngitis 1 (5.0)
Special Senses
Ear pain 1 (5.0)
Urogenital System
Dysmenorrhea 1 (5.0)
* Physiologic effect of the drug

Table 6 lists the potentially drug-related adverse events observed in at least 5% of patients in any treatment group, during the first 6 months of treatment in the add-back clinical studies, in which patients were treated with monthly LUPRON DEPOT 3.75 mg with or without norethindrone acetate co-treatment.

Table 6. Treatment-Related Adverse Events Occurring in ≥ 5% of Patients
Controlled Study (Study III) Open Label (Study IV)
LUPRON DEPOT
3.75 mg
N=51 (%)
LUPRON DEPOT
3.75 mg + norethindrone
acetate 5 mg
N=55 (%)
LUPRON DEPOT
3.75 mg + norethindrone
acetate 5 mg
N=136 (%)
Any Adverse Event 50 (98) 53 (96) 126 (93)
Body as a Whole
Asthenia 9 (18) 10 (18) 15 (11)
Headache/Migraine 33 (65) 28 (51) 63 (46)
Injection Site Reaction 1 (2) 5 (9) 4 (3)
Pain 12 (24) 16 (29) 29 (21)
Cardiovascular System
Hot Flashes/Sweats 50 (98) 48 (87) 78 (57)
Digestive System
Altered Bowel Function 7 (14) 8 (15) 14 (10)
Changes in Appetite 2 (4) 0 (0) 8 (6)
GI Disturbance 2 (4) 4 (7) 6 (4)
Nausea/Vomiting 13 (25) 16 (29) 17 (13)
Metabolic and Nutritional Disorders
Edema 0 (0) 5 (9) 9 (7)
Weight Changes 6 (12) 7 (13) 6 (4)
Nervous System
Anxiety 3 (6) 0 (0) 11 (8)
Depression/Emotional Lability 16 (31) 15 (27) 46 (34)
Dizziness/Vertigo 8 (16) 6 (11) 10 (7)
Insomnia/Sleep Disorder 16 (31) 7 (13) 20 (15)
Libido Changes 5 (10) 2 (4) 10 (7)
Memory Disorder 3 (6) 1 (2) 6 (4)
Nervousness 4 (8) 2 (4) 15 (11)
Neuromuscular Disorder 1 (2) 5 (9) 4 (3)
Skin and Appendages
Alopecia 0 (0) 5 (9) 4 (3)
Androgen-Like Effects 2 (4) 3 (5) 24 (18)
Skin/Mucous Membrane Reaction 2 (4) 5 (9) 15 (11)
Urogenital System
Breast Changes/Pain/Tenderness 3 (6) 7 (13) 11 (8)
Menstrual Disorders 1 (2) 0 (0) 7 (5)
Vaginitis 10 (20) 8 (15) 11 (8)

In the controlled clinical trial, 50 of 51 (98%) patients in the LUPRON DEPOT 3.75 mg group and 48 of 55 (87%) patients in the LUPRON DEPOT 3.75 mg + norethindrone acetate 5 mg group reported experiencing hot flashes on one or more occasions during treatment. The median number of days on which hot flashes were reported during treatment was 25 and 5 (P<0.05) in the LUPRON DEPOT 3.75 mg and LUPRON DEPOT 3.75 mg + norethindrone acetate 5 mg treatment groups, respectively. The median maximum number of hot flashes in a day during treatment was 5 and 1 (P<0.05) in the LUPRON DEPOT 3.75 mg and LUPRON DEPOT 3.75 mg + norethindrone acetate 5 mg treatment groups, respectively.

Less Common Clinical Trial Adverse Drug Reactions (<5%)

LUPRON DEPOT 3.75 mg (1-Month SR)

The following were reported in less than 5% of patients receiving LUPRON DEPOT:

Body as a Whole: Body odor, flu syndrome and injection site reactions.
Cardiovascular System: Palpitations, syncope and tachycardia.
Gastrointestinal System: Appetite changes, dry mouth and thirst.
Central/Peripheral Nervous
System:
Anxiety*, delusions, memory disorder, insomnia/sleep disorders*,
personality disorder and insomnia/sleep disorders*.
Endocrine System: Androgen-like effects.
Hemic and Lymphatic
Systems:
Ecchymosis and lymphadenopathy.
Respiratory System: Rhinitis.
Skin and Appendages: Alopecia, hair disorder and nail disorder.
Special Senses: Conjunctivitis, ophthalmologic disorders* and taste perversion.
Urogenital System: Dysuria*, lactation and menstrual disorders.
* Physiologic effect of decreased estrogen.

Abnormal Hematologic and Clinical Chemistry Findings

See WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests.

Post-Market Adverse Drug Reactions

Isolated cases of anaphylaxis have been reported. Symptoms consistent with an anaphylactoid or asthmatic process have been rarely reported.

Cases of serious venous and arterial thromboembolism have been reported, including deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke, and transient ischemic attack. Although a temporal relationship was reported in some cases, most cases were confounded by risk factors or concomitant medication use. It is unknown if there is a causal association between the use of GnRH agonists and these events.

Like other drugs in this class, mood swings, including depression, have been reported as a physiologic effect of decreased sex steroids. There have been very rare reports of suicidal ideation and attempt. Many, but not all, of these patients had a history of depression or other psychiatric illness. Patients should be counselled on the possibility of worsening of depression.

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.

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. The relationship of any of these symptoms to leuprolide acetate has not been established.

The following events have been reported during post-marketing surveillance:

Cardiovascular System: Hypotension.
Central/Peripheral Nervou
System:
Convulsion, peripheral neuropathy and spinal fracture/paralysis.
Gastrointestinal System: Hepatic dysfunction, serious liver injury.
Hemic and Lymphatic
Systems:
Decreased WBC.
Integumentary System: Photosensitivity reactions, rash and urticaria.
Miscellaneous: Hematoma, induration, inflammation, injection site reactions including
pain, and sterile abscess.
Musculoskeletal System: Tenosynovitis-like symptoms.
Respiratory System: Dyspnea, interstitial lung disease, pulmonary fibrosis.
Urogenital System: Menstrual disorders.

Refer to the “Prostatic Cancer” and “Central Precocious Puberty” LUPRON and LUPRON DEPOT Product Monographs for other reported events.

Drug interactions

Overview

Leuprolide being approximately 46% bound to plasma proteins, and a peptide that is primarily degraded by peptidase and not by cytochrome P-450 enzymes as noted in specific studies, drug interactions would not be expected to occur.

Refer to the Norlutate Product Monograph for information on the drug interactions specific to norethindrone acetate.

Drug-Drug Interactions

No pharmacokinetic-based drug-drug interaction studies have been conducted.

Drug-Food Interactions

Interactions with food have not been established.

Drug-Herb Interactions

Interactions with herbal products have not been established.

Drug-Laboratory Test Interactions

Administration of LUPRON DEPOT at therapeutic doses results in suppression of the pituitary- gonadal system. Normal function is usually restored within 4 to 12 weeks after the treatment is discontinued. Diagnostic tests of pituitary-gonadal function conducted during the treatment and within 4 to 8 weeks after discontinuation of LUPRON DEPOT therapy may therefore be misleading.

Dosage and administration

Dosing Considerations

  • LUPRON DEPOT must be administered under the supervision of a physician.
  • LUPRON DEPOT 3.75 and 11.25 mg administered intramuscularly is designed to provide continuous sustained release of leuprolide for 1 and 3 months, respectively.
NOTE: As with all parenteral products, inspect container's solution for discoloration and particulate matter before each use.

Recommended Dose and Dosage Adjustment

LUPRON DEPOT (leuprolide acetate for depot suspension) Must Be Administered under the Supervision of a Physician.

LUPRON DEPOT 3.75 mg
(1-Month SR)
LUPRON DEPOT 11.25 mg
(3-Month SR)
3.75 mg for 6 months
(6 monthly injections)
11.25 mg for 6 months
(1 injection every 3 months)

LUPRON DEPOT 3.75 mg (1-Month SR)

The recommended dose of LUPRON DEPOT (1-Month SR) is 3.75 mg administered monthly as a single intramuscular injection, after reconstitution with the special diluent. See DOSAGE AND ADMINISTRATION, Administration and CONSUMER INFORMATION. The recommended duration of the initial treatment with LUPRON DEPOT 3.75 mg alone or in combination with norethindrone acetate 5 mg daily is six months.

LUPRON DEPOT 11.25 mg (3-Month SR)

The recommended dose of LUPRON DEPOT (3-Month SR) is 11.25 mg administered as a single intramuscular injection once every three months, after reconstitution with the special diluent. See DOSAGE AND ADMINISTRATION, Administration and CONSUMER INFORMATION. The recommended duration of the initial treatment with LUPRON DEPOT 11.25 mg alone or in combination with norethindrone acetate 5 mg daily is six months.

Due to different release characteristics, a fractional dose of the 3-month depot formulation is not equivalent to the same dose of the monthly formulation and should therefore not be given.

Retreatment with LUPRON DEPOT alone cannot be recommended since safety data for retreatment are not available. If the symptoms of endometriosis recur after the course of initial therapy, and further treatment with either LUPRON DEPOT 3.75 mg (1-Month SR) or LUPRON DEPOT 11.25 mg (3-Month SR) is contemplated, combination with norethindrone acetate 5 mg daily may be considered for an additional six-month course of treatment. Retreatment beyond this additional six-month course cannot be recommended. It is recommended that bone density be assessed before retreatment begins to ensure that values are within normal limits. If norethindrone acetate is contraindicated for the individual patient, then retreatment is not recommended.

An assessment of cardiovascular risk and management of risk factors such as cigarette smoking is recommended before beginning treatment with LUPRON DEPOT and LUPRON DEPOT with norethindrone acetate.

Missed Dose

Missing an appointment by a few days should not disrupt the benefits of treatment, but keeping a consistent schedule of LUPRON DEPOT injections is an important part of treatment.

Administration

Reconstitution

Parenteral Products

The lyophilized microspheres contained in the front chamber of the prefilled dual-chamber syringe are to be reconstituted prior to intramuscular injection, in accord with the following directions:

Due to different release characteristics, a fractional dose of the 3-month depot formulation is not equivalent to the same dose of the monthly formulation and should not be given.

For LUPRON DEPOT 3.75 mg (1-Month SR) and 11.25 mg (3-Month SR)

  1. The LUPRON DEPOT powder should be visually inspected and the syringe should NOT BE USED if clumping or caking is evident. A thin layer of powder on the wall of the syringe is considered normal. The diluent should appear clear.
  2. To prepare for injection, screw the white plunger into the end stopper until the stopper begins to turn.
  3. Remember to tighten the needle by twisting the needle cap clockwise. Do not overtighten.
  4. Holding the syringe upright, release the diluent by SLOWLY PUSHING (6 to 8 seconds) the plunger until the first stopper is at the blue line in the middle of the barrel.
  5. Keep the syringe upright. Gently shake the syringe to thoroughly mix the microspheres (powder) to form a uniform suspension. The suspension will appear milky.
  6. If the microspheres adhere to the stopper or caking/clumping is present, tap the syringe against your finger to disperse. DO NOT USE if any of the powder has not gone into suspension.
  7. Keep the syringe upright. With the opposite hand, remove the needle cap without twisting and advance the plunger to expel the air from the syringe.
  8. At the time of reconstitution, inject the entire contents of the syringe intramuscularly. The suspension settles very quickly following reconstitution; therefore, LUPRON DEPOT should be mixed and used immediately.
    Note: Aspirated blood would be visible just below the luer lock connection if a blood vessel is accidentally penetrated. If present, blood can be seen through the transparent LuproLoc safety device.
  9. After injection, withdraw the needle. Immediately activate the LuproLoc safety device by pushing the arrow forward with the thumb or finger until the device is fully extended and a CLICK is heard or felt.

Although the suspension has been shown to be stable for 24 hours following reconstitution, since the product does not contain a preservative, the suspension should be discarded if not used immediately.

As with other drugs administered by injection, the injection site should be varied periodically.

Overdosage

For management of a suspected drug overdose, contact your regional Poison Control Centre.

In rats, subcutaneous administration of leuprolide acetate as a single dose of approximately 133 times the recommended human dose, expressed on a per body weight basis, resulted in dyspnea, decreased activity, and excessive scratching. There is no evidence at present that there is a clinical counterpart of this phenomenon.

In early clinical trials using daily subcutaneous 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.

In cases of overdosage, the patients should be monitored closely and management should be symptomatic and supportive.

Action and clinical pharmacology

Mechanism of Action

Leuprolide is a synthetic nonapeptide analog of naturally-occurring gonadotropin-releasing hormone (GnRH or LHRH). The analog possesses greater potency than the natural hormone. When administered as indicated, leuprolide acts as a potent inhibitor of gonadotropin production. It is chemically unrelated to steroids.

Unlike steroid hormones, leuprolide exerts specific action on the pituitary gonadotrophs and the human reproductive tract.

This specificity reduces the likelihood of secondary adverse effects such as gynecomastia, thromboembolism, edema, liver and gallbladder involvement.

Pharmacodynamics

General

Animal and human studies indicate that, following an initial stimulation, chronic administration of leuprolide acetate results in the inhibition of gonadotropin production. Consequently, ovarian or testicular steroidogenesis is suppressed. The therapeutic effect of leuprolide in the treatment of hormone-dependent tumors, such as in prostatic cancer, results from the reduction in serum gonadotropins and gonadal steroids.

Chronic administration of leuprolide acetate has resulted in inhibition of tumor growth (prostatic tumors in Noble and Dunning male rats, 7-12-dimethylbenz[α]-anthracene(DMBA)-induced mammary tumors in female rats) as well as atrophy of the reproductive organs. An additional mechanism of action, a direct effect on the gonads by down-regulation of the gonadotropin receptors, is suggested in some animal studies.

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 the levels of the gonadal steroids (testosterone and dihydrotestosterone in males and estrone and estradiol in pre-menopausal females). However, continuous administration results in decreased levels of LH and FSH in all patients. 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 are maintained as long as treatment continues.

Endometriosis

Endometriosis is a gynecologic disorder wherein endometrial tissue is found to be established in sites outside the endometrial cavity. As definitive diagnosis can only be made during surgery, the true incidence of the disease is unknown.

The etiology of the disease is unclear. An accepted theory of the etiology of endometriosis is the retrograde flow of menstrual fluid with subsequent implantation of viable fragments of endometrium within the pelvic cavity (Sampson's theory). However, this theory does not explain the extra-pelvic sites of endometriosis such as the limbs, thoracic cavity and elsewhere. It has also been suggested that chronic irritation of the peritoneum by menstrual blood may be causative. Another theory is that endometrial tissues are displaced into an implant in new sites during surgery. Genetic and immunologic factors may account for spontaneous endometriosis in a small segment of the population. It is also believed that endometriosis may be caused by lymphatic and hematogenous spread of normal endometrium to distant sites.

Endometriosis may be treated both surgically and medically. Since endometriosis resolves after oophorectomy and menopause, surgical castration may be used to treat the disease. A menopausal state may also be achieved medically. The resultant hypoestrogenic environment results in atrophic changes in both the uterine and ectopic endometrial tissue.

LUPRON DEPOT (leuprolide acetate for depot suspension) achieves a menopausal state by suppression of the pituitary-ovarian axis by inhibiting the output of gonadotropins (FSH and LH) from the pituitary gland.

In female volunteers receiving a single dose of LUPRON DEPOT 3.75 mg (1-Month SR) intramuscularly, an initial burst of leuprolide in plasma was observed. Mean plasma leuprolide levels of approximately 0.23 to 0.34 ng/mL were maintained over a period of four to five weeks, and then slowly tapered off, becoming undetectable eight weeks after injection.

In a pharmacokinetic/pharmacodynamic study of healthy female subjects (N=20), the onset of estradiol suppression was observed for individual subjects between Day 4 and week 4 after dosing. By the third week following the injection, the mean estradiol concentration (8 pg/mL) reached the menopausal range. Throughout the remainder of the dosing period, mean serum estradiol levels ranged from the menopausal to the early follicular range.

LUPRON DEPOT 11.25 mg (3-Month SR) induced amenorrhea in 85% (N=17) of subjects during the initial month and 100% during the second month following the injection. All subjects remained amenorrheic through the remainder of the 12-week dosing interval. Episodes of light bleeding and spotting were reported by a majority of subjects during the first month after the injection and in a few subjects at later time-points. Menses resumed on average 12 weeks (range 2.9 to 20.4 weeks) following the end of the 12-week dosing interval.

LUPRON DEPOT 11.25 mg (3-Month SR) produced similar pharmacodynamic effects in terms of hormonal and menstrual suppression to those achieved with monthly injections of LUPRON DEPOT 3.75 mg (1-Month SR) during the controlled clinical trials for the management of endometriosis. Similar clinical outcome to that with LUPRON DEPOT 3.75 mg (1-Month SR) administered monthly is predicted with LUPRON DEPOT 11.25 mg (3-Month SR) administered every 3 months.

Pharmacokinetics

Intramuscular injections of LUPRON DEPOT 3.75 mg (1-Month SR) and 11.25 mg (3-Month SR) provide effective plasma concentrations of leuprolide acetate over a period of one and three months, respectively. See DETAILED PHARMACOLOGY.

Leuprolide acetate is not active when given orally.

Absorption

A single dose of LUPRON DEPOT 3.75 mg (1-Month SR) was administered by intramuscular injection to healthy female volunteers. The absorption of leuprolide was characterized by an initial increase in plasma concentration, with peak concentration ranging from 4.6 to 10.2 ng/mL at four hours post-dosing. However, intact leuprolide and an inactive metabolite could not be distinguished by the assay used in the study. Following the initial rise, leuprolide concentrations started to plateau within two days after dosing and remained relatively stable for about four to five weeks with plasma concentrations of about 0.30 ng/mL.

Following a single injection of the three-month formulation of LUPRON DEPOT 11.25 mg (3-Month SR) in female subjects, a mean peak plasma leuprolide concentration of 36.3 ng/mL was observed at 4 hours. Leuprolide appeared to be released at a constant rate following the onset of steady-state levels during the third week after dosing and mean levels then declined gradually to near the lower limit of detection by 12 weeks. The mean (± standard deviation) leuprolide acetate concentration from 3 to 12 weeks was 0.23 ± 0.09 ng/mL. However, intact leuprolide and an inactive major metabolite could not be distinguished by the assay which was employed in the study. The initial burst, followed by the rapid decline to a steady-state level, was similar to the release pattern seen with the monthly formulation.

In adults, bioavailability by subcutaneous administration is comparable to that by intravenous administration. Leuprolide has a plasma half-life of 2.9 hours. See DETAILED PHARMACOLOGY.

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 14C-labelled leuprolide was shown to be metabolized to smaller inactive peptides, pentapeptide (Metabolite I), tripeptides (Metabolites II and III) and dipeptide (Metabolite IV). These fragments may be further catabolized.

The major metabolite (M-I) plasma concentrations measured in 5 prostate cancer patients reached mean 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 leuprolide concentrations.

Excretion

Following administration of LUPRON DEPOT 3.75 mg (1-Month SR) to 3 patients, less than 5% of the dose was recovered as parent and M-I metabolite in the urine.

Special Populations and Conditions

Pediatrics

A pharmacokinetic study of leuprolide acetate in children has not been performed.

Geriatrics

See WARNINGS AND PRECAUTIONS, Special Populations, Geriatrics.

Hepatic Insufficiency

The pharmacokinetics of the drug in patients with hepatic impairment have not been determined.

Renal Insufficiency

The pharmacokinetics of the drug in patients with renal impairment have not been determined.

Storage and stability

Store LUPRON DEPOT (leuprolide acetate for depot suspension) between 15 to 25°C. Protect from freezing.

Although the suspension has been shown to be stable for 24 hours following reconstitution, since the product does not contain a preservative, the suspension should be discarded if not used immediately.

Special handling instructions

It is very important to activate the LuproLoc safety device immediately after injection. This is done by pushing the arrow forward with the thumb or finger until the device is fully extended and a CLICK is heard or felt. See DOSAGE AND ADMINISTRATION, Administration,Reconstitution.

Dosage forms, composition and packaging

LUPRON DEPOT (leuprolide acetate for depot suspension) is available in two strengths: 3.75 mg (1-Month SR) and 11.25 mg (3-Month SR).

LUPRON DEPOT 3.75 mg (1-Month SR) and 11.25 mg (3-Month SR) are supplied in single dose kits containing one prefilled dual-chamber syringe with 23 G needle, two alcohol swabs, Consumer Information leaflet, Special Instructions for Use leaflet, and a Health Professional Information insert.

Listing of Non-Medicinal Ingredients

LUPRON DEPOT 3.75 mg (1-Month SR)

The front chamber of the LUPRON DEPOT 3.75 mg (1-Month SR) prefilled dual-chamber syringe contains 3.75 mg of leuprolide acetate with the following non-medicinal ingredients: DL-lactic and glycolic acids copolymer, D-mannitol and purified gelatin.

The rear chamber of diluent contains the following non-medicinal ingredients: carboxymethylcellulose sodium, D-mannitol, glacial acetic acid (to control pH), polysorbate 80 and water for injection.

When mixed with diluent, the sterile lyophilized microspheres become a suspension, which is intended as an intramuscular injection to be given once every month.

During the manufacturing process of LUPRON DEPOT (1-Month SR), acetic acid is lost, leaving the leuprolide peptide.

LUPRON DEPOT 11.25 mg (3-Month SR)

The front chamber of the LUPRON DEPOT 11.25 mg (3-Month SR) prefilled dual-chamber syringe contains 11.25 mg of leuprolide acetate with the following non-medicinal ingredients: D-mannitol and polylactic acid.

The rear chamber of diluent contains carboxymethylcellulose sodium, D-mannitol, glacial acetic acid (to control pH), polysorbate 80 and water for injection.

When mixed with diluent, the sterile lyophilized microspheres become a suspension, which is intended as an intramuscular injection to be given once every three months.

During the manufacturing process of LUPRON DEPOT (3-Month SR), acetic acid is lost, leaving the leuprolide peptide.