Lupron Depot URO: Indications, Dosage, Precautions, Adverse Effects
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Lupron Depot URO - 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, glacial acetic acid, polysorbte 80, purified gelatin, and water for injection

LUPRON
leuprolide acetate injection

LUPRON DEPOT
leuprolide acetate for depot suspension

Summary product information

Route of Administration Dosage
Form/Strength
Clinically Relevant
Non-medicinal Ingredients
LUPRON
subcutaneous multiple-dose vial/ 5 mg/mL acetic acid, benzyl alcohol, sodium chloride, sodium hydroxide
LUPRON DEPOT
intramuscular prefilled dual-chamber syringe containing sterile lyophilized microspheres / 7.5 mg (1-Month SR)

prefilled dual-chamber syringe containing sterile lyophilized microspheres / 22.5 mg (3-Month SR)

prefilled dual-chamber syringe containing sterile lyophilized microspheres / 30.0 mg (4-Month SR)
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


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


For a complete listing see DOSAGE FORMS, COMPOSITION AND PACKAGING.
Definition: SR = Slow Release

Indications and clinical use

LUPRON (leuprolide acetate injection) and LUPRON DEPOT (leuprolide acetate for depot suspension) are indicated for:

  • the palliative treatment of sex hormone responsive advanced (stage D2) carcinoma of the prostate.

LUPRON DEPOT must be administered under the supervision of a health professional.

Geriatrics (> 65 years of age):

The majority of the patients studied in the clinical trials for LUPRON and LUPRON DEPOT were 65 years and older. See CLINICAL TRIALS.

Pediatrics (< 18 years of age):

LUPRON DEPOT 22.5 mg (3-Month SR) and 30.0 mg (4-Month SR) are not indicated for use in children. LUPRON DEPOT treatment of children is covered in the LUPRON DEPOT 3.75 mg and 7.5 mg “Central Precocious Puberty” Product Monograph.

Women (> 18 years of age):

LUPRON DEPOT 22.5 mg (3-Month SR) and 30.0 mg (4-Month SR) are not indicated for use in women. LUPRON DEPOT treatment of women is covered in the LUPRON DEPOT 3.75 mg and 11.25 mg “Endometriosis” Product Monograph.

Contraindications

  • LUPRON (leuprolide acetate injection) and LUPRON DEPOT (leuprolide acetate for depot suspension) are 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.
  • LUPRON and LUPRON DEPOT are 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 and LUPRON DEPOT should use non-hormonal methods of contraception.

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

Warnings and precautions

Serious Warnings and Precautions

  • LUPRON and LUPRON DEPOT should be prescribed by a qualified physician experienced in the use of hormonal therapy in prostate cancer. LUPRON and LUPRON DEPOT should be administered under the supervision of a health professional. The following are clinically significant adverse events:

    • Clinical testosterone flare reaction in men with prostate cancer. See General.
    • Osteoporosis. See WARNINGS AND PRECAUTIONS, Endocrine and Metabolism, Changes in Bone Density.

General

LUPRON (leuprolide acetate injection) and LUPRON DEPOT (leuprolide acetate for depot suspension), like other gonadotropin-releasing hormone (LHRH) agonists, causes a transient increase in serum concentration of testosterone during the first weeks of treatment. Patients may experience worsening of symptoms or onset of new symptoms, including bone pain, neuropathy, hematuria, or ureteral or bladder outlet obstruction. Cases of spinal cord compression, which may contribute to paralysis with or without fatal complications, have been reported with LHRH agonists. If spinal cord compression or renal impairment due to ureteral obstruction develops, standard treatment of these complications should be instituted.

Patients with metastatic vertebral lesions and/or with urinary tract obstruction should begin leuprolide acetate therapy under close supervision.

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 selective serotonin reuptake inhibitors (SSRIs). Convulsions have also been reported in patients in the absence of any of the conditions mentioned above.

Patients with known allergies to benzyl alcohol, a vehicle ingredient of LUPRON, may present symptoms of hypersensitivity, usually local, in the form of erythema and induration at the injection site.

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.

Cardiovascular

Increased risk of developing myocardial infarction, sudden cardiac death and stroke has been reported in association with use of gonadotropin-releasing hormone (GnRH) agonists in men. The risk should be evaluated carefully along with cardiovascular risk factors when determining a treatment for patients with prostate cancer. Patients receiving GnRH agonists should be monitored for symptoms and signs suggestive of development of cardiovascular disease and be managed according to current clinical practice. See WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests.

Effect on QT/QTc Interval

Androgen deprivation therapy has the potential to prolong QT/QTc interval on an ECG. Physicians should consider whether the benefits of androgen deprivation therapy outweigh the potential risk in patients with congenital long QT syndrome, electrolyte abnormalities, or congestive heart failure and in patients taking Class IA (e.g. quinidine, procainamide), Class III (e.g., amiodarone, sotalol, dofetilide, ibutilide), or Class IC (e.g., flecainide, propafenone) antiarrhythmic medications.

In a randomized, active-controlled trial to compare leuprolide acetate 7.5 mg with an LHRH antagonist in patients with prostate cancer, periodic electrocardiograms were collected and evaluated. In the leuprolide cohort, a mean QTcF increase of 17 msec from baseline was reported. The percentage of subjects who experienced maximum QTcF changes of > 30 to < 60 msec and ≥ 60 msec was 41and 4%, respectively.

Dependence/Tolerance

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

Endocrine and Metabolism

Changes in Bone Density

Decreased bone mineral density can be anticipated with long-term use of an LHRH agonist. Androgen deprivation therapy is associated with increased risks of osteoporosis and skeletal bone fractures. The risk of skeletal fracture increases with the duration of androgen deprivation therapy. Assessment of osteoporosis risk and management according to clinical practice and guidelines should be considered.

In patients with significant risk factors for decreased bone mineral content and/or bone mass such as chronic alcohol and/or tobacco use, presumed or strong family history of osteoporosis or chronic use of drugs that can reduce bone mass such as anticonvulsants or corticosteroids, leuprolide acetate may pose an additional risk. In these patients, risk versus benefit must be weighed carefully before therapy with LUPRON or LUPRON DEPOT is instituted.

Hypogonadism

Long-term administration of leuprolide acetate will cause suppression of pituitary gonadotropins and gonadal hormone production with clinical symptoms of hypogonadism. These changes have been observed to reverse on discontinuation of therapy. However, whether the clinical symptoms of induced hypogonadism will reverse in all patients has not yet been established.

Reduction in Glucose Tolerance

A reduction in glucose tolerance and an increased risk in developing diabetes have been reported in men treated with androgen deprivation therapy. Patients treated with LUPRON or LUPRON DEPOT should undergo periodic monitoring of blood glucose. Diabetic patients may require more frequent monitoring when receiving LUPRON or LUPRON DEPOT.

Hematologic

Anemia is a known physiologic consequence of testosterone suppression. Assessment of anemia risk and management according to local clinical practice and guidelines should be considered.

Hepatic/Biliary/Pancreatic

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

In the postmarketing setting, cases of serious liver injury (including reports of fatal cases) have been described in which a causal association with leuprolide acetate therapy is suspected. Elevations in alanine aminotransferase (ALT) in patients receiving LUPRON DEPOT in clinical trials have been reported. Monitoring of liver function in patients treated with LUPRON or LUPRON DEPOT should be considered.

Psychiatric

Like other drugs in this class, mood swings, including depression, have been reported with LUPRON and LUPRON DEPOT (see ADVERSE REACTIONS, Clinical Trial Adverse Drug Reactions). There have been reports of suicidal ideations and attempt (see ADVERSE REACTIONS, Post-market Adverse Reactions). Patients should be counseled on the possibility of development or worsening of depression during treatment with LUPRON or LUPRON DEPOT.

Renal

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

Special Populations

Pregnant Women

LUPRON and LUPRON DEPOT 7.5 mg (1-Month SR), 22.5 mg (3-Month SR) and 30.0 mg (4-Month SR) described in this Product Monograph are not indicated for use in women. LUPRON DEPOT treatment of women is covered in the LUPRON DEPOT 3.75 mg and 11.25 mg “Endometriosis” Product Monograph.

Nursing Women

LUPRON and LUPRON DEPOT 7.5 mg (1-Month SR), 22.5 mg (3-Month SR) and 30.0 mg (4-Month SR) described in this Product Monograph are not indicated for use in women. LUPRON DEPOT treatment of women is covered in the LUPRON DEPOT 3.75 mg and 11.25 mg “Endometriosis” Product Monograph.

Pediatrics (< 18 years of age)

Safety and effectiveness of LUPRON DEPOT 22.5 mg (3-Month SR) and 30.0 mg (4-Month SR) have not been established in pediatric patients. See “Central Precocious Puberty” Product Monograph for the safety and effectiveness of LUPRON and LUPRON DEPOT in children with central precocious puberty.

Geriatrics (> 65 years of age)

In prostatic cancer clinical trials for LUPRON and LUPRON DEPOT, the majority of subjects studied were at least 65 years of age. The labelling therefore reflects the pharmacokinetics, efficacy and safety of LUPRON and LUPRON DEPOT in this population.

Monitoring and Laboratory Tests

Response to LUPRON and LUPRON DEPOT should be monitored by measuring serum levels of testosterone, as well as prostate-specific antigen and prostatic acid phosphatase. In the majority of patients, testosterone levels increased above baseline during the first week, declining thereafter to baseline levels or below by the end of the second week. In the LUPRON DEPOT 30.0 mg (4-Month SR) study, castrate levels were reached within two to four weeks, and once achieved, were maintained in most patients (45/49) for as long as the patients received their injections. See CLINICAL TRIALS.

The effects of leuprolide acetate on bone lesions may be monitored by bone scans, while its effects on prostatic lesions may be monitored by ultrasonography and/or computed tomography (CT) scan in addition to digital rectal examination.

Intravenous pyelogram, ultrasonography, or CT scan may also be utilized to diagnose or assess the status of obstructive uropathy.

Periodic monitoring of serum testosterone and Prostatic Specific Antigen (PSA) levels is recommended, especially if the anticipated clinical or biochemical response to treatment has not been achieved. It should be noted that 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.

Baseline risk factors of cardiovascular diseases should be assessed. Patients receiving LUPRON or LUPRON DEPOT should be monitored periodically for risk factors, signs and symptoms of cardiovascular diseases. In addition, baseline ECG recording and serum potassium, calcium, and magnesium levels are recommended. Monitoring of ECG and serum electrolyte levels during treatment should also be considered for those at risk for electrolyte abnormality and QTc prolongation.

Blood glucose levels and/or glycosylated hemoglobin (HbA1c) should be checked periodically in patients treated with LUPRON or LUPRON DEPOT and more frequently in diabetic patients. See WARNINGS AND PRECAUTIONS, Endocrine and Metabolism, Reduction in Glucose Tolerance.

Monitoring of liver function in patients treated with LUPRON or LUPRON DEPOT should be considered.

Adverse reactions

Adverse Drug Reaction Overview

In clinical studies, an initial rise in serum testosterone levels usually occurred in non-orchiectomized patients during the first week of treatment.

This occasionally was associated with a worsening of signs and symptoms, usually an increase in bone pain. See WARNINGS AND PRECAUTIONS. In some cases, temporary renal impairment was accompanied by mental confusion, joint pain, nausea and vomiting. In each case, leuprolide acetate administration was continued and the symptom(s) subsided in one to two weeks.

The potential for exacerbation of signs and symptoms during the first few weeks of treatment is a concern in patients with vertebral metastases and/or in patients with severe obstructive uropathy which, if aggravated, may lead to neurological problems such as temporary weakness and/or paresthesia of the lower limbs or worsening of urinary symptoms, such as hematuria and urinary tract obstruction.

Interstitial lung disease has been reported with a variable time to onset in the postmarketing 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 prostate cancer treatment, 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 and LUPRON DEPOT (1-Month SR), 22.5 mg (3-Month SR), 30.0 mg (4-Month SR)

The following possibly or probably related systemic adverse reactions were reported by 5% of the patients using LUPRON (leuprolide acetate injection) and LUPRON DEPOT (leuprolide acetate for depot suspension) 7.5 mg, 22.5 mg and 30.0 mg in clinical studies. Reactions not considered drug related are excluded.

In two clinical studies with LUPRON, hot flashes (49 to 55%), impotence/decrease in libido (3 to 10%), local reactions at injection site/ecchymosis/erythema (4 to 15%), decrease in testicular size/atrophic genitalia (7 to 13%), and itching rash (3%) were reported.

Adverse reactions reported by ≥ 5% of the patients using LUPRON DEPOT formulations are summarized in Table 1.

Table 1. Incidence (%) of Possibly or Probably Related Systemic Adverse Reactions Reported by ≥ 5% of Patients Treated with LUPRON DEPOT 7.5 mg (1 injection every month), LUPRON DEPOT 22.5 mg (1 injection every 3 months) and LUPRON DEPOT 30 mg (1 injection every 4 months)
LUPRON
DEPOT
7.5 mg
(1-Month SR)
N=56 (%)
Study III



LUPRON
DEPOT
22.5 mg
(3-Month SR)1
Non-
Orchiectomized
N=94 (%)
Studies IV and V
LUPRON
DEPOT
30.0 mg
(4-Month SR)
Non-
Orchiectomized
N=49 (%)
Study VI

LUPRON
DEPOT
30.0 mg
(4-Month SR)
Orchiectomized
N=24 (%)
Study VII2


Body as a Whole
Asthenia
Flu syndrome
General pain
Headache
Injection site reaction

3 (5.4)

4 (7.1)


7 (7.4)

25 (26.6)
6 (6.4)
13 (13.8)

6 (12.2)
6 (12.2)
16 (32.7)
5 (10.2)
4 (8.2)

1 (4.2)
0 (0.0)
1 (4.2)
1 (4.2)
9 (37.5)
Cardiovascular System
Hot flashes/sweats*

33 (58.9)

55 (58.5)

23 (46.9)

2 (8.3)
Gastrointestinal System
Nausea/vomiting
GI disorder

3 (5.4)


15 (16.0)


5 (10.2)


3 (12.5)
Metabolic and
Nutritional Disorders

Dehydration
Edema



7 (12.5)



4 (8.2)
4 (8.2)


0 (0.0)
5 (20.8)
Musculoskeletal System
Joint disorder
Myalgia


11 (11.7)

8 (16.3)
4 (8.2)

1 (4.2)
0 (0.0)
Central/Peripheral
Nervous System

Dizziness/Vertigo
Insomnia/Sleep disorders
Neuromuscular disorders
Paresthesia






6 (6.4)
8 (8.5)
9 (9.6)


3 (6.1)

3 (6.1)
4 (8.2)


2 (8.3)

1 (4.2)
1 (4.2)
Respiratory System
Dyspnea
Respiratory disorders

3(5.4)


6(6.4)


4(8.2)


1(4.2)
Skin and Appendages
Skin reaction


8 (8.5)


6 (12.2)


0 (0.0)
Urogenital System
Testicular atrophy*
Impotence*
Urinary disorders

3 (5.4)
3 (5.4)

19 (20.2)
0 (0.0)
14 (14.9)



5 (10.2)



4 (16.7)
* Physiological effects of decreased testosterone.
1: The adverse reactions reported for LUPRON DEPOT 22.5 mg (3-Month SR) are based on two clinical trials.
2: Study VII was a multicenter, open-label study designed to characterize the pharmacokinetic profile of LUPRON DEPOT 30.0 mg (4-Month SR) following a single intramuscular injection and to assess the safety of the formulation in prostatic cancer patients.

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

The following possibly or probably related systemic adverse reactions were reported by less than 5% of the patients using LUPRON and LUPRON DEPOT 7.5 mg (1-Month SR), 22.5 mg (3-Month SR) and 30.0 mg (4-Month SR) in clinical studies. Reactions not considered drug- related are excluded.

LUPRON

Cardiovascular System: Cardiac arrhythmias, congestive heart failure, electrocardiogram (ECG) changes/ischemia, high blood pressure, hypotension, myocardial infarction, murmur, phlebitis/thrombosis, pulmonary emboli, transient ischemic attack/stroke.
Central/Peripheral Nervous System: Anxiety, blurred vision, dizziness/light-headedness, headache, hearing disorder, lethargy, memory disorder, mood swings, nervousness, numbness, paresthesia, peripheral neuropathy, sleep disorders, spinal fracture/paralysis, syncope/blackouts, taste disorders.
Endocrine System: Breast tenderness or pain, gynecomastia, libido increase, thyroid enlargement.
Gastrointestinal System: Anorexia, constipation, dysphagia, gastrointestinal bleeding, gastrointestinal disturbance, hepatic dysfunction, peptic ulcer, rectal polyps.
Hemic and Lymphatic System: Anemia, decreased white blood cell (WBC).
Integumentary System: Carcinoma of skin/ear, dry skin, ecchymosis, hair loss, itching, pigmentation, skin lesions.
Musculoskeletal System: Ankylosing spondylosis, joint pain, myalgia, pelvic fibrosis, spasms.
Respiratory System: Cough, pleural rub, pneumonia, pulmonary fibrosis, pulmonary infiltrate, respiratory disorders, sinus congestion.
Urogenital System: Bladder spasms, hematuria, incontinence, penile swelling, prostate pain, urinary obstruction, urinary tract infection.
Miscellaneous: Asthenia, depression, fatigue, fever, hypoglycemia, hypoproteinemia, increased blood urea nitrogen (BUN), increased creatinine, infection/inflammation, ophthalmologic disorders, swelling (temporal bone).

LUPRON DEPOT 7.5 mg (1-Month SR)

Cardiovascular System: Angina, cardiac arrhythmia.
Central/Peripheral Nervous System: Insomnia, paresthesia.
Endocrine System: Gynecomastia, libido decrease.
Gastrointestinal System: Anorexia, diarrhea.
Integumentary System: Dermatitis, local skin reactions, hair growth.
Musculoskeletal System: Bone pain, myalgia.
Respiratory System: Dyspnea, hemoptysis.
Urogenital System: Dysuria, frequency/urgency, hematuria, testicular pain.
Miscellaneous: Asthenia, diabetes, fever/chills, hard nodule in throat, increased calcium, increased uric acid, serum glutamic oxaloacetic transaminase (SGOT) (> 2 times normal values), weight gain.

LUPRON DEPOT 22.5 mg (3-Month SR)

Body as a Whole: Enlarged abdomen, fever.
Cardiovascular System: Arrhythmia, bradycardia, heart failure, hypertension, hypotension, varicose vein.
Central/Peripheral Nervous System: Anxiety, delusions, depression, hypesthesia, libido decrease*, nervousness, paresthesia.
Digestive System: Anorexia, duodenal ulcer, increased appetite, thirst/dry mouth.
Hemic and Lymphatic System: Anemia, lymphedema.
Metabolic and Nutritional Disorders: Dehydration, edema.
Respiratory System: Epistaxis, pharyngitis, pleural effusion, pneumonia.
Special Senses: Abnormal vision, amblyopia, dry eyes, tinnitus.
Urogenital System: Gynecomastia, impotence*, penis disorders, testis disorders.
* Physiologic effects of decreased testosterone

LUPRON DEPOT 30.0 mg (4-Month SR)

Body as a Whole: Abscess, accidental injury, allergic reaction, cyst, fever, generalized edema, hernia, neck pain, neoplasm.
Cardiovascular System: Atrial fibrillation, deep thrombophlebitis, hypertension.
Digestive System: Anorexia, eructation, gastrointestinal hemorrhage, gingivitis, gum hemorrhage, hepatomegaly, increased appetite, intestinal obstruction, periodontal abscess.
Hemic and Lymphatic System: Lymphadenopathy.
Metabolic and Nutritional Disorders: Healing abnormal, hypoxia, weight loss.
Musculoskeletal System: Leg cramps, pathological fracture, ptosis.
Nervous System: Abnormal thinking, amnesia, confusion, convulsion, dementia, depression, insomnia/sleep disorders, libido decreased†, neuropathy, paralysis.
Respiratory System: Asthma, bronchitis, hiccup, lung disorder, sinusitis, voice alteration.
Skin and Appendages: Herpes zoster, melanosis.
Urogenital System: Bladder carcinoma, epididymitis, impotence, prostate disorder, testicular atrophy, urinary incontinence, urinary tract infection.
Physiologic effects of decreased testosterone.

Abnormal Hematologic and Clinical Chemistry Findings

Abnormalities of certain parameters observed in hematologic and clinical chemistry determinations were recorded, but relationship to drug is difficult to assess in this population.

The following were recorded in ≥ 5% of patients in clinical studies with LUPRON DEPOT 7.5 mg (1-Month SR), 22.5 mg (3-Month SR) and 30.0 mg (4-Month SR):

LUPRON DEPOT 7.5 mg (1-Month SR)

Lactate dehydrogenase (LDH) (> 2 times normal values), alkaline phosphatase (> 1.5 times normal values).

In the Phase 3, open-label, multicenter 24-week study of previously untreated patients with stage D2 prostate cancer (Study III), treated with LUPRON DEPOT 7.5 mg (1-Month SR) injected monthly, 1/56 (2%) patients had an asymptomatic elevation of aspartate aminotransferase (AST) > 3X ULN. This patient did not have a concomitant elevation in bilirubin. Alanine aminotransferase (ALT) was not measured in this study.

LUPRON DEPOT 22.5 mg (3-Month SR)

Increased BUN, hyperglycemia, hyperlipidemia [total cholesterol, low-density lipoprotein (LDL)-cholesterol, triglycerides], hyperphosphatemia, abnormal liver function tests, increased PT, increased PTT. Additional laboratory abnormalities reported were: decreased platelets, decreased potassium and increased WBC.

LUPRON DEPOT 30.0 mg (4-Month SR)

Abnormalities of certain parameters were observed, but their relationship to drug treatment are difficult to assess in this population. The following were recorded in 5% of patients: decreased bicarbonate, decreased hemoglobin/hematocrit/red blood cell (RBC), hyperlipidemia (total cholesterol, LDL-cholesterol, triglycerides), decreased high-density lipoprotein (HDL)-cholesterol, eosinophilia, increased glucose, increased liver function tests [alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transpeptidase (GGTP), lactate dehydrogenase (LDH)], and increased phosphorus. Additional laboratory abnormalities were reported: increased BUN and PT, leukopenia, thrombocytopenia, uricaciduria, urine abnormality.

See DRUG INTERACTIONS, Drug-Laboratory Test Interactions section for more details.

Post-Market Adverse Drug Reactions

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

There have been reports of suicidal ideation and attempt. Many, but not all, of these patients had a history of depression or other psychiatric illness.

Pituitary Apoplexy

During postmarketing 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 two 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.

Changes in Bone Density

Decreased bone density has been reported in the medical literature in men who have had orchiectomy or who have been treated with an LHRH agonist analog. In a clinical trial, 25 men with prostate cancer, 12 of whom had been treated previously with leuprolide acetate for at least six months, underwent bone density studies as a result of pain. The leuprolide acetate-treated group had lower bone density scores than the non-treated control group. From another case report, two additional men, one 64 and the other 70 years, respectively, receiving goserelin acetate, were observed to have collapsed vertebrae thought to be due to decreased bone mineral density. It can be anticipated that long periods of medical castration in men will have effects on bone density.

During postmarketing surveillance, which includes other dosage forms and other patient populations, the following adverse events were reported:

Cardiovascular System: Cardiac arrest, hypotension, myocardial infarction, and sudden cardiac death.
Central/Peripheral Nervous System: Convulsion, peripheral neuropathy, spinal fracture/paralysis.
Hemic and Lymphatic System: Decreased WBC.
Hepatobiliary Disorders: Serious liver injury (including fatal cases).
Integumentary System: Photosensitivity reactions, rash, urticaria.
Musculoskeletal System: Tenosynovitis-like symptoms.
Urogenital System: Prostate pain.
Miscellaneous: Hematoma, induration, inflammation, injection site reactions including pain, sterile abscess.
Respiratory System: Interstitial lung disease, pulmonary fibrosis.

See the “Central Precocious Puberty” and “Endometriosis” 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.

Drug-Drug Interactions

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

Since androgen deprivation treatment may prolong the QTc interval, the concomitant use of leuprolide acetate with medicinal products known to prolong the QTc interval or medicinal products able to induce torsades de pointes should be carefully evaluated. Such medicinal products include but are not limited to the examples that follow: Class IA (e.g. quinidine, disopyramide), Class III (e.g. amiodarone, dronedarone, sotalol, dofetilide, ibutilide), or Class IC (e.g. flecainide, propafenone) antiarrhythmic medicinal products, antipsychotics (e.g. chlorpromazine), antidepressants (e.g. amitriptyline, nortriptyline), opioids (e.g. methadone), macrolide antibiotics and analogues (e.g. erythromycin, clarithromycin, azithromycin), quinolone antibiotics (e.g. moxifloxacin), antimalarials (e.g. quinine), azole antifungals, 5-hydroxytryptamine (5-HT3) receptor antagonists (e.g. ondansetron), and beta-2 adrenoceptor agonists (e.g. salbutamol).

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

As expected, leuprolide acetate administration will initially affect selected serum and urine parameters in the first week of treatment: elevation of BUN, creatinine, acid phosphatase, testosterone and dihydrotestosterone can be expected. See DETAILED PHARMACOLOGY. With chronic administration, these high values will usually return to normal, or drop below baseline in the case of testosterone, dihydrotestosterone and acid phosphatase.

Dosage and administration

Dosing Considerations

  • LUPRON DEPOT (leuprolide acetate for depot suspension) must be administered under the supervision of a health professional.
  • LUPRON DEPOT 7.5 mg (1-Month SR), 22.5 mg (3-Month SR) and 30.0 mg (4-Month SR) administered intramuscularly is designed to provide continuous sustained release of leuprolide for one, three, and four 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

The recommended dose of LUPRON (leuprolide acetate injection) is 1 mg (0.2 mL), as a single daily subcutaneous injection. See DOSAGE AND ADMINISTRATION, Administration and CONSUMER INFORMATION.

LUPRON DEPOT

The recommended dose of LUPRON DEPOT (1-Month SR) is 7.5 mg administered monthly as a single intramuscular injection, after reconstitution with the special diluent. See DOSAGE AND ADMINISTRATION, Administration and CONSUMER INFORMATION.

The recommended dose of LUPRON DEPOT (3-Month SR) is 22.5 mg administered as a single intramuscular injection once every three months (12 weeks), after reconstitution with the special diluent. See DOSAGE AND ADMINISTRATION, Administration and CONSUMER INFORMATION. Due to different release characteristics, a fractional dose of this 3-Month depot formulation is not equivalent to the same dose of the monthly formulation and should therefore not be given.

The recommended dose of LUPRON DEPOT (4-Month SR) is 30.0 mg administered as a single intramuscular injection once every four months (16 weeks), after reconstitution with the special diluent. See DOSAGE AND ADMINISTRATION, Administration and CONSUMER INFORMATION. Due to different release characteristics, a fractional dose of this 4-Month depot formulation is not equivalent to the same dose of the monthly formulation and should therefore not be given.

Missed Dose

LUPRON

If the patient forgets to take the injection at the usual time, they should take it as soon as they remember, if they remember on the same day. If not, they should not take the missed dose at all; they should wait until it is time for their next dose. The patient should not take two doses at once.

The patient should not stop taking LUPRON simply because they feel better.

LUPRON DEPOT

Maintaining testosterone suppression is important in treating the symptoms of hormone- dependent prostate cancer. Missing an appointment by a few days should not disrupt the benefits of treatment, but keeping a consistent schedule of LUPRON DEPOT injection is an important part of treatment.

Administration

LUPRON

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

As a guide, the usual sites of injection are indicated below:

SUGGESTED ROTATION OF THE INJECTION SITE

Reconstitution

LUPRON DEPOT

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

Due to different release characteristics, a fractional dose of the 3-month or 4-month depot formulation is not equivalent to the same dose of the monthly formulation and should not be given.

For LUPRON DEPOT 7.5 mg (1-Month SR), 22.5 mg (3-Month SR) and 30.0 mg (4-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 (six to eight 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. If blood is present remove the needle immediately. Do not inject the medication.

  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 approximately 133 times the recommended human dose, expressed on a per body weight basis, resulted in dyspnea, decreased activity, and local irritation at the injection site.

There is no clinical experience with the effects of an acute overdose. Because the acute animal toxicity of the drug is low, adverse effects are not expected. No difference in adverse reactions was observed in patients who received either 1 or 10 mg/day leuprolide acetate for up to three years or 20 mg/day for up to two years.

Action and clinical pharmacology

Mechanism of Action

Leuprolide acetate 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 acetate acts as a potent inhibitor of gonadotropin production. It is chemically unrelated to steroids.

Unlike steroid hormones, leuprolide acetate 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 acetate 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 downregulation 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 premenopausal females). However, continuous administration results in decreased levels of LH and FSH in all patients. In males, testosterone is reduced to castrate levels. In premenopausal females, estrogens are reduced to postmenopausal levels. These decreases occur within two to four weeks after initiation of treatment, and are maintained as long as treatment continues. Castrate levels of testosterone in prostatic cancer patients have been demonstrated for periods of up to five years.

Pharmacokinetics

Intramuscular injections of LUPRON DEPOT (leuprolide acetate for depot suspension) 7.5 mg (1-Month SR), 22.5 mg (3-Month SR), and 30.0 mg (4-Month SR) provide plasma concentrations of leuprolide acetate over a period of one, three, and four months, respectively. See DETAILED PHARMACOLOGY.

Absorption

Following a single LUPRON DEPOT 7.5 mg (1-Month SR) injection to adult patients, the mean peak leuprolide plasma concentration was almost 20 ng/mL at four hours and then declined to 0.36 ng/mL at four weeks. However, intact leuprolide and an inactive major metabolite could not be distinguished by the assay used in the study. Undetectable leuprolide plasma concentrations have been observed during chronic LUPRON DEPOT 7.5 mg (1-Month SR) administration, but testosterone levels appear to be maintained at castrate levels.

The pharmacokinetic profile of LUPRON DEPOT 22.5 mg (3-Month SR) was characterized in 23 orchiectomized prostate cancer patients. Following a single injection of the three-month formulation of LUPRON DEPOT 22.5 mg (3-Month SR), a mean peak plasma leuprolide concentration of 48.9 ng/mL was observed at four hours and then declined to 0.67 ng/mL at 12 weeks. Leuprolide appeared to be released at a constant rate following the onset of steady-state level during the third week after dosing, providing steady plasma concentrations through the 12-week dosing interval. Detectable levels of leuprolide were present at all measurement points in all patients during this 12-week period. The initial burst, followed by the rapid decline to a steady-state level, was similar to the release pattern seen with the monthly formulation.

Following a single injection of LUPRON DEPOT 30.0 mg (4-Month SR) in sixteen orchiectomized prostate cancer patients, a mean plasma leuprolide concentration of 59.3 ng/mL was observed at four hours and the mean concentration then declined to 0.30 ng/mL at 16 weeks. The mean plasma concentration of leuprolide from Weeks 3.5 to 16 was 0.44 ± 0.20 ng/mL (range: 0.20 to 1.06). Leuprolide appeared to be released at a constant rate following the onset of steady-state levels during the fourth week after dosing, providing steady plasma concentrations throughout the 16-week dosing interval. 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 other depot formulations.

In adults, bioavailability by subcutaneous administration is comparable to that by intravenous administration. Leuprolide acetate 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 acetate administered intravenously revealed that the mean systemic clearance was 7.6 L/h, with a terminal elimination half-life of approximately three 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 five prostate cancer patients reached mean maximum concentration two to six 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 three 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 section.

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

LUPRON

Store LUPRON (leuprolide acetate injection) 5 mg/mL between 2 and 8°C. Protect from light. Keep in carton until use.

LUPRON DEPOT

Store LUPRON DEPOT (leuprolide acetate for depot suspension) 7.5 mg (1-Month SR), 22.5 mg (3-Month SR), and 30.0 mg (4-Month SR) between 15 and 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

LUPRON (leuprolide acetate injection) is supplied in sterile multiple dose vials of 2.8 mL for subcutaneous use. Each multiple-dose vial contains 5 mg/mL leuprolide acetate.

LUPRON is supplied as a 14-day kit. Each 14-day Patient Administration Kit contains: one vial of LUPRON, 28 swabs and 14 syringes, one Consumer Information leaflet and one Instructions for Use leaflet.

LUPRON DEPOT

LUPRON DEPOT (leuprolide acetate for depot suspension) is available three strengths: 7.5 mg (1-Month SR), 22.5 mg (3-Month SR) and 30.0 mg (4-Month SR).

LUPRON DEPOT 7.5 mg (1-Month SR), 22.5 mg (3-Month SR) and 30.0 mg (4-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

Each 2.8 mL multiple-dose vial contains benzyl alcohol as a preservative, sodium chloride for tonicity adjustment and sterile water for injection. The pH may have been adjusted with sodium hydroxide and/or acetic acid.

LUPRON DEPOT 7.5 mg (1-Month SR)

The front chamber of the LUPRON DEPOT 7.5 mg (1-Month SR) prefilled dual-chamber syringe contains: 7.5 mg 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 22.5 mg (3-Month SR)

The front chamber of the LUPRON DEPOT 22.5 mg (3-Month SR) prefilled dual-chamber syringe contains: 22.5 mg leuprolide acetate, with the following non-medicinal ingredients: D-mannitol and polylactic acid.

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 three months.

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

LUPRON DEPOT 30.0 mg (4-Month SR)

The front chamber of the LUPRON DEPOT 30.0 mg (4-Month SR) prefilled dual-chamber syringe contains: 30.0 mg leuprolide acetate, D-mannitol and polylactic acid.

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 four months.

During the manufacturing process of LUPRON DEPOT (4-Month SR), acetic acid is lost, leaving the leuprolide peptide.