Lupron CPP: Indications, Dosage, Precautions, Adverse Effects
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Lupron CPP - Product Information

Manufacture: AbbVie
Country: Canada
Condition: Endometriosis, Hirsutism, Prostate Cancer, Uterine Fibroids
Class: Gonadotropin-releasing hormone antagonists, Hormones/antineoplastics
Form: Liquid solution, Subcutaneous (SC)
Ingredients: leuprolide acetate, benzyl alcohol, sodium chloride, sterile water for injection

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 pre-filled dual chamber syringe containing sterile lyophilized microspheres 3.75 mg (1-Month SR), 7.5 mg (1-Month SR), 11.25 mg (1-Month SR), and 15.0 mg (1-Month SR) carboxymethylcellulose sodium, DL-lactic and glycolic acids copolymer, D-mannitol, gelatin, glacial acetic acid, polysorbate 80

For a complete listing see DOSAGE FORMS, COMPOSITION AND PACKAGING section.
Definition: SR = slow release

Indications and clinical use

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

  • the treatment of children with central precocious puberty.

Children should be selected using the following criteria:

  1. Clinical diagnosis of CPP (idiopathic or neurogenic) with onset of secondary sexual characteristics earlier than 8 years in females and 9 years in males.
  2. Clinical diagnosis should be confirmed prior to initiation of therapy as follows:
    • Confirmation of diagnosis by a pubertal response to a GnRH stimulation test. The sensitivity and methodology of this assay must be understood.
    • Bone age advanced one year beyond the chronological age.
  3. Baseline evaluation should also include:
    • Height and weight measurements
    • Sex steroid levels
    • Adrenal steroid level to exclude congenital adrenal hyperplasia
    • Beta human chorionic gonadotropin level to rule out a chorionic gonadotropin secreting tumor
    • Pelvic/adrenal/testicular ultrasound to rule out a steroid secreting tumor
    • Computerized tomography of the head to rule out intracranial tumor

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

Geriatrics (> 65 years of age):

Refer to the “Prostatic Cancer” Product Monograph for the efficacy and safety of LUPRON and LUPRON DEPOT in this population.

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 LUPRON DEPOT was administered on day 6 of pregnancy at test dosages of 0.00024, 0.0024, and 0.024 mg/kg (1/1200 to 1/12 the human pediatric 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 acetate is excreted in human milk; therefore, LUPRON and LUPRON DEPOT are contraindicated in patients who are breast- feeding.

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.

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, Mutagenicity and Carcinogenicity.

Central Precocious Puberty

During the early phase of therapy, gonadotropins and sex steroids rise above baseline because of the natural stimulatory effect of the drug. An increase in clinical signs and symptoms may therefore be observed. See DETAILED PHARMACOLOGY.

Non-compliance with the drug regimen or inadequate dosing may result in inadequate control of the pubertal process. The consequences of poor control include the return of pubertal signs such as menses, breast development, and testicular growth. The long-term consequences of inadequate control of gonadal steroid secretion are unknown, but may include a further compromise of adult stature.

Dependence/Tolerance

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

Endocrine and Metabolism

Changes in Bone Density

Bone loss can be expected as part of natural aging and can also be anticipated during the hypoandrogenic state caused by long-term use of leuprolide acetate. 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 acetate may pose additional risk. In these patients, risk versus benefit must be weighed carefully before initiation of leuprolide acetate therapy.

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.

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

The paediatric products LUPRON and LUPRON DEPOT 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

It is not known whether leuprolide acetate is excreted in human milk; therefore LUPRON and LUPRON DEPOT are contraindicated in patients who are breastfeeding. LUPRON DEPOT treatment of women is covered in the LUPRON DEPOT 3.75 mg and 11.25 mg “Endometriosis” Product Monograph.

Geriatrics (> 65 years of age)

Refer to the “Prostatic Cancer” Product Monograph for the efficacy and safety of LUPRON and LUPRON DEPOT in this population.

Monitoring and Laboratory Tests

Response to LUPRON and LUPRON DEPOT should be monitored 1 to 2 months after the start of therapy with a GnRH stimulation test and sex steroid levels. Measurement of bone age for advancement should be done every 6 to 12 months.

Sex steroids may increase or rise above prepubertal levels if the dose is inadequate. See WARNINGS AND PRECAUTIONS, Endocrine and Metabolism. Once a therapeutic dose has been established, gonadotropin and sex steroid levels will decline to prepubertal levels.

Adverse reactions

Adverse Drug Reaction Overview

Potential exacerbation of signs and symptoms during the first few weeks of treatment is a concern in patients with rapidly advancing central precocious puberty. See WARNINGS AND PRECAUTIONS.

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.

In two studies of children with central precocious puberty, in 2% or more of the patients receiving the drug, the following adverse reactions were reported to have a possible or probable relationship to drug as ascribed by the treating physician (see Table 1). Reactions considered not drug related are excluded.

Table 1. Adverse Reactions Reported Having a Possible or Probable Relationship to Drug in 2% or more of Patients Receiving the Drug
Number of Patients
N = 421(%)
Body as a Whole
General pain
Headache
Injection site reaction including abscess*

12 (3)
11 (3)
37 (9)
Cardiovascular System
Vasodilatation

9 (2)
Integumentary System
Acne/Seborrhea
Rash including erythema multiforme

8(2)
12 (3)
Nervous System
Emotional lability

19 (5)
Urogenital System
Vaginitis/vaginal bleeding/ vaginal discharge

13 (3)
* Most events were mild or moderate in severity.

Less Common Clinical Trial Adverse Drug Reactions (< 2%)

In these same studies, the following adverse reactions were reported by less than 2% of the patients.

Body as a Whole: Aggravation of pre-existing tumor and decreased vision, allergic
reaction, body odor, fever, flu syndrome, infection, hypertrophy.
Cardiovascular System: Bradycardia, hypertension, peripheral vascular disorder, syncope.
Digestive System: Constipation, dyspepsia, dysphagia, gingivitis, increased appetite,
nausea/vomiting.
Endocrine System: Accelerated sexual maturity, feminization, goiter.
Hemic and Lymphatic
System:
Purpura.
Metabolic and Nutritional
Disorders:
Growth retarded, peripheral edema, weight gain.
Musculoskeletal System: Arthralgia, joint disorder, myalgia, myopathy.
Nervous System: Depression, hyperkinesia, nervousness, somnolence.
Respiratory System: Asthma, epistaxis, pharyngitis, rhinitis, sinusitis.
Integumentary System: Alopecia, hair disorder, hirsutism, leukoedema, nail disorder, skin
hypertrophy, urticaria.
Urogenital System: Cervix disorder/neoplasm, dysmenorrhea, gynecomastia/breast
disorders, menstrual disorder, urinary incontinence.

Abnormal Hematologic and Clinical Chemistry Findings

The following laboratory events were recorded as adverse reactions: antinuclear antibody present and increased sedimentation rate.

See Effect on Clinical Laboratory Tests under the DRUG INTERACTIONS section.

Post-Market Adverse Drug Reactions

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

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.

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

Cardiovascular System: Hot flush, hypertension, hypotension, flushing.
Digestive System: Abdominal pain, nausea, vomiting.
Hemic and Lymphatic
System:
Decreased WBC.
Central/Peripheral Nervous
System:
Convulsion, peripheral neuropathy, spinal fracture/paralysis.
Integumentary System: Hyperhidrosis, photosensitivity reactions, rash, urticaria.
Metabolic and Nutritional Metabolic and Nutritional
Disorders:
Diabetes mellitus, weight increased
Musculoskeletal System: Tenosynovitis-like symptoms.
Respiratory System: Chest pain.
Urogenital System: Prostate pain.
Miscellaneous: Injection site reactions including pain, inflammation, sterile abscess,
induration and hematoma.

See the “Prostate Cancer” 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.

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 treatment is discontinued. Diagnostic tests of pituitary-gonadal function conducted during treatment and within 4 to 8 weeks after discontinuation of LUPRON DEPOT therapy may therefore be misleading.

As expected, (see DETAILED PHARMACOLOGY) 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. 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 physician.
  • LUPRON DEPOT 3.75 mg (1-Month SR), 7.5 mg (1-Month SR), 11.25 mg (1-Month SR) and 15 mg (1-Month SR) administered intramuscularly is designed to provide continuous sustained release of leuprolide for 1 month.
NOTE: As with all parenteral products, inspect container's solution for discoloration and particulate matter before each use.

Use in Central Precocious Puberty

The dose of leuprolide acetate must be individualized for each child. The dose is based on a mg/kg ratio of drug to body weight. Younger children require higher doses on a mg/kg ratio. For each dosage form, after 1 to 2 months of initiating therapy or changing doses, the child must be monitored with a GnRH stimulation test, sex steroids, and Tanner staging to confirm downregulation. Measurements of bone age for advancement should be monitored every 6 to 12 months. The dose should be titrated upward until no progression of the condition is noted either clinically and/or by laboratory parameters.

The first dose found to result in adequate downregulation can probably be maintained for the duration of therapy in most children. However, there are insufficient data to guide dosage adjustments as patients move into higher weight categories after beginning therapy at very young ages and low dosages. It is recommended that adequate downregulation be verified in such patients whose weight has increased significantly while on therapy.

DISCONTINUATION OF LEUPROLIDE ACETATE SHOULD BE CONSIDERED BEFORE AGE 11 FOR FEMALES AND AGE 12 FOR MALES.

Recommended Dose and Dosage Adjustment

LUPRON

The recommended starting dose is 50 mcg/kg/day administered as a single daily subcutaneous injection. If total downregulation is not achieved, the dose should be titrated upward by 10 mcg/kg/day to a maximum of 100 mcg/kg/day. This dose will be considered the maintenance dose.

LUPRON DEPOT

The recommended starting dose is 0.3 mg/kg/4 weeks (minimum 7.5 mg) administered as a single intramuscular injection, after reconstitution with the special diluent. See DOSAGE AND ADMINISTRATION, Administration. The starting dose will be dictated by the child’s weight.

Child’s Weight Total Dose
≤25 kg 7.5 mg
> 25 to ≤37.5 kg 11.25 mg
> 37.5 kg 15 mg

If total downregulation is not achieved, the dose should be titrated upward in increments of 3.75 mg every 4 weeks to a maximum of 15 mg per month. This dose will be considered the maintenance dose.

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

Regular injections are important. Adherence to 4-week drug administration schedules must be accepted if therapy is to be successful. If a shot is missed or is administered a week late, the child’s pubertal development could begin again. See WARNINGS AND PRECAUTIONS, General and WARNINGS AND PRECATIONS, Central Precocious Puberty.

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 depot formulation is not equivalent to the same dose of the monthly formulation and should not be given.

For LUPRON DEPOT 3.75, 7.5, 11.25 and 15.0 mg (1-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 333 times the recommended human pediatric dose, expressed on a per body weight basis, resulted in dyspnea, decreased activity, and excessive scratching.

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.

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 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

Human studies indicated that following an initial stimulation of gonadotropins, chronic stimulation with leuprolide acetate results in suppression or "downregulation" of these hormones and consequent suppression of ovarian and testicular steroidogenesis. These effects are reversible on discontinuation of drug therapy.

Central Precocious Puberty

Two chronic studies involving the treatment of children with central precocious puberty (CPP), demonstrated that following the administration of LUPRON (leuprolide acetate) injection and/or LUPRON DEPOT (leuprolide acetate for depot suspension), stimulated and basal gonadotropins are reduced to prepubertal levels. Testosterone and estradiol are reduced to prepubertal levels in males and females, respectively, and a reduction of gonadotropins will allow for normal physical and psychological growth and development. Natural maturation occurs when gonadotropins return to pubertal levels following discontinuation of leuprolide acetate.

The following physiological effects have been noted with the chronic administration of leuprolide acetate in CPP patients.

  • Skeletal Growth: A measurable increase in body length can be noted since the epiphyseal plates will not close prematurely.
  • Organ Growth: Reproductive organs will return to a prepubertal state.
  • Menses: Menses, if present, will cease.

Intramuscular injection of LUPRON DEPOT provides plasma concentrations of leuprolide acetate over a period of one month.

In a study of 22 children with central precocious puberty, doses of LUPRON DEPOT were given every 4 weeks and plasma levels were determined according to weight categories as summarized in Table 2.

Table 2. Determination of Leuprolide Plasma Levels According to Weight Categories in Children with Central Precocious Puberty
Patient Weight
Range (kg)
Group Weight
Average (kg)
Dose (mg) Trough Plasma
Leuprolide Level
Mean±SD (ng/mL)*
20.2 - 27.0 22.7 7.5 0.77±0.033
28.4 - 36.8 32.5 11.25 1.25±1.06
39.3 - 57.5 44.2 15.0 1.59±0.65
* Group average values determined at Week 4 immediately prior to leuprolide injection.
В Drug levels at 12 and 24 weeks were similar to respective 4 week levels.

Pharmacokinetics

Intramuscular injections of LUPRON DEPOT (leuprolide acetate for depot suspension)

3.75 mg (1-Month SR), 7.5 mg (1-Month SR), 11.25 mg (1-Month SR) and 15 mg (1-Month SR) provide plasma concentrations of leuprolide acetate over a period of one month. See DETAILED PHARMACOLOGY.

Leuprolide 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 adult 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 LUPRON DEPOT 7.5 mg (1-Month SR) intramuscular injection to adult patients, the mean peak leuprolide plasma concentration was almost 20 ng/mL at 4 hours and then declined to 0.36 ng/mL at 4 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 castrated levels.

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 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.

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.

LUPRON DEPOT

Store LUPRON DEPOT (leuprolide acetate for depot suspension) 3.75 mg (1-Month SR), 7.5 mg (1-Month SR), 11.25 mg (1-Month SR) and 15 mg (1-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 is available in sterile multiple-dose vials of 2.8 mL for subcutaneous use, containing 5 mg/mL leuprolide acetate.

LUPRON is supplied as a 14-day kit. Each 14-day Patient Administration Kit contains one vial of LUPRON, twenty-eight swabs and fourteen syringes, and one Patient Information/Instructions for Use Leaflet.

Listing of Non-Medicinal Ingredients

In addition to 5 mg/mL of leuprolide acetate, each 2.8 mL multiple dose vial contains sodium chloride for tonicity adjustment, benzyl alcohol as a preservative, and sterile water for injection, USP. The pH may have been adjusted with sodium hydroxide and/or acetic acid.

LUPRON DEPOT

LUPRON DEPOT (leuprolide acetate for depot suspension) is available in four strengths: 3.75 mg (1-Month SR), 7.5 mg (1-Month SR), 11.25 mg (1-Month SR) and 15 mg (1-Month SR).

LUPRON DEPOT (1-Month SR) is supplied in single-dose kits containing one prefilled dual- chamber syringe with 23 G needle, two alcohol swabs, Patient Information Leaflet, Special Instructions for Use, and Package Insert.

Listing of Non-Medicinal Ingredients

LUPRON DEPOT 3.75 mg (1-Month SR)

LUPRON DEPOT 3.75 mg (1-Month SR) is available in a prefilled dual-chamber syringe containing sterile lyophilized microspheres composed of leuprolide acetate incorporated in a biodegradable copolymer of lactic and glycolic acids.

The front chamber of the prefilled dual-chamber syringe contains: leuprolide acetate, purified gelatin, DL-lactic and glycolic acids copolymer, and D-mannitol.

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

LUPRON DEPOT 7.5 mg (1-Month SR)

LUPRON DEPOT 7.5 mg (1-Month SR) is available in a prefilled dual-chamber syringe containing sterile lyophilized microspheres composed of leuprolide acetate incorporated in a biodegradable copolymer of lactic and glycolic acids.

The front chamber of the prefilled dual-chamber syringe contains: leuprolide acetate, purified gelatin, DL-lactic and glycolic acids copolymer, and D-mannitol.

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

LUPRON DEPOT 11.25 mg (1-Month SR)

LUPRON DEPOT 11.25 mg (1-Month SR) is available in a prefilled dual-chamber syringe containing sterile lyophilized microspheres composed of leuprolide acetate incorporated in a biodegradable copolymer of lactic and glycolic acids.

The front chamber of the prefilled dual-chamber syringe contains: leuprolide acetate, purified gelatin, DL-lactic and glycolic acids copolymer, and D-mannitol.

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

LUPRON DEPOT 15.0 mg (1-Month SR)

LUPRON DEPOT 15.0 mg (1-Month SR) is available in a prefilled dual-chamber syringe containing sterile lyophilized microspheres composed of leuprolide acetate incorporated in a biodegradable copolymer of lactic and glycolic acids.

The front chamber of the prefilled dual-chamber syringe contains: leuprolide acetate, purified gelatin, DL-lactic and glycolic acids copolymer, and D-mannitol.

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

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.