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LUPRON DEPOT 3.75 mg/7.5 mg
Abbott/TAP Pharmaceuticals
Leuprolide Acetate
Leuprolide Acetate for Depot Suspension
Gonadotropin-releasing Hormone Analog for Management of Central Precocious Puberty in Children
 
Action And Clinical Pharmacology: 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.

Human studies indicated that following an initial stimulation of gonadotropins, chronic stimulation with leuprolide 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.

Leuprolide is not active when given orally. In adults, bioavailability by s.c. administration is comparable to that by i.v. administration. Leuprolide has a plasma half-life of 2.9 hours.

Two chronic studies involving the treatment of children with central precocious puberty (CPP), demonstrated that following the administration of leuprolide injection and/or leuprolide 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.

The following physiological effects have been noted with the chronic administration of leuprolide 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.

I.M. injection of leuprolide for depot suspension provides plasma concentrations of leuprolide over a period of 1 month.

In a study of 22 children with central precocious puberty, doses of leuprolide for depot suspension were given every 4 weeks and plasma levels were determined according to weight categories as summarized in

Pharmacokinetics: Absorption: A single dose of leuprolide for depot suspension 3.75 mg was administered by i.m. 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 4 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 2 days after dosing and remained relatively stable for about 4 to 5 weeks with plasma concentrations of about 0.30 ng/mL.

Following a single leuprolide for depot suspension 7.5 mg i.m. 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 leuprolide for depot suspension 7.5 mg administration, but testosterone levels appear to be maintained at castrate levels.

Distribution: The mean steady-state volume of distribution of leuprolide following i.v. 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 i.v. revealed that the mean systemic clearance was 7.6 L/h, with a terminal elimination half-life of approximately 3 hours based on a 2 compartment model.

In rats and dogs, administration of 4-labelled leuprolide was shown to be metabolized to smaller inactive peptides, pentapeptide (Metabolite I), tripeptide (Metabolite II and II) 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 leuprolide for depot suspension 3.75 mg to 3 patients, less than 5% of the dose was recovered as parent and M-I metabolite in the urine.

Special Populations: The pharmacokinetics of the drug in hepatic and renal impaired patients have not been determined.

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

Indications And Clinical Uses: In 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: (a) Confirmation of diagnosis by a pubertal response to a GnRH stimulation test. The sensitivity and methodology of this assay must be undertstood. (b) Bone age advanced 1 year beyond the chronological age. 3. Baseline evaluation should also include: (a) height and weight measurements; (b) sex steroid levels; (c) adrenal steroid level to exclude congenital adrenal hyperplasia; (d) beta human chorionic gonadotropin level to rule out a chorionic gonadotropin secreting tumor; (e) pelvic/adrenal/testicular ultrasound to rule out a steroid secreting tumor; (f) computerized tomography of the head to rule out intracranial tumor.

Contra-Indications: In patients with hypersensitivity to the drug or its components or similar nonapeptides. Isolated cases of anaphylaxis have been reported.

Pregnancy: Leuprolide for depot suspension is contraindicated in women who are or may become pregnant while receiving the drug. When administered on day 6 of pregnancy at test dosages of 0.00024, 0.0024 and 0.024 mg/kg (1/1 200 to 1/12 the human pediatric dose) to rabbits, it 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 2 higher doses of leuprolide for depot suspension 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.

Lactation: It is not known whether leuprolide for depot suspension is excreted in human milk; therefore, it should not be administered to a nursing mother.

Manufacturers' Warnings In Clinical States: 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 Pharmacology).

Noncompliance 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.

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

Response to leuprolide 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). Once a therapeutic dose has been established, gonadotropin and sex steroid levels will decline to prepubertal levels.

Dependence Liability: No drug-dependence has been reported with the use of leuprolide.

Drug Interactions: No pharmacokinetic based drug-drug interaction studies have been conducted.

Leuprolide being 46% bound to plasma proteins, and a peptide that is primarily degraded by peptidase and not by cytochrome P450 enzymes as noted in specific studies, drug interactions would not be expected to occur.

Drug/Laboratory Test Interactions : Administration of leuprolide for depot suspension 3.75 mg in women 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 leuprolide for depot suspension therapy may therefore be misleading.

Effect on Clinical Laboratory Tests: As expected (see Pharmacology), leuprolide 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 baselines in the case of testosterone, dihydrotestosterone and acid phosphatase.

Adverse Reactions: Potential exacerbation of signs and symptoms during the first few weeks of the treatment (see Precautions) is a concern in patients with rapidly advancing central precocious puberty.

In 2 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. Reactions considered not drug related are excluded. See Table II.

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

Body as a Whole: body odor, fever, headache, infection, hypertrophy.

Cardiovascular: syncope, vasodilation.

Digestive: dysphagia, gingivitis, nausea/vomiting.

Endocrine: accelerated sexual maturity.

Metabolic and Nutritional Disorders: peripheral edema, weight gain.

Nervous System: nervousness, personality disorder, somnolence, emotional liability.

Respiratory: epistaxis.

Integumentary: alopecia, skin striae, urticaria.

Urogenital: cervix disorder, gynecomastia/breast disorders, urinary incontinence.

Postmarketing Surveillance: During postmarketing surveillance which include other dosage forms, the following adverse events were reported: Cardiovascular: hypotension.

Hemic and Lymphatic: decreased WBC.

Central/Peripheral Nervous System: peripheral neuropathy, spinal fracture/paralysis.

Integumentary: rash, urticaria, photosensitivity reactions.

Musculoskeletal: tenosynovitis-like symptoms.

Urogenital: prostate pain.

Miscellaneous: injection site reactions including pain, inflammation, sterile abscess, induration and hematoma.

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

Symptoms And Treatment Of Overdose: Symptoms and Treatment: In rats, s.c. administration of 250 to 500 times the recommended human pediatric 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 for up to 3 years or 20 mg/day for up to 2 years.

Dosage And Administration: The dose 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.

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

Discontinuation of leuprolide should be considered before age 11 for females and age 12 for males.

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

Note: As with other parenteral products, inspect container's solution for discoloration and particulate matter before each use.

Lupron Depot: The recommended starting dose is 0.3 mg/kg/4 weeks (minimum 7.5 mg) administered as a single i.m. injection. The starting dose will be dictated by the child's weight: 25 kg: 7.5 mg; >25-37.5 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/month. This dose will be considered the maintenance dose.

The lyophilized microspheres are to be reconstituted and administered monthly as a single i.m. injection.

Special Instructions for Use: Leuprolide for depot suspension must be administered under the supervision of a physician.

The lyophilized microspheres are to be reconstituted and administered monthly as a single i.m. injection, in accord with the following directions: Vial and Ampul: 1. Using a syringe with a 22 gauge needle, withdraw 1 mL of diluent from the ampul, and inject it into the vial. (Extra diluent is provided; any remaining diluent should be discarded.) 2. Shake well to thoroughly disperse particles to obtain a uniform, homogeneous suspension. (The suspension will appear milky.) 3. Withdraw the entire contents of the vial into the syringe and inject it as directed (once a month ) at the time of reconstitution. Any reconstituted suspension not used immediately should be discarded.

Prefilled Dual-chamber Syringe: 1. Screw the white plunger into the end stopper until the stopper begins to turn. 2. Remove and discard the tamper evident tab around the base of the needle. 3. Holding the syringe upright, release the diluent by slowly pushing the plunger until the first stopper is at the blue line in the middle of the barrel. 4. Gently shake the syringe to thoroughly mix the particles to form a uniform suspension. The suspension will appear milky. 5. If the microspheres (particles) adhere to the stopper, tap the syringe against your finger. 6. Then remove the needle guard and advance the plunger to expel the air from the syringe. 7. At the time of reconstitution, inject the entire contents of the syringe i.m. as you would for a normal injection.

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

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.



Availability And Storage: Lupron: Each mL contains: leuprolide acetate 5 mg. Nonmedicinal ingredients: benzyl alcohol, sodium chloride and sterile water for injection. The pH may have been adjusted with sodium hydroxide and/or acetic acid. Multiple dose vials of 2.8 mL for s.c. use. Also supplied as 14-day kits. Each 14-day Patient Administration Kit contains: 1 vial of Lupron, 28 swabs and 14 syringes, Patient Information Leaflet, Instruction for Use Leaflet and Package Insert. Keep refrigerated between 2 and 8C.

Lupron Depot Kits (Vial and Ampul): 3.75 mg (1-month slow release): Each single-dose vial contains: leuprolide acetate 3.75 mg. Sterile lyophilized microspheres composed of leuprolide acetate incorporated in a biodegradable copolymer of lactic and glycolic acids. Nonmedicinal ingredients: DL-lactic and glycolic acids copolymer, D-mannitol and purified gelatin.

7.5 mg (1-month slow release): Each single-dose vial contains: leuprolide acetate 7.5 mg. Sterile lyophilized microspheres composed of leuprolide acetate incorporated in a biodegradable copolymer of lactic and glycolic acids. Nonmedicinal ingredients: DL-lactic and glycolic acids copolymer, D-mannitol and purified gelatin.

Each mL of the accompanying ampul of sterile diluent contains: carboxymethylcellulose sodium, D-mannitol, polysorbate 80, water for injection and acetic acid to control pH.

Supplied as kits. Each kit contains 1 vial of Lupron Depot (1-month SR), 1 ampul of sterile diluent, 1 syringe with 22 G needle, 1 additional 22 G needle, 2 alcohol swabs, Special Instructions for Use, Patient Information Leaflet and Package Insert. Store vials, kits and sterile diluent at controlled room temperature between 15 and 30C. Protect from freezing.

Prefilled Syringes: 3.75 mg (1-month slow release): Each prefilled dual-chamber syringe contains: leuprolide acetate for depot suspension 3.75 mg (1-month slow release). Sterile lyophilized microspheres composed of leuprolide incorporated in a biodegradable copolymer of lactic acid and glycolic acids. Nonmedicinal ingredients: DL-lactic and glycolic acids copolymer, D-mannitol and purified gelatin. The rear chamber of diluent contains: carboxymethylcellulose sodium, D-mannitol, glacial acetic acid USP to control pH, polysorbate 80 and water for injection.

7.5 mg (1-month slow release): Each prefilled dual-chamber syringe contains: leuprolide acetate for depot suspension 7.5 mg (1-month slow release). Sterile lyophilized microspheres composed of leuprolide incorporated in a biodegradable copolymer of lactic acid and glycolic acids. Nonmedicinal ingredients: DL-lactic and glycolic acids copolymer, D-mannitol and purified gelatin. The rear chamber of diluent contains: carboxymethylcellulose sodium, D-mannitol, glacial acetic acid USP to control pH, polysorbate 80 and water for injection.

Store prefilled syringes at controlled room temperature between 15 and 30C. Protect from freezing. Supplied as single-dose kits. Each kit contains 1 prefilled dual-chamber syringe with 23 G needle, 2 alcohol swabs, Special Instruction for Use, Patient Information Leaflet and Package Insert.

During the manufacturing process, acetic acid is lost, leaving the peptide.