Lupron (Leuprolide Acetate)

LUPRON® DEPOT® 3.75 mg

Abbott

Leuprolide Acetate for Depot Suspension

Gonadotropin-releasing Hormone Analog

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.

Bioavailability by s.c. administration is comparable to i.v. administration. Leuprolide has a plasma half-life of 2.9 hours.

I.M. injection of leuprolide for depot suspension 3.75 mg (1-month SR) provides effective plasma concentrations of leuprolide acetate over a period of 1 month.

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

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

In humans, s.c. administration of single daily doses of leuprolide 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 2 to 4 weeks after initiation of treatment and are maintained as long as treatment continues.

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

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

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

Leuprolide achieves a menopausal state by suppression of the pituitary-ovarian axis by inhibiting the output of gonadotropins (FSH and LH) from the pituitary gland.

In female volunteers receiving a single dose of leuprolide for depot suspension 3.75 mg (1-month SR) i.m., an initial burst of leuprolide in plasma was observed. Mean plasma leuprolide levels of approximately 0.23 to 0.34 ng/mL were maintained over a period of 4 to 5 weeks, and then slowly tapered off, becoming undetectable 8 weeks after injection.

Pharmacokinetics: Absorption: A single dose of leuprolide for depot suspension 3.75 mg (1-month SR) was administered by i.m. injection to healthy female volunteers. The absorption of leuprolide was characterized by an initial increase in plasma concentration, with peak concentration ranging from 4.6 to 10.2 ng/mL at 4 hours postdosing. 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 0.3 ng/mL.

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 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 leuprolide for depot suspension 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: The pharmacokinetics of the drug in hepatic-and renal-impaired patients have not been determined.

Indications And Clinical Uses: In the treatment of endometriosis, for a period of 6 months.

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

Experience with leuprolide for depot suspension for the management of endometriosis has been limited to women 18 years of age and older.

Contra-Indications: General: 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 (1/300 to 1/3 the 3.75 mg leuprolide for depot suspension human dose) to rabbits, leuprolide 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.

Patients treated with leuprolide for depot suspension should use nonhormonal methods of contraception.

Leuprolide for depot suspension is also contraindicated in patients with undiagnosed abnormal vaginal bleeding as well as in patients who are breast-feeding.

Manufacturers’ Warnings In Clinical States: General: Isolated cases of short-term worsening of signs and symptoms have been reported during initiation of leuprolide therapy: they are sometimes, but not necessarily, associated with a stimulation of the pituitary gland.

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

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

Pregnancy: Before initiating treatment with leuprolide for depot suspension, pregnancy must be ruled out (see Precautions).

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

Endometriosis: Changes in Bone Density: Since bone loss can be anticipated as part of natural menopause, it may also be expected to occur during a medically induced hypoestrogenic state caused by the long-term use of leuprolide for depot suspension. For a period of up to 6 months, this bone loss should not be important.

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 for depot suspension may pose an additional risk. In these patients, risk versus benefit must be weighed carefully before therapy with leuprolide for depot suspension is instituted.

Retreatment cannot be recommended since safety data for retreatment are not available. If the symptoms of endometriosis recur after a course of therapy, and further treatment with leuprolide for depot suspension 3.75 mg (1-month SR) is contemplated, it is recommended that bone density be assessed before retreatment begins to ensure that values are within normal limits.

A controlled study in endometriosis patients showed that vertebral bone density, as measured by dual energy x-ray absorptiometry (DEXA), decreased by an average of 4.1% at 6 months compared with the pretreatment value.

For those patients who were tested at 6 or 12 months after discontinuation of therapy, the mean bone density returned to 2.6% of pretreatment.

Earlier studies in endometriosis patients, utilizing quantitative computed tomography (QCT), demonstrated that in the few patients who were retested at 6 and 12 months, partial to complete recovery of bone density was recorded in the post-treatment period. Use of leuprolide for depot suspension for longer than 6 months or in the presence of other known risk factors for decreased bone mineral content may cause additional bone loss.

Changes in Laboratory Values During Treatment: Plasma Enzymes: During clinical trials with leuprolide for depot suspension, regular laboratory monitoring revealed that AST levels were more than twice the upper limit of normal in only one patient. There was no other clinical or laboratory evidence of abnormal liver function.

Lipids: At enrolment, 4% of leuprolide for depot suspension 3.75 mg (1-month SR) patients and 1% of the danazol patients had total cholesterol values above the normal range. These patients also had cholesterol values above the normal range at the end of treatment. Of those patients whose pretreatment cholesterol values were in the normal range, 7% of leuprolide for depot suspension patients and 9% of the danazol patients had post-treatment values above the normal range.

The mean (±SEM) pretreatment values for total cholesterol from all patients were 4.63 (0.08) mmol/L in the leuprolide for depot suspension 3.75 mg (1-month SR) group and 4.54 (0.08) mmol/L in the danazol group. At the end of treatment, the mean values for total cholesterol from all patients were 5.01 mmol/L in the leuprolide for depot suspension group and 5.03 mmol/L in the danazol group. These increases from the pretreatment values were statistically significant.

Triglycerides were increased above the upper limit of normal in 12% of the patients who received leuprolide for depot suspension 3.75 mg (1-month SR) and in 6% of the patients who received danazol.

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

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

Other Changes: In comparative studies, the following changes were seen in approximately 5 to 8% of patients. Leuprolide for depot suspension was associated with elevations of LDH and phosphorus, and decreases in WBC counts, and danazol therapy was associated with increases in hematocrit, platelet count and LDH.

The safety of retreatment as well as treatment beyond 6 months with leuprolide for depot suspension has not been established.

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

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

Before initiating treatment with leuprolide for depot suspension, pregnancy must be ruled out.

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

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

Adverse Reactions: Estradiol levels may increase during the first weeks following the initial injection, but then decline to basal levels. This transient increase in estradiol can be associated with temporary worsening of signs and symptoms (see Warnings).

Endometriosis: In 2 controlled clinical trials treating endometriosis, one comparing leuprolide for depot suspension 3.75 mg (1-month SR) with danazol (800 mg/day) and the other with placebo, the following adverse reactions (see Table I) were reported to have a possible or probable relationship to study drugs as ascribed by the treating physician in 5% or more of the patients receiving the drug.

In these same studies, the following were reported in less than 5% of patients receiving leuprolide for depot suspension.

Cardiovascular: palpitations, syncope, tachycardia.

Gastrointestinal: dry mouth, thirst, appetite changes.

Central/Peripheral Nervous System: anxiety*, personality disorder, memory disorder, delusions.

Integumentary: ecchymosis, alopecia, hair disorder.

Urogenital: dysuria*, lactation.

Miscellaneous: ophthalmologic disorders*, lymphadenopathy.

* Physiologic effect of decreased estrogen.

Postmarketing Surveillance: The following events have been reported during postmarketing surveillance: Cardiovascular: hypotension.

Gastrointestinal: hepatic dysfunction.

Hemic and Lymphatic: decreased WBC.

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

Respiratory: dyspnea.

Integumentary: rash, urticaria, photosensitivity reactions.

Musculoskeletal: tenosynovitis-like symptoms.

Urogenital: menstrual disorders.

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.

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

Symptoms And Treatment Of Overdose: Symptoms and Treatment: In rats, s.c. administration of 250 to 500 times the recommended human dose, expressed on a per body weight basis, results in dyspnea, decreased activity and local irritation at the injection site. There is no evidence at present that there is a clinical counterpart of this phenomenon.

In early clinical trials using daily s.c. leuprolide in patients with prostate cancer, doses as high as 20 mg/day for up to 2 years caused no adverse effects differing from those observed with the 1 mg/day dose.

Dosage And Administration: Endometriosis: The recommended dose is 3.75 mg administered monthly as a single i.m. injection, after reconstitution with the special diluent (see Special Instructions for Use and Patient Information). The treatment course is for 6 months.

Retreatment cannot be recommended since safety data for retreatment are not available. If the symptoms of endometriosis recur after a course of therapy, and further treatment with leuprolide for depot suspension 3.75 mg (1-month SR) is contemplated, it is recommended that bone density be assessed before retreatment begins to ensure that values are within normal limits.

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

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: Kits (Vial and Ampul): Each single-dose vial contains: leuprolide acetate for depot suspension 3.75 mg (1-month slow release). Sterile lyophilized microspheres which is 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 glacial acetic acid, USP to control pH. During the manufacturing process, acetic acid is lost, leaving the peptide. Store vials and kits at controlled room temperature between 15 and 30°C. Protect from freezing. Supplied as kits. Each kit contains: 1 vial of Lupron Depot, 1 ampul (2 mL) of sterile diluent, 1 syringe with 22G needle, 1 additional 22G needle, 2 alcohol swabs, Special Instructions for Use, Patient Information Leaflet and Package Insert.

Prefilled Syringes: Each prefilled dual-chamber syringe contains: leuprolide acetate for depot suspension 3.75 mg (1-month slow release). Sterile lyophilized microspheres which is 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. The rear chamber of diluent contains: carboxymethylcellulose sodium, D-mannitol, glacial acetic acid, USP to control pH, polysorbate 80 and water for injection USP. During the manufacturing process, acetic acid is lost, leaving the peptide. Store at controlled room temperature between 15 and 30°C. Protect from freezing. Supplied as single-dose kits. Each kit contains: 1 prefilled dual-chamber syringe with 23G needle, 2 alcohol swabs, Special Instructions for Use, Patient Information Leaflet and Package Insert.

LUPRON® DEPOT® 3.75 mg Abbott Leuprolide Acetate for Depot Suspension Gonadotropin-releasing Hormone Analog

Connected Diseases :

Prostate Cancer

General Illness Information Medical Term: Prostatic carcinoma Common Name: Prostate cancer Description: Prostate cancer is a type of cancer developing in the prostate gland. Causes:…

Endometriosis

General Illness Information Medical Term: ENDOMETRIOSIS Common Name: None Specified Description: Endometriosis is a condition in which the endometrium (i.e. the inner lining of the…

Hormonal Imbalance

General Illness Information Medical Term: Hormonal Imbalance Common Name: Hormonal disorders, Endocrine Disorders Description: Hormonal imbalance is a violation of the functioning of one or…