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Leuprolide

Class: Gonadotropins
VA Class: AN500
Chemical Name: 5-Oxo-L-prolyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-D-leucyl-L-leucyl-L-arginyl-N-ethyl-L-prolinamide acetate (salt)
Molecular Formula: C59H84N16O12•C2H4O2
CAS Number: 74381-53-6
Brands: Eligard, Lupron, Lupron Depot

Medically reviewed by Drugs.com on Jan 11, 2021. Written by ASHP.

Introduction

Antineoplastic agent and gonadotropin releasing hormone (GnRH) agonist; a synthetic nonapeptide analog of naturally occurring GnRH (luteinizing hormone releasing hormone [LHRH], gonadorelin).

Uses for Leuprolide

Prostate Cancer

Palliative treatment of advanced prostate cancer.

First-line therapy alone or in combination with an antiandrogen (e.g., flutamide, bicalutamide, nilutamide) for prostate cancer.

Treatment of locally confined (stage B2 or C) and metastatic (stage D2) prostate cancer; generally used in conjunction with an antiandrogen.

Endometriosis

Palliative treatment of endometriosis (e.g., pain relief, reduction in endometriotic lesions [dysmenorrhea and pelvic pain, tenderness, and induration]). Experience with leuprolide has been limited to women ≥18 years of age.

Used alone or in conjunction with norethindrone acetate (5 mg daily) for initial management of endometriosis.

Used in conjunction with norethindrone acetate (5 mg daily) if symptoms recur after the initial course of therapy (retreatment). Retreatment with leuprolide alone is not recommended. (See Endometriosis under Dosage and Administration and see Musculoskeletal Effects under Cautions.)

Uterine Leiomyomata

Correction of anemia associated with uterine leiomyomata (uterine fibroids) prior to surgery; used in conjunction with iron therapy. Experience with leuprolide has been limited to women ≥18 years of age.

Precocious Puberty

Treatment of central (via activation of the hypothalamic-pituitary-gonadal axis) precocious puberty (true precocious puberty, GnRH-dependent sexual precocity, complete isosexual precocity) in children (designated an orphan drug by FDA for this use).

Treatment with a GnRH analog is indicated for children (girls <8 or boys <9 years of age) who have a clinical diagnosis (confirmed by pubertal response to a GnRH stimulation test) of central idiopathic or neurogenic precocious puberty with onset of secondary sexual characteristics and subsequent rapid advancement of height, height velocity, and/or bone age (e.g., ≥1 year more advanced than their chronologic age).

Some clinicians also state that GnRH analog therapy is indicated in boys <8 years of age with a serum testosterone concentration >100 ng/dL and in girls with onset of menarche and recurrent menses at <9 years of age.

GnRH analogs are considered the therapy of choice for this condition and generally have supplanted medroxyprogesterone in this form of precocity.

GnRH analogs are ineffective as primary therapy in the treatment of GnRH-independent (peripheral; gonadal steroid secretion is independent of gonadotropin secretion) precocious puberty, including familial male precocious puberty (testotoxicosis), congenital virilizing adrenal hyperplasia (e.g., secondary to steroid 21-hydroxylase, 11β-hydroxylase, or 3β-hydroxysteroid dehydrogenase deficiency), and McCune-Albright syndrome.

Breast Cancer

Use of ovarian suppression in combination with endocrine therapy (i.e., anastrozole, exemestane, letrozole, tamoxifen) as adjuvant therapy in premenopausal women with early-stage hormone receptor-positive breast cancer may be considered a reasonable choice (accepted).

Leuprolide Dosage and Administration

General

Prostate Cancer

  • In patients with stage B2 or C prostate cancer, initiate leuprolide and antiandrogen 8 weeks prior to and continue during radiation therapy.

  • In patients with stage D2 metastatic prostate cancer, initiate leuprolide and antiandrogen therapy concomitantly and continue until disease progression.

Uterine Leiomyomata

  • Lupron Depot: Release characteristics of a fractional dose of the 11.25-mg (3-month) injectable suspension formulation are not equivalent to the same dose of the 3.75-mg (once-monthly) formulation and should not be used for monthly doses.

  • Use of the 3-month formulation of leuprolide acetate injectable suspension (Lupron Depot-3 month 11.25 mg) recommended only when 3 months of hormonal suppression is necessary.

  • Prior to initiating leuprolide therapy, consider 1-month trial of iron therapy alone, since some patients may respond adequately to iron alone.

Precocious Puberty: Baseline Evaluation Prior to Initiating Therapy

  • Measure height and weight.

  • Determine serum testosterone or estrogen concentrations in boys or girls, respectively.

  • Determine adrenal steroid and β-human chorionic gonadotropin concentrations to rule out congenital adrenal hyperplasia and chorionic gonadotropin secreting tumors, respectively.

  • Perform pelvic, adrenal, or testicular ultrasound examination to rule out steroid secreting tumors and cranial CT to rule out intracranial tumors.

Administration

Administer by IM injection or sub-Q injection.

Leuprolide acetate injection and suspension (Lupron Depot) have comparable efficacy and safety in the treatment of advanced prostate cancer. In most patients, use of the suspension may be preferred to use of the injection because of greater convenience of administration and patient compliance with therapy.

IM Administration

Administer leuprolide acetate suspension (Lupron Depot) by IM injection once monthly as the 3.75- or 7.5-mg depot 1-month formulation; once every 3 months as the 11.25- or 22.5-mg long-acting 3-month formulation; once every 4 months as the 30-mg long-acting 4-month formulation, or once every 24 weeks as the 45-mg long-acting 6-month formulation.

Release characteristics of a fractional dose of the 22.5-mg (3-month), 30-mg (4-month), or 45-mg (6-month) suspension formulation (Lupron Depot) are not equivalent to the same dose of the 7.5-mg (once-monthly) formulation and should not be used for monthly doses for treatment of prostate cancer.

Release characteristics of a fractional dose of the 11.25-mg (3-month) suspension formulation (Lupron Depot) are not equivalent to the same dose of the 3.75-mg (once-monthly) formulation and should not be used for monthly doses for treatment of endometriosis or uterine leiomyomata.

Administer leuprolide acetate suspension (Lupron Depot-Ped) by IM injection once every 4 weeks as a 3.75-, 7.5-, or 15-mg depot 1-month formulation.

Rotate injection sites periodically.

Suspension is not intended for self-administration; administer under the supervision of a clinician.

Reconstitution

Leuprolide acetate powder for injectable suspension (Lupron Depot) is available in a dual-chamber, disposable, single-use syringe; chamber 1 of the system contains leuprolide acetate lyophilized powder, and chamber 2 contains the sterile diluent supplied by the manufacturer.

Reconstitute dual-chamber, disposable, single-use syringes containing 3.75, 7.5, 11.25, 15, 22.5, 30, or 45 mg of leuprolide acetate extended-release for injectable suspension with the accompanying diluent in accordance with the instructions provided by the manufacturer.

While keeping the syringe upright, gently mix to thoroughly disperse the particles and obtain a uniform milky suspension.

Following reconstitution, immediately inject entire contents of the syringe to provide a 3.75-, 7.5-, 11.25-, 15-, 22.5-, 30-mg, or 45-mg dose, depending on the labeled concentration of the syringe used.

Sub-Q Administration

Administer leuprolide acetate injection by sub-Q injection once daily.

Administer leuprolide acetate suspension (Eligard) by sub-Q injection once monthly as a 7.5-mg formulation, once every 3 months as a 22.5-mg formulation, once every 4 months as a 30-mg formulation, or once every 6 months as a 45-mg formulation.

Administer leuprolide acetate suspension (Eligard) in an area with sufficient soft or loose sub-Q tissue (e.g., upper- or mid-abdominal area, upper buttocks). Avoid areas with excessive pigment, hair, or brawny or fibrous sub-Q tissue (nodules, lesions) or locations that could be rubbed or compressed (e.g., with a belt or clothing waistband).

Rotate injection sites periodically.

When substitution of another syringe for the one provided by the manufacturer for use with leuprolide acetate injection is required, a disposable, low-dose, U-100 insulin syringe is the only syringe that should be used.

Reconstitution

Leuprolide acetate powder for injectable suspension (Eligard) is available in a single-use kit, containing 2 separate disposable syringes; syringe 1 of the system contains leuprolide acetate powder, and syringe 2 contains the polymeric (non-gelatin-containing) delivery system (Atrigel).

Allow the kit to reach room temperature before reconstituting.

Reconstitute single-use syringes containing 7.5, 22.5, 30, or 45 mg of leuprolide acetate powder for injectable suspension with the accompanying polymeric delivery system in accordance with the instructions provided by the manufacturer.

Following reconstitution, administer within 30 minutes. Inject the entire contents of the syringe to provide a 7.5-, 22.5-, 30-, or 45-mg dose, depending on the labeled concentration used.

Dosage

Available as leuprolide acetate; dosage of injection and suspension expressed in terms of the salt.

Pediatric Patients

Central Precocious Puberty

Individualize dosage according to actual body weight; younger children (i.e., children weighing <25 kg) generally appear to require higher dosages on a mg/kg basis than older children (i.e., children weighing ≥25 kg).

Confirm inhibition of gonadotropin secretion and suppression of ovarian or testicular steroidogenesis after 1–2 months of initial therapy or when changing dosage by evaluation of GnRH stimulation test, Tanner staging, and sex steroid concentrations.

Prior to initiation of therapy, perform baseline evaluations. (See Baseline Evaluation prior to Initiating Therapy under Dosage and Administration.)

In most children, the first dosage found to adequately inhibit gonadotropin secretion and suppress ovarian or testicular steroidogenesis can be maintained for the duration of therapy.

Data currently are insufficient for specific dosage recommendations in children in whom therapy was initiated at a low dosage and at a very young age and whose weight has changed such that the patient would be in a different weight range/dose category. The manufacturer recommends that inhibition of gonadotropin secretion and suppression of ovarian or testicular steroidogenesis be monitored closely in children whose weight has increased considerably while receiving therapy.

IM

Leuprolide acetate suspension (Lupron Depot-Ped): Initially, 0.3-mg/kg (minimum 7.5 mg) every 4 weeks in girls <8 years of age or boys <9 years of age.

Initial Dosage for Children (Girls <8 Years of Age or Boys <9 Years of Age)155

Weight

Dosage of leuprolide acetate suspension (Lupron Depot-Ped)

≤25 kg

7.5 mg every 4 weeks

25–37.5 kg

11.25 mg every 4 weeks

>37.5 kg

15 mg every 4 weeks

Titrate dose upward in increments of 3.75 mg every 4 weeks until clinical or laboratory tests indicate no disease progression.

Therapy usually is continued until fusion of the epiphyses or attainment of appropriate chronologic pubertal age (e.g., consideration made at 11 and 12 years of age in girls and boys, respectively).

Sub-Q

Leuprolide acetate injection (Lupron for Pediatric Use): Initially 50 mcg/kg once daily for girls <8 years of age or boys <9 years of age. If total suppression of ovarian or testicular steroidogenesis is not achieved, titrate dosage upward by 10 mcg/kg daily to establish maintenance dosage.

Adults

Advanced Prostate Cancer
Daily Therapy with Leuprolide Acetate Injection
Sub-Q

Usually, 1 mg daily.

Dosages up to 20 mg daily have been used by some clinicians; however, dosages >1 mg daily have not resulted in a greater incidence of remission.

For patients at risk of serious adverse affects, consider initiating therapy with daily administration of leuprolide acetate injection for 2 weeks prior to IM administration of leuprolide acetate suspension (Lupron Depot) to permit discontinuance of therapy if warranted. (See Endocrine Effects under Cautions.)

Therapy with Extended-release Suspension
IM

7.5 mg once monthly as the monthly formulation (Lupron Depot), or 22.5 mg every 12 weeks as the 3-month formulation (Lupron Depot 22.5 mg for 3-month administration), or 30 mg once every 16 weeks as the 4-month formulation (Lupron Depot 30 mg for 4-month administration), or 45 mg once every 24 weeks as the 6-month formulation (Lupron Depot 45 mg for 6-month administration).

If a monthly dose is missed, a delay of ≤12 days may or may not compromise the patient’s treatment; however, if a monthly dose is missed by ≥2 weeks, serum testosterone concentrations will increase substantially.

Sub-Q

Eligard: 7.5 mg once monthly as the monthly formulation, or 22.5 mg once every 3 months as the 3-month formulation, or 30 mg once every 4 months as the 4-month formulation, or 45 mg once every 6 months as the 6-month formulation.

Endometriosis
Initial Treatment
IM

3.75 mg once monthly as the monthly formulation (Lupron Depot) for 6 consecutive months or 11.25 mg every 3 months as the 3-month formulation (Lupron Depot-3 month 11.25 mg) for a total of 6 months. Administer with or without norethindrone acetate (5 mg daily).

Retreatment If Symptoms Recur after Initial Treatment

Retreatment with additional courses of leuprolide alone is not recommended; if retreatment is considered, administer a single 6-month course of leuprolide acetate suspension in conjunction with norethindrone acetate (and elemental calcium 1 g daily).

Assess BMD prior to therapy to ensure that values are within normal limits. (See Musculoskeletal Effects under Cautions.)

IM

3.75 mg once monthly as the monthly formulation (Lupron Depot) for a total of 6 months or 11.25 mg every 3 months as the 3-month formulation (Lupron Depot-3 month 11.25 mg) for a total of 6 months. Administer in conjunction with oral norethindrone acetate (5 mg daily).

Additional courses of treatment after a single 6-month retreatment course are not recommended.

Uterine Leiomyomata
IM

3.75 mg once monthly as the monthly formulation (Lupron Depot) for up to 3 consecutive months in conjunction with iron therapy.

11.25 mg of the 3-month formulation (Lupron Depot-3 month 11.25 mg) as a single injection in conjunction with iron therapy. Use of the 3-month formulation recommended only when 3 months of hormonal suppression is necessary.

If additional therapy is considered, assess BMD prior to therapy to ensure that values are within normal limits. (See Musculoskeletal Effects under Cautions.)

Early-stage Breast Cancer†
IM

Dosage of 3.75 mg every 4 weeks has been used in combination with endocrine therapy. (See Breast Cancer under Uses.)

Prescribing Limits

Adults

Endometriosis
Initial Treatment
IM

Limit initial course of therapy to 6 months.

Retreatment If Symptoms Recur after Initial Treatment
IM

Limit retreatment of symptom recurrence to 6 months; retreatment with leuprolide alone is not recommended.

Additional courses of treatment after a single 6-month retreatment course are not recommended.

Uterine Leiomyomata
IM

Lupron Depot 3.75 mg monthly formulation: Maximum 3 consecutive months of therapy recommended.

Lupron Depot 11.25 mg (3-month formulation): A single injection of 11.25 mg recommended.

Safety and efficacy of >6 months of therapy not evaluated.

Cautions for Leuprolide

Contraindications

  • Known hypersensitivity to GnRH, GnRH analogs, or any ingredient in the respective formulations.

  • Known or suspected pregnancy. (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

  • Abnormal vaginal bleeding of unknown etiology.

  • Breast-feeding.

Warnings/Precautions

Warnings

Fetal/Neonatal Morbidity and Mortality

Expected hormonal changes increase the risk for pregnancy loss and fetal harm when administered to a pregnant woman; teratogenicity, fetotoxicity, and fetolethality demonstrated in animals.

Contraindicated in women who are or may become pregnant during therapy; exclude pregnancy before initiating therapy.

Women of childbearing potential should avoid pregnancy and use an effective nonhormonal method of contraception during therapy. If used during pregnancy or patient becomes pregnant, discontinue and apprise of potential fetal hazard.

Initial Worsening of Hormone-dependent Disease

Transient increases in serum testosterone (in men) or estrogen (in women) concentrations may result in worsening (flare) of signs and/or symptoms (e.g., increased bone pain) of hormone-dependent disease (e.g., endometriosis, prostatic carcinoma, central precocious puberty) during the initial 1–2 weeks of therapy; generally subsides during continued therapy. Concomitant antiandrogen therapy (e.g., flutamide, nilutamide) has been used to decrease disease flare severity and improve overall response rates in patients with advanced prostate cancer.

Risk of spinal cord compression which may contribute to paralysis with or without fatal complications and/or ureteral obstruction (dysuria, hematuria) in men with prostate cancer. Monitor patients with metastatic vertebral lesions and/or urinary tract obstruction closely during initial therapy for temporary weakness or paresthesia of the lower limbs and/or worsening of urinary signs and symptoms. If spinal cord compression or urinary obstruction develops, institute standard treatment.

Use with extreme caution in patients with life-threatening disease in whom rapid symptomatic relief is necessary; exacerbation of signs and/or symptoms of the disease potentially may result in a rapid fatal outcome.

Hyperglycemia

Possible hyperglycemia and increased risk of diabetes in patients receiving GnRH agonists for treatment of prostate cancer. Studies evaluating risk of diabetes in women and children receiving GnRH agonists not performed to date.

Evaluate patients for risk factors for diabetes and carefully weigh benefits and risks of GnRH agonist therapy before selecting treatment for prostate cancer.

Periodically monitor blood glucose and/or HbA1c in patients receiving GnRH agonists for treatment of prostate cancer. Manage hyperglycemia or diabetes according to current standards of care.

Combination Therapy with Norethindrone Acetate

If leuprolide acetate suspension (Lupron Depot) is used in conjunction with norethindrone acetate for management of endometriosis, consider the precautions, cautions, and contraindications associated with the concomitant agent.

Noncompliance or Inadequate Dosage in Central Precocious Puberty.

Noncompliance with dosage regimen or use of inadequate dosage may result in inadequate control of the pubertal process including return of pubertal signs (e.g., menses, breast development, testicular growth). Long-term effects of inadequate control of gonadal (sex) steroid secretion are not known; further compromise of adult stature may occur.

Sensitivity Reactions

Hypersensitivity Reactions

Serious and occasionally fatal hypersensitivity reactions, including anaphylactoid or asthmatic process reported rarely. Rash, urticaria, and photosensitivity reactions also reported.

Leuprolide acetate injection contains benzyl alcohol as a preservative. Risk of local hypersensitivity reactions (e.g., erythema, induration at the injection site); use with caution in patients with known hypersensitivity to benzyl alcohol.

Major Toxicities

Pituitary Apoplexy

Pituitary apoplexy, a clinical syndrome resulting from infarction of the pituitary gland, reported rarely. Most cases occur within 2 weeks of the first dose, sometimes within the first hour. If manifestations (e.g., sudden headache, vomiting, visual changes, ophthalmoplegia, altered mental status, sometimes cardiovascular collapse) occur, immediate medical attention required. In most cases, pituitary adenoma diagnosed.

General Precautions

Musculoskeletal Effects

Decreases in bone mineral density (BMD) have been reported in men and women. For management of endometriosis in women, concurrent use of norethindrone acetate (5 mg daily) and calcium supplementation (1 g elemental calcium daily) reduces the drug-induced loss of BMD without compromising the efficacy of the drug.

Use in women for management of endometriosis for periods exceeding 6 months, for uterine leiomyomata for periods exceeding 3 months, or in patients with other risk factors for decreased BMD (e.g., chronic alcohol and/or tobacco use, strong family history of osteoporosis, chronic use of drugs that can reduce bone mass [e.g., corticosteroids, phenytoin]) may result in additional bone loss. Carefully weigh risks and benefits of therapy. In women with risk factors for decreased BMD, consider concomitant treatment with norethindrone acetate 5 mg daily.

Cardiovascular Effects

Adverse cardiovascular effects (e.g., hypotension, MI, DVT, PE, stroke, and TIA ) reported. Possible increased risk of certain cardiovascular diseases (e.g., MI, sudden cardiac death, stroke) in patients receiving GnRH agonists for treatment of prostate cancer. Studies evaluating risk of heart disease in women and children receiving GnRH agonists not performed to date.

Evaluate patients for cardiovascular risk factors and carefully weigh benefits and risks of GnRH agonist therapy before selecting treatment for prostate cancer.

Periodically monitor patients receiving GnRH agonists for treatment of prostate cancer for manifestations of cardiovascular disease; manage cardiovascular disease according to current standards of care.

Risk of prolonged QT interval associated with long-term androgen deprivation therapy. Carefully weigh benefits and risks of androgen deprivation therapy in patients with congenital long QT syndrome, electrolyte abnormalities, or CHF and in patients taking class IA (e.g., quinidine, procainamide) or class III (e.g., amiodarone, sotalol) antiarrhythmic agents.

Patient Monitoring in Prostate Cancer

Periodically determine serum testosterone and PSA concentrations to monitor therapeutic response. Precision of testosterone assays varies; consider specific type used.

Patient Monitoring in Central Precocious Puberty

Prior to initiation of therapy, perform baseline evaluations. (See Baseline Evaluation prior to Initiating Therapy under Dosage and Administration.)

Determine serum sex steroid concentrations and perform GnRH stimulation test 1–2 months after initiation of therapy and periodically (e.g., every 6 months thereafter) to monitor therapeutic response.

Inadequate dosage may lead to increased sex steroid concentrations; once a therapeutic dosage has been achieved, gonadotropin and sex steroid concentrations will decline to prepubertal concentrations.

Determine bone age every 6–12 months.

Fertility

Suppression of fertility, generally reversible in men and women may occur. Complete reversibility reported following up to 24 weeks of continuous therapy.

Risk of amenorrhea and other menstrual changes during continuous therapy.

Lipid Abnormalities

Risk of increased LDL-cholesterol/HDL-cholesterol ratio, increased total and LDL cholesterol and triglycerides, and decreased HDL-cholesterol in women receiving leuprolide acetate alone and in conjunction with norethindrone acetate for endometriosis.

Assess and manage cardiovascular risk factors, including cigarette smoking, before initiating combined therapy with leuprolide acetate in conjunction with norethindrone acetate for endometriosis.

Specific Populations

Pregnancy

Category X. (See Fetal/Neonatal Morbidity and Mortality and also see Contraindications, under Cautions.)

Lactation

Not known whether leuprolide is distributed into milk; use not recommended. (See Contraindications under Cautions.)

Pediatric Use

Safety and efficacy of leuprolide acetate injection and leuprolide acetate injectable suspension (7.5-, 11.25-, or 15-mg pediatric formulations of Lupron Depot-Ped) for uses other than treatment of central precocious puberty not established.

Safety and efficacy of the 3.75 mg (monthly), 11.25 mg (3-month), 22.5-mg (3-month), 30-mg (4-month), or 45-mg (6-month) formulations of leuprolide acetate injectable suspension (Lupron Depot) not established.

Safety and efficacy of the 7.5-, 22.5-, 30-, 45-mg formulations of leuprolide acetate injectable suspension (Eligard) not established.

Evaluate patients prior to initiating therapy and periodically during therapy to evaluate response to the drug. (See Baseline Evaluation prior to Initiating Therapy under Dosage and Administration and also see Patient Monitoring in Central Precocious Puberty under Cautions.)

Geriatric Use

Leuprolide acetate injection or leuprolide acetate injectable suspension (7.5-, 22.5-, 30-, 45-mg formulations of Eligard or Lupron Depot): Clinical studies for use in prostate cancer have been conducted principally in patients ≥65 years of age.

Leuprolide acetate injectable suspension (11.25- or 15-mg pediatric formulations of Lupron Depot-Ped): Safety and efficacy not established in those ≥65 years of age.

Leuprolide acetate injectable suspension (3.75- or 11.25-mg formulations of Lupron Depot): Safety and/or efficacy not evaluated in women >65 years of age; not indicated.

Hepatic Impairment

Pharmacokinetics not evaluated.

Renal Impairment

Pharmacokinetics not evaluated.

Common Adverse Effects

Men with metastatic prostate cancer (leuprolide acetate injection): Hot flushes (flashes), impotence, decreased libido, testicular atrophy, general pain, ECG changes/ischemia, peripheral edema, asthenia.

Men with metastatic prostate cancer (leuprolide acetate suspension [Lupron Depot]): Hot flushes, impotence, decreased libido, testicular atrophy, general pain, GI disorders, edema, injection site reaction, urinary disorder, respiratory disorder, infection, joint disorder, peripheral edema, asthenia, fatigue/lethargy.

Men with metastatic prostate cancer (leuprolide acetate injectable suspension [Eligard]): Injection site reactions (transient burning/stinging), hot flushes, malaise and fatigue, testicular atrophy.

Women with endometriosis: Hot flushes, amenorrhea, hypercholesterolemia, depression/emotional lability, dizziness, insomnia/sleep disorder, libido changes (e.g., decreased libido), asthenia, general pain, headache, nausea/vomiting, altered bowel function, weight gain/loss, acne, skin reactions, joint disorder, vaginitis.

Women with uterine leiomyomata: Hot flushes, amenorrhea, depression/emotional lability, asthenia, general pain, headache, joint disorder, vaginitis.

Children with precocious puberty: Injection site reaction (e.g., abscess), emotional lability, general pain, acne/seborrhea, headache, rash (e.g., erythema multiforme), vaginitis/bleeding/discharge, vasodilation.

Interactions for Leuprolide

No formal drug interaction studies to date.

Metabolism does not involve CYP isoenzymes; pharmacokinetic interaction unlikely with drugs metabolized by CYP isoenzymes.

Specific Drugs and Laboratory Tests

Drug or Test

Interaction

Comments

Antiandrogen (e.g., flutamide, bicalutamide, nilutamide)

Potential additive antineoplastic effects by producing complete androgen withdrawal

Used concomitantly in prostate cancer for additive therapeutic effect

Tests, diagnostic tests of pituitary gonadotropic and gonadal function

Possible erroneous results when diagnostic tests of pituitary gonadotropic and gonadal function obtained during treatment

Normal function usually restored 3 or 1–3 months after discontinuance of the injectable suspension (Lupron Depot) or injection, respectively

Leuprolide Pharmacokinetics

Absorption

Not active when administered orally.

Rapidly and well absorbed following sub-Q administration.

Peak plasma concentrations usually attained within 4 hours following IM administration of long-acting injectable suspension (Lupron Depot) in prostate cancer patients and healthy women.

Peak plasma concentrations usually attained 3.3–5 hours following sub-Q administration of long-acting injectable suspension (Eligard) in prostate cancer patients.

Following IM administration of the long-acting injectable suspension (Lupron Depot) or sub-Q administration of the long-acting injectable suspension (Eligard), the drug is released slowly and gradually from its biodegradable copolymer-containing vehicle.

Onset

Serum testosterone concentrations reach castrate levels 2–4 weeks following administration of leuprolide acetate injection (Lupron) or the long-acting injectable suspension (Lupron Depot).

Onset of estradiol suppression occurs 4–28 days following IM administration of a single 11.25-mg dose of the long-acting injectable suspension in healthy women; mean estradiol concentration is in the menopausal range 21 days following administration.

Duration

Peak plasma concentrations remain stable for approximately 2.5 weeks following IM administration of Lupron Depot 7.5-mg in prostate cancer patients, and then decline over the next several weeks.

Steady plasma concentrations persist for 12 or 16 weeks following IM administration of Lupron Depot 22.5- or 30-mg, respectively, in prostate cancer patients.

Steady plasma concentrations persist for 4–5 or 12 weeks following IM administration of Lupron Depot 3.75- or 11.25-mg, respectively, in healthy women.

Plasma concentrations decrease to trough levels 4 weeks following IM administration of Lupron Depot 7.5-, 11.25-, or 15-mg in children with central precocious puberty.

Steady plasma concentrations persist through the 1-, 3-, 4-, or 6-month dosing interval following IM administration of the 7.5-, 22.5-, 30-, or 45-mg long-acting injectable suspension (Eligard), respectively, in prostate cancer patients. No drug accumulation observed after repeated dosing.

Serum testosterone concentrations maintained at castration levels during chronic IM administration of the long-acting injectable suspension in prostate cancer patients.

Similar changes from baseline in estradiol serum concentration observed in women with endometriosis receiving 11.25- or 3.75-mg IM doses of the long-acting suspension (Lupron Depot) every 12 weeks or every 4 weeks, respectively, for 24 weeks.

Mean serum estradiol concentrations ranged from the menopausal to the early follicular range for 12 weeks following IM administration of a single 11.25-mg dose of the long-acting injectable suspension (Lupron Depot) in healthy women.

Distribution

Extent

Not known whether leuprolide crosses the placenta or is distributed into milk.

Plasma Protein Binding

Leuprolide acetate injection: 43–49%.

Elimination

Metabolism

Metabolized mainly by peptidase to several metabolites; major metabolite (M-I) is inactive.

Elimination Route

Following IM administration of leuprolide acetate injectable suspension (3.75 mg), <5% recovered in urine as parent drug and M-I metabolite.

Half-life

Approximately 3 hours following IV administration (based on a 2-compartment model).

Stability

Storage

Sub-Q

Injection

<25°C; do not freeze. Protect from light; store vial in carton until time of use.

Injectable Suspension (Eligard)

2–8°C.

Suspension in polymeric delivery system should not be stored for >30 minutes after mixing; discard if suspension not administered within 30 minutes.

IM

Injectable Suspension (Lupron Depot or Lupron Depot-Ped)

25°C (may be exposed to 15–30°C). If not used immediately after mixing, should be discarded.

Actions

  • A synthetic nonapeptide analog of GnRH; structural modifications result in increased potency (in terms of luteinizing hormone release) compared with GnRH.

  • A potent inhibitor of gonadotropin secretion and suppresser of ovarian and testicular steroidogenesis when given continuously; decreases release through down-regulation of GnRH receptors.

  • Initially, circulating levels of LH, FSH, testosterone, dihydrotestosterone (DHT) estrone and estradiol surge transiently. Following long-term administration (generally, 2–4 weeks after initiation of therapy), produces a sustained decrease in LH and FSH secretion and a marked reduction of testicular and ovarian steroidogenesis.

  • Reductions in serum testosterone concentrations in males during therapy are comparable to those achieved after surgical castration (i.e., <50 ng/dL). Testicular and prostatic atrophy may occur.

  • During continuous therapy, reduces serum estradiol concentrations in most premenopausal women to menopausal levels.

  • Induces reductions in myometrial and leiomyomal volumes; possibly from decreased secretion of somatotropin (growth hormone) and estrogen-dependent growth factors (e.g., insulin-like growth factor I, IGF-I).

  • Reduces gonadotropins in children with central precocious puberty and resultant depression of ovarian and testicular steroidogenesis may allow for normal physical and psychological growth and development. Effects appear to be reversible; pubertal development resumes following discontinuance of the drug.

Advice to Patients

  • Importance of providing patients or caregivers administering leuprolide acetate injection adequate oral and written instructions regarding proper administration methods (including aseptic technique), use of appropriate syringe (as supplied or low-dose insulin type), drug storage, and proper disposal of used needles and syringes.

  • Importance of strict compliance with prescribed regimen even when signs and/or symptoms of the disease improve.

  • Importance of informing patients with prostate cancer that serum testosterone concentrations may increase transiently after the initial dose.

  • Risk of worsening manifestations of disease, such as symptoms (e.g., bone pain, spinal cord injury, hematuria, urethral or bladder outlet obstruction) of prostate cancer, during initial weeks of therapy.

  • Importance of informing clinicians of persistent skin reactions (burning, itching, or swelling) at injection site.

  • Risk of anaphylactoid or other hypersensitivity reactions.

  • Risk of other adverse effects, including decrease in BMD, hot flashes, joint pain, back pain, fatigue, and impotence.

  • Risk of new or worsening symptoms of depression while receiving leuprolide therapy.

  • Risk of lipid abnormalities in women receiving leuprolide acetate alone or in combination with norethindrone acetate for endometriosis.

  • Importance of promptly reporting sudden onset of headache, vomiting, or visual changes to clinician.

  • Importance of women informing their clinician if regular menstruation persists. Women also should be advised that breakthrough bleeding or ovulation (with potential for conception) may occur if one or more successive doses of the drug are missed.

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.

  • Necessity of advising women not to breast-feed.

  • Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed; necessity for clinicians to advise women to avoid pregnancy during therapy and use nonhormonal contraceptive measures. Advise pregnant women of risk to the fetus.

  • Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Leuprolide Acetate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For injectable suspension, extended-release, for IM use

3.75 mg

Lupron Depot (available as prefilled dual-chambered syringes)

Abbott

7.5 mg

Lupron Depot (available as prefilled dual-chambered syringes)

Abbott

Lupron Depot-Ped (available as prefilled dual-chambered syringes)

Abbott

11.25 mg

Lupron Depot-Ped (available as prefilled dual-chambered syringes)

Abbott

Lupron Depot (available as prefilled dual-chambered syringes)

Abbott

15 mg

Lupron Depot-Ped (available as prefilled dual-chambered syringes)

Abbott

22.5 mg

Lupron Depot (available as prefilled dual-chambered syringes)

Abbott

30 mg

Lupron Depot (available as prefilled dual-chambered syringes)

Abbott

45 mg

Lupron Depot (available as prefilled dual-chambered syringes)

Abbott

For injectable suspension, extended-release, for subcutaneous use

7.5 mg

Eligard (available in a 2-syringe Atrigel Delivery System)

Sanofi-Aventis

22.5 mg

Eligard (available in a 2-syringe Atrigel Delivery System)

Sanofi-Aventis

30 mg

Eligard (available in a 2-syringe Atrigel Delivery System)

Sanofi-Aventis

45 mg

Eligard (available in a 2-syringe Atrigel Delivery System)

Sanofi-Aventis

Injection, for subcutaneous use

5 mg/mL

Leuprolide Acetate Injection

AHFS DI Essentials™. © Copyright 2021, Selected Revisions January 11, 2021. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

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