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Leuprolide (Monograph)

Brand names: Eligard, Lupron, Lupron Depot
Drug 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

Medically reviewed by Drugs.com on Jan 1, 2024. 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).1 2 3 80 81 99 100 116 155 156 180 187 190 191 192

Uses for Leuprolide

Prostate Cancer

Palliative treatment of advanced prostate cancer.1 2 3 4 5 27 32 33 34 35 36 37 38 39 40 43 57 63 66 96 100 101 111 112 113 114 121 125 180 187 190 192 201

First-line therapy alone or in combination with an antiandrogen (e.g., flutamide, bicalutamide, nilutamide) for prostate cancer.46 86 102 111 125 182 183 184 185 195

Treatment of locally confined (stage B2 or C)200 and metastatic (stage D2) prostate cancer;200 generally used in conjunction with an antiandrogen.102 111 125 200

Endometriosis

Palliative treatment of endometriosis (e.g., pain relief, reduction in endometriotic lesions [dysmenorrhea and pelvic pain, tenderness, and induration]).5 55 71 96 105 106 107 108 116 126 131 191 Experience with leuprolide has been limited to women ≥18 years of age.105 116 126 191

Used alone or in conjunction with norethindrone acetate (5 mg daily) for initial management of endometriosis.116 191

Used in conjunction with norethindrone acetate (5 mg daily) if symptoms recur after the initial course of therapy (retreatment).116 191 Retreatment with leuprolide alone is not recommended.116 191 (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;116 181 191 used in conjunction with iron therapy.116 181 191 Experience with leuprolide has been limited to women ≥18 years of age.116 181 191

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 children155 156 157 158 159 160 161 162 163 164 165 166 177 202 203 (designated an orphan drug by FDA for this use).179

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 characteristics155 156 157 159 160 177 203 and subsequent rapid advancement of height, height velocity, and/or bone age (e.g., ≥1 year more advanced than their chronologic age).155 156 157 159 160 161 162 163 164 165 177

Some clinicians also state that GnRH analog therapy is indicated in boys <8 years of age with a serum testosterone concentration >100 ng/dL157 177 and in girls with onset of menarche and recurrent menses at <9 years of age.177 178

GnRH analogs are considered the therapy of choice for this condition and generally have supplanted medroxyprogesterone in this form of precocity.155 156 157 158 159 160 161 162 163 164 165 166 177 202 203

GnRH analogs are ineffective as primary therapy in the treatment of GnRH-independent† [off-label] (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.157 158 169 170 171 172 173 174 177 178

Breast Cancer

Use of ovarian suppression in combination with endocrine therapy (i.e., anastrozole, exemestane, letrozole, tamoxifen)† [off-label] as adjuvant therapy in premenopausal women with early-stage hormone receptor-positive breast cancer† [off-label] may be considered a reasonable choice (accepted).10010 10011 10012 10013 10023 10026 10028

Leuprolide Dosage and Administration

General

Prostate Cancer

Uterine Leiomyomata

Precocious Puberty: Baseline Evaluation Prior to Initiating Therapy

Administration

Administer by IM injection100 101 116 155 180 187 190 191 or sub-Q injection.99 156 192 193 194

Leuprolide acetate injection and suspension (Lupron Depot) have comparable efficacy and safety in the treatment of advanced prostate cancer.100 101 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.101 121

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;100 101 116 155 180 187 once every 3 months as the 11.25- or 22.5-mg long-acting 3-month formulation;100 101 116 155 180 187 190 191 once every 4 months as the 30-mg long-acting 4-month formulation,100 101 116 155 180 187 190 or once every 24 weeks as the 45-mg long-acting 6-month formulation.190

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.180 187 190

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.116 191

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.155

Rotate injection sites periodically.100 101 116 155 156

Suspension is not intended for self-administration;104 administer under the supervision of a clinician.100 101 104 116 155 180 187 190 191

Reconstitution

Leuprolide acetate powder for injectable suspension (Lupron Depot) is available in a dual-chamber, disposable, single-use syringe;100 116 155 190 191 chamber 1 of the system contains leuprolide acetate lyophilized powder, and chamber 2 contains the sterile diluent supplied by the manufacturer.100 116 155 190 191

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.100 116 155 190 191

While keeping the syringe upright, gently mix to thoroughly disperse the particles and obtain a uniform milky suspension.100 116 155 190 191

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.100 116 155 190 191

Sub-Q Administration

Administer leuprolide acetate injection by sub-Q injection once daily.99 156 193 194

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.192

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).192 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).192

Rotate injection sites periodically.1 99 192 193 194

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.98 104 193

Reconstitution

Leuprolide acetate powder for injectable suspension (Eligard) is available in a single-use kit, containing 2 separate disposable syringes;192 syringe 1 of the system contains leuprolide acetate powder, and syringe 2 contains the polymeric (non-gelatin-containing) delivery system (Atrigel).192

Allow the kit to reach room temperature before reconstituting.192

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.192

Following reconstitution, administer within 30 minutes.192 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.192

Dosage

Available as leuprolide acetate; dosage of injection and suspension expressed in terms of the salt.1 100 116 155 156 180 187 190 191 192 193 194

Pediatric Patients

Central Precocious Puberty

Individualize dosage according to actual body weight;155 156 161 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).155 156

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.155 156 159

Prior to initiation of therapy, perform baseline evaluations.155 156 (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.155 156

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.155 156 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.155 156

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.155 158

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.155

Therapy usually is continued until fusion of the epiphyses157 or attainment of appropriate chronologic pubertal age (e.g., consideration made at 11 and 12 years of age in girls and boys, respectively).155 156 157

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.156 158 If total suppression of ovarian or testicular steroidogenesis is not achieved, titrate dosage upward by 10 mcg/kg daily to establish maintenance dosage.156

Adults

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

Usually, 1 mg daily.1 99

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.2 10 22 23 33

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.101 180 187 (See Endocrine Effects under Cautions.)

Therapy with Extended-release Suspension
IM

7.5 mg once monthly as the monthly formulation (Lupron Depot),100 101 or 22.5 mg every 12 weeks as the 3-month formulation (Lupron Depot 22.5 mg for 3-month administration),180 190 or 30 mg once every 16 weeks as the 4-month formulation (Lupron Depot 30 mg for 4-month administration),187 190 or 45 mg once every 24 weeks as the 6-month formulation (Lupron Depot 45 mg for 6-month administration).190

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.101

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.192

Endometriosis
Initial Treatment
IM

3.75 mg once monthly as the monthly formulation (Lupron Depot) for 6 consecutive months116 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.191 Administer with or without norethindrone acetate (5 mg daily).116 191

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).116 191

Assess BMD prior to therapy to ensure that values are within normal limits.116 191 (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.116 191 Administer in conjunction with oral norethindrone acetate (5 mg daily).116 191

Additional courses of treatment after a single 6-month retreatment course are not recommended.116 191

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.116

11.25 mg of the 3-month formulation (Lupron Depot-3 month 11.25 mg) as a single injection in conjunction with iron therapy.191 Use of the 3-month formulation recommended only when 3 months of hormonal suppression is necessary.191

If additional therapy is considered, assess BMD prior to therapy to ensure that values are within normal limits.116 191 (See Musculoskeletal Effects under Cautions.)

Early-stage Breast Cancer† [off-label]
IM

Dosage of 3.75 mg every 4 weeks has been used in combination with endocrine therapy† [off-label].10013 (See Breast Cancer under Uses.)

Prescribing Limits

Adults

Endometriosis
Initial Treatment
IM

Limit initial course of therapy to 6 months.116 191

Retreatment If Symptoms Recur after Initial Treatment
IM

Limit retreatment of symptom recurrence to 6 months; retreatment with leuprolide alone is not recommended.116 191

Additional courses of treatment after a single 6-month retreatment course are not recommended.116 191

Uterine Leiomyomata
IM

Lupron Depot 3.75 mg monthly formulation: Maximum 3 consecutive months of therapy recommended.116

Lupron Depot 11.25 mg (3-month formulation): A single injection of 11.25 mg recommended.191

Safety and efficacy of >6 months of therapy not evaluated.191

Detailed Leuprolide dosage information

Cautions for Leuprolide

Contraindications

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.1 100 155 156 180 187 190 191 192 193 194

Contraindicated in women who are or may become pregnant during therapy;1 100 116 116 155 156 180 187 190 191 192 193 194 exclude pregnancy before initiating therapy.116 191

Women of childbearing potential should avoid pregnancy and use an effective nonhormonal method of contraception during therapy.116 191 If used during pregnancy or patient becomes pregnant, discontinue and apprise of potential fetal hazard.1 100 116 156 180 187 190 191 192 193 194

Initial Worsening of Hormone-dependent Disease

Transient increases in serum testosterone (in men) or estrogen (in women) concentrations1 10 32 33 35 99 100 108 115 116 145 146 155 156 180 187 190 191 192 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.1 10 32 33 35 99 100 108 115 116 145 146 155 156 180 187 190 191 192 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.3 49 50 102 111 130

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.1 82 100 145 187 190 192 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.99 100 180 190 192 If spinal cord compression or urinary obstruction develops, institute standard treatment.100 192

Use with extreme caution in patients with life-threatening disease in whom rapid symptomatic relief is necessary;1 2 4 exacerbation of signs and/or symptoms of the disease potentially may result in a rapid fatal outcome.1 75 99 100

Hyperglycemia

Possible hyperglycemia and increased risk of diabetes in patients receiving GnRH agonists for treatment of prostate cancer.100 189 190 Studies evaluating risk of diabetes in women and children receiving GnRH agonists not performed to date.188

Evaluate patients for risk factors for diabetes and carefully weigh benefits and risks of GnRH agonist therapy before selecting treatment for prostate cancer.100 189

Periodically monitor blood glucose and/or HbA1c in patients receiving GnRH agonists for treatment of prostate cancer.189 190 Manage hyperglycemia or diabetes according to current standards of care.100 189 190

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.116 191

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).155 156 Long-term effects of inadequate control of gonadal (sex) steroid secretion are not known; further compromise of adult stature may occur.155 156

Sensitivity Reactions

Hypersensitivity Reactions

Serious and occasionally fatal hypersensitivity reactions, including anaphylactoid or asthmatic process reported rarely.99 100 116 155 156 187 190 191 192 194 Rash, urticaria, and photosensitivity reactions also reported.99 100 116 155 156 187 190 194

Leuprolide acetate injection contains benzyl alcohol as a preservative.1 99 156 193 194 Risk of local hypersensitivity reactions (e.g., erythema, induration at the injection site); use with caution in patients with known hypersensitivity to benzyl alcohol.1 156 193 194 99

Major Toxicities

Pituitary Apoplexy

Pituitary apoplexy, a clinical syndrome resulting from infarction of the pituitary gland, reported rarely.100 116 155 190 Most cases occur within 2 weeks of the first dose, sometimes within the first hour.100 116 155 190 If manifestations (e.g., sudden headache, vomiting, visual changes, ophthalmoplegia, altered mental status, sometimes cardiovascular collapse) occur, immediate medical attention required.100 116 155 190 In most cases, pituitary adenoma diagnosed.100 116 155 190

General Precautions

Musculoskeletal Effects

Decreases in bone mineral density (BMD) have been reported in men100 190 192 193 187 and women.105 106 108 110 116 126 127 128 129 131 133 134 135 191 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.116 191

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.116 191 Carefully weigh risks and benefits of therapy.116 191 In women with risk factors for decreased BMD, consider concomitant treatment with norethindrone acetate 5 mg daily.116 191

Cardiovascular Effects

Adverse cardiovascular effects (e.g., hypotension,100 116 190 MI,100 116 190 DVT,116 PE,100 116 190 stroke,116 and TIA116 ) 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.100 189 190 192 Studies evaluating risk of heart disease in women and children receiving GnRH agonists not performed to date.188

Evaluate patients for cardiovascular risk factors and carefully weigh benefits and risks of GnRH agonist therapy before selecting treatment for prostate cancer.100 189 190 192

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.100 189 190 192

Risk of prolonged QT interval associated with long-term androgen deprivation therapy.190 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.190

Patient Monitoring in Prostate Cancer

Periodically determine serum testosterone1 64 100 190 192 193 and PSA1 64 100 192 193 concentrations to monitor therapeutic response. Precision of testosterone assays varies; consider specific type used.180 187 190 192

Patient Monitoring in Central Precocious Puberty

Prior to initiation of therapy, perform baseline evaluations.155 156 (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 therapy155 156 159 and periodically (e.g., every 6 months thereafter)159 to monitor therapeutic response.155 156 159

Inadequate dosage may lead to increased sex steroid concentrations;155 156 once a therapeutic dosage has been achieved, gonadotropin and sex steroid concentrations will decline to prepubertal concentrations.155 156

Determine bone age every 6–12 months.155 156 159

Fertility

Suppression of fertility, generally reversible in men and women may occur.5 6 7 8 12 13 88 116 180 Complete reversibility reported following up to 24 weeks of continuous therapy.99 100 101 116 180

Risk of amenorrhea and other menstrual changes during continuous therapy.69 88 105 106 110 116 147

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.116 191

Assess and manage cardiovascular risk factors, including cigarette smoking, before initiating combined therapy with leuprolide acetate in conjunction with norethindrone acetate for endometriosis.116 191

Specific Populations

Pregnancy

Category X.1 100 116 155 156 180 187 190 191 192 (See Fetal/Neonatal Morbidity and Mortality and also see Contraindications, under Cautions.)

Lactation

Not known whether leuprolide is distributed into milk; use not recommended.116 155 156 190 191 193 (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.116 155

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.116 190 191

Safety and efficacy of the 7.5-, 22.5-, 30-, 45-mg formulations of leuprolide acetate injectable suspension (Eligard) not established.192

Evaluate patients prior to initiating therapy and periodically during therapy to evaluate response to the drug.155 156 159 (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.100 190 192 193

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.155

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.116 191

Hepatic Impairment

Pharmacokinetics not evaluated.1 100 116 155 180 187 190 191 192 193 194

Renal Impairment

Pharmacokinetics not evaluated.1 100 116 155 180 187 190 191 192 193 194

Common Adverse Effects

Men with metastatic prostate cancer (leuprolide acetate injection): Hot flushes (flashes),1 2 3 4 10 32 33 34 35 36 100 101 193 impotence,1 2 33 34 36 193 decreased libido,2 10 32 33 testicular atrophy,1 193 general pain,1 ECG changes/ischemia,1 193 peripheral edema,1 193 asthenia.1 193

Men with metastatic prostate cancer (leuprolide acetate suspension [Lupron Depot]): Hot flushes,100 121 180 187 190 impotence,100 180 190 decreased libido,100 180 testicular atrophy,100 180 190 general pain,100 180 187 190 GI disorders,100 187 190 edema,100 187 190 injection site reaction,180 187 190 urinary disorder,100 180 187 190 respiratory disorder,100 190 infection,100 joint disorder,180 187 190 peripheral edema,99 100 116 190 asthenia,100 190 fatigue/lethargy.190

Men with metastatic prostate cancer (leuprolide acetate injectable suspension [Eligard]): Injection site reactions (transient burning/stinging),192 hot flushes,192 malaise and fatigue,192 testicular atrophy.192

Women with endometriosis: Hot flushes, 105 106 108 116 121 126 amenorrhea,105 106 116 hypercholesterolemia,116 depression/emotional lability,116 dizziness,116 insomnia/sleep disorder,105 libido changes (e.g., decreased libido),116 asthenia,116 general pain,116 headache,116 nausea/vomiting,116 altered bowel function, weight gain/loss,116 acne,116 skin reactions,116 joint disorder,116 vaginitis.116

Women with uterine leiomyomata: Hot flushes,116 amenorrhea,116 depression/emotional lability,116 asthenia,116 general pain,116 headache,116 joint disorder,116 vaginitis.116

Children with precocious puberty: Injection site reaction (e.g., abscess),155 156 emotional lability,155 general pain,155 156 acne/seborrhea,155 156 headache,155 rash (e.g., erythema multiforme),155 156 vaginitis/bleeding/discharge,155 156 vasodilation.155

Drug Interactions

No formal drug interaction studies to date.100 116 155 156 192

Metabolism does not involve CYP isoenzymes;116 155 156 180 187 pharmacokinetic interaction unlikely with drugs metabolized by CYP isoenzymes.116 155 156 180 187

Specific Drugs and Laboratory Tests

Drug or Test

Interaction

Comments

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

Potential additive antineoplastic effects by producing complete androgen withdrawal49 102 111 125 140 141 142 143

Used concomitantly in prostate cancer for additive therapeutic effect195 200

Tests, diagnostic tests of pituitary gonadotropic and gonadal function

Possible erroneous results when diagnostic tests of pituitary gonadotropic and gonadal function obtained during treatment 100 116 155 190 191 192 193 194

Normal function usually restored 3 or 1–3 months after discontinuance of the injectable suspension (Lupron Depot) or injection, respectively100 116 155 190 191 193 194
Leuprolide drug interactions (more detail)

Leuprolide Pharmacokinetics

Absorption

Not active when administered orally.100 101 116 155 117 118 180 187 190 191

Rapidly and well absorbed following sub-Q administration.1 29 99

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.101 116 180

Peak plasma concentrations usually attained 3.3–5 hours following sub-Q administration of long-acting injectable suspension (Eligard) in prostate cancer patients.192

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.100 101 116 155 117 118 180 187 190 192

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).100 190 193

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;191 mean estradiol concentration is in the menopausal range 21 days following administration.191

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.101

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.180 187

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.116 191

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.155

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.192 No drug accumulation observed after repeated dosing.192

Serum testosterone concentrations maintained at castration levels during chronic IM administration of the long-acting injectable suspension in prostate cancer patients.100 101

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.191

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.191

Distribution

Extent

Not known whether leuprolide crosses the placenta or is distributed into milk.82 116 155 156 191 193

Plasma Protein Binding

Leuprolide acetate injection: 43–49%.1 100 116 155 180 187 191 192 194

Elimination

Metabolism

Metabolized mainly by peptidase to several metabolites;116 155 156 180 187 major metabolite (M-I) is inactive.1 116 191 192 194

Elimination Route

Following IM administration of leuprolide acetate injectable suspension (3.75 mg), <5% recovered in urine as parent drug and M-I metabolite.100 116 180 187

Half-life

Approximately 3 hours following IV administration (based on a 2-compartment model).1 82 100 180 187

Stability

Storage

Sub-Q

Injection

<25°C;1 193 do not freeze.1 193 Protect from light; store vial in carton until time of use.1 193

Injectable Suspension (Eligard)

2–8°C.192

Suspension in polymeric delivery system should not be stored for >30 minutes after mixing;192 discard if suspension not administered within 30 minutes.192

IM

Injectable Suspension (Lupron Depot or Lupron Depot-Ped)

25°C (may be exposed to 15–30°C). 100 116 155 190 191 If not used immediately after mixing, should be discarded.100 116 155 191

Actions

Advice to Patients

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 2024, Selected Revisions January 11, 2021. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

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

References

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95. Johnson DH, Linde R, Hainsworth JD et al. Effect of a luteinizing hormone releasing hormone agonist given during combination chemotherapy on posttherapy fertility in male patients with lymphoma: preliminary observations. Blood. 1985; 65:832-6. http://www.ncbi.nlm.nih.gov/pubmed/3884062?dopt=AbstractPlus

96. Hammond CB, Ory SJ. Diagnostic and therapeutic uses of gonadotropin-releasing hormone. Arch Intern Med. 1985; 145:1690-7. http://www.ncbi.nlm.nih.gov/pubmed/2862854?dopt=AbstractPlus

97. Laue L, Comite F, Hench K et al. Precocious puberty associated with neurofibromatosis and optic gliomas: treatment with luteinizing hormone releasing hormone analogue. Am J Dis Child. 1985; 139:1097-1100. http://www.ncbi.nlm.nih.gov/pubmed/3933329?dopt=AbstractPlus

98. TAP Pharmaceuticals. Lupron information for pharmacists. Chicago, IL; 1985 Nov.

99. TAP Pharmaceuticals. Lupron (leuprolide acetate injection) prescribing information. Deerfield, IL; 1993 Aug.

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103. MacLeod TL, Eisen A, Sussmar GL. Anaphylactic reaction to synthetic luteinizing hormone-releasing hormone. Fertil Steril. 1987; 48:500-2. http://www.ncbi.nlm.nih.gov/pubmed/3305090?dopt=AbstractPlus

104. Clarke CB (TAP Pharmaceuticals, North Chicago, IL): personal communication; 1989 Aug and 1990 Jan.

105. Dlugi AM, Miller JD, Knittle J et al. Lupron depot (leuprolide acetate for depot suspension) in the treatment of endometriosis: a randomized, placebo-controlled, double-blind study. Lupron Study Group. Fertil Steril. 1990; 54:419-27. http://www.ncbi.nlm.nih.gov/pubmed/2118858?dopt=AbstractPlus

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10026. Perrone F, De Laurentiis M, De Placido S et al. Adjuvant zoledronic acid and letrozole plus ovarian function suppression in premenopausal breast cancer: HOBOE phase 3 randomised trial. Eur J Cancer. 2019; 118:178-186. http://www.ncbi.nlm.nih.gov/pubmed/31164265?dopt=AbstractPlus

10027. Chlebowski RT, Pan K, Col NF. Ovarian suppression in combination endocrine adjuvant therapy in premenopausal women with early breast cancer. Breast Cancer Res Treat. 2017; 161:185-190. http://www.ncbi.nlm.nih.gov/pubmed/27785653?dopt=AbstractPlus

10028. AHFS final determination of medical acceptance: Off-label use of endocrine therapy in combination with ovarian suppression for the adjuvant treatment of early-stage hormone receptor-positive breast cancer in premenopausal women. Published January 4, 2021.

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