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Leuprolide Acetate

Class: Antineoplastic Agents
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, Viadur

Special Alerts:

[Posted 10/20/2010] ISSUE: Gonadotropin-Releasing Hormone (GnRH) agonists will have new safety information added to the Warnings and Precautions section of the drug labels. This new information warns about increased risk of diabetes and certain cardiovascular diseases (heart attack, sudden cardiac death, stroke) in men receiving these medications for the treatment of prostate cancer.

BACKGROUND: GnRH agonists are approved to treat the symptoms (palliative treatment) of advanced prostate cancer. The benefits of GnRH agonist use for earlier stages of prostate cancer that have not spread (non-metastatic prostate cancer) have not been established. FDA’s notification to manufacturers of GnRH agonists to add this safety information is based on the Agency’s review of several published studies. Most of the studies reviewed by FDA reported small but statistically significant increased risks of diabetes and/or cardiovascular events in patients receiving GnRH agonists.

RECOMMENDATIONS: Healthcare professionals should evaluate patients for risk factors for these diseases and carefully weigh the benefits and risks of using GnRH agonists before determining appropriate treatment for prostate cancer. Patients who are receiving treatment with GnRH agonists should undergo periodic monitoring of blood glucose and/or glycosylated hemoglobin (HbA1c). Healthcare professionals should also monitor patients for signs and symptoms suggestive of development of cardiovascular disease and manage according to current clinical practice. For more information visit the FDA website at: and .

[Posted 05/03/2010] FDA notified healthcare professionals and patients of FDA’s preliminary and ongoing review which suggests an increase in the risk of diabetes and certain cardiovascular diseases in men treated with GnRH agonists, drugs that suppress the production of testosterone, a hormone that is involved in the growth of prostate cancer.

Most of the studies reviewed by FDA reported small, but statistically significant increased risks of diabetes and/or cardiovascular events in patients receiving GnRH agonists. FDA’s review is ongoing and the agency has not made any conclusions about GnRH agonists and whether they increase the risk of diabetes and cardiovascular disease in patients receiving these medications for prostate cancer.

Healthcare professionals and patients should be aware of these potential safety issues and carefully weigh the benefits and risks of GnRH agonists when determining treatment choices. FDA recommends that patients receiving GnRH agonists should be monitored for development of diabetes and cardiovascular disease. Patients should not stop their treatment with GnRH agonists unless told to do so by their healthcare professional.

Some GnRH agonists are also used in women and in children for other indications than those above. There are no known comparable studies that have evaluated the risk of diabetes and heart disease in women and children taking GnRH agonists. For more information visit the FDA website at: and .

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 ^p ^q ^r ^s ^t

Uses for Leuprolide Acetate

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

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 ^p ^q ^r ^s ^t

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 ^j

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

Endometriosis

Palliative treatment of endometriosis (e.g., pain relief, reduction in endometriotic lesions).⁵ ⁵⁵ ⁷¹ ⁹⁶ ¹⁰⁵ ¹⁰⁶ ¹⁰⁷ ¹⁰⁸ ¹¹⁶ ¹²⁶ ¹³¹ ^f Experience with leuprolide has been limited to women ≥18 years of age.¹⁰⁵ ¹¹⁶ ¹²⁶ ^f

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

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

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 (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 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

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.¹⁵⁷ ¹⁵⁸ ¹⁶⁹ ¹⁷⁰ ¹⁷¹ ¹⁷² ¹⁷³ ¹⁷⁴ ¹⁷⁷ ¹⁷⁸

Breast Cancer

Has been used in the treatment of breast cancer† in premenopausal and postmenopausal women. ²⁷ ⁵² ⁶⁹ ⁸⁷ ⁸⁹ ⁹⁶ ¹⁰⁹ ^u ^v ^w

The role of GnRH analogs in the treatment of breast cancer† remains to be elucidated but currently is being studied.⁸⁷ ⁸⁹ ^u ^v ^w

Pending further accumulation of data,⁸⁵ ⁸⁷ many clinicians currently recommend that leuprolide be limited to use in premenopausal women with breast cancer†.⁸⁷

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

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.¹¹⁶ ^f
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.^f
Prior to initiating leuprolide therapy, consider 1-month trial of iron therapy alone, since some patients may respond adequately to iron alone.¹¹⁶ ¹⁸¹ ^f

Precocious Puberty

Evaluate bone age for advancement every 6–12 months.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

Baseline Evaluation prior to Initiating Therapy

Measure height and weight.¹⁵⁵ ¹⁵⁶
Determine serum testosterone or estrogen concentrations in boys or girls, respectively.¹⁵⁵ ¹⁵⁶
Determine adrenal steroid and β-human chorionic gonadotropin concentrations to rule out congenital adrenal hyperplasia and chorionic gonadotropin secreting tumors, respectively.¹⁵⁵ ¹⁵⁶
Perform pelvic, adrenal, or testicular ultrasound examination to rule out steroid secreting tumors and cranial CT to rule out intracranial tumors.¹⁵⁵ ¹⁵⁶

Administration

Administer by IM injection,¹⁰⁰ ¹⁰¹ ¹¹⁶ ¹⁵⁵ ¹⁸⁰ ¹⁸⁷ sub-Q injection,⁹⁹ ¹⁵⁶ ^q ^r ^s ^t or sub-Q insertion.^p

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 a 3.75- or 7.5-mg depot 1-month formulation;¹⁰⁰ ¹⁰¹ ¹¹⁶ ¹⁵⁵ ¹⁸⁰ ¹⁸⁷ ^b ^e once every 3 months as 11.25- or 22.5-mg long-acting 3-month formulation;¹⁰⁰ ¹⁰¹ ¹¹⁶ ¹⁵⁵ ¹⁸⁰ ¹⁸⁷ ^c ^f or once every 4 months as a 30-mg long-acting 4-month formulation.¹⁰⁰ ¹⁰¹ ¹¹⁶ ¹⁵⁵ ¹⁸⁰ ¹⁸⁷ ^d

Release characteristics of a fractional dose of the 22.5-mg (3-month) or 30-mg (4-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

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 ^f

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 formulation¹⁰⁰ ¹⁰¹ ¹¹⁶ ¹⁵⁵ ¹⁸⁰ ¹⁸⁷ ^b ^e

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

Reconstitution

Leuprolide acetate powder for injectable suspension (Lupron Depot) is available in a dual-chamber, disposable, single-use syringe;¹⁸⁷ chamber 1 of the system contains leuprolide acetate lyophilized powder, and chamber 2 contains the sterile diluent supplied by the manufacturer.¹⁸⁷

Reconstitute dual-chamber, disposable, single-use syringes containing 3.75, 7.5, 11.25, 15, 22.5, or 30 mg of leuprolide acetate extended-release for injectable suspension with the accompanying diluent in accordance with the instructions provided by the manufacturer.¹⁸⁷ ^b ^c ^e

While keeping the syringe upright, gently mix to thoroughly disperse the particles and obtain a uniform milky suspension.¹⁸⁷ ^b ^c ^e

Following reconstitution, immediately inject entire contents of the syringe to provide a 3.75-, 7.5-, 11.25-, 15-, 22.5-, or 30-mg dose, depending on the labeled concentration of the syringe used.¹⁸⁷ ^b ^c ^e

Sub-Q Administration

Administer leuprolide acetate injection by sub-Q injection once daily.⁹⁹ ¹⁵⁶ ^a

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.^q ^r ^s ^t

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).^q ^r ^s ^t 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).^q ^r ^s ^t

Rotate injection sites periodically.¹ ⁹⁹ ^q ^r ^s ^t

When substitution of another syringe for the one provided by the manufacturer for use with leuprolide acetate injection is required, a 0.5-mL disposable, low-dose, U-100 insulin syringe is the only syringe that should be used.⁹⁸ ¹⁰⁴

Administer leuprolide acetate (Viadur) as an implant surgically inserted sub-Q in inner aspect of upper arm once every 12 months.^p

After removing old implant, insert new implant through the same incision site or the contralateral arm.^p

Consult manufacturer’s labeling for proper methods of inserting and removing implants.^p

Reconstitution

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

Allow the kit to reach room temperature before reconstituting.^q ^r ^s ^t

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.^q ^r ^s ^t

Following reconstitution, administer within 30 minutes.^q ^r ^s ^t 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.^q ^r ^s ^t

Dosage

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Available as leuprolide acetate; dosage of injection and suspension expressed in terms of the salt, and dosage of implant expressed in terms of leuprolide.¹ ¹¹⁶ ¹⁵⁵ ¹⁵⁶ ¹⁸⁰ ¹⁸⁷ ^f ^p ^q ^r ^s ^t

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

7.5 mg once monthly as the monthly formulation (Lupron Depot),¹⁰⁰ ¹⁰¹ or 22.5 mg every 3 months (84 days) as the 3-month formulation (Lupron Depot-3 month 22.5 mg),¹⁸⁰ or 30 mg once every 4 months (16 weeks) as the 4-month formulation (Lupron Depot-4 month 30 mg).¹⁸⁷

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,^q or 22.5 mg once every 3 months as the 3-month formulation,^r or 30 mg once every 4 months as the 4-month formulation,^s or 45 mg once every 6 months as the 6-month formulation.^t

Therapy with Leuprolide Acetate (Viadur) Implant

Sub-Q

One 65-mg implant every 12 months.^p

One implant delivers 120 mcg of leuprolide acetate daily for 12 months.^p

Remove implant 12 months after insertion.^p At time of implant removal, may insert another implant to continue therapy.^p

Endometriosis

Initial Treatment

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.^f Administer with or without norethindrone acetate (5 mg daily).¹¹⁶

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.¹¹⁶ ^e ^f

Assess BMD prior to therapy to ensure that values are within normal limits.¹¹⁶ ^f (See Musculoskeletal Effects under Cautions.)

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 ^f Administer in conjunction with oral norethindrone acetate (5 mg daily).¹¹⁶ ^f

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

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.^f Use of the 3-month formulation recommended only when 3 months of hormonal suppression is necessary.^f

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

Prescribing Limits

Adults

Endometriosis

Initial Treatment

Limit initial course of therapy to 6 months.^e ^f

Retreatment If Symptoms Recur after Initial Treatment

Limit retreatment of symptom recurrence to 6 months.^e ^f

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

Uterine Leiomyomata

IM

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

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

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

Cautions for Leuprolide Acetate

Contraindications

Known hypersensitivity to GnRH, GnRH analogs, or any ingredient in the respective formulations.¹ ¹⁰⁰ ¹¹⁶ ¹⁵⁵ ¹⁵⁵ ¹⁵⁶ ¹⁸⁰ ¹⁸⁷ ^p ^q ^r ^s ^t
Known or suspected pregnancy.¹¹⁶ ¹⁵⁵ ¹⁵⁶ ¹⁸⁰ ¹⁸⁷ (See Fetal/Neonatal Morbidity and Mortality under Cautions.)
Abnormal vaginal bleeding of unknown etiology.¹¹⁶ ^f
The 30 mg (4-month) formulation of leuprolide acetate injectable suspension (Lupron Depot) should not be used in women.¹⁸⁷
Formulations of leuprolide acetate injectable suspension (Eligard) and leuprolide acetate implant (Viadur) are contraindicated in women and children.^p ^q ^r ^s ^t

Warnings/Precautions

Warnings

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm and spontaneous abortion; teratogenicity, fetotoxicity, and fetolethality demonstrated in animals.¹ ¹⁰⁰ ¹⁵⁵ ¹⁵⁶ ¹⁸⁰ ¹⁸⁷ ^f ^p ^q ^r ^s ^t Leuprolide acetate injection and injectable suspension are contraindicated in women who are or may become pregnant during therapy;¹ ¹⁰⁰ ¹¹⁶ ¹¹⁶ ¹⁵⁵ ¹⁵⁶ ¹⁸⁰ ¹⁸⁷ ^f exclude pregnancy before initiating therapy.¹¹⁶ ^f

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

Endocrine Effects

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

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 ^f ^p ^q ^r ^s ^t 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 ^f ^p ^q ^r ^s ^t 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 ⁸² ¹⁴⁵ ¹⁸⁷ ^a ^q ^r ^s ^t 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 ^q ^r ^s ^t If spinal cord compression or renal impairment develops, institute standard treatment.¹⁸⁷ ^b ^p ^q ^r ^s ^t

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

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.^e ^f

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.⁹⁹ ¹⁵⁶ ¹⁸⁷ ^e ^b ^c ^e ^f ^g ^h Rash, urticaria, and photosensitivity reactions also reported.⁹⁹ ¹⁵⁶ ¹⁸⁷ ^b ^e ^g ^h

Leuprolide acetate injection contains benzyl alcohol as a preservative.¹ ⁹⁹ ¹⁵⁶ 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 ⁹⁹ ¹⁵⁶ ¹ ¹⁵⁶

General Precautions

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Musculoskeletal Effects

Decreases in bone mineral density (BMD) have been reported in men^a ^b ^c ^g ¹⁸⁷ ^p ^q ^r ^s ^t and women.¹⁰⁵ ¹⁰⁶ ¹⁰⁸ ¹¹⁰ ¹¹⁶ ¹²⁶ ¹²⁷ ¹²⁸ ¹²⁹ ¹³¹ ¹³³ ¹³⁴ ¹³⁵ ^e ^f 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.^e ^f

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.^e ^f Carefully weigh the risks and benefits of therapy.¹¹⁶

Patient Monitoring in Prostate Cancer

Periodically determine serum testosterone and PSA concentrations to monitor therapeutic response.¹ ⁶⁴ ¹⁸⁰ ¹⁸⁷ ^p ^q ^r ^s ^t Precision of testosterone assays vary; consider specific type used.¹⁸⁰ ¹⁸⁷ ^p ^q ^r ^s ^t

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

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.^e ^f

Assess cardiovascular risk factors before initiating combined therapy with leuprolide acetate in conjunction with norethindrone acetate for endometriosis.^e ^f

Implant Considerations

Implant insertion or removal is a surgical procedure.^p Carefully follow recommended procedures for insertion and removal of implant to minimize potential for complications or for implant expulsion.^p

Implants are radio-opaque (visible on radiographs) and are not affected by x-rays.^p If implant is not palpable, may use radiological imaging to locate.^p

Implants are nonferromagnetic and are not affected by magnetic resonance imaging (MRI);^p slight image distortion around the implant may occur during MRI procedures.^p

Specific Populations

Pregnancy

Category X.¹ ¹⁰⁰ ¹¹⁶ ¹⁵⁵ ¹⁵⁶ ¹⁸⁰ ¹⁸⁷ ^f ^p ^q ^r ^s ^t (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 ^a ^e ^f (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), or 30-mg (4-month) formulations of leuprolide acetate injectable suspension (Lupron Depot) not established.^c ^e ^f

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

Leuprolide acetate implant contraindicated in pediatric patients.^p (See Contraindications under Cautions.)

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, leuprolide acetate injectable suspension (7.5-, 22.5-, 30-, 45-mg formulations of Eligard) or implant: Clinical studies for use in prostate cancer have been conducted principally in patients ≥65 years of age.^a ^p ^q ^r ^s ^t

Leuprolide acetate injectable suspension (7.5-, 22.5-, 30-mg formulations of Lupron Depot): Safety and/or efficacy in those ≥65 years of age similar to that in younger adults.^b ^c ^d

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.^h

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.^e ^f

Hepatic Impairment

Pharmacokinetics not evaluated.¹ ¹¹⁶ ¹⁸⁰ ¹⁸⁷ ^b ^f ^g ^h ^p ^q ^r ^s ^t

Renal Impairment

Pharmacokinetics not evaluated.¹ ¹¹⁶ ¹⁸⁰ ¹⁸⁷ ^b ^f ^g ^h ^p ^q ^r ^s ^t

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 impotence,¹ ² ³³ ³⁴ ³⁶ decreased libido,² ¹⁰ ³² ³³ testicular atrophy,¹ general pain,¹ ECG changes/ischemia,¹ peripheral edema,¹ asthenia.¹

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

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

Men with metastatic prostate cancer (leuprolide acetate implant): Local or insertion site reactions (e.g., bruising, burning), hot flushes, asthenia.^p

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

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

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

Interactions for Leuprolide Acetate

No formal drug interaction studies to date.¹⁰⁰ ¹⁵⁵ ¹⁵⁶ ^p ^q ^r ^s ^t

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 effect^j ^k
Tests, diagnostic tests of pituitary gonadotropic and gonadal function	Possible erroneous results when diagnostic tests of pituitary gonadotropic and gonadal function obtained during treatment ^b ^c ^d ^e ^f ^g ^h ^p ^q ^r ^s ^t	Normal function usually restored 3 or 1–3 months after discontinuance of the injectable suspension (Lupron Depot) or injection, respectively^a ^b ^c ^d ^e ^f ^g ^h

Leuprolide Acetate Pharmacokinetics

Absorption

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

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.¹⁰⁰ ¹⁰¹ ¹¹⁶ ¹⁸⁰ ^b ^c ^d ^e ^f ^h

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

Peak serum concentrations occur 4 hours following sub-Q insertion of implant (Viadur).^p

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 ^q ^r ^s ^t

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).^a ^b ^c ^d

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

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.^e ^f

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.^q ^r ^s ^t No drug accumulation observed after repeated dosing.^q ^r ^s ^t

Steady-state serum concentrations persist for 12 months following sub-Q insertion of implant (Viadur).^p

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

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.^f

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.^f

Distribution

Extent

Not known whether leuprolide crosses the placenta or is distributed into milk.⁸² ¹¹⁶ ¹⁵⁵ ¹⁵⁶ ^a ^e ^f

Plasma Protein Binding

Leuprolide acetate injection: 43–49%.¹ ¹¹⁶ ¹⁸⁰ ¹⁸⁷ ^f ^g ^h ^p ^q ^r ^s ^t

Elimination

Metabolism

Metabolized mainly by peptidase to several metabolites;¹¹⁶ ¹⁵⁵ ¹⁵⁶ ¹⁸⁰ ¹⁸⁷ major metabolite (M-I) is inactive.¹ ¹¹⁶ ^f ^g ^p ^q ^r ^s ^t

Elimination Route

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

Half-life

Approximately 3 hours following IV administration (based on a 2-compartment model).¹ ⁸² ¹⁸⁰ ¹⁸⁷ ^b ^f ^g ^p ^q ^r ^s ^t

Stability

Storage

Sub-Q

Injection

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

Injectable Suspension (Eligard)

2–8°C.^q ^r ^s ^t

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

Implant

25°C (may be exposed to 15–30°C).^p

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.^b ^b ^c ^d ^h

ActionsActions

A synthetic nonapeptide analog of GnRH; ¹ ² ³ ⁸⁰ ⁸¹ ⁹⁹ ¹⁰⁰ ¹¹⁶ ¹⁵⁵ ¹⁵⁶ structural modifications result in increased potency (in terms of luteinizing hormone release) compared with GnRH.¹ ³ ⁴ ⁸ ¹⁵⁵ ¹⁵⁶
A potent inhibitor of gonadotropin secretion and suppresser of ovarian and testicular steroidogenesis when given continuously;¹ ² ⁵ ⁷ ⁸ ⁹ ¹⁰ ¹¹ ¹² ¹³ ¹⁵ ⁶⁹ ⁸³ ⁸⁷ ¹⁰⁵ ¹⁰⁵ ¹⁰⁶ ¹⁰⁹ ¹¹⁰ ¹¹⁶ ¹³¹ ¹⁵⁵ ¹⁵⁶ ¹⁵⁷ ¹⁵⁸ ¹⁵⁹ ¹⁷⁷ ^p ^q ^r ^s ^t decreases release through down-regulation of GnRH receptors.¹ ² ⁶ ⁷ ¹⁰ ¹¹ ¹² ¹³ ¹⁵ ¹⁶ ¹¹ ¹² ¹³ ¹⁴ ¹³ ¹⁹ ²⁴ ¹⁰⁵ ¹⁰⁶ ¹¹⁰ ¹¹⁶ ¹⁵⁷ ¹⁰⁹ ¹⁵⁸ ¹⁵⁹ ¹⁷⁷
Initially, circulating levels of LH, FSH, testosterone, dihydrotestosterone (DHT) estrone and estradiol surge transiently.¹ ¹⁰ ¹² ¹⁵ ²⁴ ^p ^q ^r ^s ^t 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.¹ ² ³ ⁴ ⁵ ⁷ ¹⁰ ¹¹ ¹² ¹³ ¹⁵ ²² ²³ ⁶⁹ ⁸⁹ ¹⁰⁰ ¹⁰⁵ ¹⁰⁶ ¹⁰⁹ ¹¹⁰ ¹¹⁶ ¹⁵⁵ ¹⁵⁶ ¹⁵⁷ ^p ^q ^r ^s ^t
Reductions in serum testosterone concentrations in males during therapy are comparable to those achieved after surgical castration (i.e., <50 ng/dL).¹ ³ ¹² ⁴⁷ ¹⁰⁰ ¹⁰¹ ^p ^q ^r ^s ^t Testicular and prostatic atrophy may occur.² ¹² ¹³ ²⁴
During continuous therapy, reduces serum estradiol concentrations in most premenopausal women to menopausal levels.¹ ⁵ ⁶⁹ ⁸⁹ ¹⁰⁵ ¹⁰⁶ ¹⁰⁹ ¹¹⁰ ¹¹⁶
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).¹³⁷ ¹³⁸
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.¹⁵⁵ ¹⁵⁶ ¹⁵⁷ ¹⁵⁸ ¹⁵⁹ ¹⁶⁴ ¹⁶⁷ ¹⁶⁸ ¹⁷⁷ Effects appear to be reversible; pubertal development resumes following discontinuance of the drug.¹⁵⁵ ¹⁵⁶ ¹⁵⁷ ¹⁵⁸ ¹⁵⁹ ¹⁷⁷

Advice to Patients

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Provide patient or their caregiver with a copy of manufacturer’s patient information.¹ ^l ^m ⁿ ^o ^p
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.¹ ¹⁵⁶
Importance of strict compliance with prescribed regimen even when signs and/or symptoms of the disease improve.⁶⁵ ¹ ¹⁵⁵ ¹⁵⁶
Risk of worsening manifestations of disease during initial weeks of therapy.¹
Importance of informing clinicians of persistent skin reactions (burning, itching, or swelling) at injection site.¹
Risk of anaphylactoid or other hypersensitivity reactions.¹
Risk of other adverse effects, including decrease in BMD.¹⁶⁶ ⁿ ^o
Importance of women informing their clinician if regular menstruation persists.¹⁶⁶ ^e ^f 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.¹⁶⁶ ^e ^f
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.¹
Necessity of advising women not to breast-feed.¹⁶⁶ ^f
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.¹¹⁶ ¹⁶⁶ ^e ^f ⁿ ^o
Importance of protecting the arm in which the implant was inserted from moisture for 24 hours, refraining from heavy lifting or physical activity for 48 hours, and avoiding bumping the site for a few days after implant insertion.^p Inform clinician if unusual bleeding, redness, or pain occur or if local reactions (itching, redness) persist for >2 weeks at the implant insertion site.^p
Importance of informing patients of other important precautionary information.¹ (See Cautions.)

Preparations

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

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 disposable prefilled dual-chambered syringes with diluent in second chamber)	TAP Pharmaceuticals
		7.5 mg	Lupron Depot (available as disposable prefilled dual-chambered syringes with diluent in second chamber)	TAP Pharmaceuticals
			Lupron Depot-Ped (available as disposable prefilled dual-chambered syringes with diluent in second chamber)	TAP Pharmaceuticals
		11.25 mg	Lupron Depot-Ped (available as disposable prefilled dual-chambered syringes with diluent in second chamber)	TAP Pharmaceuticals
			Lupron Depot–3 Month (available as disposable prefilled dual-chambered syringes with diluent in second chamber)	TAP Pharmaceuticals
		15 mg	Lupron Depot-Ped (available as disposable prefilled dual-chambered syringes with diluent in second chamber)	TAP Pharmaceuticals
		22.5 mg	Lupron Depot–3 Month (available as disposable prefilled dual-chambered syringes with diluent in second chamber)	TAP Pharmaceuticals
		30 mg	Lupron Depot–4 Month (available as disposable prefilled dual-chambered syringes with diluent in second chamber)	TAP Pharmaceuticals
	For injectable suspension, extended-release, for subcutaneous use	7.5 mg	Eligard (available with Atrigel Delivery System extended-release prefilled syringe with needle)	Sanofi-Aventis
		22.5 mg	Eligard (available with Atrigel Delivery System extended-release prefilled syringe with needle)	Sanofi-Aventis
		30 mg	Eligard (available with Atrigel Delivery System extended-release prefilled syringe with needle)	Sanofi-Aventis
		45 mg	Eligard (available with Atrigel Delivery System extended-release prefilled syringe with needle)	Sanofi-Aventis
	Implant	72 mg	Viadur (available as kit with bandages, drapes, 10 mL lidocaine hydrochloride 2%, needles, syringe, surgical instruments, swabsease prefilled syringe with needle)	Bayer
Parenteral	Injection, for subcutaneous use	5 mg/mL	Leuprolide Acetate Injection (available as 14-day patient administration kit with multiple-dose vial, 14 disposable syringes and swabs and 6 multiple-dose vials)	Eon, Teva
			Lupron (with benzyl alcohol 9 mg/mL; available as 14-day patient administration kit with multiple-dose vial, 14 disposable syringes and swabs and 6 multiple-dose vials; with disposable syringes)	TAP Pharmaceuticals
			Lupron for Pediatric Use (with benzyl alcohol 9 mg/mL; with disposable syringes)	TAP Pharmaceuticals

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 04/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Leuprolide Acetate 1MG/0.2ML Kit (SANDOZ): 1/$339.98 or 3/$959.93

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions December 01, 2010. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

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

References

1. TAP Pharmaceuticals. Lupron (leuprolide acetate) prescribing information. Chicago, IL; 1998 Jul.

2. Smith JA Jr. Androgen suppression by a gonadotropin releasing hormone analogue in patients with metastatic carcinoma of the prostate. J Urol. 1984; 131:1110-2. [IDIS 186498] [PubMed 6427478]

3. The Leuprolide Study Group. Leuprolide versus diethylstilbestrol for metastatic prostate cancer. N Engl J Med. 1984; 311:1281-6. [IDIS 192417] [PubMed 6436700]

4. Soloway MS. Newer methods of hormonal therapy for prostate cancer. Urology. 1984; 24(Suppl):30-40. [IDIS 198972] [PubMed 6437034]

5. Cutler GB, Hoffman AR, Swerdloff RS et al. Therapeutic applications of luteinizing-hormone-releasing hormone and its analogs. Ann Intern Med. 1985; 102:643-57. [IDIS 199422] [PubMed 3920942]

6. Heber D, Dodson R, Peterson M et al. Counteractive effects of agonistic and antagonistic gonadotropin-releasing hormone analogs on spermatogenesis: sites of action. Fertil Steril. 1984; 41:309-13. [PubMed 6421624]

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8. Vilchez-Martinez JA, Pedroza E, Coy DH et al. Prolonged release of LH and FSH and depletion of pituitary gonadotropin content after administration of [d-leu⁶, desgly-NH₂¹⁰]-LH-RH ethylamide¹ (39686). Proc Soc Exp Biol Med. 1977; 154:427-30. [PubMed 322156]

9. Vilchez-Martinez JA, Coy DH, Arimura A et al. Synthesis and biological properties of [Leu-6]-LH-RH and [d-leu-6,desgly-NH₂¹⁰]-LH-RH ethylamide. Biochem Biophys Res Commun. 1974; 59:1226-32. [PubMed 4607145]

10. Vance MA, Smith JA Jr. Endocrine and clinical effects of leuprolide in prostatic cancer. Clin Pharmacol Ther. 1984; 36:350-4. [IDIS 191246] [PubMed 6432399]

11. Bambino TH, Schreiber JR, Hsueh AJW. Gonadotropin-releasing hormone and its agonist inhibit testicular luteinizing hormone receptor and steroidogenesis in immature and adult hypophysectomized rats. Endocrinology. 1980; 107:908-17. [PubMed 6250797]

12. Smith JA Jr, Urry RL. Testicular histology after prolonged treatment with a gonadotropin-releasing hormone analogue. J Urol. 1985; 133:612-4. [PubMed 3920405]

13. Labrie F, Cusan L, Seguin C et al. Antifertility effects of LHRH agonists in the male rat and inhibition of testicular steroidogenesis in man. Int J Fertil. 1980; 25:157-70. [PubMed 6108924]

14. Clayton RN. Gonadotropin-releasing hormone modulation of its own pituitary receptors: evidence for biphasic regulation. Endocrinology. 1982; 111:152-60. [PubMed 6282566]

15. Warner B, Santen R, Demers L. Effects of [d/leu⁶,des-gly-NH₂, pro-ethylamide⁹]-GnRH (leuprolide) on steroidogenesis when used to treat prostatic carcinoma. J Androl. 1982; 3:14.

16. Tcholakian RK, De la Cruz A, Chowdhury M et al. Unusual anti-reproductive properties of the analog [d-leu⁶,des-gly-NH₂¹⁰]-luteinizing hormone-releasing hormone ethylamide in male rats. Fertil Steril. 1978; 30:600-3. [PubMed 363462]

17. Belanger A, Auclair C, Ferland L et al. Time-course of the effect of treatment with a potent LHRH agonist on testicular steroidogenesis and gonadotropin receptor levels in the adult rat. J Steroid Biochem. 1980; 13:191-6. [PubMed 6247573]

18. Evans RM, Doelle GC, Lindner J et al. A luteinizing-hormone-releasing hormone agonist decreases biological activity and modifies chromatographic behavior of luteinizing hormone in man. J Clin Invest. 1984; 73:262-6. [IDIS 180427] [PubMed 6228566]

19. Auclair C, Kelly PA, Coy DH et al. Potent inhibitory activity of [d-leu⁶,des-gly-NH₂¹⁰] LHRH ethylamide on LH/hCG and PRL testicular receptor levels in the rat. Endocrinology. 1977; 101:1890-3. [PubMed 201452]

20. Rajfer J, Swerdloff RS, Heber D. The pituitary gland is the primary site of action of GnRH agonist (d-leu⁶,des-gly¹⁰-GnRH ethylamide) in the male. Fertil Steril. 1982; 38:277-8.

21. Sharpe RM, Fraser HM. Inhibition of maturational changes in Leydig cell function by treatment of rats with an agonist of LH-RH. J Reprod Fertil. 1980; 60:359-68. [PubMed 6776279]

22. Santen RJ, Demers LM, Max DT et al. Long term effects of administration of a gonadotropin-releasing hormone superagonist analog in men with prostatic carcinoma. J Clin Endocrinol Metab. 1984; 58:397-400. [PubMed 6420439]

23. Santen RJ, Warner B. Evaluation of synthetic agonist analogue of gonadotropin-releasing hormone (leuprolide) on testicular androgen production in patients with carcinoma of prostate. Urology. 1985; 25(Suppl):53-7. [IDIS 198971] [PubMed 3918377]

24. Warner B, Worgul TJ, Drago J et al. Effect of very high dose d-leucine⁶-gonadotropin-releasing hormone proethylamide on the hypothalamic-pituitary-testicular axis in patients with prostatic cancer. J Clin Invest. 1983; 71:1842-53. [PubMed 6408125]

25. Pollack A, Block NL, Stover BJ et al. Effects of the gonadotropin-releasing hormone agonist [d-leu⁶,desgly-NH₂¹⁰, proethylamide⁹]-GnRH (leuprolide) on R3327-G rat prostatic tumor growth. J Urol. 1984; 131:399-403. [PubMed 6422059]

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a. TAP Pharmaceuticals. Lupron Injection (leuprolide acetate) prescribing information. Lake Forest, IL; 2004 Nov.

b. TAP Pharmaceuticals. Lupron Depot 7.5 mg (leuprolide acetate for depot suspension) prescribing information. Lake Forest, IL; 2004 Aug.

c. TAP Pharmaceuticals. Lupron Depot-3 Month 22.5 mg (leuprolide acetate for depot suspension) prescribing information. Lake Forest, IL; 2004 Aug.

d. TAP Pharmaceuticals. Lupron Depot-4 Month 30 mg (leuprolide acetate) for depot suspension prescribing information. Lake Forest, IL; 2004 Aug.

e. TAP Pharmaceuticals. Leupron Depot 3.75 mg (leuprolide acetate for depot suspension) prescribing information. Lake Forest, IL; 2004 Aug.

f. TAP Pharmaceuticals. Leupron Depot-3 Month 11.25 mg (leuprolide acetate for depot suspension) prescribing information. Lake Forest, IL; 2004 Aug.

g. TAP Pharmaceuticals. Lupron (leuprolide acetate) injection for pediatric use prescribing information. Lake Forest, IL; 2004 Nov.

h. TAP Pharmaceuticals. Lupron Depot-Ped 7.5 mg, 11.25 mg and 15 mg (leuprolide acetate for depot suspension) prescribing information. Lake Forest, IL; 2004 Aug.

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p. Viadur (leuprolide acetate implant) prescribing information. Bayer Pharmaceuticals Corporation. West Haven, CT; 2004 Nov.

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s. Eligard 30 mg (leuprolide acetate for injectable suspension) prescribing information. Sanofi-Synthelabo Inc., New York, NY; 2004 Aug.

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