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
IM
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
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.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.)
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 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
IM
Limit initial course of therapy to 6 months.e f
Retreatment If Symptoms Recur after Initial Treatment
IM
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 mena 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 acetat
