Leuprolide, a synthetic nonapeptide analog of naturally occurring porcine or ovine gonadotropin-releasing hormone (GnRH, luteinizing hormone-releasing hormone, gonadorelin),1, 2, 3, 80, 81, 116, 155, 190, 191, 192, 204, 205 is used as an antineoplastic agent and for its endocrine effects.1, 2, 3
Leuprolide acetate is used for the 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, 111, 112, 113, 114, 121, 190, 192, 201, 205 The drug is available in various commercial preparations for this use, including an injection solution for subcutaneous administration, a depot suspension for IM administration, and an injectable suspension for subcutaneous administration.1, 190, 192 Leuprolide is also available as the mesylate salt in an injectable emulsion for subcutaneous use in the treatment of advanced prostate cancer.205 Use of long-acting depot formulations of the drug may be preferred over use of daily injections because of greater convenience of administration and patient compliance with therapy.121, 211, 213
The majority of clinical studies with leuprolide acetate have been performed in patients with prostate cancer clinically diagnosed as stage D2 (i.e., tumor with metastases to distant lymph nodes, bone, and/or viscera).3, 32, 33, 34, 35, 36, 41, 43, 111, 121 Responses to leuprolide acetate therapy generally have been evaluated based on the criteria of the National Prostatic Cancer Project (NPCP).3, 32, 33, 34, 36, 40, 42, 43, 121
Leuprolide acetate (1 mg daily by subcutaneous injection) was compared with diethylstilbestrol (DES) therapy in patients with stage D2 prostate tumors in a prospective, randomized, multicenter study (Leuprolide Study Group).3, 43 Results showed that leuprolide and DES produced comparable objective and subjective responses1, 3, 43 and had similar survival rates after 2 years of treatment.1, 3 The median duration of clinical response was 60 or 61 weeks for leuprolide or DES, respectively.3, 43
The depot formulation of leuprolide acetate administered once monthly for the treatment of advanced prostate cancer was evaluated in an open-label, multicenter clinical study in 56 patients with stage D2 prostatic adenocarcinoma who had no prior treatment.121, 190 The primary objective was to determine if a 7.5-mg IM dose of leuprolide acetate given once every 4 weeks as the depot suspension would reduce and maintain serum testosterone to castrate range (≤50 ng/dL),121, 190 Results showed that 94% of the patients achieved serum testosterone suppression to castration levels within 30 days of starting therapy and, within 66 days, all patients achieved serum testosterone levels ≤50 ng/dL.190 Secondary endpoints included objective tumor response, which was assessed by clinical evaluations of tumor burden at weeks 12 and 24 of treatment.190 A complete, partial, or stable disease response was achieved in 77% of patients at week 12 and 84% of patients at week 24.190
Leuprolide acetate depot suspension administered every 12 weeks for the treatment of advanced prostate cancer was evaluated in 2 open-label multicenter studies in a combined total of 92 patients.190, 211 The primary objective of the study was to determine if a 22.5-mg IM dose of leuprolide acetate given once every 12 weeks as the depot suspension would reduce and maintain serum testosterone to castrate range (≤50 ng/dL),190, 211 Serum testosterone was suppressed to castration levels within 30 days in 87 of 92 (95%) patients and within an additional 2 weeks in 3 patients.190, 211 During the initial 24 weeks of treatment, 85% of patients achieved a complete, partial, or stable disease response.190, 211
Leuprolide acetate depot suspension administered every 16 weeks for the treatment of advanced prostate cancer was evaluated in an open-label, multicenter clinical study in 49 patients with stage D2 prostatic adenocarcinoma who had no prior treatment.190, 212 The primary objective was to determine if a 30-mg IM dose of leuprolide acetate given once every 16 weeks as the depot suspension would reduce and maintain serum testosterone to castration levels.190, 212 The mean serum testosterone was suppressed to castration levels (≤50 ng/dL) within 30 days of treatment initiation in 94% of patients and in 100% of patients within 6 weeks of the 32-week study period.190 A complete, partial, or stable disease response was achieved in 86% of patients at 16 weeks.190
Leuprolide acetate depot suspension administered every 24 weeks for the palliative treatment of advanced prostate cancer was evaluated in an open-label, multicenter clinical study in 151 patients.190, 213 The drug was administered as 2 IM injections of leuprolide acetate depot suspension 45 mg at 24-week intervals.190, 213 The primary objective was to determine if this dosage regimen would reduce serum testosterone to castration levels (50 ng/dL).190, 213 Serum testosterone was suppressed in 93.4% of patients evaluated from week 4 to week 48.190, 213
Leuprolide acetate injectable suspension for subcutaneous use (Eligard®) was evaluated for the palliative treatment of advanced prostate cancer in several open-label, multicenter studies in patients with Jewett stage A-D prostate cancer; each study evaluated a different dosage strength of the drug administered subcutaneously (7.5 mg, 22.5 mg, 30 mg, and 45 mg).192 The primary efficacy outcome measure in these studies was the reduction and maintenance of serum testosterone to castration levels (≤50 ng/dL) over the defined duration of therapy.192 Breakthrough from maintenance of castration levels was defined as a serum testosterone level ≥50 ng/dL.192 In patients receiving leuprolide acetate 7.5 mg every month for 6 months, once testosterone suppression was achieved, no patients experienced breakthrough concentrations at any time during the study.192 In patients receiving leuprolide acetate 22.5 mg every 3 months for 6 months, once testosterone suppression was achieved, only 1 patient had breakthrough concentrations after the initial injection, but remained below the threshold for the duration of the study.192 In patients receiving leuprolide acetate 30 mg every 4 months for 8 months, once testosterone suppression was achieved, 3 patients had breakthrough concentrations during the study.192 In patients receiving leuprolide acetate 45 mg every 6 months for 12 months, once testosterone suppression was achieved, 1 patient had breakthrough concentrations during the study.192
Leuprolide mesylate injectable emulsion for subcutaneous use (Camcevi®) was evaluated for the treatment of advanced prostate cancer in an open-label study in 137 patients.205, 206 The primary outcome was medical castration rate, defined as achieving and maintaining serum testosterone suppression to castration levels (50 ng/dL) by week 4 through week 48 of treatment.205, 206 Leuprolide mesylate was administered subcutaneously at a dose of 42 mg initially on day 0 and on week 24 of the study.205 Leuprolide mesylate injectable emulsion significantly reduced serum testostrone levels to ≤50 ng/dL in 98.5% of patients by week 4 and in 97% of patients by the end of the study period (day 336).205, 206
In guidelines from the National Institutes of Health (NIH) and the American Urological Association (AUA), hormonal therapy (also referred to as androgen deprivation therapy) is considered the standard treatment for advanced/metastatic prostate cancer.201, 216 Hormonal therapy can be achieved with surgery (bilateral orchiectomy) or medical castration using gonadotropin-releasing hormone (GnRH) agonists (e.g., leuprolide) or antagonists.201, 216 Randomized controlled studies have shown that combination therapy with androgen deprivation therapy and an androgen pathway-directed agent (e.g., abiraterone acetate, apalutamide, enzalutamide) results in longer overall survival than androgen deprivation therapy alone; therefore, such combination therapy should be considered.201, 216
Leuprolide acetate appears to be at least as effective as orchiectomy2, 4, 5, 6, 201 or estrogen therapy (specifically diethylstilbestrol [DES], no longer commercially available in the US) in previously untreated patients with advanced prostate cancer.1, 2, 3, 5, 35, 43, 66
Leuprolide is used alone for management of endometriosis, including pain relief and reduction of endometriotic lesions; the drug also is used in combination with norethindrone acetate for initial management of the painful symptoms of endometriosis and for management of recurrence of symptoms.5, 55, 71, 96, 105, 106, 107, 108, 116, 126, 131, 191
Leuprolide, like other GnRH analogs, produces a reversible hypoestrogenic state, which is thought to be principally responsible for the beneficial effects observed in endometriosis.105, 106, 107, 108, 116, 126, 127, 128, 129, 131 A 6-month course of leuprolide therapy can provide symptomatic (e.g., pain) relief105, 116, 126 and a reduction in endometriotic lesions,105, 116, 126 and some degree of improvement has persisted for at least 1 year following completion of a course of therapy in many patients.105, 116, 126
Use of norethindrone acetate in combination with leuprolide is referred to as add-back therapy, and is intended to reduce the loss of bone mineral density and reduce vasomotor symptoms associated with leuprolide treatment.116, 191 The total duration of therapy with leuprolide plus add-back therapy should not exceed 12 months because of concerns about an adverse impact on bone mineral density.116, 191
In a controlled study comparing 3.75-mg doses of IM leuprolide acetate depot suspension and placebo administered every 4 weeks for 6 doses in women with varying stages of laparoscopy-confirmed endometriosis, leuprolide was more effective than placebo in relieving dysmenorrhea and pelvic pain, tenderness, and induration by the third month of therapy and at completion of therapy; the drug also appeared to ameliorate dyspareunia in most patients.105, 116 Symptoms recurred within 3-12 months after completion of therapy in most patients who enrolled in a posttreatment follow-up.105, 116 Dysmenorrhea recurred within 6 months in 57% of patients, although this symptom still had not returned to baseline severity in 33% of patients after 1 year.105 Pain returned to baseline severity within 3 months in 54% of patients with moderate to severe pretreatment pelvic pain; however, 37% of those with this pretreatment severity exhibited some degree of relief after 1 year.105 Pelvic tenderness was absent in 58% of patients throughout the follow-up period, and pelvic induration was absent in 67% of patients at 1 year.105 Because safety has only been established to date for a single 6-month course of leuprolide monotherapy and because of concerns about potential long-term effects on bone density, retreatment with leuprolide alone currently is not recommended.116, 191 If retreatment with leuprolide is considered following recurrence of endometriosis, the potential benefits and possible risks should be weighed carefully, and bone density should be assessed and be within normal limits before initiating another course of leuprolide; a second course of leuprolide should be administered only in combination with norethindrone acetate.116, 191
Results from 2 clinical studies, 12 months in duration, indicate that concurrent hormonal therapy with norethindrone acetate 5 mg daily significantly reduces the loss of bone mineral density associated with leuprolide therapy without decreasing the efficacy of leuprolide in relieving the symptoms of endometriosis.116, 191 All patients also received supplementation with elemental calcium (1 g daily).116, 191
The American College of Obstetricians and Gynecologists (ACOG) guidelines on endometriosis include GnRH agonists such as leuprolide for the management of pain in women with endometriosis.217 GnRH agonists are highly effective in reducing the pain syndromes associated with endometriosis, but are not superior to other methods such as combined oral contraceptives.217 GnRH agonists may cause significant adverse effects such as osteopenia, which may be reversible with short-term use, but may not be reversible with long-term use.217 Therefore, add-back regimens (using either sex-steroid hormones or other specific bone-sparing agents) are recommended in women undergoing long-term therapy (e.g., for more than 6 months) with a GnRH agonist in addition to daily calcium supplements.217
Leuprolide is used in combination with iron therapy for the preoperative hematologic improvement of women with anemia caused by uterine leiomyomata (uterine fibroids) for whom 3 months of hormonal suppression is deemed necessary.116, 181, 191
The manufacturer recommends up to 3 months of consecutive monthly injections or one injection of the long-acting 3-month formulation as the duration of such leuprolide therapy.116, 191 Prior to initiating therapy with leuprolide, the clinician may wish to consider a 1-month trial of iron therapy alone, since some patients may respond adequately to such therapy;116, 181, 191 if the patient does not respond adequately to iron alone, leuprolide may then be added.116, 191
In controlled clinical trials, monthly IM administration of 3.75 mg of leuprolide acetate suspension for a period of 3 or 6† months was shown to decrease uterine and fibroid volume, allowing for relief of clinical symptoms(e.g., abdominal bloating, pelvic pain, and pressure).116, 181 Excess vaginal bleeding (menorrhagia and menometrorrhagia) decreased, resulting in improvement in hematologic parameters.116, 181 In one controlled clinical trial where enrollment was based on hematologic parameters (hematocrit of 30% or less and/or hemoglobin of 10.2 g/dL or less),116, 181 administration of leuprolide 3.75 mg IM once monthly with concomitant iron therapy produced an increase in hematocrit of 6% or greater and an increase in hemoglobin concentration of 2 g/dL or greater in 77% of patients at 3 months.116 The mean change in hematocrit and hemoglobin concentration was 10.1% and 4.2 g/dL, respectively.116 Clinical response to therapy was defined as a hematocrit of 36% or greater and a hemoglobin concentration of 12 g/dL or greater, which would allow patients to perform autologous blood donation prior to surgery;116, 181 75% of patients treated met these criteria at 3 months.116 At 3 months, 80% of patients experienced relief from menorrhagia or menometrorrhagia, although episodes of spotting or menstrual-like bleeding were noted in some patients.116 A decrease of 25% or greater was seen in uterine and myoma volumes in 60 and 54% of patients treated, respectively; treatment also was associated with relief of symptoms such as bloating, pelvic pain, and pressure.116, 181
In other controlled clinical trials where enrollment was not based on hematologic status, treatment with leuprolide resulted in a decrease of mean uterine or myoma volume of 41 or 37%, respectively, as evidenced by ultrasound or magnetic resonance imaging.116 Decrease in symptoms, including excessive vaginal bleeding or pelvic discomfort, also was observed.116 Although benefit was observed at 3 months, additional improvement was seen with another 3 months of therapy.116 Of the 95% of patients experiencing amenorrhea during leuprolide therapy, 61, 25, or 4% developed amenorrhea during the first, second, or third month of therapy, respectively.116 Posttreatment follow-up in a small number of the 77% of patients who experienced a 25% or greater decrease in uterine volume while on leuprolide therapy found that menses usually returned within 2 months of stopping therapy, and mean time to return to pretreatment uterine volume was 8.3 months if not corrected surgically.116 Regrowth did not appear to be related to pretreatment uterine volume.116 The symptoms associated with uterine leiomyomata that are not corrected surgically will recur following discontinuance of leuprolide therapy.116, 186
The American College of Obstetricians and Gynecologists (ACOG) guidelines recommend the use of GnRH agonists such as leuprolide for the management of symptomatic uterine leiomyomas.219 For the management of bleeding symptoms and uterine enlargement, GnRH agonists, with or without add-back hormonal therapy, are recommended for the short-term treatment of abnormal uterine bleeding associated with leiomyomas (AUB-L) and uterine enlargement associated with uterine leiomyomas and also as a bridge to other treatment strategies (e.g., interventional procedures, surgery, menopause).219 Treatment with GnRH agonists has been associated with reductions in leiomyoma size and overall size of the uterus, decreased AUB-L and dysmenorrhea, and improvement in quality of life measures (i.e., days of bleeding, pelvic pressure, pelvic pain, urinary frequency, and constipation).219 The guidelines also state that leiomyoma regrowth, often back to pretreatment levels, is observed between 3 and 9 months after cessation of treatment, which supports the use of leuprolide as a bridge therapy.219
A report by the Agency for Healthcare Research and Quality (AHRQ) noted that GnRH agonists and other treatments, including mifepristone, ulipristal, and uterine artery embolism (UAE), reduce fibroid size, and improve symptoms and quality of life based on a review of the clinical literature.220 GnRH treatment also significantly improved pain symptoms, including pelvic pressure, pelvic and abdominal pain, and dysmenorrhea, compared to baseline.220 Extended follow-up of women who discontinue GnRH agonists was not available; therefore, information about potential harms was limited.220
Leuprolide acetate is used for the treatment of central precocious puberty (CPP) in pediatric patients; use of the drug or another GnRH analog currently is considered the therapy of choice for this condition and generally has supplanted medroxyprogesterone in the treatment of this form of precocity.155, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 177, 202, 203 For the treatment of CPP, leuprolide acetate depot suspension (Lupron Depot-Ped®) is indicated for pediatric patients ≥1 year of age and leuprolide acetate injectable suspension (Fensolvi®) is indicated for pediatric patients ≥2 years of age.155, 204 Leuprolide is designated an orphan drug by FDA for use in this condition.179
Leuprolide acetate depot suspension (Lupron Depot-Ped®) administered IM once monthly for the treatment of CPP was evaluated in a prospective, open-label, multicenter trial.155, 214 Included in the trial were 49 female patients <9 years of age and 6 male patients <10 years of age.155, 214 Male patients were excluded from study analysis due to low patient enrollment.214 Patients were treated once monthly every 28 days until the appropriate age for entry into puberty.155, 214 Dose adjustments were made in 3.75-mg increments, if necessary, based on results of GnRH stimulation tests and hormonal parameters.155, 214 Primary measured outcomes included the assessment of clinical sexual characteristics evaluated by Tanner staging and the decrease in serum gonadotropin and sex steroid concentrations to prepubertal levels.155, 214 Suppression of peak stimulated luteinizing hormone (LH) to <1.75 IU/L during treatment was achieved in 96% of patients at 1 month.155 There were 5 female patients that required an increased dosage to obtain or retain suppression over the course of treatment.155, 214 There was a reduction in average incremental growth rate from 10.6 cm/year at baseline to 5-6 cm/year during the first phase of the study period (72 weeks of therapy) and then 4-4.5 cm/year from week 72 to week 192.214 By the end of the treatment period, the average height standard deviation z-score changed from a baseline of 1.6 to 0.7 and the mean ratio of bone age to chronological age decreased from baseline (1.5 to 1.1).155
Leuprolide acetate depot suspension (Lupron Depot-Ped®) administered once every 3 months for the treatment of CPP was evaluated in a phase 3, randomized, open-label trial.155, 207 Enrolled were 84 patients, 76 female patients and 8 male patients, between 1 and 11 years old.155, 215 Patients were randomized to a leuprolide acetate dose of 11.25 mg or 30 mg injected IM every 3 months.155, 215 The primary outcome was the percentage of patients with suppressed LH from month 2 through month 6 (peak-stimulated LH below 4 IU/L).155, 215 From 2-6 months of treatment, 95.2% of patients in the leuprolide acetate 30-mg group and 78.6% of patients in the leuprolide acetate 11.25-mg group achieved suppression of peak-stimulated LH below 4 IU/L.155 There were 9 treatment failures in the 11.25-mg group and 2 failures in the 30-mg group; treatment failure was defined as peak-stimulated LH >4 IU/L.215
Leuprolide acetate injectable suspension (Fensolvi®) was evaluated in a phase 3, open-label, multicenter clinical trial.204, 207 There were 64 patients enrolled, 62 females and 2 males (4 to 9 years of age), who were diagnosed with CPP.204 Patients received at least one subcutaneous injection of leuprolide acetate 45 mg every 24 weeks.204, 207 The primary outcome was the percentage of patients with suppressed LH at week 24 (peak-stimulated LH below 4 IU/L).207 Suppression of peak-stimulated LH below 4 IU/L was achieved in 87% of all patients at week 24.204, 207 At 12 months, 98% of female patients and 50% of male patients maintained suppression of estradiol or testosterone.204
The American Academy of Pediatrics (AAP) addresses the evaluation and management of children with CPP in a clinical report.221 The authors state that the use of GnRH analogs is supported by a 2009 consensus statement developed by North American and European pediatric endocrine societies, particularly to preserve height potential.221, 222 Other reasons to consider treatment for which there are no published studies include prevention of early menarche and the accompanying psychological ramifications and suppression of sexual maturation in girls who are emotionally immature.221 If the goals of therapy do not include preservation of growth potential, use of a less costly therapy with long-acting medroxyprogesterone injection may be considered.221
Factors that influence the decision of when to stop GnRH treatment depend on the primary goal(s) of therapy including maximizing height, synchronizing puberty with peers, ameliorating psychological distress, and facilitating care of the developmentally-delayed child.222 Experts conclude that it is reasonable to consider these parameters as well as parent and patient preferences.222
Ovarian suppression has been used in combination with endocrine therapy (i.e., anastrozole, exemestane, letrozole, tamoxifen) as adjuvant therapy in premenopausal women with early-stage hormone receptor-positive breast cancer†.10010, 10011, 10013, 10023, 10026
Efficacy and safety of ovarian suppression in combination with endocrine therapy as adjuvant therapy in premenopausal women with early-stage hormone receptor-positive breast cancer have been studied in several open-label, randomized, phase 3 studies.10010, 10011, 10013, 10026
In the Suppression of Ovarian Function Trial (SOFT), 3066 premenopausal women with early-stage hormone receptor-positive breast cancer were randomized to receive 5 years of treatment with tamoxifen 20 mg daily, tamoxifen 20 mg daily and ovarian suppression, or exemestane 25 mg daily and ovarian suppression.10010 Ovarian suppression could be achieved with triptorelin 3.75 mg administered by IM injection every 28 days, bilateral oophorectomy, or bilateral ovarian irradiation.10010 Approximately one-half (53%) of patients enrolled in the study had received prior adjuvant chemotherapy.10010 The primary analysis involved comparison of tamoxifen and ovarian suppression with tamoxifen alone.10010 At a median follow-up of 8 years, disease-free survival and overall survival were prolonged, without a reduction in distant recurrences, in women receiving tamoxifen and ovarian suppression compared with those receiving tamoxifen alone; a disease-free survival benefit and a reduction in distant recurrences were observed, without an overall survival benefit, in women receiving exemestane and ovarian suppression compared with those receiving tamoxifen alone.10012 (See Table 1.)
Treatment and Efficacy Measure | Hazard Ratio (vs tamoxifen) | Absolute Improvement (vs tamoxifen)a |
|---|---|---|
Tamoxifen and Ovarian Suppression |
|
|
Disease-free survival | 0.76 | 4.2% |
Overall survival | 0.67 | 1.8% |
Freedom from distant recurrence | 0.86 | . . . |
Exemestane and Ovarian Suppression |
|
|
Disease-free survival | 0.65 | 7% |
Overall survival | 0.85 | . . . |
Freedom from distant recurrence | 0.73 | 2.8% |
aPercentage point difference in occurrence rates for the indicated treatment versus tamoxifen for events occurring at significantly different rates.
Subgroup analysis in the SOFT study suggested that the relative clinical benefits of the 3 treatments generally were similar regardless of prior use of adjuvant chemotherapy; however, no difference in disease-free survival was observed with the addition of ovarian suppression to tamoxifen therapy in patients at lower risk of breast cancer recurrence (i.e., older age, node-negative disease, low-grade tumor, smaller tumor size) who had not required prior adjuvant chemotherapy.10010, 10012, 10017 The absolute benefit of combined endocrine and ovarian suppression therapy was greater in higher-risk patients who had received adjuvant chemotherapy.10012 The absolute difference in 8-year disease-free survival rates between women receiving exemestane and ovarian suppression and those receiving tamoxifen alone was greater in women at higher risk of breast cancer recurrence (i.e., younger age, larger or high-grade tumor, lymph node involvement10010, 10012 ) who had received prior adjuvant chemotherapy (9%) compared with those in the lower-risk cohort (5.2%).10012 The absolute difference in 8-year disease-free survival rates between women receiving tamoxifen and ovarian suppression and those receiving tamoxifen alone also was greater in women in the higher-risk cohort (5.3%) compared with those in the lower-risk cohort (3.2%).10012
A combined analysis of the SOFT study and the Tamoxifen and Exemestane Trial (TEXT) included data for 4690 premenopausal women with hormone receptor-positive operable breast cancer who were randomized to receive ovarian suppression and either exemestane 25 mg daily or tamoxifen 20 mg daily for 5 years.10011 Ovarian suppression could be achieved with triptorelin 3.75 mg administered by IM injection every 28 days, bilateral oophorectomy, or bilateral ovarian irradiation.10011 In patients who received adjuvant chemotherapy in the TEXT study, triptorelin was initiated concomitantly with chemotherapy.10011 Approximately one-half (57.4%) of patients in the combined analysis received adjuvant chemotherapy.10011 A 5-year disease-free survival benefit and higher 5-year rates of freedom from breast cancer and freedom from distant recurrence were observed in women receiving exemestane and ovarian suppression compared with those receiving tamoxifen and ovarian suppression.10011 Beneficial effects of combined exemestane and ovarian suppression therapy on disease-free survival and distant recurrences were maintained at 8 years.10012 (See Table 2.) Musculoskeletal symptoms (89.9 versus 77.8%) and osteoporosis (42.2 versus 27.9%) occurred more frequently in exemestane-treated patients compared with tamoxifen-treated patients.10012
Efficacy Measure | Exemestane and Ovarian Suppression (%) | Tamoxifen and Ovarian Suppression (%) |
|---|---|---|
Disease-free survival, 5 years | 91.1 | 87.3 |
Overall survival, 5 years | 95.9 | 96.9 |
Freedom from breast cancer, 5 years | 92.8 | 88.8 |
Freedom from distant recurrence, 5 years | 93.8 | 92 |
Disease-free survival, 8 years | 86.8 | 82.8 |
Overall survival, 8 years | 93.4 | 93.3 |
Freedom from distant recurrence, 8 years | 91.8 | 89.7 |
In the HOBOE study, 1065 premenopausal women with early-stage hormone receptor-positive breast cancer were randomized to receive 5 years of treatment with tamoxifen 20 mg daily, letrozole 2.5 mg daily, or letrozole 2.5 mg daily in combination with zoledronic acid 4 mg IV every 6 months; all patients received ovarian suppression with triptorelin 3.75 mg by IM injection every 4 weeks for 5 years or until the age of 55 years.10026 The majority (62.6%) of patients had received prior neoadjuvant or adjuvant chemotherapy.10026 At a median follow-up of approximately 5.3 years, a substantial disease-free survival benefit was observed in women receiving letrozole in combination with zoledronic acid and ovarian suppression (hazard ratio of 0.52, which corresponded to an absolute improvement in disease-free survival of 7.9%) but not in those receiving letrozole and ovarian suppression (hazard ratio of 0.72 with a 95% confidence interval of 0.48-1.07), compared with women receiving tamoxifen and ovarian suppression.10026 No difference in overall survival was observed among the 3 treatment groups.10026 However, at the time of the analysis, only 81% of the number of events required for final analysis had occurred.10026 Among patients receiving either letrozole or tamoxifen in combination with ovarian suppression, hypercholesterolemia (30.4 versus 20.3%), arthralgia (44.5 versus 22%), bone pain (29 versus 15.3%), insomnia (8.1 versus 4.2%), sensory neuropathy (13 versus 7.7%), and vaginal dryness ( 20.8 versus 11.7%) occurred more frequently in those receiving letrozole, while endometrial abnormalities (3 versus 6.8%) occurred more frequently in those receiving tamoxifen.10026
In the E-3193/INT-0142 study, 345 premenopausal women with early-stage hormone receptor-positive breast cancer were randomized to receive tamoxifen 20 mg daily with or without ovarian suppression for 5 years.10013 Ovarian suppression therapy could be achieved with goserelin 3.6 mg implanted subcutaneously every 4 weeks, leuprolide acetate 3.75 mg by IM injection every 4 weeks, bilateral oophorectomy, or bilateral ovarian irradiation.10013 Patients enrolled in the study had baseline characteristics associated with lower risk of breast cancer recurrence (i.e., node-negative disease, tumor size of 3 cm or less, no prior adjuvant chemotherapy, median age 45 years).10013, 10017 At a median follow-up of approximately 9.9 years, results of this study were consistent with those of the SOFT study, demonstrating no difference in disease-free or overall survival between lower-risk women receiving tamoxifen and ovarian suppression and those receiving tamoxifen alone; however, interpretation of the results is limited by failure to meet the accrual goal of 1600 patients for superiority testing.10013, 10017 In this study, the addition of ovarian suppression to tamoxifen therapy was associated with increased menopausal symptoms, decreased sexual function, increased breast cancer-specific symptoms, and lower quality of life during the first 3 years of therapy.10013
Use of adjuvant exemestane or tamoxifen therapy in combination with ovarian suppression improved disease-free survival rates compared with tamoxifen alone in premenopausal women with early-stage hormone receptor-positive breast cancer in the SOFT study;10012 however, more deaths occurred despite fewer distant recurrences in women receiving exemestane and ovarian suppression compared with those receiving tamoxifen and ovarian suppression.10012, 10016 Factors contributing to the discordance between distant recurrence rates and overall survival in women receiving exemestane and ovarian suppression have not been elucidated; however, some clinicians suggest that incomplete and/or intermittent estrogen suppression with GnRH agonists used to achieve ovarian suppression may be a potential mechanism.10016, 10025, 10027 In the combined analysis of the SOFT and TEXT studies, clinical benefits (i.e., disease-free survival, freedom from distant recurrence) were observed in women receiving exemestane and ovarian suppression compared with those receiving tamoxifen and ovarian suppression;10012 however, in the HOBOE study, no difference in disease-free survival was observed between women receiving letrozole and ovarian suppression and those receiving tamoxifen and ovarian suppression.10026
The role of adding ovarian suppression to adjuvant endocrine therapy has not been fully elucidated; however, no discernible benefit from the addition of ovarian suppression to tamoxifen therapy has been observed in premenopausal women at lower risk of disease recurrence (i.e., older age, node-negative disease, low-grade tumor, smaller tumor size) in the SOFT and E-3193/INT-0142 studies, whereas a disease-free survival advantage was observed in a cohort of women at higher risk of disease recurrence (i.e., younger age, high-grade tumor, increased risk of lymph node involvement) receiving ovarian suppression in addition to exemestane or tamoxifen therapy in the SOFT study.10012, 10017
Based on current evidence,10010, 10011, 10012, 10013, 10023, 10026 use of endocrine therapy (i.e., anastrozole, exemestane, letrozole, tamoxifen) in combination with ovarian suppression as adjuvant therapy may be considered a reasonable choice (accepted) in premenopausal women with early-stage hormone receptor-positive breast cancer at higher risk of disease recurrence (i.e., younger age, larger or high-grade tumor, increased risk of lymph node involvement) and those who received prior adjuvant chemotherapy.10028 ASCO states that the duration of adjuvant GnRH agonist therapy should not exceed 5 years, since the toxicity of long-term (e.g., beyond 5 years) use of GnRH agonist-induced ovarian suppression has not been determined and comparative data for alternative treatment durations are lacking.10017, 10018 Although inconsistent estrogen suppression may occur in premenopausal women receiving combined ovarian suppression and endocrine therapy, routine monitoring of serum estradiol concentrations is not recommended since there is insufficient evidence to support specific monitoring guidelines and validated estradiol assays are not widely available;10016, 10017, 10020, 10025 however, ASCO recommends monitoring for physiologic changes that would suggest recovery of ovarian function.10017 ASCO states that clinicians should consider recurrence risk, adverse effects, patient preference, quality of life, consequences for childbearing, and the potential for ambiguity regarding the status of ovarian function (e.g., in women with chemotherapy-induced amenorrhea, hysterectomy-induced amenorrhea, incomplete ovarian suppression, or noncompliance with ovarian suppression therapy) when considering the addition of ovarian suppression therapy to adjuvant endocrine therapy.10017, 10018
Leuprolide has been utilized for in vitro fertilization protocols for controlled ovarian hyperstimulation†.230 GnRH agonists such as leuprolide also have been used for pubertal hormone suppression in transgender persons undergoing gender-affirming hormone therapy†.229
Leuprolide acetate is administered by subcutaneous or IM injection depending on the formulation and indication.14, 116, 155, 190, 191, 192, 204 Leuprolide acetate depot suspension (e.g., Lupron Depot®, Lupron Depot-Ped®) is administered by IM injection.116, 155, 190, 191 Leuprolide acetate injectable suspension (Eligard®, Fensolvi®) and leuprolide acetate injection are administered by subcutaneous injection.1, 192, 204
Leuprolide mesylate emulsion (Camcevi®) is administered by subcutaneous injection.205
Extended-release or depot formulations of leuprolide have different release characteristics.116, 155, 190, 191, 192, 204 Do not use partial syringes, a combination of syringes, or substitute other extended-release products to achieve a particular dose.116, 155, 190, 191, 192, 204
Some formulations of leuprolide are not intended for self-administration and should be administered by a healthcare professional only (e.g., Camcevi®, Eligard®, Fensolvi®, Lupron®, Lupron Depot-Ped®); consult the manufacturer's prescribing information for details.155, 190, 191, 192, 204, 205
Store leuprolide acetate injection at a temperature of less than 25°C in carton until time of use and protect from light; avoid freezing.1
Store leuprolide acetate powder for injectable suspension (Lupron Depot®, Lupron Depot-Ped®) and its diluent at a controlled room temperature of 25°C; excursions permitted to temperatures ranging from 15-30°C.116, 155, 190, 191 It is not necessary to store the drug or its diluent under refrigeration; avoid freezing.116, 155, 190, 191
Store leuprolide acetate injectable suspension (Eligard® and Fensolvi®) at 2-8°C.192, 204 Once outside the refrigerator, Eligard® and Fensolvi® may both be stored at 15-30°C in their original packaging for up to 8 weeks prior to reconstitution and administration.192, 204
Store leuprolide mesylate injectable emlusion (Camcevi®) at 2-8°C in carton until time of use and protect from light; do not freeze or shake.205
Leuprolide acetate powder for injectable extended release suspension (Lupron Depot®, Lupron Depot-Ped®) is provided in dual-chamber, disposable, single-use syringes and should be reconstituted with the accompanying diluent in accordance with the instructions provided by the manufacturer.116, 155, 190, 191, 192 Following reconstitution, administer the drug within 2 hours.116, 155, 190, 191 Rotate injection sites with each injection.116, 155, 190, 191 Consult the manufacturer's prescribing information for additional details on preparation and administration of the drug.116, 155, 190, 191
Leuprolide acetate injection is administered subcutaneously as single daily injections in the palliative treatment of prostate cancer.1
Leuprolide acetate for injectable suspension (Eligard®) is administered subcutaneously and provides continuous release of the drug over a 1-, 3-, 4-, or 6-month period for the palliative treatment of prostate cancer.192 The commercially available powder should be reconstituted with the supplied prefilled diluent using aseptic technique and gloves prior to administration.192 Allow the drug to reach room temperature prior to reconstitution; once mixed, administer the drug within 30 minutes or discard.192 Select a specific injection location in an area with sufficient soft or loose subcutaneous tissue that does not have excessive pigment, nodules, lesions, or hair and has not been recently used.192 Rotate injection sites with each injection.192 Consult the manufacturer's prescribing information for additional details on preparation and administration of the drug.192
Leuprolide mesylate injectable emulsion (Camcevi®) is administered subcutaneously once every 6 months for the palliative treatment of advanced prostate cancer.205 The prefilled syringe should be removed from the refrigerator and allowed to sit at room temperature for 30 minutes prior to administration.205 Select a location for administration with sufficient soft or loose subcutaneous tissue that has not recently been used; avoid brawny or fibrous subcutaneous tissue and areas that could be rubbed or compressed (e.g., with a belt or clothing waistband).205 The injection should be administered by inserting the needle at a 90º angle to the skin surface using aseptic technique.205 Consult the manufacturer's prescribing information for additional details on preparation and administration of the drug.205
Leuprolide acetate for injectable suspension (Fensolvi®) is administered by subcutaneous injection once every 6 months for the treatment of central precocious puberty (CPP).204 The drug must be administered by a healthcare professional.204 The commercially available lyophilized drug must be reconstituted with the supplied prefilled diluent using aseptic technique and gloves prior to administration; the final concentration after reconstitution is 45 mg/0.375 mL.204 Allow the drug to reach room temperature before reconstitution to allow for easier administration.204 Following reconstitution, administer the drug within 30 minutes or discard.204 Recommended injection sites include the abdomen, upper buttocks, or another location with adequate amounts of subcutaneous tissue that does not have excessive pigment, nodules, lesions, or hair; avoid areas with brawny or fibrous subcutaneous tissue or locations that could be rubbed or compressed (i.e., by a belt or clothing waistband).204 Rotate injection sites with each injection.204 Consult the manufacturer's prescribing information for additional details on preparation and administration of the drug.204
Leuprolide acetate for depot suspension (Lupron Depot®): For the treatment of advanced prostate cancer, the usual dosage of leuprolide acetate as the depot suspension (Lupron Depot®) is 7.5 mg IM once monthly (every 4 weeks),190 22.5 mg IM once every 12 weeks, 30 mg IM once every 16 weeks, or 45 mg IM once every 24 weeks.190 Because of different release characteristics, a fractional dose of the 22.5-, 30-, or 45-mg suspension formulations or a combination of doses of this or other depot formulations should not be used concurrently.190
Leuprolide acetate for injectable suspension (Eligard®): For the treatment of advanced prostate cancer, the recommended dosage of leuprolide acetate injectable suspension (Eligard®) by subcutaneous injection is 7.5 mg once monthly, 22.5 mg once every 3 months, 30 mg once every 4 months, or 45 mg once every 6 months.192
Leuprolide acetate injection: For the treatment of advanced prostate cancer, the recommended dosage of leuprolide acetate injection is 1 mg daily given by subcutaneous administration.1 Some clinicians have increased leuprolide dosages up to 20 mg daily, but dosages higher than 1 mg daily have not resulted in a greater incidence of remission.2, 10, 22, 23, 33
Leuprolide mesylate injectable emulsion (Camcevi®): The recommended dosage of leuprolide mesylate injectable emulsion (Camcevi®) for the treatment of advanced prostate cancer is 42 mg by subcutaneous injection once every 6 months.205
For the initial treatment of endometriosis, the usual dosage of leuprolide acetate for depot suspension (Lupron Depot®) is 3.75 mg given as a single IM injection of the monthly formulation once monthly for 1 to 6 doses (maximum treatment duration of 6 months) or 11.25 mg given as a single IM injection of the 3-month formulation for 1 to 2 doses (maximum treatment duration of 6 months).116, 191 Leuprolide may be administered with or without norethindrone acetate (5 mg daily).116, 191
If retreatment is considered following recurrence of endometriosis, bone density should be assessed and be within normal limits before initiating another course of leuprolide.116, 191 Retreatment with an additional course of leuprolide alone is not recommended; if retreatment is considered, a single 6-month course of leuprolide acetate depot suspension (Lupron Depot®) in conjunction with norethindrone acetate (and elemental calcium 1 g daily) may be administered.116, 191 Treatment should not exceed 12 months due to concerns about adverse impact on bone mineral density.116, 191
For the hematologic improvement of anemia associated with uterine leiomyomata (uterine fibroids) prior to surgery, the usual dosage of leuprolide acetate for depot suspension (Lupron Depot®) is a single course of 3.75-mg doses administered IM once monthly for up to 3 consecutive months116 or a single IM injection of 11.25 mg as the long-acting 3-month formulation;191 iron therapy also is administered concomitantly.116, 191 Because of different release characteristics, a fractional dose of the 11.25-mg suspension formulation is not equivalent to the same dose of the once-monthly formulation and should not be used for monthly doses.191
For the treatment of central precocious puberty (CPP), dosage of leuprolide acetate for depot suspension (Lupron Depot-Ped®) should be individualized 155 The drug may be given as a single IM injection once monthly, every 3 months, or every 6 months.155 Select the appropriate syringe for the intended dosing frequency.155
Leuprolide acetate for injectable suspension (Fensolvi®) is administered by subcutaneous injection once every 6 months for the treatment of CPP.204
Once-monthly Therapy (Leuprolide Acetate for Depot Suspension [Lupron Depot-Ped®])
Initial dosage of leuprolide acetate for depot suspension (Lupron Depot-Ped®) for the treatment of pediatric patients with CPP should be individualized.155 The starting dosage is based on the patient's weight (see Table 1).155 Dosage adjustment may be necessary with changes in body weight.155
Weight | Once-monthly Recommended Dosage |
|---|---|
≤25 kg | 7.5 mg |
25-37.5 kg | 11.25 mg |
>37.5 kg | 15 mg |
If satisfactory hormonal and clinical suppression is not achieved with the initial starting dose, increase the dosage to the next available higher dose.155 Treatment should be discontinued at the appropriate age of onset of puberty.155
Monitor response with a GnRH stimulation test, basal luteinizing hormone (LH), or serum concentration of sex steroid levels beginning 1 to 2 months following initiation of therapy, with changing doses, or further as judged clinically appropriate in order to confirm maintenance of efficacy.155 Assess height (for calculation of growth rate) and bone age every 6 to 12 months.155
Once Every 3 Months Therapy (Leuprolide Acetate for Depot Suspension [Lupron Depot-Ped®])
For the treatment of CPP, leuprolide acetate for depot suspension (Lupron Depot-Ped®) is also available for once every 3 months dosing.155 A dose of 11.25 mg or 30 mg should be given once every 3 months (12 weeks) as a single-dose IM injection.155 Treatment should be discontinued at the appropriate age of onset of puberty.155
Monitor response with a GnRH stimulation test, basal LH, or serum concentration of sex steroid levels at months 2 to 3, month 6, and further as judged clinically appropriate in order to confirm maintenance of efficacy.155 Assess height (for calculation of growth rate) and bone age every 6 to 12 months.155
Once Every 6 Months Therapy (Leuprolide Acetate for Depot Suspension [Lupron Depot-Ped®]
For the treatment of CPP, leuprolide acetate for depot suspension (Lupron Depot-Ped®) is also available for once every 6 months dosing.155 A dose of 45 mg should be given once every 6 months (24 weeks) as a single-dose IM injection.155 Treatment should be discontinued at the appropriate age of onset of puberty.155
Monitor response with a GnRH stimulation test, basal LH, or serum concentration of sex steroid levels at months 5 to 6 and further as judged clinically appropriate in order to confirm maintenance of efficacy.155 Assess height (for calculation of growth rate) and bone age every 6 to 12 months.155
Once Every 6 Months Therapy (Leuprolide Acetate for Injectable Suspension [Fensolvi®])
If the for injectable suspension is used for the treatment of CPP in pediatric patients ≥2 years of age, the recommended dosage is 45 mg administered by subcutaneous injection once every 6 months.204 Treatment should be discontinued at the appropriate age of onset of puberty.204 Monitor response with a GnRH agonist stimulation test, basal serum LH levels, or serum concentration of sex steroid levels at 1 to 2 months following initiation of therapy and as needed to confirm adequate suppression of pituitary gonadotropins, sex steroids, and progression of secondary sexual characteristics.204
Measure height (for calculation of growth velocity) every 3 to 6 months and monitor bone age periodically.204 If treatment with leuprolide is not adequate, it may be necessary to switch to an alternative GnRH agonist with the ability for dosage adjustment.204
The manufacturers make no specific dosage recommendations for patients with hepatic impairment.1, 116, 155, 191, 192, 204, 205
The manufacturers make no specific dosage recommendations for patients with renal impairment.1, 116, 155, 191, 192, 204, 205
Like other GnRH agonists, leuprolide causes an initial increase in serum testosterone or estrogen levels during the first weeks of treatment.1, 190, 192, 205 A worsening (flare) of signs and/or symptoms of hormone-dependent disease (e.g., endometriosis, prostatic cancer) has occasionally occurred during the initial 1-2 weeks of leuprolide therapy (secondary to the initial leuprolide-induced stimulation of pituitary release of gonadotropins and resultant ovarian and testicular steroidogenesis) and then subsided during continued therapy.1, 10, 32, 33, 35, 108, 115, 116, 145, 146 In pediatric patients, this can cause an increase in the signs and symptoms of puberty, such as vaginal bleeding, during the first weeks of therapy or after subsequent doses.155, 204
Isolated cases of ureteral obstruction and spinal cord compression have been observed, which may contribute to paralysis with or without fatal complications, in men with prostate cancer.1, 190, 192, 205 A small number of patients may experience a temporary increase in bone pain, which can be managed symptomatically.1, 190, 192, 205 Patients with metastatic vertebral lesions and/or with urinary tract obstruction should be closely observed during the first few weeks of therapy.1, 190, 192, 205
Following the first dose of leuprolide for treatment of endometriosis, uterine leiomyomata, or central precocious puberty, sex steroids temporarily rise above baseline because of the physiologic effect of the drug.116, 155, 204 Therefore, an increase in symptoms may be observed during the initial days of therapy, but should dissipate with continued therapy.116, 155, 204
GnRH agonists, including leuprolide, may cause metabolic changes such as hyperglycemia, diabetes mellitus, and hyperlipidemia in patients receiving these drugs for the treatment of prostate cancer.1, 190, 192, 205 Non-alcoholic fatty liver disease, including cirrhosis, has occurred in the postmarketing setting.190 Hyperglycemia may represent development of diabetes mellitus or worsening of glycemic control in patients with diabetes.1, 190, 192, 205
Monitor for changes in serum lipids, blood glucose, and/or glycosylated hemoglobin (HbA1c) in patients receiving leuprolide and manage according to current practice guidelines.1, 190, 192, 205
GnRH agonists, including leuprolide, may increase the risk of certain cardiovascular diseases (e.g., myocardial infarction, sudden cardiac death, stroke) in patients receiving these drugs for the treatment of prostate cancer.1, 189, 190, 192, 205 The risk appears low, but should be evaluated carefully along with cardiovascular risk factors when determining the treatment plan for patients with prostate cancer.1, 190, 192, 205 Patients receiving leuprolide should be monitored for symptoms and signs suggestive of the development of cardiovascular disease and managed according to current clinical practice guidelines.1, 190, 192, 205
Androgen deprivation therapy is associated with prolongation of the QT/QTc interval.1, 190, 192, 205 Clinicians should carefully weigh the benefits and risks of androgen deprivation therapy in patients with congenital long QT syndrome, congestive heart failure, frequent electrolyte abnormalities, and in patients receiving drugs known to prolong the QT interval.1 190, 192, 205 Correct any electrolyte abnormalities.1, 190, 192, 205 Consider monitoring electrocardiograms and electrolytes periodically.1, 190, 192, 205
Psychiatric events, including symptoms of emotional lability (e.g., crying, irritability, impatience, anger, aggression), have been reported in pediatric patients receiving GnRH agonists, including leuprolide.155, 204 Monitor pediatric patients receiving leuprolide for the development or worsening of psychiatric symptoms during therapy.155, 204
Depression may occur or worsen during therapy with GnRH agonists, including leuprolide, in female patients receiving treatment for endometriosis and/or uterine leiomyomatas.116, 191 Carefully observe female patients for depression, particularly those with a history of depression, and consider whether the risks of continued therapy outweigh the benefits.116, 191 Refer women with new or worsening depression to a mental health professional, as appropriate.116, 191
Seizures have been reported in patients receiving GnRH agonists, including leuprolide.116, 155, 190, 191, 192, 204, 205 Cases were reported in patients with or without a history of convulsion-related disorders (e.g., epilepsy, cerebrovascular disorders, CNS anomalies or tumors) or receiving concomitant medications associated with seizures (e.g., bupropion, selective serotonin-reuptake inhibitors).116 155, 190, 191, 192, 204 Patients who experience seizures should be managed according to current standards of care. 190 192 205
Pseudotumor cerebri (idiopathic intracranial hypertension) has been reported in pediatric patients receiving GnRH agonists, including leuprolide.155, 204 Monitor patients for signs and symptoms (e.g., headaches, papilledema, blurred vision, diplopia, loss of vision, pain behind the eye or pain with eye movement, tinnitus, dizziness, nausea).155, 204
Monitor serum levels of testosterone following injection of leuprolide in patients receiving the drugs for the treatment of prostate cancer.1, 190, 192, 205 In the majority of patients treated with leuprolide, testosterone levels increased above baseline during the first week, and then declined thereafter to castration levels (<50 ng/dL) within 4 weeks.1, 190, 192, 205
Lupron Depot®3.75 and Lupron Depot® 11.25 mg induce a hypoestrogenic state resulting in loss of bone mineral density (BMD), some of which may not be reversible after treatment discontinuation.116, 191 In women with major risk factors for decreased BMD (e.g., chronic alcohol use [more than 3 units each day], tobacco use, strong family history of osteoporosis, chronic use of medications that decrease BMD [such as anticonvulsants and corticosteroids]), use of Lupron Depot® may pose an additional risk.116, 191 Carefully weigh the risks and benefits of this therapy in these patients.116, 191 The duration of Lupron Depot®treatment is limited by the risk of loss of BMD.116, 191 When using Lupron Depot® for the management of endometriosis, addition of norethindrone acetate (add-back therapy) is effective in reducing BMD loss that occurs with leuprolide acetate.116, 191 Do not retreat with Lupron Depot® without concurrent norethindrone acetate.116, 191 Assess BMD before retreatment.116, 191
Leuprolide may cause fetal harm if administered to a pregnant female, based on data from animal reproduction studies and the drug's mechanism of action.116, 190, 191, 192, 205 Leuprolide is contraindicated during pregnancy; pregnancy status should be verified prior to initiating therapy.116, 190, 191, 192, 205 Discontinue leuprolide if a female becomes pregnant during treatment and apprise of the potential fetal risk.116, 190, 191, 192, 205 Advise females of reprodutive potential to notify their clinician if they become pregnant.116, 190, 191, 192, 205
Some leuprolide dosage regimens may inhibit ovulation and menstruation; however, contraception is not ensured.116, 190, 191, 192, 205 If contraception is indicated, females of reproductive potential should be advised to use non-hormonal methods of contraception while on therapy.116, 190, 191, 192, 205
Hypersensitivity reactions, including anaphylaxis, have been reported with leuprolide use.1, 116, 155, 190, 191, 192, 204, 205 Leuprolide is contraindicated in patients with a history of hypersensitivity to gonadotropin-releasing hormone (GnRH) or GnRH agonist analogs.1, 116, 155, 190, 191, 192, 204, 205 In clinical trials, adverse events of asthma were reported in women with preexisting histories of asthma, sinusitis, and environmental or drug allergies.116, 191 Symptoms consistent with an anaphylactoid or asthmatic process have been reported during postmarketing experience.1 116 190, 191 205
Leuprolide acetate injection may cause fetal harm when administered to a pregnant female based on findings from animal studies and the drug's mechanism of action.1, 116, 155, 190, 191, 192, 204, 205 Discontinue leuprolide if pregnancy occurs during treatment and inform patients of potential risk to the fetus.116, 191 Leuprolide is contraindicated in pregnant females.116 155 191, 204
Based on animal reproduction studies, leuprolide may be associated with an increased risk of pregnancy complications, including early pregnancy loss and fetal harm.116, 191, 204 In animal reproduction studies, subcutaneous administration of leuprolide acetate to rabbits during the period of organogenesis caused embryofetal toxicity, decreased fetal weights, and a dose-dependent increase in major fetal abnormalities in animals at doses less than the recommended human dose based on body surface area using an estimated daily dose.116 155, 191, 204 Similar studies in rats showed increased fetal mortality and decreased fetal weights but no increase in fetal malformations at doses less than the recommended human dose based on body surface area using an estimated daily dose.116, 155 191, 204
There are no data on the presence of leuprolide in either animal or human milk, the effects on breastfed infants, or the effects on milk production.116, 191, 204 The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for leuprolide and any potential adverse effects on the breastfed infant from the drug or underlying maternal condition.116, 191, 204
Females and Males of Reproductive Potential
Exclude pregnancy in women of reproductive potential prior to initiating leuprolide if clinically indicated.116, 155 191, 204
When used at the recommended dose and dosing interval for the treatment of endometriosis and uterine leiomyomata, leuprolide usually inhibits ovulation and stops menstruation.116 155, 191 Contraception, however, is not ensured by taking leuprolide.116, 191, 204 If contraception is indicated, advise women to use nonhormonal methods of contraception while on treatment with leuprolide.116, 191, 204
Continuous leuprolide therapy may impair fertility in males as a result of the drug's pharmacologic effects.5, 6, 7, 8, 12, 13, 88, 190 Continuous leuprolide therapy may also impair fertility in females as a result of decreased gonadotropin release and subsequent inhibition of estrogen production, ovulation, and corpus luteum formation.5, 88, 116, 191 Clinical and pharmacologic studies in adults (>18 years of age) receiving leuprolide acetate and similar analogs have shown reversibility of fertility suppression when the drugs were discontinued after continuous administration for periods of up to 24 weeks.116 155, 191 204
Safety and effectiveness of leuprolide acetate depot suspension for treatment of central precocious puberty (Lupron Depot-Ped®) have been established in pediatric patients ≥1 year of age.155 Safety and effectiveness of leuprolide acetate for injectable suspension for treatment of central precocious puberty (Fensolvi®) have been established in pediatric patients ≥2 years of age.204
Safety and efficacy of leuprolide were established in older adult male patients for the treatment of prostate cancer; in clinical trials; 69-80% of patients were ≥65 years of age.1, 190, 192, 205
Leuprolide is not indicated in postmenopausal women and has not been studied in this population.116, 191
The pharmacokinetics of leuprolide in patients with impaired hepatic function have not been determined to date.1, 116, 155, 191, 192, 204, 205
The pharmacokinetics of leuprolide in patients with impaired renal function have not been determined to date.1, 116, 155, 191, 192, 204, 205
Common adverse reactions occurring in >10% of males receiving leuprolide for the treatment of prostate cancer include hot flashes/sweats, general pain, hypertension, testicular atrophy, injection site reaction, GI disorders, joint disorders, musculoskeletal pain, urinary disorder, and lethargy/fatigue.1, 190, 192, 205
Common adverse reactions occurring in >10% of females receiving leuprolide for the treatment of endometriosis and uterine leiomyomata include hot flashes/sweats, headache, vaginitis, depression/emotional lability, general pain, asthenia, weight gain/loss, nausea/vomiting, decreased libido, dizziness, constipation, diarrhea, acne, and skin reactions.116 191
Common adverse reactions occurring in ≥10% or more of pediatric patients receiving leuprolide for the treatment of central precocious puberty include injection site reactions (including pain), nasopharyngitis, pyrexia, headache, psychiatric events, and cough.155, 204
No formal drug interaction studies have been performed to date with leuprolide.1, 116, 155, 191, 192, 204
Metabolism of leuprolide does not involve cytochrome P-450 (CYP) isoenzymes;1, 116, 155, 191 pharmacokinetic interactions associated with CYP isoenzymes are therefore unlikely to occur with leuprolide.1, 116, 155, 191
Combined therapy with a GnRH analog (e.g., leuprolide) and an antiandrogen (e.g., megestrol, flutamide) in patients with prostate cancer may produce additive antineoplastic effects by producing complete androgen withdrawal.49, 102, 111, 140, 141, 142, 143, 144, 195, 200 These drugs are used concomitantly in prostate cancer for additive therapeutic effect195, 200
Diagnostic Tests of Pituitary Gonadotropic and Gonadal Functions
Due to the suppression of the pituitary-gonadal system by leuprolide, results of diagnostic tests of pituitary gonadotropic and gonadal functions conducted during and after treatment with leuprolide may be affected.190, 192
Leuprolide is a gonadotropin-releasing hormone (GnRH) analog that shares the action of the naturally occurring hormone.1, 2, 3, 5, 10, 116, 155, 190, 191, 192, 204, 205
Leuprolide differs structurally from naturally occurring GnRH by the presence of the d-isomer of leucine at position 6 and an ethylamide group replacing glycine at position 10.2, 3, 4 These structural modifications result in increased potency of leuprolide (in terms of luteinizing hormone release) compared with natural GnRH.1, 3, 4, 8, 155, 190, 191, 192, 204, 205 The drug does not appear to affect receptor affinity for gonadotropins.11, 14 The pharmacology of leuprolide is complex and several mechanisms of action may be involved.6, 7 Repeated dosing of leuprolide results in suppression of the pituitary-gonadal system and decreased secretion of gonadotropins (e.g., follicle stimulating hormone [FSH] and luteinizing hormone [LH]), which suppresses ovarian and testicular steroidogenesis.1, 116 155, 190, 191, 192, 204, 205 This inhibitory effect is reversible upon discontinuance of therapy.155, 204 The drug does not appear to affect receptor affinity for gonadotropins.11, 14
Leuprolide is a peptide that is primarily metabolized by peptidase into smaller inactive peptides.1, 116, 155 191 204, 205 Because of its polypeptide nature, leuprolide acetate is destroyed in the GI tract and, therefore, usually is administered parenterally.1, 28, 116, 155, 191 Following subcutaneous administration, leuprolide acetate is rapidly and almost completely absorbed.29 In adults, bioavailability of leuprolide acetate following subcutaneous administration is comparable to that following IV† administration.1 Bioavailability of the drug reportedly is about 94% in rats following subcutaneous administration.29 Following IM administration of the long-acting depot suspension (Lupron Depot®) or subcutaneous administration of the long-acting injectable suspension (Eligard®, Fensolvi®), or emulsion (Camcevi®), the drug is released slowly and gradually from its biodegradable copolymer-containing vehicle (after an initial, rapid absorption of immediately available drug), thus providing a prolonged duration of action.116, 117, 118, 155, 190, 191, 192, 204, 205 Plasma protein binding of leuprolide has been reported to range from 43-49%.1, 116 155 190, 191, 192, 204, 205 In healthy male volunteers, the terminal elimination half-life of leuprolide following IV administration was approximately 3 hours (based on a 2-compartment model).1, 155, 190, 205 The pharmacokinetics of leuprolide in patients with impaired renal or hepatic function have not been determined to date.1, 116, 155, 191, 192, 204, 205
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
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.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Parenteral | For depot suspension, for IM injection | 3.75 mg | Lupron Depot® (available as prefilled dual-chambered syringes) | AbbVie |
7.5 mg | Lupron Depot® (available as prefilled dual-chambered syringes) | AbbVie | ||
Lupron Depot-Ped® (available as prefilled dual-chambered syringes) | AbbVie | |||
11.25 mg | Lupron Depot® (available as prefilled dual-chambered syringes) | AbbVie | ||
Lupron Depot-Ped® (available as prefilled dual-chambered syringes) | AbbVie | |||
15 mg | Lupron Depot-Ped® (available as prefilled dual-chambered syringes) | AbbVie | ||
22.5 mg | Lupron Depot® (available as prefilled dual-chambered syringes) | AbbVie | ||
30 mg | Lupron Depot® (available as prefilled dual-chambered syringes) | AbbVie | ||
Lupron Depot-Ped® (available as prefilled dual-chambered syringes) | AbbVie | |||
45 mg | Lupron Depot® (available as prefilled dual-chambered syringes) | AbbVie | ||
For injectable suspension, for subcutaneous use | 45 mg | Eligard® | Tolmar Pharmaceuticals | |
Fensolvi® | Tolmar Pharmaceuticals | |||
Injection, for subcutaneous use | 5 mg/mL* | Leuprolide Acetate Injection |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Parenteral | Injectable emulsion, for subcutaneous use | 42 mg (of leuprolide) | Camcevi® (available as a prefilled syringe) | Foresee Pharmaceuticals |
1. Sun Pharmaceuticals. Leuprolide acetate injection prescribing information. Cranbury, NJ; 2022 Aug.
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. [PubMed 6427478]
3. The Leuprolide Study Group. Leuprolide versus diethylstilbestrol for metastatic prostate cancer. N Engl J Med . 1984; 311:1281-6. [PubMed 6436700]
4. Soloway MS. Newer methods of hormonal therapy for prostate cancer. Urology . 1984; 24(Suppl):30-40. [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. [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]
7. Rajfer J, Swerdloff RS, Heber DM. Testicular histology following chronic gonadotropin-releasing hormone agonist treatment. Fertil Steril . 1984; 42:765-71. [PubMed 6436070]
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. [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. [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. [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]
26. Okada H, Sakura Y, Kawaji H et al. Regression of rat mammary tumors by a potent luteinizing hormone-releasing hormone analogue (leuprolide) administered vaginally. Cancer Res . 1983; 43:1869-74. [PubMed 6403230]
27. Schally AV, Redding TW, Comaru-Schally AM. Potential use of analogs of luteinizing hormone-releasing hormones in the treatment of hormone-sensitive neoplasms. Cancer Treat Rep . 1984; 68:281-9. [PubMed 6362868]
28. Okada H, Yamazaki I, Ogawa Y et al. Vaginal absorption of a potent luteinizing hormone-releasing hormone analog (leuprolide) in rats I: absorption by various routes and absorption enhancement. J Pharm Sci . 1982; 71:1367-71. [PubMed 6818337]
29. Yamazaki I. Serum concentration patterns of an LHRH agonist, gonadotrophins and sex steroids after subcutaneous, vaginal, rectal and nasal administration of the agonist to pregnant rats. J Reprod Fertil . 1984; 72:129-36. [PubMed 6433008]
30. Tharandt L, Schulte H, Benker G et al. Binding of luteinizing hormone releasing hormone to human serum proteins—influence of a chronic treatment with a more potent analogue of LH-RH. Horm Metab Res . 1979; 11:391-4. [PubMed 381140]
31. Koch Y, Baram T, Hazum E et al. Resistance to enzymic degradation of LH-RH analogues possessing increased biological activity. Biochem Biophys Res Commun . 1977; 74:488-91. [PubMed 319798]
32. The Takeda-Abbott Prostatic Cancer Study Group. leuprolide (d-leu-Des Gly10-Pro9-NH Et-LHRH) in the therapy of advanced prostatic carcinoma. In: Spitzy KH, Karrer K, eds. Proceedings of the 13th International Congress of Chemotherapy. 1983; 242:49-53.
33. Smith JA Jr, Glode LM, Max DT et al. Clinical effects of gonadotropin-releasing hormone analogue in metastatic carcinoma of prostate. Urology . 1985; 25:106-14. [PubMed 3918369]
34. Winfield H, Trachtenberg J. A comparison of a powerful luteinizing hormone releasing hormone analogue agonist and estrogen in the treatment of advanced prostatic cancer. J Urol . 1984; 131:1107-9. [PubMed 6427477]
35. Lee M, Stobnicki M, Ray P et al. Preliminary evaluation of the safety and efficacy of leuprolide versus diethylstilbestrol in the treatment of stage D2 prostatic adenocarcinoma. In: Spitzy KH, Karrer K, eds. Proceedings of the 13th International Congress of Chemotherapy. 1983; 242:54-8.
36. Trachtenberg J. The treatment of metastatic prostatic cancer with a potent luteinizing hormone releasing hormone analogue. J Urol . 1983; 129:1149-52. [PubMed 6406688]
37. Torti FM. Hormonal therapy for prostate cancer. N Engl J Med . 1984; 311:1313-4. [PubMed 6436701]
38. Henahan J. New prostate cancer drugs: few CV effects? JAMA . 1983; 250:2097-9. Editorial.
39. Stein BS, Smith JA Jr. DES lead-in to use of luteinizing hormone releasing hormone analogs in treatment of metastatic carcinoma of prostate. Urology . 1985; 25:350-3. [PubMed 3920802]
40. Yamanaka H, Makino T, Yajima H et al. Efficacy of (d-LEU6)-DES GLY-NH210-LHRH ethylamide against prostatic cancer. Prostate . 1985; 6:27-34. [PubMed 3918298]
41. Klein LA. Prostatic carcinoma. N Engl J Med . 1979; 300:824-33. [PubMed 106277]
42. Schmidt JD, Scott WW, Gibbons R et al. Chemotherapy programs of the National Prostatic Cancer Project (NPCP). Cancer . 1980; 45:1937-46. [PubMed 6445225]
43. Garnick MB, Glode LM, Smith JA et al. Leuprolide: a review of its effects in comparison with diethylstilboestrol in the treatment of advanced cancer of the prostate. Br J Clin Pract . 1985; 39:73-6. [PubMed 3921047]
44. Paulson DF. Management of metastatic prostatic cancer. Urology . 1985; 25(Suppl):49-52. [PubMed 3918376]
45. Tolis G, Ackman D, Stellos A et al. Tumor growth inhibition in patients with prostatic carcinoma treated with luteinizing hormone-releasing hormone agonists. Med Sci . 1982; 79:1658-62.
46. Elder JS, Catalona WJ. Management of newly diagnosed metastatic carcinoma of the prostate. Urol Clin North Am . 1984; 11:283-95. [PubMed 6428022]
47. Drago JR, Rohner T, Santen R et al. Leuprolide: a review of its effects in animals and man. Br J Clin Pract . 1985; 39:77-9. [PubMed 3921048]
48. Kirk D. Prostatic carcinoma. BMJ . 1985; 290:875-6. [PubMed 3919825]
49. Labrie F, Dupont A, Belanger A et al. New approach in the treatment of prostate cancer: complete instead of partial withdrawal of androgens. Prostate . 1983; 4:579-94. [PubMed 6415630]
50. Faure N, Lemay A, Laroche B et al. Preliminary results on the clinical efficacy and safety of androgen inhibition by an LHRH agonist alone or combined with an antiandrogen in the treatment of prostatic carcinoma. Prostate . 1983; 4:601-24. [PubMed 6415632]
51. Brendler CB. Hormonal therapy of prostatic cancer. J Urol . 1985; 133:650. [PubMed 3920407]
52. Harvey HA, Lipton A, Santen RJ et al. Phase II study of a gonadotropin-releasing hormone analog (leuprolide) in postmenopausal advanced breast cancer patients. Proc Am Soc Clin Oncol . 1981; 22:444.
53. Comite F, Cutler GB, Rivier J et al. Short-term treatment of idiopathic precocious puberty with a long-acting analogue of luteinizing hormone-releasing hormone. N Engl J Med . 1981; 305:1546-50. [PubMed 6458765]
54. Chang RJ, Laufer LR, Meldrum DR et al. Steroid secretion in polycystic ovarian disease after ovarian suppression by a long-acting gonadotropin-releasing hormone agonist. J Clin Endocrinol Metab . 1983; 56:897-903. [PubMed 6403570]
55. Corbin A. From contraception to cancer: a review of the therapeutic applications of LHRH analogues as antitumor agents. Yale J Biol Med . 1982; 55:27-47. [PubMed 6810559]
56. Schwarzstein L, Aparicio NJ, Turner D et al. d -Leucine-6-luteinizing hormone-releasing hormone ethylamide in the treatment of normogonadotropic oligoasthenospermia. Fertil Steril 1978; 29:332-5.
57. Jacobi GH, Wenderoth UK. Gonadotropin-releasing hormone analogues for prostate cancer: untoward side effects of high-dose regimens acquire a therapeutical dimension. Eur Urol . 1982; 8:129-34. [PubMed 6281023]
58. Grayhack JT, Kozlowski JM. Endocrine therapy in the management of advanced prostatic cancer: a case for early introduction of treatment. Urol Clin North Am . 1980; 7:639-43. [PubMed 7456176]
59. Glode LM, Robinson J, Gould SF. Protection from cyclophosphamide-induced testicular damage with an analogue of gonadotropin-releasing hormone. Lancet . 1981; 1:1132-4. [PubMed 6112490]
60. Tarnavsky GK, Reeves JJ. Pituitary binding of LNRH [sic: LHRH] analogs. J Anim Sci . 1976; 43:307.
61. Linde R, Doelle GC, Alexander N et al. Reversible inhibition of testicular steroidogenesis and spermatogenesis by a potent gonadotropin-releasing hormone agonist in normal men: an approach toward the development of a male contraceptive. N Engl J Med . 1981; 305:663-7. [PubMed 6267464]
62. Heber D, Swerdloff RS. Male contraception: synergism of gonadotropin-releasing hormone analog and testosterone in suppressing gonadotropin. Science . 1980; 209:936-8. [PubMed 6773142]
63. Anon. Drugs of choice for cancer chemotherapy. Med Lett Drugs Ther . 1993; 35:43-50. [PubMed 8487743]
64. Gittes RF. Serum acid phosphatase and screening for carcinoma of the prostate. N Engl J Med . 1983; 309:852-3. [PubMed 6888470]
66. Anon. Leuprolide for prostatic cancer. Med Lett Drugs Ther . 1985; 27:71-2. [PubMed 2410765]
67. Heber D, Swerdloff RS. Gonadotropin-releasing hormone analog and testosterone synergistically inhibit spermatogenesis. Endocrinology . 1981; 108:2019-21. [PubMed 6783399]
68. Corbin A, Beattie CW, Rees R. Postcoital contraceptive effects of agonist analogs of luteinizing hormone-releasing hormone. Fertil Steril . 1977; 28:471-5. [PubMed 321265]
69. Harvey HA, Lipton A, Max DT et al. Medical castration produced by the GnRH analogue leuprolide to treat metastatic breast cancer. J Clin Oncol . 1985; 3:1068-72. [PubMed 3926958]
70. DeSombre ER, Johnson ES, White WF. Regression of rat mammary tumors effected by a gonadoliberin analog. Cancer Res . 1976; 36:3830-3. [PubMed 782692]
71. Meldrum DR, Chang RJ, Lu J et al. “Medical oophorectomy” using a long-acting GnRH agonist—a possible new approach to the treatment of endometriosis. J Clin Endocrinol Metab . 1982; 54:1081-3. [PubMed 6801075]
72. Guitelman A, Mancini AM, Aparicio NJ et al. Effect of d-leucine-6-luteinizing hormone-releasing hormone ethylamide in patients with hypogonadotropic hypogonadism with anosmia. Fertil Steril . 1979; 32:308-11. [PubMed 385362]
73. Tharandt L, Schulte H, Benker G et al. Treatment of isolated gonadotropin deficiency in men with synthetic LH-RH and a more potent analogue of LH-RH. Neuroendocrinology . 1977; 24:195-207. [PubMed 345145]
74. Frick J, Danner C, Kunit G et al. The effect of chronic administration of a synthetic LH-RH analogue intranasally in cryptorchid boys. Int J Androl . 1980; 3:469-78. [PubMed 6108293]
75. Kahan A, Delrieu F, Amor B et al. Disease flare induced by d-Trp6-LHRH analog in patients with metastatic prostatic cancer. Lancet . 1984; 1:971-2. [PubMed 6143912]
76. Glode LM, Robinson J, Gould SF et al. Protection of spermatogenesis during chemotherapy. Drugs Exp Clin Res . 1982; 8:367-78.
77. Happ J, Weber T, Krause U et al. Gonadotropin secretion after subcutaneous and intravenous stimulation with d-Leu6-des-Gly10-GnRH-ethylamide in healthy human males. Infertility . 1978; 1:87-99.
78. Bhasin S, Heber D, Steiner BS et al. Hormonal effects of gonadotropin-releasing hormone (GnRH) agonist in the human male. III. Effects of long term combined treatment with GnRH agonist and androgen. J Clin Endocrinol Metab . 1985; 60:998-1003. [PubMed 3920237]
79. Bartfai G, Sas M, Morvay J et al. Effects of LHRH and long-acting LHRH on serum LH and FSH levels of healthy women. J Endrocrinol Invest . 1981; 4:359-62.
80. Matsuo H, Baba Y, Nair RMG et al. Structure of the porcine LH- and FSH-releasing hormone. I: the proposed amino acid sequence. Biochem Biophys Res Commun . 1971; 43:1334-9. [PubMed 4936338]
81. Burgus R, Butcher M, Amoss M et al. Primary structure of the ovine hypothalamic luteinizing hormone-releasing factor (LRF). Proc Nat Acad Sci USA . 1972; 69:278-82. [PubMed 4550508]
82. Page JG (TAP Pharmaceuticals, North Chicago, IL): personal communication; 1985 Sep.
83. Fujino M, Fukuda T, Shinagawa S et al. Synthetic analogs of luteinizing hormone releasing hormone (LH-RH) substituted in position 6 and 10. Biochem Biophys Res Commun . 1974; 60:406-13. [PubMed 4608231]
84. Eidne KA, Flanagan CA, Millar RP. Gonadotropin-releasing hormone binding sites in human breast carcinoma. Science . 1985; 229:989-91. [PubMed 2992093]
85. Miller WR, Scott WN, Morris R et al. Growth of human breast cancer cells inhibited by a luteinizing hormone-releasing hormone agonist. Nature . 1985; 313:231-33. [PubMed 2982100]
86. Reviewers' comments (personal observations); 1985 Sep.
87. Manni A, Santen R, Harvey H et al. Treatment of breast cancer with GnRH. Endocr Rev . (in press).
88. Nillius SJ, Bergquist C. LHRH agonists for female contraception. In: Vickery BH, Nestor JJ Jr, Hafez ESE, eds. LHRH and its analogs: contraceptive and therapeutic applications. Boston, MA: MTP Press Ltd; 1984:207-17.
89. Harvey HA, Lipton A, Max DT. LHRH analogs for human mammary carcinoma. In: Vickery BH, Nestor JJ Jr, Hafez ESE, eds. LHRH and its analogs: contraceptive and therapeutic applications. Boston, MA: MTP Press Ltd; 1984:329-35.
90. Flouret G, Stetler-Stevenson MA, Carone FA et al. Enzymatic degradation of LHRH and analogs. In: Vickery BH, Nestor JJ Jr, Hafez ESE, eds. LHRH and its analogs: contraceptive and therapeutic applications. Boston, MA: MTP Prss Ltd; 1984:397-410.
91. Barron J, Griffiths E, Tsalacopoulos G et al. Metabolism of [d-Trp6] LHRH. In: Vickery BH, Nestor JJ Jr, Hafez ESE, eds. LHRH and its analogs: contraceptive and therapeutic applications. Boston, MA: MTP Press Ltd; 1984:411-9.
92. Byar DP. The Veterans Administration Cooperative Urological Research Group's studies of cancer of the prostate. Cancer . 1973; 32:1126-30. [PubMed 4585929]
93. Veterans Administration Co-operative Urological Research Group. Treatment and survival of patients with cancer of the prostate. Surg Gynecol Obstet . 1967; 124:1011-7. [PubMed 6022476]
94. Waxman J. Cancer, chemotherapy, and fertility. BMJ . 1985; 290:1096-7. [PubMed 3921121]
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. [PubMed 3884062]
96. Hammond CB, Ory SJ. Diagnostic and therapeutic uses of gonadotropin-releasing hormone. Arch Intern Med . 1985; 145:1690-7. [PubMed 2862854]
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. [PubMed 3933329]
101. TAP Pharmaceuticals. Lupron Depot® (leuprolide acetate for depot suspension) monograph: the next generation of GnRH agonist analogs. Chicago, IL; 1989. Publication No. 97-9625.
102. Crawford ED, Eisenberger MA, McLeod DG et al. A controlled trial of leuprolide with and without flutamide in prostatic carcinoma. N Engl J Med . 1989; 321:419-24. [PubMed 2503724]
103. MacLeod TL, Eisen A, Sussmar GL. Anaphylactic reaction to synthetic luteinizing hormone-releasing hormone. Fertil Steril . 1987; 48:500-2. [PubMed 3305090]
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. [PubMed 2118858]
106. Tummon IS, Pepping ME, Binor Z et al. A randomized, prospective comparison of endocrine changes induced with intranasal leuprolide or danazol for treatment of endometriosis. Fertil Steril . 1989; 51:390-4. [PubMed 2522062]
107. Seltzer VL, Benjamin F. Treatment of pulmonary endometriosis with a long-acting GnRH agonist. Obstet Gynecol . 1990; 76(5 Part 2):929-31. [PubMed 2120647]
108. Rivlin ME, Miller JD, Kreuger RP et al. Leuprolide acetate in the management of ureteral obstruction caused by endometriosis. Obstet Gynecol . 1990; 75(3 Part 2):532-6. [PubMed 2106110]
109. Dowsett M, Mehta A, Mansi J et al. A dose-comparative endocrine-clinical study of leuprorelin in premenopausal breast cancer patients. Br J Cancer . 1990; 62:834-7. [PubMed 2123115]
110. Friedman AJ, Lobel SM, Rein MS et al. Efficacy and safety considerations in women with uterine leiomyomas treated with gonadotropin-releasing hormone agonists: the estrogen threshold hypothesis. Am J Obstet Gynecol . 1990; 163(4 Part 1):1114-9. [PubMed 2145765]
111. Crawford ED, Blumenstein BA, Goodman PJ et al. Leuprolide with and without flutamide in advanced prostate cancer. Cancer . 1990; 66(Suppl):1039-44. [PubMed 2118417]
112. Giraud B. Interim report of a large French multicentre study of efficacy and safety of 3.75 mg leuprorelin depot in metastatic prostatic cancer. J Int Med Res . 1990; 18(Suppl 1):84-9. [PubMed 1691113]
113. O'Brien A, Hibberd M. Clinical efficacy and safety of a new leuprorelin acetate depot formulation in patients with advanced prostatic cancer. J Int Med Res . 1990; 18(Suppl 1):57-68. [PubMed 2108886]
114. Rizzo M, Mazzei T, Mini E et al. Leuprorelin acetate depot in advanced prostatic cancer: a phase II multicenter trial. J Int Med Res . 1990; 18(Suppl 1):114-25. [PubMed 2108883]
115. Thompson IM, Zeidman EJ, Rodriguez FR. Sudden death due to disease flare with luteinizing hormone-releasing hormone agonist therapy for carcinoma of the prostate. J Urol . 1990; 144:1479-80. [PubMed 2122011]
116. AbbVie Inc. Leupron Depot® 3.75 mg (leuprolide acetate for depot suspension) prescribing information. North Chicago, IL; 2023 Oct. [Web]
117. Mazzei T, Mini E, Rizzo M et al. Human pharmacokinetic and pharmacodynamic profiles of leuprorelin acetate depot in prostatic cancer patients. J Int Med Res . 1990; 18(Suppl 1):42-56. [PubMed 2108885]
118. Toguchi H. Pharmaceutical manipulation of leuprorelin acetate to improve clinical performance. J Int Med Res . 1990; 18(Suppl 1):35-41. [PubMed 2138986]
119. Meyer BR, Kreis W, Eschbach J et al. Transdermal versus subcutaneous leuprolide: a comparison of acute pharmacodynamic effect. Clin Pharmacol Ther . 1990; 48:340-5. [PubMed 2121407]
120. Lemay A. Clinical appreciation of LHRH analogue formulations. Horm Res . 1989; 32(Suppl 1):93-102. [PubMed 2533161]
121. Sharifi R, Soloway M, The Leuprolide Study Group. Clinical study of leuprolide depot formulation in the treatment of advanced prostate cancer. J Urol . 1990; 143:68-71. [PubMed 2104638]
122. Matsubara M. [Effects of intranasal administration of LHRH superanalogue on endogenous LHRH and gonadotropins in humans.] (Japanese; with English abstract.). Nippon Naibunpi Gakkai Zasshi . 1986; 62:837-42. [PubMed 3096798]
123. Yamazaki I. Serum concentration patterns of an LHRH agonist, gonadotrophins and sex steroids after subcutaneous, vaginal, rectal and nasal administration of the agonist to pregnant rats. J Reprod Fertil . 1984; 72:129-36. [PubMed 6433008]
124. Meyer BR, Kreis W, Eschbach J et al. Successful transdermal administration of therapeutic doses of a polypeptide to normal human volunteers. Clin Pharmacol Ther . 1988; 44:607-12. [PubMed 3143511]
126. Miller JD. Leuprolide acetate for the treatment of endometriosis. Prog Clin Biol Res . 1990; 323:337-41. [PubMed 2106145]
127. Barbieri RL. New therapy for endometriosis. N Engl J Med . 1988; 318:512-4. [PubMed 2963214]
128. Henzl MR, Corson SL, Moghissi K et al. Administration of nasal nafarelin as compared with oral danazol for endometriosis: a multicenter double-blind comparative clinical trial. N Engl J Med . 1988; 318:485-9. [PubMed 2963213]
129. Anon. Nafarelin for endometriosis. Med Lett Drugs Ther . 1990; 32:81-2. [PubMed 2143265]
130. Kuhn JM, Billebaud T, Navratil H et al. Prevention of a gonadotropin-releasing hormone analogue (buserelin) in metastatic prostatic carcinoma by administration of an antiandrogen (nilutamide). N Engl J Med . 1989; 321:413-8. [PubMed 2503723]
131. Tummon IS, Ali A, Pepping ME et al. Bone mineral density in women with endometriosis before and during ovarian suppression with gonadotropin-releasing hormone agonists or danazol. Fertil Steril . 1988; 49:792-6. [PubMed 3129312]
132. Lindsay R. Estrogen therapy in the prevention and management of osteoporosis. Am J Obstet Gynecol . 1987; :1347-51. [PubMed 3578455]
133. Dawood MY, Lewis V, Ramos J. Cortical and trabecular bone mineral content in women with endometriosis: effect of gonadotropin-releasing hormone agonist and danazol. Fertil Steril . 1989; 52:21-6. [PubMed 2501109]
134. Johansen JS, Riis BJ, Hassager C et al. The effect of a gonadotropin-releasing hormone agonist analog (nafarelin) on bone metabolism. J Clin Endocrinol Metab . 1988; 67:701-6. [PubMed 2971080]
135. Gudmundsson JA, Ljunghall S, Bergquist C et al. Increased bone turnover during gonadotropin-releasing hormone superagonist-induced ovulation inhibition. J Clin Endocrinol Metab . 1987; 65:159-63. [PubMed 2953749]
136. Friedman AJ. Vaginal hemorrhage associated with degenerating submucous leiomyomata during leuprolide acetate. Fertil Steril . 1989; 52:152-4. [PubMed 2501108]
137. Friedman AJ, Rein MS, Pandian MR et al. Fasting serum growth hormone and insulin-like growth factor-I and -II concentrations in women with leiomyomata uteri treated with leuprolide acetate or placebo. Fertil Steril . 1990; 53:250-3. [PubMed 2105242]
138. Rein MS, Friedman AJ, Pandian MR et al. The secretion of insulin-like growth factors I and II by explant cultures of fibroids and myometrium from women treated with a gonadotropin-releasing hormone agonist. Obstet Gynecol . 1990; 76:388-94. [PubMed 2116610]
139. Surrey ES, Gambone JC, Lu JK et al. The effects of combining norethindrone with a gonadotropin-releasing hormone agonist in the treatment of symptomatic endometriosis. Fertil Steril . 1990; 53:620-6. [PubMed 2108056]
140. Crawford ED. Hormonal therapy of prostatic carcinoma: defining the challenge. Cancer . 1990; 66:1035-8. [PubMed 2203516]
141. Dupont A, Labrie F, Giguere M et al. Combination therapy with flutamide and [D-Trp6]LHRH ethylamide for stage C prostatic carcinoma. Eur J Cancer Clin Oncol . 1988; 24:659-66. [PubMed 3289945]
142. Labrie F, Dupont A, Giguere M et al. Benefits of combination therapy with flutamide in patients relapsing after castration. Br J Urol . 1988; 61:341-6. [PubMed 3289676]
143. Labrie F, Dupont A, Belanger A. Complete androgen blockade for the treatment of prostate cancer. In: DeVita VT Jr, Hellman S, Rosenberg A, eds. Important advances in oncology 1985 . Philadelphia: JB Lippincott; 1985:193-217.
144. Crawford ED, Davis MA. Luteinizing hormone-releasing hormone analogues in the treatment of prostate cancer. Cancer Treat Res . 1988; 39:25-38. [PubMed 2908606]
145. Wojciechowski NJ, Carter CA, Skoutakis VA et al. Leuprolide: a gonadotropin-releasing hormone analog for the palliative treatment of prostatic cancer. Drug Intell Clin Pharm . 1986; 20:746-51. [PubMed 2429815]
146. Sharifi R, Lee M, Ojeda L et al. Comparison of leuprolide and diethylstilbestrol for stage D2 adenocarcinoma of prostate. Urology . 1985; 26:117-24. [PubMed 3927551]
147. Friedman AJ, Harrison-Atlas D, Barbieri RL et al. A randomized, placebo-controlled, double-blind study evaluating the efficacy of leuprolide acetate depot in the treatment of uterine leiomyomata. Fertil Steril . 1989; 51:251-6. [PubMed 2492232]
148. Waibel-Treber S, Minne HW, Scharla SH et al. Reversible bone loss in women treated with GnRH-agonists for endometriosis and uterine leiomyoma. Hum Reprod . 1989; 4:384-8. [PubMed 2526152]
149. Matta WH, Shaw RW, Hesp R et al. Reversible trabecular bone density loss following induced hypo-estrogenism with the GnRH analogue buserelin in premenopausal women. Clin Endocrinol . (Oxford) 1988; 29:45-51.
150. Scharla SH, Minne HW, Schaible A et al. Decreases of plasma 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) and loss of spinal bone mass in women during treatment with GnRH agonists. Proc Workshop Vitam D; Volume 7 (Vitam D): Mol Cell Clin Endocrinol . 1988:840-1.
151. Dodson WC, Hughes CL, Whitesides DB et al. The effect of leuprolide acetate on ovulation induction with human menopausal gonadotropins in polycystic ovary syndrome. J Clin Endocrinol Metab . 1987; 65:95-100. [PubMed 2953752]
152. Lewinthal D, Taylor PJ, Pattinson HA et al. Induction of ovulation with leuprolide acetate and human menopausal gonadotropin. Fertil Steril . 1988; 49:585-8. [PubMed 3127242]
153. Kelly AC, Jewelewicz R. Alternate regimens for ovulation induction in polycystic ovarian disease. Fertil Steril . 1990; 54:195-202. [PubMed 2116328]
154. Radwanska E, Rawlins RG, Tummon I et al. Successful use of gonadotropin-releasing hormone agonist leuprolide for in vitro fertilization in a patient with polycystic ovarian disease and infertility unresponsive to standard treatment. Fertil Steril . 1988; 49:356-9. [PubMed 3123281]
155. AbbVie Inc. Lupron Depot-Ped® (leuprolide acetate for depot suspension). North Chicago, IL; 2023 Apr.
157. Kaplan SL, Grumbach MM. Pathophysiology and treatment of sexual precocity. J Clin Endocrinol Metab . 1990; 71:785-9. [PubMed 2205623]
158. Stein DT. Southwestern Internal Medicine Conference: new developments in the diagnosis and treatment of sexual precocity. Am J Med Sci . 1992; 303:53-71. [PubMed 1728875]
159. Clemons RD, Kappy MS, Stuart TE et al. Long-term effectiveness of depot gonadotropin-releasing hormone analogue in the treatment of children with central precocious puberty. Am J Dis Child . 1993; 147:653-7. [PubMed 8506834]
160. Neely EK, Hintz RL, Parker B et al. Two-year results of treatment with depot leuprolide acetate for central precocious puberty. J Pediatr . 1992; 121:634-40. [PubMed 1403402]
161. Cook JS, Doty KL, Conn PM et al. Assessment of depot leuprolide acetate dose-adequacy for central precocious puberty. J Clin Endocrinol Metab . 1992; 74:1206-9. [PubMed 1569169]
162. Parker KL, Baens-Bailon RG, Lee PA. Depot leuprolide acetate dosage for sexual precocity. J Clin Endocrinol Metab . 1991; 73:50-2. [PubMed 1904452]
163. Sklar CA, Rothenberg S, Blumberg D et al. Suppression of the pituitary-gonadal axis in children with central precocious puberty: effects on growth, growth hormone, insulin-like growth factor-I, and prolactin secretion. J Clin Endocrinol Metab . 1973; 73:734-8.
164. Lee PA, Page JG, the Leuprolide Study Group. Effects of leuprolide in the treatment of central precocious puberty. J Pediatr . 1989; 114:321-4. [PubMed 2492599]
165. Kappy MS, Stuart T, Perelman A. Efficacy of leuprolide therapy in children with central precocious puberty. Am J Dis Child . 1988; 142:1061-4. [PubMed 3140654]
166. Kappy M, Stuart T, Perelman A et al. Suppression of gonadotropin secretion by a long-acting gonadotropin-releasing hormone analog (leuprolide acetate, Lupron Depot) in children with precocious puberty. J Clin Endocrinol Metab . 1989; 69:1087-9. [PubMed 2507570]
167. Oerter KE, Manasco P, Barnes KM et al. Adult height in precocious puberty after long-term treatment with deslorelin. J Clin Endocrinol Metab . 1991; 73:1235-40. [PubMed 1955504]
168. Kauli R, Kornreich L, Laron Z. Pubertal development, growth and final height in girls with sexual precocity after therapy with the GnRH analogue D-TRP-6-LHRH: a report on 15 girls, followed after cessation of gonadotrophin suppressive therapy. Hormone Res . 1990; 33:11-7. [PubMed 2142928]
169. Feuillan PP, Jones J, Cutler GB Jr. Long term testolactone therapy for precocious puberty in girls with the McCune-Albright syndrome. J Clin Endocrinol Metab . 1993; 77:647-51. [PubMed 8370686]
170. Foster CM, Comite F, Pescovitz OH et al. Variable response to a long-acting agonist of luteinizing hormone-releasing hormone in girls with McCune-Albright syndrome. J Clin Endocrinol Metab . 1984; 59:801-5. [PubMed 6434582]
171. Rosenthal SM, Grumbach MM, Kaplan SL. Gonadotropin-independent familial sexual precocity with premature Leydig and germinal cell maturation (familial testotoxicosis): effects of a potent luteinizing hormone-releasing factor against and medroxyprogesterone acetate in four cases. J Clin Endocrinol Metab . 1983; 57:571-9. [PubMed 6223935]
172. Wierman ME, Beardsworth DE, Mansfield MJ et al. Puberty without gonadotropins: a unique mechanism of sexual development. N Engl J Med . 1985; 312:65-72. [PubMed 3917301]
173. Holland FJ, Fishman L, Bailey JD et al. Ketoconazole in the management of precocious puberty not responsive to LHRH-analogue therapy. N Engl J Med . 1985; 312:1023-8. [PubMed 2984563]
174. Laue L, Jones J, Barnes KM et al. Treatment of familial male precocious puberty with spironolactone, testolactone, and desorelin. J Clin Endocrinol Metab . 1993; 76:151-5. [PubMed 8421081]
175. Holland FJ, Kirsch SE, Selby R. Gonadotropin-independent precocious puberty (“testotoxicosis”): influence of maturational status on response to ketoconazole. J Clin Endocrinol Metab . 1987; 64:328-33. [PubMed 3539979]
176. Kaufman FR, Costin G, Reid BS. Autonomous ovarian hyperfunction followed by gonadotrophin-dependent puberty in McCune-Albright syndrome. Clin Endocrinol (Oxford) . 1986; 24:239-42.
177. Grumbach MM, Styne DM. Sexual precocity. In: Wilson JD, Foster DW, eds. Williams textbook of endocrinology. 8th ed. Philadelphia: WB Saunders; 1992:1186-1221.
178. Reviewers' comments (personal observations).
179. Food and Drug Administration. Search orphan drug designations and approvals. From FDA website. Accessed 2020 Sept 30. [Web]
181. Stovall TG, Muneyyirci-Delale O, Summitt RL et al. GnRH agonist and iron versus placebo and iron in the anemic patient before surgery for leiomyomas: a randomized controlled trial. Obstet Gynecol . 1995; 86(1):65-71. [PubMed 7784025]
182. Vogelzang NJ. One hundred thirteen men with hormone-refractory prostate cancer died today. J Clin Oncol . 1996; 14:1753-5. [PubMed 8656242]
183. Prostate Cancer Trialists' Collaborative Group. Maximum androgen blockade in advanced prostate cancer: an overview of 22 randomized trials with 3283 deaths in 5710 patients. Lancet . 1995; 346:265-9. [PubMed 7630245]
185. Schellhammer P, Sharifi R, Block N et al. A controlled trial of bicalutamide versus flutamide, each in combination with luteinizing hormone-releasing hormone analogue therapy, in patients with advanced prostate cancer. Urology . 1995; 45:745-52. [PubMed 7538237]
186. Friedman AJ, Harrison-Atlas D, Barbieri RL et al. A randomized, placebo-controlled, double-blind study evaluating the efficacy of leuprolide acetate depot in the treatment of uterine leiomyomata. Fertil Steril . 1989; 51:251-6. [PubMed 2492232]
188. Food and Drug Administration. GnRH agonists: Safety review of drug class used to treat prostate cancer (sold under the brand names Lupron, Zoladex, Trelstar, Viadur, Vantas, Eligard, Synarel, and generics). Rockville, MD; 2010 May 3. From FDA web site. [Web]
189. Food and Drug Administration. GnRH agonists: label change--increased risk of diabetes and certain cardiovascular diseases (update). Rockville, MD; 2010 Oct 20. From FDA web site. [Web]
190. AbbVie Inc. Lupron Depot® (leuprolide acetate for depot suspension) prescribing information. North Chicago, IL; 2024 Mar.
191. AbbVie Inc. Lupron Depot® 11.25 mg (leuprolide acetate for depot suspension) prescribing information. North Chicago, IL; 2023 Oct.
192. Tolmar Pharmacueticals Inc. Eligard® (leuprolide acetate) for injectable suspension, for subcutaneous use prescribing information. Fort Collins, CO; 2024 Jan.
195. Anon. Drugs of choice for cancer. Treat Guide Med Lett . 2003; 1:41-52.
196. Breast cancer. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2011 Jul 14. Available from website. Accessed 2011 Jul 30. [Web]
197. Sharma R, Beith J, Hamilton A. Systematic review of LHRH agonists for the adjuvant treatment of early breast cancer. Breast . 2005;14:181-91. [PubMed 15927827]
198. Prowell TM, Davidson NE. What is the role of ovarian ablation in the management of primary and metastatic breast cancer today? Oncologist . 2004;9:507-17.
199. Tanaka T, Niimi H, Matsuo N et al. Results of long-term follow-up after treatment of central precocious puberty with leuprorelin acetate: evaluation of effectiveness of treatment and recovery of gonadal function. J Clin Endocrinol Metab . 2005;90:1371-6. [PubMed 15598675]
200. Genpharm ULC. Flutamide capsules prescribing information. Toronto, ON; 2008 May. Available from website. Accessed 2011 Jul 19. [Web]
201. Prostate cancer. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2024 Mar 11 Available from website. Accessed 2024 Apr 16. [Web]
202. Chen M, Eugster EA. Central Precocious Puberty: Update on Diagnosis and Treatment. Paediatr Drugs . 2015; 17:273-81. [PubMed 25911294]
203. Kaplowitz P, Bloch C, Section on Endocrinology, American Academy of Pediatrics.. Evaluation and Referral of Children With Signs of Early Puberty. Pediatrics . 2016; 137 [PubMed 26668298]
204. Tolmar Pharmacueticals Inc. Fensolvi® (leuprolide acetate) for injectable suspension, for subcutaneous use prescribing information. Fort Collins, CO; 2022 Nov.
205. Accord BioPharma Inc. Camcevi® (leuprolide mesylate) injectable emulsion, for subcutaneous use prescribing information. Raleigh, NC; 2024 Mar.
206. Shore N, Mincik I, DeGuenther M, et al. World J Urol. In. A phase 3, open-label, multicenter study of a 6-month pre-mixed depot formulation of leuprolide mesylate in advanced prostate cancer patients. 2020:111-119.
207. Klein KO, Freire A, Gryngarten MG, et al. Phase 3 Trial of a Small-volume Subcutaneous 6-Month Duration Leuprolide Acetate Treatment for Central Precocious Puberty. J Clin Endocrinol Metab. 2020;105(10):e3660-e3671.
211. Sharifi R, Bruskewitz RC, Gittleman MC, Graham SD, Jr., Hudson PB, Stein B. Clin Ther. In. Leuprolide acetate 22.5 mg 12-week depot formulation in the treatment of patients with advanced prostate cancer. 1996:647-657.
212. Sharifi R, Knoll LD, Smith J, Kramolowsky E. Urology. In. Leuprolide acetate (30-mg depot every four months) in the treatment of advanced prostate cancer. 1998:271-276.
213. Spitz A, Young JM, Larsen L, Mattia-Goldberg C, Donnelly J, Chwalisz K. Prostate Cancer Prostatic Dis. In. Efficacy and safety of leuprolide acetate 6-month depot for suppression of testosterone in patients with prostate cancer. 2012:93-99.
214. Lee PA, Neely EK, Fuqua J, et al. Int J Pediatr Endocrinol. In. Efficacy of Leuprolide Acetate 1-Month Depot for Central Precocious Puberty (CPP): Growth Outcomes During a Prospective, Longitudinal Study. 2011:7.
215. Lee PA, Klein K, Mauras N, et al. J Clin Endocrinol Metab. In. Efficacy and safety of leuprolide acetate 3-month depot 11.25 milligrams or 30 milligrams for the treatment of central precocious puberty. 2012:1572-1580.
216. Lowrance W, Dreicer R, Jarrard DF, et al. Updates to advanced prostate cancer.: AUA/SUO guideline. J Urol. 2023;209(6):1082-90. [Web]
217. American College of Obstetricians and Gynecologists. Obstetrics & Gynecology. Practice Bulletin. Management of Endometriosis. 2010:223-36.
219. American College of Obstetricians and Gynecologists. Obstetrics & Gynecology. Practice Bulletin. Management of Symptomatic Uterine Leiomyomas. 2021:e100-115.
220. Hartmann KE, Fonnesbeck C, Surawicz T,et al.. Management of Uterine Fibroids. Comparative Effectiveness Review No. 195. (Prepared by the Vanderbilt Evidence-based Practice Center under Contract No. 290-2015-00003-I.) AHRQ Publication No. 17(18)-EHC028- EF. Rockville, MD: Agency for Healthcare Research and Quality; 2017 Dec.
221. Kaplowitz P, Bloch C, the Section On Endocrinology. Evaluation and Referral of Children With Signs of Early Puberty: Clinical Report. Pediatrics. 2016;137:e20153732
222. Carel JC, Eugster EA, Rogol A, et al. Consensus statement on the use of gonadotropin-releasing hormone analogs in children.. Pediatrics, 2009, 123, pp.e752-62.
229. Hembree WC, Cohen-Kettenis PT, Gooren L, et al. J Clin Endocrinol Metab. In. Endocrine Treatment of Gender-Dysphoric/Gender-Incongruent Persons: An Endocrine Society Clinical Practice Guideline. 2017:3869-3903.
230. Siristatidis CS, Gibreel A, Basios G, Maheshwari A, Bhattacharya S. Gonadotrophin-releasing hormone agonist protocols for pituitary suppression in assisted reproduction. Cochrane Database Syst Rev. 2015(11):CD006919.
10010. Francis PA, Regan MM, Fleming GF et al. Adjuvant ovarian suppression in premenopausal breast cancer. N Engl J Med . 2015; 372:436-46. [PubMed 25495490]
10011. Pagani O, Regan MM, Walley BA et al. Adjuvant exemestane with ovarian suppression in premenopausal breast cancer. N Engl J Med . 2014; 371:107-18. [PubMed 24881463]
10012. Francis PA, Pagani O, Fleming GF et al. Tailoring Adjuvant Endocrine Therapy for Premenopausal Breast Cancer. N Engl J Med . 2018; 379:122-137. [PubMed 29863451]
10013. Tevaarwerk AJ, Wang M, Zhao F et al. Phase III comparison of tamoxifen versus tamoxifen plus ovarian function suppression in premenopausal women with node-negative, hormone receptor-positive breast cancer (E-3193, INT-0142): a trial of the Eastern Cooperative Oncology Group. J Clin Oncol . 2014; 32:3948-58. [PubMed 25349302]
10016. Pan K, Bosserman LD, Chlebowski RT. Ovarian Suppression in Adjuvant Endocrine Therapy for Premenopausal Breast Cancer. J Clin Oncol . 2019; 37:858-861. [PubMed 30742565]
10017. Burstein HJ, Lacchetti C, Anderson H et al. Adjuvant Endocrine Therapy for Women With Hormone Receptor-Positive Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update on Ovarian Suppression. J Clin Oncol . 2016; 34:1689-701. [PubMed 26884586]
10018. Burstein HJ, Lacchetti C, Anderson H et al. Adjuvant Endocrine Therapy for Women With Hormone Receptor-Positive Breast Cancer: ASCO Clinical Practice Guideline Focused Update. J Clin Oncol . 2019; 37:423-438. [PubMed 30452337]
10020. Dowsett M, Lønning PE, Davidson NE. Incomplete Estrogen Suppression With Gonadotropin-Releasing Hormone Agonists May Reduce Clinical Efficacy in Premenopausal Women With Early Breast Cancer. J Clin Oncol . 2016; 34:1580-3. [PubMed 26729430]
10023. Gnant M, Mlineritsch B, Stoeger H et al. Adjuvant endocrine therapy plus zoledronic acid in premenopausal women with early-stage breast cancer: 62-month follow-up from the ABCSG-12 randomised trial. Lancet Oncol . 2011; 12:631-41. [PubMed 21641868]
10024. Gnant M, Mlineritsch B, Stoeger H et al. Zoledronic acid combined with adjuvant endocrine therapy of tamoxifen versus anastrozol plus ovarian function suppression in premenopausal early breast cancer: final analysis of the Austrian Breast and Colorectal Cancer Study Group Trial 12. Ann Oncol . 2015; 26:313-20. [PubMed 25403582]
10025. Bellet M, Gray KP, Francis PA et al. Twelve-Month Estrogen Levels in Premenopausal Women With Hormone Receptor-Positive Breast Cancer Receiving Adjuvant Triptorelin Plus Exemestane or Tamoxifen in the Suppression of Ovarian Function Trial (SOFT): The SOFT-EST Substudy. J Clin Oncol . 2016; 34:1584-93. [PubMed 26729437]
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. [PubMed 31164265]
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. [PubMed 27785653]
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.