Lupron Depot (leuprolide acetate for depot suspension) - 4 indications

Scroll down for information on each indication:

• central precocious puberty; approved 1993
• prostate cancer; approved July 1997
• endometriosis and to improve anemia from uterine fibroids; approved 2001

General Information

Lupron Depot (leuprolide acetate for depot suspension) is a gonadotropin releasing hormone (GnRH) agonist.

Lupron Depot is specifically indicated for the following conditions:

• for the management of endometriosis, including pain relief and reduction of endometriotic lesions
• for use with iron therapy before fibroid surgery to improve anemia from fibroids
• for the palliative treatment of advanced prostate cancer
• for the treatment of children with central precocious puberty (CPP)

Lupron Depot is supplied as a suspension for intramuscular administration. Scroll down for recommended dosing/administration for each condition. 

Mechanism of Action

Lupron Depot is in a class of drugs known as gonadotropin releasing hormone (GnRH) analogs. It works by inhibiting the production of the hormone testosterone, which may play a significant role in the growth of prostate cancer. Decreasing the levels of testosterone in the body may also alleviate bone pain and some urinary problems that may be associated with metastatic prostate cancer. 

Side Effects

Adverse effects associated with the use of Lupron Depot for endometriosis and uterine fibroids may include, but are not limited to, the following:

• hot flashes/sweats
• headache/migraine
• decreased libido
• depression/emotional lability
• dizziness
• nausea/vomiting
• pain
• vaginitis
• weight gain

Adverse effects associated with the use of Lupron Depot for prostate cancer may include, but are not limited to, the following:

• hot flashes/sweats
• injection site reaction/pain
• general pain
• swelling
• testicular shrinkage
• difficulty urinating
• fatigue/weakness
• headache
• joint, gastrointestinal, and respiratory problems

Adverse effects associated with the use of Lupron Depot for central precocious puberty may include, but are not limited to, the following:

Lupron Depot received 1 time each month:

• injection site reactions
• weight gain
• pain throughout body
• headache
• acne or seborrhea
• erythema multiforme
• mood changes
• vaginitis
• vaginal bleeding
• vaginal discharge

Lupron Depot received every 3 months:

• injection site pain
• weight gain
• headache
• mood changes
• injection site swelling 

Indication 1 - central precocious puberty

approved 1993

Dosing/Administration

Once Month Administration:

Lupron Depot is administered as a single intramuscular injection once a month. The starting dose will be dictated by the child's weight:

Body Weight	Recommended Dose
≤ 25 kg	7.5 mg
> 25-37.5 kg	11.25 mg
> 37.5 kg	15 mg

 

If adequate hormonal and clinical suppression is not achieved with the starting dose, it should be increased to the next available higher dose (e.g. 11.25 mg or 15 mg at the next monthly injection). Similarly, the dose may be adjusted with changes in body weight. The injection site should be varied periodically. The goal of therapy is to suppress pituitary gonadotropins and peripheral sex steroids, and to arrest progression of secondary sexual characteristics. Hormonal and clinical parameters should be monitored after 1–2 months of initiating therapy and with each dose change to ensure adequate pituitary gonadotropin suppression. Once a dose that results in adequate hormonal suppression is found, it can often be maintained for the duration of therapy in most children. Lupron Depot should be discontinued at the appropriate age of onset of puberty at the discretion of the physician.

3-month administration: 

Lupron Depot 11.25 mg or 30 mg for 3-month administration should be administered once every three months (12 weeks) as a single intramuscular injection. Regardless of the dose chosen, the goal of therapy is to suppress pituitary gonadotropins and peripheral sex steroids, and to arrest progression of secondary sexual characteristics. Hormonal and clinical parameters should be monitored during treatment, for instance at month 2-3, month 6 and further as judged clinically appropriate, to ensure adequate suppression. In case of inadequate suppression, other available GnRH agonists indicated for the treatment of CPP should be considered. Lupron Depot should be discontinued at the appropriate age of onset of puberty at the discretion of the physician.

Clinical Trial Results

One Month Formulation

55 CPP subjects (49 females and 6 males, naïve to previous GnRHa treatment), were treated with Lupron Depot 1-month formulations until age appropriate for entry into puberty and a subset of 40 subjects were then followed post-treatment. Treatment Period Data: During the treatment period, Lupron Depot suppressed gonadotropins and sex steroids to prepubertal levels. Suppression of peak stimulated LH concentrations to < 1.75 mIU/mL was achieved in 96% of subjects by month 1. Five subjects required increased doses of study drug to achieve or retain LH suppression. . The mean ± SD age at the start of treatment was 7 ± 2 years and the duration of treatment was 4 ± 2 years. Six months after the treatment period was finished, the mean peak stimulated LH was 20.6 ± SD 13.7 mIU/mL (n=30). Suppression (defined as regression or no change) of the clinical/physical signs of puberty was achieved in most patients. In females, suppression of breast development ranged from 66.7 to 90.6% of subjects during the first 5 years of treatment. The mean stimulated estradiol was 15.1 pg/mL at baseline, decreased to the lower level of detection (5.0 pg/mL) by Week 4 and was maintained there during the first 5 years of treatment. In males, suppression of genitalia development ranged from 60% to 100% of subjects during the first 5 years of treatment. The mean stimulated testosterone was 347.7 ng/dL at baseline and was maintained at levels no greater than 25.3 ng/dL during the first 5 years of treatment. In many subjects, growth rate decreased on treatment, as did bone age: chronological age ratio. Follow-up data: 35 females and 5 males participated in a post-treatment follow-up period to assess reproductive function (in females) and final height. At 6 months post-treatment, most subjects reverted to pubertal levels of LH (87.9%) and clinical signs of resumption of pubertal progression were evident with increase in breast development in girls (66.7%) and increase in genitalia development in boys (80%). Of the 40 patients evaluated in the follow-up, 33 were observed until they reached final or near final adult height. These patients had a mean increase in final adult height compared to baseline predicted adult height. The mean final adult height standard deviation score was -0.2. After stopping treatment, regular menses were reported for all female subjects who reached 12 years of age during follow-up.

Three Month Formulation

In a randomized, open-label clinical study of Lupron Depot 3-Month formulations, 84 subjects (76 female, 8 male) between 1 and 11 years of age received the Lupron Depot 11.25 mg or 30 mg for 3-month administration formulation. Each dose group had an equal number of treatment-naïve patients who had pubertal LH levels and patients previously treated with GnRHa therapies who had prepubertal LH levels at the time of study entry. The percentage of subjects with suppression of peak-stimulated LH to < 4.0 mIU/mL, as determined by assessments at months 2, 3 and 6 is 78.6% in the 11.25 mg dose and 95.2% in the 30 mg dose. For the Lupron Depot 11.25 mg dose for 3-month administration, 93% (39/42) of subjects and for Lupron Depot 30 mg dose for 3-month administration 100% (42/42) of subjects had sex steroid (estradiol or testosterone) suppressed to prepubertal levels at all visits. Clinical suppression of puberty in female patients was observed in 29 of 32 (90.6%) and 28 of 34 (82.4%) of patients in the 11.25 mg and 30 mg groups, respectively, at month 6. Clinical suppression of puberty in males was observed in 1 of 2 (50.0%) and 2 of 5 (40.0%) patients in the 11.25 mg and 30 mg groups, respectively, at month 6. In subjects with complete data for bone age, 29 of 33 (87.9 %) in the 11.25 mg group and 30 of 40 in the 30 mg group (75.0% ) had a decrease in the ratio of bone age to chronological age at month 6 compared to screening.

Indication 2 - prostate cancer

approved July 1997

Dosing/Administration

Lupron Depot is available in the following formulations: 

• 7.5 mg for 1-month administration
• 22.5 mg for 3-month administration
• 30 mg for 4-month administration
• 45 mg for 6-month administration

Dosage	7.5 mg for 1- Month Administration	22.5 mg for 3- Month Administration	30 mg for 4- Month Administration	45 mg for 6- Month Administration
Recommended dose	1 injection every 4 weeks	1 injection every 12 weeks	1 injection every 16 weeks	1 injection every 24 weeks

 

Clinical Trial Results

Lupron Depot 7.5 mg for 1-Month Administration

In an open-label, non-comparative, multicenter clinical study of Lupron Depot 7.5 mg for 1- month administration, 56 patients with stage D2 prostatic adenocarcinoma and no prior systemic treatment were enrolled. The objectives were to determine if a 7.5 mg depot formulation of leuprolide injected once every 4 weeks would reduce and maintain serum testosterone to castrate range (≤50 ng/dL), to evaluate objective clinical response, and to assess the safety of the formulation. During the initial 24 weeks, serum testosterone was measured weekly, biweekly, or every four weeks and objective tumor response assessments were performed at Weeks 12 and 24. Once the patient completed the initial 24-week treatment phase, treatment continued at the investigator's discretion. In the majority of patients, serum testosterone increased by 50% or more above baseline during the first week of treatment. Serum testosterone suppressed to the castrate range within 30 days of the initial depot injection in 94% (51/54) of patients for whom testosterone suppression was achieved (2 patients withdrew prior to onset of suppression) and within 66 days in all 54 patients. Mean serum testosterone suppressed to castrate level by Week 3. The median dosing interval between injections was 28 days.

Lupron Depot 22.5 mg for 3-Month Administration

In clinical studies, serum testosterone was suppressed to castrate within 30 days in 87 of 92 (95%) patients and within an additional two weeks in three patients. Two patients did not suppress for 15 and 28 weeks, respectively. Suppression was maintained in all of these patients with the exception of transient minimal testosterone elevations in one of them, and in another an increase in serum testosterone to above the castrate range was recorded during the 12 hour observation period after a subsequent injection. This represents stimulation of gonadotropin secretion. An 85% rate of "no progression" was achieved during the initial 24 weeks of treatment. A decrease from baseline in serum PSA of ≥90% was reported in 71% of the patients and a change to within the normal range (≤3.99 ng/mL) in 63% of the patients.

Lupron Depot 30 mg for 4-Month Administration

In an open-label, noncomparative, multicenter clinical study of Lupron Depot 30 mg for 4- month administration, 49 patients with stage D2 prostatic adenocarcinoma (with no prior treatment) were enrolled. The objectives were to determine whether a 30 mg depot formulation of leuprolide injected once every 16 weeks would reduce and maintain serum testosterone levels at castrate levels (≤ 50 ng/dL), and to assess the safety of the formulation. The study was divided into an initial 32-week treatment phase and a long-term treatment phase. Serum testosterone levels were determined biweekly or weekly during the first 32 weeks of treatment. Once the patient completed the initial 32-week treatment period, treatment continued at the investigator's discretion with serum testosterone levels being done every 4 months prior to the injection. In the majority of patients, testosterone levels increased 50% or more above the baseline during the first week of treatment. Mean serum testosterone subsequently suppressed to castrate levels within 30 days of the first injection in 94% of patients and within 43 days in all 49 patients during the initial 32-week treatment period. 

Lupron Depot 45 mg for 6-Month Administration

An open-label, non-comparative, multicenter clinical study of Lupron Depot 45 mg for 6- month administration enrolled 151 patients with prostate cancer. The study drug was administered as two intramuscular injections of Lupron Depot 45 mg at 24 week intervals (139/151 received 2 injections), and patients were followed for a total of 48 weeks. Among 148 patients who had testosterone value at Week 4, serum testosterone was suppressed to castrate levels (< 50 ng/dL) from Week 4 through Week 48 in an estimated 93.4% of patients. One patient failed to achieve testosterone suppression by Week 4, and eight patients had escapes from suppression (any testosterone value > 50 ng/dL after castrate levels were achieved). Mean testosterone levels increased to 608 ng/dL from a baseline of 435 ng/dL during the first week of treatment. By Week 4, the mean testosterone concentration had decreased to below castrate levels (16 ng/dL).

Indication 3 - endometriosis and to improve anemia from uterine fibroids

approved 2001

Dosing/Administration

Endometriosis

• Monotherapy: Lupron Depot 3.75 mg is indicated for management of endometriosis, including pain relief and reduction of endometriotic lesions.
• In Combination with Norethindrone Acetate: Lupron Depot 3.75 mg in combination with norethindrone acetate is indicated for initial management of the painful symptoms of endometriosis and for management of recurrence of symptoms.

Uterine Leiomyomata (Fibroids)

• Lupron Depot 3.75 mg, used concomitantly with iron therapy, is indicated for the preoperative hematologic improvement of women with anemia caused by fibroids for whom three months of hormonal suppression is deemed necessary. Consider a one-month trial period on iron alone, as some women will respond to iron alone. Lupron Depot 3.75 mg may be added if the response to iron alone is considered inadequate.

Clinical Trial Results

Endometriosis

• Lupron Depot Monotherapy
  • In controlled clinical studies, Lupron Depot 3.75 mg monthly for six months was shown to be comparable to danazol 800 mg/day in relieving the clinical sign/symptoms of endometriosis (pelvic pain, dysmenorrhea, dyspareunia, pelvic tenderness, and induration) and in reducing the size of endometrial implants as evidenced by laparoscopy. The clinical significance of a decrease in endometriotic lesions is not known, and laparoscopic staging of endometriosis does not necessarily correlate with the severity of symptoms. Lupron Depot 3.75 mg monthly induced amenorrhea in 74% and 98% of the women after the first and second month of treatment, respectively. Most of the remaining women reported episodes of only light bleeding or spotting. In the first, second and third post-treatment months, normal menstrual cycles resumed in 7%, 71% and 95% of women, respectively, excluding those who became pregnant.
• Lupron Depot with Norethindrone Acetate Add-Back Therapy
  • Two clinical studies with treatment duration of 12 months were conducted to evaluate the effect of co-administration of Lupron Depot 3.75 mg and norethindrone acetate on the loss of bone mineral density (BMD) associated with Lupron Depot 3.75 mg and on the efficacy of Lupron Depot in relieving symptoms of endometriosis. All women in these studies received calcium supplementation with 1000 mg elemental calcium. A total of 242 women were treated with monthly administration of Lupron Depot 3.75 mg (13 injections) and 191 of them were co-administered 5 mg norethindrone acetate taken daily. Suppression of menses (menses was defined as three or more consecutive days of menstrual bleeding) was maintained throughout treatment in 84% and 73% of women receiving leuprolide acetate and norethindrone acetate, in the controlled study and open label study, respectively. The median time for menses resumption after treatment with leuprolide acetate and norethindrone acetate was 8 weeks. Data also highlighted that co-administration of leuprolide acetate and norethindrone acetate 5 mg daily is effective in significantly reducing the loss of bone mineral density that occurs with Lupron Depot 3.75 mg and in relieving symptoms of endometriosis.

Uterine Fibroids

Lupron Depot 3.75 mg monthly for a period of three to six months was studied in four controlled clinical trials.

In one of these clinical studies, enrollment was based on hematocrit ≤ 30% and/or hemoglobin ≤ 10.2 g/dL. Administration of Lupron Depot 3.75 mg monthly, concomitantly with iron, produced an increase of ≥ 6% hematocrit and ≥ 2 g/dL hemoglobin in 77% of women at three months of therapy. The mean change in hematocrit was 10.1% and the mean change in hemoglobin was 4.2 g/dL. Clinical response was judged to be a hematocrit of ≥ 36% and hemoglobin of ≥ 12 g/dL, thus allowing for autologous blood donation prior to surgery. At two and three months, respectively, 71% and 75% of women met this criterion. These data suggest however, that some women may benefit from iron alone or 1 to 2 months of Lupron Depot 3.75 mg.

Excessive vaginal bleeding (menorrhagia or menometrorrhagia) decreased in 80% of women at three months. Episodes of spotting and menstrual-like bleeding were noted in 16% of women at final visit. In this same study, a decrease in uterine volume and myoma volume of ≥25% was seen in 60% and 54% of women, respectively. The mean fibroid diameter was 6.3 cm at pretreatment and decreased to 5.6 cm at the end of treatment. Lupron Depot 3.75 mg was found to relieve symptoms of bloating, pelvic pain, and pressure.

In three other controlled clinical trials, enrollment was not based on hematologic status. Mean uterine volume decreased by 41% and myoma volume decreased by 37% at final visit as evidenced by ultrasound or MRI. The mean fibroid diameter was 5.6 cm at pretreatment and decreased to 4.7 cm at the end of treatment. These women also experienced a decrease in symptoms including excessive vaginal bleeding and pelvic discomfort. Ninety-five percent of these women became amenorrheic with 61%, 25%, and 4% experiencing amenorrhea during the first, second, and third treatment months respectively. In addition, post-treatment follow-up was carried out in one clinical trial for a small percentage of women on Lupron Depot 3.75 mg (N=46) among the 77% who demonstrated a ≥ 25% decrease in uterine volume while on therapy. Menses usually returned within two months of cessation of therapy. Mean time to return to pretreatment uterine size was 8.3 months. Regrowth did not appear to be related to pretreatment uterine volume.  

Changes in Bone Density

In one of the studies for fibroids described above, when Lupron Depot 3.75 mg was administered for three months in women with uterine fibroids, vertebral trabecular bone mineral density, as assessed by quantitative digital radiography (QDR), revealed a mean decrease of 2.7% compared with baseline. Six months after discontinuation of therapy, a trend toward recovery was observed.