July 27, 2016
Recommended Topic Related To:

Lupron Depot

"In men with prostate cancer, regular aspirin use is associated with a slower rate of disease progression and a reduced risk of dying from the disease, according to a new study.

The findings come from an analysis of data from the large"...

A A A

Lupron Depot




CLINICAL PHARMACOLOGY

Mechanism Of Action

Leuprolide acetate, a GnRH agonist, acts as an inhibitor of gonadotropin secretion. Animal studies indicate that following an initial stimulation, continuous administration of leuprolide acetate results in suppression of ovarian and testicular steroidogenesis. This effect was reversible upon discontinuation of drug therapy.

Administration of leuprolide acetate has resulted in inhibition of the growth of certain hormone dependent tumors (prostatic tumors in Noble and Dunning male rats and DMBA-induced mammary tumors in female rats) as well as atrophy of the reproductive organs.

Pharmacodynamics

In humans, administration of leuprolide acetate results in an initial increase in circulating concentrations of luteinizing hormone (LH) and follicle stimulating hormone (FSH), leading to a transient increase in concentrations of the gonadal steroids (testosterone and dihydrotestosterone in males, and estrone and estradiol in premenopausal females). However, continuous administration of leuprolide acetate results in decreased concentrations of LH and FSH. In males, testosterone is reduced to castrate concentrations. In premenopausal females, estrogens are reduced to postmenopausal concentrations. These decreases occur within two to four weeks after initiation of treatment, and castrate concentrations of testosterone in prostatic cancer patients have been demonstrated for more than five years.

Leuprolide acetate is not active when given orally.

Pharmacokinetics

Absorption

LUPRON DEPOT 7.5 mg For 1-Month Administration

Following a single injection of LUPRON DEPOT 7.5 mg for 1-month administration to patients, mean plasma measured concentrations were 20 ng/mL at 4 hours and 0.36 ng/mL at 4 weeks. However, intact leuprolide and an inactive major metabolite could not be distinguished by the assay which was employed in the study.

LUPRON DEPOT 22.5 mg For 3-Month Administration

Following a single injection of LUPRON DEPOT 22.5 mg for 3-month administration in patients, mean peak plasma concentrations were 48.9 ng/mL at 4 hours and then declined to 0.67 ng/mL at 12 weeks. Leuprolide appeared to be released at a constant rate following the onset of steady-state concentrations during the third week after dosing, providing steady plasma concentrations through the 12-week dosing interval. However, intact leuprolide and an inactive major metabolite could not be distinguished by the assay which was employed in the study. The initial burst, followed by a decline to a steady-state concentration, was similar to the release pattern seen with the monthly formulation.

LUPRON DEPOT 30 mg For 4-Month Administration

Following a single injection of LUPRON DEPOT 30 mg for 4-month administration in sixteen orchiectomized prostate cancer patients, mean plasma concentrations were 59.3 ng/mL at 4 hours and then declined to 0.30 ng/mL at 16 weeks. Mean plasma concentrations from weeks 3.5 to 16 was 0.44 ± 0.20 ng/mL (range: 0.20-1.06). Leuprolide appeared to be released at a constant rate following the onset of steady-state concentrations during the fourth week after dosing, providing steady plasma concentrations throughout the 16-week dosing interval. However, intact leuprolide and an inactive major metabolite could not be distinguished by the assay which was employed in the study. The initial burst, followed by a decline to a steady-state concentration, was similar to the release pattern seen with the other depot formulations.

LUPRON DEPOT 45 mg For 6-Month Administration

Following a single injection of LUPRON DEPOT 45 mg for 6-month administration in 26 prostate cancer patients, mean peak plasma concentration of 6.7 ng/mL was observed at 2 hours and then declined to 0.07 ng/mL at 24 weeks. Leuprolide appeared to be released continuously following the onset of steady-state concentrations during the third week after dosing providing steady plasma concentrations through the 24-week dosing interval. The initial burst, followed by a decline to a steady-state concentration, was similar to the release pattern seen with the other depot formulations. In this study, mean plasma concentration-time profiles were similar after the first and second dose.

Distribution

The mean steady-state volume of distribution of leuprolide following intravenous bolus administration to healthy male volunteers was 27 L. In vitro binding to human plasma proteins ranged from 43% to 49%.

Elimination

The mean systemic clearance of leuprolide following intravenous bolus administration to healthy male volunteers was 7.6 L/h, and terminal elimination half-life was approximately 3 hours based on a two compartment model.

Following administration of LUPRON DEPOT 3.75 mg to 3 patients, less than 5% of the dose was recovered as parent and M-I metabolite in the urine.

Clinical Studies

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 1month 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. Data from the initial 24-week treatment phase are summarized in this section.

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. One escape from suppression (2 consecutive testosterone values greater than 50 ng/dL after achieving castrate level) was noted at Week 18, associated with a substantial dosing delay. In this patient, serum testosterone returned to the castrate range at the next monthly measurement. Serum testosterone was minimally above the castrate range on a single occasion for 4 other patients. No clinical significance was attributed to these rises in testosterone.

Figure 8: LUPRON DEPOT 7.5 mg for 1-Month Administration
Mean Serum Testosterone Concentrations

LUPRON DEPOT 7.5 mg for 1-Month Administration: Mean Serum Testosterone Concentrations   - Illustration

Secondary efficacy endpoints evaluated included objective tumor response, assessed by clinical evaluations of tumor burden (complete response, partial response, objectively stable, and progression), as well as changes in local disease status, assessed by digital rectal examination, and changes in prostatic acid phosphatase (PAP). These evaluations were performed at Weeks 12 and 24. The objective tumor response analysis showed a “no progression” (ie. complete or partial response, or stable disease) in 77% (40/52) of patients at Week 12, and in 84% (42/50) of patients at Week 24. Local disease improved or remained stable in all (42) patients evaluated at Week 12 and in 98% (41/42) of patients elevated at Week 24. PAP normalized or decreased at Week 12 and/or 24 in the majority of patients with elevated baseline PAP.

Periodic monitoring of serum testosterone and PSA levels is recommended, especially if the anticipated clinical or biochemical response to treatment has not been achieved. It should be noted that results of testosterone determinations are dependent on assay methodology. It is advisable to be aware of the type and precision of the assay methodology to make appropriate clinical and therapeutic decisions.

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.

Figure 9: LUPRON DEPOT 22.5 mg for 3-Month Administration Mean Serum Testosterone Concentrations

LUPRON DEPOT 22.5 mg for 3-Month Administration: Mean Serum Testosterone Concentrations   - Illustration

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.

Periodic monitoring of serum testosterone and PSA levels is recommended, especially if the anticipated clinical or biochemical response to treatment has not been achieved. It should be noted that results of testosterone determinations are dependent on assay methodology. It is advisable to be aware of the type and precision of the assay methodology to make appropriate clinical and therapeutic decisions.

LUPRON DEPOT 30 mg For 4-Month Administration

In an open-label, noncomparative, multicenter clinical study of LUPRON DEPOT 30 mg for 4month 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. The median dosing interval between injections was 112 days. One escape from suppression (two consecutive testosterone values greater than 50 ng/dL after castrate levels achieved) was noted at Week 16. In this patient, serum testosterone increased to above the castrate range following the second depot injection (Week 16) but returned to the castrate level by Week 18. No adverse reactions were associated with this rise in serum testosterone. A second patient had a rise in testosterone at Week 17, then returned to the castrate level by Week 18 and remained there through Week 32. In the long-term treatment phase two patients experienced testosterone elevations, both at Week 48. Testosterone for one patient returned to the castrate range at Week 52, and one patient discontinued the study at Week 48 due to disease progression.

Secondary efficacy endpoints evaluated in the study were the objective tumor response as assessed by clinical evaluations of tumor burden (complete response, partial response, objectively stable and progression) and evaluations of changes in prostatic involvement and prostate-specific antigen (PSA). These evaluations were performed at Weeks 16 and 32 of the treatment phase. The long-term treatment phase monitored PSA at each visit (every 16 weeks). The objective tumor response analysis showed “no progression” (i.e. complete or partial response, or stable disease) in 86% (37/43) of patients at Week 16, and in 77% (37/48) of patients at Week 32. Local disease improved or remained stable in all patients evaluated at Week 16 and/or 32. For patients with elevated baseline PSA, 50% (23/46) had a normal PSA (less than 4.0 ng/mL) at Week 16, and 51% (19/37) had a normal PSA at Week 32.

Periodic monitoring of serum testosterone and PSA levels is recommended, especially if the anticipated clinical or biochemical response to treatment has not been achieved. It should be noted that results of testosterone determinations are dependent on assay methodology. It is advisable to be aware of the type and precision of the assay methodology to make appropriate clinical and therapeutic decisions.

Using historical comparisons, the safety and efficacy of LUPRON DEPOT 30 mg for 4-month administration appear similar to the other LUPRON DEPOT formulations.

Figure 10: LUPRON DEPOT 30 mg for 4-Month Administration Mean Serum Testosterone Concentrations

LUPRON DEPOT 30 mg for 4-Month Administration: Mean Serum Testosterone Concentrations   - Illustration

LUPRON DEPOT 45 mg For 6-Month Administration

An open-label, non-comparative, multicenter clinical study of LUPRON DEPOT 45 mg for 6month 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% (two-sided 95% CI: 89.2%, 97.6%) 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).

Periodic monitoring of serum testosterone levels is recommended, especially if the anticipated clinical or biochemical response to treatment has not been achieved. Testosterone determinations are dependent on assay methodology and it is advisable to be aware of the type and precision of the assay methodology to make appropriate clinical and therapeutic decisions.

Figure 11 below shows the mean testosterone concentration at various time points.

Figure 11: LUPRON DEPOT 45 mg for 6-Month Administration Serum Testosterone Concentrations (Mean + SE)

LUPRON DEPOT 45 mg for 6-Month Administration: Mean Serum Testosterone Concentrations   - Illustration

Last reviewed on RxList: 6/28/2016
This monograph has been modified to include the generic and brand name in many instances.

Lupron Depot - User Reviews

Lupron Depot User Reviews

Now you can gain knowledge and insight about a drug treatment with Patient Discussions.

Here is a collection of user reviews for the medication Lupron Depot sorted by most helpful. Patient Discussions FAQs

Report Problems to the Food and Drug Administration

 

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.


Cancer

Get the latest treatment options.