Lupron Depot 3.75 mg

Leuprolide acetate is a synthetic nonapeptide analog of naturally occurring gonadotropin-releasing hormone (GnRH or LH-RH). The analog possesses greater potency than the natural hormone. The chemical name is 5-oxo-L-prolyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-Dleucyl-L-leucyl-L-arginyl-N-ethyl-L-prolinamide acetate (salt) with the following structural formula:

LUPRON DEPOT is available in a prefilled dual-chamber syringe containing sterile lyophilized microspheres which, when mixed with diluent, become a suspension intended as a monthly intramuscular injection.

The front chamber of LUPRON DEPOT 3.75 mg prefilled dual-chamber syringe contains leuprolide acetate (3.75 mg), purified gelatin (0.65 mg), DL-lactic and glycolic acids copolymer (33.1 mg), and D-mannitol (6.6 mg). The second chamber of diluent contains carboxymethylcellulose sodium (5 mg), D-mannitol (50 mg), polysorbate 80 (1 mg), water for injection, USP, and glacial acetic acid, USP to control pH.

During the manufacture of LUPRON DEPOT 3.75 mg, acetic acid is lost, leaving the peptide.

Clinical Trials

Estradiol levels may increase during the first weeks following the initial injection of LUPRON, but then decline to menopausal levels. This transient increase in estradiol can be associated with a temporary worsening of signs and symptoms (see WARNINGS section).

As would be expected with a drug that lowers serum estradiol levels, the most frequently reported adverse reactions were those related to hypoestrogenism.

The monthly formulation of LUPRON DEPOT 3.75 mg was utilized in controlled clinical trials that studied the drug in 166 endometriosis and 166 uterine fibroids patients. Adverse events reported in ≥ 5% of patients in either of these populations and thought to be potentially related to drug are noted in the following table.

Table 2 : ADVERSE EVENTS REPORTED TO BE CAUSALLY RELATED TO DRUG IN ≥ 5% OF PATIENTS

In one controlled clinical trial utilizing the monthly formulation of LUPRON DEPOT, patients diagnosed with uterine fibroids received a higher dose (7.5 mg) of LUPRON DEPOT. Events seen with this dose that were thought to be potentially related to drug and were not seen at the lower dose included glossitis, hypesthesia, lactation, pyelonephritis, and urinary disorders. Generally, a higher incidence of hypoestrogenic effects was observed at the higher dose.

Table 3 lists the potentially drug-related adverse events observed in at least 5% of patients in any treatment group during the first 6 months of treatment in the add-back clinical studies.

In the controlled clinical trial, 50 of 51 (98%) patients in the LD group and 48 of 55 (87%) patients in the LD/N group reported experiencing hot flashes on one or more occasions during treatment. During Month 6 of treatment, 32 of 37 (86%) patients in the LD group and 22 of 38 (58%) patients in the LD/N group reported having experienced hot flashes. The mean number of days on which hot flashes were reported during this month of treatment was 19 and 7 in the LD and LD/N treatment groups, respectively. The mean maximum number of hot flashes in a day during this month of treatment was 5.8 and 1.9 in the LD and LD/N treatment groups, respectively.

Table 3 : TREATMENT-RELATED ADVERSE EVENTS OCCURRING IN ≥ 5% OF PATIENTS

Changes In Bone Density

In controlled clinical studies, patients with endometriosis (six months of therapy) or uterine fibroids (three months of therapy) were treated with LUPRON DEPOT 3.75 mg. In endometriosis patients, vertebral bone density as measured by dual energy x-ray absorptiometry (DEXA) decreased by an average of 3.2% at six months compared with the pretreatment value. Clinical studies demonstrate that concurrent hormonal therapy (norethindrone acetate 5 mg daily) and calcium supplementation is effective in significantly reducing the loss of bone mineral density that occurs with LUPRON treatment, without compromising the efficacy of LUPRON in relieving symptoms of endometriosis.

LUPRON DEPOT 3.75 mg plus norethindrone acetate 5 mg daily was evaluated in two clinical trials. The results from this regimen were similar in both studies. LUPRON DEPOT 3.75 mg was used as a control group in one study. The bone mineral density data of the lumbar spine from these two studies are presented in Table 4.

Table 4 : MEAN PERCENT CHANGE FROM BASELINE IN BONE MINERAL DENSITY OF LUMBAR SPINE

When LUPRON DEPOT 3.75 mg was administered for three months in uterine fibroid patients, 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. Use of LUPRON DEPOT for longer than three months (uterine fibroids) or six months (endometriosis) or in the presence of other known risk factors for decreased bone mineral content may cause additional bone loss and is not recommended.

Changes In Laboratory Values During Treatment

Endometriosis

During early clinical trials with LUPRON DEPOT 3.75 mg, regular laboratory monitoring revealed that AST levels were more than twice the upper limit of normal in only one patient. There was no clinical or other laboratory evidence of abnormal liver function.

In two other clinical trials, 6 of 191 patients receiving LUPRON DEPOT 3.75 mg plus norethindrone acetate 5 mg daily for up to 12 months developed an elevated (at least twice the upper limit of normal) SGPT or GGT. Five of the 6 increases were observed beyond 6 months of treatment. None were associated with elevated bilirubin concentration.

In clinical trials with LUPRON DEPOT 3.75 mg, five (3%) patients had a post-treatment transaminase value that was at least twice the baseline value and above the upper limit of the normal range. None of the laboratory increases were associated with clinical symptoms.

Lipids

In earlier clinical studies, 4% of the LUPRON DEPOT 3.75 mg patients and 1% of the danazol patients had total cholesterol values above the normal range at enrollment. These patients also had cholesterol values above the normal range at the end of treatment.

Of those patients whose pretreatment cholesterol values were in the normal range, 7% of the LUPRON DEPOT 3.75 mg patients and 9% of the danazol patients had post-treatment values above the normal range.

The mean (±SEM) pretreatment values for total cholesterol from all patients were 178.8 (2.9) mg/dL in the LUPRON DEPOT 3.75 mg groups and 175.3 (3.0) mg/dL in the danazol group. At the end of treatment, the mean values for total cholesterol from all patients were 193.3 mg/dL in the LUPRON DEPOT 3.75 mg group and 194.4 mg/dL in the danazol group. These increases from the pretreatment values were statistically significant (p < 0.03) in both groups.

Triglycerides were increased above the upper limit of normal in 12% of the patients who received LUPRON DEPOT 3.75 mg and in 6% of the patients who received danazol.

At the end of treatment, HDL cholesterol fractions decreased below the lower limit of the normal range in 2% of the LUPRON DEPOT 3.75 mg patients compared with 54% of those receiving danazol. LDL cholesterol fractions increased above the upper limit of the normal range in 6% of the patients receiving LUPRON DEPOT 3.75 mg compared with 23% of those receiving danazol. There was no increase in the LDL/HDL ratio in patients receiving LUPRON DEPOT 3.75 mg but there was approximately a two-fold increase in the LDL/HDL ratio in patients receiving danazol.

In two other clinical trials, LUPRON DEPOT 3.75 mg plus norethindrone acetate 5 mg daily was evaluated for 12 months of treatment. LUPRON DEPOT 3.75 mg was used as a control group in one study. Percent changes from baseline for serum lipids and percentages of patients with serum lipid values outside of the normal range in the two studies are summarized in the tables below.

Table 5 : SERUM LIPIDS: MEAN PERCENT CHANGES FROM BASELINE VALUES AT TREATMENT WEEK 24

Changes from baseline tended to be greater at Week 52. After treatment, mean serum lipid levels from patients with follow up data returned to pretreatment values.

Table 6 : PERCENTAGE OF PATIENTS WITH SERUM LIPID VALUES OUTSIDE OF THE NORMAL RANGE

Low HDL-cholesterol ( < 40 mg/dL) and elevated LDL-cholesterol ( > 160 mg/dL) are recognized risk factors for cardiovascular disease. The long-term significance of the observed treatment-related changes in serum lipids in women with endometriosis is unknown. Therefore assessment of cardiovascular risk factors should be considered prior to initiation of concurrent treatment with LUPRON and norethindrone acetate.

In patients receiving LUPRON DEPOT 3.75 mg, mean changes in cholesterol (+11 mg/dL to +29 mg/dL), LDL cholesterol (+8 mg/dL to +22 mg/dL), HDL cholesterol (0 to +6 mg/dL), and the LDL/HDL ratio (-0.1 to +0.5) were observed across studies. In the one study in which triglycerides were determined, the mean increase from baseline was 32 mg/dL.

Other Changes

The following changes were seen in approximately 5% to 8% of patients. In the earlier comparative studies, LUPRON DEPOT 3.75 mg was associated with elevations of LDH and phosphorus, and decreases in WBC counts. Danazol therapy was associated with increases in hematocrit, platelet count, and LDH. In the hormonal add-back studies LUPRON DEPOT in combination with norethindrone acetate was associated with elevations of GGT and SGPT.

Hematology: (see Clinical Studies section) In LUPRON DEPOT 3.75 mg treated patients, although there were statistically significant mean decreases in platelet counts from baseline to final visit, the last mean platelet counts were within the normal range. Decreases in total WBC count and neutrophils were observed, but were not clinically significant.

Chemistry: Slight to moderate mean increases were noted for glucose, uric acid, BUN, creatinine, total protein, albumin, bilirubin, alkaline phosphatase, LDH, calcium, and phosphorus. None of these increases were clinically significant.

Postmarketing

The following adverse reactions have been identified during postapproval use of LUPRON DEPOT. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

During postmarketing surveillance, the following adverse events were reported. Like other drugs in this class, mood swings, including depression, have been reported. There have been rare reports of suicidal ideation and attempt. Many, but not all, of these patients had a history of depression or other psychiatric illness. Patients should be counseled on the possibility of development or worsening of depression during treatment with LUPRON.

Symptoms consistent with an anaphylactoid or asthmatic process have been rarely reported. Rash, urticaria, and photosensitivity reactions have also been reported.

Localized reactions including induration and abscess have been reported at the site of injection. Symptoms consistent with fibromyalgia (eg: joint and muscle pain, headaches, sleep disorder, gastrointestinal distress, and shortness of breath) have been reported individually and collectively.

Other events reported are:

Hepato-biliary disorder: Rarely reported serious liver injury

Injury, poisoning and procedural complications: Spinal fracture

Investigations: Decreased WBC

Musculoskeletal and Connective tissue disorder: Tenosynovitis-like symptoms

Nervous System Disorder: Convulsion, peripheral neuropathy, paralysis

Vascular Disorder: Hypotension

Cases of serious venous and arterial thromboembolism have been reported, including deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke, and transient ischemic attack.

Although a temporal relationship was reported in some cases, most cases were confounded by risk factors or concomitant medication use. It is unknown if there is a causal association between the use of GnRH analogs and these events.

Pituitary Apoplexy

During post-marketing surveillance, rare cases of pituitary apoplexy (a clinical syndrome secondary to infarction of the pituitary gland) have been reported after the administration of gonadotropin-releasing hormone agonists. In a majority of these cases, a pituitary adenoma was diagnosed, with a majority of pituitary apoplexy cases occurring within 2 weeks of the first dose, and some within the first hour. In these cases, pituitary apoplexy has presented as sudden headache, vomiting, visual changes, ophthalmoplegia, altered mental status, and sometimes cardiovascular collapse. Immediate medical attention has been required.

See other LUPRON DEPOT and LUPRON Injection package inserts for other events reported in different patient populations.

In rats subcutaneous administration of 250 to 500 times the recommended human dose, expressed on a per body weight basis, resulted in dyspnea, decreased activity, and local irritation at the injection site. There is no evidence that there is a clinical counterpart of this phenomenon. In early clinical trials using daily subcutaneous leuprolide acetate in patients with prostate cancer, doses as high as 20 mg/day for up to two years caused no adverse effects differing from those observed with the 1 mg/day dose.