2.1 LUTRATE DEPOT 22.5 mg for 3-Month Administration

LUTRATE DEPOT must be administered under the supervision of a physician.

In patients treated with GnRH analogues for prostate cancer, treatment is usually continued upon development of metastatic castration-resistant prostate cancer.

The recommended dose of LUTRATE DEPOT 22.5 mg for 3-month administration is one injection every 12 weeks. Do not use concurrently a fractional dose, or a combination of doses of this or any depot formulation due to different release characteristics.

Incorporated in a depot formulation, the lyophilized microspheres must be reconstituted and administered every 12 weeks as a single intramuscular injection.

2.2 Reconstitution Instructions for LUTRATE DEPOT

• Reconstitute and administer the lyophilized microspheres as a single intramuscular injection.
• The suspension should be administered immediately after reconstitution.
• As with other drugs administered by intramuscular injection, the injection site should be alternated periodically.
• Visually inspect LUTRATE DEPOT powder (white to off-white powder). DO NOT USE the vial if clumping or caking is evident. A thin layer of powder on the wall of the vial is considered normal prior to mixing with the diluent. The diluent contained in the prefilled syringe should appear clear and colorless.
• Use ONLY the provided diluent for reconstitution of LUTRATE DEPOT. DO NOT use other diluents.
• The reconstituted product is a suspension of milky, white color appearance.

LUTRATE DEPOT is packaged in a commercial kit. Each kit contains:

• One vial containing 22.5 mg of leuprolide acetate as lyophilized microspheres.
• One prefilled syringe containing 2 mL of mannitol for injection.
• One MIXJECT transfer device including one needle.

Please read the instructions completely before you begin.

MIXJECT Preparation

Wash your hands with soap and hot water and put on gloves1 immediately prior to preparing the injection. Place the tray on a clean, flat surface that is covered with a sterile pad or cloth. Remove the MIXJECT device, the backstop, the prefilled syringe containing the solvent for reconstitution and the LUTRATE DEPOT vial.

Remove the Flip-Off button from the top of the vial, revealing the rubber stopper. Place the vial in a standing upright position on the prepared surface. Disinfect the rubber stopper with the alcohol wipe. Discard the alcohol wipe and allow the stopper to dry. Insert the backstop to the flange of the syringe until you feel it snap in place. Proceed to MIXJECT Activation.

MIXJECT Activation

1. Peel the cover away from the blister pack containing the vial adapter (MIXJECT). Do not remove the vial adapter from the blister pack. Place the blister pack containing the vial adapter firmly on the vial top, piercing the vial. Push down gently until you feel it snap in place.
2. Remove the cap from the syringe barrel and then, remove the blister pack from the vial adapter. Connect the syringe to the vial adapter by screwing it clockwise into the opening on the side of the vial adapter. Be sure to gently twist the syringe until it stops turning to ensure a tight connection.
   
3. While holding the vial, place your thumb on the plunger rod and push the plunger rod in all the way to transfer the diluent from the pre-filled syringe into the vial. Do not release the plunger rod.
   
4. Keeping the plunger rod depressed, gently swirl the vial for approximately one minute until a uniform milky-white suspension is obtained. This will ensure complete mixing of LUTRATE DEPOT and the sterile mannitol solution diluent. The suspension will now have a milky appearance. In order to avoid separation of the suspension, proceed to the next steps without delay.
   
5. Invert the MIXJECT system so that the vial is at the top. Grasp the MIXJECT system firmly by the syringe and pull back the plunger rod slowly to draw the reconstituted LUTRATE DEPOT into the syringe.
   
   Return the vial to its upright position, and disconnect the vial adapter from the MIXJECT syringe assembly by grabbing firmly the syringe and turning the plastic cap of the vial adapter clockwise. Grasp only the plastic cap when removing.
   
6. Keep the syringe UPRIGHT. With the opposite hand pull the needle cap upward. Advance the plunger to expel the air from the syringe. The syringe containing LUTRATE DEPOT is now ready for administration. The suspension should be administered immediately after reconstitution.
   
7. After cleaning the injection site with an alcohol swab, administer the intramuscular injection by inserting the needle at a 90 degree angle into the gluteal area, anterior thigh, or deltoid; injection sites should be alternated (see Figure).
   
   NOTE: If a blood vessel is accidentally penetrated, aspirated blood will be visible just below the luer lock. If blood is present, remove the needle immediately. Do not inject the medication.
8. Inject the entire contents of the syringe intramuscularly.
9. Withdraw the needle. Once the syringe has been withdrawn, immediately discard the needle into a suitable sharps container. Dispose the syringe according to local regulations/procedures.

5.1 Tumor Flare

Initially, LUTRATE DEPOT, like other GnRH agonists, causes increases in serum levels of testosterone to approximately 50% above baseline during the first weeks of treatment. Ureteral obstruction and spinal cord compression have been observed, which may contribute to paralysis with or without fatal complications. Transient worsening of symptoms may develop. Patients may experience a temporary increase in bone pain, which can be managed symptomatically.

Patients with metastatic vertebral lesions and/or with urinary tract obstruction should be closely observed during the first few weeks of therapy.

5.2 Metabolic Syndrome

The use of GnRH agonists may lead to metabolic changes such as hyperglycemia, diabetes mellitus, and hyperlipidemia. Non-alcoholic fatty liver disease, including cirrhosis, occurred in the post-marketing setting. Hyperglycemia may represent new-onset diabetes mellitus or worsening of glycemic control in patients with pre-existing diabetes. Monitor for changes in serum lipids, blood glucose and/or glycosylated hemoglobin (HbA1c) in patients receiving a GnRH agonist, and manage according to current treatment guidelines.

5.3 Cardiovascular Diseases

Increased risk of developing myocardial infarction, sudden cardiac death and stroke has been reported in association with use of GnRH agonists in men. The risk appears low based on the reported odds ratios, and should be evaluated carefully along with cardiovascular risk factors when determining a treatment for patients with prostate cancer. Patients receiving a GnRH agonist should be monitored for symptoms and signs suggestive of development of cardiovascular disease and be managed according to current clinical practice.

5.4 Effect on QT/QTc Interval

Androgen deprivation therapy may prolong the QT/QTc interval. Providers should consider whether the benefits of androgen deprivation therapy outweigh the potential risks in patients with congenital long QT syndrome, congestive heart failure, frequent electrolyte abnormalities, and in patients taking drugs known to prolong the QT interval. Electrolyte abnormalities should be corrected. Consider periodic monitoring of electrocardiograms and electrolytes.

5.5 Convulsions

Postmarketing reports of convulsions have been observed in patients on leuprolide acetate therapy. These included patients with a history of seizures, epilepsy, cerebrovascular disorders, central nervous system anomalies or tumors, and in patients on concomitant medications that have been associated with convulsions such as bupropion and SSRIs. Convulsions have also been reported in patients in the absence of any of the conditions mentioned above. Patients receiving a GnRH agonist who experience convulsion should be managed according to current clinical practice.

5.6 Severe Cutaneous Adverse Reactions

Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP), may occur in patients receiving LUTRATE DEPOT; including cases with visceral involvement and/or requiring skin grafts [see Adverse Reactions (6.2)].

Monitor patients for the development of SCARs. Advise patients of the signs and symptoms of SCARs (e.g., a prodrome of fever, flu-like symptoms, mucosal lesions, progressive skin rash, or lymphadenopathy).

If a SCAR is suspected, interrupt LUTRATE DEPOT until the etiology of the reaction has been determined. Consultation with a dermatologist is recommended. If a SCAR is confirmed, or for other grade 4 skin reactions, permanently discontinue LUTRATE DEPOT.

5.7 Laboratory Tests

Monitor serum levels of testosterone following injection of LUTRATE DEPOT 22.5 mg for 3-month administration. In the majority of patients, testosterone levels increased above baseline during the first week, and then declined thereafter to castrate levels (< 50 ng/dL) within four weeks. [see Clinical Studies (14) and Adverse Reactions (6)].

5.8 Embryo-Fetal Toxicity

Based on findings in animal studies, LUTRATE DEPOT may cause fetal harm when administered to a pregnant woman. In animal developmental and reproductive toxicology studies, administration of the monthly formulation of leuprolide acetate on day 6 of pregnancy (sustained exposure was expected throughout the period of organogenesis) caused adverse embryo-fetal toxicity in animals at doses less than the human dose, based on body surface area, using an estimated daily dose. Advise pregnant patients and females of reproductive potential of the potential risk to the fetus [see Use in Specific Populations (8.1)].

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

LUTRATE DEPOT 22.5 mg for 3-Month Administration

In a clinical trial of LUTRATE DEPOT 22.5 mg for 3-month administration, patients were treated for 24 weeks with 157/163 receiving two injections. The table includes adverse reactions were reported in 5% or more of the patients during the treatment period as well as the incidence of these adverse reaction that were considered, by the treating physician, to be at least possibly related to LUTRATE DEPOT. Grade 3-4 adverse reactions reported as treatment-emergent in 13% of patients and treatment-related 4% of patients.

In the same study, erectile dysfunction and testicular atrophy were reported in patients on LUTRATE DEPOT 22.5 mg.

Laboratory abnormalities

During the treatment period, at least a one grade change in laboratory values was seen (>10%) in the following: anemia, increased triglyceride, hyperglycemia, increased cholesterol, increased creatine kinase, leukopenia, increased AST, increased creatinine, and increased ALT.

6.2 Post-marketing Experience

The following adverse reactions have been identified during post approval use of gonadotropin-releasing hormone agonists. 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.

Mood swings, including depression, have been reported. There have been very 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 LUTRATE DEPOT.

Symptoms consistent with an anaphylactoid or asthmatic process have been rarely (incidence rate of about 0.002%) reported. Rash, urticaria, and photosensitivity reactions have also been reported.

Pituitary apoplexy: During postmarketing 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.

Localized reactions including induration and abscess have been reported at the site of injection.

Symptoms consistent with fibromyalgia (e.g., joint and muscle pain, headaches, sleep disorders, gastrointestinal distress, and shortness of breath) have been reported individually and collectively.

Changes in Bone Density: Decreased bone density has been reported in the medical literature in men who have had orchiectomy or who have been treated with a GnRH agonist analog. In a clinical trial, 25 men with prostate cancer, 12 of whom had been treated previously with leuprolide acetate for at least six months, underwent bone density studies as a result of pain. The leuprolide acetate-treated group had lower bone density scores than the nontreated control group. It can be anticipated that long periods of medical castration in men will have effects on bone density.

Immune Disorders: Anaphylaxis

Psychiatric Disorders: Depression

Cardiovascular System - hypotension, myocardial infarction, pulmonary embolism

Respiratory, Thoracic and Mediastinal disorder - Pneumonitis, interstitial lung disease

Hepato-biliary disorder - serious drug-induced liver injury, non-alcoholic fatty liver disease

Skin reactions – rash, urticaria, photosensitivity, erythema multiforme, bullous dermatitis, exfoliative dermatitis, DRESS, SJS/TEN, and AGEP

Blood and Lymphatic System - decreased WBC

Central/Peripheral Nervous System - convulsion, peripheral neuropathy, spinal fracture/paralysis

Endocrine System - diabetes mellitus

Musculoskeletal System - tenosynovitis-like symptoms

Urogenital System - prostate pain

7.1 Drug/Laboratory Test Interactions

Administration of LUTRATE DEPOT in therapeutic doses results in suppression of the pituitary-gonadal system. Normal function is usually restored within three months after treatment is discontinued. Due to the suppression of the pituitary-gonadal system by LUTRATE DEPOT, diagnostic tests of pituitary gonadotropic and gonadal functions conducted during treatment and up to three months after discontinuation of LUTRATE DEPOT may be affected.

8.1 Pregnancy

Risk summary

Based on findings in animal studies and mechanism of action, LUTRATE DEPOT may cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available data in pregnant women to inform the drug-associated risk. In animal developmental and reproductive toxicology studies, administration of a monthly formulation of leuprolide acetate on day 6 of pregnancy (sustained exposure was expected throughout the period of organogenesis) caused adverse embryo-fetal toxicity in animals at doses less than the human dose based on body surface area using an estimated daily dose (see data). Advise pregnant patients and females of reproductive potential of the potential risk to the fetus.

Animal Data

Major fetal malformations were observed in developmental and reproductive toxicology studies in rabbits after a single administration of the monthly formulation of leuprolide acetate on day 6 of pregnancy at doses of 0.00024, 0.0024, and 0.024 mg/kg (approximately 1/1600 to 1/16 the human dose based on body surface area using an estimated daily dose in animals and humans). Since a depot formulation was utilized in the study, a sustained exposure to leuprolide acetate was expected throughout the period of organogenesis and to the end of gestation. Similar studies in rats did not demonstrate an increase in fetal malformations, however, there was increased fetal mortality and decreased fetal weights with the two higher doses of the monthly formulation of leuprolide acetate in rabbits and with the highest dose (0.024 mg/kg) in rats.

8.2 Lactation

The safety and efficacy of LUTRATE DEPOT have not been established in females. There is no information regarding the presence of LUTRATE DEPOT in human milk, the effects on the breastfed child, or the effects on milk production. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in a breastfed child from LUTRATE DEPOT, a decision should be made to discontinue breastfeeding or discontinue the drug, taking into account the importance of the drug to the mother.

8.3 Females and Males of Reproductive Potential

Infertility

Males

Based on findings in animals and mechanism of action, LUTRATE DEPOT may impair fertility in males of reproductive potential [see Nonclinical Toxicology (13.1)].

8.4 Pediatric Use

The safety and effectiveness of LUTRATE DEPOT in pediatric patients have not been established.

8.5 Geriatric Use

In the clinical trials for LUTRATE DEPOT in prostate cancer 74% of the patients studied were at least 65 years of age. Hot flushes occurred with equal frequency in those less than or at least 65 years of age.

12.1 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 (prostate tumors in Noble and Dunning male rats and DMBA-induced mammary tumors in female rats) as well as atrophy of the reproductive organs.

12.2 Pharmacodynamics

In humans, administration of leuprolide acetate results in an initial increase in circulating levels of luteinizing hormone (LH) and follicle stimulating hormone (FSH), leading to a transient increase in levels 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 levels of LH and FSH. In males, testosterone is reduced to below castrate threshold. In premenopausal females, estrogens are reduced to postmenopausal concentrations. These decreases occur within two to four weeks after initiation of treatment. Long-term studies have shown that continuation of therapy with leuprolide acetate maintains testosterone below the castrate level for more than five years.

Leuprolide acetate is not active when given orally.

12.3 Pharmacokinetics

Absorption

Following two sequential injections of LUTRATE DEPOT 22.5 mg administered with a 3-month interval, plasma leuprolide acetate  concentrations were similar among both cycles. After first administration, mean plasma leuprolide concentration of 46.8 ng/mL was observed at approximately 2 hours and the mean concentration then declined until next injection.

Distribution

The mean steady-state volume of distribution of leuprolide acetate 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 acetate 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.

Upon administration with different leuprolide acetate formulations, the major metabolite of leuprolide acetate is a pentapeptide (M- 1) metabolite.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Two-year carcinogenicity studies were conducted with leuprolide acetate in rats and mice. In rats, a dose-related increase of benign pituitary hyperplasia and benign pituitary adenomas was noted at 24 months when the drug was administered subcutaneously at high daily doses (0.6 to 4 mg/kg). There was a significant but not dose-related increase of pancreatic islet cell adenomas in females and of testicular interstitial cell adenomas in males (highest incidence in the low dose group). In mice, no leuprolide acetate-induced tumors or pituitary abnormalities were observed at a dose as high as 60 mg/kg for two years. Patients have been treated with leuprolide acetate for up to three years with doses as high as 10 mg/day and for two years with doses as high as 20 mg/day without demonstrable pituitary abnormalities. No carcinogenicity studies have been conducted with LUTRATE DEPOT.

Genotoxicity studies were conducted with leuprolide acetate using bacterial and mammalian systems. These studies provided no evidence of mutagenic effects or chromosomal aberrations.

Leuprolide acetate may reduce male and female fertility. Administration of leuprolide acetate to male and female rats at dose of 0.024, 0.24, and 2.4 mg/kg as monthly depot formulation for up to 3 months (approximately as low as 1/30 of the human dose based on body surface area using an estimated daily dose in animals and humans) caused atrophy of the reproductive organs, and suppression of reproductive function. These changes were reversible upon cessation of treatment.

14.1 LUTRATE DEPOT 22.5 mg for 3-Month Administration

The efficacy of LUTRATE DEPOT 22.5 mg was evaluated in an open-label, multicenter, non-controlled, multiple dose clinical trial which enrolled 162 evaluable patients with prostate cancer. Patients were administered LUTRATE DEPOT 22.5 mg intramuscularly in 2 doses (157 received 2 injections) with a 3-month interval.

The median age was 71 years (range; 47-91), 62% White, and 30% Black or African-American.

Castrate levels of serum testosterone (<50 ng/dL) were achieved and maintained from Day 28 to 168 in 94.3% (95% CI:89.4, 97.0) of patients. On Day 28, 160 of the 162 (98.8%) patients had castrate testosterone levels. One patient did not achieve a castrate level and one had a missing value. Testosterone escapes (any value > 50 ng/dL after castrate levels were achieved) occurred in four patients. In addition, three patients had a single unevaluable testosterone level after Day 28 that was considered to be non-castrate in this analysis.

Figure 1. Mean testosterone plasma levels during treatment with two three-month IM injections of LUTRATE DEPOT 22.5 mg