LUTRATE DEPOT

1 INDICATIONS AND USAGE LUTRATE DEPOT 22.5 mg for 3-month administration (leuprolide acetate) is indicated for treatment of advanced prostate cancer. LUTRATE DEPOT is a gonadotropin-releasing hormone (GnRH) agonist indicated for: Treatment of advanced prostate cancer. ( 1 )

2 DOSAGE AND ADMINISTRATION Due to different release characteristics, the dosage strengths are not additive and must be selected based upon the desired dosing schedule ( 2 ). LUTRATE DEPOT 22.5 mg for 3 months administration, given as a single intramuscular injection every 12 weeks. ( 2.1 ) 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. Table 1. LUTRATE DEPOT Recommended Dosing Dosage 22.5 mg for 3-Month Administration Recommended Dose 1 injection every 12 weeks 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 gloves 1 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 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. 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. 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. 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. 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 . 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. 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. Inject the entire contents of the syringe intramuscularly. 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. fig 1.jpg fig 2.jpg Fig 3.jpg fig 4.jpg fig 5.jpg ifig 6.jpg fig 7.jpg fig 8.jpg fig 9.jpg fig 10.jpg

4 CONTRAINDICATIONS LUTRATE DEPOT is contraindicated in: Hypersensitivity LUTRATE DEPOT is contraindicated in individuals with known hypersensitivity to GnRH agonists or any of the excipients in LUTRATE DEPOT. Reports of anaphylactic reactions to GnRH agonists have been reported in the medical literature. Hypersensitivity to GnRH, GnRH agonist or any of the excipients in LUTRATE DEPOT. ( 4 ).

5 WARNINGS AND PRECAUTIONS Tumor Flare: Increased serum testosterone (~50% above baseline) during first week of treatment; monitor serum testosterone and PSA. ( 5.7 ) Transient worsening of symptoms, or additional signs and symptoms of prostate cancer during the first few weeks of treatment. ( 5.1 ) Patients may experience a temporary increase in bone pain which can be managed symptomatically. ( 5.1 ) Ureteral obstruction and spinal cord compression have been reported with GnRH agonists, which may contribute to paralysis with or without fatal complications. ( 5.1 ) Metabolic Syndrome: The use of GnRH agonists may lead to an increased risk of metabolic changes such as hyperglycemia, diabetes, hyperlipidemia, and non-alcoholic fatty liver disease. Monitor for signs and symptoms of metabolic syndrome including lipids, blood glucose level and/or HbA1c and manage according to current treatment guidelines. ( 5.2 ) Cardiovascular Diseases: Increased risk of myocardial infarction, sudden cardiac death and stroke has been reported in association with use of GnRH analogs in men. Monitor for cardiovascular disease and manage according to current clinical practice. ( 5.3 ) Effect on QT/QTc Interval: Androgen deprivation therapy may prolong QT interval. Consider risks and benefits. ( 5.4 ) Convulsions have been observed in patients with or without a history of predisposing factors. Manage convulsions according to the current clinical practice. ( 5.5 ) Severe Cutaneous Adverse Reactions (SCARs), including Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), may occur in patients treated with LUTRATE DEPOT. Interrupt LUTRATE DEPOT if signs or symptoms of SCARs develop. Permanently discontinue if SCARs are confirmed. ( 5.6 ) Monitor serum levels of testosterone following injection of LUTRATE DEPOT 22.5 mg for 3-month administration. ( 5.7 ) Embryo-Fetal Toxicity: LUTRATE DEPOT may cause fetal harm. ( 5.8 , 8.1 ) 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) ].

7 DRUG INTERACTIONS No pharmacokinetic-based drug-drug interaction studies have been conducted with LUTRATE DEPOT. 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.

6 ADVERSE REACTIONS The following is discussed in more detail in other sections of the labeling: Tumor Flare [see Warnings and Precautions (5.1) ] Metabolic Syndrome [ see Warnings and Precautions (5.2) ] Cardiovascular Disease [see Warnings and Precautions (5.3) ] Effect on QT/QTc Interval [ see Warnings and Precautions (5 .4) ] Convulsions [see Warnings and Precautions (5.5) ] Severe Cutaneous Adverse Reactions [see Warnings and Precautions (5.6) ] Most common adverse reactions (incidence > 10%) are hot flushes, upper respiratory infection, fatigue, diarrhea, pollakiuria, arthralgia, and injection site pain ( 6 ) . As with other GnRH agonist, other adverse reactions, including decreased bone density and rare cases of pituitary apoplexy may occur. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Avyxa Pharma, LLC at 1-888-520-0954 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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. CTCAE v.3 1 Includes cold sweat, flushing, hot flush, hyperhidrosis, and night sweats 2 Includes influenza, influenza-like illness, nasal congestion, nasopharyngitis, rhinorrhea, upper respiratory tract infection and congestion Table 2. Adverse Reactions Reported in ≥ 5% of Patients LUTRATE DEPOT 22.5 mg for 3-Month Administration N = 163 (%) Grade 1-4 Treatment-Emergent Treatment-Related Hot Flush/Flushing 1 128 (79) 127 (78) Upper Respiratory Infection 2 28 (17) 0 Fatigue/Asthenia 24 (15) 22 (13) Diarrhea 21 (13) 2 (1) Pollakiuria 20 (12) 3 (2) Arthralgia/Arthritis 18 (11) 2 (1) Injection Site Pain/Discomfort 18 (11) 15 (9) Constipation 15 (9) 1 (0.6) Extremity Pain 14 (9) 0 Nausea 14 (9) 4 (2) Nocturia 14 (9) 3 (2) Abdominal Pain/Discomfort 13 (8) 1 (0.6) Urinary Tract Pain 13 (8) 2 (1) Dizziness 12 (7) 2 (1) Headache/Sinus Headache 12 (7) 1 (0.6) Urinary Tract Infection 12 (7) 0 Bone Pain 11 (7) 4 (2) Back Pain 10 (6) 1 (0.6) Hypertension/Blood Pressure Increased 10 (6) 0 Pruritus/Generalized Pruritus 9 (6) 3 (2) 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

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.