Leuprolide Acetate

1 INDICATIONS AND USAGE VABRINTY is indicated for the treatment of advanced prostate cancer. VABRINTY is a gonadotropin releasing hormone (GnRH) agonist indicated for the treatment of advanced prostate cancer. ( 1 )

2 DOSAGE AND ADMINISTRATION VABRINTY is administered subcutaneously based on the following recommended dose and schedule: 7.5 mg subcutaneously every month ( 2.1 ) 22.5 mg subcutaneously every 3 months ( 2.1 ) 30 mg subcutaneously every 4 months ( 2.1 ) 45 mg subcutaneously every 6 months ( 2.1 ) See Full Prescribing Information for preparation and administration instructions. ( 2.2 , 2.3 ) 2.1 Recommended Dosage VABRINTY is administered subcutaneously and provides continuous release of leuprolide acetate over a one-, three-, four-, or six-month treatment period (Table 1). VABRINTY must be administered by a healthcare provider. The injection delivers the dose of leuprolide acetate incorporated in a polymer formulation. Table 1. VABRINTY Recommended Dosing Dosage 7.5 mg 22.5 mg 30 mg 45 mg Recommended dose 1 injection every month 1 injection every 3 months 1 injection every 4 months 1 injection every 6 months As with other drugs administered by subcutaneous injection, the injection site should vary periodically. The specific injection location should be an area with sufficient soft or loose subcutaneous tissue. In clinical trials, the injections were administered in the upper- or mid-abdominal area. Avoid areas with brawny or fibrous subcutaneous tissue or locations that could be rubbed or compressed (i.e., with a belt or clothing waistband). In patients treated with GnRH analogues for prostate cancer, treatment is usually continued upon development of metastatic castration-resistant prostate cancer. 2.2 Preparation Instructions Use aseptic technique throughout the procedure. As with other similar agents, the use of gloves is recommended during mixing and administration. Allow the product to reach room temperature before mixing. Once mixed, the product must be administered within 30 minutes or it should be discarded. VABRINTY is packaged in a carton containing: Tray containing pre-connected syringe system and desiccant pack Prescribing information Sterile safety needle and cap (located under the tray in carton) Follow the detailed instructions below to ensure correct preparation of VABRINTY prior to administration: Step 1 On a clean field open the tray by tearing off the foil from the corner and remove the contents. Discard the desiccant pack. Remove the pre-connected syringe system from the tray. Open the sterile safety needle package by peeling back the paper tab. Note: Syringe A and Syringe B should not be lined-up yet. The product should only be administered with the co-packaged, sterile safety needle. Step 2 Grasp the latching button on the coupling device with your finger and thumb and press until you hear a snapping sound. The two syringes will be aligned. Do not bend the pre-connected syringe system. Step 3 Holding the syringes in a horizontal position, transfer the liquid contents of Syringe A into the leuprolide acetate powder contained in Syringe B. Thoroughly mix the product for 60 cycles by pushing the contents back and forth between both syringes to obtain a uniform suspension. A cycle is one push of the Syringe A plunger and one push of the Syringe B plunger. When thoroughly mixed, the suspension will appear light tan to tan (VABRINTY 7.5 mg) or colorless to pale yellow (VABRINTY 22.5 mg, 30 mg, and 45 mg). Note: Product must be mixed as described; shaking will NOT provide adequate mixing. Do not bend. Step 4 After mixing, hold the syringes vertically (upright) with Syringe B (wide syringe) on the bottom. The syringes should remain securely coupled. Transfer all of the mixed product into Syringe B by depressing the Syringe A plunger and slightly withdrawing the Syringe B plunger. Step 5 While ensuring the Syringe A plunger is fully pushed down, hold the coupling device and unscrew Syringe B. This will disconnect Syringe B from the coupling device. Syringe A will remain attached to the coupling device. Note: Small air bubbles will remain in the formulation – this is acceptable. Do not purge the air bubbles from Syringe B as product may be lost! Step 6 Continue to hold Syringe B upright with the open end at the top. Hold back the white plunger on Syringe B to prevent loss of the product, and attach the safety needle and cap (the safety needle is located under the tray). Gently screw clockwise with approximately a three-quarter turn until the safety needle and cap are secure. Do not overtighten, as the needle hub may become damaged which could result in leakage of the product during injection. The safety shield may also be damaged if the safety needle and cap are screwed with too much force. Step 7 Move the safety shield away from the needle and towards the syringe. Pull off the cap immediately prior to administration. Note: Should the needle hub appear to be damaged, or leak, the product should NOT be used. The damaged safety needle and cap should NOT be replaced and the product should NOT be injected. In the event of damage to the needle hub, use a new replacement VABRINTY carton. mixing step2 step3 step4 step5 step6 step7 2.3 Administration Instructions 1. Select an injection site on the abdomen, upper buttocks, or another location with adequate amounts of subcutaneous tissue that does not have excessive pigment, nodules, lesions, or hair and hasn’t recently been used. 2. Cleanse the injection-site area with an alcohol swab (not enclosed). 3. Using the thumb and forefinger, grab and bunch the area of skin around the injection site. 4. Using your dominant hand, insert the needle quickly at a 90° angle to the skin surface. The depth of penetration will depend on the amount and fullness of the subcutaneous tissue and the length of the needle. After the needle is inserted, release the skin. 5. Inject the drug using a slow, steady push and press down on the plunger until the syringe is empty. Make sure all the drug has been injected before removing the needle. 6. Withdraw the needle quickly at the same 90° angle used for insertion. 7. Immediately following the withdrawal of the needle, activate the safety shield using a finger/thumb or flat surface and push until it completely covers the needle tip and locks into place. 8. An audible and tactile “click” verifies a locked position. 9. Check to confirm the safety shield is fully engaged. Discard all components safely in an appropriate biohazard container. admin1 admin admin

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Tumor Flare [see Warnings and Precautions ( 5.1 )] Hyperglycemia and Diabetes [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 in clinical studies (incidence ≥ 5%): Malaise, fatigue, hot flashes/sweats, and testicular atrophy. ( 6.1 ) As with other GnRH agonists, other adverse reactions, including decreased bone density and rare cases of pituitary apoplexy have been reported. ( 6.1 , 6.2 ) To report SUSPECTED ADVERSE REACTIONS, contact Uronova Pharmaceuticals, Inc. at 877-712-4575 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trial 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. The safety of all VABRINTY formulations was evaluated in clinical trials involving patients with advanced prostate cancer. In addition, the safety of VABRINTY 7.5 mg was evaluated in 8 surgically castrated males (Table 4). VABRINTY, like other GnRH analogs, caused a transient increase in serum testosterone concentrations during the first one to two weeks of treatment. Therefore, potential exacerbations of signs and symptoms of the disease during the first weeks of treatment are of concern in patients with vertebral metastases and/or urinary obstruction or hematuria. If these conditions are aggravated, it may lead to neurological problems such as weakness and/or paresthesia of the lower limbs or worsening of urinary symptoms [see Warnings and Precautions ( 5.7 )] . During the clinical trials, injection sites were closely monitored. Refer to Table 3 for a summary of reported injection site adverse reactions. Table 3. Reported Injection Site Adverse Reactions VABRINTY 7.5 mg 22.5 mg 30 mg 45 mg Study number AGL9904 AGL9909 AGL0001 AGL0205 Number of patients 120 117 90 111 Treatment 1 injection every month up to 6 months 1 injection every 3 months up to 6 months 1 injection every 4 months up to 8 months 1 injection every 6 months up to 12 months Number of injections 716 230 175 217 Transient burning/ stinging 248 (34.6%) injections; 84% reported as mild 50 (21.7%) injections; 86% reported as mild 35 (20%) injections; 100% reported as mild3 35 (16%) injections; 91.4% reported as mild Pain (generally brief and mild) 4.3% of injections (18.3% of patients) 3.5% of injections (6.0% of patients) 2.3% of injections2 (3.3% of patients) 4.6% of injections 4 Erythema (generally brief and mild) 2.6% of injections (12.5% of patients) 0.9% of injections 1 (1.7% of patients) 1.1% of injections (2.2% of patients) - Bruising (mild) 2.5% of injections (11.7% of patients) 1.7% of injections (3.4% of patients) - 2.3% of injections 5 Pruritus 1.4% of injections (9.2% of patients) 0.4% of injections (0.9% of patients) - - Induration 0.4% of injections (2.5% of patients) - - - Ulceration 0.1% of injections (> 0.8% of patients) - - - Erythema was reported following 2 injections of VABRINTY 22.5 mg. One report characterized the erythema as mild and it resolved within 7 days. The other report characterized the erythema as moderate and it resolved within 15 days. Neither patient experienced erythema at multiple injection times. A single reaction reported as moderate pain resolved within two minutes and all 3 mild pain reactions resolved within several days following injection of VABRINTY 30 mg. Following injection of VABRINTY 30 mg, three of the 35 burning/stinging reactions were reported as moderate. Transient pain was reported as mild in intensity in nine of ten (90%) events and moderate in intensity in one of ten (10%) events following injection of VABRINTY 45 mg. Mild bruising was reported following 5 (2.3%) study injections and moderate bruising was reported following 2 (<1%) study injections of VABRINTY 45 mg. These localized adverse reactions were non-recurrent over time. No patient discontinued therapy due to an injection site adverse reaction. The following possibly or probably related systemic adverse reactions occurred during clinical trials with VABRINTY, and were reported in > 2% of patients (Table 4). Reactions considered not drug-related are excluded. Table 4. Summary of Possible or Probably Related Systemic Adverse Reactions Reported by > 2% of Patients Treated with VABRINTY VABRINTY 7.5 mg 7.5 mg 22.5 mg 30 mg 45 mg Study number AGL9904 AGL9802 AGL9909 AGL0001 AGL0205 Number of patients 120 8 117 90 111 Treatment 1 injection every month up to 6 months 1 injection (surgically castrated patients) 1 injection every 3 months up to 6 months 1 injection every 4 months up to 8 months 1 injection every 6 months up to 12 months Body system Adverse Reaction Number (percent) Body as a whole Malaise and fatigue 21 (17.5%) - 7 (6.0%) 12 (13.3%) 13 (11.7%) Weakness - - - - 4 (3.6%) Nervous system Dizziness 4 (3.3%) - - 4 (4.4%) - Vascular Hot flashes/sweats 68 (56.7%) * 2 (25.0%)* 66 (56.4%) * 66 (73.3%) * 64 (57.7%)* Renal/urinary Urinary frequency - - 3 (2.6%) 2 (2.2%) - Nocturia - - - 2 (2.2%) - Gastrointestinal Nausea - - 4 (3.4%) 2 (2.2%) - Gastroenteritis/colitis 3 (2.5%) - - - - Skin Pruritus - - 3 (2.6%) - - Clamminess - - - 4 (4.4%) * - Night sweats - - - 3 (3.3%) * 3 (2.7%) * Alopecia - - - 2 (2.2%) - Musculoskeletal Arthralgia - - 4 (3.4%) - - Myalgia - - - 2 (2.2%) 5 (4.5%) Pain in limb - - - - 3 (2.7%) Reproductive Testicular atrophy 6 (5.0%)* - - 4 (4.4%)* 8 (7.2%) * Gynecomastia - - - 2 (2.2%)* 4 (3.6%) * Testicular pain - - - 2 (2.2%) - Psychiatric Decreased libido - - - 3 (3.3%) * - *Expected pharmacological consequences of testosterone suppression. In the patient populations studied with VABRINTY 7.5 mg, a total of 86 hot flashes/sweats adverse reactions were reported in 70 patients. Of these, 71 reactions (83%) were mild; 14 (16%) were moderate; 1 (1%) was severe. In the patient population studied with VABRINTY 22.5 mg, a total of 84 hot flashes/sweats adverse reactions were reported in 66 patients. Of these, 73 reactions (87%) were mild; 11 (13%) were moderate; none were severe. In the patient population studied with VABRINTY 30 mg, a total of 75 hot flash adverse reactions were reported in 66 patients. Of these, 57 reactions (76%) were mild; 16 (21%) were moderate; 2 (3%) were severe. In the patient population studied with VABRINTY 45 mg, a total of 89 hot flash adverse reactions were reported in 64 patients. Of these, 62 reactions (70%) were mild; 27 (30%) were moderate; none were severe. In addition, the following possibly or probably related systemic adverse reactions were reported by < 2% of the patients treated with VABRINTY in these clinical studies. Body system Adverse Reactions General Sweating, insomnia, syncope, rigors, weakness, lethargy Gastrointestinal Flatulence, constipation, dyspepsia Hematologic Decreased red blood cell count, hematocrit and hemoglobin Metabolic Weight gain Musculoskeletal Tremor, backache, joint pain, muscle atrophy, limb pain Nervous Disturbance of smell and taste, depression, vertigo Psychiatric Insomnia, depression, loss of libido* Renal/urinary Difficulties with urination, pain on urination, scanty urination, bladder spasm, blood in urine, urinary retention, urinary urgency, incontinence, nocturia, nocturia aggravated Reproductive/ Urogenital Testicular soreness/pain, impotence*, decreased libido*, gynecomastia*, breast soreness/tenderness*, testicular atrophy*, erectile dysfunction, penile disorder*, reduced penis size Skin Alopecia, clamminess, night sweats*, sweating increased* Vascular Hypertension, hypotension * Expected pharmacological consequences of testosterone suppression. 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. It can be anticipated that long periods of medical castration in men will have effects on bone density. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of VABRINTY. 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. 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. Nervous System - Convulsions Respiratory System - Interstitial lung disease Skin reactions- Erythema multiforme, SJS/TEN