Leuprolide

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 )

12.1 Mechanism of Action Leuprolide acetate, a gonadotropin releasing hormone (GnRH) agonist, acts as an inhibitor of gonadotropin secretion when given continuously in therapeutic doses. Animal and human studies indicate that after an initial stimulation, chronic administration of leuprolide acetate results in suppression of testicular and ovarian steroidogenesis. This effect is reversible upon discontinuation of drug therapy.

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 Sy

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

5 WARNINGS AND PRECAUTIONS Tumor Flare: Transient increase in serum levels of testosterone during treatment may result in worsening of symptoms or onset of new signs and symptoms during the first few weeks of treatment, including bone pain, neuropathy, hematuria, bladder outlet obstruction, ureteral obstruction, or spinal cord compression. Monitor patients at risk closely and manage as appropriate. ( 5.1 , 5.7 ) Hyperglycemia and diabetes: Hyperglycemia and an increased risk of developing diabetes have been reported in men receiving GnRH analogs. Monitor blood glucose level and manage according to current clinical practice. ( 5.2 ) Cardiovascular diseases: Increased risk of myocardial infarction, sudden cardiac death and stroke has been reported 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 the 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, occurred in patients treated with VABRINTY. Interrupt VABRINTY if signs or symptoms of SCARs develop. Permanently discontinue if SCARs are confirmed. ( 5.6 ) Embryo-Fetal Toxicity: May cause fetal harm. ( 5.8 , 8.1 ) 5.1 Tumor Flare VABRINTY 7.5 mg, 22.5 mg, and 30 mg like other GnRH agonists, causes a transient increase in serum concentrations of testosterone during the first week of treatment. VABRINTY 45 mg causes a transient increase in serum concentrations of testosterone during the first two weeks of treatment. Patients may experience worsening of symptoms or onset of new signs and symptoms during the first few weeks of treatment, including bone pain, neuropathy, hematuria, or bladder outlet obstruction. Cases of ureteral obstruction and/or spinal cord compression, which may contribute to paralysis with or without fatal complications, have been observed in the treatment of advanced prostate cancer using GnRH agonists. Patients with metastatic vertebral lesions and/or with urinary tract obstruction should be closely observed during the first few weeks of therapy. If spinal cord compression or ureteral obstruction develops, standard treatment of these complications should be instituted. 5.2 Hyperglycemia and Diabetes Hyperglycemia and an increased risk of developing diabetes have been reported in men receiving GnRH agonists. Hyperglycemia may represent development of diabetes mellitus or worsening of glycemic control in patients with diabetes. Monitor blood glucose and/or glycosylated hemoglobin (HbA1c) periodically in patients receiving a GnRH agonist and manage with current practice for treatment of hyperglycemia or diabetes. 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 convul

4 CONTRAINDICATIONS Hypersensitivity VABRINTY is contraindicated in patients with hypersensitivity to GnRH, GnRH agonist analogs or any of the components of VABRINTY. Anaphylactic reactions to synthetic GnRH or GnRH agonist analogs have been reported in the literature. Known hypersensitivity to GnRH, GnRH agonist analogs or any of the components of VABRINTY ( 4 )