Leuprolide Acetate

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 )

VABRINTY is an injectable suspension of leuprolide acetate available in a pre-connected syringe system and packaged with a sterile safety needle and cap (Table 2), a desiccant, prescribing information and instructions for use. The pre-connected syringe system consists of syringe A and syringe B connected using a coupling device. Syringe A contains the in situ polymeric extended release technology and the syringe B contains leuprolide acetate powder. When reconstituted, VABRINTY is administered as a single dose. Refer to Table 10 for details of the description of the dosage form before and after mixing [see How Supplied/Storage and Handling ( 16 )] . Table 2. Specifications for VABRINTY Sterile Safety Needle and Cap VABRINTY strength Gauge Length 7.5 mg 20-gauge 5/8-inch 22.5 mg 20-gauge 5/8-inch 30 mg 20-gauge 5/8-inch 45 mg 18-gauge 5/8-inch Injectable suspension: 7.5 mg ( 3 ) Injectable suspension: 22.5 mg ( 3 ) Injectable suspension: 30 mg ( 3 ) Injectable suspension: 45 mg ( 3 )

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 )

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 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), and erythema multiforme, occurred in patients receiving VABRINTY [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 VABRINTY 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 VABRINTY.

5.7 Laboratory Tests Monitor VABRINTY response by periodic measurement of serum concentrations of testosterone and prostate specific antigen. In the majority of patients, testosterone levels increased above Baseline during the first week, declining thereafter to Baseline levels or below by the end of the second or third week. Castrate levels were generally reached within two to four weeks. Castrate testosterone levels were maintained for the duration of the treatment with VABRINTY 7.5 mg. No increases to above the castrate level occurred in any of the patients. Castrate levels were generally maintained for the duration of treatment with VABRINTY 22.5 mg. Once castrate levels were achieved with VABRINTY 30 mg, most (86/89) patients remained suppressed throughout the study. Once castrate levels were achieved with VABRINTY 45 mg, one patient (< 1%) experienced a breakthrough, with testosterone levels > 50 ng/dL. Results of testosterone determinations are dependent on assay methodology. It is advisable to be aware of the type and precision of the assay methodology to make appropriate clinical and therapeutic decisions. Drug/Laboratory Test Interactions: Therapy with VABRINTY results in suppression of the pituitary-gonadal system. Results of diagnostic tests of pituitary gonadotropic and gonadal functions conducted during and after VABRINTY therapy may be affected.

5.8 Embryo-Fetal Toxicity Based on findings in animal studies and mechanism of action, VABRINTY may cause fetal harm when administered to a pregnant woman. In animal developmental and reproductive studies, major fetal abnormalities were observed after administration of leuprolide acetate throughout gestation in rats. Advise pregnant patients and females of reproductive potential of the potential risk to the fetus [see Use in Specific Populations (8.1), Clinical Pharmacology ( 12.1 )] .

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. […]

Females and males of reproductive potential: VABRINTY may impair fertility. ( 8.3 ) Pediatric: Safety and effectiveness in pediatric patients have not been established. ( 8.4 ) Geriatric: This label reflects clinical trials for VABRINTY in prostate cancer where the majority of subjects were at least 65 years of age ( 8.5 ).

8.1 Pregnancy Risk Summary Based on findings in animal studies and mechanism of action, VABRINTY 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. Expected hormonal changes that occur with VABRINTY treatment increase the risk for pregnancy loss. In animal developmental and reproductive studies, major fetal abnormalities were observed after administration of leuprolide acetate throughout gestation in rats. Advise pregnant patients and females of reproductive potential of the potential risk to the fetus (see Data) . Data Animal Data In animal developmental and reproductive studies, major fetal abnormalities were observed after administration of leuprolide acetate throughout gestation. There were increased fetal mortality and decreased fetal weights in rats and rabbits. The effects of fetal mortality are expected consequences of the alterations in hormonal levels brought about by this drug.

8.2 Lactation The safety and efficacy of VABRINTY have not been established in females. There is no information regarding the presence of VABRINTY 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 VABRINTY, 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 mechanism of action, VABRINTY may impair fertility in males of reproductive potential [see Clinical Pharmacology ( 12.1 )] .

8.4 Pediatric Use The safety and effectiveness of VABRINTY in pediatric patients have not been established.

8.5 Geriatric Use The majority of the patients (approximately 70%) studied in the clinical trials were age 70 and older. Clinical studies of VABRINTY did not include sufficient numbers of younger adult patients to determine if patients 65 years of age and older respond differently than younger adult patients.

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.