NUMBRINO

1 INDICATIONS AND USAGE NUMBRINO (cocaine hydrochloride) nasal solution is indicated for the induction of local anesthesia of the mucous membranes when performing diagnostic procedures and surgeries on or through the nasal cavities in adults. NUMBRINO (cocaine hydrochloride) nasal solution is an ester local anesthetic indicated for the introduction of local anesthesia of the mucous membranes for diagnostic procedures and surgeries on or through the nasal cavities of adults. ( 1 )

2 DOSAGE AND ADMINISTRATION For intranasal use only. ( 2.1 ) Do not apply to damaged nasal mucosa. ( 2.1 ) NUMBRINO should not be substituted for other nasal cocaine products unless determined by FDA to be substitutable. ( 2.1 ) The recommended dose of NUMBRINO ranges from 40 mg to 160 mg, depending on the nasal surface area to be anesthetized and the procedure to be performed. ( 2.2 ) NUMBRINO should be administered by means of cotton or rayon applicator pledgets applied to the nasal mucosa. ( 2 ) One pledget will absorb one mL of NUMBRINO nasal solution. ( 2.2 ) Preparation and Application: Draw up 4 mL NUMBRINO 4% nasal solution into a syringe calibrated in mL. Apply 2 mL NUMBRINO nasal solution to the top of four stacked pledgets. Turn the stacked pledgets over and apply 2 mL NUMBRINO nasal solution to the other side. ( 2.3 ) NUMBRINO nasal solution should be evenly distributed on all pledgets. ( 2.3 ) Following soaking, place a maximum of two pledgets in each nasal cavity. ( 2.3 ) Leave pledgets in place for up to 20 minutes. ( 2.3 ) Pledgets should be removed immediately upon any sign or symptom of an adverse event. ( 2.2 ) 2.1 Important Dosage and Administration Instructions NUMBRINO (cocaine hydrochloride) is for intranasal use only. Do not apply NUMBRINO to damaged nasal mucosa. Unless the FDA has determined that these products can be substituted, do not substitute NUMBRINO for other intranasal cocaine products because this may result in different local and/or systemic exposures. 2.2 Dosing Recommendations The recommended dose of NUMBRINO ranges from 40 mg to 160 mg, depending on the nasal mucosal area to be anesthetized and the procedure to be performed. Each pledget absorbs one mL of NUMBRINO nasal solution. A maximum of two soaked cotton or rayon pledgets may be placed in each nasal cavity, for a total dose of 160 mg for NUMBRINO nasal solution 4%. The total dose for any one procedure or surgery should not exceed 3 mg/kg cocaine hydrochloride. The recommended size of the cotton or rayon pledgets for use with NUMBRINO measure ½ inch x 3 inch (sold separately). 2.3 Preparation and Administration of NUMBRINO via Pledgets Draw up 4 mL NUMBRINO into a syringe calibrated in mL. Stack four pledgets and apply 2 mL of solution to the top of the stacked pledgets. Turn the stacked pledgets over and apply 2 mL of solution to the other side. NUMBRINO should be evenly distributed on all pledgets. Following NUMBRINO application to pledgets, place One (1) or two (2) pledgets in each nasal cavity, for a maximum of 2 pledgets used per nostril. Leave pledgets in place for up to 20 minutes. Remove pledgets and continue with the procedure. Discard pledgets, and dispose of any unused pledgets and remaining solution in accordance with institutional procedures for CII products. Pledgets should be removed immediately upon any sign or symptom of an adverse event.

4 CONTRAINDICATIONS NUMBRINO is contraindicated in: patients with a known history of hypersensitivity to cocaine hydrochloride, other ester-based local anesthetics, or any other component of the nasal solution [see Warnings and Precautions ( 5.5 )] . Hypersensitivity to cocaine, or any component of NUMBRINO. ( 4 )

5 WARNINGS AND PRECAUTIONS NUMBRINO is for TOPICAL USE ONLY. NOT FOR INJECTION OR OPHTHALMIC USE. ( 5 ) Seizures: NUMBRINO may lower the convulsive threshold. Monitor patients for development of seizures. Blood Pressure and Heart Rate Increases: Monitor vital signs, including heart rate and rhythm, in patients after receiving NUMBRINO. Avoid use of NUMBRINO in patients with a recent or active history of myocardial infarction, coronary artery disease, congestive heart failure, irregular heart rhythm, abnormal ECG, uncontrolled hypertension, or thyrotoxicosis. 5.1 Potential for Abuse and Dependence Central nervous system (CNS) stimulants, including cocaine hydrochloride, have a high potential for abuse and dependence [see Drug Abuse and Dependence ( 9.2 , 9.3 )] . 5.2 Seizures It has been reported in the literature that cocaine hydrochloride may lower the convulsive threshold. The risk may be higher in patients with a history of seizures or in patients with prior electroencephalogram (EEG) abnormalities without seizures, but has been reported in patients with no prior history or EEG evidence of seizures. Monitor patients for development of seizures. 5.3 Blood Pressure and Heart Rate Increases As reported in the literature, cocaine hydrochloride causes an increase in observed blood pressure and heart rate. In the Phase 3 clinical studies with NUMBRINO, increases in blood pressure and heart rate were observed following pledget removal. Monitor for changes in vital signs, including heart rate and rhythm, after administration of NUMBRINO. Avoid use of NUMBRINO in patients with a history of myocardial infarction, coronary artery disease, congestive heart failure, irregular heart rhythm, abnormal ECG, or uncontrolled hypertension. Avoid use of additional vasoconstrictor agents such as epinephrine or phenylephrine with NUMBRINO. If concomitant use is unavoidable, prolonged vital sign and ECG monitoring may be required. Although not reported in the NUMBRINO clinical trials, myocardial infarction has been reported in the literature, and can occur when the drug has been used as recommended [see Adverse Reactions ( 6 )] . 5.4 Toxicology Screening The time after cocaine administration for which cocaine and its metabolites can be detected in plasma and urine depends on the sensitivity of the utilized assay method. The cocaine hydrochloride and its metabolites in NUMBRINO may be detected in plasma for up to one week after administration. Cocaine hydrochloride and its metabolites may be detected in urine toxicology screening for longer than one week after administration. 5.5 Known Hypersensitivity or Idiosyncrasy to the Sympathomimetic Amines NUMBRINO is contraindicated in patients with a known history of hypersensitivity to cocaine or to the components of the nasal solution. Cocaine is a sympathetic neuronal catecholamine reuptake inhibitor, which may potentiate the actions of concomitantly administered sympathomimetic amines. 5.6 Ophthalmic Use NUMBRINO is NOT FOR OPHTHALMIC USE. Cocaine can cause sloughing of the corneal epithelium and should not be used in the eyes. Pitting and ulceration of the cornea has been reported in the literature.

7 DRUG INTERACTIONS Epinephrine, Phenylephrine: There have been reports of myocardial ischemia, myocardial infarction, and ventricular arrhythmias with concomitant use during nasal surgery. Avoid use of additional vasoconstrictor agents with NUMBRINO. If concomitant use is unavoidable, prolonged vital sign and ECG monitoring may be required. ( 5.3 , 7.2 ) Disulfiram: Disulfiram treatment increases plasma cocaine exposure. Avoid using NUMBRINO in patients taking disulfiram. ( 7.3 ) CNS stimulants: Concomitant administration may result in nervousness, irritability, or possibly convulsions. ( 7.1 ) Cholinesterase inhibitors: Concomitant administration may increase the risk of cocaine toxicity. ( 7.4 ) Sympathomimetics, postganglionic blocking agents, and tricyclic antidepressants: Concomitant administration may increase the risk of cardiovascular adverse reactions. ( 7.5 , 7.6 ) Monoamine-oxidase inhibitors: Concomitant administration may potentiate the effects and toxicity of monoamine-oxidase inhibitors. ( 7.7 ) 7.1 Central Nervous System Stimulants Concurrent use of other central nervous system stimulants with cocaine may result in excessive stimulation, leading to nervousness, irritability, or possibly convulsions, or cardiac arrhythmias. 7.2 Epinephrine, Phenylephrine There are reports in the published literature of myocardial ischemia, myocardial infarction, and ventricular arrhythmias after concomitant administration of topical intranasal cocaine with epinephrine and phenylephrine during nasal and sinus surgery. Avoid use of additional vasoconstrictor agents such as epinephrine and phenylephrine with NUMBRINO during nasal and sinus surgery. If concomitant use is unavoidable, prolonged vital sign and ECG monitoring may be required. 7.3 Disulfiram Published literature reported that disulfiram treatment increased plasma cocaine exposure (AUC and C max ), by several folds after acute intranasal cocaine administration. Another literature reported that co-administration of disulfiram increased AUC of plasma cocaine by several folds after intravenous cocaine administration [see Clinical Pharmacology ( 12.3 )] . Avoid using NUMBRINO in patients taking disulfiram. Consider using other local anesthesia. 7.4 Cholinesterase Inhibitors Cocaine has been described in literature to be primarily metabolized and inactivated by non-enzymatic ester hydrolysis and hepatic carboxylesterase, and also by plasma cholinesterase, hepatic carboxylesterase, and CYP3A4. The pharmacokinetics of NUMBRINO in patients with reduced plasma cholinesterase activity has not been studied. Plasma cholinesterase activity may be decreased by chronic administration of certain monoamine oxidase inhibitors, oral contraceptives, glucocorticoids, antimyasthenics (neostigmine), cyclophosphamide, and possibly thiotepa. It may also be diminished by administration of irreversible plasma cholinesterase inhibitors such as echothiophate, organophosphate insecticides, and certain antineoplastic agents. Patients with reduced plasma cholinesterase (pseudocholinesterase) activity may have reduced clearance and increased exposure of plasma cocaine after administration of NUMBRINO. Because cocaine is metabolized by multiple enzymes, the effect of reduced plasma cholinesterase activity on cocaine exposure may be limited. No dosage adjustment of NUMBRINO is needed in patients with reduced plasma cholinesterase. Monitor patients with reduced plasma cholinesterase activity for adverse reactions such as clinically-relevant increases in heart rate or blood pressure. 7.5 Postganglionic Blocking Agents Agents such as reserpine potentiate cocaine-induced sympathetic stimulation; concurrent use may increase the risk of hypertension and cardiac arrhythmias that may be life-threatening. 7.6 Tricyclic Antidepressants Tricyclic antidepressants may increase the activity of the sympathetic nervous system, which may also be increased by administration of cocaine hydrochloride. 7.7 Monoamine-Oxidase Inhibitors Cocaine hydrochloride may potentiate the effects and toxicity of MAO inhibitors.

6 ADVERSE REACTIONS The following treatment-emergent adverse events are discussed in more detailed in other sections of the labeling: Increases in Blood Pressure and Heart Rate [see Warnings and Precautions ( 5.3 )] The most common adverse reactions (> 1%) occurring in patients treated with NUMBRINO were hypertension, tachycardia, and sinus tachycardia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Omnivium Pharmaceuticals LLC at 1-888-807-1048 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. NUMBRINO nasal solution has been evaluated in one Phase 1 study, one QT study and two Phase 3 studies, which included 702 adult subjects who received a single application of NUMBRINO nasal solution 4%, NUMBRINO nasal solution 10%, or placebo. The randomized, double-blind, placebo controlled Phase 3 studies were conducted in adult patients undergoing diagnostic procedures and surgeries on or through the mucous membranes of the nasal cavities, of which 316 received NUMBRINO nasal solution 4%, 318 received NUMBRINO nasal solution 10%, and 168 received placebo. Safety was evaluated for up to 7 days after dosing. In a Phase 3 study, patients received a mean dose of 126 mg (80 to 160 mg, N=259) of cocaine hydrochloride using NUMBRINO nasal solution 4% and a mean dose of 319 mg (200 to 400 mg, N=259) of cocaine hydrochloride using NUMBRINO nasal solution 10% as a single application. The most common adverse reactions reported with NUMBRINO 4% are included in Table 1 (preexisting nasal conditions are not included). There were two patients treated with NUMBRINO nasal solution 4% who withdrew due to an adverse reaction. One patient developed anxiety and systolic hypertension and one patient developed intermittent paroxysmal tachycardia. Both patients developed symptoms within 10 minutes of nasal pledget application. Three patients treated with NUMBRINO nasal solution 10% required premature removal of pledgets due to nausea and diastolic hypertension; mild intermittent paroxysmal hypertension and paroxysmal tachycardia; and vasovagal syncope with bradycardia. Table 1. Common Adverse Reactions with NUMBRINO in > 1% of Treated Patients MedDRA System Organ Class and Preferred Term NUMBRINO, 4% (N=259) n, % NUMBRINO, 10% (N=259) n, % Placebo (N=128) n, % Vascular Disorders 203 (78) 224 (87) 86 (67) Hypertension 201 (78) 220 (85) 85 (66) Cardiac Disorders 31 (12) 47 (18) 10 (8) Tachycardia 12 (5) 28 (11) 1 (1) Bradycardia 8 (3) 1 (0.4) 5 (4) Sinus tachycardia 6 (2) 9 (4) 0 Investigations 13 (5) 30 (12) 8 (6) QRS prolonged 4 (2) 8 (3) 3 (2) QT interval prolonged 7 (3) 10 (4) 3 (2) 6.2 Postmarketing Experience The following adverse reactions have been identified during use of Cocaine Hydrochloride Nasal Solution. 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. Nervous system disorders: Headache, Seizure Cardiac disorders: Hypertension, tachycardia, atrial and ventricular arrhythmias, myocardial ischemia and infarction Psychiatric disorders: Anxiety

8.1 Pregnancy Risk Summary There are no available data on the use of NUMBRINO in pregnant women to identify a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Adverse maternal and fetal/neonatal outcomes have been seen in women with chronic cocaine abuse during pregnancy ( see Data ) . In published animal reproduction studies, cocaine administered to pregnant females during the gestational period produced hydronephrosis (0.5 times the human reference dose (HRD) of 37.5 mg via the 4% solution), developmental delays in the offspring (1.5 times the HRD), cerebral hemorrhage and fetal edema (2.0 times the HRD), reduced fetal body weights and brain weights (2.6 times the HRD), and reduced fetal survival (3.7 times the HRD). Single dose administration of cocaine intravenously during organogenesis in mice produced cryptochidism, anophthalmia, exencephaly, and delayed ossification at 7.8 times the HRD. In rats, a single dose of cocaine administered by intraperitoneal injection produced edematous fetuses, hemorrhages and limb defects at 12.9 times the HRD ( see Data ) . The estimated background risk of major birth defects and miscarriage for the indicated population(s) are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Human Data There are no available data on the use of intranasal cocaine hydrochloride solution in pregnant women to inform a drug-associated risk for major congenital malformations or miscarriage. There are published data describing adverse developmental outcomes in women with chronic cocaine abuse during pregnancy. The published case-control and observational studies examining the effect of in utero cocaine exposure on fetal growth parameters, after controlling for confounding variables, found exposure was associated with reduced fetal growth compared with non-drug-abuse populations. Published data from a large number of studies of women with chronic cocaine abuse during pregnancy are inconsistent in their findings with regard to congenital malformations, prematurity, miscarriage, premature rupture of membranes and gestational hypertension. The applicability of the findings from these studies of chronic abuse in pregnancy to a single topical exposure is limited. Animal Data Formal animal reproduction and development studies have not been conducted with intranasal cocaine hydrochloride. However, reproduction and development studies with cocaine have been reported in the published literature. Exposure margins below are based on body surface area comparison to the human reference dose (HRD) of 37.5 mg (estimated amount absorbed from the 160 mg (4%) cocaine-soaked pledgets). Hydronephrosis was noted in embryos from pregnant rats treated wtih cocaine 2.1 mg/kg (0.5 times the HRD) and higher from Gestation Day 0 to 9. Cerebral hemorrhage and endematous fetuses were noted at 2.2 times the HRD and above). Developmental delays and altered spontaneous exploratory behavior in response to cocaine were reported in rat pups born to dams treated intravenously with 6 mg/kg cocaine (1.5 times the HRD) from Gestation Day 8 to 20 in the absence of maternal toxicity. Reduced fetal body and brain weights and alterations in fetal central neurotransmitter levels were noted following treatment of pregnant mice with 20 mg/kg cocaine from gestation days 8 to 12 or 12 to 18 (2.6 times the HRD). Reduced fetal survival was noted when pregnant nonhuman primates were dosed with 0.3 mg/kg/h cocaine (3.7 times the HRD on per day basis) via a subcutaneous minipump from Gestation Day 24 to birth. Exencephaly, cryptochidism, hydronephrosis, anophthalmia, delayed ossification, limb anomalies, and cerebral and intra-abdominal hemorrhage were reported following a single subcutaneous injection of 60 mg/kg cocaine (7.8 times the HRD) to pregant mice between Gestation Day 7 to 12. No significant maternal toxicity was reported at this dose. Deficits in associational learning were reported when pregnant rats were treated with cocaine during gestation (10.3 times the HRD) in the absence of maternal toxicity. Hemorrhage, fetal edema, and limb defects were reported when pregnant rats were administered a single injection of cocaine at a dose of 50 mg/kg/day or higher (12.9 times the HRD) during Gestation Day 9 to 19. Increased resorptions were noted at doses higher than 70 mg/kg/day (18.1 times the HRD) when administered on Gestation Day 16. No adverse effects were reported at a dose of 40 mg/kg (10.3 times the HRD). Fetal deaths, decreased fetal body weights, edematous fetuses and single incidences of cleft palate and hypertrophic ventricle were observed when pregnant rats were treated with intraperitoneal cocaine at 60 mg/kg (15.5 times the HRD) from Gestation Day 8 to 12. Maternal toxicity was noted at this dose (mortality). No adverse effect level for fetal and maternal toxicity was noted at 50 mg/kg/day (13 times the HRD). Decreased body weights, overall body length and crown circumference of offspring were reported when pregnant Rhesus monkeys were treated with escalating doses up to 7.5 mg/kg cocaine TID intramuscularly per day for 5 days per week from prior to conception to term (11.6 times the HRD).