Cocaine Hydrochloride Nasal

1 INDICATIONS AND USAGE 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. Cocaine hydrochloride nasal solution is an ester local anesthetic 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. ( 1 )

2 DOSAGE AND ADMINISTRATION For intranasal use only. ( 2.1 ) Do not apply to damaged nasal mucosa. ( 2.1 ) Cocaine hydrochloride should not be substituted for other nasal cocaine products unless determined by FDA to be substitutable. ( 2.1 ) The recommended dose of cocaine hydrochloride ranges from 40 mg to 160 mg, depending on the nasal surface area to be anesthetized and the procedure to be performed. ( 2.2 ) Cocaine hydrochloride should be administered by means of cotton or rayon applicator pledgets applied to the nasal mucosa. ( 2 ) One pledget will absorb one mL of cocaine hydrochloride nasal solution. ( 2.2 ) Preparation and Application: Draw up 4 mL cocaine hydrochloride 4% nasal solution into a syringe calibrated in mL. Apply 2 mL cocaine hydrochloride nasal solution to the top of four stacked pledgets. Turn the stacked pledgets over and apply 2 mL cocaine hydrochloride nasal solution to the other side. ( 2.3 ) Cocaine hydrochloride 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 Cocaine hydrochloride is for intranasal use only. Do not apply cocaine hydrochloride to damaged nasal mucosa. Unless the FDA has determined that these products can be substituted, do not substitute cocaine hydrochloride for other intranasal cocaine products because this may result in different local and/or systemic exposures. 2.2 Dosing Recommendations The recommended dose of cocaine hydrochloride 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 cocaine hydrochloride 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 cocaine hydrochloride 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 cocaine hydrochloride measure ½ inch x 3 inch (sold separately). 2.3 Preparation and Administration of Cocaine Hydrochloride via Pledgets Draw up 4 mL cocaine hydrochloride 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. Cocaine hydrochloride should be evenly distributed on all pledgets. Following cocaine hydrochloride 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.

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 cocaine hydrochloride 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. Cocaine hydrochloride 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 cocaine hydrochloride nasal solution 4%, cocaine hydrochloride 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 cocaine hydrochloride nasal solution 4%, 318 received cocaine hydrochloride 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 cocaine hydrochloride nasal solution 4% and a mean dose of 319 mg (200 to 400 mg, N=259) of cocaine hydrochloride using cocaine hydrochloride nasal solution 10% as a single application. The most common adverse reactions reported with cocaine hydrochloride 4% are included in Table 1 (preexisting nasal conditions are not included). There were two patients treated with cocaine hydrochloride 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 cocaine hydrochloride 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 Cocaine Hydrochloride in > 1% of Treated Patients MedDRA System Organ Class and Preferred Term Cocaine Hydrochloride, 4% (N=259) n, % Cocaine Hydrochloride, 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

12.3 Pharmacokinetics Cocaine hydrochloride is an aqueous solution of cocaine hydrochloride for topical use only. Absorption Application of cocaine hydrochloride for 20 minutes by pledget administration to the nasal mucosa in healthy adults may reduce the systemic absorption of the applied dose of cocaine hydrochloride compared to the systemic absorption after non-pledget administration. The estimated mean systemic absorption of cocaine from a single 160 mg dose (4 mL, 4%) was 23.44% of the topically applied dose. ( Table 2 ). Table 2. Systemic Absorption of Cocaine Hydrochloride in Healthy Adult Subjects Minimized by Pledget Administration (single nasal dose of 160 mg Cocaine Hydrochloride Topical Solution over 20 minutes) Cocaine Hydrochloride Dose (4 mL) Age Range (yr) Application Time (min) Estimated 1 Systemic Absorption Mean C max (ng/mL) Median T max (min) C max (ng/mL) 160 mg (4%) 20-40 20 23.44% 142.68 n=33 30 142.7 1 Estimated absorbed dose was calculated by subtracting the residual amount of drug in the pledgets from the administered dose; T max includes time 0 (the start of pledget insertion to pledget removal (20 minutes) to the time C max was observed, i.e. 10 minutes after removal of the pledgets. Distribution Cocaine has been described in literature as approximately 84-92% bound to human plasma proteins. Cocaine is extensively distributed to tissues and crosses the blood brain barrier. Its volume of distribution is approximately 2 L/kg. Cocaine crosses the placenta by simple diffusion and accumulates in the fetus after repeated use. Elimination Metabolism Cocaine is metabolized by two major hydrolytic pathways. Cocaine is metabolized by hydrolysis to benzoylecgonine (major, but inactive metabolite) by hepatic carboxylesterase-1. Cocaine is also metabolized by hydrolysis to ecgonine methyl ester (major, but inactive metabolite) by plasma butyrylcholinesterase and hepatic carboxylesterase-2. Cocaine is minimally metabolized by hydrolysis to ecgonine (minor, inactive metabolite) by carboxylesterase-2. Cocaine is N-demethylated by the CYP3A4 enzyme system to produce the active metabolite, norcocaine. Total systemic exposure of norcocaine is less than one percent that observed with cocaine. Excretion Cocaine is excreted almost exclusively in the urine, as metabolites. Only a minor fraction of cocaine is eliminated unchanged in the urine (<5%). The apparent elimination half-life of cocaine following administration of cocaine hydrochloride (by pledgets) was 1.54 hours) for the 4% concentration. Specific Populations Geriatric Patients The pharmacokinetics of cocaine hydrochloride in patients over the age of 65 has not of been studied. Patients with Hepatic Impairment The pharmacokinetics of cocaine hydrochloride in patients with hepatic impairment has not been studied. Patients with Renal Impairment The pharmacokinetics of cocaine hydrochloride in patients with renal impairment has not been studied. Drug-drug Interactions: Disulfiram It has been reported in the published literature that disulfiram treatment increased plasma cocaine exposure, including both AUC and C max , by several folds after acute intranasal cocaine administration. Another published literature reported that co-administration of disulfiram increased AUC of plasma cocaine by several folds after intravenous cocaine administration [see Drug Interactions ( 7.1 )] .