Numbrino Drug Information

(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.

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.

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).

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 or two 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.

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 203 224 86 Hypertension 201 220 85 Cardiac Disorders 31 47 10 Tachycardia 12 28 1 Bradycardia 8 1 5 Sinus tachycardia 6 9 0 Investigations 13 30 8 QRS prolonged 4 8 3 QT interval prolonged 7 10 3

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

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.

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.

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 . Avoid using NUMBRINO in patients taking disulfiram. Consider using other local anesthesia.

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.

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.

Tricyclic Antidepressants Tricyclic antidepressants may increase the activity of the sympathetic nervous

system, which may also be increased by administration of cocaine hydrochloride.

Monoamine-Oxidase Inhibitors Cocaine hydrochloride may potentiate the effects and toxicity of

MAO inhibitors.

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).

Pediatric Use Safety and effectiveness of NUMBRINO in pediatric patients under the age of 18 have not been established. Published studies state that in juvenile male rats, 30 mg/kg subcutaneous cocaine administration for longer than 7 days (7.8 times the HRD) produced testicular necrosis. Treatment of juvenile male rats with 15 mg/kg (3.9 times the HRD) for 100 days resulted in abnormal sperm morphology and reduced pregnancy rates.

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 . Hypersensitivity to cocaine, or any component of NUMBRINO.

No cases of overdose with NUMBRINO were reported in clinical trials. Reported blood pressure and heart rate increases were greater with NUMBRINO nasal solution 10% than with NUMBRINO nasal solution 4%. In the case of an overdose, consult with a Certified Poison Control Center (1-800-222-1222) for up-to-date guidance and advice for treatment of overdosage. Individual patient response to cocaine varies widely.

Toxic symptoms may occur idiosyncratically at low doses. Manifestations of cocaine overdose associated with illicit use of cocaine reported in literature and based on reports in FDA’s Adverse Events Reporting System (AERS) database include death, cardio-respiratory arrest, cardiac arrest, respiratory arrest, tachycardia, myocardial infarction, agitation, aggression, restlessness, tremor, hyperreflexia, rapid respiration, confusion, assaultiveness, hallucinations, panic states, hyperpyrexia, and rhabdomyolysis. Fatigue and depression usually follow the central nervous system stimulation.

Other reactions include arrhythmias, hypertension or hypotension, circulatory collapse, nausea, vomiting, diarrhea, and abdominal cramps. Fatal poisoning is usually preceded by convulsions and coma. Because cocaine is significantly distributed to tissues and rapidly metabolized, dialysis and hemoperfusion are not effective.

Acidification of the urine does not significantly enhance cocaine elimination.