PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

PRINCIPAL DISPLAY PANEL - 4 mL Bottle Carton

NDC 64950-362-04
COCAINE
HYDROCHLORIDE
nasal solution

CII

160 mg/4 mL

For Topical Use Only.
Not for Injection or Ophthalmic Use

Single-unit

Each 1 mL contains:
Cocaine Hydrochloride, USP
40 mg

(equivalent to 142.4 mg/4 mL [35.6 mg/mL] cocaine)

Rx Only
4 mL

Genus
Lifesciences Inc.

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DESCRIPTION SECTION

11 DESCRIPTION

COCAINE HYDROCHLORIDE nasal solution for intranasal use contains a 4% solution, 160 mg/4 mL (40 mg/mL), equivalent to 142.4 mg/4 mL (35.6 mg/mL) cocaine, an ester local anesthetic.

The chemical name for cocaine hydrochloride is (1R,2R,3S,5S) methyl 3-(benzoyloxy)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate hydrochloride. The molecular formula is C 17H 21NO 4∙HCl and the molecular weight is 339.81. The structural formula is:

Inactive ingredients are anhydrous citric acid, D&C Yellow No. 10, FD&C Green No. 3, sodium benzoate, and purified water.

CLINICAL PHARMACOLOGY SECTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Cocaine hydrochloride is a local anesthetic of the ester type. Cocaine hydrochloride prevents conduction in nerve fibers by reversibly blocking sodium channels and preventing the transient rise in sodium conductance necessary for generation of an action potential.

12.2 Pharmacodynamics

Cardiac Electrophysiology

The effect of COCAINE HYDROCHLORIDE nasal solution on the QTc interval was evaluated in a randomized, positive- and placebo-controlled four-period crossover thorough QTc study in 24 healthy subjects. No clinically relevant QTc prolongation was observed at the highest clinically relevant concentrations with a single therapeutic dose.

12.3 Pharmacokinetics

Absorption

The pharmacokinetics of COCAINE HYDROCHLORIDE nasal solution have been assessed in 74 healthy adult subjects across 4 studies. Following intranasal application of two 40 mg pledgets applied to each nasal cavity (160 mg cocaine hydrochloride total dose) for 20 minutes, the geometric mean (SD) cocaine C maxwas 43.2 (1.73) ng/mL. The median (range) time to peak plasma concentration (t max) was 0.42 (0.25 – 1.75) hours after pledget application.

Distribution

Cocaine has been described in literature as approximately 84 – 92% bound to human plasma proteins, binding primarily to alpha-1-acid glycoprotein (AAG) and albumin.

In studies with COCAINE HYDROCHLORIDE nasal solution, the apparent volume of distribution (Vd/F) of cocaine after intranasal administration is 3,877 ± 1,266 L.

Elimination

Metabolism

Cocaine has been described in literature to be primarily metabolized and inactivated by non-enzymatic ester hydrolysis and hepatic carboxylesterase 1 to form benzoylecgonine (BE), and by plasma cholinesterase and hepatic carboxylesterase 2 to form ecgonine methyl ester (EME). In human liver microsomes, cocaine undergoes CYP3A4 mediated N-demethylation to produce a minor metabolite, norcocaine, which is pharmacologically active.

Excretion

Cocaine has been described in literature to be primarily eliminated by biotransformation to inactive metabolites, BE and EME. Less than 10% of the administered dose is excreted unchanged in the urine. BE and EME are both predominantly excreted by the kidneys.

In studies with COCAINE HYDROCHLORIDE nasal solution, 0-32 hour urinary recoveries of cocaine, BE, and EME as a percentage of dose were approximately 0.1%, 2.0%, and 1.0%, respectively. The mean elimination half-life of cocaine was 1.0 to 1.7 hours; with longer plasma sampling (32 hours) and a highly sensitive assay, mean half-life values of 5.0 to 8.0 hours were observed at very low plasma concentrations.

The apparent clearance of cocaine after intranasal administration of COCAINE HYDROCHLORIDE nasal solution (CL/F) is 3096 ± 1276 L/h.

Specific Populations

In studies with COCAINE HYDROCHLORIDE nasal solution, cocaine exposure (i.e., C max, AUC last, and AUC inf) was slightly higher in females than males whereas t maxand half-life were similar in males and females. COCAINE HYDROCHLORIDE nasal solution pharmacokinetics are not affected by age or weight.

Renal Impairment

In a pharmacokinetic study of COCAINE HYDROCHLORIDE nasal solution in subjects with normal and severe renal impairment (eGFR 15-29 mL/min/1.73 m 2), mean AUC and C maxwere slightly higher in subjects with severe renal impairment compared to those with normal renal function and clearance was slightly lower [see Use in Specific Populations (8.6)].

Hepatic Impairment

In a pharmacokinetic study of COCAINE HYDROCHLORIDE nasal solution in subjects with normal, Child-Pugh Class B, and Child-Pugh Grade C hepatic impairment, there was a minimal effect of hepatic impairment on cocaine C max. In moderately impaired subjects (n=9) there was a higher than two-fold increase in AUC (79.2 ng.h/mL in normal subjects to 225 ng.h/mL in Child-Pugh Grade B subjects) and the clearance was reduced by more than half (1735 L/h in normal 629 L/h in Child-Pugh Grade B subjects). In severely impaired subjects (n=3) there was an eighty percent increase in AUC (79.2 ng.h/mL in normal subjects to 142 ng.h/mL in Child-Pugh Grade C subjects) and the clearance was reduced to half (1735 L/h in normal 959 L/h in Child-Pugh Grade C subjects) [see Use in Specific Populations (8.7)].

Drug Interaction Studies

Cocaine has been found to be a CYP2D6 inhibitor in in-vitro studies employing human liver microsomes. In vitro transporter inhibition studies also found cocaine to be an inhibitor of OCT2. However, the relatively low plasma concentrations of cocaine resulting from therapeutic doses of COCAINE HYDROCHLORIDE nasal solution are not expected to raise significant drug-drug interaction concerns.

Disulfiram

It has been reported in the published literature that disulfiram treatment increased plasma cocaine exposure, including both AUC and C max, by several fold after acute intranasal cocaine administration. Other published literature reported that co-administration of disulfiram increased AUC of plasma cocaine by several fold after intravenous cocaine administration [see Drug Interactions (7.1)] .

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INDICATIONS & USAGE SECTION

Highlight: 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)

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.

DOSAGE FORMS & STRENGTHS SECTION

Highlight: Nasal solution: 160 mg/4 mL (40 mg/mL or 4%) cocaine hydrochloride, equivalent to 142.4 mg/4 mL (35.6 mg/mL) cocaine, in a single-unit bottle.**(3) **

3 DOSAGE FORMS AND STRENGTHS

COCAINE HYDROCHLORIDE nasal solution is provided as a 4% solution, 160 mg/4 mL (40 mg/mL), equivalent to 142.4 mg/4 mL (35.6 mg/mL) cocaine, and is a clear, green-colored solution in a single-unit bottle.

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CONTRAINDICATIONS SECTION

Highlight: Known hypersensitivity to cocaine hydrochloride, other ester-based anesthetics, or any other component of COCAINE HYDROCHLORIDE nasal solution. (4)

4 CONTRAINDICATIONS

COCAINE HYDROCHLORIDE nasal solution is contraindicated in patients with a known history of hypersensitivity to cocaine hydrochloride, other ester-based anesthetics, or any other component of the product.

BOXED WARNING SECTION

WARNING: ABUSE AND DEPENDENCE

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USE IN SPECIFIC POPULATIONS SECTION

Highlight: * Pregnancy: May cause fetal harm.(8.1)

• Lactation: Avoid breastfeeding for 48 hours after treatment.(8.2)
• Hepatic Impairment: Monitor for adverse reactions such as headache, epistaxis, and clinically-relevant increases in heart rate or blood pressure. Do not administer a second dose within 24 hours of the first dose.(8.7)

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

In animal studies conducted in accordance with good laboratory practices, malformations including vertebral and rib abnormalities were reported when pregnant rabbits were treated with 16 mg/kg cocaine hydrochloride during organogenesis (8 times the adult human exposure following administration of pledgets containing 160 mg of cocaine) and increased pup mortality was noted when pregnant rats were exposed to cocaine hydrochloride during pregnancy at 47 times the adult human AUC exposures. Published rodent studies testing high exposures to cocaine during organogenesis report various malformations at 17 to 34 times the adult human AUC exposures following administration of pledgets containing 160 mg of cocaine.

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 adverse developmental outcomes. 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 uterococaine 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 other developmental outcomes.

Prospective studies controlling for polydrug use (marijuana, alcohol, tobacco) and lifestyle factors, have not demonstrated any association between cocaine abuse and specific major or minor fetal anomalies or other forms of fetal harm (premature birth, stillbirth, miscarriage, low birth weight, reduced head circumference, or placental abruption).

The applicability of the findings from these studies of chronic abuse in pregnancy to a single topical exposure is limited.

Animal Data

No clear evidence of fetal malformations was noted in a study where pregnant rats were treated subcutaneously with up to 30 mg/kg cocaine hydrochloride (48 times the human adult exposure based on AUC following administration of pledgets containing 160 mg of cocaine) from Gestation Day 7 through 17 in the absence of overt maternal rat toxicity. However, a single high-dose fetus was reported with both meningoencephalocele and anophthalmia (unilateral).

Malformations, including vertebral and rib anomalies, were observed when pregnant rabbits were treated subcutaneously with 16 mg/kg cocaine hydrochloride (8 times the human adult exposure based on AUC exposures following administration of pledgets containing 160 mg of cocaine) from Gestation Day 7 through 20. This dose level was associated with evidence of maternal toxicity (convulsions, decreased body weight gain). No adverse effects were noted in animals treated with 8 mg/kg (1.5 times the adult human AUC following administration of pledgets containing 160 mg of cocaine).

An increased incidence of pup mortality between Postnatal Day (PND) 0 to PND 4 and decreased pup body weights from PND 1 to PND 21 were noted when pregnant rats were treated from GD 6 through Lactation Day 20 with 20 mg/kg cocaine hydrochloride (47 times the adult human AUC following administration of pledgets containing 160 mg of cocaine) in the absence of overt maternal toxicity. There was no adverse effect on pre- or postnatal development at 6 mg/kg (7 times the human adult AUC exposure following administration of pledgets containing 160 mg cocaine).

Published studies in pregnant mice suggest that high exposure to cocaine (approximately 17-32 times the adult human AUC following administration of pledgets containing 160 mg of cocaine) produced adverse fetal effects including: exencephaly, cerebral hemorrhage, hydrocephalus, immaturely developed cerebral ventricles, limb anomalies, incomplete bone ossification, hydronephrosis, cryptorchidism, dilated or cystic ureters, and cleft lip/palate.

In a published nonhuman primate study, no adverse effects on physical development or cognitive function were noted after 1 mg/kg cocaine was administered via intramuscular injection three times a day (TID) (approximately 5 times the adult human AUC following administration of pledgets containing 160 mg of cocaine). However, higher exposures to cocaine decreased body weights, overall body length and crown circumference of offspring from pregnant Rhesus monkeys treated with escalating doses up to 7.5 mg/kg cocaine TID intramuscularity per day for 5 days per week from prior to conception to term (39 times the adult human AUC following administration of pledgets containing 160 mg of cocaine).

8.2 Lactation

Risk Summary

Based on limited case reports in published literature, cocaine is present in human milk at widely varying concentrations. Based on its pharmacochemical characteristics, high concentrations of cocaine are expected in breast milk with systemic exposure. The applicability of these findings to a single topical exposure with limited systemic absorption is unclear. No studies have evaluated cocaine concentrations in milk after topical administration of COCAINE HYDROCHLORIDE nasal solution.

Cocaine is detected in human breastmilk in chronic abuse situations and is expected to be at higher concentrations in milk than in maternal blood based on its physicochemical characteristics. Breastfeeding immediately after administration of COCAINE HYDROCHLORIDE nasal solution could result in infant plasma concentrations that are approximately half the anticipated maximum maternal plasma concentrations at the clinical dose of 160 mg. The effects of this cocaine plasma concentration in an infant are unknown, but no level of cocaine exposure is considered safe for a breastfed infant.

Adverse reactions have occurred in infants ingesting cocaine through breastmilk, including vomiting, diarrhea, convulsions, hypertension, tachycardia, agitation and irritability. The long-term effects on infants exposed to cocaine through breast milk are unknown. There are no data on the effects of COCAINE HYDROCHLORIDE nasal solution on milk production.

Because of the potential for serious adverse reactions in breastfed infants, advise nursing women that breastfeeding is not recommended during treatment with COCAINE HYDROCHLORIDE nasal solution and to pump and discard breastmilk for 48 hours after use of COCAINE HYDROCHLORIDE nasal solution.

8.4 Pediatric Use

The safety and effectiveness of COCAINE HYDROCHLORIDE nasal solution in pediatric patients (17 years of age and younger) has not been evaluated.

Animal Data

Adverse CNS-related clinical signs within the first several days of dosing and decreased body weights were observed when juvenile rat pups were dosed subcutaneously with 25 mg/kg cocaine hydrochloride (15 and 32 times the adult human AUC exposure following administration of pledgets containing 160 mg of cocaine for males and females, respectively) from PND 7 to PND 28. No adverse effects were noted in pups dosed with 12.5 mg/kg (7 times the adult human AUC exposure following administration of pledgets containing 160 mg of cocaine).

A single mortality (male) and transient CNS signs were observed in male and female juvenile rat pups that were dosed subcutaneously up to 25 mg/kg cocaine hydrochloride (113 times the adult human AUC exposure) from PND 28 to PND 56. No adverse effects were noted in male pups dosed with 12.5 mg/kg or female pups dosed with 25 mg/kg (84 and 117 times the adult human AUC exposure following administration of pledgets containing 160 mg of cocaine, respectively).

8.5 Geriatric Use

Of the total number of subjects in the Phase 3 study, 12.1% of those who received COCAINE HYDROCHLORIDE nasal solution were 65 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience and pharmacokinetic data [see Clinical Pharmacology (12.3)] has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

8.6 Renal Impairment

No dosage adjustment of COCAINE HYDROCHLORIDE nasal solution is needed in patients with mild, moderate, or severe renal impairment [see Clinical Pharmacology (12.3)] .

8.7 Hepatic Impairment

No dosage adjustment of COCAINE HYDROCHLORIDE nasal solution is needed in patients with hepatic impairment. Monitor patients with hepatic impairment for adverse reactions such as headache, epistaxis, and clinically-relevant increases in heart rate or blood pressure and do not administer a second dose of COCAINE HYDROCHLORIDE nasal solution to these patients within 24 hours of the first dose [see Clinical Pharmacology (12.3)] .

8.8 Patients with Reduced Plasma Cholinesterase Activity

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 [see Clinical Pharmacology (12.3)] . Pharmacokinetics of COCAINE HYDROCHLORIDE nasal solution in patients with reduced plasma cholinesterase activity has not been studied.

Genetic abnormalities of plasma cholinesterase (e.g., patients who are heterozygous or homozygous for atypical plasma cholinesterase gene), disease conditions such as malignant tumors, severe liver or kidney disease, decompensated heart disease, infections, burns, anemia, peptic ulcer, or myxedema or other physiological states such as pregnancy may lead to reduced plasma cholinesterase activity. Patients with reduced plasma cholinesterase (pseudocholinesterase) activity may have reduced clearance and increased exposure of plasma cocaine after administration of COCAINE HYDROCHLORIDE nasal solution.

Since cocaine is metabolized by multiple enzymes, the effect of reduced plasma cholinesterase activity on cocaine exposure may be limited. No dosage adjustment of COCAINE HYDROCHLORIDE nasal solution is needed in patients with reduced plasma cholinesterase. Monitor patients with reduced plasma cholinesterase activity for adverse reactions such as headache, epistaxis, and clinically-relevant increases in heart rate or blood pressure.

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OVERDOSAGE SECTION

10 OVERDOSAGE

No cases of overdose with COCAINE HYDROCHLORIDE nasal solution were reported in clinical trials. Blood pressure and heart rate increases were greater with cocaine hydrochloride solution 8% than with COCAINE HYDROCHLORIDE nasal solution.

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.

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SPL UNCLASSIFIED SECTION

Manufactured by and Distributed by:
Genus Lifesciences Inc.
514 North 12 thStreet
Allentown, PA 18102

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