no evidence of maternal toxicity in these studies under the conditions tested.

In another published study, behavioral alterations in primate infants as assessed by a primate neonatal behavioral assessment battery were demonstrated following 10 mg/kg twice a day oral cocaine adminis- tration to pregnant Rhesus monkeys from GD 40 to 102 (6.7 times the HRD).

8.2 Lactation Risk Summary

Based on limited case reports in published literature, cocaine is pres- ent in human milk at widely varying concentrations. Based on its phar- macochemical 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 ab- sorption is unclear. No studies have evaluated cocaine concentrations in milk after topical administration of COCAINE HYDROCHLORIDE.

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 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 on milk production.

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

8.3 Females and Males of Reproductive Potential Infertility


Published animal studies suggest that cocaine can alter female re- productive hormone levels, disrupt the estrous cycle, and reduce ovulation at doses less than the HRD based on body surface area [See Nonclinical Toxicology (13.1)].

8.4 Pediatric Use

The safety and effectiveness of COCAINE HYDROCHLORIDE in pedi- atric patients (17 years of age and younger) has not been evaluated.

In juvenile male rats, 15 mg/kg subcutaneous cocaine administration for longer than 7 days (2.5 times the HRD) produced testicular necrosis, abnormal sperm morphology, and reduced pregnancy rates.

8.5 Geriatric Use

Of the total number of subjects in the Phase 3 study, 12.1% of those who received COCAINE HYDROCHLORIDE 4% were 65 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical ex- perience 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 can- not be ruled out.

8.6 Renal Impairment

No dosage adjustment of COCAINE HYDROCHLORIDE 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 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 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 metabo- lized and inactivated by non-enzymatic ester hydrolysis and hepat- ic carboxylesterase, and also by plasma cholinesterase, hepatic carboxylesterase and CYP3A4 [see Clinical Pharmacology (12.3)]. Pharmacokinetics of COCAINE HYDROCHLORIDE in patients with re- duced 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 plas- ma cocaine after administration of COCAINE HYDROCHLORIDE.

Since cocaine is metabolized by multiple enzymes, the effect of re- duced plasma cholinesterase activity on cocaine exposure may be limited. No dosage adjustment of COCAINE HYDROCHLORIDE is need- ed 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.

9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance

COCAINE HYDROCHLORIDE contains cocaine, a Schedule II con- trolled substance.

9.2 Abuse

COCAINE HYDROCHLORIDE contains cocaine, a substance with a high potential for abuse. COCAINE HYDROCHLORIDE can be misused and abused, which can lead to addiction. COCAINE HYDROCHLORIDE may also be diverted for abuse purposes [see Warnings and Precautions (5.1)].

Drug abuse is the intentional non-therapeutic use of a prescription drug, even once, for its rewarding psychological or physiological ef- fects. Drug addiction is a cluster of behavioral, cognitive, and physi- ological phenomena that develop after repeated substance use and includes: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, in- creased tolerance, and sometimes a physical withdrawal. Drug abuse of a substance may occur without progression to drug addiction. “Drug-seeking” behavior is very common in persons with substance use disorders.

Drug abuse and addiction are conditions that are separate and dis- tinct from physical dependence and tolerance [see Dependence (9.3)]. Health care providers should be aware that abuse and addiction may occur in the absence of symptoms indicative of physical dependence and tolerance.

Individuals who abuse stimulants may use COCAINE HYDROCHLORIDE for abuse purposes. Adverse events associated with abuse of cocaine include euphoria, excitation, irritability, restlessness, anxiety, paranoia, confusion, headache, psychosis, hypertension, stroke, seizures, dilat- ed pupils, nausea, vomiting, and abdominal pain. Intranasal abuse can produce damage to the nostrils (e.g., ulceration and deviated septum). Abuse of cocaine can result in overdose, convulsions, unconscious- ness, coma, and death [see Overdosage (10)]. Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV.

COCAINE HYDROCHLORIDE, like all prescription drugs with abuse potential, can be diverted for non-medical use into illicit channels of distribution. In order to minimize these risks, effective accounting pro- cedures should be implemented, in addition to routine procedures for handling controlled substances.

9.3 Dependence Physical dependence is a state that develops as a result of physio- logical adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. COCAINE HYDROCHLORIDE is approved for topical single use during diagnostic procedures and sur- geries, so physical dependence and withdrawal symptoms are unlike- ly to develop. Although COCAINE HYDROCHLORIDE is not indicated for chronic therapy, repeated misuse or abuse of this product may lead to physical dependence.


No cases of overdose with COCAINE HYDROCHLORIDE were reported in clinical trials. Blood pressure and heart rate increases were greater with Cocaine Hydrochloride 8% than with COCAINE HYDROCHLORIDE 4%.

In the case of an overdose, consult with a certified poison control cen- ter (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 co- caine reported in literature and based on reports in FDA’s Adverse Events Reporting System (AERS) database include death, cardio-re- spiratory arrest, cardiac arrest, respiratory arrest, tachycardia, myo- cardial infarction, agitation, aggression, restlessness, tremor, hyper- reflexia, rapid respiration, confusion, assaultiveness, hallucinations, panic states, hyperpyrexia, and rhabdomyolysis. Fatigue and depres- sion usually follow the central nervous system stimulation. Other re- actions 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 me- tabolized, dialysis and hemoperfusion are not effective. Acidification of the urine does not significantly enhance cocaine elimination.

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/4mL (35.6 mg/mL) cocaine free-base, an ester local anesthetic.

The chemical name for cocaine hydrochloride is methyl (1S,3S,4R,5R)- 3-benzoyloxy-8-methyl-8-azabicyclo[3.2.1]octane-4-carboxylate hydrochloride. The molecular formula is C17H21NO4•HCl and the mo- lecular weight is 339.81. The structural formula is:

ing sodium channels and preventing the transient rise in sodium con- ductance 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-con- trolled four-period crossover thorough QTc study in 24 healthy sub- jects. 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 Cmax

dian (range) time to peak plasma concentration (tmax

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, 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 car- boxylesterase 1 to form benzoylecgonine (BE), and by plasma cho- linesterase 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, 0-32 hour urinary recov- eries of cocaine, BE, and EME as a percentage of dose were approx- imately 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 (CL/F) is 3096 ± 1276 L/h.

Specific Populations

In studies with COCAINE HYDROCHLORIDE, cocaine exposure (i.e., Cmax

whereas tmax

and half-life were similar in males and females. COCAINE HYDROCHLORIDE pharmacokinetics are not affected by age or weight.

were slightly higher in subjects with severe renal impairment compared to those with normal renal function and clear- ance was slightly lower [see Use in Specific Populations (8.6)].

Renal Impairment In a pharmacokinetic study of COCAINE HYDROCHLORIDE in subjects with normal and severe renal impairment (eGFR 15-29 mL/min/1.73 m2), mean AUC and Cmax

Hepatic Impairment In a pharmacokinetic study of COCAINE HYDROCHLORIDE in subjects with normal, Child-Pugh Class B, and Child-Pugh Grade C hepatic im- pairment, there was a minimal effect of hepatic impairment on cocaine Cmax

, AUClast, and AUCinf) was slightly higher in females than males

was 43.2 (1.73) ng/mL. The me- ) was 0.42 (0.25 –

. 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 per- cent 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 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 em- ploying 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 dos- es of COCAINE HYDROCHLORIDE are not expected to raise significant drug-drug interaction concerns.


It has been reported in the published literature that disulfiram treat- ment increased plasma cocaine exposure, including both AUC and Cmax

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

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 block-

, 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)].

Please see Full Prescribing Information at eae8-4d17-bb35-813ba9805448

FDA #30-244 rev 0818 r1

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