Cocaine Hydrochloride (Page 3 of 4)

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.

9 DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance

COCAINE HYDROCHLORIDE nasal solution contains cocaine, a Schedule II controlled substance.

9.2 Abuse

GOPRELTO contains cocaine, a substance with a high potential for abuse. COCAINE HYDROCHLORIDE nasal solution can be misused and abused, which can lead to addiction. COCAINE HYDROCHLORIDE nasal solution 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 effects. Drug addiction is a cluster of behavioral, cognitive, and physiological 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, increased 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 distinct 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 nasal solution for abuse purposes. Adverse events associated with abuse of cocaine include euphoria, excitation, irritability, restlessness, anxiety, paranoia, confusion, headache, psychosis, hypertension, stroke, seizures, dilated 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, unconsciousness, coma, and death [see Overdosage (10)] . Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV.

COCAINE HYDROCHLORIDE nasal solution, 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 procedures 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 physiological 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 nasal solution is approved for topical single use during diagnostic procedures and surgeries, so physical dependence and withdrawal symptoms are unlikely to develop. Although GOPRELTO is not indicated for chronic therapy, repeated misuse or abuse of this product may lead to physical dependence.

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.

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 17 H 21 NO 4 ∙HCl and the molecular weight is 339.81. The structural formula is:

Chemical Structure

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 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 max was 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 max and 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 max were 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)] .

All MedLibrary.org resources are included in as near-original form as possible, meaning that the information from the original provider has been rendered here with only typographical or stylistic modifications and not with any substantive alterations of content, meaning or intent.

This site is provided for educational and informational purposes only, in accordance with our Terms of Use, and is not intended as a substitute for the advice of a medical doctor, nurse, nurse practitioner or other qualified health professional.

Privacy Policy | Copyright © 2024. All Rights Reserved.