Cocaine (Mucosal-Local)


VA CLASSIFICATION
Primary: NT300
Secondary: OR600

Note: Controlled substance classification—

Note: Controlled substance classification


U.S.—Schedule II

Canada—N
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Anesthetic-vasoconstrictor (mucosal-local)—

Indications

Accepted

Anesthesia, local1—Cocaine hydrochloride is indicated to provide local anesthesia and vasoconstriction of accessible mucous membranes, especially in the oral, laryngeal, and nasal cavities, {01} {02} {05} {06} {07} {08} {09} {10} {11} {19} prior to instrumentation (e.g., bronchoscopy) or surgical procedures. Cocaine's toxicity must be considered prior to its use, especially when it is being applied to the tracheobronchial tree. {29}
—Although cocaine is an acceptable topical anesthetic for dental procedures, it is no longer extensively used in dentistry because of its toxicity. {08}

Unaccepted
Cocaine is not indicated for administration by injection {38} and is not recommended for application to ``closed'' mucous surfaces, such as those of the urethra or bladder, {19} {33} because of the increased risk of severe toxic reactions.
1 Not included in Canadian product labeling.

1 Not included in Canadian product labeling.



Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    339.82 {02} {03} {04}

Mechanism of action/Effect:

Anesthetic, local—Acts primarily by blocking {32} both the initiation and conduction of nerve impulses {01} {02} {05} {06} {11} {12} by decreasing the neuronal membrane's permeability to sodium ions. This reversibly stabilizes the membrane and inhibits depolarization, resulting in the failure of a propagated action potential and subsequent conduction blockade.

Vasoconstrictor—Cocaine is a potent indirect-acting sympathomimetic agent, {05} {07} i.e., it interferes with the uptake of norepinephrine by adrenergic nerve terminals {01} {05} {06} {10} {12} {19} and increases the concentration of this neurotransmitter at postsynaptic receptor sites. {12} Norepinephrine acts on alpha-adrenergic receptors in blood vessels to produce vasoconstriction, which facilitates examination and surgery by reducing congestion, swelling, and bleeding at the site of application. {29}


Other actions/effects:

Cocaine's indirect sympathetic nervous system–stimulating activity results in potentiation of the effects of endogenous catecholamines, i.e., epinephrine and dopamine as well as norepinephrine. This leads to systemic, as well as local, vasoconstriction; {01} {05} {06} {10} {11} {12} {19} increased heart rate, {06} {12} {19} arterial blood pressure, {12} {20} and blood glucose concentrations; {12} {19} mydriasis; {01} {05} {12} {19} and a risk of cardiac arrhythmias. {12} Tachycardia and hypertension may increase myocardial work and oxygen demand; {12} {20} in some patients, especially those with predisposing cardiovascular disease, myocardial ischemia may result. {12}

Cocaine is a potent {19} central nervous system (CNS) stimulant. {05} {06} {11}

Cocaine has pyrogenic activity that may result from CNS stimulation–induced increases in muscular activity {01} {05} {06} {12}(which increases heat production) {01} {05} {06} as well as vasoconstriction (which decreases heat loss through the skin). {01} {05} {06} There is some evidence that cocaine also produces pyresis via a direct effect on the heat-regulating centers in the CNS. {06} {12}

Cocaine has convulsant activity that may result from its {32} pyrogenic activity as well as from its CNS effects. {12}

Cocaine also blocks the uptake of dopamine, {12} {13} thereby increasing the concentration of dopamine at postsynaptic receptor sites {13} and stimulating dopaminergic neurotransmission. {12} {13} However, repeated use of cocaine may cause dopamine depletion in the CNS. {12} Studies have indicated that dopaminergic stimulation may be responsible for the development of cocaine-induced euphoria, {12} {13} whereas dopamine depletion {12} may be responsible for the occurrence of dysphoria {12} {19} and/or mental depression {19} following cessation of repeated cocaine use and may lead to psychological dependence on the drug. {12} {19} Cocaine abuse may also lead to physical dependence. {33}

Topical application of cocaine to the oral or nasal mucosa decreases local sensory acuity; i.e., reduces or abolishes senses of taste and smell. {02} {05}

Absorption:

Cocaine is readily absorbed from all mucous membranes. {01} {02} {05} {06} {19} Although cocaine's local vasoconstrictive effect may limit to some extent its rate of absorption {19} (measurable quantities have been reported to remain in the nasal mucosa for 3 hours after application), {13} the rate of absorption may exceed the rate of metabolism and/or excretion, leading to a significant risk of systemic toxicity. {19} Entry of cocaine into the brain may be especially rapid following application to the nasal mucosa, particularly if the medication is applied as a fine-mist spray. {13} Also, cocaine is more readily absorbed from inflamed {05} {06} {19} or damaged {19} tissue.

Biotransformation:

Cocaine is hydrolyzed by plasma {01} {05} {06} {12} {13} {19} and hepatic {12} {13} {19} cholinesterases. The primary metabolites are benzoylecgonine and ecgonine methyl ester. {12} {13} Small quantities are also demethylated in the liver {05} {13} {19} to an active metabolite, norcocaine, which has local anesthetic activity and, in vitro , inhibits norepinephrine uptake. {13} Metabolism of cocaine is generally rapid, {01} {02} {19} but may be significantly decreased or slowed in individuals with low levels of plasma or hepatic cholinesterase activity. {12} {13} {19}

Half-life:

Elimination—1 {01} {06} {13} to 1.5 {05} {13} {19} hours; subject to wide inter- and intraindividual variability, but independent of the route of administration. {13}

Onset of action:

Approximately 1 minute. {05} {07} {13}

Time to peak effect:

Approximately 5 minutes. {02} {05}

Duration of action:

Approximately 30 minutes {02} {05} to 1 hour {07} (average, 20 to 40 minutes) {19}, depending on the concentration. {05} {07} {19}

Elimination:
    Renal, {02} {05} {06} {19} primarily as metabolites. {05} {19} Approximately 10 to 20% of a dose may be excreted as unchanged cocaine, depending on the acidity of the urine (with larger quantities being excreted in acidic urine). {19} The rate at which cocaine and its metabolites are cleared from the body is dose-dependent. Following intranasal administration of a single dose of about 100 mg, significant quantities of cocaine may appear in the urine for at least 10 hours, and significant quantities of its major metabolites may appear in the urine for 2 to 2.5 days. {30} {31}
    In breast milk—Cocaine is excreted in breast milk. {28}


Precautions to Consider

Carcinogenicity/Mutagenicity

Long-term studies have not been done. {01}

Pregnancy/Reproduction

Pregnancy—
Cocaine has high water and lipid solubility and may therefore cross the placenta by simple diffusion. {14} Although studies have not been done in pregnant women receiving cocaine clinically, {01} {02} the possibility should be considered that pregnant women may be especially sensitive to the effects of cocaine because of reduced plasma cholinesterase activity resulting in decreased or slower cocaine metabolism. {12} {13} {14} Human fetuses {12} {13} {14} and neonates {28} also exhibit low cholinesterase activity. Use of cocaine by a pregnant woman 1 or 2 days prior to delivery may result in the appearance of measurable quantities of benzoylecgonine in the neonate's urine for up to 5 days after birth. {12} {28}

Studies in cocaine-abusing pregnant women have shown that cocaine may increase the risk of spontaneous abortion; {12} {15} premature labor and stillbirth associated with abruptio placentae, {12} {14} {15} with onset of labor occurring shortly after use of cocaine during the third trimester; {14} congenital malformations; {12} {14} {15} decreased fetal growth (reduced neonatal birth weight, length, and head circumference); {14} and neonatal neurobehavioral impairment. {12} {15} The congenital malformations reported in these studies include transposition of the great arteries, hypoplastic right heart syndrome, exencephaly, interparietal encephalocele, parietal bone defects, {14} and, in one infant, major malformations of the urinary tract, with bilateral hydronephrosis and bilateral cryptorchidism. {15} Also, one infant born to a mother who had used cocaine intranasally 15 hours prior to delivery displayed convulsions, right-sided muscle weakness, intermittent tachycardia, and hypertension at birth and was found to have had a cerebral infarction. {12} It has been proposed that these effects result from cocaine-induced placental vasoconstriction {12} {14} {15} as well as maternal hypertension, {12} {14} {15} cardiac arrhythmias, {14} and hyperpyrexia, {14} which decrease the flow of blood and nutrients {12} {14} to the fetus and also increase the risk of spontaneous abortion or premature labor. {12} {14} {15} Because of these adverse effects, and because less toxic local anesthetics are available, it is recommended that cocaine not be administered to pregnant women. {33}

In animal studies, cocaine increased the fetal resorption rate in rats {14} and mice, {14} {16} decreased fetal weight in rats, and caused edema in the rat fetus. {14} In another study, administration of cocaine to CF-1 mice on one of Days 7 through 12 of gestation caused skeletal abnormalities (malformed sternebrae, fused sternebrae, and polysternebrae), exencephaly, cryptorchidism, hydronephrosis, butterfly xiphoid, ocular defects (including anophthalmia or malformed or missing lenses), and delayed ossification of the paws or skull. The occurrence of specific malformations or abnormalities was dependent on the day of administration and coincided with the period of ontogenesis for the structures involved. {16} Also, in a study in pregnant ewes, cocaine increased maternal blood pressure and uterine vascular resistance, decreased uterine blood flow, and caused hypoxemia, hypertension, and tachycardia in the fetuses. {17}

FDA Pregnancy Category C. {01} {02}

Breast-feeding

Cocaine is distributed into human breast milk. Symptoms of cocaine intoxication, including tachycardia, tachypnea, hypertension, irritability, and tremulousness, occurred in a breast-fed infant whose mother used cocaine intranasally. The symptoms appeared within 3 hours after the mother first used cocaine and persisted for as long as significant quantities of the drug and/or its metabolites appeared in the infant's urine. Cocaine and benzoylecgonine were present in the breast milk for up to 36 hours, and in the infant's urine for up to 60 hours, after the mother's last dose of the drug. {28} Another infant, whose mother applied cocaine to her nipples to relieve soreness prior to breast-feeding, developed convulsions. {34} Neonates may be especially susceptible to cocaine-induced toxicity {12} {13} because of low levels of cholinesterase activity resulting in decreased and/or slowed inactivation of the drug. If clinical use of cocaine is unavoidable, temporary cessation of breast-feeding is recommended. {02} {05}

Pediatrics

Because of cocaine's toxicity, it is recommended that the medication not be administered to children younger than 6 years of age. {35} For children 6 years of age or older, it is recommended that cocaine be used with caution and {36} in reduced dosage. {01} {05}


Geriatrics


The risk of cocaine-induced adverse effects may be increased in geriatric patients, who are more likely to have cerebrovascular disease, and are therefore more likely to be adversely affected by sympathetic stimulation, than are younger adults. Also, elderly males may be especially sensitive to the effects of cocaine because of reduced plasma cholinesterase activity resulting in decreased or slower cocaine metabolism. {12} {13} A reduction in dosage is recommended. {01} {05} {19}

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Anesthetics, hydrocarbon inhalation,{07} such as:
» Chloroform
» Cyclopropane
Enflurane
» Halothane
Isoflurane{37}
Methoxyflurane
» Trichloroethylene    (administration of cocaine prior to or shortly after anesthesia with chloroform, cyclopropane, halothane, or trichloroethylene may increase the risk of ventricular fibrillation or other severe ventricular arrhythmias, especially in patients with pre-existing heart disease, because these anesthetics greatly sensitize the myocardium to the effects of sympathomimetics; great caution and especially careful patient monitoring are recommended if concurrent use is necessary)

    (isoflurane, and, to a lesser extent, enflurane or methoxyflurane, may also sensitize the myocardium to the effects of sympathomimetics; caution in concurrent use is recommended)


Antidepressants, tricyclic{19} or
Digitalis glycosides or
» Levodopa{19} or
» Methyldopa{19}    (concurrent use with cocaine may increase the risk of cardiac arrhythmias; if use of cocaine is necessary in patients receiving these medications, it is recommended that cocaine be administered with caution, in reduced dosage, and in conjunction with electrocardiographic monitoring)


Antihypertensives, especially:
» Postganglionic blocking antihypertensive agents, i.e., guanadrel or guanethidine{07}{12}    (cocaine may decrease the antihypertensive effects of these medications; careful monitoring of the patient is recommended)

    (postganglionic blocking agents such as guanadrel or guanethidine may potentiate cocaine-induced sympathetic stimulation; concurrent use may increase the risk of hypertension and cardiac arrhythmias)


» Beta-adrenergic blocking agents, possibly including ophthalmic betaxolol, levobunolol, metipranolol or timolol    (cocaine may inhibit the therapeutic effects of systemic beta-adrenergic blocking agents)

    (although systemic beta-adrenergic blocking agents are recommended to reduce tachycardia, myocardial ischemia, and/or arrhythmias induced by cocaine [see Treatment of overdose ], concurrent use of a systemic beta-adrenergic blocking agent with cocaine may increase the risk of hypertension, excessive bradycardia, and possibly heart block, because beta-blockade may leave cocaine's alpha-adrenergic activity unopposed; {20} {21} the risk of these adverse effects may be decreased with labetalol because labetalol also has some alpha-adrenergic blocking activity, although its beta-adrenergic blocking activity predominates; {22} the possibility of adverse effects should also be considered if cocaine is administered to patients receiving ophthalmic beta-adrenergic blocking agents, which are extensively absorbed and cause significant systemic beta-adrenergic blockade {33})


» Cholinesterase inhibitors,{12}{13} such as:
Antimyasthenics
Cyclophosphamide
Demecarium
Echothiophate
Insecticides, neurotoxic, possibly including large quantities of topical malathion
Isoflurophate
Thiotepa    (inhibition of cholinesterase activity by these agents reduces or slows cocaine metabolism, thereby increasing and/or prolonging its effects and increasing the risk of toxicity; cholinesterase inhibition caused by echothiophate, demecarium, or isoflurophate may persist for weeks or months after the medication has been discontinued)


» CNS stimulation–producing medications, other (see Appendix II )    (concurrent use with cocaine may result in excessive CNS stimulation, leading to nervousness, irritability, insomnia, or possibly convulsions or cardiac arrhythmias; close observation is recommended)


» Monoamine oxidase (MAO) inhibitors, including furazolidone, procarbazine, and selegiline{05}{07}{19}    (MAO inhibitors may prolong and intensify the cardiac stimulant and vasopressor effects of cocaine because of release of catecholamines that accumulate in intraneuronal storage sites during MAO inhibitor therapy, resulting in headache, cardiac arrhythmias, vomiting, or sudden and severe hypertensive and/or hyperpyretic crises; cocaine should not be administered during, or within 14 days following, administration of an MAO inhibitor)

    (phenelzine also inhibits cholinesterase activity and may reduce or slow cocaine metabolism, thereby increasing and/or prolonging its effects and increasing the risk of toxicity)


Nitrates    (cocaine may reduce the antianginal effects of these medications)


» Sympathomimetics, other, especially:
Dobutamine or
Dopamine{19} or
Epinephrine, topical{02}{05}{06}{07}{19}{29}    (in addition to increasing CNS stimulation, concurrent use may increase the cardiovascular effects of either or both medications and the risk of adverse effects)

    (concurrent use of epinephrine with cocaine [especially intranasal application of ``cocaine mud'', {05} {06} {07} {19} a potentially lethal substance {19} obtained by moistening cocaine crystals or flakes with an epinephrine solution] is not recommended because of the high risk of hypertensive episodes {02} {05} {29} and cardiac arrhythmias; {02} {05} {06} {29} also, concurrent topical use of cocaine and epinephrine is unnecessary {02} {05} {06} because epinephrine does not provide additional local vasoconstriction, slow absorption of cocaine from the mucosa, or prolong cocaine's duration of action {05} {06} {29})


Thyroid hormones    (concurrent use may increase the effects of either these medications or cocaine; thyroid hormones enhance the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease; dosage adjustment is recommended, although the risk is reduced in euthyroid patients)



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
Blood pressure and
Body temperature and
Glucose, blood, concentrations and
Heart rate    (may be increased; even low doses of cocaine may increase blood pressure by 15 to 20% and heart rate by 30 to 50%, {19} although transient bradycardia may occur initially; the extent to which these values are increased may depend on patient predisposition as well as dosage)


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist
» Cardiovascular disease,{05}{07}{12} especially
» Angina pectoris{12}{19} or
» Myocardial infarction, history of{12}    (risk of severe hypertension, myocardial ischemia, angina, and/or myocardial infarction in patients with these predisposing conditions)


» Cardiac arrhythmias or history of{19} or
» Convulsions, history of{19}    (may be induced or exacerbated by cocaine)


» Cerebrovascular disease    (risk of cerebrovascular accident and subarachnoid hemorrhage {12} {33})


» Decreased cholinesterase activity, genetic or induced by disease, including carcinoma{13} or hepatic disease;{12}{13} administration of or exposure to cholinesterase inhibitors;{12}{13} or, to a lesser extent, pregnancy{12}{13}    (metabolism of cocaine is decreased or slowed, leading to increased and/or prolonged effects and increased risk of toxicity)


» Hypertension,{05}{07} not optimally controlled or
» Thyrotoxicosis{05}{07}    (cocaine-induced potentiation of endogenous catecholamines is detrimental to patients with these conditions; extreme caution is warranted)


Infection, local, at area of application{01}    (may alter pH at area of application, leading to decrease or loss of local anesthetic effect)


Sensitivity to cocaine, history of
» Tourette's syndrome    (may be exacerbated, probably because of cocaine's dopaminergic activity {18})


» Traumatized mucosa, severe    (increased risk of systemic toxicity because of enhanced cocaine absorption {05} {06} {19})


» Caution is also required in elderly, debilitated, or acutely ill patients, who may be especially sensitive to the effects of the medication.

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

» Blood pressure and
» Cardiac rhythm and
Core body temperature and
» Heart rate    (monitoring recommended because of the risk of hypertension, tachycardia, ventricular arrhythmias, and hyperpyrexia; when low doses are administered, tachycardia may initially {19} be preceded by bradycardia {01} {05} {06} {10} {11} {19} caused by central vagal stimulation, {05} {06} {11} {19} although only tachycardia caused by central and peripheral sympathetic stimulation {05} {06} occurs following moderate or high doses {01} {05} {06} {10} {11})




Side/Adverse Effects

Note: Many of cocaine's systemic adverse effects are due to excessive sympathetic activity {10} {19} and may be caused by rapid absorption, {13} {19} decreased patient tolerance, {01} or, rarely, {19} hypersensitivity. {01} {19} Toxic reactions are relatively uncommon with appropriate use of usual clinical doses.
The fatal dose of cocaine has been reported to be 1.2 grams. However, patient sensitivity to the effects of the medication is highly variable; adverse effects have been reported with as little as 20 mg. {01} {02} {05}
Acute toxicity may occur very rapidly. {01} {12} {19} Manifestations of systemic cocaine toxicity may occur in 3 stages (early stimulation, advanced stimulation, and depression). Although many of the signs and symptoms of early stimulation would not necessarily require medical intervention under other circumstances, their occurrence following use of cocaine indicates that prompt action is required, because progression from one stage of toxicity to the next may be very rapid. {13} {19}

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Signs and symptoms of systemic toxicity
Early stimulation
    
Cardiac/cardiovascular effects, including increased blood pressure{02}{05}{06}{07}{10}{11}{12}{19}
increased heart rate{01}{02}{05}{06}{07}{10}{11}{19}
premature ventricular contractions{19} (irregular heartbeat), vasoconstriction{19}
    
chills{01}{02}{05}{06} and fever{01}{02}{05}{12}{19}
    
CNS effects, including agitation
excitement
nervousness
restlessness
apprehension{13}{19}
irritability{01}{02}{05}{07}
confusion{01}{02}{05}
dizziness or lightheadedness{19}
hallucinations
sudden headache{01}{02}{05}{19}
inability to remain still{13}{19}
mood or mental changes, including elation or euphoria{19} {02}{05}{07}{12}{13}{19}
dysphoria{05} or dysphoric agitation{12}
paranoid ideation{12}{13} or psychosis{12}{13}{19}
preconvulsive movements{19}
talkativeness{01}{02}{05}{19}
generalized tics{19} or twitching of small muscles —especially of the face, fingers, or feet{13}{19}
    
gastrointestinal effects, including abdominal pain{01}{02}{05}{12}
nausea or vomiting{01}{02}{05}{12}{19}
    
grinding of teeth{19}
    
increased sweating{19}
    
rapid breathing{02}{10}{19}
    
unusually large pupils{01}{02}{05}{19} —sometimes with bulging of eyes{01}{02}{05}

Note: Hallucinations may be auditory, gustatory, olfactory, visual (e.g., ``snow lights''), and/or tactile (e.g., formication [``cocaine bugs''], which may induce picking or stroking movements). {05} {13} {19}
Tachycardia occurring after low doses of cocaine may initially be preceded by bradycardia. {01} {05} {06} {10} {11} {19}


Advanced stimulation
    
Cardiac arrhythmias, including ventricular arrhythmias such as ventricular tachycardia and fibrillation{11}{12}{19} (blue discoloration of fingernails, lips, or skin{19}; decreased blood pressure{06}{19}; rapid, irregular, or weak pulse{19})
    
CNS hemorrhage{12}{19}
    
congestive heart failure{01}{02}{05}{13}{19}
    
convulsions, tonic-clonic{01}{02}{05}{12}{19} —may progress to status epilepticus{19}
    
decreased responsiveness to stimuli{19}
    
delirium{01}{02}{05}{12}
    
hyperreflexia{19}
    
loss of bladder or bowel control{19}
    
malignant encephalopathy{19}
    
myocardial ischemia{12}
    
respiratory and/or cardiac weakness{01}{02}{05}{13}{19}

Depression
    
Loss of reflexes{13}{19}
    
flaccid muscular paralysis{19}
    
fixed, dilated pupils{19}
    
loss of consciousness{01}{02}{05}{13}
    
ashen gray cyanosis{19}
    
pulmonary edema{19}
    
cardiac,{12}{19} circulatory,{13}{19} and/or respiratory{01}{02}{05}{12}{13}{19} failure —may be fatal




Those indicating need for medical attention only if continuing or bothersome
Incidence more frequent
—following application to oral or nasal mucosa    
Loss of sense of smell and/or taste{01}{02}{05}{12}{13}

With repeated intranasal application
    
Rebound hyperemia{19} (stuffy nose)
    
rhinitis, chronic (sneezing or sniffling, continuing)—may lead to chronic sinusitis and increased risk of upper respiratory infections{19}
Note: With repeated or prolonged intranasal use, ischemic damage to the mucosa may occur {02} {05} and may lead to atrophy of the nasal mucosa, {12} necrosis of septal tissue, {12} {23} and septal perforation. {01} {12} {13} {19} {23}







Overdose
For specific information on the agents used in the management of cocaine overdose, see:    • Benzodiazepines (Systemic) monograph;
   • Beta-adrenergic Blocking Agents (Systemic) monograph;
   • Calcium Channel Blocking Agents (Systemic) monograph;
   • Lidocaine (Systemic) monograph;
   • Nitrates (Systemic) monograph;
   • Nitroprusside (Systemic) monograph;
   • Phentolamine (Systemic) monograph;
   • Sodium Bicarbonate (Systemic) monograph; and/or
   • Thiopental in Anesthetics, Barbiturate (Systemic) monograph.

For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Acute
    
Cardiac arrhythmias
    
cardiovascular depression
    
convulsions
    
hypertension
    
hyperthermia
    
metabolic acidosis
    
myocardial ischemia


Treatment of overdose


To decrease absorption:
Measures to limit absorption in cases of overdosage (with recreational use of cocaine), such as administration of activated charcoal {05} or gastric lavage {02} {05} (if the drug had been ingested orally) or application of a tourniquet (if the drug had been injected), {02} {05} may be of some value if they can be instituted rapidly. {05} However, because severe cocaine toxicity may develop very quickly, instituting the measures described below for treatment of cocaine-induced toxicity must always take precedence.



Specific treatment:
For cardiac arrhythmias—Administering propranolol {05} {10} {12} {19} {20} (1 mg intravenously, repeated at 1-minute intervals as needed up to a total of 6 mg) {19} or other beta-adrenergic blocking agents is recommended to treat tachycardia or other cardiac arrhythmias. However, pure beta-adrenergic blocking agents such as propranolol do not reduce cocaine-induced hypertension and may actually increase the risk of hypertension, {20} {21} bradycardia, and possibly heart block by leaving unopposed cocaine's alpha-adrenergic stimulating activity. {20} {21} Labetalol, which also has some alpha-adrenergic blocking activity (although its beta-adrenergic blocking activity predominates) has been recommended instead. {22} Administration of a pure alpha-adrenergic blocking agent such as phentolamine (5 mg intravenously, repeated every 15 to 20 minutes as needed) may also be required. {10} Lidocaine hydrochloride (50 to 100 mg as a single intravenous injection, followed by infusion at a rate of 2 to 4 mg per minute as needed) or other antiarrhythmics may also be administered. {19} In addition, cardiac massage {10} and/or electrical defibrillation {10} {23} may be required for ventricular fibrillation.

For cardiovascular depression—Placing the patient in a 30-degree head down (Trendelenburg) position is recommended to increase venous return to the heart. {19} Blood pressure should be maintained with intravenous fluids; {05} administration of vasopressors is dangerous. {05} {19} For severe cardiovascular depression, cardiopulmonary resuscitation may be required, but inotropic agents should be given with great caution. {19}

For convulsions—If convulsions do not respond to respiratory support, administration of a benzodiazepine such as diazepam {01} {02} {05} {12} {19} {23} (5 to {37} 10 mg intravenously, repeated as needed) {02} or an ultrashort-acting barbiturate such as thiopental or thiamylal (in 50- to 100-mg increments every 2 to 3 minutes, intravenously) is recommended. The fact that these agents, especially the barbiturates, may cause circulatory depression when administered intravenously must be kept in mind. A neuromuscular blocking agent {19} {32} has also been recommended to decrease the muscular manifestations of persistent convulsions; artificial respiration is mandatory if such an agent is used. However, succinylcholine may cause fasciculations and/or malignant hyperthermia, which may cause further problems in these patients. Other neuromuscular blocking agents may be less hazardous. {19}

For hypertension—Administering phentolamine, labetalol, or a vasodilator such as nitroprusside. {24}

For hyperthermia—Applying external cooling measures, {19} {23} such as a cooling blanket, sponging with ice water, and/or using fans. {19}

For metabolic acidosis—Administering bicarbonate. {19}

For myocardial ischemia—Administering nitrates, cardioselective {36} beta-adrenergic blocking agents, and/or calcium-channel blocking agents. {20}



Monitoring:
Monitoring vital signs and core body temperature continuously. {19}



Supportive care:
Securing and maintaining a patent airway, administering 100% oxygen, and instituting assisted or controlled respiration as required. In some patients, endotracheal intubation may be necessary. {01} {02} {05} {19}

Establishing intravenous lines using an isotonic or hypotonic intravenous solution; hypertonic or hyperosmolar solutions should be avoided. All medications must be administered intravenously because cocaine-induced vasoconstriction may prevent absorption following intramuscular administration. {19}

Minimizing all forms of sensory stimulation {02} {19} may be advisable, since these hyperstimulated patients may be agitated and/or paranoid and may become aggressive. {19}

Patients in whom intentional overdose is known or suspected should be referred for psychiatric consultation.



Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Cocaine (Mucosal-Local).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before receiving this medication
»   Conditions affecting use, especially:
Sensitivity to cocaine

Pregnancy—Cocaine crosses the placenta; spontaneous abortions, premature labor, and adverse effects on the fetus or neonate have resulted from cocaine abuse during pregnancy





Breast-feeding—Cocaine is distributed into breast milk and has caused convulsions, high blood pressure, fast heartbeat, breathing problems, trembling, and unusual irritability in nursing infants





Use in children—Caution required because of cocaine's toxicity






Use in the elderly—Increased risk of adverse effects
Other medications, especially beta-adrenergic blocking agents, guanadrel, guanethidine, levodopa, methyldopa, other CNS stimulants, cholinesterase inhibitors, monoamine oxidase inhibitors, and other sympathomimetics
Other medical problems, especially cardiovascular, cardiac, or cerebrovascular disease, conditions predisposing to decreased pseudocholinesterase activity, convulsions (history of), hypertension, thyrotoxicosis, Tourette's syndrome, and severely traumatized mucosa

Proper use of this medication

Proper dosing

Precautions after receiving this medication
Caution if being tested for possible drug use because cocaine and/or its metabolites may be present in blood and/or urine for several days after administration {38}


Side/adverse effects
Signs and symptoms of potential side effects, especially abdominal pain; chills; confusion; dizziness or lightheadedness; excitement, nervousness, or restlessness; fast or irregular heartbeat; general feeling of discomfort or illness; hallucinations; headache, sudden; increased sweating; mood or mental changes; and nausea


General Dosing Information
Safe and effective clinical use of cocaine depends upon careful patient selection, proper dosage, correct administration technique, adequate precautions, and readiness for emergencies. Resuscitative equipment, trained personnel, oxygen, and other required medications should be immediately available. {01} {05} {19}

The dosage of cocaine depends on the technique of anesthesia, the area to be anesthetized, the vascularity of the tissues at the application site, and the patient's tolerance. Because of cocaine's toxicity, the lowest dosage that provides adequate anesthesia should be used. {01} {02} {05} {07} {19}

The recommended adult doses are given as a guideline for use in the average adult. The actual dosage and maximum dosage must be individualized, based on the age, size, and physical status of the patient and the expected rate of systemic absorption from the administration site. Lower concentrations and/or lower total dosage are recommended for pediatric, geriatric, acutely ill, or debilitated patients.

A standard textbook should be consulted for specific techniques and procedures applicable to the use of mucosal-local anesthetics for individual diagnostic procedures.

Premedication with a benzodiazepine such as {37} diazepam, which has anxiolytic, anticonvulsant, and muscle relaxant properties, may reduce the incidence and/or severity of some cocaine-induced adverse effects. {19}

Tolerance to the effects of cocaine may develop with repeated application. {02} {05} {07}

Repeated use of cocaine may lead to the development of psychological {02} {05} {07} {13} {19} and physical {33} dependence.

For treatment of adverse effects
Recommended treatment consists of the following:

   • Minimizing all forms of sensory stimulation {02} {19} may be advisable, since these hyperstimulated patients may be agitated and/or paranoid and may become aggressive. {19}
   • Treatment of CNS effects in patients who are not in immediate danger may include administering diazepam (2.5 to 5 mg) or a short-acting barbiturate (50 to 75 mg of amobarbital or secobarbital) for symptoms of CNS stimulation, such as hyperactivity or agitation; {19} chlorpromazine {08} or haloperidol {24} for paranoia or psychosis; or tricyclic antidepressants {08} (with great caution, because of the risk of cardiac arrhythmias) for mental depression associated with heavy cocaine abuse or withdrawal.


Mucosal-Local Dosage Forms

COCAINE HYDROCHLORIDE (CRYSTALS/FLAKES) USP

Usual adult dose
Anesthetic-vasoconstrictor (mucosal-local)1
Topical, to the mucosa, a known (preweighed) quantity being applied via moistened cotton-tipped applicators. {29}


Usual adult prescribing limits
400 mg, although the lowest effective dose should be used.

Usual pediatric dose
Dosage has not been established.

Size(s) usually available:
U.S.—
Available as bulk chemical.

Canada—
Available as bulk chemical.

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a well-closed, light-resistant container.

Note: Controlled substance in both the U.S. and Canada.



COCAINE HYDROCHLORIDE TABLETS FOR TOPICAL SOLUTION USP

Usual adult dose
Anesthetic-vasoconstrictor (mucosal-local)
Topical, to the mucosa, as a 1 to 4% solution. {02} The medication may be applied by means of cotton applicators, packs, or spray, or by instillation. {01} {05} Concentrations greater than 4% are generally not recommended because of difficulty in controlling dosage and the increased risk of toxic reactions. {02} {05} {07}


Usual adult prescribing limits
400 mg, although the lowest effective dose should be used. {36} {39} {40}

Usual pediatric dose
Children up to 6 years of age—Use is not recommended. {33}

Children 6 years of age and older—Dosage must be individualized by the physician.

Strength(s) usually available
U.S.—


135 mg (Rx)[Generic](lactose)

Canada—
Not commercially available.

Note: This product is not to be dispensed directly to the patient.


Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a well-closed, light-resistant container.

Preparation of dosage form:
To prepare a 4% solution—Dissolve 1 tablet in 3.4 mL of distilled water.

Incompatibilities:
Solutions of cocaine hydrochloride are incompatible with alkali and with alkaloidal precipitants. {09}

Note: Controlled substance in the U.S.



COCAINE HYDROCHLORIDE TOPICAL SOLUTION

Usual adult dose
Anesthetic-vasoconstrictor (mucosal-local)
Topical, to the mucosa, as a 1 to 4% solution. {02} The medication may be applied by means of cotton applicators, packs, or spray, or by instillation. {01} {05} Concentrations greater than 4% are generally not recommended because of the difficulty in controlling dosage and the increased risk of toxic reactions. {02} {05} {07}


Usual adult prescribing limits
400 mg, although the lowest effective dose should be used. {36} {39} {40}

Usual pediatric dose
Children up to 6 years of age—Use is not recommended. {33}

Children 6 years of age and older—Dosage must be individualized by the physician.

Strength(s) usually available
U.S.—


4% (40 mg per mL) (Rx)[Generic]


4% (40 mg per mL) (Rx)[Generic] (sterile){41}


10% (100 mg per mL) (Rx)[Generic]


10% (100 mg per mL) (Rx)[Generic] (sterile){41}

Canada—
Not commercially available. Compounding (using cocaine hydrochloride crystals/flakes) is required for preparation of this dosage form.

Note: This product is not to be dispensed directly to the patient.


Packaging and storage:
Store between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer.

Stability:
Ethylene oxide is recommended for sterilization of the external surface of glass bottles containing the solution. Do not steam autoclave. {01}

Incompatibilities:
Solutions of cocaine hydrochloride are incompatible with alkali and with alkaloidal precipitants. {09}

Note: Controlled substance in the U.S.



COCAINE HYDROCHLORIDE VISCOUS TOPICAL SOLUTION

Usual adult dose
Anesthetic-vasoconstrictor (mucosal-local)
Topical, to the mucosa, as a 1 to 4% solution. {02} The medication may be applied by means of cotton applicators or packs, or by instillation. {25} Concentrations greater than 4% are generally not recommended because of the difficulty in controlling dosage and the increased risk of toxic reactions. {02} {05} {07}


Usual adult prescribing limits
400 mg, although the lowest effective dose should be used. {36} {39} {40}

Usual pediatric dose
Children up to 6 years of age—Use is not recommended. {33}

Children 6 years of age and older—Dosage must be individualized by the physician.

Strength(s) usually available
U.S.—


4% (40 mg per mL) (Rx)[Generic]


10% (100 mg per mL) (Rx)[Generic]

Canada—
Not commercially available.

Note: This product is not to be dispensed directly to the patient.


Packaging and storage:
Store between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer.

Stability:
Ethylene oxide is recommended for sterilization of the external surface of glass bottles containing the solution. Do not steam autoclave. {01}

Incompatibilities:
Solutions of cocaine hydrochloride are incompatible with alkali and with alkaloidal precipitants. {09}

Note: Controlled substance in the U.S.

1 Not included in Canadian product labeling.



Revised: 07/14/1994



References

Note: References used in the development and earlier revisions of this monograph have not yet been incorporated into the computer database and, therefore, are not listed below. Citations for information not yet referenced in the monograph will be provided upon request.

  1. Package insert, Cocaine Hydrochloride Topical Solution, Roxane, revised 8/86 (rec'd 8/87).
  1. Package insert, Cocaine Hydrochloride Tablets for Topical Solution, Lilly, revised 7/84 (rec'd 10/87).
  1. USAN and the USP dictionary of drug names. Rockville: The U.S. Pharmacopeial Convention; 1988.
  1. United States Pharmacopeia XXI / National Formulary XVI. The U.S. Pharmacopeial Convention; 1985.
  1. AHFS Drug Information. Bethesda: American Society of Hospital Pharmacists; 1987: 1446-7.
  1. Goodman and Gilman's The pharmacological basis of therapeutics, 7th ed. New York: Pergamon Press; 1985: 309.
  1. AMA Drug Evaluations, 6th ed. Chicago: American Medical Association; 1986: 140, 283, 357, 522.
  1. Ciancio SG, Borgault PC. Clinical pharmacology for dental professionals, 2nd ed. Littleton: PSG; 1984: 122-3.
  1. Accepted dental therapeutics, 40th ed. Chicago: American Dental Association Council on Dental Therapeutics; 1984: 199.
  1. Vickers MD, Schneiden H, Wood-Smith FG. Drugs in anaesthetic practice, 6th ed. Boston: Butterworths, 1984: 217-9.
  1. Wood M, Wood, AJJ. Drugs and anesthesia: Pharmacology for anesthesiologists. Baltimore: Williams and Wilkins; 1982: 362-3.
  1. N Engl J Med 1986; 315: 1495-1500.
  1. Cocaine: Pharmacology, effects, and treatment of abuse; National Institute on Drug Abuse Research Monograph Series 50, 1984: 15-53, 72-91, 102.
  1. J Pediatr 1987; 110: 93-6.
  1. N Engl J Med 1985; 313: 666-9.
  1. Res Comm Subst Abuse 1984; 5: 279-302.
  1. JAMA 1987; 257: 957-61.
  1. N Engl J Med 1986; 315: 398 (letter).
  1. Ann Emerg Med 1982; 11: 562-72.
  1. JAMA 1987; 257: 979-80.
  1. Ann Intern Med 1985; 14: 1112-3.
  1. Ann Emerg Med 1987; 16: 922.
  1. Medical Letter 1984; 26: 51-2.
  1. Medical Letter 1987; 29: 83.
  1. Package insert, Cocaine Hydrochloride Viscous Topical Solution, Roxane (U.S.), rev. 5/91 (rec'd 3/92).
  1. HOLD
  1. HOLD
  1. Pediatrics 1987; 80: 836-8.
  1. Otolaryngol Clin North Am 1981; 14: 521-31.
  1. J Anal Toxicol 1984; 8: 23-5.
  1. J Anal Toxicol 1985; 9: 241-5.
  1. Panelist Comment, draft 1988.
  1. Panel Consensus, draft 1988.
  1. J Pediatr 1988; 112: 134-135.
  1. Reviewer Comment, draft 1988.
  1. Panelist Comment, draft 1988.
  1. Panelist Comment, draft 1988.
  1. Panelist Comment, draft 1988.
  1. Panelist Comment, draft 1988.
  1. Panelist Comment, draft 1988.
  1. Cocaine hydrochloride topical solution (sterile) package insert (Roxane—US), Rev 3/94, Rec 7/97.
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