BRIEF SUMMARY WARNING: ABUSE AND DEPENDENCE
CNS stimulants, including cocaine hydrochloride, have a high potential for abuse and dependence [see Warnings and Precautions (5.1).]
1 INDICATIONS AND USAGE
Cocaine hydrochloride nasal solution is indicated for the induction of local anesthesia of the mucous membranes when performing di- agnostic procedures and surgeries on or through the nasal cavities in adults.
2 DOSAGE AND ADMINISTRATION 2.1 Important Dosage and Administration Instructions
• COCAINE HYDROCHLORIDE is for intranasal use only. • Do not apply COCAINE HYDROCHLORIDE to damaged nasal mucosa.
2.2 Dosing Recommendation for Adults
The recommended dose of COCAINE HYDROCHLORIDE is two soaked cottonoid pledgets placed in each nasal cavity. It is recommended to use cottonoid pledgets that measure 1.3 cm x 4 cm (sold separately).
Each pledget absorbs 1 mL of cocaine hydrochloride, equivalent to 40 mg cocaine hydrochloride, for a total dose for four pledgets of 160 mg. The total dose for any one procedure or surgery should not exceed 160 mg, or 3 mg/kg, cocaine hydrochloride.
2.3 Preparation and Administration of COCAINE HYDROCHLORIDE Pledgets
Pour the full contents of one 4 mL (160 mg) bottle of COCAINE HYDROCHLORIDE into a small container. Soak four cottonoid pledgets until the solution is fully absorbed.
Following soaking, place two pledgets in each nasal cavity against the septum.
Leave pledgets in place for up to twenty minutes. Remove pledgets and continue with the procedure. Discard pledgets and dispose of any unused portion of solution in accordance with institutional procedures for CII products.
3 DOSAGE FORMS AND STRENGTHS
COCAINE HYDROCHLORIDE nasal solution is provided as a 4% solu- tion, 160 mg/4 mL (40 mg/mL), equivalent to 142.4 mg/4mL (35.6 mg/ mL) cocaine free-base, and is a clear, green-colored solution in a single-use bottle.
COCAINE HYDROCHLORIDE is contraindicated in patients with a known history of hypersensitivity to cocaine hydrochloride, other es- ter-based anesthetics, or any other component of the product.
5 WARNINGS AND PRECAUTIONS 5.1 Potential for Abuse and Dependence
Central nervous system (CNS) stimulants, including cocaine hydro- chloride, have a high potential for abuse and dependence [see Drug Abuse and Dependence (9.2, 9.3)].
It has been reported in the literature that cocaine hydrochloride may lower the convulsive threshold. The risk may be higher in patients with a history of seizures or in patients with prior electroencephalogram (EEG) abnormalities without seizures, but has been reported in patients with no prior history or EEG evidence of seizures. Monitor patients for development of seizures.
5.3 BLOOD PRESSURE AND HEART RATE INCREASES As reported in the literature, CNS stimulants, including cocaine hy- drochloride, cause an increase in observed blood pressure and heart rate. In the Phase 3 clinical study with COCAINE HYDROCHLORIDE, increases in blood pressure and heart rate were observed for 60 minutes or longer post-pledget removal. While the increases alone may not be expected to have clinical consequences, monitor for vital sign changes, including heart rate and rhythm, after administration of COCAINE HYDROCHLORIDE.
Avoid use of COCAINE HYDROCHLORIDE in patients with a recent or active history of uncontrolled hypertension, unstable angina, myocar- dial infarction, coronary artery disease, or congestive heart failure. Avoid use of additional vasoconstrictor agents such as epinephrine or phenylephrine with COCAINE HYDROCHLORIDE. If concomitant use is unavoidable, prolonged vital sign and ECG monitoring may be required [see Drug Interactions (7)].
5.4 Urine Toxicology Screening
Advise patients that the cocaine hydrochloride in COCAINE HYDROCHLORIDE may be detected in urine toxicology screening for up to one week post-administration. Patients with renal impairment may have cocaine metabolites detected for longer than one week post-administration.
6 ADVERSE REACTIONS 6.1 Clinical Trial Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
COCAINE HYDROCHLORIDE has been evaluated in four Phase 1 stud- ies and one Phase 3 study, which included 647 adult subjects who re- ceived a single topical intranasal dose of COCAINE HYDROCHLORIDE. The randomized, double-blind, controlled Phase 3 study was conduct- ed in adult patients undergoing diagnostic procedures and surgeries on or through the mucous membranes of the nasal cavities, of which 278 received COCAINE HYDROCHLORIDE 4%, 275 received Cocaine
Hydrochloride 8%, and 95 received placebo. Safety was evaluated for up to 7 days after dosing.
The most commonly reported adverse reactions (>1 patient) to occur in the Phase 3 study with COCAINE HYDROCHLORIDE 4% were head- ache and epistaxis. Two adverse reactions of headache were severe (Table 1).
No premature discontinuations due to an adverse event, serious ad- verse events, or deaths were reported in the Phase 3 clinical study.
Table 1: Common Adverse Reactions with COCAINE HYDROCHLORIDE in > 1 Patient
System Organ Class / Preferred Term
Nervous System Disorders Headache
Psychiatric Disorders Anxiety
7 DRUG INTERACTIONS 7.1 Disulfiram
Published literature reported that disulfiram treatment increased plas- ma cocaine exposure, including both AUC and Cmax
, by several fold af-
ter acute intranasal cocaine administration. Other literature reported that co-administration of disulfiram increased AUC of plasma cocaine by several fold after intravenous cocaine administration [see Clinical Pharmacology (12.3)].
Avoid using COCAINE HYDROCHLORIDE in patients taking disulfiram. Consider using other local anesthetic agents.
7.2 Epinephrine, Phenylephrine
There are reports in the published literature of myocardial ischemia, myocardial infarction, and ventricular arrhythmias after concomitant administration of topical intranasal cocaine with epinephrine and phenylephrine during nasal and sinus surgery.
Avoid use of additional vasoconstrictor agents such as epinephrine and phenylephrine with COCAINE HYDROCHLORIDE during nasal and sinus surgery. If concomitant use is unavoidable, prolonged vital sign and ECG monitoring may be required [see Warnings and Precautions (5.3)].
7.3 Inhibitors of plasma cholinesterase (pseudocholinesterase) 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.
Plasma cholinesterase activity may be decreased by chronic admin- istration of certain monoamine oxidase inhibitors, oral contraceptives, or glucocorticoids. It may also be diminished by administration of ir- reversible plasma cholinesterase inhibitors such as echothiophate, organophosphate insecticides, and certain antineoplastic agents. Patients with reduced plasma cholinesterase (pseudocholinesterase) activity may have reduced clearance and increased exposure of 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.
8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary
There are no available data on the use of COCAINE HYDROCHLORIDE in pregnant women to inform a drug-associated risk for adverse devel- opmental outcomes. Adverse maternal and fetal/neonatal outcomes have been seen in women with chronic cocaine abuse during preg- nancy (see Data).
In published animal reproduction studies, cocaine administered to pregnant females during the gestational period produced cryptor- chidism, hydronephrosis, hemorrhage, hydrocephalus, cleft palate, delayed ossification, and limb anomalies in mice at 1.7 times the hu- man reference dose (HRD) of 58 mg based on body surface area and produced mortality, fetal edema, and microencephaly in rats at greater than 8.3 times the HRD based on body surface area.
Single dose administration of cocaine intravenously during organo- genesis in mice produced cryptorchidism, anophthalmia, exenceph- aly, and delayed ossification at 1.7 times the HRD based on body sur- face area in mice. In rats, a single dose of cocaine administered by intraperitoneal injection produced edematous fetuses, hemorrhages and limb defects at 6.7 times the HRD based on body surface area (See Data). Based on animal data, advise pregnant women of the potential risk to a fetus.
All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated back- ground risk of major birth defects and miscarriage in clinically recog- nized pregnancies is 2 - 4% and 15 - 20%, respectively.
7 (3%) 3 (1%) 0 Cocaine
(N=275) 4 (2%)
Respiratory, Thoracic, and Mediastinal Disorders Epistaxis
2 (1%) 2 (1%) 1 (1%) 0 0
Data Human Data
There are no available data on the use of intranasal cocaine hydro- chloride solution in pregnant women to inform a drug-associated risk adverse developmental outcomes. There are published data describ- ing adverse developmental outcomes in women with chronic cocaine abuse during pregnancy. The published case-control and observation- al studies examining the effect of in utero cocaine exposure on fetal growth parameters, after controlling for confounding variables, found exposure was associated with reduced fetal growth compared with non-drug- abuse populations. These effects were seen with heavy chronic use but not with lower level use associated with exposures 10- to 100-fold above the Cmax
at the clinical dose of 160 mg. 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.
Formal animal reproduction and development studies have not been conducted with intranasal cocaine hydrochloride. However, repro- duction and development studies with cocaine have been reported in the published literature. Exposure margins for the following published studies are based on body surface area conversion using a human reference dose (HRD) of 58 mg, which is 36% of the maximum rec- ommended human dose of 160 mg that is estimated to be absorbed from the pledgets.
Cerebral hemorrhage, hydrocephalus, limb anomalies, and incomplete ossification of femoral bones were observed when pregnant mice were administered 20 mg/kg/day cocaine intravenously (1.7 times the HRD) from Gestation Day (GD) 6 to 15. No maternal toxicity was observed.
In another intravenous study, incomplete ossification (sternum and su- praoccipital bone), hydrocephalus, hydronephrosis and cryptochidism were reported when pregnant mice were administered 20 mg/kg/day of cocaine (1.7 times the HRD) from Gestation Day 9 to 12. No adverse effects were observed following 10 mg/kg/day of cocaine (0.84 times the HRD). No maternal toxicity was observed.
In different strains of mice, immaturely developed cerebral ventricles, hydronephrosis, dilated or cystic ureters, and cleft lip/palate were not- ed at doses greater than 40 mg/kg/dose (3.4 times the MRHD) when administered from Gestation Day 6 to 10 to pregnant females. These adverse findings were not present at a dose of 20 mg/kg/day (1.7 times the MRHD). No evidence of maternal toxicity was noted.
Following a single subcutaneous injection of cocaine at 60 mg/kg (5 times the HRD) to pregnant mice between Gestation Day 7 to 12, exen- cephaly, cryptochidism, hydronephrosis, anophthalmia, and delayed ossification were reported. In addition, visceral malformations that included limb anomalies, cerebral and intra-abdominal hemorrhage were observed at this dose. No significant maternal toxicity was noted at this dose.
In pregnant rats administered cocaine subcutaneously (40-90 mg/kg/ day) from Gestation Day 7 to 19, dose-dependent increase in incidenc- es of fetal and maternal mortality and decreased body weight were observed at doses greater than 60 mg/kg/day (10 times the HRD). Fetal edema and hemorrhage were observed in cocaine-treated litters at 10 times the HRD and microencephaly at 15 times the HRD. No adverse effects were noted following 50 mg/kg/day (8.3 times the HRD).
In another rat study, fetal and maternal deaths, decreased fetal body weights, edematous fetuses and single incidences of cleft palate and hypertrophic ventricle were observed after intraperitoneal cocaine in- jection at 60 mg/kg/day (10 times the HRD) from Gestation Day 8 to 12. No adverse effect level for fetal and maternal toxicity was noted at 50 mg/kg/day (8.3 times the HRD).
Following single injection of cocaine at a dose of 50 mg/kg/day or higher (8.3 times the HRD) during Gestation Day 9 to 19, hemorrhage and edema was observed when only external malformations were evaluated. Increased resorptions were noted at doses higher than 70 mg/kg/day (12 times the HRD) when administered on Gestation Day 16. No adverse effects were reported at a dose of 40 mg/kg (6.7 times the HRD).
In published rat studies, prenatal cocaine administration produced hypoactivity in the pups and abnormal open field activity (5 times the HRD) and deficits in associational learning (6.7 times the HRD) in the absence of maternal toxicity. Decreased birth weights, pup body weight gain (6.7 to 10 times the HRD) and increased still births and postnatal mortality (13 times the HRD) were noted in the presence of maternal toxicity (decreased body weights and mortality).
A published study reported 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 three times a day (TID) intramuscularly per day for 5 days per week from prior to conception to term (7.5 times the HRD).
In other published studies, there were no adverse effects on physi- cal development or cognitive testing of the offspring from pregnant Rhesus monkeys treated with 0.3, 1.0, or escalating doses up to 8.5 mg/ kg TID intramuscularly per day cocaine from Gestation Day 28 to term five days per week (0.3, 1.0, or up to 8.6 times the HRD). There was
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