2.1 Important Dosage and Administration Instructions

• GOPRELTO is for intranasal use only.
• Do not apply GOPRELTO to damaged nasal mucosa.

2.2 Dosing Recommendation for Adults

The recommended dose of GOPRELTO is two soaked cottonoid pledgets placed in each nasal cavity, equivalent to 40 mg cocaine hydrochloride per pledget, for a total dose of 160 mg for four pledgets.

The total dose for any one procedure or surgery should not exceed 160 mg, or 3 mg/kg, cocaine hydrochloride. The recommended size of cottonoid pledgets for use with GOPRELTO measure 1.3 cm x 4 cm (sold separately).

2.3 Preparation and Administration of GOPRELTO Pledgets

Pour the full contents of one 4 mL (160 mg) bottle of GOPRELTO 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.

5.1 Potential for Abuse and Dependence

Central nervous system (CNS) stimulants, including cocaine hydrochloride, have a high potential for abuse and dependence [ see Drug Abuse and Dependence ( 9.2, 9.3)].

5.2 Seizures

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, cocaine hydrochloride causes an increase in observed blood pressure and heart rate. In the Phase 3 clinical study with GOPRELTO, increases in blood pressure and heart rate were observed for 60 minutes or longer following pledget removal. Monitor for vital sign changes, including heart rate and rhythm, after administration of GOPRELTO.

Avoid use of GOPRELTO in patients with a recent or active history of uncontrolled hypertension, unstable angina, myocardial infarction, coronary artery disease, or congestive heart failure. Avoid use of additional vasoconstrictor agents such as epinephrine or phenylephrine with GOPRELTO. If concomitant use is unavoidable, prolonged vital sign and ECG monitoring may be required [see Drug Interactions ( 7)].

5.4 Toxicology Screening

The cocaine hydrochloride in GOPRELTO may be detected in plasma for up to one week after administration. Cocaine hydrochloride and its metabolites may be detected in urine toxicology screening for longer than one week after administration.

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.

GOPRELTO has been evaluated in four Phase 1 studies and one Phase 3 study, which included 647 adult subjects who received a single topical intranasal 160 mg dose (four pledgets), of GOPRELTO. The randomized, double-blind, controlled Phase 3 study was conducted in adult patients undergoing diagnostic procedures and surgeries on or through the mucous membranes of the nasal cavities, of which 278 received GOPRELTO (4% solution), 275 received cocaine hydrochloride solution 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 GOPRELTO (4% solution) were headache and epistaxis. Two adverse reactions of headache were severe (Table 1).

No premature discontinuations due to an adverse event, serious adverse events, or deaths were reported in the Phase 3 clinical study.

7.1 Disulfiram

Published literature reported that disulfiram treatment increased plasma cocaine exposure, including both AUC and C max, by several fold after 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 GOPRELTO 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 GOPRELTO 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 metabolized and inactivated by nonenzymatic ester hydrolysis and hepatic carboxylesterase, and also by plasma cholinesterase, hepatic carboxylesterase, and CYP3A4 [see Clinical Pharmacology ( 12.3)]. The pharmacokinetics of GOPRELTO in patients with reduced plasma cholinesterase activity has not been studied.

Plasma cholinesterase activity may be decreased by chronic administration of certain monoamine oxidase inhibitors, oral contraceptives, or glucocorticoids. It may also be diminished by administration of irreversible 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 plasma cocaine after administration of GOPRELTO.
Since cocaine is metabolized by multiple enzymes, the effect of reduced plasma cholinesterase activity on cocaine exposure may be limited. No dosage adjustment of GOPRELTO 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.

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 utero cocaine exposure on fetal growth parameters, after controlling for confounding variables, found exposure was associated with reduced fetal growth compared with non-drugabuse 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 GOPRELTO.

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 GOPRELTO 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 longterm effects on infants exposed to cocaine through breast milk are unknown. There are no data on the effects of GOPRELTO 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 GOPRELTO and to pump and discard breastmilk for 48 hours after use of GOPRELTO.

8.4 Pediatric Use

The safety and effectiveness of GOPRELTO 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 GOPRELTO 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 GOPRELTO is needed in patients with mild, moderate, or severe renal impairment [ see Clinical Pharmacology ( 12.3)].

8.7 Hepatic Impairment

No dosage adjustment of GOPRELTO 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 GOPRELTO 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 nonenzymatic ester hydrolysis and hepatic carboxylesterase, and also by plasma cholinesterase, hepatic carboxylesterase and CYP3A4 [see Clinical Pharmacology ( 12.3)]. Pharmacokinetics of GOPRELTO 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 GOPRELTO.

Since cocaine is metabolized by multiple enzymes, the effect of reduced plasma cholinesterase activity on cocaine exposure may be limited. No dosage adjustment of GOPRELTO 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.

9.1 Controlled Substance

GOPRELTO contains cocaine, a Schedule II controlled substance.

9.2 Abuse

GOPRELTO contains cocaine, a substance with a high potential for abuse. GOPRELTO can be misused and abused, which can lead to addiction. GOPRELTO 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 GOPRELTO 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.

GOPRELTO, 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. GOPRELTO 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.

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 GOPRELTO (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 GOPRELTO (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 GOPRELTO, 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 nonenzymatic 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 GOPRELTO, 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 GOPRELTO (CL/F) is 3096 ± 1276 L/h.

Specific Populations

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

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

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis
Long-term animal studies to evaluate the carcinogenic potential of cocaine have not been conducted.

Mutagenesis
In published studies, cocaine was genotoxic in the in vitro chromosomal aberration assay, the in vitro sister chromatid exchange assay, the in vitro micronucleus assay, and the in vitro hypoxanthine-guanine phosphoribosyltransferase (hgprt) assay. Cocaine was equivocal in a published in vivo micronucleus assay and the in vivo comet assay (liver). Cocaine was not mutagenic in the in vitro bacterial reverse mutation assay (Ames assay).

Impairment of Fertility

No adverse effects on fertility or early embryonic development were reported in a study where male rats were administered up to 20 mg/kg cocaine hydrochloride via subcutaneous injection for 28 days prior to mating and female rats were treated with the same dose for 14 days prior to mating through Gestation Day 7. The 20 mg/kg/dose resulted in AUC exposures that were 31 times (males) and 47 times (females) the adult human AUC following administration of pledgets containing 160 mg of cocaine.