Data from FDA - Curated by EPG Health - Last updated 25 January 2018

Indication(s)

1 INDICATIONS AND USAGE GOPRELTO (cocaine hydrochloride) nasal solution is indicated for the induction of local anesthesia of the mucous membranes when performing diagnostic procedures and surgeries on or through the nasal cavities in adults. GOPRELTO (cocaine hydrochloride) nasal solution is an ester local anesthetic indicated for the induction of local anesthesia of the mucous membranes when performing diagnostic procedures and surgeries on or through the nasal cavities in adults. (1)

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Advisory information

contraindications
4 CONTRAINDICATIONS GOPRELTO is contraindicated in patients with a known history of hypersensitivity to cocaine hydrochloride, other ester-based anesthetics, or any other component of the product. Known hypersensitivity to cocaine hydrochloride, other ester-based anesthetics, or any other component of GOPRELTO. (4)
Adverse reactions
6 ADVERSE REACTIONS The most common adverse reactions (>0.5%) occurring in patients treated with GOPRELTO (cocaine hydrochloride) nasal solution 4% were headache and epistaxis. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Pharm-Olam at 1-866-511-6754 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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. Table 1: Common Adverse Reactions with GOPRELTO in > 1 Patient System Organ Class / Preferred Term GOPRELTO 4% (N=278) Cocaine Hydrochloride Solution 8% (N=275) Placebo (N=95) Nervous System Disorders Headache 7 (3%) 4 (2%) 1 (1%) Respiratory, Thoracic, and Mediastinal Disorders Epistaxis 3 (1%) 2 (1%) 0 Psychiatric Disorders Anxiety 0 2 (1%) 0

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION For intranasal use only. (2.1) Recommended dose: two pledgets, each containing 40 mg of cocaine hydrochloride, applied to each nasal cavity. (2.2) Do not apply to damaged nasal mucosa. (2.1) Preparation and Application: –In a small container, soak four pledgets in the full contents (4 mL) of one bottle of GOPRELTO until the solution is fully absorbed. Each pledget absorbs 1 mL of solution, equivalent to 40 mg cocaine hydrochloride. (2.2, 2.3) –Following soaking, place two pledgets in each nasal cavity against the septum. (2.3) –Leave pledgets in place for up to 20 minutes. (2.3) 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 × 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.
Use in special populations
8 USE IN SPECIFIC POPULATIONS Pregnancy: May cause fetal harm. (8.1) Lactation: Avoid breastfeeding for 48 hours after treatment. (8.2) Hepatic Impairment: Monitor for adverse reactions such as headache, epistaxis, and clinically-relevant increases in heart rate or blood pressure. Do not administer a second dose within 24 hours of the first dose. (8.7) 8.1 Pregnancy Risk Summary There are no available data on the use of GOPRELTO in pregnant women to form the basis for a drug-associated risk analysis for adverse developmental outcomes. Adverse maternal and fetal/neonatal outcomes have been seen in women with chronic cocaine abuse during pregnancy (see Data ). In published animal reproduction studies, cocaine administered to pregnant females during the gestational period produced cryptorchidism, hydronephrosis, hemorrhage, hydrocephalus, cleft palate, delayed ossification, and limb anomalies in mice at 1.7 times the human 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 organogenesis in mice produced cryptorchidism, anophthalmia, exencephaly, and delayed ossification at 1.7 times the HRD based on body surface 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 background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 - 4% and 15 - 20%, respectively. 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-drug-abuse 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 Formal animal reproduction and development studies have not been conducted with intranasal cocaine hydrochloride. However, reproduction 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 recommended 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 supraoccipital 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 noted at doses greater than 40 mg/kg/day (3.4 times the HRD) 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 HRD). 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, exencephaly, 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 incidences 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 injection 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 physical 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 no evidence of maternal toxicity in these studies under the conditions tested. In another published study, behavioral alterations in primate infants as assessed by a primate neonatal behavioral assessment battery were demonstrated following 10 mg/kg twice a day oral cocaine administration to pregnant Rhesus monkeys from GD 40 to 102 (6.7 times the HRD). 8.2 Lactation Risk Summary Based on limited case reports in published literature, cocaine is 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 long-term 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. 8.3 Females and Males of Reproductive Potential Infertility Females Published animal studies suggest that cocaine can alter female reproductive hormone levels, disrupt the estrous cycle, and reduce ovulation at doses less than the HRD based on body surface area [See Nonclinical Toxicology (13.1)]. 8.4 Pediatric Use The safety and effectiveness of GOPRELTO in pediatric patients (17 years of age and younger) has not been evaluated. In juvenile male rats, 15 mg/kg subcutaneous cocaine administration for longer than 7 days (2.5 times the HRD) produced testicular necrosis, abnormal sperm morphology, and reduced pregnancy rates. 8.5 Geriatric Use Of the total number of subjects in the Phase 3 study, 12.1% of those who received 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.

Interactions

7 DRUG INTERACTIONS Disulfiram: Increases plasma cocaine exposure. Avoid using GOPRELTO in patients taking disulfiram. (7) Epinephrine, Phenylephrine: There have been reports of myocardial ischemia, myocardial infarction, and ventricular arrhythmias with concomitant use during nasal surgery. Avoid use of additional vasoconstrictor agents with GOPRELTO. If concomitant use is unavoidable, prolonged vital sign and ECG monitoring may be required. (5.3, 7) 7.1 Disulfiram Published literature reported that disulfiram treatment increased plasma cocaine exposure, including both AUC and Cmax, 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.

More information

Category Value
Authorisation number NDA209963
Agency product number XH8T8T6WZH
Orphan designation No
Product NDC 64950-359
Date Last Revised 26-12-2017
Type HUMAN PRESCRIPTION DRUG
RXCUI 1995293
Storage and handling Store upright at 20° to 25°C (68° to 77°F); excursions permitted to 15°-30°C (59°-86°F) [see USP, Controlled Room Temperature (CRT)]. Avoid freezing.
Marketing authorisation holder Genus Lifesciences Inc.
Warnings WARNING: ABUSE AND DEPENDENCE CNS stimulants, including cocaine hydrochloride, have a high potential for abuse and dependence [see Warnings and Precautions (5.1). WARNING: ABUSE AND DEPENDENCE See full prescribing information for complete boxed warning. CNS stimulants, including cocaine hydrochloride, have a high potential for abuse and dependence. (5.1)