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.