Included as part of the "PRECAUTIONS" Section
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].
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.
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 studies with NUMBRINO, increases in blood pressure and heart rate were observed following pledget removal. Monitor for changes in vital signs, including heart rate and rhythm, after administration of NUMBRINO.
Avoid use of NUMBRINO in patients with a history of myocardial infarction, coronary artery disease, congestive heart failure, irregular heart rhythm, abnormal ECG, or uncontrolled hypertension. Avoid use of additional vasoconstrictor agents such as epinephrine or phenylephrine with NUMBRINO. If concomitant use is unavoidable, prolonged vital sign and ECG monitoring may be required.
Although not reported in the NUMBRINO clinical trials, myocardial infarction has been reported in the literature, and can occur when the drug has been used as recommended [see ADVERSE REACTIONS].
The time after cocaine administration for which cocaine and its metabolites can be detected in plasma and urine depends on the sensitivity of the utilized assay method. The cocaine hydrochloride and its metabolites in NUMBRINO 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.
Known Hypersensitivity Or Idiosyncrasy To The Sympathomimetic Amines
NUMBRINO is contraindicated in patients with a known history of hypersensitivity to cocaine or to the components of the nasal solution. Cocaine is a sympathetic neuronal catecholamine reuptake inhibitor, which may potentiate the actions of concomitantly administered sympathomimetic amines.
NUMBRINO is NOT FOR OPHTHALMIC USE. Cocaine can cause sloughing of the corneal epithelium and should not be used in the eyes. Pitting and ulceration of the cornea has been reported in the literature.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Long-term studies in animals have not been performed to evaluate the carcinogenic potential of cocaine.
Cocaine hydrochloride was not mutagenic in an in vitro bacterial reverse mutation assay (Ames test) and was not clastogenic in an in vitro chromosomal aberrations assay or in the in vivo rat micronucleus test.
Impairment Of Fertility
Studies in animals to characterize the effects of cocaine on fertility have not been completed. There are published studies that provide some information on the potential impact of cocaine on fertility. Exposure margins below are based on body surface area comparison to the human reference dose (HRD) of 37.5 mg (estimated amount absorbed from the 160 mg cocaine-soaked pledgets).
Suppression of estrous/menstrual cyclicity and ovulation was reported 1.3 to 2.6 times and 2 times the HRD in rats and monkeys, respectively.
In a published study in older male rats (16 weeks) 30 mg/kg cocaine SC (7.8 times the HRD) for 72 days prior to mating did not alter male fertility or alter male reproductive tissue histopathology but did increase the incidence of abnormal sperm and resulted in hyperactivity of next generation offspring.
Use In Specific Populations
There are no available data on the use of NUMBRINO in pregnant women to identify a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal 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 hydronephrosis (0.5 times the human reference dose (HRD) of 37.5 mg via the 4% solution), developmental delays in the offspring (1.5 times the HRD), cerebral hemorrhage and fetal edema (2.0 times the HRD), reduced fetal body weights and brain weights (2.6 times the HRD), and reduced fetal survival (3.7 times the HRD).
Single dose administration of cocaine intravenously during organogenesis in mice produced cryptochidism, anophthalmia, exencephaly, and delayed ossification at 7.8 times the HRD. In rats, a single dose of cocaine administered by intraperitoneal injection produced edematous fetuses, hemorrhages and limb defects at 12.9 times the HRD (see Data).
The estimated background risk of major birth defects and miscarriage for the indicated population(s) are unknown. 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.
There are no available data on the use of intranasal cocaine hydrochloride solution in pregnant women to inform a drug-associated risk for major congenital malformations or miscarriage. 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 congenital malformations, prematurity, miscarriage, premature rupture of membranes and gestational hypertension. 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, reproduction and development studies with cocaine have been reported in the published literature. Exposure margins below are based on body surface area comparison to the human reference dose (HRD) of 37.5 mg (estimated amount absorbed from the 160 mg (4%) cocaine-soaked pledgets).
Hydronephrosis was noted in embryos from pregnant rats treated wtih cocaine 2.1 mg/kg (0.5 times the HRD) and higher from Gestation Day 0 to 9. Cerebral hemorrhage and endematous fetuses were noted at 2.2 times the HRD and above).
Developmental delays and altered spontaneous exploratory behavior in response to cocaine were reported in rat pups born to dams treated intravenously with 6 mg/kg cocaine (1.5 times the HRD) from Gestation Day 8 to 20 in the absence of maternal toxicity.
Reduced fetal body and brain weights and alterations in fetal central neurotransmitter levels were noted following treatment of pregnant mice with 20 mg/kg cocaine from gestation days 8 to 12 or 12 to 18 (2.6 times the HRD).
Reduced fetal survival was noted when pregnant nonhuman primates were dosed with 0.3 mg/kg/h cocaine (3.7 times the HRD on per day basis) via a subcutaneous minipump from Gestation Day 24 to birth.
Exencephaly, cryptochidism, hydronephrosis, anophthalmia, delayed ossification, limb anomalies, and cerebral and intra-abdominal hemorrhage were reported following a single subcutaneous injection of 60 mg/kg cocaine (7.8 times the HRD) to pregant mice between Gestation Day 7 to 12. No significant maternal toxicity was reported at this dose.
Deficits in associational learning were reported when pregnant rats were treated with cocaine during gestation (10.3 times the HRD) in the absence of maternal toxicity.
Hemorrhage, fetal edema, and limb defects were reported when pregnant rats were administered a single injection of cocaine at a dose of 50 mg/kg/day or higher (12.9 times the HRD) during Gestation Day 9 to 19. Increased resorptions were noted at doses higher than 70 mg/kg/day (18.1 times the HRD) when administered on Gestation Day 16. No adverse effects were reported at a dose of 40 mg/kg (10.3 times the HRD).
Fetal deaths, decreased fetal body weights, edematous fetuses and single incidences of cleft palate and hypertrophic ventricle were observed when pregnant rats were treated with intraperitoneal cocaine at 60 mg/kg (15.5 times the HRD) from Gestation Day 8 to 12. Maternal toxicity was noted at this dose (mortality). No adverse effect level for fetal and maternal toxicity was noted at 50 mg/kg/day (13 times the HRD).
Decreased body weights, overall body length and crown circumference of offspring were reported when pregnant Rhesus monkeys were treated with escalating doses up to 7.5 mg/kg cocaine TID intramuscularly per day for 5 days per week from prior to conception to term (11.6 times the HRD).
Based on 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 NUMBRINO.
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 NUMBRINO 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 NUMBRINO on milk production.
Because of the potential for serious adverse reactions in breastfed infants, advise a lactating woman that breastfeeding is not recommended during treatment with NUMBRINO and to pump and discard breastmilk for 48 hours after use of NUMBRINO.
Females And Males Of Reproductive Potential
Published animal studies suggest that cocaine can alter female reproductive hormone levels, disrupt the estrous cycle, and reduce ovulation at doses approximately 1 to 2 times the HRD based on body surface area [see Nonclinical Toxicology].
Safety and effectiveness of NUMBRINO in pediatric patients under the age of 18 have not been established.
Published studies state that in juvenile male rats, 30 mg/kg subcutaneous cocaine administration for longer than 7 days (7.8 times the HRD) produced testicular necrosis. Treatment of juvenile male rats with 15 mg/kg (3.9 times the HRD) for 100 days resulted in abnormal sperm morphology and reduced pregnancy rates.
Of the 802 subjects in the two Phase 3 studies with NUMBRINO 13 subjects (1.6%) were age 65 and older, and one subject (0.1%) was 75 years of age or older.
No untoward or unexpected adverse reactions were seen in elderly patients who received NUMBRINO compared to those subjects that were under the age of 65.
However, hypertension was observed in all geriatric subjects receiving NUMBRINO. Special precaution should be given when determining the dose of NUMBRINO for geriatric patients, commensurate with their age and physical status.
According to literature, cocaine is eliminated predominantly by metabolism in humans. The clearance of NUMBRINO 4% has not been evaluated in subjects with hepatic impairment when compared to patients with normal hepatic function, and sufficient data are not available in literature to guide dosing in these subjects. Thus, NUMBRINO should be avoided in patients with hepatic impairment [see CLINICAL PHARMACOLOGY].
According to literature, cocaine is eliminated predominantly by metabolism in humans, with little excreted unchanged in the urine. The pharmacokinetics of NUMBRINO in patients with renal impairment has not been studied. Based on information available on the metabolism and excretion of cocaine, dose initiation in patients with renal impairment should follow a conservative approach. Monitor patients with renal impairment for adverse reactions such as clinically-relevant increases in heart rate or blood pressure [see CLINICAL PHARMACOLOGY].
Pharmacokinetics of NUMBRINO 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 NUMBRINO.
Because cocaine is metabolized by multiple enzymes, the effect of reduced plasma cholinesterase activity on cocaine exposure may be limited. No dosage adjustment of NUMBRINO is needed in patients with reduced plasma cholinesterase. Monitor patients with reduced plasma cholinesterase activity for adverse reactions such as, clinically-relevant increases in heart rate or blood pressure [see CONTRAINDICATIONS].