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
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
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
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.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Long-term animal studies to evaluate the carcinogenic
potential of cocaine have not been conducted.
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
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 58 mg (estimated amount absorbed from the 160 mg cocaine-soaked
Acute parenteral administration of cocaine to female rats
increased luteinizing hormone and progesterone by approximately 2-fold at 0.3
to 2.5 times the HRD. Suppression of estrous/menstrual cyclicity and ovulation
was reported in rats at 0.8 times the HRD and in monkeys at 0.3 times the human
In a published study, adult (12-week old) male rats
treated subcutaneously with 15 mg/kg cocaine (2.5 times the HRD) daily for at
least 28 days prior to mating demonstrated increased apoptosis of germ cells.
Studies in younger male rats demonstrated more pronounced effects [see
In a second published study in older male rats (16 weeks)
30 mg/kg cocaine SC (5 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
Use In Specific Populations
There are no available data on the use of GOPRELTO in
pregnant women to form the basis for a drugassociated 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
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.
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.
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
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).
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
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
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.
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 less than the HRD based on body surface area [See Nonclinical
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.
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] has not identified differences in responses between
the elderly and younger patients, but greater sensitivity of some older
individuals cannot be ruled out.
No dosage adjustment of GOPRELTO is needed in patients
with mild, moderate, or severe renal impairment [see CLINICAL PHARMACOLOGY].
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].
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]. 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.