Included as part of the PRECAUTIONS section.
Cases of methemoglobinemia have been reported in
association with local anesthetic use. Although all patients are at risk for
methemoglobinemia, patients with glucose-6-phosphate dehydrogenase deficiency,
congenital or idiopathic methemoglobinemia, cardiac or pulmonary compromise,
infants under 6 months of age, and concurrent exposure to oxidizing agents or
their metabolites are more susceptible to developing clinical manifestations of
the condition. If local anesthetics must be used in these patients, close
monitoring for symptoms and signs of methemoglobinemia is recommended.
Signs of methemoglobinemia may occur immediately or may
be delayed some hours after exposure, and are characterized by a cyanotic skin
discoloration and/or abnormal coloration of the blood. Methemoglobin levels may
continue to rise; therefore, immediate treatment is required to avert more
serious central nervous system and cardiovascular adverse effects, including
seizures, coma, arrhythmias, and death. Discontinue ORAQIX and any other oxidizing
agents. Depending on the severity of the signs and symptoms, patients may
respond to supportive care, i.e., oxygen therapy, hydration. A more severe
clinical presentation may require treatment with methylene blue, exchange transfusion,
or hyperbaric oxygen.
Do Not Inject
Oraqix should not be used with standard dental syringes.
Only use this product with the Oraqix blunt-tipped applicator and the dispenser
which is available from DENTSPLY Pharmaceutical.
Allergic and anaphylactic reactions associated with
lidocaine or prilocaine in Oraqix can occur. These reactions may be characterized
by urticaria, angioedema, bronchospasm, and shock. If these reactions occur
they should be managed by conventional means.
Avoid Contact With Eyes
Oraqix coming in contact with the eye should be avoided
because animal studies have demonstrated severe eye irritation. A loss of
protective reflexes may allow corneal irritation and potential abrasion. If eye
contact occurs, immediately rinse the eye with water or saline and protect it
until normal sensation returns. In addition, the patient should be evaluated by
an ophthalmologist, as indicated.
History Of Drug Sensitivity
Patients allergic to paraminobenzoic acid derivatives
(procaine, tetracaine, benzocaine, etc.) have not shown cross sensitivity to
lidocaine and/or prilocaine. However, Oraqix should be used with caution in
patients with a history of drug sensitivities, especially if the etiologic
agent is uncertain.
Severe Hepatic Disease
Patients with severe hepatic disease, because of their
inability to metabolize local anesthetics normally, are at greater risk of
developing toxic plasma concentrations of lidocaine and prilocaine.
Patient Counseling Information
Inform patients that use of local anesthetics may cause
methemoglobinemia, a serious condition that must be treated promptly. Advise
patients or caregivers to seek immediate medical attention if they or someone
in their care experience the following signs or symptoms: pale, gray, or blue
colored skin (cyanosis); headache; rapid heart rate; shortness of breath;
lightheadedness; or fatigue.
Patients should be cautioned to avoid injury to the
treated area, or exposure to extreme hot or cold temperatures, until complete
sensation has returned.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Long-term studies in animals have not been performed to
evaluate the carcinogenic potential of either lidocaine or prilocaine. Chronic
oral toxicity studies of o-toluidine, a metabolite of prilocaine, have shown
that this compound is a carcinogen in both mice and rats. The tumors associated
with o-toluidine included hepatocarcinomas/ adenomas in female mice, multiple
occurrences of hemangiosarcomas/hemangiomas in both sexes of mice, sarcomas of
multiple organs, transitional-cell carcinomas/papillomas of urinary bladder in
both sexes of rats, subcutaneous fibromas/fibrosarcomas and mesotheliomas in
male rats, and mammary gland fibroadenomas/adenomas in female rats. These
findings were observed at the lowest tested dose of 150 mg/kg/day or greater
over two years (estimated daily exposures in mice and rats were approximately 6
and 12 times, respectively, the estimated exposure to o-toluidine at the
maximum recommended human dose of 8.5g of Oraqix gel on a mg/m² basis). Thus,
the no effect dose is less than 6 to 12 times the estimated exposure to
o-toluidine at the maximum recommended human dose, assuming 100%
bioavailability of prilocaine from the Oraqix gel. Complete conversion of prilocaine
to its metabolite o-toluidine on a molar basis is assumed. This gives a
conversion on a weight basis of about 50% for prilocaine base (dependent on the
molecular weights, i.e. 220 for prilocaine base and 107 for o-toluidine).
The mutagenic potentials of lidocaine and prilocaine have
been tested in the Ames Salmonella reverse mutation assay, an in vitro
chromosome aberrations assay in human lymphocytes and in an in vivo mouse
micronucleus assay. There was no indication of any mutagenic effects for either
compound in these studies. o-Toluidine, metabolite of prilocaine, was positive
in Escherichia coli DNA repair and phage-induction assays. Urine concentrates
from rats treated orally with 300 mg/kg o-toluidine were mutagenic to
Salmonella typhimurium in the presence of metabolic activation. Several other
tests on o-toluidine, including reverse mutations in five different Salmonella
typhimurium strains with or without metabolic activation, and single strand
breaks in DNA of V79 Chinese hamster cells, were negative.
Impairment Of Fertility
The effect of lidocaine on fertility was examined in the
rat model. Administration of 30 mg/kg, s.c. (180 mg/m² or 1.4-fold the maximum
recommended human oral dose for one treatment session assuming 100% bioavailability
of lidocaine) to the mating pair did not produce alterations in fertility or general
reproductive performance of rats. There are no studies that examine the effect
of lidocaine or prilocaine on sperm parameters. The effects of prilocaine on
fertility was examined in rats treated for 8 months with 10 or 30 mg/kg, s.c.
lidocaine or prilocaine (60 mg/m² and 180 mg/m² on a body surface area basis,
respectively up to 1.4-fold the maximum recommended exposure for a single
procedure assuming 100% bioavailability of lidocaine and prilocaine). This time
period encompassed 3 mating periods. There was no evidence of altered
Use In Specific Populations
Pregnancy Category B
Reproduction studies have been performed in rats with
lidocaine, prilocaine and a 1:1 (weight: weight) mixture of the two compounds.
There was no evidence of harm to the fetus at subcutaneous doses of up to 30mg/kg
lidocaine (estimated exposure was approximately equivalent to the expected
lidocaine exposure at the maximum recommended human dose of Oraqix (lidocaine
and prilocaine periodontal gel) 2.5% / 2.5% on a mg/m² basis).
Following intramuscular prilocaine doses of up to 300
mg/kg (estimated exposure was approximately 11 times the expected prilocaine
exposure at the maximum recommended human dose of Oraqix gel on a mg/m² basis),
there was no evidence of impaired fertility or harm to the fetus. Similarly,
subcutaneous administration of a lidocaine and prilocaine mixture of 40 mg/kg
of each compound (estimated exposures were approximately 1.5 times the expected
lidocaine and prilocaine exposures at the maximum recommended human dose of
Oraqix gel on a mg/m² basis) produced no teratogenic, embryotoxic, or fetotoxic
effects. Reproductive toxicology studies of lidocaine were also conducted in
rabbits. There was no evidence of harm to the fetus at a dose of 5 mg/kg, s.c.
(60 mg/m²). Treatment of rabbits with 15 mg/kg (180 mg/m²) produced evidence of
maternal toxicity and evidence of delayed fetal development, including a
non-significant decrease in fetal weight (7%) and an increase in minor skeletal
anomalies (skull and sternebral defects, reduced ossification of the
phalanges). The effects of lidocaine and prilocaine on post-natal development
was examined in rats treated for 8 months with 10 or 30 mg/kg, s.c. lidocaine
or prilocaine (60 mg/m² and 180 mg/m² on a body surface area basis,
respectively up to 1.4-fold the maximum recommended exposure for a single procedure).
This time period encompassed 3 mating periods. There was no evidence of altered
post-natal development in any offspring; however, both doses of either drug
reduced the average number of pups per litter surviving until weaning of
offspring from the first 2 mating periods. In a separate study, the effect of
prilocaine on pre- and postnatal development was examined in rats treated with
up to 60 mg/kg, s.c. (up to 2.8 times the maximum recommended human dose of
prilocaine in Oraqix gel on a mg/m² basis) from Day 6 of gestation to weaning.
There was no evidence of altered post-natal development, viability, or reproductive
capacity in any offspring. All the above calculations of exposure are assuming
100% bioavailability of lidocaine and prilocaine after Oraqix administration.
There are, however, no adequate and well-controlled studies in pregnant women.
Because animal reproduction studies are not always predictive of human
response, Oraqix should be used during pregnancy only if the benefits outweigh
the risks. Reproduction studies on the Oraqix drug product, including the
inactive ingredients, have not been conducted.
Lidocaine and, possibly, prilocaine are excreted in
breast milk. Caution should be exercised when Oraqix is administered to nursing
Safety and effectiveness in pediatric patients have not
been established. Very young children are more susceptible to methemoglobinemia.
There have been reports of clinically significant methemoglobinemia in infants
and children following excessive applications of lidocaine 2.5% topical cream [See
WARNINGS AND PRECAUTIONS].
Of the total number of subjects in clinical studies of
Oraqix, 7% were aged 65 and over, while 1% were aged 75 and over. No overall
differences in safety or effectiveness were observed between these subjects and
younger subjects. Other reported clinical experience has not identified
differences in responses between elderly and younger patients, but greater
sensitivity of some older individuals cannot be ruled out.
Dose selection for an elderly patient should be cautious,
usually starting at the low end of the dosing range, reflecting the greater
frequency of decreased hepatic, renal, or cardiac function, and of concomitant
disease or other drug therapy.