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
PLIAGLIS 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.
- Application of PLIAGLIS for
longer times than those recommended or application of PLIAGLIS over larger
surface areas than those recommended could result in absorption of lidocaine
and tetracaine at doses that could lead to serious adverse effects [see
- When PLIAGLIS is used concomitantly
with other products containing local anesthetic agents, consider the amount
absorbed from all formulations since the systemic toxic effects are thought to
be additive and potentially synergistic with lidocaine and tetracaine.
- PLIAGLIS is not recommended for
use on mucous membranes or on areas with a compromised skin barrier because
these uses have not been adequately studied. Application to broken or inflamed
skin may result in toxic blood concentrations of lidocaine and tetracaine from
- Use PLIAGLIS with caution in
patients who may be more sensitive to the systemic effects of lidocaine and
tetracaine, including the acutely ill or debilitated.
- Patients with severe hepatic
disease or pseudocholinesterase deficiency, because of their inability to
metabolize local anesthetics normally, are at a greater risk of developing
toxic plasma concentrations of lidocaine and tetracaine.
Risks Of Secondary Exposure To Children
Used PLIAGLIS contains a large
amount of lidocaine and tetracaine. The potential exists for a small child or
pet to suffer serious adverse effects from ingesting PLIAGLIS, although this
risk with PLIAGLIS has not been evaluated. After use, replace the cap securely
on the tube. It is important to store and dispose of PLIAGLIS out of the reach
of children and pets.
Allergic or anaphylactic
reactions have been associated with lidocaine and tetracaine and may occur with
other components of PLIAGLIS. They are characterized by urticaria, angioedema, bronchospasm,
and shock. If an allergic reaction occurs, seek emergency help immediately.
Avoid contact of PLIAGLIS with
the eyes based on the findings of severe eye irritation with the use of similar
products in animals. Also, the loss of protective reflexes may predispose to
corneal irritation and potential abrasion. If eye contact occurs, immediately
wash out the eye with water or saline and protect the eye until sensation
Lidocaine has been shown to
inhibit viral and bacterial growth. The effect of PLIAGLIS on intradermal
injections of live vaccines has not been determined.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Long-term studies in animals have not been performed to
evaluate the carcinogenic potential of either lidocaine or tetracaine.
The mutagenic potential of lidocaine base and tetracaine
base has been determined in the in vitro Ames bacterial reverse mutation assay,
the in vitro chromosome aberration assay using Chinese hamster ovary cells, and
the in vivo mouse micronucleus assay. Lidocaine was negative in all three
assays. Tetracaine was negative in the in vitro Ames assay and the in vivo mouse
micronucleus assay. In the in vitro chromosome aberration assay, tetracaine was
negative in the absence of metabolic activation, and equivocal in the presence
of metabolic activation.
Impairment Of Fertility
Lidocaine did not affect fertility in female rats when
given via continuous subcutaneous infusion via osmotic minipumps up to doses of
250 mg/kg/day (35-fold higher than the level of lidocaine contained in the
lowest approved dose of PLIAGLIS based on a mg/m² body surface area
comparison). Lidocaine treatment did not affect overall fertility in male rats
when given as subcutaneous doses up to 60 mg/kg (8-fold higher than the level
of lidocaine contained in the lowest approved dose of PLIAGLIS based on a mg/m²
basis), although the treatment caused an increased copulatory interval and led
to a dose-related decrease in homogenization resistant sperm head count, daily
sperm production, and spermatogenic efficiency. Tetracaine did not affect
fertility in male or female rats when given as subcutaneous doses up to 7.5
mg/kg (equivalent to the level of tetracaine in the lowest approved dose of PLIAGLIS
on a mg/m² basis).
Use In Specific Populations
Pregnancy Category B
No adequate and well-controlled studies have been
conducted in pregnant women. PLIAGLIS should be used during pregnancy only if
the potential benefit justifies risk to the fetus. Lidocaine was not teratogenic
in rats at doses up to 60 mg/kg (8-fold higher than the level of lidocaine
contained in the lowest approved dose of PLIAGLIS based on a mg/m² body surface
area comparison). Lidocaine was not teratogenic in rabbits at doses up to 15 mg/kg
(4-fold higher than the level of lidocaine in the lowest approved dose of
PLIAGLIS on a mg/m² basis).
Tetracaine was not teratogenic in rats given subcutaneous
doses up to 10 mg/kg or in rabbits up to 5 mg/kg (equivalent to the level of
tetracaine in the lowest approved dose of PLIAGLIS on a mg/m² basis). Lidocaine
and tetracaine given as a 1:1 eutectic mixture of 10 mg/kg each was not teratogenic
in rats (equivalent to the level of the active components in the lowest
approved dose of PLIAGLIS on a mg/m² basis. Lidocaine and tetracaine given as a
1:1 eutectic mixture of 5 mg/kg each was not teratogenic in rabbits (equivalent
to the level of the active components in the lowest approved dose of PLIAGLIS
on a mg/m² basis).
Lidocaine containing 1:100,000 epinephrine at a dose of 6
mg/kg (approximately equivalent to the level of lidocaine in the lowest
approved dose PLIAGLIS on a mg/m² basis) injected into the masseter muscle of
the jaw or into the gum of the lower jaw of pregnant Long-Evans hooded rats on
gestation day 11, lead to developmental delays in neonatal behavior among
offspring. Developmental delays were observed for negative geotaxis, static
righting reflex, visual discrimination response, sensitivity and response to
thermal and electrical shock stimuli, and water maze acquisition. The
developmental delays of the neonatal animals were transient with responses
becoming comparable to untreated animals later in life. The clinical relevance
of the animal data is uncertain. Pre- and post-natal maturational, behavioral,
or reproductive development was not affected by maternal subcutaneous
administration of tetracaine during gestation and lactation up to doses of 7.5
mg/kg (equivalent to the level of tetracaine in the lowest approved dose of
PLIAGLIS on a mg/m² basis).
Labor And Delivery
Neither lidocaine nor tetracaine is contraindicated in
labor and delivery. In humans, the use of lidocaine for labor neuraxial
analgesia has not been associated with an increased incidence of adverse fetal
effects either during delivery or during the neonatal period. Tetracaine has
also been used as a neuraxial anesthetic for cesarean section without apparent
adverse effects on offspring. Should PLIAGLIS be used concomitantly with other
products containing lidocaine and/or tetracaine, total doses contributed by all
formulations must be considered.
Lidocaine is excreted into human milk and it is not known
if tetracaine is excreted into human milk. Therefore, caution should be
exercised when PLIAGLIS is administered to a nursing mother since the
milk:plasma ratio of lidocaine is 0.4 and is not determined for tetracaine. In
a prior report, when lidocaine was used as an epidural anesthetic for cesarean section
in 27 women, a milk:plasma ratio of 1.07 ±0.82 was found by using AUC values.
Following single dose administration of 20 mg of lidocaine for a dental
procedure, the point value milk:plasma ratio was similarly reported as 1.1 at
five to six hours after injection. Thus, the estimated maximum total daily dose
of lidocaine delivered to the infant via breast milk would be approximately 36
mcg/kg. Based on these data and the low concentrations of lidocaine and tetracaine
found in the plasma after topical administration of PLIAGLIS in recommended
doses, the small amount of these primary compounds and their metabolites that
would be ingested orally by a suckling infant is unlikely to cause adverse
effects [see CLINICAL PHARMACOLOGY].
Safety and effectiveness of PLIAGLIS in pediatric
patients have not been established. Unintended exposure in pediatric patients
could possibly lead to serious adverse effects [see WARNINGS AND PRECAUTIONS]. In a trial of PLIAGLIS in pediatric patients aged 5 to 17 years undergoing
venipuncture (blood draw or intravenous line placement), PLIAGLIS applied for
30 minutes failed to show efficacy over placebo in reducing the pain associated
with the procedure.
Of the total number of subjects treated with PLIAGLIS in
controlled clinical studies, 161 subjects were 65 years and older, while 50
subjects were over 75 years of age. No overall differences in safety and
effectiveness were observed between these subjects and younger subjects. However,
increased sensitivity in individual patients aged 65 years and older cannot be ruled
out [see CLINICAL PHARMACOLOGY].