Included as part of the PRECAUTIONS section.
Application of a SYNERA patch
for longer duration than recommended, or the simultaneous or sequential
application of multiple SYNERA patches, could result in sufficient absorption
of lidocaine and tetracaine to result in serious adverse effects [see
Storage And Disposal
Used SYNERA patches contain a
large amount of lidocaine and tetracaine (at least 90% of the initial amount).
The potential exists for a child or pet to suffer serious adverse effects from
chewing or ingesting a new or used SYNERA patch. It is important for patients
to store and dispose of SYNERA out of the reach of children and pets.
Avoidance Of Exposure To Eyes And Mucous Membranes
- Contact of SYNERA with the eyes should be avoided 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 returns.
- SYNERA is not recommended for use on mucous membranes or
on areas with a compromised skin barrier because these uses have not been
studied. Application to broken or inflamed skin may result in toxic blood
concentrations of lidocaine and tetracaine from increased absorption.
Magnetic Resonance Imaging
The integrated heating component contains iron powder;
therefore, the SYNERA patch must be removed before a patient undergoes magnetic
- Several local anesthetics, including tetracaine, have
been associated with methemoglobinemia. The risk of methemoglobinemia is
greatest for patients with congenital or idiopathic methemoglobinemia, and
infants under the age of twelve months who are receiving treatment with methemoglobin-inducing
- Very young patients or patients with glucose-6-phosphate
dehydrogenase deficiencies have an increased risk of methemoglobinemia.
- Patients taking concomitant drugs associated with
drug-induced methemoglobinemia such as sulfonamides, acetaminophen,
acetanilide, aniline dyes, benzocaine, chloroquine, dapsone, naphthalene,
nitrates and nitrites, nitrofurantoin, nitroglycerin, nitroprusside, pamaquine,
para-aminosalicylic acid, phenacetin, phenobarbital, phenytoin, primaquine, and
quinine are also at greater risk for developing methemoglobinemia.
- There have been no reports of methemoglobinemia with
SYNERA. However, providers are cautioned to carefully apply SYNERA to ensure
that the areas of application and duration of application are consistent with
those recommended for the intended population.
Allergic or anaphylactoid reactions associated with
lidocaine, tetracaine, or other components of SYNERA can occur. They are
characterized by urticaria, angioedema, bronchospasm, and shock. If an allergic
reaction occurs, it should be managed by conventional means.
Special Patient Populations
- SYNERA should be used with caution in patients who may be
more sensitive to the systemic effects of lidocaine and tetracaine particularly
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.
Lidocaine has been shown to inhibit viral and bacterial
growth. The effect of SYNERA on intradermal injections of live vaccines has not
Patient Counseling Information
- Advise patients to read the FDA-approved patient labeling
(Instructions for Use).
- Advise patients that SYNERA is a patch containing two
medicines (lidocaine and tetracaine) that are known as local anesthetics, and a
heating component. These medicines are used to lessen the pain associated with
superficial venous access and superficial dermatological procedures such as
excision, electrodessication and shave biopsy of skin lesions.
- Advise patients that SYNERA should be applied immediately
after opening the pouch. Instruct patients to not cut or remove the top cover
of the patch as this could result in thermal injury.
- Advise patients that keeping a patch on longer than
recommended or applying multiple patches simultaneously or sequentially could
result in systemic absorption sufficient to result in serious adverse effects
that are typical of drugs in this class.
- Advise patients that the patch must be removed before
magnetic resonance imaging.
- Advise patients that SYNERA is contraindicated in
patients with a known history of sensitivity to lidocaine, tetracaine, local
anesthetics of the amide or ester type, or any other component of the product
and in patients with para-aminobenzoic acid (PABA) hypersensitivity.
- Advise patients that SYNERA should be used with caution
in patients who may be more sensitive to the systemic effects of lidocaine and
tetracaine, including the acutely ill, the debilitated, and those with
compromised hepatic function. Patients with severe hepatic disease or
pseudocholinesterase deficiency are at greater risk of developing toxic plasma
- Advise patients that SYNERA should be used with caution
in patients receiving class I antiarrhythmics and/or other local anesthetics,
because the systemic toxic effects may be additive and potentially synergistic
with lidocaine and tetracaine.
- Advise patients not to use SYNERA if they have a history
- Advise patients to avoid contact of SYNERA with the eyes
due to potential irritation or abrasion. If contact occurs, immediately wash
the eye with water or saline, and protect it until sensation returns.
- Advise patients that SYNERA should only be applied to
intact skin. Inform patients that exposure of the skin to SYNERA may result in
erythema, blanching and edema; these reactions are generally mild, resolving
spontaneously soon after the patch is removed.
- Advise patients that SYNERA is not for use on mucous
membranes or on areas with broken skin.
- Advise patients that if skin irritation or a burning
sensation occurs during application, the product should be removed.
- Inform patients of the signs of an allergic or
anaphylactoid reaction (urticaria, angioedema, bronchospasm, and shock).
Instruct patients to seek immediate emergency help if these occur.
- Advise patients that SYNERA may lead to diminished or
blocked sensation in the treated skin; therefore, patients should avoid
inadvertent trauma (rubbing, scratching, or exposure to heat or cold) before
complete sensation returns.
- Advise patients to contact their healthcare professional
if they don't recall where to apply the patch.
- Instruct patients to store SYNERA and to discard used
patches out of the reach of children and pets.
- The effect of SYNERA 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 (1500 mg/m² or 43-fold higher than the SDA). Although
lidocaine treatment of male rats increased the copulatory interval and lead to
a dose-related decreased homogenization resistant sperm head count, daily sperm
production, and spermatogenic efficiency, the treatment did not affect overall
fertility in male rats when given subcutaneous doses up to 60 mg/kg (360 mg/m² or 8-fold the SDA). Tetracaine did not affect fertility in male or female
rats when given subcutaneous doses up to 7.5 mg/kg (45 mg/m² or
1-fold the SDA). Multiples of exposure are based on an SDA of 70 mg each of
lidocaine and tetracaine in SYNERA patch for 30 minutes to a 60 kg person (43
Use In Specific Populations
Pregnancy Category B
Lidocaine was not teratogenic in rats given subcutaneous
doses up to 60 mg/kg (360 mg/m² or 8-fold the Single Dermal
Administration (SDA)) or in rabbits up to 15 mg/kg (180 mg/m² or
4-fold the SDA). Tetracaine was not teratogenic in rats given subcutaneous
doses up to 10 mg/kg (60 mg/m² or 1-fold the SDA) or in rabbits up
to 5 mg/kg (60 mg/m² or 1-fold the SDA). SYNERA components
(lidocaine and tetracaine) given as a 1:1 eutectic mixture were not teratogenic
in rats (60 mg/m² or 1-fold the SDA) or rabbits (120 mg/m² or
3-fold the SDA).
Lidocaine, contained 1:100,000 epinephrine, at a dose of
6 mg/kg (2-fold the SDA) injected into the masseter muscle of the jaw or into
the gum of the lower jaw of Long-Evans hooded pregnant rats on Gestation Day 11
led 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 postnatal 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 (45 mg/m² or 1-fold the SDA).
No adequate and well-controlled studies have been
conducted in pregnant women. Because animal studies are not always predictive
of human response, SYNERA should be used during pregnancy only if the potential
benefit justifies the potential risk to the fetus.
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 SYNERA 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 SYNERA 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
μg/kg. Based on these data and the low concentrations of lidocaine and
tetracaine found in the plasma after topical administration of SYNERA 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].
The safety and effectiveness of SYNERA have been
established in pediatric patients 3 years and older based on adequate and
well-controlled studies [see Clinical Studies]. While efficacy has not
been established for children less than 3 years of age, the safety of SYNERA in
infants has been evaluated in one study in which 34 infants 4 to 6 months of
age received SYNERA. The recommended application time for the patch for
pediatric patients is the same as for adults. Simultaneous or sequential
application of more than two SYNERA patches to children is not recommended as
it has not been adequately studied.
Use In Geriatric Patients
In the controlled clinical studies, 139 patients over 65
years of age, including 41 patients over 75 years of age, received SYNERA.
Visual Analog Scale (VAS) pain score differences between SYNERA and placebo
were considerably lower in the geriatric subjects than in the rest of the adult
population. No overall differences in safety were observed between geriatric
subjects and younger subjects. However, increased sensitivity in individual
patients greater than 65 years of age cannot be ruled out. After intravenous
dosing, the elimination half-life of lidocaine is significantly longer in
elderly patients (2.5 hours) than in younger patients (1.5 hours).