Included as part of the PRECAUTIONS section.
Cardiovascular Thrombotic Events
Clinical trials of several COX-2 selective and
nonselective NSAIDs of up to three years duration have shown an increased risk
of serious cardiovascular (CV) thrombotic events, including myocardial
infarction (MI) and stroke, which can be fatal. Based on available data, it is
unclear that the risk for CV thrombotic events is similar for all NSAIDs. The
relative increase in serious CV thrombotic events over baseline conferred by
NSAID use appears to be similar in those with and without known CV disease or
risk factors for CV disease. However, patients with known CV disease or risk
factors had a higher absolute incidence of excess serious CV thrombotic events,
due to their increased baseline rate. Some observational studies found that
this increased risk of serious CV thrombotic events began as early as the first
weeks of treatment. The increase in CV thrombotic risk has been observed most
consistently at higher doses.
To minimize the potential risk for an adverse CV event in
NSAID-treated patients, use the lowest effective dose for the shortest duration
possible. Physicians and patients should remain alert for the development of
such events, throughout the entire treatment course, even in the absence of
previous CV symptoms. Patients should be informed about the symptoms of serious
CV events and the steps to take if they occur.
There is no consistent evidence that concurrent use of
aspirin mitigates the increased risk of serious CV thrombotic events associated
with NSAID use. The concurrent use of aspirin and an NSAID, such as diclofenac,
increases the risk of serious gastrointestinal (GI) events [see Gastrointestinal Bleeding, Ulceration and Perforation].
Status Post Coronary Artery Bypass Graft (CABG) Surgery
Two large, controlled clinical trials of a COX-2
selective NSAID for the treatment of pain in the first 10– 14 days following
CABG surgery found an increased incidence of myocardial infarction and stroke.
NSAIDs are contraindicated in the setting of CABG [see CONTRAINDICATIONS].
Observational studies conducted in the Danish National
Registry have demonstrated that patients treated with NSAIDs in the post-MI
period were at increased risk of reinfarction, CV-related death, and all-cause mortality
beginning in the first week of treatment. In this same cohort, the incidence of
death in the first year post-MI was 20 per 100 person years in NSAID-treated
patients compared to 12 per 100 person years in non-NSAID exposed patients.
Although the absolute rate of death declined somewhat after the first year
post-MI, the increased relative risk of death in NSAID users persisted over at
least the next four years of follow-up.
Avoid the use of LICART in patients with a recent MI
unless the benefits are expected to outweigh the risk of recurrent CV
thrombotic events. If LICART is used in patients with a recent MI, monitor
patients for signs of cardiac ischemia.
Gastrointestinal Bleeding, Ulceration And Perforation
NSAIDs, including diclofenac, cause serious
gastrointestinal (GI) adverse events including inflammation, bleeding,
ulceration, and perforation of the esophagus, stomach, small intestine, or
large intestine, which can be fatal. These serious adverse events can occur at
any time, with or without warning symptoms, in patients treated with NSAIDs.
Only one in five patients who develop a serious upper GI
adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding,
or perforation caused by NSAIDs occurred in approximately 1% of patients
treated for 3-6 months, and in about 2% - 4% of patients treated for one year.
However, even short-term NSAID therapy is not without risk.
Risk Factors For GI Bleeding, Ulceration, And Perforation
Patients with a prior history of peptic ulcer disease
and/or GI bleeding who used NSAIDs had a greater than 10-fold increased risk
for developing a GI bleed compared to patients without these risk factors.
Other factors that increase the risk of GI bleeding in patients treated with
NSAIDs include longer duration of NSAID therapy; concomitant use of oral
corticosteroids, aspirin, anticoagulants, or selective serotonin reuptake
inhibitors (SSRIs); smoking; use of alcohol; older age; and poor general health
status. Most postmarketing reports of fatal GI events occurred in elderly or
debilitated patients. Additionally, patients with advanced liver disease and/or
coagulopathy are at increased risk for GI bleeding.
Strategies To Minimize The GI Risks In NSAID-Treated
- Use the lowest effective dosage for the shortest possible
- Avoid administration of more than one NSAID at a time.
- Avoid use in patients at higher risk unless benefits are
expected to outweigh the increased risk of bleeding. For such patients, as well
as those with active GI bleeding, consider alternate therapies other than
- Remain alert for signs and symptoms of GI ulceration and
bleeding during NSAID therapy.
- If a serious GI adverse event is suspected, promptly
initiate evaluation and treatment, and discontinue LICART until a serious GI
adverse event is ruled out.
- In the setting of concomitant use of low-dose aspirin for
cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding [see DRUG INTERACTIONS].
In clinical trials of oral diclofenac containing
products, meaningful elevations (i.e., more than 3 times the ULN) of AST (SGOT)
were observed in about 2% of approximately 5,700 patients at some time during
diclofenac treatment (ALT was not measured in all studies).
In an open-label, controlled trial of 3,700 patients
treated with oral diclofenac sodium for 2-6 months, patients were monitored
first at 8 weeks and 1,200 patients were monitored again at 24 weeks.
Meaningful elevations of ALT and/or AST occurred in about 4% of the 3,700
patients and included marked elevations (greater than 8 times the ULN) in about
1% of the 3,700 patients. In that open-label study, a higher incidence of
borderline (less than 3 times the ULN), moderate (3-8 times the ULN), and
marked (greater than 8 times the ULN) elevations of ALT or AST was observed in
patients receiving diclofenac when compared to other NSAIDs. Elevations in
transaminases were seen more frequently in patients with osteoarthritis than in
those with rheumatoid arthritis.
Almost all meaningful elevations in transaminases were
detected before patients became symptomatic. Abnormal tests occurred during the
first 2 months of therapy with diclofenac in 42 of the 51 patients in all
trials who developed marked transaminase elevations.
In post-marketing reports, cases of drug-induced
hepatotoxicity have been reported in the first month, and in some cases, the
first 2 months of therapy, but can occur at any time during treatment with
diclofenac. Post-marketing surveillance has reported cases of severe hepatic
reactions, including liver necrosis, jaundice, fulminant hepatitis with and
without jaundice, and liver failure. Some of these reported cases resulted in
fatalities or liver transplantation.
In a European retrospective population-based,
case-controlled study, 10 cases of diclofenac associated drug-induced liver
injury with current use compared with non-use of diclofenac were associated
with a statistically significant 4-fold adjusted odds ratio of liver injury. In
this particular study, based on an overall number of 10 cases of liver injury
associated with diclofenac, the adjusted odds ratio increased further with
female gender, doses of 150 mg or more, and duration of use for more than 90
Physicians should measure transaminases at baseline and
periodically in patients receiving long-term therapy with diclofenac, because
severe hepatotoxicity may develop without a prodrome of distinguishing
symptoms. The optimum times for making the first and subsequent transaminase
measurements are not known. Based on clinical trial data and post-marketing
experiences, transaminases should be monitored within 4 to 8 weeks after
initiating treatment with diclofenac. However, severe hepatic reactions can
occur at any time during treatment with diclofenac.
If abnormal liver tests persist or worsen, if clinical
signs and/or symptoms consistent with liver disease develop, or if systemic
manifestations occur (e.g., eosinophilia, rash, abdominal pain, diarrhea, dark
urine, etc.), LICART should be discontinued immediately.
Inform patients of the warning signs and symptoms of
hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice,
right upper quadrant tenderness, and “flu-like” symptoms). If clinical signs
and symptoms consistent with liver disease develop, or if systemic
manifestations occur (e.g., eosinophilia, rash, etc.), discontinue LICART
immediately, and perform a clinical evaluation of the patient. To minimize the
potential risk for an adverse liver related event in patients treated with
LICART, use the lowest effective dose for the shortest duration possible. Exercise
caution when prescribing LICART with concomitant drugs that are known to be
potentially hepatotoxic (e.g., acetaminophen, antibiotics, anti-epileptics).
NSAIDs, including LICART, can lead to new onset or
worsening of preexisting hypertension, either of which may contribute to the
increased incidence of CV events. Patients taking angiotensin converting enzyme
(ACE) inhibitors, thiazide diuretics, or loop diuretics may have impaired
response to these therapies when taking NSAIDs [see DRUG INTERACTIONS].
Monitor blood pressure (BP) during the initiation of
NSAID treatment and throughout the course of therapy.
Heart Failure And Edema
The Coxib and traditional NSAID Trialists’ Collaboration
meta-analysis of randomized controlled trials demonstrated an approximately
two-fold increase in hospitalizations for heart failure in COX-2
selective-treated patients and nonselective NSAID-treated patients compared to
placebo-treated patients. In a Danish
National Registry study of patients with heart failure,
NSAID use increased the risk of MI, hospitalization for heart failure, and
Additionally, fluid retention and edema have been
observed in some patients treated with NSAIDs. Use of diclofenac may blunt the
CV effects of several therapeutic agents used to treat these medical conditions
(e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]) [see
Avoid the use of LICART in patients with severe heart
failure unless the benefits are expected to outweigh the risk of worsening
heart failure. If LICART is used in patients with severe heart failure, monitor
patients for signs of worsening heart failure.
Renal Toxicity And Hyperkalemia
Long-term administration of NSAIDs has resulted in renal
papillary necrosis and other renal injury.
Renal toxicity has also been seen in patients in whom
renal prostaglandins have a compensatory role in the maintenance of renal
perfusion. In these patients, administration of an NSAID may cause a
dose-dependent reduction in prostaglandin formation and, secondarily, in renal
blood flow, which may precipitate overt renal decompensation. Patients at
greatest risk of this reaction are those with impaired renal function, dehydration,
hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE
inhibitors or ARBs, and the elderly. Discontinuation of NSAID therapy is
usually followed by recovery to the pretreatment state.
No information is available from controlled clinical
studies regarding the use of LICART in patients with advanced renal disease.
The renal effects of LICART may hasten the progression of renal dysfunction in
patients with pre-existing renal disease.
Correct volume status in dehydrated or hypovolemic
patients prior to initiating LICART. Monitor renal function in patients with
renal or hepatic impairment, heart failure, dehydration, or hypovolemia during
use of LICART [see DRUG INTERACTIONS]. Avoid the use of LICART in
patients with advanced renal disease unless the benefits are expected to
outweigh the risk of worsening renal function. If LICART is used in patients
with advanced renal disease, monitor patients for signs of worsening renal
Increases in serum potassium concentration, including
hyperkalemia, have been reported with use of NSAIDs, even in some patients
without renal impairment. In patients with normal renal function, these effects
have been attributed to a hyporeninemic-hypoaldosteronism state.
Diclofenac has been associated with anaphylactic
reactions in patients with and without known hypersensitivity to diclofenac and
in patients with aspirin-sensitive asthma [see CONTRAINDICATIONS and Exacerbation Of Asthma Related To Aspirin Sensitivity].
Seek emergency help if an anaphylactic reaction occurs.
Exacerbation Of Asthma Related To Aspirin Sensitivity
A subpopulation of patients with asthma may have
aspirin-sensitive asthma, which may include chronic rhinosinusitis complicated
by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to
aspirin and other NSAIDs. Because cross-reactivity between aspirin and other
NSAIDs has been reported in such aspirin-sensitive patients, LICART is
contraindicated in patients with this form of aspirin sensitivity [see CONTRAINDICATIONS].
When LICART is used in patients with preexisting asthma (without known aspirin
sensitivity), monitor patients for changes in the signs and symptoms of asthma.
Serious Skin Reactions
NSAIDs, including diclofenac, can cause serious skin
adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome
(SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious
events may occur without warning. Inform patients about the signs and symptoms
of serious skin reactions, and to discontinue the use of LICART at the first
appearance of skin rash or any other sign of hypersensitivity. LICART is
contraindicated in patients with previous serious skin reactions to NSAIDs [see
Premature Closure Of Fetal Ductus Arteriosus
Diclofenac may cause premature closure of the fetal
ductus arteriosus. Avoid use of NSAIDs, including LICART, in pregnant women
starting at 30 weeks of gestation (third trimester) [see Use In Specific
Anemia has occurred in NSAID-treated patients. This may
be due to occult or gross blood loss, fluid retention, or an incompletely
described effect on erythropoiesis. If a patient treated with LICART has any
signs or symptoms of anemia, monitor hemoglobin or hematocrit.
NSAIDs, including LICART, may increase the risk of
bleeding events. Co-morbid conditions such as coagulation disorders,
concomitant use of warfarin, other anticoagulants, antiplatelet agents (e.g.,
aspirin), serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine
reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for
signs of bleeding [see DRUG INTERACTIONS].
Masking Of Inflammation And Fever
The pharmacological activity of LICART in reducing
inflammation, and possibly fever, may diminish the utility of these diagnostic
signs in detecting infections.
Because serious GI bleeding, hepatotoxicity, and renal
injury can occur without warning symptoms or signs, consider monitoring
patients on long-term NSAID treatment with a CBC and a chemistry profile
periodically [see above].
Accidental Exposure In Children
Even a used LICART contains a large amount of diclofenac
epolamine (as much as 170 mg). The potential therefore exists for a small child
or pet to suffer serious adverse effects from chewing or ingesting a new or
used LICART. It is important for patients to store and dispose of LICART out of
the reach of children and pets.
Avoid contact of LICART with eyes and mucosa. Advise
patients that if eye contact occurs, immediately wash out the eye with water or
saline and consult a physician if irritation persists for more than an hour.
Oral Nonsteroidal Anti-inflammatory Drugs
Concomitant use of oral and topical NSAIDs may result in
a higher rate of hemorrhage, more frequent abnormal creatinine, urea and
hemoglobin. Do not use LICART in combination with an oral NSAID unless the
benefit outweighs the risk and periodic laboratory evaluations are conducted.
Patient Counseling Information
Advise the patient to read the FDA-approved patient
labeling (Medication Guide) that accompanies each prescription dispensed, as
well as the Directions for Use on the product packaging. Inform patients,
families, or their caregivers of the following information before initiating
therapy with LICART and periodically during the course of ongoing therapy.
Cardiovascular Thrombotic Events
Advise patients to be alert for the symptoms of
cardiovascular thrombotic events, including chest pain, shortness of breath,
weakness, or slurring of speech, and to report any of these symptoms to their
health care provider immediately [see WARNINGS AND PRECAUTIONS].
Gastrointestinal Bleeding, Ulceration, And Perforation
Advise patients to report symptoms of ulcerations and
bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to
their health care provider. In the setting of concomitant use of low-dose
aspirin for cardiac prophylaxis, inform patients of the increased risk for and
the signs and symptoms of GI bleeding [see WARNINGS AND PRECAUTIONS].
Inform patients of the warning signs and symptoms of
hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, diarrhea, jaundice,
right upper quadrant tenderness, and “flu-like” symptoms). If these
occur, instruct patients to stop LICART and seek immediate medical therapy [see
WARNINGS AND PRECAUTIONS].
Heart Failure And Edema
Advise patients to be alert for the symptoms of
congestive heart failure including shortness of breath, unexplained weight
gain, or edema and to contact their healthcare provider if such symptoms occur [see
WARNINGS AND PRECAUTIONS].
Inform patients of the signs of an anaphylactic reaction
(e.g., difficulty breathing, swelling of the face or throat). Instruct patients
to seek immediate emergency help if these occur [see CONTRAINDICATIONS and
WARNINGS AND PRECAUTIONS].
Serious Skin Reactions
Advise patients to stop LICART immediately if they
develop any type of rash and to contact their healthcare provider as soon as
possible [see WARNINGS AND PRECAUTIONS].
Advise females of reproductive potential who desire
pregnancy that NSAIDs, including LICART, may delay or prevent rupture of
ovarian follicles, which has been associated with a reversible infertility in
some women [see Use In Specific Populations]
Premature Closure Of The Fetal Ductus Arteriosus
Advise pregnant women to avoid use of LICART and other
NSAIDs starting at 30 weeks’ gestation because of the risk of the premature
closure of the fetal ductus arteriosus. Advise females of reproductive
potential to contact their healthcare provider with a known or suspected
pregnancy [see WARNINGS AND PRECAUTIONS and Use In Specific
Avoid Concomitant Use Of Other NSAIDs
Inform patients that the concomitant use of LICART with
other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended
due to the increased risk of gastrointestinal toxicity, and little or no
increase in efficacy [see WARNINGS AND PRECAUTIONS and DRUG
INTERACTIONS]. Alert patients that NSAIDs may be present in
“over-the-counter” medications for treatment of colds, fever, or insomnia.
Use Of NSAIDs And Low-Dose Aspirin
Inform patients not to use low-dose aspirin concomitantly
with LICART until they talk to their healthcare provider [see DRUG
Instruct patients to avoid contact of LICART with the
eyes and mucosa. Advise patients that if eye contact occurs, immediately wash
out the eye with water or saline and consult a physician if irritation persists
for more than an hour [see WARNINGS AND PRECAUTIONS].
Special Application Instructions
Instruct patients that, if LICART begins to peel-off, the
edges of the topical system may be taped down. If problems with adhesion
persist, patients may overlay the topical system with a mesh netting sleeve,
where appropriate (e.g., to secure topical systems applied to ankles, knees, or
elbows). The mesh netting sleeve (e.g., Curad® Hold Tite™, Surgilast® Tubular
Elastic Dressing) must allow air to pass through and not be occlusive
- Instruct patients that LICART may not be applied to
non-intact or damaged skin resulting from any etiology, e.g., exudative
dermatitis, eczema, infected lesion, burns or wounds.
- Instruct patients not to wear LICART when bathing or
- Instruct patients to avoid contact with eyes.
- Instruct patients to wash hands after applying, handling
or removing the topical system.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Long-term studies in animals have not been performed to
evaluate the carcinogenic potential of either diclofenac epolamine or LICART.
Diclofenac epolamine is not mutagenic in Salmonella
typhimurium strains, nor does it induce an increase in metabolic aberrations in
cultured human lymphocytes, or the frequency of micronucleated cells in the
bone marrow micronucleus test performed in rats.
Impairment Of Fertility
Male and female Sprague Dawley rats were administered 1,
3, or 6 mg/kg/day diclofenac epolamine via oral gavage (males treated for 60
days prior to conception and during mating period, females treated for 14 days
prior to mating through day 19 of gestation). Diclofenac epolamine treatment
with 6 mg/kg/day resulted in increased early resorptions and post-implantation
losses; however, no effects on the mating and fertility indices were found. The
6 mg/kg/day dose corresponds to 3 times the maximum recommended daily exposure
in humans based on a body surface area comparison.
Use In Specific Populations
Published literature reports
that use of NSAIDs, including LICART, after 30 weeks’ gestation increases the
risk of premature closure of the fetal ductus arteriosus. Data from
observational studies regarding potential embryofetal risks of NSAID use,
including diclofenac, in women in the first or second trimester of pregnancy
are inconclusive. Avoid use of NSAIDs, including LICART, in pregnant women
starting at 30 weeks of gestation (third trimester) (see Clinical
Considerations and Data).
In animal reproduction studies, diclofenac epolamine
administered orally to pregnant rats and rabbits during the period of
organogenesis produced embryotoxicity at approximately 3 and 7 times, respectively,
the topical exposure from the maximum recommended human dose (MRHD) of LICART.
In rats, increased incidences of skeletal anomalies and maternal toxicity were
also observed at this dose. Diclofenac epolamine administered orally to both
male and female rats prior to mating and throughout the mating period, and
during gestation and lactation in females produced embryotoxicity at doses
approximately 3 and 7 times, respectively, the topical exposure from the MRHD (see
Based on animal data, prostaglandins have been shown to
have an important role in endometrial vascular permeability, blastocyst
implantation, and decidualization. In animal studies, administration of
prostaglandin synthesis inhibitors such as diclofenac, resulted in increased pre-
and post-implantation loss.
The estimated background risk of major birth defects and
miscarriage for the indicated population is 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%,
Fetal/Neonatal Adverse Reactions
Avoid use of NSAIDs in pregnant women after 30 weeks’
gestation because NSAIDs, including LICART, can cause premature closure of the
fetal ductus arteriosus.
Published literature reports that use of NSAIDs,
including diclofenac, after 30 weeks’ gestation may cause constriction of the
patent ductus arteriosus and premature closure of the fetal ductus arteriosus.
Pregnant Sprague Dawley rats were administered 1, 3, or 6
mg/kg diclofenac epolamine via oral gavage daily from gestation days 6 to15.
Maternal toxicity, embryotoxicity, and increased incidence of skeletal
anomalies were noted with 6 mg/kg/day diclofenac epolamine, which corresponds
to 3-times the maximum recommended daily exposure in humans based on a body
surface area comparison. Pregnant New Zealand White rabbits were administered
1, 3, or 6 mg/kg diclofenac epolamine via oral gavage daily from gestation days
6 to18. No maternal toxicity was noted; however, embryotoxicity was evident at
6 mg/kg/day group which corresponds to 7-times the maximum recommended daily
exposure in humans based on a body surface area comparison.
Male rats were orally administered diclofenac epolamine
(1, 3, 6 mg/kg) for 60 days prior to mating and throughout the mating period,
and females were given the same doses 14 days prior to mating and through
mating, gestation, and lactation. Embryotoxicity was observed at 6 mg/kg
diclofenac epolamine (3-times the maximum recommended daily exposure in humans
based on a body surface area comparison), and was manifested as an increase in
early resorptions, post-implantation losses, and a decrease in live fetuses.
The number of live born and total born were also reduced as was F1 postnatal
survival, but the physical and behavioral development of surviving F1 pups in
all groups was the same as the deionized water control, nor was reproductive
performance adversely affected despite a slight treatment-related reduction in
Data from published literature reports with
oral preparations of diclofenac indicate the presence of small amounts of
diclofenac in human milk (see Data). There are no data on the effects on
the breastfed infant or the effects on milk production. The developmental and
health benefits of breastfeeding should be considered along with the mother’s
clinical need for LICART and any potential adverse effects on the breastfed
infant from LICART or from the underlying maternal condition.
One woman treated orally with a diclofenac salt, 150
mg/day, had a milk diclofenac level of 100 mcg/L, equivalent to an infant dose
of about 0.03 mg/kg/day. Diclofenac was not detectable in breast milk in 12
women using diclofenac (after either 100 mg/day orally for 7 days or a single
50 mg intramuscular dose administered in the immediate postpartum period). The
relative bioavailability for LICART is < 1% of a single 50 mg diclofenac
Females And Males Of Reproductive Potential
Based on the mechanism of action, the use of prostaglandin-mediated
NSAIDs, including LICART may delay or prevent rupture of ovarian follicles,
which has been associated with reversible infertility in some women [see CLINICAL
PHARMACOLOGY]. Published animal studies have shown that administration of
prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin-
mediated follicular rupture required for ovulation. Small studies in women
treated with NSAIDs have also shown a reversible delay in ovulation. Consider
withdrawal of NSAIDs, including LICART, in women who have difficulties
conceiving or who are undergoing investigation of infertility.
The safety and effectiveness of LICART in pediatric
patients have not been established.
Elderly patients, compared to younger patients, are at
greater risk for NSAID-associated serious cardiovascular, gastrointestinal,
and/or renal adverse reactions. If the anticipated benefit for the elderly
patient outweighs these potential risks, start dosing at the low end of the
dosing range, and monitor patients for adverse effects [see WARNINGS AND
Clinical studies of LICART did not include sufficient
numbers of subjects aged 65 and over to determine whether they respond
differently from younger subjects. Other reported clinical experience has not
identified differences in responses between the elderly and younger patients.