CONTRAINDICATIONS
Tablets: Diclofenac in all formulations, immediate-release, delayed-release and
extended-release, is contraindicated in patients with hypersensitivity to diclofenac and
diclofenac-containing products. Diclofenac should not be given to patients who have
experienced asthma, urticaria, or other allergic-type reactions after taking aspirin or other
NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to diclofenac have been
reported in such patients (see WARNINGS, Anaphylactic Reactions and
PRECAUTIONS, Pre-Existing Asthma).
Ophthalmic Solution: Diclofenac sodium ophthalmic solution is contraindicated in
patients who are hypersensitive to any component of the medication.
WARNINGS
Tablets
Gastrointestinal
Peptic ulceration and gastrointestinal bleeding have been reported in patients receiving
diclofenac. Physicians and patients should therefore remain alert for ulceration and
bleeding in patients treated chronically with diclofenac even in the absence of previous GI
tract symptoms. It is recommended that patients be maintained on the lowest dose of
diclofenac sodium, consistent with achieving a satisfactory therapeutic response.
Risk of GI Ulcerations, Bleeding, and Perforation With NSAID Therapy: Serious
gastrointestinal toxicity such as bleeding, ulceration, and perforation can occur at any
time, with or without warning symptoms, in patients treated chronically with NSAID
therapy. Although minor upper gastrointestinal problems, such as dyspepsia, are
common, usually developing early in therapy, physicians should remain alert for ulceration
and bleeding in patients treated chronically with NSAIDs even in the absence of previous
GI tract symptoms. In patients observed in clinical trials of several months to 2 years'
duration, symptomatic upper GI ulcers, gross bleeding, or perforation appear to occur in
approximately 1% of patients for 3-6 months, and in about 2-4% of patients treated for 1
year. Physicians should inform patients about the signs and/or symptoms of serious GI
toxicity and what steps to take if they occur.
Studies to date have not identified any subset of patients not at risk of developing peptic
ulceration and bleeding. Except for a prior history of serious GI events and other risk
factors known to be associated with peptic ulcer disease, such as alcoholism, smoking,
etc., no risk factors (e.g., age, sex) have been associated with increased risk. Elderly or
debilitated patients seem to tolerate ulceration or bleeding less well than other individuals,
and most spontaneous reports of fatal GI events are in this population. Studies to date
are inconclusive concerning the relative risk of various NSAIDs in causing such reactions.
High doses of any NSAID probably carry a greater risk of these reactions, although
controlled clinical trials showing these do not exist in most cases. In considering the use of
relatively large doses (within the recommended dosage range), sufficient benefit should be
anticipated to offset the potential increased risk of GI toxicity.
Hepatic Effects
Elevations of 1 or more liver tests may occur during diclofenac therapy. These laboratory
abnormalities may progress, may remain unchanged, or may be transient with continued
therapy. Borderline elevations (i.e., less than 3 times the ULN [=the Upper Limit of the
Normal Range]), or greater elevations of transaminases occurred in about 15% of
diclofenac-treated patients. Of the hepatic enzymes, ALT (SGPT) is the one
recommended for the monitoring of liver injury.
In clinical trials, meaningful elevations (i.e., more than 3 times the ULN) of AST (SGOT)
(ALT was not measured in all studies) occurred in about 2% of approximately 5700
patients at some time during delayed-release treatment. In a large, open, controlled trial,
meaningful elevations of ALT and/or AST occurred in about 4% of 3700 patients treated
for 2-6 months, including marked elevations (i.e., more than 8 times the ULN) in about
1% of the 3700 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 (>8 times the ULN)
elevations of ALT or AST was observed in patients receiving diclofenac when compared
to other NSAIDs. Transaminase elevations were seen more frequently in patients with
osteoarthritis than in those with rheumatoid arthritis (see ADVERSE REACTIONS).
In addition to the enzyme elevations seen in clinical trials, postmarketing surveillance has
found rare cases of severe hepatic reactions, including liver necrosis, jaundice and
fulminant fatal hepatitis with and without jaundice. Some of these rare reported cases
underwent liver transplantation.
Physicians should measure transaminases 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. In the largest U.S. trial (open-label) that
involved 3700 patients monitored first at 8 weeks and 1200 patients monitored again at
24 weeks, almost all meaningful elevations in transaminases were detected before
patients became symptomatic. In 42 of the 51 patients in all trials who developed marked
transaminase elevations, abnormal tests occurred during the first 2 months of therapy with
diclofenac. Postmarketing experience has shown severe hepatic reactions can occur at
any time during treatment with diclofenac. Cases of drug-induced hepatotoxicity have
been reported in the first month, and in some cases, the first 2 months of therapy. Based
on these experiences, transaminases should be monitored within 4-8 weeks after iniating
treatment with diclofenac (see PRECAUTIONS, Laboratory Tests). As with other
NSAIDs, 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, etc.), diclofenac should be discontinued immediately.
To minimize the possibility that hepatic injury will become severe between transaminase
measurements, physicians should inform patients of the warning signs and symptoms of
hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant
tenderness, and "flu-like" symptoms), and the appropriate action patients should take if
these signs and symptoms appear.
Anaphylactic Reactions
As with other NSAIDs, anaphylactoid reactions may occur in patients without prior
exposure to diclofenac. Diclofenac should not be given to patients with the aspirin triad.
The triad typically occurs in asthmatic patients who experience rhinitis with or without
nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or
other nonsteriodal anti-inflammatory drugs. Fatal reactions have been reported in such
patients (see CONTRAINDICATIONS and PRECAUTIONS, Pre-Existing Asthma).
Emergency help should be sought in cases where an anaphylactoid reaction occurs.
Advanced Renal Disease
In cases with advanced kidney disease, treatment with diclofenac, as with other
NSAIDs, should only be initiated with close monitoring of the patient's kidney functions
(see PRECAUTIONS, Renal Effects).
Pregnancy
In late pregnancy, diclofenac should, as with other NSAIDs, be avoided because it will
cause premature closure of the ductus arteriosus (see PRECAUTIONS, Pregnancy,
Teratogenic Effects, Pregnancy Category B and Labor and Delivery).
Ophthalmic Solution
With some nonsteroidal anti-inflammatory drugs, there exists the potential for increased
bleeding time due to interference with thrombocyte aggregation. There have been reports
that ocularly applied nonsteroidal anti-inflammatory drugs may cause increased bleeding
of ocular tissues (including hyphemas) in conjunction with ocular surgery.
There is the potential for cross-sensitivity to acetylsalicylic acid, phenylacetic acid
derivatives, and other nonsteroidal anti-inflammatory agents. Therefore, caution should be
used when treating individuals who have previously exhibited sensitivities to these drugs.
PRECAUTIONS
General
Tablets
Diclofenac immediate-release, delayed-release and extended-release tablets should not
be used concomitantly with other diclofenac-containing products since they also circulate
in plasma as the diclofenac anion.
Fluid Retention and Edema: Fluid retention and edema have been observed in some
patients taking diclofenac. Therefore, as with other NSAIDs, diclofenac should be used
with caution in patients with a history of cardiac decompensation, hypertension, or other
conditions predisposing to fluid retention.
Hematologic Effects:
Renal Effects: As a class, NSAIDs have been associated with renal papillary necrosis
and other abnormal renal pathology in long-term administration to animals. In oral
diclofenac studies in animals, some evidence of renal toxicity was noted. Isolated
incidents of papillary necrosis were observed in a few animals at high doses (20-120
mg/kg) in several baboon subacute studies. In patients treated with diclofenac, rare cases
of interstitial nephritis and papillary necrosis have been reported (see ADVERSE
REACTIONS).
A second form of renal toxicity, generally associated with NSAIDs, is seen in patients
with conditions leading to a reduction in renal blood flow or blood volume, where renal
prostaglandins have a supportive role in the maintenance of renal perfusion. In these
patients, administration of an NSAID results in a dose-dependent decrease in
prostaglandin synthesis and, secondarily, in a reduction of renal blood flow, which may
precipitate overt renal failure. Patients at greatest risk of this reaction are those with
impaired renal function, heart failure, liver dysfunction, those taking diuretics, and the
elderly. Discontinuation of NSAID therapy is typically followed by recovery to the
pretreatment state.
Cases of significant renal failure in patients receiving diclofenac have been reported from
marketing experience, but were not observed in over 4000 patients in clinical trials during
which serum creatinine and BUN values were followed serially. There were only 11
patients (0.3%) whose serum creatinine and concurrent serum BUN values were greater
than 2.0 mg/dl and 40 mg/dl, respectively, while on diclofenac (mean rise in the 11
patients: creatinine 2.3 mg/dl and BUN 28.4 mg/dl).
Since diclofenac metabolites are eliminated primarily by the kidneys, patients with
significantly impaired renal function should be more closely monitored than subjects with
normal renal function.
Porphyria: The use of diclofenac in patients with hepatic porphyria should be avoided.
To date, 1 patient has been described in whom diclofenac probably triggered a clinical
attack of porphyria. The postulated mechanism, demonstrated in rats, for causing such
attacks by diclofenac, as well as some other NSAIDs, is through stimulation of the
porphyrin precursor delta-aminolevulinic acid (ALA).
Aseptic Meningitis: As with other NSAIDs, aseptic meningitis with fever and coma has
been observed on rare occasions in patients on diclofenac therapy. Although it is
probably more likely to occur in patients with systemic lupus erythematosus and related
connective tissue diseases, it has been reported in patients who do not have an underlying
chronic disease. If signs or symptoms of meningitis develop in a patient on diclofenac, the
possibility of its being related to diclofenac should be considered.
Pre-Existing Asthma: About 10% of patients with asthma may have aspirin-sensitive
asthma. The use of aspirin in patients with aspirin-sensitive asthma has been associated
with severe bronchospasm which can be fatal. Since cross-reactivity, including
bronchospasm, between aspirin and other nonsteroidal anti-inflammatory drugs has been
reported in such aspirin-sensitive patients, diclofenac should not be administered to
patients with this form of aspirin sensitivity and should be used with caution in all patients
with pre-existing asthma.
Other Precautions: The pharmacologic activity of diclofenac may reduce fever and
inflammation, thus diminishing their utility as diagnostic signs in detecting underlying
conditions.
In order to avoid exacerbation of manifestations of adrenal insufficiency, patients who
have been on prolonged corticosteroid treatment should have their therapy tapered
slowly rather than discontinued abruptly when diclofenac is added to the treatment
program.
Blurred and/or diminished vision, scotomata, and/or changes in color vision have been
reported. If a patient develops such complaints while receiving diclofenac, the drug
should be discontinued and the patient should have an ophthalmologic examination which
includes central visual fields and color vision testing.
Ophthalmic Solution
It is recommended that diclofenac sodium ophthalmic solution, like other NSAIDs, be
used with caution in surgical patients with known bleeding tendencies or who are
receiving other medications that may prolong bleeding time.
Diclofenac sodium ophthalmic solution may slow or delay healing.
Results from clinical studies indicate that diclofenac sodium ophthalmic solution has no
significant effect upon intraocular pressure; however, elevations in intraocular pressure
may occur following cataract surgery.
Information for the Patient
Tablets
Diclofenac, like other drugs of its class, is not free of side effects. The side effects of
these drugs can cause discomfort and, rarely, more serious side effects, such as
gastrointestinal bleeding, and more rarely, liver toxicity (see WARNINGS, Hepatic
Effects), which may result in hospitalization and even fatal outcomes.
NSAIDs are often essential agents in the management of arthritis and have a major role in
the management of pain, but they also may be commonly employed for conditions that
are less serious.
Physicians may wish to discuss with their patients the potential risks (see WARNINGS,
PRECAUTIONS, and ADVERSE REACTIONS) and likely benefits of NSAID
treatment, particularly when the drugs are used for less serious conditions where
treatment without NSAIDs may represent an acceptable alternative to both the patient
and physician.
Because serious GI tract ulceration and bleeding can occur without warning symptoms,
physicians should follow chronically treated patients for the signs and symptoms of
ulceration and bleeding and should inform them of the importance of this follow-up (see
WARNINGS, Gastrointestingal Effects, Risk of GI Ulcerations, Bleeding, and
Perforation with NSAID Therapy). If diclofenac is used chronically, patients should also
be instructed to report any signs and symptoms that might be due to hepatotoxicity of
diclofenac; these symptoms may become evident between visits when periodic liver
laboratory tests are performed (see WARNINGS, Hepatic Effects, and Laboratory
Tests).
Laboratory Tests
Tablets
Hepatic Effects: Transaminases and other hepatic enzymes should be monitored in
patients treated with NSAIDs. For patients on diclofenac therapy, it is recommended that
a determination be made within 4 weeks of initiating therapy and at intervals thereafter. If
clinical signs and symptoms consistent with liver disease develop, or if systemic
manifestations occur (e.g., eosinophilia, rash, etc.) and abnormal liver tests are detected,
persist or worsen, diclofenac should be discontinued immediately.
Hematologic Effects: Patients on long-term treatment with NSAIDs, including
diclofenac, should have their hemoglobin or hematocrit checked periodically for signs or
symptoms of anemia. Appropriate measures should be taken in case such signs of anemia
occur.
Protein Binding
Tablets
In vitro, diclofenac interferes minimally or not at all with the protein binding of salicylic
acid (20% decrease in binding), tolbutamide, prednisolone (10% decrease in binding), or
warfarin. Benzylpenicillin, ampicillin, oxacillin, chlortetracyclline, doxycycline, cephalothin,
erythromycin, and sulfamethoxazole have no influence in vitro on the protein binding of
diclofenac in human serum.
Drug/Laboratory Test Interactions
Tablets
Effect on Blood Coagulation: Diclofenac increases platelet aggregation time but does
not affect bleeding time, plasma thrombin clotting time, plasma fibrinogen, or factors V
and VII to XII. Statistically significant changes in prothrombin and partial thromboplastin
times have been reported in normal volunteers. The mean changes were observed to be
less than 1 second in both instances, however, and are unlikely to be clinically important.
Diclofenac is a prostaglandin synthetase inhibitor, however, and all drugs that inhibit
prostaglandin synthesis interfere with platelet function to some degree; therefore, patients
who may be adversely affected by such an action should be carefully observed.
Carcinogenesis, Mutagenesis, and Impairment of Fertility
Tablets
Long-term carcinogenicity studies in rats given diclofenac sodium up to 2 mg/kg/day (or
12 mg/m2/day, approximately the human dose) have revealed no significant increases in
tumor incidence. There was a slight increase in benign mammary fibroadenomas in
mid-dose-treated (0.5 mg/kg/day or 3 mg/m2/day) female rats (high-dose females had
excessive mortality), but the increase was not significant for this common rat tumor. A
2-year carcinogenicity study conducted in mice employing diclofenac at doses up to 0.3
mg/kg/day (0.9 mg/m2/day) in males and 1 mg/kg/day (3 mg/m2/day) in females did not
reveal any oncogenic potential. Diclofenac sodium did not show mutagenic activity in in
vitro point mutation assays in mammalian (mouse lymphoma) and microbial (yeast,
Ames) test systems and was nonmutagenic in several mammalian in vitro and in vivo
tests, including dominant lethal and male germinal epithelial chromosomal studies in mice,
and nucleus anomaly and chromosomal aberration studies in Chinese hamsters.
Diclofenac sodium administered to male and female rats at 4 mg/kg/day (24 mg/m2/day)
did not affect fertility.
Ophthalmic Solution
Long-term carcinogenicity studies in rats given diclofenac sodium ophthalmic solution up
to 2 mg/kg/day (approximately the human oral dose) revealed no significant increases in
tumor incidence. There was a slight increase in benign rat mammary fibroadenomas in
mid-dose females (high-dose females had excessive mortality) but the increase was not
significant for this common rat tumor. A 2-year carcinogenicity study conducted in mice
employing oral diclofenac sodium ophthalmic solution up to 2 mg/kg/day did not reveal
any oncogenic potential. Diclofenac sodium ophthalmic solution did not show mutagenic
potential in various mutagenicity studies including the Ames test. Diclofenac sodium
ophthalmic solution administered to male and female rats at 4 mg/kg/day did not affect
fertility.
Pregnancy, Teratogenic Effects, Pregnancy Category B (Tablets); Pregnancy
Category C (Ophthalmic Solution)
Reproduction studies have been performed in mice given diclofenac sodium (20
mg/kg/day with the ophthalmic solution and up to 20 mg/kg/day or 60 mg/m2/day with
the tablets) and in rats and rabbits given diclofenac sodium (for ophthalmic solution up to
10 mg/kg/day; for tabltes up to 10 mg/kg/day or 60 mg/m2/day for rats, and 80
mg/m2/day with tablets for rabbits) and have revealed no evidence of teratogenicity
despite the induction of maternal toxicity and fetal toxicity. In rats, maternally toxic doses
were associated with dystocia, prolonged gestation, reduced fetal weights and growth,
and reduced fetal survival. Diclofenac has been shown to cross the placental barrier in
mice and rats.
There are, however, no adequate and well-controlled studies in pregnant women.
Because animal reproduction studies are not always predictive of human response, this
drug should be used during pregnancy unless the b enefits to the mother justify the
potential risk to the fetus. Because of the risk to the fetus resulting in premature closure of
the ductus arteriosus, diclofenac should be avoided in late pregnancy.
Nonteratogenic Effects
Ophthalmic Solution: Because of the known effects of prostaglandin
biosynthesis-inhibiting drugs on the fetal cardiovascular system (closure of the ductus
arteriosus), the use of diclofenac sodium ophthalmic solution during late pregnancy should
be avoided.
Labor and Delivery
Tablets: The effects of diclofenac on labor and delivery in pregnant women are unknown.
Because of the known effects of prostaglandin-inhibiting drugs on the fetal cardiovascular
system (closure of ductus arteriosus), use of diclofenac during late pregnancy should be
avoided and, as with other nonsteroidal anti-inflammatory drugs, it is possible that
diclofenac may inhibit uterine contraction and delay parturition.
Nursing Mothers
Tablets: Because of the potential for serious adverse reactions in nursing infants from
diclofenac, a decision should be made whether to discontinue nursing or to discontinue
the drug, taking into account the importance of the drug to the mother.
Pediatric Use
Safety and effectiveness of diclofenac sodium in pediatric patients have not been
established.
Geriatric Use
Tablets: Of the more than 6000 patients treated with diclofenac sodium in U.S. trials,
31% were older than 65 years of age. No overall difference was observed between
efficacy, adverse event or pharmacokinetic profiles of older and younger patients. As
with any NSAID, the elderly are likely to tolerate adverse reactions less well than
younger patients.