Cardiovascular Effects
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, myocardial infarction, and stroke, which
can be fatal. All NSAIDs, both COX-2 selective and nonselective, may have a
similar risk. Patients with known CV disease or risk factors for CV disease may
be at greater risk. To minimize the potential risk for an adverse CV event in
patients treated with an NSAID, the lowest effective dose should be used for
the shortest duration possible. Physicians and patients should remain alert for
the development of such events, even in the absence of previous CV symptoms.
Patients should be informed about the signs and/or 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 does increase the risk of serious GI
events (see GI WARNINGS, GI Effects).
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 (see CONTRAINDICATIONS).
Hypertension
NSAIDs, can lead to onset of new hypertension or worsening
of preexisting hypertension, either of which may contribute to the increased
incidence of CV events. Patients taking thiazides or loop diuretics may have
impaired response to these therapies when taking NSAIDs. NSAIDs, including
Voltaren® (diclofenac sodium enteric-coated tablets), should be used with
caution in patients with hypertension. Blood pressure (BP) should be monitored
closely during the initiation of NSAID treatment and throughout the course of
therapy.
Congestive Heart Failure and Edema Renal Effects
Fluid retention and edema have been observed in some
patients taking NSAIDs. Voltaren should be used with caution in patients with
fluid retention or heart failure.
Gastrointestinal (GI) Effects: Risk of GI Ulceration,
Bleeding, and Perforation
NSAIDs, including Voltaren, can cause serious
gastrointestinal (GI) adverse events including inflammation, bleeding,
ulceration, and perforation of the 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 occur in approximately 1% of patients treated for 3-6 months, and in
about 2%-4% of patients treated for one year. These trends continue with longer
duration of use, increasing the likelihood of developing a serious GI event at
some time during the course of therapy. However, even short-term therapy is not
without risk.
NSAIDs should be prescribed with extreme caution in those
with a prior history of ulcer disease or gastrointestinal bleeding. Patients
with a prior history of peptic ulcer disease and/or gastrointestinal bleeding who use NSAIDs have a greater than 10-fold increased risk for developing a GI
bleed compared to patients with neither of these risk factors. Other factors
that increase the risk for GI bleeding in patients treated with NSAIDs include
concomitant use of oral corticosteroids or anticoagulants, longer duration of
NSAID therapy, smoking, use of alcohol, older age, and poor general health
status. Most spontaneous reports of fatal GI events are in elderly or
debilitated patients and therefore, special care should be taken in treating
this population.
To minimize the potential risk for an adverse GI event in
patients treated with an NSAID, the lowest effective dose should be used for
the shortest possible duration. Patients and physicians should remain alert for
signs and symptoms of GI ulceration and bleeding during NSAID therapy and
promptly initiate additional evaluation and treatment if a serious GI adverse
event is suspected. This should include discontinuation of the NSAID until a
serious GI adverse event is ruled out. For high risk patients, alternate
therapies that do not involve NSAIDs should be considered.
Renal Effects
Caution should be used when initiating treatment with
Voltaren in patients with considerable dehydration<.
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 a
nonsteroidal anti-inflammatory drug 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, heart failure, liver
dysfunction, those taking diuretics and ACE inhibitors, and the elderly. Discontinuation
of NSAID therapy is usually followed by recovery to the pretreatment state.
Advanced Renal Disease
No information is available from controlled clinical studies
regarding the use of Voltaren in patients with advanced renal disease.
Therefore, treatment with Voltaren is not recommended in these patients with
advanced renal disease. If Voltaren therapy must be initiated, close monitoring
of the patient's renal function is advisable.
Hepatic Effects
Elevations of one or more liver tests may occur during
therapy with Voltaren. 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 [ULN = the upper limit of the normal range])
or greater elevations of transaminases occurred in about 15% of
diclofenac-treated patients. Of the markers of hepatic function, ALT (SGPT) is
recommended for the monitoring of liver injury.
In clinical trials, meaningful elevations (i.e., more than 3
times the ULN) of AST (GOT) (ALT was not measured in all studies) occurred in
about 2% of approximately 5,700 patients at some time during diclofenac treatment. In
a large, open-label, controlled trial of 3,700 patients treated 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 patients and included marked elevations (i.e., more 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 ( > 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 postmarketing 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. Postmarketing 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.
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. Based on clinical trial data and postmarketing 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.), Voltaren 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, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and
“flu-like” symptoms), and the appropriate action patients should take
if these signs and symptoms appear.
To minimize the potential risk for an adverse liver related
event in patients treated with Voltaren, the lowest effective dose should be
used for the shortest duration possible. Caution should be exercised in
prescribing Voltaren with concomitant drugs that are known to be potentially
hepatotoxic (e.g., antibiotics, anti-epileptics).
Anaphylactoid Reactions
As with other NSAIDs, anaphylactoid reactions may occur in
patients without known prior exposure to Voltaren. Voltaren should not be given
to patients with the aspirin triad. This symptom complex 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 NSAIDs. (See CONTRAINDICATIONS
and PRECAUTIONS, Preexisting Asthma.) Emergency help should be
sought in cases where an anaphylactoid reaction occurs.
Skin Reactions
NSAIDs, including Voltaren, can cause serious skin adverse
events such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and
toxic epidermal necrolysis (TEN), which can be fatal. These serious events may
occur without warning. Patients should be informed about the signs and symptoms
of serious skin manifestations and use of the drug should be discontinued at
the first appearance of skin rash or any other sign of hypersensitivity.
Pregnancy
In late pregnancy, as with other NSAIDs, Voltaren should be
avoided because it may cause premature closure of the ductus arteriosus.