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 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).
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®-XR (diclofenac sodium extended-release)
tablets, USP, 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
Fluid retention and edema have been observed in some patients taking NSAIDs.
Voltaren-XR should be used with caution in patients with fluid retention or
Gastrointestinal (GI) Effects: Risk of GI Ulceration, Bleeding, and Perforation
NSAIDs, including Voltaren-XR, 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.
Caution should be used when initiating treatment with Voltaren-XR 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 non-steroidal anti-inflammatory drug (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-XR in patients with advanced renal disease. Therefore, treatment
with Voltaren-XR is not recommended in these patients with advanced renal disease.
If Voltaren-XR therapy must be initiated, close monitoring of the patient's
renal function is advisable.
Elevations of one or more liver tests may occur during therapy with Voltaren-XR.
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
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-XR
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
To minimize the potential risk for an adverse liver related event in patients
treated with Voltaren-XR, the lowest effective dose should be used for the shortest
duration possible. Caution should be exercised in prescribing Voltaren-XR with
concomitant drugs that are known to be potentially hepatotoxic (e.g., antibiotics,
As with other NSAIDs, anaphylactic reactions may occur both in patients with
the aspirin triad and in patients without known sensitivity to NSAIDs or known
prior exposure to Voltaren-XR. Voltaren-XR 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.) Anaphylaxis-type reactions
have been reported with NSAID products, including with diclofenac products,
such as Voltaren-XR. Emergency help should be sought in cases where an anaphylactic
NSAIDs, including Voltaren-XR, 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.
In late pregnancy, as with other NSAIDs, Voltaren-XR should be avoided because
it may cause premature closure of the ductus arteriosus.