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 WARNINGS;
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 CATAFLAM in patients with a recent MI
unless the benefits are expected to outweigh the risk of recurrent CV
thrombotic events. If CATAFLAM 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 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 use 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 CATAFLAM 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
PRECAUTIONS; DRUG INTERACTIONS).
In clinical trials of 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 a large, 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 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
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.
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 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.), CATAFLAM 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
CATAFLAM immediately, and perform a clinical evaluation of the patient.
To minimize the potential risk for an adverse liver
related event in patients treated with CATAFLAM, use the lowest effective dose
for the shortest duration possible. Exercise caution when prescribing CATAFLAM
with concomitant drugs that are known to be potentially hepatotoxic (e.g.,
acetaminophen, antibiotics, anti-epileptics).
NSAIDs, including CATAFLAM can lead to new onset of
hypertension or worsening of preexisting hypertension, either of which may
contribute to the increased incidence of CV events. Patients taking angiotensin
converting enzyme (ACE) inhibitors, thiazides diuretics or loop diuretics may
have impaired response to these therapies when taking NSAIDs (see
PRECAUTIONS; 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 hospitalization 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 death.
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
PRECAUTIONS; DRUG INTERACTIONS).
Avoid the use of CATAFLAM in patients with severe heart
failure unless the benefits are expected to outweigh the risk of worsening
heart failure. If CATAFLAM 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 CATAFLAM in patients with advanced renal disease.
The renal effects of CATAFLAM may hasten the progression of renal dysfunction
in patients with preexisting renal disease.
Correct volume status in dehydrated or hypovolemic
patients prior to initiating CATAFLAM. Monitor renal function in patients with
renal or hepatic impairment, heart failure, dehydration, or hypovolemia during
use of CATAFLAM (see PRECAUTIONS; DRUG INTERACTIONS). Avoid the
use of CATAFLAM in patients with advanced renal disease unless the benefits are
expected to outweigh the risk of worsening renal function. If CATAFLAM is used
in patients with advanced renal disease, monitor patients for signs of
worsening renal function.
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, WARNINGS;
Exacerbation of Asthma Related to Aspirin Sensitivity).
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, CATAFLAM is
contraindicated in patients with this form of aspirin sensitivity (see CONTRAINDICATIONS).
When CATAFLAM is used in patients with preexisting asthma (without known
aspirin sensitivity), monitor patients for changes in the signs and symptoms of
Serious Skin Reactions
NSAIDs, including diclofenac, 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. Inform patients about the signs and symptoms of
serious skin reactions and discontinue the use of CATAFLAM at the first
appearance of skin rash or any other sign of hypersensitivity. CATAFLAM 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 CATAFLAM, in pregnant women
starting at 30 weeks of gestation (third trimester) (see PRECAUTIONS; Pregnancy).
Anemia has occurred in NSAID-treated patients. This may be
due to occult or gross blood loss, fluid retention, or an incompletely
described effect upon erythropoiesis. If a patient treated with CATAFLAM has
any signs or symptoms of anemia, monitor hemoglobin or hematocrit.
NSAIDs, including CATAFLAM, may increase the risk of
bleeding events. Co-morbid conditions such as coagulation disorders,
concomitant use of warfarin and 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 PRECAUTIONS; DRUG