Cardiovascular Thromboic 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 ...
Cardiovascular Thromboic 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 CVdisease. 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
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).
Post-MI Patients
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 NSAIDtreated
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 diclofenac sodium delayedrelease
tablets in patients with a recent MI unless the benefits are expected
to outweigh the risk of recurrent CV thrombotic events. If diclofenac sodium
delayed-release tablets are 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 patients
- Use the lowest effective dosage for the shortest possible duration.
- 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 NSAIDs.
- 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 diclofenac sodium delayed-release tablets 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).
Hepatotoxicity
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 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.
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 days.
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.), diclofenac 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 diclofenac immediately, and perform a clinical evaluation of the patient.
To minimize the potential risk for an adverse liver related event in patients treated
with diclofenac, use the lowest effective dose for the shortest duration possible.
Exercise caution when prescribing diclofenac with concomitant drugs that are
known to be potentially hepatotoxic (e.g., acetaminophen, antibiotics, antiepileptics).
Hypertension
NSAIDs, including diclofenac, 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 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 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 diclofenac in patients with severe heart failure unless the benefits
are expected to outweigh the risk of worsening heart failure. If diclofenac is used
in patients with severe heart failure, monitor patients for signs of worsening heart failure.
Renal Toxicity and Hyperkalemia
Renal Toxicity
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 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 diclofenac in patients with advanced renal disease. The renal effects
of diclofenac 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 diclofenac.
Monitor renal function in patients with renal or hepatic impairment,heart failure,dehydration,
or hypovolemia during use of diclofenac (see
PRECAUTIONS; Drug Interactions). Avoid the
use of diclofenac in patients with advanced renal disease unless the benefits are expected
to outweigh the risk of worsening renal function. If diclofenac is used in patients with
advanced renal disease, monitor patients for signs of worsening renal function.
Hyperkalmia
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.
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 crossreactivity
between aspirin and other NSAIDs has been reported in such aspirinsensitive patients,
diclofenac is contraindicated in patients with this form of aspirin sensitivity (see
CONTRAINDICATIONS). When diclofenac 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. NSAIDs can also cause fixed drug eruption (FDE). FDE may present as a
more severe variant known as generalized bullous fixed drug eruption (GBFDE), which
can be life-threatening. These serious events may occur without warning. Inform patients
about the signs and symptoms of serious skin reactions, and to discontinue the use
of diclofenac at the first appearance of skin rash or any other sign of hypersensitivity.
Diclofenac is contraindicated in patients with previous serious skin reactions to NSAIDs
(see
CONTRAINDICATIONS).
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported
in patients taking NSAIDs such as Diclofenac Sodium. Some of these events have been
fatal or life-threatening. DRESS typically, although not exclusively, presents with fever,
reaction, lymphadenopathy, and/or facial swelling. Other clinical anifestations may include
hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis. Sometimes
symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present.
Because this disorder is variable in its presentation, other organ systems not noted here
may be involved. It is important to note that early manifestations of hypersensitivity, such
as fever or lymphadenopathy, may be present even though rash is not evident. If such
signs or symptoms are present, discontinue Diclofenac Sodium and evaluate the patient
immediately.
Fetal Toxicity
Premature Closure of Fetal Ductus Arteriosus
Avoid use of NSAIDs, including Diclofenac Sodium, in pregnant women at about 30 weeks
gestation and later. NSAIDs including Diclofenac Sodium, increase the risk of premature
closure of the fetal ductus arteriosus at approximately this gestational age.
Oligohydramnios/Neonatal Renal Impairment
Use of NSAIDs, including Diclofenac Sodium, at about 20 weeks gestation or later in
pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some
cases, neonatal renal impairment.These adverse outcomes are seen, on average, after days
to weeks of treatment, although oligohydramnios has been infrequently reported as soon
as 48 hours after NSAID initiation. Oligohydramnios is often, but not always, reversible with
treatment discontinuation. Complications of prolonged oligohydramnios may, for example,
include limb contractures and delayed lung maturation. In some postmarketing cases of
impaired neonatal renal function, invasive procedures such as exchange transfusion or
dialysis were required. If NSAID treatment is necessary between about 20 weeks and 30
weeks gestation, limit Diclofenac Sodium use to the lowest effective dose and shortest
duration possible. Consider ultrasound monitoring of amniotic fluid if Diclofenac Sodium
treatment extends beyond 48 hours. Discontinue Diclofenac Sodium if oligohydramnios
occurs and follow up according to clinical practice [see
PRECAUTIONS; Pregnancy].
Hematologic Toxicity
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 diclofenac, has any signs or symptoms of anemia, monitor hemoglobin or
hematocrit. NSAIDs, including diclofenac, may increase the risk of bleeding events. Comorbid
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
PRECAUTIONS; Drug Interactions).
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