Regarding misoprostol:
See boxed CONTRAINDICATIONS AND WARNINGS.
Regarding diclofenac:
See boxed CONTRAINDICATIONS AND WARNINGS.
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 WARNINGS,
Gastrointestinal Effects - Risk of Ulceration, Bleeding and Perforation).
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, including ARTHROTEC, 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 ARTHROTEC, 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. ARTHROTEC
should be used with caution in patients with fluid retention or heart failure.
Gastrointestinal Effects - Risk of Ulceration, Bleeding and Perforation
NSAIDs, including ARTHROTEC, 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 treated
with neither of these risk factors. Other factors that increase the risk of 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 ulcerations
and bleeding during NSAID therapy and promptly initiate additional evaluation and
treatment if a serious GI 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
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
ARTHROTEC contains diclofenac. Diclofenac metabolites are eliminated primarily by
the kidneys. The extent to which the metabolites may accumulate in patients with
renal failure has not been studied. Therefore, treatment with ARTHROTEC is not recommended
in these patients with advanced renal disease. If ARTHROTEC therapy must be initiated,
close monitoring of the patient’s renal function is advisable.
Hepatic effects
In clinical trials with ARTHROTEC, meaningful elevation of ALT (SGPT, more than 3 times the ULN) occurred in 1.6% of 2,184 patients treated with ARTHROTEC and in 1.4% of 1,691 patients treated with diclofenac sodium. These increases were generally transient, and enzyme levels returned to within the normal range upon discontinuation of therapy with ARTHROTEC. The misoprostol component of ARTHROTEC does not appear to exacerbate the hepatic effects caused by the diclofenac sodium component.
Elevations of one or more liver tests may occur during therapy with diclofenac, a component of ARTHROTEC. 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 (SGOT) (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.), ARTHROTEC 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.
To minimize the potential risk for an adverse liver related event in patients treated with ARTHROTEC, the lowest effective dose should be used for the shortest duration possible. Caution should be exercised in prescribing ARTHROTEC with concomitant drugs that are known to be potentially hepatotoxic (e.g., antibiotics, anti-epileptics).
Anaphylactic reactions
As with other NSAIDs, anaphylactic reactions may occur in patients without known
prior exposure to ARTHROTEC. ARTHROTEC 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). Anaphylactic reactions may also occur
to the misoprostol component of ARTHROTEC. Emergency help should be sought in cases
where an anaphylactic reaction occurs. Allergic reactions have been reported by
less than 0.1% of patients who received ARTHROTEC in clinical trials, and there
have been rare reports of anaphylaxis in the marketed use of ARTHROTEC outside of
the United States.
Skin Reactions
NSAIDs, including ARTHROTEC, 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 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, ARTHROTEC should be avoided because it
may cause premature closure of the ductus arteriosus.