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FDA Safety Changes: Naprosyn/Anaprox and Other Prescription NSAIDs
The US Food and Drug Administration (FDA) has approved safety labeling revisions to advise of the potential risks for allergic reactions, gastrointestinal tract bleeding, and cardiovascular events associated with use of prescription nonsteroidal anti-inflammatory drugs, such as naproxen sodium, diclofenac potassium, diclofenac sodium, diflunisal, etodolac, fenoprofen, flurbiprofen, indomethacin, ketoprofen, oxaprozin, oxaprozin potassium, mefenamic acid, nabumetone, piroxicam, and sulindac.
New NSAID Labeling Advises of Risks for Allergic Reactions, CV and GI EventsOn January 24, the FDA approved safety labeling revisions for naproxen sodium tablets (Naprosyn, Anaprox), suspension (Naprosyn), and delayed-release tablets (EC-Naprosyn, Anaprox DS; all made by Roche Laboratories, Inc) to warn of the potential risks for allergic reactions, gastrointestinal (GI) tract bleeding, and cardiovascular (CV) events associated with their use.
The FDA also emphasized the importance of limiting the use of naproxen and other nonsteroidal anti-inflammatory drug (NSAID) therapy to the lowest effective dose for the shortest possible duration to minimize the risks for these events while achieving individual patient treatment goals. Other treatment options should be considered in patients at increased risk for GI or CV effects.
Clinical trials of up to 3 years' duration have linked several cyclooxgenase 2 selective and nonselective NSAIDs to an increased risk for serious and potentially fatal CV thrombotic events, myocardial infarction, and stroke. According to the FDA, all NSAIDs may have similar risks that increase with duration of use and in the presence of existing CV disease and/or related risk factors.
Clinicians are advised to remain alert for the development of CV events, even in the absence of previous symptoms. The FDA notes that there is no consistent evidence that concurrent use of low-dose aspirin mitigates the risk for thrombotic events, and concomitant use of both drugs does increase the risk for serious GI events.
An increased incidence of myocardial infarction and stroke has also been observed in 2 large, controlled, clinical trials of cyclooxgenase 2 selective NSAIDs for pain relief after coronary artery bypass graft surgery; use of NSAIDs is therefore contraindicated in this setting.
The FDA notes that all NSAIDs can lead to the onset of new hypertension or worsening of preexisting disease of which either may contribute to an increased incidence of CV events. Because patient response to thiazides or loop diuretics may be impaired, close monitoring of blood pressure is recommended.
Fluid retention and edema have also been observed in some patients taking NSAIDs, and they should therefore be prescribed with caution in patients with fluid retention, hypertension, or heart failure.
The FDA also warned that NSAIDs are associated with an increased risk for serious and potentially fatal GI adverse events, particularly in the elderly. Inflammation, bleeding, ulceration, and perforation of the stomach or small/large intestines may occur at any time during therapy and without warning symptoms; only 20% of patients who develop a serious upper GI tract adverse event while receiving NSAID therapy are symptomatic.
As with CV adverse events, the risk for GI events increases with duration of therapy. After 3 to 6 months of treatment, the risk for upper GI ulcers, gross bleeding, or perforation is approximately 1% and is more than doubled (2% to 4%) at 1 year. The FDA notes that even short-term therapy is not without risk.
Because patients with a prior history of peptic ulcer disease and/or GI tract bleeding have a greater than 10-fold increased risk for developing a GI tract bleed, meloxicam should be prescribed with extreme caution in this population.
Other factors that increase the risk of bleeding include concomitant use of oral corticosteroids or anticoagulants, smoking, alcohol consumption (3 or more drinks/day), older age (> 60 years), and poor general health status. Because most spontaneous reports of fatal GI events are in elderly or debilitated patients, special care should be taken in treating this population.
Clinicians are advised to remain alert for signs and symptoms of GI ulceration and bleeding. If a serious GI event is suspected, additional evaluation and treatment should be initiated promptly and NSAID therapy discontinued until the event is ruled out.
Patients should be advised to take NSAID products with food or milk in the event of stomach upset and to seek immediate medical attention if they feel faint, vomit blood, or have bloody or tarry stools.
The FDA warned that long-term administration of NSAIDs has also been linked to papillary necrosis and other renal injuries. In patients for whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion, NSAIDs may cause a dose-dependent reduction in prostaglandin formation that may precipitate overt renal decompensation.
Patients with impaired renal function, heart failure, liver dysfunction, the elderly, and those taking diuretics and angiotensin-converting enzyme inhibitors are at greatest risk for this reaction. The FDA notes that discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.
Use of NSAIDs in patients with advanced renal disease is not recommended due to a lack of safety data from controlled clinical studies. If therapy must be administered, renal function should be monitored closely.
NSAIDs also have been linked to reports of anaphylactoid reactions, some of which have occurred in patients without known prior exposure to the causative agent. NSAIDs should not be used in patients with the aspirin triad, a symptom complex that 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.
In addition, serious and potentially fatal dermatologic adverse events can occur without warning, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis. Therapy should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity.
Patients should be advised to discontinue NSAID use and seek medical attention immediately if they develop symptoms of hypersensitivity, such as hives, facial swelling, asthma, shock, skin reddening, rash, and blisters.
Patients who are pregnant should not use NSAIDs during pregnancy, particularly during the last 3 months of gestation, because of the risks for premature closure of the ductus arteriosus.
The above warnings also apply to other NSAIDs, including flurbiprofen tablets (Ansaid, made by Pfizer, Inc); diclofenac potassium immediate-release tablets (Cataflam, made by Novartis Pharmaceuticals Corp); sulindac tablets (Clinoril, made by Merck & Co, Inc); oxaprozin caplets (Daypro, made by Pfizer); oxaprozin potassium tablets (Daypro Alta, made by Pfizer); diflunisal tablets (Dolobid, made by Merck); piroxicam capsules (Feldene, made by Pfizer); and indomethacin capsules, oral suspension, and suppositories (Indocin, made by Merck).
They also apply to etodolac capsules and tablets (Lodine, made by Wyeth Pharmaceuticals, Inc); etodolac extended-release tablets (Lodine XL, made by Wyeth); ibuprofen 100-mg/5-mL suspension and tablets (Motrin, made by McNeil Consumer & Specialty Pharmaceuticals); fenoprofen calcium capsules (Nalfon, made by Pedinol Pharmacal, Inc); naproxen controlled-release tablets (Naprelan made by Elan Pharmaceutical Research Corp); ketoprofen capsules and extended-release capsules (Orudis and Oruvail, made by Wyeth); mefenamic acid capsules (Ponstel, made by First Horizon Pharmaceutical Co); nabumetone tablets (Relafen, made by GlaxoSmithKline); and diclofenac sodium enteric-coated and extended-release tablets (Voltaren and Voltaren XR, made by Novartis).