visual impairment
Naproxen Adverse Reactions
The most frequently reported reactions to naproxen are gastrointestinal. Constipation, pyrosis, abdominal pain, and nausea/vomiting occur in 3 - 9% of patients. Diarrhea, dyspepsia, and stomatitis are reported less frequently (1 - 3%). Adverse effects reported by patients with rheumatoid arthritis appear to be more severe and frequent with higher dosages (1.5 g/day) than with lower dosages (750 mg/day). Severe GI effects, including peptic ulcer with or without GI perforation, GI bleeding, colitis, melena, or hematemesis have occurred in fewer than 1% of patients and may not be preceded by early GI manifestations. The risk of severe GI events is increased by a history of peptic ulcer disease or GI bleed. Smoking, alcohol usage, concomitant usage of anticoagulants or oral corticosteroids, older age, longer duration of NSAID therapy, and poor general health status may increase the risk for GI bleeding. Gastrointestinal bleeding or erosive gastritis can be minor or life-threatening and may result from a combination of direct irritant action on the stomach mucosa and a prolonged bleeding time, due to changes in platelet aggregation. Occult GI bleeding occurs in many patients and is not necessarily correlated with GI distress. Older patients appear to be greater affected by GI ulceration or bleeding; most fatal GI events occur in older or debilitated patients.
Rare cases of esophagitis have been reported in patients receiving NSAIDs, such as naproxen. NSAID-induced esophagitis is characterized by sudden onset odynophagia, pyrosis (heartburn), retrosternal pain, and dysphagia. Severe complications such as esophageal ulceration, esophageal stricture, bleeding, and perforation have been reported rarely. Risk factors for NSAID-induced esophageal effects include taking the medication without water and at night. Symptoms usually resolve within days to weeks after stopping the medication.
Naproxen has been shown to cause platelet dysfunction; this effect, however, is transient and reversible. As inhibition of platelet aggregation appears to correlate with effective plasma concentrations of the drug, the individual half-life of each NSAID determines the duration of this effect. Naproxen glucuronide, a metabolite of naproxen, may cause immune-mediated thrombocytopenia. Widespread petechial hemorrhages were noted 10 - 25 days after naproxen initiation in 3 individuals. All 3 adults had improvement in their platelet counts from 3 - 8 x109/L to within the normal concentration range 5 - 7 days after naproxen discontinuation and prednisone receipt. The sera from each patient had antibodies against platelets in the presence of naproxen glucuronide. Other hematologic effects (< 1%) due to naproxen include agranulocytosis, leukopenia, eosinophilia, granulocytopenia, and neutropenia. Aplastic anemia and hemolytic anemia have been associated with naproxen, but a causal relationship is unknown. Blood loss from gastrointestinal damage caused by naproxen is usually not significant. However, blood loss over time can result in iron deficiency anemia. Patients on prolonged therapy should undergo regular blood monitoring. Interpretation of the hematocrit and hemoglobin should be considered in relation to the fluid status, as naproxen can cause fluid retention.
Adverse CNS reactions occurring with a frequency of 3 - 9% include headache, dizziness, and drowsiness or fatigue. Vertigo and lightheadedness are reported in 1 - 3% of patients. Other CNS reactions occur less frequently (< 1%), including depression, insomnia, malaise, muscle weakness (myasthenia), and an inability to concentrate (impaired concentration). Overuse of naproxen by headache-prone patients frequently produces drug-induced rebound headache accompanied by dependence on symptomatic medication, tolerance (refractoriness to prophylactic medication), and withdrawal symptoms. In this case, overuse of naproxen has been defined as taking 3 or more doses per day more often than 5 days per week. The frequency of use may be more important than the dose. Features of a rebound headache include morning headache, end-of-dosing interval headache, or headache improvement with discontinuation of overused medication. Stopping the symptomatic medication may result in a period of increased headache and then headache improvement. Analgesic overuse may be responsible for the transformation of episodic migraine or episodic tension headache into daily headache and may perpetuate the syndrome.
Naproxen has been associated with aseptic meningitis (incidence of < 1% in clinical trials) but a causal relationship has not been established. Ibuprofen has been the most common NSAID implicated in this adverse reaction; however, cases have been reported with sulindac, tolmetin, diclofenac, ketoprofen, rofecoxib, and piroxicam. Aseptic meningitis from one NSAID does not preclude use of another NSAID; most patients can be treated with another drug without incident. However, one patient with Sjogren’s syndrome experienced aseptic meningitis after receipt of naproxen, ibuprofen, and rofecoxib at different times; aseptic meningitis developed about a week after each drug exposure, and the symptoms abated roughly 2 days following each drug cessation. The occurrence of aseptic meningitis is not related to NSAID chemical class or prostaglandin inhibition. A Type III or IV immunological hypersensitivity reaction is the proposed mechanism of action. Drug-induced aseptic meningitis usually occurs shortly after drug initiation but can occur after years of drug usage. Although NSAID-induced aseptic meningitis is primarily reported in patients with systemic lupus erythematosus (SLE), healthy patients and patients with other disease states such as ankylosing spondylitis, connective tissue disease, osteoarthritis, and rheumatoid arthritis have developed NSAID-induced aseptic meningitis. Symptoms of aseptic meningitis include confusion, drowsiness, general feeling of illness, severe headache, nausea, nuchal rigidity, and photophobia. As aseptic meningitis is a diagnosis of exclusion, the suspected drug should be discontinued and not restarted unless a rechallenge is desired.
Otic effects, such as tinnitus (3 - 9%) and hearing loss (< 1%) have occurred with naproxen during clinical trials. Also, 6 cases of hearing loss have been reported in the literature. Two of the 6 patients had a post-treatment audiogram, which revealed a permanent severe bilateral sensorineural hearing loss. Of the other patients, 2 had recovery and 2 had no recovery of their hearing loss. Tinnitus and hearing loss have also occurred with the nonsteroidal anti-inflammatory drugs (NSAIDs) piroxicam and ketorolac. The hearing loss from NSAID usage is believed to be due to altered cochlear sensory cell function from tissue ischemia as a result of an imbalance between vasodilatory prostaglandins and vasoconstricting leukotrienes. Although no known morphologic changes are known to occur, hearing loss may be permanent. Coadministration of other ototoxic drugs, such as gentamicin or furosemide, may increase the risk of ototoxicity. Most ototoxic drugs have at least additive ototoxic interactions. Further, NSAIDs can be nephrotoxic, and impaired renal function can increase the ototoxic potential of NSAIDs. Patients taking long-term NSAIDs should be directly questioned about tinnitus and hearing loss.
Visual impairment, such as blurred vision has been reported in 1 - 3% of patients.
Jaundice, pancreatitis, and fatal hepatitis or hepatic failure have been reported in fewer than 1% of patients receiving naproxen. Elevated hepatic enzymes occur in up to 15% of patients receiving NSAIDs. Elevations that are greater than three times the upper limit of normal have occurred in fewer than 1% of patients that received naproxen. Hepatic enzyme abnormalities may progress, stabilize, or regress with continued naproxen use. Naproxen should be discontinued if elevated liver-function tests persist or worsen, or if signs or symptoms of hepatic disease develop.
Renal disease including interstitial nephritis, nephrotic syndrome, hematuria, glomerulonephritis, hyperkalemia, renal failure (unspecified), and renal papillary necrosis have occurred in fewer than 1% of patients receiving naproxen. It is well known that vasodilatory renal prostaglandins and the potent vasoconstrictor angiotensin II work in concert to maintain renal blood flow. Inhibition of renal prostaglandins by NSAIDs can cause renal insufficiency and, thus, fluid retention. Edema (peripheral edema) occurred in 3 - 9% of patients receiving naproxen. Hypertension was not noted in clinical trials, but fluid retention caused by naproxen can elevate blood pressure, especially in patients with hypertension. In adults (76% White, 14% Black) with stable hypertension (systolic <150 mmHg) and normal renal function, the mean change from baseline in average 24-hour systolic pressure was -0.8 ± 1.1 mmHg and diastolic pressure was -1 ± 0.6 mmHg after 6 weeks of naproxen 500 mg twice daily. Blood pressure was measured every 20 minutes during 24-hour ambulatory monitoring, and no antihypertensive drug changes were allowed (all patients took at least an angiotensin converting enzyme inhibitor or an angiotensin-2 receptor blocker). Similar findings were obtained when blood pressure was measured in a clinic between 7 and 11 in the morning. Of the 101 patients, an increase in the systolic blood pressure of 0 - 10 mmHg occurred in 37%, an increase in 10 - 20 mmHg occurred in 7%, and a greater than 20 mmHg increase occurred in 2%. Furthermore, of 57 patients who had a baseline ambulatory systolic blood pressure less than 135 mmHg, 11 had a reading of 135 mmHg or higher at week 6. Exacerbations of congestive heart failure has been reported with a frequency of less than 1%. Monitoring of the patient’s fluid status and renal function is recommended.
Pruritus, skin eruptions, and ecchymoses occur in 3 - 9% of patients. Diaphoresis and purpura occur in 1 - 3% of patients. Other dermatologic reactions occur less frequently (< 1%), including rash (unspecified), urticaria, alopecia, photosensitivity reaction resembling porphyria cutanea tarda, and epidermolysis bullosa and photosensitive dermatitis. Three patients developed pseudoporphyria during treatment with over-the-counter naproxen 400 mg/day four to five times weekly for osteoarthritis for an unspecified length of time. The patient had skin fragility, blistering, tense bullae and/or shallow erosions predominantly on sun-exposed areas. Histological analyses were consistent with porphyria, but urine and plasma porphyrins were within normal limits. Skin lesions resolved within 1 - 6 months of naproxen discontinuation. No recurrences were seen during 15 - 34 months of follow-up. Toxic epidermal necrolysis, erythema multiforme, and Stevens-Johnson syndrome have been associated with naproxen but a causal relationship is unknown. Similar to other NSAIDS, use of naproxen may also result in exfoliative dermatitis. Although rash is reported in fewer than 1% of patients, it may be indicative of a hypersensitivity response. Patients should be instructed to discontinue the medication and contact their health care provider if erythema, rash, blisters, or related skin reactions develop. Eosinophilic pneumonitis, vasculitis, and anaphylactoid reactions including anaphylactic shock and angioedema occurred in < 1% of patients in clinical trials of naproxen. Dyspnea occurred in 3 - 9% of patients whereas palpitations occurred in 1 - 3% of patients. Allergic reactions to naproxen are more likely in patients with asthma; naproxen is contraindicated for use in patients with aspirin-sensitive asthma, or the aspirin triad because of the approximate 5% cross-sensitivity that occurs between aspirin and NSAIDs. The triad typically occurs in patients with asthma who experience rhinitis with or without nasal polyps, or who experience severe, potentially fatal, acute bronchospasm after taking aspirin or other NSAIDs.
[ Last revised: 2/24/2006 9:21:00 PM ]
References
. Silberstein SD. Drug-induced headache. Neuro Clinic N America 1998;16:107 - 23.
. Nabumetone/naproxen/oxaprozin: Pseudoporphyria: 6 case reports. Reactions Weekly 2003;953:12.
. Ashwath ML, Katner HP. Recurrent aseptic meningitis due to different non-steroidal anti-inflammatory drugs including rofecoxib. Postgrad Med J 2003;79:295 - 6.
. Warltier DC, Sprung J, Bourke DL, et al. Perioperative hearing impairment. Anesthesiology 2003;98:241 - 57.
. Chapman P. Naproxen and sudden hearing loss. J Laryngol Otol 1982;96:163 - 6.
. Sowers JR, White WB, Pitt B, et al. The effects of cyclooxygenase-2 inhibitors and nonsteroidal anti-inflammatory therapy on 24-hour blood pressure in patients with hypertension, osteoarthritis, and type 2 diabetes mellitus. Arch Intern Med 2005;165:161 - 8.
. Bougie D, Aster R. Immune thrombocytopenia resulting from sensitivity to metabolites of naproxen and acetaminophen. Blood 2001;97:3846 - 50.
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