Nonsteroidal Antiinflammatory Drugs (NSAIDs)

Nonsteroidal antiinflammatory drugs (NSAIDs) have been associated with anaphylactic reactions in persons with and without known hypersensitivity to NSAIDs and in persons with aspirin-sensitive asthma.[32122][56268]

Anemia has occurred in persons treated with nonsteroidal antiinflammatory drugs (NSAIDs). This may be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis. If a person treated with an NSAID develops any signs or symptoms of anemia, monitor hemoglobin and hematocrit.[32122][56268]

Nonsteroidal antiinflammatory drugs (NSAIDs) cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and GI 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. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occurred in approximately 1% of persons treated for 3 to 6 months, and in about 2% to 4% of persons treated for 1 year. However, even short-term NSAID therapy is not without risk. To minimize GI risks in NSAID-treated persons, use the lowest effective dosage for the shortest possible duration, and avoid administration of more than 1 NSAID at a time. In the setting of concomitant low-dose aspirin use for cardiac prophylaxis, monitor more closely for evidence of GI bleeding.[32122][56268]

The Coxib and traditional NSAID Trialists' Collaboration meta-analysis of randomized controlled trials demonstrated an approximately 2-fold increase in hospitalizations for heart failure in COX-2 selective-treated subjects and nonselective nonsteroidal antiinflammatory drug (NSAID)-treated subjects compared to placebo-treated subjects. In a Danish National Registry study of persons 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 persons treated with NSAIDs.[32122][56268]

Elevated hepatic enzymes of 3 times or more the upper limit of normal (ULN) have been reported in approximately 1% of nonsteroidal antiinflammatory drug (NSAID)-treated subjects in clinical trials. In addition, rare, sometimes fatal, cases of severe hepatic injury, including fulminant hepatitis, hepatic necrosis, and hepatic failure have been reported. Elevated hepatic enzymes of less than 3 times ULN may occur in up to 15% of persons treated with NSAIDs. If clinical signs and symptoms consistent with hepatic disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue the NSAID immediately, and perform a clinical evaluation of the patient.[32122][56268]

Increases in serum potassium concentration, including hyperkalemia, have been reported with nonsteroidal antiinflammatory drug (NSAID) use. In persons with normal renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism state.[32122][56268]

Nonsteroidal antiinflammatory drugs (NSAIDs) can lead to new onset of hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of cardiovascular events. Monitor blood pressure during the initiation of NSAID treatment and throughout the course of therapy.[32122][56268]

Clinical trials of several cyclooxygenase-2 (COX-2) selective and nonselective nonsteroidal antiinflammatory drugs (NSAIDs) of up to 3 years duration have shown an increased risk of serious cardiovascular thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for cardiovascular thrombotic events is similar for all NSAIDs. Some observational studies found that this increased risk of serious cardiovascular thrombotic events began as early as the first weeks of treatment. In 2 large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10 to 14 days after coronary artery bypass graft (CABG) surgery, an increased incidence of myocardial infarction and stroke was noted. Observational studies conducted in the Danish National Registry have demonstrated that persons treated with NSAIDs in the post-MI period were at increased risk of reinfarction, cardiovascular-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 persons compared to 12 per 100 person years in non-NSAID exposed persons. 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 4 years of follow-up. The increase in cardiovascular 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.[32122][56268]

Long-term administration of nonsteroidal antiinflammatory drugs (NSAIDs) has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in persons in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state. The renal effects of NSAIDs may hasten the progression of renal dysfunction in persons with preexisting renal disease; monitor for signs of worsening renal function.[32122][56268]

Nonsteroidal antiinflammatory drugs (NSAIDs) can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Discontinue NSAID use at the first appearance of skin rash or any other sign of hypersensitivity. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has also been reported in persons taking NSAIDs. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations 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. 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 NSAID use and evaluate the patient immediately.[32122][56268]

Nonsteroidal antiinflammatory drugs (NSAIDs) may diminish the antihypertensive effect of ACE inhibitors, angiotensin receptor blockers, or beta-blockers. Monitor blood pressure during concurrent use of NSAIDs and antihypertensive medications. In older persons or persons who are volume-depleted or have compromised renal function, concurrent of ACE inhibitors or angiotensin receptor blockers and NSAIDs may result in deterioration of renal function, including possible acute renal failure; monitor for worsening renal function. These effects are usually reversible. When these medications are used together, ensure adequate hydration and assess renal function prior to concomitant use and periodically thereafter.[32122][56268]

Concomitant use of nonsteroidal antiinflammatory drugs (NSAIDs) with medications that interfere with hemostasis may increase the risk of serious bleeding; monitor for signs of bleeding during concomitant use. NSAIDs and anticoagulants, such as warfarin, have a synergistic effect on bleeding. The concomitant use of NSAIDs and anticoagulants has an increased risk of serious bleeding compared to the use of either medication alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of medications that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.[32122][56268][56624]

Concomitant use of nonsteroidal antiinflammatory drugs (NSAIDs) and aspirin may increase the risk of serious bleeding; therefore, concomitant use of NSAIDs and analgesic doses of aspirin is generally not recommended. Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone and is associated with a significantly increased incidence of gastrointestinal adverse reactions as compared to use of the NSAID alone.[56268] Naproxen and ibuprofen may interfere with the antiplatelet effect of aspirin and increase the risk for adverse cardiovascular events. For persons taking low-dose aspirin for cardioprotection who require analgesics, consider use of an NSAID that does not interfere with the antiplatelet effect of aspirin, or non-NSAID analgesics, as appropriate.[32122][35893] NSAIDs are not substitutes for low-dose aspirin for cardiovascular protection.[32122][35893][56268]

Concomitant use of nonsteroidal antiinflammatory drugs (NSAIDs) and corticosteroids may increase the risk for gastrointestinal ulceration or bleeding; monitor for signs of bleeding during concomitant use.[32122][56268]

Concomitant use of nonsteroidal antiinflammatory drugs (NSAIDs) and cyclosporine may increase the risk for nephrotoxicity; monitor serum creatinine and for signs of worsening renal function during concomitant use.[28404][32122][56268]

A decline in glomerular filtration rate or tubular secretion due to nonsteroidal antiinflammatory drug (NSAID) use may impair the excretion of digoxin. Concomitant use of NSAIDs and digoxin may result in increased serum digoxin concentrations and a prolonged digoxin half-life; monitor serum digoxin concentrations during concomitant use.[28272][32122][56268]

Nonsteroidal antiinflammatory drugs (NSAIDs) have been shown to reduce the natriuretic effect of loop diuretics and thiazide diuretics in some individuals, likely due to NSAID inhibition of renal prostaglandin synthesis. Monitor for loss of diuretic efficacy, including antihypertensive effects, and signs of worsening renal function during concomitant use.[32122][56268]

Concomitant use of nonsteroidal antiinflammatory drugs (NSAIDs) and lithium may result in increased plasma lithium concentrations and reduced renal lithium clearance, likely due to NSAID inhibition of renal prostaglandin synthesis. Monitor lithium concentrations and for signs of lithium toxicity during concomitant use. Indomethacin and piroxicam have been reported to significantly increase steady-state plasma lithium concentrations, and selective cyclooxygenase-2 (COX-2) inhibitors may have the same effect. In healthy subjects, mean steady-state lithium plasma concentrations increased approximately 17% in subjects receiving lithium 450 mg twice daily with celecoxib 200 mg twice daily as compared to subjects receiving lithium alone.[32122][47399][56268]

Concomitant use of nonsteroidal antiinflammatory drugs (NSAIDs) and high-dose methotrexate has been associated with unexpectedly severe and fatal gastrointestinal and hematologic toxicity. Use NSAIDs and lower doses of methotrexate with caution due to increased risk for methotrexate toxicity, such as neutropenia, thrombocytopenia, or renal dysfunction; monitor for signs of methotrexate toxicity during concomitant use.[32122][56268][61900][67469]

Concomitant use of nonsteroidal antiinflammatory drugs (NSAIDs) with salicylates or other NSAIDs increases the risk of gastrointestinal toxicity, with little or no increase in efficacy; concomitant use is not recommended.[32122][56268]

Concomitant use of nonsteroidal antiinflammatory drugs (NSAIDs) and pemetrexed may increase the risk of pemetrexed-associated myelosuppression as well as gastrointestinal toxicity and nephrotoxicity. Avoid NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) for 2 days before and after administration of pemetrexed. In the absence of data regarding any potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), interrupt the dosing of these NSAIDs for at least 5 days before and 2 days after pemetrexed administration. Monitor for myelosuppression and gastrointestinal and renal toxicity during concomitant use in persons with a creatinine clearance (CrCl) of 45 to 79 mL/minute.[32122][56268]

Nonsteroidal antiinflammatory drugs (NSAIDs) are contraindicated in persons with known salicylate hypersensitivity or NSAID hypersensitivity and in persons with a history of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such persons. A subpopulation of persons with asthma may have aspirin-sensitive asthma, which may include chronic rhinosinusitis complicated by nasal polyps, severe and potentially fatal acute bronchospasm, and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has been reported, NSAIDs are contraindicated in persons with aspirin-sensitive asthma. When an NSAID is used in persons with preexisting asthma without known aspirin sensitivity, monitor for changes in the signs and symptoms of asthma.[32122][56268] Celecoxib is also contraindicated in persons who have demonstrated allergic-type reactions to sulfonamides.[56268] Celecoxib contains a sulfonamide side chain; however, celecoxib does not contain the aromatic amine or the N1-substituent that are present in sulfonamide antibiotics. These components of the chemical structures are thought to play essential roles in the pathogenesis of hypersensitivity reactions to sulfonamide antibiotics. Differences in chemical structure and subsequent metabolism provide rationale that the incidence of cross-sensitivity between celecoxib and sulfonamide antibiotics may be low.[26922]

Nonsteroidal antiinflammatory drugs (NSAIDs) are contraindicated in the setting of coronary artery bypass graft surgery (CABG). An increased incidence of myocardial infarction and stroke was found in clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10 to 14 days after CABG surgery. NSAIDs may cause an increased risk of serious cardiovascular thromboembolism, including myocardial infarction or stroke, which can be fatal. Some observational studies found that this increased risk of serious cardiovascular (CV) thrombotic events began as early as the first weeks of treatment; the increase in CV risk has been most consistently observed at higher doses. 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, persons with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Current evidence is insufficient to determine if the risk of an event is higher or lower for any particular NSAID compared to other NSAIDs. There is no consistent evidence that concomitant use of aspirin mitigates the increased risk for cardiovascular thrombotic events.[32122][56268][59937] Guidelines recommend against NSAID use in persons presenting with and hospitalized for ST-elevation myocardial infarction (STEMI) due to increased risk of mortality and CV complications associated with their use.[55688] Observational data from a national registry demonstrated that persons treated with NSAIDs in the post-MI period were at increased risk of reinfarction, cardiovascular-related death, and all-cause mortality beginning the first week of treatment. An increased relative risk of death in NSAID users continued during the follow-up period of 4 years. Data demonstrate that persons treated with NSAIDs were more likely to die in the first year after myocardial infarction compared to those not treated with NSAIDs.[44130] Avoid NSAID use in persons with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If an NSAID is used in persons with severe heart failure, monitor for signs of worsening heart failure. Blunting of the cardiovascular effects of several therapeutic agents used to treat fluid retention or edema has been observed with NSAID use. A meta-analysis of randomized, controlled trials demonstrated an approximately 2-fold increase in hospitalizations for heart failure among non-selective and COX-2 selective-treated subjects compared to placebo. Consider the sodium content of naproxen sodium in persons requiring severe sodium restriction. NSAIDs can lead to new onset of hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Persons taking NSAIDs may have impaired response to angiotensin-converting enzyme inhibitors, thiazide diuretics, or loop diuretics. Closely monitor blood pressure during NSAID receipt.[32122][56268] A meta-analysis demonstrated that the effect of NSAIDs on blood pressure is the greatest in hypertensive individuals receiving antihypertensive medication. Normotensive subjects receiving antihypertensive therapy had higher increases in blood pressure than subjects with uncontrolled hypertension or normotensive subjects receiving no hypertensive therapy.[27388] Caution is recommended when administering NSAIDs to persons with cardiac disease, cardiomyopathy, cardiac arrhythmias (e.g., tachycardia), significant coronary artery disease (including acute myocardial infarction, angina, or history of myocardial infarction), peripheral vascular disease, cerebrovascular disease (e.g., stroke, transient ischemic attack), hypertension, pre-existing kidney disease, or fluid retention. Use the lowest effective dose for the shortest duration possible to minimize the potential risk for an adverse cardiovascular event.[59937]

Nonsteroidal antiinflammatory drugs (NSAIDs) may increase the risk of bleeding events; coagulation disorders or concomitant use of warfarin, other anticoagulants, antiplatelet drugs, selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor for signs of bleeding, including gastrointestinal bleeding. NSAIDs cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and GI 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. Persons with a prior history of peptic ulcer disease and/or GI bleeding who use NSAIDs have a more than 10-fold increased risk for developing a GI bleed compared to persons without risk factors. Other factors that increase the risk of GI bleeding in persons treated with NSAIDs include longer duration of NSAID therapy, concomitant oral corticosteroids, anticoagulant therapy, aspirin, or SSRIs, tobacco smoking, ethanol ingestion, older age, and poor general health status. Most postmarketing reports of fatal GI events occurred in elderly or debilitated persons. Additionally, persons with advanced liver disease or coagulopathy are at increased risk for GI bleeding. To minimize GI risks in NSAID-treated persons, use the lowest effective dosage for the shortest possible duration, and avoid administration of more than 1 NSAID at a time. In the setting of concomitant low-dose aspirin use for cardiac prophylaxis, monitor more closely for evidence of GI bleeding. Avoid NSAID use in higher risk populations unless the benefits are expected to outweigh the risks of bleeding; consider alternate therapy in higher risk persons as well as those with active GI bleeding.[32122][56268]

Correct volume status in dehydrated or hypovolemic persons before starting nonsteroidal antiinflammatory drug (NSAID) therapy. Monitor renal function in persons with renal impairment, heart failure, dehydration, or hypovolemia during NSAID use. Avoid NSAID use in persons with advanced renal disease or renal failure unless the benefits are expected to outweigh the risk of worsening renal function. If use NSAIDs in persons with advanced renal disease, monitor for signs and symptoms of worsening renal function. Renal toxicity has been observed in persons in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these persons, NSAID use may cause a dose-dependent reduction in prostaglandin formation, and secondarily, renal blood flow, which may precipitate overt renal decompensation. Persons at greatest risk of this reaction are those with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics and angiotensin converting enzyme inhibitors or angiotensin receptor blockers, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.[32122][56268]

Use nonsteroidal antiinflammatory drugs (NSAIDs) with caution in persons with hepatic disease; avoidance, dosage reduction, or hepatic enzyme monitoring may be necessary. Persons with advanced hepatic disease are at increased risk for gastrointestinal bleeding. Elevated hepatic enzymes have been reported with NSAID use.[32122][56268]

The pharmacological activity of nonsteroidal antiinflammatory drugs (NSAIDs) in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting an infection.[32122][56268]

Nonsteroidal antiinflammatory drugs (NSAIDs) are contraindicated in persons with previous serious skin reactions due to NSAIDs. The use of NSAIDs may cause serious and potentially fatal skin reactions including Drug Reaction and Eosinophilia and Systemic Symptoms (DRESS), erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN). Discontinue NSAID use at the first appearance of skin rash or hypersensitivity.[32122][56268]

Avoid nonsteroidal antiinflammatory drug (NSAID) use during the third trimester of pregnancy (starting at 30 weeks of gestation) due to the risk of premature closure of the fetal ductus arteriosus and persistent pulmonary hypertension in the neonate. If NSAID treatment is deemed necessary between 20 to 30 weeks of pregnancy, limit use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if NSAID treatment extends beyond 48 hours. Discontinue the NSAID if oligohydramnios occurs and follow up according to clinical practice. Use of NSAIDs around 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment.[32122][56268][66040]

Nonsteroidal antiinflammatory drugs (NSAIDs) may pose a reproductive risk by delaying or preventing prostaglandin-mediated rupture of ovarian follicles, which has been associated with reversible infertility. Small studies of women treated with NSAIDs demonstrated a reversible delay in ovulation. Consider withdrawal of NSAIDs in women who have difficulties conceiving or who are undergoing infertility evaluation.[32122][56268]