nytoin, sulfinpyrazone, naproxen, warfarin, methotrexate, and possibly corticosteroids. [when salsalate tablets, usp is administered with aspirin, its protein binding is reduced, although the clearance of free salsalate tablets, usp is not altered. the clinical significance of this interaction is not known; however,] as with other nsaids, concomitant administration of salsalate and aspirin is not generally recommended because of the potential of increased adverse effects. furosemide clinical studies, as well as post marketing observations, have shown that salsalate tablets, usp can reduce the natriuretic effect-of furosemide and thiazides in some patients. this response has been attributed to inhibition of renal prostaglandin synthesis. during concomitant therapy with nsaids, the patient should be observed closely for signs of renal failure (see precautions, renal effects ), as well as to assure diuretic efficacy. lithium nsaids have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. the mean minimum lithium concentration increased 15% and the renal clearance was decreased by approximately 20%. these effects have been attributed to inhibition of renal prostaglandin synthesis by the nsaid. thus, when nsaids and lithium are administered concurrently, subjects should be observed carefully for signs of lithium toxicity. methotrexate nsaids have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. this may indicate that they could enhance the toxicity of methotrexate. caution should be used when nsaids are administered concomitantly with methotrexate. warfarin the effects of warfarin and nsaids on gi bleeding are synergistic, such that users of both drugs together have a risk of serious gi bleeding higher than users of either drug alone.

cians 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 nsaid does increase the risk of serious gi events (see gi warnings ). 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 salsalate tablets, usp, can lead to onset of new hypertension or worsening of pre-existing 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 salsalate tablets, usp, 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. salsalate tablets, usp should be used with caution in patients with fluid retention or heart failure. gastrointestinal effects risk of ulceration, bleeding, and perforation nsaids, including salsalate tablets, usp, 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 1 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 with neither of these risk factors. other factors that increase the risk for 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 ulceration and bleeding during nsaid therapy and promptly initiate additional evaluation and treatment if a serious gi adverse 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 no information is available from controlled clinical studies regarding the use of salsalate tablets, usp in patients with advanced renal disease. therefore, treatment with salsalate tablets, usp is not recommended in these patients with advanced renal disease. if salsalate tablets, usp therapy must be initiated, close monitoring of the patient's renal function is advisable. anaphylactoid reactions as with other nsaids, anaphylactoid reactions may occur in patients without known prior exposure to salsalate tablets, usp. salsalate tablets, usp should not be given to patients with the aspirin trial. 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 ). emergency help should be sought in cases where an anaphylactoid reaction occurs. skin reactions nsaids, including salsalate tablets, usp, 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 the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity. fetal toxicity premature closure of fetal ductus arteriosus avoid use of nsaids, including salsalate tablets, usp, in pregnant women at about 30 weeks gestation and later. nsaids, including salsalate tablets, usp, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age. oligohydramnios/neonatal renal impairment use of nsaids, including salsalate tablets, usp, 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 salsalate tablets, usp use to the lowest effective dose and shortest duration possible. consider ultrasound monitoring of amniotic fluid if salsalate tablets, usp treatment extends beyond 48 hours. discontinue salsalate tablets, usp if oligohydramnios occurs and follow up according to clinical practice (see use in specific populations ).

decision is made to discontinue corticosteroids. the pharmacological activity of salsalate tablets, usp in reducing [fever and] inflammation may diminish the utility of these diagnosis signs in detecting complications of presumed noninfectious, painful conditions.

it may not be evident for 3 to 4 days, when plasma salicylate levels have achieved steady state. there is no evidence for development of tissue tolerance (tachyphylaxis), but salicylate therapy may induce increased activity of metabolizing liver enzymes, causing a greater rate of salicyluric acid production and excretion, with a resultant increase in dosage requirement for maintenance of therapeutic serum salicylate levels. children dosage recommendations and indications for salsalate use in children have not been established.

nytoin, sulfinpyrazone, naproxen, warfarin, methotrexate, and possibly corticosteroids. [when salsalate tablets, usp is administered with aspirin, its protein binding is reduced, although the clearance of free salsalate tablets, usp is not altered. the clinical significance of this interaction is not known; however,] as with other nsaids, concomitant administration of salsalate and aspirin is not generally recommended because of the potential of increased adverse effects. furosemide clinical studies, as well as post marketing observations, have shown that salsalate tablets, usp can reduce the natriuretic effect-of furosemide and thiazides in some patients. this response has been attributed to inhibition of renal prostaglandin synthesis. during concomitant therapy with nsaids, the patient should be observed closely for signs of renal failure (see precautions, renal effects ), as well as to assure diuretic efficacy. lithium nsaids have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. the mean minimum lithium concentration increased 15% and the renal clearance was decreased by approximately 20%. these effects have been attributed to inhibition of renal prostaglandin synthesis by the nsaid. thus, when nsaids and lithium are administered concurrently, subjects should be observed carefully for signs of lithium toxicity. methotrexate nsaids have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. this may indicate that they could enhance the toxicity of methotrexate. caution should be used when nsaids are administered concomitantly with methotrexate. warfarin the effects of warfarin and nsaids on gi bleeding are synergistic, such that users of both drugs together have a risk of serious gi bleeding higher than users of either drug alone.

bryofetal risks of nsaid use in women in the first or second trimesters of pregnancy are inconclusive. in general u.s. population, all clinically recognized pregnancies, regardless of drug exposure, have a background rate of 2-4% for major malformations, and 15-20% for pregnancy loss. reproductive studies conducted in rats and rabbits have not demonstrated evidence of developmental abnormalities. however, animal reproduction studies are not always predictive of human response. based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. in animal studies, administration of prostaglandin synthesis inhibitors such as salsalate, resulted in increased pre- and post-implantation loss. prostaglandins also have been shown to have an important role in fetal kidney development. in published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses. clinical considerations fetal/neonatal adverse reactions premature closure of fetal ductus arteriosus avoid use of nsaids in women at about 30 weeks gestation and later in pregnancy, because nsaids, including salsalate tablets, usp, can cause premature closure of the fetal ductus arteriosus (see data ). oligohydramnios/neonatal renal impairment if an nsaid is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. if salsalate tablets, usp treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. if oligohydramnios occurs, discontinue salsalate tablets, usp and follow up according to clinical practice (see data ). data human data because of the known effects of nonsteroidal anti-inflammatory drugs on fetal cardiovascular system (closure of ductus arteriosus), use during pregnancy (particularly starting at 30 weeks of gestation, or third trimester) should be avoided. premature closure of fetal ductus arteriosus published literature reports that the use of nsaids at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus. oligohydramnios/neonatal renal impairment published studies and postmarketing reports describe maternal nsaid use at about 20 weeks gestation or later in pregnancy associated with 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. in many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. there have been a limited number of case reports of maternal nsaid use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis. methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. these limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal nsaid use. because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant exposed to nsaids through maternal use is uncertain. animal data reproductive studies conducted in rats and rabbits have not demonstrated evidence of developmental abnormalities. however, animal reproduction studies are not always predictive of human response. there are no adequate and well-controlled studies in pregnant women.

levels within the desired therapeutic range (10 to 30 mg/100 ml) throughout the 12-hour intervals. therapeutic blood levels continue for up to 16 hours after the last dose. the parent compound does not show capacity-limited biotransformation, nor does it accumulate in the plasma on multiple dosing. food slows the absorption of all salicylates including salsalate. the mode of anti-inflammatory action of salsalate and other nonsteroidal anti-inflammatory drugs is not fully defined. although salicylic acid (the primary metabolite of salsalate) is a weak inhibitor of prostaglandin synthesis in vitro , salsalate appears to selectively inhibit prostaglandin synthesis in vivo 1 , providing anti-inflammatory activity equivalent to aspirin 2 and indomethacin 3 . unlike aspirin, salsalate does not inhibit platelet aggregation 4 . the usefulness of salicylic acid, the active in vivo product of salsalate, in the treatment of arthritic disorders has been established 5,6 . in contrast to aspirin, salsalate causes no greater fecal gastrointestinal blood loss than placebo 7 .

lthough serious gi tract ulcerations and bleeding can occur without warning symptoms, patients should be alert for the signs and symptoms of ulcerations and bleeding, and should ask for medical advice when observing any indicative sign or symptoms including epigastric pain, dyspepsia, melena, and hematemesis. patients should be apprised of the importance of this follow-up (see warnings, gastrointestinal effects : risk of ulceration, bleeding, and perforation ). salsalate tablets, usp like other nsaids can cause serious skin side effects such as exfoliative dermatitis, sjs, and ten, which may result in hospitalizations and even death. although serious skin reactions may occur without warning, patients should be alert for the signs and symptoms of skin rash and blisters, fever, or other signs of hypersensitivity such as itching, and should ask for medical advice when observing any indicative signs or symptoms. patients should be advised to stop the drug immediately if they develop any type of rash and contact their physicians as soon as possible. patients should promptly report signs or symptoms of unexplained weight gain or edema to their physicians. patients should be informed of the warning signs and symptoms hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and "flulike" symptoms). if these occur, patients should be instructed to stop therapy and seek immediate medical therapy. patients should be informed of the signs of an anaphylactoid reaction (e.g. difficulty breathing, swelling of the face or throat). if these occur, patients should be instructed to seek immediate emergency help (see warnings ). limit use of nsaids, including salsalate tablets, usp, between about 20 to 30 weeks in pregnancy due to the risk of oligohydramnios/fetal renal dysfunction. avoid use of nsaids in women at about 30 weeks gestation and later in pregnancy due to the risks of oligohydramnios/fetal renal dysfunction and premature closure of the fetal ductus arteriosus (see warnings , use in specific populations ).