ted to inhibition of renal prostaglandin synthesis. during concomitant therapy with nsaids, the patient should be observed closely for signs of renal failure (see warnings: 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. phenobarbital chronic administration of phenobarbital, a known enzyme inducer, may be associated with a decrease in the plasma half-life of fenoprofen. when phenobarbital is added to or withdrawn from treatment, dosage adjustment of nalfon tablets may be required.

ze the potential risk for an adverse cv event in nsaid-treated patients, use the lowest effective dose for the shortest duration possible. physicians and patients should remain alert for the development of such events, throughout the entire treatment course, 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, such as nalfon, increases the risk of serious gastrointestinal (gi) events (see gi warnings ). status post coronary artery bypass graft (cabg) surgery two large, controlled clinical trials of a cox-2 selective nsaid for the treatment of pain in the first 10 to 14 days following cabg surgery found an increased incidence of myocardial infarction and stroke. nsaids are contraindicated in the setting of cabg (see contraindications ). post-mi patients observational studies conducted in the danish national registry have demonstrated that patients treated with nsaids in the post-mi period were at increased risk of reinfarction, cv-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 patients compared to 12 per 100 person years in non-nsaid exposed patients. 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. avoid the use of nalfon tablets in patients with a recent mi unless the benefits are expected to outweigh the risk of recurrent cv thrombotic events. if nalfon tablets are used in patients with a recent mi, monitor patients for signs of cardiac ischemia. hypertension nsaids, including nalfon, 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 nalfon, 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. heart failure and edema 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 patients and nonselective nsaid-treated patients compared to placebo-treated patients. in a danish national registry study of patients 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 patients treated with nsaids. use of fenoprofen calcium may blunt the cv effects of several therapeutic agents used to treat these medical conditions [e.g., diuretics, ace inhibitors, or angiotensin receptor blockers (arbs)] (see drug interactions ). avoid the use of nalfon tablets in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. if nalfon tablets are used in patients with severe heart failure, monitor patients for signs of worsening heart failure. gastrointestinal effects risk of ulceration, bleeding and perforation nsaids, including nalfon tablets, 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 to 6 months, and in about 2% to 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 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 a 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 decomposition. 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 nalfon tablets in patients with advanced renal disease. therefore, treatment with nalfon tablets is not recommended in patients with advanced renal disease (see contraindications ). anaphylactoid reactions as with other nsaids, anaphylactoid reactions may occur in patients without known prior exposure to fenoprofen. nalfon tablets 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 ). emergency help should be sought in cases where an anaphylactoid reaction occurs. skin reactions nsaids, including nalfon tablets, 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. drug reaction with eosinophilia and systemic symptoms (dress) drug reaction with eosinophilia and systemic symptoms (dress) has been reported in patients taking nsaids such as nalfon tablets. 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. it is important to note that 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 nalfon tablets and evaluate the patient immediately. fetal toxicity premature closure of fetal ductus arteriosus avoid use of nsaids, including nalfon tablets, in pregnant women at about 30 weeks gestation and later. nsaids including nalfon tablets, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age. oligohydramnios/neonatal renal impairment use of nsaids, including nalfon tablets, 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 nalfon tablets use to the lowest effective dose and shortest duration possible. consider ultrasound monitoring of amniotic fluid if nalfon tablets treatment extends beyond 48 hours. discontinue fenoprofen calcium tablets if oligohydramnios occurs and follow up according to clinical practice (see precautions; pregnancy ). ocular studies to date have not shown changes in the eyes attributable to the administration of nalfon tablets. however, adverse ocular effects have been observed with other anti-inflammatory drugs. eye examinations, therefore, should be performed if visual disturbances occur in patients taking fenoprofen. central nervous system caution should be exercised by patients whose activities require alertness if they experience cns side effects while taking nalfon tablets. hearing since the safety of nalfon tablets has not been established in patients with impaired hearing, these patients should have periodic tests of auditory function during prolonged therapy with fenoprofen.

otal daily dosage should not exceed 3200 mg. nalfon tablets may be administered with meals or with milk. although the total amount absorbed is not affected, peak blood levels are delayed and diminished. patients with rheumatoid arthritis generally seem to require larger doses of nalfon tablets than do those with osteoarthritis. the smallest dose that yields acceptable control should be employed. although improvement may be seen in a few days in many patients, an additional 2 to 3 weeks may be required to gauge the full benefits of therapy.

fenoprofen vs. 2.3% placebo), nausea (7.7% vs. 7.1%), constipation (7% vs. 1.5%), vomiting (2.6% vs. 1.9%), abdominal pain (2% vs. 1.1%) and diarrhea (1.8% vs. 4.1%). the drug was discontinued because of adverse gastrointestinal reactions in less than 2% of patients during premarketing studies. nervous system: the most frequent adverse neurologic reactions were headache (8.7% vs. 7.5%) and somnolence (8.5% vs. 6.4%). dizziness (6.5% vs. 5.6%), tremor (2.2% vs. 0.4%) and confusion (1.4% vs. none) were noted less frequently. fenoprofen was discontinued in less than 0.5% of patients because of these side effects during premarketing studies. skin and appendages: increased sweating (4.6% vs. 0.4%), pruritus (4.2% vs. 0.8%) and rash (3.7% vs. 0.4%) were reported. fenoprofen was discontinued in about 1% of patients because of an adverse effect related to the skin during premarketing studies. special senses: tinnitus (4.5% vs. 0.4%), blurred vision (2.2% vs. none) and decreased hearing (1.6% vs. none) were reported. fenoprofen was discontinued in less than 0.5% of patients because of adverse effects related to the special senses during premarketing studies. cardiovascular: palpitations (2.5% vs. 0.4%). fenoprofen was discontinued in about 0.5% of patients because of adverse cardiovascular reactions during premarketing studies. miscellaneous: nervousness (5.7% vs. 1.5%), asthenia (5.4% vs. 0.4%), peripheral edema (5% vs. 0.4%), dyspnea (2.8% vs. none), fatigue (1.7% vs. 1.5%), upper respiratory infection (1.5% vs. 5.6%) and nasopharyngitis (1.2% vs. none). adverse drug reactions reported in < 1% of patients during clinical trials digestive system: gastritis, peptic ulcer with/without perforation, gastrointestinal hemorrhage, anorexia, flatulence, dry mouth and blood in the stool. increases in alkaline phosphatase, ldh, sgot, jaundice and cholestatic hepatitis, aphthous ulcerations of the buccal mucosa, metallic taste and pancreatitis (see precautions ). cardiovascular: atrial fibrillation, pulmonary edema, electrocardiographic changes and supraventricular tachycardia. genitourinary tract: renal failure, dysuria, cystitis, hematuria, oliguria, azotemia, anuria, interstitial nephritis, nephrosis and papillary necrosis (see warnings ). hyper sensitivity: angioedema (angioneurotic edema). hematologic: purpura, bruising, hemorrhage, thrombocytopenia, hemolytic anemia, aplastic anemia, agranulocytosis and pancytopenia. nervous system: depression, disorientation, seizures and trigeminal neuralgia. special senses: burning tongue, diplopia and optic neuritis. skin and appendages: exfoliative dermatitis, toxic epidermal necrolysis, stevens-johnson syndrome and alopecia. miscellaneous: anaphylaxis, urticaria, malaise, insomnia, tachycardia, personality change, lymphadenopathy, mastodynia and fever.

ted to inhibition of renal prostaglandin synthesis. during concomitant therapy with nsaids, the patient should be observed closely for signs of renal failure (see warnings: 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. phenobarbital chronic administration of phenobarbital, a known enzyme inducer, may be associated with a decrease in the plasma half-life of fenoprofen. when phenobarbital is added to or withdrawn from treatment, dosage adjustment of nalfon tablets may be required.

n the first or second trimesters of pregnancy are inconclusive. reproductive studies conducted in rats and rabbits have not demonstrated evidence of developmental abnormalities when given daily oral doses of 50 or 100 mg/kg fenoprofen calcium, respectively (0.15 and 0.6 times the maximum human daily dose of 3200 mg based on body surface area comparisons). however, animal reproduction studies are not always predictive of human response. because of the known effects of nonsteroidal anti-inflammatory drugs on the fetal cardiovascular system (closure of ductus arteriosus), use during pregnancy (particularly late pregnancy) should be avoided. 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 fenoprofen, 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. the estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. all pregnancies have a background risk of birth defect, loss, or other adverse outcomes. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. 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 nalfon tablets, can cause premature closure of the fetal ductus arteriosus (see warnings; fetal toxicity). 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 nalfon tablets treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. if oligohydramnios occurs, discontinue nalfon tablets and follow up according to clinical practice (see warnings; fetal toxicit y). data human data there are no adequate and well-controlled studies of in pregnant women. 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.

lity (i.e., a decrease in the number of joints having limited motion). the use of nalfon in combination with gold salts or corticosteroids has been studied in patients with rheumatoid arthritis. the studies, however, were inadequate in demonstrating whether further improvement is obtained by adding nalfon to maintenance therapy with gold salts or steroids. whether or not nalfon used in conjunction with partially effective doses of a corticosteroid has a “steroid-sparing” effect is unknown. in patients with osteoarthritis, the anti-inflammatory and analgesic effects of nalfon have been demonstrated by reduction in tenderness as a response to pressure and reductions in night pain, stiffness, swelling and overall disease activity (as assessed by both the patient and the investigator). these effects have also been demonstrated by relief of pain with motion and at rest and increased range of motion in involved joints. in patients with rheumatoid arthritis and osteoarthritis, clinical studies have shown fenoprofen to be comparable to aspirin in controlling the aforementioned measures of disease activity, but mild gastrointestinal reactions (nausea, dyspepsia) and tinnitus occurred less frequently in patients treated with fenoprofen than in aspirin-treated patients. it is not known whether fenoprofen calcium causes less peptic ulceration than does aspirin. in patients with pain, the analgesic action of nalfon has produced a reduction in pain intensity, an increase in pain relief, improvement in total analgesia scores and a sustained analgesic effect. under fasting conditions, fenoprofen is rapidly absorbed and peak plasma levels of 50 mcg/ml are achieved within 2 hours after oral administration of 600 mg doses. good dose proportionality was observed between 200 mg and 600 mg doses in fasting male volunteers. the plasma half-life is approximately 3 hours. about 90% of a single oral dose is eliminated within 24 hours as fenoprofen glucuronide and 4’ hydroxy-fenoprofen glucuronide, the major urinary metabolites of fenoprofen. fenoprofen is highly bound (99%) to albumin. the concomitant administration of antacid (containing both aluminum and magnesium hydroxide) does not interfere with absorption of nalfon. there is less suppression of collagen-induced platelet aggregation with single doses of fenoprofen calcium than there is with aspirin.

mptoms 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 ). serious skin reactions, including dress advise patients to stop taking nalfon tablets immediately if they develop any type of rash or fever and to contact their healthcare provider as soon as possible (see warnings ). heart failure and edema : advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur (see warnings ). patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness and "flu- like" 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 ). fetal toxicity inform pregnant women to avoid use of nalfon tablets and other nsaids starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus. if treatment with nalfon tablets is needed for a pregnant woman between about 20 to 30 weeks gestation, advise her that she may need to be monitored for oligohydramnios, if treatment continues for longer than 48 hours (see warnings; fetal toxicity , precautions; pregnancy ).