Feldene Flash

Piroxicam.

Each flash tab also contains the following excipients: Aspartame, citric acid, gelatin and mannitol.
Piroxicam, a member of the chemical class of nonsteroidal anti-inflammatory agents, is N-heterocyclic carboxamides of 1,2-benzothiazine-1,1-dioxide. It is an amphoteric compound. It exhibits a weakly acidic 4-hydroxy proton (pKa 5.1) and a weakly basic pyridinyl nitrogen (pKa 1.8) as determined by ultraviolet absorption spectrophotometry in methanol-water (2.5/97.5, v/v) solvent medium.
Piroxicam occurs as a white to off-white crystalline solid, poorly soluble in water, dilute acid and most organic solvents. It is slightly soluble in alcohols and in aqueous alkaline solution.

Pharmacology: Pharmacodynamics: Feldene is a nonsteroidal anti-inflammatory agent which also possesses analgesic and antipyretic properties. Edema, erythema, tissue proliferation, fever and pain can all be inhibited in laboratory animals by the administration of Feldene Flash. It is effective regardless of the etiology of the inflammation. While its mode of action is not fully understood, independent studies in vitro as well as in vivo have shown that piroxicam interacts at several steps in the immune and inflammation responses through: Inhibition of prostanoid synthesis, including prostaglandins, through a reversible inhibition of the cyclooxygenase enzyme; inhibition of neutrophil aggregation; inhibition of polymorphonuclear cell and monocyte migration to the area of inflammation; inhibition of lysosomal enzyme release from stimulated leucocytes; inhibition of superoxide anion generation by the neutrophil; and reduction of both systemic and synovial fluid rheumatoid factor production in patients with seropositive rheumatoid arthritis.
It is established that piroxicam does not act by pituitary-adrenal axis stimulation. In vitro studies have not revealed any negative effects on cartilage metabolism.
Pharmacokinetics: Absorption: Feldene Flash is well absorbed following oral administration. With food, there is a slight delay in the rate but not the extent of absorption following oral administration. Stable plasma concentrations are maintained throughout the day on a once-daily dosage. Continuous treatment with 20 mg daily for periods of 1 year produces similar blood levels to those seen once a steady state is first achieved.
Drug plasma concentrations are proportional for 20-mg doses and generally peak within 3-5 hrs after medication. A single 20-mg dose generally produces peak piroxicam plasma levels of 1.5-2 mcg/mL while maximum drug plasma concentrations, after repeated daily ingestion of piroxicam 20 mg, usually stabilize at 3-8 mcg/mL. Most patients have approximate steady-state plasma levels within 7-12 days.
Treatment with a loading dose regimen of 40 mg daily for the first 2 days followed by 20 mg daily thereafter allows a high percentage (approximately 76%) of steady-state levels to be achieved immediately following the 2nd dose. Steady-state levels, area under the curves and elimination half-life are similar to that following a 20 mg daily dose regimen.
Elimination/Biotransformation: Feldene Flash is extensively metabolized and <5% of the daily dose is excreted unchanged in urine and feces. One important metabolic pathway is hydroxylation of the pyridyl ring of the Feldene Flash side chain, followed by conjugation with glucuronic acid and urinary elimination. The plasma half-life is approximately 50 hrs in man.
Toxicology: Preclinical Safety Data: Subacute and chronic toxicity studies have been carried out in rats, mice, dogs and monkeys, using doses which ranged from 0.3-25 mg/kg daily. The latter dose is approximately 90 times the recommended human dose level. The only pathology seen was that characteristically associated with the animal toxicology of nonsteroidal anti-inflammatory agents eg, renal papillary necrosis and gastrointestinal lesions. With regards to the latter, the monkey proved to be quite resistant to this effect and the dog unusually sensitive.

Variety of conditions requiring anti-inflammatory activity eg, rheumatoid arthritis, osteoarthritis (arthrosis, degenerative joint disease), ankylosing spondylitis, acute musculoskeletal disorders and acute gout.

Rheumatoid Arthritis, Osteoarthritis (Arthrosis, Degenerative Joint Disease), Ankylosing Spondylitis: Recommended Starting Dose: 20 mg given as a single daily dose. The majority of patients will be maintained on 20 mg daily. A relatively small group of patients may be maintained on 10 mg daily. Some patients may require up to 30 mg daily given in single or divided doses. Long-term administration of doses ≥30 mg carries an increased risk of gastrointestinal side effects.
Acute Gout: Therapy should be initiated by a single dose of 40 mg followed on the next 4-6 days with 40 mg daily, given in single or divided doses. Feldene Flash is not indicated for long-term management of gout.
Acute Musculoskeletal Disorders: Therapy should be initiated with 40 mg daily for the first 2 days given in single or divided doses. For the remainder of the 7-14 day treatment period, the dose should be reduced to 20 mg daily.
Children: Dosage recommendations have not been established.
Administration: Feldene Flash should be placed on the tongue to disperse and then swallowed with the saliva. It dissolves almost instantly in the mouth in the presence of saliva.

In the event of overdosage with Feldene Flash, supportive and symptomatic therapy is indicated. Studies indicate that administration of activated charcoal may result in reduced absorption and reabsorption of piroxicam, thus reducing the total amount of active drug available.

Known hypersensitivity to piroxicam or to any of the excipients of Feldene Flash. Active peptic ulcerations or history of recurrent ulceration. The potential exists for cross-sensitivity to acetylsalicylic acid and other nonsteroidal anti-inflammatory drugs (NSAIDs). Feldene Flash should not be given to patients in whom acetylsalicylic acid and other NSAIDs induce the symptoms of asthma, nasal polyps, angioedema or urticaria. Patients with severe renal, hepatic and heart failure.

Cardiovascular Risk: NSAIDs may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction and stroke, which can be fatal. This risk may increase with duration use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk (see Precautions for further information).
Feldene Flash is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery (see Precautions for further information).
Gastrointestinal Risk: NSAIDs cause an increased risk of serious gastrointestinal adverse events including inflammation, ulceration and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk for serious gastrointestinal events (see Precautions for further informations).

The use of piroxicam with concomitant NSAIDs including COX-2 inhibitors should be avoided.
Cardiovascular Effects: NSAIDs may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction and stroke, which can be fatal. All NSAIDs, both COX-2 selective and nonselective, may have a similar risk. This risk may increase with duration of use. Patients with known cardiovascular disease or risk factors for cardiovascular disease may be at greater risk. To minimize the potential risk for an adverse cardiovascular event in patients treated with piroxicam, the lowest effective dose should be used for the shortest duration possible. Physicians and patients should remain alert for the development of such events, even in the absence of previous cardiovascular symptoms. Patients should be informed about the signs and/or symptoms of serious cardiovascular toxicity, and the steps to take if they occur (see Warnings).
There is no consistent evidence that concurrent use of acetylsalicylic acid mitigates the increased risk of serious cardiovascular thrombotic events associated with NSAID use. The concurrent use of acetylsalicylic acid and an NSAID does increase the risk of serious gastrointestinal events (see following texts on Gastrointestinal Effects under Precautions).
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 Warnings).
Fluid Retention and Edema: As with other drugs known to inhibit prostaglandin synthesis, fluid retention and edema have been observed in some patients taking NSAIDs, including piroxicam. Therefore, piroxicam should be used with caution in patients with compromised cardiac function and other conditions predisposing to or worsened by, fluid retention. Patients with preexisting congestive heart failure or hypertension should be closely monitored.
Hypertension: NSAIDS, including piroxicam can lead to onset of new hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of cardiovascular events. Patients taking thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs. NSAIDs, including piroxicam, should be used with caution in patients with hypertension. Blood pressure should be monitored closely during the initiation of NSAID treatment with Feldene Flash and throughout the course of therapy.
Gastrointestinal (GI) Effects: Risk of GI Ulceration, Bleeding, and Perforation: NSAIDs, including piroxicam, can cause serious 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 1 in 5 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 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.
Nonsteroidal anti-inflammatory drugs should be prescribed with extreme caution in patients with a prior history of ulcer disease or GI bleeding. Patients with a prior history of ulcer disease and/or GI bleeding, and who use NSAIDs, have a greater than 10-fold higher 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 the 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 NSAIDs, 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.
Feldene Flash should be withdrawn if peptic ulceration or GI bleeding occur.
Renal Effects: In rare cases, NSAIDS may cause interstitial nephritis, glomerulitis, papillary necrosis and nephrotic syndrome. NSAIDS inhibit the synthesis of renal prostaglandin which plays a supportive role in the maintenance of renal perfusion in patients whose renal blood flow and blood volume are decreased. In these patients, administration of an NSAID may precipitate overt renal decompensation which is typically followed by recovery to pretreatment state upon discontinuation of NSAID therapy. Patients at greatest risk of such a reaction are those with congestive heart failure, liver cirrhosis, nephrotic syndrome and overt renal disease. Such patients should be carefully monitored while receiving NSAID therapy.
Caution should be used when initiating treatment with piroxicam in patients with severe dehydration. Caution is also recommended in patients with kidney disease (see Contraindications).
Because of extensive renal excretion of piroxicam and its biotransformation products lower doses of piroxicam should be considered in patients with impaired renal function, and they should be carefully monitored (see Pharmacokinetics under Actions and Contraindications).
Skin Reactions: Serious skin reactions, some of them fatal, including exfoliative dermatitis, Steven-Johnsons syndrome and toxic epidermal necrolysis, have been reported very rarely in association with the use of NSAIDs, including piroxicam. Patients appear to be at highest risk for these events early in the course of therapy, the onset of the event occurring in the majority of cases within the 1st month of treatment. Piroxicam should be discontinued at the 1st appearance of skin rash, mucosal lesions or any other sign of hypersensitivity.
Ophthalmologic Effects: Because of reports of adverse eye findings with NSAIDs, it is recommended that patients who develop visual complaints during treatment with Feldene Flash have an ophthalmic evaluation.
General: For patients with phenylketonuria, because of its aspartame content, Feldene Flash contains phenylalanine 0.07 mg and 0.14 mg per 10-mg dose and 20-mg dose, respectively.
Effects on the Ability to Drive or Operate Machinery: Not applicable.
Use in pregnancy & lactation: Although no teratogenic effects were seen in animal testing, the use of Feldene Flash during pregnancy is not recommended. Feldene Flash inhibits prostaglandin synthesis and release through a reversible inhibition of the cyclooxygenase enzyme. This effect, as with other nonsteroidal anti-inflammatory agents has been associated with an increased incidence of dystocia and delayed parturition in pregnant animals when drug administration was continued into late pregnancy. NSAIDs are also known to induce premature closure of the ductus arteriosus in infants.
The presence of piroxicam in breast milk has been determined during initial and long-term dosing conditions (52 days). Piroxicam appeared in breast milk at about 1-3% of the maternal plasma concentration. No accumulation of piroxicam occurred in milk relative to that in plasma during treatment. Feldene Flash is not recommended for use in nursing mothers as the clinical safety has not been established.

Although no teratogenic effects were seen in animal testing, the use of Feldene Flash during pregnancy is not recommended. Feldene Flash inhibits prostaglandin synthesis and release through a reversible inhibition of the cyclooxygenase enzyme. This effect, as with other nonsteroidal anti-inflammatory agents has been associated with an increased incidence of dystocia and delayed parturition in pregnant animals when drug administration was continued into late pregnancy. NSAIDs are also known to induce premature closure of the ductus arteriosus in infants.
The presence of piroxicam in breast milk has been determined during initial and long-term dosing conditions (52 days). Piroxicam appeared in breast milk at about 1-3% of the maternal plasma concentration. No accumulation of piroxicam occurred in milk relative to that in plasma during treatment. Feldene Flash is not recommended for use in nursing mothers as the clinical safety has not been established.

Feldene Flash is generally well tolerated. Gastrointestinal symptoms are the most commonly encountered adverse effects but in most instances do not interfere with the course of therapy. These adverse reactions include stomatitis, anorexia, epigastric distress, nausea, constipation, abdominal discomfort, flatulence, diarrhea, abdominal pain and indigestion. Gastrointestinal bleeding, perforation and ulceration (see Precautions) have been reported with Feldene Flash. Objective evaluations of gastric mucosal appearances and intestinal blood loss show that Feldene Flash 20 mg daily administered either in single or divided daily doses is significantly less irritating to the gastrointestinal tract than acetylsalicylic acid.
Long-term administration of 30-mg doses or higher carries an increased risk of gastrointestinal adverse effects.
Other than the gastrointestinal symptoms, edema, mainly of the ankle, has been reported in a small percentage of patients and the possibility of precipitating congestive cardiac failure in elderly patients or those with compromised cardiac function should therefore be borne in mind.
Central nervous system effects eg, dizziness, headache, somnolence, insomnia, depression, nervousness, hallucinations, mood alterations, dream abnormalities, mental confusion, paresthesias and vertigo have been reported rarely.
Nervous System Disorders: Aseptic meningitis, dizziness, headache, somnolence, paresthesia, vertigo, aseptic meningitis.
Swollen eyes, blurred vision and eye irritations have been reported. Routine ophthalmoscopy and slit-lamp examination have revealed no evidence of ocular changes. Malaise and tinnitus may occur.
Skin and Subcutaneous Tissue Disorders: Exfoliative dermatitis, erythema multiforme (see Precautions). Dermal hypersensitivity reactions, usually in the form of skin rash and pruritus have been reported. Onycholysis and alopecia have rarely been reported. Photoallergic reactions have infrequently been associated with therapy. As with other NSAIDs, toxic epidermal necrolysis (Lyell's disease) and Stevens-Johnson syndrome may develop in rare cases. Vesiculo bullous reactions have been reported rarely.
Hypersensitivity reactions eg, anaphylaxis, bronchospasm, urticaria/angioedema, vasculitis and "serum sickness" have been reported rarely.
Anorectal reactions to suppositories have presented as local pain, burning, pruritus and tenesmus. Rare instances of rectal bleeding have occurred.
Reversible elevations of BUN and creatinine have been reported.
Decreases in hemoglobin and hematocrit, unassociated with obvious GI bleeding, have occurred. Anemia has been reported. Thrombocytopenia and nonthrombocytopenic purpura (Henoch-Schoenlein), leucopenia and eosinophilia have been reported. Rare cases of aplastic and hemolytic anemia. Epistaxis has rarely been reported.
Changes in different liver function parameters have been observed. As with most other NSAIDs, some patients may develop increased serum transaminase levels during treatment with Feldene Flash. Severe hepatic reactions, including jaundice and cases of fatal hepatitis have been reported. Although such reactions are rare, if abnormal liver function tests persist or worsen, if clinical signs and symptoms consistent with liver disease develop or if systemic manifestations occur (eg, eosinophilia, rash, etc), Feldene Flash should be discontinued.
Rare cases of pancreatitis have been reported.
Palpitations and dyspnea have been reported rarely.
Anecdotal cases of positive ANA and of hearing impairment have been reported rarely in patients receiving Feldene Flash.
Metabolic abnormalities eg, hypoglycemia, hyperglycemia, increased or decreased weight have been reported rarely.

Nonsteroidal anti-inflammatory drugs may cause sodium, potassium and fluid retention, and may interfere with the natriuretic action of diuretic agents. These properties should be kept in mind when treating patients with compromised cardiac function or hypertension since they may be responsible for a worsening of those conditions.
Cardiac Glycosides (Digoxin and Digitoxin): NSAIDs may exacerbate cardiac failure, reduce glomerular filtration rate (GFR) and increase plasma glycoside levels. Concomitant administration of digoxin or digitoxin had no effect on the plasma levels of piroxicam of either drug.
Bleeding has been reported rarely when Feldene Flash has been administered to patients on coumarin-type anticoagulants. Patients should be monitored closely if Feldene Flash and oral anticoagulants are administered together.
Feldene Flash, like other NSAIDs, decreases platelet aggregation and prolongs bleeding time. This effect should be kept in mind when bleeding times are determined.
As with other NSAIDs, the use of Feldene Flash in conjunction with acetylsalicylic acid or the concomitant use of 2 NSAIDs is not recommended because data are inadequate to demonstrate that these combination produces greater improvement than that achieved with the drug alone and the potential for adverse reactions is increased.
Studies in man have shown that the concomitant administration of Feldene Flash and acetylsalicylic acid resulted in a reduction of plasma levels of piroxicam to about 80% of the normal values. Concomitant administration of antacids had no effect on piroxicam plasma levels. Neither did concurrent therapy with Feldene Flash and digoxin, or Feldene Flash and digitoxin affect the plasma levels of either drug.
Antihypertensives including Diuretics, Angiotensin-Converting Enzyme (ACE) Inhibitors and Angiotensin II/Antagonists (AIIA): NSAIDs can reduce the efficacy of diuretics and other anti-hypertensive drugs.
In patients with impaired renal function (eg, dehydrated patients or elderiy patients with the renal function compromised), the co-administration of an ACE inhibitor or an AIIA with a cyclooxygenase inhibitor can increase the deterioration of the renal function, including the possibility of acute renal failure, which is usually reversible. The occurrence of these interactions should be considered in patients taking piroxicam with a diuretic, an ACE inhibitor or an AIIA.
Therefore, the concomitant administration of these drugs should be done with caution, especially in elderly patients. Patients should be adequately hydrated and the need to monitor the renal function should be assessed in the beginning of the concomitant treatment and periodically thereafter.
Cholestyramine: Cholestyramine has been shown to enhance the oral clearance and decrease the half-life of piroxicam. To minimize this interaction, it is prudent to administer piroxicam at least 2 hrs before or 6 hrs after cholestyramine.
Corticosteroids: Increased risk of gastrointestinal ulceration or bleeding.
Cyclosporine: Increased risk of nephrotoxicity.
Methotrexate: Decreased elimination of methotrexate.
Tacrolimus: Possible increased risk of nephrotoxicity when NSAIDs are given with tacrolimus.
Feldene Flash is highly protein bound and therefore might be expected to displace other protein bound drugs. The physician should closely monitor patients for change in dosage requirements when administering Feldene Flash to patients on highly protein bound drugs. NSAIDs, including Feldene Flash, have been reported to increase steady-state plasma lithium levels. It is recommended that these levels be monitored when initiating, adjusting and discontinuing Feldene Flash.
Results of 2 separate studies indicate a slight increase in absorption of piroxicam following cimetidine administration but no significant changes in elimination parameters occur. Cimetidine increases the area under the curve (AUC_{0-120 hrs}) and C_max of piroxicam by approximately 13-15%. Elimination rate constants and half-life show no significant differences. The small but significant increase in absorption is unlikely to be clinically significant.

Store in a dry place below 30°C.

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

M01AC01 - piroxicam ; Belongs to the class of non-steroidal antiinflammatory and antirheumatic products, oxicams.

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