Tolfenamic Acid
Adverse Effects and Precautions As for NSAIDs in general, like mefenamic acid whose record follows as below:
WARNINGS
Gastrointestinal (GI) Effects--Risk of GI Ulceration, Bleeding, and Perforation
Serious gastrointestinal toxicity, such as inflammation, bleeding, ulceration, and perforation of the stomach, small intestine or large intestine, can occur at any time, with or without warning symptoms, in patients treated with non-steroidal anti-inflammatory drugs (NSAIDs). Minor upper gastrointestinal problems, such as dyspepsia, are common and may also occur at any time during NSAID therapy. Therefore, physicians and patients should remain alert for ulceration and bleeding, even in the absence of previous GI tract symptoms. Patients should be informed about the signs and/or symptoms of serious GI toxicity and the steps to take if they occur. The utility of periodic laboratory monitoring has not been demonstrated, nor has it been adequately assessed. Only one in five patients, who develop a serious upper GI adverse event on NSAID therapy, is symptomatic. It has been demonstrated that upper GI ulcers, gross bleeding or perforation, caused by NSAIDs, appear to occur in approximately 1% of patients treated for 3-6 months, and in about 2-4% of patients treated for one year. These trends continue, thus 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. 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, the lowest effective dose should be used for the shortest possible duration. For high risk patients, alternate therapies that do not involve NSAIDs should be considered.
Studies have shown that patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding and who use NSAIDs, have a greater than 10-fold risk for developing a GI bleed than patients with neither of these risk factors. In addition to a past history of ulcer disease, pharmacoepidemiological studies have identified several other cotherapies or comorbid conditions that may increase the risk for GI bleeding such as: treatment with oral corticosteroids, treatment with anticoagulants, longer duration of NSAID therapy, smoking, alcoholism, older age, and poor general health status.
Anaphylactoid Reactions
As with other NSAIDs, anaphylactoid reactions may occur in patients without known prior exposure to Ponstan. Ponstan 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.
Advanced Renal Disease
In cases with preexisting advanced kidney disease, treatment with Ponstan is not recommended (see CONTRAINDICATIONS ).
Pregnancy
In late pregnancy, as with other NSAIDs, Ponstan should be avoided because it may cause premature closure of the ductus arteriosus.
PRECAUTIONS
General
Ponstan cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids.
Because Ponstan reduces inflammation, it may diminish the diagnostic signs for detecting complications of presumed noninfectious, painful conditions.
Hepatic Effects
Borderline elevations of one or more liver function tests may occur in up to 15% of patients taking NSAIDs, including Ponstan. These laboratory abnormalities may progress, may remain unchanged, or may be transient with continuing therapy. Notable elevations of ALT or AST (approximately three or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with NSAIDs. In addition, rare cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver necrosis and hepatic failure, some of them with fatal outcomes have been reported.
A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, should be evaluated for evidence of the development of a more severe hepatic reaction while on therapy with Ponstan. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (eg, eosinophilia, rash, etc.), Ponstan should be discontinued.
Renal Effects
Caution should be used when initiating treatment with Ponstan in patients with considerable dehydration. It is advisable to rehydrate patients first and then start therapy with Ponstan. Ponstan is not recommended in patients with pre-existing kidney disease (see CONTRAINDICATIONS ).
Long-term administration of Ponstan has resulted in renal papillary necrosis and other renal medullary changes. Renal toxicity has also been seen in patients in which 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-dependant 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 nonsteroidal anti-inflammatory drug therapy is usually followed by recovery to the pretreatment state.
Ponstan metabolites are eliminated primarily by the kidneys. The extent to which the metabolites may accumulate in patients with renal failure has not been studied.
Hematological Effects
Anemia is sometimes seen in patients receiving NSAIDs, including Ponstan. This may be due to fluid retention, GI loss, or an effect upon erythropoiesis. Patients on long-term treatment with NSAIDs, including Ponstan, should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia.
All drugs which inhibit the biosynthesis of prostaglandins may interfere to some extent with platelet function and vascular responses to bleeding.
NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin, their effect on platelet function is quantitatively less, or shorter duration, and reversible. Ponstan does not generally affect platelet counts, or partial thromboplastin time (PTT), but may prolong prothrombin time (PT). Patients receiving Ponstan who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored.
Fluid Retention and Edema
Fluid retention and edema have been observed in some patients taking NSAIDs. Therefore, as with other NSAIDs, Ponstan should be used with caution in patients with fluid retention, hypertension, or heart failure.
Preexisting Asthma
Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthma has been associated with severe bronchospasm which can be fatal. Since cross reactivity, including bronchospasm, between aspirin and other nonsteroidal anti-inflammatory drugs has been reported in such aspirin-sensitive patients, Ponstan should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with preexisting asthma.
Information for Patients
Ponstan, like other drugs of its class, can cause discomfort and, rarely, more serious side effects, such as gastrointestinal bleeding, which may result in hospitalization and even fatal outcomes. Although 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. Patients should be apprised of the importance of this follow-up (see WARNING , Risk of Gastrointestinal Ulceration, Bleeding and Perforation ).
Patients should report to their physicians signs or symptoms of gastrointestinal ulceration or bleeding, skin rash, weight gain, or edema.
Patients should be informed of the warning signs and symptoms of hepatotoxicity (eg, 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 also be instructed to seek immediate emergency help in the case of an anaphylactoid reaction (see WARNINGS ).
In late pregnancy, as with other NSAIDs, Ponstan should be avoided because it may cause premature closure of the ductus arteriosus.
NSAIDs are often essential agents in the management of arthritis and have a major role in the treatment of pain, but they also may be commonly employed for conditions which are less serious.
Physicians may wish to discuss with their patients the potential risks (see WARNINGS , PRECAUTIONS , and ADVERSE REACTIONS sections) and likely benefits of NSAID treatment, particularly when the drugs are used for less serious conditions where treatment without NSAIDs may represent an acceptable alternative to both the patient and physician.
Laboratory Tests
Patients on long-term treatment with NSAIDs should have their CBC and a chemistry profile checked periodically. If clinical signs and symptoms consistent with liver or renal disease develop, systemic manifestations occur (eg, eosinophilia, rash, etc.) or if abnormal liver tests persist or worsen, Ponstan should be discontinued.
ADVERSE REACTIONS
In patients taking Ponstan or other NSAIDs, the most frequently reported adverse experiences occurring in approximately 1-10% of patients are:
Gastrointestinal experiences including--abdominal pain, constipation, diarrhea, dyspepsia, flatulence, gross bleeding/perforation, heartburn, nausea, GI ulcers (gastric/duodenal), vomiting, abnormal renal function, anemia, dizziness, edema, elevated liver enzymes, headaches, increased bleeding time, pruritus, rashes, tinnitus
Additional adverse experiences reported occasionally and listed here by body system include:
Body as a whole--fever, infection, sepsis
Cardiovascular system--congestive heart failure, hypertension, tachycardia, syncope
Digestive system--dry mouth, esophagitis, gastric/peptic ulcers, gastritis, gastrointestinal bleeding, glossitis, hematemesis, hepatitis, jaundice
Hemic and lymphatic system--ecchymosis, eosinophilia, leukopenia, melena, purpura, rectal bleeding, stomatitis, thrombocytopenia
Metabolic and nutritional--weight changes
Nervous system--anxiety, asthenia, confusion, depression, dream abnormalities, drowsiness, insomnia, malaise, nervousness, paresthesia, somnolence, tremors, vertigo
Respiratory system--asthma, dyspnea
Skin and appendages--alopecia, photosensitivity, pruritus, sweat
Special senses--blurred vision
Urogenital system--cystitis, dysuria, hematuria, interstitial nephritis, oliguria/polyuria, proteinuria, renal failure
Other adverse reactions, which occur rarely are:
Body as a whole--anphylactoid reactions, appetite changes, death
Cardiovascular system--arrhythmia, hypotension, myocardial infarction, palpitations, vasculitis
Digestive system--eructation, liver failure, pancreatitis
Hemic and lymphatic system--agranulocytosis, hemolytic anemia, aplastic anemia, lymphadenopathy, pancytopenia
Metabolic and nutritional--hyperglycemia
Nervous system--convulsions, coma, hallucinations, meningitis
Respiratory--respiratory depression, pneumonia
Skin and appendages--angioedema, toxic epidermal necrosis, erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, urticaria
Special senses--conjunctivitis, hearing impairment
Dysuria, most commonly in males, probably due to local irritation of the
urethra by a metabolite. has also been reported. Tremor,
euphoria, and fatigue have also occurred.
Effects on the lungs. Pulmonary infiltration has been asso-
ciated with tolfenamic acid treatment in 6 patients.
Interactions
For interactions associated with NSAIDs see mefenamic acid whose record is as below :
Drug Interactions
Aspirin As with other NSAIDs, concomitant administration of Ponstan and aspirin is not generally recommended because of the potential of increased adverse effects.
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.
ACE inhibitors: Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors.
Furosemide Clinical studies, as well as post-marketing observations, have shown that NSAIDs 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 of Ponstan with furosemide, 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.
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.
Antacids: In a single dose study (n=6), ingestion of an antacid containing 1.7-gram of magnesium hydroxide with 500-mg of mefenamic acid increased the Cmax and AUC of mefenamic acid by 125% and 36%, respectively. 1
A number of compounds are inhibitors of CYP2C9 including fluconazole, lovastatin and trimethoprim. Drug interaction studies of mefenamic acid of these compounds have not been conducted. The possibility of altered safety and efficacy should be considered when Ponstan is used concomitantly with these drugs.
Drug/Laboratory Test Interactions
Ponstan may prolong prothrombin time. 4 Therefore, when the drug is administered to patients receiving oral anticoagulant drugs, frequent monitoring of prothrombin time is necessary.
A false-positive reaction for urinary bile, using the diazo tablet test, may result after mefenamic acid administration. If biliuria is suspected, other diagnostic procedures, such as the Harrison spot test, should be performed.
Pregnancy
Teratogenic Effects: Pregnancy Category C. Reproduction studies have been performed in rats, rabbits, and dogs. Rats given up to 10 times the human dose showed decreased fertility, delay in parturition, and a decreased rate of survival to weaning. Rabbits at 2.5 times the human dose showed an increase in the number of resorptions. There were no fetal anomalies observed in these studies nor in dogs at up to 10 times the human dose. 4
However, animal reproduction studies are not always predictive of human response. There are no adequate and well-controlled studies in pregnant women. Ponstan should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nonteratogenic Effects: 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.
Labor and Delivery
In rat studies with NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, an increased incidence of dystocia, delayed parturition, and decreased pup survival occurred. The effects of Ponstan on labor and delivery in pregnant women are unknown.
Nursing Mothers
Trace amounts of Ponstan may be present in breast milk and transmitted to the nursing infant. 7 Because of the potential for serious adverse reactions in nursing infants from Ponstan, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric Use
Safety and effectiveness in pediatric patients below the age of 14 have not been established.
Geriatric Use
As with any NSAID, caution should be exercised in treating the elderly (65 years and older).
Pharmacokinetics
Tolfenamic acid is readily absorbed from the gastro-intestinal
Tract. Time to peak plasma concentrations depends on the for-
mulation: peak plasma concentrations are reached about 60 to
90 minutes alter administration of tablets, but take about
2 hours to be reached when using the capsules. Tolfenamic
acid is about 99% bound to plasma proteins. The plasma half-
life is about 2 hours. Tolfenamic acid is metabolised in the
liver : the metabolites and unchanged drug are conjugated
with glucoronic acid. About 90% of an ingested dose is ex-
creted in the urine and the remainder in the faeces.
Uses and Administration
Tolfenamic acid an anthranilic acid derivative related to
mefenamic acid , is an NSAID. In the treatment
of acute attacks of migraine tolfenamic acid is given in a using
dose of 200 mg when the first symptoms appear: if a satisfac-
tory response is not obtained this dose may be repeated once
after I to 2 hours if using the tablets, or 2 lo 3 hours it using
the capsules. Tolfenamic acid has also been given for the re-
iiefof mild to moderate pain in disorders such as dysmenor-
rhoea. rheumatoid arthritis, or osteoarthritis in doses of I DO
to 200 mg three times daily by mouth.