Tolfenamic acid

NSAIDs may enhance the effects of anti-coagulants, such as warfarin. In patients treated with anti-coagulants, close monitoring of blood coagulation is recommended.

Increased risk of gastrointestinal ulceration or bleeding.

Increased risk of gastrointestinal bleeding.

NSAIDs may exacerbate cardiac failure, reduce GFR and increase plasma glycoside levels.

Reduced anti-hypertensive effect.

Reduced diuretic effect. Diuretics can increase the risk of nephrotoxicity of NSAIDs.

Animal data indicate that NSAIDs can increase the risk of convulsions associated with quinolone antibiotics. Patients taking NSAIDs and quinolones may have an increased risk of developing convulsions.

Increased risk of nephrotoxicity.

The effect of lithium may be increased due to decreased elimination of lithium.

Decreased elimination of methotrexate.

NSAIDs should not be used for 8-12 days after mifepristone administration as NSAIDs can reduce the effect of mifepristone.

Possible increased risk of nephrotoxicity when NSAIDs are given with tacrolimus.

Increased risk of haematological toxicity when NSAIDs are given with zidovudine. There is evidence of an increased risk of haemarthroses and haematoma in HIV haemophiliacs receiving concurrent treatment with zidovudine and ibuprofen.

Caution is required if administered to patients suffering from, or with a previous history of, bronchial asthma since NSAIDs have been reported to precipitate bronchospasm in such patients.

Appropriate monitoring and advice are required for patients with a history of hypertension and/or mild to moderate congestive heart failure as fluid retention and oedema have been reported in association with NSAID therapy.

Clinical trial and epidemiological data suggest that use of some NSAIDs (particularly at high doses and in long term treatment) may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke). There are insufficient data to exclude such a risk for tolfenamic acid.

Patients with uncontrolled hypertension, congestive heart failure, established ischaemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should only be treated with tolfenamic acid after careful consideration. Similar consideration should be made before initiating longer-term treatment of patients with risk factors for cardiovascular disease (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking).

Inhibition of prostaglandin synthesis may adversely affect the pregnancy and/or the embryo/foetal development. Data from epidemiological studies suggest an increased risk of miscarriage and of cardiac malformation and gastroschisis after use of a prostaglandin synthesis inhibitor in early pregnancy. The absolute risk for cardiovascular malformation was increased from less than 1%, up to approximately 1.5%. The risk is believed to increase with dose and duration of therapy. In animals, administration of a prostaglandin synthesis inhibitor has been shown to result in increased pre- and post-implantation loss and embryo-foetal lethality. In addition, increased incidences of various malformations, including cardiovascular, have been reported in animals given a prostaglandin synthesis inhibitor during the organogenetic period. During the first and second trimester of pregnancy, tolfenamic acid should not be given unless clearly necessary. If tolfenamic acid is used by a woman attempting to conceive, or during the first and second trimester of pregnancy, the dose should be kept as low and duration of treatment as short as possible.

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may expose the foetus to:

• cardiopulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary hypertension)
• renal dysfunction, which may progress to renal failure with oligo-hydroamniosis

the mother and the neonate, at the end of the pregnancy, to:

• possible prolongation of bleeding time, an anti-aggregating effect which may occur even at very low doses
• inhibition of uterine contractions resulting in delayed or prolonged labour.

Consequently, tolfenamic acid is contraindicated during the third trimester of pregnancy.

In limited studies so far available, NSAIDs can appear in breast milk in very low concentrations. NSAIDs should, if possible, be avoided when breastfeeding.

Undesirable effects such as dizziness, drowsiness, fatigue and visual disturbances are possible after taking NSAIDs. If affected, patients should not drive or operate machinery.

Tolfenamic acid is well tolerated at the recommended dosage.

The following side effects have been observed:

Gastrointestinal: The most commonly-observed adverse events are gastrointestinal in nature. Peptic ulcers, perforation or GI bleeding, sometimes fatal, particularly in the elderly, may occur. Nausea, vomiting, diarrhoea, flatulence, constipation, dyspepsia, abdominal pain, melaena, haematemesis, ulcerative stomatitis, exacerbation of colitis and Crohn’s disease have been reported following administration. Less frequently, gastritis has been observed. Pancreatitis has been reported very rarely.

Hypersensitivity: Hypersensitivity reactions have been reported following treatment with NSAIDs. These may consist of (a) non-specific allergic reactions and anaphylaxis (b) respiratory tract reactivity comprising asthma, aggravated asthma, bronchospasm or dyspnoea, or © assorted skin disorders, including rashes of various types, pruritus, urticaria, purpura, angioedema and, more rarely exfoliative and bullous dermatoses (including epidermal necrolysis and erythema multiforme).

Cardiovascular and cerebrovascular: Oedema, hypertension and cardiac failure have been reported in association with NSAID treatment. Clinical trial and epidemiological data suggest that use of some NSAIDs (particularly at high doses and in long term treatment) may be associated with an increased risk of arterial thrombotic events (for example myocardial infarction or stroke).

Other adverse reactions reported less commonly include:

Renal: Nephrotoxicity in various forms, including interstitial nephritis, nephrotic syndrome and renal failure. Harmless dysuria in the form of smarting during urination may occur occasionally, most commonly in males. The occurrence is correlated with the concentration of a metabolite and is most probably due to a local irritating effect of the urethra. Increased consumption of liquid or reduction of the dose diminishes the risk of smarting. The urine may, due to coloured metabolites, become a little more lemon coloured.

Hepatic: Abnormal liver function, hepatitis and jaundice.

Neurological and special senses: Visual disturbances, optic neuritis, headaches, paraesthesia, reports of aseptic meningitis (especially in patients with existing auto-immune disorders, such as systemic lupus erythematosus, mixed connective tissue disease), with symptoms such as stiff neck, headache, nausea, vomiting, fever or disorientation, depression, confusion, hallucinations, tinnitus, vertigo, tremor, euphoria, dizziness, malaise, fatigue and drowsiness.

Haematological: Thrombocytopenia, neutropenia, agranulocytosis, aplastic anaemia and haemolytic anaemia.

Dermatological: Bullous reactions including Stevens Johnson Syndrome and Toxic Epidermal Necrolysis (very rare). Photosensitivity.