Meclofenamate dosing

Eideriy Age appears to increase the possibility of adverse reactions to NSAIDs. The risk of serious ulcer disease is increased this risk appears to increase with dose. Ketorolac is cleared more slowly by the elderly use caution and reduce dosage. Pregnancy Category B (ketoprofen, naproxen, naproxen sodium, flurbiprofen, diclofenac, fenoprofen, ibuprofen, indomethacin, meclofenamate, sulindac). 

Indomethacin and sulindac are slightly selective for COX-1. Meclofenamate and ibuprofen are approximately equipotent on COX-1 and COX-2, whereas celecoxib = diclofenac < rofecoxib = lumiracoxib < etoricoxib in inhibition of COX-2 (listed in order of increasing average selectivity). Aspirin acetylates and inhibits both enzymes covalently. Low doses (< 100 mg/day) inhibit preferentially, but not exclusively, platelet COX-1, whereas higher doses inhibit both systemic COX-1 and COX-2. 

Koup, J. R., Tucker, E., Thomas, D. J., Kinkel, A. W., Sedman, A. J., Dyer, R., Sharoky, M. A single and multiple dose pharmacokinetic and metabolism study of meclofenamate sodium, Biopharm. Drug Dispos. 1990, 11, 1-15. 

Flufenamic acid and meclofenamic acid are anthranilic acid derivatives similar to mefenamic acid. The withdrawal rate because of adverse effects is 7-31% and is higher in longterm studies. Flufenamic acid and meclofenamic acid are not widely prescribed and so there is little evidence to show whether they have any advantages over other NSAIDs. Both have a high incidence of gastrointestinal adverse effects (30-60% of patients at recommended doses). Diarrhea affects 11 6% of patients (SEDA-4, 68) (SEDA-6, 99) (SEDA-7, 116) (SEDA-14, 95). Thrombocytopenia with positive rechallenge has been described (1). Rashes occur in under 10% of patients. Meclofenamic acid exacerbates psoriasis in psoriatic arthropathy (2). 

Meclofenamic acid is an anthranilic acid derivative that is typically administered orally to horses. The pharmacokinetics of this NSAID in horses has been well defined. For example, the plasma half-life in horses has been determined in several studies and varies between 0.7 and 1.4 h (Johansson et al 1991, Snow et al 1981). Absorption is variable after oral dosing with estimates of bioavailability ranging from 60 to 90% and peak plasma concentrations occurring 1-3 h after administration (Johansson et al 1991). The effect of ingesta on the absorption of meclofenamic acid from the gastrointestinal tract has not been determined definitively. In one study, the absorption rate of the NSAID was the same in ponies whether they were fasted or fed (Snow et al 1981). However, another study found that absorption of meclofenamic acid was delayed in horses allowed free access to hay (May Lees 1999). In horses, the liver metabolizes meclofenamic acid primarily by oxidation to an active hydroxymethyl metabolite, which may be further oxidized to an inactive carboxyl metabolite (Plumb 1999). 

The efficacy of meclofenamic acid as an antiinflammatory agent in horses has been determined in a number of studies using the recommended doses (Table 14.1) (Galbraith McKellar 1996, Johansson et al 1991, Tobin 1979). It is known for its slow onset of action, requiring 36-96 h of therapy before clinical effects are evident (Boothe 1995). It has also been proposed to be particularly effective in the treatment of acute and chronic laminitis, although its superiority over other NSAIDs in the treatment of these conditions has not been definitively proven (Lees Higgins 1985). In one study, meclofenamic acid was shown to decrease the accumulation of lactate and increase the lactate threshold in an exercise tolerance test carried out in seven standardbred horses (Johansson et al 1991). 

Meclofenamate is indicated in the relief of mild to moderate pain (50 mg/6 hours) in the treatment of primary dysmenorrhea (100 mg t.i.d.) and in acnte and chronic rhenmatoid arthritis and osteoarthritis (200 to 400 mg/day in 3 to 4 equal doses). Meclofenamate is a nonsteroidal antiinflammatory agent that has analgesic and antipyretic properties. The menstrual cycle is associated with two potentially incapacitating events dysmenorrhea and the premenstrnal syndrome. Substantial evidence indicates that the excessive production of prostaglandin 2 is the major sonrce of painful menstruation. The nonsteroidal antiinflammatory drngs such as aspirin, ibuprofen, meclofenamate, mefenamic acid, and naproxen are used to treat dysmenorrhea. 

Meclofenamate is rapidly absorbed, with peak plasma concentration occurring in 1 honr. It is extensively metabolized to an active metabolite (3-hydroxymethyl metabolite of meclofenamic acid) and at least six other less well-characterized minor metabolites. Only this active metabolite has been shown to inhibit cyclooxygenase activity in vitro with approximately one-fifth the activity of meclofenamate sodium. The 3-hydroxymethyl metabolite of meclofenamic acid with a mean half-life of approximately 15 hours does accumulate following mnltiple dosing. Approximately 70% of the administered dose is excreted... 

Meclofenamate sodium is rapidly and almost completely absorbed following oral administration, reaching peak plasma levels within 2 hours. It is highly bound to plasma proteins (99%) and has a plasma half-life of 2 to 4 hours. Metabolism involves oxidation of the methyl group, aromatic hydroxylation, monodehalogenation, and conjugation. Urinary excretion accounts for approximately 75% of the administered dose. The major metabolite is the product of 3 -methyl oxidation and has been shown to possess anti-inflammatory activity (Fig. 36.21). 

The one pharmacodynamic study below, that also measured gastrointestinal blood loss, found increased bleeding when anti-inflammatory doses of aspirin were given with sodium meclofenamate. ... 

Banks, R.A., Beilin, L.J. and Soltys, J. (1983). Dose-dependent effects of meclofenamate on peripheral vasculature of conscious rabbits. Clin. Sci., 64, 471-474... 

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