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Ponstel (mefenamic acid) is a non-steroidal anti-inflammatory drug (NSAID) that exhibits anti-inflammatory, analgesic, and antipyretic activities in animal models. The mechanism of action of Ponstel (mefenamic acid) , like that of other NSAIDs, is not completely understood but may be related to prostaglandin synthetase inhibition.
Mefenamic acid is rapidly absorbed after oral administration. In two 500-mg single oral dose studies, the mean extent of absorption was 30.5 mcg/hr/mL (17%CV).1,2 The bioavailability of the capsule relative to an IV dose or an oral solution has not been studied.
Following a single 1-gram oral dose, mean peak plasma levels ranging from 10-20 mcg/mL3 have been reported. Peak plasma levels are attained in 2 to 4 hours and the elimination half-life approximates 2 hours. Following multiple doses, plasma levels are proportional to dose with no evidence of drug accumulation. In a multiple dose trial of normal adult subjects (n=6) receiving 1-gram doses of mefenamic acid four times daily, steady-state concentrations of 20 mcg/mL were reached on the second day of administration, consistent with the short half-life.
The effect of food on the rate and extent of absorption of mefenamic acid has not been studied. Concomitant ingestion of antacids containing magnesium hydroxide has been shown to significantly increase the rate and extent of mefenamic acid absorption (see PRECAUTIONS: DRUG INTERACTIONS).1
Mefenamic acid has been reported as being greater than 90% bound to albumin.9 The relationship of unbound fraction to drug concentration has not been studied. The apparent volume of distribution (Vzss/F) estimated following a 500-mg oral dose of mefenamic acid was 1.06 L/kg.2
Based on its physical and chemical properties, Ponstel (mefenamic acid) is expected to be excreted in human breast milk.
Mefenamic acid is metabolized by cytochrome P450 enzyme CYP2C9 to 3-hydroxymethyl mefenamic acid (Metabolite I). Further oxidation to a 3-carboxymefenamic acid (Metabolite II) may occur.10 The activity of these metabolites has not been studied. The metabolites may undergo glucuronidation and mefenamic acid is also glucuronidated directly. A peak plasma level approximating 20 mcg/mL was observed at 3 hours for the hydroxy metabolite and its glucuronide (n=6) after a single 1-gram dose. Similarly, a peak plasma level of 8 mcg/mL was observed at 6-8 hours for the carboxy metabolite and its glucuronide.3
Approximately fifty-two percent of a mefenamic acid dose is excreted into the urine primarily as glucuronides of mefenamic acid (6%), 3-hydroxymefenamic acid (25%) and 3- carboxymefenamic acid (21%). The fecal route of elimination accounts for up to 20% of the dose, mainly in the form of unconjugated 3-carboxymefenamic acid.3
The elimination half-life of mefenamic acid is approximately two hours. Half-lives of metabolites I and II have not been precisely reported, but appear to be longer than the parent compound.3 The metabolites may accumulate in patients with renal or hepatic failure. The mefenamic acid glucuronide may bind irreversibly to plasma proteins. Because both renal and hepatic excretion are significant pathways of elimination, dosage adjustments in patients with renal or hepatic dysfunction may be necessary. Ponstel (mefenamic acid) should not be administered to patients with preexisting renal disease or in patients with significantly impaired renal function.
TABLE 1: Pharmacokinetic Parameter Estimates for Mefenamic
|PK Parameters|| Normal Healthy Adults
|Oral clearance (L/hr)||21.23||38|
|Apparent volume of distribution; Vz/F (L/kg)||1.06||60|
|Half-life; t ½ (hrs)||2 to 4||NA|
Ponstel (mefenamic acid) has not been adequately investigated in pediatric patients less than 14 years of age. A study in 17 preterm infants administered 2 mg/kg indicated that the half-life was about five times as long as adults, consistent with the low activity of metabolic enzymes in newborn infants. The mean Cmax in this study was 4 mcg/mL (range 2.9-6.1). The mean time to maximum concentration (Tmax) was 8 hours (range 2-18 hrs).11
Pharmacokinetic differences due to race have not been identified.
Mefenamic acid pharmacokinetics have not been studied in patients with hepatic dysfunction. As hepatic metabolism is a significant pathway of mefenamic acid elimination, patients with acute and chronic hepatic disease may require reduced doses of Ponstel (mefenamic acid) compared to patients with normal hepatic function.
Mefenamic acid pharmacokinetics have not been investigated in subjects with renal insufficiency. Given that mefenamic acid, its metabolites and conjugates are primarily excreted by the kidneys, the potential exists for mefenamic acid metabolites to accumulate. Ponstel (mefenamic acid) should not be administered to patients with preexisting renal disease or in patients with significantly impaired renal function.
In controlled, double-blind, clinical trials, Ponstel (mefenamic acid) was evaluated for the treatment of primary spasmodic dysmenorrhea. The parameters used in determining efficacy included pain assessment by both patient and investigator; the need for concurrent analgesic medication; and evaluation of change in frequency and severity of symptoms characteristic of spasmodic dysmenorrhea. Patients received either Ponstel (mefenamic acid) , 500 mg (2 capsules) as an initial dose of 250 mg every 6 hours, or placebo at onset of bleeding or of pain, whichever began first. After three menstrual cycles, patients were crossed over to the alternate treatment for an additional three cycles. Ponstel (mefenamic acid) was significantly superior to placebo in all parameters, and both treatments (drug and placebo) were equally tolerated.
1. Neuvonen PJ, Kivisto KT: Enhancement of drug absorption by antacids. An unrecognized drug interaction. Clin Pharmacokinet. 27:120-8, Aug 1994.
2. Tall AR, Mistilits SP: Studies on Ponstan (mefenamic acid): I. Gastro-intestinal blood loss; II. Absorption and excretion of a new formulation. J Int Med Res (UK). 1975, 3 (3) p176-82.
3. Winder CV, Kaump DH, Glazko et al: Experimental observations of flufenamic, mefenamic, and meclofenamic acids. AnnPhys Med (Eng), Suppl p7-49.1967.
9. Champion GD, Graham GG: Pharmacokinetics of non-steroidal anti-inflammatory agents. Aust NZ J Med. 8 (Supp 1): 94-100, Jun 1978.
10. McGurk KA, Remmel RP, Hosagrahara VP, Tosh D, Burchell B: Reactivity of mefenamic acid 1-o- acyl glucuronide with proteins in vitro and ex vivo. Drug Metab Dispos. Aug 1996, 24 (8) p842-9.
11. Ito K, Niida Y, Sato J et al: Pharmacokinetics of mefenamic acid in preterm infants with patent ductus arteriosus. Acta Paediatr JPN. 36 (4): 387-91, 1994.
Last reviewed on RxList: 3/25/2008
This monograph has been modified to include the generic and brand name in many instances.
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