Dicyclomine 10 mg, Mefenamic Acid 250 mg Tablets

Dicyclomine relieves smooth muscle spasm of the gastrointestinal tract. Animal studies indicate that this action is achieved via a dual mechanism:

Atropine did not affect responses to these two agonists. In vivo studies in cats and dogs showed dicyclomine to be equally potent against acetylcholine (ACh)- or barium chloride (BaCl2)-induced intestinal spasm while atropine was at least 200 times more potent against effects of ACh than BaCl2. Tests for mydriatic effects in mice showed that dicyclomine was approximately 1/500 as potent as atropine; antisialagogue tests in rabbits showed dicyclomine to be 1/300 as potent as atropine.

Absorption and Distribution — In man, dicyclomine is rapidly absorbed after oral administration, reaching peak values within 60-90 minutes. Mean volume of distribution for a 20 mg oral dose is approximately 3.65 L/kg suggesting extensive distribution in tissues.

Elimination — The metabolism of dicyclomine was not studied. The principal route of excretion is via the urine (79.5% of the dose). Excretion also occurs in the feces, but to a lesser extent (8.4%). Mean half-life of plasma elimination in one study was determined to be approximately 1.8 hours when plasma concentrations were measured for 9 hours after a single dose. In subsequent studies, plasma concentrations were followed for up to 24 hours after a single dose, showing a secondary phase of elimination with a somewhat longer half-life.

Mefenamic acid has analgesic, anti-inflammatory, and antipyretic properties. The mechanism of action of mefenamic acid, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2).

Mefenamic acid is a potent inhibitor of prostaglandin synthesis in vitro. Mefenamic acid concentrations reached during therapy have produced in vivo effects. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models.

Prostaglandins are mediators of inflammation. Because mefenamic acid is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues.

Absorption — 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). 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 to 20 mcg/mL have been reported. Peak plasma levels are attained in 2 to 4 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.

Distribution — Mefenamic acid has been reported as being greater than 90 % bound to albumin. 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.

Based on its physical and chemical properties, mefenamic acid is expected to be excreted in human breast milk [see Use in Specific Populations (8.2)].

Metabolism — 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. The activity of these metabolites has not been studied. The metabolites may undergo glucuronidation and mefenamic acid is also glucuronidated directly. The mefenamic acid glucuronide may bind irreversibly to plasma proteins. 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 to 8 hours for the carboxy metabolite and its glucuronide.

Excretion — 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.

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. The metabolites may accumulate in patients with renal or hepatic failure.

Specific Populations — Race: Pharmacokinetic differences due to race have not been identified.

Hepatic Impairment : Mefenamic acid pharmacokinetics have not been studied in patients with hepatic dysfunction.

Renal Impairment : Mefenamic acid pharmacokinetics have not been investigated in subjects with renal insufficiency.

Drug Interaction Studies — Aspirin: When NSAIDs were administered with aspirin, the protein binding of NSAIDs were reduced, although the clearance of free NSAID was not altered. The clinical significance of this interaction is not known. See Table 1 for clinically significant drug interactions of NSAIDs with aspirin [see Drug Interactions (7.1)].

Antacid: 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.

Lithium: The mean minimum lithium concentration increased 15 %, and the renal clearance decreased by approximately 20 %.