Mefenamic Acid 250 mg, Tranexamic Acid 500 mg Uncoated Tablets

Tranexamic acid is a synthetic lysine amino acid derivative, which diminishes the dissolution of hemostatic fibrin by plasmin. In the presence of tranexamic acid, the lysine receptor binding sites of plasmin for fibrin are occupied, preventing binding to fibrin monomers, thus preserving and stabilizing fibrin’s matrix structure.

The antifibrinolytic effects of tranexamic acid are mediated by reversible interactions at multiple binding sites within plasminogen. Native human plasminogen contains 4 to 5 lysine binding sites with low affinity for tranexamic acid (K d= 750 µmol/L) and 1 with high affinity (K d= 1.1 µmol/L). The high affinity lysine site of plasminogen is involved in its binding to fibrin. Saturation of the high affinity binding site with tranexamic acid displaces plasminogen from the surface of fibrin. Although plasmin may be formed by conformational changes in plasminogen, binding to and dissolution of the fibrin matrix is inhibited.

Absorption — After a single oral administration of 1300 mg of tranexamic acid tablets, the peak plasma concentration (C max) occurred at approximately 3 hours (T max). The absolute bioavailability of tranexamic acid tablets in women aged 18‑ 49 is approximately 45%. Following multiple oral doses (1300 mg tablets three times daily) administration of tranexamic acid tablets for 5 days, the mean C maxincreased by approximately 19% and the mean area under the plasma concentration-time curve (AUC) remained unchanged, compared to a single oral dose administration (1300 mg). Plasma concentrations reached steady state at the 5th dose of tranexamic acid tablets on Day 2.

The mean plasma pharmacokinetic parameters of tranexamic acid determined in 19 healthy women following a single (1300 mg) and multiple (1300 mg tablets three times daily for 5 days) oral dose of tranexamic acid tablets are shown in Table 3.

Effect of food : Tranexamic acid tablets may be administered with or without food. A single dose administration (1300 mg) of tranexamic acid tablets with food increased both C maxand AUC by 7% and 16%, respectively.

Distribution — Tranexamic acid is 3% bound to plasma proteins with no apparent binding to albumin. Tranexamic acid is distributed with an initial volume of distribution of 0.18 L/kg and steady-state apparent volume of distribution of 0.39 L/kg.

Tranexamic acid crosses the placenta. The concentration in cord blood after an intravenous injection of 10 mg/kg to pregnant women is about 30 mg/L, as high as in the maternal blood.

Tranexamic acid concentration in cerebrospinal fluid is about one tenth of the plasma concentration.

The drug passes into the aqueous humor of the eye achieving a concentration of approximately one tenth of plasma concentrations.

Elimination — Most elimination post intravenous administration occurred during the first 10 hours, giving an apparent elimination half-life of approximately 2 hours. The mean terminal half-life of tranexamic acid is approximately 11 hours. Plasma clearance of tranexamic acid is 110-116 mL/min.

Metabolism — A small fraction of the tranexamic acid is metabolized.

Excretion — Tranexamic acid is eliminated by urinary excretion primarily via glomerular filtration with more than 95% of the dose excreted unchanged. Excretion of tranexamic acid is about 90% at 24 hours after intravenous administration of 10 mg/kg.

Pediatric Patients — Tranexamic acid tablets are indicated for females of reproductive age (not approved for use in premenarcheal girls). In a randomized, single dose, two-way crossover study of two dose levels (650 mg and 1,300 mg), pharmacokinetics of tranexamic acid was evaluated in 20 female adolescents (12 to 16 years of age) with heavy menstrual bleeding. The C maxand AUC values after a single oral dose of 650 mg in the adolescent females were 32 – 36% less than those after a single oral dose of 1,300 mg in the adolescent females. The C maxand AUC values after a single oral dose of 1300 mg in the adolescent females were 20 – 25% less than those in the adult females given the same dose in a separate study. [See Use in Specific Populations (8.4)]

Patients with Renal Impairment — The effect of renal impairment on the disposition of tranexamic acid tablets has not been evaluated. Urinary excretion following a single intravenous injection of tranexamic acid declines as renal function decreases. Following a single 10 mg/kg intravenous injection of tranexamic acid in 28 patients, the 24-hour urinary fractions of tranexamic acid with serum creatinine concentrations 1.4 – 2.8, 2.8 – 5.7, and greater than 5.7 mg/dL were 51, 39, and 19%, respectively. The 24-hour tranexamic acid plasma concentrations for these patients demonstrated a direct relationship to the degree of renal impairment. Therefore, a lower dosage is needed in patients with renal impairment [see Dosage and Administration (2.2) ].

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 %.