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Meclofenamate (Meclofenamate Sodium) - Description and Clinical Pharmacology

 
 



DESCRIPTION

Meclofenamate sodium, USP is N-(2,6-dichloro-m-tolyl) anthranilic acid, sodium salt, monohydrate. It is an anti-inflammatory drug for oral administration. Meclofenamate sodium capsules, USP contain 50 mg or 100 mg meclofenamic acid as the sodium salt and the following inactive ingredients: colloidal silicon dioxide, FD&C Blue No. 1, gelatin, magnesium stearate, microcrystalline cellulose, pregelatinized starch, FD&C Red No. 3, sodium lauryl sulfate, titanium dioxide and D&C Yellow No. 10.

The structural formula of meclofenamate sodium is:

Molecular Formula: C14H10Cl2NNaO2•H2O

It is a white to creamy white, odorless to almost odorless, crystalline powder with melting point 287° to 291°C, molecular weight 336.15, and it is freely soluble in water.

CLINICAL PHARMACOLOGY

Pharmacodynamics

Meclofenamate sodium is a non-steroidal agent which has demonstrated anti-inflammatory, analgesic, and antipyretic activity in laboratory animals. The mode of action, like that of other non-steroidal anti-inflammatory agents, is not known. Therapeutic action does not result from pituitary-adrenal stimulation. In animal studies, meclofenamate sodium was found to inhibit prostaglandin synthesis and to compete for binding at the prostaglandin receptor site. In vitro, meclofenamate sodium was found to be an inhibitor of human leukocyte 5-lipoxygenase activity. These properties may be responsible for the anti-inflammatory action of meclofenamate sodium. There is no evidence that meclofenamate sodium alters the course of the underlying disease.

In several human isotope studies, meclofenamate sodium, at a dosage of 300 mg/day, produced a fecal blood loss of 1 to 2 mL per day, and 2 to 3 mL per day at 400 mg/day. Aspirin, at a dosage of 3.6 g/day, caused a fecal blood loss of 6 mL per day.

In a multiple-dose, 1-week study in normal human volunteers, meclofenamate sodium had little or no effect on collagen-induced platelet aggregation, platelet count, or bleeding time. In comparison, aspirin suppressed collagen-induced platelet aggregation and increased bleeding time. The concomitant administration of antacids (aluminum and magnesium hydroxides) does not interfere with absorption of meclofenamate sodium.

Pharmacokinetics

Meclofenamate sodium is rapidly absorbed in man following single and multiple oral doses with peak plasma concentrations occurring in 0.5 to 2 hours. Based on a comparison to a suspension of meclofenamic acid, meclofenamate sodium is completely bioavailable.

The plasma concentrations of meclofenamic acid decline monoexponentially following oral administration. In a study in ten healthy subjects following a single oral dose the apparent elimination half-life ranged from 0.8 to 5.3 hours. After the administration of meclofenamate sodium for 14 days every 8 hours, the apparent elimination half-life ranged from 0.8 to 2.1 hours with no evidence of accumulation of meclofenamic acid in plasma (see Table).

TABLE SUMMARY OF MECLOFENAMATE SODIUM PHARMACOKINETIC PARAMETERS
Mean (Range) Parameter Values (n=10)
  Meclofenamic Acid 100 mg 1 Metabolite I 2

Cmax mcg/mL 3

4.8 (1.8 to 7.2)

1 (0.5 to 1.5)

tmax hr 4

0.9 (0.5 to 1.5)

2.4 (0.5 to 4)

Cmin mcg/mL 5

0.2 (0.5 to 1.5)

0.4 (0.2 to 1.1)

Cl/F mL/min 6

206 (126 to 342)

---

Vd/F liters 7

23.3 (9.1 to 43.2)

---

t1/2 hr 8

1.3 (0.8 to 2.1)

15.3 9

% of Dose in Urine Unconjugated

0 ---

0.5 (0 to 1.2)

Total

2.7 (0 to 4.5)

21.6 (7.5 to 32.6)

1 Administered every 8 hours for 14 days
2 3-Hydroxymethyl metabolite of meclofenamic acid with 20% activity of meclofenamate sodium in vitro
3 Peak plasma concentration
4 Time to peak plasma concentration
5 Trough plasma concentration
6 Oral clearance
7 Oral distribution volume
8 Elimination half-life
9 Estimated from mean data

Meclofenamic acid is extensively metabolized to an active metabolite (Metabolite I; 3-hydroxymethyl metabolite of meclofenamic acid) and at least six other less well characterized minor metabolites. Only this Metabolite I has been shown in vitro to inhibit cyclooxygenase activity with approximately one fifth the activity of meclofenamate sodium. Metabolite I (3-hydroxymethyl metabolite of meclofenamic acid) with a mean half-life of approximately 15 hours did accumulate following multiple dosing. After the administration of 100 mg meclofenamate sodium for 14 days every 8 hours, Metabolite I reached a peak plasma concentration of only 1 mcg/mL. By contrast, the peak concentration was 4.8 mcg/mL for the parent compound on both days 1 and 14. Therefore, the accumulation of Metabolite I is probably not clinically significant.

Approximately 70% of the administered dose is excreted by the kidneys with 8% to 35% excreted as predominantly conjugated species of meclofenamic acid and Metabolite I (see Table). Other metabolites, whose excretion rates are unknown, account for the remaining 35% to 62% of the dose excreted in the urine. The remainder of the administered dose (approximately 30%) is eliminated in the feces (apparently through biliary excretion). There is insufficient experience to know if meclofenamate sodium or its metabolites accumulate in patients with compromised renal or hepatic function. Therefore, meclofenamate sodium should be used with caution in these patients (see PRECAUTIONS). Trace amounts of meclofenamate sodium are excreted in human breast milk.

Meclofenamic acid is greater than 99% bound to plasma proteins over a wide drug concentration range.

Unlike most NSAIDs, which when administered with food have a decrease in rate but not in extent of absorption, meclofenamic acid is decreased in both. It has been reported that following the administration of meclofenamate sodium capsules one-half hour after a meal, the average extent of bioavailability decreased by 26%, the average peak concentration (Cmax) decreased 4-fold and the time to Cmax was delayed by 3 hours.

Clinical Studies

Controlled clinical trials comparing meclofenamate sodium with aspirin demonstrated comparable efficacy in rheumatoid arthritis.

The meclofenamate sodium treated patients had fewer reactions involving the special senses, specifically tinnitus, but more gastrointestinal reactions, specifically diarrhea.

The incidence of patients who discontinued therapy due to adverse reactions was similar for both the meclofenamate sodium and aspirin-treated groups.

The improvement with meclofenamate sodium reported by patients and the reduction of the disease activity as evaluated by both physicians and patients with rheumatoid arthritis are associated with a significant reduction in number of tender joints, severity of tenderness, and duration of morning stiffness.

The improvement reported by patients and as evaluated by physicians in patients treated with meclofenamate sodium for osteoarthritis is associated with a significant reduction in night pain, pain on walking, degree of starting pain, and pain on passive motion. The function of knee joints also improved significantly.

Meclofenamate sodium has been used in combination with gold salts or corticosteroids in patients with rheumatoid arthritis. Studies have demonstrated that meclofenamate sodium contributes to the improvement of patients' conditions while maintained on gold salts or corticosteroids. Data are inadequate to demonstrate that meclofenamate sodium in combination with salicylates produces greater improvement than that achieved with meclofenamate sodium alone.

In controlled clinical trials of patients with mild to moderate pain, meclofenamate sodium 50 mg provided significant pain relief. In these studies of episiotomy and dental pain, meclofenamate sodium 100 mg demonstrated additional benefit in some patients. The onset of analgesic effect was generally within one hour and the duration of action was 4 to 6 hours.

In controlled clinical trials of patients with dysmenorrhea, meclofenamate sodium 100 mg t.i.d. provided significant reduction in the symptoms associated with dysmenorrhea.

In randomized double-blind crossover trials of meclofenamate sodium 100 mg t.i.d. versus placebo in women with heavy menstrual blood loss (MBL), meclofenamate sodium treatment was usually associated with a reduction in menstrual flow.

The graph below is a scatter plot of menstrual flow from the average of two menstrual periods on meclofenamate sodium treatments (vertical axis) versus two menstrual periods on placebo (horizontal axis) for 55 women. Of note, although the amount of reduction in MBL was variable, some degree of reduction occurred in 90% of women in this study.

The points on the graph represent the mean MBL for each subject when treated for two periods with placebo and two periods with meclofenamate sodium. To ease in interpretation, the following examples may be helpful. Point A represents a woman who had MBL of 459 mL while on placebo, and 405 mL on meclofenamate sodium. Point B represents a woman who had MBL of 472 mL while on placebo, and 64 mL when treated with meclofenamate sodium.

In association with this reduction in menstrual blood loss, the duration of menses was decreased by one day; tampon/pad usage was decreased by an average of two per day on the 2 days of heaviest flow; and symptoms of dysmenorrhea were significantly reduced.

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