A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Meclofenamate Pharmacology, Pharmacokinetics, Studies, Metabolism - Meclofenamate
Meclofenamate Pharmacology, Pharmacokinetics, Studies, Metabolism - Meclofenamate
CLINICAL PHARMACOLOGY
Pharmacodynamics
Meclofenamate sodium
is a nonsteroidal agent
which has demonstrated anti-inflammatory, analgesic,
and antipyretic
activity in laboratory
animals. The mode of action,
like that of other nonsteroidal 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, one-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 10 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 mgb
|
| Cmax µg/mLl
|
4.8 (1.8-72)
|
| tmax hr2 |
0.9 (0.5-1.5)
|
| Cmin pg/mL3
|
0.2 (0.5-1.5)
|
| CVF mL/min4
|
206.0 (126-342)
|
| Vd/F liters5
|
23.3 (9.1-43.2)
|
| t1/2 hr6
|
1.3 (0.8-2.1)
|
| % of Dose
in Urine
Unconjugated
|
0 a
|
| Total |
2.7 (0-4.5)
|
|
Metabolite a
|
| Cmax µg/mL1
|
1.0 (0.5-1.5)
|
| tmax hr2
|
2.4 (0.5-4.0)
|
| Cmin µg/mL3
|
0.4 (0.2-1.1)
|
| Cl/F mL/min4
|
-
|
| Vd/F liters5
|
-
|
| t1/2 hr6
|
153c
|
| % of Dose
in Urine
Unconjugated
|
0.5 (0-1.2)
|
| Total |
21.6 (7.5-32.6)
|
- a 3-Hydroxymethyl metabolite
of meclofenamic acid with 20% activity
of meclofenamate sodium
in vitro
- b Administered every 8 hours
for 14 days
- c Estimated from mean
data
- 1 Peak plasma
concentration
- 2 Time to peak plasma
concentration
- 3 Trough plasma
concentration
- 4 Oral clearance
- 5 Oral distribution
volume
- 6 Elimination half-life
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 pg/mL. By contrast, the peak concentration
was 4.8 pg/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%-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 fourfold 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.
In association
with this reduction
in menstrual blood loss,
the duration of menses
was decreased by 1 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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