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
Anaprox Pharmacology, Pharmacokinetics, Studies, Metabolism - Naproxen Sodium
Anaprox Pharmacology, Pharmacokinetics, Studies, Metabolism - Naproxen Sodium
CLINICAL PHARMACOLOGY
Naproxen is a nonsteroidal anti-inflammatory drug
(NSAID), with analgesic
and antipyretic
properties. As with other NSAIDs, its mode
of action is not fully
understood; however, its ability
to inhibit prostaglandin
synthesis may be involved
in the anti-inflammatory effect.
Pharmacokinetics
Although naproxen itself is well absorbed, the sodium
salt form
is more rapidly absorbed resulting in higher peak plasma
levels for a given dose. Approximately 30% of the total naproxen
sodium dose
in Naprelan is present
in the dosage form
as an immediate release
component. The remaining naproxen sodium
is coated as microparticles to provide sustained release
properties. After oral
administration, plasma levels of naproxen are detected within 30
minutes of dosing, with peak plasma
levels occurring approximately 5 hours after dosing. The observed
terminal elimination
half-life of naproxen
from both immediate
release naproxen sodium
and Naprelan is approximately 15 hours. Steady state
levels of naproxen are achieved in 3 days and the degree
of naproxen accumulation in the blood
is consistent with this.
Pharmacokinetic Parameters at Steady State Day 5 (Mean of
24 Subjects)
Parameter
(units) |
naproxen 500 mg
Q12h/5 days
(1000 mg) |
Naprelan 2 x 500 mg
tablets (1000 mg)
Q24h/5 days |
| |
Mean |
SD |
Range |
Mean |
SD |
Range |
AUC 0-24
(mcgxh/mL) |
1446 |
168 |
1167 - 1858 |
1448 |
145 |
1173 - 1774 |
Cmax
(mcg/mL) |
95 |
13 |
71 - 117 |
94 |
13 |
74 - 127 |
Cavg
(mcg/mL) |
60 |
7 |
49 - 77 |
60 |
6 |
49 - 74 |
Cmin
(mcg/mL) |
36 |
9 |
13 - 51 |
33 |
7 |
23 - 48 |
Tmax
(hrs) |
3 |
1 |
1 - 4 |
5 |
2 |
2 - 10 |
Absorption
Naproxen itself is rapidly and completely absorbed from the GI
tract with an in vivo
bioavailability of 95%. Based on the pharmacokinetic profile, the
absorption phase
of Naprelan occurs in the first 4-6 hours after administration.
This coincides with disintegration of the tablet
in the stomach, the
transit of the sustained release microparticles through the small
intestine and into
the proximal large intestine. An
in vivo imaging
study has been performed in healthy volunteers which confirms rapid
disintegration
of the tablet matrix
and dispersion of
the microparticles.
The absorption rate
from the sustained release
particulate component
of Naprelan is slower than that for conventional naproxen sodium
tablets. It is this prolongation of drug
absorption processes
which maintains plasma
levels and allows for once daily dosing.
Food Effects: No significant
food effects were observed
when twenty-four subjects were given a single dose
of Naprelan 500 mg either
after an overnight fast
or 30 minutes after a meal. In
common with conventional naproxen and naproxen sodium
formulations, food causes
a slight decrease in the rate
of naproxen absorption
following Naprelan administration.
Distribution
Naproxen has a volume
of distribution of 0.16 L/kg. At
therapeutic levels
naproxen is greater than 99% albumin-bound. At
doses of naproxen greater than 500 mg/day there is a less than proportional
increase in plasma levels
due to an increase in clearance caused by saturation
of plasma protein
binding at higher doses. However the concentration
of unbound naproxen continues to increase proportionally to dose.
Naprelan exhibits similar dose
proportional characteristics.
Metabolism
Naproxen is extensively metabolized to 6-0-desmethyl naproxen and
both parent and metabolites
do not induce metabolizing enzymes.
Elimination
The elimination
half-life of Naprelan and conventional naproxen is approximately
15 hours. Steady state conditions are attained after 2-3 doses of
Naprelan. Most of the drug is excreted in the urine,
primarily as unchanged naproxen (less than 1%), 6-0-desmethyl naproxen
(less than 1%) and their glucuronide
or other conjugates (66-92%). A small amount (<5%) of the drug
is excreted in the feces. The rate
of excretion has been
found to coincide closely with the rate
of clearance from
the plasma. In patients with
renal failure
metabolites may accumulate.
Special Populations
Pediatric Use: No pediatric
studies have been performed with Naprelan, thus safety of Naprelan
in pediatric populations
has not been established.
Renal Insufficiency: Naproxen pharmacokinetics have not
been determined in subjects with renal
insufficiency. Given that naproxen is metabolized and conjugates
are primarily excreted by the kidneys, the potential
exists for naproxen metabolites to accumulate in the presence of
renal insufficiency.
Clinical Studies
Rheumatoid Arthritis
The use of Naprelan for the management of the signs and symptoms
of rheumatoid arthritis
was assessed in a 12 week double-blind, randomized, placebo
and active-controlled study in 348 patients. Two Naprelan 500 mg
tablets (1000 mg) once daily and naproxen 500 mg
tablets twice daily (1000 mg) were more effective than placebo.
Clinical effectiveness
was demonstrated at one week and continued for the duration of the
study.
Osteoarthritis
The use of Naprelan for the management of the signs and symptoms
of osteoarthritis
of the knee was assessed in a 12 week double-blind, placebo
and active-controlled study in 347 patients. Two Naprelan 500 mg
tablets (1000 mg) once daily and naproxen 500 mg tablets twice
daily (1000 mg) were more effective than placebo. Clinical effectiveness
was demonstrated at one week and continued for the duration of the
study.
Analgesia
The onset of the analgesic effect of Naprelan was seen within 30
minutes in a pharmacokinetic/pharmacodynamic study of patients with
pain following oral
surgery. In controlled clinical
trials, naproxen has been used in combination with gold, D-penicillamine,
methotrexate and corticosteroids. Its use in combination with salicylate
is not recommended because there is evidence
that aspirin increases
the rate of excretion
of naproxen and data are inadequate to demonstrate that naproxen
and aspirin produce
greater improvement over that achieved with aspirin alone. In
addition, as with other NSAIDs
the combination may result in higher frequency
of adverse events than demonstrated for either product alone.
Special Studies
In a double-blind randomized, parallel group
study, 19 subjects received either two Naprelan 500 mg
tablets (1000 mg) once daily or naproxen 500 mg
tablets (1000 mg) twice daily for 7 days. Mucosal biopsy
scores and endoscopic scores were lower in the subjects who received
Naprelan. In another double-blind,
randomized, crossover
study, 23 subjects received two Naprelan 500 mg
tablets (1000 mg) once daily, naproxen 500 mg
tablets (1000 mg) twice daily and aspirin
650 mg four times daily (2600 mg) for 7 days each. There were
significantly fewer duodenal erosions seen with Naprelan than with
either naproxen or aspirin. There were significantly fewer gastric
erosions with both Naprelan and naproxen than with aspirin.
The clinical significance
of these findings is unknown.
Individualization of Dosage
Rheumatoid Arthritis, Osteoarthritis, And Ankylosing Spondylitis
Naprelan like other NSAIDs shows considerable variation
in response. The recommended starting dose of Naprelan in adults
is two Naprelan 375 mg tablets
(750 mg) once daily, or two Naprelan 500 mg
tablets (1000 mg) once daily. Patients already taking naproxen 250
mg, 375 mg or 500 mg
twice daily (morning and evening) may have their total daily dose
replaced with Naprelan as a single daily dose.
During long-term administration, the dose
of Naprelan may be adjusted up or down
depending on the clinical response of the patient.
In patients who tolerate lower doses of Naprelan well, the dose
may be increased to three Naprelan 500 mg
tablets (1500 mg) once daily for limited periods when a higher level
of anti-inflammatory/analgesic activity
is required. When treating patients, especially at the higher dose
levels, the physician
should observe sufficient increased clinical
benefit to offset the
potential increased
risk. The lowest effective dose should be sought and used in every
patient.
Symptomatic improvement in arthritis
usually begins within one week; however, treatment
for two weeks may be required to achieve a therapeutic
benefit. A lower dose should
be considered in patients with renal
or hepatic impairment
or in elderly patients (see PRECAUTIONS).
Studies indicate that although total plasma
concentration
of naproxen is unchanged, the unbound plasma
fraction of naproxen
is increased in the elderly. Caution is advised when high doses
are required and some adjustment
of dosage may be required
in elderly patients. As with
other drugs used in the elderly it is prudent to use the lowest
effective dose.
Analgesia, Dysmenorrhea, Bursitis, And Tendinitis
The recommended starting dose is two Naprelan 500 mg
tablets (1000 mg) once daily. For patients requiring greater analgesic
benefit, three Naprelan 500 mg
tablets (1500 mg) may be used for a limited period. Thereafter,
the total daily dose should not exceed two Naprelan 500 mg
tablets (1000 mg).
Acute Gout
The recommended dose on
the first day is two or three Naprelan 500 mg
tablets (1000-1500 mg) once daily, followed by two Naprelan 500
mg tablets (1000 mg) once
daily, until the attack
has subsided.
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