ANSAID Tablets contain flurbiprofen, a nonsteroidal anti-inflammatory drug
that exhibits antiinflammatory, analgesic, and antipyretic activities in animal
models. The mechanism of action of ANSAID (flurbiprofen) , like that of other nonsteroidal anti-inflammatory
drugs, is not completely understood but may be related to prostaglandin synthetase
The mean oral bioavailability of flurbiprofen from ANSAID (flurbiprofen) Tablets 100 mg is
96% relative to an oral solution. Flurbiprofen is rapidly and non-stereoselectively
absorbed from ANSAID (flurbiprofen) , with peak plasma concentrations occurring at about 2 hours
(see Table 1). Administration of ANSAID (flurbiprofen) with either food or antacids
may alter the rate but not the extent of flurbiprofen absorption. Ranitidine
has been shown to have no effect on either the rate or extent of flurbiprofen
absorption from ANSAID (flurbiprofen) .
The apparent volume of distribution (Vz/F) of both R- and S-flurbiprofen is
approximately 0.12 L/Kg. Both flurbiprofen enantiomers are more than 99% bound
to plasma proteins, primarily albumin. Plasma protein binding is relatively
constant for the typical average steady-state concentrations ( ≤ 10 μg/mL)
achieved with recommended doses. Flurbiprofen is poorly excreted into human
milk. The nursing infant dose is predicted to be approximately 0.1 mg/day in
the established milk of a woman taking ANSAID 200 mg/day (see PRECAUTIONS,
Several flurbiprofen metabolites have been identified in human plasma and urine.
These metabolites include 4'-hydroxy-flurbiprofen, 3', 4'-dihydroxy-flurbiprofen,
3'-hydroxy-4'-methoxyflurbiprofen, their conjugates, and conjugated flurbiprofen.
Unlike other arylpropionic acid derivatives (eg, ibuprofen), metabolism of R-flurbiprofen
to S-flurbiprofen is minimal. In vitro studies have demonstrated that cytochrome
P4502C9 (CYP2C9) plays an important role in the metabolism of flurbiprofen to
its major metabolite 4'-hydroxy-flurbiprofen (see Special Populations).
The 4'hydroxy-flurbiprofen metabolite showed little anti-inflammatory activity
in animal models of inflammation. In vitro studies also demonstrated glucuronidation
of both enantiomers of flurbiprofen and 4'-hydroxy-flurbiprofen. UGT2B7 is the
predominant UGT isozyme responsible for the glucuronidation. Flurbiprofen does
not induce enzymes that alter its metabolism.
The total plasma clearance of unbound flurbiprofen is not stereoselective,
and clearance of flurbiprofen is independent of dose when used within the therapeutic
Following dosing with ANSAID, less than 3% of flurbiprofen is excreted unchanged
in the urine, with about 70% of the dose eliminated in the urine as flurbiprofen,
4'-hydroxy-flurbiprofen, and their acyl-glucuronide conjugates. Because renal
elimination is a significant pathway of elimination of flurbiprofen metabolites,
dosing adjustment in patients with moderate or severe renal dysfunction may
be necessary to avoid accumulation of flurbiprofen metabolites. The mean terminal
disposition half-lives (t½) of R- and S-flurbiprofen are similar, about 4.7
and 5.7 hours, respectively. There is little accumulation of flurbiprofen following
multiple doses of ANSAID (flurbiprofen) .
Table 1: Mean (SD) R,S-Flurbiprofen Pharmacokinetic Parameters
Normalized to a 100 mg Dose of ANSAID (flurbiprofen)
(18 to 40 years)
(65 to 83 years)
|End Stage Renal
(23 to 42 years)
(31 to 61 years)
|Peak Concentration (Tg/mL)
|Time of Peak Concentration (h)
|Urinary Recovery of Unchanged Flurbiprofen (% of Dose)
|Area Under the Curve (AUC)¶ (Tg h/mL)
|Apparent Volume of Distribution (Vz/F, L)
|Terminal Disposition Half-life (t½, h)
|*100 mg single-dose
† Steady-state evaluation of 100 mg every 12 hours
‡200 mg single-dose
§ Calculated from mean parameter values of both flurbiprofen enantiomers
¶ AUC from 0 to infinity for single doses and from 0 to the end of
the dosing interval for multiple-doses
# Value for S-flurbiprofen
The pharmacokinetics of flurbiprofen have not been investigated in pediatric
No pharmacokinetic differences due to race have been identified.
Flurbiprofen pharmacokinetics were similar in geriatric arthritis patients,
younger arthritis patients, and young healthy volunteers receiving ANSAID (flurbiprofen) Tablets
100 mg as either single or multiple doses.
Hepatic metabolism may account for > 90% of flurbiprofen elimination, so
patients with hepatic disease may require reduced doses of ANSAID (flurbiprofen) Tablets compared
to patients with normal hepatic function. The pharmacokinetics of R- and S-flurbiprofen
were similar, however, in alcoholic cirrhosis patients (N=8) and young healthy
volunteers (N=8) following administration of a single 200 mg dose of ANSAID
Flurbiprofen plasma protein binding may be decreased in patients with liver
disease and serum albumin concentrations below 3.1 g/dL (see PRECAUTIONS,
Poor Metabolizers of CYP2C9 Substrates
Patients who are known or suspected to be poor CYP2C9 metabolizers based on
previous history/experience with other CYP2C9 substrates (such as warfarin and
phenytoin) should be administered flurbiprofen with caution as they may have
abnormally high plasma levels due to reduced metabolic clearance.
Renal clearance is an important route of elimination for flurbiprofen metabolites,
but a minor route of elimination for unchanged flurbiprofen ( ≤ 3% of total
clearance). The unbound clearances of R- and S-flurbiprofen did not differ significantly
between normal healthy volunteers (N=6, 50 mg single dose) and patients with
renal impairment (N=8, inulin clearances ranging from 11 to 43 mL/min, 50 mg
multiple doses). Flurbiprofen plasma protein binding may be decreased in patients
with renal impairment and serum albumin concentrations below 3.9 g/dL. Elimination
of flurbiprofen metabolites may be reduced in patients with renal impairment
(see WARNINGS, Renal Effects).
Flurbiprofen is not significantly removed from the blood into dialysate in
patients undergoing continuous ambulatory peritoneal dialysis.
(see also PRECAUTIONS: DRUG INTERACTIONS)
Administration of ANSAID (flurbiprofen) to volunteers under fasting conditions or with antacid
suspension yielded similar serum flurbiprofen-time profiles in young adult subjects
(n=12). In geriatric subjects (n=7), there was a reduction in the rate but not
the extent of flurbiprofen absorption.
Concurrent administration of ANSAID and aspirin resulted in 50% lower serum
flurbiprofen concentrations. This effect of aspirin (which is also seen with
other nonsteroidal anti-inflammatory drugs) has been demonstrated in patients
with rheumatoid arthritis (n=15) and in healthy volunteers (n=16) (see PRECAUTIONS: DRUG INTERACTIONS).
Beta-adrenergic blocking agents
The effect of flurbiprofen on blood pressure response to propranolol and atenolol
was evaluated in men with mild uncomplicated hypertension (n=10). Flurbiprofen
pretreatment attenuated the hypotensive effect of a single dose of propranolol
but not atenolol. Flurbiprofen did not appear to affect the beta-blocker-mediated
reduction in heart rate. Flurbiprofen did not affect the pharmacokinetic profile
of either drug (see PRECAUTIONS: DRUG INTERACTIONS).
In normal volunteers (n=9), pretreatment with cimetidine or ranitidine did
not affect flurbiprofen pharmacokinetics, except for a small (13%) but statistically
significant increase in the area under the serum concentration curve of flurbiprofen
in subjects who received cimetidine.
In studies of healthy males (n=14), concomitant administration of flurbiprofen
and digoxin did not change the steady state serum levels of either drug.
Studies in healthy volunteers have shown that, like other nonsteroidal anti-inflammatory
drugs, flurbiprofen can interfere with the effects of furosemide. Although results
have varied from study to study, effects have been shown on furosemide-stimulated
diuresis, natriuresis, and kaliuresis. Other nonsteroidal anti-inflammatory
drugs that inhibit prostaglandin synthesis have been shown to interfere with
thiazide and potassium-sparing diuretics (see PRECAUTIONS: DRUG INTERACTIONS).
In a study of 11 women with bipolar disorder receiving lithium carbonate at
a dosage of 600 to 1200 mg/day, administration of 100 mg ANSAID (flurbiprofen) every 12 hours
increased plasma lithium concentrations by 19%. Four of 11 patients experienced
a clinically important increase ( > 25% or > 0.2 mmol/L). Nonsteroidal anti-inflammatory
drugs have also been reported to decrease the renal clearance of lithium by
about 20% (see PRECAUTIONS: DRUG INTERACTIONS).
In a study of six adult arthritis patients, coadministration of methotrexate
(10 to 25 mg/dose) and ANSAID (flurbiprofen) (300 mg/day) resulted in no observable interaction
between these two drugs.
Oral Hypoglycemic Agents
In a clinical study, flurbiprofen was administered to adult diabetics who were
already receiving glyburide (n=4), metformin (n=2), chlorpropamide with phenformin
(n=3), or glyburide with phenformin (n=6). Although there was a slight reduction
in blood sugar concentrations during concomitant administration of flurbiprofen
and hypoglycemic agents, there were no signs or symptoms of hypoglycemia.