Ansaid

CLINICAL PHARMACOLOGY

Pharmacodynamics

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 inhibition.

Pharmacokinetics

Absorption

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) .

Distribution

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, Nursing Mothers).

Metabolism

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 range.

Excretion

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)

Pharmacokinetic Parameter Normal Healthy Adults*
(18 to 40 years)
N=15
Geriatric Arthritis Patients†
(65 to 83 years)
N=13
End Stage Renal Disease Patients*
(23 to 42 years)
N=8
Alcoholic Cirrhosis Patients‡
(31 to 61 years)
N=8
Peak Concentration (Tg/mL) 14 (4) 16 (5) 9§ 9§
Time of Peak Concentration (h) 1.9 (1.5) 2.2 (3) 2.3§ 1.2§
Urinary Recovery of Unchanged Flurbiprofen (% of Dose) 2.9 (1.3) 0.6 (0.6) 0.02 (0.02) NA||
Area Under the Curve (AUC) (Tg h/mL) 83 (20) 77 (24) 44§ 50§
Apparent Volume of Distribution (Vz/F, L) 14 (3) 12 (5) 10§ 14§
Terminal Disposition Half-life (t½, h) 7.5 (0.8) 5.8 (1.9) 3.3# 5.4#
*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
||Not available
¶ 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

Special Populations

Pediatric

The pharmacokinetics of flurbiprofen have not been investigated in pediatric patients.

Race

No pharmacokinetic differences due to race have been identified.

Geriatric

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 insufficiency

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 tablets.

Flurbiprofen plasma protein binding may be decreased in patients with liver disease and serum albumin concentrations below 3.1 g/dL (see PRECAUTIONS, Hepatic Effects).

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 insufficiency

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.

Drug-Drug Interactions

(see also PRECAUTIONS: DRUG INTERACTIONS)

Antacids

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.

Aspirin

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).

Cimetidine, Ranitidine

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.

Digoxin

In studies of healthy males (n=14), concomitant administration of flurbiprofen and digoxin did not change the steady state serum levels of either drug.

Diuretics

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).

Lithium

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).

Methotrexate

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.

Last reviewed on RxList: 9/10/2010
This monograph has been modified to include the generic and brand name in many instances.

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