CLINICAL PHARMACOLOGY
Pharmacodynamics
Flurbiprofen tablets contain flurbiprofen, a non-steroidal anti-inflammatory drug that exhibits anti-inflammatory, analgesic, and antipyretic activities in animal models. The mechanism of action of flurbiprofen, like that of other non-steroidal anti-inflammatory drugs, is not completely understood but may be related to prostaglandin synthetase inhibition.
Pharmacokinetics
Absorption
The mean oral bioavailability of flurbiprofen from flurbiprofen tablets 100 mg is 96% relative to an oral solution. Flurbiprofen is rapidly and non-stereoselectively absorbed from flurbiprofen tablets, with peak plasma concentrations occurring at about 2 hours (see Table 1). Administration of flurbiprofen tablets 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 flurbiprofen tablets.
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 mcg/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 flurbiprofen tablets 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’-methoxy-flurbiprofen, their conjugates, and conjugated flurbiprofen. Unlike other arylpropionic acid derivatives (e.g., ibuprofen), metabolism of R-flurbiprofen to S-flurbiprofen is minimal. In vitro studies have demonstrated that cytochrome P450 2C9 plays an important role in the metabolism of flurbiprofen to its major metabolite, 4’hydroxy-flurbiprofen. The 4’-hydroxy- flurbiprofen metabolite showed little anti-inflammatoy activity in animal models of inflammation. 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 flurbiprofen tablets, less than 3% of flurbiprofen is excreted unchanged in the urine, with about 70% of the dose eliminated in the urine as parent drug and metabolites. 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 flurbiprofen tablets.
Table 1:Mean (SD) R,S-Flurbiprofen Pharmacokinetic ParametersNormalized to a 100 mg Dose of Flurbiprofen Tablets |
* 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
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| 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# |
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 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 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 flurbiprofen tablets.
Flurbiprofen plasma protein binding may be decreased in patients with liver disease and serum albumin concentrations below 3.1g/dL (see PRECAUTIONS, Hepatic Effects).
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 PRECAUTIONS, 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 flurbiprofen tablets 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 flurbiprofen tablets and aspirin resulted in 50% lower serum flurbiprofen concentrations. This effect of aspirin (which is also seen with other non-steroidal 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 non-steroidal 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 non-steroidal 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 flurbiprofen tablets every 12 hours increased plasma lithium concentrations by 19%. Four of 11 patients experienced a clinically important increase (> 25% or > 0.2 mmol/L). Non-steroidal anti-inflammatory drugs have also been reported to decrease the renal clearances 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 flurbiprofen tablets (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.
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