Flurbiprofen

FLURBIPROFEN- flurbiprofen tablet
CARACO PHARMACEUTICAL LABORATORIES, LTD.

BOXED WARNING

Cardiovascular Risk

  • NSAIDs may cause an increased risk of serious cardiovascular thrombotic events,myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk (See WARNINGS).
  • Flurbiprofen tablet, USP is contraindicated for treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS).

Gastrointestinal Risk

  • NSAIDs cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk for serious gastrointestinal events (See WARNINGS).

DESCRIPTION

Flurbiprofen tablet, USP contain flurbiprofen, which is a member of the phenylalkanoic acid derivative group of nonsteroidal anti-inflammatory drugs. Flurbiprofen tablet, USP are white, oval, film-coated tablets for oral administration. Flurbiprofen is a racemic mixture of (+)S- and (-)R- enantiomers. Flurbiprofen is a white or slightly yellow crystalline powder. It is slightly soluble in water at pH 7.0 and readily soluble in most polar solvents. The chemical name is [1,1′-biphenyl]-4-acetic acid, 2-fluoro-alphamethyl-, (±)-. The molecular weight is 244.26. Its molecular formula is C15 H13 FO2 and it has the following structural formula:

Image from Drug Label Content

Each tablet, for oral administration contains 50 mg or 100 mg of Flurbiprofen. In addition, each tablet contains the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone, titanium dioxide, polydextrose, hydroxypropyl methylcellulose, polyethylene glycol, yellow iron oxide, black iron oxide, glyceryl triacetate.

CLINICAL PHARMACOLOGY

Pharmacodynamics

Flurbiprofen tablet, USP contain flurbiprofen, a nonsteroidal anti-inflammatory drug that exhibits anti-inflammatory, analgesic, and antipyretic activities in animal models. The mechanism of action of Flurbiprofen tablet, USP, 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 Flurbiprofen tablet, USP 100 mg is 96% relative to an oral solution. Flurbiprofen is rapidly and non-stereoselectively absorbed from Flurbiprofen tablet, USP, with peak plasma concentrations occurring at about 2 hours (see Table 1). Administration of Flurbiprofen tablet, USP 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 tablet, USP.

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 Flurbiprofen tablet, USP 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 (eg, 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-inflammatory 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 tablet, USP, 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 tablet, USP.

Table 1. Mean (SD) R,S-Flurbiprofen Pharmacokinetic Parameters Normalized to a 100 mg Dose of Flurbiprofen tablet, USP
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
* 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 װ 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
Peak Concentration(Tg/mL) 14 (4) 16 (5)
Time of Peak Concentration (h) 1.9 (1.5) 2.2 (3) 2.3§ 1.2§
Urinary Recovery of UnchangedFlurbiprofen (% of Dose) 2.9 (1.3) 0.6 (0.6) 0.02 (0.02) NAװ
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§
TerminalDisposition 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 tablet, USP 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, USP 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, USP.

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).

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.

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