Sulindac

SULINDAC- sulindac tablet
PD-Rx Pharmaceuticals, Inc.

Cardiovascular Thrombotic Events

  • Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use [see Warnings and Precautions ].

  • Sulindac tablets are contraindicated in the setting of coronary artery bypass graft (CABG) surgery [see Contraindications and 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

Sulindac is a non-steroidal, anti-inflammatory indene derivative designated chemically as (Z)-5-fluoro-2-methyl-1- [[ p -(methylsulfinyl)phenyl]methylene]-1 H -indene-3-acetic acid. It is not a salicylate, pyrazolone or propionic acid derivative. Sulindac, a yellow crystalline compound, is a weak organic acid practically insoluble in water below pH 4.5, but very soluble as the sodium salt or in buffers of pH 6 or higher.

Sulindac, USP is available in 150 mg and 200 mg tablets for oral administration. Each tablet contains the following inactive ingredients: magnesium stearate, microcrystalline cellulose, starch (corn) and stearic acid.

Following absorption, sulindac undergoes two major biotransformations—reversible reduction to the sulfide metabolite, and irreversible oxidation to the sulfone metabolite. Available evidence indicates that the biological activity resides with the sulfide metabolite.

The structural formulas of sulindac and its metabolites are:

Structural formulas of sulindac and its metabolites
(click image for full-size original)

C 20 H 17 FO 3 S M.W. 356.42

CLINICAL PHARMACOLOGY

Pharmacodynamics

Sulindac is a non-steroidal anti-inflammatory drug (NSAID) that exhibits anti-inflammatory, analgesic and antipyretic activities in animal models. The mechanism of action, like that of other NSAIDs, is not completely understood but may be related to prostaglandin synthetase inhibition.

Pharmacokinetics

Absorption

The extent of sulindac absorption from sulindac tablets is similar as compared to sulindac solution.

There is no information regarding food affect on sulindac absorption. Antacids containing magnesium hydroxide 200 mg and aluminum hydroxide 225 mg per 5 mL have been shown not to significantly decrease the extent of sulindac absorption.

TABLE 1
PHARMACOKINETIC
PARAMETERS
NORMAL ELDERLY
T max Age 19-41 (n=24) Age 65-87 (n=12) 400 mg qd
(200 mg tablet) 2.54 ± 1.52 S
3.38 ± 2.30 S 5.75 ± 2.81 SF
4.88 ± 2.57 SP 6.83 ± 4.19 SP
4.96 ± 2.36 SF
(150 mg tablet)
3.90 ± 2.30 S
5.85 ± 4.49 SP
6.15 ± 3.07 SF
Renal Clearance (200 mg tablet)
68.12 ± 27.56 mL/min S
36.58 ± 12.61 mL/min SP
(150 mg tablet)
74.39 ± 34.15 mL/min S
41.75 ± 13.72 mL/min SP
Mean effective Half life (h) 7.8 S
16.4 SF
S = Sulindac
SF = Sulindac Sulfide
SP = Sulindac Sulfone

Distribution

Sulindac, and its sulfone and sulfide metabolites, are 93.1, 95.4, and 97.9% bound to plasma proteins, predominantly to albumin. Plasma protein binding measured over a concentration range (0.5-2.0 mcg/mL) was constant. Following an oral, radiolabeled dose of sulindac in rats, concentrations of radiolabel in red blood cells were about 10% of those in plasma. Sulindac penetrates the blood-brain and placental barriers. Concentrations in brain did not exceed 4% of those in plasma. Plasma concentrations in the placenta and in the fetus were less than 25% and 5% respectively, of systemic plasma concentrations. Sulindac is excreted in rat milk; concentrations in milk were 10 to 20% of those levels in plasma. It is not known if sulindac is excreted in human milk.

Metabolism

Sulindac undergoes two major biotransformations of its sulfoxide moiety: oxidation to the inactive sulfone and reduction to the pharmacologically active sulfide. The latter is readily reversible in animals and in man. These metabolites are present as unchanged compounds in plasma and principally as glucuronide conjugates in human urine and bile. A dihydroxydihydro analog has also been identified as a minor metabolite in human urine.

With the twice-a-day dosage regimen, plasma concentrations of sulindac and its two metabolites accumulate: mean concentration over a dosage interval at steady state relative to the first dose averages 1.5 and 2.5 times higher, respectively, for sulindac and its active sulfide metabolite.

Sulindac and its sulfone metabolite undergo extensive enterohepatic circulation relative to the sulfide metabolite in animals. Studies in man have also demonstrated that recirculation of the parent drug sulindac and its sulfone metabolite is more extensive than that of the active sulfide metabolite. The active sulfide metabolite accounts for less than six percent of the total intestinal exposure to sulindac and its metabolites.

Biochemical as well as pharmacological evidence indicates that the activity of sulindac resides in its sulfide metabolite. An in-vitro assay for inhibition of cyclooxygenase activity exhibited an EC 50 of 0.02 μM for sulindac sulfide. In-vivo models of inflammation indicate that activity is more highly correlated with concentrations of the metabolite than with parent drug concentrations.

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