PROBENECID- probenecid tablet, film coated
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Probenecid is a uricosuric and renal tubular transport blocking agent.
The chemical name for probenecid is 4-[(dipropylamino) sulfonyl] benzoic acid (molecular weight 285.37). It has the following structural formula:
C H NO S 13 19 4
Probenecid, USP is a white or nearly white, fine, crystalline powder. Probenecid is soluble in dilute alkali, in alcohol, in chloroform, and in acetone; it is practically insoluble in water and in dilute acids.
Each tablet for oral administration contains 500 mg of probenecid and the following inactive ingredients: colloidal silicon dioxide, hypromellose, magnesium stearate, microcrystalline cellulose, polydextrose, polyethylene glycol, sodium carbonate, sodium lauryl sulfate, sodium starch glycolate, cornstarch, titanium dioxide, triacetin, FD&C Yellow #6, D&C Yellow #10, and FD&C Blue #2.
Probenecid is a uricosuric and renal tubular blocking agent. It inhibits the tubular reabsorption of urate, thus increasing the urinary excretion of uric acid and decreasing serum urate levels. Effective uricosuria reduces the miscible urate pool, retards urate deposition, and promotes resorption of urate deposits.
Probenecid inhibits the tubular secretion of penicillin and usually increases penicillin plasma levels by any route the antibiotic is given. A 2-fold to 4-fold elevation has been demonstrated for various penicillins.
Probenecid also has been reported to inhibit the renal transport of many other compounds including aminohippuric acid (PAH), aminosalicylic acid (PAS), indomethacin, sodium iodomethamate and related iodinated organic acids, 17-ketosteroids, pantothenic acid, phenolsulfonphthalein (PSP), sulfonamides, and sulfonylureas. See also . Drug Interactions
Probenecid decreases both hepatic and renal excretion of sulfobromophthalein (BSP). The tubular reabsorption of phosphorus is inhibited in hypoparathyroid but not in euparathyroid individuals.
Probenecid does not influence plasma concentrations of salicylates, nor the excretion of streptomycin, chloramphenicol, chlortetracycline, oxytetracycline, or neomycin.
Probenecid tablets are indicated for the treatment of the hyperuricemia associated with gout and gouty arthritis.
As an adjuvant to therapy with penicillin or with ampicillin, methicillin, oxacillin, cloxacillin, or nafcillin, for elevation and prolongation of plasma levels by whatever route the antibiotic is given.
Hypersensitivity to probenecid.
Children under 2 years of age.
Not recommended in persons with known blood dyscrasias or uric acid kidney stones.
Therapy with probenecid should not be started until an acute gouty attack has subsided.
Exacerbation of gout following therapy with probenecid may occur; in such cases colchicine or other appropriate therapy is advisable.
Probenecid increases plasma concentrations of methotrexate in both animals and humans. In animal studies, increased methotrexate toxicity has been reported. If probenecid is given with methotrexate, the dosage of methotrexate should be reduced and serum levels may need to be monitored.
In patients on probenecid the use of salicylates in either small or large doses is contraindicated because it antagonizes the uricosuric action of probenecid. The biphasic action of salicylates in the renal tubules accounts for the so-called “paradoxical effect” of uricosuric agents. In patients on probenecid who require a mild analgesic agent the use of acetaminophen rather than small doses of salicylates would be preferred.
Rarely, severe allergic reactions and anaphylaxis have been reported with the use of probenecid. Most of these have been reported to occur within several hours after readministration following prior usage of the drug.
The appearance of hypersensitivity reactions requires cessation of therapy with probenecid.
Probenecid crosses the placental barrier and appears in cord blood. The use of any drug in women of childbearing potential requires that the anticipated benefit be weighed against possible hazards.
Hematuria, renal colic, costovertebral pain, and formation of uric acid stones associated with the use of probenecid in gouty patients may be prevented by alkalization of the urine and a liberal fluid intake (see ). In these cases when alkali is administered, the acid-base balance of the patient should be watched. DOSAGE AND ADMINISTRATION
Use with caution in patients with a history of peptic ulcer.
Probenecid has been used in patients with some renal impairment, but dosage requirements may be increased. Probenecid may not be effective in chronic renal insufficiency particularly when the glomerular filtration rate is 30 mL/minute or less. Because of its mechanism of action, probenecid is not recommended in conjunction with a penicillin in the presence of renal impairment. known
A reducing substance may appear in the urine of patients receiving probenecid. This disappears with discontinuance of therapy. Suspected glycosuria should be confirmed by using a test specific for glucose.
When probenecid is used to elevate plasma concentrations of penicillin or other beta-lactams, or when such drugs are given to patients taking probenecid therapeutically, high plasma concentrations of the other drug may increase the incidence of adverse reactions associated with that drug. In the case of penicillin or other beta-lactams, psychic disturbances have been reported.
The use of salicylates antagonizes the uricosuric action of probenecid (see ). The uricosuric action of probenecid is also antagonized by pyrazinamide. WARNINGS
Probenecid produces an insignificant increase in free sulfonamide plasma concentrations, but a significant increase in total sulfonamide plasma levels. Since probenecid decreases the renal excretion of conjugated sulfonamides, plasma concentrations of the latter should be determined from time to time when a sulfonamide and probenecid are coadministered for prolonged periods. Probenecid may prolong or enhance the action of oral sulfonylureas and thereby increase the risk of hypoglycemia.
It has been reported that patients receiving probenecid require significantly less thiopental for induction of anesthesia. In addition, ketamine and thiopental anesthesia were significantly prolonged in rats receiving probenecid.
The concomitant administration of probenecid increases the mean plasma elimination half-life of a number of drugs which can lead to increased plasma concentrations. These include agents such as indomethacin, acetaminophen, naproxen, ketoprofen, meclofenamate, lorazepam, and rifampin. Although the clinical significance of this observation has not been established, a lower dosage of the drug may be required to produce a therapeutic effect, and increases in dosage of the drug in question should be made cautiously and in small increments when probenecid is being coadministrated. Although specific instances of toxicity due to this potential interaction have not been observed to date, physicians should be alert to this possibility.
Probenecid given concomitantly with sulindac had only a slight effect on plasma sulfide levels, while plasma levels of sulindac and sulfone were increased. Sulindac was shown to produce a modest reduction in the uricosuric action of probenecid, which probably is not significant under most circumstances.
In animals and in humans, probenecid has been reported to increase plasma concentrations of methotrexate (see ). WARNINGS
Falsely high readings for theophylline have been reported in an study, using the Schack and Waxler technique, when therapeutic concentrations of theophylline and probenecid were added to human plasma. in vitro
The following adverse reactions have been observed and within each category are listed in order of decreasing severity.
headache, dizziness. Central Nervous System:
precipitation of acute gouty arthritis. Metabolic:
hepatic necrosis, vomiting, nausea, anorexia, sore gums. Gastrointestinal:
nephrotic syndrome, uric acid stones with or without hematuria, renal colic, costovertebral pain, urinary frequency. Genitourinary:
anaphylaxis, fever, urticaria, pruritus. Hypersensitivity:
aplastic anemia, leukopenia, hemolytic anemia which in some patients could be related to genetic deficiency of glucose-6-phosphate dehydrogenase in red blood cells, anemia. Hematologic:
dermatitis, alopecia, flushing. Integumentary:
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