WARNINGS
Exacerbation of gout following therapy with probenecid and colchicine may occur; in such cases additional 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 and colchicine is given with methotrexate, the dosage of methotrexate should be reduced and serum levels may need to be monitored.
In patients on probenecid and colchicine 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 and colchicine 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 and colchicine. 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 and colchicine.
Colchicine has been reported to adversely affect spermatogenesis in animals. Reversible azoospermia has been reported in one patient.
PRECAUTIONS
General
Hematuria, renal colic, costovertebral pain, and formation of uric acid stones associated with the use of probenecid and colchicine in gouty patients may be prevented by alkalization of the urine and a liberal fluid intake (see DOSAGE AND ADMlNlSTRATION). In these cases when alkali is administered, the acid-base balance of the patient should be watched.
Use with caution in patients with a history of peptic ulcer.
Probenecid and colchicine has been used in patients with some renal impairment but dosage requirements may be increased. Probenecid and colchicine may not be effective in chronic renal insufficiency particularly when the glomerular filtration rate is 30 mL/minute or less.
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.
Adequate animal studies have not been conducted to determine the carcinogenicity potential of probenecid or this drug combination. Since colchicine is an established mutagen, its ability to act as a carcinogen must be suspected and administration of probenecid and colchicine should involve a weighing of the benefit-vs-risk when long-term administration is contemplated.
Drug Interactions
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 WARNINGS). The uricosuric action of probenecid is also antagonized by pyrazinamide.
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 and colchicine 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 co-administrated. 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 in vitro study, using the Schack and Waxler technique, when therapeutic concentrations of theophylline and probenecid were added to human plasma.
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