Action And Clinical Pharmacology: Probenecid is a uricosuric and a blocking agent of tubular secretion of organic anions. 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 inhibits the tubular excretion and increases blood levels of cephalosporins (other than cephaloridine). tag_IndicationsIndications
Indications And Clinical Uses: For treatment of hyperuricemia associated with all stages of gout and gouty arthritis, except a presenting acute attack.
As an adjuvant to therapy with penicillin G or V, or with ampicillin, methicillin, oxacillin, cloxacillin, nafcillin, carbenicillin or the cephalosporins (other than cephaloridine), for elevation and prolongation of plasma levels by whatever route the antibiotic is given.
Asymptomatic hyperuricemia seems to occur in a significant percentage of relatives of gouty patients. Probenecid may be given prophylactically to these persons to forestall acute gouty attacks and urate deposition in tissues.
By virtue of its effective uricosuric activity, probenecid may be used to control the hyperuricemia induced or aggravated by the many diuretics employed for the treatment of edema and hypertension (e.g., thiazides and similar diuretics).
Contra-Indications: Hypersensitivity to probenecid or to any component of this medication. 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.
Manufacturers’ Warnings In Clinical States: In patients on probenecid the use of salicylates in either small or large doses is contraindicated because it antagonizes the uricosuric action of probenecid. In patients on probenecid who require a mild analgesic agent the use of acetaminophen rather than small doses of salicylates would be preferred.
The appearance of hypersensitivity reactions requires cessation of therapy with probenecid.
Pregnancy: 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.
Precautions: Hematuria, renal colic, costovertebral pain, and formation of urate stones associated with the use of probenecid in gouty patients may be prevented by alkalization of the urine and a liberal fluid intake. Sufficient sodium bicarbonate (3 to 7.5 g daily) or potassium citrate (7.5 g daily) is recommended to maintain alkaline urine. With such quantities of alkali, the acid-base balance of the patient should be watched.
Alkalization of the urine is recommended until the serum urate level returns to normal (upper normal limit in males is about 6 mg/100 mL and in females, it is about 5 mg/100 mL) and tophaceous deposits disappear, i.e., during the period when urinary excretion of uric acid is at high level. After the miscible pool of urates decreases to normal (about 1 g) and deposited urates are resorbed and eliminated, alkalization of the urine probably is unnecessary, since the urinary uric acid concentration is lower and less likely to cause crystallization.
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/min or less. Because of its mechanism of action, probenecid is not recommended in conjunction with a penicillin in the presence of known renal impairment.
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.
Lactation: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when probenecid is administered to a nursing mother.
Drug Interactions: The use of ASA antagonizes the uricosuric action of probenecid (see Warnings). The uricosuric action of probenecid is also antagonized by pyrazinamide.
Since probenecid decreases the renal excretion of conjugated sulfonamides, plasma concentrations of the latter should be determined from time to time when a sulfa drug and probenecid are coadministered for prolonged periods. Probenecid may prolong or enhance the action or oral sulfonylureas and thereby increase the risk of hypoglycemia.
Caution should be used if probenecid is administered simultaneously with methotrexate. Probenecid has been reported to decrease the tubular secretion of methotrexate and to potentiate toxicity.
Probenecid increases the mean plasma elimination half-life of a number of other drugs which can lead to increased peak plasma concentrations. These drugs include acetaminophen, naproxen, indomethacin, ketoprofen, meclofenamate, lorazepam, rifampin, acyclovir, ganciclovir and zidovudine. The clinical significance of this effect on plasma elimination half-life is not known; however, adjustment in the usual dosage of these drugs may be required.
In addition to its effect on the excretion of uric acid, the penicillins, and the cephalosporins (other than cephaloridine), probenecid decreases the urinary excretion of p-aminosalicylic acid (PAS), p-aminohippuric acid (PAH), phenolsulfonphthalein (PSP), pantothenic acid, 17-ketosteroids, sodium iodomethamate and related iodinated organic acids. Probenecid decreases both hepatic and renal excretion of sulfobromophthalein (BSP). The renal tubular reabsorption of phosphorus is inhibited in hypoparathyroid but not in euparathyroid individuals.
Laboratory Test Interactions : A reducing substance may appear in the urine of patients receiving probenecid which may produce a false-positive Benedict’s test leading to the possibility of a false diagnosis of glycosuria. However, this disappears with discontinuance of therapy.
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.
Adverse Reactions: Headache, gastrointestinal symptoms, (e.g., anorexia, nausea, vomiting), urinary frequency, hypersensitivity reactions (including anaphylaxis, dermatitis, pruritus, urticaria, fever and Stevens-Johnson syndrome), sore gums, flushing, alopecia, dizziness, and anemia have occurred; also hemolytic anemia which in some instances could be related to genetic deficiency of glucose-6-phosphate dehydrogenase in red blood cells. Toxic epidermal necrolysis has been reported rarely after combination therapy of colchicine and probenecid. Nephrotic syndrome, leukopenia, hepatic necrosis, and aplastic anemia occur rarely.
In gouty patients, exacerbation of gout, and uric acid stones with or without hematuria, renal colic, or costovertebral pain, have been observed.
Symptoms And Treatment Of Overdose: Symptoms and Treatment: In the event of overdosage, symptomatic and supportive measures should be employed along with gastric lavage. If signs of CNS excitation are present, a short-acting barbiturate may be given parenterally.
Dosage And Administration: Gout: Therapy with probenecid should not be initiated until an acute gouty attack has subsided. However, if an acute attack is precipitated during therapy, the drug may be continued without changing the dosage, and therapeutic doses of colchicine, indomethacin or other appropriate therapy should be given to control the acute attack.
The recommended dosage for adults is 0.25 g (1/2 tablet) twice a day for 1 week, followed by 0.5 g (1 tablet) twice a day thereafter.
Some degree of renal impairment is common in patients with gout, therefore, a daily dosage of 1 g may be adequate for many patients. If necessary, however, the daily dosage may be increased every 4 weeks by increments of 0.5 g (within tolerance, and usually not beyond 2 g daily) if symptoms of gouty arthritis are not controlled or the 24-hour uric acid excretion is not above 700 mg.
Probenecid may not be effective in chronic renal insufficiency particularly when the glomerular filtration rate is 30 mL/min or less.
Gastric intolerance may be indicative of overdosage, and may be corrected by reducing the dosage without losing the therapeutic response.
Probenecid should be continued at a dosage that will maintain a normal serum uric acid level. When acute attacks have been absent for 6 months or more and serum uric levels remain within normal limits, the daily dosage of probenecid may be decreased by 1 tablet every 6 months to a minimum effective dosage. The maintenance dosage should not be reduced to the point where serum uric acid levels tend to rise.
Penicillin Therapy of Gonorrhea: For the treatment of uncomplicated gonorrhea in men or women, a single 1 g (2 tablets) dose of probenecid should be given with adequate doses of either oral ampicillin or aqueous procaine penicillin G injected i.m. If oral ampicillin is used, probenecid should be administered simultaneously. If parenteral penicillin is administered, the dose of probenecid should be given preferably at least 30 minutes before the injection.
Treatment of Contacts: Patients with known exposure to gonorrhea should receive the same treatment as those known to have gonorrhea.
Penicillin and Cephalosporin Therapy (general): The recommended dosage for adults is 2 g (4 tablets) daily in divided doses, reduced in older patients suspected of having renal impairment. Because of its mechanism of action, probenecid is not recommended for concurrent use with penicillin in the presence of known renal impairment.
The recommended dosage for children 2 years of age or older is 25 mg/kg (or 0.7 g/mbody surface) of body weight initially, followed by 40 mg/kg (or 1.2 g/mbody surface) daily in divided doses every 6 hours (see Table I). The adult dosage, however is recommended for children weighing more than 50 kg.
The phenolsulfonphthalein (PSP) excretion test may be used to determine the effectiveness of probenecid in retarding penicillin excretion and maintaining therapeutic levels. The renal clearance of PSP is reduced to about one-fifth of the normal rate when dosage of probenecid is adequate.
Availability And Storage: Each white, discoid-shaped (round), uncoated tablet, flat with a beveled edge, bisected on one side, coded MSD 501 on the other, contains: probenecid 500 mg. Nonmedicinal ingredients: calcium stearate, cornstarch, gelatin and magnesium carbonate. Bottles of 100. Store at 15 to 30°C. (Shown in Product Recognition Section)
BENEMID® MSD Probenecid Uricosuric Agent