probenecid 500 mg tablet

Uses

Hyperuricemia Associated with Gout

Probenecid is used to lower serum urate concentrations in the treatment of chronic gouty arthritis and tophaceous gout. The drug is indicated in patients with frequent disabling attacks of gout. The presence of elevated serum urate concentrations alone usually is not considered by most clinicians to be an indication for therapy. However, some clinicians believe that therapy should be initiated when serum urate concentrations exceed 9 mg/dL (by the colorimetric method) because these concentrations are often associated with increased joint changes and renal complications. Probenecid is also indicated when there are visible tophi or when serum urate concentrations are greater than 8.5-9 mg/dL in a patient with a family history of tophi or low uric acid excretion. The goal of probenecid therapy is to lower serum urate concentrations to about 6 mg/dL. By decreasing serum urate concentrations, probenecid prevents or reduces chronic joint changes and tophi formation, eventually reduces the frequency of acute gout attacks, and may improve renal function in gouty patients.

Since probenecid has no analgesic or anti-inflammatory activity, it is of no value in the treatment of acute gout attacks and will exacerbate and prolong inflammation during the acute phase. Probenecid should not be started until 2-3 weeks after an acute gout attack. The drug may increase the frequency of acute attacks during the first 6-12 months of therapy, even when normal or subnormal serum urate concentrations have been maintained. Therefore, prophylactic doses of colchicine should be administered concurrently during the first 3-6 months of probenecid therapy. (The usefulness of the commercially available fixed-dosage preparation of probenecid combined with colchicine is limited, however, because the colchicine present exceeds the amount required by most patients.) Acute attacks may occur in spite of prophylactic therapy, but usually become less severe and are of briefer duration after several months of probenecid therapy. During these acute attacks, probenecid should be continued without changing dosage and full therapeutic doses of colchicine or other anti-inflammatory agents should be administered.

In early uncomplicated gout, either a uricosuric agent or allopurinol may be used. Probenecid may be effective in gouty patients with mild renal impairment, but large doses may be required. The drug is not effective, however, when chronic renal insufficiency exists, particularly in patients with moderate to severe renal impairment (creatinine clearance of less than 50 mL/minute). Since uricosuric agents tend to increase urinary uric acid concentrations and the risk of stone formation, they should be avoided; allopurinol is preferred in patients with urinary uric acid excretion of greater than 900 mg/day or with gouty nephropathy, urinary tract stones or obstruction, or azotemia. Although sulfinpyrazone produces fewer rashes and hypersensitivity reactions than does probenecid, the latter drug is preferred because adverse GI and hematologic effects occur less frequently and are less severe than with sulfinpyrazone. Patients who are refractory to or cannot tolerate probenecid may respond to sulfinpyrazone or allopurinol. The activity of allopurinol and uricosurics is additive and when administered concomitantly, smaller doses of each drug can be used. Combined use of the 2 types of drugs is especially effective in the presence of tophaceous deposits. Some clinicians have suggested concurrent administration of sulfinpyrazone and probenecid if the uricosuric response to one of these drugs is insufficient at maximum therapeutic dosages.

Hyperuricemia Secondary to Other Causes

Probenecid has been used effectively and is commonly employed to promote uric acid excretion in hyperuricemia secondary to the administration of thiazide and related diuretics, furosemide, ethacrynic acid, pyrazinamide, or ethambutol. Uricosurics should not be used to treat hyperuricemia secondary to cancer chemotherapy, radiation, or myeloproliferative neoplastic diseases because they may increase the risk of uric acid nephropathy.

Other Uses

Probenecid is used as an adjuvant to therapy with penicillin G or V, ampicillin, oxacillin, cloxacillin, methicillin (no longer commercially available in the US), or nafcillin to elevate and prolong the plasma concentrations of these antibiotics when administered orally or parenterally. Probenecid is also used concomitantly with amoxicillin, cephalosporin antibiotics, or some other β-lactam antibiotics (e.g., cefoxitin). Combined antibiotic and probenecid therapy rarely is necessary and should be limited to those situations in which high plasma and tissue antibiotic concentrations are necessary. Combined therapy with penicillin antibiotics and probenecid may be indicated for infections caused by bacteria that are only moderately sensitive to the antibiotic. In addition, probenecid is used concurrently with amoxicillin as one of the US Centers for Disease Control's (CDC) recommended alternative treatments for uncomplicated gonococcal infections caused by susceptible nonpenicillinase-producing Neisseria gonorrhoeae; with cefuroxime axetil as part of one CDC-recommended alternative treatment for uncomplicated gonococcal infections caused by susceptible penicillinase-producing Neisseria gonorrhoeae; and with cefoxitin as part of the CDC-recommended treatment for acute pelvic inflammatory disease in ambulatory adults and adolescents. Probenecid is also used concurrently with penicillin G procaine as part of one CDC-recommended treatment for neurosyphilis in ambulatory patients in whom compliance with therapy can be ensured. Although not currently included in the CDC's recommended regimens for the treatment of gonococcal infections, probenecid also has been used concurrently with amoxicillin or penicillin G procaine for the management of infections caused by penicillin-susceptible N. gonorrhoeae.

Because of its effects on CSF concentrations of HVA and 5-HIAA, probenecid has been used in the diagnosis of parkinsonian syndrome and mental depression.

Dosage and Administration

Administration

Probenecid is administered orally. Adverse GI effects may be minimized by taking the drug with food or antacids, or may require dosage reduction. Daily urine output should be maintained at a minimum of 2-3 L in all patients, and alkalinization of the urine is desirable.

Dosage

Dosage of probenecid should be adjusted according to the response and tolerance of the patient.

Hyperuricemia Associated with Gout

In the treatment of gout, low doses of probenecid are used initially to reduce the possibility of flare-up of acute gouty attacks and to prevent massive uricosuria. However, patients previously controlled with other uricosuric therapy may begin probenecid at full maintenance dosage. The usual adult dosage of probenecid is 250 mg twice daily during the first week of therapy, followed by 500 mg twice daily. Serum urate concentrations usually reach a minimum within a few days after beginning therapy. If lower dosages do not control gouty arthritis symptoms or if the 24-hour uric acid excretion is not above 700 mg, daily dosage may be increased every 4 weeks by increments of 500 mg to a maximum of 2-3 g daily, especially in patients with mild renal impairment. Probenecid may not be effective and should be avoided in patients with moderate to severe renal impairment (creatinine clearance of less than 50 mL/minute). After acute attacks of gout have been absent for 6 months and serum urate concentrations have been controlled, it may be possible to reduce the dosage. Daily dosage may be reduced by 500 mg every 6 months as long as serum urate concentrations remain controlled. Uricosuric therapy should be continued indefinitely; irregular dosage schedules may lead to increased serum urate concentrations.

Other Uses

When used in conjunction with a penicillin, the usual adult dosage of probenecid is 500 mg 4 times daily. This dosage should be decreased in older patients with impaired renal function. In children 2-14 years of age, a probenecid dose of 25 mg/kg or 700 mg/m is given initially followed by 40 mg/kg daily or 1.2 g/m daily, given in 4 divided doses. Children weighing more than 50 kg may receive the adult dosage.

As alternative treatments for acute, uncomplicated gonorrhea in adults and children weighing 45 kg or more, the CDC currently recommends that 1 g of probenecid be administered orally with 3 g of oral amoxicillin for infections caused by susceptible nonpenicillinase-producing Neisseria gonorrhoeae or with cefuroxime axetil for infections caused by susceptible penicillinase-producing Neisseria gonorrhoeae; each of these treatments is followed by therapy with doxycycline 100 mg twice daily for 7 days. The usual diagnostic and follow-up procedures associated with the treatment of sexually transmitted diseases should be followed.

For the treatment of acute pelvic inflammatory disease in ambulatory patients when the infection is caused by susceptible N. gonorrhoeae, Chlamydia trachomatis, or other commonly encountered susceptible organisms, the CDC and many clinicians suggest that adults and adolescents may receive a single 1-g oral dose of probenecid with a single 2-g IM dose of cefoxitin, followed by oral doxycycline 100 mg twice daily for 10-14 days or oral tetracycline hydrochloride 500 mg 4 times daily for 10-14 days.

When penicillin G procaine is used for the treatment of neurosyphilis in adults, the CDC states that an oral probenecid dosage of 500 mg 4 times daily should be administered in conjunction with 2.4 million units of penicillin G procaine IM once daily for 10-14 days, followed by 2.4 million units of penicillin G benzathine IM weekly for 3 doses without probenecid.

To diagnose parkinsonian syndrome or mental depression, 500 mg of probenecid has been given every 12 hours for 5 doses. CSF samples were obtained 12 hours after the last dose and were assayed for 5-HIAA or HVA. CSF concentrations of HVA in parkinsonian patients and of 5-HIAA in mentally depressed patients were lower than those in healthy patients.

Cautions

Adverse Effects

In therapeutic dosage, probenecid is usually well tolerated and has a low incidence of adverse effects. The most frequent adverse effects include headache, anorexia, nausea, and vomiting. Other reported adverse effects include dizziness, flushing, sore gums, alopecia, urinary frequency, leukopenia, and anemia. Nephrotic syndrome, hepatic necrosis, and aplastic anemia occur rarely. Mild to moderately severe hemolytic anemia, which in some patients could be related to genetic deficiency of glucose-6-phosphate dehydrogenase, has also been reported.

Hypersensitivity reactions which may be characterized by dermatitis, pruritus, fever, sweating, hypotension, and anaphylactic reaction occur rarely. Most cases of severe allergic reactions and anaphylaxis have been reported to occur within several hours after administration in patients who had previously received the drug. If a hypersensitivity reaction occurs in patients receiving probenecid, the drug should be discontinued. If rash occurs during administration of penicillin with probenecid and the causative agent cannot be determined, discontinuance of both drugs may be necessary.

Probenecid increases the concentration of uric acid in the renal tubules and, in some gouty patients, may promote development of uric acid stones which may cause renal colic, hematuria, and costovertebral pain. This is most likely to occur when probenecid therapy is initiated. Maintenance of a large volume of alkaline urine increases the solubility of uric acid and thus reduces the risk of stone formation in the kidneys. The drug may also increase the frequency of acute gouty attacks during the first 6-12 months of therapy.

Precautions and Contraindications

Probenecid should be used cautiously in patients with a history of peptic ulcer. The drug should not be used in patients with blood dyscrasias or uric acid kidney stones. It is also recommended that the drug not be used with a penicillin in patients with known renal impairment. Probenecid should be discontinued if a hypersensitivity reaction occurs and is contraindicated in patients with known hypersensitivity to the drug.

Pediatric Precautions

Probenecid is contraindicated in children younger than 2 years of age.

Pregnancy

Pregnancy

With the exception of one neonatal death not definitely related to probenecid therapy, the drug has been used during pregnancy without adverse effect to the mother or child.

Drug Interactions

Weak Organic Acids

Probenecid inhibits renal tubular secretion of many weak organic acids. The drug inhibits secretion of penicillins, most cephalosporins, and some other β-lactam antibiotics, thereby increasing plasma concentrations of the anti-infectives. When probenecid is used concomitantly with one of these anti-infective agents, the possibility that increased plasma concentrations of the anti-infective agent may result in an increased incidence of adverse reactions associated with the anti-infective agent should be considered; psychic disturbances have been reported in patients receiving probenecid concomitantly with a penicillin or other β-lactam antibiotic. Total plasma sulfonamide concentrations are also elevated by probenecid; however, free sulfonamide concentrations are not altered and concomitant use of the drugs is not therapeutically useful. By blocking renal secretion of nitrofurantoin, probenecid may reduce the efficacy of the urinary tract anti-infective and may also increase its toxic potential; concurrent administration of these drugs should be avoided whenever possible. Tubular secretion and hepatic uptake of rifampin are also inhibited by probenecid, but the small increases in plasma concentrations of the antituberculosis agent are not clinically important. Probenecid may also inhibit renal elimination of methotrexate, resulting in increased serum concentrations of methotrexate and methotrexate toxicity. If probenecid and methotrexate are administered concurrently, dosage of methotrexate should be reduced and patients should be carefully monitored for signs of adverse effects of methotrexate; serum methotrexate concentrations may need to be monitored.

Theoretically, hypoglycemia may result from probenecid-induced elevations of plasma concentrations of chlorpropamide and other oral sulfonylurea antidiabetic agents. In one patient, probenecid reportedly prolonged clotting time by inhibiting secretion of heparin during concomitant therapy. Elevated plasma concentrations of aminosalicylic acid and dapsone may be caused by concomitant administration of probenecid, thus increasing the possibility of toxic effects from these agents. Probenecid also inhibits tubular secretion of pantothenic acid and riboflavin, and intestinal absorption of riboflavin, but the importance of these interactions is not known.

Nonsteroidal Anti-inflammatory Agents

The uricosuric actions of probenecid and salicylates are mutually antagonistic. Salicylate-induced uricosuria is inhibited by usual doses of probenecid. However, probenecid-induced uricosuria appears to be inhibited principally when the serum salicylate concentration exceeds 50 mcg/mL. Salicylates are generally contraindicated during uricosuric therapy, but occasional doses of salicylates for analgesia or antipyresis in patients receiving probenecid may be insufficient to produce a clinically important interaction; alternatively, if an analgesic or antipyretic is required during probenecid therapy, acetaminophen may be used. (See Drug Interactions: Other Drugs.)

When probenecid is administered concomitantly with indomethacin, plasma concentration, plasma half-life, and therapeutic effects of indomethacin have been reported to increase. The mechanisms of this interaction remain unknown but have been attributed to blockade of renal tubular secretion of indomethacin and to an interference with the biliary clearance of indomethacin. Although the clinical importance of the interaction has not been established, a decreased total daily dose of indomethacin may produce a satisfactory therapeutic response when indomethacin and probenecid are used concurrently and increases in indomethacin dosage, if necessary, should be made carefully and in small increments. Indomethacin does not interfere with the uricosuric action of probenecid.

Although the clinical importance has not been determined to date, concomitant administration of probenecid with some other nonsteroidal anti-inflammatory agents (e.g., ketoprofen, meclofenamate, naproxen, sulindac) increases the plasma elimination half-lives and plasma concentrations of these agents. Concomitant administration of probenecid and sulindac increases plasma concentrations of sulindac and its sulfone metabolite but has only a slight effect on plasma concentrations of the sulfide metabolite. Sulindac causes a slight reduction in the uricosuric action of probenecid, but this effect is probably not clinically important in most patients. When probenecid is administered concomitantly with ketoprofen, total and free plasma concentrations of ketoprofen are substantially increased as a result of decreased protein binding of ketoprofen, decreased total apparent plasma clearance of ketoprofen, and decreased apparent plasma clearance of free ketoprofen. In addition, probenecid appears to inhibit conjugation of ketoprofen and renal excretion of ketoprofen conjugates. The manufacturer of ketoprofen states that concomitant use of the drug and probenecid is not recommended.

Drugs that Increase Serum Uric Acid

Many drugs may increase serum urate concentrations, including most diuretics, pyrazinamide, diazoxide, alcohol, and mecamylamine. If these drugs are administered during uricosuric therapy, probenecid dosage may need to be increased. Antineoplastic agents also increase serum urate concentrations; however, uricosurics may increase the risk of uric acid nephropathy and should not be used in patients receiving cancer chemotherapy.

Other Drugs

Probenecid inhibits the renal secretion of sulfinpyrazone and its active metabolite, but these 2 uricosuric drugs may be given concurrently without adverse interaction. Uricosuric drugs promote excretion of allopurinol's active metabolite, but it is generally agreed that the effects of allopurinol and uricosurics are additive and the combination is usually used to therapeutic advantage.

Although the clinical importance has not been determined, concomitant administration of probenecid with acetaminophen or lorazepam reportedly increases the plasma elimination half-lives and peak plasma concentrations of these drugs.

Probenecid increases the urinary excretion of insulin, but this effect is not clinically important. Furosemide and ethacrynic acid naturesis is inhibited by probenecid. Probenecid increases excretion of calcium, magnesium, and citrate in patients taking thiazide diuretics, but does not antagonize thiazide-induced naturesis.

It has been reported that patients receiving probenecid may require substantially lower amounts of thiopental sodium (no longer commercially available in the US) for induction of anesthesia. Ketamine and thiopental sodium anesthesia is substantially prolonged in rats receiving probenecid.

Administration of probenecid (500 mg every 6 hours) with oral ganciclovir has resulted in a 53% increase in the AUC of ganciclovir; renal clearance of ganciclovir decreased 22%, which is consistent with an interaction involving competition for renal tubular secretion. Because valganciclovir is rapidly and extensively converted to ganciclovir, interactions associated with ganciclovir are expected to occur in patients receiving valganciclovir.

Pharmacokinetics

Absorption

Probenecid is rapidly and completely absorbed from the GI tract. Plasma probenecid concentrations of 40-60 mcg/mL produce maximal inhibition of renal penicillin excretion, while concentrations of 100-200 mcg/mL produce a uricosuric effect. Plasma probenecid concentrations of 25 mcg/mL are reached 30 minutes after a single 1-g oral dose; plasma concentrations peak in 2-4 hours and remain above 30 mcg/mL for 8 hours. Following a single 2-g oral dose, peak plasma concentrations of 150-200 mcg/mL are reached in 4 hours and concentrations above 50 mcg/mL are sustained for 8 hours.

Probenecid usually produces maximal renal clearance of uric acid 30 minutes after being administered and exerts its effect on plasma penicillin concentrations after about 2 hours. Because blood probenecid concentrations are difficult to determine, serum urate concentrations should be used to monitor uricosuric therapy. The 15-minute IV phenolsulfonphthalein (PSP) excretion test can be used as an index to the probenecid dosage required to decrease penicillin secretion. Probenecid dosage is adequate when renal clearance of the dye is reduced to approximately 20% of the normal rate.

Distribution

At a plasma concentration of 14 mcg/mL, about 75% of the drug is bound to proteins. Probenecid concentrations in the CSF are approximately 2% of plasma concentrations. The drug also crosses the placenta.

Elimination

Following oral administration of 2 g of probenecid, plasma half-life of the drug ranges from 4-17 hours; the half-life decreases as the dose decreases from 2 g to 500 mg.

Probenecid is slowly metabolized by the liver to probenecid monoacyl glucuronide, two monohydroxylated compounds, a carboxylated metabolite, and an N-depropylated compound. These metabolites may possess some uricosuric activity. Small amounts of probenecid are filtered at the glomeruli, but most of the drug is actively secreted at the proximal tubule. Renal tubular reabsorption of the drug is nearly complete in acidic urine; however, probenecid metabolites are not reabsorbed as extensively as the parent compound. Alkalinization of the urine decreases reabsorption of probenecid. Although this also increases excretion of the drug, probenecid's efficacy is not appreciably decreased. After 2 days, 5-11% of a single 2-g oral probenecid dose is excreted in urine as unchanged drug, 16-33% as its monoacyl glucuronide, and the remainder as approximately equal amounts of the 4 other metabolites.