Drug class: Uricosuric Agents

Medically reviewed by Drugs.com on Jul 31, 2023. Written by ASHP.

Introduction

Uricosuric and renal tubular transport blocking agent.

Uses for Probenecid

Hyperuricemia Associated with Gout

Reduction of serum uric acid concentrations in chronic gouty arthritis and tophaceous gout in patients with frequent disabling gout attacks.

Management of gout when there are visible tophi or when serum urate concentrations exceed 8.5–9 mg/dL and patient has family history of tophi or low urate excretion.

Not usually recommended for management of asymptomatic hyperuricemia; however, some clinicians have suggested that therapy be initiated when serum urate concentrations exceed 9 mg/dL (by colorimetric method) because these concentrations often are associated with increased joint changes and renal complications.

Of no value in treatment of acute gout attacks (due to lack of analgesic or anti-inflammatory activity).

Fixed combination of probenecid and colchicine (probenecid/colchicine): Treatment of chronic gouty arthritis complicated by frequent, recurrent, acute gout attacks. Probenecid/colchicine has limited usefulness for prophylactic therapy because colchicine content in the fixed combination exceeds amount required for prophylaxis in most patients.

Hyperuricemia Secondary to Other Causes

Has been used effectively to promote uric acid excretion in hyperuricemia secondary to the administration of thiazide and related diuretics^{† [off-label]}, furosemide^{† [off-label]}, ethacrynic acid^{† [off-label]}, pyrazinamide^{† [off-label]}, or ethambutol^{† [off-label]}.

Not recommended to treat hyperuricemia secondary to cancer chemotherapy, radiation, or myeloproliferative neoplastic diseases because of increased risk of uric acid nephropathy.

Use with Anti-infectives

Used for therapeutic advantage to decrease clearance and increase plasma concentrations of certain β-lactam antibacterials. Also used to reduce clearance of cidofovir and decrease nephrotoxicity associated with the antiviral.

Used concomitantly with IM penicillin G procaine for treatment of neurosyphilis.

Used concomitantly with IM cefoxitin for treatment of mild to moderately severe acute pelvic inflammatory disease (PID) or treatment of uncomplicated urogenital or anorectal gonorrhea.

Used concomitantly with IV cidofovir for management of cytomegalovirus (CMV) retinitis.

Probenecid Dosage and Administration

General

Hyperuricemia Associated with Gout

• Adjust dosage according to individual response and tolerance.

• Maintain fluid intake to yield daily urine output of ≥2–3 L; alkalinization of urine is desirable. (See Renal Effects under Cautions.)

• Administer prophylactic doses of colchicine concurrently during first 3–6 months of probenecid therapy because probenecid may increase frequency of acute gout attacks during first 6–12 months of therapy. Initiate colchicine prior to uricosuric therapy since sudden changes in serum urate concentrations may precipitate acute attacks.

• Initially, low probenecid doses are recommended to reduce possibility of flare-up of acute gouty attacks and to prevent massive uricosuria. If acute attack occurs during therapy, continue probenecid without changing dosage and administer full therapeutic doses of colchicine or other anti-inflammatory agents. (See Acute Gout Attacks under Cautions.)

• Serum urate concentrations usually reach a minimum within a few days after beginning therapy.

Use with Anti-infectives

• The 15-minute IV phenolsulfonphthalein (PSP) excretion test can be used to determine effectiveness of probenecid in decreasing penicillin excretion. Probenecid dosage is adequate when renal clearance of the dye is reduced to approximately 20% of the normal rate.

Administration

Oral Administration

Administer orally.

Adverse GI effects may be minimized by administration with food or antacids; dosage reduction may be required.

Dosage

Pediatric Patients

Use with Anti-infectives

General Dosage (Use with Penicillin Therapy)

Oral

Children 2–14 years of age: Manufacturer recommends initial dose of 25 mg/kg (or 700 mg/m²) followed by maintenance dosage of 40 mg/kg (or 1.2 g/m²) daily given in 4 divided doses.

Children weighing >50 kg: Manufacturer recommends 2 g daily given in divided doses.

Adults

Hyperuricemia Associated with Gout

Oral

Initially, 250 mg twice daily for one week, initiated 2–3 weeks after an acute gout attack. Subsequently, increase to 500 mg twice daily.

Patients previously controlled with other uricosuric therapy: Initially, 500 mg twice daily.

If gouty arthritis is not controlled or if 24-hour uric acid excretion is <700 mg, increase daily dosage by 500 mg every 4 weeks as tolerated to a maximum of 2–3 g daily.

If acute attacks have been absent ≥6 months and serum urate concentrations are controlled, consider decreasing daily dosage by 500 mg every 6 months.

Continue therapy indefinitely; irregular dosage schedules may lead to increased serum urate concentrations.

Probenecid/Colchicine Fixed Combination

Oral

Manufacturer recommends initial dosage of 1 tablet (probenecid 500 mg in fixed combination with colchicine 0.5 mg) once daily for 1 week, then 1 tablet twice daily. If gouty arthritis is not controlled or if 24-hour uric acid excretion is not >700 mg, increase daily dosage by 1 tablet every 4 weeks as tolerated (generally not exceeding 4 tablets [probenecid 2 g and colchicine 2 mg] daily).

If acute attacks have been absent ≥6 months and serum urate concentrations are controlled, manufacturer recommends reducing dosage by 1 tablet every 6 months as long as serum urate concentrations remain controlled.

Probenecid/colchicine has limited usefulness for prophylactic therapy because colchicine content in the fixed combination exceeds amount required for prophylaxis in most patients.

Use with Anti-infectives

General Dosage (Use with Penicillin Therapy)

Oral

Manufacturer recommends 2 g daily in divided doses.

Neurosyphilis

Oral

CDC and others recommend 500 mg 4 times daily for 10–14 days in conjunction with IM penicillin G procaine regimen (2.4 million units of penicillin G once daily for 10–14 days); some clinicians recommend that this regimen be followed by a regimen of IM penicillin G benzathine (2.4 million units of penicillin G once weekly for up to 3 weeks) without probenecid.

PID

Oral

CDC recommends 1 g as a single dose in conjunction with IM cefoxitin (2 g as a single dose), followed by oral doxycycline (100 mg twice daily for 14 days) with or without oral metronidazole (500 mg twice daily for 14 days).

Uncomplicated Gonorrhea

Oral

Urogenital or anorectal gonorrhea: CDC recommends 1 g as a single dose in conjunction with IM cefoxitin (2 g as a single dose).

CMV Retinitis

Oral

Use 3-dose regimen of probenecid for each cidofovir dose. Give 2 g of probenecid 3 hours prior to initiation of each cidofovir IV infusion and give 1-g doses of probenecid at 2 and 8 hours after completion of each cidofovir IV infusion (total of 4 g of probenecid for each cidofovir dose).

Prescribing Limits

Adults

Hyperuricemia Associated with Gout

Oral

Maximum 2–3 g daily.

Special Populations

Hepatic Impairment

No specific dosage recommendations.

Renal Impairment

Hyperuricemia Associated with Gout

Oral

May need to increase dosage. (See Renal Impairment under Cautions.)

Geriatric Patients

No dosage adjustments except those related to renal impairment.

Cautions for Probenecid

Contraindications

• Known hypersensitivity to probenecid.

• Children <2 years of age.

• Known blood dyscrasias.

• Uric acid kidney stones.

• Initiation of probenecid during acute gout attack. (See Acute Gout Attacks under Cautions.)

Warnings/Precautions

Warnings

Acute Gout Attacks

May exacerbate and prolong inflammation during acute gout attacks. Do not initiate probenecid until after acute gout attack subsides.

Possible increased frequency of acute gout attacks during first 6–12 months of probenecid therapy. If acute attacks occur during therapy, continue probenecid and administer colchicine or other anti-inflammatory agents to control the acute attack.

Interactions

Salicylates contraindicated in patients receiving probenecid. (See Specific Drugs under Interactions.)

Probenecid increases plasma concentrations of methotrexate; methotrexate toxicity reported when probenecid used concomitantly in animals. (See Specific Drugs under Interactions.)

Sensitivity Reactions

Hypersensitivity Reactions

Severe allergic reactions and anaphylaxis reported rarely; most cases occurred within several hours after administration of probenecid in patients who previously received the drug. Hypersensitivity may be characterized by dermatitis, pruritus, fever, sweating, and hypotension.

If hypersensitivity reaction occurs, discontinue probenecid.

General Precautions

Renal Effects

Possible development of uric acid stones due to increased concentration of uric acid in renal tubules; may result in hematuria, renal colic, costovertebral pain. Usually occurs when probenecid is initiated.

May be prevented by alkalinization of the urine and adequate hydration. (See General under Dosage and Administration.) Monitor acid-base balance if alkali is administered.

Peptic Ulcer

Use with caution in patients with history of peptic ulcer.

Use of Fixed Combinations

When used in fixed combination with colchicine (probenecid/colchicine), consider cautions, precautions, and contraindications associated with colchicine.

Specific Populations

Pregnancy

Probenecid crosses placenta and appears in cord blood; evaluate risks and benefits when considering use in women of childbearing potential.

Lactation

Distribution into human milk expected; effects on nursing infant not known. Caution advised because of potential risks to nursing infants.

Pediatric Use

Contraindicated in children <2 years of age.

Geriatric Use

Consider age-related decreases in renal function when selecting dosage; adjust dosage if necessary.

Renal Impairment

Increased dosage may be required. Manufacturer states may not be effective in gouty patients with chronic renal insufficiency, especially those with GFR ≤30 mL/minute. Avoidance of probenecid use in patients with moderate to severe renal impairment (Cl_cr <50 mL/minute) has been suggested.

Because of its mechanism of action, concomitant use with penicillin therapy not recommended in patients with known renal impairment.

Common Adverse Effects

Headache, vomiting, nausea, anorexia.

Drug Interactions

Weak Organic Acids

Probenecid inhibits renal tubular secretion of many weak organic acids, thereby increasing plasma concentrations of weak organic acids.

Specific Drugs and Laboratory Tests

Probenecid Pharmacokinetics

Absorption

Bioavailability

Rapidly and completely absorbed following oral administration, with peak plasma concentration attained within 2–4 hours.

Onset

Following oral administration, maximal renal clearance of uric acid is reached after 30 minutes; exerts its effect on plasma penicillin concentrations after 2 hours.

Distribution

Extent

CSF concentrations of probenecid are about 2% of plasma concentrations.

Crosses placenta and appears in cord blood. Not known whether distributed into milk; however, distribution into milk is expected.

Plasma Protein Binding

Approximately 75%.

Elimination

Metabolism

Slowly metabolized, principally by the liver, to metabolites that may possess some uricosuric activity.

Elimination Route

Excreted principally in the urine as monoacyl glucuronide and unchanged drug. Alkalinization of urine increases renal probenecid excretion.

Half-life

Dose dependent; 4–17 hours.

Stability

Storage

Oral

Tablets

Probenecid: 20–25°C in well-closed container.

Probenecid/colchicine: 20–25°C in well-closed, light-resistant container.

Actions

• Competitively inhibits active reabsorption of urate at the proximal convoluted tubule, increasing urinary excretion of uric acid and reducing serum urate concentrations.

• Competitively inhibits tubular secretion of weak organic acids (e.g., penicillins, most cephalosporins, some other β-lactam anti-infectives) and substantially increases plasma concentrations of acidic drugs eliminated principally by renal secretion.

• Mechanism(s) of action responsible for inhibition of renal tubular transport not known; may inhibit transport enzymes that require a source of high energy phosphate bonds and/or nonspecifically interfere with substrate access to protein receptor sites on the kidney tubules.

Advice to Patients

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as concomitant illnesses.

• Potential for drug to increase incidence of gouty arthritis attacks during therapy initiation. Continue probenecid during acute attacks, without changing dose, and add therapeutic dosages of colchicine or other anti-inflammatory agents.

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.

• Importance of informing patients of other important precautionary information. (See Cautions.)

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

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