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Probenecid

Class: Uricosuric Agents
VA Class: MS400
Chemical Name: 4-[(dipropylamino)sulfonyl]benzoic acid
Molecular Formula: C13H19NO4S
CAS Number: 57-66-9

Medically reviewed by Drugs.com. Last updated on Aug 10, 2020.

Introduction

Uricosuric and renal tubular transport blocking agent.b

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.100 b

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.b

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.b

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

Fixed combination of probenecid and colchicine (probenecid/colchicine): Treatment of chronic gouty arthritis complicated by frequent, recurrent, acute gout attacks.101 Probenecid/colchicine has limited usefulness for prophylactic therapy because colchicine content in the fixed combination exceeds amount required for prophylaxis in most patients.b

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, furosemide, ethacrynic acid, pyrazinamide, or ethambutol.b

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

Use with Anti-infectives

Used for therapeutic advantage to decrease clearance and increase plasma concentrations of certain β-lactam antibacterials.100 110 155 344 Also used to reduce clearance of cidofovir and decrease nephrotoxicity associated with the antiviral.109 110

Used concomitantly with IM penicillin G procaine for treatment of neurosyphilis.155 344

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.344

Used concomitantly with IV cidofovir for management of cytomegalovirus (CMV) retinitis.109 110 155

Probenecid Dosage and Administration

General

Hyperuricemia Associated with Gout

  • Adjust dosage according to individual response and tolerance.100 b

  • Maintain fluid intake to yield daily urine output of ≥2–3 L; alkalinization of urine is desirable.100 b (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.b Initiate colchicine prior to uricosuric therapy since sudden changes in serum urate concentrations may precipitate acute attacks.124 125 127 129

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

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

Use with Anti-infectives

  • The 15-minute IV phenolsulfonphthalein (PSP) excretion test can be used to determine effectiveness of probenecid in decreasing penicillin excretion.100 b Probenecid dosage is adequate when renal clearance of the dye is reduced to approximately 20% of the normal rate.100 b

Administration

Oral Administration

Administer orally.100

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

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.100

Children weighing >50 kg: Manufacturer recommends 2 g daily given in divided doses.100

Adults

Hyperuricemia Associated with Gout
Oral

Initially, 250 mg twice daily for one week, initiated 2–3 weeks after an acute gout attack.100 b Subsequently, increase to 500 mg twice daily.100 b

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

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.100 b

If acute attacks have been absent ≥6 months and serum urate concentrations are controlled, consider decreasing daily dosage by 500 mg every 6 months.100 b

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

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.101 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).101

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.101

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

Use with Anti-infectives
General Dosage (Use with Penicillin Therapy)
Oral

Manufacturer recommends 2 g daily in divided doses.100

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);155 344 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.155

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).344

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).344

CMV Retinitis
Oral

Use 3-dose regimen of probenecid for each cidofovir dose.109 155 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).109 155

Prescribing Limits

Adults

Hyperuricemia Associated with Gout
Oral

Maximum 2–3 g daily.100 b

Special Populations

Hepatic Impairment

No specific dosage recommendations.100

Renal Impairment

Hyperuricemia Associated with Gout
Oral

May need to increase dosage.100 (See Renal Impairment under Cautions.)

Geriatric Patients

No dosage adjustments except those related to renal impairment.100

Cautions for Probenecid

Contraindications

  • Known hypersensitivity to probenecid.100

  • Children <2 years of age.100

  • Known blood dyscrasias.100

  • Uric acid kidney stones.100

  • Initiation of probenecid during acute gout attack.100 (See Acute Gout Attacks under Cautions.)

Warnings/Precautions

Warnings

Acute Gout Attacks

May exacerbate and prolong inflammation during acute gout attacks.b Do not initiate probenecid until after acute gout attack subsides.100

Possible increased frequency of acute gout attacks during first 6–12 months of probenecid therapy.100 If acute attacks occur during therapy, continue probenecid and administer colchicine or other anti-inflammatory agents to control the acute attack.100

Interactions

Salicylates contraindicated in patients receiving probenecid.100 (See Specific Drugs under Interactions.)

Probenecid increases plasma concentrations of methotrexate;100 methotrexate toxicity reported when probenecid used concomitantly in animals.100 (See Specific Drugs under Interactions.)

Sensitivity Reactions

Hypersensitivity Reactions

Severe allergic reactions and anaphylaxis reported rarely;100 most cases occurred within several hours after administration of probenecid in patients who previously received the drug.100 Hypersensitivity may be characterized by dermatitis, pruritus, fever, sweating, and hypotension.b

If hypersensitivity reaction occurs, discontinue probenecid.100

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.100 b Usually occurs when probenecid is initiated.b

May be prevented by alkalinization of the urine and adequate hydration.100 b (See General under Dosage and Administration.) Monitor acid-base balance if alkali is administered.100

Peptic Ulcer

Use with caution in patients with history of peptic ulcer.100 b

Use of Fixed Combinations

When used in fixed combination with colchicine (probenecid/colchicine), consider cautions, precautions, and contraindications associated with colchicine.101

Specific Populations

Pregnancy

Probenecid crosses placenta and appears in cord blood;100 evaluate risks and benefits when considering use in women of childbearing potential.100

Lactation

Distribution into human milk expected; effects on nursing infant not known.114 Caution advised because of potential risks to nursing infants.114

Pediatric Use

Contraindicated in children <2 years of age.100

Geriatric Use

Consider age-related decreases in renal function when selecting dosage; adjust dosage if necessary.100

Renal Impairment

Increased dosage may be required.100 Manufacturer states may not be effective in gouty patients with chronic renal insufficiency, especially those with GFR ≤30 mL/minute.100 Avoidance of probenecid use in patients with moderate to severe renal impairment (Clcr <50 mL/minute) has been suggested.b

Because of its mechanism of action, concomitant use with penicillin therapy not recommended in patients with known renal impairment.100

Common Adverse Effects

Headache,100 b vomiting,100 b nausea,100 b anorexia.100 b

Interactions for Probenecid

Weak Organic Acids

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

Specific Drugs and Laboratory Tests

Drug or Test

Interaction

Comments

Acetaminophen

Possible increased peak plasma concentrations of acetaminophen102

Select and adjust acetaminophen dosage with care; lower dosages may be adequate100

Alcohol

Potential for increased serum urate concentrationsb

May need to increase probenecid dosageb

Antidiabetic agents, oral (sulfonylureas)

Possible increased plasma concentrations of oral sulfonylurea antidiabetic agents; may increase risk of hypoglycemia100 b

β-Lactam anti-infectives (e.g., ampicillin, methicillin, nafcillin, oxacillin, penicillin G, cefoxitin)

Decreased renal excretion and increased plasma concentrations of β-lactam anti-infectives100 110 111 112

May increase risk of adverse effects associated with the β-lactam anti-infective;100 psychic disturbances reported when used with penicillin or other β-lactams100

Used concomitantly with penicillin G procaine or cefoxitin for therapeutic advantage100 110 155 344

Cidofovir

Decreased renal clearance of cidofovir109

Used concomitantly with cidofovir for therapeutic advantage109 110

Diazoxide

Potential for increased serum urate concentrationsb

May need to increase probenecid dosageb

Diuretics, loop (furosemide, ethacrynic acid)

Potential for increased serum urate concentrationsb

Inhibits furosemide and ethacrynic acid naturesisb

May need to increase probenecid dosageb

Diuretics, thiazide

Increased excretion of calcium, magnesium, and citrate; does not antagonize thiazide-induced naturesisb

Ganciclovir, valganciclovir

Ganciclovir: Increased AUC and decreased renal excretion of ganciclovir107 108

Valganciclovir: Increased AUC and decreased renal excretion of ganciclovir expected107

Ketamine

Substantially prolonged anesthesia reported in rats100

Lorazepam

Possible increased peak plasma concentrations of lorazepam100

Select and adjust lorazepam dosage with care; lower dosage may be adequate100

Methotrexate

Increased serum concentrations of methotrexate;100 concomitant use in animals resulted in methotrexate toxicity100

Reduce methotrexate dosage and monitor carefully100

NSAIAs (indomethacin, ketoprofen, meclofenamate, naproxen, sulindac)

Increased plasma concentrations of NSAIAs100 103 104 105

Sulindac: Possible decreased uricosuric action of probenecid103

Select and adjust NSAIA dosage with care; lower dosage may be adequate100

Changes in uricosuric action unlikely to be clinically important103

Ketoprofen: Concomitant use not recommended104

Nitrofurantoin

Possible inhibition of renal excretion of nitrofurantoin and decreased nitrofurantoin urine concentrations with possible decreased efficacy in treatment of UTIs;113 may increase risk of nitrofurantoin-associated adverse effects113

Avoid concomitant use whenever possibleb

Pyrazinamide

Pyrazinamide antagonizes uricosuric action of probenecid; potential for increased serum urate concentrations100 b

May need to increase probenecid dosageb

Rifampin

Possible inhibition of tubular secretion and hepatic uptake of rifampin resulting in small increases in plasma concentrations of rifampinb

Not considered clinically importantb

Salicylates

Reduced uricosuric effect of probenecid100 b

Concomitant use contraindicated100

Sulfonamides

Increased total sulfonamide plasma concentrations;100 free sulfonamide plasma concentrations not affected100

Concomitant use not therapeutically usefulb

If used concomitantly for prolonged periods, monitor plasma concentrations of the sulfonamide100

Tests for theophylline

Possible interference with Schack and Waxler assay resulting in falsely elevated theophylline concentrations100

Tests for urinary glucose

Possible interference with tests using cupric sulfate reagent (Benedict’s Qualitative Reagent, Clinitest, Fehling’s Solution) resulting in false-positive glycosuria;100 b may be caused by a reducing substance in urine which disappears with discontinuance of therapy100 b

Use glucose oxidase reagent (Clinistix, Tes-Tape)100 b

Thiopental

Lower doses of thiopental (not commercially available in US) reportedly needed for anesthesia in patients receiving probenecid;100 substantially prolonged anesthesia reported in rats100

Probenecid Pharmacokinetics

Absorption

Bioavailability

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

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.b

Distribution

Extent

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

Crosses placenta and appears in cord blood.100 Not known whether distributed into milk; however, distribution into milk is expected.114

Plasma Protein Binding

Approximately 75%.b

Elimination

Metabolism

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

Elimination Route

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

Half-life

Dose dependent; 4–17 hours.b

Stability

Storage

Oral

Tablets

Probenecid: 20–25°C in well-closed container.100

Probenecid/colchicine: 20–25°C in well-closed, light-resistant container.101

Actions

  • Competitively inhibits active reabsorption of urate at the proximal convoluted tubule, increasing urinary excretion of uric acid and reducing serum urate concentrations.100 b

  • 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.100 b

  • 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.b

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.100

  • Potential for drug to increase incidence of gouty arthritis attacks during therapy initiation.100 b Continue probenecid during acute attacks, without changing dose, and add therapeutic dosages of colchicine or other anti-inflammatory agents.b

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.100

  • Importance of informing patients of other important precautionary information.100 (See Cautions.)

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

Probenecid

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

500 mg*

Probenecid Tablets

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

Probenecid and Colchicine

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

500 mg Probenecid and Colchicine 0.5 mg*

Probenecid and Colchicine Tablets

AHFS DI Essentials™. © Copyright 2021, Selected Revisions August 10, 2020. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

100. Actavis Pharma. Probenecid tablets prescribing information. Parsippany, NJ; 2016 Dec.

101. Actavis Pharma. Probenecid and colchicine tablets prescribing information. Parsippany, NJ; 2016 Dec.

102. Benemid (probenecid) tablets prescribing information. In: Huff BB, ed. Physicians’ desk reference. 41st ed. Oradell, NJ: Medical Economics Company Inc; 1987 (Suppl B):B10-1.

103. Clinoril (sulindac) tablets prescribing information. In: Huff BB, ed. Physicians’ desk reference. 41st ed. Oradell, NJ: Medical Economics Company Inc; 1987:1251-3.

104. Orudis (ketoprofen) capsules prescribing information. In: Huff BB, ed. Physicians’ desk reference. 41st ed. Oradell, NJ: Medical Economics Company Inc; 1987:2179-81.

105. Naprosyn (naproxen) prescribing information. In: Huff BB, ed. Physicians’ desk reference. 41st ed. Oradell, NJ: Medical Economics Company Inc; 1987(Suppl B):B22-4.

106. Upton RA, Williams RL, Buskin JN et al. Effects of probenecid on ketoprofen kinetics. Clin Pharmacol Ther. 1982; 31:705-12. http://www.ncbi.nlm.nih.gov/pubmed/7075118?dopt=AbstractPlus

107. Roche. Valcyte (valganciclovir hydrochloride) tablets prescribing information. Nutley, NJ; 2001 Mar.

108. Roche. Cytovene-IV (ganciclovir sodium for injection) and Cytovene (ganciclovir capsules) prescribing information. Nutley, NJ; 2000 Sep.

109. Mylan Institutional LLC. Cidofovir anhydrous injection prescribing information. Rockford, IL; 2012 Nov.

110. Grayson ML, ed. Kucers' the use of antibiotics: a clinical review of antibacterial, antifungal, antiparasitic, and antiviral drugs. 7th ed. Boca Raton, FL: CRC Press; 2018:23-90,3531-71.

111. Pfizer Laboratories. Penicillin G procaine injectable suspension for deep IM injection only prescribing information. New York, NY; 2019 Nov.

112. Sagent Pharmaceuticals. Cefoxitin for injection for IV use prescribing information. Schaumburg, IL; 2018 Sep.

113. Procter and Gamble Pharmaceuticals. Macrobid (nitrofurantoin) monohydrate/macrocrystals capsules prescribing information. Cincinnati, OH; 2009 Jan.

114. Probenecid. In: Briggs GG, Freeman RK, Yaffe SJ. Drug in pregnancy and lactation: a reference guide to fetal and neonatal risk. 7th ed. Philadelphia: Lippincott Williams & Wilkins; 2005:1342-3

124. Harris MD, Siegel LB, Alloway JA. Gout and hyperuricemia. Am Fam Physician. 1999; 59:925-34. http://www.ncbi.nlm.nih.gov/pubmed/10068714?dopt=AbstractPlus

125. Davis JC. A practical approach to gout. Postgrad Med. 1999; 106:115-23. http://www.ncbi.nlm.nih.gov/pubmed/10533512?dopt=AbstractPlus

127. Star VL, Hochberg MC. Prevention and management of gout. Drugs. 1993; 45:212-22. http://www.ncbi.nlm.nih.gov/pubmed/7681372?dopt=AbstractPlus

129. Emmerson BT. Management of gout. N Engl J Med. 1996; 334:445-51. http://www.ncbi.nlm.nih.gov/pubmed/8552148?dopt=AbstractPlus

155. Panel on Opportunistic Infection in Adults and Adolescents with HIV. Guidelines for the prevention and treatment of opportunistic infections in adults and adolescents with HIV. Accessed January 16, 2020. Updates may be available at HHS AIDS Information (AIDSinfo) website https://aidsinfo.nih.gov/guidelines

344. Workowski KA, Bolan GA. Sexually Transmitted Diseases Treatment Guidelines, 2015. MMWR Recomm Rep. 2015; 64(RR-03):1-137. Updates may be available at CDC website. http://www.ncbi.nlm.nih.gov/pubmed/26042815?dopt=AbstractPlus

b. AHFS drug information 2020. Snow EK, ed. Probenecid. Bethesda, MD: American Society of Health-System Pharmacists; 2020.