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Probenecid

Pronunciation

Class: Uricosuric Agents
VA Class: MS400
CAS Number: 57-66-9
Brands: Col-Probenecid

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.a 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

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

Probenecid/colchicine fixed-dosage preparation has limited usefulness for prophylactic therapy because colchicine present exceeds the amount required by 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

Infections

Used for therapeutic advantage to increase concentrations of certain β-lactam anti-infectives in the treatment of gonorrhea, neurosyphilis, or pelvic inflammatory disease (PID); do not use alone for treatment of gonorrhea, neurosyphilis, or PID.a c

Used as an adjunct to IM cefoxitin for treatment of uncomplicated urogenital and anorectal gonorrhea in adults and adolescents;c considered an alternative regimen by CDC.c

Used as an adjunct to IM penicillin G procaine for treatment of neurosyphilis if compliance can be ensured; considered an alternative regimen by CDC.c

Used as an adjunct to IM cefoxitin for treatment of PID; considered a regimen of choice by CDC.c

Diagnostic Agent

Has been used in diagnosis of parkinsonian syndrome† and mental depression.b

Probenecid Dosage and Administration

General

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

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

Hyperuricemia Associated with Gout

  • Administer prophylactic doses of colchicine concurrently during the first 3–6 months of probenecid therapy because probenecid may increase the frequency of acute gout attacks during the first 6–12 months of therapy.b 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 the 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

Infections

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

Administration

Oral Administration

Administer with food or antacids to minimize GI effects.a b (See Common Adverse Effects under Cautions.)

Dosage

Pediatric Patients

Infections
General Dosage (Probenecid and Penicillin Therapy)
Oral

Children 2–14 years of age: Initial dose of 25 mg/kg (or 700 mg/m2); subsequently, 40 mg/kg (or 1.2 g/m2) daily, given in 4 divided doses daily (given as an adjunct with a penicillin).a b

Children weighing >50 kg: 500 mg 4 times daily (given as an adjunct with a penicillin).a b

Uncomplicated Gonorrhea
Oral

Adolescents: 1 g as a single dose as an adjunct to IM cefoxitin (2 g as a single dose).c

Neurosyphilis
Oral

Adolescents: 500 mg 4 times daily for 10–14 days as an adjunct to IM penicillin G procaine (2.4 million units 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 once weekly for up to 3 weeks).c

PID
Oral

Adolescents: 1 g as a single dose as an adjunct to IM cefoxitin (2 g as a single dose); followed by a 14-day regimen of oral doxycycline (100 mg twice daily) with or without oral metronidazole (500 mg twice daily).c

Adults

Hyperuricemia Associated with Gout
Oral

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

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

Probenecid/Colchicine Fixed-Combination Therapy
Oral

Fixed-dosage preparation has limited usefulness for prophylactic therapy because colchicine present exceeds the amount required by most patients.b

Manufacturer recommends initial dosage of probenecid 500 mg in fixed combination with colchicine 0.5 mg (1 tablet) daily for 1 week, then 1 tablet twice daily.e If gouty arthritis is not controlled or if 24-hour uric acid excretion is ≤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).e

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.e

Infections
General Dosage (Probenecid and Penicillin Therapy)
Oral

500 mg 4 times daily as an adjunct to a penicillin.a b

Uncomplicated Gonorrhea
Oral

1 g as a single dose as an adjunct to IM cefoxitin (2 g as a single dose).c

Neurosyphilis
Oral

500 mg 4 times daily for 10–14 days as an adjunct to IM penicillin G procaine (2.4 million units 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 once weekly for up to 3 weeks).c

PID
Oral

1 g as a single dose as an adjunct to IM cefoxitin (2 g as a single dose); followed by a 14-day regimen of oral doxycycline (100 mg twice daily) with or without oral metronidazole (500 mg twice daily).c

Diagnosis of Parkinson’s Disease or Mental Depression
Oral

500 mg every 12 hours for 5 doses.b Obtain CSF levels for homovanillic acid (HVA)(Parkinson’s disease) or 5-hydroxyindoleacetic acid (5-HIAA) (mental depression) 12 hours after last dose.b

Prescribing Limits

Adults

Hyperuricemia Associated with Gout
Oral

Maximum 2–3 g daily.a b

Special Populations

Hepatic Impairment

No specific dosage recommendations at this time.a

Renal Impairment

Dosage requirements may be increased in patients with mild renal impairment (Clcr ≥50 mL/minute).a b Use not recommended in patients with moderate to severe renal impairment (Clcr <50 mL/minute). b (See Renal Impairment under Cautions.)

Geriatric Patients

No dosage adjustments except those related to renal impairment. a

Cautions for Probenecid

Contraindications

  • Known blood dyscrasias.a b

  • Uric acid kidney stones.a b

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

  • Children <2 years of age.a b

  • Known hypersensitivity to probenecid or any ingredient in the formulation.a b

Warnings/Precautions

Warnings

Acute Gout Attacks

May exacerbate and prolong inflammation during acute gout attacks.b Initiate therapy 2–3 weeks after acute gout attack subsides.a b

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

Interactions

Methotrexate toxicity reported during concomitant probenecid therapy. a (See Specific Drugs under Interactions.)

Concomitant use with salicylates is not recommended.a (See Specific Drugs under Interactions.)

Sensitivity Reactions

Hypersensitivity Reactions

Severe allergic reactions (e.g., dermatitis, pruritus, fever, sweating, hypotension) and anaphylaxis reported rarely; typically occurs within several hours after administration in patients who previously received the drug.a If hypersensitivity reaction occurs, discontinue therapy.a

If rash occurs during concomitant administration with a penicillin and causative agent cannot be determined, discontinuance of both drugs may be necessary.b

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.a b Usually occurs when therapy is initiated.b

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

Peptic Ulcer

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

Use of Fixed Combinations

When used in fixed combination with colchicine, consider the cautions, precautions, and contraindications associated with colchicine.e

Specific Populations

Pregnancy

Category C.d

Lactation

Distribution into human milk is expected; however, effects on nursing infant not known.d Caution advised if probenecid is used because of potential risk to nursing infants.d

Pediatric Use

Use contraindicated in children <2 years of age.a

Geriatric Use

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

Renal Impairment

Not effective in gouty patients with moderate to severe renal impairment (Clcr <50 mL/minute); avoid use in these patients.b May be effective in gouty patients with mild renal impairment (Clcr ≥50 mL/minute), but increased dosages may be required.a b

Concomitant use with a penicillin or other β-lactams not recommended in patients with known renal impairment.a

Common Adverse Effects

Headache, a b vomiting, a b nausea, a b anorexia.a 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 adequatea

Alcohol

Potential for increased serum urate concentrationsa b

May need to increase probenecid dosageb

Allopurinol

Probenecid increases excretion of allopurinol’s active metabolite

Used concomitantly for additive therapeutic effectb

Antidiabetic agents, oral (sulfonylureas)

Possible increased plasma concentrations of oral sulfonylurea antidiabetic agents resulting in hypoglycemiaa b

Antineoplastic agents

Increased serum urate concentrations; possible uric acid nephropathyb

Avoid concomitant useb

β-Lactam antibiotics

Decreased renal excretion of β-lactam antibiotics and increased concentrations of β-lactam antibioticsa

Psychic disturbances reported with concomitant use101

Used concomitantly for additive therapeutic effecta

Consider adverse effects of increased antibiotic concentrationsa

Diazoxide

Potential for increased serum urate concentrationsa b

May need to increase probenecid dosageb

Diuretics, loop (furosemide, ethacrynic acid)

Potential for increased serum urate concentrationsa b

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

Possible increase in AUC and decrease in renal excretion of ganciclovir

107 108

Ketamine

Possible prolonged anesthesiaa

Reported in animal studiesa

Lorazepam

Possible increased peak plasma concentrations of lorazepam102

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

Methotrexate

Increased serum concentrations of methotrexate and methotrexate toxicitya b

Reduce methotrexate dosage and monitor carefullya

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

Increased plasma concentrations of NSAIAsa 102 103 104 105

Sulindac: Possible decreased uricosuric action of probenecid102 103

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

Changes in uricosuric action unlikely to be clinically important102 103

Concomitant use of ketoprofen and probenecid not recommended104

Nitrofurantoin

Possible inhibition of renal excretion of nitrofurantoin resulting in increased risk of adverse effects and decreased efficacy in treatment of UTIsb

Avoid concomitant useb

Pyrazinamide

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

Concomitant use not recommendeda

Sulfinpyrazone

Probenecid inhibits the renal secretion of sulfinpyrazoneb

May be administered concurrently without adverse interactionb

Sulfonamides (i.e., sulfa antibiotics)

Increased serum concentrations of total sulfonamidea

Free sulfonamide concentrations not altered; concomitant use not therapeutically usefula

Tests for theophylline

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

Tests for urinary glucose

Possible interference with tests using cupric sulfate reagent (Benedict’s Qualitative Reagent, Clinitest, Fehling’s Solution) resulting in false-positive glycosuriaa b

May be caused by a reducing substance in the urine which disappears with discontinuance of therapya b

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

Thiopental

Possible increased serum concentrations of thiopentala 101

Reduced thiopental dosages may be requireda

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 the drug are about 2% of plasma concentrations.b Crosses the placenta; not known whether distributed into milk; however, distribution into milk is expected.b d

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

15–30°C.a

Actions

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

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

  • Potential for drug to increase incidence of gouty arthritis attacks during therapy initiation.a 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.a

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

Preparations

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

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

Probenecid

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

500 mg*

Tablets, film-coated

500 mg*

Probenecid Tablets

Lannett, Mylan, Watson

* 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*

Col-Probenecid

Watson

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Colchicine-Probenecid 0.5-500MG Tablets (WATSON LABS): 30/$35.99 or 90/$95.97

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions August 1, 2008. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

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

References

100. Centers for Disease Control. Sexually transmitted diseases treatment guidelines 1989. MMWR Morb Mortal Wkly Rep. 1989; 38(Suppl 8S):1-43.

101. Merck Sharp & Dohme. Benemid (probenecid) prescribing information. In: Huff BB, ed. Physicians’ desk reference. 40th ed. Oradell, NJ: Medical Economics Company, Inc; 1986(Suppl A):A22.

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. [IDIS 152190] [PubMed 7075118]

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.

a. Watson Laboratories, Inc. Probenecid prescribing information. Corona, CA; 2003 Jul.

b. AHFS drug information 2008. McEvoy GK, ed. Probenecid. Bethesda, MD: American Society of Health-System Pharmacists; 2008:2792-5.

c. Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines, 2006. MMWR. 2006; 55(RR11):1-94.

d. 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

e. Watson Laboratories, Inc. Probenecid and colchicine tablets prescribing information. Corona, CA. 2006 Mar.

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