Probenecid

Probenecid is a an Uricosuric Agent belonging to pharmacology class of renal tubular transport blocking agent.

Probenecid can be used in the treatment of Hyperuricemia, Sexually transmitted infections. It is also used to treat and prevent Cidofovir nephrotoxicity.

Probenecid is Rapidly and completely absorbed from the GI tract. Time to peak plasma concentration: 2-4 hr and Crosses the placenta; concentrations in the CSF are approx 2% of plasma concentrations. Plasma protein binding: 85-95% and Slowly get metabolized by the liver to probenecid monoacyl glucuronide, 2 monohydroxylated compounds, a carboxylated metabolite and an N-depropylated compound and get excreted Via urine, mainly as metabolites. Plasma half-life: <5 to >8 hr.

The common side effects associated with Probenecid include Anorexia, dyspepsia, gastroesophageal reflux disease, gingival pain, nausea, vomiting.

Probenecid is available in the form of Tablets.

The molecule is available in India, USA, Japan, Germany.

Probenecid belonging to the renal tubular transport blocking agent acts a Uricosuric Agent.

Increases plasma levels of weak organic acids (penicillins, cephalosporins, or other beta-lactam antibiotics) by competitively inhibiting their renal tubular secretion; competitively hinder the reabsorption of uric acid at the proximal convoluted tubule, thereby promoting its excretion and lowering serum uric acid levels.

Probenecid is available in Tablet

Oral: Administer with food to minimize GI effects. Maintain adequate fluid intake.

Probenecid can be used in the treatment of Hyperuricemia, Sexually transmitted infections. It is also used to treat and prevent Cidofovir nephrotoxicity.

The use of probenecid lowers blood urate levels and increases urine excretion of uric acid by blocking the tubular reabsorption of urate. Additionally, subtherapeutic doses of probenecid may lower urate's plasma binding and prevent the kidneys from secreting uric acid. Probenecid may block transport enzyme that need a source of high energy phosphate bonds and/or interfere non-specifically with substrate access to protein receptor sites on the kidney tubules, although the exact mechanism by which the drug reduces renal tubular transport is unknown.

Probenecid is approved for use in the following clinical indications

• Hyperuricemia, gout prevention: Treatment of hyperuricemia associated with gout or gouty arthritis.

• Sexually transmitted infections, as a pharmacokinetic enhancer to prolong beta lactam serum levels: Adjunctive agent to beta-lactams for the elevation and prolongation of plasma levels.

Although not approved there have been certain off labelled uses documented for Probenecid which includes:

Cidofovir nephrotoxicity, prevention

Cidofovir nephrotoxicity, prevention (off-label use): Oral: 2 g as a single dose administered 3 hours before cidofovir infusion, followed by 1 g at 2 hours and 8 hours after cidofovir infusion.

Hyperuricemia, gout prevention (alternative agent): Oral: 250 mg twice daily for 1 week, followed by 500 mg twice daily; may increase dose by 500 mg every 4 weeks as tolerated if symptoms are not controlled; usual maintenance dose: ≤2 g/day in divided doses.

Sexually transmitted infections, as a pharmacokinetic enhancer to prolong beta-lactam serum levels (adjunctive agent):

Gonococcal infection, uncomplicated: Oral: 1 g as a single dose in combination with single-dose IM cefoxitin.

Neurosyphilis, including ocular and otosyphilis:

Note: Reserve for patients unable to receive IV therapy.

Oral: 500 mg 4 times daily in combination with IM procaine penicillin for 10 to 14 days.

Pelvic inflammatory disease, mild to moderate: Oral: 1 g as a single dose in combination with IM cefoxitin as a single dose plus doxycycline and metronidazole.

• Tablet: 500 mg

Tablet

• Dose Adjustment in Kidney impairment patient:

GFR >30 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling.

GFR ≤30 mL/minute: Reduced efficacy with kidney impairment; other agents are recommended

• Dose Adjustment in Hepatic Patient:

Preexisting hepatic impairment:

Mild to moderate impairment (Child-Pugh class A or B): No dosage adjustment necessary.

Severe impairment (Child-Pugh class C): There are no dosage adjustments provided in the manufacturer's labeling (has not been studied); use caution.

Hepatotoxicity during treatment:

ALT or AST >3 times ULN (in the clinical context of potential liver injury [eg, fatigue, anorexia, right upper quadrant pain, dark urine, jaundice]): Interrupt Probenecid therapy and evaluate. Do not reinitiate Probenecid if liver injury is confirmed or no alternate etiology for liver test abnormalities is identified.

ALT or AST >3 times ULN and serum total bilirubin >2 times ULN without alternative etiology: Permanently discontinue.

• Dose Adjustment in Pediatric Patients:

Prolongation of penicillin serum levels:

Children ≥2 years and Adolescents: Note: Dosing for some indication-specific dosing may vary.

Patient weight ≤50 kg: Oral: Initial: 25 mg/kg/dose or 700 mg/m²/dose as a single dose; maintenance: 40 mg/kg/day or 1,200 mg /m²/day in 4 divided doses; maximum dose: 500 mg.

Patient weight >50 kg: Oral: 500 mg 4 times daily.

Gonorrhea, uncomplicated infections of cervix, urethra, and rectum:

Adolescents >45 kg: Oral: 1,000 mg as a single dose with cefoxitin; Note: Combination of ceftriaxone and azithromycin is preferred

Pelvic inflammatory disease:

Adolescents: Oral: 1,000 mg as a single dose with cefoxitin in combination with doxycycline with/without metronidazole .

Neurosyphilis:

Adolescents: Oral: 500 mg 4 times daily with procaine penicillin for 10 to 14 days; alternative therapy to aqueous penicillin G therapy .

Cidofovir nephrotoxicity, prevention:

Limited data available; various regimens have been reported:

Infants, Children, and Adolescents: Note: The manufacturer's labeling considers use in patients <2 years of age to be contraindicated; however, clinical studies have included younger ages (including infants) for this indication.

Weight-based dosing: Oral: 25 to 40 mg/kg/dose (maximum dose: 2,000 mg) administered 3 hours before cidofovir infusion and 10 to 20 mg/kg/dose (maximum dose: 1,000 mg) at 2 to 3 hours and 8 to 9 hours after cidofovir infusion.

BSA-based dosing: Oral: 1,000 or 1,250 mg/m²/dose administered 3 hours prior to cidofovir, followed by 500 to 1,250 mg/m²/dose 1 to 2 hours and 8 hours after completion.

The dietary restriction should be individualized as per patient requirements.

Probenecid may be contraindicated in the following conditions:-

Hypersensitivity to probenecid or any component of the formulation; blood dyscrasias; uric acid kidney stones; children <2 years of age; initiation during an acute gout attack.

The treating physician must closely monitor the patient and keep pharmacovigilance as follows

Concerns related to adverse effects:

• Hypersensitivity reaction: Has been associated with rare, severe hypersensitivity reactions, including anaphylaxis. Discontinue therapy if reaction occurs.

• Gout: May cause exacerbation of acute gouty attack.

Disease-related concerns:

• G6PD deficiency: Use caution in patients with G6PD deficiency; may increase risk for hemolytic anemia.

• Peptic ulcer disease: Use with caution in patients with peptic ulcer disease.

• Kidney impairment: Monotherapy may not be effective in patients with a CrCl ≤30 mL/minute. The American College of Rheumatology guidelines for the management of gout do not recommend probenecid as first-line or an alternative first-line urate-lowering therapy in patients with moderate to severe chronic kidney disease.

There is no sufficient scientific evidence traceable regarding use and safety of Probenecid in concurrent use with alcohol.

There is no sufficient scientific evidence traceable regarding use and safety of Probenecid in concurrent use with any particular food.

Category B2

Probenecid crosses the placental barrier and appears in cord blood. The use of any medicine in women of childbearing potential requires that the anticipated benefit be weighed against possible hazards. Reproduction studies in the rabbit and the rat at doses up to 10 times the recommended human dose have shown no evidence of teratogenic effects to the fetus due to probenecid.

Because animal reproduction studies are not always predictive of human response, probenecid should be used during pregnancy only if clearly needed. It is not known whether the medicine is excreted in human milk. Because many medicines are excreted in human milk, caution should be exercised when probenecid is administered to a nursing mother.

There is no sufficient scientific evidence traceable regarding use and safety of Probenecid in concurrent use with any particular food.

The adverse reactions related to Probenecid can be categorized as

Common Adverse effects: Anorexia, dyspepsia, gastroesophageal reflux disease, gingival pain, nausea, vomiting

Less Common Adverse effects: Anemia, aplastic anemia, hemolytic anemia (in G6PD deficiency), leukopenia

Rare Adverse effects: Polyuria, renal colic, Fever.

The clinically relevant drug interactions of Probenecid is briefly summarized here

Methotrexate toxicity can be increased. Increases in peak plasma concentrations of paracetamol, naproxen, indometacin, ketoprofen, meclofenamate, lorazepam, rifampicin, aciclovir, ganciclovir, and zidovudine are possible. could reduce the renal excretion of conjugated sulfonamides. Can make oral sulfonylureas work longer or better, which raises the risk of hypoglycemia. Probenecid's uricosuric effect may be countered with pyrazinamide.

The common side of Probenecid include the following

Anorexia, dyspepsia, gastroesophageal reflux disease, gingival pain, nausea, vomiting.

Pediatric population

For two years of age or older the recommended dosage is 25 mg/kg (or 0.7 g/m2 body surface) of body weight initially, followed by 40 mg/kg (or 1.2 g/m² body surface) daily in divided doses every six hours. For children weighing more than 50 kilograms the adult dose is recommended. The phenolsulfonphthalein (PSP) excretion test may be used to determine the effectiveness of probenecid in retarding penicillin excretion and maintaining therapeutic levels. When the dose of probenecid is adequate, the renal clearance of PSP is reduced to about one-fifth of the normal rate. This product is not able to deliver all approved dose regime.

Symptoms: CNS stimulation, convulsions, respiratory failure.

Management: Symptomatic and supportive treatment along w/ gastric lavage. IV short-acting barbiturates may be given.

Pharmacodynamics:

When chronic gouty arthritis is worsened by frequent, recurrent acute gout attacks, probenecid, a uricosuric and renal tubular blocking drug, is used in conjunction with colchicine to treat the condition. It prevents urate from being reabsorbed at the proximal convoluted tubule, increasing uric acid excretion in the urine and lowering serum urate levels as a result. The miscible urate pool is decreased by effective uricosuria, which also delays urate deposition and encourages the resorption of urate deposits. Many weak organic acids, such as penicillins, the majority of cephalosporins, and some other -lactam antibiotics, are competitively inhibited from being secreted at the proximal and distal tubles by probenecid. This causes an increase in the plasma concentrations of acidic medications that are primarily eliminated by renal secretion, but only a minor increase in the case when the drug is primarily eliminated by filtration.

Pharmacokinetics:

Absorption: Rapidly and completely absorbed from the GI tract. Time to peak plasma concentration: 2-4 hr.

Distribution: Crosses the placenta; concentrations in the CSF are approx 2% of plasma concentrations. Plasma protein binding: 85-95%.

Metabolism: Slowly metabolized by the liver to probenecid monoacyl glucuronide, 2 monohydroxylated compounds, a carboxylated metabolite and an N-depropylated compound.

Excretion: Via urine, mainly as metabolites. Plasma half-life: <5 to >8 hr.

1. https://www.uptodate.com/contents/Probenecid -drug-information?search=Probenecid &source=panel_search_result&selectedTitle=1~148&usage_type=panel&kp_tab=drug_general&display_rank=1#F154338
2. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/022352s017lbl.pdf
3. https://www.medicaid.nv.gov/Downloads/provider/Probenecid _2015-1215.pdf
4. https://www.mims.com/india/drug/info/Probenecid ?type=full&mtype=generic#mechanism-of-action