Probenecid and Colchicine (Systemic)


VA CLASSIFICATION
Primary: MS400

Commonly used brand name(s): Col-Probenecid; ColBenemid; Proben-C.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

Not commercially available in Canada.



Category:


Antigout agent—

Indications

Accepted

Gouty arthritis, chronic (treatment)—Probenecid and colchicine combination is indicated for the treatment of chronic gouty arthritis in patients having frequent, recurrent acute attacks {01}.
—Probenecid is used to control hyperuricemia {02} {03} {04} {05} {06}. Therapy with this uricosuric agent is recommended only for patients whose 24-hour renal excretion of urate is 800 mg (4.8 mmol) or lower (i.e., patients who are hyperuricemic as a result of underexcretion, rather than overproduction, of urate) {02} {03} {05}. The aim of probenecid therapy is to reduce the number of acute gout attacks {02} {05} {06}. Probenecid therapy should not be initiated during an acute attack {01} {02} {04} {05} {06} {07} because it may produce fluctuations in urate concentration {02} that may result in prolongation of the attack {04} or initiation of a new attack {02} {05}. Even when probenecid therapy is started several weeks after an acute attack, the frequency of acute attacks may be increased during the early months of therapy {02} {03} {04} {05} {06} {07}. Therefore, prophylactic doses of the colchicine in this combination medication are usually administered for the first 3 to 6 months of probenecid therapy {02} {04}.

Unaccepted
Probenecid is not recommended in circumstances in which there is an especially high risk of adverse effects associated with crystallization and deposition of urate in renal tissues, such as formation of renal calculi and uric acid nephropathy {02} {03} {04} {05} {06}. It therefore should not be used for treatment of gout in patients whose 24-hour urate excretion exceeds 800 mg (4.8 mmol) {02} {03} or who have extensive tophi {02} {06}. Allopurinol, which decreases the quantity of urate that reaches the kidneys in addition to decreasing the concentration of urate in the blood, is recommended in these circumstances {02} {05} {06} {07}.


Pharmacology/Pharmacokinetics

Probenecid—See Probenecid (Systemic) .

Colchicine—See Colchicine (Systemic) .


Precautions to Consider

Probenecid—See Probenecid (Systemic) .

Colchicine—See Colchicine (Systemic) .


Side/Adverse Effects
Probenecid—See Probenecid (Systemic) .
Colchicine—See Colchicine (Systemic) .



Overdose
For more information on the agents used in the management of probenecid and colchicine overdose, see:

Acetazolamide in Carbonic Anhydrase Inhibitors (Systemic) monograph;


Allopurinol (Systemic) monograph;


Atropine in Anticholinergics/Antispasmodics (Systemic) monograph;


Diazepam in Benzodiazepines (Systemic) monograph;


Morphine in Opioid (Narcotics) Analgesics (Systemic) ;


Paregoric (Systemic) monograph; and/or


Potassium Citrate in Citrates (Systemic) monograph.


For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Probenecid
Specific treatment—

For uric acid calculi or urate nephropathy:

Recommended measures include administration of large quantities of fluids and of allopurinol to increase urine flow and reduce uric acid formation, respectively {08}. A urinary pH of 6 to 6.5 should be achieved and maintained by administration of alkali {08} {13} such as potassium citrate {08} {13}. If necessary to maintain the desired urinary pH through the night, acetazolamide may also be given at bedtime {08}. Other interventions designed to facilitate removal of renal calculi may also be needed {08}. See the package inserts or Acetazolamide in Carbonic Anhydrase Inhibitors (Systemic) , Allopurinol (Systemic) , and/or Potassium Citrate in Citrates (Systemic) for specific dosing guidelines for use of these products.

For convulsions:

Administering appropriate anticonvulsive therapy such as intravenous diazepam {14}. See the package insert or Diazepam in Benzodiazepines (Systemic) for specific dosing guidelines for use of this product.

Supportive care—Monitoring the patient and instituting supportive treatment as needed.



Colchicine:



For early signs of overdose:
Discontinuing colchicine administration.

Specific treatment—Administering paregoric or other opioid antidiarrheals for diarrhea. See the package inserts or Atropine in Anticholinergics/Antispasmodics (Systemic) or Paregoric (Systemic) for specific dosing guidelines for use of these products.

Administering morphine or atropine for stomach pain. See the package insert or morphine in Opioid (Narcotic) Analgesics (Systemic) for specific dosing guidelines for use of this product.



For severe overdose:
To decrease absorption—Removing unabsorbed medication via gastric lavage.

Monitoring—Monitoring hemodynamic, cardiac, and respiratory status and blood electrolytes.

To enhance elimination—Hemodialysis or peritoneal dialysis may also be of value; however, their usefulness has been questioned because of colchicine's high degree of tissue binding.

Supportive care—Correcting dehydration and instituting other measures to prevent or treat shock.

Correcting electrolyte imbalances and metabolic acidosis.

Assisting respiration and instituting other symptomatic or supportive treatment as required for other symptoms, including seizures, infection, disseminated intravascular coagulation, or bone marrow failure. Patients in whom intentional overdose is known or suspected should be referred for psychiatric consultation.



Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Probenecid and Colchicine (Systemic).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Allergic reaction to probenecid or sensitivity to colchicine, history of

Pregnancy—Probenecid crosses the placenta; colchicine reported to be teratogenic in humans





Use in the elderly—Increased susceptibility to cumulative colchicine toxicity
Other medications, especially antibiotics, antivirals, bone marrow depressants or blood dyscrasia–causing medications, indomethacin, ketoprofen, antineoplastic agents, aspirin or other salicylates, including bismuth subsalicylate, heparin, methotrexate, nitrofurantoin, or zidovudine
Other medical problems, especially alcohol abuse, severe cardiac or gastrointestinal disorders; cancer being treated by cytolytic medication or radiation (x-ray) therapy; kidney stones or other kidney problems, especially if caused by uric acid, or history of; renal function impairment; hepatic function impairment; stomach ulcer or other stomach problems, and blood dyscrasias

Proper use of this medication
Taking with food or an antacid to minimize gastric irritation

Importance of not taking more medication than the amount prescribed

Several months of continuous therapy may be required for maximum effectiveness

» Medication does not relieve acute attacks of gout but rather helps to prevent them; need to continue taking probenecid and colchicine with medication prescribed for gout attacks

Importance of high fluid intake and compliance with therapy for alkalinization of urine, if prescribed

» Proper dosing
Missed dose: Taking as soon as possible; not taking if almost time for next dose; not doubling doses

» Proper storage

Precautions while using this medication
Regular visits to physician to check progress during therapy

Caution if any laboratory tests required; possible interference with test results

Diabetics: May cause false results with copper sulfate urine sugar tests, but not with glucose enzymatic urine sugar tests

» Aspirin or other salicylates may decrease uricosuric effects of probenecid; checking with physician regarding concurrent use, since effect is dependent on salicylate dose and duration of use

» Possibility that alcohol taken in large amounts may increase the risk of colchicine-induced gastrointestinal toxicity; also, may increase uric acid concentrations and thereby reduce effectiveness of medication

» For patients taking high doses (4 tablets a day): Discontinuing at once and notifying physician as soon as possible if symptoms of gastrointestinal toxicity occur


Side/adverse effects
Signs and symptoms of potential side effects, especially renal calculi, allergic dermatitis, anaphylaxis, anemia, aplastic anemia, hemolytic anemia, fever, hepatic necrosis, leukopenia, nephrotic syndrome, pain in back and/or ribs, renal colic, urate nephropathy, colchicine-induced gastrointestinal toxicity, and peripheral neuritis


General Dosing Information
Probenecid and colchicine combination therapy should not be initiated until 2 to 3 weeks {04} after an acute attack of gout has subsided {01} {04}; however, if an acute attack occurs in a patient already receiving the medication, it should be continued at the same dose while additional colchicine or a nonsteroidal anti-inflammatory drug (NSAID) is given to relieve the attack {01} {04} {07}.

The medication may be administered with food or an antacid to minimize gastric irritation. If gastrointestinal irritation continues, colchicine-induced gastrointestinal toxicity should be considered; a reduction in colchicine dosage may be necessary. Administration of supplemental probenecid, or administration of colchicine and probenecid separately, may be necessary to achieve maximum benefit with minimal side effects. {11}

Determination of serum or urine (24-hour) uric acid concentrations may be necessary for proper dosing. {04} {06} {08} {09}

To reduce the risk of urate stone formation, a high fluid intake (no less than 2.5 to 3 liters daily) {01} {02} {07} and maintenance of an alkaline urine by administration of sodium bicarbonate (3 to 7.5 grams daily), {01} potassium citrate (7.5 grams daily), {10} or acetazolamide (250 mg daily) {06} are recommended. The risk of urate stone formation is highest during the first few weeks of probenecid therapy {01} {06} {07}, when urate excretion is high {01}; after hyperuricemia has been controlled and urinary excretion of uric acid decreases, the need for these measures is reduced. {01} {06} {07}

Higher doses of probenecid may be required in patients with mild renal function impairment. However, it is recommended that dosage be reduced in geriatric patients with possible renal function impairment. {12}

Probenecid may not be effective in patients with chronic renal insufficiency. {01} {02} {03} {04} {06} {08} Probenecid's efficacy begins to decrease when the patient's creatinine clearance is 80 mL per minute, {04} and the medication is completely ineffective when the creatinine clearance is lower than 30 mL per minute. {05} {08}


Oral Dosage Forms

PROBENECID AND COLCHICINE TABLETS USP

Usual adult dose
Antigout agent
Initial: Oral, 1 tablet a day for one week {01}.

Maintenance: Oral, 1 tablet two times a day {01}. In nongeriatric patients, if this dose does not control symptoms or if the 24-hour uric acid excretion is not above 700 mg, the daily dosage may be increased by 1 tablet every four weeks as tolerated (usually not above 4 tablets per day) {01}. If the increase in colchicine dosage is not desired or tolerated, administration of additional probenecid alone may be required {11}.

Note: The initial dose may be eliminated, and treatment started with the usual maintenance dose, when patients previously controlled with other uricosuric therapy are transferred to probenecid {12}.
When acute attacks of gout have not occurred for at least six months, and the serum uric acid concentrations remain within normal limits, the daily dose may be reduced by 1 tablet every six months until the lowest effective maintenance dose is reached {01}. Alternatively, prophylactic use of colchicine may be discontinued and the patient treated with maintenance doses of probenecid alone {11}.



Usual pediatric dose
Dosage has not been established.

Strength(s) usually available
U.S.—


500 mg of probenecid and 500 mcg (0.5 mg) of colchicine (Rx) [ColBenemid] [Col-Probenecid] [Proben-C][Generic]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a well-closed, light-resistant container.



Revised: 08/27/1994



References

Note: All references used in the development and earlier revisions of this monograph have not yet been incorporated into the computer database and, therefore, are not listed below. Citations for information not yet referenced in the monograph will be provided upon request.

  1. Prescribing information ColBenemid, MSD (U.S.), rev 5/89, in: Physician's desk reference, 46th ed. Montvale: Medical Economics Data; 1992: 1436-7.
  1. AMA drug evaluations annual. Chicago: American Medical Association; 1992: 1413, 1820, 1829, 1831-3, 1837-8, 1899.
  1. Speight TM, ed. Avery's drug treatment. Principles and practice of clinical pharmacology and therapeutics, 3rd ed. Baltimore: Williams and Wilkins; 1987: 542, 944-7, 1377, 1399.
  1. McEvoy GK, ed. AHFS drug information. Bethesda: American Society of Hospital Pharmacists; 1992: 1578-80.
  1. Rakel RE, ed. Conn's current therapy. Philadelphia: W.B. Saunders; 1991: 501-4.
  1. Kelley WN, Harris ED Jr, Ruddy S, Sledge CB, eds. Textbook of rheumatology, 2nd ed. Philadelphia: W.B. Saunders; 1985: 857-60, 1382-8.
  1. Gilman AG, Rall TW, Nies AS, Taylor P, eds. Goodman and Gilman's The pharmacological basis of therapeutics, 8th ed. New York: Pergamon Press; 1990: 679, 743-6, 1070-1, 1073.
  1. Wilson JD, Braunwald E, Isselbacher KJ, Petersdorf RG, Martin JB, Fauci AS, Root R, eds. Harrison's principles of internal medicine, 12th ed. New York: McGraw-Hill; 1991: 1204-5; 1834-41.
  1. Panelist comment, approved by consensus, 1987 revision, Probenecid (Systemic) monograph.
  1. Prescribing information Benemid (probenecid), MSD (Canada), in: Krogh CME, ed. Compendium of pharmaceuticals and specialties, 26th ed. Ottawa: Canadian Pharmaceutical Association; 1991: 173.
  1. Panel consensus, Probenecid and Colchicine (Systemic) monograph, draft 1984.
  1. Panel consensus, Probenecid (Systemic) monograph, 3/92 draft.
  1. Wyngaarden JB, Smith LH, eds. Cecil textbook of medicine, 18th ed. Philadelphia: WB Saunders; 1988: 643.
  1. Prescribing information Valium Injectable (diazepam), Roche (U.S.), in: Physician's desk reference, 46th ed. Montvale: Medical Economics Data; 1992: 1937-9.
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