Probenecid and colchicine contains probenecid, which is a uricosuric agent, and colchicine, which has antigout activity, the mechanism of which is unknown.

Probenecid is the generic name for 4-[(dipropylamino) sulfonyl]benzoic acid. The structural formula is represented below:

Probenecid is a white or nearly white, fine crystalline powder.

C13H19NO4S       M.W. 285.36

It is soluble in dilute alkali, in alcohol, in chloroform, and in acetone; it is practically insoluble in water and in dilute acids.

Colchicine is an alkaloid obtained from various species of Colchicum. The chemical name for colchicine is (S)-N-(5,6,7,9-tetrahydro-1,2,3,10-tetramethoxy-9-oxobenzo[α]heptalen-7-yl) acetamide. The structural formula is represented below:

C22H25NO6       M.W. 399.44

Colchicine consists of pale yellow scales or powder; it darkens on exposure to light. Colchicine is soluble in water, freely soluble in alcohol and in chloroform, and slightly soluble in ether.

Each tablet for oral administration contains 500 mg of probenecid and 0.5 mg of colchicine. Each tablet also contains the following inactive ingredients: colloidal silicon dioxide, crospovidone, magnesium stearate, microcrystalline cellulose, sodium lauryl sulfate and sodium starch glycolate.

Probenecid is a uricosuric and renal tubular blocking agent. It inhibits the tubular reabsorption of urate, thus increasing the urinary excretion of uric acid and decreasing serum urate levels. Effective uricosuria reduces the miscible urate pool, retards urate deposition, and promotes resorption of urate deposits.

Probenecid inhibits the tubular secretion of penicillin and usually increases penicillin plasma levels by any route the antibiotic is given. A 2-fold to 4-fold elevation has been demonstrated for various penicillins.

Probenecid also has been reported to inhibit the renal transport of many other compounds including aminohippuric acid (PAH), aminosalicylic acid (PAS), indomethacin, sodium iodomethamate and related iodinated organic acids, 17-ketosteroids, pantothenic acid, phenolsulfonphthalein (PSP), sulfonamides, and sulfonylureas. See also Drug Interactions.

Probenecid decreases both hepatic and renal excretion of sulfobromophthalein (BSP). The tubular reabsorption of phosphorus is inhibited in hypoparathyroid but not in euparathyroid individuals.

Probenecid does not influence plasma concentrations of salicylates, nor the excretion of streptomycin, chloramphenicol, chlortetracycline, oxytetracycline, or neomycin.

The mode of action of colchicine in gout is unknown. It is not an analgesic, though it relieves pain in acute attacks of gout. It is not a uricosuric agent and will not prevent progression of gout to chronic gouty arthritis. It does have a prophylactic, suppressive effect that helps to reduce the incidence of acute attacks and to relieve the residual pain and mild discomfort that patients with gout occasionally feel.

In man and certain other animals, colchicine can produce a temporary leukopenia that is followed by leukocytosis.

Colchicine has other pharmacologic actions in animals: It alters neuromuscular function, intensifies gastrointestinal activity by neurogenic stimulation, increases sensitivity to central depressants, heightens response to sympathomimetic compounds, depresses the respiratory center, constricts blood vessels, causes hypertension by central vasomotor stimulation, and lowers body temperature.

For the treatment of chronic gouty arthritis when complicated by frequent, recurrent acute attacks of gout.

Hypersensitivity to this product or to probenecid or colchicine.

Probenecid and colchicine tablets are contraindicated in children under 2 years of age.

Not recommended in persons with known blood dyscrasias or uric acid kidney stones.

Therapy with probenecid and colchicine should not be started until an acute gouty attack has subsided.

Exacerbation of gout following therapy with probenecid and colchicine may occur; in such cases additional colchicine or other appropriate therapy is advisable.

Probenecid increases plasma concentrations of methotrexate in both animals and humans. In animal studies, increased methotrexate toxicity has been reported. If probenecid and colchicine is given with methotrexate, the dosage of methotrexate should be reduced and serum levels may need to be monitored.

In patients on probenecid and colchicine the use of salicylates in either small or large doses is contraindicated because it antagonizes the uricosuric action of probenecid. The biphasic action of salicylates in the renal tubules accounts for the so-called "paradoxical effect" of uricosuric agents. In patients on probenecid and colchicine who require a mild analgesic agent the use of acetaminophen rather than small doses of salicylates would be preferred.

Rarely, severe allergic reactions and anaphylaxis have been reported with the use of probenecid and colchicine. Most of these have been reported to occur within several hours after readministration following prior usage of the drug.

The appearance of hypersensitivity reactions requires cessation of therapy with probenecid and colchicine.

Colchicine has been reported to adversely affect spermatogenesis in animals. Reversible azoospermia has been reported in one patient.

To report SUSPECTED ADVERSE REACTIONS, contact Ingenus Pharmaceuticals NJ, LLC at 1-877-748-1970 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

The following adverse reactions have been observed and within each category are listed in order of decreasing severity.

Probenecid

Central Nervous System: headache, dizziness.

Metabolic: precipitation of acute gouty arthritis.

Gastrointestinal: hepatic necrosis, vomiting, nausea, anorexia, sore gums.

Genitourinary: nephrotic syndrome, uric acid stones with or without hematuria, renal colic, costovertebral pain, urinary frequency.

Hypersensitivity: anaphylaxis, fever, urticaria, pruritus.

Hematologic: aplastic anemia, leukopenia, hemolytic anemia which in some patients could be related to genetic deficiency of glucose-6-

phosphate dehydrogenase in red blood cells, anemia.

Integumentary: dermatitis, alopecia, flushing.



Colchicine

Side effects due to colchicine appear to be a function of dosage. The possibility of increased colchicine toxicity in the presence of hepatic

dysfunction should be considered. The appearance of any of the following symptoms may require reduction of dosage or discontinuance of the drug.

Central Nervous System: peripheral neuritis.

Musculoskeletal: muscular weakness.

Gastrointestinal: nausea, vomiting, abdominal pain, or diarrhea may be particularly troublesome in the presence of peptic ulcer or spastic colon.

Hypersensitivity: urticaria.

Hematologic: aplastic anemia, agranulocytosis.

Integumentary: dermatitis, purpura, alopecia.

At toxic doses, colchicine may cause severe diarrhea, generalized vascular damage, and renal damage with hematuria and oliguria.

Therapy with probenecid and colchicine should not be started until an acute gouty attack has subsided. However, if an acute attack is precipitated during therapy, probenecid and colchicine may be continued without changing the dosage, and additional colchicine or other appropriate therapy should be given to control the acute attack.

The recommended adult dosage is 1 tablet of probenecid and colchicine daily for one week, followed by 1 tablet twice a day thereafter.

Some degree of renal impairment may be present in patients with gout. A daily dosage of 2 tablets may be adequate. However, if necessary, the daily dosage may be increased by 1 tablet every four weeks within tolerance (and usually not above 4 tablets per day) if symptoms of gouty arthritis are not controlled or the 24 hour uric acid excretion is not above 700 mg. As noted, probenecid may not be effective in chronic renal insufficiency particularly when the glomerular filtration rate is 30 mL/minute or less.

Gastric intolerance may be indicative of overdosage, and may be corrected by decreasing the dosage.

As uric acid tends to crystallize out of an acid urine, a liberal fluid intake is recommended, as well as sufficient sodium bicarbonate (3 to 7.5 g daily) or potassium citrate (7.5 g daily) to maintain an alkaline urine (see PRECAUTIONS).

Alkalization of the urine is recommended until the serum urate level returns to normal limits and tophaceous deposits disappear, i.e., during the period when urinary excretion of uric acid is at a high level. Thereafter, alkalization of the urine and the usual restriction of purine-producing foods may be somewhat relaxed.

Probenecid and colchicine (or probenecid) should be continued at the dosage that will maintain normal serum urate levels. When acute attacks have been absent for six months or more and serum urate levels remain within normal limits, the daily dosage of probenecid and colchicine may be decreased by 1 tablet every six months. The maintenance dosage should not be reduced to the point where serum urate levels tend to rise.

Probenecid and Colchicine Tablets, USP 500 mg/0.5 mg are bisected, white, capsule-shaped tablets debossed with CL025 on one side and supplied in bottles of 100.

Bottles of 100 (NDC 50742-263-01)

Dispense in well-closed, light resistant container with child-resistant closure.

Store at controlled room temperature 20°– 25° C (68°– 77°F).

[See USP Controlled Room Temperature]. Protect from light.

Manufactured for:

Ingenus Pharmaceuticals, LLC

Orlando, FL 32839-6408

Rx only

554000

Revised: 03/2019

ingenus

ingenus

NDC 50742-263-01

Probenecid and Colchicine Tablets, USP

500 mg/0.5 mg

Rx only

100 Tablets