Dosing and uses of Colchicine/probenecid
Adult dosage forms and strengths
colchicine/probenecid
tablet
- 0.5mg/500mg
Chronic Gouty Arthritis
Indicated for treatment of chronic gouty arthritis when complicated by frequent, recurrent acute attacks of gout
1 tablet (0.5 mg/500 mg) PO qDay for 1 week, then increase to 1 tablet BID thereafter
May be increased by 1 tablet q4wk within tolerance (and usually not above 4 tablets/day) if symptoms not controlled or the 24 hour uric acid excretion is <700 mg
Renal Impairment
Dosage requirements may be increased with renal impairment
CrCl <30 mL/min: Probenecid not effective with low urine output
Dosing Considerations
Do not start until an acute gouty attack has subsided; however, if an acute attack is precipitated during therapy, colchicine/probenecid may be continued without changing the dosage, and additional colchicine or other appropriate therapy should be given to control the acute attack
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 and sodium bicarbonate (3-7.5 g/day) or potassium citrate (7.5 g/day) to maintain an alkaline urine
Pediatric dosage forms and strengths
Safety and efficacy not established
Colchicine/probenecid adverse (side) effects
Frequency not defined
Probenecid
- CNS: 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
- Adverse effects appear to be dose dependent; increased colchicine toxicity may occur with hepatic dysfunction
- CNS: 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, may cause severe diarrhea, generalized vascular damage, and renal damage with hematuria and oliguria
Warnings
Contraindications
Hypersensitivity
Blood dyscrasias
Uric acid kidney stones Initiation of therapy during an acute gouty attack
Cautions
Exacerbation of gout may occur; in such cases additional colchicine or other appropriate therapy required
Probenecid increases plasma concentrations of methotrexate; if combination must be used, reduce methotrexate dose and monitor methotrexate serum levels
Salicylates antagonize probenecid’s uricosuric effect
Rare occurrence of severe allergic reactions and anaphylaxis reported; most within several hours after readministration following prior usage of the drug; discontinue colchicine/probenecid if this occurs
Hematuria, renal colic, costovertebral pain, and formation of uric acid stones associated with the use may be prevented by alkalization of the urine and a liberal fluid intake
History of peptic ulcer
Increased dosage requirements may be needed with renal impairment
Pregnancy and lactation
Pregnancy category: C; While not studied in the treatment of gout, data from a limited number of published studies found no evidence of an increased risk of miscarriage, stillbirth, or teratogenic effects among pregnant women using colchicine to treat familial Mediterranean fever
Lactation: Colchicine is distributed in breast milk; limited information suggests breastfed infants receive <10% of maternal weight-adjusted dose; caution advised and observe infant for adverse effects if breastfeeding
Pregnancy categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA: Information not available.
Pharmacology of Colchicine/probenecid
Mechanism of action
Colchicine: Inhibits leukocyte migration, decreased phagocytosis in joint, decreased lactic acid production by neutrophils resulting in reducing uric acid crystal deposition and decreasing inflammation
Probenecid: Uricosuric and renal tubular blocking agent
Absorption
Bioavailability: 25-50% (colchicine); >90% (probenecid)
Onset initial: 12-24 hr (colchicine);1 hr initial (probenecid)
Onset maximum: 48-72 hr (colchicine); 3 hr (probenecid)
Peak Plasma Time: 0.5-2 hr (colchicine); 1-5 hr (probenecid)
Distribution
Protein Bound: 10-30% (colchicine); 85-95% to albumin (probenecid)
Vd: 2 L (colchicine); 11 L (probenecid)
Metabolism
Colchicine is metabolized by CYP3A4; partially deacetylated in the liver; undergo enterohepatic circulation
Probenecid is metabolized in the liver to hydroxylated metabolites, N-despropyl metabolite, probenecid acylglucuronide
Elimination
Half-life: 4.4 hr (colchicine); 3-17 hr (probenecid)
Dialyzable: No (colchicine)
Renal clearance: 0.7 L/hr/kg (colchicine)
Excretion: 10-20% feces (colchicine); 75-88% urine (probenecid)
