What are the approved indications, dosing regimens, contraindications, and alternative therapies for colchicine?

Colchicine Indications

Colchicine has three FDA-approved indications: treatment of acute gout flares, prophylaxis of gout flares, and treatment of Familial Mediterranean Fever (FMF). 1

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FDA-Approved Indications & Dosing

1. Acute Gout Flare Treatment

• Dosing regimen: 1.2 mg (two tablets) at the first sign of flare, followed by 0.6 mg (one tablet) one hour later—total maximum dose 1.8 mg over one hour. 1
• Critical timing: Must be initiated within 36 hours of symptom onset; efficacy declines sharply after this window, with optimal benefit when started within 12 hours. 2, 3
• Evidence base: This low-dose regimen achieves ≥50% pain reduction with a number-needed-to-treat of 3–5 and causes significantly fewer gastrointestinal adverse effects (23% diarrhea) compared to obsolete high-dose protocols (77% diarrhea). 2, 3

2. Gout Flare Prophylaxis

• Standard dosing: 0.6 mg once or twice daily (maximum 1.2 mg/day) for adults and adolescents older than 16 years. 1
• Duration when initiating urate-lowering therapy: Prophylaxis should continue for at least 6 months, or for 3 months after achieving target serum urate <6 mg/dL when no tophi are present; if tophi are present, continue for 6 months after reaching target. 2, 3
• Rationale: Urate-lowering agents (allopurinol, febuxostat, pegloticase) mobilize urate from tissue deposits, triggering acute flares; colchicine prophylaxis reduces flare incidence from 77% to 33% during this period. 1

3. Familial Mediterranean Fever (FMF)

• Adult dosing: 1.2 to 2.4 mg daily, administered in one or two divided doses; titrate in 0.3 mg increments to control disease while monitoring tolerability. 1
• Pediatric dosing (≥4 years):
  • Ages 4–6 years: 0.3–1.8 mg daily
  • Ages 6–12 years: 0.9–1.8 mg daily
  • Adolescents >12 years: 1.2–2.4 mg daily 1
• Treatment goals: Achieve complete control of unprovoked attacks and suppress subclinical inflammation (measured by serum amyloid A protein and C-reactive protein) to prevent AA amyloidosis and other long-term complications. 4
• Guideline recommendation: Treatment should start as soon as a clinical diagnosis is made (EULAR Level of Evidence 1b, Grade A). 4
• Monitoring: Response, toxicity, and compliance should be assessed every 6 months; liver enzymes require regular monitoring, with dose reduction if elevated >2× upper limit of normal. 4

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Absolute Contraindications

Drug Interactions Creating Fatal Toxicity Risk

• Patients with renal OR hepatic impairment who are taking strong CYP3A4 or P-glycoprotein inhibitors must NOT receive colchicine due to risk of fatal toxicity, multiorgan failure, and death. 2, 1
• Specific contraindicated inhibitors: clarithromycin, erythromycin, cyclosporine, ketoconazole, ritonavir, verapamil, atazanavir, darunavir, indinavir, itraconazole, lopinavir, nefazodone, nelfinavir, saquinavir, telithromycin, tipranavir. 2, 1
• Mechanism: These inhibitors raise colchicine plasma concentrations by 93–103%, leading to cardiovascular collapse, acute renal failure, and documented fatalities. 2

Severe Renal Impairment

• Colchicine is absolutely contraindicated when creatinine clearance <30 mL/min or eGFR <30 mL/min because of exponentially increased risk of fatal toxicity. 2, 3

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Dose Adjustments for Drug Interactions & Renal Impairment

Strong CYP3A4 Inhibitors (if no alternative available)

• Gout flare prophylaxis: Reduce from 0.6 mg twice daily to 0.3 mg once daily. 1
• Acute gout treatment: Reduce from 1.2 mg + 0.6 mg (1 hour later) to 0.6 mg × 1 dose + 0.3 mg (1 hour later); do not repeat for at least 3 days. 1
• FMF: Reduce maximum daily dose from 1.2–2.4 mg to 0.6 mg (may be given as 0.3 mg twice daily). 1

Moderate CYP3A4 Inhibitors

• Examples: diltiazem, erythromycin, fluconazole, verapamil, grapefruit juice. 1
• Gout flare prophylaxis: Reduce from 0.6 mg twice daily to 0.3 mg twice daily OR 0.6 mg once daily. 1
• Acute gout treatment: Reduce from 1.2 mg + 0.6 mg to 1.2 mg × 1 dose only; do not repeat for at least 3 days. 1
• FMF: Reduce maximum daily dose from 1.2–2.4 mg to 1.2 mg (may be given as 0.6 mg twice daily). 1

P-glycoprotein Inhibitors

• Examples: cyclosporine, ranolazine. 1
• Dosing adjustments: Identical to strong CYP3A4 inhibitors (see above). 1

Renal Impairment (without drug interactions)

• Mild-to-moderate impairment (CrCl 30–80 mL/min): Use standard acute regimen (1.2 mg + 0.6 mg) with close monitoring; reduce prophylactic dose to 0.6 mg once daily. 2, 3
• Severe impairment (CrCl <30 mL/min): Colchicine is contraindicated; select alternative therapy. 2, 3

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Alternative Therapies When Colchicine Is Contraindicated

For Acute Gout Flares

• Oral corticosteroids: Prednisone 30–35 mg daily for 5 days (no taper needed) or 0.5 mg/kg/day for 5–10 days; Level A evidence shows equal efficacy to NSAIDs with fewer adverse events (27% vs 63%). 2, 3
• NSAIDs: Full FDA-approved doses (naproxen 500 mg twice daily, indomethacin 50 mg three times daily, sulindac 200 mg twice daily) until complete resolution; avoid in severe renal impairment (eGFR <30 mL/min), heart failure, cirrhosis, or active peptic ulcer disease. 2, 3
• Intra-articular corticosteroid injection: Triamcinolone 40 mg for knee, 20–30 mg for ankle; excellent option for monoarticular or oligoarticular involvement of accessible large joints. 2, 3

For Gout Flare Prophylaxis

• Low-dose NSAID with proton-pump inhibitor: Naproxen 250 mg twice daily with omeprazole 20 mg daily for at least 6 months. 2, 3
• Low-dose prednisone: <10 mg/day as second-line prophylaxis when colchicine and NSAIDs are contraindicated. 2, 3

For FMF (Colchicine-Resistant or Intolerant Patients)

• IL-1 blockers: Rilonacept, canakinumab, or anakinra are indicated when patients fail to respond to maximum tolerated colchicine dose after 6 months or cannot tolerate colchicine. 4
• Definition of resistance: Patients experiencing ≥1 attack per month despite maximally tolerated colchicine dose for at least 6 months, with confirmed adherence. 4

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Off-Label Indications with High-Quality Evidence

Acute & Recurrent Pericarditis

• Efficacy: Colchicine halves the risk of pericarditis recurrence (relative risk 0.50,95% CI 0.42–0.60) in >1,600 patients across multiple trials. 5
• Dosing: 0.5–1.0 mg daily, typically for 3–6 months depending on clinical response. 6, 7

Secondary Prevention of Cardiovascular Events

• Indication: Patients with acute or chronic coronary syndromes already on statins and antiplatelet agents. 5
• Efficacy: Low-dose colchicine (0.5 mg daily) reduces risk of cardiovascular death, myocardial infarction, ischemic stroke, and ischemia-driven revascularization by >30% (relative risk 0.63,95% CI 0.49–0.81) in >11,000 patients followed up to 5 years. 5

Behçet's Syndrome

• Use: Treatment of mucocutaneous manifestations and serositis. 8, 9

COVID-19

• Emerging evidence: May improve outcomes in hospitalized patients, though further randomized controlled trials are required. 9

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Safety Profile & Common Adverse Effects

Gastrointestinal Toxicity

• Incidence: 23–26% with low-dose regimen (1.8 mg total), 77–100% with obsolete high-dose protocols. 2, 3
• Management strategies: Start at subtherapeutic dose (0.5 mg/day) and increase gradually by 0.5 mg in divided doses; consider dietary modification (temporary reduction of dairy products), split doses, antidiarrheal agents, or oral desensitization protocols. 4

Neuromuscular Toxicity

• Manifestations: Muscle pain, weakness, tingling or numbness in extremities; risk amplified in patients on statins with renal impairment. 2, 1
• Action required: Discontinue colchicine immediately and seek medical evaluation; monitor creatine phosphokinase (CPK) in patients with decreased renal function. 4, 1

Bone Marrow Suppression

• Rare but serious: Agranulocytosis, aplastic anemia, thrombocytopenia may occur; patients should report unusual bleeding, bruising, or signs of infection. 1

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Special Populations

Pregnancy & Lactation

• Colchicine should NOT be discontinued during conception, pregnancy, or lactation; current evidence does not justify amniocentesis. 4
• Male fertility: Men do not need to stop colchicine prior to conception; in rare cases of proven colchicine-related azoospermia or oligospermia, temporary dose reduction or discontinuation may be considered. 4

Pediatric Use

• Gout: Colchicine is NOT recommended for pediatric prophylaxis or treatment of gout flares. 1
• FMF: Approved for children ≥4 years with age-based dosing (see FDA-approved dosing above). 1

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Critical Clinical Pitfalls to Avoid

• Never use obsolete high-dose regimens (0.5 mg every 2 hours until relief or toxicity); they cause severe diarrhea in most patients without added benefit. 2, 3
• Never initiate colchicine after 36 hours from gout symptom onset; efficacy drops dramatically. 2, 3
• Never combine colchicine with strong CYP3A4/P-gp inhibitors in patients with any degree of renal or hepatic impairment. 2, 1
• Never discontinue urate-lowering therapy (allopurinol, febuxostat) during an acute gout flare if the patient is already on it; continue the medication and treat the flare separately. 2, 3
• Never omit colchicine prophylaxis when starting urate-lowering therapy; flare rates roughly double without it. 2, 3
• Never delay acute gout treatment beyond 24 hours; effectiveness of all agents declines sharply. 2, 3