What are the side effects of colchicine?

Colchicine Side Effects

Colchicine causes dose-dependent gastrointestinal toxicity (especially severe diarrhea), and can lead to life-threatening multi-organ failure, particularly when combined with CYP3A4/P-glycoprotein inhibitors or in patients with renal/hepatic impairment. 1

Gastrointestinal Side Effects

Most common and earliest manifestation:

• Diarrhea is the most frequent side effect, occurring in up to 20% of patients at therapeutic doses and often the first sign of impending toxicity 2, 1
• Nausea and vomiting typically develop within the first 24 hours of treatment 2, 3
• Abdominal pain is particularly common in patients with familial Mediterranean fever 1
• High-dose regimens cause severe gastrointestinal symptoms - the traditional high-dose gout protocol (1g loading, then 0.5mg every 2-3 hours) is "very toxic, even within a very short treatment period" 4

Management approach: Reduce dose, divide daily dosing, modify diet, or use anti-diarrheal medications 2

Hematologic Toxicity

Life-threatening bone marrow suppression:

• Pancytopenia can occur, especially with intravenous administration or drug interactions 3, 5
• Prolonged treatment can cause hematological abnormalities 4
• Disseminated intravascular coagulation may develop in severe toxicity 2

Warning signs requiring immediate medical attention: 1

• Unusual bleeding or bruising
• Increased infections
• Pale or gray color to lips, tongue, or palms

Neuromuscular Toxicity

Myopathy and neuropathy - often underrecognized:

• Muscle weakness or pain can develop, particularly with long-term therapy 1, 5
• Numbness or tingling in fingers or toes 1
• Colchicine-induced myopathy may be more frequent than previously recognized, requiring careful monitoring in patients on chronic therapy 5
• Risk dramatically increases when combined with statins or fibrates 6, 7

Multi-Organ Dysfunction in Severe Toxicity

Sequential phases of colchicine poisoning: 3

1. Initial phase (10-24 hours): Gastrointestinal symptoms mimicking gastroenteritis
2. Intermediate phase (24 hours to 7 days): Multi-organ dysfunction including:
   • Acute renal failure 2, 3
   • Respiratory failure 2
   • Cardiac arrhythmias 2, 7
   • Neurological alterations 2
   • Shock 2
   • Death from rapidly progressive multi-organ failure and sepsis 3
3. Recovery phase: Typically occurs within weeks if patient survives 3

Critical Drug Interactions

Life-threatening interactions with CYP3A4/P-glycoprotein inhibitors: 1, 7

• Macrolide antibiotics (clarithromycin, erythromycin - NOT spiramycin): Risk of life-threatening pancytopenia 6, 7
• Azole antifungals (ketoconazole): Increased colchicine concentrations 3
• Cyclosporine: Aggravates neuromuscular adverse effects 6
• Grapefruit juice: Increases risk of serious side effects 1
• Statins and fibrates: Additive myotoxicity risk 6, 7

The FDA label explicitly warns: "Do not take Colchicine if you have liver or kidney problems and you take certain other medicines. Serious side effects, including death, have been reported." 1

Dose-Related Toxicity

Narrow therapeutic index with no clear distinction between therapeutic and toxic doses: 3

• Lowest reported lethal oral doses: 7-26 mg 3
• High fatality rate after acute ingestions exceeding 0.5 mg/kg 3
• Standard high-dose regimens cause serious gastrointestinal side effects in most patients 4

Special Populations Requiring Dose Adjustment

Renal impairment: 2, 1

• Avoid in severe renal impairment (eGFR <30 mL/min) 2
• Pre-existing renal failure increases risk of adverse effects 6
• Patients at risk may require lower doses (0.5 mg three times daily) 2

Hepatic impairment: 2, 1

• Elimination half-life may increase up to seven times in cirrhosis 2
• Treat with extreme caution 2

Monitoring Requirements

• Monitor every 6 months for response, toxicity, and compliance in patients on chronic therapy 2
• Watch for early signs of toxicity, especially diarrhea in elderly and renally impaired patients 6
• Blood tests should be performed periodically 1

Pregnancy and Lactation

• Colchicine crosses the placenta but no evidence of fetal toxicity exists 3, 5
• Excreted in breast milk; discuss risks/benefits with healthcare provider 1, 3
• Should not be used by pregnant women due to cytogenic effects and reported association with Down's syndrome 5

Fatal Toxicity Warning

No effective antidote exists - management is primarily supportive as there are no effective means to eliminate colchicine from tissues and blood 2, 3. The experimental Fab fragment antibodies are not commercially available 3.