What are the adverse reactions of colchicine?

Adverse Reactions of Colchicine

Colchicine causes gastrointestinal adverse effects in up to 20% of patients at therapeutic doses, with diarrhea being the most common reaction, occurring in 23% of patients on low-dose regimens and 77% on high-dose regimens. 1

Gastrointestinal Adverse Effects

The gastrointestinal tract is the primary site of colchicine toxicity and these symptoms typically present within 24 hours of treatment initiation. 1

Common GI manifestations include:

• Diarrhea (17.9% vs 13.1% in placebo, RR 2.4) – the most frequent adverse reaction 2, 3
• Abdominal cramping and pain 4, 1
• Nausea and vomiting 1
• Hyperperistalsis 4

The severity and frequency of GI symptoms are directly dose-dependent. Severe diarrhea occurred in 19% and vomiting in 17% of patients taking high-dose regimens (4.8 mg over 6 hours) but did not occur with the recommended low-dose regimen (1.8 mg over 1 hour). 1

Management of GI Symptoms

These GI symptoms should be viewed as dose-limiting if severe, as they can herald the onset of more significant toxicity. 1

Management strategies include:

• Dose reduction or splitting into divided doses 4, 5
• Dietary modification (temporary reduction of dairy products, as lactose intolerance may contribute) 4, 1
• Anti-diarrheal and spasmolytic agents 4
• Gradual dose escalation starting at 0.5 mg/day and increasing by 0.5 mg increments 4

Hematologic Toxicity

Prolonged colchicine treatment can cause serious hematological abnormalities, particularly with drug interactions or intravenous administration. 5

Hematologic adverse events include:

• Pancytopenia 5, 1
• Leukopenia and granulocytopenia 1
• Thrombocytopenia 1
• Aplastic anemia 1

Development of any cytopenia mandates immediate discontinuation of colchicine. 5 Increased infections may be a warning sign of hematologic toxicity requiring immediate medical attention. 5

Neuromuscular Toxicity

Myalgias occur in 21% of colchicine users versus 18% of placebo patients (RR 1.16). 2

Neuromuscular manifestations include:

• Myopathy and muscle weakness 1
• Elevated creatine phosphokinase (CPK) 1
• Rhabdomyolysis 1
• Sensory-motor neuropathy 1
• Myotonia 1

The risk of myotoxicity is markedly increased when colchicine is combined with statins, particularly atorvastatin and simvastatin. 5 Clinicians should monitor closely for muscle symptoms (weakness, myalgia, tenderness) at every visit and obtain CK testing if symptoms appear. 5

Hepatobiliary Toxicity

Elevated liver enzymes (AST, ALT) can occur with colchicine use. 1 Liver adverse events were reported in 1.9% of colchicine users versus 1.1% in comparator groups (RR 1.6). 3

Regular monitoring of liver enzymes is recommended at minimum every 6 months. 5, 6

Dermatologic Reactions

Dermatologic adverse effects include:

• Alopecia (hair loss) 1, 7
• Maculopapular rash 1
• Purpura 1

Reproductive Effects

Colchicine can cause:

• Azoospermia (absence of sperm) 1
• Oligospermia (low sperm count) 1

However, colchicine has not been shown to adversely affect reproductive potential in males or females overall, crosses the placenta without evidence of fetal toxicity, and is considered compatible with lactation. 8

Life-Threatening Toxicity and Overdose

Colchicine has a narrow therapeutic index with no clear distinction between nontoxic, toxic, and lethal doses. 8 The lowest reported lethal oral doses are 7-26 mg, with high fatality rates after acute ingestions exceeding 0.5 mg/kg. 8

Colchicine toxicity presents in three sequential phases:

1. Gastrointestinal phase (10-24 hours): Severe gastroenteritis with "cholera-like syndrome," massive fluid losses, dehydration 5, 8

2. Multi-organ dysfunction phase (24 hours to 7 days): Acute renal failure, respiratory failure, cardiac arrhythmias, disseminated intravascular coagulation, neurological alterations, shock, and sepsis 5, 8

3. Recovery or death phase: Death typically results from rapidly progressive multi-organ failure; recovery, if it occurs, takes weeks 8

Critical Drug Interactions Leading to Toxicity

Colchicine should never be combined with strong CYP3A4 or P-glycoprotein inhibitors, as these can increase colchicine plasma levels by 200-300% and cause potentially fatal toxicity. 6

Absolutely contraindicated combinations include:

• Macrolide antibiotics (clarithromycin, erythromycin) – can be fatal 5, 6, 8, 7
• Calcineurin inhibitors (cyclosporine, tacrolimus) 5, 6
• Azole antifungals (ketoconazole) 8
• HIV protease inhibitors 5, 6
• Calcium channel blockers (verapamil, diltiazem) 5

High-Risk Populations Requiring Dose Adjustment

Patients with renal or hepatic impairment are at significantly higher risk of toxicity and require dose adjustments. 5, 9

Specific considerations:

• Severe renal impairment (eGFR <30 mL/min): Colchicine should be avoided 5, 6
• Moderate renal impairment (CrCl 30-50 mL/min): Close monitoring required; standard dosing may lead to supratherapeutic levels 6
• Hepatic cirrhosis: Elimination half-life may increase up to sevenfold, dramatically increasing toxicity risk 5, 9

Mandatory Monitoring Requirements

All patients on colchicine require laboratory monitoring at minimum every 6 months (more frequently with renal impairment): 5, 6

• Complete blood count (to detect cytopenias) 5, 6
• Creatine phosphokinase (CPK) (to detect muscle toxicity) 5, 6
• Liver enzymes (AST, ALT) 5, 6
• Renal function (creatinine, eGFR) 5, 6
• Urinalysis (at least yearly, more often for poorly controlled disease) 6

Immediate discontinuation is required if any of the following develop: progressive muscle weakness, severe diarrhea with systemic symptoms, cytopenias, acute worsening of renal function, or neuropathy. 5, 6