Colchicine

Colchicine is a plant-derived alkaloid with anti-inflammatory action, used for acute gout flares, flare prophylaxis during urate lowering, familial Mediterranean fever, acute and recurrent pericarditis, Behcet disease and cardiovascular risk reduction. It has a narrow therapeutic index, and interacting drugs and renal impairment cause fatal toxicity.

Class. Anti-inflammatory alkaloid, microtubule polymerisation inhibitor.

Mechanism. It binds tubulin and prevents microtubule assembly, impairing neutrophil chemotaxis, adhesion and degranulation, and suppressing NLRP3 inflammasome activation and interleukin 1 beta release.

Pharmacokinetics. Oral bioavailability about 45 percent, peak at 1 to 2 hours, large volume of distribution with concentration in leucocytes, half-life 27 to 31 hours. Metabolised by CYP3A4 and a P-glycoprotein substrate. About 40 to 65 percent is renally excreted unchanged, and it is not removed by dialysis.

Acute gout flare (start within 12 to 24 hours of onset).

• 1 mg orally, then 0.5 mg 1 hour later.

• Maximum dose: 1.5 mg in the first 24 hours; do not repeat a course within 3 days.

• Do not give a flare regimen to a patient already taking prophylactic colchicine without reducing the dose.

Gout flare prophylaxis (when starting urate-lowering therapy). 0.5 mg once or twice daily for up to 6 months, or for 3 months after reaching target serum urate with no flares.

Familial Mediterranean fever (colchicine is the drug of choice).

• Adults: 1 to 2 mg daily in one or two doses; may increase to 3 mg daily.

• Children under 5 years: 0.5 mg daily; 5 to 10 years: 1 to 1.5 mg daily; over 10 years: 1.5 to 2 mg daily.

• Lifelong; do not stop in the presence of renal amyloid risk.

Acute and recurrent pericarditis. 0.5 mg twice daily for patients of 70 kg or more, 0.5 mg once daily for under 70 kg, for 3 months (6 months in recurrent disease), with an anti-inflammatory drug.

Cardiovascular risk reduction (stable coronary disease or after myocardial infarction). 0.5 mg once daily.

Behcet disease and calcium pyrophosphate disease (specialist). 0.5 mg twice daily to 1 mg daily.

Loading dose. None except the gout flare first dose of 1 mg. Titration: increase slowly to avoid diarrhoea.

Renal dose adjustment.

• eGFR 30 to 60 mL/min: use the lowest dose and monitor; for prophylaxis, 0.5 mg once daily.

• eGFR under 30 mL/min: flare treatment is a single dose of 0.5 mg not repeated within 2 weeks; prophylaxis not over 0.5 mg on alternate days with specialist oversight, or avoid.

• Dialysis: single 0.5 mg dose for a flare, not repeated within 2 weeks.

Hepatic adjustment. Reduce the dose in mild to moderate impairment; avoid in severe impairment, especially with renal impairment.

Contraindications. Concurrent strong CYP3A4 or P-glycoprotein inhibitors in patients with renal or hepatic impairment, severe renal impairment with a flare regimen, and blood dyscrasia. Hypersensitivity.

Boxed-warning-level risks. Fatal overdose and fatal interactions are the dominant hazards: neuromyopathy, rhabdomyolysis, marrow suppression and multi-organ failure.

Adverse effects. Common: diarrhoea, nausea, vomiting, abdominal pain (early signs of toxicity; stop). Serious: neuromyopathy and rhabdomyolysis, pancytopenia and aplastic anaemia, hepatotoxicity, renal failure, multi-organ failure in overdose, alopecia, peripheral neuropathy.

Major interactions. Clarithromycin, erythromycin, telithromycin, ciclosporin, ritonavir, ketoconazole, itraconazole, verapamil and diltiazem (raise levels; avoid, or reduce the dose by 50 to 75 percent in patients with normal renal and hepatic function). Statins, fibrates and digoxin (myopathy). Grapefruit juice. CYP3A4 and P-glycoprotein inducers (rifampicin) lower levels.

Common prescribing errors. Repeating the flare regimen too soon; prescribing a flare regimen to a patient already on prophylaxis; co-prescribing clarithromycin; not reducing the dose in renal impairment; confusing colchicine with other tablets in children.

Toxicity and management. Toxic effects begin with vomiting and diarrhoea within 24 hours, followed by multi-organ failure, marrow suppression and death at 24 to 72 hours. Ingestion over 0.5 mg/kg is serious and over 0.8 mg/kg is usually fatal. Management is supportive and in a critical care setting: decontamination if early, fluid and electrolyte replacement, and granulocyte colony-stimulating factor for neutropenia. There is no specific antidote and haemodialysis does not help.

Special groups.

• Pregnancy: acceptable and continued in familial Mediterranean fever; avoid for gout unless essential.

• Breastfeeding: compatible at usual doses.

• Children: weight and age based as stated for familial Mediterranean fever.

• Older adults: lower doses and closer monitoring because of reduced renal clearance.

• Kidney impairment: reduce the dose as stated.

• Liver impairment: reduce or avoid.

• Region: macrolide antibiotics, azole antifungals and ritonavir-boosted antiretrovirals are widely used in East Africa; check before prescribing or dispensing colchicine.

Formulations. 0.5 mg tablets (and 0.6 mg in some regions); oral solution in some regions. Take with or without food and with water.

Baseline. Creatinine and eGFR, liver enzymes, full blood count, creatine kinase if on a statin, and a full medicine review for interacting drugs.

Monitoring. Full blood count, creatinine and liver enzymes at baseline and every 3 to 6 months in long-term use. Ask about diarrhoea, muscle weakness and numbness at each visit.

Stop or hold thresholds. Diarrhoea, vomiting or abdominal pain (stop and reassess), muscle pain or weakness with raised creatine kinase, cytopenia, or a new interacting drug.

Referral and escalation. Refer urgently for any suspected overdose or toxic features. Refer to a rheumatologist for familial Mediterranean fever not controlled at 2 to 3 mg daily.