Colchicine and Microtubule Inhibition

Colchicine is an alkaloid that binds tubulin and stops microtubule formation. At low doses it is an anti-inflammatory drug for gout, familial Mediterranean fever (FMF), pericarditis, Behcet disease and cardiovascular prevention. The margin between a useful and a toxic dose is narrow, and overdose is life threatening.

Mechanism. Microtubule disruption stops neutrophil migration, inflammasome (NLRP3) activation and release of interleukin 1 beta. Higher doses stop cell division, which explains marrow and gut toxicity. Other microtubule inhibitors, the vinca alkaloids and taxanes, are cytotoxic cancer drugs with different dosing.

Pharmacokinetics. Oral bioavailability about 45%; peak at 1 to 2 hours; large volume of distribution; half-life 20 to 40 hours; CYP3A4 and P-glycoprotein substrate; about 40% renal elimination, with enterohepatic recirculation.

Dosing.

• Gout flare (low-dose regimen): 1 mg at first sign, then 0.5 mg 1 hour later; then 0.5 mg once or twice daily until the flare resolves. Do not repeat the course within 3 days.
• Gout prophylaxis when starting urate-lowering therapy: 0.5 mg once or twice daily for 3 to 6 months.
• Familial Mediterranean fever: 1 to 2 mg daily in one or two doses (adults); children 0.5 mg to 1.5 mg daily by age and weight; increase if attacks persist.
• Acute and recurrent pericarditis: 0.5 mg twice daily (0.5 mg once daily if under 70 kg) for 3 months, with an anti-inflammatory drug.
• Cardiovascular prevention after myocardial infarction: 0.5 mg once daily.
• Behcet disease (mucocutaneous): 1 to 2 mg daily.

Dose reductions.

• Creatinine clearance 30 to 59 mL/min: lower the dose and watch; under 30 mL/min: 0.5 mg daily or less for prophylaxis, and a single flare dose with no repeat for 2 weeks.
• Dialysis: single 0.6 mg dose only, not repeated for 2 weeks.
• Strong CYP3A4 or P-glycoprotein inhibitors: halve the dose or avoid; clarithromycin and ritonavir are the usual causes.

Formulations. 0.5 mg tablets are used in many regions; 0.6 mg and 1 mg strengths exist in other regions, so check the label.

• First-line. Gout flares when NSAIDs are unsuitable (alongside or instead of them); prophylaxis during urate-lowering therapy; familial Mediterranean fever; recurrent pericarditis.
• Alternative. Gout flares: glucocorticoid or NSAID instead; FMF resistant to colchicine: interleukin 1 inhibitors.
• Specialist. Behcet disease, cardiovascular secondary prevention, post-pericardiotomy syndrome, amyloidosis prevention in FMF.
• Emergency. Overdose or poisoning.

Selection. Choose when NSAIDs are contraindicated (kidney disease, heart failure, peptic ulcer, anticoagulation) and the dose can be adjusted to kidney function and interacting drugs. For flares, treat within 12 to 24 hours of onset for best effect.

Contraindications. Concurrent strong CYP3A4 and P-glycoprotein inhibitors in renal or hepatic impairment; severe renal or hepatic impairment (for repeated dosing); blood dyscrasias; hypersensitivity.

Serious adverse effects.

• Diarrhoea, nausea, vomiting and abdominal pain (first sign of toxicity; stop the drug).
• Myopathy and neuropathy, more with statins, fibrates and renal impairment.
• Marrow suppression (neutropenia, thrombocytopenia, pancytopenia) and alopecia.
• Overdose over 0.5 mg/kg is serious and over 0.8 mg/kg usually fatal: vomiting, watery diarrhoea, shock, multi-organ failure, then marrow aplasia at 4 to 7 days.

Major interactions. Clarithromycin, erythromycin, ketoconazole, itraconazole, ritonavir and cobicistat, ciclosporin, diltiazem, verapamil (raise levels; fatal toxicity reported); statins and fibrates (myopathy); rifampicin and St John’s wort lower levels.

Common prescribing errors.

• Full-dose repeated courses in renal impairment.
• Prescribing with clarithromycin or an antiretroviral booster without a dose change.
• Using high-dose flare regimens (hourly doses until diarrhoea).
• Continuing after diarrhoea starts.
• Leaving tablets accessible to children (a few tablets can kill).

Special groups.

• Pregnancy: used in FMF to prevent attacks and amyloidosis; continue under specialist care.
• Breastfeeding: low milk levels; generally acceptable at usual doses.
• Children: FMF dosing by age; avoid for gout.
• Older adults: start low; check creatinine clearance.
• Kidney: reduce dose; avoid in severe disease or dialysis except single doses.
• Liver: reduce dose in severe impairment.
• East Africa: boosted antiretroviral regimens (ritonavir or cobicistat) and macrolide antibiotics are common, so check each prescription; colchicine may be widely available, so counsel on safe storage and the stopping rule for diarrhoea.

Monitoring. Creatinine clearance before starting; full blood count, liver tests and creatine kinase for long-term use; bowel symptoms; muscle weakness; drug review at each change.

Referral and escalation. Severe vomiting or diarrhoea; muscle weakness; falling counts; suspected overdose (urgent resuscitation, activated charcoal if early, intensive care); poor response in FMF.

Comparison with alternative classes. Colchicine is cheap, oral and effective for crystal and autoinflammatory disease, but has a narrow range and many interactions. NSAIDs and glucocorticoids act faster in gout; interleukin 1 inhibitors treat colchicine-resistant FMF.