Safer prescribing of high-risk medicines: Colchicine – extremely toxic in overdose

Colchicine has a narrow therapeutic index, which means that the range between therapeutic and toxic doses is small, and in some cases they overlap.¹ Acute overdose exceeding 0.5 mg/kg is usually fatal.¹ Fatalities have been associated with doses as low as 7 mg. In contrast, patients have survived doses up to 60 mg.⁵ In a case series of nine patients presenting with colchicine overdose in the Auckland region over a 15 year period, eight died.⁶ Four of the patients had taken an accidental overdose of colchicine (ranging from 18 – 24 mg) due to lack of knowledge about the medicine.⁶ Colchicine is particularly toxic to children and even one or two tablets can cause serious toxicity.⁵

Gastrointestinal disturbance is usually the first sign of toxicity

Abdominal pain, diarrhoea, nausea and vomiting are usually the first symptoms of colchicine toxicity. A burning sensation in the throat, abdomen or on the skin has also been reported. These symptoms, particularly diarrhoea, can also occur with doses within the therapeutic range. Later features of toxicity (24 hours to seven days after ingestion) include tachypnoea, electrolyte disorders (e.g. hypocalcaemia, hypophosphataemia), hypovolaemia, haematological effects (e.g. leukopaenia, thrombocytopaenia), cardiac dysrhythmias, renal failure and liver damage.^{1, 5, 6} The cause of death is usually progressive multiple organ failure and sepsis.¹

Adverse effects can occur even at “safe” doses

Prior to 2005, colchicine dose instructions included the advice to continue dosing until the pain settled or gastrointestinal adverse effects occured. The standard dose instructions have now been changed to improve safety. Patients are advised to stop taking colchicine immediately if they experience abdominal pain, diarrhoea, nausea or vomiting, or a burning feeling in their throat, stomach or on their skin.⁵

Table 1 shows the current New Zealand dosing recommendations for colchicine used in patients with gout.^{7, 8} Internationally, specifically in Australia and the United States, even lower doses are recommended. A study comparing low-dose colchicine (1.2 mg followed by 0.6 mg in 1 hour; 1.8 mg total) with high-dose colchicine (1.2 mg followed by 0.6 mg every hour for 6 hours; 4.8 mg total) found that efficacy of the low-dose regimen was comparable to the high-dose regimen, however, there was a significant reduction in the rate of adverse effects with the low dose regimen.⁹ The lower dosing regimen is now recommended in colchicine guidelines in Australia and the United States.

Interactions increase the risk of colchicine toxicity

The risk of colchicine toxicity is increased when inhibitors of cytochrome P450 3A4 (CYP3A4) or P-glycoprotein (P-gp) are taken concurrently, e.g. some azole antifungals (e.g. fluconazole), calcium channel blockers (e.g. diltiazem, verapamil) and macrolide antibiotics (e.g. erythromycin) (see New Zealand Formulary for full list).⁸

If these medicines are required at the same time as colchicine, the dose of colchicine should be reduced and the patient monitored for symptoms and signs of colchicine toxicity. These combinations are contraindicated in patients with renal or hepatic impairment, as this increases the risk of toxicity.¹⁰

Table 1: Recommended colchicine dosing regimen^{7, 8}

All patients with known or suspected overdose of colchicine, or displaying symptoms of colchicine toxicity, should be immediately referred to hospital. There is no specific antidote for colchicine when taken in overdose and treatment options are limited. Haemodialysis and haemoperfusion are not effective because colchicine has a large volume of distribution, binds significantly to plasma proteins and has rapid distribution.⁶ If a patient presents soon after ingestion, repeated doses of activated charcoal can be given to remove colchicine from the gastrointestinal tract. Although colchicine is rapidly absorbed from the gastrointestinal tract, removal of even a small amount can improve the patient’s prognosis.⁶ Patients who do not present soon after ingestion, and those with pre-existing renal or hepatic impairment, have a less favourable prognosis.⁶ Patients with colchicine toxicity are managed with supportive care.

Avoiding adverse effects

Manage gout more effectively

Patients who frequently use colchicine for acute gout flares should be encouraged to take long-term urate-lowering treatment, e.g. allopurinol. Preventative treatment will reduce the frequency of flares, and therefore reduce the need for acute treatment with colchicine, and the risk of toxicity.¹¹ Urate-lowering treatment is indicated for patients with gout who: experience recurrent flares, e.g. two or more in one year, have tophi, concomitant renal impairment or changes characteristic of gout on x-ray. Ideally, urate-lowering treatment should be initiated early before there has been any erosive damage to joints and before tophi have appeared.

For further information, see: “ An update on the management of gout”, BPJ 51 (Mar, 2013).

Provide patients with clear instructions

Patients are at risk of overdose if they have a poor understanding of how to take colchicine and its potential adverse effects. Appropriate patient education includes:

• Providing clear advice about how to take colchicine, especially the maximum dose
• Advising patients to stop taking colchicine and see their doctor if they develop nausea, vomiting or diarrhoea; unusual bleeding or bruising; muscle pain or weakness; or numbness or tingling in their fingers or toes
• Ensuring patients are aware that colchicine is not an analgesic for general use and should not be used to manage pain not due to gout
• Advise patients to tell a doctor or pharmacist about all the medicines they take and to check before taking new medicines

Advice should be tailored to the patient’s level of health literacy. This is particularly important for patients for whom English is not their first language. Of the four accidental overdose cases reported in Auckland, three of those patients were of Pacific Island descent. It is possible that language barriers, cultural differences and health literacy may have been contributing factors to these accidental overdoses.⁶

A patient information handout on colchicine is available from: www.saferx.co.nz/colchicine-patient-guide.pdf