Published: December 1998

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Colchicine Toxicity Prompts Dosage Change

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Prescriber Update 17: 9-–11
December 1998

Medsafe Editorial Team

The maximum dose of colchicine in an acute attack of gout should be 6mg (10 tablets). Colchicine should be taken at an initial dose of 1.2mg followed by 1 tablet every 2 hours until the gouty pain is relieved, gastrointestinal symptoms develop, or the maximum dose is reached. In elderly patients, those who weigh less than 50kg and those with co-existing renal or hepatic disease, alternative therapy should be used or a maximum dose of 3mg colchicine observed. Patients with suspected overdose should be admitted to a hospital with intensive supportive facilities.

The dosage instructions for colchicine have recently been changed to reflect the fact that it is possible to take a fatal dose before gaining relief from the symptoms of gout or developing diarrhoea.

6mg maximum dose in acute gout

The approved dosage instructions for colchicine in the treatment of acute gout now recommend a starting dose of 1.2mg (two 0.6mg tablets), followed by 1 tablet 2-hourly until the pain is relieved or diarrhoea or other gastrointestinal symptoms develop, up to a maximum dose of 6mg (10 tablets).

3mg maximum dose for at risk patients

In elderly patients, those who weigh less than 50kg and those with renal or hepatic impairment, other treatments such as a non-steroidal anti-inflammatory agent (NSAIA) or high dose (20-40mg) short duration oral prednisone or prednisolone should be considered. If colchicine is prescribed for these patients the maximum total dose should be 3mg.

Intensive regimen should not be repeated for 3 days

An intensive regimen of colchicine therapy should not be repeated until an interval of at least three days has elapsed between courses. Nevertheless, maintenance therapy of one tablet daily may be commenced the day following treatment for an acute attack.

Dose reduction based on published evidence of toxicity

The two major changes in the dosage instructions relate to frequency of administration and maximum dose.

Previously no maximum was stated in the approved dosage instructions. The maximum recommended dose has been set by reference to the following:

• Standard textbooks such as Avery's Drug Treatment which advises a maximum of 6mg;¹
• Published cases of death occurring after doses of 6 or 7 mg;²
• Sources which indicate survival may follow excessive ingestion of up to 0.5 mg/kg with intensive supportive care;^3,4
• Maximum approved doses in other countries, for example the United Kingdom where 10mg is the recommended maximum;⁵ and
• Advice from the New Zealand Rheumatology Association which reviewed the literature and agreed that 6mg was a suitable maximum dose.⁶

The recommended frequency of administration has been halved, to further reduce the chance of serious toxicity occurring. The new frequency is similar to that recommended in Australia and the United Kingdom.

Steroids recommended for colchicine therapeutic failures

For a patient who has not gained adequate pain relief from the maximum dose of colchicine, alternatives are intramuscular corticotrophin 40-80IU or oral prednisone 20-50 mg/day for 3 days.¹

Co-administration of NSAIAs with colchicine should be avoided

While either a NSAIA or colchicine can be used as first line therapy for acute gout, they should not be co-prescribed as both medicines compete for excretion at the same site in the kidney. In addition to competition for excretion, use of NSAIAs is associated with decreased renal blood flow. Increased colchicine toxicity, due to delayed renal excretion, is the end result of these pharmacodynamic effects.

Hospitalisation essential for suspected overdose

If there is a high probability of colchicine toxicity, for example because of intentional overdose or dose in excess of 6mg in high risk patients, prompt admission to a facility with access to intensive supportive treatment is essential.

In overdose, early use of activated charcoal will minimise absorption. Repeated doses of charcoal will assist with the elimination of colchicine reabsorbed into the intestines through enterohepatic recycling. Diarrhoea should not be treated as it is the primary route of elimination. The period 24-72 hours after ingestion is critical and multisystem organ failure may occur. The key to patient management is full supportive care.

Serious toxicity with colchicine is an adverse reaction of current concern. Please report all New Zealand cases to the New Zealand Centre for Adverse Reactions Monitoring.

References

1. Brooks PM. Rheumatic disorders. In Speight TM, Holford NHG (Eds). Avery's Drug Treatment 4^th Ed, Adis International, Auckland, 1997, p.1151.
2. Macleod JG, Phillips L. Hypersensitivity to colchicine. Ann Rheum Dis 1947;6:224-9.
3. Murray SS, Kramlinger KG, McMichan JC, Mohr DN. Acute toxicity after excessive ingestion of colchicine. Mayo Clin Proc 1983;58:528-32.
4. Dodds AJ, Lawrence PJ, Biggs JC. Colchicine overdose. Med J Aust 1978;2:91-2.
5. Brit Nat Formulary, British Medical Association and Royal Pharmaceutical Society of Great Britain, No. 35, March 1998, p.441-2.
6. Personal Communication, Dr JP Petrie, Secretary, New Zealand Rheumatology Association, Feb 1998.