Colchicine for acute gout: updated information about dosing and drug interactions Colchicine for acute gout: updated information about dosing and drug interactions

New evidence illustrates that low-dose colchicine is effective for acute gout, and highlights the risk of serious interactions with some commonly prescribed medicines.^1,2

Health professionals should be aware of:

• the revised dosing recommendations for colchicine in acute gout
• the need to avoid colchicine, or adjust the dose, in patients with renal or hepatic impairment and/or who are taking drugs that interact with colchicine (Box 1).

Existing concerns about colchicine dosing and toxicity

Vomiting and diarrhoea commonly occur when colchicine is repeatedly dosed at 1-hour or 2-hour intervals for acute gout.^1,3 These are the first signs of colchicine toxicity, and may precede rare adverse effects including muscle damage, neuropathy, multiple organ failure and bone marrow suppression.⁴ Patients with renal or hepatic impairment may be particularly susceptible to severe colchicine toxicity (Box 2).^2,5-7

Increasing awareness of toxicity led prescribing guidelines to recommend lower colchicine doses and extended dosing intervals.^8-10 Case reports and expert opinion suggested that the treatment benefit could be maintained at lower colchicine doses, but no data from controlled trials were available until recently.^1,11

New evidence to support the use of low-dose colchicine in acute gout

Recent trial evidence demonstrates that low-dose colchicine (2 tablets followed by 1 tablet 1 hour later) is effective when prescribed within 12 hours of onset of an acute gout flare, with a low incidence of gastrointestinal adverse effects (Table 1).¹ A higher dose (2 tablets followed by 1 tablet every hour for 6 hours) offered no additional clinical benefit, but increased the risk of gastrointestinal toxicity. This study was conducted in the United States, where colchicine is available as 0.6 mg tablets rather than the 0.5 mg tablets available in Australia.

Table 1: Safety and efficacy of low-dose colchicine in acute gout¹

* 1.2 mg initially followed by 0.6 mg every hour for 6 hours

^†1.2 mg initially followed by 0.6 mg 1 hour later

^‡Statistically significant difference compared with placebo

^§Statistically significant difference compared with placebo and low- dose colchicine

Drug interactions increase risk of colchicine toxicity

Concurrently prescribing colchicine and inhibitors of cytochrome P450 3A4 (CYP3A4) or P-glycoprotein (P-gp) increases the potential for colchicine toxicity (Box 1).^2,5 The US Food and Drug Administration reported that of 117 cases of fatal colchicine toxicity at therapeutic doses (≤ 2 mg/day), more than half occurred in patients who were taking clarithromycin at the same time.² However, a possible role for renal impairment or prolonged colchicine dosing cannot be excluded in these cases.

Fatal and non-fatal colchicine toxicity has occurred in patients taking colchicine and concomitant erythromycin, cyclosporin, statins and calcium-channel blockers, including verapamil and diltiazem.^2,12

Box 1: Common inhibitors of CYP3A4 and/or P-gp that may increase the risk of colchicine toxicity^2,12-14

Revised dosing recommendations and use in renal and hepatic impairment

Consider colchicine for acute gout when nonsteroidal anti-inflammatory drugs (NSAIDs) and corticosteroids are contraindicated or not tolerated.¹⁵ The Australian Medicines Handbook recommends colchicine 1 mg followed by 0.5 mg 1 hour later for acute gout (maximum dose 1.5 mg per treatment course). No additional colchicine should be administered for at least 3 days, when a repeat course may be considered. Refer to Box 2 for information about prescribing colchicine in specific patient populations

Because of the potential for serious toxicity, colchicine should be stopped if abdominal pain, nausea, vomiting or diarrhoea develops, irrespective of whether joint pain has been relieved.^16,17

Box 2: Colchicine prescribing considerations^2,5,15,18

A smaller colchicine pack size of 30 tablets will replace the existing 100-tablet pack later this year.¹⁹ Prescribers should consider prescribing the number of colchicine tablets sufficient for the patient's needs (see Provide patients with clear instructions about colchicine use).

Provide patients with clear instructions about colchicine use

Inform patients that colchicine can effectively relieve the pain of acute gout at doses lower than those they may have used in the past. An analgesic such as paracetamol can be taken while waiting for colchicine to take effect during an acute gout flare.¹⁵

Self-care strategies include placing an ice pack on the affected joint and using a simple device such as a cardboard box to keep bedclothes off it at night.^10,20 Advise patients to elevate the limb and avoid unnecessary clothing such as socks and shoes, when possible.²⁰

Counsel patients experiencing an acute gout flare on the revised colchicine dosing regimen:¹⁵

• take 2 colchicine tablets initially, followed by 1 colchicine tablet 1 hour later
• do not take more than 3 colchicine tablets (1.5 mg) during a course of treatment for an acute gout flare
• do not repeat the course of treatment for at least 3 days.

Discuss the safe and effective use of colchicine in acute gout. Advise patients to:^2,15

• tell their doctor and pharmacist about all the medicines they take, and to check before taking any new medicines
• 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 the fingers or toes
• avoid eating grapefruit and drinking grapefruit juice when taking colchicine
• be aware that colchicine is not a painkiller and should not be used for other causes or types of pain.

References

1. Terkeltaub RA, Furst DE, Bennett K, et al. High versus low dosing of oral colchicine for early acute gout flare: Twenty-four-hour outcome of the first multicenter, randomized, double-blind, placebo-controlled, parallel group, dose-comparison colchicine study. Arthritis Rheum 2010;62:1060-8. [PubMed]
2. US Food and Drug Administration. Information for healthcare professionals: New safety information for colchicine (marketed as Colcrys). 2009. http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm174382.htm (accessed 18 January 2009).
3. Ahern MJ, Reid C, Gordon TP, et al. Does colchicine work? The results of the first controlled study in acute gout. Aust N Z J Med 1987;17:301-4. [PubMed]
4. Putterman C, Ben-Chetrit E, Caraco Y, et al. Colchicine intoxication: clinical pharmacology, risk factors, features, and management. Semin Arthritis Rheum 1991;21:143-55. [PubMed]
5. Australian Adverse Drug Reactions Committee. Fatal interactions and reactions with colchicine: beware CYP3A4 inhibitors. Australian Adverse Drug Reactions Bulletin 2008;27, Number 5, Oct 2008. http://www.tga.gov.au/adr/aadrb/aadr0810.htm
6. Wilbur K, Makowsky M. Colchicine myotoxicity: case reports and literature review. Pharmacotherapy 2004;24:1784-92. [PubMed]
7. Kubler PA. Fatal colchicine toxicity. Med J Aust 2000;172:498-9. [PubMed]
8. Rheumatology Writing Group. Therapeutic Guidelines: Rheumatology. Version 1. Melbourne: Therapeutic Guidelines Ltd, 2006.
9. Zhang W, Doherty M, Bardin T, et al. EULAR evidence based recommendations for gout. Part II: Management. Report of a task force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis 2006;65:1312-24. [PubMed]
10. Jordan KM, Cameron JS, Snaith M, et al. British Society for Rheumatology and British Health Professionals in Rheumatology guideline for the management of gout. Rheumatology (Oxford) 2007;46:1372-4. [PubMed]
11. Morris I, Varughese G, Mattingly P. Colchicine in acute gout. BMJ 2003;327:1275-6. [PubMed]
12. Anonymous. Colchicine: serious interactions. Prescrire Int 2008;17:151-3. [PubMed]
13. Baxter K, ed. Stockley's Drug Interactions [online] London: Pharmaceutical Press 2009. <http://www.medicinescomplete.com/> (accessed 19 March 2010).
14. Klasco RK, ed. Drugdex System (electronic version). Thomson Micromedex, Greenwood Village, Colorado, USA, 2010. http://www.thomsonhc.com (accessed 5 February 2010).
15. Rossi S, ed. Australian Medicines Handbook 2010. Adelaide: Australian Medicines Handbook Pty Ltd, 2010.
16. Aspen Pharmacare Australia. Colgout product information. 19 December 2008.
17. Aspen Pharmacare Australia. Lengout product information. 19 December 2008.
18. Medicines and Healthcare products Regulatory Agency. Colchicine: reminder on risk of serious and fatal toxicity in overdose. Drug Safety Update 2009;3:5. http://www.mhra.gov.uk/Publications/Safetyguidance/DrugSafetyUpdate/index.htm
19. Personal communication. Aspen Pharmacare Australia.
20. National Health Service Clinical Knowledge Summaries. Gout - Management. 2007. http://www.cks.nhs.uk/gout (accessed 18 January 2010).