Dosing colchicine in acute gouty arthritis

Let’s start with a patient case.  An elderly patient with multiple comorbidities is being treated in the hospital for heart failure when he develops an acute gouty attack.  His past medical history, among other things, includes CKD (Stage 4).  Should colchicine be used in this patient and if so, what dose would be indicated?

The American College of Rheumatology guidelines for the treatment of acute gout consider colchicine, NSAIDs, and corticosteroids all first line monotherapy (Evidence A) for moderate severity pain in 1-2 joints.  A combination of these is appropriate to consider in severe pain (Evidence C).  Since all have the same grade evidence for first line therapy, agent selection should be based on prior response, comorbidities, and patient preference while also considering each agent’s drug interactions. 

Colchicine is a viable option for gout attacks that have begun within 36 hours (Evidence C).  In the recent past, typical dosing for colchicine included a 1.2mg loading dose, followed by 0.6mg every one to two hours as needed for pain or until gastrointestinal intolerance was met.  This is not the current dose recommended by the ACR or FDA.  New dosing came about with FDA approval of colchicine (Colcrys) in 2009 specifying a dose of 1.2mg orally once, followed by 0.6mg one hour later, not to be repeated for two weeks in those with severe renal dysfunction.  This change was largely the results of the first multicentered, randomized, double-blind, placebo-controlled, dose-comparison study of colchicine¹. 

*Results of their dose comparison is displayed in the graph above– “low dose” refers to the 1.8mg maximum described above and “high dose” refers to a six hour dosing strategy like that described further above, up to a maximum of 4.8mg.  Note that efficacy is similar.  Adverse events were significantly less in the low-dose group.

Back to the patient case:

• Colchicine is a viable option if started within 36 hours on onset of acute gout
• A dosing strategy of 1.2mg orally once, then 0.6mg in one hour is recommended
• No renal adjustment needs to be made but the colchicine course should not be repeated for two weeks

Background:

Colchicine, in the form of plant extracts (colchicum autumnale shown above), has been used for the treatment of acute gout for over 2000 years and  a relatively pure form of colchicine has been isolated and in use since 1883.  By the time the FDA began requiring that all new drugs demonstrate safety in 1938 and efficacy in 1962, colchicine did not need to meet these requirements and was “grandfathered” into the market.  Due to this unapproved/grandfathered status and the fact that the generic colchicine was manufactured by several different companies, there was little incentive (read: no company stood to make money) to ever perform a dose-finding study prior to 2006.

Prior to 2010, there was only one randomized placebo-controlled study examining the use of colchicine in gout and it included ~40 patients².  As part of the FDA’s Unapproved Drug Initiative in 2006, URL Pharma supported the study whose graph is shown above¹ and applied for a brand name version “Colcrys” for the treatment of acute gout.  The application was approved, increasing the cost of colchicine from generic (pennies/tablet) to brand ($4-5/tablet).

Colchicine is transported by p-glycoprotein, is metabolized by CYP3A4, and is eliminated renally and in the bile.  If scheduled dosing is used for any indication, renal adjustment and drug interactions need to be taken into account and dosage adjustments made.

Take home point:

• Look in the prescribing information, Lexicomp, or Micromedex when dosing this drug and checking for interactions

References:

1. Terkeltaub RA, Furst DE, Bennett K, Kook KA, Crockett RS, Davis MW, 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.

2.  Ahern MJ, Reid C, Gordon TP, McCredie M, Brooks PM, Jones M. Does colchicine work? The results of the first controlled study in acute gout. Aust NZ J Med 1987;17:301-4.

photo by AnyMotion