Life-Threatening Colchicine Drug Interactions John R

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drugINTERACTIONS: insights and observations Life-threatening Colchicine Drug Interactions John R. Horn, PharmD, FCCP,and Philip D. Hansten, PharmD

after starting clarithromycin. He subse- Table Drs. Horn and Hansten are both pro- quently developed multiorgan failure Selected Drugs That Inhibit fessors of pharmacy at the University and died.1 Another patient on col- of Washington School of Pharmacy. P-glycoprotein chicine developed fever, diarrhea, and For an electronic version of this arti- Amiodarone Nicardipine abdominal pain 3 days after starting cle, including references if any, visit Clarithromycin Propafenone clarithromycin.2 He went on to develop www.hanstenandhorn.com. Cyclosporine Quinidine dehydration, pancytopenia, and acido- Diltiazem Ritonavir sis, but he survived. Two other patients Erythromycin Saquinavir ew drugs have been around as on colchicine died from agranulocyto- Indinavir Tacrolimus long as colchicine—it was men- sis when clarithromycin was given con- Itraconazole Tamoxifen tioned at least as far back as currently.3 F Ketoconazole Verapamil the time of Nero. Colchicine can be Similar life-threatening reactions Nelfinavir very effective in the treatment of gout have been reported in patients on and familial Mediterranean fever. Un- colchicine who received concomitant fortunately, however, its therapeutic therapy with other PGP inhibitors.4-7 In Managing Interactions effects (primarily on white blood cells) most cases, colchicine toxicity has Colchicine should not be used with can lead to life-threatening toxicity if occurred in patients on chronic clarithromycin or erythromycin, and colchicine plasma concentrations be- colchicine therapy who are then start- given the potential for fatal outcomes, come too high. One of the causes of ed on a PGP inhibitor. In one case, how- it would be prudent to avoid all PGP dangerously elevated colchicine con- ever, a patient on chronic verapamil inhibitors with colchicine (Table). centrations is interaction with other developed colchicine toxicity after tak- If it is absolutely necessary to use a drugs. ing colchicine for only 2 days.7 PGP inhibitor with colchicine, consider decreasing the colchicine dose (or Drugs that Interact with Colchicine Other Clinical Evidence stopping the colchicine) during treat- Colchicine is a known substrate for P- Additional evidence of an interaction ment with the PGP inhibitor. The glycoprotein (PGP), a transmembrane between colchicine and PGP inhibitors patient should be advised to immedi- protein that acts to eliminate drugs by comes from a retrospective case–con- ately report any evidence of colchicine expelling them into the bile, urine, and trol study of 116 patients who received toxicity such as fever, diarrhea, abdom- intestine and acting as a blood–brain bar- colchicine and clarithromycin during inal pain, myalgia, muscle weakness, or rier. The drugs reported to cause col- the same admission.8 Nine of the 88 paresthesias. chicine toxicity (eg, clarithromycin, eryth- patients who received both drugs con- Because many drugs inhibit PGP, romycin, cyclosporine, verapamil) are currently died, whereas only 1 of the colchicine should be handled in the PGP inhibitors, and it is likely that PGP 28 patients who received the drugs in same way that warfarin is. The addition inhibition is the mechanism for the seri- sequence died. Most of the patients of any new medication—whether or ous toxicity that has been reported. It who died had pancytopenia. not it has been shown to interact— also is possible that cytochrome P-450 should be a signal for the pharmacist 3A4 (CYP3A4) inhibitors may increase Predisposing Factors for to remind the patient to be alert for P colchicine plasma concentrations through Interactions evidence of colchicine toxicity. T CYP3A4 inhibition, but this effect is Many of the patients who had an inter- speculative. action had renal insufficiency, and this condition is presumed to have con- Reports of Adverse Outcomes tributed to the severity of the reactions. Colchicine toxicity is not a pretty sight, Because these interactions result from For a list of references, send a and the reported reactions have been elevated colchicine plasma concentra- stamped, self-addressed envelope to: life-threatening or fatal. One patient on tions, anything that increases colchicine References Department, Attn. A. Stahl, Pharmacy Times, 241 Forsgate Drive, colchicine was admitted with fever, diar- levels—such as large doses or hepatic Jamesburg, NJ 08831; or send an e-mail rhea, myalgia, and abdominal pain 4 days disease—could increase the risk. request to: [email protected].