drugINTERACTIONS: insights and observations Life ...

1 drugINTERACTIONS: insights and Times|May 2006n111 Few drugs have been around aslong as colchicine it was men-tioned at least as far back asthe time of Nero. Colchicine can bevery effective in the treatment of goutand familial Mediterranean fever. Un-fortunately, however, its therapeuticeffects (primarily on white blood cells)can lead to life -threatening toxicity ifcolchicine plasma concentrations be-come too high. One of the causes ofdangerously elevated colchicine con-centrations is interaction with that Interact with ColchicineColchicine is a known substrate for P-glycoprotein (PGP),a transmembraneprotein that acts to eliminate drugs byexpelling them into the bile, urine, andintestine and acting as a blood brain bar-rier. The drugs reported to cause col-chicine toxicity (eg, clarithromycin, eryth-romycin, cyclosporine, verapamil) arePGP inhibitors, and it is likely that PGPinhibition is the mechanism for the seri-ous toxicity that has been reported.

2 Italso is possible that cytochrome P-4503A4 (CYP3A4) inhibitors may increasecolchicine plasma concentrations throughCYP3A4 inhibition, but this effect is of Adverse Outcomes Colchicine toxicity is not a pretty sight,and the reported reactions have beenlife-threatening or fatal. One patient oncolchicine was admitted with fever, diar-rhea,myalgia, and abdominal pain 4 daysafter starting clarithromycin. He subse-quently developed multiorgan failureand patient on col-chicine developed fever, diarrhea, andabdominal pain 3 days after went on to developdehydration, pancytopenia, and acido-sis, but he survived. Two other patientson colchicine died from agranulocyto-sis when clarithromycin was given life -threatening reactionshave been reported in patients oncolchicine who received concomitanttherapy with other PGP cases, colchicine toxicity hasoccurred in patients on chroniccolchicine therapy who are then start-ed on a PGP inhibitor.

3 In one case, how-ever,a patient on chronic verapamildeveloped colchicine toxicity after tak-ing colchicine for only 2 Clinical EvidenceAdditional evidence of an interactionbetween colchicine and PGP inhibitorscomes from a retrospective case con-trol study of 116 patients who receivedcolchicine and clarithromycin duringthe same of the 88patients who received both drugs con-currently died, whereas only 1 of the28 patients who received the drugs insequence died. Most of the patientswho died had Factors forInteractionsMany of the patients who had an inter-action had renal insufficiency, and thiscondition is presumed to have con-tributed to the severity of the these interactions result fromelevated colchicine plasma concentra-tions, anything that increases colchicinelevels such as large doses or hepaticdisease could increase the InteractionsColchicine should not be used withclarithromycin or erythromycin,andgiven the potential for fatal outcomes,it would be prudent to avoid all PGPinhibitors with colchicine (Table).

4 If it is absolutely necessary to use aPGP inhibitor with colchicine, considerdecreasing the colchicine dose (orstopping the colchicine) during treat-ment with the PGP inhibitor. Thepatient should be advised to immedi-ately report any evidence of colchicinetoxicity such as fever, diarrhea, abdom-inal pain, myalgia, muscle weakness, many drugs inhibit PGP,colchicine should be handled in thesame way that warfarin is. The additionof any new medication whether ornot it has been shown to interact should be a signal for the pharmacistto remind the patient to be alert forevidence of colchicine Colchicine Drug InteractionsJohn R. Horn, PharmD, FCCP, and Philip D. Hansten, PharmDDrs. Horn and Hansten are both pro-fessors of pharmacy at the Universityof Washington School of an electronic version of this arti-cle, including references if any, a list of references, send a stamped, self-addressed envelope to: References Department, Attn.

5 A. Stahl, Pharmacy Times, 241 Forsgate Drive, Jamesburg, NJ 08831; or send an e-mailrequest to: Drugs That Inhibit P-glycoproteinAmiodarone Clarithromycin CyclosporineDiltiazem ErythromycinIndinavirItraconazoleKetocon azoleNelfinavirNicardipinePropafenoneQui nidineRitonavir SaquinavirTacrolimusTamoxifenVerapamil