Major drug interactions with cyclosporine and tacrolimus

1 Major drug interactions with cyclosporine and tacrolimusMajor drug interactions with cyclosporine (CsA) and tacrolimus (TAC):1,2 Increased immunosuppressant concentration Decreased immunosuppressant concentrationInteracting classInteracting agentsEffect(s)Management suggestions AnticonvulsantsCarbamazepine, pentobarbital, phenobarbital, phenytoin, primodone CsA or TAC concentrationClosely monitor CsA or TAC serum con-centration. Effect of CYP3A4 induction may occur over , itraconazole, ketoconazole (oral), posaconazole, voriconazole CsA or TAC concentrationAdditive QTc prolongation due to fluconazole or voriconazole with TACC losely monitor CsA or TAC serum concentration.

2 The following empiric initial dose adjustments may be considered. For TAC: decrease dose by 66% if initiating posaconazole or voriconazole, or by 40% if initiating fluconazole 200 mg/dayFor CsA: decrease dose by 50% if initiating voriconazole, or by 25% if initiating posaconazole or fluconazole 200 , quinine, quinidine CsA or TAC concentrationAdditive QTc prolongation due to tacrolimus with anti-malarialsClosely monitor CsA or TAC serum concentration. Monitor for QTc prolongation if antima-larial treatment must be initiated in a patient receiving , rifampin CsA or TAC concentrationClosely monitor CsA or TAC serum and hepatitis C virus (HCV)

3 AntiretroviralsAtazanavir, cobicistat, darunavir, delavirdine, fosamprenavir, indina-vir, lopinavir-ritonavir, nelfinavir, ritonavir, saquinavir, tipranavir CsA or TAC concentrationCsA may increase protease inhibitor concentrationsClosely monitor CsA or TAC serum used with CsA, monitor protease inhibitor(s) for toxicity and serum concentrations where available. Early consultation with HIV/HCV infectious diseases specialist is , etravirine, nevirapine, tipranavir CsA or TAC concentrationClosely monitor CsA or TAC serum antibioticsClarithromycin, eryth-romycin CsA or TAC concentrationConsider substituting a noninteracting antibiotic.

4 Azithromycin and spiramycin are less likely to of 4BC Provincial Renal Agency Suite 700-1380 Burrard St. Vancouver, BC V6Z 2H3 January 2016 Continued on next anti-infectivesChloramphenicol, le-vofloxacin, metronida-zole, norfloxacin ( with CsA), tetracycline, tigecycline CsA or TAC concentrationClosely monitor CsA or TAC serum , nilotinib, sunitinib, tamoxifen, vandetanib, vemu-rafenib CsA or TAC concentrationClosely monitor CsA or TAC serum agents that are dependent upon CYP3A4 and/or P-gp for metabolism ( doxorubicin, vinblastine)

5 CsA, and to a lesser degree TAC, may antineoplastic or vinblastine may CsA or TAC concentrationMonitor antineoplastic for exaggerated toxicity and monitor CsA or TAC serum concentration when used with doxorubicin or CsA or TAC concentrationIncreased QTc prolongation with TACC losely monitor CsA or TAC serum concentration. Avoid crizotinib with TAC or monitor for QTc , clonaz-epam, diazepam, flu-razepam, midazolam, triazolam benzodiazepine concentration with CsAMonitor benzodiazepine effect to deter-mine whether dose alteration , dronedar-one, lidocaine (sys-temic), quinidine CsA or TAC concentrationAdditive QTc prolongation with TA CClosely monitor CsA or TAC serum concentration.

6 Avoid QTc prolonging agents with TAC or closely monitor for QTc (direct thrombin inhibitors and direct factor Xa inhibitors)Apixaban, dabigatran, rivaroxaban anticoagulant concentrationMonitor for signs of excessive antico-agulation. Avoid in patients receiving CsA or TAC with renal insufficiency (CrCl < 50 mL/min).Calcium channel blockers (CCB)Diltiazem, verapamil CsA or TAC concentra-tionClosely monitor CsA or TAC serum concentration. Amlodipine, felodipine, nifedipine TAC concentrationClosely monitor TAC serum , felodipine, nifedipine, nimodipine dihydropyridine CCB con-centration with CsAMonitor for exaggerated dihydropyridine CCB of 4BC Provincial Renal Agency Suite 700-1380 Burrard St.

7 Vancouver, BC V6Z 2H3 January 2016 Continued on next drug interactions with cyclosporine and tacrolimusHMG-CoA reductase inhibitors ( statins )Atorvastatin, lovastatin, pravastatin, rosuvas-tatin, simvastatin statin concentration and risk of statin toxicity including myotoxicity with CsATAC does not appear to alter atorvastatin concentrations in one pK study. There is one case report associating TAC and simvastatin usage with simvastatin. Fluvastatin and pravastatin may have a lower risk of interaction.

8 Avoid using maximum doses of statins as the statin blood levels are likely higher than expected from the cardiovascularCarvedilol, dipyri-damole, propranolol, reserpine CsA or TAC concentrationClosely monitor CsA or TAC serum concentration. TAC is less likely to be altered than CsA. DietaryGrapefruit juice and grapefruit CsA or TAC concentrationAvoid grapefruit juice and grapefruit with CsA or , cimetidine, fosaprepitant CsA or TAC concentrationClosely monitor CsA or TAC serum concentrationMetoclopramide CsA or TAC concentrationOctreotide CsA (orally administered)

9 Additive QTc prolongation with TA CCsA microemulsion may be less likely to interact with CsA concentrationClosely monitor CsA serum concentra-tionOmeprazole, lansopra-zole TAC concentrationPantoprazole and rabeprazole are less likely to and anti-goutAnti-goutAllopurinol CsA concentration. The mechanism is unknown. Closely monitor CsA serum concentra-tionColchicine colchicine effects more pro-nounced with renal and/or hepatic for toxicity and consider dose reduction if co-administration is un-avoidable.

10 For patients with normal renal and hepatic function, the following dose reductions are suggested: acute gout: mg once followed by mg one hour later. Do not repeat before 72 hours. Gout prophylaxis: reduce dose by 50%; double interval. HerbsSt. Johns wort CsA or TAC concentrationAvoid St. John's wort with CsA or TAC concentrationAvoid Schisandra with CsA or preparations CsA concentrationClosely monitor CsA serum concentra-tionTestosterone prepa-rations (including danazol, methyltestos-terone, testosterone) CsA or TAC concentrationClosely monitor CsA or TAC serum concentration if concurrent use cannot be of 4BC Provincial Renal Agency Suite 700-1380 Burrard St.