Major drug interactions with cyclosporine and tacrolimus Major drug interactions with cyclosporine (CsA) and tacrolimus (TAC):1,2 éé Increased immunosuppressant concentration êê Decreased immunosuppressant concentration Interacting class Interacting agents Effect(s) Management suggestions Anticonvulsants Carbamazepine, êê CsA or TAC concentration Closely monitor CsA or TAC serum con- pentobarbital, centration. Effect of CYP3A4 induction phenobarbital, may occur over weeks. phenytoin, primodone Antimicrobials Antifungals Fluconazole, éé CsA or TAC concentration Closely monitor CsA or TAC serum itraconazole, concentration. The following empiric ketoconazole (oral), Additive QTc prolongation due initial dose adjustments may be posaconazole, to fluconazole or voriconazole considered. voriconazole with TAC For TAC: • decrease dose by 66% if initiating posaconazole or voriconazole, or by 40% if initiating fluconazole ≥ 200 mg/day For CsA: • decrease dose by 50% if initiating voriconazole, or by 25% if initiating posaconazole or fluconazole ≥ 200 mg/day. Antimalarials Mefloquine, quinine, é CsA or TAC concentration Closely monitor CsA or TAC serum quinidine concentration. Additive QTc prolongation due to tacrolimus with anti- Monitor for QTc prolongation if antima- malarials larial treatment must be initiated in a patient receiving tacrolimus. Antimycobacterial Rifabutin, rifampin êê CsA or TAC concentration Closely monitor CsA or TAC serum concentration. HIV and hepatitis Atazanavir, cobicistat, éé CsA or TAC concentration Closely monitor CsA or TAC serum C virus (HCV) darunavir, delavirdine, concentration. antiretrovirals fosamprenavir, indina- CsA may increase protease vir, lopinavir-ritonavir, inhibitor concentrations If used with CsA, monitor protease nelfinavir, ritonavir, inhibitor(s) for toxicity and serum saquinavir, tipranavir concentrations where available. Early consultation with HIV/HCV infectious diseases specialist is recommended. Efavirenz, etravirine, êê CsA or TAC concentration Closely monitor CsA or TAC serum nevirapine, tipranavir concentration. Macrolide antibiotics Clarithromycin, eryth- éé CsA or TAC concentration Consider substituting a noninteracting romycin antibiotic. Azithromycin and spiramycin are less likely to interact. Continued on next page... BC Provincial Renal Agency • Suite 700-1380 Burrard St. • Vancouver, BC • V6Z 2H3 • 604.875.7340 • BCRenalAgency.ca January 2016 1 of 4 Major drug interactions with cyclosporine and tacrolimus Other anti-infectives Chloramphenicol, le- é CsA or TAC concentration Closely monitor CsA or TAC serum vofloxacin, metronida- concentration. zole, norfloxacin (with CsA), tetracycline, tigecycline Antineoplastic Bicalutamide, nilotinib, é CsA or TAC concentration Closely monitor CsA or TAC serum sunitinib, tamoxifen, concentration. vandetanib, vemu- rafenib Antineoplastic agents CsA, and to a lesser degree Monitor antineoplastic for exaggerated that are dependent TAC, may é antineoplastic toxicity and monitor CsA or TAC upon CYP3A4 and/or concentrations. serum concentration when used with P-gp for metabolism doxorubicin or vinblastine. (e.g. doxorubicin, Doxorubicin or vinblastine may vinblastine) ê CsA or TAC concentration Crizotinib é CsA or TAC concentration Closely monitor CsA or TAC serum concentration. Increased QTc prolongation with TAC Avoid crizotinib with TAC or monitor for QTc prolongation. Benzodiazepines Alprazolam, clonaz- é benzodiazepine Monitor benzodiazepine effect to deter- epam, diazepam, flu- concentration with CsA mine whether dose alteration needed. razepam, midazolam, triazolam Cardiovascular Antiarrhythmics Amiodarone, dronedar- é CsA or TAC concentration Closely monitor CsA or TAC serum one, lidocaine (sys- concentration. temic), quinidine Additive QTc prolongation with TAC Avoid QTc prolonging agents with TAC or closely monitor for QTc prolongation. Anticoagulants Apixaban, dabigatran, é anticoagulant concentration Monitor for signs of excessive antico- (direct thrombin rivaroxaban agulation. inhibitors and direct factor Xa inhibitors) Avoid in patients receiving CsA or TAC with renal insufficiency (CrCl < 50 mL/min). Calcium channel Diltiazem, verapamil é é CsA or TAC concentra- Closely monitor CsA or TAC serum blockers (CCB) tion concentration. Amlodipine, felodipine, é é TAC concentration Closely monitor TAC serum concentra- nifedipine tion. Amlodipine, felodipine, é dihydropyridine CCB con- Monitor for exaggerated dihydropyridine nifedipine, nimodipine centration with CsA CCB effects. Continued on next page... BC Provincial Renal Agency • Suite 700-1380 Burrard St. • Vancouver, BC • V6Z 2H3 • 604.875.7340 • BCRenalAgency.ca January 2016 2 of 4 Major drug interactions with cyclosporine and tacrolimus HMG-CoA reductase Atorvastatin, lovastatin, é statin concentration and Avoid simvastatin. inhibitors (“statins”) pravastatin, rosuvas- risk of statin toxicity including Fluvastatin and pravastatin may have a tatin, simvastatin myotoxicity with CsA lower risk of interaction. TAC does not appear to alter Avoid using maximum doses of statins atorvastatin concentrations as the statin blood levels are likely in one pK study. There is one higher than expected from the dose. case report associating TAC and simvastatin usage with rhabdomyolysis. Other cardiovascular Carvedilol, dipyri- é CsA or TAC concentration Closely monitor CsA or TAC serum damole, propranolol, concentration. TAC is less likely to be reserpine altered than CsA. Dietary Grapefruit juice and é CsA or TAC concentration Avoid grapefruit juice and grapefruit with grapefruit CsA or TAC. Gastrointestinal Aprepitant, cimetidine, é CsA or TAC concentration Closely monitor CsA or TAC serum fosaprepitant concentration Metoclopramide é CsA or TAC concentration Octreotide é CsA (orally administered) CsA microemulsion may be less likely to interact with octreotide. Additive QTc prolongation with TAC Orlistat êê CsA concentration Closely monitor CsA serum concentra- tion Omeprazole, lansopra- é TAC concentration Pantoprazole and rabeprazole are less zole likely to interact. Glucocorticoids and anti-gout Anti-gout Allopurinol éé CsA concentration. The Closely monitor CsA serum concentra- mechanism is unknown. tion Colchicine é colchicine toxicity. Monitor for toxicity and consider dose reduction if co-administration is un- Toxic effects more pro- avoidable. nounced with renal and/or hepatic insufficiency. For patients with normal renal and hepatic function, the following dose reductions are suggested: acute gout: 0.6 mg once followed by 0.3 mg one hour later. Do not repeat before 72 hours. Gout prophylaxis: reduce dose by 50%; double interval. Herbs St. Johns wort êê CsA or TAC concentration Avoid St. John's wort with CsA or TAC. Schisandra é TAC concentration Avoid Schisandra with CsA or TAC. Hormones Estrogen preparations é CsA concentration Closely monitor CsA serum concentra- tion Testosterone prepa- é CsA or TAC concentration Closely monitor CsA or TAC serum rations (including concentration if concurrent use cannot danazol, methyltestos- be avoided. terone, testosterone) Continued on next page... BC Provincial Renal Agency • Suite 700-1380 Burrard St. • Vancouver, BC • V6Z 2H3 • 604.875.7340 • BCRenalAgency.ca January 2016 3 of 4 Major drug interactions with cyclosporine and tacrolimus Hypnotic (also see zopiclone, zolpidem é in hypnotic concentration Monitor hypnotic effect to determine benzodiazepines with CsA whether dose alteration is needed. above) Hypoglycemic Sulfonylureas including é CsA concentration Monitor CsA concentrations closely. gliclazide, glimepiride, glyburide Immunosuppres- Cyclosporine (CsA) Increased risk of serious Alteration of mycophenolate dosing is sant renal, hematologic, and other usually required when CsA is initiated, toxicities in combination with stopped, or added. sirolimus When used with everolimus, reduction êê mycophenolate concen- of CsA dose and target concentration is tration generally necessary. éé everolimus concentration It is suggested that oral doses of siro- limus be administered four hours after éé sirolimus (with cyclospo- cyclosporine doses. rine microemulsion) Tacrolimus (TAC) Increased risk of serious renal, Avoid concomitant use with sirolimus. hematologic, or other toxicities with sirolimus If everolimus is used with TAC, closely monitor everolimus serum concentra- é everolimus concentration tions. Psychiatry Desipramine, halo- é CsA or TAC concentration Consider antidepressants that do not peridol, fluoxetine, interact; closely monitor CsA or TAC fluvoxamine, sertraline, serum concentration if used. trazodone Pimozide Elevated pimozide level and/or Avoid use of pimozide due to increased increased QTc prolongation risk of cardiotoxicity. Other Bosentan êê CsA or TAC concentration Closely monitor CsA or TAC serum concentration. Cinacalcet ê CsA or TAC concentration Sevelamer ê TAC concentration êê CsA concentration References 1. Major drug interactions with immunosuppressants: Lexi-interact 1978-2016 2. Baxter K, Baxter P, Claire, L. Immunosuppressant monograph: Stockley’s drug interactions 10th ed. 2013 BC Provincial Renal Agency • Suite 700-1380 Burrard St. • Vancouver, BC • V6Z 2H3 • 604.875.7340 • BCRenalAgency.ca January 2016 4 of 4.