RX FOCUS Drug Interactions “Contraindication” Versus “Avoid Concomitant Use” BY JOHN R. HORN, PHARMD, FCCP, AND PHILIP D. HANSTEN, PHARMD IN THE OFFICIAL PRESCRIBING INFORMATION OF inducers in this category; data show a 62% decrease PHARMACEUTICAL PRODUCTS, drug interactions are in the ivabradine AUC with the use of St. John’s wort often listed in 2 categories: “contraindicated” and and an 80% decrease with the use of carbamazepine.4,5 “avoid concomitant use.” Is this a distinction without a difference? The Medline Plus definition of “contra- PRACTICAL CONSIDERATIONS indication” is “…a specific situation in which a drug, With regard to ivabradine drug interactions, is there procedure, or surgery should not be used because it may a practical difference between the designations of be harmful to the person.” Other official definitions “contraindicated” and “avoid concomitant use?” First, JOHN R. HORN, PHARMD, FCCP are similar to this, which raises the question, how is regarding CYP3A4 inducers, it could be argued that this different from “avoid concomitant use?” Let us they should never be given with ivabradine because iv- explore this issue using, as an example, ivabradine abradine plasma concentrations would almost always (Corlanor), a drug used to treat heart failure. be subtherapeutic. Thus, it would seem that CYP3A4 in- ducers might be best listed as “contraindicated” rather INTERACTIVE PROPERTIES OF than under “avoid concurrent use.” IVABRADINE Regarding “strong” CYP3A4 inhibitors, given that Ivabradine is primarily metabolized by CYP3A4 in ivabradine has potentially serious dose-dependent PHILIP D. HANSTEN, PHARMD the gut and liver, and its bioavailability is only about adverse cardiovascular effects, it seems reasonable 40% due to first-pass metabolism. Inhibitors of CY- to make every effort to avoid ketoconazole and other P3A4 can substantially increase ivabradine plasma “strong” CYP3A4 inhibitors. (Itraconazole, clarithro- AUTHOR BIO concentrations through reduction in first-pass metabo- mycin, telithromycin, nelfinavir, and nefazodone are Drs. Horn and Hansten lism and systemic metabolism of CYP3A4 by the liv- listed, but there are others.) It is conceivable, howev- are both professors er.1 As expected, CYP3A4 inducers can substantially er, that a prescriber might—under very special cir- of pharmacy at the reduce the bioavailability of ivabradine. University of Washington cumstances—weigh the benefits versus the risks and School of Pharmacy. Because ivabradine slows the heart rate, it can cause choose to give one of the strong inhibitors while care- For an electronic additive bradycardia with the use of other drugs that fully monitoring for ivabradine toxicosis (possibly version of this article, slow the heart rate, such as digoxin and amiodarone. also with a reduction in ivabradine dose). So, it might including references, visit (Note that beta-blockers are usually given concurrently be difficult to argue, for example, that “under abso- hanstenandhorn.com. with ivabradine, so that is not considered a drug inter- lutely no circumstances whatsoever should ivabradine action.) Isolated case reports have appeared suggesting ever be given with clarithromycin.” that the risk of torsades de pointes may be increased Regarding “moderate” CYP3A4 inhibitors such as when ivabradine is combined with drugs such as dilti- diltiazem or verapamil, it is reasonable to assume that azem plus ranolazine or azithromycin, but additional the risk average is less than the risk of giving keto- evidence is needed to assess the clinical importance of conazole with ivabradine. However, we know there is these purported interactions.2,3 substantial overlap regarding the danger of “strong” versus “moderate” CYP3A4 inhibitors, depending “CONTRAINDICATED” INTERACTIONS on a host of factors involving various patient charac- The product information for ivabradine lists concur- teristics and the dosage regimens of the 2 drugs. Of rent use of “strong CYP3A4 inhibitors” as contrain- 2 patients on ivabradine, one may be given a strong dicated. Although no specific details of the studies CYP3A4 inhibitor with no adverse effects and anoth- are given, the data presented show that the potent er given a moderate CYP3A4 inhibitor followed by a CYP3A4 inhibitor ketoconazole increases ivabradine life-threatening reaction. area under the curve (AUC) by approximately 7-fold. SUMMARY “AVOID CONCOMITANT USE” INTER- Among patients on ivabradine, it would clearly be best ACTIONS to avoid “strong” and “moderate” CYP3A4 inhibitors. The product information for ivabradine also presents The decision to use either type of inhibitor should be data suggesting that “moderate” CYP3A4 inhibitors, made with full consideration of the benefits and risks, such as diltiazem and verapamil, can produce a mean and with close monitoring for ivabradine adverse ef- FOR REFERENCES, GO TO PHARMACYTIMES.COM/ increase in the ivabradine AUC of approximately 2- to fects. It is hard to imagine a scenario in which a CYP3A4 PUBLICATIONS/ISSUE. 3-fold. It also lists St. John’s wort and other CYP3A4 inducer would be justified in a patient on ivabradine. ® 36 JULY 2016 PHARMACYTIMES.COM Pg 36 PT_0716_RxDrugInter.indd 36 7/6/16 2:06 PM.