Dear Editor
We read with great interest the study by Peniston et alCitation1 who performed a randomized controlled trial to examine the frequency and type of adverse events (AEs) in patients with osteoarthritis who received concurrent therapy of topical diclofenac sodium 1% gel (DSG), and drugs known to have potential drug–drug interactions (DDIs) with diclofenac; and concluded that such co-medication had little impact on the frequency of AEs in this population.
The results of this studyCitation1 provide very useful information for clinical practice, ie, DSG may be a safe alternative to oral diclofenac when a pain reliever needs to be co-medicated with CYP2C9 substrates like warfarin antidiabetic sulfonylurea derivatives. DDIs between topically and systemically coadministered medications are easily neglected by clinicians, which brings about potential risk of patient safety. Peniston et alCitation1 answered a scientific question in clinical therapeutics. We completely appreciate their rigorous study and original spirit of exploration. We would like to discuss and share our perspectives in the following paragraphs.
The Joint Commission International (JCI) accreditation standard has strict requirements for rational drug use. Appropriateness review of real or potential DDIs among all current medications is a mandatory task for auditing pharmacists.Citation2 Peniston et al’s study further prompted us to better understand JCI requirements. We performed a PubMed search covering the period from 1988 to 21 June 2013, using the search terms “topical” and “drug interaction” and additional filters (species: humans; languages: English). Nine hundred and twenty-eight articles were detected. Inclusion criteria included studies or case reports describing DDIs between topically and systemically coadministered medications even if results of some clinical trials show no clinical significance. Fifteen articles were finally included under this search strategy. The full text of each article was critically reviewed, and data interpretation was performed. lists the literature describing DDIs between topically and systemically coadministered medications, except Peniston et al’s study.
Table 1 Drug-drug interactions (DDI) between topically and systemically coadministered medications
For each DDI, the object drug is defined as the medication whose pharmacokinetics and/or pharmacodynamics may be modified by the drug interaction process. The precipitant drug is defined as the medication responsible for affecting the pharmacologic action or the pharmacokinetic properties of the object drug.Citation16 Our literature review showed an interesting fact that topically administered medications could play a role of object drug in addition to a role of precipitant.
Some factors may influence the likelihood of DDI between topically and systemically administered medications and they are as follows: (1) percentage of body surface area to which the topical formulation is applied; (2) age of the patient – the very old and very young are more likely to exhibit DDI; (3) genetic factors may affect the magnitude of DDI (eg, DDI between timolol eye drops and oral quinidine is dependent on CYP2D6 phenotype; poor metabolizers have a higher risk for DDIs with a low systemic concentration of a topical imidazole derivative than extensive metabolizers do);Citation5,Citation17 (4) method of application-medications applied under occlusion are more likely to cause DDI; (5) condition of the stratum corneum-topical formulations applied to mucous membranes, genital skin, or thin, macerated or ulcerated skin are more susceptible to be systemically absorbed; and (6) other concomitantly used medications are also involved in the DDI mechanism, eg, topical terbinafine (precipitant drug) impaired CYP2D6-mediated drug metabolism of diltiazem and elevated diltiazem level increased the magnitude of CYP3A4-mediated metabolism inhibition toward acenocoumarol (object drug).Citation9
Methods used for judging whether there are DDIs between topically and systemically administered medications are as follows: (1) pharmacokinetic interaction study; (2) randomized controlled clinical trials focusing on overall tolerability of topical formulation with concomitant use of systemically administered medication; and (3) case analysis by using the Horn Drug Interaction Probability Scale or Naranjo scale.Citation9,Citation10,Citation18
In conclusion, Peniston et al’sCitation1 study brought an interesting and important topic to clinicians and patients who should be careful of potential therapeutic hazards due to DDIs between topically and systemically coadministered medications.
Acknowledgments
This work was supported by Zhejiang Provincial Bureau of Health (No 2012KYA090), and Zhejiang Provincial Bureau of Traditional Chinese Medicine (No 2011ZB075).
Disclosure
The authors report no conflicts of interest in this work.
References
- PenistonJHGoldMSWiemanMSAlwineLKTolerability of diclofenac sodium 1% gel with concomitant medications known to interact with diclofenacThey Clin Risk Manag20139153159
- Joint Commission InternationalJCI accreditation standards for hospitals [webpage on the Internet]Oak Brook, ILJoint Commission International2010 Available from: http://wwwjointcommissioninternational.org/common/pdfs/jcia/IAS400_Standards_Lists_Only.pdfAccessed March 20, 2013
- ThiboutotDMWillmerJSharataHHalderRGarrettSPharmacokinetics of dapsone gel, 5% for the treatment of acne vulgarisClin Pharmacokinet20074669771217655376
- HigginbothamEJTopical beta-adrenergic antagonists and quinidine. A risky interactionArch Ophthalmol19961147457468639090
- EdekiTIHeHWoodAJPharmacogenetic explanation for excessive beta-blockade following timolol eye drops. Potential for oral-ophthalmic drug interactionJAMA1995274161116137474246
- KovacMMiticGKovacZMiconazole and nystatin used as topical antifungal drugs interact equally strongly with warfarinJ Clin Pharm Ther201237454821332566
- LangPGJrLeClercqAHIncrease in anticoagulant effect of warfarin in a patient using econazole creamJ Am Acad Dermatol200655S117S11917052529
- DevarajAO’BeirneJPVeaseyRDunkAAInteraction between warfarin and topical miconazole creamBMJ20023257712114237
- Morales-MolinaJAArrebolaMARoblesPAManganaJCPossible interaction between topical terbinafine and acenocoumarolAnn Pharmacother2009431911191219843835
- WeyPFPetitjeansFLionsCOuld-AhmedMEscarmentJLaryngeal dyspnea in relation to an interaction between acenocoumarol and topical econazole lotionAm J Geriatr Pharmacother2008617317718775393
- JossJDLeBlondRFPotentiation of warfarin anticoagulation associated with topical methyl salicylateAnn Pharmacother20003472973310860133
- YipASChowWHTaiYTCheungKLAdverse effect of topical methylsalicylate ointment on warfarin anticoagulation: an unrecognized potential hazardPostgrad Med J1990663673692371186
- PatersonCAJacobsDRasmussenSYoungbergSPMcGuinnessNRandomized, open-label, 5-way crossover study to evaluate the pharmacokinetic/pharmacodynamic interaction between furosemide and the non-steroidal anti-inflammatory drugs diclofenac and ibuprofen in healthy volunteersInt J Clin Pharmacol Ther20114947749021781648
- Topical imidazole derivatives and drug interactions Available from: http://www.lareb.nl/larebcorporatewebsite/media/publicaties/kwb_2009_3_imida.pdfAccessed April 8, 2009
- RenoultEHubertJTrechotPHestinDKesslerML’HermiteJEffect of topical rifamycin SV treatment on cyclosporin A blood levels in a renal transplant recipientEur J Clin Pharmacol19914044334342050183
- LiWZengSYuLSZhouQPharmacokinetic drug interaction profile of omeprazole with adverse consequences and clinical risk managementTher Clin Risk Manag2013925927123745048
- AlexandraJFPautasEGouin-ThibaultISiguretVLoriotMAOveranticoagulation with coumarin and cutaneous azole therapyAnn Intern Med200814863363518413637
- HornJRHanstenPDChanLNProposal for a new tool to evaluate drug interaction casesAnn Pharmacother20074167468017389673