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Clinical Pharmacist Pharmacy Department Empresa Pública Hospital de Poniente Ctra. de Almerimar s/n 04700 El Ejido Almería, Spain fax 34 950 02 25 99 joseantonio.morales{at}ephpo.es
Clinical Hematologist Hematology Department Empresa Pública Hospital de Poniente
Director Pharmacist Pharmacy Department Empresa Pública Hospital de Poniente
PhD Candidate Hospital Pharmacy Resident Pharmacy Department Empresa Pública Hospital de Poniente
Published Online, October 20, 2009. www.theannals.com, DOI 10.1345/aph.1M299
Case Report. In August 2008, a 71-year-old white man presented with pain in his left calf, inflammation, petechiae, and bleeding lesions on his back and scalp. He had previously been diagnosed with chronic gastritis, arterial hypertension, dyslipidemia, and noninsulin-dependent diabetes mellitus and had been receiving acenocoumarol treatment for atrial fibrillation since 2004. He reported no significant changes in his diet or treatment (diltiazem 60 mg twice daily, lansoprazole 30 mg twice daily, atorvastatin 20 mg once daily, metformin 850 mg 3 times daily). Nine months before the symptoms appeared, he was diagnosed with seborrheic dermatitis on his head and back, for which he was treated with topical ciclopirox olamine 1.5% and mometasone furoate 0.1%, without improvement. In July 2008, the patient had begun treatment with topical terbinafine (1% Lamisil spray solution) once daily. Monthly international normalized ratio (INR) values with 13 mg of acenocoumarol per week as maintenance dose over the past year had been between 2.0 and 3.0 (target anticoagulation level). After 15 days of terbinafine treatment, he developed the symptoms previously described. At presentation, a blood sample via venipuncture was evaluated; his INR readings were greater than 8. Acenocoumarol and terbinafine were stopped and a single dose of phytonadione 10 mg was given. When the patient's INR went below the therapeutic range, subcutaneous bemiparin 5000 IU daily was initiated. After 6 days, acenocoumarol at a dose of 13 mg/week was restarted. After 1 week, INR readings were within the therapeutic range. Liver function tests were normal. After 12 months, INR monthly controls values were stable. The Horn Drug Interaction Probability Scale indicated a possible interaction between terbinafine and acenocoumarol.5
Discussion. In patients treated concurrently with oral terbinafine and warfarin, Warwick and Corrall3 reported an increase in INR levels, while Gupta and Ross4 reported a decrease. However, other authors have observed no interaction between these drugs.6
In our case, 2 mechanisms might explain this interaction. First, the drugs involved are extensively bound to plasma proteins. Introduction of topical terbinafine could have produced a displacement of acenocoumarol from plasma protein-binding sites. This may be clinically relevant in the elderly, in whom serum protein binding decreases. Visser et al.6 have reported that men and older patients treated with antifungal agents and coumarins have a higher bleeding risk. Second, despite the fact that acenocoumarol is mainly metabolized by CYP2C9, other isozymes could also be involved.6 It is possible that terbinafine, an inhibitor of CYP2D6, decreased the clearance of diltiazem, which is mebtabolized by CYP2D6.6 Therefore, diltiazem, a potent inhibitor of CYP3A4, may have decreased the clearance of acenocoumarol (weakly mebtabolized by CYP3A4).7 At the time of writing, this theory had not been confirmed.
In conclusion, it is not well known what percentage of topical terbinafine is absorbed nor the role of drugs, factors, or mechanisms involved in this interaction. Further research must address these questions. Therefore, acenocoumarol should be closely monitored while a patient is using terbinafine spray.
Footnotes
Financial disclosure: None reported
References
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