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  1. Q. Khalil,
  2. C. J. Glueck,
  3. M. Winiarska,
  4. P. Wang
  1. Cholesterol Center, Jewish Hospital, Cincinnati, OH


To report interaction of Cymbalta (duloxetine hydrochloride) with warfarin leading to persistent, severe elevation of an INR. A 44 year old woman, homozygous for the factor V Leiden mutation, receiving warfarin (10 mg/day) for 1 year after an ischemic stroke, with a stable INR (2.17 ± 0.51) for the year, was evaluated by us 30 days after development of petechiae-purpura (day 94, Fig. 1). Serial measures were taken for INR and liver function tests (LFTs), and plasma warfarin was measured on day 85. Measures were taken on day 94 for fibrinogen, vitamin K-dependent clotting factors, and with repeat measures of factors II and X on day 98 (Fig. 1). No drugs taken daily over the previous year were changed (warfarin, atorvastatin, lamotrigine, topiramate, clorazepam, albuterol); however, Cymbalta (30 mg/day), a selective serotonin and norepinephrine reuptake inhibitor (SSNRI), was added by the psychiatrist at day 0 and was continued until day 94. Having unexpectedly high INR (5.0) on day 55, warfarin was stopped, but Cymbalta was continued. Despite cessation (documented by pill count) of warfarin, INR continued to rise to > 19 on day 85, when plasma warfarin level was 5.3 μg/mL (therapeutic range 2-8 μg/mL), 30 days after the last warfarin dose. INR was briefly reduced to 2.7 only by vitamin K (IV) on day 85. On day 94, with INR 6.4, 39 days after stopping warfarin, factors II, VII, and X had low values; LFTs and fibrinogen remained normal. On day 94, duloxetine was stopped, and by day 98, INR had fallen to 1.2, with factor II increasing to 48% and factor X to 54%. On day 105, INR was 0.9. The metabolism of warfarin involves several CY P450 isoenzymes (CY P 1A2, 2D6, 2C9, 2C19, and 3A4). Duloxetine inhibits CYP1A2 and CYP2D6 and could potentially interact with warfarin. Duloxetine is also highly protein bound in plasma (> 90%) and when given with warfarin, another highly protein-bound drug, could displace warfarin, possibly resulting in a toxic effect. Our case emphasizes the need to closely monitor for the toxic drug interactions between the 2 drugs.

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