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Clinical Specialist Department of Medical Sciences Clinical Pharmacology University of Uppsala Akademiska sjukhuset, Ing 61 75185 Uppsala, Sweden fax 46 18 6113703 gabriella.scordo{at}medsci.uu.se
Professor Department of Medical Sciences Clinical Pharmacology University of Uppsala
Research Nurse Department of Medical Sciences Clinical Pharmacology University of Uppsala
Clinical Specialist Warfarin Clinic Clinical Chemistry Central Hospital Karlstad, Sweden
Associate Professor Department of Medical Sciences Clinical Pharmacology University of Uppsala
Published Online, February 26, 2008. www.theannals.com, DOI 10.1345/aph.1K544
Case 1. An 80-year-old woman receiving warfarin for atrial fibrillation for 15 years (INR 2-3 while taking 22.5 mg/wk) was prescribed noscapine 50 mg 3 times daily for cough. Other medications were unchanged. Thirteen days after starting noscapine, the patient's INR was higher than 6.0. Noscapine was withdrawn and the warfarin dosage was reduced to 17.5 mg/wk. One week later the patient's INR was 1.6. She was prescribed her usual warfarin dose, and the INR was stabilized at 3.0.
Case 2. A 78-year-old woman taking warfarin for atrial fibrillation for 5 years (INR 2.1-2.5 while taking 20.0 mg/wk) was prescribed noscapine 50 mg 3 times daily for cough. Other medications were unchanged. After 2 weeks, the patient's INR was 3.5; one week after that, it was 5.7. Noscapine was withdrawn and the warfarin dosage was reduced to 15.0 mg/wk. Three days later, the patient's INR decreased to 3.6 and one week later to 2.4. She was prescribed her usual warfarin dose and the INR was stabilized at 2.1.
Case 3. A 54-year-old woman treated with warfarin for deep venous thrombosis for 2 years (INR 2.1-3.0 while taking 41.3 mg/wk) self-medicated with noscapine 50 mg 3 times daily and acetaminophen 1 g twice a day for 3 days because of common cold with cough and fever. Other medications remained unchanged. One week after starting noscapine, the patient's INR was higher than 6.0. Noscapine was withdrawn, and 4 days later the patient's INR was 1.3.
Case 4. A 71-year-old woman receiving warfarin for atrial fibrillation for 5 years (INR 2.1-3.0 while taking 20.0 mg/wk) self-medicated with noscapine 50 mg 3 times daily and diclofenac 50 mg 3 times daily for common cold with cough, fever, and back pain. Other medications were unchanged. One week later, the patient's INR was 4.4. Noscapine and diclofenac were withdrawn, and the INR decreased to 2.87 in one week.
Discussion. The patients' ages (range 54-80 y) were within the age range of most Swedish warfarin users.2 All cases had a positive dechallenge (Figure 1). No vitamin K or other treatment to decrease INR was administered. All long-term medications were unchanged, and were unlikely to have contributed to the INR elevation. Furthermore, no significant pharmacokinetic interaction has been reported between warfarin or noscapine and any of the concomitant medications. Using the Horn et al.3 probability scale for drug interactions, a warfarin-noscapine interaction was found to be probable in all cases, even if acetaminophen and diclofenac could have contributed in cases 3 and 4, respectively.
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Including our 4 patients, 11 cases of increased INR and 1 hemorrhage due to coadministration of warfarin and noscapine have been reported to the SWEDIS. Noscapine administration is associated with a 91% reduction in hepatic microsomal cytochrome P450 content, and a 36% decline in the nicotinamide adenine dinucleotide phosphate-oxidase cytochrome c reductase activity in rats.4 An in vitro study suggested that noscapine inhibits the warfarin-metabolizing enzymes CYP2C9 and CYP3A4.1 Coadministration of warfarin and noscapine should therefore be avoided.
References
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