Zafirlukast Warfarin

Morkunas A, Graeme K. Zafirlukast warfarin drug interaction with gastrointestinal bleeding. J Toxicol 1997 35 501. 

Administration of zafirlukast and aspirin increases plasma levels of zafirlukast, When zafirlukast is administered with warfarin, there is an increased effect of the anti coagulant. Administration of zafirlukast and theophylline or erythromycin may result in a decreased level of zafirlukast. Administration of montelukast with other drugs has not revealed any adverse responses. Administration of montelukast with aspirin and NSAIDs is avoided in patients with known aspirin sensitivity. Administration of zileuton with propranolol increases the activity or the propranolol with theophylline increases serum theophylline levels and with warfarin may increase prothrombin time (PT). A prothrombin blood test should be done regularly in the event dosages of warfarin need to be decreased. 

Drugs that may affect zafirlukast include aspirin, erythromycin, and theophylline. Drugs that may be affected by zafirlukast include warfarin. 

Zafirlukast and montelukast are well tolerated. Zafirlukast increases plasma concentrations of warfarin and decreases the concentrations of theophylline and erythromycin. In rare cases, treatment of patients with CysLT receptor antagonists is associated with the development of Churg-Strauss syndrome, a condition marked by acute vasculitis, eosinophilia, and a worsening of pulmonary symptoms. Because these symptoms often appear when patients are given the leukotriene receptor antagonists when they are being weaned from oral corticosteroid therapy, it is not clear whether they are related to the action of the antagonists or are due to a sudden reduction in corticosteroid therapy. 

ANTICOAGULANTS - ORAL LEUKOTRIENE ANTAGONISTS Zafirlukast t anticoagulant effect Zafirlukast inhibits CYP2C9-mediated metabolism of warfarin Monitor INR at least weekly until stable... 

Zafirlukast reduces the clearance of warfarin, resulting in a clinically significant prolongation of prothrombin time (10). The mechanism for this interaction is thought to be inhibition of cytochrome P450 enzymes, such as CYP2C9. 

CYP2C9 20 10 Celecoxib Diclofenac Fluoxetine Fluvastatin Ibuprofen Irbesarten Naproxen Amitriptyline Phenytoin Tolbutamide Torsemide S-warfarin Rosiglitazone Amiodarone Fluconazole Fluvoxamine Fluvastatin Isoniazid Sertraline Sulfaphenazole Trimethoprin Zafirlukast Rifampin Clotrimazole Carbamazepine Hyperforin Phenobarbital Ritonavir... 

C9 Amiodarone, chloramphenicol, cimetidine, isoniazid, metronidazole, SSRIs, zafirlukast Barbiturates, chloramphenicol, doxorubicin, ibuprofen, phenytoin, chlorpromazine, steroids, tolbutamide, (S>warfarin... 

Zafirlukast increases the anticoagulant effects of warfarin and bleeding has been seen. Pranlukast is predicted to interact similarly. In contrast, montelukast did not alter the pharmacokinetics or anticoagulant effects of single-dose warfarin. 

In a placebo-controlled study, 16 healthy subjects taking zafirlukast 80 mg twice daily for 10 days were given a single 25-mg dose ofwarfarin on day 5. The mean AUC of S-warfarin was increased by 63% and the half-life by 36%, but the pharmacokinetics ofR-warfarin were not significantly changed. The mean prothrombin time increased by 35%. ... 

Information appears to be limited to these reports but the interaction with zafirlukast would seem to be established. If zafirlukast is given to patients stabilised on warfarin, monitor prothrombin times well and be alert for the need to reduce the warfarin dosage to avoid over-anticoagulation. Other coumarins might be expected to be affected similarly. Pranlukast is also predicted to interact, as it is also an inhibitor of CYP2C9. In contrast, mon-telukast does not appear to interact with warfarin, and no warfarin dose adjustments are predicted to be needed on concurrent use. 

Suttle AB, Vargo DL, WilkinsonLA, Birmingham BK, Lasseter K. Effect of zafirlukast on the pharmacokinetics of R- and S-warfarin in heStlty men. Clin Pharmacol The r 991) 61, 186. 

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