This randomized, double-blind, crossover study investigated the potential effects of tolterodine ((R)-N,N-diisopropyl-3-(2-hydroxy-5-methyl-phenyl)-3-phenylpropanamine, CAS 124937-51-5), an antimuscarinic agent for the treatment of the overactive bladder, on the anticoagulant actions and pharmacokinetics of single-dose warfarin (CAS 81-81-2) in 20 healthy male volunteers. In terms of study design, volunteers randomly received oral tolterodine L-tartrate (2 mg twice daily) or matching placebo for 7 days, with a single oral dose of warfarin (25 mg) administered on day 4 of each treatment period. R-(+)- and S-(-)-warfarin pharmacokinetics were estimated from plasma levels measured up to 96 h post-dose, in conjunction with assessment of prothrombin time and factor VII activity. Pharmacokinetics of tolterodine and its active 5-hydroxymethyl metabolite ((R)-N,N-diisopropyl-3-(2-hydroxy-5-hydroxymethyl-phenyl)-3-phenylpropanamine; 5-HM), in the presence and absence of warfarin, were also determined. Relative to placebo, tolterodine had no discernible effect on the anticoagulant actions of warfarin. Point estimates of the tolterodine: placebo ratios for prothrombin time and factor VII activity were 1.00 (90% confidence interval [CI]: 0.91-1.10) and 0.91 (90% CI: 0.83-0.99), respectively, consistent with equivalence. No clinically significant changes in the pharmacokinetics of R-(+)- and S-(-)-warfarin were noted. Serum concentration-time profiles and the pharmacokinetics of tolterodine and 5-HM were similar in the presence and absence of warfarin. There were no safety concerns. These findings indicate that co-administration of tolterodine and warfarin is safe and well tolerated, with no clinically significant pharmacodynamic or kinetic interaction in healthy volunteers

AIMS: Solifenacin succinate is used for the treatment of overactive bladder (OAB). The potential for pharmacokinetic and/or pharmacodynamic interactions between solifenacin and warfarin or digoxin was investigated. METHODS: The solifenacin-warfarin study was a two-period crossover trial conducted in healthy males. Subjects received warfarin on the 10th day of 16 days of dosing with either solifenacin or placebo. The solifenacin-digoxin study was an one-sequence crossover trial conducted in healthy males and females. Following a phase-in period for digoxin, solifenacin was administered concomitantly with the drug on days 9-18. RESULTS: The AUC(PT; 0-168 h) following a single dose of warfarin was unchanged in the presence of solifenacin [point estimate = 1.005; 90% confidence interval (CI) 0.98, 1.02)]. The AUC(0-infinity) values for both warfarin enantiomers were also unchanged. A small increase in the C(max) of digoxin was observed during treatment with solifenacin, but for AUC(ss,tau) and C(max) the 90% CI fell within the prespecified interval of 0.80-1.25. Combined administration of solifenacin and warfarin or digoxin was well tolerated. CONCLUSIONS: Since the pharmacokinetics and pharmacodynamics of a single dose of warfarin and the steady-state pharmacokinetics of digoxin were not affected by coadministration of solifenacin in healthy subjects, the need for dosing adjustments for digoxin and/or warfarin does not seem warranted

A 53-year-old woman with a history of deep vein thrombosis and pulmonary embolism was receiving warfarin to prevent thromboembolic complications; her international normalized ratio (INR) had been stable for 1 month. Extended-release tolterodine 4 mg/day was then prescribed to manage overactive bladder. On her next anticoagulation clinic visit, the patient's INR had increased, although the dosage of warfarin had been reduced when the tolterodine had been prescribed. Due to the absence of other contributing factors and the temporal relationship between tolterodine and prolonged INR, the event was determined to be a probable drug interaction. When patients are prescribed tolterodine and warfarin concurrently, clinicians should monitor INR carefully, and a reduction in warfarin dosage may be required

OBJECTIVE: To report two cases of warfarin therapy in which the addition of tolterodine resulted in prolonged international normalized ratios (INRs). CASE SUMMARY: Two patients, each receiving warfarin for stroke prophylaxis in association with chronic atrial fibrillation, developed adverse effects after the initiation of tolterodine for urinary disorders. Other medications for concurrent medical diagnoses had remained unchanged. One patient had an episode of prostatitis, which was treated with levofloxacin immediately prior to tolterodine initiation. The warfarin dosage had remained constant for many weeks in both patients prior to and during the tolterodine trials. In each patient, the initiation of tolterodine was associated with a significant increase in the patient's INR measured 10-14 days later. Thus, tolterodine was ineffective in both patients and was discontinued one to two days before the elevated INRs were determined during routine clinic visits. INRs determined approximately two weeks after tolterodine was discontinued were similar to those obtained during the period before the use of the drug; the warfarin dosage remained unchanged. Rechallenge with tolterodine was not attempted in either patient. DISCUSSION: Several aspects of the reported cases support the validity of a proposed drug interaction when tolterodine is initiated in a patient stabilized on warfarin therapy. The temporal association of the course of tolterodine with an elevated INR, the return to the previous warfarin dose-INR response relationship after tolterodine discontinuation, and the absence of other causes for the elevated INR were factors found in both patients. Possible mechanisms to explain the suggested drug interaction are explored. CONCLUSIONS: Until further data are available, clinicians should be vigilant for a possible drug interaction when tolterodine therapy is initiated in a patient maintained on warfarin therapy