Increased warfarin doses and decreased international normalized ratio response after nationwide generic switching.
OBJECTIVE
Our objective was to examine possible changes in the effectiveness of warfarin after a nationwide generic substitution of formulations in 1998.


METHODS
In the computerized records of a health maintenance organization database, we identified 975 patients who took warfarin continuously over two 6-month periods, before (period 1) and after (period 2) the generic switch. In this sample we performed a retrospective, between-period paired comparison of warfarin doses dispensed and international normalized ratio (INR) levels maintained, as well as of the apparent warfarin sensitivity index (calculated as INR/Warfarin dose [in milligrams per day]).


RESULTS
Overall, for period 2, doses were 26.5% higher and INR 4.2% lower, with a 14.7% reduction in warfarin sensitivity index (P <.001). The findings were strongest in the 61 of 975 patients (6.3%) dispensed the lowest maintenance doses (<1.0 mg/d), with minimal change at greater than 3 mg/d. In 94 other patients (9.6%) in whom doses were unchanged, INR (median with 5th and 95th percentiles) dropped to subtherapeutic levels, from 2.2 (1.8, 3.0) to 1.7 (1.3, 1.8) (P <.001). There were no adverse events, expressed as no change in hospital admissions. Apparent warfarin sensitivity was reduced in period 2 by 15% to 20% (P <.001) across all period 1 INR levels.


CONCLUSIONS
Because a general unidirectional change in INR response per unit warfarin dose cannot be explained by biologic mechanisms or confounding, we conclude that slightly reduced bioavailability (within the acceptable bioequivalence range) of the new formulation led to overestimated period 2 doses and reduced apparent warfarin sensitivity in all patient subgroups (by period 1 dose or INR), which was most prominent in those individuals with the lowest maintenance dose requirements.
Halkin
Hillel
H
Maccabi Healthcare Services and Tel Aviv University School of Medicine, Israel. hhalkin@sheba.health.gov.il
Shapiro
Jonathan
J
Kurnik
Daniel
D
Loebstein
Ronen
R
Shalev
Varda
V
Kokia
Ehud
E
D000925:Anticoagulants / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D016208:Databases, Factual; D004305:Dose-Response Relationship, Drug; D016568:Drugs, Generic / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D006279:Health Maintenance Organizations; D019934:International Normalized Ratio; D007557:Israel / Q000453:epidemiology; D008499:Medical Records; D012189:Retrospective Studies; D013810:Therapeutic Equivalency; D016896:Treatment Outcome; D014859:Warfarin / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use
D000925:Anticoagulants; D016568:Drugs, Generic; D014859:Warfarin