CURRICULUM VITAE Jukka Rantanen, Professor Ph.D. EDUCATION: Docent (Phys. Pharm.) Department of Pharmacy, University of Helsinki Department of Pharmacy, University of Helsinki EMPLOYMENTS: Professor Viikki Drug Discovery Technology Center (DDTC), University of Helsinki, Finland Department of Industrial and Physical Pharmacy, Purdue University (IN), USA Viikki Drug Discovery
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Ijp_dec_04.pmdComparison of the clinical efficacy of three brands of warfarin M. H. Namazi, Z. K. Yousefi, M. G. Shirazi, M. Shaykholeslami, H. Vakili, M. R. Moatamedi, M. Safi, Objective: To compare the clinical efficacy of three brands of warfarin.
Material and Methods: Thirty-six patients (mean age 51.8±12.7 years, 12 males, 24 females) withdifferent indications for anticoagulant therapy were randomly placed in 3 groups. Each groupstarted with one of the three brands of warfarin (Orion from Finland=Brand A, Cipla from India=Brand B and Ferrer from Spain=Brand C) and crossed over to another after 4 weeks. Patients were fol- lowed up at weekly visits, checking prothrombin time (PT), International Normalized Ratio (INR) and any complications. The cardiologist and patients were unaware of the warfarin brand used.
Number of dose changes, mean dose changes (mg), target INR achievement in the last week and the mean stable dose (mg) were compared between the three brands.
Results: Mean number of dose changes throughout the 4-week course was 1.6±1.2 times for brand A, 1.2±1.1 times for brand B and 1.3±0.9 times for brand C (P=0.24). The amount of total dose changes was similar (0.70±0.6 mg for brand A, 0.63±0.9 mg for brand B and 0.72±0.8 mg for brand C, P=0.89). The rate of target INR achievement in the last week was similar (46.9% for brand A, 50% for brand B and 50% for brand C). Thirty-four per cent of patients treated with brand A, 28% with brand B, and 32% with brand C did not achieve target INR. The required dose for the stable target INR was 4.6±2.2 mg, 5.3±2.2 mg and 5.3±2.4 mg in patients treated with brands A, Band C respectively (P=0.61). There were no complications except 2 cases of drug discontinuationby the physician for extreme overdose, (i.e. INR>4.5 that needed drug discontinuation).
Conclusion: Orion, Cipla and Ferrer warfarin products were similar regarding target INR achieve-ment, the required dose and number of dose changes.
KEY WORDS: INR, oral anticoagulant, prothrombin time Introduction
comparable to the brand Coumadin in its effectiveness,ability to maintain stable anticoagulation, and safety.5-7 When Warfarin is a common anticoagulant which is used in a initiating anticoagulant therapy or when converting patients variety of clinical settings. The drug is vital to many patients from the brand Coumadin to generic warfarin, additional at increased risk of thromboembolic complications, and is of- monitoring of the International Normalized Ratio (INR) may ten prescribed for patients with artificial heart valves, be needed. In 1980, conversion from DuPont crystalline arrhythmias or other conditions that increase the risk of co- warfarin to an amorphous warfarin caused an increase in agulation. Studies have shown the beneficial effects of warfa- the number of patients whose anticoagulation was poorly rin administration in the prevention of stroke in patients with In Iran, generic warfarin is mainly supplied by Orion Cor- Different formulations and brands of warfarin are avail- poration (Orion Pharmaceutica, Espoo, Finland). The process able. Warfarin sodium has been added to the formulary as of import and distribution of this product, for various reasons, the generic alternative to the brand Coumadin, which is the is not constant and reliable, imposing serious risks due to eleventh most prescribed medication in the United States.3 unwanted drug discontinuation or dose change. Therefore, we The Food and Drugs Administration of USA (FDA) has designed this study to compare the efficacy and side-effects granted some products of generic warfarin an “AB” rating, of Orion warfarin with two other brands, in order to devise indicating a therapeutic equivalence to the brand Coumadin.4 recommendations for the replacement of Orion warfarin with Clinical trials have demonstrated that generic warfarin is Indian J Pharmacol | December 2004 | Vol 36 | Issue 6 | 360-362 Material and Methods
P=0.89). Table 1 shows the amount of dose change in eachvisit and the total dose change for each brand.
This was a randomized double-blind crossover clinical trial.
Figure 1 compares mean INR values in each week for the The patients were those visiting Modarres Hospital heart clinic, three brands. Except a sharp and statistically significant in- or those hospitalized in Modarres Hospital, who had indica- crease in INR at the second visit for brand A, the differences tions for anticoagulation therapy. All patients had optimal In- between mean INR for the brands in each visit were insignifi- ternational Normalized Ratio (INR), i.e. 2-3 for atrial fibrilla- cant. Target INR was defined for each patient according to tion and 2.5-3.5 for valvular heart disease. Patients were ex- his/her disease. Patients receiving the three brands achieved cluded if they did not receive warfarin, could not come to the the target INR at the same rate (46.9% for brand A, 50% for hospital for weekly visits or did not cooperate, or had dis- brand B and 50% for brand C). Thirty-four per cent of patients eases interfering with warfarin metabolism. Also, patients on treated with brand A, 28% of patients treated with brand B, drugs interacting with warfarin such as phenytoin, phenobar- and 32% of patients treated with brand C did not achieve tar- bital, cimetidine and amiodarone were excluded. An appropri- get INR. Over-treatment, i.e. INR>upper limit of target range, ate review committee approved the study protocol.
was seen in 19%, 22% and 18% of patients treated with brand Patients were briefed on the study protocol and objectives A, brand B and brand C respectively (P=0.98). The required and then, were asked to sign an informed consent if they were dose for the stable target INR was 4.6±2.2 mg, 5.3±2.2 mg willing to participate. The sample size was calculated based and 5.3±2.4 mg in patients treated with brand A, B and C on mean necessary dose change in groups assuming al- respectively (P=0.61). There were no complications except 2 pha=0.05, beta=0.2, SD=0.7 and a difference of 0.5. So 36 cases of drug discontinuation by the physician for extreme patients were randomly allocated into one of the three treat- overdose. No major hemorrhagic or thromboembolic events ment groups. Each group received one of the study drugs: A (Orion warfarin 5 mg tablets, Orion Pharmaceutica, Espoo,Finland), B (Warf5, CIPLA, Mumbai, India) and C (Warfarin 5 Discussion
mg tablets, Ferrer, Spain). The formulations were identical inshape and size. The patients and the attending physicians were The results of this study demonstrated similar effects of the three brands of equal strength (5 mg) oral warfarin (Orion, Each group received the prescribed drug for four weeks.
Cipla and Ferrer). This similarity was demonstrated through During this period, they were visited weekly. In these weeklyvisits, prothrombin (PT) and INR were checked and the pa-tients were asked about the possible complications. The at- tending cardiologist recorded the data and decided whether a The total amount of dose change and dose change (mg) in each
dose adjustment was necessary. Target INR was defined ac- visit for the three brands
cording to the indication: 2-3 for atrial fibrillation or 2.5-3.5for valvular heart disease and prosthetic valves. After four weeks the patients were switched to the next drug (e.g. A to B) and the same method was used. The patients were once more switched to the next drug, till all completed the 12-week dura- tion and had used all the three brands in the course. Blood samples were centrifuged for 5 min and after plasma separa- tion at 37° C, 0.2 ml thromboplastin and 0.1 ml plasma were added to measure PT. Biomerieux table was used to deter-mine INR.
Data are presented as percentage and mean+SD. Repeated measures ANOVA was used to assess the differences amongthe three brands used. A P value less than 0.05 was consid-ered significant.
The mean age of patients was 51.8±12.7 years. Their av- erage weight was 64.4±14.0 kg. Twenty-four patients werefemale. Patients received warfarin for the following diagnoses:Valvular heart disease (44.4%), atrial fibrillation (50%), andother conditions (5.6%).
The mean number of dose changes throughout the 4-week courses was 1.6±1.2 times for brand A, 1.2±1.1 times forbrand B and 1.3±0.9 times for brand C (P=0.24). The amount *P<0.05 compared with other brands and other visits of total dose changes was similar (0.70±0.6 mg for brand A,0.63±0.9 mg for brand B and 0.72±0.8 mg for brand C, Figure 1: Mean INR for different brands of warfarin
Indian J Pharmacol | December 2004 | Vol 36 | Issue 6 | 360-362 the rate of achievement of target INR and number and amount In another cohort study, Milligan and associates10 deter- of dose changes. Other studies have examined the effect of mined whether a Health Maintenance Organization (HMO) can switching from one type of warfarin to another. Such studies add generic warfarin to its formulary without adversely af- focus mainly the switch from coumadin to generic warfarin.
fecting warfarin management or increasing adverse events.
Most of them have also shown that such a switch is usually Data were collected 8 months prior to and 10 months after harmless and does not have serious effects on anticoagula- the introduction of generic warfarin (Barr Laboratories, tion. In two randomized crossover clinical trials Neutel and Pomona, NY) to an HMO’s formulary. In this study the change Smith5 and Handler et al 6 compared coumadin and generic did not significantly affect INR control, warfarin management, warfarin. They treated patients for 21-28 days. In these trials, or adverse events. Authors suggested that HMOs can safely the change in the mean baseline INR to overall INR was – 0.10 substitute at least 1 generic formulation of warfarin without and –0.20 for Barr and – 0.01 and – 0.02 for DuPont products respectively. Both studies found no significant difference in In two cases at a family medicine center anticoagulation the average INR values. There was no difference in the ad- clinic in Oklahoma city, Hope and Havrda11 reported sub-thera- verse effects between the two drugs. Both concluded that the peutic INR values after a switch from Coumadin to generic two products were equivalent. Swenson7 studied a cohort of warfarin, while all other variables were kept consistent dem- patients at a managed-care organization and determined the onstrating the need for close monitoring of the INR when pa- safety and effectiveness of switching to generic warfarin. This tients are switched between brands of warfarin.
study was not blinded and patients seen during routine visits Although some findings such as Hope and Havrda’s re- at two anticoagulation clinics were asked to volunteer to use port11 underscore the importance of close monitoring if a switch generic warfarin (Barr Laboratories) instead of coumadin for in warfarin brand is done, most studies show safe switch from eight weeks. Patients (n = 210) who had therapeutic INR val- one warfarin brand to another. This is especially important for ues at the baseline visit and had received anticoagulation with our patients, since Orion warfarin is not always available. Since coumadin for three months were enrolled in the study. The it is very important to maintain a steady and acceptable level control group (n = 105) consisted of patients who declined or of anticoagulation over the time for all the patients, it is some- were not asked to change the drug. Mean INR values were times necessary to switch to a different brand when the cur- compared before and after enrollment. The difference between rent brand is not available. Our results demonstrate that such the two groups was not significant and of negligible clinical switching is harmless in patients taking warfarin as a prophy- meaning. Among the patients who had a dosage change, there was no significant difference in the variability of the INR be-fore versus after enrollment. Patients in either group did not References
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DuPont warfarin or receive Apothecon warfarin for four weeks, Handler J, Nguyen TT. A blinded, randomized, crossover study comparing the with weekly evaluation of dosage and INR changes, safety and efficacy and safety of generic warfarin sodium to Coumadin®. Prev Cardiol efficacy. Subsequently, patients crossed over and received the other product for four weeks. Neither the propensity for a dos- Swenson CN, Fundak G. Observational cohort study of switching warfarin so- age change or an INR change nor the magnitude of a dosage dium products in a managed care organization. Am J Health Syst Pharm change or INR change appeared related to a particular warfa- Richton-Hewett S, Foster E, Apstein CS. Medical and economic consequences rin product (NS for each variable after each study period).
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10. Milligan PE, Banet GA, Waterman AD, Gatchel SK, Gage BF. Substitution of of treatment was similar for both groups (<1.8, n = 9 for generic warfarin for Coumadin in an HMO setting. Ann Pharmacother both products, or >3.2, n = 9 for DuPont, n=10 for Apothecon). No major hemorrhagic or thromboembolic events 11. Hope KA, Havrda DE. Subtherapeutic INR values associated with a switch to generic warfarin. Ann Pharmacother 2001;35:183-7.
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PHARMACOTHERAPY AND BPD DIMEFF, L.A., MCDAVID, J., & LINEHAN, M.M.(1999) Double-Blind Pharmacotherapy Outcome Studies Using BPD SamplesDouble-blind randomized six-week acute treatmentEleven of the total N (13.8%) failed to complete at least three weeks of the trial. Bothtrial with BPD outpatients (n=80). Each conditionmedications resulted in statistically significant improvements com