Clinical Study Synopsis

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1 Clinical Study Synopsis This Clinical Study Synopsis is provided for patients and healthcare professionals to increase the transparency of Bayer's clinical research. This document is not intended to replace the advice of a healthcare professional and should not be considered as a recommendation. Patients should always seek medical advice before making any decisions on their treatment. Healthcare Professionals should always refer to the specific labelling information approved for the patient's country or region. Data in this document or on the related website should not be considered as prescribing advice. The study listed may include approved and non-approved formulations or treatment regimens. Data may differ from published or presented data and are a reflection of the limited information provided here. The results from a single trial need to be considered in the context of the totality of the available clinical research results for a drug. The results from a single study may not reflect the overall results for a drug. The following information is the property of Bayer HealthCare AG. Reproduction of all or part of this report is strictly prohibited without prior written permission from Bayer HealthCare AG. Commercial use of the information is only possible with the written permission of the proprietor and is subject to a license fee. Please note that the General Conditions of Use and the Privacy Statement of bayerhealthcare.com apply to the contents of this file.

2 Test Product Study Sponsor: Study Number: Study Phase: I Clinical Trial Results Synopsis Bayer HealthCare AG Study Design Description NCT Official Study Title: Randomized, placebo-controlled, parallel-group study in healthy male subjects to investigate the pharmacodynamics during the switching procedure from warfarin to rivaroxaban Therapeutic Area: Cardiology/Coagulation Name of Test Product: Name of Active Ingredient: Dose and Mode of Administration: Reference Therapy/Placebo Rivaroxaban (Xarelto, BAY ) Rivaroxaban Treatment A was the test treatment. Rivaroxaban 20 mg immediate release tablet orally once daily was administered in Treatment A (warfarin + rivaroxaban) and Treatment C (rivaroxaban; reference treatment) from Day 0 to Day 3. Reference Therapy: Warfarin was an interacting drug. Dose and Mode of Administration: Placebo was reference drug. Vitamin K was an antidote. Treatment B (warfarin + placebo) was the reference treatment. Treatment A Treatment B Treatment C Days -6 and -5: 10 mg warfarin (Coumadin ) once daily or lower depending on international normalized ratio (INR) Days -4 to -1: 2.5, 5, 10, 12.5, or 15 mg warfarin (Coumadin ) once daily depending on INR Days 0 to 3: 20 mg rivaroxaban once daily Day 5: 10 mg vitamin K (Konakion ) once daily Days -6 and -5: 10 mg warfarin (Coumadin ) once daily or lower depending on INR Days -4 to -1: 2.5, 5, 10, 12.5, or 15 mg warfarin (Coumadin ) once daily depending on INR Days 0 to 3: 1 tablet matching placebo once daily Day 5: 10 mg vitamin K (Konakion ) once daily Days 0 to 3: 20 mg rivaroxaban once daily All 3 drugs were given orally. Page 1 of 16

3 Duration of Treatment: Treatment A and C: Rivaroxaban was given from Days 0-3 (4 days) Treatment B: Placebo was given from Days 0-3 (4 days) Treatment A and B: Warfarin was given from Days -6 to Day -1 (7 days) Treatment A and B: Vitamin K was given on Day 5 (1 day) Studied period: Date of first subjects first visit: 11 NOV 2008 Date of last subjects last visit: 10 NOV 2009 Premature Study Suspension / Termination: Substantial Study Protocol Amendments: No Amendment no. 1 (dated 20 FEB 2009) specified the following changes: The participation of a second study center: the study was continued and completed as a multi-center study. A more precise definition of the pre-study examination: Genotyping was conducted on a separate visit prior to the pre-study examination. The pre-study examination itself was conducted within 2 weeks prior to the first drug administration. Due to a new investigator s brochure some changes in the adverse events section were made. Amendment no. 2 (dated 19 MAY 2009) specified the following changes: A new definition of the blocking period for the subjects between two clinical trials was introduced. The minimum time between participation in a prior clinical trial and genotyping was 4 weeks. The minimum time between participation in a prior clinical trial and the pre-study examination was 3 months. The time points of several measurements of coagulation parameters in Groups A and B were switched in order to collect data concerning the difference of the applied INR analysis methods. The following time points of the prothrombin time (PT)(s, INR), partial thromboplastin time (PTT) and HepTest measurements were switched: -6d00h00min to -6d08h00min -5d00h00min to -5d08h00min -4d00h00min to -4d08h00min -3d00h00min to -3d08h00min -2d00h00min to -2d08h00min. No additional blood samples were taken. Study Centre(s): The study was conducted at 2 study centers in Germany. Methodology: A special condition for this study was the genotyping for SNPs (single nucleotide polymorphisms) in the genes encoding CYP 2C9 and VKORC1. Only individuals who were homozygous for the wild type allele 2C9*1 and carriers of the C-allele at positions 6484 and 7566 of the VKORC1 gene, respectively, were randomized. A sample for the pharmacogenetic analysis was taken at a separate examination visit prior to the pre-study examination (at a separate visit per Amendment 1, dated 20 FEB 2009). The total duration of the study was planned to be approximately 20 weeks including replacement of subjects. Page 2 of 16

4 On non-profile days, the study drug (or the interacting drug warfarin or placebo) was administered in the morning after breakfast. On profile days, in all treatments, the study drug was administered in the morning after a standard breakfast. Rivaroxaban or placebo were administered only if INR (pre-dose) was <3.0. Otherwise, the second profile day (0d) was postponed and INR measurements repeated 24 hours later. Blood sampling for pharmacodynamic assessment [coagulation parameters] was done at Screening, on Day -0 (at 22h00min, 21h00min, 20h00min, 18h00min, 16h00min, 12h00min, and 08h00min), Day 0 (00h00min, 01h00min, 02h00min, 03h00min, 04h00min, 06h00min, 08h00min, and 12h00min), Day 1 (00h00min, 03h00min, 06h00min, and 12h00min), Days 2 and 3 (00h00min and 03h00min), and Days 4, 5, and 6 (00h00min). Indication/ Main Inclusion Criteria: Blood sampling for pharmacokinetics (PK) was done for all the three groups (from Day 0 to Day 6). Follow-up took place at a maximum of 7 days after the last drug administration. Follow-up period for adverse events was at least seven days for all adverse events with active follow-up, and another 23 days thereafter, the investigator was required to report every serious adverse event of which he or she became aware. Indication: Not applicable Study Objectives: Inclusion criteria Overall: Healthy male subjects, 18 to 45 years of age, with body mass index (BMI) between 18 and 29 kg/m 2. Subjects who were homozygous for the wild type allele 2C9*1 and carriers of the C-allele at positions 6484 and 7566 of the VKORC1 gene, respectively. Not applicable Primary: To investigate the pharmacodynamics while switching from warfarin (dosed to steady state; INR ) to rivaroxaban treatment (20 mg od). Secondary: To assess the safety, tolerability, and pharmacokinetics during this switching procedure. Page 3 of 16

5 Evaluation Criteria Pharmacodynamics: AUCtau and Emax for: prothrombin time (PT) (s), PT(INR), activated partial thromboplastin time (aptt), anti-xa, Factor Xa inhibition, Factor IIa, Factor VIIa activity, Factor Xa activity (HepTest), endogenous thrombin potential (ETP) (lag time, peak, AUC), prothrombinase-induced clotting time (PiCT) (primary parameter for statistical analysis: Emax for PT(s)). Efficacy (Primary): Emax (Maximum Effect) on PT (coagulation test) Emax,BA (Baseline adjusted maximum effect) on PT (coagulation test) Efficacy (Secondary): AUC(0-tn) of PT (coagulation test) AUCBA(0-tn) (Baseline adjusted AUC) of PT (coagulation test) Emax on PT (Measured as INR=International Normalized Ratio) AUC(0-tn) for PT (Measured as INR) Emax on Factor Xa activity AUC(0-tn) of Factor Xa Activity Emax on Anti-Factor Xa activity AUC(0-tn) of Anti-Factor Xa activity Emax on aptt (Activated Partial Thromboplastin Time) AUC(0-tn) of aptt Emax on HepTest (coagulation test) AUC(0-tn) of HepTest (coagulation test) Emax on PiCT (Prothrombinase-induced Clotting Time) AUC(0-tn) of PiCT Emax on ETP AUC(0-tn) of ETP AUC Emax on ETP Lag Time AUC(0-tn) of ETP Lag Time Emax on ETP Peak AUC(0-tn) of ETP Peak Emax on ETP Peak Time AUC(0-tn) of ETP Peak Time Emax on Factor VIIa Activity AUC(0-tn) of Factor VIIa Activity Emax on Factor IIa Activity AUC(0-tn) of Factor IIa Activity Safety: Incidence of abnormal findings in measurements for objective tolerability such as vital parameters, ECG-findings, laboratory findings, and the occurrence of adverse events after drug administration Page 4 of 16

6 Pharmacokinetics: Primary parameters: For R- and S-warfarin: t1/2 after last dose For rivaroxaban: AUC(0-24) and Cmax after 1 st dose Secondary parameters: For R- and S- warfarin: Ctrough,ss, Ctrough,ss/D at and after the last dose For rivaroxaban: AUC(0-24)norm, Cmax,norm, and tmax after first dose; Cpeak and Ctrough for 2 nd - 4 th dose; t1/2 after the last dose. Statistical Methods: Pharmacodynamics: Other parameters: Points terminal The kinetic characteristics AUC(0 tn), AUCabs(0 tn), Emax,abs, and Emax of PT prolongation were analyzed in an explorative manner. To compare kinetics between the treatments, these characteristics were logarithmized and analyzed using ANOVA including a treatment effect. Point estimates and exploratory one-sided 90% confidence intervals for the treatment ratios were calculated by re-transformation of the logarithmic results. Efficacy (Primary): Not applicable Efficacy (Secondary): Not applicable Number of Subjects: Safety: Descriptive statistics were used. Pharmacokinetics: The pharmacokinetic characteristics of rivaroxaban AUC(0-24) and Cmax after the first dose and t1/2 of warfarin after the last dose were analyzed assuming log-normally distributed data. The logarithms of these characteristics were analyzed using analysis of variance (ANOVA) including a treatment effect. Point estimates (LS-means) and exploratory 95% confidence intervals for the ratios were calculated by re-transformation of the logarithmic data using the inter-individual standard deviation of the ANOVA. Subject planned: 84 subjects (28 subjects per group), minimum number of valid subjects with complete study treatments: 75 subjects (25 subjects per group) Number of subjects enrolled: 96 Number of subject who completed the study: 83 Number of subjects analyzed: 84 Page 5 of 16

7 Results Summary Subject Disposition and Baseline Study Results Overall, 96 subjects were enrolled into this study, 55 by ClinPharmCologne and 41 by CRS Moenchengladbach. A total of 83 subjects completed the study according to protocol and 13 subjects discontinued the study prematurely. Of these 13 subjects who terminated the study prematurely, 5 did not receive any study medication, 7 received warfarin only prior to termination, and 1 subject in the warfarin/rivaroxaban group discontinued prematurely due to a drug-related adverse event. Table 1 summarizes the details of study completion, premature termination and analysis sets. Table 1: Disposition of subjects In general, subjects included into the study complied with the inclusion criteria with regard to age and BMI. They were healthy as evidenced by their medical history records, physical examination, safety laboratory, ECG, and vital signs assessments. Page 6 of 16

8 Summary statistics for demographic data are displayed in Table 2. Table 2: Demographics, safety set, n=91 Results Summary Pharmacodynamics Pharmacodynamics: A total of 84 subjects were included in the PK/PD set, 28 subjects per treatment group. The statistical evaluation provided median changes of PD parameters from baseline per time point and an evaluation of the effect vs time curve providing AUC and Emax (relative and absolute changes). Baseline was defined as the last measurement prior to start of warfarin dosing in the warfarin/rivaroxaban group (A) and the warfarin/placebo group (B). In the rivaroxaban group (C) baseline was the measurement immediately prior to first dosing with rivaroxaban. With respect to the primary PD variable, PT, the following results were obtained: The prothrombin time assay was designed to measure Vitamin K antagonists. Rivaroxaban also influences PT, but the degree of the changes is dependent on the assay. The slope of the Neoplastin PT versus plasma concentration is steeper than for Innovin PT. Therefore, the Neoplastin assay was used to assess the pharmacodynamic effects of rivaroxaban. Page 7 of 16

9 PT(s) were only measured with the Neoplastin assay: Warfarin treatment alone prolonged PT(s) by a factor of 1.87 over baseline i.e., by 11.2 seconds. The warfarin effect decreased over the placebo treatment period following warfarin in the warfarin/placebo group B and was returned to pretreatment baseline in the morning of Day 3d, 4 days after the last warfarin dose. Rivaroxaban alone (group C) caused a PT prolongation with a maximum of 7 s, which was 1.6 times baseline and in the range expected for treatment with the 20 mg dose (Emax of the effect vs time curve). PT returned to baseline 24 hours after each rivaroxaban dose. After the switch from warfarin to rivaroxaban, a maximum PT prolongation of 45 s, 4.4 times baseline (geometric mean Emax of the effect vs time curve) was observed on Day 0d. Individual PT values close to 90 s were observed 1 hour after dosing on Day 0d. As the warfarin effect declined, baseline conditions were reached in the morning of Day 4d prior to rivaroxaban dosing. The rivaroxaban effect returned to pretreatment baseline 24 hours after the last dosing at a time when no warfarin effect was present any longer. PT(INR): In this study, 3 different assays were used for determination of PT(INR). (i) The Neoplastin assay was used by Bayer's central laboratory for INR profiles on Day -1 and Days 0d to 5d. This assay was predefined to be used for the pharmacodynamics assessment. (ii) The Innovin assay was used at the local laboratory for monitoring of PT(INR) during the warfarin treatment phase. (iii) The Hemosense point-of-care device was used in a subset of subjects of the warfarin/rivaroxaban group A during Day 0d. Overall correlations between the Innovin assay and the Neoplastin assay as well as between the Hemosense point-of-care device and the Neoplastin assay were high (Pearson's correlation coefficient 0.94 and 0.89, respectively, p<0.0001). Correlation plots showed a more stringent correlation in the INR range up to 2.0, a less stringent correlation for PT INR values above 2.0. The following results refer to the Neoplastin assay: Immediately prior to the switch from warfarin to rivaroxaban or placebo, median INR values (Neoplastin assay) were 2.2 (range: , warfarin/rivaroxaban group A) and 2.3 (range: , warfarin/placebo group B). Six subjects were included in the rivaroxaban or placebo phase with INR slightly below 2.0 (Neoplastin assay on 0d00h00m). For the subjects with INRs below 2.0, the lowest value measured at that time was an INR of 1.9, which was considered appropriate for the start of rivaroxaban/placebo. In the placebo phase of the warfarin/placebo group (B) median INRs decreased steadily over the course of 4 days. Baseline conditions were reached in the morning of Day 4d. Emax of the time vs effect curve reflects the status after warfarin dosing with an increase of INR values 2.25 times baseline. Rivaroxaban alone (C) induced moderate increases of INR up to 1.8 times baseline (Emax of the time vs effect curve) as expected from previous studies with the 20 mg dose. INR returned to baseline 24 hours after dosing. Switching from warfarin to rivaroxaban increased the INR ratio from 2.2 at the end of the warfarin treatment to a maximum of 6.7 times of its normal pre-treatment values at 3 hours after dosing on Day 0d (Emax of the time vs effect curve). Individual absolute INR values in the range of 4.19 to were reached at a time 27 hours after the last dose of warfarin and 3 hours after the first dose of rivaroxaban. PT(INR) values above 3.0 were observed in all 28 subjects on Day 0d and remained above this value for a mean of 12.6 hours. After dosing on the following Day 1d, 25 subjects showed INR values above 3.0 which remained there for Page 8 of 16

10 a mean of 7.5 hours, and 8 subjects showed INR values above 3.0 on Day 2d. After Day 2d, no subject with PT(INR) values greater than 3.0 was observed. The effects of warfarin/rivaroxaban were more than additive but not exponential considering the effects of warfarin/placebo and rivaroxaban alone. Over the course of treatment, median INR values declined and pretreatment baseline conditions after the switch were reached prior to dosing on Day 4d. As expected, PT picks up the effects of both warfarin and rivaroxaban. Table 6 provides an overview of the statistical analysis of the key parameter PT(s). Table 6: Assessment of treatment effects on PT(s), geometric means (treatment effects), LS mean (test/reference), PK/PD set, n=84 The following effects were observed on the secondary PD parameters: Factor Xa inhibition: Warfarin treatment induced a median Factor Xa inhibition of 41% to 42% compared to baseline on 0d00h00m. Under placebo following warfarin, this warfarin induced effect declined over the 4 days of treatment. Rivaroxaban as a 20 mg dose inhibited Factor Xa activity by 50% (Emax of the effect vs time curve), an effect that lasted for about 24 hours after dosing. Rivaroxaban following warfarin led to a maximum inhibition of 76% (Emax). The peak effect of rivaroxaban and warfarin was roughly additive considering the effects of warfarin/placebo and rivaroxaban alone. Trough inhibition of Factor Xa activity prior to dosing with rivaroxaban decreased over the treatment course as the warfarin effect declined. As expected, inhibition of Factor Xa picks up the effects of both warfarin and rivaroxaban. Anti-Factor Xa activity: Warfarin treatment and placebo following warfarin did not affect anti-factor Xa activity. Page 9 of 16

11 Effects of rivaroxaban following warfarin (A) were comparable to effects of rivaroxaban alone (C). With start of dosing, anti-factor Xa activity increased to a maximum of 15.8 times baseline (Emax of the time vs effect curve). The increase was transient with a peak 3 to 4 hours after dosing. Within 24 hours anti-factor Xa activity decreased to 1.5 times baseline. The anti-factor Xa activity test does not pick up the warfarin effect and is therefore capable of monitoring rivaroxaban without warfarin interference. aptt: Warfarin alone prolonged aptt by a median factor of 1.24 to Placebo following warfarin had no additional effect and PT prolongation declined over the course of treatment. Rivaroxaban alone prolonged aptt by a factor of 1.41 times baseline (Emax of the effect vs time curve). The effect returned to pretreatment baseline after 24 hours. After administration of rivaroxaban following warfarin treatment, the maximum aptt prolongation was 1.84 times baseline (Emax of the time vs effect curve), thus additive considering the effects of warfarin/placebo and rivaroxaban alone. Trough aptt prolongations prior to dosing with rivaroxaban decreased over the treatment course up to Day 3d as the warfarin effect declined. HepTest: Warfarin treatment and placebo following warfarin did not affect HepTest. Maximum effects after rivaroxaban alone were HepTest prolongations 2.01 times baseline (Emax of the time vs effect curve), which is in line with the experience from previous studies. The effect was reversed 24 hours after dosing. Rivaroxaban following warfarin induced HepTest prolongations 2.15 times baseline (Emax of the time vs effect curve). Peak prolongations were seen 3 to 4 hours after dosing and returned to pretreatment baseline 24 hours. HepTest does not pick up the warfarin effect and is therefore capable of monitoring rivaroxaban without warfarin interference. PiCT: Warfarin treatment and placebo following warfarin did not affect PiCT. Rivaroxaban alone prolonged PiCT to a maximum of 2.7 times baseline, rivaroxaban following warfarin to 3.2 times baseline (Emax of the time vs effect curve). The peak effect was observed 3 hours after dosing. After 24 hour and prior to the next rivaroxaban dose, PiCT had almost returned to baseline. The PiCT test does not pick up the warfarin effect and is therefore capable of monitoring rivaroxaban without warfarin interference. ETP: Warfarin treatment over 6 days reduced ETP AUC to 0.44 of baseline and ETP peak to 0.45 of baseline. It prolonged ETP lag time by the factor 1.59 and time to peak by the factor 1.30 (median change from baseline). Page 10 of 16

12 Placebo following warfarin led to a recovery of warfarin-induced changes over a period of 5 days. Rivaroxaban alone induced a maximum decrease of ETP AUC to 0.55 of baseline and a maximum decrease of ETP peak to 0.15 of baseline (1/Emax of the time vs effect curve). ETP lag time, and consequently ETP time to peak, were prolonged after rivaroxaban alone by a factor of 2.57 and 3.79 times baseline, respectively (Emax of the time vs effect curve). The effect of rivaroxaban alone was short lasting, but not did not return to pretreatment baseline after 24 hours. After rivaroxaban following warfarin, ETP AUC reduction was pronounced with a maximum of 0.24 of its baseline value (1/Emax of the time vs effect curve). Similar results were obtained for ETP peak: Warfarin/rivaroxaban caused a considerable additional maximal decrease of ETP peak to 0.05 of baseline (1/Emax of the time vs effect curve). With warfarin pretreatment, prolongations of ETP lag time and ETP time to peak were more pronounced than after rivaroxaban alone. The maximal effects for prolongations of ETP lag time and time to peak were 4.0 and 4.2 times baseline. Trough results for all four parameters returned to baseline on Day 5d, that is 48 hours after the last dose of rivaroxaban and 6 days after the last dose of warfarin. Factor VIIa: Warfarin over 6 days reduced Factor VIIa to 0.15 of its baseline values. With placebo following warfarin Factor VIIa recovered over the 5 days observation period. Rivaroxaban alone also decreased Factor VIIa to 0.74 of baseline (1/Emax of the time vs effect curve) for a period up to 8 hours after dosing. Over the course of the rivaroxaban treatment, small decreases were observed after dosing to 0.81 to 0.87 of baseline. Values returned to baseline 24 hours after dosing. Rivaroxaban following warfarin caused an additional decrease of Factor VIIa to 0.08 of baseline (1/Emax of the time vs effect curve). Overall, Factor VIIa activity recovered from warfarin-induced changes over the rivaroxaban treatment period. After each dosing a moderate short-lasting decrease of Factor VIIa activity was observed. Baseline was reached on Day 4d. The effect of treatment with rivaroxaban alone does not necessarily indicate a direct impact of rivaroxaban on factor VII activity. The assay does not measure factor VII activity directly, but rather indirectly via a clotting time involving all factors downstream of Factor VII. Therefore, the effect observed may reflect a sensitivity of the coagulometric assay principle used since this assay relies on the activity of Factor X. Factor IIa: After the last dose of warfarin, Factor IIa content was reduced to 0.36 of its baseline status. During the placebo phase following warfarin, Factor IIa recovered and reached baseline conditions on Day 5d. Rivaroxaban alone did not relevantly affect Factor IIa. Rivaroxaban following warfarin and placebo following warfarin showed similar profiles with Page 11 of 16

13 regard to Factor IIa activity. Pre-treatment conditions were reached by Day 5d, 6 days after the last warfarin dose. This study evaluated the influences of warfarin and rivaroxaban on a wide variety of clotting tests during the switching period from warfarin to rivaroxaban. Relevant agonistic effects were observed for PT, which showed more than additive effects after the switch than expected from results of warfarin/placebo (B) and rivaroxaban alone (C). Other tests like Factor Xa activity inhibition, aptt prolongation and ETP (decrease of AUC and peak height as well as prolongation of ETP lag time and time to peak) showed additive effects during the switching period from warfarin to rivaroxaban. For monitoring of the rivaroxaban effect, the tests for anti-factor Xa activity, PiCT and HepTest are recommendable since they reliably show rivaroxaban effects but do not pick up warfarin effects. In conclusion, it depends on the type of tests that are used to follow the pharmacodynamic effects during the switching period from warfarin to rivaroxaban whether over-additive, additive, or no additive effect was observed.ot applicable Results Summary Safety In this study, 91 healthy male subjects were included in the safety set. In addition to the randomly assigned treatments, subjects who discontinued treatment during the warfarin phase (n=7) were evaluated in a separate group. Drug exposure in this group varied with respect to dose and duration of treatment. For the purpose of presenting safety data, treatment periods of warfarin were combined (n=63) and displayed separately from treatment periods of rivaroxaban following warfarin (A, n=28), of placebo following warfarin (B, n=28) and from rivaroxaban alone (C, n=28). Forty-two of the 91 healthy subjects (46%) reported at least one treatment emergent adverse event. Of these, 89 events were of mild, and 7 of moderate intensity. Drug-related events occurred in 12 of 91 subjects (13%). With respect to treatments, 8% of the subjects experienced at least one treatment-emergent and drug-related adverse event during treatment with warfarin, 21% after rivaroxaban following warfarin, no subject after placebo following warfarin, and 11% of the subjects after rivaroxaban alone. No event was severe or serious and all were resolved by the end of the study. Warfarin-related were single cases of mild and short-lasting abdominal discomfort, diarrhea, and dyspepsia. One subject reported hyperhidrosis with headache. An injection-site hematoma was reported in one subject with a start during warfarin treatment. No clinically significant changes of laboratory parameters were reported. One subject was withdrawn from treatment due to a sustained PT INR value above 3.0. Warfarin treatment was stopped after 5 days, but PT INR did not decrease. After 3 days, the investigator administered Vitamin K. After dosing with rivaroxaban following warfarin, a drug-related alanine transaminase (ALT) elevation occurred which caused premature discontinuation of rivaroxaban treatment. In this case, the subject presented with elevated ALT prior to first dosing with rivaroxaban. As ALT values further increased, rivaroxaban was stopped on Day 3d. ALT values reached a peak of 4.12 times the upper limit of normal (ULN) on Day 5d. After that time, ALT decreased and reached close to normal conditions 18 days after the last dose. The increase was reported as a mild, drug-related adverse event. Page 12 of 16

14 Otherwise, single cases of drug-related mild dizziness with headache, multiple erosions of the tongue and elevated lipase values occurred after rivaroxaban following warfarin. Another case of lipase elevation was reported as non-drug related. Mild bleeding events occurred in 2 subjects and were reported as drug-related gingival bleeding in both cases starting about one day after the first rivaroxaban dose. One of the subjects also developed an injection-site hematoma. All bleeding events were drug-related. Rivaroxaban-related events after rivaroxaban alone included single cases of mild epistaxis, injection-site hematoma, and elevated lipase. Another case of lipase elevation was reported as non-drug related. Drug-related bleeding events were mild and short-lasting nasal bleeding (Medical Dictionary for Regulatory Activities (MedDRA) preferred term: epistaxis) and an injection-site hematoma. Vital signs and ECG assessments were not affected by any of the treatment regimens. In the following (Table 3), drug-related adverse events are presented. The calculation of the relative start refers to the first day of rivaroxaban or placebo administration. This day was considered Day 0 (00d00h00min). Page 13 of 16

15 Table 3: Summary of study drug-related adverse events, safety set, n=91 Page 14 of 16

16 Results Summary Pharmacokinetics Eighty-four subjects were included in the PK set for analysis of their pharmacokinetic data, 56 of them received warfarin in doses of 2.5 to 15 mg over 6 days. Rivaroxaban pharmacokinetic characteristics showed no differences between subjects with (A) and without preceding warfarin treatment (C). 95% confidence intervals calculated for the ratios "warfarin/rivaroxaban"/"warfarin/placebo" of AUC(0-24) and Cmax were completely contained in the reference range for bioequivalence of (0.80, 1.25). Table 4 summarizes the key pharmacokinetic parameters of rivaroxaban as geometric means and coefficients of variation as well as ranges. Table 4: Rivaroxaban pharmacokinetic parameters in plasma following oral administration of 20 mg rivaroxaban after warfarin treatment and rivaroxaban alone, geometric means/%cv (range), PK/PD set, n=56 Terminal half-life was calculated for R- and S-warfarin after the last warfarin dose. No difference was apparent between subjects who received subsequent rivaroxaban and subjects on subsequent placebo. 95% confidence intervals constructed for the ratio "rivaroxaban"/"placebo" of t1/2 were completely contained in the reference range for bioequivalence (0.80, 1.25). Table 5 summarizes key pharmacokinetic parameters of R- and S-warfarin. Table 5: Warfarin pharmacokinetic parameters in plasma following oral administration of warfarin over 6 days at doses of 2.5 to 15 mg od, geometric means/%cv (range), PK/PD set, n=56 Page 15 of 16

17 Conclusion(s) In this study, rivaroxaban was safe and well tolerated. After switching from steady state warfarin to 20 mg rivaroxaban at INR values between 2.0 and 3.0, over-additive agonistic effects were observed for PT(s) and PT(INR). PT prolongation was 4.4 times baseline (45 seconds) after the switch compared to 1.6 times baseline (7 seconds) after rivaroxaban alone (Emax of the effect vs time curve). The combined maximum relative effect of warfarin/rivaroxaban on INR measured by Neoplastin assay was 6.1 times baseline compared to 1.6 times baseline after rivaroxaban alone (median on 0d03h00m). Rivaroxaban enhanced the effect of warfarin on Factor Xa activity, aptt, and ETP. Combined effects were additive for Factor Xa activity and roughly additive for ETP and aptt. Rivaroxaban induced changes were reversible within 24 hours. Warfarin-induced changes were reversed about 4 days after the last warfarin dose. Anti-Factor Xa, HepTest and PiCT were not affected by warfarin. Maximum effects observed in this study after the switch from warfarin to rivaroxaban were increases of anti-factor Xa activity by times baseline (median relative changes), prolongation of HepTest 2.15 over baseline (Emax) and prolongation of PiCT 3.16 over baseline (Emax). Tests of anti-factor Xa, HepTest, and PiCT are capable of detecting rivaroxaban effects independently from warfarin effects. Warfarin treatment reduced Factor VIIa to 0.15 of its baseline value. Rivaroxaban alone also mildly decreased Factor VIIa to 0.74 of baseline (1/Emax). The additional effect of rivaroxaban on the warfarin-induced reduction was small and considered to be due to influences on the assay but not as a true effect. Rivaroxaban had no relevant additional effect on warfarin-induced Factor IIa. Therefore, it depends on the type of tests that are used to follow the pharmacodynamic effects during the switching period from warfarin to rivaroxaban whether over-additive, additive, or no additive effect was observed. Preceding warfarin treatment did not influence the pharmacokinetics of rivaroxaban after switching from warfarin to rivaroxaban. PK parameters, AUC(0-24), and Cmax on the first day of treatment were comparable between rivaroxaban alone and rivaroxaban with preceding warfarin treatment. Rivaroxaban did not influence the terminal half-life of warfarin during switching from warfarin to rivaroxaban. T1/2 of R- and S-warfarin was comparable between subsequent rivaroxaban and placebo. Date Created or Date Last Updated: Publication(s): None 05 MAR 2012 Date of Clinical Study Report: 18 OCT 2010 Page 16 of 16

18 Appendix to Clinical Study Synopsis for study Investigational Site List Marketing Authorization Holder in Germany Name Bayer Pharma AG Postal Address D Berlin Deutschland Sponsor in Germany (if applicable) Legal Entity Name Postal Address Bayer HealthCare AG D-51368, Leverkusen, Germany List of Investigational Sites No Facility Name Street ZIP Code City Country 1 CRS Clinical-Research-Services Mönchengladbach GmbH Hindenburgstrasse Mönchengladbach GERMANY 2 MEDA Manufacturing GmbH, ClinPharmCologne MEDA Manufacturing GmbH ClinPharmCologne Neurather Ring Köln GERMANY Page 1 of 1

19 Appendix to Clinical Study Synopsis Product Identification Information Product Type US Brand/Trade Name(s) Brand/Trade Name(s) ex-us Generic Name Main Product Company Code Drug Xarelto Xarelto rivaroxaban BAY Other Company Code(s) Chemical Description Other Product Aliases IUPAC Name: 5-Chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4- morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2- thiophenecarboxamide Date of last Update/Change: 04 Mar 2013

Clinical Study Synopsis

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