Summary Basis of Decision for Xarelto ®
Review decision
The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.
Product type:
Xarelto®
Rivaroxaban, 10 mg, Tablet, Oral
Bayer Inc.
Submission control no: 119111
Date issued: 2009-02-13
Foreword
Health Canada's Summary Basis of Decision (SBD) documents outline the scientific and regulatory considerations that factor into Health Canada regulatory decisions related to drugs and medical devices. SBDs are written in technical language for stakeholders interested in product-specific Health Canada decisions, and are a direct reflection of observations detailed within the evaluation reports. As such, SBDs are intended to complement and not duplicate information provided within the Product Monograph.
Readers are encouraged to consult the 'Reader's Guide to the Summary Basis of Decision - Drugs' to assist with interpretation of terms and acronyms referred to herein. In addition, a brief overview of the drug submission review process is provided in the Fact Sheet entitled 'How Drugs are Reviewed in Canada'. This Fact Sheet describes the factors considered by Health Canada during the review and authorization process of a drug submission. Readers should also consult the 'Summary Basis of Decision Initiative - Frequently Asked Questions' document.
The SBD reflects the information available to Health Canada regulators at the time a decision has been rendered. Subsequent submissions reviewed for additional uses will not be captured under Phase I of the SBD implementation strategy. For up-to-date information on a particular product, readers should refer to the most recent Product Monograph for a product. Health Canada provides information related to post-market warnings or advisories as a result of adverse events (AE).
For further information on a particular product, readers may also access websites of other regulatory jurisdictions. The information received in support of a Canadian drug submission may not be identical to that received by other jurisdictions.
Other Policies and Guidance
Readers should consult the Health Canada website for other drug policies and guidance documents. In particular, readers may wish to refer to the 'Management of Drug Submissions Guidance'.
1 Product and submission information
Brand name:
Manufacturer/sponsor:
Medicinal ingredient:
International non-proprietary Name:
Strength:
Dosage form:
Route of administration:
Drug identification number(DIN):
- 02316986
Therapeutic Classification:
Non-medicinal ingredients:
Film-coating: Ferric oxide red, hypromellose, polyethylene glycol, titanium dioxide
Submission type and control no:
Date of Submission:
Date of authorization:
® XARELTO is a trademark of Bayer AG, used under license by Bayer Inc.
2 Notice of decision
On September 15, 2008, Health Canada issued a Notice of Compliance to Bayer Inc. for the drug product, Xarelto.
Xarelto contains the medicinal ingredient rivaroxaban which is a highly selective, direct, antithrombin independent factor Xa inhibitor with high oral bioavailability.
Xarelto is indicated for the prevention of venous thromboembolic events (VTE) in patients who have undergone elective total hip replacement or total knee replacement surgery.
Factor Xa (FXa) directly converts prothrombin to thrombin which leads to fibrin clot formation and activation of platelets by thrombin. Xarelto selectively inhibits FXa, thereby diminishing thrombin-mediated activation of coagulation.
The market authorization was based on quality, non-clinical, and clinical information submitted. The efficacy and safety of Xarelto were evaluated primarily from two pivotal non-inferiority Phase III studies. In both studies, Xarelto was statistically and clinically superior to the comparator drug in preventing Total VTE and Major VTE in patients who had undergone elective total hip replacement or total knee replacement surgery. The safety profile was generally similar to the comparator drug in these two pivotal studies. However, treatment-emergent bleeding events were slightly numerically higher for Xarelto than that for the comparator which may be due to a more potent antithrombotic effect of Xarelto.
Xarelto (10 mg, rivaroxaban) is presented as tablets. The recommended dose of Xarelto for VTE prevention in patients following elective total hip replacement or elective total knee replacement surgery is one tablet (10 mg) once daily. The duration of treatment depends on the type of surgery. Dosing guidelines are available in the Product Monograph.
Contraindications for Xarelto include the following:
- Hepatic disease (including Child-Pugh Class B and C) associated with coagulopathy and a clinically relevant bleeding risk
- Clinically significant active bleeding, including hemorrhagic manifestations, and bleeding diathesis
- Lesions at increased risk of clinically significant bleeding, e.g., cerebral infarction (hemorrhagic or ischemic) within the last six months, and patients with spontaneous impairment of hemostasis
- Concomitant systemictreatment with strong inhibitors of both the cytochrome P450 enzyme CYP3A4, and the active transporter P-glycoprotein
- Pregnancy
- Nursing women
- Hypersensitivity to Xarelto or to any ingredient in the formulation
Xarelto should be administered under the conditions stated in the Product Monograph taking into consideration the potential risks associated with the administration of this drug product. Detailed conditions for the use of Xarelto are described in the Product Monograph.
Based on the Health Canada review of data on quality, safety, and effectiveness, Health Canada considers that the benefit/risk profile of Xarelto is favourable for the prevention of venous thromboembolic events (VTE) in patients who have undergone elective total hip replacement or total knee replacement surgery.
3 Scientific and Regulatory Basis for Decision
3.1 Quality Basis for Decision
3.1.1 Drug Substance (Medicinal Ingredient)
General Information
Rivaroxaban, the medicinal ingredient of Xarelto, is a direct Factor Xa (FXa) inhibitor. FXa directly converts prothrombin to thrombin through the prothrombin complex which leads to fibrin clot formation and activation of platelets by thrombin. Xarelto selectively inhibits FXa, thereby diminishing thrombin-mediated activation of coagulation.
Manufacturing Process and Process Controls
Rivaroxaban is manufactured via a multi-step synthesis. Each step of the manufacturing process is considered to be controlled within acceptable limits:
- The sponsor has provided information on the quality and controls for all materials used in the manufacture of the drug substance.
- The drug substance specifications are found to be satisfactory. Impurity limits meet International Conference on Harmonisation (ICH) requirements.
The processing steps have been evaluated and the appropriate ranges for process parameters have been established.
Characterization
The structure of rivaroxaban is considered to be adequately elucidated and the representative spectra have been provided. Physical and chemical properties have been described and are found to be satisfactory.
Impurities and degradation products arising from manufacturing and/or storage were reported and characterized. These products were found to be within ICH established limits and therefore, are considered to be acceptable.
Control of Drug Substance
The drug substance specifications used for quality control are considered acceptable.
Copies of the analytical methods and, where appropriate, validation reports are considered satisfactory for all analytical procedures used for release and stability testing of rivaroxaban.
Batch analysis results were reviewed and all results comply with the specifications and demonstrate consistent quality of the batches produced.
The drug substance packaging is considered acceptable.
Stability
Based on the long-term and accelerated stability data submitted, the proposed shelf-life for the drug substance is supported and considered to be satisfactory.
3.1.2 Drug Product
Description and Composition
Xarelto (10 mg rivaroxaban) film-coated tablets are light red, round, biconvex, and have a diameter of 6 mm. Each tablet has the Bayer Cross on one side and 10 and a triangle on the other side. The tablets are supplied in bottles of 50 and 120 tablets, and in blisters of 10, 30, and 100 tablets.
Each tablet contains 10 mg of rivaroxaban and the following non-medicinal ingredients in the tablet core: cellulose microcrystalline, croscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate, and sodium lauryl sulfate. The film-coating consists of ferric oxide red, hypromellose, polyethylene glycol, and titanium dioxide.
All excipients (non-medicinal ingredients) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. The compatibility of rivaroxaban with the excipients is demonstrated by the stability data presented on the proposed commercial formulation.
Pharmaceutical Development
Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review.
Manufacturing Process and Process Controls
The manufacturing process uses conventional manufacturing techniques, namely: mixing, wet granulation, drying, sieving, blending, compression, film-coating, and polishing. The method of manufacturing is considered acceptable and the process is considered adequately controlled within justified limits.
Control of Drug Product
Xarelto is tested to verify that the identity, appearance, content uniformity, dissolution, and levels of degradation products and microbiological impurities are within acceptance criteria. The test specifications and analytical methods are considered acceptable; the shelf-life and the release limits, for individual and total degradation products, are within acceptable limits.
Degradation products were not found; therefore, the specification contains only limits for any unspecified and sum of all degradation products according to ICH (Q3B).
Stability
Based on the long-term and accelerated stability data submitted, the proposed 36-month shelf-life is considered acceptable when Xarelto tablets are packaged in the proposed bottles and blisters, and stored at 15-30°C.
The compatibility of the drug product with the container closure system was demonstrated through stability studies. The container closure system met all validation test acceptance criteria.
3.1.3 Facilities and Equipment
The design, operations, and controls of the facilities and equipment that are involved in the production are considered suitable for the activities and products manufactured.
All of the proposed manufacturing sites comply with the requirements of Division 2 of the Food and Drug Regulations.
All sites are compliant with Good Manufacturing Practices (GMP).
3.1.4 Adventitious Agents Safety Evaluation
The magnesium stearate used in the formulation is from vegetable origin.
The lactose monohydrate used in the formulation is manufactured from food-grade cow's milk sourced from healthy animals in the same conditions as milk collected for human consumption, and therefore is considered acceptable.
3.1.5 Conclusion
The Chemistry and Manufacturing information submitted for Xarelto has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes.
3.2 Non-Clinical Basis for Decision
3.2.1 Pharmacodynamics
Rivaroxaban was shown to be a competitive, selective, and direct FXa inhibitor. It inhibited human FXa with >10,000-fold selectivity compared to other serine proteases, and demonstrated anticoagulant effects in human plasma.
In vivo, rivaroxaban given prophylactically showed dose-dependent antithrombotic activity in both venous and arterial thrombosis models in rats. In addition, oral rivaroxaban (3.0 mg/kg) reduced thrombus growth in a treatment model in rabbits. The antithrombotic effect of rivaroxaban was primarily attributed to the inhibition of FXa. Rivaroxaban did not directly affect platelet aggregation in vitro. Bleeding times in rats and rabbits were not significantly affected at antithrombotic doses below the ED50 (the effective dose for 50% of the population).
The overall results of the safety pharmacology studies with rivaroxaban showed no adverse effects on the central nervous system, cardiovascular and respiratory systems, renal function and metabolism, and gastrointestinal tract. In studies addressing the risk for QT-prolongation in humans, no biologically relevant findings were observed in cardiovascular in vitro and in vivo studies (hERG potassium channel, action potential assay, and ECG recordings of anesthetized dogs).
3.2.2 Pharmacokinetics
Absorption
The absorption of radioactivity after oral administration of radiolabelled rivaroxaban was moderate in rats (approx. 67%) and almost complete in dogs (approx. 92%). Rivaroxaban was rapidly absorbed in rats and dogs. Bioavailability of rivaroxaban in the dose range of the pharmacokinetic (PK) studies was 60% in rats and 60-86% in dogs. The bioavailability values can be fully explained by the extent of absorption and the expected low blood clearance in rats and dogs. The plasma concentrations of rivaroxaban were almost dose-proportional within the dose ranges of the PK studies in rats and dogs.
Distribution
The volume of distribution was moderate, amounting to 0.3 L/kg for rats and to 0.4 L/kg for dogs.
The plasma protein binding of rivaroxaban was moderate to high, concentration- and species-dependent. The fraction unbound to plasma proteins was approximately 1.3% in rats and 10.4% in dogs, at rivaroxaban concentrations between 0.1 to 3 mg/L.
Rivaroxaban-related radioactivity showed moderate tissue affinity in rats. Higher radioactivity concentrations were detected in the excretory organs, liver and kidneys, in comparison with blood, but the majority of the organs and tissues contained radioactivity concentrations similar to blood. Penetration of the blood-brain barrier was very limited. Affinity to melanin-containing tissues was minor. The placental barrier was penetrated to a moderate extent, with lower radioactivity concentrations in all fetal organs and tissues compared to maternal blood concentrations. With the exception of the brain, fetal organ and tissue exposure was lower than the concentrations found in the analogous maternal organs.
The amount of secretion into the milk of lactating rats was low.
Metabolism
In mice, rats, and dogs, the oxidative degradation of the morpholinone moiety was the major site of biotransformation of rivaroxaban. Following oral administration of rivaroxaban, unchanged rivaroxaban was the main compound in plasma at all investigated time points, independent of the species. The most prominent of the identified minor metabolites in plasma was M-1 (morpholinone ring oxidation leading to its cleavage) but no major circulating metabolites were detected in rats or dogs. In mice, the metabolite M-1 was considered as a major metabolite and accounted for 15% of the systemic drug exposure (AUC).
In in vitro investigations, rivaroxaban exhibited no inhibitory and no inductive potential on major human CYP isoforms, and no inhibitory potential on P-glycoprotein. With regard to the potential for CYP-mediated drug-drug interactions between rivaroxaban and potential co-medications, ketoconazole and ritonavir were identified as the most potent inhibitors of the oxidative CYP3A4/3A5-mediated metabolic pathways of rivaroxaban. No interactions were observed with CYP3A4 substrates and only low interaction was observed with moderate CYP3A4 inhibitors.
Excretion
Rivaroxaban and its metabolites were eliminated via the renal and biliary/fecal routes.
3.2.3 Toxicology
Single-Dose Toxicity
Rivaroxaban had low acute toxicity in rodents. No deaths occurred following a single oral dose of 500 mg/kg in mice and rats or following an intravenous injection of 25 mg/kg in mice. These doses represent the maximal doses that could be administered due to the viscosity of the dosing solutions.
Repeat-Dose Toxicity
The principal findings in the oral repeat-dose studies were the prolongation of coagulation representing an expected exaggerated pharmacologic response. Prolongations in prothrombin time and activated thromboplastin time were associated with clinical, hematologic, and pathologic evidence of hemorrhage in dogs. These hemorrhages were life-threatening at higher dose levels and systemic exposures.
Despite prolongation of thromboplastin time, clinical or pathologic evidence of overt hemorrhages generally did not occur in mice and rats, although clinical pathology changes (mildly increased reticulocytes and bilirubin) were suggestive of increased red blood cell turnover presumed to reflect subclinical hemorrhage. However, treatment-related hemorrhage occurred at the higher systemic exposures resulting from intravenous injection of rivaroxaban at 100 mg/kg in rats. Overt hemorrhage occurred in oral reproductive toxicity studies in rats and rabbits, mainly reflecting intrauterine hemorrhage. Hematoma in the testis also occurred in one male rat in the male fertility study.
The repeat-dose oral administration of rivaroxaban at dose levels that resulted in systemic exposures of unbound drug that were large multiples of those anticipated in humans (up to 47-fold in mice, 60-fold in rats, and 66-fold in dogs) did not produce overt target organ toxicity unrelated to hemorrhage in rodents or dogs. Slight to mild transient increases in alanine aminotransferase (ALT) occurred in rats at ≥50 mg/kg/day without evidence of treatment-related histopathologic changes in the liver. Distinct treatment-related increases in transaminases were not identified in the repeat-dose dog studies. However, the relevance of a marked increase in ALT for one dog administered 50 mg/kg/day for 52 weeks was questionable.
Genotoxic/Mutagenic Toxicity
Rivaroxaban was non-genotoxic in the tests for gene mutation in bacteria, in the in vitro chromosome aberration tests, and in the in vivo micronucleus test.
Carcinogenicity
Carcinogenicity data are not required to support the proposed duration of prophylactic administration in humans (up to 35 days). Carcinogenicity studies are ongoing to provide supporting data for long-term use of rivaroxiban for future indications.
Reproductive and Developmental Toxicity
Rivaroxaban administration had no impact on fertility and early embryonic development in rats. Maternal tolerability, as well as embryo-fetal and pre and early postnatal development were impacted due to maternal toxicity. The toxicity in the dams was secondary to effects mainly reflecting the anti-coagulative properties of rivaroxaban. The increased incidence of common fetal malformations in rats and rabbits correlated with and was considered secondary to maternal toxicity. There was no evidence of a primary teratogenic effect in rats or rabbits. In any event, rivaroxaban is contraindicated in pregnancy in view of the propensity to cause bleeding.
3.2.4 Summary and Conclusion
The pharmacology and toxicology studies support the use of Xarelto for the proposed indication.
Rivaroxaban is an oral, direct FXa inhibitor that inhibited thrombus formation in established rat, mouse, and rabbit models at doses that did not increase bleeding times. An extended battery of safety pharmacology studies with special emphasis on cardiac safety and hemostasis revealed no rivaroxaban-related adverse findings.
A comprehensive program of non-clinical toxicology studies has been conducted to support the submitted new drug submission for rivaroxaban. Studies have been conducted to satisfactory scientific standards and no unanticipated toxicities have emerged that would preclude the intended clinical usage for rivaroxaban.
3.3 Clinical basis for decision
3.3.1 Pharmacodynamics
In the Phase I dose escalation studies, rivaroxaban inhibited FXa in a dose-dependent manner closely following the pharmacokinetic profile. Other global clotting tests were also affected in a dose-dependent way. The most sensitive test which followed a linear correlation to plasma concentration was prothrombin time (PT) when using Neoplastin®. Although the activated partial thomboplastin time (aPTT) and HepTest® were also prolonged dose-dependently, their correlations to plasma concentrations either did not discriminate well due to a flat slope of the correlation curve or due to a curvilinear relationship. Therefore, both parameters are not considered optimal to assess the pharmacodynamic effects. Rivaroxaban had no influence on anti-thrombin III or Factor IIa activity thus supporting its selectivity for Factor Xa.
Results of investigations of the ETP (endogenous thrombin potential) have shown that rivaroxaban influences both the intrinsic and extrinsic pathways of the coagulation cascade. A prolonged influence of rivaroxaban beyond 24 hours was observed at the peak level of ETP, suggesting that pharmacological effects may be present beyond 24 hours after doses of 30 mg.
3.3.2 Pharmacokinetics
Absorption
Rivaroxaban tablets were rapidly absorbed with a maximum plasma concentration 2-4 hours after oral administration. Administration of the 10 mg tablet with food resulted in no significant food effects. The rivaroxaban plasma concentrations increased dose-proportionally up to a dose of 15 mg. Oral bioavailability of rivaroxaban was high (approx. 100%) for the 10 mg dose. No evidence of relevant accumulation occurred after multiple doses.
Distribution
The volume of distribution was moderate, and the plasma protein binding was high, with albumin being the main binding protein in human plasma. The fraction unbound to human plasma proteins was 5.1%.
Metabolism
Rivaroxaban is metabolized by the liver through the cytochrome P450 system. The oxidative degradation was catalyzed by the isozymes CYP3A4/3A5 and CYP2J2. Hydrolysis of the amide bonds also contributed to the biotransformation.
Unchanged rivaroxaban was the most important component in human plasma, and its metabolite M-1 was the main metabolite identified in the excreta. No major or active circulating metabolites were present.
Excretion
Rivaroxaban and its metabolites were excreted via the renal and biliary/fecal routes.
Drug Interactions
Due to the involvement of both CYP3A4/3A5 in rivaroxaban oxidative metabolism and P-gp (P-glycoprotein) and Bcrp (breast cancer resistance protein) in its active renal secretion, drugs that are strong inhibitors or inducers of these enzymes and/or transporter proteins have the potential to influence rivaroxaban plasma concentration. Concomitant systemic use of the strong inhibitors of both CYP3A4 and P-gp, such as ketoconazole or ritonavir, increased rivaroxaban plasma concentrations (AUC and Cmax) to a clinically relevant degree which may lead to an increased bleeding risk. Rifampicin, classified as a strong CYP3A4 and P-gp inducer, significantly reduced rivaroxaban plasma exposure by 50%.
Special Populations
Hepatic Insufficiency
Patients with moderate liver cirrhosis showed a 2.3 fold increase in AUC compared to healthy volunteers.
Patients with severe liver cirrhosis and severe liver impairment leading to coagulopathy and bleeding risk were not studied in the clinical studies, therefore Xarelto is contraindicated in patients with hepatic disease (including Child Pugh Class B and C) associated with coagulopathy and a clinically relevant bleeding risk.
Renal Insufficiency
A single Phase I study in subjects given a single oral dose of 10 mg rivaroxaban showed that subjects with mild, moderate, and severe renal impairment (creatinine clearance 50-79, 30-49 and <30 mL/min, respectively) had AUC increased by 1.4, 1.5 and 1.6-fold, increased inhibition of FactorXa activity by 1.5, 1.9 and 2.0-fold; and increased prothrombin time by 1.3, 2.2 and 2.4-fold, respectively, compared to subjects with no impaired renal function. However in the three Phase III studies, bleeding in patients with impaired renal function (mild to moderate impairment) was not different from patients with normal creatinine clearance. Based on these results, and given that patients with severe renal impairment were excluded from the Phase III studies, the uncertainty regarding the use of Xarelto in such patients was addressed by having the Product Monograph state that Xarelto is not recommended in patients with severe renal impairment and that it should be used with caution in patients with reduced renal function.
3.3.3 Clinical Efficacy
The clinical efficacy of Xarelto (rivaroxaban) for the prevention of venous thromboembolic events (VTE) in patients who have undergone elective total hip replacement (THR) or total knee replacement surgery (TKR) was evaluated in three Phase III studies (RECORD 1, 2 and 3), and four dose-ranging Phase II studies.
Both RECORD 1 and RECORD 3 were randomized, double-blind, double-dummy, multicentre, multinational studies. RECORD 1 (n=4541) was conducted in patients undergoing elective THR surgery while RECORD 3 (n=2531) was conducted in patients undergoing elective TKR surgery. In both studies, Xarelto 10 mg once daily (OD, first dose administered 6-8 hours post-operatively) was compared with subcutaneous enoxaparin 40 mg OD (first dose administered 12 hours pre-operatively). The enoxaparin dose used in the studies was a lower dose than what is authorized in Canada. The dose of enoxaparin authorized for use in thromboprophylaxis in conjunction with elective THR or TKR surgery in Canada is subcutaneous 30 mg twice daily with the first dose administered 12 to 24 hours post-operatively. Studies comparing the safety and efficacy of the lower dose of enoxaparin used in the studies versus the higher authorized Canadian dose were not available.
The primary endpoint was total VTE, which was the composite of any deep vein thrombosis (DVT, distal or proximal), non-fatal pulmonary embolism (PE), and death from all causes. The main endpoint was major VTE which was the composite of proximal DVT, non-fatal PE, and VTE-related death.
In RECORD 1 and RECORD 3, Xarelto was statistically and clinically superior to enoxaparin in preventing total VTE and major VTE. Based on the primary endpoint, both studies met their pre-specified non-inferiority and superiority objectives compared to enoxaparin. Most components of the primary composite endpoint were reduced in the presence of Xarelto compared with enoxaparin, including proximal DVT, distal DVT, and VTE-related death. These findings on the primary efficacy variables were corroborated with sensitivity testing and are consistent with results from other rivaroxaban studies. Analyses of the secondary efficacy parameters also favoured Xarelto over enoxaparin. Specifically, with the main secondary endpoint (incidence of the composite endpoint comprising proximal DVT, non-fatal PE, and VTE-related death) there was a lower incidence in patients treated with Xarelto compared to enoxaparin (0.2% vs. 2.0% for RECORD 1, and 1.0% vs. 2.6% for RECORD 3) demonstrating superiority over enoxaparin. Relative risk reductions in total VTE in comparison to enoxaparin were 69.7% (RECORD 1) and 49.3% (RECORD 3) in comparison to enoxaparin.
In the Phase III study, RECORD 2 (n=2509), the safety and efficacy results were not directly comparable because of the different treatment duration in the Xarelto group and enoxaparin group. Xarelto was administered for 35 ± 4 days (as done in RECORD 1) while enoxaparin was administered for only 10-14 days. However, the results obtained in RECORD 2 were in agreement with those for RECORD 1.
3.3.4 Clinical Safety
The clinical safety of Xarelto was predominately evaluated from the two pivotal Phase III studies, RECORD 1 and RECORD 3. The Phase III study, RECORD 2, and the Phase II dose-ranging studies provided supporting data for the safety profile of Xarelto. In RECORD 1, patients undergoing THR were treated with Xarelto 10 mg OD orally (n=2209 patients) or the comparator drug enoxaparin 40 mg OD subcutaneously (n=2224 patients). The treatment period for both groups was 35±4 days post-operatively. In RECORD 3, the study population consisted of patients undergoing TKR surgery. A total of 1220 patients were treated with Xarelto 10 mg OD orally and 1239 patients were treated with enoxaparin 40 mg OD subcutaneously. Both groups received the study drug for 12±2 days post-operatively. In RECORD 1 and RECORD 3, the safety profile of Xarelto was generally similar to that of the comparator drug, enoxaparin. However, the incidence of treatment-emergent bleeding events was slightly higher for Xarelto than that for the comparator drug enoxaparin, which may be due to a more potent antithrombotic effect of Xarelto.
Bleeding Events
In RECORD 1, the incidence of treatment-emergent major and non-major clinically relevant bleeding events was numerically higher in the Xarelto group (3.2% Xarelto vs. 2.5% enoxaparin), as well as all treatment-emergent bleeding events (6.0% Xarelto vs. 5.9% enoxaparin) were numerically slightly higher for the Xarelto group. The incidence of treatment-emergent major bleeding events was numerically higher for the Xarelto group compared to the enoxaparin group (0.3% Xarelto vs. 0.1% enoxaparin). The rates of major bleedings including surgical site bleedings associated with a fall in hemoglobin ≥2 g/dL or leading to infusion of ≥2 units whole blood/packed cells, were numerically higher in the Xarelto group than the enoxaparin group (1.8% vs. 1.5%).
In RECORD 3, the incidence of treatment-emergent major bleeding events in both treatment groups was <1%, and no fatal bleeding events were reported. The incidence of major or non-major clinically relevant bleeding events and all bleeding events (major and non-major) was similar between the two groups. In general, the incidence of treatment-emergent and treatment-related adverse events, including those that were serious, was similar between the two treatment groups; however there were fewer deaths in the Xarelto group than in the enoxaparin group (0 versus 6, respectively).
Liver Function and Thrombocytopenia
In RECORD 1, the incidence rates of abnormal liver function tests and thrombocytopenia were similar in both treatment groups. Some patients in each drug group experienced abnormal liver enzyme elevations and one case of thrombocytopenia was reported in each group. The number of patients in this study with significant post-operative abnormalities in liver function tests and platelets was too small for a 35-day study to draw a conclusion regarding any potential effect of either study drug on hepatic function. Further evaluation of liver function tests in a larger number of subjects is planned using an integrated analysis.
In RECORD 3, the liver enzyme elevations appeared to be similar between the treatment groups and transient, with results returning to normal range prior to the end of the study except for one of the Xarelto patients who had an ALT (alanine transaminase) elevation >3X the upper limit of normal. The number of patients with significant post-operative abnormalities in liver function tests was too small to draw a conclusion regarding any potential effect of either study drug on hepatic function.
3.4 Benefit/Risk Assessment and Recommendation
3.4.1 Benefit/Risk Assessment
Adequate evidence was submitted to demonstrate the effectiveness of Xarelto 10 mg OD when given orally to prevent venous thromboembolic events (VTE) in patients who have undergone elective total hip replacement or total knee replacement surgery. In the pivotal studies, Xarelto was statistically and clinically superior to enoxaparin in preventing total VTE and major VTE. The safety profile of Xarelto was generally similar to that of the comparator drug, enoxaparin. However, the incidence of treatment-emergent bleeding events was slightly higher for Xarelto than that for the comparator drug enoxaparin, which may be due to a more potent antithrombotic effect of Xarelto.
Overall, the studies demonstrated that Xarelto was well-tolerated and associated with a manageable safety profile. Based on the safety and efficacy profile, the benefits of Xarelto therapy seem to outweigh the risks. Restrictions to manage risks associated with the identified safety concerns have been incorporated into the Xarelto Product Monograph.
3.4.2 Recommendation
Based on the Health Canada review of data on quality, safety, and effectiveness, Health Canada considers that the benefit/risk profile of Xarelto is favourable for the prevention of venous thromboembolic events in patients who have undergone elective total hip replacement or total knee replacement surgery treatment. The New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations.
4 Submission Milestones
Submission Milestones: Xarelto®
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting: | 2007-10-17 |
| Submission filed: | 2007-12-31 |
| Screening | |
| Screening Acceptance Letter issued: | 2008-01-29 |
| Review 1 | |
| Quality Evaluation complete: | 2008-07-22 |
| Clinical Evaluation complete: | 2008-09-10 |
| Labelling Review complete: | 2008-09-10 |
| NOC issued by Director General: | 2008-09-15 |