Information about dabigatran (Pradaxa in Europe, Pradax in Canada) for the prevention of venous thromboembolic events (VTE), from Health Canada.

On June 10, 2008, Health Canada issued a Notice of Compliance to Boehringer Ingelheim Canada Ltd. for the drug product, Pradax.

Pradax contains the medicinal ingredient dabigatran etexilate used in its salt form, dabigatran etexilate mesilate. Pradax is an anticoagulant.

Pradax is indicated for the prevention of venous thromboembolic events (VTE) in patients who have undergone elective total hip replacement or total knee replacement surgery. Dabigatran etexilate is a prodrug which is converted in plasma and liver to the active drug, dabigatran. Dabigatran is a competitive, reversible, direct thrombin inhibitor. Since thrombin enables the conversion of fibrinogen into fibrin during the coagulation cascade, thrombin inhibition prevents the development of thrombus. Dabigatran inhibits free thrombin, fibrin-bound thrombin and thrombin-induced platelet aggregation.

The market authorization was based on quality, non-clinical, and clinical information submitted. The clinical trial database evaluated >8,000 patients in the three Phase III pivotal studies. Each one of the pivotal studies was designed as a non-inferiority study in which dabigatran was compared to enoxaparin. The pre-specified primary efficacy endpoint was total VTE and all-cause mortality. Pradax was found to be non-inferior to enoxaprin in total VTE and all-cause mortality. Similar results were obtained for major VTE and VTE-related mortality. The adverse reactions that were attributed to dabigatran were those of bleeding or signs of bleeding which are typical of an anticoagulant.

Pradax (75 mg and 110 mg, dabigatran etexilate) is presented as capsules. The recommended dose of Pradax is 220 mg once daily taken orally as two capsules of 110 mg in patients with intact renal function. Treatment should normally be initiated within 1-4 hours of completed surgery once hemostasis is secured. Additional dosing guidelines are available in the Product Monograph.

Pradax is contraindicated for patients with known hypersensitivity to dabigatran or dabigatran etexilate or to any ingredient in the formulation or component of the container.

Pradax is also contraindicated for patients with the following conditions:
Severe renal impairment;
Haemorrhagic manifestations, bleeding diathesis, or patients with spontaneous or pharmacological impairment of haemostasis;
Lesions at risk of clinically significant bleeding, e.g. cerebral infarction (hemorrhagic or ischemic) within the last 6 months;
Concomitant treatment with strong P-glycoprotein inhibitors, e.g. quinidine.

Pradax 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 Pradax 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 Pradax is favourable for the prevention of VTE in patients who have undergone elective total hip replacement or total knee replacement surgery.

An excerpt of the Summary Basis of Decision, detailing clinical pharmadynamic and pharmacokinetic aspects, along with recommendations from Health Canada:

3.3 Clinical Basis for Decision
3.3.1 Pharmacodynamics

Dose-escalating studies conducted with patients undergoing primary elective total hip replacement surgery evaluated the pharmacokinetic/pharmacodynamic (PK/PD) characteristics of dabigatran, by determining plasma drug concentrations and coagulation parameter values and correlating these with clinical safety and efficacy. The blood coagulation parameters: activated partial thromboplastin time (aPTT), prothrombin time (PT), as measured by International Normalised Ratio (INR), ecarin clotting time (ECT), and thrombin time (TT) were measured in parallel with the dabigatran plasma concentrations. A correlation between dabigatran plasma levels and the degree of anticoagulant effect, was established as seen by prolongations of aPTT, INR, ECT, and TT. Evidence of a linear relationship was observed between ECT, and TT, whereas aPTT increased in a nonlinear manner with plasma concentrations. A linear relationship between plasma concentration and INR was observed as well, however, this assay lacks sensitivity within a clinically-relevant plasma concentrations range.

3.3.2 Microbiology

Dabigatran etexilate mesilate (the salt form of dabigatran etexilate) was rapidly absorbed and then rapidly converted to its active form, dabigatran. Peak plasma concentrations of dabigatran occurred 1‑2 hours after drug administration in healthy volunteers. The time to reach the peak plasma concentration (tmax) was delayed to approximately 6 hours in the immediate post-operative orthopaedic surgery patient. Administration of food resulted in an increase of the median tmax from 2 to 4 hours post dose, along with an increase in AUC of 27% and Cmax of 9%.

Dabigatran demonstrated low (approx. 35%) and concentration-independent plasma protein binding, resulting in relatively low potential for protein binding displacement interactions. The volume of distribution of dabigatran was 60–70 L, indicating moderate extravascular distribution. The average measured blood cell-plasma ratio of <0.3 demonstrates that dabigatran does not readily penetrate into the red blood cells.

Following oral administration, dabigatran etexilate is rapidly converted by non-specific plasma and hepatic esterases to dabigatran. Dabigatran etexilate was only transiently detectable in plasma. Two intermediates, BIBR 951 CL (an active thrombin inhibitor) and BIBR 1087 SE (inactive), were detectable at very low concentrations for <6 hours following oral dosing of up to 600 mg. Dabigatran is subject to glucuronidation forming pharmacologically active acylglucuronides. The sum of the four dabigatran glucuronide isomers is approximately 20% of the exposure (AUC) of dabigatran.

Following an intravenous dose of radiolabelled dabigatran, 85% of the dose was excreted in the urine within 168 hours in healthy male volunteers. An additional 6% was excreted in the faeces, indicative that dabigatran is primarily cleared by the kidneys. The rate of renal clearance of dabigatran was similar to the glomerular filtration rate which suggests that the drug is eliminated via filtration without any net tubular secretion or absorption.

The excretion of dabigatran into human breast milk was not investigated.
Drug Interaction Studies

The in vitro investigations demonstrated that the human cytochrome P450 system did not play a major role in the metabolism of dabigatran etexilate, and that dabigatran etexilate (not dabigatran) served as a substrate of P-glycoprotein (P-gp). Potent P-gp inducers or inhibitors may affect dabigatran exposure.

Drug interaction studies were performed to assess the effects of dabigatran with pantoprazole, atorvastatin (CYP 3A4 and P-gp substrate), diclofenac (CYP 2C9 substrate, UGT 2B7 substrate, weak inhibitor of UGT 1A1), digoxin (P-gp substrate), amiodarone (CYP 2C9, 2D6 and 3A4 inhibitor, and P-gp inhibitor), and quinidine (P-gp inhibitor). Concomitant use with potent P-gp inhibitors, e.g. quinidine, is contraindicated.
Special Populations

Elderly Patients
An increase in drug exposure (40-60%) was reported in elderly subjects (>65 years of age) compared to younger subjects.

Renal Impairment
Subjects with renal impairment had substantially higher dabigatran exposure and demonstrated a longer half-life of dabigatran because of lower renal clearance of dabigatran compared with the control group with normal renal function. In subjects with severe renal impairment, dabigatran exposure was approximately 6 times higher, necessitating the contraindication of this drug in this patient population. In patients with moderate renal impairment, administration of dabigatran with dose adjustment would be appropriate. Monitoring of renal function during and before exposure to dabigatran should be considered. The low dabigatran clearance in the uraemic patients was expected because renal excretion is the predominant route of elimination for systemic dabigatran.

Hepatic Impairment
Any differences observed between patients with moderate hepatic impairment and healthy control volunteers in the pharmacodynamic studies were not deemed relevant in respect to the pharmacokinetic or pharmacodynamic properties of dabigatran. However, this data is based on limited numbers of patients studied using a single oral dose of 150 mg dabigatran. The use of dabigatran in patients with moderate or severe hepatic impairment is not recommended as they were excluded from clinical studies.

3.3.3 Pharmacokinetics

The clinical trial database included results from >8,000 patients in three randomized, double-blind, parallel group, pivotal Phase III studies. The dabigatran etexilate dose regimens tested in the each of the Phase III studies were 220 mg once daily (QD), and 150 mg QD, each initiated with a half dose on the day of surgery. Enoxaparin was selected as the comparator for the Phase III studies as it is considered to be the standard therapy for venous thromboembolic events (VTE) prevention following major orthopaedic surgery. Two total knee replacement (TKR) studies were carried out, with the REMODEL study that used enoxaparin 40 mg QD as the comparator regimen conducted primarily in Europe, and the REMOBILIZE study that evaluated enoxaparin 30 mg twice daily (BID) in the United States. Another study called RENOVATE conducted in Europe compared the effects of dabigratan with enoxaparin 40 mg QD in patients undergoing total hip replacement (THR).

All of the pivotal studies in the Phase III programme were non-inferiority studies, and the pre-specified composite primary efficacy endpoint was total VTE and all-cause mortality. The composite of major VTE and VTE-related death was a pre-specified secondary endpoint of each of the Phase III studies, as were also each of the individual components of the two composite endpoints, total VTE and all-cause mortality, and major VTE and VTE-related mortality.

Each of the two European pivotal Phase III studies (REMODEL in TKR and RENOVATE in THR) demonstrated the non-inferiority of both doses of dabigatran etexilate studied compared to enoxaparin, 40 mg QD. For the primary endpoint (total VTE and all-cause mortality) and for the secondary endpoint (major VTE and VTE-mortality), the point estimate for the 220 mg dose of dabigatran etexilate was slightly better than the point estimate for enoxaparin, while for the comparison between 150 mg dabigatran etexilate and enoxaparin, enoxaparin was slightly better. This pattern of slightly better results for dabigatran 220 mg QD compared to enoxaparin and slightly worse results for dabigatran 150 mg QD compared to enoxaparin was maintained through all study protocol pre-specified sensitivity analyses, and therefore is considered a robust finding in these studies. The major bleeding and clinically relevant bleeding results were not materially divergent from these reported efficacy results.

The non-inferiority margin in the rate of total VTE and all-cause mortality (the primary endpoint) was not achieved in REMOBILIZE, the North American TKR study. The difference in total VTE rates in this study was primarily driven by a difference in distal DVT. It should be noted that this TKR study differed from the European TKR study in three potentially important ways. First, the time to first oral study medication dose was later in the North American study (in order to be acceptable for U.S. local practice, the protocol specified the initial dabigatran etexilate dosing window as 6-12 hours post-surgery compared to 1-4 hours post-surgery for the EU TKR and THR studies). Second, the treatment duration was longer in the North American study than in the European TKR study, at a protocol-specified duration of 12-15 days, rather than 6-10 for the European TKR study, REMODEL. Third, the comparator dose and regimens were different: i.e., enoxaparin 60 mg daily was administered in divided doses in the North American TKR study, compared to 40 mg given once daily for both EU Phase III studies. It is possible that if dabigatran were to be used 1-4 hours post-surgery, rather than 6-12 hours, greater effectiveness in VTE prevention could be expected. Earlier use at 1-4 hours post-surgery, as used in the European studies, should result in an acceptable risk of bleeding, with benefit approaching that of enoxaparin 30 mg BID, and likely equivalent to or better than enoxaparin 40 mg QD in VTE prevention in TKR. In the REMOBILIZE study that used enoxaparin 30 mg BID as a comparator, substantially lower incidences of the VTE endpoints were seen compared to other similar studies that used enoxaparin 40 mg QD. This is in concordance with the clinical reviewer’s opinion that enoxaparin 30 mg BID results in meaningfully greater anticoagulant effect relevant to VTE prevention than 40 mg QD.

In summary, dabigatran 220 mg QD given 1-4 hours after elective total knee replacement or total hip replacement is an effective option in the prevention of total VTE, major VTE, and VTE-related death.

3.3.4 Clinical Efficacy

The safety database included clinical data from 7,942 patients who received at least one dose of dabigatran etexilate. Results were taken from 30 Phase I studies, two Phase II, and three pivotal Phase III studies in the target indication of prevention of VTE in patients undergoing total hip or knee joint replacement surgery. Of the 7,942 patients who received at least one dose of dabigatran etexilate, 5,419 participated in the Phase III primary VTE prevention programme. More than 3,600 patients received at least 10 days of dabigatran etexilate, and >2,000 patients received at least 28 days of dabigatran etexilate to date.

Overall, the occurrence of total adverse events, adverse events leading to study drug discontinuation, and serious adverse events were similar between the study drug and comparator, for both the treatment period and during the 2-3 month extended follow-up period. The only adverse events clearly associated with dabigatran etexilate, and in which a dose response was observed, were those of bleeding or signs of bleeding, which is to be expected for an anticoagulant. The two dosing regimens of dabigatran etexilate in the pivotal trials were not associated with excess bleeding when compared to enoxaparin. A combination of coagulation laboratory assays (e.g., aPTT, thrombin time, etc.) can be used for a rapid assessment to evaluate if excessive anticoagulant effects of dabigatran are present when severe bleeding occurs. Conservative management including circulatory support with transfusions as needed and diuresis may be recommended.

Dabigatran is excreted primarily through the kidneys. Patients who develop acute renal failure should discontinue Pradax (dabigatran etexilate) therapy as significant drug accumulation can occur. The use of Pradax in patients with severe renal impairment is contraindicated. There is evidence of a linear relationship between degree of renal impairment and plasma concentration of dabigatran following oral administration of dabigatran etexilate. Accordingly, caution should be employed when Pradax is to be used in patients with moderate renal impairment. The degree of renal impairment may be expected to affect the pharmacodynamic effect, along with the risk of bleeding, therefore a baseline assessment of renal function should be undertaken before the initiation of treatment. Furthermore, during treatment periodic monitoring of renal function is advised since dosage adjustments or discontinuation of the study drug may need to be undertaken.

3.4. Benefit/Risk Assessment and Recommendation

3.4.1 Benefit/Risk Assessment

Adequate evidence was submitted to demonstrate the effectiveness of Pradax 220 mg once daily when given orally 1-4 hours after major orthopaedic surgery, in both total knee replacement and total hip replacement in the prevention of total VTE, major VTE, and VTE-related death. A lower dose of Pradax, namely 150 mg once daily, should be considered in patients over the age of 75 years, and should be used in all patients with moderate renal impairment, since these patients have been shown to have elevations in serum concentrations of dabigatran, which may be accompanied with an enhanced risk of bleeding. Use in severe renal impairment is contraindicated due to markedly increased exposure to dabigatran and the consequent increased risk of bleeding.

The only clearly identified safety risk associated with dabigatran etexilate is, as expected, a dose-related increase in total bleeding and major bleeding. Given the effectiveness of Pradax that was demonstrated in prevention of VTE-related adverse events following major orthopedic surgery, the absolute increase in bleeding is not considered materially different from that seen with enoxaparin, the standard comparator treatment used.

In conclusion, Pradax appears to be a useful oral treatment for the prevention of VTE following major orthopedic surgery in patients without severe renal impairment.

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 Pradax is favourable in 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.

Source: Summary Basis of Decision (SBD): PRADAX. Health Canada (PDF full text)

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