RIDGEFIELD, Conn., July 8, 2019 /PRNewswire/ -- Boehringer Ingelheim today announced results from two pediatric studies of Pradaxa®, which were presented at the International Society on Thrombosis and Haemostasis (ISTH) 2019 Congress in Melbourne, Australia.
The Phase IIb/III DIVERSITY study showed Pradaxa to be as effective and to have a comparable safety profile to the current standard of care (SOC) for the treatment of acute venous thromboembolism (VTE) in children. A favorable safety profile for Pradaxa was also established in a second study, the first of its kind to assess a direct oral anticoagulant (DOAC) for the secondary prevention of VTE in children with persistent VTE risk factors.
Current SOC for treatment and prevention of VTE in children have several limitations, including the need for frequent monitoring and non-oral means of administration. The aim of these new Pradaxa studies was to provide additional insight and knowledge on anticoagulation in pediatric patients with VTE, or at risk of recurrent VTE.
"There is a tremendous unmet need for treatments to help manage the risk of venous thromboembolism in pediatric patients," said Mohamed Eid, M.D., M.P.H., M.H.A., vice president, Clinical Development & Medical Affairs, Boehringer Ingelheim Pharmaceuticals, Inc. "We are proud to share the results of these studies, which we believe will help enhance our understanding of the role of anticoagulants in managing venous thromboembolism in pediatric patients."
Pradaxa is not approved in any country for pediatric patients with VTE. The studies form part of the ongoing commitment from Boehringer Ingelheim to expanding scientific knowledge of thrombosis care. The safety and efficacy profile of Pradaxa in adults has been proven and well-documented in the extensive RE-VOLUTION® clinical trial program.
About the DIVERSITY study, Ablisetti M et al The DIVERSITY trial (NCT01895777) is an open-label, randomized, multicenter, Phase IIb/III trial that evaluated the efficacy and safety of Pradaxa vs SOC (low molecular weight heparin or vitamin K antagonist) in children aged from birth to <18 years old with acute VTE requiring anticoagulation therapy for three months.
The combined efficacy endpoint was the proportion of children with recurrent VTE, VTE-related death, and thrombus resolution. The secondary endpoints included safety as determined by bleeding events, and pharmacokinetic/pharmacodynamic relationships.
The results from the DIVERSITY trial demonstrated that Pradaxa was non-inferior to the SOC for pediatric patients at high risk of VTE, with comparable bleeding rates.
About the secondary VTE prevention study, Brandao L et al This open-label, single-arm, prospective cohort, Phase III trial is the first study of its kind to describe outcomes in children treated with a direct oral anticoagulant for secondary VTE prevention. In the study, approximately 200 children received Pradaxa for up to 12 months. The primary endpoints for this study included VTE recurrence, bleeding events and mortality at six and 12 months.
The study showed a low overall frequency of recurrent VTEs and any major bleeding events. Based on these results, the authors concluded that this trial showed favorable safety results with Pradaxa in children with VTE and persistent thrombosis risk factors.
About Pradaxa (dabigatran etexilate mesylate)
Indications and Usage Pradaxa® (dabigatran etexilate mesylate) capsules is indicated:
to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation
for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) in patients who have been treated with a parenteral anticoagulant for 5-10 days
to reduce the risk of recurrence of DVT and PE in patients who have been previously treated
for the prophylaxis of DVT and PE in patients who have undergone hip replacement surgery
IMPORTANT SAFETY INFORMATION ABOUT PRADAXA WARNING: (A) PREMATURE DISCONTINUATION OF PRADAXA INCREASES THE RISK OF THROMBOTIC EVENTS, (B)SPINAL/EPIDURAL HEMATOMA (A) PREMATURE DISCONTINUATION OF PRADAXA INCREASES THE RISK OF THROMBOTIC EVENTS Premature discontinuation of any oral anticoagulant, including Pradaxa, increases the risk of thrombotic events. If anticoagulation with Pradaxa is discontinued for areason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant (B) SPINAL/EPIDURAL HEMATOMA Epidural or spinal hematomas may occur in patients treated with Pradaxa who are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomasmay result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developingepidural or spinal hematomas in these patients include:
use of indwelling epidural catheters
concomitant use of other drugs that affect hemostasis, such as non-steroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants
a history of traumatic or repeated epidural or spinal punctures
a history of spinal deformity or spinal surgery
optimal timing between the administration of Pradaxa and neuraxial procedures is not known
Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary. Consider thebenefits and risks before neuraxial intervention in patients who are or will be anticoagulated.
CONTRAINDICATIONS Pradaxa is contraindicated in patients with: - active pathological bleeding; - known serious hypersensitivity reaction (e.g., anaphylactic reaction or anaphylactic shock) to Pradaxa; - mechanical prosthetic heart valve
WARNINGS & PRECAUTIONS
Increased Risk of Thrombotic Events after Premature Discontinuation Premature discontinuation of any oral anticoagulant, including Pradaxa, in the absence of adequate alternative anticoagulation increases the risk of thrombotic events. If Pradaxa is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant and restart Pradaxa as soon as medically appropriate.
Risk of Bleeding
Pradaxa increases the risk of bleeding and can cause significant and, sometimes, fatal bleeding. Promptly evaluate any signs or symptoms of blood loss (e.g., a drop in hemoglobin and/or hematocrit or hypotension). Discontinue Pradaxa in patients with active pathological bleeding.
Risk factors for bleeding include concomitant use of medications that increase the risk of bleeding (e.g., anti-platelet agents, heparin, fibrinolytic therapy, and chronic use of NSAIDs). Pradaxa's anticoagulant activity and half-life are increased in patients with renal impairment.
Reversal of Anticoagulant Effect: A specific reversal agent (idarucizumab) for dabigatran is available when reversal of the anticoagulant effect of dabigatran is needed:
For emergency surgery/urgent procedures
In life-threatening or uncontrolled bleeding
Hemodialysis can remove dabigatran; however clinical experience for hemodialysis as a treatment for bleeding is limited. Prothrombin complex concentrates or recombinant Factor VIIa may be considered but their use has not been evaluated. Protamine sulfate and vitamin K are not expected to affect dabigatran anticoagulant activity. Consider administration of platelet concentrates where thrombocytopenia is present or long-acting antiplatelet drugs have been used.
Thromboembolic and Bleeding Events in Patients with Prosthetic Heart Valves The use of Pradaxa is contraindicated in patients with mechanical prosthetic valves due to a higher risk for thromboembolic events, especially in the post-operative period, and an excess of major bleeding for Pradaxa vs. warfarin. Use of Pradaxa for the prophylaxis of thromboembolic events in patients with AFib in the setting of other forms of valvular heart disease, including bioprosthetic heart valve, has not been studied and is not recommended.
Effect of P-gp Inducers & Inhibitors on Dabigatran Exposure Concomitant use of Pradaxa with P-gp inducers (e.g., rifampin) reduces exposure to dabigatran and should generally be avoided. P-gp inhibition and impaired renal function are major independent factors in increased exposure to dabigatran. Concomitant use of P-gp inhibitors in patients with renal impairment is expected to increase exposure of dabigatran compared to either factor alone. Reduction of Risk of Stroke/Systemic Embolism in NVAF
For patients with moderate renal impairment (CrCl 30-50 mL/min), reduce the dose of Pradaxa to 75 mg twice daily when dronedarone or systemic ketoconazole is coadministered with Pradaxa.
For patients with severe renal impairment (CrCl 15-30 mL/min), avoid concomitant use of Pradaxa and P-gp inhibitors.
ADVERSE REACTIONS The most serious adverse reactions reported with Pradaxa were related to bleeding.
Most frequent adverse reactions leading to discontinuation of Pradaxa were bleeding & gastrointestinal (GI) events.
Pradaxa 150 mg resulted in higher rates of major and any GI bleeds compared to warfarin.
In patients ≥75 years of age, the risk of major bleeding may be greater with Pradaxa vs warfarin.
Patients on Pradaxa 150 mg had an increased incidence of GI adverse reactions. These were commonly dyspepsia (including abdominal pain upper, abdominal pain, abdominal discomfort, and epigastric discomfort) and gastritis-like symptoms (including GERD, esophagitis, erosive gastritis, gastric hemorrhage, hemorrhagic gastritis, hemorrhagic erosive gastritis, and GI ulcer)
Other Measures Evaluated In NVAF patients, a higher rate of clinical MI was reported in patients who received Pradaxa (0.7/100 patient-years for 150 mg dose) than in those who received warfarin (0.6).
USE IN SPECIFIC POPULATIONS Pregnancy: The limited available data on PRADAXA use in pregnant women are insufficient to determine drug-associated risks for adverse developmental outcomes. Lactation: Breastfeeding is not recommended. Geriatric: Risk of bleeding increases with age.
About Boehringer Ingelheim Pharmaceuticals, Inc. Boehringer Ingelheim Pharmaceuticals, Inc., based in Ridgefield, Conn., is the largest U.S. subsidiary of Boehringer Ingelheim Corporation.
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