Updated Phase III Results Reinforce Safety and Efficacy of Praxbind® (idarucizumab) in Urgent Situations

RIDGEFIELD, Conn., Nov. 15, 2016 /PRNewswire/ -- Boehringer Ingelheim Pharmaceuticals, Inc. today announced updated results from data for 494 patients participating in the ongoing phase III RE-VERSE AD™ study, which showed that administration of 5g of idarucizumab immediately reversed the anticoagulant effect of dabigatran, the active ingredient in Pradaxa® (dabigatran etexilate mesylate). Idarucizumab, marketed in the U.S. as Praxbind®, is the first specific reversal agent for a novel oral anticoagulant (NOAC) approved by the U.S. Food and Drug Administration (FDA), and RE-VERSE AD is the largest patient study investigating a reversal agent for a NOAC. The updated results from this expanded interim analysis were presented today at the American Heart Association (AHA) Scientific Sessions 2016 in New Orleans, Louisiana.

RE-VERSE AD includes the types of patients healthcare professionals may treat in real world emergency settings. The study enrolled patients treated with dabigatran who had uncontrolled or life-threatening bleeding (Group A, n=298, 60%) or required emergency surgery or an invasive procedure (Group B, n=196, 40%). This includes severely ill or injured patients (e.g., patients in an automobile accident with multiple injuries, patients with aortic aneurysm, patients receiving an organ transplant) who as such require urgent reversal of dabigatran.

The primary endpoint of reversal of the anticoagulant effect of dabigatran within four hours was 100 percent, as measured by diluted thrombin time (dTT) and ecarin clotting time (ECT) (95% CI, 100-100). Of note, reversal was evident immediately after administration of idarucizumab. For Group A patients with extracranial bleeding, median time to confirmation of hemostasis was 3.5 to 4.5 hours, depending on anatomical location. The source of bleeding was similar to the previous interim analysis (45% GI, 33% ICH). In Group B, 93 percent of patients experienced normal hemostasis during surgery, and the median time to the operating room was 1.6 hours after administration of idarucizumab.

No safety signals attributed to idarucizumab were detected. All serious adverse events reported were considered to be related to the index event or comorbidities rather than to study treatment. Thrombotic events occurred in 6.3 percent (31/494) of patients within 90 days after idarucizumab administration. Approximately two-thirds of these patients received no anticoagulation prior to the event. Mortality rates were 12.3 percent (Group A) and 12.4 percent (Group B) at 30 days, and 18.7 percent (Group A) and 18.5 percent (Group B) at 90 days.

"The availability of idarucizumab as a reversal agent for dabigatran is an important development in anticoagulation care, and RE-VERSE AD is the most robust examination of its real-world use and impact," said Dr. Charles Pollack, lead investigator of RE-VERSE AD, Professor of Emergency Medicine, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia. "These results further support that, although idarucizumab is likely to be rarely used, a specific reversal agent provides an important therapeutic option for physicians and patients."

"The growing body of evidence for idarucizumab adds to Boehringer Ingelheim's legacy of firsts in cardiovascular disease," said Sabine Luik, MD, senior vice president, Medicine & Regulatory Affairs, Boehringer Ingelheim Pharmaceuticals, Inc. "We believe this research and these results help drive our understanding of the contribution of idarucizumab for patient care."

About RE-VERSE AD™
RE-VERSE AD is an ongoing phase III global study that includes patients taking PRADAXA who require urgent procedures or have uncontrolled bleeding. The primary endpoint was the maximum percentage reversal of the pharmacodynamic anticoagulant effect of dabigatran within 4 hours after the administration of idarucizumab, based on central laboratory determination of dTT or ECT.

The study is the first of its kind in patients, and has been underway since May 2014, enrolling up to 500 patients in more than 35 countries.

There are serious risks to consider when treating patients with PRAXBIND, including warnings and precautions for thromboembolic risk, re-elevation of coagulation parameters, hypersensitivity reactions and risks of serious adverse reactions in patients with hereditary fructose intolerance due to sorbitol excipient. The most frequently reported adverse reactions (≥5%) in PRAXBIND-treated healthy volunteers was headache (12/224, 5%) and in the Phase III RE-VERSE AD study in patients were hypokalemia (9/123, 7%), delirium (9/123, 7%), constipation (8/123, 7%), pyrexia (7/123, 6%) and pneumonia (7/123, 6%).

Please see more complete details of these risks in the "About PRAXBIND" section.

About Praxbind® (idarucizumab)

INDICATIONS AND USAGE
PRAXBIND is indicated in patients treated with Pradaxa® when reversal of the anticoagulant effects of dabigatran is needed:

• For emergency surgery/urgent procedures
• In life‐threatening or uncontrolled bleeding

This indication is approved under accelerated approval based on a reduction in unbound dabigatran and normalization of coagulation parameters in healthy volunteers.  Continued approval for this indication may be contingent upon the results of an ongoing cohort case series study.

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS
Thromboembolic Risk

• Dabigatran-treated patients have underlying diseases predisposing them to thromboembolic events.  Reversing dabigatran therapy exposes patients to the thrombotic risk of their underlying disease.  To reduce this risk, resumption of anticoagulant therapy should be considered as soon as medically appropriate.

Re-elevation of Coagulation Parameters

• Elevated coagulation parameters (e.g., activated partial thromboplastin time or ecarin clotting time) have been observed in a limited number of PRAXBIND-treated patients.  If reappearance of clinically relevant bleeding together with elevated coagulation parameters is observed or if patients requiring a second emergency surgery/urgent procedure have elevated coagulation parameters, an additional full dose may be considered.

Hypersensitivity Reactions

• There is insufficient clinical experience evaluating risk of hypersensitivity to idarucizumab, but a possible relationship could not be excluded.  Risk of hypersensitivity (e.g., anaphylactoid reaction) to idarucizumab or excipients needs to be weighed cautiously against the potential benefit.  If serious allergic reaction occurs, immediately discontinue PRAXBIND and institute appropriate treatment.

Risk in Patients with Hereditary Fructose Intolerance

• PRAXBIND contains 4 g sorbitol as an excipient.  When prescribing PRAXBIND in patients with hereditary fructose intolerance consider the total daily amount of sorbitol/fructose consumption from all sources as serious adverse reactions (e.g. hypoglycemia, hypophosphatemia, metabolic acidosis, increase in uric acid, acute liver failure and death) may occur.

ADVERSE REACTIONS

• The most frequently reported adverse reaction in ≥5% of idarucizumab-treated healthy volunteers was headache (12/224).   The most frequently reported adverse reactions in ≥5% of patients were hypokalemia (9/123), delirium (9/123), constipation (8/123), pyrexia (7/123) and pneumonia (7/123). 
• As with all proteins there is a potential for immunogenicity with idarucizumab.  In treated patients, treatment-emergent antibodies with low titers were observed (9/224).

USE IN SPECIFIC POPULATIONS

Pregnancy and Nursing Mothers

• PRAXBIND should be given to a pregnant or nursing woman only if clearly needed.

Please see full Prescribing Information.

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

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 a reason 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 hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural 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 the benefits 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).

Please see full Prescribing Information, including boxed WARNING and Medication Guide.

About Boehringer Ingelheim
Boehringer Ingelheim Pharmaceuticals, Inc., based in Ridgefield, CT, is the largest U.S. subsidiary of Boehringer Ingelheim Corporation.

Boehringer Ingelheim is one of the world's 20 leading pharmaceutical companies. Headquartered in Ingelheim, Germany, the company operates globally with 146 affiliates and more than 47,000 employees. Since its founding in 1885, the family-owned company has been committed to researching, developing, manufacturing and marketing novel treatments for human and veterinary medicine.

Boehringer Ingelheim is committed to improving lives and providing valuable services and support to patients and families. Our employees create and engage in programs that strengthen our communities. To learn more about how we make more health for more people, visit our Corporate Social Responsibility Report.

In 2015, Boehringer Ingelheim achieved net sales of about $15.8 billion (14.8 billion euros). R&D expenditure corresponds to 20.3 percent of its net sales.

For more information please visit www.us.boehringer-ingelheim.com, or follow us on Twitter @BoehringerUS.

Boehringer Ingelheim Pharmaceuticals, Inc. either owns or uses the trademarks Pradaxa®, Praxbind® and RE-VERSE AD™ under license.

SOURCE Boehringer Ingelheim Pharmaceuticals, Inc.

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