FDA Approves Praxbind® (idarucizumab), Specific Reversal Agent for Pradaxa® (dabigatran etexilate mesylate)

Ridgefield, CT, October, 16, 2015 – Boehringer Ingelheim Pharmaceuticals, Inc. today announced the U.S. Food and Drug Administration (FDA) granted approval of Praxbind® (idarucizumab). PRAXBIND is indicated for patients treated with Pradaxa® (dabigatran etexilate mesylate), when reversal of the anticoagulant effects of dabigatran is needed for emergency surgery/urgent procedures or 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.
 

“We are very pleased to offer PRAXBIND, the first specific reversal agent for a novel oral anticoagulant, now approved by the FDA,” said Sabine Luik, MD, senior vice president, Medicine & Regulatory Affairs, Boehringer Ingelheim Pharmaceuticals, Inc. “With this approval, Boehringer Ingelheim is again leading the evolution of anticoagulation care, as we did with the introduction of PRADAXA. While we anticipate that PRAXBIND will be rarely used in clinical practice, the availability of a specific reversal agent has the potential to give physicians and patients added assurance in choosing PRADAXA.”

The FDA granted PRAXBIND Breakthrough Therapy Designation and the application received Priority Review. PRAXBIND was approved under an Accelerated Approval Pathway. The application included data from healthy volunteers as well as results from an interim analysis of the RE-VERSE AD™ trial (NCT02104947). In the studies, the reversal effects of PRAXBIND were evident immediately, within minutes after administration of 5 grams of PRAXBIND. No procoagulant effect was observed after the administration of PRAXBIND.

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 and in the Phase III RE-VERSE AD study were hypokalemia, delirium, constipation, pyrexia and pneumonia.

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

“The emergence of novel oral anticoagulants, or NOACs, marked a significant advancement in anticoagulation care. While general management strategies for NOAC-related bleeding are available, until today, there was no option for specific and immediate reversal of the anticoagulant effect of a NOAC in a patient in rare emergencies where speed matters, such as life-threatening bleeding or the need to quickly perform surgery or interventions,” said Dr. Charles Pollack, lead investigator of RE-VERSE AD, Professor of Emergency Medicine, Sidney Kimmel Medical College, Thomas Jefferson University in Philadelphia. “The availability of PRAXBIND now provides a unique option for reversing anticoagulation in patients taking PRADAXA.”

PRAXBIND will be available from major U.S. hospital pharmacy distributors. Boehringer Ingelheim is committed to making PRAXBIND available as quickly as possible.

About the PRAXBIND Clinical Trial Program
PRAXBIND was discovered and developed by Boehringer Ingelheim scientists. The research program was initiated in 2009, before PRADAXA was launched in the U.S. in 2010.

The company completed three phase I trials of PRAXBIND in healthy volunteers, and included these data in the PRAXBIND biologics license application (BLA) it submitted to the U.S. Food and Drug Administration.

Boehringer Ingelheim is continuing to evaluate PRAXBIND in RE-VERSE AD™, a phase III global study that includes patients taking PRADAXA who have uncontrolled bleeding or require emergency procedures. The study is the first of its kind in patients, and has been underway since May 2014, enrolling patients in more than 35 countries. Data from an interim analysis from RE-VERSE AD was also included in the PRAXBIND application.

About Praxbind® (idarucizumab)

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.

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.

Please see full Prescribing Information.

About Pradaxa® (dabigatran etexilate mesylate) Capsules

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 venous thrombosis and pulmonary embolism in patients who have been treated with a parenteral anticoagulant for 5-10 days;
• to reduce the risk of recurrence of deep venous thrombosis and pulmonary embolism in patients who have been previously treated

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.

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:  There is a specific agent that reverses the anticoagulation effect of PRADAXA in the rare event of an emergency. Hemodialysis can remove dabigatran; however clinical experience for hemodialysis as a treatment for bleeding is limited. Activated prothrombin complex concentrates, recombinant Factor VIIa, or concentrates of factors II, IX or X 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. 

Treatment and Reduction in the Risk of Recurrence of DVT/PE

• For patients with CrCl <50 mL/min, avoid use of PRADAXA and concomitant P-gp inhibitors

ADVERSE REACTIONS
The most serious adverse reactions reported with PRADAXA were related to bleeding.

Drug hypersensitivity reactions were reported in ≤ 0.1% of patients receiving PRADAXA.

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 the Boehringer Ingelheim Cares Foundation Patient Assistance Programs
For more than 125 years, Boehringer Ingelheim has been focused on improving the lives of patients. In keeping with the company commitment to do the most good for the most people, Boehringer Ingelheim works hard to ensure its medicines are accessible to everyone who needs them, including senior citizens and families on limited incomes. The Boehringer Ingelheim Cares Foundation Patient Assistance Programs (BI-PAP) make Boehringer Ingelheim medicines available free of charge to patients who are without pharmaceutical insurance coverage, and who meet certain household income levels.

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 2014, Boehringer Ingelheim achieved net sales of about $ 16.96 billion dollars (13.3 billion euros). R&D expenditure corresponds to 19.9 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.

Related Materials

• PRAXBIND Full Prescribing Information
• Evolution of Anticoagulation Timeline
• Sabine Luik Approval Video
• Dr. Pollack video