PRODU)CT DETAILS 

Name of the drug-      PRAXIBIND

Active ingriendents-   Idarucizumab

FDA approved use-    For use in patients who are taking the antioagulant Pradaxa                                         ( dabigatran ) during emergency situations when there is a                                                need to      reverse Pradaxa's blood thinning effects

Date of Approval         10/16/2015

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use PRAXBIND safely and effectively.

See full prescribing information for PRAXBIND. PRAXBIND® (idarucizumab) injection, for intravenous use

Initial U.S. Approval: 2015

INDICATIONS AND USAGE

­ PRAXBIND is a humanized monoclonal antibody fragment (Fab) 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 (1) 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.

ADVERSE REACTIONS-

• In healthy volunteers, the most frequently reported adverse reactions in greater than or equal to 5% of subjects treated with idarucizumab was headache.

 • In patients, the most frequently reported adverse reactions in greater than or equal to 5% of patients treated with idarucizumab were hypokalemia, delirium, constipation, pyrexia, and pneumonia.

CONTRAINDICATIONS--

­ • None 

WARNINGS AND PRECAUTIONS--

 • Thromboembolic Risk: Reversing dabigatran therapy exposes patients to the thrombotic risk of their underlying disease. Resume anticoagulant therapy as soon as medically appropriate.

• Re-elevation of Coagulation Parameters: In patients with elevated coagulation parameters and reappearance of clinically relevant bleeding or requiring a second emergency surgery/urgent procedure, an additional 5 g dose of PRAXBIND may be considered.

 • Hypersensitivity reactions: Discontinue administration and evaluate.

 • Risks of Serious Adverse Reactions in Patients with Hereditary Fructose Intolerance due to Sorbitol Excipient: Patients with hereditary fructose intolerance may be at risk of adverse reactions.

DOSAGE AND ADMINISTRATION-

­ For intravenous use only

. • The recommended dose of PRAXBIND is 5 g, provided as two separate vials each containing 2.5 g/50 mL idarucizumab.

 • There is limited data to support administration of an additional 5 g of PRAXBIND. 

DOSAGE FORMS AND STRENGTHS-

­ Injection: 2.5 g/50 mL solution in a single-use vial 

PATIENT COUNSELING INFORMATION

Thromboembolic Risk-                                                                                                       Inform patients that reversing dabigatran therapy exposes them to the thromboembolic risk of their underlying disease. To reduce this risk, resumption of anticoagulant therapy should be considered as soon as the patient is sufficiently stable [

Recurrence of Bleeding -                                                                                                Inform patients to get immediate medical attention for any signs or symptoms of bleeding

Hypersensitivity Reactions-                                                                                             Inform patients of signs and symptoms of allergic hypersensitivity reactions such as anaphylactoid reactions that may be experienced during or after injection of PRAXBIND [

Risk of Serious Adverse Reactions-                                                                               in Patients with Hereditary Fructose Intolerance due to Sorbitol Excipient Inform patients with hereditary fructose intolerance (HFI) that PRAXBIND contains sorbitol.

Parenteral administration of sorbitol in patients who have HFI has been associated with reports of hypoglycemia, hypophosphatemia, metabolic acidosis, increase in uric acid, acute liver failure with breakdown of excretory and synthetic function, and death and may occur during or after injection of PRAXBIND

Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, CT 06877 USA US License No. 2006 Product of Germany

CLINICAL PHARMACOLOGY

1. Mechanism of Action-                                                                                            Idarucizumab is a specific reversal agent for dabigatran. It is a humanized monoclonal antibody fragment (Fab) that binds to dabigatran and its acylglucuronide metabolites with higher affinity than the binding affinity of dabigatran to thrombin, neutralizing their anticoagulant effect.

2. Pharmacodynamics -                                                                                                    In healthy subjects aged 45 to 64 years, the plasma concentrations of unbound dabigatran were reduced to below the lower limit of quantification immediately after the administration of 5 g idarucizumab. Subjects’ diluted thrombin time (dTT), ECT, aPTT, thrombin time (TT), and activated clotting time (ACT) parameters returned to baseline levels (see Figure 4 and Figure 5).

This reduction of dabigatran plasma concentration was observed over the entire observation period of at least 24 hours.

3.Geraitric patients-                                                                                                          Similar findings were also observed in elderly subjects (aged 65 to 80 years) as well as subjects with mild and moderate renal impairment 

In a limited number of patients, re-distribution of dabigatran from the periphery to plasma led to re-elevation of dTT, ECT, aPTT, and TT [see Warnings and Precautions (5.2)].

Re-dosing with 2.5 g idarucizumab in 6 healthy subjects aged 45-64 years at 2 months after first infusion revealed no differences in safety and no indication of allergic reactions 

No changes in the pharmacokinetics or pharmacodynamics of dabigatran were noted upon re-initiation 24 hours after the administration of idarucizumab

Cardiac Electrophysiology -                                                                                          Clinical trials with idarucizumab in healthy subjects measured heart rate and electrocardiogram (ECG) parameters (waveform morphology, P wave duration, and PR, QRS, QT, and QTc intervals).

There were no clinically relevant abnormal findings related to ECG.

Drug Interactions-                                                                                                                   In vitro Assessment of Drug Interactions In vitro data suggest that the inhibition of dabigatran by idarucizumab is not affected by coagulation factor concentrates [3- or 4-factor prothrombin complex concentrates (PCCs), activated PCC, or recombinant Factor VIIa].

Assessment of Drug Interactions in Animal Studies -                                                   The potential effect of the binding of idarucizumab to dabigatran in the presence of volume replacement agents (e.g., crystalloids, colloids, and retransfusion of washed red blood cells) was investigated in swine

The results of this study suggest that neutralization of dabigatran anticoagulant activity is not influenced by 50% hemodilution with routinely used volume replacement strategies.

4. Pharmacokinetics-                                                                                                    There were no obvious differences in the idarucizumab plasma concentration time profiles when idarucizumab was administered alone or after pretreatment with dabigatran. A dose-dependent increase in the fraction of unchanged idarucizumab excreted in urine was observed.

Distribution -                                                                                                            Idarucizumab exhibited multiphasic disposition kinetics and limited extravascular distribution. Following the intravenous infusion of a 5 g dose, the geometric mean volume of distribution at steady state (Vss) was 8.9 L (geometric coefficient of variation (gCV 24.8%)).

Elimination-                                                                                                                  Idarucizumab was rapidly eliminated with a total clearance of 47.0 mL/min (gCV 18.4%), an initial half-life of 47 minutes (gCV 11.4%), and a terminal half-life of 10.3 h (gCV 18.9%).

After intravenous administration of 5 g idarucizumab, 32.1% (gCV 60.0%) of the dose was recovered in urine within a collection period of 6 hours and less than 1% in the following 18 hours. The remaining part of the dose is assumed to be eliminated via protein catabolism, mainly in the kidney.

Metabolism-                                                                                                                     Several pathways have been described that may contribute to the metabolism of antibodies. All of these pathways involve biodegradation of the antibody to smaller molecules, i.e., small peptides or amino acids which are then reabsorbed and incorporated in the general protein synthesis. Specific Populations Age, Sex, Race and Body Weight 

 USE IN SPECIFIC POPULATIONS

1. Pregnancy Risk Summary There are no adequate and well-controlled studies of PRAXBIND in pregnant women to inform on associated risks.

Animal reproductive and development studies have not been conducted with idarucizumab. It is also not known whether PRAXBIND can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity.

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

The background risk of major birth defects and miscarriage for the indicated population is unknown.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Clinical Considerations Labor or Delivery PRAXBIND has not been studied for use during labor and delivery. Safety and effectiveness of PRAXBIND during labor and delivery have not been studied in clinical trials.

2. Lactation Risk Summary -                                                                                             There are no data on the effects of PRAXBIND on the breastfed child or on milk production.

It is not known whether idarucizumab is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when PRAXBIND is administered to a nursing woman.

3.Lactation-                                                                                                                           The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for PRAXBIND and any potential adverse effects on the breastfed child from PRAXBIND or from the underlying maternal condition.

4. Pediatric Use-                                                                                                           Safety and effectiveness have not been established in pediatric patients.

5, Geriatric Use -                                                                                                                 A total of 111 (90%) patients treated with idarucizumab in the case series trial were 65 years of age and older, and 74 (60%) were 75 years of age and older.

No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled ou

6. Renal Impairment-                                                                                                         Renal impairment did not impact the reversal effect of idarucizumab 

No dose adjustment is required in renally impaired patients.

7. Hepatic Impairment-                                                                                                        No formal studies of PRAXBIND in patients with hepatic impairment have been conducted.