DRUG INTERACTIONS

 

1. Inhibitors of P-gp

 BEVYXXA is a substrate of P-gp and concomitant use of P-gp inhibitors 

 (e.g., amiodarone, azithromycin, verapamil, ketoconazole, clarithromycin) 

 results in an increased exposure of BEVYXXA 

 

 Reduce the dose of BEVYXXA for patients receiving or starting concomitant

  P-gp inhibitors

 

 Anticoagulants, Antiplatelets, and Thrombolytics

 Co-administration of anticoagulants, antiplatelet drugs, and thrombolytics

  may increase the risk of bleeding. 

  Promptly evaluate any signs or symptoms of blood loss if patients are treated 

  concomitantly with anticoagulants, aspirin, other platelet aggregation inhibitors, 

  and/or NSAIDs

 

U.S. FDA APPROVED  DRUGS DURING 2017

 

Sr.No-  23  

  

Name of the  Drug-      Bevyxxa      

 

Active Ingredient-         Betrixaban                                                                                                                                                                                                                                   Pharmacological Classification- 

 

                       For the propylaxis of venous thromboembolism (VTE) in adult

                       patients hopitalized for an acute medical illness                                        

                                                                                                                                                             

Date of Approval-          06-23-2017

 

 (Ref- FDA approved List 2017)

 

                                                                                                                                              HIGHLIGHTS OF PRESCRIBING INFORMATION 

 

These highlights do not include all the information needed to use BEVYXXA

 safely and effectively. 

See full prescribing information for BEVYXXA.

 

BEVYXXA ™ (betrixaban) capsules, for oral use 

Initial U.S. Approval: 2017

 

 WARNING: SPINAL/EPIDURAL HEMATOMA

 See full prescribing information for complete boxed warning.

 Epidural or spinal hematomas may occur in patients treated with betrixaban 

 who are receiving neuraxial anesthesia or undergoing spinal puncture. 

 

 The risk of these events may be increased by the use of in-dwelling 

 epidural catheters or the concomitant use of medical products affecting hemostasis.

 These hematomas may result in long-term or permanent paralysis. 

 Consider these risks when scheduling patients for spinal procedures. 

 

  INDICATIONS AND USAGE

 

 BEVYXXA is a factor Xa (FXa) inhibitor indicated for the prophylaxis of

 venous thromboembolism (VTE) in adult patients hospitalized for an 

 acute medical illness who are at risk for thromboembolic complications 

 due to moderate or severe restricted mobility and other risk factors for VTE. 

 

 Limitations of Use:

 Safety and efficacy of BEVYXXA have not been established in patients with

 prosthetic heart valves because this population has not been studied. 

 

                                                                                                                                                                                                   

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               

 

ADVERSE REACTIONS 

 

Most common adverse reaction (incidence >5%) is bleeding. 

 CONTRAINDICATIONS

 

 Active pathological bleeding. 

 Severe hypersensitivity reaction to betrixaban BEVYXXA. 

 

 WARNINGS AND PRECAUTIONS 

 

Risk of Bleeding: 

 Can cause serious, potentially fatal bleeding.

 Promptly evaluate signs and symptoms of blood loss. 

 

Severe Renal Impairment: 

 Increased risk of bleeding events; reduce BEVYXXA dose 

 

Concomitant P-gp Inhibitors: 

 Increased risk of bleeding events; reduce BEVYXXA dose 

 

INDICATIONS AND USAGE

 

 BEVYXXA is a factor Xa (FXa) inhibitor indicated for the prophylaxis of

 venous thromboembolism (VTE) in adult patients hospitalized for an 

 acute medical illness who are at risk for thromboembolic complications 

 due to moderate or severe restricted mobility and other risk factors for VTE. 

 

 Limitations of Use:

 Safety and efficacy of BEVYXXA have not been established in patients with

 prosthetic heart valves because this population has not been studied. 

 

 DOSAGE AND ADMINISTRATION

 The recommended dose of BEVYXXA is an initial single dose of 160 mg,

 followed by 80 mg once daily, taken at the same time each day with food.

 The recommended duration of treatment is 35 to 42 days. 

 

 Reduce dose for patients with severe renal impairment. 

 Reduce dose for patients on P-glycoprotein (P-gp) inhibitors.

 

 DOSAGE FORMS AND STRENGTH

 Capsules: 40 mg and 80 mg 

 

 PATIENT COUNSELING INFORMATION

 

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

 

 Risk of Bleeding 

 Advise patients that it might take longer than usual for bleeding to stop, and that 

 they may bruise or bleed more easily when treated with BEVYXXA. 

 

 Instruct patients to report any unusual bleeding to their physician.

 Instruct patients to tell their physicians and dentists that they are taking 

 BEVYXXA, and/or any other products known to affect bleeding 

 (including nonprescription products, such as aspirin or NSAIDs), before any

  surgery or medical or dental procedure is scheduled and before any new 

 drug is taken.

 

 Use in Patients with Severe Renal Impairment

 Advise patients that the risk of bleeding is higher in people who have severe 

 kidney problems (severe renal impairment) 

 

 Spinal/Epidural Hematoma 

 Advise patients having neuraxial anesthesia or spinal puncture to watch for

  signs and symptoms of spinal or epidural hematomas, such as numbness 

 or weakness of the legs, or bowel, or bladder dysfunction 

 

 Instruct patients to contact their physician immediately if any of these 

 symptoms occur.

 

 Pregnancy and Lactation 

 Advise female patients to inform their physicians if they are pregnant

 or plan to become pregnant or are breastfeeding or intend to breastfeed 

 during treatment with BEVYXXA.

 

 How to Take BEVYXXA Instruct patients to take BEVYXXA with food, 

 and instruct patients on what to do if a dose is missed 

 

 Manufactured for:

 Portola Pharmaceuticals, Inc.

 South San Francisco, California 94080 USA

 

 

 CLINICAL PHARMACOLOGY

 

1. Mechanism of Action

 Betrixaban is an oral FXa inhibitor that selectively blocks the active site 

 of FXa and does not require a cofactor (such as Anti-thrombin III) for activity. 

  Betrixaban inhibits free FXa and prothrombinase activity. 

 By directly inhibiting FXa, betrixaban decreases thrombin generation (TG).

  Betrixaban has no direct effect on platelet aggregation.

 

2. Pharmacodynamics

 Inhibition of FXa by betrixaban results in an inhibition of thrombin generation 

 at clinically relevant concentrations, and the maximum inhibition of thrombin

  generation coincides with the time of peak betrixaban concentrations.

 

 Cardiac Electrophysiology

 In a study that evaluated the effect of betrixaban on the QT interval, 

 a concentration-dependent increase in the QTc interval was observed.

 

  Based on the observed concentration-QTc relationship a mean

   (upper 95% CI) QTc prolongation of 4 ms (5 ms) is predicted for 

  80 mg betrixaban and 13 ms (16 ms) for a 4.7-fold increase in exposure 

 

3. Pharmacokinetics

 Within the anticipated therapeutic dose range a two-fold increase in dose 

 resulted in a three-fold increase in exposure in the single ascending dose study.

 A two-fold increase in betrixaban exposure was observed after repeat dosing, 

 and the time to steady-state is 6 days (without an initial loading dose).

 

  Absorption

 The oral bioavailability of betrixaban for an 80 mg dose is 34%, and peak 

 concentrations occurred within 3 to 4 hours. Betrixaban is also a substrate of P-gp.

 

 Effect of Food

 When administered with a low-fat (900 calories, 20% fat) or high-fat

 (900 calories, 60% fat)  meal, Cmax and AUC were reduced as compared to the

  fasting state by an average of 70% and 61% for low-fat and 50% and 48% 

 for high-fat, respectively. The effect of food on betrixaban

 

 PK could be observed for up to 6 hours after meal intake.

 

 Distribution

 The apparent volume of distribution is 32 L/kg. In vitro plasma protein 

  binding is 60%.

 

 Elimination

 The effective half-life of betrixaban is 19 to 27 hours.

 

 Metabolism

 Unchanged betrixaban is the predominant component found in human plasma. 

 Two inactive major metabolites formed by CYP-independent hydrolysis comprise

  the other components in plasma, accounting for 15 to 18% of the circulating 

 drug-related material. 

 

 Less than 1% of the minor metabolites could be formed via metabolism 

 by the following CYP enzymes; 1A1, 1A2, 2B6, 2C9, 2C19, 2D6, and 3A4.

 

  Excretion

  Following oral administration of radio-labeled betrixaban approximately 

 85% of the administered compound was recovered in the feces and 

 11% recovered in the urine.

 

 In a study of 12 intravenous betrixaban a median value of 17.8% of the 

 absorbed dose was observed as unchanged betrixaban in urine.

 

 Specific Populations

 Male and Female Patients

 No clinically significant changes in betrixaban pharmacokinetics were 

 observed between males and females.

 

 Patients with Renal Impairment

 In a dedicated renal impairment study mean AUC0-24 on day 8 was 

 increased by 1.89, 2.27 and 2.63-fold in 

 mild  (eGFRMDRD . 60 to < 90 mL/min/1.73 m2), 

 moderate (eGFRMDRD . 30 to < 60 mL/min/1.73 m2) and 

 severe renal (eGFRMDRD . 15 to < 30 mL/min/1.73 m2) impaired 

 patients respectively compared to healthy volunteers..

 

 Patients with Hepatic Impairment

 Studies with betrixaban in patients with hepatic impairment have not been 

 conducted and the impact of hepatic impairment on the exposure to 

 betrixaban has not been evaluated..

 

 

 USE IN SPECIFIC POPULATIONS

 

1. Pregnancy

 Risk Summary

 There are no data with the use of BEVYXXA in pregnant women, but treatment is 

 likely to increase the risk of hemorrhage during pregnancy and delivery.

 

 Betrixaban was studied in reproductive and developmental toxicology studies

 in rats and rabbits during the period of organogenesis at exposures

 up to 44 times the recommended clinical dose of 80 mg daily. 

 

Although betrixaban was not associated with adverse developmental 

fetal outcomes in animals, maternal toxicity (i.e., hemorrhage) was

identified in these studies.

 

 BEVYXXA should be used during pregnancy only if the potential benefit outweighs

 the potential risk to the mother and fetus.

 Adverse outcomes in pregnancy occur regardless of the health of the mother

 or the use of medications. 

 

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 to 4% and 15 to 20%, respectively.

 

2.Lactation

 Risk Summary

 No data are available regarding the presence of betrixaban or its metabolites

 in human milk, the effects of the drug on the breastfed infant, or the effects 

 of the drug on milk production. 

 

 The developmental and health benefits  of breastfeeding should be considered 

 along with the mothers clinical  need for BEVYXXA and any potential adverse 

 effects on the breast-fed child from BEVYXXA or from the underlying 

 maternal condition.

 

3. Pediatric Use

 Safety and effectiveness in pediatric patients have not been established.

 

4.Geriatric Use

 Of the total number of patients in the APEX clinical study 90% were 65 years

 and over, while 68.6% were greater than or equal to 75 years. 

 No clinically significant differences in safety or effectiveness were 

 observed between older and younger patients.

 

5.Renal Impairment

 Patients with severe renal impairment (CrCl . 15 to < 30 mL/min computed

 by Cockcroft-Gault using actual body weight) may have an increased 

 risk of bleeding events. 

 Reduce the BEVYXXA dose for patients with severe renal impairment. 

 

 Monitor patients closely and promptly evaluate any signs or symptoms

 of blood loss in these patients..

 

 No dose adjustment is needed for mild or moderate renal impairment

 (CrCl > 30 mL/min, computed by Cockcroft-Gault using actual body weight).

 

6.Hepatic Impairment

 BEVYXXA has not been evaluated in patients with hepatic impairment, 

because these patients may have intrinsic coagulation abnormalities. 

 Therefore, the use of BEVYXXA is not recommended in patients with

 hepatic impairment..

 

 OVERDOSAGE

 Overdose of BEVYXXA increases the risk of bleeding