final presentation _ anti-coagulation

8/3/2019 Final Presentation _ Anti-Coagulation

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Update on Newer Anti-

coaguation agentsVishal BarochiaPharmD candidate 2012


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Anti-coagulations by Class


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Newer Agents


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Dabigatran (Pradaxa)


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18,113 patients with A-fib randomized toblinded fixed doses of dabigatran 150 or110mg Vs. unblinded dose adjusted warfarin

Primary endpoint: prevention of Stroke orsystemic embolism, hemorrhagic stroke

Safety outcomes: Bleeding risks

Patient population: The mean age of the patients was 71 years The mean CHADS2 score = 2.1 Previous stroke or transient Ischemic attack

Re-Ly Trial


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Results


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Results


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Primary Efficacy Endpoint: Stroke andSystemic Embolismv PRADAXA was shown to significantly reduce the

incidence of stroke (including hemorrhagic) and

systemic embolism by 35 percent compared towarfarin (PRADAXA 150mg 2.2%/yr; warfarin3.4%/yr; p


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Marketed by:FDA ApprovalClass

Boehringer Ingelheim PharmaceuticlsOctober 2010Direct Thrombin Inhibitor/Factor IIa inhibitor

Indication Reduce the risk of stroke and systemic

embolism in patients with non-valvularatrial fibrilation

Dose Crcl >30 ml/min = 150 mg PO twice dailyCrcl 15-30 ml/min = 75 mg PO twice daily

Crcl


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Dabigatran Interactions


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PRADAXA can be taken with or without foodDO NOT crush, chew or open the capsule.

This medication is good for 60 days after youopen the bottlePradaxa should only be dispensed and storedin the original bottle or blister pack.

Take PRADAXA exactly as prescribed. NEVER

take two doses at the same time unlessinstructed by your doctorDO NOT take PRADAXA while you are onwarfarin (Coumadin, Jantoven)

Inform your doctor about any changes in

Patient education


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OD may lead to hemorrhagic complications

No antidotes available

Management of OD: Excreted primarily via kidney = maintain

adequate diuresis Only 35 % protein bound = Dialysis CAN

work Transfusion of FFP or RBC Activated prothrombin complex concentrates Recombinant factor VIIa Concentrates of coagulation factors II, IX, or X

Overdose/Antidote


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Rivaroxaban (Xarelto)- Bayer healthcare


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Direct Factor Xa inhibitor

Pure ( S)-enantiomer

Insoluble in water and aqueous media

Rivaroxaban

5-Chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide


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RECORD 1

Drug

Dose Durationof

therapy

VTEPrevention study


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Xarelto 10 mg once daily was significantlysuperior to subcutaneous enoxaparin 40 mgin the prevention of VTE in patientsundergoing elective hip replacement

surgery, while maintaining a similar and lowrate of major and non-major bleeding.

RECORD 1

58/1558

18/1558

6/22092/2224


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RECORD 2

Drug

Dose Durationof

therapy

VTEPrevention study


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5 week prophylaxis treatment with onetablet of Xarelto 10 mg once daily wassignificantly more effective than short-termtherapy (2 weeks) with subcutaneous

enoxaparin 40 mg for the prevention of VTEin patients undergoing elective hipreplacement surgery, with a similar and lowrate of major and non-major bleeding

RECORD 2

17/864

81/

869


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RECORD 3

Drug

Dose Durationof

therapy

VTEPreventi

on study


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one tablet of Xarelto 10 mg once daily wassignificantly superior to subcutaneousenoxaparin 40 mg in the prevention of VTE inpatients undergoing elective kneereplacement surgery, while maintaining asimilar and low rate of major and non-majorbleeding

RECORD 3

79/824

166/874

7/12206/1239


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RECORD 4

Drug

Dose Durationof

therapy

VTEPreventi

on study


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In RECORD4, one tablet of Xarelto 10 mgonce daily was non inferior to enoxaparin atthe North American dose of 30 mg twicedaily in reducing the incidence of VTE inadult patients undergoing elective kneereplacement surgery. However Xeralto wasnot superior to enoxaparin 30 mg twice daily.

RECORD 4

97/959 67/

965

4/1580 10/1526


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Approved onCompanyCategory

July 1st 2011Bayer healthcareFactor Xa inhibitor

MOA: Factor Xa inhibition: Highly selective,

direct, antithrombin independent

Indication Prophylaxis for post operative inpatients undergoing knee or hip

replacement surgery

Dose

Administratio

10 mg P.O. once daily

initial dose (as early as) 6 to 10 hours

Rivaroxaban - Basics


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Duration of therapy

Elective hip replacement surgery = 35days (5 weeks)Elective knee replacement surgery = 12days (2 weeks)

Metabolism v CYP3A4 (Major DI), CYP2j2v Oxidation and Hydrolysis

Route of Elimination Urine > feces (50% unchanged)

Protein

Binding

94 - 96 % (mainly albumin)

Rivaroxaban - Basics


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Spinal/Epidural Anesthesia or Puncture +Anticoagulant therapy

Increased risk of epidural and spinal hematomawhich can result in long-term or permanent

paralysis

Recommendations:

Boxed Warning

At lease 18hours

At least 6hoursDose of Rivaroxa

banDose of Rivaroxa

banRemovalof EpiduralCatheter


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Drug Interaction


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Inducers: rivaroxaban concentration Carbamazepine, phenytoin St Johns wort Rifampin

Concomitant use unavoidable: dose to 20mg once daily (take with food)

Inhibitors: rivaroxaban concentration Ketoconazole , Itraconazole

USE: Clarithromycin, erythromycin (clinicallyinsignificant effect)

Ritonavir, conivaptin

Drug interaction:Combined P-gp and CYP3A4


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Renal insufficiency: Avoid use in severe renal impairment Crcl


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Hepatic disease associated withcoagulopathy Child-Pugh Class B and CSevere renal impairment (Crcl < 30 ml/min)Concomitant systemic treatment withstrong inhibitor CYP 3A4 and P-gpDuring Pregnancy and Breastfeeding

Avoid Use

Contraindications Hypersensitivity to active substance or

any excipients Active major bleeding


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PK/PD


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PK/PD


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OD = hemorrhage

Specific antidote NOT available

OD Treatment: Activated charcoal (to reduce absorption)

Dialysis DOES NOT work (due to high plasmaprotein binding)

Overdose and Antidote


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Taken with or without food. You may crushthe tablet and mix with food

Store at room temperature

Take exactly as directed, DO NOT double thedose

Missed dose

Patient Information


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Apixaban (Eliquis)

Pipeline AgentPfizer/Bristol-Myers Squibb


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Apixaban (Eliquis)


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Study Design


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Relatively long half life of the drug

Double blind, double dummy design

Use of encrypted POC INR monitoring

Inclusion of the full risk spectrum of patients

with CHADS2 score of 1.

Important Features of ARISTOTLE


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News Alerts


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Drug Out of pocketCost

Medicarecoverage?

Sales forcast

Warfarin $4 per monthYes $0.4B (2006) $0.2B

(2014)

Pradaxa ~ $250 permonth

Yes By May 2011,5% of usblood thinnermarket

Xarelto ~ $780 permonth

No $100 millionfor approveduse.

Cost Comparison


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Pradaxa (dabigatran etexilate mesylate)capsules for oral use [product information].Ridgefield, CT: Boehringer IngelheimPharmaceuticals Inc, Oct 2010.Connolly SJ, Ezekowitz MD at el, RE-LYSteering Committee and InvestigatorsDabigatran versus warfarin in patients withatrial fibrillation. N Engl J Med.2009;361(12):11391151.Xarelto (rivaroxaban) film coated oral tablets[product information]. Titusville, NJ: JanssenPharmaceuticals, Inc.Eriksson BI, Borris LC, Friedman RJ, et al.Rivaroxaban versus enoxaparin for

Sources


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final presentation _ anti-coagulation

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