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Azithromycin an increased Risk CV Death ?

Presenter : Mr. THEERASIN YOMA ID .54191014 School of Pharmacy; Eastern Asia University

01148601 seminar; 18/03/15

AGENDA

1

Introduction

2

Background

Azithromycin andRisk of Cardiovascular Death

FAD: Safety Announcement

Cardiovascular Events and Safety Outcomes Associated with Azithromycin Therapy

CONCLUSION

34

5

Case Report 2006-2007

Case Report 2527-2555

2012

2013

2014

THEERASIN YOMA

THAI FDA APPROVE ZITHROMAX (Azithromycin)Capsules 250 mg : 21 Nov 2004

INTRODUCTION Azithromycin

U.S FDA APPROVE ZITHROMAX (Azithromycin)capsules 250 mg: 1 Nov. 1991 ( Discontinued Drug Products)

Tablets 250 mg&600mg : Feb.

&Jun 1996

Tablets 500 mg : May 2002

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OutlineINTRODUCTION

MOA

Azithromycin binds to the 23S rRNA of the bacterial 50S ribosomal subunit.

It blocks protein synthesis by inhibiting the transpeptidation/translocation step of protein synthesis and by inhibiting the assembly of the 50S ribosomal subunit.

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Gram-positive bacteria (+) Staphylococcus aureus Streptococcus agalactiae Streptococcus pneumoniae Streptococcus pyogenes

Gram-negative bacteria (-) Haemophilus ducreyi Haemophilus influenzae Moraxella catarrhalis Neisseria gonorrhoeae

Other bacteria Chlamydophila pneumoniae Chlamydia trachomatis Mycoplasma pneumoniae

INTRODUCTION

Susceptibility

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INTRODUCTION

Indication (U.S FDA)

Acute bacterial sinusitis

Community-acquired pneumonia

Mycoplasma pneumoniae&Streptococcus pneumoniae

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INTRODUCTION

1. Treat LRI for Pt. cant use others drug 2. Treat. non-tuberculous mycobacterium (NTM)3. Azithromycin Dose 2 g O.D For Pt. early syphiliscant use penicillin or Doxycycline or Ceftriaxone

National List of Essential Medicines (Thailand) : 30 2556

Indication[National List of Essential Medicines (Thailand)]

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INTRODUCTION

DOSE & Administration

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INTRODUCTION

ADR

More 1 % : diarrhea/loose stools (4-5%), nausea (3%) and abdominal pain (2-3%)

1% or less : Cardiovascular: Palpitations, chest pain. Gastrointestinal: Dyspepsia, flatulence, vomiting, melena Genitourinary: Monilia, vaginitis and nephritis. Nervous System: Dizziness, headache, vertigo General: Fatigue. Allergic: Rash, pruritus, photosensitivity and angioedema.

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ADR

Post-Marketing Experience: Allergic: Arthralgia, edema, urticaria and angioedema

Cardiovascular : Arrhythmias including ventricular tachycardia and hypotension. There have been rare reports of QT prolongation and torsades de pointes. Gastrointestinal: Anorexia, constipation, dyspepsia, General: Asthenia, paresthesia, fatigue, malaise and anaphylaxisGenitourinary: Interstitial nephritis and acute renal failure

INTRODUCTION

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Presenter Mr. THEERASIN YOMA ID: 54191014 School of Pharmacy; Eastern Asia University

Azithromycin-induced QT prolongation in elderly patient.

BACKGROUND

Russo V, Puzio G, Siniscalchi N.

Acta Biomed. 2006 Apr;77(1):30-2.

P: male patients 65 years old HPI: idiopathic dilated cardiomyopathy.CC: community-acquired pneumonia

Ceftriaxone IV 1 g O.D Azithromycin IV 0.5 g azithromycin oral 0.25 g

BACKGROUND

slightly and disappear

ECG showed QT prolongation off AZT

QT interval returned to the normal value

6 hr

2 Day

THEERASIN YOMA

Presenter Mr. THEERASIN YOMA ID: 54191014 School of Pharmacy; Eastern Asia University

Azithromycin as a cause of QT-interval prolongation and torsade de pointes in the absence of

other known precipitating factors

BACKGROUND

Kezerashvili A, Khattak H, Barsky A, Nazari R, Fisher JD.

J Interv Card Electrophysiol. 2007 Apr;18(3):243-6. Epub 2007 Jun 2

P: Female patient aged 55 Year HPI: hypertension and a pacemaker for intermittent

symptomatic bradycardia. CC: Staphylococcus aureus gentamicin and vancomycin

found to cause TdP again

severe acute renal failure &hemodialysis off genta.

Atypical pneumonia azithromycin 500 mg O.D

QT prolongation and TdP.

7 Day

BACKGROUND

7 Day

Off AZT

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BACKGROUND Spontaneous Reports of Adverse Drug Reaction 2527-2555

BACKGROUNDAgents Associated with Drug-Use Mentions for Chronic Sinusitis and Bronchitis, According to U.S. Office-BasedPhysician Practices (January 2002December 2011)

Cardiovascular Risks with Azithromycin and Other Antibacterial Drugs; Andrew D. Mosholder,(/2013)THEERASIN YOMA

Presenter Mr. THEERASIN YOMA ID: 54191014

01148601 seminar

School of Pharmacy; Eastern Asia University

Azithromycin and Risk of Cardiovascular Death

Wayne A. Ray, Ph.D., Katherine T. Murray, M.D., Kathi Hall, B.S., Patrick G. Arbogast, Ph.D., and C. Michael Stein, M.B., Ch.B.

N Engl J Med 2012;366:1881-90.

Impact factor2014 : 54.42

ALLPPT.com _ Free Powerpoint Templates, Diagrams and Charts

Erythomycin&Clarithromycin(1996-2002)

Increase the risk of serious venticular arrhytmia

associated with an increasedrisk of Sudden cardiac death

Azithromycin (2001-2007)

There are reports of pt. with normal

baseline QT intervals in whom AZT had

arrhytamia-related adverse cardiac

effects

QT prolongationTorsades de pointes polymorphic ventricular tachycardia

Azithromycin

Accumulating evidence

suggests AZT also may

have proarrhythmic

effects

Azithromycin (2009)

FDA Adverse Event

Reporting System

includes 20 reports of

torsades de pointes

BG

BACKGROUND

To assess the knowledge of patients who

took Azithromycin as compared with persons who did not take Antibiotic and with patients who took other selected Antibiotic, have an

increased risk of cardiovascular death, particularly sudden cardiac death.

OBJECTIVE &RESEARCH QUESION

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RESEARCH METHODOLODY

Study Type Retrospective Study , Non-Randomized Comparison Gr.

: Cohort Study

Duration Patients who had been prescribed Azithromycin

between 1992 through 2006 (14 years)

Data Source Persons enrolled in Tennessee Medicaid

Program ; Medicaid pharmacy files

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RESEARCH METHODOLODY(con.)

Study DesignScreen prescribed cohort of persons enrolled in Tennessee Medicaid

Computerized Medicaid Data

Azithromycin Control

Amoxy

VS

Matched control periods & Frequency matchedpropensity score

No ATB Others ATB

Ciproflox.Levoflox.

(347,795)

(1,391,180)

(1,348,672)

(264,626)

(193,906)THEERASIN YOMA

Retrospective: Computerized Medicaid Data

control propensity score

AZT VS NO ATB & other ATB


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ALLPPT.com _ Free Powerpoint Templates, Diagrams and Charts

InCLUSION CRITERIA

30 74 years of age No life- threatening non-cardiovascular Had Not Received a diagnosis of drug abuse Had Not Resided in Nursing Home in last year Had not been hospitalized in the prior 30 day Required at least 365 days at Medical enrollment Regular use of Medical care

** Control (No ATB) add :Could not have uses any study ATB During the period 30 Days.

Eligibility


ExCLUSION CRITERIA

Persons at high risk for death from causes unrelated to a short term effect of proarrhythmic medication

Eligibility


The primary study End points

were Cardiovascular Death

and Dearth from any cause

Study End Points


Means of the

product-limit

method

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Relative risk

STATISTIC ANALYSIS

Cox

regression

models; HR

Risk score

for CVD

All analyses with SAS software, Ver.3.9 All Report P values are 2-side

Poissonregressionmodel

RESULTS Cumulative incidence of Death among Patients during 5-Day Cou

rse of Azithromycin, as Compared with Persons Who Received N

o ATB Treatment and Pt. who took Amoxicillin, According to C

ause of Death

Sig.

Sig.

Sig.

Sig.

No sig.

No sig.

No sig.

No sig.

No sig.

No sig.

RESULTS

Sig. No.Sig.

Sig.

Cumulative Incidence of Cardiovascular Death and Death from

Any Cause among Patients Who Took Azithromycin and Persons Who Did Not Take Study Antibiotics during a 10-Day Period.(Con).

Sig. No.Sig.

Sig.

Sig. No.Sig.

v

RESULTS Cumulative Incidence of Cardiovascular Death and Death from

Any Cause among Patients Who Took Azithromycin and Persons Who Did Not Take Study Antibiotics during a 10-Day Period.

v

Sig. No.Sig.

Sig.

RESULTS Cumulative Incidence of Cardiovascular Death

and Death from Any Cause for Patients Who TookAzithromycin or Amoxicillin during a 10-Day Period

Sig. No.Sig.

Sig.

RESULTS Cumulative Incidence of Cardiovascular Deathand Death from Any Cause for Patients Who TookAzithromycin or Amoxicillin during a 10-Day Period

Sig. No.Sig.

Sig.

RESULTS

Excess Risk of Cardiovascular Death with Azithromycin as Compared with Amoxicillin, According to Decile of Cardiovascular Risk Score

.

59%

245 (63-576)

DISCUSSION

Limitations of study

Matched control periods & Frequencymatched propensity score

Prospective study

Retrospective study

CONCLUSION

During 5 days of azithromycin therapy, there was a smallabsolute increase in cardiovascular deaths.

As compared with amoxicillin, there were 47 additional Cardiovascular deaths per 1 million courses of Azithromycin therapy; for patients in the highest decline of base line risk of cardiovascular disease, there were 245 additional cardiovascular deaths per 1 million

FAD: Safety Announcement WARNINGS!!!

THEERASIN YOMA

Presentor

Mr. THEERASIN YOMA

54191014

01148601 seminar

School of Pharmacy; Eastern Asia University

Cardiovascular Events and SafetyOutcomes Associated with AzithromycinTherapy: A Meta-Analysis of RandomizedControlled Trials

Ziyad S. Almalki, BPharm, PhD student; Jeff Jianfei Guo, BPharm, PhD

Am Health Drug Benefits.2014;7(6):318-328

A meta-analysis

1990 through September 2013.

Identify relevant randomized clinical trials

PT: the risk for CV events : treat. azithromycin therapy orplacebo in Pt. infection or for the secondary prevention of coronary events.

1 End points: mortality, hospitalization, and coronary intervention

RESEARCH METHODOLODY :METHODS

No heterogeneity was observed (I2 = 0%)

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RESEARCH METHODOLODY :METHODS

Flow Diagram of the Articles Reviewed

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The findings in this meta-analysis indicate that thereis no increased risk for mortality or for CV events withthe use of azithromycin therapy among patients enrolledin the treatment or prevention clinical trials included inthis analysis.

Future research considerations are warrantedto study a larger number of patients with preexistingbacterial infection and CV risk factors, and longer follow-up duration of trials is needed to detect any potentiallong-term negative or positive effects, including CV effects,of azithromycin therapy

CONCLUSION

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Selected Randomized Clinical Trials with Azithromycin Therapy

RESULTS

Effect of Azithromycin Treatment on Total Mortality

RESULTS

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Effect of Antibiotic Treatment on Hospitalization rate

RESULTS

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Effect of Antibiotic Treatment on Coronary Intervention rate

RESULTS

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Azithromycin an increased Risk CV Death ?

Presenter : Mr. THEERASIN YOMA ID .54191014 School of Pharmacy; Eastern Asia University

01148601 seminar; 18/03/15

CONCLUSION

Review of Research and case report Azithromycin. it wasfound that azithromycin increased the risk of fatal arrhythmias, specifically QT Prolongation and TdP, especially patientsCardiovascular risk factors. affect increased Risk CV Deathalthough the risk was a small but as a pharmacist It shouldantibiotic smart use in patients for decrease risk CV deathand drug resistant. Consider of Indication, Safety, Efficacy,Cost

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PATSIYAKUN KANITNOI Adviser

ANAN UDOMBHORNPRABHA

Acknowledgement

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Thank You For Attention

THEERASIN YOMA

THEERASIN YOMA

สัมมนา present

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