Transcript Adverse Drug Reactions

Adverse Drug Reactions
Jerrold H. Levy, MD
Professor of Anesthesiology
Emory University School of Medicine
Director of Cardiothoracic Anesthesiology
Emory Healthcare
Atlanta, Georgia
Introduction
• Any drug can cause an ADR
• Perioperatively, multiple agents
are administered
• Occult antigens pose major
problems (ie, latex, additives)
• Fatal ADRs leading cause of death
• ADR costs may lead to an
additional $1.56-$4 billion/yr in US
Incidence of Reactions
• 5% adults in US are allergic to
• >1 drugs
• 30% of medical inpatients develop
an ADR
• 3% of all hospital admissions are
due to ADRs
• Risk of an allergic reaction is
approximately 1-3% for most drugs
WHO Definition of ADRs
Any noxious, unintended, undesired
effect of a drug which occurs at doses
used for prophylaxis, diagnosis, or
therapy, excluding therapeutic failures,
intentional and accidental overdose
and drug abuse, and does not include
AEs due to errors in drug
administration.
PREDICTABLE REACTIONS
• Dose dependent
• Related to drug’s actions
• Occur in normal patients
• 80% of adverse effects
PREDICTABLE REACTIONS
• Overdosage or toxicity
• Side effects
• Secondary/Indirect effects
• Drug interactions
UNPREDICTABLE
REACTIONS
• Dose-independent
• Not related to drug’s actions
• Related to immune response
(allergy)
Safety and Pharmaceutical Agents
•Safety and efficacy must be shown for
a drug to be FDA approved
•Costs also drive considerations of how
drugs are used in clinical practice or
approved by regulatory agencies
•Generic drugs can be approved
without rigorous testing required of
new drugs tested in clinical studies
Safety and Pharmaceutical Agents (2)
• Costs also determine the use of
pharmaceutical agents.
• Clinicians may accept the lack of
safety data when one agent is
significantly cheaper to use.
• Safety data incurs significant costs
• Significant costs are associated with
severe ADRs when they occur
ADR Prevention Study
(JAMA 1995;274;29,35, NEJM 1991:324;377)
• Rate of ADRs 6.5/100 admissions
• 28% ADRs were preventable and
serious
• ADRs increase LOS 1.9 days and
increase hospital costs $1939 (not
including costs of injuries)
• The annual national cost of drugrelated M&M is enormous
Costs associated with ADRs
(JAMA 1997; 277: 307-311)
• Prospective study to compare LOS
and total charges
• 247 ADRs in 204 patients
• 57% significant, 30% serious, 12%
life-threatening, and 1% fatal
• Nonpreventable ADRs: analgesics
(30%), antibiotics (30%), oncologic
agents (8%), and sedatives (7%)
Costs associated with ADRs
(JAMA 1997; 277: 307-311) (2)
• The largest % preventable ADRs
were caused by analgesics (29%),
sedatives (10%), antibiotics (9%),
and antipsychotics (7%)
• Allergic complications occurred in
7% of patients, and cardiovascular
complications in 16%
Costs associated with ADRs
(JAMA 1997; 277: 307-311) (3)
• An ADR was associated with
$2,595 of additional costs not
including the costs of injuries
• Annual ADR costs for the two
Harvard hospitals = $5.6 million
• Estimated preventable ADR
costs are in the billions
Detecting ADRs
• Clinical trials often do not include
certain patient populations where
the drug may be potentially used,
including pregnant women or
children, although recently the
FDA has encouraged companies
to study these patient populations
by extending patent time
Detecting ADRs (2)
• Premarketing trials frequently do
not have sufficient power to
reliably detect important ADRs,
which may occur at rates of 1 in
10,000 or fewer drug exposures
• FDA drug approval does not
exclude the possibility of rare but
serious ADRs
ADR detection methods
• Premarketing clinical trials
• Post approval spontaneous case
reports
• Aggregate population-based data
sources
• Computerized data collections
• Postmarketing studies
• Case reports
Case Reports
One of the methods to detect the
potential for a pharmacologic
agent to produce serious ADRs
have been noted first in case
reports. Unusual or rare events
that occur during initial drug use
are more likely to be detected by
case reports (JAMA 1999:281;824)
FDA Reporting Mechanisms:
MEDWATCH
• To improve the detection of
previously unknown serious ADRs
and knowledge about regulatory
actions taken in response to
reporting of these events, FDA
introduced MEDWATCH in 1993
FDA Reporting Mechanisms:
MEDWATCH (2)
• FDA encourages health
professionals to monitor for and
report serious adverse events and
product problems to FDA
MedWatch Program (3)
• MedWatch is designed to
educate health professionals
about the critical importance of
being aware of, monitoring for,
and reporting adverse events
and problems to FDA
MedWatch Program (4)
• Designed to enhance the
effectiveness of postmarketing
surveillance of medical products
as they are used in clinical
practice and to rapidly identify
significant health hazards
associated with these products.
MedWatch Program (5)
• To increase awareness of drug and
device-induced disease
• To clarify what should (and should
not) be reported to the agency
• To facilitate reporting by operating a
single system for health professionals
to report AEs and product problems
• To provide regular feedback to the
health care community about safety
issues involving medical products
Incidence and risk of perioperative
anaphylactic reactions
• 1 in 2,500-5,000 patients
• Incidence of perioperative
anaphylactic reactions has been
suggested to be increasing
• Most of the information in the US is
from case reports and, to a lesser
extent, retrospective studies
Risk of Anaphylaxis (1)
Even if the risk of an anaphylactic
reaction is small, if the drug is
administered to millions, the actual
number of reactions is important to
consider. This is important for latex
sensitive pts, or as we examine new
pharmacologic or different
preparations of drugs that are
introduced into practice.
Risk of Anaphylaxis (2)
• Propofol was first solubilized in
Cremophor, a solvent with a known risk
of ADRs; changed to intralipid
• Generic form of propofol contains a
sulfiting agent not tested in clinical trials
• Clinical manifestations of true allergic
reactions often may be mistakenly
attributed to predictable ADRs and may
often go unreported
Risk of Anaphylaxis (3)
• Anesthetic agents including propofol
cause hypotension and dose-related
vasodilation by direct and indirect
mechanisms
• Bronchospasm may occur during
laryngoscopy and intubation under
light planes of anesthesia
• Clinicians may confuse true allergic
reactions with known drug effects
Agents most often implicated
in perioperative anaphylaxis
• Antibiotics
• Blood products
• Drug additives/preservatives
• Muscle relaxants
• Proteins (latex and protamine)
Antibiotics
• Penicillin and cephalosporins
• Vancomycin
Blood Products
• Whole blood, RBCs
• Platelets
• FFP, cryoprecipitate
• Immunoglobulins
• Fibrin glue
Drug Additives/Preservatives
• Includes sulfites and parabens,
used as preservatives in parenteral
solutions
• Additives/preservatives that may
be included in IV drugs should be
considered in the etiology of occult
anaphylaxis
Drug Additives/Preservatives(2)
• In allergic patients who ingest
sulfites, gastric pH generates sulfur
dioxide producing bronchospasm,
coughing, or asthma
• The problem we face as clinicians is
a lack of data on the incidence and
risk of hypersensitivity reactions to
intravenous sulfites
Drug Additives/Preservatives (3)
• Patients with multiple drug
allergies and those with reactive
airway disease are potentially at a
greater risk for an allergic
response to sulfite-containing
solutions
Risk factors for Latex Allergy
• Allergy to bananas, avocados,
kiwis, mangos
• Healthcare workers
• Children with urogenital
abnormalities, spina bifida
Latex Allergy in Anesthesiologists
• 24% incidence irritant/contact
dermatitis
• 12.5% incidence of latex-specific
anti-IgE
• 10% were clinically asymptomatic
although IgE positive
Brown RH: Anesthesiology 1998;89:287
Latex Allergy in Anesthesiologists
• Atopy was a risk factor for
sensitization
• Brown suggests by avoiding latex
exposure, progression to
symptomatic disease may be
prevented
Brown RH: Anesthesiology 1998;89:287
Protamine
• Isolated from salmon sperm
• Complex set of ADRs
• 0.6-2% reactions in NPH
diabetics
• Multiple mechanisms for
reactions
Management of the Allergic Patient
• Greater risk of anaphylaxis in pts
with an allergic history or atopy
receiving an iv anesthetic
• 46% pt with anaphylaxis had a
history of allergy or atopy (LaForest)
• 44.4% atopy in pt with anaphylaxis
(compared to 5- 22%) (Moscicki)
SUMMARY
• Any drug can produce some form
of ADR
• Significant untoward risks, costs,
and increased hospital stays
associated with ADRs
• Allergy, atopy, or asthma pts have
been suggested to be at an
increased risk
SUMMARY (2)
• Antibiotics, blood products, drug
preservatives (sulfites and
methylparabens) and polypeptides
(ie, aprotinin, latex, and protamine)
may be associated with a higher
incidence of reactions
• Drug avoidance whenever
possible is still the best method to
avoid an ADR
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