Adverse Drug Reactions

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Adverse Drug Reactions

• Jerrold H. Levy, MD
• Professor of Anesthesiology
• Emory University School of Medicine
• Director of Cardiothoracic Anesthesiology
• Emory Healthcare
• Atlanta, Georgia

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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

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Incidence of Reactions

• 5 adults in US are allergic to
• gt1 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

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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.

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PREDICTABLE REACTIONS

• Dose dependent
• Related to drugs actions
• Occur in normal patients
• 80 of adverse effects

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PREDICTABLE REACTIONS

• Overdosage or toxicity
• Side effects
• Secondary/Indirect effects
• Drug interactions

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UNPREDICTABLE REACTIONS

• Dose-independent
• Not related to drugs actions
• Related to immune response (allergy)

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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

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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

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ADR Prevention Study (JAMA 199527429,35, NEJM
1991324377)

• 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 drug-related MM is
  enormous

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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)

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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

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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

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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

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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

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ADR detection methods

• Premarketing clinical trials
• Post approval spontaneous case reports
• Aggregate population-based data sources
• Computerized data collections
• Postmarketing studies
• Case reports

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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
  1999281824)

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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

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FDA Reporting Mechanisms MEDWATCH (2)

• FDA encourages health professionals to monitor
  for and report serious adverse events and product
  problems to FDA

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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

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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.

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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

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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

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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.

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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

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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

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Agents most often implicated in perioperative
anaphylaxis

• Antibiotics
• Blood products
• Drug additives/preservatives
• Muscle relaxants
• Proteins (latex and protamine)

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Antibiotics

• Penicillin and cephalosporins
• Vancomycin

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Blood Products

• Whole blood, RBCs
• Platelets
• FFP, cryoprecipitate
• Immunoglobulins
• Fibrin glue

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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

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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

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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

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Risk factors for Latex Allergy

• Allergy to bananas, avocados, kiwis, mangos
• Healthcare workers
• Children with urogenital abnormalities, spina
  bifida

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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 199889287

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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 199889287

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Protamine

• Isolated from salmon sperm
• Complex set of ADRs
• 0.6-2 reactions in NPH diabetics
• Multiple mechanisms for reactions

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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)

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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

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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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