Adverse Drug Reactions

1. Adverse Drug Reactions Jerrold H. Levy, MD Professor of Anesthesiology Emory University School of Medicine Director of Cardiothoracic Anesthesiology Emory Healthcare Atlanta, Georgia

2. 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

3. 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

4. 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.

5. PREDICTABLE REACTIONS • Dose dependent • Related to drug’s actions • Occur in normal patients • 80% of adverse effects

6. PREDICTABLE REACTIONS • Overdosage or toxicity • Side effects • Secondary/Indirect effects • Drug interactions

7. UNPREDICTABLE REACTIONS • Dose-independent • Not related to drug’s actions • Related to immune response (allergy)

8. 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

9. 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

10. 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 drug-related M&M is enormous

11. 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%)

12. 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%

13. 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

14. 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

15. 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

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

17. 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)

18. 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

19. FDA Reporting Mechanisms:MEDWATCH (2) • FDA encourages health professionals to monitor for and report serious adverse events and product problems to FDA

20. 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

21. 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.

22. 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

23. 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

24. 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.

25. 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

26. 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

27. Agents most often implicated in perioperative anaphylaxis • Antibiotics • Blood products • Drug additives/preservatives • Muscle relaxants • Proteins (latex and protamine)

28. Antibiotics • Penicillin and cephalosporins • Vancomycin

29. Blood Products • Whole blood, RBCs • Platelets • FFP, cryoprecipitate • Immunoglobulins • Fibrin glue

30. 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

31. 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

32. 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

33. Risk factors for Latex Allergy • Allergy to bananas, avocados, kiwis, mangos • Healthcare workers • Children with urogenital abnormalities, spina bifida

34. 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

35. 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

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

37. 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)

38. 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

39. 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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