Presentation on theme: "Drug and Therapeutics Committee"— Presentation transcript:
1 Drug and Therapeutics Committee Session 4. Assessing and ManagingMedicine Safety
2 Objectives Describe the significance of— Understand— Adverse drug reactions (ADRs)Medication and prescribing errorsUnderstand—Principles of medicine safety evaluationManagement of spontaneous case reports of ADRs and medication and prescribing errorsThe process of monitoring, evaluating, and preventing ADRs and adverse drug events
3 Outline Key Definitions Introduction ADRs—Pre- and postmarketing surveillanceCausalityImplications for the DTCAdverse Drug Events and Medication ErrorsActivitiesSummary
4 Key Definitions (1) Adverse drug reaction (ADR) Side effect A noxious and unintended response to a medicine that occurs at normal therapeutic doses used in humans for prophylaxis, diagnosis, or therapy of disease, or for the modification of physiologic functionThe word “effect” is used interchangeably with “reaction.”Side effectAny unintended effect of a pharmaceutical product occurring at normal therapeutic doses and is related to its pharmacological properties. Such effects may be well-known and even expected and require little or no change in patient management.Serious adverse effectAny untoward medical occurrence that occurs at any dose and results in death, requires hospital admission or prolonged hospital stay, results in persistent or significant disability, or is life threatening
5 Key Definitions (2) Adverse drug event Causality Signal Any untoward medical occurrence that may be present during treatment with a medicine but does not necessarily have a causal relationship with this treatment. Adverse drug events include medication errors and overdoses.CausalityThe probability that a particular medicine is responsible for an isolated effect or ADR.SignalReported information on a possible causal relationship between and adverse event and a medicine, the relationship being previously unknown or incompletely documented. Usually more than one signal report is required to generate a signal, depending on the seriousness of the event and the quality of the information.
6 Key Definitions (3) Prescribing error Medication error Negligence Incorrect medicine ordering by a prescriberMedication errorAdministration of a medicine or dose that differs from the written orderNegligenceMedical decision making or care below the accepted standards of practice
7 IntroductionADRs and events constitute a serious problem increasing morbidity and mortality and health care costs worldwide.Overall incidence of ADRs in hospitalized patients in the United States in 1998 was 6.7%, and fatalities were 0.32%.Lazarou, J., B. H. Pomeranz, and P.N. Corey Incidence of Adverse Drug Reactions in Hospitalized Patients: A Meta-analysis of Prospective Studies. JAMA 279 (15):120–25.ADRs resulted in approximately 250,000 admissions a year in the United KingdomProjected costs of ADRs to the United Kingdom’s National Health Service was £466 million (€ 680 million; USD 870 million)Hitchen, L Adverse Drug Reactions Result in UK Admissions a Year BMJ 332:1109Pirmohamed, M. et al Adverse Drug Reactions as Cause of Admission to Hospital: Prospective Analysis of 18,820 Patients. BMJ 329:15–19.
8 Adverse Drug Reactions (1) Patient injury caused by a medicine taken in therapeutic dosesType A—Exaggerated pharmacological responsePharmacodynamic (e.g., bronchospasm from beta-blockers)Toxic (e.g., deafness from aminoglycoside overdose)Type B—Nonpharmacological, often allergic, responseMedicine-induced diseases (e.g., antibiotic-associated colitis)Allergic reactions (e.g., penicillin anaphylaxis)Idiosyncratic reactions (e.g., aplastic anemia with chloramphenicol)
9 Adverse Drug Reactions (2) Type C—Continuous or long term (time related)Osteoporosis with oral steroidsType D—Delayed (lag time)Teratogenic effects with anticonvulsants or lisinoprilType E—Ending of use (withdrawal)Withdrawal syndrome with benzodiazepinesType F—Failure of efficacy (no response)Resistance to antimicrobials
10 Determining Medicine Safety: Identifying and Managing ADRs Premarketing clinical trialsAnimal studies, human studies—Phases I, II, IIICannot identify ADRs with incidence < 1%Unproven ADRs listing for legal protection of manufacturerPostmarketing surveillanceSpontaneous reportingPostmarketing clinical trials—Phase IVOther methods—observational studies, meta-analysis, case reportsDetermining causalityActions taken to manage new ADRs
11 Postmarketing Surveillance of ADRs: Spontaneous Reports Best method for detecting new ADRsNecessary because many ADRs not detected in pre- or postmarketing studiesInitiated by physicians, pharmacists, nurses, patientsProblems include underreporting, inaccurate reporting that may not show causality, and high false positive rates
12 Postmarketing Surveillance of ADRs: Clinical Studies Postmarketing clinical studiesDone to determine efficacy and safety (Phase IV trials)Generally poor in detecting ADRs because—RCTs often insufficient for assessing ADRs, so observational cohort and cases control studies are usedNonrepresentative patient selectionNarrow medicine indications and dosing structureLimited concomitant medicine use
13 Postmarketing Surveillance: Other Methods Observational studies provide limited identification of new ADRsLarge databases in the United States and Europe from national health programs, HMOs, health insurance programs can provide data for case control or cohort studiesCohort studies useful for assigning causalityPublished case reports—provide limited information about ADRsMeta-analysis of published papers—provide identification of new ADRs by increasing the power of the clinical studies
14 Actions for Newly Discovered ADRs “Dear Doctor” letters—describe a new safety concern about a particular medicinePackage insert revisionsFor significant safety concernsManufacturers must change the official labeling and the package insert to reflect the new safety concernTypically approved by the regulatory authorityMedicine recalls (voluntary and compulsory)For serious safety concernsMay be voluntary or imposed by the regulatory authority
15 Determining Causality of an ADR Factors in determining causalityStrength of the associationConsistency of the observed evidenceTemporality of the relationshipADR that occurs in association with a medicine does not mean the medicine is responsibleDelayed reactions do not rule out the medicine as causing the ADRDose-response relationshipConfounding factors
16 Classifying Causality of an ADR Certain causality—when a clinical event (including laboratory test abnormality) occurs in a plausible time relationship to medicine administration and cannot be explained by concurrent disease or other medicines or chemicals; re-administration of the medicine causes a similar reactionProbable or likely causality—when a clinical event occurs with a reasonable time sequence to medicine administration and is unlikely to be due to any concurrent disease or other medicine administrationPossible causality—when a clinical event occurs with a reasonable time sequence to medicine administration, but which could be explained by concurrent disease or other medicine administrationUnlikely causality—when a clinical event (including laboratory test abnormality) occurs in temporal relationship to medicine administration that makes a causal relationship improbable, and when other medicines, chemicals, or underlying disease provide plausible explanations
17 Classifying Causality of an ADR: Naranjo Algorithm QuestionYesNoDo Not KnowAre there previous conclusive reports on this reaction?+1Did the adverse event appear after the suspected medicine was administered?+2-1Did the adverse reaction improve when the medicine was discontinued or a specific antagonist was administered?Did the adverse reaction reappear when the medicine was re- administered?Are there alternate causes (other than the medicine) that could solely have caused the reaction?Was the medicine detected in the blood (or other fluids) in a concentration known to be toxic?Was the reaction more severe when the dose was increased or less severe when the dose was decreased?Did the patient have a similar reaction to the same or similar medicines in any previous exposure?Was the adverse event confirmed by objective evidence?Total the score to determine the category of the reaction. The categories are defined as follows: Definite>9; Probable 5–8; Possible 1–4; Doubtful 0.
18 Implications for DTC Surveillance of ADRs Monitoring and managing ADRs requires setting up surveillance systemsUse of local surveillance (tracking and reporting) system run by the DTCUse of standardized reporting formsAnalysis of reported ADRs to be done by selected DTC committee memberReporting of serious and recurring ADRs to regulatory authorities and manufacturers
19 Potential Role of DTC in ADR Reporting Process of reporting to higher facilityand directly to national centerLocal levelHealth Facility DTCProvincial HospitalDTCNationalPharmacovigilanceUnit
20 Managing ADRs Step 1. Evaluate the nature of the event. Obtain a detailed history of the patient.Identify and document the clinical reaction. Look up suspected medicines and known ADRs in the literature and match them with the reactions described by the patientClassify the severity of the reaction.Severe—fatal or life threateningModerate—requires antidote, medical procedure, or hospitalizationMild—symptoms require discontinuation of therapyIncidental—mild symptoms; patient can chose whether to discontinue treatment or not
21 Managing ADRs Step 2. Establish the cause. Use the Naranjo algorithm (or other system) to assess the patient’s reaction.Evaluate the quality of the medicine.Check for a medication error.
22 Managing ADRs . Step 3. Take corrective and follow-up action. Corrective action will depend on cause and severitySevere ADRsEducate and monitor prescribers.Change the formulary or standard treatment guideline if necessary to substitute a medicine that is safer or that is easier to use by staff.Modify patient monitoring procedures.Notify drug regulatory authorities and manufacturers.All ADRsEducate and warn patients.
23 Prevention of ADRsSchematic of preventable and unavoidable adverse events
24 DTC's Role in Preventing ADRs Review ADR reports regularly and inform professional staff of the incidence and impact of ADRs in the region.Discuss changes in the formulary or standard treatment guidelines for significant or recurring problems with ADRs.Educate staff, especially providers, concerning ADRs.Identify medicines on the formulary that are “high risk” and should be monitored closely by physicians and pharmacists.Identify “high-risk” patient populations, including pregnant women, breast-feeding women, the elderly, children, and patients with renal or liver dysfunction; close monitoring of these patient populations by physicians and pharmacists will help prevent serious adverse reactions.Review medication errors and product quality complaints to ensure they are not contributing to the incidence of ADR at the hospital.
25 Adverse Drug Events (1)An adverse drug event is any untoward medical occurrence that may be present during treatment with a medicine but does not necessarily have a causal relationship with this treatment.Adverse drug events include medication errors.
26 Adverse Drug Events (2)* Primary medicines involved were antibiotics (25%), cardiovascular medicines (17%), analgesics (9%), and anticoagulants (9%)Types of medicine use error—Wrong medicine prescribed (21%)Prescribed despite known allergy (6%)Incorrect frequency (5%)Wrong dose (8%)Missed dose (5%)Medicine interaction (3%)Record review of 15,000 inpatients in 1992Adverse events 2.9% (30% due to negligence)55% adverse events were non-operative; 19% were due to medicines0.56% adverse drug events35% drug adverse events due to negligence*Thomas, E.J., D.M. Studdert, H.R. Burstin, et al Incidence and Types of Adverse Events and Negligent Care in Utah and Colorado. Medical Care 38(3):261–271.
27 Causes of Adverse Drug Events* Record review of 4,031 inpatients247 (6.1%) adverse drug events; 70 (28%) preventable194 (4.8%) additional errors without patient harm detected264 errors were due to—Physician ordering (39%)Transcription (12%)Nurse administration (38%)Pharmacy dispensing (11%)Reasons for error included—Lack of prescriber knowledge (37%)Inadequate checking of medicine identity or dose (15%)Incomplete patient information (14%)Inaccurate transcription (11%)Failure to note medicine allergy information (9%)*Bates, D.W., D.J. Cullen, N. Laird, et al Incidence of Adverse Drug Events and Potential Adverse Drug Events. Implications for Prevention. ADE Prevention Study Group. JAMA 274(1):29–34.
28 Cost of Adverse Drug Events* Record review of 4,031 inpatients re-analyzed by case controlComparison controlling for level of care, severity, and co-morbidity (paired regression)247 adverse drug events were estimated to have—Extended hospitalization by 2.2 daysIncreased cost of 3,244 U.S. dollars (USD)70 adverse drug events due to errors were estimated to have—Extended hospitalization by 4.6 daysIncreased cost of USD 5,857Bates, D.W., N. Spell, and D.J. Cullen The Costs of Adverse Drug Events in Hospitalized Patients. ADS Study Group. JAMA 277(4):307–311.
29 Medication Errors (1)Administration of medicine or dose that differs from written orderMedicine prescribed but not givenAdministration of a medicine not prescribedMedicine given to the wrong patientWrong medicine or IV fluid administeredWrong dose or strength givenWrong dosage form given
30 Medication Errors (2) Medicine given for wrong duration Wrong preparation of a dose (e.g., incorrect dilution)Incorrect administration technique (e.g., unsterile injection)Medicine given to a patient with known allergyWrong route of administration usedWrong time or frequency of administration
31 Causes of Medication Errors Human factorsHeavy staff workload and fatigueInexperience, lack of training, poor handwriting, and oral ordersWorkplace factorsPoor lighting, noise, interruptions, excessive workloadPharmaceutical factorsExcessive prescribingConfusing medicine nomenclature, packaging, or labelingIncreased number or quantity of medicines per patientFrequency and complexity of calculations needed to prescribe, dispense, or administer a medicineLack of effective policies and procedures
32 When Medication Errors Occur (1) Medicine Ordering or PrescribingTranscribingDispensingMEDICATIONERRORMedication errors can be defined as any error in the medication use process. As outlined in the chart above, this includes medicine ordering, transcribing, dispensing, administering, or monitoring.AdministeringMonitoring
33 When Medication Errors Occur (2) Medicine Ordering or Prescribing77.8%Transcribing5.8%MEDICATIONERRORDispensing1.0%Medication errors can be defined as any error in the medication use process. As outlined in the chart above, this includes medicine ordering, transcribing, dispensing, administering, or monitoring.Administering12.8%Monitoring0.5%Fortescue E.B., et al Prioritizing Strategies for Preventing Medication Errors and Adverse Drug Events in Pediatric Inpatients. Pediatrics 111:722–29.
34 Preventing Medication Errors (1) Establish consensus group of physicians, nurses, and pharmacists to select best practicesIntroduce a punishment-free system to collect and record information about medication-related errorsDevelop written procedures with guidelines and checklists for IV fluids and high-risk medicines (e.g., insulin, heparin, narcotics)
35 Preventing Medication Errors (2) Require legible handwriting and complete spelling of medicine nameUse standardized notationDoses given in mg, mcg, gLeading zero used for values < 1 and no trailing zero (e.g., 0.2 mg instead .2 mg; 2 mg instead of 2.0 mg)Write route of administration on all ordersWrite out directions completely (e.g., “daily” not “QD” or “OD”)
36 Preventing Medication Errors (3) Limit use of telephone and oral orders to emergency situationsConfirm identity of patients before administering medicationUse standard administration times for hospitalized patientsFor look alike and sound alike names, establish a policy requiring that prescribers write both brand and generic namesUse pharmacy staff to help prevent errors
37 Using Pharmacists to Prevent Errors New York, USA*Pharmacists assigned to monitor medication ordersDetected and corrected 2,103 significant errors during one year (4 errors/1,000 medication orders)Massachusetts, USA**Pharmacists assigned to make rounds with the intensive care unit teamMade 366 recommendations on medicines; 362 acceptedReduction in preventable adverse drug events due to prescribing errors from 10.4 to 3.5 per 1,000 patient-days*Dean, B., M. Schachter, C. Vincent, et al Causes of Prescribing Errors in Hospital Inpatients: a Prospective Study. Lancet 359 (9315):1373–78.**Leape, L.L., D.J. Cullen, M.D. Clapp, et al. Pharmacist Participation on Physician Rounds and Adverse Drug Events in the Intensive Care Unit. JAMA 282(3):267–70.
38 Activities Activity 1 Activity 2 Activity 3 Case history: Penicillin Anaphylaxis ReportedActivity 2Case history: Acute Respiratory Infection in a Two-Year OldActivity 3Serious ADRs with Phen-Fen Combination Medicine
39 Summary (1)DTCs can contribute significantly to improved medicine safety by—Assessing the safety of all new medicines before placing on the formularyImplementing systems to monitor the occurrence of ADRsManaging and evaluating suspected ADRs, assigning causality, and taking corrective action when necessary
40 Summary (2) Reporting ADRs to regulatory authorities and manufacturers Preventing the occurrence of ADRs and events by—ADR monitoring and reportingCareful evaluation of patients before prescribing, especially high-risk patientsEducate staff