PHARMACOVIGILANCE: WHEN ADVERSE DRUG EVENTS OCCUR. Bartlomiej Piechowski-Jozwiak, MD Rabih Dabliz, Pharm.D., FISMP

PHARMACOVIGILANCE: WHEN ADVERSE DRUG EVENTS OCCUR Bartlomiej Piechowski-Jozwiak, MD Rabih Dabliz, Pharm.D., FISMP

Disclosure Information PHARMACOVIGILANCE Bartlomiej Piechowski-Jozwiak, MD Rabih Dabliz, Pharm.D., FISMP I have no financial relationship to disclose. AND I will not discuss off label use and/or investigational use in my presentation. - List References here

Objectives Describe the difference between adverse drug reactions and medication errors Describe the role of pharmacovigilance in detection and prevention of adverse drug reactions Demonstrate how to classify and assess adverse drug reactions Use the elements of an effective medication event reporting system to increase reporting

WHAT ARE ADVERSE DRUG EVENTS? Any untoward medical occurrence that may present during treatment with a pharmaceutical product but which does not necessarily have a causal relationship with this treatment 1 This includes: - Adverse Drug Reactions - Medication Errors - Allergic Reactions - Overdoses 1. World Health Organization (WHO). WHO Draft Guidelines for Adverse Event Reporting and Learning Systems. Geneva: WHO, 2005.

WHAT ARE ADVERSE DRUG EVENTS? ADVERSE DRUG REACTION (ADR) A response to a drug which is noxious and unintended and which occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of disease or for the medication of physiologic function. MEDICATION ERROR Any preventable event that may cause or lead to inappropriate medication use or patient harm while the medication is in the control of the health care professional, patient, or consumer 1. World Health Organization (WHO). WHO Draft Guidelines for Adverse Event Reporting and Learning Systems. Geneva: WHO, 2005.

ADVERSE DRUG REACTIONS Bartlomiej Piechowski-Jozwiak, MD

WHAT IS PHARMACOVIGILANCE? The science and activities relating to the detections, assessment, understanding and prevention of adverse effects or any other drugrelated problem - World Health Organization 1. http://www.who.int/medicines/areas/quality_safety/safety_efficacy/pharmvigi/en/

WHY IS PHARMACOVIGILANCE NEEDED?

CLASSIC EXAMPLES OF SERIOUS ADRs MEDICATION Statins Thalidomide istotretinoin Aminophenazone (amidopyrine) Chloramphenicol Clioquinol Erythromycin estolate Fluothane Methyldopa Oral contraceptives Practolol Reserpine ADVERSE DRUG REACTION Rhabdomyolysis Congenital malformations Congenital malformations Agranulocytosis Aplastic anemia Myelooptic neuropathy (SMON) Cholestatic hepatitis Hepatocellular hepatitis Haemolytic anaemia Thromboembolism Sclerosing peritonitis Depression

OBJECTIVES OF PHARMACOVIGILANCE PROGRAMS Improvement of patient care and safety Improvement of public health and safety Contribution to the assessment of benefit, harm, effectiveness and risk of medicines Promotion of: - Education and clinical training - Effective communication to the public - Rational and safe use of medicines

HOW POST-MARKETING REPORTS GET TO FDA EVENT REPORT SYSTEM (FAERS) Contribution to the 5% Consumers Patients Healthcare Prof. FAERS* Database Regulatory Requirement 85% Manufacturer

HOW POST-MARKETING REPORTS GET TO FDA EVENT REPORT SYSTEM (FAERS) Safety Alerts Based on FAERS

PHARMACOVIGILANCE REPORTING Spontaneous reporting - Most common form of reporting - Performed by healthcare professionals/drug manufacturers Other methods of collecting safety data National pharmacovigilance centers WHO Program for International Drug Monitoring

WHO Program for International Drug Monitoring 1968 1978 1990 2018 Established in response to the thalidomide disaster Approximately 10,000 babies were born with deformities Started out as 10 countries Became WHO Collaborating Center for International Drug Monitoring Named Uppsala Monitoring Center Includes 131 countries as of September 2018 1. Uppsala Monitoring Centre. https://www.who-umc.org 2. http://www.who.int/medicines/areas/quality_safety/safety_efficacy/pv_fast_facts/en/

Uppsala Monitoring Centre An Independent, self-funded, non-profit organization Largest global database of Individual Case Safety Reports (VigiBase TM ) on behalf of WHO Technical support and guidance to national centres in PV practice Support for countries with reporting and data management VigiFlow, a web-based system integrating international standards to record and manage ICSRs Training sessions, publications of scientific data 1. Uppsala Monitoring Centre. https://www.who-umc.org 2. http://www.who.int/medicines/areas/quality_safety/safety_efficacy/pv_fast_facts/en/

VigiBase TM Flow of Information Reporters PV Center VigiBase Manufacturer Communication Analysis

TIPS FOR IDENTIFICATION OF ADRs BY HEALTHCARE PROFESSIONALS New or worsening symptoms Atypical lab or diagnostic procedures ordered Abrupt, unexpected discontinuation of a drug or a substantial dosage increase or reduction New orders for antidotes: - Naloxone - Flumazenil - Diphenhydramine - Antiemetics - Vitamin K - Sodium polystyrene sulfonate - Corticosteroids - Antidiarrheals

CLASSIFICATION OF ADRs

CLASSIFICATION OF ADRs

NARANJO ADR PROBABILITY SCALE

LIVERPOOL ADR CAUSALITY TOOL

SIGNALS A signal is a set of data constituting reported information on a possible, not previously known/documented, causal relationship because an adverse event and a drug 1. Edwards IR, Aronson JK. Adverse drug reactions: definitions, diagnosis, and management. Lancet 2000;356:1255-9.

SIGNAL DEFINITION 1992 2009 1997

VigiBase TM Flow of Information

DETERMINING SIGNAL PROBABILITY (PROPORTIONAL REPORTING RATIO) 1. Evans SJ et al. Use of proportional reporting ratios (PRRs) for signal generation from spontaneous adverse drug reaction reports. Pharmacoepidemiol Drug Saf. 2001 Oct-Nov;10(6):483-6.

PROPORTIONAL REPORTING RATIO (RIFBUTIN AND UVEITIS) 1. Evans SJ et al. Use of proportional reporting ratios (PRRs) for signal generation from spontaneous adverse drug reaction reports. Pharmacoepidemiol Drug Saf. 2001 Oct-Nov;10(6):483-6.

PROPORTIONAL REPORTING RATIO (RIFBUTIN AND UVEITIS) 1. Evans SJ et al. Use of proportional reporting ratios (PRRs) for signal generation from spontaneous adverse drug reaction reports. Pharmacoepidemiol Drug Saf. 2001 Oct-Nov;10(6):483-6.

REPORTING ADVERSE EVENTS Premarketing Trials Postmarketing surveillance Ministry/Departments of Health Pharmacovigilance Centers FDA Adverse Event Reporting System Institute for Safe Medication Practices MEDMARX Published Reports Uppsala Monitoring Center

Assessment Question 1 A 76-year-old patient is prescribed intravenous vancomycin 1500 mg every 12 hours on August 10. e patient s SCr on the morning of August 10 is 2.3 mg/dl, peaking at 5.4 mg/dl on August 15. Trough vancomycin level is 24.6 mcg/ml on August 16. Renal sonography is normal, and serum electrolytes are normal. According to the Naranjo algorithm, which one of the following ratings is most appropriate for the possible ADR of vancomycin and acute kidney injury in this patient? A. Highly Probably B. Probably C. Possible D. Doubtful

Assessment Question 2 N.P. is a 54-year-old man with superior vena cava stenosis, end-stage kidney disease, severe pruritus, and asthma. He is taken to the radiology suite for an angioplasty procedure. e patient is administered intravenous fentanyl 200 mcg, midazolam 4 mg, and morphine 10 mg. N.P. tolerates the procedure well, but in the recovery area, he has acute anxiety and tachypnea, with oxygen saturation levels decreasing to 89% 92%. Two doses each of flumazenil 0.5 mg and naloxone 0.4 mg are administered, and his oxygen saturation increases to 93% 95% The nurse circulator on N.P. s unit calls the pharmacotherapy specialist and asks whether an ADR report should be completed. Which one of the following is the best response to this question? A. Circulating nurse does not need to complete an ADR form because the reaction to fentanyl is expected. B. Patient s end-stage kidney disease should have limited the dosages of sedation agents, so an ADR form should be completed. C. Use of naloxone in 0.4-mg doses is dangerous, and an ADR report should be completed to enforce education on the use of reversal agents. D. No significant clinical harm occurred, so an ADR form should not be completed.

Assessment Question 2 N.P. is a 54-year-old man with superior vena cava stenosis, end-stage kidney disease, severe pruritus, and asthma. He is taken to the radiology suite for an angioplasty procedure. e patient is administered intravenous fentanyl 200 mcg, midazolam 4 mg, and morphine 10 mg. N.P. tolerates the procedure well, but in the recovery area, he has acute anxiety and tachypnea, with oxygen saturation levels decreasing to 89% 92%. Two doses each of flumazenil 0.5 mg and naloxone 0.4 mg are administered, and his oxygen saturation increases to 93% 95% The nurse circulator on N.P. s unit calls the pharmacotherapy specialist and asks whether an ADR report should be completed. Which one of the following is the best response to this question? A. Circulating nurse does not need to complete an ADR form because the reaction to fentanyl is expected. B. Patient s end-stage kidney disease should have limited the dosages of sedation agents, so an ADR form should be completed. C. Use of naloxone in 0.4-mg doses is dangerous, and an ADR report should be completed to enforce education on the use of reversal agents. D. No significant clinical harm occurred, so an ADR form should not be completed.

MEDICATION ERRORS Rabih Dabliz, Pharm.D., FISMP

Do You Have a Safety Culture in Your Organization?

Polling Question 1 Hospitals A and B are two 300-bed academic hospitals located within 200 meters of each other and offering similar clinical services to the community. During their monthly quality meeting, Hospital A reports 50 medication events while Hospital B reports 250. In which hospital do you feel safer? A. Hospital A B. Hospital B

Polling Question 1 Hospitals A and B are two 300-bed academic hospitals located within 200 meters of each other and offering similar clinical services to the community. During their monthly quality meeting, Hospital A reports 50 medication events while Hospital B reports 250. In which hospital do you feel safer? A. Hospital A B. Hospital B

EVENT REPORTING REPORTED

EVENT REPORTING REPORTED ACTUAL

What are the Barriers to Reporting in Your Organization?

DETECTING MEDICATION ERRORS

1. INCIDENT REPORT REVIEW Most frequently used in healthcare facilities Based on voluntary reporting Can be done by: - Paper - Telephone - E-mail - Electronic Under-reporting is a major drawback

1. INCIDENT REPORT REVIEW The Reporter needs to only answer 3 questions: 1. What happened? 2. Why do you think it happened? 3. How can it be prevented?

2. PATIENT CHART REVIEW Concurrent or retrospective medical record review Conducted by trained healthcare providers Helps detect prescribing and monitoring incidents

3. DIRECT OBSERVATION Observes medication administration at the bedside Helps identify administration and dispensing errors Not useful for prescribing/monitoring errors Optimize the audit process by developing a standardized audit tool that can be easily utilized by different members of the team

3. DIRECT OBSERVATION (SAMPLE AUDIT TOOL)

4. PHARMACIST INTERVENTIONS Helps identify prescribing errors and therapy optimization by tracking the various types of interventions performed by Pharmacist: - IV to PO - Renal/hepatic adjustment - Drug monitoring - Clinical Interventions - Medication Reconciliation

4. PHARMACIST INTERVENTIONS # Interventions per Month # & Type of Intervention per Pharmacist

5. TRIGGER TOOLS Helps identify potential adverse events using different triggers via detection of: 1. Certain Antidotes 2. Results from Laboratory Tests 3. Clinical Events

5. TRIGGER TOOLS Patient List Includes a column which flags patients who received an Antidote in Last 72 hours

5. TRIGGER TOOLS Once patient is identified, a customized report in the chart lists the antidote that was administered including: Date Time Dose Date & Time Antidote name & Dose Given

What to Do With the Data?

USING THE DATA Monthly or Quarterly Medication Safety/Quality Committees Dashboards Direct Feedback to Reporter Newsletters

REPORTING DASHBOARD

Additional Literature/References World Health Organization (WHO). WHO Draft Guidelines for Adverse Event Reporting and Learning Systems. Geneva: WHO, 2005. World Health Organization. Pharmacovigilance. http://www.who.int/medicines/areas/quality_safety/safety_efficacy/pharmvigi/en/ World Health Organization (WHO). Fast Facts on Pharmacovigilance. http://www.who.int/medicines/areas/quality_safety/safety_efficacy/pv_fast_facts/en Edwards IR, Aronson JK. Adverse drug reactions: definitions, diagnosis, and management. Lancet 2000;356:1255-9 Evans SJ et al. Use of proportional reporting ratios (PRRs) for signal generation from spontaneous adverse drug reaction reports. Pharmacoepidemiol Drug Saf. 2001 Oct- Nov;10(6):483-6.