Pharmacovigilance Workshop The workshop is designed to introduce pharmacovigilance to graduate students and working professionals interested in drug safety as a career field. After a brief introduction of publicly available data sources, each team received a case study that detailed a specific safety concern that resulted in a significant safety update of product labeling or product withdrawal. Medicines may be withdrawn from markets because of risks to patients or business reasons. Change of benefit: risk profile is usually prompted by adverse effects that were either not previously detected, are more frequent, or more severe than anticipated based on the results of Phase III clinical trials. Market withdrawals are triggered by adverse events that were only made apparent from postmarketing surveillance data collected from population-wide use over more extended periods of time. The sources of information the regulatory agencies use when deciding on market withdrawal include meta-analyses and pooled analyses of data from clinical trials, clinical trials, spontaneous case reports, laboratory studies, observational studies, animal studies, and reviews of existing safety data. In the U.S., individual case safety reports are collected in the FDA Adverse Event Reporting System (FAERS). In Europe, medication side effects are sent to national regulatory authorities and in the EU pharmacovigilance database EudraVigilance. The participants learned where to find clinical trials, market authorizations, and product labeling. After the introductory presentation, each team received a case study that detailed a specific safety issue that resulted in a significant safety update of product labeling or product withdrawal. Each case study received product labeling and several scientific publications that discussed the safety concern in depth. Each team prepared a presentation with detailed overview of their assigned case study. Are you interested in drug safety? Try this for yourself! Case studies: Mylotarg (Gemtuzumab ozogamicin): no benefit, risk of death Roaccutane (isotretinoin): teratogenic effect Lariam (mefloquine): neuropsychiatric side effects Zyprexa (olanzapine): stroke in patients with dementia Avandia (rosiglitazone): myocardial infarction, death due to cardiovascular causes Seroxat (paroxetine): suicidality Xyrem (sodium oxybate): diversion, abuse Coumadin (warfarin): bleeding https://www.aretezoe.com/pharmacovigilance-workshop

1. PHARMACOVIGILANCE WORKSHOP
Veronika Valdova
ARETE-ZOE, LLC
9/7/2022
PV WORKSHOP: EXPLORE PUBLICLY AVAILABLE
DATA SOURCES IN DRUG SAFETY
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CASE STUDIES

2. CASE STUDIES
• Gemtuzumab ozogamicin
• Isotretinoin
• Mefloquine
• Olanzapine
• Paroxetine
• Rosiglitazone
• Sodium oxybate
• Warfarin
PV WORKSHOP: EXPLORE PUBLICLY AVAILABLE DATA SOURCES IN DRUG SAFETY

3. Drug Safety Case Studies
9/7/2022 P V W O R K S H O P : E X P L O R E P U B L I C L Y A V A I L A B L E D A T A S O U R C E S I N D R U G S A F E T Y 3
Use provided materials and templates to compile a
presentation on your assigned case study:
– EudraVigilance ADRs reported in Europe
– FAERS ADRs reported in the U.S.
– SmPC Summary of Product Characteristics (Europe)
– PI Prescribing Information (USA)
– Study registry ClinicalTrials.gov
– PubMed Literature database

4. MYLOTARG (GEMTUZUMAB OZOGAMICIN)
In May 2000, monoclonal antibody Mylotarg received
accelerated approval by the FDA for the treatment of
Acute Myeloid Leukemia (AML) with CD33 positive for
patients who had experienced a relapse. In June 2010,
Mylotarg was withdrawn because a clinical trial showed
that the drug increased patient death and added no
benefit over conventional cancer therapies. In 2017, it
was reintroduced for newly diagnosed AML in the U.S.
and a year later for the same indication in Europe.
PV WORKSHOP: EXPLORE PUBLICLY AVAILABLE DATA SOURCES IN DRUG SAFETY

5. MYLOTARG
(GEMTUZUMAB OZOGAMICIN)
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SAFETY CONCERN: NO BENEFIT, RISK OF DEATH
• Indications, target population (US vs. EU)
• Contraindications
• Boxed warning (US) / Black triangle warning (EU)
• Data from pharmacovigilance databases – FAERS and EudraVigilance
• Ongoing clinical trials
• Published literature
• Evidence for withdrawal
• BONUS: Approval /withdrawal timeline

6. ROACCUTANE (ISOTRETINOIN)
Roaccutane was first approved in the U.S. in 1982 for
the treatment of severe acne. Due to its serious
teratogenic effect, isotretinoin must not be used by
female patients who are or may become pregnant.
Despite the Risk Evaluation and Mitigation Strategy
(REMS) program, that includes Pregnancy Prevention
Program (PPP), System to Manage Accutane Related
Teratogenicity (SMART) and iPLEDGE (a mandatory
distribution program in the United States for
isotretinoin) pregnancies on isotretinoin still occur.
PV WORKSHOP: EXPLORE PUBLICLY AVAILABLE DATA SOURCES IN DRUG SAFETY

7. ROACCUTANE
(ISOTRETINOIN)
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SAFETY CONCERN: TERATOGENIC EFFECT
• Indications, target population (US vs. EU)
• Contraindications
• Boxed warning (US) / Black triangle warning (EU)
• Data from pharmacovigilance databases – FAERS and EudraVigilance
• Ongoing clinical trials
• Published literature
• REMS: Medication guide
• BONUS: iPLEDGE registry

8. LARIAM (MEFLOQUINE)
Antimalarial mefloquine was formulated at Walter Reed
Army Institute of Research (WRAIR) in the 1970s.
Mefloquine was approved by the FDA in 1989. The drug was
extensively used by the U.S. Army for the prophylaxis of
malaria. In December 2002, an article was published about
a series of murders and suicides at Fort Bragg. Army
epidemiologist Dr. Remington Nevin made a case that the
rate of occurrence and severity of psychiatric adverse
events is significantly higher than what is declared on the
label and explained the biological mechanism of toxicity.
Psychiatric side effects of mefloquine are subject to legal
action in Canada, Ireland and the U.S.
PV WORKSHOP: EXPLORE PUBLICLY AVAILABLE DATA SOURCES IN DRUG SAFETY

9. LARIAM
(MEFLOQUINE)
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SAFETY CONCERN: NEUROPSYCHIATRIC SIDE EFFECTS
• Indications, target population (US vs. EU)
• Contraindications
• Boxed warning (US) / Black triangle warning (EU)
• Data from pharmacovigilance databases – FAERS and EudraVigilance
• Ongoing clinical trials
• Published literature
• Antimalarials in military medicine
• BONUS: Limitations of post-market surveillance systems (rates of occurrence)

10. ZYPREXA (OLANZAPINE)
Olanzapine, first approved in 1996, is an atypical
antipsychotic that is indicated for the treatment of
schizophrenia and manic or mixed episodes of bipolar
disorder. The drug was extensively promoted and used for
numerous other indications (PTSD, depression, anxiety or
dementia). In 2004, the Committee on the Safety of
Medicines issued a warning that olanzapine should not be
given to elderly patients with dementia. In 2005, the FDA
issued Black Box warning regarding the risk of stroke in
elderly patients with dementia. In 2009, Eli Lilly agreed to
pay $1.4 billion to resolve Department of Justice allegations
of off-label promotion.
PV WORKSHOP: EXPLORE PUBLICLY AVAILABLE DATA SOURCES IN DRUG SAFETY

11. ZYPREXA
(OLANZAPINE)
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SAFETY CONCERN: STROKE IN PATIENTS WITH DEMENTIA
• Indications, target population (US vs. EU)
• Contraindications
• Boxed warning (US) / Black triangle warning (EU)
• Data from pharmacovigilance databases – FAERS and EudraVigilance
• Ongoing clinical trials
• Published literature
• Common off-label uses
• BONUS: Off-label use vs. off-label promotion

12. SEROXAT (PAROXETINE)
Paroxetine is an SSRI antidepressant that was first approved
in 1992. In 2000s, Seroxat was linked to increased risk of
violence and suicides. This is explained by the affinity of
paroxetine to cytochrome CYP2D6. Due to individual
variability in metabolism of the drug, there are major
differences in response to treatment. In 2015, Clinical
Pharmacogenetics Implementation Consortium (CPIC)
published a guideline for CYP2D6 and CYP2C19 genotypes
for dosing SSRIs. In 2017, it was decided that GSK must
pay $3 million to a woman who sued GSK over the death of
her husband, who committed suicide after taking generic
version of paroxetine.
PV WORKSHOP: EXPLORE PUBLICLY AVAILABLE DATA SOURCES IN DRUG SAFETY

13. SEROXAT
(PAROXETINE)
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SAFETY CONCERN: SUICIDALITY
• Indications, target population (US vs. EU)
• Contraindications
• Boxed warning (US) / Black triangle warning (EU)
• Data from pharmacovigilance databases – FAERS and EudraVigilance
• Ongoing clinical trials
• Published literature
• Dolin vs. GSK
• BONUS: Pharmacogenomic interactions

14. AVANDIA (ROSIGLITAZONE)
In 1999, new antidiabetic drug rosiglitazone was introduced
under brand name Avandia by SmithKline Beecham. A year
later, the company merged with GlaxoWellcome, forming
pharmaceutical giant GlaxoSmithKline (GSK). In 2007, Dr.
Nissan published a metaanalysis, in which he proved
Avandia increases the risk of heart attacks by 43%. The
drug was discussed in hearing in the U.S. House of
Representatives in 2007 and again in the U.S. Senate three
years later. Avandia was withdrawn from the market in
2010. In 2013, safety restrictions were lifted in the U.S. but
remained in the EU.
PV WORKSHOP: EXPLORE PUBLICLY AVAILABLE DATA SOURCES IN DRUG SAFETY

15. AVANDIA
(ROSIGLITAZONE)
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SAFETY CONCERN: MYOCARDIAL INFARCTION, DEATH FROM CARDIOVASCULAR CAUSES
• Indications, target population (US vs. EU)
• Contraindications
• Boxed warning (US) / Black triangle warning (EU)
• Data from pharmacovigilance databases – FAERS and EudraVigilance
• Ongoing clinical trials
• Published literature
• Dr. Nissen’s meta-analysis
• BONUS: Approval / Withdrawal timeline, hearings before the U.S. Congress

16. XYREM (SODIUM OXYBATE)
Xyrem is indicated for the treatment of cataplexy or
excessive daytime sleepiness in patients with narcolepsy.
Xyrem was approved by the FDA in 2002 with a strict risk
evaluation and mitigation strategy (REMS) program. The
drug is also part of a control program to prevent diversion
to the black market where it is used as a date rape drug. In
2007, Jazz pleaded guilty to misbranding charges for
promoting Xyrem off-label. In 2012, in U.S. v. Caronia, the
court held “that the government cannot prosecute
pharmaceutical manufacturers and their representatives
under the FDCA for speech promoting the lawful, off -label
use of an FDA-approved drug.”
PV WORKSHOP: EXPLORE PUBLICLY AVAILABLE DATA SOURCES IN DRUG SAFETY

17. XYREM
(SODIUM OXYBATE)
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SAFETY CONCERN: DIVERSION, ABUSE
• Indications, target population (US vs. EU)
• Contraindications
• Boxed warning (US) / Black triangle warning (EU)
• Data from pharmacovigilance databases – FAERS and EudraVigilance
• Ongoing clinical trials
• Published literature
• REMS
• BONUS: GHB abuse

18. COUMADINE (WARFARIN)
Warfarin is a coumarin anticoagulant that was first
approved for medical use in 1954. Bleeding is the primary
concern for patients on warfarin. Bleeding associated with
anticoagulants, opioid overdose and hypoglycemia
associated with antidiabetics are top priority concerns
according to the National Action Plan that monitors adverse
drug events in U.S. hospitals. Bleeding is a serious expected
event (listed on drug label) and as such is not subject to
expedited reporting. In 2011, Clinical Pharmacogenetics
Implementation Consortium (CPIC) published a guideline for
CYP2C9 and VKORC1 genotypes and warfarin dosing.
PV WORKSHOP: EXPLORE PUBLICLY AVAILABLE DATA SOURCES IN DRUG SAFETY

19. COUMADINE
(WARFARIN)
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SAFETY CONCERN: BLEEDING
• Indications, target population (US vs. EU)
• Contraindications
• Boxed warning (US) / Black triangle warning (EU)
• Data from pharmacovigilance databases – FAERS and EudraVigilance
• Ongoing clinical trials
• Published literature
• Bleeding associated with anticoagulants in the National Action Plan
• Impact on reporting systems: serious expected event, not subject to expedited reporting
• BONUS: Pharmacogenomic considerations in dosing

20. THANK YOU
Veronika Valdova
veronikav@arete-zoe.com
https://www.aretezoe.com /
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