Adverse Drug Reactions
to Biopharmaceuticals
A New Challenge
Sheila C Noble
Senior Pharmacist
Yellow Card Centre, Scotland
(Centre for Adverse Reactions to Drugs,
Scotland)
CARDS
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ADRs and
Biopharmaceuticals
Types of reactions to biological agents - the
new challenge
Overview of significant ADRs and how to
reduce the risk
Reporting ADRs to biopharmaceuticals
CARDS
Standard drugs vs
Biopharmaceuticals
Penicillin (MW 350)
Trastuzumab (MW 145,000)
CARDS Types of Adverse Reactions
to Biopharmaceuticals
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ADRs to regular xenobiotics
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Types ABCDE
Augmented, Bizarre, Chronic, Delayed, End of
treatment
Suggested classification of ADR to
biopharmaceuticals
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Types α β    (Pichler WJ, 2006*)
*Pichler WJ. Adverse Side Effects to Biological Agents. Allergy;61:912-920
(2006)
CARDS Pichler classification of
biopharmaceuticals ADRs(1)
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Alpha (α)
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High cytokine administration
cytokine release syndrome
CARDS Pichler classification of
biopharmaceuticals ADRs(2)
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Beta (β)
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Hypersensitivity – three forms of allergy
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Immediate IgE
Delayed IgG mediated reactions
Delayed T-cell mediated reactions
CARDS
Risk of allergy with MABs
High Chimeric – mixed mouse/human
DNA
Low
- ximab
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Humanised – 95% human
- zumab
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Human – fully human
- mumab
CARDS Pichler classification of
biopharmaceuticals ADRs(3)
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Gamma ()
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Immune (cytokine) imbalance syndromes – immunological
features but not due to high cytokines or hypersensitivity.
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Immunodeficiency e.g. recurrence of latent infection
Autoimmunity e.g. Lupus with infliximab
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Autoinflammatory e.g.psoraisis with TNFα blockers or IFN α
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Varied and rare – individual predisposition such as
atopy or co-morbidity
CARDS Pichler classification of
biopharmaceuticals ADRs(4)
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Delta ()
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Cross reactivity.
Antibodies generated to an antigen overexpressed on tumour cells might cross react with
normal cells which express this antigen to a lower
degree.
Cetuximab blocks EGFR - acneform lesions
Traztuzumab and CCF
CARDS Pichler classification of
biopharmaceutical ADRs (5)
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Epsilon ()
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Non-immunological side effects due to unknown
functions of the biological agent given or targeted
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Psychiatric ADRs with Interferon α
CARDS
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TGN1412 at Northwick
Park
To treat B-cell Chronic Lymphocytic Leukemia
(CD28)
Aimed to stimulate T-cell production
Resulted in cytokine storm (TNFα, IFN IL-10)
(Type α reaction) and T lymphopenia
Animal model varied from human CD28 T surface
receptor
Lab Animals not previously exposed to infection
CARDS
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How to avoid future
clinical trial disasters
Regulation of first-in-human trials
Access to info on unpublished studies
Share safety info on Phase I trials
Consult with outside experts
Cautious calculation of initial doses
Cautious rate of admin
Give new agents sequentially with adequate gaps
Consider using patients rather than healthy volunteers
Highly qualified principal investigator
Appropriate facilities, equipment and staff
CARDS
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Cardiac Side Effects with
Trastuzumab
Trastuzumab (Herceptin) assoc with asymptomatic
reversible reduced LV function or CCF
Trastuzumab my interfere with HER2 signalling and
function in myocytes ( cross reactivity reaction)
Trastuzumab can increase cardiotoxicity with
anthracyclines
Assess cardiac function before treatment, monitor
during and following treatment, treat with ACEIs,
beta blockers diuretics as appropriate. Avoid
anthracyclines in combination with Herceptin.
CARDS
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Cardiac Side Effects with
anti-TNFα agents
TNFα serum levels elevated in CHF
ATTACH trial - infliximab for CCF
Infliximab worsened CCF
TNFα increases NO production ->
vasodilation to maintain blood flow ??
Anti TNFα drugs also assoc with de novo
CCF
Monitor closely if mild CCF & stop prn
Submit a Yellow Card
CARDS
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Infections with TNFα
antagonists
TNFα stimulates macrophage function to
control intracellular infections
Anti-TNFα therapy allows underlying disease
to multiply & spread
Do not give if active disease TB, sepsis,
opportunistic infection.
Screen for latent TB (treat)
Avoid infection and be alert for signs of
infection (atypical as fever masked)
CARDS Progressive Multifocal
Leucoencephalopathy (PML)
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PML – demyelinating, fatal,
from JC virus
Identified with efalizumab,
rituximab, natalizumab (
immune imbalance)
Efalizumab (Raptiva) for
psoraisis
Marketing Authorisation
withdrawn June 09 due to
unfavourable risk/benefit
Photograph courtesy of Pharmaceutical Journal
CARDS
PML (2) - Natalizumab
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Symptoms of PML may mimic MS
Patients with anti-JC virus antibodies >44
times more likely to develop PML 1
Inc risk if previously treated with
immunosupressants +/or > 2yr treatment
At least 212 cases of PML with monotherapy
Tx Plasma exchange,Mirtazapine, Mefloquine
Recovery complicated by IRIS
Patients to carry PML alert cards – regular
MRI
1. NEJM 366:1870-80 2012
CARDS
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Leukemias with anti-TNFα
FDA reported increased incidence of
malignancies in adolescents & children
treated with TNFα blockers ( immune
imbalance)
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Confounding factors – RA and Crohn’s have
independent cancer risk
Warn patients/parents to be alert to
signs/symptoms (wt loss, swollen lymph
nodes, bruising/bleeding)
Monitor
CARDS
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Infusion reactions to
biopharmaceuticals
Any biopharmaceutical could cause IgE
infusion reaction (β) – Anaphylaxis kit ready
Rituximab cetuximab and infliximab – pretreat with antihistamines/paracetamol/
glucocorticoid
Initial low and slow regimen
In RA concomitant use of methotrexate as
appropriate reduced production of antibodies
CARDS
Reporting ADRs
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Submit Yellow Cards for all ADRs to Black
Triangle Biopharmaceuticals including
Biosimilars
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State specific Brands & Batch Numbers
Report Serious ADRs only if well established
drug for well-established licensed indication
Report via www.mhra.gov.uk/yellowcard or
on paper Yellow Cards