Adverse Drug Reactions to Biopharmaceuticals A New Challenge Sheila C Noble Senior Pharmacist Yellow...
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Transcript of Adverse Drug Reactions to Biopharmaceuticals A New Challenge Sheila C Noble Senior Pharmacist Yellow...
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 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
ADRs to regular xenobiotics Types ABCDE Augmented, Bizarre, Chronic, Delayed, End of
treatment Suggested classification of ADR to
biopharmaceuticals 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)
Alpha (α) High cytokine administration cytokine release syndrome
CARDS Pichler classification of biopharmaceuticals ADRs(2)
Beta (β) Hypersensitivity – three forms of allergy
Immediate IgE Delayed IgG mediated reactions Delayed T-cell mediated reactions
CARDSRisk of allergy with MABs
Chimeric – mixed mouse/human DNA - ximab
Humanised – 95% human
- zumab
Human – fully human
- mumab
High
Low
CARDS Pichler classification of biopharmaceuticals ADRs(3)
Gamma () Immune (cytokine) imbalance syndromes – immunological
features but not due to high cytokines or hypersensitivity.
Immunodeficiency e.g. recurrence of latent infection Autoimmunity e.g. Lupus with infliximab Autoinflammatory e.g.psoraisis with TNFα blockers or IFN α
Varied and rare – individual predisposition such as atopy or co-morbidity
CARDS Pichler classification of biopharmaceuticals ADRs(4)
Delta () Cross reactivity. Antibodies generated to an antigen over-
expressed 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)
Epsilon () Non-immunological side effects due to unknown
functions of the biological agent given or targeted Psychiatric ADRs with Interferon α
CARDS 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 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 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 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 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)
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
CARDSPML (2) - Natalizumab
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
CARDSLeukemias with anti-TNFα
FDA reported increased incidence of malignancies in adolescents & children treated with TNFα blockers ( immune imbalance)
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 Infusion reactions to biopharmaceuticals
Any biopharmaceutical could cause IgE infusion reaction (β) – Anaphylaxis kit ready
Rituximab cetuximab and infliximab – pre-treat with antihistamines/paracetamol/ glucocorticoid
Initial low and slow regimen In RA concomitant use of methotrexate as
appropriate reduced production of antibodies
CARDSReporting ADRs
Submit Yellow Cards for all ADRs to Black Triangle Biopharmaceuticals including Biosimilars 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