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