Safety of IVIgG

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Safety of IVIgG

• Elspeth McIntosh
• SNBTS Medical Information and
• Pharmacovigilance Manager

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Plasma

• Non-UK Plasma - USA or Germany
• All suppliers audited by SNBTS and approved by
  the MHRA
• Unpaid donors wherever possible
• Meet Red Book/EU Blood Directive and/or FDA
  requirements
• Donor selection as per the UK
• Epidemiological data satisfactory

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Plasma Testing

• Plasma tested for
• HBsAg
• Anti- HCV
• Anti-HIV
• ALT
• PCR for HCV, HBV, HIV, Parvovirus B19

• Plasma pools tested for
• HBsAg
• Anti- HCV
• Anti-HIV
• PCR for HCV, HBV, HIV, Parvovirus B19

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Product Safety

• Full Traceability From Donor To Final Product
• Notification System For Advising Of Post Donation
  Infections
• Validated Virus Elimination Step(s)
• Control Of Process To Prevent Re-contamination
  After Virus Elimination Step
• Clinical Trial Data
• Post Marketing Surveillance

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Virus Inactivation and Removal

• Devise methods that will selectively inactivate
  and/or remove viruses without undue product
  damage/loss.
• Study relevant test viruses in scaled-down
  process.
• Ensure that method is capable of giving the
  degree of virus inactivation/removal required.

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Virus Inactivation and Removal

• Scale-up the process to ensure that the
  small-scale results can be fully reproduced at
  production scale.
• Validate the production scale operation to ensure
  that this has been achieved.
• Monitor and control the operations to prove that
  the procedure has been accomplished correctly on
  every occasion.

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Virus Safety

• Cold ethanol fractionation
• pH4/pepsin virus inactivation
• effective against
• enveloped viruses e.g. HIV, Hep B and C
• and non-enveloped viruses e.g. Hep A

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vCJD Precautions

• All PFC plasma imported from countries with no
  vCJD cases and little or no BSE.
• Donors selection processes designed to exclude
  those who may represent a risk.
• Decontamination of UK fractionation facilities
  before processing of non-UK plasma in 1998.

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vCJD Precautions

• Very low level of infectivity in plasma pool
  should an infective donation be processed.
• Research work identifies the potential for prion
  reduction during manufacturing.
• So
• Very low risk of vCJD being transmitted via PFC
  products.

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SNBTS IVIgG Clinical Use

• SNBTS IVIgG supplied since 1985
• 270kgs used every year
• Licensed for use in
• 1o and 2o Hypogammaglobulinaemia
• Children with HIV
• Bone Marrow Transplant
• Kawasaki Disease
• ITP
• Guillain Barre Syndrome

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Antibody Profile

• Adenovirus
• Chlamydia
• CMV
• Coxsackie B2
• Epstein Barr
• Herpes Simplex
• Influenza A B

• Measles
• Mumps
• Mycoplasma
• Q fever
• RSV
• Rotavirus
• Varicella Zoster

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Serious ADRs

• Serious Reactions to IVIgG are rare but the
  follwing are well described.
• Acute Renal Failure
• Anaphylaxis/Anaphylactoid Reactions
• Aseptic Meningitis
• Hypertension
• Haemolytic Reactions

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Non Serious ADRs

• Idiosyncratic batch related reactions -
• One or more of the following symptoms pyrexia,
  rigors, backache, nausea/vomiting, malaise,
  breathlessness, rash, hyper or hypotension,
  headache.

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IVIgG for Neonatal Use

• 6000 patients, 32 studies.
• Cochrane Review - Prevention of infection in
  pre-term/LBW infants
• Cochrane Review - Treatment of infection in
  neonates.
• Cochrane Reviews - Isoimmune haemolytic jaundice
  in neonates

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Neonatal Use - SNBTS IVIgG

• Small trial early 1990s
• Randomised to IVIgG or 5 Dextrose
• Study to small to produce significant results
• No product related adverse events
• AND
• No reports of neonatal reactions in routine use.

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Neonatal ADRs

• Cochrane Reports
• No Serious Adverse Reactions.
• Non-serious Adverse Reactions transient, included
  hypotension, tachycardia, and haemolysis
• related to too rapid infusion of placebo or
  immunoglobulins.
• One study - increase in respiratory rate
  following the first infusion of IVIG

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Causality

• Temporal relationship
• Pharmacological plausibility
• Recognised class effect
• Dechallenge/rechallenge
• Underlying illness and medications
• Irreversible events
• Transient/episodic events

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Topics covered

• Plasma selection
• Virus safety
• vCJD
• Clinical use of SNBTS IVIgG
• Neonatal experience
• Adverse reactions

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Conclusion

• SNBTS IVIgG is a well established product.
• Steps in place to reduce risk of virus
  transmission/vCJD.
• Low overall risk of adverse reactions.