Safety of IVIgG

1. Safety of IVIgG Elspeth McIntosh SNBTS Medical Information and Pharmacovigilance Manager

2. 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

3. 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

4. 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

5. 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.

6. 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.

8. 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

9. 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. CJD (sporadic) has been transmitted by: medical products prepared from human pituitary glands human tissue medical procedures no association between CJD and prior blood transfusion. no excess CJD in recipients of blood products. no CJD in populations of heavily treated patients. no CJD in individuals exposed to products derived from donors who then developed CJD. Evidence of vCJD transmission by red cell transfusion Exclude following as donors: family history of CJD, previously treated with hormones prepared using pituitary glands, human growth hormone, human gonadotrophin, recipients of dura mater, corneal grafts, persons resident in the UK for more than 6 months between 1980�96. decontamination of UK fractionation facilities (PFC, BPL). severe cleaning (NaOH/ Hypochlorite + heat) new equipment new reagents, components, etc . CJD (sporadic) has been transmitted by: medical products prepared from human pituitary glands human tissue medical procedures no association between CJD and prior blood transfusion. no excess CJD in recipients of blood products. no CJD in populations of heavily treated patients. no CJD in individuals exposed to products derived from donors who then developed CJD. Evidence of vCJD transmission by red cell transfusion Exclude following as donors: family history of CJD, previously treated with hormones prepared using pituitary glands, human growth hormone, human gonadotrophin, recipients of dura mater, corneal grafts, persons resident in the UK for more than 6 months between 1980�96. decontamination of UK fractionation facilities (PFC, BPL). severe cleaning (NaOH/ Hypochlorite + heat) new equipment new reagents, components, etc .

10. 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.

11. 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

12. Antibody Profile Adenovirus Chlamydia CMV Coxsackie B2 Epstein Barr Herpes Simplex Influenza A + B Measles Mumps Mycoplasma Q fever RSV Rotavirus Varicella Zoster

13. 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

14. 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.

15. 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 Ohlsson A, Lacy JB. Intravenous immunoglobulin for preventing infection in preterm and/or low-birth-weight infants. The Cochrane Database of Systematic Reviews 2004, Issue 1. Art. No.: CD000361. DOI: 10.1002/14651858.CD000361.pub2 5000 babies - 19 studies Ohlsson A, Lacy JB. Intravenous immunoglobulin for suspected or subsequently proven infection in neonates. The Cochrane Database of Systematic Reviews 2004, Issue 1. Art. No.: CD001239. DOI: 10.1002/14651858.CD001239.pub2. 553 patients - 6 studies Alcock GS, Liley H. Immunoglobulin infusion for isoimmune haemolytic jaundice in neonates. The Cochrane Database of Systematic Reviews 2002, Issue 3. 189 patients - 7 studies Ohlsson A, Lacy JB. Intravenous immunoglobulin for preventing infection in preterm and/or low-birth-weight infants. The Cochrane Database of Systematic Reviews 2004, Issue 1. Art. No.: CD000361. DOI: 10.1002/14651858.CD000361.pub2 5000 babies - 19 studies Ohlsson A, Lacy JB. Intravenous immunoglobulin for suspected or subsequently proven infection in neonates. The Cochrane Database of Systematic Reviews 2004, Issue 1. Art. No.: CD001239. DOI: 10.1002/14651858.CD001239.pub2. 553 patients - 6 studies Alcock GS, Liley H. Immunoglobulin infusion for isoimmune haemolytic jaundice in neonates. The Cochrane Database of Systematic Reviews 2002, Issue 3. 189 patients - 7 studies

16. 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.

17. 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 No major adverse effects of IVIG were reported in any of the studies.� Ohlsson A, Lacy JB. Intravenous immunoglobulin for preventing infection in preterm and/or low-birth-weight infants. �There were no reported adverse reactions as a consequence of IVIg� Alcock GS, Liley H. Immunoglobulin infusion for isoimmune haemolytic jaundice in neonates. Ohlsson A, Lacy JB. Intravenous immunoglobulin for suspected or subsequently proven infection in neonates. Other reports - most side effects were transient and included hypotension, tachycardia, and haemolysis. These side effects were felt to be related to too rapid infusion of placebo or immunoglobulins. Spady et al noted a small but significant increase in respiratory rate following the first infusion of IVIG No major adverse effects of IVIG were reported in any of the studies.� Ohlsson A, Lacy JB. Intravenous immunoglobulin for preventing infection in preterm and/or low-birth-weight infants. �There were no reported adverse reactions as a consequence of IVIg� Alcock GS, Liley H. Immunoglobulin infusion for isoimmune haemolytic jaundice in neonates. Ohlsson A, Lacy JB. Intravenous immunoglobulin for suspected or subsequently proven infection in neonates. Other reports - most side effects were transient and included hypotension, tachycardia, and haemolysis. These side effects were felt to be related to too rapid infusion of placebo or immunoglobulins. Spady et al noted a small but significant increase in respiratory rate following the first infusion of IVIG

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

19. Topics covered Plasma selection Virus safety vCJD Clinical use of SNBTS IVIgG Neonatal experience Adverse reactions

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