Immunoglobulins for Intravenous Administration (IVIGs) How to Use Them & Do They Differ?

Transcription

1 Immunoglobulins for Intravenous Administration (IVIGs) How to Use Them & Do They Differ? Tor-Einar Svae, Medical Engineer Senior Vice President, Scientific & Medical Affairs, Immunology & Hematology Octapharma USA Inc., Hoboken, New Jersey New England Chapter INS, Waltham, MA October 9, 2014

2 Disclaimer Conflict of interest I am currently employed by Octapharma USA Inc., Department for Scientific & Medical Affairs Compliance The information given is factual and complete to the best of my knowledge, and any discussion of topics beyond the labeling of US IVIGs has been requested covered by the invitee ( from September 11, 2014) The black box warning for the class of products discussed (IVIG) will be addressed during the presentation This presentation is for educational use only

3 Overview I. US immunoglobulin market and trends II. IVIGs approved in the US and their intended use III. Adverse drug reactions (ADRs) following the use of IVIG and how to mitigate the risk for such events IV. Manufacturing and formulation of IVIGs and the impact on their ADR profile V. IVIGs ADR profile and the clinical relevance of optimal product selection

4 Immunoglobulins Intravenous administration (IVIG) Immune modulation and replacement therapy 5% (50 mg/ml) also 3-6% 10% (100 mg/ml) also 9-12% Hybrids IV for SC administration 10% (100 mg/ml) 10% (100 mg/ml) with rhuph20 as facilitator Subcutaneous administration (SCIG) Replacement therapy 16% (160 mg/ml) 16.5% (165 mg/ml) 20% (200 mg/ml)

5 Replacement therapy vs. immune modulation Diversity Replacement therapy Immune modulation Stability

6 Consumption of immunoglobulins (IgG total) in 2013 by selected countries Grifols Meeting Report 2014.

7 World distribution of IVIG by area in 2012 based on usage in kg MRB Report 2012.

8 Historical US consumption of immunoglobulins (IgG total) In 2012 SCIG accounts for 8.1% of the US consumption of IgG total MRB Report 2012.

9 Bioavailability & serum concentrations over time after IVIG vs. SCIG infusion Infusion-related adverse reactions End of dose weakening (break-through infections?) Jolles et al, Biol Ther 2011; DOI /s

10 Indications for which IVIG is used today Most of this is off-label!!! (Not necessarily the main IVIG volume)

11 Indications approved by the FDA for IVIGs & SCIG IVIG product PID CLL ITP KD CIDP MMN Carimune NF 3-12% X X Bivigam 10% Flebogamma 5% Flebogamma 10% X X X Gammagard Liquid 10% (also SCIG for PID) X X Gammagard S/D both 5 and 10% X X X X Gammaked 10% (=Gamunex-C 10%, also SCIG for PID) X X X Gammaplex 5% X X Gamunex-C 10% (also SCIG for PID) X X X Octagam 5% X Octagam 10% X Privigen 10% X X Hizentra 20% (only SCIG) X FDA approved US package inserts 2014.

12 Top-10 indications for IVIG/SCIG in the US in 2012 (not all FDA approved) Estimated largest growth (up to 3%) until 2017 will be in Solid Organ Transplant and Bone Marrow Transplant (BMTx) MRB Report

13 Doses & intervals approved by the FDA for IVIGs & SCIG Indication Dose [mg/kg] Interval PID (both IVIG & SCIG) IVIG: SCIG: above/4 or 2* IVIG: Every 3-4 weeks SCIG: Weekly or Biweekly CLL (IVIG only) 400 Every 3-4 weeks ITP (IVIG only) (total: 2000) For 5-2 consecutive days KD (IVIG only) 400 or 1000 For 4 consecutive days or single dose CIDP (IVIG only) Loading 2000 Maintenance 1000 Every 3 weeks MMN (IVIG only) *Correction factor 1.37 and 1.53, if used FDA approved US package inserts (based on clinical response) Monthly

14 Infusion speed of 5% vs. 10% IVIGs start vs. max 3 phases every 30 minutes 3 phases every 30 minutes FDA approved US package inserts Dosing ranges from 0.2 to 2.4 ( x 5-2) g/kg every 3-4 weeks or as a single infusion event

15 Common ADRs with 5% and 10% IVIGs Might be less serious than with 5% FDA approved US package inserts Berger M. J Allergy Clin Immunol Pract 2013; 1:

16 Patients with ADRs by infusion of 5% IVIG & recommended infusion speed ramp-up Berger M. J Clin Immunol 2004; 24:

17 Generic black box warning issued by the FDA for IVIGs in the US WARNING: THROMBOSIS, RENAL DYSFUNCTION, and ACUTE RENAL FAILURE See full prescribing information for complete boxed warning Thrombosis may occur with immune globulin intravenous (IVIG) products, including {product}. Risk factors may include: advanced age, prolonged immobilization, hypercoagulable conditions, history of venous or arterial thrombosis, use of estrogens, indwelling vascular catheters, hyperviscosity, and cardiovascular risk factors. Renal dysfunction, acute renal failure, osmotic nephrosis, and death may occur in predisposed patients with IVIG products, including {product}. Renal dysfunction and acute renal failure occur more commonly with IVIG products containing sucrose. {product} does {not} contain sucrose. For patients at risk of thrombosis, renal dysfunction or acute renal failure administer {product} at the minimum dose and infusion rate practicable. Ensure adequate hydration in patients before administration. Monitor for signs and symptoms of thrombosis and assess blood viscosity in patients at risk for hyperviscosity. FDA approved US package inserts 2014.

18 ADRs following IVIG infusion Occurring as often as in 20-80% of patients at one time or another and 5-30% of the infusions More often in autoimmune, neurological, and hematological patients than in subjects with various immune deficiencies ~60% are immediate, i.e. during-within 6 hours Mild/common: Headache, chills/rigors, fever (pyrexia), flushing, muscular/joint pain (myalgia/ arthralgia), back pain, abdominal pain, nausea, vomiting, anxiety, discomfort (malaise), fatigue, infusion site pain/thrombosis/swelling/ erythema, hypotension, hypertension, tachycardia Severe/rare: Hypersensitivity reactions (more common) with everything from urticaria, itching, flushing, chest tightness, dyspnea, wheezing, acute anxiety, circulatory collapse to anaphylaxis (IgE mediated, anti-iga(?), shortly after infusion start), anaphylactoid reaction (not IgE mediated, after some hours), transfusionrelated acute lung injury (TRALI, within 6 hours) Stiehm ER. Transf Med Rev 2013; 27: Berger M. J Allergy Immunol Pract 2013; 1:

19 ADRs following IVIG infusion ~40% are delayed, i.e. after 6 hours-1 week (~half within 72 hours) Mild-moderate/common-less common: Persistent headache, migraine, aseptic meningitis, hyponatremia, neutropenia, diarrhea, direct Coombs positive, hemolytic anemia, serum sickness with arthritis, dermatologic complications (e.g. eczema) Severe/rare: Renal complications from elevated BUN/ creatinine via oliguria to renal failure (for dialysis and/ or transplantation), thromboembolic complications (transient cerebral ischemia attacks, stroke, myocardial infarct, deep venous thrombosis, and pulmonary embolism), hemolysis (possibly followed by hemoglobinuria and renal failure), pulmonary complications (e.g. pulmonary edema and pleural effusion), enterocolitis (in prematures) <1% late, i.e. 1 week-months Moderate/less common: Interference with vaccine effectiveness (especially live virus vaccines such as measles, mumps, and rubella) and/or immune diagnosis Stiehm ER. Transf Med Rev 2013; 27: Berger M. J Allergy Immunol Pract 2013; 1:

20 Patient risk factors for IVIG infusion ADRs Anti-IgA (of IgG or IgE class) Fever/infection (e.g. sepsis) at time of infusion Autoimmunity (inflammatory state) Advanced/older age (>65 years) Dehydration Diabetes mellitus Renal insufficiency Concurrent use of nephrotoxic drugs Prior/current cardiovascular disease or thrombosis Hypertension Elevated serum proteins/hyperviscosity High lipids/cholesterol Estrogen use Hereditary hypercoagulable state such as Factor V Leiden Obesity (use of adjusted body weight in 100+ kg patients) Prolonged immobility/air travel Permanent indwelling venous catheter (e.g. Portacath) Stiehm ER. Transf Med Rev 2013; 27: Berger M. J Allergy Immunol Pract 2013; 1:

21 Infusion risk factors for IVIG infusion ADRs First infusion Long intervals (>6 months) between infusions Prior history of infusion reaction to any immunoglobulin Product (even lot) switch No pre- or post-infusion hydration IV infusion of ml/10 kg normal saline or 5% dextrose in water within minutes before, and/or drink ml/10 kg ±24 (+72) hours before/after, infusion No pre-medication E.g. analgesics, non-steroidal anti-inflammatory drugs (NSAID), antihistamines, and/or corticosteroids + aspirin and heparin Large dose single (limit to mg/kg/day) or overall Rapid infusion and aggressive ramp-up Anti-IgA problem(?) start at mg/kg/min ( test dose ); renal and thromboembolic complications(?) not more than mg/kg/min at maximum and double ramp-up time from a normal start at mg/kg/min to 1 hour Brand-specific issue 5% vs. 10% product and ADR profile/fingerprint select in a prophylactic manner? Stiehm ER. Transf Med Rev 2013; 27: Berger M. J Allergy Immunol Pract 2013; 1:

22 What to do when things go wrong? No patients are alike no universal formula exists no size fits all Be vigilant especially with sleeping (long infusion times) and unconscious patients (no self-control ) Reduce infusion speed to initial, or Stop infusion completely Await for possible correction of ADR Think, consult, decide, and act!!! Treat ADR [always have adrenalin (Epinephrin) available can alone be lifesaving] Resume infusion at a lower speed than when ADR emerged, or Delay infusion to next day, if necessary Select a better product for that particular patient i.e. provide optimal care?

23 Human plasma as raw material for IVIGs Diversity is needed to make an ideal polyvalent immunoglobulin concentrate Buchacher A & Iberer G. Biotechnol J 2006; 1:

24 Front-end harvesting of crude IgG fraction Plasma Supernatant (I+)II+III Cryoprecipitate FVIII/VWF Fibrinogen Cryosupernatant Optional removal of precipitate I Optional harvesting of ATIII, FIX, PCC Supernatant (I+)II+III Precipitate (I+)II+III Precipitate (I+)III (waste) Precipitate II (IVIG/SCIG path) ph Alcohol Temperature Filtrate (I+)II+III Precipitate IV (waste) Filtrate IV (albumin path) Buchacher A & Iberer G. Biotechnol J 2006; 1:

25 Down-stream manufacturing of IVIGs Reconstituted precipitate II Paste cleaning + UF/DF Virus removal and/or inactivation (Chromatography purification) (Low ph treatment) UF/DF + formulation Filling (+lyophilization) to final product Buchacher A & Iberer G. Biotechnol J 2006; 1:

26 Manufacturing strategy & accompanying proteins/hemagglutinins Anti-A/anti-B antibodies Anti-A/anti-B antibodies IgG-accompanying proteins IgG-accompanying proteins Purity as high as 95-98% IgG of total protein Berger M. J Allergy Clin Immunol Pract 2013; 1:

27 IVIG-induced hemolysis development First new 10% IVIG enters the market (3.7%) Desborough MJ, et al. Transf Med ; doi: /tme Daw Z, et al. Transfusion 2008; 48:

28 IVIG formulations Stabilizers Mostly in the range mmol/l Monosaccharides/sugar alcohols (glucose and D-sorbitol) Disaccharides (sucrose and maltose) Amino acids (glycine and L-proline) Others such as albumin, PEG, Polysorbate 80, NaCl in smaller amounts ph (acidity) 10% liquid ( ) < 5% liquid ( ) < % lyophilized ( ) Osmolality Mainly dependent on the stabilizer amount and composition Mostly in the range mosmol/kg (overall ) Viscosity Dependent on both the IgG concentration and stabilizer amount and composition 5% ( mpas s at +20 C) < 10% ( mpas s at +20 C) human plasma IgA Mostly in the range mg/g IgG (overall ) FDA approved US package inserts Viscosity tested in-house.

29 IVIG formulation properties of concern in patients with various risk factors Risk factors Volume load from 5% vs. 10% High sugar (sucrose?) content High sodium content High osmolality (viscosity?) Low ph IgA L-proline D-sorbitol/ fructose Maltose Geriatric age X X X X Pediatric age X X X X Renal impairment X X X X X Cardiovascular disease Thromboembolic disorders Obesity Immobility (Pre)diabetes melitus X X X X X X X (glucose) X X May interfere with old glucose tests IgA deficiency with anti-iga X Hyperprolinemia X Hereditary fructose intolerance X Corn allergy X E.g. Chérin P & Cabane J. Biodrugs 2010; 24:

30 Desire to drop sucrose due to renal failures Sucrose Sucrose Glucose Fructose Haemodialysis Osmotic nephrosis

31 Desire to shorten the IV infusion time to save costs 5% 10% Higher concentrations lower volume Cutting costs Higher infusion speed

32 Desire to switch to non-sugar IVIGs & 10% solutions

33 Moving further away from physiological ph ph

34 Shape changes of RBCs caused by the environment Hypotonic Normotonic Hypertonic

35 Age-dependent RBC selection by the spleen 100,000,000,000 = = ~30 ml red blood cells per day 3 μm

36 ADR retrospective study US IVIGs Main data sources read-out date February 2012 The Plasma Proteins Market in the United States 2010 report from July 2011 (The Marketing Research Bureau, Inc., US) Study period January 2004 to December 2011 Products ADRs Six largest IVIGs on the US market, as well as in the rest of the World Those which emerged for at least 3 (50%) out of 6 products

37 ADR retrospective study US IVIGs Volume IVIG usage tons STD treatment doses 0.4 gr/kg x 70 kg = 28 gr 9,876,550 doses ADRs 10,544 ADRs per million STD treatment episodes 1147 (~1-10% when corrected for underreporting)

38 ADR fingerprint of IVIG over 10 years Debes A, et al. Pharmacoepidemiology and Drug Safety 2007; 16:

39 ADR fingerprint of IVIGs over 13 years Dashti-Khavidaki S, et al. J Investig Allergol Clin Immunol 2009; 19:

40 ADR overall fingerprint of key IVIGs in the US over 8 years Top-50 ADRs 400 [n] No. 51 PULMONARY EMBOLISM (TEE) 0 CHILLS/RIGORS HEADACHE DYSPNOEA FEVER/PYREXIA NAUSEA VOMITING HAEMOLYSIS INFUSION RELATED REACTION RASH (ALL) URTICARIA BACK PAIN HYPERSENSITIVITY/ALLERGY MENINGITIS ASEPTIC ANAPHYLACTIC REACTION/SHOCK PRURITUS TACHYCARDIA BLOOD PRESSURE INCREASED HYPERTENSION CHEST PAIN HAEMOLYTIC ANAEMIA TREMOR FATIGUE DRUG INTOLERANCE ERYTHEMA ANAPHYLACTOID REACTION DIZZINESS HYPOTENSION ABDOMINAL DISCOMFORT/PAIN MALAISE OXYGEN SATURATION DECREASED COUGH HAEMOGLOBIN DECREASED CHEST DISCOMFORT PAIN BODY TEMPERATURE INCREASED HYPERHIDROSIS/INCREASED SWEATING DIARRHOEA DEATH RENAL FAILURE ACUTE ASTHENIA BLOOD PRESSURE DECREASED PNEUMONIA FLUSHING RENAL FAILURE (OTHERS) PAIN IN EXTREMITY ANXIETY INFLUENZA LIKE ILLNESS CYANOSIS CONVULSION NECK PAIN

41 ADR newcomers per million STD treatment episodes Top-50 ADRs [n/million STD] No. 51 PULMONARY EMBOLISM (TEE) 0 CHILLS/RIGORS HEADACHE DYSPNOEA FEVER/PYREXIA NAUSEA VOMITING HAEMOLYSIS INFUSION RELATED REACTION RASH (ALL) URTICARIA BACK PAIN HYPERSENSITIVITY/ALLERGY MENINGITIS ASEPTIC ANAPHYLACTIC REACTION/SHOCK PRURITUS TACHYCARDIA BLOOD PRESSURE INCREASED HYPERTENSION CHEST PAIN HAEMOLYTIC ANAEMIA TREMOR FATIGUE DRUG INTOLERANCE ERYTHEMA ANAPHYLACTOID REACTION DIZZINESS HYPOTENSION ABDOMINAL DISCOMFORT/PAIN MALAISE OXYGEN SATURATION DECREASED COUGH HAEMOGLOBIN DECREASED CHEST DISCOMFORT PAIN BODY TEMPERATURE INCREASED HYPERHIDROSIS/INCREASED SWEATING DIARRHOEA DEATH RENAL FAILURE ACUTE ASTHENIA BLOOD PRESSURE DECREASED PNEUMONIA FLUSHING RENAL FAILURE (OTHERS) PAIN IN EXTREMITY ANXIETY INFLUENZA LIKE ILLNESS CYANOSIS CONVULSION NECK PAIN

42 ADR fingerprint of IVIG A with newcomers Top-50 ADRs [n/million STD] Anaphylactic reaction/shock Hemolysis Death Anaphylactoid reaction Thromboembolic events CHILLS/RIGORS FEVER/PYREXIA HEADACHE DYSPNOEA NAUSEA URTICARIA VOMITING ANAPHYLACTIC REACTION/SHOCK RASH (ALL) HYPERSENSITIVITY/ALLERGY HAEMOLYSIS BACK PAIN ERYTHEMA TACHYCARDIA BLOOD PRESSURE INCREASED PRURITUS TREMOR HYPERTENSION DEATH MENINGITIS ASEPTIC DIZZINESS MALAISE DRUG INTOLERANCE FATIGUE HYPOTENSION ABDOMINAL DISCOMFORT/PAIN COUGH ANAPHYLACTOID REACTION OXYGEN SATURATION DECREASED CHEST PAIN DIARRHOEA INFUSION RELATED REACTION CYANOSIS BLOOD PRESSURE DECREASED CHEST DISCOMFORT HYPERHIDROSIS/INCREASED SWEATING FLUSHING ANXIETY NECK PAIN CONVULSION PULMONARY EMBOLISM FEELING COLD BODY TEMPERATURE INCREASED PAIN IN EXTREMITY INFLUENZA LIKE ILLNESS PAIN HYPOXIA PNEUMONIA MUSCULOSKELETAL STIFFNESS MUSCLE SPASMS

43 ADR fingerprint of IVIG B with newcomers Top-50 ADRs [n/million STD] Hemolysis Anaphylactoid reaction Renal failure Anaphylactic reaction/shock 10 0 HAEMOLYSIS DYSPNOEA HAEMOLYTIC ANAEMIA INFUSION RELATED REACTION HEADACHE NAUSEA HAEMOGLOBIN DECREASED FEVER/PYREXIA VOMITING CHILLS/RIGORS RASH (ALL) MENINGITIS ASEPTIC CHEST PAIN HYPERTENSION BACK PAIN COOMBS TEST POSITIVE HYPERSENSITIVITY/ALLERGY BLOOD LACTATE DEHYDROGENASE INCREASED FATIGUE URTICARIA CHEST DISCOMFORT TACHYCARDIA BLOOD BILIRUBIN INCREASED PRURITUS BODY TEMPERATURE INCREASED ASTHENIA PNEUMONIA HYPOTENSION TREMOR PAIN HYPERHIDROSIS/INCREASED SWEATING ANAPHYLACTOID REACTION OXYGEN SATURATION DECREASED BLOOD PRESSURE INCREASED ARTHRALGIA ABDOMINAL DISCOMFORT/PAIN RENAL FAILURE (OTHERS) SEPSIS/SEPTIC SHOCK WHEEZING RESPIRATORY RATE INCREASED DIZZINESS DIARRHOEA MYALGIA DRUG INTOLERANCE PAIN IN EXTREMITY ASPARTATE AMINOTRANSFERASE INCREASED ERYTHEMA RENAL FAILURE ACUTE FLUSHING ANAPHYLACTIC REACTION/SHOCK

44 ADR fingerprint of IVIG C with newcomers Change to end 2013 Top-50 ADRs [n/million STD] Hemolysis Renal failure Thromboembolic events 5 0 VOMITING NAUSEA INFUSION RELATED REACTION HEADACHE CHILLS/RIGORS FEVER/PYREXIA HAEMOLYTIC ANAEMIA DYSPNOEA HAEMOLYSIS ANAEMIA HAEMOLYTIC AUTOIMMUNE HYPERTENSION HAEMOGLOBIN DECREASED RESPIRATORY FAILURE TACHYCARDIA ASTHENIA URTICARIA PRURITUS CHEST DISCOMFORT MENINGITIS ASEPTIC CHEST PAIN MALAISE OXYGEN SATURATION DECREASED INFLUENZA LIKE ILLNESS FATIGUE DRUG INTOLERANCE DIZZINESS ABDOMINAL DISCOMFORT/PAIN RENAL FAILURE (OTHERS) COOMBS TEST POSITIVE WHEEZING MYOCARDIAL INFARCTION CEREBROVASCULAR ACCIDENT ANAEMIA BLOOD CULTURE POSITIVE SINUSITIS CHROMATURIA BRONCHOSPASM BLOOD LACTATE DEHYDROGENASE INCREASED RESPIRATORY DISTRESS PHOTOPHOBIA ERYTHEMA PAIN HYPERHIDROSIS/INCREASED SWEATING DIARRHOEA BLOOD PRESSURE DECREASED BLOOD CREATINE INCREASED FEELING ABNORMAL HYPOXIA PALLOR BLOOD BILIRUBIN INCREASED

45 ADR fingerprint of IVIG D with newcomers Top-50 ADRs [n/million STD] Renal failure Anaphylactoid reaction Anaphylactic reaction/shock Thromboembolic events 5 0 RENAL FAILURE ACUTE HEADACHE CHILLS/RIGORS FEVER/PYREXIA INFUSION RELATED REACTION BLOOD CREATINE INCREASED RASH (ALL) RENAL FAILURE (OTHERS) NAUSEA DYSPNOEA CHEST PAIN ANAPHYLACTOID REACTION PAIN DIALYSIS VOMITING MENINGITIS ASEPTIC DRUG INTOLERANCE HYPOTENSION TREMOR ASTHENIA BLOOD PRESSURE INCREASED TACHYCARDIA ABDOMINAL DISCOMFORT/PAIN BODY TEMPERATURE INCREASED RESPIRATORY DISTRESS PRURITUS DIZZINESS ANURIA ANAPHYLACTIC REACTION/SHOCK FATIGUE DEHYDRATION CONFUSIONAL STATE OXYGEN SATURATION DECREASED HYPERHIDROSIS/INCREASED COLD SWEAT LEUKOCYTOSIS RESTLESSNESS URTICARIA BACK PAIN AGITATION MUSCULAR WEAKNESS BLOOD CULTURE POSITIVE ASTHMA NECK PAIN MYALGIA SEPSIS/SEPTIC SHOCK MYOCARDIAL INFARCTION NEUTROPENIA HYPERSENSITIVITY/ALLERGY ERYTHEMA

46 ADR fingerprint of IVIG E with newcomers Top-50 ADRs 35 [n/million STD] Renal failure Anaphylactoid reaction Thromboembolic events Hemolysis DYSPNOEA CHILLS/RIGORS HEADACHE BACK PAIN COUGH OXYGEN SATURATION DECREASED BLOOD PRESSURE INCREASED WHEEZING RENAL FAILURE ACUTE PRURITUS NECROTISING COLITIS CHEST PAIN NAUSEA RASH (ALL) ABDOMINAL DISCOMFORT/PAIN HYPOAESTHESIA VOMITING URTICARIA DRUG INTOLERANCE ANAPHYLACTOID REACTION DIZZINESS MALAISE PAIN DIARRHOEA TREMOR MUSCULAR WEAKNESS FEVER/PYREXIA HYPERTENSION ERYTHEMA CHEST DISCOMFORT BODY TEMPERATURE INCREASED PAIN IN EXTREMITY DEEP VEIN THROMBOSIS PARAESTHESIA CEREBROVASCULAR ACCIDENT RESPIRATORY DISTRESS COLD SWEAT CONFUSIONAL STATE FEELING HOT ABDOMINAL DISTENSION INFUSION RELATED REACTION MENINGITIS ASEPTIC HAEMOLYTIC ANAEMIA HYPOTENSION ANXIETY FEELING COLD HEART RATE INCREASED MUSCLE SPASMS PALLOR ASPARTATE AMINOTRANSFERASE INCREASED

47 ADR fingerprint of IVIG F with newcomers Top-50 ADRs [n/million STD] Anaphylactoid reaction Thromboembolic events Anaphylactic reaction/shock 10 0 INFUSION RELATED REACTION NAUSEA HEADACHE VOMITING DYSPNOEA RASH (ALL) FEVER/PYREXIA MALAISE CEREBROVASCULAR ACCIDENT CHILLS/RIGORS DRUG INTOLERANCE NEUTROPENIA CONFUSIONAL STATE BLOOD PRESSURE INCREASED CONVULSION LOSS OF CONSCIOUSNESS ANAPHYLACTOID REACTION CHEST DISCOMFORT CARDIO-RESPIRATORY ARREST WHITE BLOOD CELL COUNT DECREASED TREMOR FATIGUE HYPERHIDROSIS/INCREASED SWEATING OEDEMA PERIPHERAL PRURITUS PAIN DEEP VEIN THROMBOSIS ASPARTATE AMINOTRANSFERASE INCREASED LIP SWELLING BLOOD ALKALINE PHOSPHATASE INCREASED CHEST PAIN HYPOTENSION COUGH BODY TEMPERATURE INCREASED ASTHENIA CYANOSIS PULMONARY EMBOLISM ARTHRALGIA MYALGIA PALLOR GENERAL PHYSICAL HEALTH DETERIORATION CARDIAC ARREST THROMBOCYTOPENIA DISORIENTATION SKIN DISCOLOURATION NEUROPATHY PERIPHERAL URTICARIA BACK PAIN MENINGITIS ASEPTIC ANAPHYLACTIC REACTION/SHOCK

48 Renal failure & related events profiles [n/million STD] There was a correlation between renal failure and sucrose (+ D-sorbitol), volume, sodium, and osmolality, but not with the other sugars as well as secondary to hemolysis (possible also an effect from low ph) IVIG A IVIG B IVIG C IVIG D IVIG E IVIG F RENAL FAILURE ACUTE RENAL FAILURE (OTHERS) BLOOD CREATINE INCREASED DIALYSIS ANURIA

49 Thromboembolic events profile [n/million STD] There was no correlation between thromboembolic events and volume, sodium, or osmolality IVIG A IVIG B IVIG C IVIG D IVIG E IVIG F PULMONARY EMBOLISM DEEP VEIN THROMBOSIS MYOCARDIAL INFARCTION MYOCARDIAL ISCHAEMIA

50 Anaphylactoid & anaphylactic reactions/ shock profile 80 IgA ~37 μg/ml [n/million STD] There was {no/a} correlation between anaphylactoid & anaphylactic reactions/shock and IgA content 30 IgA ~46 μg/ml IgA ~720 μg/ml IgA 200 μg/ml 20 IgA 25 μg/ml IgA 50 μg/ml 10 0 IVIG A IVIG B IVIG C IVIG D IVIG E IVIG F ANAPHYLACTIC REACTION/SHOCK ANAPHYLACTOID REACTION

51 Hemolysis & related events profile [n/million STD] There was a correlation between hemolysis and manufacturing/formulation principles, but not osmolality IVIG A IVIG B IVIG C IVIG D IVIG E IVIG F HAEMOLYSIS HAEMOLYTIC ANAEMIA HAEMOGLOBIN DECREASED COOMBS TEST POSITIVE BLOOD LACTATE DEHYDROGENASE INCREASED ANAEMIA BLOOD BILIRUBIN INCREASED ANAEMIA HAEMOLYTIC AUTOIMMUNE

52 Hemolysis following IVIG infusion reported in EU BfArM Paul-Ehrlich-Institut (PEI) Germany. Bulletin Zur Arzneimittelsicherheit 2012.

53 EU experience with CP approved IVIGs skewed non-igg-related ADRs Dependent on IgG infusion

54 European country experience with ADRs after complete IVIG switch IVIG F + IVIG A = =1344 kg = 47,990 STD treatment episodes Relis, Troll, and IMS Health Reports

55 European country experience with ADRs after complete IVIG switch Ratio = 3.04 p = Relis, Troll, and IMS Health Reports

56 European country experience with ADRs after complete IVIG switch With IVIG F Besides a single case of thromboembolic event in the period from product launch in 1994 to 2009, the ADRs reported for IVIG F have been pretty uneventful and typical for IVIGs historically seen The only ADR that happened twice or more was exanthema (widespread rash) With IVIG A The ADRs occurred 3 times more often Thromboembolic events were more frequent The types of ADRs seen were also new for the first time in history Fatalities (deaths) were reported after the use of IVIG in the country Hemolysis has been reported after the use of IVIG in the country The rate of allergic reactions was even unusually high for IVIG A compared to historical data with IVIG F (~50% of all the ADRs reported for IVIG A) The country s experience follow the same pattern seen in the US for IVIG A vs. IVIG F according to Relis, Troll, and IMS Health Reports

57 Short case report IVIG & ADR Young adult (26 y) female with CVID on same IVIG (F) product for 15 years every monthly infusion was uneventful ( Feeling good!!! ) Had to change IVIG (A) due to business tender first infusion set-up thereafter was the same Experienced moderate side effects early during first infusion headache, fever, chills, rash, tightness of chest Infusion was stopped, patient got non-steroidal anti-inflammatory drug (NSAID), corticosteroid, and antihistamine, after which infusion could continue at a lower (initial) speed and be completed ADR was assumed to be related to the switch to a new IVIG, but no change back to original product was accepted by payer and patient was expected to develop tolerability to new IVIG Allergic reactions worsened significantly over next six monthly infusion, despite a reduced infusion speed (new lots) and pre-medication (hydration was normal), ending up with a fullblown, life-threatening anaphylactic shock treated at ICU after adrenalin injection at infusion center recovered, but infusion was not completed and could not be resumed next day Patient was switched to SCIG and weekly infusions using a pump (no pre-medication done), but struggled with infusion site reactions and compliance issues (felt handling was difficult) Went back to original IVIG (based on an application for medical reasons ) tolerability was good as from first infusion, but still with pre-medication (causing 48 hours sleeping problems) After third infusion the pre-medication was stopped and the subsequent infusions went well until today (2 years later) I got my quality of life back!!!

58 Summary Immunoglobulins, both IVIG and SCIG, are widely used for patients with immune deficiencies (replacement therapy) and a broad range of autoimmune and inflammatory disorders (immune modulation) Half of the World production of immunoglobulins is used in North America, the consumption is increasing rapidly, and there is a trend towards more use of SCIG Most indications are off-label, but the main volume of immunoglobulins is used in FDA approved indications ADRs are pretty common when immunoglobulins are used, especially IVIGs, ranging from mild to severe and from immediate to late occurring

59 Summary IVIGs are different, especially in terms of manufacturing and formulation, which (might) impact the ADR profile of these products The single features of IVIGs allow clinicians to match the best product to the patients based on clinical conditions and comorbidities, although some historical assumptions do not correlate well with the clinical findings Pharmacovigilance (PV) data provides additional important information to the overall clinical performance ( fingerprint ) of an IVIG product or class In combination, the individual single features and PV data are helpful in providing the most optimal care for patients in receipt of IVIG

60