Immune Globulin Therapies
Melvin Berger, M.D., Ph.D.,
Rainbow, Babies & Children’s Hospital
Case Western Reserve University, Cleveland, OH
• Consulting: AHIP (CDC), CSL-Behring, FFF, Grifols,
Pfizer, Talecris
• Speaker’s bureaus: CSL-Behring, Talecris
• Research support: Talecris, NIH
• Advisory Committees/Councils: IDF, CIS
• Off label: Dosages, Use of IGIV by sub-cu route
Objectives
• 1. Understand Indications for IgG Replacement Therapy
• 2. Learn Rationale for Selecting IgG Dosing Regimen
• 3. Discuss Advantages and Disadvantages of IV and
Sub-cu Routes of IgG Delivery
• 4. Learn How to Transition Patients From IV to
Sub-cu Therapy
Major Antibody Deficiency Syndromes:
Bruton’s (X-linked) Agammaglobulinemia
Transient Hypogam. of Infancy
(Delayed Maturation of Humoral Immunity)
Common Variable Immune Deficiency
Hyper IgM Syndromes (X-linked and others)
SCID s/p HSCT
IgA Deficiency
Criteria for Determining the Need for
Immunoglobulin Replacement Therapy
“It must be demonstrated that:
1. The patient has significant and clearly documented
infectious morbidity
2. Other disorders (allergy, anatomic defects) have
been sought and treated aggressively.
3. Other modes of therapy (antimicrobial, anti-
inflammatory) inadequate or poorly tolerated
4. There is a laboratory abnormality confirming
immunodeficiency ―
Practice Parameters of Joint Council of Allergy, Asthma and Immunology
Bonilla FA, et al. Ann Allergy, Asthma, and Immunology. 2005;94:S1-S63.
What is Immune Globulin (Human) ?
• Made from Pooled Plasma From >10,000 Donors
• All use cold ethanol fractionation (Cohn)
• Content >95% IgG: IgA and other constituents
vary in different products
• Stabilizers, chemical treatments and forms vary
• All products use multiple safety steps beginning
with donor selection, screening, specific viral
inactivation/removal steps in manufacture
• Usual regimen: 300-800 mg/kg Q 21-28 days IV or
50-200 mg/kg/wk sub-cutaneously (SC)
Higher doses in pts with sinus, lung disease
• True anaphylaxis rare, even with IgA def. patients
Landmarks in the History of
Immunoglobulin Replacement Therapy
Janeway and Gitlin prefer IM IVIG introduced and becomes Renewed interest
injections, and this becomes standard therapy due to in SCIG as alternative to
standard of care in US2 reduction of bacterial and IV therapy, especially for
non-bacterial infections4 home use5
1952 1953 1955 1980 1990s 2006
Bruton treats first patient diagnosed Berger introduces battery- First Sub-cu
with agammaglobulinemia with SC injections of powered pumps to slowly IgG
immune serum globulin (ISG)1 administer IM ISG by SC route3 Licensed in US
1. Bruton OC. Pediatrics. 1952;9:722-728.
2. Berger M. Clin Immunol. 2004;112:1-7.
3. Berger M. et al. Ann Intern Med. 1980;98:55-56.
4. Quartier P. et al. Jour Pediatrics. 1999;134:5:589-596.
5. Abrahamsen TG. Et al. Pediatrics. 1996;98:1127-1131.
Infection Frequency Is Reduced by
Immunoglobulin Replacement
90
80
70
60
Patients
(%) with at 50
least one 40
infection1 30
20
10
0
Before Diagnosis/Treatment Post IVIG Treatment
Busse PJ, et al. J Allergy Clin Immunol. 2002;109:1001-1004.
Skull S, Kemp A. Arch Dis Child. 1996;74:527-530.
Increased Efficacy of 0.05 gr/kg/wk vs 0.025 gr/kg/wk ISG (im)
UK MRC Working Party on Hypogammaglobulinemia Study
c. 1957, published by HMSO 1970
____________________________________
Condition p
• Febrile Episodes 500 mg/dL on 600 mg/kg/mo
2. Infections: Major Minor
IgG 500 3 16
―….in patients with chronic sinopulmonary disease doses
of IVIG that give serum IgG>500 mg/dL provide better
protection against infection‖
Effects of Higher Doses and Higher Serum IgG Levels in
Gamunex® Licensing Trial
(Roifman et al , Int. Immunopharm 3: 1325- 1333, 2003)
Dose “Validated” Infections
IGIV-C IGIV-SD
400 mg/kg 10.5 23.8
Level
900 mg/dL 5.6 19.2
Efficacy of High vs. Standard doses
of IGIV in PIDD Patients
standard high p
(adults 300 mg/kg/mo) (600 mg/kg/mo)
(kids 400 mg/kg/mo) (800 mg/kg/mo)
Infections 3.5±2.6 2.5±2.4 0.004
Days Infected 33 21 0.015
n=41 2/3 adults
Eijkhout et al Ann Int Med 135: 165-174, 2002.
Infections in Recent IgG Licensing Trials
Author Product SBI CI Other Inf.
• Ochs Vivaglobin (SC) 2006 0.04 (99) 0-0,014 4.43
• Church Gammagard Liq 2006 0 (95) 0-0.06 3.5
• Berger Flebogam 5% 2004 0.06 (99) 0-0.18 2.99
• Ochs Octagam 5% 2004 0.1 ( 98) 0.03-0.28 3.41
• DeGracia Flebogam 5% 2004 0.05 (SD) 0.15 2.2
• Roifman Gamunex 10% 2003 0.16* NR
SBI= serious bacterial infections: pneumonia, meningitis, visceral abscess,
osteomyelitis/septic arthritis, bacteremia/sepsis
*= ―validated‖ sinusitis and pneumonia. SBIs not reported per se.
Adverse Effects of IVIG
• Related to Underlying Infection
• Rate Related
• Non-Rate Related
• Related to High Dose Rx
Adverse Effects of IgG
• True Anaphylaxis-very rare
• “Anaphylactoid” (Rate related)
• Febrile
• Excess Fluid Volume and/or Salt Load
• Headache-Migraine- Aseptic Meningitis
• Renal Complications
• Thrombotic Complications
• Local Site Reactions from SCIG
• Viral Transmission (potential)
Renal and Thrombotic Complications
• Renal failure most often related to sucrose in certain products,
usually transient
• Hyperviscosity may occur in patients with pre-disposing factors
receiving high doses of IVIG
• Activation of leukocytes and/or platelets may occur, resulting in
clots or TRALI
Headache, Migraine, Aseptic Menningitis
•? Different reactions or a spectrum- mild headaches common,
usually rate-related
•Onset of severe migraine or meningitis symptoms may be delayed?
•Severe headaches and/or aseptic meningitis more frequent with high
dose Rx and in neurologic diseases
Pierce and Jain: Transfusion Med Rev 17: 241 (2003)
Pharmacokinetics of IgG after IV Infusion
Serum IgG Levels in 34 year old Male with XLA
30 gr 5% IVIG (406 mg/kg) 12 gr 16% ISG Q 7 days =
1600
Q 3 weeks 36 gr in 3 weeks
1400
1200
Total IgG
1000
800
600
400
0 2 4 6 8 10 12 14 16 18 20 22 0 7 14 21
Days Days
Mean Serum IgG Levels Over Course of Two
Weeks During Steady-State on Treatment With
An Approved SCIG Therapy*
*non-IND 3002 EU
CSLBehring, Data on File.
Systemic Adverse Events During IM, IV,
and SC Immunoglobulin Infusions
Based on separate studies, not a head-to-head evaluation
50
45
40
35 IMIG (1893 injections)
30
25 IVIG (387 infusions)
20
SCIG (3232 infusions)
15
10
5
0
Percentage of Patients with Systemic Adverse
Reaction(s) *P<.001 vs SC infusion
Gardulf A, et al. Lancet. 1991; 338:162.
Reported Rates of Adverse Effects of
Subcutaneous IgG Infusionsa
Berger. Clin Immunol 2004;
Comparison of IV and SQ Dosing
• 70 kg patient receiving 500 mg/kg q 4 wks :
35 grams = 700 ml of 5% IV solution or
350 ml of 10% IV solution
= 220 ml of 16% sub-cu solution
= 55 ml/wk (2-3 sites- 2.5 hrs, 1 site-6-8 hrs)
= 20 ml every 3rd day (11/mo)
= 10 ml every weekday
Sub-cu needles then (1976) and now
27 gauge
9 mm
Sof-set
Syringe Driver Pumps
Graseby MS16A Crono
Freedom 60
SCIG Reactions in CE1200 Study
___________________________________________
• Local reactions occurred in most patients initially.
• Reactions clearly decreased with continued therapy
• Multiple studies report systemic reactions <1% in
patients on sub-cu. Severe rxns extremely rare.
• Local reactions mostly mild or moderate
• Only 3 subjects withdrew because of injection-site AEs
Ochs et al
SCIg: Mild Injection-Site reaction
Data on File. ZLB Behring.
SCIg: Moderate Injection-Site Reaction
Data on File. ZLB Behring.
SCIG Injection-Site Reactions by Gender
3001 NA Study 3002 EU non-IND Study
Subjects with Injection-site reactions (%)
Subjects with Injection-site reactions (%)
Infusion Infusion
CSL Behring. Data on File.
Side Effects to Expect
with SCIG Infusion
Site reactions
• Redness • Bruising
• Swelling — • Blanching of site
potential to last 1-3
days • Leaking at the site
• Discomfort • Warm to the touch
• Itchiness • Burning Sensation
• Rash — local or
generalized
Which Route to Use?
Advantages of SC and IV Administration
Subcutaneous Intravenous
No venous access Convenient and well tolerated
by most patients
Slow administration and gradual Ability to give large volumes
absorption reduces headaches and per infusion allows intermittent
other adverse events dosing (every 21-28 days)
Maintains more consistent IgG levels
Facilitates self or home infusion,
increasing patient autonomy – may
improve patient’s self-image and
sense of control
Convenient and well tolerated by
most patients
Berger M. Clin Immunol. 2004;112:1-7.
Which Route to Use?
Disadvantages of SC and IV Administration
Subcutaneous Intravenous
Relatively small volume per Requires venous access and
infusion requires frequent trained personnel in most
dosing – at least once a week in situations
most cases
Ability to self-infuse requires Large shift in IgG levels during
reliable and adherent patient dosing may cause adverse
effects at or just after peak, and
during low troughs
Infrequent dosing may result in
low troughs and could increase
the infection rate
Berger M. Clin Immunol. 2004;112:1-7.
SCIG Dose and IgG Trough Levels in North
American and (EU+Brazil) Clinical Trials
3001 NA 3002 EU (non-IND)
n=51 n=47
SCIG dose (% of IVIG) 136 SCIG dose (% of IVIG) 101
SCIG dose (mg/kg/wk) 158 SCIG dose (mg/kg/wk) 89
86
IgG increase during SCIG 255 IgG increase during SCIG
Therapy (mg/dL) therapy (mg/dL)
IgG level (mg/dL) on SCIg 1040 IgG level (mg/dL) on SCIG 922
CSL Behring, Data on File, Ochs et al, J Clin Immunol 26: 265 (2006)
SCIG Doses and Infections in North American and
(Europe+Brazil) Clinical Trials
3001 NA 3002 EU
n=51 n=47
Mean dose of SCIG Mean dose of SCIG
158 89
(mg/kg) (mg/kg)
Range SCIG dose Range SCIG dose
34–352 51–147
(mg/kg/week) (mg/kg/week)
Annual rate of serious Annualized rate of
bacterial infections 0.04 serious bacterial 0.04
per subject infections/subject
Annual rate of Annualized rate of
4.4 4.3
other infections other infections
CSL Behring, Data on File, Ochs et al, J Clin Immunol 26: 265 (2006)
Promoting Patient Autonomy
Home/Partner/Parent Administration of IVIG
Subcutaneous IgG:
self infusion possible
usually smaller doses given more frequently
may decrease adverse events by dampening
variations in serum IgG level
Careful selection of patients and appropriate
follow-up essential
Home-Based SCIG Therapy Improves
HRQoL
Mean Sum Score of Life Quality Index
105
100 95 94
95
Mean sum score
90
85 82 *
80
74*
75
70
65
60
55
50
Children (n=15) Adults (n=22)
Baseline After 10 months of home therapy with SCIG
*F-Test 10-months vs. baseline: P<.05
Gardulf A et al. J Allergy Clin Immunol. 2004;114:936-942.
North America QoL Study
Nicolay U et al. J Clin Immunol 2006; 26: 65–72.
Patient Selection
• If Sub-cu is indicated to avoid complications or
adverse effects from IV, home therapy will often be
preferred because limitations on dose that can be
given per sub-cu infusion dictates frequent dosing
• If flexibility or home therapy is desired as primary
goal, (pt’s schedule, distance from infusion center),
sub-cu will be attractive because it is safer and
requires less technical skill (at starting IV )
Who: Patients in whom sub-cu might be
preferred
• Poor venous access
• Adverse effects: anaphylactoid reactions, post-
infusion migraines, risk of renal failure or
hyperviscosity, thromboses
• Patients who “run out of gas” at end of IV dosing
interval
• Patients who are remote from infusion facility
(college students)
• Patients who work, go to school, or have busy
schedule- convenience
• Patients who want to feel independent
Important Issues for the Doctor-
Patient Discussion
Medication-Related Process-Related
Dose (frequency, dose, and time) :
Insurance issues
IV vs SC, schedule
Leasing vs purchasing a
Adherence and follow-up pump- responsibility for
maintenance
Adverse reactions
Home care company ?
Patients can return to IV after
When to call your doctor
trying SC
Stepwise Approach : Plan
• Determine monthly IgG dose in grams
• Divide by unit dose of IgG (ex: 1.6 or 3.6 gr)
= number of 10 or 20 cc bottles/month
• Determine volume and number of sites per infusion.
• Guideline: 0.1 to 0.25 ml/kg/site/hr
(avg adult: approx. 10 ml/site/hr)
• Select pump
• Divide number of bottles by number per infusion to
get infusions per month
• Arrange schedule with patient
• Start SCIg 1 week after last IV infusion or load naïve
patient with 5-6 SC doses (opportunity to train pt).
Simplified Approach: Rule of 2’s
• Two bottles, two sites, two hours:
40 ml (6.4 grams) at 10 ml per site per hr in
teenager or adult: 25.6 gr/month
20 ml (3.2 grams) at 5 ml per site per hr in child:
12.9 grams per month
Give one or two extra doses per month or up to two
per week to achieve higher monthly dose.
Adjust sites and time as tolerated.
Training Patient
• Train a trainer &/or use home care company with
expertise
• Use video, checklist, ―buddy system‖.
• Have patient return to office to demonstrate their
procedure.
• Web resources: http://
cc.nih.gov/ccc/patient_education/pepubs/subq.pdf
Excellent source for selecting sites and techniques
for
sub-cu injections from NIH clinical center nurses
Guidelines for IgG Therapy
(Regardless of Route)
• Dose and Interval- Individualize
• Route- Location, Logistics, cost
• Treat the patient, not the numbers:
monitor and document outcome. Follow-up
determined by clinical status of pt.
• Use of IgG levels
• Adverse Effects: Rate related (IV), Non-rate
related. Replacement different than high dose
• Safety Monitoring: Liver & Renal Fxn, CBC
Conclusions
• Antibody Replacement is a mainstay of
treatment for PID
• IgG mainly is replaced
• IgG replacement should be individualized:
both IV and Sub-cu preparations available in
the US. Dose Requirements may vary
• Current Ig preparations are believed safe, but
we must always be cautious and monitor pts.
Courtesy of D. Sedlak, Duke U.
General refs on PIDD and IgG RX
• Bonilla FA, Bernstein IL, Khan DA, et.al. Practice
parameter for the diagnosis and management of primary
immunodeficiency.
Ann Allergy Asthma Immunol. 2005 May; 94 (5 Suppl 1)
:S1-63.
• Orange JS, Hossny EM, Weiler CR, et al. Use of
intravenous immunoglobulin in human disease:
A review of evidence
J Allergy Clin Immunol. 2006 Apr;117(4 Suppl):S525-53.
Sub-cu IgG Refs
• Ochs HD, Gupta S, Kiessling P, Safety and efficacy of self-administered
subcutaneous immunoglobulin in patients with primary immunodeficiency
diseases. J Clin Immunol. 2006 May;26(3):265-73.
• Gardulf A, Nicolay U, Asensio O,. Rapid subcutaneous IgG replacement
therapy is effective and safe in children and adults with primary
immunodeficiencies--a prospective, multi-national study. J Clin Immunol. 2006
Mar;26(2):177-85
• Gardulf A, Nicolay U. Replacement IgG therapy and self-therapy at home
improve the health-related quality of life in patients with primary antibody
deficiencies. Curr Opin Allergy Clin Immunol. 2006 Dec;6(6):434-42.
• Nicolay U, Kiessling P, Berger M,. Health-related quality of life and treatment
satisfaction in North American patients with primary immunedeficiency
diseases receiving subcutaneous IgG self-infusions at home. J Clin Immunol.
2006 Jan;26(1):65-72.
• Berger M. Subcutaneous immunoglobulin replacement in primary
immunodeficiencies. Clin Immunol. 2004 Jul;112(1):1-7. Review.
Study Design of PK Substudy 3001 NA
Start weekly
SCIG at 120%
IVIG
Individualized SCIG Dose Adjustment
Serum
IgG
Level
IVIG Wash-in/ Efficacy 12
Equilibration 1 Wash-out Months
3 months month 3 months
PK Substudy
-3 -2 -1 0 1 2 3 4 5 6 7 8 16
Months
IVIG Assessment of Final AUC
AUC Serum IgG Evaluation for
trough vs. non-inferiority
target levels
Kiessling P, et al. Data on File. ZLB Behring.
Fractionating Total Dose into More Frequent Small
Infusions Evens Out IgG Level Over Time