Immune Globulin Stewardship:Antibody Stewardship

Considerations for the HealthSystem Pharmacist

Eric M. Tichy, PharmD, BCPS, FCCP, FASTManager, Clinical Pharmacy ServicesYale-New Haven Hospital, New Haven, CTeric.tichy@ynhh.org

Disclosure

– Received educational grants from Baxalta Bioscience and Grifols

– Consulted for Baxalta Bioscience and Grifols– Owns stock investments in Halozyme Therapeutics– This presentation will include discussion of off-

label information

Pharmacist Learning Objectives

• Define antibody/immunoglobulin (IG) “stewardship”

• Advocate for the role of the pharmacist as the “steward” of IG management

• Describe the clinically relevant differences between IG products

Technician Learning Objectives

• Outline the importance of IVIg preparation technique

• Explain the difference in stability with the various IgIV products

• List what IgIV products are available as a liquid formulation

What is Antibody Stewardship?

• Stewardship: care, handling and management of resources

• Immunoglobulin = antibody

• Pharmacist:– Ensure appropriate product selection– Monitor for appropriate utilization– Develop protocols/guidelines for use– Manage supply of a finite resource– Provide Education

IVIg = “Liquid Gold”

• Current price of gold per ounce: $11141

• 1 ounce = 28.3gm

• 1gm IVIg = $702

• IVIg = $1981 per ounce

• Top 5 drug budget item3

1. Wall Street Journal, August 20152. Cardinal Health, May 20153. Schumock GT, et al. Am J Health Syst Pharm. 2015.

Immunoglobulin Structure

Mackay and Rosen. N Engl J Med, 2001;345:747-55

Mechanisms of IgIV

1. Activation of phagocytosis

2. Precipitation, agglutination & neutralization of antigens

3. Compliment mediated and NK cell cytolysis

1. Neutralization of autoantibodies

2. Down regulation of B & T Cell Function

3. Regulation of apoptosis

1. Neutralization of super antigens

2. Elimination of compliment-activating immune complexes

Anti-infective Immunomodulatory

Harvey RD. Pharmacotherapy 2005;25:71-2S

Immunoglobulin IV Products• First introduced in the 1970’s– Immune deficiency

• Pooled Polyvalent Immune globulin (antibody) extracted from human donors– Plasmapheresis– Blood donation

• Great differentiation and refinement of the products have occurred over time

• Wide expansion of use in last two decades• Numerous products available• 3rd & 4th Generation currently on market

Main Uses of IgIV• Primary Immune Deficiency• Neurological

– Chronic inflammatory polyneuropathy (CIDP)– Guillain-Barre Syndrome (GBS)– Multifocal Motor Neuropathy (MMN)

• Hematology/Oncology– Idiopathic Thrombocytopenia Purpura (ITP)

• Pediatrics– Kawasaki’s Syndrome

• Solid Organ Transplant– Treatment of rejection– Desensitization

Jolles S, et al. Clin Exp Immunol. 2005.

Most Influential Prescribers

• Immunology– Large percentage of use at most centers– Patients on chronic therapy

• Other uses are short-term– Often one time use or short course (few days or weeks)

• Need to have consensus with immunology prescribers on acceptable formulary product

• Other specialties depending on institution practice (Neurology)

Significant Pharmaceutical Considerations

• Sodium Content• Stabilizer• Concentration• Osmolality & Osmolarity• Immune Globulin A Content• Infusion rates• pH

1. Siegel J. Pharmacotherapy. 2005.2. Radosevich M, Burnouf T. Vox Sang. 2010.3. Mark SM. Hosp Pharm. 2011.

Which products are on your formulary?

A. Flebogamma DIFB. BivigamC. PrivigenD. Gamunex-CE. Gammagard Liquid

F. Gammagard S/DG. GammakedH. OctagamI. CarimuneJ. Other

Pharmaceutical Considerations Between Generations

• Direct tolerability comparison are lacking– Product features may predict impact on patient and

incidence of adverse effects– 4th generation products have few significant

differences• Stabilizers (glycine, proline, maltose or sorbitol)

– 3rd generation products each have unique properties that need active management• Carimune• Octagam 5%• Gammagard S/D

4th Generation Products

• Products– Gammagard Liquid– Bivigam– Flebogamma DIF 10%– Privigen– Gamunex– Gammaked– Octagam 10%

• Properties– Trace or no sodium– Physiologic Osm

(300mOsm/kg)– Similar infusion rates– Low IgA content

(<50 mcg/ml)– 10% concentration– Liquid (premixed)– Room temperature

storage

Which of the following stabilizing agents is associated with acute renal failure?

A. ProlineB. SucroseC. GlycineD. MaltoseE. Sorbitol

Carimune

• High IgA content (720 mcg/ml)– May influence risk of adverse reactions

• Lyophilized– Requires reconstitution– High osmolarity/osmolality at concentration >6%

• Requires greater volumes for infusion• Longer infusion times

• 5 - 10% Sucrose Stabilized– Risk of renal dysfunction– No impact of blood sugar

Acute Renal Failure

• Risk factors– Chronic Kidney Disease– Sepsis– Volume depletion– High doses– Associated with fast infusions?

• Hyperosmolar insult: swelling & vacuolization of proximal tubular epithelia

• Carbohydrates: sucrose most common– Listed as risk for all products

Cantu TG, et al. Am J Kid Dis 1995;25:228-34

Cellular Edema with Vacuolization

Cantu TG, et al. Am J Kid Dis 1995;25:228-34

Immunoglobulin A

• All IVIg products contain some IgA• Patients with IgA deficiency and ability to

produce antibody may develop anti-IgA antibodies

• Increases incidence of adverse reactions– Anaphylactic shock

• Rare condition and screening not recommended

Gammagard S/D Low IgA• Trace IgA content (lowest)– Generally reserved for patients intolerant to IgA– Regular IgA product removed from market 2013

• Lyophilized– Requires reconstitution to 5% concentration– High osmolality/osmolarity (636 mOsm/kg)

• 2% Glucose stabilized– Increases serum blood glucose

Common IgIV Adverse Effects• Anaphylactoid reactions

– Chills, flushing, tachycardia, fever, shortness of breath nausea/vomiting, back/chest pain, headache, rigors

• Mechanism– Compliment activation– Presence of trace amounts of kinins & cytokines– Stimulation of monocytes and cytokine release

• Associated with:– Rapid infusion– 1st infusion– Higher dose

• Pre medication may help– acetaminophen & diphenhydramine

Rare & Serious Adverse Effects

• Hemolysis– Products contain anti A and B antibodies– Risk when high doses administered

• Aseptic meningitis• Thrombosis• Transfusion related lung injury• Transmission of infections diseases

Volume and Rate of Infusion• Volume for 70 gm dose– 5% 1400 ml– 6% 1166 ml– 10% 700 ml

• Minimum infusion time– 6% 8 hours– 10% 3 hours

• Critical for volume sensitive patients– Protein colloid– Renal dysfunction, heart failure, volume overload,

elderly, etc

Switching Between Products

• Products should not be mixed• Interchange between products should be done with

caution– Patients may require retitration– Individuals may tolerate products differently– Major patient satisfaction issue– Major issue for patients on chronic IgIV therapy

• Gammaked = Gamunex C– Exception to general rule in IgVI market

1. Younger ME, et al. J Infus Nurs. 2013. 2. Ameratunga R, et al. J Clin Exp Immunol. 2004.3. Berger M, et al. Clin Immunol. 2011.

Subcutaneous Route• Optimal kinetics for immune deficiency• Facilitates home therapy / self infusion• Fewer systemic adverse reactions• Does not require IV access• Several products approved for SC route

– Weekly (conventional) dosing schedules• May require dose adjustments when converting from IV

– Monthly dosing schedules – Ig Infusion 10% with Recombinant Human Hyaluronidase (IgHy)

• May not appropriate for many indications– Limits volume / dose of infusion

1. Berger M. Clin Focus Primary Immune Deficiencies. 2008.2. Misbah et al. Clin Exp Immunol. 2009.3. Wasserman RL, et al. J Allergy Clin Immunol. 2012. 4. Gardulf A. Biodrugs. 2007;21(2):105-116

Intravenous and Subcutaneous Pharmacokinetics

Wasserman RL, et al. J Allergy Clin Immunol. 2012.

Product Availability• Vial Size– 1 gm, 2.5 gm vial size relevant for pediatric

patients• Supply of grams– Shortages common historically– 340B product– Ability to provide supply guarantee

• Impact on supply of other plasma products– Albumin• Cost of bundled product also relevant

Inpatient vs. Outpatient Use

• All products have different CPT Codes– Except Gamunex C and Gammaked

• Inpatient use can easily be converted• Outpatient switch requires operational effort– New prescription– Insurance authorization– Risk of coverage denial

Reimbursement per GramProduct HCPCS/APC HOPPS

GAMMAGARD S/D J1566 $61.82

GAMMAGARD Liquid 10% J1569 $78.90

OCTAGAM 5% J1568 $67.98

FLEBOGAMMA 5% J1572 $69.86

GAMUNEX 10%

J1561 $73.80GAMUNEX-C 10%

GAMMAKED 10%

PRIVIGEN 10% J1459 $68.76

GAMMAPLEX 5% Liquid J1557 $74.58HIZENTRA Subcutaneous 20% J1559 $71.50

Consideration Gammagard Liquid 10%

Gamunex-C 10%

&

Gammaked*

Privigen 10% Flebogamma 5% & 10%

Octagam

5% & 10%

Gammagard

SD

Low IgA

Carimune NF

Manufacturer Baxalta Healthcare Grifols CSL Behring Grifols Octapharma USA

Baxalta Healthcare CSL Behring

Concentration 10% 10% 10% 5% & 10% 5% & 10% 5% 6%

Form Liquid Liquid Liquid Liquid liquid lyophilized lyophilized

Sodium Content Trace Not detectable Trace Trace Not detectable 0.85% 0.9%

Stabilizer Glycine Glycine Proline Sorbitol Maltose Glucose Sucrose

Osmolality / Osmolarity

240-300 mOsm/kg 258 mOsm/kg 240-440 mOsm/kg 240-370 mOsm/kg

310-380 mOsm/kg

636 mOsm/kg 690 mOsm/kg

IgA Content37 mcg/mL 46 mcg/mL <25mcg/mL <6mcg/mL <200 mcg/mL < 1 mcg/mL >720 mcg/mL

pH 4.6 – 5.1 4 - 4.5 4.6 - 5 5.5 5.1 - 6 6.4 – 7.2 6.4 – 6.8

Supply Size (Grams)

30, 20, 10, 5, 2.5, 1 20, 10, 5, 2.5, 1 20, 10, 5 20, 10, 5 1, 2.5, 5, 10, 25 5, 10 3, 6, 12

Shelf Life

24 months Room Temp; 36 months refrigerated

6 months Room Temp; 36 months refrigerated

36 months Room Temp

24 months Room Temp

24 months Room Temp

24 months Room Temp

24 months Room Temp

Pharmacist is theImmunoglobulin Steward

• Develop and monitor protocols for Ig use• Ensure appropriate product selection for the

formulary• Educate patients about risks and benefits of

therapy• Manage & contain cost– Ensure appropriate use– Facilitate patient transition to outpatient setting– Contracting (direct or 340B)

Learning Assessment

• Which of the following is an expected role of an immunoglobulin steward?

– A – Pooler of immunoglobulin vials– B – Manage medication use evaluations– C – Scheduling patient visits– D – Verify immunoglobulin orders

Questions

Eric.Tichy@ynhh.org