Use of Subcutaneous IgG in Patients on Concomitant Anticoagulant and Antiplatelet Therapy Mark R. Stein,1 Kelly Farnan,1 Danielle Eufrasio,1 Carla Duff, 2 Jerry Hunter,3 Diana Ochoa,4 Marie-Claude Levasseur,5 Loris Aro,6 Annette Zampelli7   1Allergy Associates of the Palm Beaches, North Palm Beach, FL, USA; 2University of South Florida, Tampa, FL, USA; 3Arizona Allergy Associates, Phoenix, AZ, USA; 4Allergy/Immunology Research Center of North Texas, Dallas, TX, USA; 5University Health Center, Sainte-Justine Hospital, Montreal, QC, Canada; 6Toronto Allergy Group, Toronto, ON, Canada; 7CSL Behring, LLC, King of Prussia, PA, USA The International Nursing Group for Immunodeficiencies October 3-6, 2012, Florence, Italy

Disclosures and Acknowledgments MRS has served as a speaker, consultant, and/or investigator for Baxter Healthcare Corp, CSL Behring, Merck, and Teva. CD, JH, MCL, and LA are nurse consultants for CSL Behring. DO is a nurse consultant for CSL Behring and has served on an advisory board for Baxter Healthcare. AZ is employed by CSL Behring. This presentation was supported by CSL Behring, LLC. Medical writing and editorial support was provided by Daniel McCallus, PhD, of Complete Publication Solutions, LLC, and was funded by CSL Behring, LLC.

Introduction Primary or Secondary Immunodeficiency Disease (PIDD/SIDD) Standard treatment: Intravenous immunoglobulin (IVIG)1 Subcutaneous immunoglobulin (SCIG)1 High prevalence of thrombotic risks in the general population2 Many patients with PIDD/SIDD are also prescribed anticoagulant and antiplatelet (AC/AP) drugs for the treatment and prophylaxis of thrombotic, cardiac, and vascular diseases3 Some disorders associated with PIDD have congenital cardiovascular manifestations that require AC/AP 1. Fried AJ and Bonilla FA. Clin Microbiol Rev. 2009;22(3):396-414. 2. Heidenreich PA, et al. Circulation. 2011;123(8):933-944. 3. Alexander KP and Peterson ED. Circulation. 2010;121(17):1960-1970.

Rationale and Objective Infusion-site bleeding or bruising at the site of SCIG administration due to the activity of AC/AP medication was theoretical concern Objective To establish the safety of concomitant SCIG and AC/AP therapy

Study Design Multicenter retrospective chart review of tolerability data Patient inclusion criteria: PIDD or SIDD Receiving treatment with 20% SCIG (Hizentra®, CSL Behring, LLC, King of Prussia, PA) or 16% SCIG (Vivaglobin®, CSL Behring, LLC; no longer available in the United States) Prescribed concomitant AC/AP medications

Patient Descriptions 26 of the total 33 patients were part of a larger (n=47) retrospective single-center study on safety and efficacy of SCIG in the elderly Parameter Patients, n (%) N=47 PIDD diagnosis Hypogammaglobulinemia 29 (61.7) IgG subclass deficiency or specific antibody deficiency 9 (19.1) Hypogamma globulinemia and subclass deficiency or specific antibody deficiency or another immunodeficiency 9 (19.1 Medical history Serious acute bacterial infections 31 (68.1) Chronic infections 44 (93.6) Comorbid conditions COPD 7 (14.9) Type 1 diabetes 4 (8.5) Type 2 diabetes 3 (6.4) Stein et al. Postgrad Med. 2011; 123:186-93.

Patient Descriptions Cont. Concomitant medication use in the larger study population Parameter Patients, n (%) N=47 Brochodilators/inhaled corticosteroids 29 (61.7) Proton pump inhibitors 21 (44.7) Statins/antilipidemics Nasal sprays 17 (36.2) Antihistamines 16 (34.0) Diuretics/antihypertensives Antidepressants 11 (23.4) Bone resorption inhibitors 10 (21.3) Thyroid hormone 9 (19.1) Stein et al. Postgrad Med. 2011; 123:186-93.

AC/AP Use: Patient Descriptions 33 patients total 26 from larger single-center in elderly, 7 from other centers Age Median: 70 years Range: 3−89 years AC/AP medications Included: Aspirin, warfarin, clopidogrel, and heparin Used for: Treatment and/or prophylaxis for thrombotic and vascular diseases ie, pulmonary embolism, congenital heart disease, chronic atrial fibrillation/flutter

Concomitant AC/AP Medications The most common concomitant medication was aspirin (18/33 patients, 55%) A large percentage of patients were on warfarin (10/33 patients, 30%) Few patients used clopidogrel alone or aspirin combined with either clopidogrel or heparin (5/33 patients, 12%) Types of concomitant AC/AP medications in patients treated with SCIG

Patient SCIG Administration Parameters SCIG was administered using a variety of different regimens Mean duration of use, months (range) 22.2 (5−49) Mean total dose, mg/kg/month 441 Number of sites per infusion 1 2-3 ≥4 3 21 9 Method of SCIG Administration Syringe Pump Push 30 Site of infusion Abdomen Arm Thigh Multiple body areas 24 5 SCIG administration frequency >1X/week Weekly Every 2 weeks 27

Results Local site reactions Mild, transient, and similar to those previously described4 Infusion-site bleeding/bruising: observed in only 1 patient A 62-year-old white male Immune thrombocytopenic purpura and SIDD Receiving aspirin (81 mg/day) SCIG dose of 710 mg/kg per month via syringe push, 20 mL in 1 site (abdomen), 4 times per week Reported mild bruising during the first month of SCIG treatment 4. Jolles S, et al. Clin Immunol. 2011;141(1):90-120.

Case Study 1 21-year-old female First SCIG treatment 16% SCIG dose of 696 mg/kg per month via syringe push Concomitant warfarin therapy (5 mg/d) for treatment of prior pulmonary embolism First SCIG treatment Two 5 mL push injections (2 hours apart), followed by two 10 mL injections (1 hour apart) No photo available Subsequent SCIG treatments One 20 mL push injection in one site over 15 minutes 3 times per week Patient outcomes No bruising, bleeding, or skin reactions at the infusion site, despite increase in general bruisability since starting warfarin After 8 months of well-tolerated SCIG, restarted IVIG for personal reasons Before Week 4 Infusion After Week 4 Infusion

Case Study 2 33-year-old female First SCIG treatment 16% SCIG dose of 750 mg/kg per month via syringe push Concomitant warfarin therapy (alternating 9/10 mg/day) for chronic atrial flutter First SCIG treatment Two 5 mL push injections (2 hours apart), followed by two 10 mL injections (1 hour apart) Subsequent SCIG treatments One 20 mL push injection in one site over 15 minutes 3 times per week Patient outcomes No bruising, bleeding, or skin reactions at the infusion site Before After First SCIG treatment Before After Week 4 Infusion

Conclusions The concurrent use of AC/AP medications in this group of patients with PIDD or SIDD aged 3-89 years did not increase the occurrence of local site complications after 16% SCIG or 20% SCIG treatment. In patients with PIDD or SIDD and comorbid cardiovascular or thrombotic disorders treated with AC/AP medications, the use of 16% or 20% SCIG was well tolerated.