The University of Mississippi Medical Center The University of Mississippi Health Care. Pharmacy and Therapeutics Committee Medication Use Evaluation

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1 The University of Mississippi Medical Center The University of Mississippi Health Care Pharmacy and Therapeutics Committee Medication Use Evaluation June 2012 Objective The goal of this medication use evaluation (MUE) is to assess the use and selection of different products of intravenous immune globulin (IVIG) in the University of Mississippi Medical Center (UMMC). Background Immunoglobulin therapy has been used for over 100 years. IVIG first became available in the 1960s. It is used in patients who lack primary humoral immunity. Indications for IVIG have expanded in the past few years. It is now approved by the Food and Drug Administration (FDA) for primary immunodeficiency, idiopathic thrombocytopenic purpura, B cell chronic lymphocytic leukemia, chronic inflammatory demyelinating polyneuropahty, Kawasaki syndrome, and pediatric HIV infection. It is approved for prophylaxis for measles, hepatitis A, and varicella as well as post exposure prophylaxis for rubella in pregnancy. It is also used in many other types of patients the evidence for these off-label uses is stronger in some cases and weaker in others. For the past several years, IVIG market availability has expanded to include additional formulations. No IVIG product is identical. UMMC routinely carries three different formulations Carimune, Gamunex, and Gammagard S/D. Privigen is used for some pediatrics. Each formulation has different production, purification and stabilization, which can have different clinical safety and tolerability implications. Methodology Data was collected from patients who received IVIG during the period of January 1, 2011 to August 15, The population of patients receiving IVIG was approximately one-half children (82) and one-half adults (81). Fifty charts were reviewed for this MUE. Patients were grouped into adult and children. A random number generator was used to select patients reviewed based on group (25 children and 25 adults). Data was recorded on appropriate data collection forms for each patient. Data collected was analyzed for demographics, indication, location of patient, product selection, dosing weight, baseline studies of immunological, renal and hematologic, dispensing, administration, and monitoring which included adverse drug reactions, anaphylaxis, thrombocytopenia and neutropenia. Renal dysfunction was defined as SCr>1.4. Results The results of IVIG usage at UMMC are summarized in the following pages.

2 Page 2 of 8 Table 1: Demographics of Adults Average Age Gender Female Male Race African American White Median Weight Table 2: Demographics of Children Average Age Gender Female Male Race African American White Not Identified Median Weight 49.6 years (range years) 76% (19/25) 24% (6/25) 20% (10/50) 80% (40/50) 81.4 kg range ( kg) 9.4 years (range 1-20 years) 40% (10/25) 60% (15/25) 20% (10/50) 78% (39/50) 2% (1/50) 36.5 kg (range kg)

3 Page 3 of 8 Chart 1: IVIG Usage by FDA Indications (N=50 Patients) *CIDP= Chronic Inflammatory Demyelinating Polyneuropathy Although the majority of indications for IVIG products were non FDA approved, all but eight were off label indications on Micromedex or indications in which Medicare would provide the hospital with reimbursement on an outpatient basis. Chart 2: Prescribing Location (N=151 Doses) Outpatient Children 17% Adult ICU 4% Adult Hospital 11% Outpatient Adult 29% Children's Hospital 39%

4 Page 4 of 8 Chart 3: Baseline Immunological and Renal Studies Baseline Immunological Studies Performed? (N=50) 56% 44% Percentage of Patients IgA Deficient? (N=28) 25% 75% Yes Baseline Renal Function Assessed? (N=50) 84% 16% No Baseline Renal Function Within Normal Range? (N=42) 83% 17% 0% 20% 40% 60% 80% 100% For the patients who were IgA deficient, all but two received appropriate IVIG products that were low in IgA content. Both patients were outpatient and only received Carimune for their first dose of multiple IVIG doses. There indications to recieve IVIG were Common Variable Immune Deficiency and Bordetella Pertussis. All but two of the patients who had low renal function received a non Carimune product. The IVIG indications for the two patients that received Carimune were idiopathic thrombocytopenic purpura and hand cellulitis abcess. Chart 4: Baseline Hematologic Studies Baseline Platelet Counts Assessed? (N=50) 92% 8% Baseline Platelet Counts Within Normal Range? (N=46) 63% 47% Yes Baseline WBC Assessed? (N=50) 92% 8% No Baseline WBC Within Normal Range? (N=46) 89% 11% 0% 20% 40% 60% 80% 100% The reason the number of patients without normal platelet count was high was because one indication for IVIG is thrombocytopenia. Seven patients had an indication for idiopathic thrombocytopenic purpura which was 25% of those patients without normal platelet counts.

5 Page 5 of 8 Chart 5: Dispensing Information Orders Entered With Correct Dose (N=151) Orders Without Specific Product Indicated for Adults (N=63) Orders Without Specific Product Indicated for Childrens (N=88) 54% 100% 86% Order Clarification Written (N=150) Order Dosed on Actual Body Weight in Adults (N=25) Number of Adult Patients Without Weight Listed (N=25) 13% 16% 84% When the order for generic IVIG was written for adults, Carimune was dispensed 38 times. Gamunex was dispensed 13 times with 3 patients having renal dysfunction and 7 patients having IgA deficiency. Gammagard S/D and Privigen were dispensed one time each. For pediatrics with a generic IVIG order, Gamunex was dispensed 38 times with 1 pediatrics with renal dysfuction and 13 pediatrics who were IgA deficient. Carimune was dispensed 10 times. There were 9 clarification orders for adults and 11 for children. Table 3: IVIG Total Costs for % 20% 40% 60% 80% 100% Product Total Cost Carimune $1,334,381,43 Gamunex $887, Gammagard S/D $58, Privigen $11, Total $2,291, Chart 6: Dispensing Parameters (N=151) 1% 2% 38% 60% Carimune Gammagard S/D Gamunex Privigen

6 Page 6 of 8 Administration/ Monitoring 100% of doses were noted on MAR (1 MAR Could not be found) The rate was specified in 72% (108/151) of the orders. The rate of administration was between the FDA recommendation of ml/kg/hr when the patient s weight was known and a doctor or pharmacist specified the rate. A rate decrease to <2mL/kg/hr was noted in all patients with renal insufficiency (N=7) Anaphylaxis was not noted with any dosage administration Adverse Effects o One patient s platelets decreased by 50% (Patient was being treated with IVIG for Kidney Transplant Rejection) o One patient s serum creatinine doubled from 0.86 to 1.53 (Patient was being treated with IVIG for Lupus Pantocytopenia) Discussion In Mississippi, 34% of adults are obese. 1 Determining the dose of IVIG products in obese patients is a concern for the population of Mississippi. All studies that have been conducted with IVIG products used actual body weight, but morbidly obese patients were excluded in most studies. 2 There have been several case reports of serious and fatal thromboembolic events in patients during or in short temporal relation to IVIG infusion. 2,3,4,5,6,7 One proposed mechanism for the prothrombotic effects was an increase of plasma and blood viscosity. 3 Obese patients have an increase in their overall volume of distribution but IVIG products have very little distribution in adipose tissue. 2 A suggestion for dosing from a case series report was decreasing the dose of IVIG product given to obese patients to prevent an increase in serum levels of IVIG in the intravascular compartment. 3 Seigel, in an IVIG Medication Safety Summary Report, recommends using an adjusted body weight if BMI > 30 kg/m 2. 2 Summary Just over half (54%) of dosages reviewed in this MUE were given to patients on an inpatient basis. The majority of the indications to receive IVIG were not FDA approved but most were either on the Medicare reimbursement list or an off label indication on Micromedex. Of the patients tested for IgA deficiency, 25% (7/28) were IgA deficient. When patients baseline renal function was assessed, 17% were found outside the normal range (7/42). The most common product given was Carimune. The rate of infusion was specified on the doctors order 72% of the time. In all orders reviewed in the evaluation, actual body weight was used for the dose calculation of the amount of IVIG product given. Only two patients experienced adverse effects (one with an increase serum creatinine and the other with a drop in platelet count).

7 Page 7 of 8 Recommendations The Department of Pharmacy Services will continue to educate staff to intervene and communicate appropriate IVIG products based upon renal function and IgA levels. Also, we recommend the use of adjusted body weight in IVIG dosing for adult patients. References: 1. CDC. Adult Obesity Facts. Atlanta, GA: U.S. Department of Health and Human Services. May Seigal, J. IVIG Medication Safety: A Stepwise Guide to Product Selection and Use. Pharmacy Practice News Special Edition. 2011;38: Hefer D, Jaloudi M. Thromboembolic events as an emerging adverse effect during high dose intravenous immunoglobulin therapy in elderly patients: a case report and discussion of the relevant literature. Ann Hematol 2005;84: Emerson G, Herndon C, Sreih A, Thrombotic complications after intravenous immunoglobulin therapy in two patients. Pharmacotherapy Dec;22(12): Pui-Ying Iroh Tam, Richardson M, Grewal S. Fatal case of bilateral internal jugular vein thrombosis following IVIG infusion in an adolescent girl treated for ITP. Am. J. Hemtaol. 2007;83: White DA, Leonard MC. Acute stroke with high dose intravenous immune globulin. Am J Health Syst Pharm. 2007;64: Hefer D, Jaloudi M. Thromboembolic events as an emerging adverse effect during high dose intravenous immunoglobulin therapy in elderly patients: a case report and discussion of the relevant literature. Ann Hematol. 2005;84:

8 Page 8 of 8 Appendix A: Indications for Patients Treated with IVIG Indication Number of People Treated with Indication Idiopathic Thrombocytopenic Purpura 7 ALL 4 AML 3 T Cell Lymphoma* 3 Common Variable Immune Deficiency 2 Guilline Barre Syndrome 2 Inflammatory Myopathy 2 IgG 2 Subclass Deficiency 2 Kawasaki syndrome 2 Kidney Transplant Complications 2 Myasthenia Gravis 2 Anaplastic Large Cell Lymphoma* 1 Aplastic Anemia 1 Autoimmune hemolytic anemia 1 Autonomic Neuropathy* 1 Bordetella Pertussis* 1 B cell chronic lymphocytic leukemia 1 Hand Cellulitis Abscess* 1 Leukoencephalopathy* 1 Lupus Pancytopenia 1 Medulla Blastoma* 1 MG Mestinoma 1 SCID Omenn Syndrome 1 Opsoclonus Myoclonus Syndrome* 1 Peds Congenital Syndrome 1 Progressive Ascending Parenthesis* 1 Progressive Polyneuropathy 1 Status Epileptic 1 T Cell ALL 1 Viral Myocarditis 1 *No FDA indication, off-label evidence available on Micromedex or not on Medicare reimbursement list.