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Evaluating Dose Ratio of Subcutaneous to Intravenous Immunoglobulin Therapy Among Patients With Primary Immunodeficiency Disease Switching to 20% Subcutaneous Immunoglobulin Therapy
Girishanthy Krishnarajah, MPH, MBA/MS, PhD; Jee-Yeon K. Lehmann, PhD; Brian Ellman, MBA; Rachel H. Bhak, MS; Maral DerSarkissian, PhD; Deane Leader, Jr, PhD, MBA; Ann L. Bullinger, PharmD; and Mei

Evaluating Dose Ratio of Subcutaneous to Intravenous Immunoglobulin Therapy Among Patients With Primary Immunodeficiency Disease Switching to 20% Subcutaneous Immunoglobulin Therapy

Girishanthy Krishnarajah, MPH, MBA/MS, PhD; Jee-Yeon K. Lehmann, PhD; Brian Ellman, MBA; Rachel H. Bhak, MS; Maral DerSarkissian, PhD; Deane Leader, Jr, PhD, MBA; Ann L. Bullinger, PharmD; and Mei
BACKGROUND: Current prescribing information recommends that physicians apply a dose ratio of 1.37:1 (1.53:1 prior to January 2015) in the United States (US) when switching patients with primary immunodeficiency disease (PI) from intravenous (IVIG) therapy to most subcutaneous therapy ([SCIG], except the 10% SCIG human hyaluronidase and immune globulin). However, a dose ratio of 1:1 was studied and approved for the European Union (EU). The dose-adjustment ratio used by prescribers in real-world US clinical practice is unknown.
OBJECTIVES: To examine real-world Hizentra 20% SCIG-to-IVIG dose ratios in the US after PI patients are switched from IVIG to 20% SCIG (Hizentra).
METHODS: A retrospective longitudinal study was conducted using prescription shipment data of patients with PI from specialty pharmaceutical and service providers from 2011 to 2016.  Patients who had at least 1 shipment of IVIG prior to switching to 20% SCIG (Hizentra) and subsequently received at least 1 more 20% SCIG (Hizentra) shipment in the following 6 months were included. Monthly 20% SCIG (Hizentra) doses following a switch from IVIG were calculated for each 2-month interval by summing daily doses that were estimated by dividing shipped volume by days between shipments. Mean monthly IVIG dose was calculated from the total volume shipped prior to switch. Per-patient dose ratios of Hizentra 20% SCIG-to-IVIG were calculated by dividing monthly 20% SCIG (Hizentra) dose by monthly IVIG dose during each 2-month interval. To minimize the influence of outliers, median dose ratios were reported. Dose ratios at months 2 to 4, 4 to 6, and 6 to 8 were compared with the dose ratio at months 0 to 2 using the Wilcoxon signed rank test. A sensitivity analysis excluding pediatric patients was conducted to assess the impact of changes in weight.
RESULTS: Data from 278 patients who met the inclusion criteria showed that median Hizentra 20% SCIG-to-IVIG dose ratios were 1.14:1 at 0 to 2 months post switch, 1.09:1 at 2 to 4 months, and stabilized at 1.05:1 at 4 to 6 and 6 to 8 months post switch. Median dose ratios at months 2 to 4, 4 to 6, and 6 to 8 were statistically significantly lower than the median dose ratio at 0 to 2 months post switch (all P <.001). Similar results were seen in the sensitivity analysis excluding pediatric patients.
CONCLUSIONS: Real-world data indicate that patients were switched to 20% SCIG (Hizentra) from IVIG at dose ratios lower than recommended by US prescribing information but similar to prescribing information in the EU. The initial dose ratio of 1.14:1 at 0 to 2 months stabilized to 1.05:1 at 4 to 6 and 6 to 8 months, which was consistent with reports of dose-equivalent switching patterns used in management of PI in clinical practice in the US.
Am J Manag Care. 2016;22:S475-S481
KEY TAKE-AWAYS:
  • For most subcutaneous immunoglobulin G (SCIG) products (except the 10% SCIG human hyaluronidase and immune globulin), United States (US) prescrib-ing information recommends that patients with primary immunodeficiency dis-ease (PI) be switched from intravenous immunoglobulin G (IVIG) replacement therapy to SCIG replacement therapy at a dose ratio of 1:1.37, while a dose ratio of 1:1 was approved in the European Union (EU).
  • Previous research indicates that treatment with SCIG at equivalent doses to IVIG (i.e., 1:1 dose ratio) effectively protects patients with PI against infection, although real-world dose ratios have not been studied.
  • Real-world specialty pharmacy data indicate that patients are switched from IVIG to 20% SCIG (Hizentra) at dose ratios lower than current recommendations in US prescribing information, and close to the EU-approved dose ratio of 1:1.
  • The dose ratio recommended in US prescribing information may be higher than necessary for effective treatment of PI.
Primary immunodeficiency diseases (PI) comprise more than 200 rare genetic diseases characterized by increased susceptibility to serious and/or recurrent infections as a result of an individual’s compromised immune system.1 Awareness and diagnosis of PI has increased over the last 40 years, and in 2007, results from a survey suggested that the estimated prevalence of diagnosed PI in the United States (US) is approximately 1 in 1200 persons.2 Clinical symptoms generally include recurrent or difficult-to-treat infections, poor growth or weight loss, recurrent deep abscesses of the organs or skin, and swollen lymph glands or an enlarged spleen.3 Patients with PI experience significantly higher hospitalization rates, as well as increased limitations on physical, school, and social activities. For example, in 2011, the Jeffrey Modell Centers Network reported that the average patient with PI in the US had a significant burden of 12 physician, emergency department, or hospital visits and 5 days of hospitalization annually in the year following diagnosis.4 Annual infection-related costs are estimated to be $18,368 among patients with PI.5 In addition, more than 50% of PI are associated with antibody deficiencies (often resulting in recurrent serious bacterial infections of the respiratory tract) that negatively impact patients’ life expectancy and put patients at increased risk of comorbidities such as autoimmune diseases and inflammatory and lymphoproliferative disorders.6
Immunoglobulin G (IgG) replacement therapy can be administered to the patient either intravenously (IVIG) or subcutaneously (SCIG), with the 2 routes demonstrating equivalent efficacy in preventing bacterial and other infections, such as pneumonia, sinusitis, and otitis media. Both therapies may also help prevent hospitalizations due to infection, as well as improve other important quality-of-life–related outcomes.6 In addition, SCIG is associated with lower rates of systemic adverse reactions and provides easier patient access to treatment as it is self-administered and does not require a visit to the clinic for infusion. SCIG has been shown to be generally more cost-effective than IVIG, largely due to fewer lost work or school days. As demonstrated in previous studies, the net cost savings after switching from IVIG to SCIG at a 1:1.5 dose ratio is between $755 and $4115 per patient, depending on the cost that is considered to be saved for having successfully avoided infections.7,8

Hizentra (Immune Globulin Subcutaneous [Human] 20% Liquid; 20% SCIG) is the first 20% SCIG therapy indicated for PI in adults and pediatric patients 2 years of age and older.9 It was approved after 2 pivotal trials in the US and Europe, which had durations greater than 60 and 40 weeks, respectively. Its higher concentration of 20%, as compared with 10% and 16% products, was formulated for lower-volume subcutaneous administration.10 In addition, 20% SCIG (Hizentra) is also self-administered and can be stored at temperatures up to 25°C.11,12

Due to differences in pharmacokinetics between IVIG and SCIG preparations (i.e., differences in bioavailability, as measured by the area under the serum concentration-time curve [serum AUC]), the FDA requires manufacturers to calculate a dose-adjustment coefficient between the 2 treatment routes that ensures equivalent systemic exposure within margins of 80% to 125%.9 Specifically, a pharmacokinetic study of 20% SCIG (Hizentra) indicated that the monthly dose of SCIG that provides equivalent systemic exposure to IVIG was 1.53 times the dose of IVIG.13 In January 2015, the FDA approved reduction of the dose adjustment factor to 1.37 on the basis of data from pharmacometric modeling and simulations. This dose-adjustment factor is consistent with the class of SCIG therapies, except the 10% SCIG human hyaluronidase and immune globulin. As such, current prescribing information for 20% SCIG (Hizentra) in the US recommends that patients switching from IVIG therapy to 20% SCIG (Hizentra) are dosed at 1.37 times their previous IVIG dose.14 However, prescribing information in the European Union (EU) recommends equivalent dosing between IVIG and 20% SCIG (Hizentra).6 An analysis of cross-sectional data from a major home care provider showed that dosing patterns may vary across patient populations or route of administration, with lower doses prescribed for patients on SCIG than with IVIG.12 Previous research also indicates that treatment with 20% SCIG (Hizentra) at equivalent doses to IVIG (i.e., at a 1:1 ratio) is well-tolerated and effective in protecting against infections in patients with PI.10 As a result, a number of studies have raised questions about whether dose-adjustment coefficients are needed.10,11,13,15

The objective of this study was to evaluate and provide real-world evidence of dose ratios in the US after patients with PI were switched from IVIG to 20% SCIG (Hizentra).

Methods

Study Design and Patient Selection

A retrospective longitudinal study was conducted using shipment data on prescriptions dispensed from specialty pharmaceutical and service providers (SPs) from 2011 to 2016. SPs fill prescriptions for specialty drugs, such as IgG replacement therapy, that are not available at local retail pharmacies, due to higher costs or complexity of handling and administration. The database contained information from more than 40 different SPs and included data on patient diagnoses; details about the drugs shipped, such as strength, volume, vial quantity, and mode of administration; prescriber specialty; patient weight; and patient demographics, including age, sex, and geographic region. Shipped volume (in grams) was used to calculate the dose in this study because volume prescribed or consumed is not available in the data. The study, therefore, implicitly assumes that patients were administered the total volume of therapy shipped. There are no strong reasons to believe that patients were administered a volume different than that shipped. Even if patients were not administered all of the shipments they received, it is unlikely that this phenomenon would impact calculations of SCIG and IVIG dose differentially. Moreover, if patients were administered only a portion of volume shipped, the current study would tend to overestimate the SCIG-to-IVIG dose ratios.

The study design scheme is presented in Figure 1. The study population included PI patients who switched from IVIG therapy to 20% SCIG (Hizentra). PI patients were identified using ICD-9-CM (279) or ICD-10-CM (D80-D84) diagnosis codes. Patients who switched from IVIG to 20% SCIG (Hizentra) were identified as patients who had at least 1 IVIG shipment prior to the first 20% SCIG (Hizentra) shipment observed in the database. All patients were required to have at least 2 shipments of 20% SCIG (Hizentra), including the first 20% SCIG (Hizentra) shipment, which defined the switch date, and at least 1 shipment of 20% SCIG (Hizentra) at least 6 months after the switch date. Patients were also required to be at least 2 years old at 6 months before the switch date and have no claims for IVIG during the 6 months following the switch.

Treatment, Outcomes, and Covariates

Baseline demographic, provider, and payer characteristics were assessed at the time of switch; these included sex, weight, geographic location of provider, type of PI diagnosis, specialty of provider, and payer type. Age was assessed at 6 months prior to switch.

The outcomes of interest were within-patient Hizentra 20% SCIG-to-IVIG monthly dose ratios at months 0 to 2 (0-60 days), 2 to 4 (61-120 days), 4 to 6 (121-180 days), and 6 to 8 (181-240 days) after the patient switched to 20% SCIG (Hizentra) from an IVIG therapy.

Statistical Analysis

Baseline demographic, provider, and payer characteristics were described with frequency distributions for categorical variables and with means, standard deviations (SDs), medians, and interquartile ranges (IQRs) for continuous variables.

Mean daily IVIG dose (g/day) prior to the switch to 20% SCIG  (Hizentra) was calculated as the total volume of IVIG therapy shipped to the patient prior to the switch date divided by the number of days between the first and the last IVIG shipment date plus 30 days to account for time associated with the last shipment (based on the median number of days between shipments observed in the database). The mean daily IVIG dose was multiplied by 30 to calculate the average monthly IVIG dose (g/month).

The data show that shipments of 20% SCIG (Hizentra) were sent to patients in variable intervals (mean, SD, and mode of the duration of time between shipments were 27, 19, and 28 days, respectively). This observed nonuniformity in shipment intervals could have implications on the calculation of mean monthly 20% SCIG (Hizentra) dose because a simple aggregation of shipments by month could result in the mean monthly dose being automatically inflated or deflated based on the frequency of shipments. Therefore, to assess the volume of 20% SCIG (Hizentra) that was intended for treatment of each patient, mean monthly 20% SCIG (Hizentra) dose was calculated assuming that the duration of time between shipments reflected the number of days that a particular prescription shipment was used by the patient (as noted above, the mean duration between 20% SCIG (Hizentra) shipments was 27 days). Specifically, daily 20% SCIG (Hizentra) doses (g/day) were first estimated by dividing the shipped volume in each shipment by the number of days to the next shipment. These estimated daily doses were aggregated for each 2-month period following the switch date, and average monthly doses (g/month) were calculated by dividing the aggregated daily doses by 2 months.

For each patient, Hizentra 20% SCIG-to-IVIG dose ratios were calculated for each 2-month period post switch by dividing the patient’s mean monthly 20% SCIG (Hizentra) dose by his or her mean monthly IVIG dose prior to the switch. If a patient did not have a shipment in a given 2-month period, the patient’s dose ratio from the last period was carried forward. This last observation carried forward approach for imputing missing data is commonly used in health outcomes research.16

Median (IQR) dose ratios at each 2-month interval were then calculated in order to minimize the impact of outliers and were plotted for the study population. Dose ratios at 2 to 4, 4 to 6, and 6 to 8 months were compared with the dose ratio at 0 to 2 months using the Wilcoxon signed rank test to account for the paired nature of the data.

Sensitivity Analysis

Patient weight was available for only 82% of the study population and was not regularly recorded for each shipment. Because healthcare providers prescribe SCIG and IVIG dose based on patient weight, mean monthly dose ratios were calculated assuming that patient weight did not change substantially over the course of the 8-month observation period. Although this is a reasonable assumption to make for adults, it may not be valid for pediatric patients. Therefore, a sensitivity analysis was conducted excluding pediatric patients younger than 8 years of age from the study population to reduce the effects of changes in patient weight on dose calculations.

Results

Baseline Demographic, Provider, and Payer Characteristics

 
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