Infliximab is a monoclonal anti-tumor necrosis factor-α (TNF-α) antibody that is increasingly used for the treatment of pediatric inflammatory bowel disease (IBD). It is a costly medication that is supplied in 100-mg vials, and administered by intravenous infusion. Dosing of infliximab for IBD is generally initiated at 5 mg/kg of body weight (1). After an initial induction sequence, dosing typically begins at 8-week intervals (1,2). The present retail cost in the United States is $790 per 100-mg vial, which equates to $2370 per dose (excluding facility, equipment, and staffing fees) for a 60-kg patient receiving the standard dose of 5 mg/kg. The drug is routinely administered every 6 to 8 weeks resulting in $15,405 to $20,382 per year in drug costs alone.
In some practices, the administered dose of infliximab is thought to be rounded to a convenient increment such as to the nearest 100 mg. The extent to which this rounding practice varies is unknown. Rounding of doses is potentially important because the degree of immune suppression is dose dependent, and the delivered milligram of drug may affect the effectiveness of therapy and potential for infectious and malignant complications (3). When rounded upward, infliximab increases immunosuppression and potentially exposes patients to increased risks of infections. When rounded downward, infliximab may lead to undertreatment of disease, which may lead to increased disease-related complications. This is of increased importance in pediatrics in which small absolute changes in dose (eg, 50 mg) may result in proportionately larger changes in dose per body weight for small children (eg, 5 mg/kg), potentially magnifying the effect of any dosage adjustment in patients with lower body weight.
We aimed to determine the range of practice patterns regarding prescribing infliximab to children and adolescents with IBD. To accomplish this, we surveyed prescribing clinicians participating in the ImproveCareNow (ICN) Network, a collaborative chronic care network for pediatric IBD with >30 university, multispecialty group, and private pediatric gastroenterology practices throughout the United States and 1 in London, England.
This study was approved by the University of Michigan institutional review board. The survey was targeted at clinicians participating in the ICN Network. Attending physicians, nurse practitioners, and physician assistants who take care of pediatric patients with IBD (independently or while supervising house staff) were included. Trainees (including fellows and residents) and nurses were excluded.
We designed a survey to query clinicians’ prescribing and dosing practices. We included additional questions about staffing of pediatric gastroenterology practices. The survey was pilot tested with physicians in our local practice for readability and clarity. Minor adjustments to the questions were made before use. Pilot data were not included in the final analysis.
The survey was administered in 2 phases. Paper surveys were distributed at the national ICN meeting in Chicago, IL, held on March 19, 2011. Subsequently, each site participating in ICN was individually contacted to identify a list of every eligible clinician who cares for patients with IBD, but who did not complete a survey at the national meeting.
Surveys were then mailed to all individuals identified above. Participation was limited to the practices that were active, participating members of ICN at the time of the initial survey distribution in March 2011. Each survey sent by post included an addressed and stamped return envelope and US $5 cash as an incentive.
The responses documented on the returned survey forms were manually entered into separate database files in SPSS version 19 (SPSS Inc, Chicago, IL) by 2 research assistants (S.J.E., B.H.S.) independently. The SPSS data files were then converted to Stata 11 format with StatTransfer 11 (Circle Systems, Seattle, WA). The double-data entries were then reconciled in Stata 11 (StataCorp, College Station, TX). Discrepancies were resolved by consensus. Analyses including descriptive analyses, Student t test, and χ2 analyses were performed with Stata 12.1.
Thirty-one practice sites were active participants in ICN at the time of this study. A total of 286 clinicians were identified as eligible to participate in this study. This population of interest included 248 attending physicians, 32 nurse practitioners, and 3 physician assistants. Five nurses were misidentified as nurse practitioners and were excluded, leaving 27 nurse practitioners. In total, 279 surveys were distributed, of which 209 were returned with at least partial completion (75%). This includes 180 (73%) attending physicians, 25 (89%) nurse practitioners, and 1 physician assistant (33%). One respondent did not identify his or her role. Two surveys were completed by nurses who were previously misidentified as nurse practitioners and subsequently were excluded, leaving a total of 207 surveys for analysis.
Responses to questions on rounding of infliximab doses are summarized in Table 1. Thirty-eight percent (78/207) of respondents indicated that their practice has no uniform approach to rounding infliximab doses. Eight percent (16/207) indicated that their practice does not round doses at all, which we considered to be a uniform approach. A uniform approach was more common in practices with fewer physicians (7 ± 1 vs 17 ± 4; P = 0.08). Of 114 who indicated that their practice does have a uniform approach to rounding doses (Fig. 1), 43% (n = 49 from 22 different practices) indicated that their strategy always is to round the dose of infliximab up to the nearest 100 mg, and 33% (n = 37 from 18 different practices) indicated their practice rounds up or down to the nearest 100 mg, and 0.9% (n = 1) indicated that their practice strategy always is to round down to the nearest 100 mg. Two additional respondents indicated that they round up or down to the nearest 100 mg if the dose is “close” (1 specified if within 20 mg). An additional 6 respondents round up or down to smaller intermediate doses. Their handwritten responses indicated that they round to the nearest 20- or 50-mg increment. In total, 38.6% (n = 44) of respondents indicated that they round doses down at least occasionally. Of note, despite claiming a uniform approach across their practices, there was considerable disagreement between clinicians within a given practice. For example, 13 of the practices had representatives that claimed a uniform approach, yet provided different rounding strategies in their response.
If the dose escalation of infliximab is clinically warranted, 69.6% (144/207) of respondents indicated that they increase the dose from 5 mg/kg directly to 10 mg/kg, whereas 22.7% (47/207) increase to an intermediate dose such as 7.5 mg/kg. Two respondents (1.0%) noted that they escalate the dose by 100-mg increments as needed. One respondent (0.5%) indicated that dose escalation is determined by infliximab serum level. One responded that the practice starts at 10 mg/kg for most patients and “occasionally decrease the dose.”
Regarding the practice of routine steroid premedication before each infliximab infusion (Fig. 2), 28.2% of respondents (58/206) indicated that they always premedicate with steroids, and 12.1% (25/206) never premedicate with steroids. Of the 114 indicating “it depends,” 94.7% (n = 108) premedicate with steroids if there has been a previous infusion reaction, 11.4% (n = 13) premedicate if treating with infliximab monotherapy (with no other concomitant immunosuppressing drug), 40.4% (n = 46) premedicate before infliximab infusions if anti-infliximab antibodies are present, and 45.6% (n = 52) premedicate if there has been a prolonged lapse between treatment doses. For the purpose of this survey, prolonged lapse was considered to be >8 weeks between doses. A few respondents indicated that they premedicate if lapse is >12 weeks between infusions.
Respondents from 10 practices indicated that the pharmacy automatically adjusts the dose of infliximab. The pharmacies of 2 of these practices always round infliximab doses up to the nearest 100-mg interval, whereas the pharmacies of 8 practices round up or down to the nearest 100 mg. In general, respondents indicated that there was greater uniformity of rounding practice when the responsibility for rounding is given to pharmacists (15/19, 79%) or nurses (5/6, 83%), compared with when the physicians (43/104, 41%) or all clinicians (35/54, 65%) are responsible for rounding. Comparing states in which nurse practitioners practice independently with those in which nurse practitioners require supervision, we found no difference in the proportion of nurse practitioners who have responsibility for determining infliximab dosing (independent 26/32 vs supervised 127/145, χ2 = 0.9; P = 0.34).
Regarding duration of infusion, respondents from all 31 practices indicated that their practice infuses infliximab for 2 hours or longer. One respondent indicated that the practice routinely infuses for 4-hour duration. Clinicians from 11 practices (35.5%) indicated that they also run infusions for durations shorter than 2 hours. Clinicians from 2 practices indicated their strategy for selecting patients is to run 1-hour duration infusions of infliximab. Most indicated that they wait until the patient has tolerated 4 to 5 infusions before initiating rapid infusions. One respondent waits until the patient has tolerated 8 to 10 doses at 2-hour durations. And 1 indicated that a subgroup of the patients who receive their infusions in an adult infusion room receive their infliximab infused over 1-hour durations.
In this large sample of practicing clinicians, there was little consistency of practice pattern with regard to rounding of infliximab doses for children and adolescents with IBD. The infliximab dosing practices are generally more consistent when determined by pharmacists or nurse practitioners than when dosing is determined by physicians. Smaller practices also tend to have greater internal consistency of dosage rounding strategies than larger practices.
The inconsistency of dose-rounding strategies is of more than academic interest. Increasing evidence suggests that IBD outcomes are dose responsive (4). If rounding of doses results in significantly lower than intended doses of infliximab, then undertreatment may adversely affect outcomes. This may be a more important issue for smaller (lighter-weight) patients in whom a small change in dosing has a proportionately greater effect on immunosuppression. For example, if a 30-kg child is prescribed 150 mg (5 mg/kg), but the dose is rounded down to 100 mg, this would decrease the delivered dose to 3.3 mg/kg. The dose of 3 mg/kg may be appropriate for rheumatoid arthritis, but is not believed to be effective for IBD (5).
The incidence of serious infectious complications increases with greater immunosuppression (3,6). Likewise, the small but significant incidence of malignancies is also likely increased with greater immunosuppression (3,7). Therefore, if rounding of doses results in a substantially greater degree of immunosuppression, then this potentially puts patients at increased risk for adverse outcomes. To illustrate the importance of this for smaller children, rounding the dose of infliximab up to the nearest 100 mg may result in a significant increase in dose for a 25-kg child for whom a 5-mg/kg dose is intended. If the practice is to round the dose up to a whole-vial (100 mg) increment, then instead of prescribing 125 mg (5 mg/kg), the child would receive 200 mg (8 mg/kg), or a 60% increased dose. In contrast, if an 85-kg adolescent was to be prescribed 425 mg (5 mg/kg) of infliximab, but the dose is rounded up to 500 mg, this would deliver an 18% increased dose. Thus, the effect of rounding has a disproportionately greater effect on smaller children.
The effect that dosing has on cost of care is also not inconsequential. The retail cost of a 100-mg vial of infliximab in the United States is presently $790. If administered routinely every 8 weeks, then the cumulative drug cost for a 60-kg patient equates to $15,405/year (excluding facility, equipment, and staffing fees). If rounding the dose of infliximab results in 1 fewer vial used per infusion, the differential cost for rounding each dose every 8 weeks during the course of 1 year is $5135. There may be financial pressures to decrease the number of vials used, or the physician may be compelled to round the dose up to “not waste” the unused portion of a vial of infliximab; however, if rates of remission and rates of adverse events are indeed dose dependent, then these dose-rounding decisions have important health-related implications, in addition to cost considerations.
We also found that the practice of premedication with steroids before infliximab infusion is inconsistently implemented. The most commonly cited reason for premedication was for patients who had a history of earlier infusion reaction (52% of respondents). The other reasons respondents indicated that they premedicate patients with steroids were as a matter of routine for all patients (28%), if there had been a prolonged lapse in therapy (24%), or if the patient had positive anti-infliximab antibodies (22%). None of these practices is strongly evidence based (8,9). The question of whether premedication with steroids improves outcomes or decreases the incidence of adverse events remains unclear. Further research is needed to determine whether steroid premedication should be widely implemented or used in select instances.
The extent to which patients are affected by rounding of infliximab doses in practice is unknown. Whether or not the practice of rounding doses is different for smaller children than for larger-sized children is also unknown. These questions, as well as how variation in dosing and administration practice affects serum trough levels of infliximab and the formation of antibodies to infliximab, are important to answer if we are to determine whether the practice of rounding doses is innocuous or whether it has detrimental effects on patient outcomes.
The authors thank the many members of the ImproveCareNow Network for their participation in this survey.
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