Journal of Neuroscience Nursing:
Effect of Oral Antihistamine on Local Injection Site Reactions With Self-Administered Glatiramer Acetate
Pardo, Gabriel; Boutwell, Christine; Conner, Jill; Denney, Douglas; Oleen-Burkey, MerriKay
Gabriel Pardo, MD MS, is the director of the MS Center of Oklahoma, Mercy's NeuroScience Institute, Oklahoma City, OK.
Christine Boutwell, MD, is a neurologist in Kansas City, MO.
Jill Conner, PhD, is the director of Medical Operations at Teva Neuroscience, Kansas City, MO.
Douglas Denney, PhD, is a professor of psychology at the University of Kansas, Lawrence, KS.
Question or comments about this article may be directed to MerriKay Oleen-Burkey, PhD, at email@example.com. She is the director of Outcomes Research, Teva Neuroscience, Kansas City, MO.
Patients with multiple sclerosis often use injectable medication such as glatiramer acetate or interferons to treat their disease. Subcutaneous injections may be associated with local injection site reactions (LISRs), which can include itching, pain, swelling, or redness. Although not serious, these side effects are bothersome and can have a negative impact on adherence to the therapeutic regimen, particularly in early phases of treatment. This randomized parallel group study of 83 patients with multiple sclerosis who had recently begun glatiramer acetate therapy investigated whether administration of an oral antihistamine (cetirizine hydrochloride; Zyrtec, 10 mg) prior to each daily subcutaneous injection of glatiramer acetate would lower the incidence of LISRs compared with an oral placebo. Data for the outcome measures were derived from patient diaries and from the clinic during the baseline and the treatment periods. The primary outcome measure comparing the number of LISRs at 5 minutes after injection over 2 weeks was slightly but not significantly lower in patients who received cetirizine compared with patients who received placebo. Within-group comparisons showed that there was a significant reduction in mean LISR score from the 2-week baseline period to the 2-week cetirizine treatment period (0, 2, and 5 minutes after treatment). Both groups showed decreases in the average bothersome ratings from the baseline to treatment periods. Use of cetirizine did not affect the type of LISRs that was reported at any time point. There were no safety concerns with the concurrent administration of cetirizine with glatiramer acetate. Because there were no statistically significant differences on the primary end point between patient groups taking cetirizine and those taking placebo prior to glatiramer acetate injections, cetirizine use as a strategy to reduce LISRs in patients on glatiramer acetate therapy cannot be recommended at this time.
Six drugs have been approved by the U.S. Food and Drug Administration for treatment of multiple sclerosis (MS), all of which are given by subcutaneous (SC) or intramuscular injection or intravenous infusion. Local injection site reactions (LISRs) are not uncommon following SC injection and may contribute to nonadherence, particularly early in treatment (Frohman et al., 2004; Galetta & Markowitz, 2005; Jolly et al., 2008; Wingerchuk, 2006). Glatiramer acetate (Copaxone) is an immunomodulatory agent that is approved by the Food and Drug Administration for the reduction of relapses in patients with relapsing-remitting MS (Johnson et al., 1995). The mechanism of action of glatiramer acetate is believed to involve immunomodulatory activity on monocytes, the development of anti-inflammatory TH2 polarized CD4 T cells, increased production of neurotrophic factors, and restoration of deficiencies in CD4+CD25+ Foxp3+ regulatory T-cells (Weber, Hohlfeld, & Zamvil, 2007). Glatiramer acetate has a favorable safety profile and is generally well tolerated. The most common adverse effects are LISRs (Johnson et al., 1995), which can be troublesome for some patients self-injecting glatiramer acetate (SC), particularly those early in treatment who may be vulnerable to discontinuation (Jolly et al., 2008).
The current program of research is aimed at providing evidence-based guidance to physicians and nurses who are advising patients with bothersome LISRs to use glatiramer acetate. Such information could potentially improve patients' adherence to the medication. Major types of LISRs observed for more than 350 patients taking glatiramer acetate in previous studies fell into the following categories: reddened, warm to touch, painful, raised area around the injection site, trace of blood, and bubble at the injection site (Table 1; Jolly et al., 2008). Data compiled by Teva Neuroscience through its Shared Solutions patient support program shows that the first 60-90 days after initiating therapy is a vulnerable time for therapy discontinuation due to LISRs (Parker & Beach, 2007). Patients are gaining their first experiences with self-injection but have not yet begun to see tangible treatment benefits. Anecdotally, some patients who experience local inflammation and/or the wheal and flare response have used antihistamines prior to their injections of glatiramer acetate to alleviate injection site reactions. Histamine has long been recognized as the prototypical mediator in inflammatory skin conditions, with the H1 receptor subtype being associated with many aspects of allergic inflammation in skin (Greaves, 2005). In this clinical trial, the oral H1 antihistamine cetirizine hydrochloride, available only by prescription when this study was conducted, was tested to determine whether this agent could reduce or prevent the symptoms of LISRs. Cetirizine was chosen as the antihistamine for this study because it is more potent than other antihistamines in wheal and flare tests, has a short onset of action (1.0 ± 0.5 hours), and has little sedative effect relative to most other H1 antihistamines (del Cuvillo et al., 2006; Grant, Danielson, Rihoux, & DeVos, 1999).
Male and female patients with relapsing-remitting MS who had been self-injecting glatiramer acetate for 3 months or less participated in this randomized, double-blind, placebo-controlled study. The Sterling Institutional Review Board (IRB), an independent IRB not affiliated with an academic institution or a research hospital, provided research review services for each of the study sites. The IRB reviewed the clinical research protocol, participant informed consent documents, and investigator credentials to ensure compliance with federal regulations and to confirm that research participants were appropriately informed about the risks and benefits associated with participating in this research study. Patients provided informed consent prior to enrollment. As a part of the study, patients attended three clinic visits. During visit 1, the study investigator observed the patient's self-injection of glatiramer acetate, and the patient was trained on how to evaluate LISRs and to record their evaluations in a daily diary. If patients achieved a concordance level of at least 75% with that of their study investigator, they were provided with a 14-day self-injection diary to record their self-injections administered according to usual practices (baseline period). During visit 2, patients returned their first 14-day diary, were randomized to either the oral antihistamine or placebo, and were provided with a second 14-day diary to record their self-injections (treatment period). These injections were also to be administered according to usual practices, but the patient was instructed to take a pill at least 30 minutes prior to each injection. During visit 3, patients returned their second 14-day diary and performed another self-injection that was observed by the study investigator. Concordance between the evaluator of the LISRs and that of the patient was checked.
During the baseline and the treatment periods, patients administered a daily self-injection of glatiramer acetate (20 mg; Teva Pharmaceuticals Inc., Petach Tiqva, Israel) in accordance with usual practices. These included warming the prefilled glass syringe to room temperature, loading it into the autoject 2 for glass syringe (Owen Mumford LTD), adjusting the depth setting for the area of injection, and ensuring rotation of injection sites. During the treatment period, patients were instructed to take a single encapsulated tablet of cetirizine (10 mg; Pfizer Inc., New York) or a placebo capsule with water at least 30 minutes prior to each daily self-injection of glatiramer acetate.
Patients made daily diary records of the occurrence and type of LISRs at 0, 2, and 5 minutes after injection of glatiramer acetate during each 14-day period (Figure 1). In the planning of the study, no consistent characterization of a LISR associated with an immunomodulator was found in the MS literature. The types of LISRs captured in this study were instead based on documentation in Teva Neuroscience files involving direct observations and patient self-reports associated with nearly 1,000 SC self-injections of glatiramer acetate by over 120 patients. From these records, the most common types of LISRs were defined and listed in the diary as described in Table 1. Development of the time course for observing LISRs in this study was also based on this database. These files indicated that LISRs were seldom visible immediately after injection but appeared over the first 1 to 2 minutes after injection and tended to reach maximum severity in terms of size and/or intensity by approximately 5 minutes after injection. For these reasons, the assessment times selected for LISRs were immediately (0 minute), 2 minutes, and 5 minutes after injection.
Data for the outcome measures were derived from patient diaries and from the clinic during the baseline period and the treatment period. The primary outcome measure was the total number of LISRs at 5 minutes after injection summed across the full 14-day period and prorated to 14 days, when necessary, if the period was slightly longer or shorter for a particular patient. Secondary outcome measures included the total number of LISRs immediately following the injection (0 minute) and at 2 minutes after injection and the average of the patients' bothersome ratings of how "bothersome" each injection was, as recorded daily on a 10-point scale (1 = not bothersome, 10 = severely bothersome).
No previous studies of the effects of oral antihistamines on LISRs were available. Therefore, the appropriate sample size (n = 80) was estimated on the basis of investigations testing the efficacy of other techniques (e.g., warm compresses; Jolly et al., 2008) for reducing these types of reactions. Independent sample t tests (for continuous variables) and chi-square analyses (for categorical variables) were used to compare the two treatment groups in terms of demographics and disease-related characteristics. Independent t tests were also used to compare the two groups with respect to their baseline values on the outcome measures-prior to the start of antihistamine treatment. The main analysis applied to the primary and secondary outcome measures was a 2 × 2 (Group × Period) mixed factorial analysis of variance. The interaction terms from this analysis allow one to compare the change occurring over the course of the treatment period for patients taking cetirizine and those taking placebo. Paired sample t tests were also used to assess the difference between the baseline period and the treatment period separately for each group.
In addition, it was thought that daily antihistamine might have a greater effect on some types of LISRs than on others. Therefore, post hoc analyses using the same analysis of variance design and paired t tests were performed on a modified LISR score composed of those site reactions that might be most responsive to antihistamine treatment: reddened, warm to the touch, and raised area around the injection site. Because the oral antihistamine could potentially require several days to reach a therapeutic level during the treatment period, post hoc analyses were also conducted to examine only the outcome scores for the final week of each period rather than the whole 2-week period. Another post hoc analysis evaluated whether there were differences in the severity of reaction scores recorded by patients during the baseline and treatment periods. This was done by assigning a severity score to each patient based on the percentage of days in each period that the patient recorded between zero and six types of LISRs.
Patient Disposition and Preliminary Analyses
A total of 85 patients were randomized, with 46 in the cetirizine group and 39 in the placebo group. All but one of the patients in each group completed the study (98%) and participated in the evaluations. Most of the 83 patients who completed the study were women (82%) and White (89%). Their average age was 44.1 years, and their average age at MS diagnosis was 40.5 years. Demographic and disease-related information for the patients in the cetirizine and placebo groups is presented in Table 2. The patients in these two groups were well matched, with no significant differences between the groups on any of the demographic or disease-related variables.
The two groups were also compared with respect to the baseline values of the outcome measures. No significant differences between the cetirizine group and the placebo group were found in terms of the total number of LISRs at 0, 2, or 5 minutes after injection or the average bothersome rating during the baseline period.
The results for the outcome variables during the baseline and treatment periods are presented in Table 3. Each outcome variable was subjected to a 2 (Group) times; 2 Period) mixed factorial analysis of variance. The focus of this analysis was the Group × Period interaction, and the results (i.e., p value) pertaining to this interaction are shown in the last column of Table 3. Also shown are the results for paired sample t tests comparing the baseline and treatment means for each separate group.
Although the decline in total LISRs from baseline to the treatment period was consistently greater for the etirizine group than for the placebo group, the Group × Period interaction was only significant for the number of LISRs recorded immediately after injection (p = .029). The interaction was not significant at 2 minutes after injection or at 5 minutes after injection, the primary outcome measure for the study. Neither was this interaction significant in the case of the average bothersome ratings. Paired sample t tests, however, revealed statistically significant declines from the baseline to the treatment period on each of the outcome measures for the cetirizine group. The placebo group also showed small declines on these measures during this same period, but only the decline in average bothersome ratings attained significance for this group.
The results for the primary outcome measure, total LISRs at 5 minutes after injection, are displayed in Figure 2. Although the number of LISRs after cetirizine treatment was significantly decreased compared with baseline (p = .003), the change after cetirizine compared with placebo was not statistically significant.
Additional analyses were performed on three post hoc reformulations of the outcome data. First, based on the notion that some of the specific types of LISRs might be more responsive to an oral antihistamine than to others, a modified LISR score was formulated by combining just the scores recorded for reddened, warm to the touch, and raised area around the injection site. Second, because the oral antihistamine might require several days to reach a therapeutic level during the treatment period, post hoc analyses were also conducted to examine the scores of the outcome measures only during the final 7 days of each period rather than the full 14-day period. Analyses of these two reformulated outcome measures resulted in the same findings as the total LISRs summed over the full 14-day periods: significant declines from the baseline to the treatment period at each postinjection recording for the cetirizine group, but not for the placebo group. Finally, the LISR data were examined to determine the number of days each patient recorded 0, 1, 2, 3, 4, 5, or 6 different site reactions during the baseline or the treatment period. In computing these daily severity scores, the postinjection time was ignored, and the different types of LISRs were aggregated across all three time intervals. Analysis of these daily severity scores indicated fewer days on which multiple reactions occurred for patients taking cetirizine compared with placebo (data not shown).
The safety of using cetirizine concurrently with glatiramer acetate was assessed by monitoring patients' reports of adverse events during visits to the clinical site or during telephone contacts. No pattern of adverse events was apparent, and furthermore most of these reports (8 of 10) were made by patients assigned to the placebo group. Thus, the concurrent administration of cetirizine was well tolerated.
Human skin mast cells and basophils release histamine in response to a variety of stimuli. It has long been believed that histamine release may play a role in cutaneous responses such as wheal and flare reactions and may contribute to LISRs (Grant, 2000). This clinical trial was designed to evaluate whether an oral antihistamine, cetirizine, was useful in preventing or reducing LISRs caused by the SC self-injection of glatiramer acetate.
This study was only partially successful in demonstrating that cetirizine administration prior to these injections reduced the occurrence of LISRs. A difference in LISRs between cetirizine and placebo occurred immediately after injection, and patients using cetirizine showed significant reductions in LISRs between the baseline and treatment periods at each of the postinjection time intervals, whereas patients using the placebo did not. However, the effect sizes for the changes in LISRs from baseline to treatment were quite small for the cetirizine group, with Cohen's d ranging from.29 to.31 for the different postinjection intervals. These small effect sizes call into question the clinical significance of the reductions that occurred for the cetirizine group.
The results of this study do not support a recommendation that patients take cetirizine prior to glatiramer acetate injection to reduce the occurrence of LISRs. However, it may be that there are elements of the study that should be modified for future study. For instance, since the inception of this study, research based on wheal response following intradermal injection of histamine suggests that the therapeutic window for cetirizine to have a maximum effect on reducing raised areas around injection sites and redness of the skin is between 5 and 8 hours after oral dosing and is unlike the maximum plasma concentration of the drug, which is reached at 1.0 ± 0.5 hours (del Cuvillo et al., 2006; Grant et al. 1999). Thus, it is possible that an effect might have been seen if cetirizine had been taken several hours prior to the glatiramer acetate injection instead of 30 minutes. Due to the long duration of action of cetirizine (24 hours), once-a-day dosing is often recommended. Cetirizine's low volume of distribution, which is less than that of exchangeable water in the body, enhances its exposure to H1 cell surface receptors in skin (Greaves, 2005), providing additional support for its selection over other antihistamines.
Several post hoc statistical analyses were performed to further explore the data, and a few of these analyses revealed trends in the data that may also warrant further study. For instance, some benefit of cetirizine was seen for the warm to the touch type of LISRs. The analyses of the derived severity scores suggest that there were fewer and milder reactions in patients taking cetirizine as compared with placebo patients. Further study of antihistamines and other techniques that may effectively reduce the frequency and severity of LISRs with each of the immunomodulatory therapies is needed.
The challenges concerning therapy adherence are well known to the nurses who work with patients with MS. LISRs are a common reason that patients decide not to use their therapy as prescribed or to stop their therapy. Evidence that techniques may reduce the frequency and severity of LISRs may help nurses to encourage their nonadherent patients to stay on therapy and resume their self-injection regimens.
A number of techniques have been explored for reduction of LISRs, such as use of warm compresses, cold compresses, local anesthetics, oral NSAIDs, topical corticosteroids, and injection site rotation, with varying degrees of success (Galetta & Markowitz, 2005; Jolly et al., 2008; Wingerchuk, 2006). Oral antihistamine treatment prior to self-injection of glatiramer acetate did not result in a statistically significant reduction in the number of LISRs at 5 minutes after injection in this study. However, there were indications of some biologic effect with the use of cetirizine, suggesting that this clinical study could be used to assist in the design of further clinical trials. Patients and healthcare providers have long recognized that LISRs are troublesome and may contribute to nonadherence (Miller & Jezewski, 2006), highlighting the importance of further research in this area.
The authors thank Nita Cogburn, PhD (Overland Park, KS), and Pippa Loupe, PhD (Teva Neuroscience, Kansas City, MO), for assistance with this article.
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