Are Clozapine Patients at Risk For Blood Dyscrasias With Concomitant Tamiflu® Use?

by Tammie Lee Demler, PharmD, and Eileen Trigoboff, RN, DNS
Drs. Demler and Trigoboff are from Buffalo Psychiatric Center in Buffalo, New York, and are also with the State University of New York at Buffalo.

Psychiatry (Edgemont) 2009;6(11):29–33

Funding

There was no funding for the development and writing of this article.

Financial disclosure

The authors have no conflicts of interest relevant to the content of this article.

Abstract

Flu vaccination is the best protection against seasonal flu; however, as mutated strains of the flu develop and/or unvaccinated people are exposed to the wild virus, antiviral prophylaxis becomes more important. High-risk patients, such as those institutionalized, are particularly vulnerable to adverse drug events and possibly even more so during the course of active viral infection. As clinicians pursue antiviral treatment, it is important to know the potential risks of prescribing concurrent medication regimens. The objective of this study was to contribute to the evolving literature by evaluating the occurrence of blood dyscrasias with concurrent use of oseltamivir and clozapine (a drug used to treat refractory schizophrenia). This study was a retrospective chart review conducted at a 240-bed New York State mental health facility during an influenza outbreak where oseltamivir was distributed to the vast majority of inpatients. The records of 32 patients treated with concurrent oseltamivir and clozapine were assessed for alterations in white blood count and/or absolute neutrophil count at designated periods and compared to baseline lab values. A repeated measures ANOVA was used to analyze the data.

Results: No changes in white blood cell were noted as a result of concomitant oseltamivir and clozapine therapy in the study sample; however, there were statistically significant differences between the absolute neutrophil count from before oseltamivir and the two time periods following oseltamivir administration. Cautions are detailed regarding concomitant use; however, proactive clozapine discontinuation prior to antiviral treatment is unwarranted.

Key Words

influenza, clozapine, oseltamivir, concomitant risks, agranulocytosis

Introduction

Influenza can have a great impact on the general population. According to the National Center for Health Statistics, influenza and pneumonia were ranked 7th leading cause of death in the United States.[1] In special patient populations (such as in long-term care, geriatrics, or chronic medical or mental illness) it can have an even more marked effect due to complications. For patients with medical comorbidities, influenza contributes to increasing healthcare costs as well as patient mortality.[2-4]

There exists a strong emphasis for influenza prophylaxis in the United States. This comes in the form of annual influenza vaccines available as a trivalent inactivated intramuscular injection and a live attenuated vaccine administered intranasally. Flu vaccination clinics are held frequently, often at no charge. To improve access to flu administration, states within the United States have been passing laws to allow pharmacists to immunize adults with influenza vaccination. As the incidence of H1N1 (Swine Flu) virus has dramatically risen, our at-risk population is at an even greater disadvantage with the suggested requirement of two vaccination administrations during the fall of 2009. The two injections will include the seasonal flu vaccine and a primary vaccine booster of the HIN1 vaccine. While no vaccination can address all viral mutations, the potential prophylaxis of this double vaccine preparation is enhanced.

Should a person become infected with influenza, medications are readily available as treatment options. Oseltamivir (brand name Tamiflu®) is one of the most recent anti-influenza medications available. Oseltamivir is classified as a neuraminidase inhibitor, effective against both Influenza type A and B, and has been shown to reduce the duration and intensity of influenza symptoms in adults and children over the age of 1. Antiviral therapy will likely be the mainstay of treatment.
Nausea and vomiting are two of the most common side effects of oseltamivir. The infrequent side effect manifested as a blood dyscrasia is a risk factor that may be accentuated with psychiatric medications. Psychiatrically disordered individuals may be at higher risk for blood dyscrasias when treated with clozapine, also known to increase the risk of blood dyscrasias.

Study Objective

The objective of this study was to determine if there was a substantiated association among oseltamivir, clozapine, and blood dyscrasias for a sample of psychiatric inpatients.

Background

A literature review examined the relationships among clozapine, influenza, and blood dyscrasias and oseltamivir. A literature review was conducted via EMBASE and MEDLINE from 1975 to 2008. Oseltamivir is an oral neuraminidase inhibitor that is indicated for the treatment and prophylaxis of Influenza A and B.[2] The intended use of oseltamivir is an adjunctive therapy to the influenza vaccine. Oseltamivir selectively inhibits the neuraminidase enzymes of influenza, but does not inhibit human neuraminidase, which ultimately prevents the release of virions from infected cells.[5,6] Other mechanisms of oseltamivir include the penetration of virions into respiratory epithelial cells preventing the formation of viral aggregates, further prohibiting the viral activation by respiratory mucosa, subsequently inhibiting cytokines including interleukin 1 and tumor necrosis factor. It has been hypothesized that the psychiatric effects of oseltamivir may be in part due to the increased dopamine levels in the prefrontal cortex, as measured in the brains of rats by microdialysis. Yoshino et al[3] systemically administered oseltamivir at 25mg/kg or 100mg/kg intraperitoneally, which resulted in extracellular dopamine when compared to controls. Research to identify the potential causes or contributing factors of the reported psychiatric symptomatology could clarify this association.

Due to influenza’s high prevalence and risk of death, resulting in approximately 36,000 deaths and 200,000 hospitalizations per year, it is important to recognize all potential negative outcomes of influenza infection. In the case of influenza and blood dyscrasias, the connection has not been thoroughly examined, which substantiates the importance of this investigation. One of the more common medications used to treat influenza is oseltamivir.[4]

An atypical antipsychotic, clozapine, has a well-documented adverse event of reducing the white blood cell count for a small percentage of people, and has been known to cause agranulocytosis (white blood cell (WBC) <500/mm3) in patients.[7,8] If oseltamivir also causes blood dyscrasias, a patient who is receiving both oseltamivir and clozapine while developing a blood abnormality would need to have the cause carefully determined. Examining any relationship among clozapine, influenza, and blood dyscrasias will help distinguish the cause of the abnormality. Physiologic immune response to influenza A or B includes an increase in white blood cell counts in order to help combat infection. Immune response studies are lacking concerning the use of oseltamivir in both healthy and those with chronic illness. In studies of naturally acquired and experimentally induced influenza, treatment with oseltamivir did not impair normal humoral antibody response to infection.[9] Patients receiving clozapine treatment may already have altered levels of white blood cells or neutrophils as a result of the clozapine treatment itself. The addition of the antiviral oseltamivir may have an impact on hematological parameters of clozapine patients. This study evaluated the effect for this subgroup of patients. Patients who have been stabilized on clozapine must continue to receive uninterrupted therapy in order to achieve remission and recovery. Those who have therapeutic gaps due to nonadherence or a discontinuation by a provider for a variety of reasons will likely experience less robust improvement longitudinally once clozapine is reinitiated. For this reason it is important for a clinician who is faced with clozapine-treated patients with possible influenza infection to have evidence-based information about the association of oseltamivir’s effects on blood component values. Blood dyscrasias, like leukopenia, neutropenia, or pancytopenia, commonly have been seen in the early stages of viral infections.[10–12] One of the more commonly documented occurrences has been viral hepatitis linked to anemia.[13,14] While viral hepatitis and blood dyscrasias have been documented as a concurrent condition, there has been very little published literature involving a possible connection between influenza virus and blood abnormalities. Influenza has a possible association with mild leukopenia, but other blood dyscrasias, such as thrombocytopenia, anemia, or pancytopenia, have not been so clearly linked.[15] Laboratory values used to diagnose blood dyscrasia can vary slightly among institutions, but in general they fall in a similar range.[16,25] This study used the white blood cells and absolute neutrophil count values. A general reference range for adults includes WBC between 4.5 to 10.0x103/mm3, with WBC differential in peripheral blood breaking down into polymorphonuclear neutrophils (PMNS) at 50 to 65 percent; bands 0 to 5 percent; eosinophils 0 to 3 percent; basophils 1 to 3 percent; lymphocytes 25 to 35 percent; and monocytes 2 to 6 percent.[17] Published case studies report that the influenza virus alone has the ability to cause blood dyscrasias in all patient ages.[12,15,18–20] Diagnoses include cytopenia, pancytopenia, aplastic anemia, marked thrombocytopenia, marked leukopenia, and marked neutropenia due to the influenza virus. Neutropenia ranges between a drop in ANC below 1,800/mm3 to 1,400/mm3 depending on race and age, but clinical manifestation typically did not develop until the drop was below 1,000/mm3.[21,22] Regarding the correlation between oseltamivir and blood dyscrasias, it appears that there is a less than one percent chance of a patient developing anemia while on the medication.[5,26] The association between oseltamivir and blood dyscrasias has been explored in the product monograph for oseltamivir; however, the monograph did not report any blood dyscrasias as an adverse event occurring in greater than or equal to one percent of patients (dose of 75mg twice daily for the treatment of naturally acquired influenza). The monograph did list anemia as an adverse event that occurred in less than one percent of patients receiving oseltamivir. The severity of the anemia was not discussed. An interaction report in Clinical Pharmacology and the oseltamivir and clozapine monographs recorded no association or interactions between clozapine and oseltamivir.[5,6,23] Our study examined the inpatient records of a state psychiatric facility within the time frame including a naturalistic blood draw schedule and administration of oseltamivir. Statistical examination of the data focused on the blood dyscrasia evidence of each patient. Results

The sample of 32 subjects, all treated with clozapine, did not include any single subject who at the baseline/first laboratory testing exhibited a blood dyscrasia. A one-way repeated measures analysis of variance (ANOVA) was used to analyze the blood values of 32 subjects who were being treated with clozapine and then, after baseline blood work was completed, received oseltamivir. There were three sets of laboratory values for WBC and ANC included in the analysis for all subjects who were treated with clozapine throughout the time frame of this study—one baseline set prior to treatment with oseltamivir (T1) and two sets taken one month (T2) and two months (T3) after treatment with oseltamivir. There was a set of WBC/ANC bloodwork obtained between T1 and T2 that was not included in the analysis as the authors determined that the administration of oseltamivir was in many cases too brief a time-frame and therefore most likely not sufficient to offer clinically valid information.

A portion of data in raw form did not meet the assumptions for a repeated measures ANOVA, and a Z score transformation was conducted. All assumptions for a repeated measures ANOVA were met with data in Z score transformed versions.

The WBC analysis showed no significant difference from either the time of the first set of laboratory tests (T1) to the second or to the third sets of laboratory tests (T2 and T3). The ANC analysis, on the other hand, showed a statistically significant difference in the ANC values from T1 to both T2 (p>0.045) and to T3 (p>0.030). These results, focusing on the specific blood component ANC, represent a more precise view of the changes in blood values that occurred with this sample in the two months following administration of oseltamivir. Note that in no subject was the ANC level at a level that was clinically significant. This analysis did not differentiate the subjects who had symptoms of influenza from those who did not. No statistically significant difference was found between the ANC measurements in T2 and T3.

Discussion

There is support in the literature that the influenza virus possesses the ability to produce various blood dyscrasias in some patients.[12,15,18–20] A patient with schizophrenia was found to have neutropenia and leukopenia correlated to her influenza B infection.[12,18] There was also a report of a previously healthy man who developed aplastic anemia most likely to due to an influenza A infection.[19] The published blood dyscrasia cases were transient, in that they resolved in a short amount of time.

The possibility of the antiviral oseltamivir causing a blood dyscrasia has a very low likelihood, with the oseltamivir monograph reporting anemia occurring in less than one percent of the patient population.[5] No case reports or case studies in the literature at the time of this article reported blood dyscrasias with patients who had influenza and were being treated with clozapine. The coadministration of clozapine and oseltamivir did not produce a drug-drug interaction resulting in an adverse effect to a patient in an interaction report, monograph reviews, and through a literature search.[5,6,23] It can be concluded that influenza does pose a risk for blood dyscrasias as an extremely rare event (six cases were found over a 30-year time span). Reported cases included pediatric and adult patients, as well as the immunocompromised.[12,15,18–20] Generally, oseltamivir does not cause blood abnormalities besides a small risk for anemia, and there is no causative association among the combination of influenza, treatment with clozapine, and blood dyscrasias or clozapine and oseltamivir in the literature.[5,6,23]

This study’s results with a small sample (N=32) of clozapine-treated individuals indicated no statistically significant difference in the WBC values following administration of oseltamivir. The ANC values, however, were statistically significantly different from T1 to T2 and T3.

Treatment with clozapine raises the risk of agranulocytosis such that there needs to be regular monitoring. Adding other medications that carry similar risk increases the joint probability of a blood dyscrasia. Statistically, converting the raw data to Z scores could be seen as potentially having a dampening effect on the direction of the results. Statistically significant results in light of Z score transformation deserves careful interpretation. The results pattern found with this study appears to fit this general risk topography and it appears possible that oseltamivir administration can add to or amplify this risk.

There are important cautionary factors, however, that prohibit drawing this inference conclusively and would indicate the need for further research. The retrospective design of this study limits the inferential significance of the results, and there was no control group. Conclusive results cannot be derived as the absence of data on possible coexisting factors (i.e., illness) that could also depress the ANC affect the interpretation of the results. An unknown number of patients could have had influenza, which also can lower the ANC. The low N and the lack of replication to date are further weaknesses of the design.

Further studies in this regard would ideally be prospective, incorporate a control group, feature adequate data collection on both other medications and the patients’ overall medical condition, and be large enough to include sufficient numbers of patients. Using a variety of sites and seasons to address the prevalence of influenza in late fall, winter, and early spring would be helpful as well. Only a valid, reliable, and consistent finding that oseltamivir administration amplifies the risk for blood dyscrasias should impact practice. Practitioners at that point may exercise extra caution when considering oseltamivir combined with other factors with this population.

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