Errors in prescribing HIV-1 protease inhibitors

Errors in Prescribing HIV-1 Protease Inhibitors Peter J. Ungvarski, MS, RN, FAAN, ACRN, and James E. Rottner, MPA Objective: The purpose of this study was to describe and quantify errors in dosage frequency associated with written medical orders, compared to manufacturer's recommendations and current therapeutic recommendations for protease inhibitors, for persons living with HIV disease~AIDS who were receiving home care services. Methods: A convenience sample was used for a univariate descriptive study to collect information from client records on the dosing intervals prescribed f o r three protease inhibitors: indinavir, ritonavir, and saquinavir. The study took place between December 1, 1996, and January 15, 1997, at a certified home health agency (CHHA) in New York City. The final sample accrued consisted of 202 adults who were receiving home care. The mean age of the sample was 42 years (SD = 9.43), ranging from 24 to 69years. The majority were people o f color, and Medicaid was the principle payor source for all health care needs. The main outcome measure was the number of errors in dosage frequency documented in written medical orders for protease inhibitors Results: Protease inhibitors were ordered for 91 (45.1%) of the sample. Of the total number of medical orders for protease inhibitors, according to manufacturer's recommendations and current therapeutic recommendations, incorrect dosing schedules were noted in 36 (39.6%) of the records. Additional findings included errors in the dosages of drug prescribed and orders for protease inhibitors as monotherapy. Conclusions: Errors identified with ordering protease inhibitors included the incorrect frequency, the incorrect dose, and the ordering of protease inhibitor as a monotherapeutic agent instead of in combination with other recommended antiretroviral agents. Making clinicians aware of these problems may assist in reducing the incidence of these errors.

Key words: medication errors, HIV protease inhibitors, prescriptions, drug T h e development and spread of pathogens resistant to multiple drugs is becoming an increasing challenge to biomedical science (Stephenson, 1996; Tenover & Hughes, 1996). Since the introduction of antiretroviral therapy to manage human immunedeficiencyvirus type 1 (HIV-1) in 1987, the major limiting factor in the long-term efficacy of treatment has been the development of phenotype, genotype, and cross resistance to nucleoside analogs, protease inhibitors, and non-nucleoside reverse transcriptase inhibitors, whether administered alone, as monotherapy, or in combination (Chang, 1993; Coffin, 1995; Condra et al., 1995; Condra et al., 1996; Deeks, Smith, Holedniy, & Kahn, 1997; Demeter et al., 1997; Eberle et al., 1995; Jacobsen et al., 1996; Molla et al., 1996; Nielsen, Bruun, Mathiesen, Pedersen, & Gerstoft, 1996; Ragni, 1993; Schmit et al., 1996; St. Clair et al., 1991; Richman et al., 1994). The development of drug resistance and the resulting loss of efficacy is thought to be related to the high rate of HIV-1 mutation and high levels of replication with as many as 10~~viral particles produced each day (Perelson, Neuman, Markowitz, Leonard, & Ho, 1996; Salminen et al., 1996). Clinical observations appear to indicate that ~viral resistance tends to occur more frequently when HIV-1 is exposed to subtherapeutic levels of a protease inhibitor (Molla et al., 1996). Factors contributing to the developmentof subtherapeutic levPeter J. Ungvarski, MS, RN, FAAN, ACRN, is a clinical nurse specialist in HIV infection at The Visiting Nurse Service of New York; James E. Rottner, MPA, is the operations manager of AIDS Services at The Visiting Nurse Service of New York.

JOURNAL OF THE ASSOCIATION OF NURSES IN AIDS CARE, Vol. 8, No. 4, July/August 1997, 55-61 Copyright 9 1997 Association of Nurses in AIDS Care

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Ungvarski, Rottner / Errors in Prescribing

els include, but are not limited to, (a) inappropriate use of protease inhibitors, (b) underdosing, and (c) erratic adherence to the prescribed drug regimen (Decks et al., 1997; Dobkin, 1996) Errors in the prescribing and management of drag therapy have been identified and linked to adverse drug events (Bates, Boyle, Vander Vliet, Schneider, Leape, 1995; Bates, Cullen, et al., 1995; Leape, 1994; Leape et al., 1995; Leape et al. 1991; Lesar & Briceland, 1996; Lesar, Briceland, & Stein, 1997). According to Bates, Cullen and colleagues (1995), there is a general lack of awareness of this problem. A majority of errors have been found to occur in the ordering stage, which include (a) the wrong dose, (b) known allergy, (c) wrong frequency, and (d) drug-todrug interactions (Bates, Boyle, et al., 1995). Approximately 6% to 11% of written orders have been found to be associated with dosage frequency errors (Bates, Boyle, et al., 1995; Bates, Cullen, et al., 1995; Lesar et al., 1997). Since the development of HIV- 1 drug resistance has been linked to subtherapeutic levels of prescribed antiretroviral agents, errors in dosage frequency have the potential to promote suboptimal serum plasma levels of the agent being administered. The purpose of this study was to describe and quantify errors in dosage frequency associated with written medical orders, compared to manufacturer's recommendations and current therapeutic recommendations for protease inhibitors, for persons living with HIV disease/AIDS who were receiving home care services.

Methods Design and Setting A convenience sample was used for a univariate descriptive study to collect information on the dosing intervals prescribed for three protease inhibitors: indinavir, ritonavir, and saquinavir. The population studied were clients living with HIV disease/AIDS who were receiving home care services from a certified home health agency (CHHA) in New York City that provides service to persons residing in the Bronx, Brooklyn, Manhattan, and Queens. The study took place between December 1, 1996, and January 15, 1997.

Sample The sample consisted of adults who were receiving home care. Inclusion criteria consisted of adolescents or adults, diagnosed with HIV/AIDS, whether or not any antiretroviral therapy was ordered, who had been admitted to the CHHA for at least 4 weeks and had signed medical orders. Persons under the age of 13 years were excluded, because protease inhibitors are under investigation for the pediatric population.

l~t~men~ Adata collection form was developed as a check-off list to collect information on the medical orders and included client record number, age, gender, race/ethnicity, and a list of currently approved antiretroviral agents including nucleoside analogs (didanosine, lamivudine, stavudine, zalcitabine, and zidovudine), protease inhibitors (indinavir, ritonavir, and saquinavir), and a non-nucleoside reverse transcriptase inhibitor (nevirapine). Other antiretrovirals under study could also be listed. Additionally, the dosage and schedule ordered for each drug were requested to be recorded. Information was obtained from the Health Care Financing Administration (HCFA) form 485, Home Health Certification and Plan of Treatment, which was signed by the physician responsible for care.

Procedure and Analysis Meetings were held with the registered nurses, referred to as the Coordinator of Care (COC), who are responsible for managing the home care service for clients with HIV/AIDS, to instruct them on filling out the data collection forms. They were asked to fill out the data collection form on all cases involving clients with HIV/AIDS. The CHHAuses a case-mix approach to HIV/AIDS care, and the case assignments are by a designated geographic region as opposed to assigning by diagnosis, so the case mix for each nurse is diverse and includes clients with other diagnoses, for example, cardiacs, diabetics, and so on. Because the burden of routine paperwork is extensive for home care nurses, the decision whether or not to complete a form was left to the discretion of each COC. The decision to submit a form was self-determined by the COC, based on

JANAC Vol. 8, No. 4, July/August 1997 Table 2. Orders for Protease Inhibitors (N = 202)

Table 1. Characteristics of Sample (N = 202) Number (Percentage)

Characteristic Gender Female Male Race or ethnic group Hispanic Black White Asian or Pacific Islander Primary Health Care Payor Source Medicaid Medicare Private Other or none Secondary Health Care Payor Source None Medicaid AIDS Drug Assistance Program Other

57

88 (43.6) 114 (56.4) 98 (48.5) 76 (37.6) 23 (11.4) 5 (2.5) 163 (80.7) 25 (12.4) 6 (3.0) 8 (4.0) 164 (81.2) 28 (13.9) 7 (3.5) 3 (1.5)

whether she or he felt she or he had time to complete the requested information, and was not related to any clinical judgments regarding any client. Of the approximately 1,500 patients listed as active within the CHHA during the study period, 223 (14.8%) data collection forms were returned. Because of incomplete data recording, 21 forms were excluded. All data were entered by the SPSS/PC+ data entry program. Simple descriptive statistics were calculated for all data. Findings describing and quantifying dosing errors for the protease inhibitors were then compared to the manufacturer's package insert. Finally, the manufacturers for each of the three protease inhibitors were telephoned to verify the dosing schedule listed on the package insert.

Results Atotal 223 data entry forms were returned. The final sample consisted of 202 participants. The mean age of the sample was 42 years (SD = 9.43), ranging from 24 to 69 years. The majority were people of color, and Medicaid was the principle payor source for all health care needs. Table 1 illustrates the sample characteristics. According to the Centers for Disease Control and Prevention 1993 Classification System for HIV Infection, all sample participants were definitively

Drug(s) lndinavir Ritonavir Saquinavir Saquinavir + indinavir Saquinavir + ritonavir None ordered

Number (Percentage) 43 (21.3) 7 (3.5) 38 (18.8) 2 (1.13) 1 (0.5) 111 (54.9)

diagnosed as Category C, AIDS-indicator conditions (Centers for Disease Control and Prevention, 1992). Of the total (N = 202) number of cases reviewed, 28 (13.9%) had no antiretroviral therapy ordered. The majority of clients, 174 (86.1%), had either a nucleoside analog, non-nucleoside reverse transcriptase inhibitor, or protease inhibitor ordered, either alone or in combination. Eighty-two (40.5%) of the sample were receiving nucleoside analogs either alone or in combination with other nucleoside analogs, and one client was receiving a nucleoside analog with a non-nucleoside reverse transcriptase inhibitor. Protease inhibitors were ordered for a total of 91 (45.1%) of the clients. For 88 (43.5%) of the clients, the protease inhibitor was ordered alone or in combination with a nucleoside analog, and for 3 (1.4%), combination protease inhibitor therapy was ordered. Table 2 illustrates the prescribing patterns for protease inhibitors, and Table 3 illustrates the patterns of nucleoside analogs ordered in combination with protease inhibitors. Dosing schedules ranged from once every day to every 12 hours. Table 4 illustrates dosing schedules prescribed. The total amount of drug to be taken in milligrams (mg) for each dose ordered for the protease inhibitors was (a) for indinavir orders, 31 of 37 clients (83.7%), had 800mg ordered; (b) for ritonavir, 5 of 6 (83.3%), had 600mg ordered; and (c) for saqinavir orders, 25 of 34 clients (73.5%), had 600mg ordered. Dosage was not reported on the data collection forms for indinavir, saqinavir, and ritonavir for 7, 2, and 5 clients, respectively. Manufacturer's package inserts recommended dosage and frequency were (a) for indinavir, "800mg (two 400mg capsules) orally every 8 hours" (Merck and Company, Inc., 1996); (b) for ritonavir, "600mg twice dally. . . . 600mg b.i.d." (Abbott Laboratories, 1996);

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Ungvarski, Rottner / Errors in Prescribing

Table 3.

Combinations of Protease Inhibitors Ordered With Nucleoside Analogs (n = 91)

Protease Inhibitor

Indinavir (n = 43) ordered with

Ritonavir (n = 7) ordered with

Nucleoside Analog

Didanosine Lamivudine Lamivudine + stavudine Stavudine Zalcitabine Zalcitabine + stavudine Zidovudine Zidovudine + didanosine Zidovudine + zalcitabine Zidovudine + lamivudine Zidovudine + lamivudine + stavudine None (on monotherapy) . l.amivudine + stavudine Stavudine Zidovudine None (on monotherapy)

Saquinavir (n = 38) Didanosine + lamivudine ordered with Lamivudine l.amivudine + stavudine Stavudine Zalcitabine + lamivudine + stavudine Zalcitabine + stavudine Zidovudine Zidovudine + lamivudine Zidovudine + lamivudine + stavudine Zidovudine + zalcitabine + lamivudine + stavudine None (on monotherapy)

Number (Percentage)

2 (4.7) 6 (14.0) 14 (32.6) 2 (4.7) I (2.3) 1 (2.3) 1 (2.3) 1 (2.3) 1 (2.3) 10 (23.3) 1 (2.3) 2 (4.7) 2 (28.6) 1 (14.3) 2 (28.6) 2 (28.6) 4 5 7 3

(10.5) (13.2) (18.4) (7.9)

1 (2.6) 3 (7.9) 1 (2.6) 9 (23.7) 1 (2.6) 1 (2.6) 3 (7.9)

Note: Two orders were for saquinavir and ritonavir combination, and one order was for saquinavir and indinavir combination.

and (c) for saquinavir "three 200rag capsules three times daily" (Invirase, 1996). According to telephone consultations with the manufacturers, (a) indinavir "must be taken every 8 hours to maintain blood levels" (Merck & Co., Inc.); (b) for ritonavir, "although the package insert states b.i.d., the drug must be taken ql2h in order to maintain adequate blood levels" (Abbott Laboratories); and (c) for saquinavir, "it didn't matter whether the drug was taken t.i.d, or q8h" (Roche Laboratories). Comparing the information provided in

Table 4.

Dosing Schedules for Protease Inhibitors (n = 94)

Schedule Every day (q.d.) Twice a day (b.i.d.) Three times a day (t.i.d.) Every 8 hours (q8h) Every 12 hours (ql2h)

Indinavir Ritonavir Saquinavir (n = 44) (n = 9) (n = 41) --22 (50) 22 (50) --

-7 (77.8) --2 (22.2)

1 (2.4) 1 (2.4) 31 (75.7) 8 (19.5)

Note: Percentages are in parentheses. 88 cases had a single protease inhibitor ordered and 3 cases had two protease inhibitors ordered for a total of 94 orders.

the package insert with the drug orders, (a) indinavir was ordered according to recommendations (q8h) for 22 (50%) of the clients; (b) saquinavir was ordered according to recommendations (t.i.d.) for 31 (75.7%) of the clients; and (c) for ritonavir, when the prescribing clinician followed the manufacturer's package insert (b.i.d.), it was ordered as recommended for 7 (77.8%) of the clients for whom it was prescribed. Discussion This study was designed to describe and quantify errors in dosage frequency associated with written medical orders for protease inhibitors. When considering the instructions provided in the package inserts, the dosing frequency recommendations were followed for 55 (60.4%) of the total (n = 91) clients receiving either indinavir, saquinavir, or ritonavir. Errors in dosing frequency for indinavir were noted in 22 (50%) of the records of clients for whom it was ordered, because it was ordered t.i.d instead of q8h. Based upon manufacturer's recommendations for the dosing frequency of saquinavir, the fact that it was ordered q8h rather than t.i.d would not appear to be of any clinical significance. However, the fact that saquinavir was ordered once a day for one patient and twice a day for another patient is certainly inconsistent with therapeutic recommendations. A dilemma exists with regard to orders for ritonavir. If one considers the package insert supplied by the manufacturer for b.i.d dosing, then it was ordered correctly for the majority, 7 (77.8%) of clients taking the drug. However, comparing ritonavir orders with what the manufacturer revealed in a telephone inquiry, it actually was ordered incorrectly for these 7 (77.8%) clients.

JANAC Vol.8, No. 4, July/August1997 59

There appears to be a lack of regard for the dosing schedule times associated with prescriptions written in terms of the number of times per day versus specified intervals during the course of a day, for example, t.i.d versus q8h. However, the interpretation of a dosing schedule written as t.i.d (three times a day) is usually interpreted by physicians, nurse practitioners, nurses, physician assistants, and health educators as either 9 a.m., 1 p.m., and 5 p.m., or 10 a.m., 2 p.m., and 6 p.m. In most instances, the client is instructed to take the drug within an 8-hour period, leaving a 16hour period when no drug is taken. If therapeutic levels of a protease inhibitor are dependent upon an equal distribution period related to the time of drug ingestion, clinicians need to be made aware of this problem and order the drug appropriately so that all health care providers involved in the plan of care may provide accurate and correct information. One method of circumventing this issue, adopted by the CHHA in which this study was performed, is to inform referring physicians that clients will be taught to take all antiretroviral therapy at spaced intervals throughout the day regardless of t.i.d or b.i.d, orders. This policy has met with little resistance from physicians and has facilitated client teaching by the nurses. However, this has created additional paperwork for both the referring physician and the COC in that a signed medical order must be obtained for this change. Additionally, suboptimal dosages were noted to be ordered for 16.3%, 16.7%, and 26.5% of the clients receiving indinavir, ritonavir, and saquinavir, respectively. When HIV is exposed to low dose or subtherapeutic levels of a protease inhibitor, HIV replication is allowed to continue and resistance to these drugs develops (Carpenter et al., 1996; Deeks et al., 1997; Mellors, 1996; Molla et al., 1996). When this occurs, the COC has been advised to contact the referring physician to verify the order and to ask if this is an incremental induction schedule. An ethical problem arises when the referring physician indicates that the order is a maintenance schedule and will not change the order despite the evidence that this may limit the durability and efficacy of the drugs ordered. Data also revealed that for 7 (7.6%) clients, a protease inhibitor was prescribed as a monotherapeutic agent. Protease inhibitor monotherapy using indinavir,

saquinavir, and ritonavir has been shown to result in phenotype, genotype, and cross resistance (Condra et al., 1995; Condra et al., 1996; Ebele et al. 1995; Jacobsen et al., 1996; Mellors, 1996; MoUa et al., 1996; Schmit et al., 1996). Current recommendations are to avoid protease inhibitor monotherapy (Deeks et al., 1997). A major limitation of this study was that the data were drawn from client records. The authors were not able to identify if the HCFA form 485 was prepared by a physician, nurse practitioner, or physician assistant. Experience has shown that many of the clients referred to the CHHA are being cared for by mid-level primary care providers. Although orders are written by nurse practitioners, or physician assistants, the New York State Department of Health requires a physician's signature on the medical order form for home care services. Because the sample was limited to a population who were predominantly people of color and Medicaid recipients, potential differences in prescribing patterns among clients from other socioeconomic strata as well as different racial/ethnic backgrounds could not be observed. For these reasons, as well as the fact that the participants were an accidental or convenience sample, and confined to people with HIV disease/AIDS receiving home care services who were living in New York City, generalizations about the findings may be limited.

Conclusions Although the primary purpose of this study was to describe and quantify errors in dosage frequency associated with written medical orders for protease inhibitor therapy, the results identified three errors in ordering phase: (a) the wrong dosing frequency, (b) the wrong dose, and (c) the ordering of protease inhibitor as a monotherapeutic agent instead of in combination with other recommended antiretroviral agents. Making clinicians aware of these problems may assist in reducing the incidence of these errors. Further studies are needed to identify the extent to which these errors occur among primary care providers caring for people living with HIV/AIDS across settings, as well as to identify interventions that will help to prevent these occurrences.

60 Ungvarski, Rottner / Errors in Prescribing

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