Economic Evaluation of Oseltamivir Phosphate for Postexposure Prophylaxis of Influenza in Long-Term Care Facilities
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Economic Evaluation of Oseltamivir Phosphate for Postexposure
Prophylaxis of Influenza in Long-Term Care Facilities
Nancy A. Risebrough, MPhil Candidate, z Susan K. Bowles, PharmD, k z
Andrew E. Simor, MD, FRCP(C),w§ Alison McGeer, MD, FRCP(C),#
and Paul I. Oh, MD, FRCP(C) §
OBJECTIVES: To compare the cost-effectiveness of os- prophylaxis strategies were more cost-effective than no
eltamivir postexposure prophylaxis during influenza A out- prophylaxis.
breaks with that of amantadine postexposure prophylaxis CONCLUSION: Despite high influenza vaccination rates,
or no postexposure prophylaxis in long-term care facilities influenza outbreaks continue to emerge in LTCFs, necessi-
(LTCFs). tating cost-effective measures to further limit the spread of
DESIGN: Cost-effectiveness analysis based on decision an- influenza and related complications. Although amantadine
alytic model from a government-payer perspective. has a lower acquisition cost than oseltamivir, it is associated
SETTING: A Canadian LTCF, with high staff vaccination, with more adverse events, lower efficacy, and individualized
at the beginning of influenza season. dosing requirements, leading to higher overall costs and
PARTICIPANTS: Elderly, influenza-vaccinated patients more influenza-like illness cases than oseltamivir. Therefore
living in a Canadian LTCF. the use of oseltamivir postexposure prophylaxis is more
cost-effective than the current standard of care with aman-
MEASUREMENTS: Incremental costs (or savings) per in-
tadine prophylaxis or no prophylaxis. J Am Geriatr Soc
fluenza-like illness case avoided compared with usual care.
53:444–451, 2005.
RESULTS: From a government-payer perspective, this
Key words: postexposure prophylaxis; oseltamivir; influ-
analysis showed that oseltamivir was a dominant strategy
enza; long-term care; cost-effectiveness
because it was associated with the fewest influenza-like ill-
ness cases, with cost savings of $1,249 per 100 patients in
2001 Canadian dollars compared with amantadine and
$3,357 per 100 patients compared with no prophylaxis.
Costs for amantadine dose calculation and hospitalization
for adverse events contributed to amantadine being a more-
expensive prophylaxis strategy than oseltamivir. Both
I nfluenza remains a serious public health concern in Can-
ada, the United States, and Europe and is associated with
clinically important morbidity and mortality. During any
given season, infection rates are estimated between 10% to
20% in the general population1–3 but are higher in the
From the Health Outcomes and PharmacoEconomics Research Center, long-term care environment.2,4 The nursing home (NH)
Sunnybrook and Women’s College Health Sciences Centre, and wDepartment population is also at significant risk of influenza-related
of Microbiology, Sunnybrook and Women’s College Health Sciences Center, complications, with rates of pneumonia during outbreak
Toronto, Canada; zSchool of Pharmacy, Center for Evidence-Based Phar- situations reported to range from 10% to 42%5 and case-
macotherapy, Aston University, Birmingham, United Kingdom; §University of
Toronto, Toronto, Canada; kCollege of Pharmacy, Dalhousie University, fatality rates of 30% to 55%.6,7
Halifax, Nova Scotia, Canada; zDepartment of Pharmacy, Capital District Annual influenza immunization of staff and residents is
Health Authority, Halifax, Nova Scotia, Canada; and #Department of the most important strategy in the prevention of outbreaks
Microbiology, Mount Sinai Hospital, Toronto, Canada; Cardiac Rehabi- in NHs.8–10 However, despite high staff and resident vac-
litation and Secondary Prevention Program, Toronto Rehabilitation Institute,
Toronto, Canada. cination rates, influenza outbreaks continue to occur an-
nually.4,11,12 With influenza outbreaks, North American
None of the authors have a financial interest in Hoffmann-La Roche.
Funding provided by an unrestricted grant from Hoffmann-La Roche, guidelines recommend the use of antiviral agents to prevent
Canada. The funding agreement gave investigators full control of all study further transmission of influenza virus.13,14 Although sev-
methods and the right to publish study findings. This study was presented eral agents are approved for influenza prophylaxis in other
at the IV International Symposium of Respiratory Viral Infections, Curaçao,
jurisdictions, amantadine is the only antiviral agent cur-
Netherlands Antilles, December 2001.
rently approved in Canada for this indication. However,
Address correspondence to Nancy A. Risebrough, The HOPE Research
Center, Sunnybrook & Women’s College Health Sciences Center, Affiliated
amantadine’s side-effect profile,15 its inactivity against in-
with the University of Toronto, 2075 Bayview Avenue, Rm E2 40, Toronto, fluenza B,16 and growing concern regarding resistance lim-
ON M4N 3M5, Canada. E-mail: nancy.risebrough@sw.ca its its use.17–19
JAGS 53:444–451, 2005
r 2005 by the American Geriatrics Society 0002-8614/05/$15.00JAGS MARCH 2005–VOL. 53, NO. 3 ECONOMIC EVALUATION OF OSELTAMIVIR 445
Outbreak Death
No prophylaxis
No outbreak New ILI No
complication
AMA resistance Treat in
Outbreak - begin PEP Complication LTCF
Vaccinated elders No resistance AE - discontinue Transfer to
AMA PEP Well hospital
living in LTCF
No outbreak No AE
Outbreak - begin PEP
OSE PEP
No outbreak
Figure 1. Model of agents for postexposure prophylaxis after a nursing home influenza outbreak. AMA 5 amantadine; OSE 5
oseltamivir; PEP 5 postexposure prophylaxis; AE 5 adverse event; ILI 5 influenza-like illness; LTCF 5 long-term care facility.
Oseltamivir is a neuraminidase inhibitor that demon- prophylaxis is considered the current standard of care and
strates activity against influenza A and B, has been shown to has been demonstrated to be the most cost-effective option
be effective as treatment and prophylaxis,20–22 and appears when comparing amantadine postexposure prophylaxis
to be well tolerated by older people.20,23 In the United and seasonal prophylaxis.27 There are a number of LTCFs
Kingdom, the National Institute of Clinical Evaluation has that do not use amantadine prophylaxis; thus, including a
recently tentatively recommended against amantadine and no prophylaxis comparator was appropriate. Rimantadine,
in favor of oseltamivir as postexposure prophylaxis in NH a newer generation of amantadine, which has been evalu-
patients during an influenza outbreak.24 In Canada, be- ated in LTCF residents, is only available in the United States
cause the acquisition cost of oseltamivir ($4.20 per day) is and was therefore not considered. Postexposure prophy-
considerably more expensive than amantadine ($0.518 per laxis with zanamivir, another neuraminidase inhibitor ad-
day) and the use of oseltamivir is becoming more wide- ministered by inhaler, was not considered in this analysis
spread for influenza A outbreaks, an economic analysis was because of practical difficulties in drug administration in
conducted to compare the cost-effectiveness of oseltamivir elderly subjects.28
used for postexposure prophylaxis in long-term care facil-
ities (LTCFs) with that of amantadine postexposure prophy- Outcome Measurement
laxis and no prophylaxis. The primary outcome was the occurrence of influenza-like
illness, defined as fever plus at least one of the following
METHODS symptoms: cough, rhinorrhea, nasal congestion, and sore
From a single government-payer perspective, a decision an- throat. It is important to note the difference between influ-
alytic model was developed with a 30-day time frame. enza-like illness and laboratory-confirmed influenza-like
Thirty days reflects the approximate length of one institu- illness. Although trials typically highlight laboratory-con-
tional outbreak.25 The model is illustrated in Figure 1. firmed influenza-like illness (Table 1), in a clinical setting,
the first few cases of influenza-like illness will be confirmed
Setting with laboratory testing, and subsequent cases will rarely
A hypothetical cohort of elderly persons living in a Cana- have laboratory confirmation. Thus the prevention of in-
dian LTCF who received influenza vaccination was consid- fluenza-like illness without laboratory confirmation is the
ered. The analysis began at the start of an influenza season relevant outcome to this analysis.
to permit the inclusion of amantadine dose calculation costs
accrued at the beginning of each influenza season. For this Decision Analysis Model
analysis, only influenza A outbreaks were considered. Post- A model was developed using decision analysis software
exposure prophylaxis was initiated after an influenza out- (TreeAge 3.5, TreeAge Software Inc., Williamstown, MA)
break, defined as three or more laboratory-confirmed (Figure 1). Model inputs are listed in Table 2. During the
influenza-like illness cases over a 48- to 72-hour period.26 1999/2000 influenza season, 205 of 508 (40%) Ontario
Prophylaxis continued for 12 days based on trial protocols. LTCFs experienced an influenza outbreak.4 More than 85%
of the outbreaks were influenza A. Influenza B outbreaks
Treatment Comparators were not considered in the model. During outbreaks, and in
The following comparators were considered. the absence of prophylaxis, studies suggest that 17% (range
1. No prophylaxis 2–43%) of vaccinated residents exposed to influenza A de-
2. Amantadine postexposure prophylaxis velop influenza-like illness.11,20,26,32–34,36–38,49 In the base-
3. Oseltamivir postexposure prophylaxis case, without prophylaxis, some patients require anti-
biotics, develop severe complications, or die during a
In each of the scenarios, no antiviral treatment was given 30-day period. A proportion in the amantadine strategy
to new emergent influenza-like illness cases while on prophy- develops resistance. A portion in both postexposure prophy-
laxis. Currently in many Canadian provinces, amantadine laxis strategies discontinues therapy because of drug-rel-
prophylaxis is recommended13,14,26 and routinely used in ated adverse events and develops influenza-like illness at the
most LTCFs after influenza A outbreaks.12 Postexposure rate of no prophylaxis. In the postexposure prophylaxis446 RISEBROUGH ET AL. MARCH 2005–VOL. 53, NO. 3 JAGS
Table 1. Efficacy in Prevention of Influenza-like Illness (ILI) and Laboratory-confirmed ILI Compared with Placebo
ILI Elderly Nursing Lab-Confirmed ILI Elderly ILI Nonelderly Lab-Confirmed ILI Nonelderly
Home Residents Nursing Home Residents Living in the Community Living in the Community
Prophylaxis
Regimen %
Oseltamivir 6320 9220 6223 7423
8929
Amantadine F F 6230 7130
7831 9131
Rimantadine 6032 5032 6531 8531
strategies, the base case (an analytic method to identify eltamivir and amantadine) that reduced influenza-like ill-
results of the primary inputs, compared with the sensitivity ness and subsequent death.
analysis, which is a variance of the primary input values) Amantadine has a narrow therapeutic index, with fre-
influenza-like illness attack rate (17%) was adjusted by the quent toxicity compounded by renal dysfunction. In a re-
relative risk reduction of preventing influenza-like illness cent survey of Canadian LTCFs, 77% of facilities with an
compared with placebo, as was the proportion who required amantadine postexposure prophylaxis policy reported rou-
antibiotics, developed a complication, or died. tine assessment of renal function and individualized am-
antadine dose calculation before the influenza season.12 In
the current analysis, all patients in the amantadine postex-
Efficacy posure prophylaxis had amantadine dose calculated before
In estimating the postexposure prophylaxis efficacy to pre- influenza season for a cost of $15.52 per patient for the
vent influenza-like illness, it was assumed that postexposure serum creatinine laboratory test.46 To be conservative and
prophylaxis (or outbreak prophylaxis) would be at least as bias against a favorable result for oseltamivir, the cost of
efficacious as seasonal prophylaxis, because there are cur- pharmacist or nursing time to review the patient’s chart and
rently no randomized, controlled trials evaluating os- calculate amantadine dose was not included in the base case
eltamivir as postexposure prophylaxis, and amantadine analysis but was tested in the sensitivity analysis.
efficacy would be similar to rimantadine, because there are In addition, an observational study showed that 9.8%
no randomized, controlled trials of amantadine as postex- of patients with individualized amantadine dosage discon-
posure prophylaxis in the NH resident population. Rim- tinued because of adverse events.36 Approximately 12.5%
antadine has been evaluated in the elderly NH resident of these subjects required hospitalization for falls, halluci-
population.32 In trials comparing seasonal prophylaxis in nations, or delirium.40 It was conservatively estimated that
NH residents with placebo, oseltamivir prevented 63% of patients would be hospitalized for 2 days at an average of
influenza-like illness cases,20 whereas rimantadine prevent- $500 per day in an acute care hospital. In contrast, patients
ed 60% of influenza-like illness cases.32 These probabilities who discontinued oseltamivir did not require any specific
were incorporated into the analysis. treatment.21–23
In a recent case series of elderly living in nine Ontario In each strategy, a proportion of patients with an in-
NHs, antibiotic use, serious complications, hospitaliza- fluenza-like illness was treated with a 10-day antibiotic
tions, and death were 22% to 60% and 78% to 100% course (sulfamethoxazole1trimethoprim) at a cost of
lower in patients who developed influenza-like illness while $3.30.45,47 With an influenza complication, patients treat-
receiving amantadine postexposure prophylaxis or os- ed in the LTCF received a 10-day antibiotic course of am-
eltamivir postexposure prophylaxis, respectively, than in oxicillin-clavulanate at a cost of $40.08.45,47
patients with no prophylaxis.34 In this model, the rates of
antibiotic use, complications, and death with amantadine
postexposure prophylaxis and oseltamivir postexposure RESULTS
prophylaxis were half those with no therapy. Base case results are presented in Table 3. Prophylaxis
strategies were less expensive and provided better outcomes
than no prophylaxis. Compared with no prophylaxis, im-
Cost Measurement and Evaluation plementing a postexposure prophylaxis strategy would save
Resource utilization and unit costs in 2001 Canadian dol- between $2,109 and $3,357 per 100 patients in medical
lars are summarized in Table 2. The cost of transfer to an care costs and prevent between 2.8 and 4.2 influenza-like
acute care facility for treatment of influenza complication illness cases per 100 patients over a 30-day period. Os-
was estimated at $4,072 ($1,466–21,062) based on the av- eltamivir postexposure prophylaxis was less expensive than
erage of all hospitalizations for influenza (case mix group amantadine postexposure prophylaxis (saved $1,248 per
(CMG) 104) or other respiratory procedures (CMG 129) in 100 patients), with marginally better clinical outcomes.
2000/2001 in Ontario.48 The cost of CMG 104 or 129 with Approximately one influenza-like illness case was prevented
potentially life-threatening complexity codes cost in 100 patients treated with oseltamivir (Table 3). The
$21,062.48 In the current analysis, for patients dying of greater cost with amantadine postexposure prophylaxis
influenza complications, the same cost as a surviving patient was mainly due to amantadine dose calculation costs. Dif-
was used to bias against the prophylaxis products (os- ferences in the number of influenza-like illness casesJAGS MARCH 2005–VOL. 53, NO. 3 ECONOMIC EVALUATION OF OSELTAMIVIR 447
Table 2. Model Inputs
Parameter Value Range Source
Median days on prophylaxis before 3 2–5 Assumption
discontinuing due to AE
Median days on prophylaxis before 6 1–12 Assumption
developing ILI (then discontinue)
33–35
Median days on prophylaxis if no ILI 12 11–23
12
Proportion of institutions with influenza 40 31–64
outbreak during influenza season,%
11,20,26,32–34,36–38
Attack rate in vaccinated institutionalized 17 2–43
elderly receiving no prophylaxis,%
Probability of event given ILI (no PEP),%
22,26,35
Antibiotic use 65 50–75
34,38
Serious complication 20 17–48
26,34,38,
Death 11 8–22
26,34,38
Probability of hospitalization due to 60 45–83
ILI complication,%
Efficacy in preventing ILI,%
31–32
AMA 60 60–90
20,39
OSE 63 63–93
12,34,39
Probability of AMA resistance,% 24 0–30
Probability of event given ILI (AMA or OSE PEP),%
Antibiotic use 33 0–65 Assumed a 50% reduction
Serious complication 10 0–20 Assumed a 50% reduction
Death 5.5 0–11 Assumed a 50% reduction
18,37,40–42
Proportion with AMA dose adjusted to 7.0 2.2–40
100 mg every other day,%
36,34,38
Dropout due to AE,% 0–17
AMA (dose adjusted) 9.8
20,23
OSE 2 0–3
AE dropouts requiring hospitalization,%
40,43–44
AMA 12.5 0–22
20,23
OSE 0 0–5
Cost per daily dose,$
AMA (100 mg/d) 0.52 0.26–0.78 Ontario Drug Benefit Formulary45
OSE (75 mg/d) 4.20 2.10–6.30 Canadian manufacturers
wholesale price 2001
Serum creatinine test,$ 15.52 0.00–31.04 Ministry of Health Physician
Schedule of Benefits46
Oral antibiotic,$
Moderate-severe pneumonia 3.30 3.30–57.30 Ontario Anti-infective
Severe pneumonia 40.08 Review Panel 47
Hospitalization due to AE (2 days),$ 1,000 500–2,000 Assumption
Hospitalization for Influenza or 4,072 2,500–5,285 Ontario Case
Respiratory infection (average of CMG 104 or 129),$ Costing Initiative48
Death due to ILI in acute hospital,$ 4,072 2,500–5,285 Ontario Case Costing Initiative48
AMA 5 amantadine; OSE 5 oseltamivir; AE 5 adverse event; ILI 5 influenza-like illness; PEP 5 postexposure prophylaxis; CMG 5 case mix group.
between oseltamivir and amantadine were attributed to sitivity analyses were performed, varying probability and
amantadine resistance and differential adverse-event drop- costs estimates to identify the most important variables af-
out rates. In the oseltamivir strategy, drug acquisition costs fecting the cost-effectiveness of the strategies. Sensitivity
accounted for 59% of the overall treatment cost, compared analysis of the efficacy of the prophylaxis strategies varied
with the amantadine strategy, for which drug acquisition from approximately 60% to 90% relative risk reduction
accounted for only 5% of the overall treatment cost. compared with placebo based on ranges from clinical trials
and observational studies. Sensitivity analyses were con-
ducted to reflect best- and worst-case scenarios for am-
Sensitivity Analysis antadine and oseltamivir prophylaxis strategies.
The effect of changes in estimates of input variables was The cost of amantadine dose calculation was in-
examined over all clinically relevant ranges. One-way sen- vestigated in a number of ways. First, the cost of a serum448 RISEBROUGH ET AL. MARCH 2005–VOL. 53, NO. 3 JAGS
Table 3. Base case and Incremental Results per 100 Patients Over a 30-Day Period
Cost (2001 CDN$) Outcome
Strategy Drug Acute Care Otherw Total ILI Cases Hospitalizations Deaths
OSE PEP 1,934 1,282 38 3,254 2.6 0.16 0.15
AMA PEP 214 2,677 1,612 4,503 4.0 0.28 0.26
No prophylaxis 0 6,369 242 6,611 6.8 0.82 0.75
Incremental comparisonsz
OSE PEP vs no PEP 3,357 4.20 0.66 0.60
AMA PEP vs no PEP 2,108 2.80 0.54 0.49
OSE PEP vs AMA PEP 1,249 1.40 0.12 0.11
Drug-related adverse events and influenza-like illness (ILI)-related complications requiring acute care.
w
Laboratory tests, monitoring, and ILI-related antibiotics.
z
Negative indicates a cost savings or fewer clinical events.
AMA 5 amantadine; OSE 5 oseltamivir; PEP 5 postexposure prophylaxis; CDN 5 Canadian.
creatinine test was varied from 50% to 200% of the base less than 2 minutes per patient to review the chart and cal-
case cost to reflect the two possible situations: (1) half of culate creatinine clearance. Thus, this analysis is sensitive to
patients required a laboratory test to be completed specif- the cost of amantadine dose calculation, but the likelihood
ically for amantadine dose calculation in any given year at a that the actual cost for laboratories with or without phar-
cost of $15.52 per test and (2) the serum creatinine labo- macist time would be less than $3.00 per person is highly
ratory test was twice the cost of baseline estimate. In these unlikely, and oseltamivir prophylaxis remains the least ex-
scenarios, amantadine postexposure prophylaxis remained pensive strategy.
more expensive than oseltamivir postexposure prophylaxis. Varying the incidence adverse events, the attack rate,
Second, the combined cost of baseline serum creatinine outbreak rate, and rate of amantadine resistance based on
laboratory and the cost of nurse or pharmacist time to re- clinical relevant ranges did not change the base case con-
view the patient chart and calculate the creatinine clearance clusions. The base case analysis presents the scenario of
were considered. With an estimated 15 minutes to review similar efficacy between amantadine and oseltamivir prophy-
the patient chart and calculate creatinine clearance at a laxis. No postexposure prophylaxis trials are currently
prorated average hourly wage including benefits, this cost available; thus, outbreak efficacy was assumed to be sim-
would be $15.99 per patient. ilar to that found in seasonal prophylaxis trials. Oseltamivir
The cost of amantadine dose calculation was an im- efficacy (63% relative risk reduction) was based on a sea-
portant cost contributor in this analysis. All patients in the sonal prophylaxis randomized, placebo-controlled trial in
amantadine strategy incurred this cost in preparation for NHs.20 Amantadine was assumed to equal the efficacy of
the influenza season, even though an estimated 40% of in- rimantadine 100 mg/d (60% relative risk reduction) based
stitutions would have an outbreak and then begin prophy- on a seasonal prophylaxis randomized, placebo-controlled
laxis. This reflects current clinical practice because trial also in NH residents.31,32 The efficacy of postexposure
amantadine dose would be calculated at the beginning of prophylaxis is potentially greater than values tested in the
influenza season and be an incurred cost regardless of base case analysis. Increasing efficacy from 60% to 90%
whether there was a subsequent influenza outbreak. It was reduced the amantadine cost to $3,931, with 2.6 influenza-
not until the cost of the serum creatinine test was less than like illness cases per 100 patients. With oseltamivir, in-
$3.00 per test that the amantadine strategy became less creasing efficacy from 63% to 93% reduced the cost to
expensive than the oseltamivir strategy. This is an 81% unit $2,423, with 0.8 influenza-like illness cases per 100 pa-
laboratory cost reduction from baseline or the test only tients. Amantadine resistance and adverse-event dropout
conducted in approximately one in five residents (i.e., 4 of 5 rate contribute to differences in influenza-like illness cases
patients already have recent serum creatinine value and not between amantadine and oseltamivir.
require this test specifically for amantadine dose calcula- Although not available in Canada, rimantadine has
tion). In addition, the added cost of pharmacist/nurse time been available in the United States since 1993. The scenario
to review and calculate the creatinine clearance ($15.99 per of rimantadine (100 and 200 mg/d) postexposure prophy-
person) was considered. With the serum creatinine cost and laxis, without the need for creatinine clearance testing for
pharmacist time, the total cost of amantadine strategy was dose adjustment, was considered. The significant adverse
$6,101 per 100 patients. This was $2,847 per 100 patients event rate, defined as adverse event requiring discontinua-
higher than the oseltamivir prophylaxis strategy but still tion, myocardial infarction, fall resulting in fracture, and
remained $510 less expensive per 100 patients than the no- hyperglycemic event, compared with placebo, was consid-
prophylaxis strategy. Considering both variables, to be cost ered (9%, 100 mg/d, 11%, 200 mg/d).32 The cost of rim-
neutral compared with the oseltamivir prophylaxis strategy, antadine was estimated based on the average drug
19 of 20 patients would have to already have a recent serum acquisition cost relative to oseltamivir daily dose in the
creatinine value in their chart and not require any addi- United States. In the United states, rimantadine 100 mg is
tional laboratory tests, and the pharmacists would require 32% of the cost of oseltamivir 75 mg/d (US $2.20 vs USJAGS MARCH 2005–VOL. 53, NO. 3 ECONOMIC EVALUATION OF OSELTAMIVIR 449
$6.91).50 Using these inputs, the analysis showed that, if modeling analysis could also be applied to influenza B; os-
rimantadine were available in Canada and priced at 32% of eltamivir postexposure prophylaxis would save medical
the cost of oseltamivir, rimantadine 100 mg/d would be the costs and improve patient outcomes compared with am-
least costly postexposure prophylaxis strategy. Outcomes antadine postexposure prophylaxis and no prophylaxis.
did not change compared with the base case amantadine Based on the current model analysis parameters, this
analysis. At 34% of the drug acquisition cost of oseltamivir, analysis would also be relevant to other regions with high
rimantadine and oseltamivir prophylaxis strategies were NH resident and staff vaccination rates. In the 1999/2000
equivalent in cost. Rimantadine 200 mg/d prophylaxis was Ontario influenza season, higher attack rates (17.6%) and
more expensive than oseltamivir prophylaxis but less ex- longer outbreak duration (12.8 days) were reported in
pensive than no prophylaxis. LTCFs with low (o70%) LTCF staff vaccination rates than
Good and poor case scenarios for the amantadine and in institutions with high (490%) staff vaccination rates
oseltamivir strategies were evaluated. The good case sce- (16.1% and 10.0 days, respectively).4 Compared with the
nario for the amantadine prophylaxis included 90% effi- current analysis, lower staff vaccination rates would extend
cacy, 0% hospitalization for adverse events, 10% of the outbreak duration and number of days of antiviral
outbreaks amantadine resistant, and $0 cost for pharma- prophylaxis, therefore increasing overall drug acquisition
cist dose calculation. In this scenario, amantadine cost $184 cost in the prophylaxis strategies. This would decrease the
less than oseltamivir, with 0.8 fewer influenza-like illness margin of medical care cost savings with the prophylaxis
cases per 100 patients. The poor case scenario for amanta- strategies compared with no postexposure prophylaxis.
dine prophylaxis included 60% efficacy, 30% amantadine It is important to note the limitations of this analysis.
resistant outbreaks, $15.99 per person for pharmacist dose Prospective data over an influenza season were preferred
calculation time, and 3% with a fall leading to a hip frac- but were unavailable, so a modeling analysis based on clin-
ture, costing $9,000 in acute care for 5% of those patients. ical and observational studies was necessary. Influenza
In this scenario, amantadine cost $6,207, with 4.2 new in- prophylaxis trials are limited, with no postexposure proph-
fluenza-like illness cases per 100 patients and was more ylaxis trials reported for oseltamivir or amantadine. The
expensive than no prophylaxis. The good case scenario for assumption of similar efficacy of preventing influenza-like
oseltamivir prophylaxis included 93% efficacy and 0% illness in seasonal and postexposure prophylaxis in LTCFs
dropout due to adverse events and kept all other variable situations was made because no postexposure trials were
identical to the base case. In this scenario, oseltamivir re- available. This assumption likely underestimated the true
mained the least expensive ($2,331 per 100 patients) with cost-effectiveness of postexposure prophylaxis strategies. In
the best clinical outcomes (0.6 new influenza-like illness the absence of data, a number of assumptions were made,
cases per 100 patients). The poor case scenario for os- and where possible the estimate was selected to bias against
eltamivir prophylaxis with 60% efficacy and 3% dropout oseltamivir. All model uncertainties were tested in an ex-
due to adverse events resulted in a cost of $3,383, with 2.8 tensive sensitivity analysis.
new influenza-like illness cases per 100 patients. In this poor The conclusions of this analysis remained consistent
case scenario, oseltamivir still remained less expensive with when varying model parameters over clinically relevant
better clinical outcomes than the amantadine or no prophy- ranges, attesting to the robustness of this analysis. The cost
laxis basecase strategies. This supports the robustness of the of amantadine dose calculation was a large contributor to
conclusions. the great overall treatment cost of the amantadine prophy-
laxis strategy compared with oseltamivir prophylaxis. In
the base case analysis, the additional cost of nurse or phar-
DISCUSSION macist time required to calculate creatinine clearance was
From a government-payer perspective, this analysis showed excluded to bias against the oseltamivir strategy. In Canada,
that oseltamivir postexposure prophylaxis would save this test has a cost of $15.52 per person including specimen
$3,357 per 100 patients and amantadine postexposure documentation fee, which is 250% of the amantadine drug
prophylaxis would save $2,109 per 100 patients compared acquisition cost for 12 days ($6.22). Even if only half of the
with no prophylaxis, with improved patient outcomes. The residents required the laboratory test specifically for am-
cost savings with prophylaxis is due to reduced costs asso- antadine dose calculation, or the test had a 50% lower cost
ciated with influenza-like illness complications. The exten- ($7.76), amantadine postexposure prophylaxis would still
sive sensitivity analyses support the robustness of these remain a more expensive strategy than oseltamivir postex-
conclusions and the adoption of postexposure prophylaxis posure prophylaxis. Only when the test was needed in one
strategies. Indeed, at the time of this analysis, in one Ca- of five residents or the test cost less than $3.00 was am-
nadian region (Ontario), oseltamivir was increasingly being antadine postexposure prophylaxis a less costly strategy
used for prophylaxis during influenza B outbreaks33 and for than oseltamivir.
prophylaxis against influenza A in residents at high risk of This analysis is relevant to other countries with high
amantadine-related adverse effects or in facilities experi- resident and staff influenza vaccination rates that currently
encing amantadine-resistant strains.34 use amantadine for influenza A or no prophylaxis for in-
Oseltamivir is effective in controlling influenza A and B fluenza A or B. In jurisdictions that currently use amanta-
outbreaks, whereas amantadine is only effective in control- dine prophylaxis, this analysis would apply only to those
ling influenza A. There is considerable debate about wheth- who routinely adjust amantadine dose before the influenza
er the severity of influenza A and B are comparable. Based season. In the United States, the advisory committee on
on limited data, it appears that, in elderly populations, in- immunization practices has approved the use of oseltamivir
fluenza A and B are comparably severe. In this case, the for treatment and prevention in individuals aged 13 and450 RISEBROUGH ET AL. MARCH 2005–VOL. 53, NO. 3 JAGS
over. Amantadine and rimantadine are available in the 14. Bridges C, Fukuda K, Cox NJ et al. Prevention and control of influenza: Rec-
United States for influenza prevention, but rimantadine is ommendations of the Advisory Committee on Immunization Practices (ACIP).
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