Zanamivir for the prevention of influenza in adults and children age 5 years and older.

Abstract

On a yearly basis there are 3-5 million severe cases and 250,000-500,000 deaths worldwide attributed to influenza. Four antiviral medications are currently available on the market; however, resistance has resulted in the armamentarium being shrunk to two remaining active treatment options for influenza. These two neuraminidase inhibitors, oseltamivir and zanamivir, are recommended for the treatment and prophylaxis of influenza A and B in children and adults. Zanamivir, which is the focus of this review, is an inhaled antiviral that has shown benefit in the community, household, and nursing home population for post-exposure prophylaxis. Zanamivir protection rates range from 67%-84% in clinical trials of adults and children. Although the influenza vaccine remains the best modality to combat the disease, zanamivir may also assist in decreasing morbidity associated with influenza A and B.

Full text

Page 1

Therapeutics and Clinical Risk Management 2007:3(3) 461–465
© 2007 Dove Medical Press Limited. All rights reserved
461
R E V I E W
Zanamivir for the prevention of infl uenza in adults
and children age 5 years and older
Lea S Eiland1
Edward H Eiland2
1Auburn University Harrison School
of Pharmacy, Huntsville, AL, USA
2Huntsville Hospital, Huntsville, AL,
USA
Correspondence: Lea S Eiland
UAB/Division of Pediatrics,
301 Governors Drive, Huntsville,
AL, 35801, USA
Tel +1 256 551 4445
Fax +1 256 551 4453
Email eilanls@auburn.edu
Abstract: On a yearly basis there are 3–5 million severe cases and 250,000–500,000 deaths
worldwide attributed to infl uenza. Four antiviral medications are currently available on the
market; however, resistance has resulted in the armamentarium being shrunk to two remaining
active treatment options for infl uenza. These two neuraminidase inhibitors, oseltamivir and
zanamivir, are recommended for the treatment and prophylaxis of infl uenza A and B in
children and adults. Zanamivir, which is the focus of this review, is an inhaled antiviral that has
shown benefi t in the community, household, and nursing home population for post-exposure
prophylaxis. Zanamivir protection rates range from 67%–84% in clinical trials of adults and
children. Although the infl uenza vaccine remains the best modality to combat the disease,
zanamivir may also assist in decreasing morbidity associated with infl uenza A and B.
Keywords: fl u, prophylaxis, neuraminidase inhibitors, Relenza, community, household,
nursing home
Infl uenza is responsible for 3–5 million severe cases and 250,000–500,000 deaths
worldwide annually (WHO 2003). Infl uenza produces a seasonal epidemic in both
developed and developing countries. Death and hospitalizations mainly occur in the
high-risk populations such as the elderly and those with chronic illnesses. Humans are
affected by infl uenza type A and B resulting in an upper respiratory tract infection.
Vaccination against the infl uenza virus serves as the best prevention when combat-
ing the virus. However, the vaccine does not protect all due to the antigenic shift of
the virus strains as it travels the world. Though antiviral medications do not replace
the vaccine, they are utilized for prophylaxis and relief of symptoms associated with
infl uenza.
Two classes of antiviral agents have demonstrated effi cacy against the infl uenza
virus: M2 ion channel inhibitors (adamantanes derivatives: amantadine and rimanta-
dine) and neuraminidase inhibitors (oseltamivir and zanamivir). The adamantanes have
effi cacy against infl uenza type A, where as the neuraminidase inhibitors are effective
for both type A and B. All antiviral agents can be used for prophylaxis or treatment
of infl uenza. Yet, over the past three years the infl uenza virus has shown increased
resistance to the adamantanes worldwide with an associated increase from 1.9% to
12.3% (CDC 2006). Due to this growth in resistance and specifi c isolates identifi ed in
2005–2006, the treatment and prophylaxis with these therapeutic agents are no longer
recommended in the US. Therefore, the neuraminidase inhibitors may see increased
use worldwide during subsequent fl u seasons.
This review will focus on zanamivir, a neuraminidase inhibitor, for the prophylaxis
of infl uenza in children and adults. Zanamivir is a micronized, dry powder inhaled
antiviral agent that inhibits the neuraminidase molecule active site on the surface of
the infl uenza virus. This is thought to prevent infection and distribution of the virus

Page 2

Therapeutics and Clinical Risk Management 2007:3(3)
462
Eiland and Eiland
to uninfected cells. Zanamivir is indicated for prophylaxis of
infl uenza type A and B in children 5 years of age and older.
It is only commercially available in an inhaled form due to
poor oral bioavailability and should be used with a diskhaler®
(Glaxo Wellcome UK Ltd, Middlesex, UK) device, which is
provided with the medication. The medication is provided in
foil blister packs (rotadisks) which are inserted individually
and replaced in the diskhaler®. Each rotadisk contains 4 doses
and provides 5 mg per dose. Five rotadisks are packaged
with the diskhaler®. The prophylaxis dose for all ages of
zanamivir is 10 mg (two 5 mg blisters) inhaled once daily,
at the same time each day, for 10 days of therapy. Zanamivir
should be initiated within 1.5 days of symptom onset for the
index case in a household setting. For a community outbreak,
zanamivir should be initiated within 5 days of identifi cation
and be administered for a total of 28 days of therapy. Data
is not available regarding the use of zanamivir if the recom-
mended initiation time frame has past.
Intranasal zanamivir has been evaluated but provided no
greater effi cacy than placebo or when added to the inhaled
formulation; thus, intranasal administration is not currently
recommended and a dosage formulation is not available
(Kaiser et al 2000). An IV formulation of zanamivir was
studied in one trial (Calfee et al 1999); however, this dosage
form is not marketed.
Zanamivir has low protein binding and is excreted primar-
ily unchanged in the urine. No adjustment is needed for renal
dysfunction as zanamivir has limited systemic absorption.
Zanamivir appears to be well tolerated as adverse effects are
reported as being similar to placebo and diffi cult to distin-
guish from the infl uenza virus. The most common adverse
effects seen are headache, throat, and tonsil pain, and cough
and nasal symptoms. Zanamivir lacks drug interactions and
does not affect cytochrome P450 enzymes. Administering
the live intranasal fl u vaccine concurrently with zanamivir
may inhibit the vaccine replication. It is recommended to
administer the vaccine at least 24 hours after zanamivir ces-
sation and to not provide zanamivir until 2 weeks following
the vaccine. Caution should be utilized in patients with
milk allergy considering that each blister contains 20 mg of
lactose or milk protein. Zanamivir has not been studied in
pregnancy and should only be used if the benefi t outweighs
the risk to the fetus and mother. However, its low systemic
absorption may be a possible benefi t for use considering this
pharmacodynamic parameter.
In addition, patients with chronic airway disease such as
asthma or chronic obstructive pulmonary disease (COPD)
should avoid zanamivir due to bronchospasm concerns.
Although previous data found pulmonary function not
signifi cantly affected by zanamivir (Cass et al 2000), post
marketing reports led to the warning. If a patient routinely
takes bronchodilators, it is recommended that the patient
administer the bronchodilator prior to the zanamivir dose.
However, if bronchospasms or a decline in respiratory func-
tion occurs after utilization, it is recommended to discontinue
the product and seek treatment if warranted.
Concerns exist regarding the patient administration
technique and use of the inhaler. Although the diskhaler®
does not require coordination with releasing the dose and in-
spiration, the device may be diffi cult to use for some patient
populations. In the pediatric population, it is challenging
to have a young child inhale appropriately and obtain the
desired quantity of drug. A parent may place zanamivir into
the end of a straw prior to blowing through the straw forc-
ing the medication into the child’s throat which has been
shown to be effi cacious (Imuta et al 2003). Thirty-eight
elderly patients were assessed on their use of the device
(Diggory et al 2001). After a 15 minute education period,
these patients demonstrated use of the device. Patients
could receive up to fi ve additional minutes of education
after the initial period. Ten patients achieved perfect scores
regarding the demonstration. After 24 hours, the patients
were again asked to show how to use the device. Only fi ve
patients had perfect scores and in general most patients
scores decreased, p < 0.001. In this study, the elderly had
trouble primarily with loading the disk in the device and
priming the device. The straw technique may be useful in
the elderly population as well.
Prophylaxis studies
Zanamivir has several studies evaluating its use as a pro-
phylactic agent for infl uenza in children and adults. The fi rst
double-blind trial randomized 1107 adults (18–64 years) to
zanamivir (10 mg daily) or placebo for 4 weeks at the start
of the 1997 infl uenza season (Monto et al 1999). The most
prominent virus of 2006 was A/Sydney/5/97 (H3N2) which
was not in the annual vaccine. The primary outcome was
the number of individuals who had symptomatic, labora-
tory-confi rmed infl uenza. This was defi ned as a rise in titers
and/or isolation of the infl uenza virus, and two or more of the
following on three concurrent diary cards: cough, headache,
sore throat, myalgia, feverishness, or temperature ?37.8 ºC.
Patients recorded symptoms and temperatures twice daily
on the diary cards that were checked weekly and were asked

Page 3

Therapeutics and Clinical Risk Management 2007:3(3)
463
Zanamivir Prophylaxis for Infl uenza
to contact the study center if any respiratory symptoms
developed. Only 14% of patients in the study received
the infl uenza vaccine. Symptomatic, laboratory-confi rmed
clinical infl uenza occurred in 2% and 6.1% of the zanamivir
group versus placebo, respectively. Zanamivir provided a
67% effi cacy in prevention laboratory-confi rmed clinical
infl uenza versus placebo, p < 0.001. It also provided 84%
effi cacy against laboratory-confi rmed infl uenza with fever,
p = 0.001. Zanamivir was 43% effi cacious against all febrile
illnesses, p = 0.009 and 31% effi cacious against infl uenza
infection, with or without symptoms, p = 0.03. In the subset
of unvaccinated patients, zanamivir decreased symptomatic,
laboratory-confi rmed infl uenza by 60% (p = 0.009) and
confi rmed infl uenza with fever by 81% (p = 0.004). Overall,
no difference in adverse effects was found between groups
and compliance was high in both groups. A severe adverse
effect was found in 1 patient in each group. Four patients in
the zanamivir group and seven patients in the placebo group
discontinued the medication due to drug-related events,
specifi cs were not stated.
Another study evaluated zanamivir for a community
outbreak in high-risk patients 12 years of age or older. (Data
on File, Relenza 2000) This multi-center, double-blind study
randomized patients from various countries to zanamivir 10 mg
daily or placebo for 28 days during December 2000–April
2001. Therapy was initiated within 5 days of identifying the
community outbreak. There were 1678 patients randomized
to the zanamivir group and 1685 patients in the placebo
group. Patient ages ranged from 12–94 years of age, mean
60 years. Fifty-six percent of the patients were over 65 years
of age. Sixty-seven percent and 68% of the zanamivir and
placebo group, respectively, had received the fl u vaccine for
the season. This intention-to-treat analysis determined only 4
patients (0.2%) in the zanamivir group developed symptomatic
infl uenza with confi rmed serology/culture versus 23 patients
(1.4%) in the placebo group, p < 0.001. Symptomatic infl uenza
was defi ned as two of the following symptoms reported for
3 consecutive days on diary cards: feverish or temperature
?37.8 ºC, headache, cough, sore throat, or muscle/joint
aches and pains. Only 4 patients in the zanamivir group
and 21 patients in the placebo group were diagnosed with
symptomatic infl uenza with culture/serology positive results
on Day 2–28 (95% confi dence interval [CI] 0.07, 0.49). This
was similar for Day 3–28 as well (95% CI 0.07, 0.52). Adverse
effects were similar between both groups. Five percent of
patients in each group withdrew from the study for similar
reasons, specifi cs were not provided in the study.
Kaiser and colleagues (2000) randomized 575 patients
(age 13–65 years) to inhaled zanamivir, intranasal zanami-
vir, inhaled and intranasal zanamivir, or placebo after close
contact with people who had infl uenza-like illnesses for
no longer than 4 days. Close contact was defi ned as living
in the same home, sleeping in the same room, or confi ned
in the same room for extended periods of time. This was a
multicenter trial conducted during the 1995–1996 infl uenza
season. Unstable chronic illness, infl uenza vaccination, or
anti-infl uenza medications during the previous days were trial
exclusions. Treatment medication or placebo was adminis-
tered for 5 days. No signifi cant difference was found between
the four groups for patients developing proven infl uenza after
exposure; however, the trial did not reach its power as 840
patients were not enrolled. The inhaled zanamivir appeared
to prevent more infections than the intranasal zanamivir
or placebo; however, this was not statistically signifi cant.
Intranasal zanamivir produced results similar to those of
the placebo group. The authors determined that intranasal
route was not effective and acknowledged that fi ve days of
prophylactic therapy may not be suffi cient, thus studies of
longer duration are warranted.
The Zanamivir Family Study Group conducted a mul-
ticenter, double-blind, parallel, placebo controlled study of
zanamivir for prophylaxis in a family setting from December
1998 to April 1999 (Hayden et al 2000). Families with 2–5
people, one being an adult and at least one a child, age 5–17
years, were enrolled once one person developed infl uenza-
like illness. All eligible family members began taking
zanamivir or placebo within 36 hours of symptom onset in
the index case. Patients who were immunocompromised,
pregnant, breast feeding, were taking an antiviral medication,
or less than 5 years of age were excluded from the study.
The index case was administered the treatment regimen of
zanamivir or placebo. Three hundred thirty-seven families
(1158 participants) were randomized to treatment or pla-
cebo. Both infl uenza A and B were confi rmed in the study.
The primary end point was the proportion of families who
had one or more family members (household contacts) that
developed symptomatic, laboratory-confi rmed infl uenza.
Symptomatic was defi ned as possessing at least two of
the following: temperature ?37.8 ºC, feverishness, cough,
headache, sore throat, or myalgia on three consecutive diary
card entries. This occurred in 4.1% of families in the zana-
mivir group versus 19% of families in the placebo group,
p < 0.001. Families with laboratory-confi rmed infl uenza in
the index case experienced a proportionally higher incidence

Page 4

Therapeutics and Clinical Risk Management 2007:3(3)
464
Eiland and Eiland
of infl uenza, 8% for the zanamivir group versus 29% in the
placebo group, p < 0.001. Overall, zanamivir provided a 79%
protection rate from infl uenza among families. Based on
examining symptom onset ≥1 day after prophylaxis initiation,
zanamivir’s protection rate increased to 84%, p < 0.001. No
development of resistance to zanamivir was seen in the study
via viral sequencing. Three patients discontinued zanamivir
due to adverse effects. One stopped the medication due
to gastrointestinal pain and discomfort and the other two
patients stopped due to headaches. Of those patients with
asthma requiring medication, 11% of the placebo group had
an exacerbation versus 6% in the zanamivir group.
In the previous study, protection could occur from
treating the index case, thus decreasing viral shedding;
therefore, Monto and colleagues (2002) evaluated zanamivir
prophylaxis in 487 families in which the index case was not
treated. This multicenter, double-blind, parallel, placebo-
controlled trial randomized families (1291 contacts) to
zanamivir or placebo for 10 days. Index patients were
only tested for the infl uenza virus, but not treated. Family
inclusions were the same as the above study and subjects
had to start therapy within 36 hours of symptom onset in
the index patient. One hundred and thirty-two contacts had
been vaccinated for infl uenza. The zanamivir and placebo
group were similar regarding vaccination. The primary
end point was laboratory–confi rmed infl uenza in families
during the period of prophylaxis, day 1–11. This study was
conducted from June 2000–April 2001 and both infl uenza
type A and B were documented. Zanamivir reduced the
occurrence of symptomatic, laboratory-confi rmed infl uenza
by 81% in households, p < 0.001. A similar reduction
was also seen when evaluating individual contacts versus
families. No evidence of resistance was found in clinical
isolates. Infl uenza-like illness was the common adverse
effect seen in the study, yet zanamivir was well tolerated in
all. Fifty-eight patients were classifi ed to have an underlying
respiratory condition, mostly asthma. Two of these patients
had bronchospasms and both were in the placebo group.
Three studies have specifi cally evaluated zanamivir effi -
cacy in the nursing home population for prophylaxis. The fi rst
pilot study randomized patients to zanamivir 10 mg inhaled
and 4.4 mg intranasal twice daily or rimantadine 100 mg once
daily for 14 days for infl uenza A outbreaks (Schilling et al
1998). For infl uenza B outbreaks, patients received zanami-
vir as stated or no medication. Study nurses administered
the medications for the pilot. Sixty-fi ve patients received
zanamivir and 23 received rimantadine for an infl uenza A
outbreak. No patients in the zanamivir group developed
laboratory-confi rmed infl uenza A; although, one patient in
the rimantadine group was positive. Eight patients versus one
in the zanamivir group developed a respiratory illness versus
placebo, respectively. Thirty-fi ve patients received zanamivir
versus 17 who received nothing for an infl uenza B outbreak.
Again, no patients had laboratory-confi rmed infl uenza B in
the zanamivir group. One patient who did not receive the
medication was infl uenza B positive. Only one patient in
the zanamivir group had a respiratory illness, versus three
who did not receive zanamivir. No serious adverse effects
were reported with zanamivir. Most patients complained of
nasal symptoms (16%), gastrointestinal symptoms (8%), and
throat irritation (7%). Forty patients with mild to moderate
COPD did not have a difference in severity or incidence of
adverse effects.
A larger multicenter, double-blind trial randomized 489
asymptomatic nursing home patients to zanamivir (10 mg
inhaled daily) or placebo for 14 days after an infl uenza outbreak
was recognized (Ambrozaitis et al 2005). The study occurred
over three infl uenza seasons, thus a few patients (n = 5) were
randomized twice. Twice weekly evaluation for respiratory
illness was conducted. Only 9% of patients were vaccinated.
Approximately 85% of patients were considered high-risk
(age ?65 years, diabetes, respiratory, or cardiac condition).
Symptomatic, laboratory-confi rmed infl uenza occurred in 6%
and 9% of the zanamivir and placebo patients, respectively,
p = 0.355. All cases occurred in a site where no one had the
vaccination and more than half of the failures occurred within
2 days of the outbreak. Collectively, zanamivir provided
a 32% protection versus placebo. Laboratory-confi rmed
influenza with fever occurred in 2% of the zanamivir
and 6% of the placebo group, p = 0.043. This equates to
zanamivir providing 70% protection against febrile infl uenza.
Complications of the infl uenza illness and adverse effects of
zanamivir were not signifi cantly different between groups.
No evidence of zanamivir resistance was found in isolates.
A similar study was conducted in the US at multiple
sites over the same three year period (Gravenstein et al
2005). There were 375 patients were randomized to inhaled
zanamivir (10 mg daily) or placebo for 14 days. For infl u-
enza A outbreaks, rimantadine (100 mg daily) or placebo
tablets was also administered. Overall, 482 randomizations
occurred as some patients were randomized twice or three
times (zanamivir: 238, rimantadine: 231, placebo: 13).
Almost all patients were vaccinated for the current infl uenza
season and 96% of patients were considered high-risk (as

Page 5

Therapeutics and Clinical Risk Management 2007:3(3)
465
Zanamivir Prophylaxis for Infl uenza
stated previously). Symptoms were assessed in each patient
throughout the study. Only 3% of patients in the zanamivir
group versus 8% of the rimantadine group developed symp-
tomatic, laboratory-confi rmed infl uenza A, p = 0.038. This
results in 61% additional protection using zanamivir versus
rimantadine. Almost half of the failures occurred within the
fi rst two days. When evaluating days 2–15, 2% versus 7% of
patients developed symptomatic, laboratory positive infl u-
enza with zanamivir or rimantadine, respectively, p = 0.024.
Zanamivir showed an additional 68% effi cacy over riman-
tadine. When examining days 3–15, zanamivir provided an
additional 77% effi cacy. Only 1% of zanamivir versus 6%
of rimantadine patients developed symptomatic, laboratory
confi rmed infl uenza, p = 0.02. No signifi cant differences
were seen between the groups in regards to adverse effects.
Complications occurred in 3% of patients on rimantadine
versus 1% of patients on zanamivir, p = 0.109. No resistance
was identifi ed with zanamivir in the isolates; however, 38%
were resistant to rimantadine.
Intravenous formulation
An intravenous formulation of zanamivir was studied in 16
healthy males who were inoculated with the virus (Calfee
et al 1999). This double-blind study randomized patients to
zanamivir 600 mg IV over 30 minutes twice daily for 5 days
or placebo. The medication was provided 4 hours prior to an
H1N1 virus exposure. Symptoms were assessed twice daily
throughout the period. Serologic infection was identifi ed
in one patient in the zanamivir group, p < 0.005; however,
no viral shedding was found, p < 0.005. One patient in the
zanamivir group versus seven in the placebo group had fever,
p < 0.05. Prophylactic intravenous zanamivir was found to be
well-tolerated and protected against the infl uenza A virus.
Conclusion
Although the infl uenza vaccine remains the optimal inter-
vention for prevention, zanamivir has proven effi cacy and
safety for post-exposure prophylaxis of infl uenza A and B
viruses in adults and children. Zanamivir has been evaluated
in the community, home, and nursing home setting. Caution
should be used in patients with underlying airway diseases.
Education on the appropriate use of the device is warranted
in all patient populations.
References
Ambrozaitis A, Gravenstein S, van Essen GA, et al. 2005. Inhaled zanamivir
versus placebo for the prevention of infl uenza outbreaks in an unvac-
cinated long-term care population. J Am Med Dir Assoc, 6:367–74.
Calfee DP, Peng AW, Cass LM, et al.1999. Safety and effi cacy of intrave-
nous zanamivir in preventing experimental human infl uenza A virus
infection. Antimicrob Agents Chemother, 43:1616–20.
Cass LM, Gunawardena KA, Macmahon MM, et al. 2000. Pulmonary func-
tion and airway responsiveness in mild to moderate asthmatics given
repeated inhaled doses of zanamivir. Respir Med, 94:166–73.
[CDC] Centers for Disease Control. 2006. CDC recommends against the
use of amantadine and rimantadine for the treatment or prophylaxis
of infl uenza in the United States during the 2005–06 infl uenza season
[online]. Accessed 10 September 2006. URL: http://www.cdc.gov/fl u/
han011406.htm.
Data on fi le. 2000. Relenza, RM1998/00520/00, Study NAIA3004 Report
Synopsis, pp 4–8.
Gravenstein S, Drinka P, Osterweil D, et al. 2005. Inhaled zanamivir versus
rimantadine for the control of infl uenza in a highly vaccinated long-term
care population. J Am Med Dir Assoc, 6:359–66.
Diggory P, Fernandez C, Humphrey A, et al. 2001. Comparison of elderly
people’s technique in using two dry powder inhalers to deliver zana-
mivir: randomised controlled trial. BMJ, 322:577–9.
Hayden FG, Gubareva LV, Monto AS, et al. 2000. Inhaled zanamivir for
the prevention of infl uenza in families. Zanamivir Family Study Group.
N Engl J Med, 343:1282–9.
Imuta F, Toyoda M, Toyoda T. 2003. New application method of zanamivir
with a straw. Pediatr Int, 45:366–7.
Kaiser L, Henry D, Flack NP, et al. 2000. Short-term treatment with zana-
mivir to prevent infl uenza: results of a placebo-controlled study. Clin
Infect Dis, 30:587–9.
Monto AS, Robinson DP, Herlocher ML, et al.1999. Zanamivir in the
prevention of infl uenza among healthy adults: a randomized controlled
trial. JAMA, 282:31–5.
Monto AS, Pichichero ME, Blanckenberg SJ, et al. 2002. Zanamivir pro-
phylaxis: an effective strategy for the prevention of infl uenza types A
and B within households. J Infect Dis,186:1582–8.
Schilling M, Povinelli L, Krause P, et al. 1998. Effi cacy of zanamivir for
chemoprophylaxis of nursing home infl uenza outbreaks. Vaccine,
16:1771–4.
[WHO] World Health Organization. 2003. Infl uenza fact sheet [online].
Accessed 10 September 2006. URL: http://www.who.int/mediacen-
tre/factsheets/fs211/en/.