Download For influenza B

Zanamivir in the Management
of Influenza A and B
Introduction to Relenza
Relenza has unsurpassed efficacy in the treatment and
prophylaxis of influenza infection1-6
Relenza reduces potentially life threatening complications of
influenza3
Relenza has an established safety profile7
Viral resistance to Relenza is extremely rare
Stockpiles of antivirals should contain significant amounts of
Relenza
– The UK Royal Society of Medicine recommend Relenza
should represent 50% of the stockpile8
1. Monto et al. J Antimicrob Chemother 1999; 44 (Topic B): 23-29; 2. Makela et al. J Infect 2000; 40: 42-48; 3. The Mist Study Group. Lancet 1998; 352:
1877-1881; 4. Hayden et al. NEJM 2000; 343 (18): 1282-1289; 5. Monto et al. J Infect Dis 2002: 186; 1582-1588; 6. Monto et al. JAMA 1999; 282: 31-35. 7.
Relenza, SPC, GSK, September 2006; 8. Pandemic influenza: science to policy. Royal Society and the Academy of Medical Sciences. Policy document
36/06. November 2006.
Relenza Indications
(In Most European Countries)
Relenza is indicated for the treatment of influenza A and B
virus in adults and children ≥ 5 years of age
Relenza is indicated for post-exposure prophylaxis of
influenza A and B in adults and children ≥ 5 years of age
following contact with a clinically diagnosed case in a
household
In exceptional circumstances, Relenza may be considered
for seasonal prophylaxis during a community outbreak
(e.g., mismatch between vaccine and circulating strain,
and a pandemic)
Relenza SPC. GlaxoSmithKline; 2006.
Relenza Delivered Direct to the
Respiratory Tract and Acts Rapidly
Drug levels in the lung following
inhalation (ng/mL; induced sputum)1
Immediate
~6,900 (> 1,000-fold IC50)
6 hours
1,366 (> 670-fold IC50)
12 hours
304 (> 300-fold IC50)
24 hours
47 (> 50-fold IC50)
Relenza begins to work within 10 seconds2
1. Cass et al. 1999; Peng et al. 2000; 2. Moscona A. NEJM 2005; 353: 1363-1373.
Relenza Acts Rapidly to Suppress Viral
Replication and Shedding
Drug levels that are more than 1,000-fold above the concentration
needed to inhibit the virus (IC50) are achieved immediately following
inhalation of a 10 mg dose
High local concentrations maximises NA inhibition and rate of onset of
inhibition
– Could limit emergence of resistance
Maximises suppression of virus replication – significantly reduces virus
excretion in the throat and nasopharynx1
– Could limit spread of virus from respiratory tract
Zanamivir associated with significantly more rapid reduction in viral
shedding vs placebo within 24 hours of initiating treatment
1. Puhakka et al Scand J Infect Dis 2003; 35:52-58.
Relenza Has Unsurpassed Efficacy in the
Treatment of Influenza
Shortens the duration of influenza symptoms1
Effective in treatment of influenza A and B
Effective in adults and children (≥ 5 years)
Significantly reduces (28% less) use of antibiotics for
influenza complications such as sinusitis and
bronchitis2
1. Relenza SPC. GlaxoSmithKline 2006; 2 Monto et al J Antimicrob Chemother 1999; 44:23-29.
Relenza Reduces Duration of Illness and
Complications in High-Risk Patients
Pooled analysis of 750 patients at high risk of influenza
complications*
Median time to alleviation of symptoms (compared to
placebo)1.5 days earlier (p=0.003)
Incidence of complications requiring antibiotics reduced by
28% compared with placebo (p=0.028) in patients with
confirmed influenza
• High-risk patients defined as elderly (≥65 years of age) patients with or without underlying medical conditions,
patients with chronic respiratory disease (asthma or COPD), or significant cardiovascular disease (excluding those
with hypertension only).
GlaxoSmithKline, Data on file.
Relenza Has Unsurpassed Efficacy in the
Prophylaxis of Influenza Infection
Study design
Study
Setting
Nr. subjects
Protective
efficacy vs
placebo
Post-exposure
prophylaxis
Hayden et al
NEJM 2000;
343;1282-1289
Household
contacts
337 families
79%
Post-exposure
prophylaxis
Monto et al
JID 2002;
186:1582-1588
Household
contacts
487 families
81%
Seasonal
prophylaxis
Monto et al
JAMA 1999;
282:31-35
Healthy adults
(University)
1,107
67%
Seasonal
prophylaxis
LaForce et al
Clin Ther 2007;
29(8):1579-1590
High risk
3,363
83%
Relenza Has Excellent Efficacy in
Post-Exposure Prophylaxis
Monto Study
N = 487 households with suspected case of influenza
Incidence of households with ≥1 family member diagnosed
with symptomatic, laboratory-confirmed influenza
Relenza
n = 10/245 (4.1%)
Placebo
P<.001
n = 46/242 (19%)
0
25
Number Of Families
81% protective efficacy rate vs placebo
Monto AS et al. J Infect Dis 2002;186:1582-1588.
50
Relenza Has Activity Against H5N1
and Oseltamivir-Resistant H5N1
Intranasal zanamivir protects mice against lethal challenge
with influenza A/HK/156/97 (H5N1)1
– Reduced viral replication in lungs
– Reduced mortality and morbidity
– Prevented viral spread to the brain2
Clinical isolate of oseltamivir-resistant H5N1 (H274Y) from
treated child in Vietnam
– Susceptible to treatment with Relenza
in the ferret3
A further oseltamivir-resistant strain (294S) has been
isolated from two patients who died from H5N1 in Egypt in
December 2006
– The oseltamivir-resistant strain in Egypt was shown
susceptible to Relenza4
1. Gubareva et al. JID 1998; 178:1592-1596; 2. Leneva et al. AAC 2001; 45:1216-1224; 3. Le et al.
Nature 2005; 437:1108; 4. WHO warns of Tamiflu resistance – 19th January 2007. Available from:
http://WWW.pharmatimes.com/clinicalnews/articles/10228-tamiflu-resistance.aspx?src=cn,
ACCESSED 12th November 2007.
Relenza Treatment Reduces Viral Shedding
Study in military personnel receiving standard Relenza
treatment course
– 8.48 log10 mean reduction in viral shedding in throat
swabs (copies/ml x h) area under the curve over the
first 48 hours, compared with placebo (p=0.003)
– 56% patients (vs 29% for placebo) have unquantifiable
virus in throat swabs at 48h (p≤0.001)
– Similar reduction in virus in nasopharynx
This may impact transmissability of infection
Puhakka et al. Scand J Infect Dis 2003; 35:52-58.
Study Comparing Efficacy of Relenza and
Oseltamivir
Study Suggests Zanamivir Has Superior Efficacy
Compared with Oseltamivir Against Influenza B
For influenza A, marginally significant differences
between duration of fever after first dose of zanamivir
(31.8 ± 8.4 h) and oseltamivir (35.5 ± 23.9 h) (p < 0.05)
For influenza B, duration of fever with zanamivir (35.8 ±
22.4 h) significantly shorter vs oseltamivir (52.7 ± 31.3 h)
(p < 0.001).
Therapy (zanamivir or oseltamivir) was the major
determinant affecting duration of fever for influenza B
Kawai et al. J Infect 2007 Oct 12; [Epub ahead of print].
Relenza Has Established Safety Profile
Adverse events profile similar to placebo in clinical trials:
treatment and prophylaxis in adults/adolescents/paediatric,
including elderly and high risk
CNS, gastrointestinal and other systemic effects are
comparable to placebo
Minimal potential to cross blood-brain barrier
May be taken with or without food
Long-term prophylaxis (4 months) safety study planned
Relenza SPC. GlaxoSmithKline; 2006.
Relenza Has a Simple Standard Dose and Minimal
Potential to Cause Drug Interactions
Renally excreted as unchanged drug
No need to adjust dosing in children, elderly or
those with chronic disease (incl. renal)
Does not affect cytochrome P450 isoenzymes
No clinically significant drug interactions
expected, based on data from in vitro studies
Does not interfere with inactivated influenza
vaccination
Relenza SPC GlaxoSmithKline; 2006.
Summary of Adverse Events With 1.5% Incidence
During Treatment in Adults and Adolescents
Adverse event
Relenza
10 mg BID (%)
(n = 1,132)
Placebo (%)
(n = 1,520)
2
3
3
1
2
2
2
3
2
2
3
4
3
2
3
3
3
2
2
<1
Headaches
Diarrhea
Nausea
Vomiting
Nasal signs and symptoms
Bronchitis
Cough
Sinusitis
Ear, nose and throat infections
Dizziness
Relenza prescribing information. GlaxoSmithKline; 2006.
Safety Considerations
Safety and efficacy not demonstrated in high-risk patients with severe/unstable
underlying medical conditions including severe asthma and other chronic respiratory
disease
There have been very rare reports of bronchospasm and/or decline in respiratory
function in patients taking Relenza
– Refer to warnings/precautions in SPC
Due to the limited experience, patients with severe asthma require a careful
consideration of the risk in relation to the expected benefit, and Relenza should not be
administered unless close medical monitoring and appropriate clinical facilities are
available in case of bronchoconstriction.
In patients with persistent asthma or severe COPD, management of the underlying
disease should be optimised during therapy with Relenza
There is no evidence of causal association with neuropsychiatric side effects in any age
groups with Relenza
Used in more than 14,000 patients in clinical trials
Relenza SPC. GlaxoSmithKline; 2006.
Relenza Treatment Dosing
Administered to respiratory tract by oral inhalation using
DISKHALER
Treatment should begin as soon as possible, within 48
hours of symptom onset for adults, and within 36 hours for
children
Recommended dose for treatment of influenza in adults
and children  5 years of age is two inhalations (2 x 5 mg)
twice daily for 5 days
Relenza SPC. GlaxoSmithKline; 2006.
Relenza Prophylaxis Dosing
Post-exposure prophylaxis
– Recommended dose for prevention of influenza, following
close contact with an individual is two inhalations (2 x 5
mg) once daily for 10 days
– Therapy should begin as soon as possible and within 36
hours of exposure to an individual
Seasonal prophylaxis
– Recommended dose for prevention of influenza during a
community outbreak is two inhalations (2 x 5 mg) once
daily for up to 28 days
Plans in place for long-term (4-month) prophylaxis study
Relenza SPC. GlaxoSmithKline; 2006..
Relenza is Delivered Direct to the Site of
Action via Inhalation
Mouthpiece
Cover
Piercing Needle
Rotadisk
Inhalation
Powder
DISKHALER is Easy to Use
Diskhaler commonly used to deliver asthma medications
Diskhaler studied in 171 asthmatic children aged 4-11
years
Device satisfaction questionnaire completed by their
parents/caregivers
Ease of Use of Diskhaler
Data on file: GSK.
Very Easy / Easy
89%
Neutral
7%
Difficult
3%
Very Difficult
1%
Viral Resistance
Neuraminidase (NA) Inhibitors Bind to NA
Receptor
Reproduced from Moscona A. N Engl J Med 2005;353:1363-1373, with permission.
Mechanism of Resistance to Oseltamivir
Reproduced from Moscona A. N Engl J Med 2005;353:1363-1373, with permission
The Structure of Zanamivir May Confer A Lower
Propensity for Resistance Than Oseltamivir
OH
O
OH
H
OH
O
OH
O
H
O
OH
O
OH
OH
AcNH
OH
AcNH
OR
OH
NH2
HN
NH
Zanamivir/Relenza
No conformational
change required to allow
binding
H
O
AcNH
NH2
Neu5Ac2en/DANA
(Natural Substrate)
Oseltamivir/Tamiflu
Conformational change
of active site required
to allow binding
Oseltamivir does not fit well into the sialic acid binding site of the viral
neuraminidase, whereas zanamivir binds tightly with the viral neuraminidase
This may explain the observed differences in development of resistance
Resistance to Oseltamivir Observed More
Commonly than with Zanamivir
Resistance to oseltamivir seen in 1% adults, 4-18% paediatrics
– Different resistance mutations observed for different influenza
subtypes1,2,3
There are no reports of resistance during zanamivir treatment in
immunocompetent patients
– One resistant influenza B isolate was identified in an
immunocompromised child4 treated with zanamivir for 15 days
Resistance to either neuraminidase inhibitor is difficult to generate in
vitro – requires several passages.
Oseltamivir-resistant mutants may remain sensitive to zanamivir
1. Kiso M et al. Lancet 2004; 364: 759-65; 2. Ward P et al. J Antimicrob Chemoter 2005; 55(Suppl. 1): 13-21; 3. The Writing
Committee of the World Health Organisation (WHO) N Engl J Med, 2005; 353: 1374-85; 4. Gubareva L et al. J Infect Dis 1998;
178:1257-62.
Oseltamivir Resistant Subtypes of Virus with Potential for
Transmission Remain Sensitive to Zanamivir
Mutant Subtype
Selected
by
Resistance
Oseltamivir
(Fold-shift)
Resistance
Zanamivir
(Fold-shift)
Potential for
Transmission
292K
A/N2
Oseltamivir
R (>8,000)
R (4 - 25)
Unlikely
152K
B
Zanamivir
R (13 -100)
R (9 -150)
Unlikely
274Y*
A/N1
Oseltamivir
R (400 - 900)
S
Possible
119V
A/N2
Oseltamivir
R (130 - 277)
S
Possible
198N
B
Oseltamivir
R (9)
R (9)
Possible
A/N2*
Oseltamivir
R (300)
S
Possible
A/N1* #
Oseltamivir
R (12-15)
S (3 - 4.8)
Possible
B
Oseltamivir
R (high)
R(7)
Not Known
294S
402S
* Reported in human case(s) of avian flu treated with oseltamivir in Vietnam,
patients in Turkey
# and
from
1. Wetherall et al. J Clin Microbiol 2003; 41:742-50; 2. Guvareva et al. J Infect Dis 2001;183: 523-531; 3. Guvareva et al. Virus
Res 2004;103: 199-203.; 4. Kiso et al. Lancet 2004; 364: 759-765; 5. Mishin et al. Antimicrob Agents Chemother 2005; 49: 45154520; 6. Ison et al. J Infect Dis 2006 15;193: 765-772; 7. De Jong et al. NEJM 2005; 353:2667-2672; 8. Le et al. Nature
2005;437:1108. 9. Hatakeyama et al. JAMA 2007.
Summary of In Vitro Resistance Studies
Resistance to both inhibitors difficult to generate in vitro
– requires several passages
Both NA and HA mutations selected and both can confer
resistance in vitro
NA mutations selected plus NA subtype
Zanamivir
R292K
Oseltamivir
E119G
N9, N2 (human), B
E119A or D N2 (avian)
N2 (avian)
R292K
H274Y
E119D
N2 (human)
N1 (human)
N9
Many HA mutations selected around 1st and 2nd sialic acid
binding site lead to reduced binding affinity
H274Y H5N1 Isolate From the Clinic was
Susceptible to Relenza in the Ferret Model
Drug sensitivity of H5N1 viral clones isolated from a human patient
Virus titre (log10 PFU per ml)
6
Open symbols: mock treated
Oseltamivir-sensitive virus
Closed circles: oseltamivir treated
5
4
Closed triangles: zanamivir treated
O
3
2
Zn
≤1
1
6
5
4
3
5
7
9
5
7
Days post infection
9
Oseltamivir-resistant virus
O
3
2
Zn
1
Le et al. Nature 2005;437:1108.
3
In Vitro Activity Against Different NAs
Human subtypes (Mean IC50 values >1,000 isolates)1
– A/H1N1, zanamivir 0.76 nM, oseltamivir 1.2 nM
– AH3N2, zanamivir 1.82 nM, oseltamivir 0.5 nM
– B, zanamivir 2.28 nM, oseltamivir 8.8 nM
Avian subtypes (range of published IC50 values)
– H5N1, zanamivir 1-10 nM, oseltamivir 6.1-7.9 nM2,3
– H9N2, zanamivir 6-12 nM, oseltamivir 9.6-15.7 nM2,3
– H6N1, zanamivir 5-23.6 nM, oseltamivir 27.8-44.4 nM4
1. McKimm-Breshkin et al. Antimicrob Agents Chemother. 2003; 47: 2264-2272; 2. Leneva et al. Antiviral Res
2000; 48:101-115; 3. Govorkova et al. Antimicrob Agents Chemother 2001; 45: 2723-2732; 4. Leneva et al.
Antimicrob Agents Chemother 2001; 45: 1216-1224.
Relenza concentrations (ng/ml)
Relenza Therapeutic Respiratory Concentrations
(Estimated Steady State for q12h Dosing)
Sputum samples
Mean IC50 (H1N1)n=139
Mean IC50 (H3N2)n=767
Mean IC50 (B)n=148
10000
1000
2nd Dose
100
10
1
Combined Fluorescent &
Chemiluminescent NA
assays
0.1
0
2
4
6
8 10 12
16 18 20 22 24
Time after dosing (h)
Peng et al. Antimicrobial Agents Chemother 2000; 44: 1974-1976; McKimm-Breschkin et al. Antimicrobial
Agents Chemother 2003; 47: 2264-2272.
Relenza concentrations (ng/ml)
Relenza Therapeutic Respiratory Concentrations
at Steady State for QD Prophylaxis Dosing
Sputum samples
Mean IC50 (H1N1)n=139
Mean IC50 (H3N2)n=767
Mean IC50 (B)n=148
10000
1000
Ctrough Prophylaxis
100
10
2nd Dose
1
Combined Fluorescent &
Chemiluminescent NA Assays
0.1
0
6
12
24
Time after dosing (h)
Peng et al. Antimicrobial Agents Chemother 2000; 44: 1974-1976; McKimm-Breschkin et al. Antimicrobial
Agents Chemother 2003; 47: 2264-2272.
Risk of Resistance to Relenza is Low
In vitro studies have shown that mutations in both
haemagglutinin and neuraminidase genes are selected
during resistance development over prolonged passage1-5
Mutations in two genes may be required to produce
resistance to Relenza6
– The risk of this occurring within 5 days of treatment is
low
Just one mutation (NA) appears to be required to produce
a very high level resistance to oseltamivir7,8
.
1. Barnett et al. Virology 1999; 265: 286-295; 2. Blick et al. Virology 1995; 214: 475-484; 3. Blick et al. Virology 1998; 246:
95-103; 4. Gubareva et al. J Virol 1997; 71: 3385-3390; 5. McKimm-Breschkin et al. Virol 1996; 225: 240-242; 6. Gubareva
et al. J Infect Dis 1998; 178: 1257-1262; 7. Le et al. Nature 2005; 437: 11088; 8. De Jong et al. NEJM 2005; 353 (25): 2667
The Favourable Resistance Profile of Zanamivir is
Important in Choice of Antivirals for Stockpiling
“...although both (Relenza [zanamivir] and Tamiflu [oseltamivir]) have similar
efficacy, zanamivir has … a favourable resistance profile. The resistance
factor would be an important consideration in a pandemic situation”
Tsang et al. Lancet 2005; 366; 533-534.
“If this frequent emergence of resistant mutants is found to be a general
occurrence in children, it is a serious concern, especially since children are an
important source of the spread of infection in the community.”
Moscona A. NEJM 2005; 353: 1363-1373.
“Resistant strains have been generated in vitro and such strains have also been
found in a small proportion of patients during or after treatment with
oseltamivir. Oseltamivir-resistant strains have also been detected in
individuals not exposed to oseltamivir”
“The development of viral resistance is possible and might have a substantial
impact on the clinical usefulness of oseltamivir”
EMEA Report 2007.
An Antiviral Stockpile of 20-25% Could
Provide 67% Reduction in Hospitalisations
Estimated hospitalisations
per 100,000 population
200
180
160
140
120
100
All groups
Children and study
At-risk groups
Working population
80
60
40
20
0
0
5,000
10,000
15,000
20,000
25,000
Stockpiled antivirals per 100,000 population
Adapted from Gani et al. Emerg Infect Dis 2005;11: 1355-1362.
Based on 1957 pandemic
Estimated hospitalisations per 100,000 population when different antiviral treatment strategies are applied
French Government Has Ordered Antivirals to Cover
54% of the Population With 28% of the Stockpile
Being Relenza
"These 33 million antiviral treatments will far exceed
requirements for covering 25% of the population,
the figure recommended by WHO "
"This will enable resistance risks to be prevented
and a more flexible and adaptable approach to be
taken to the strategies implemented in
accordance with the characteristics of the virus
and the pandemic"
Presentation of the French Government’s Updated Plan to Combat the Avian Influenza Pandemic Published on 6 January
2006. Available from: http://www.info-france-usa.org/news/statmnts/2006/avianflu.pdf
U.S. Department of Health & Human Services (HHS)
Recommends 20% of Stockpile Should be Relenza
HHS has focused its recent antiviral stockpiling
efforts on purchasing Tamiflu and Relenza even
though recent reports have surfaced that some
strains of the H5N1 virus are becoming resistant
to Tamiflu
In response, HHS has changed its stockpiling
strategy to decrease the target share of Tamiflu
held in reserve from 90% to 80% and increase
the share of Relenza from 10% to 20%
The Congress of the United States Congressional Budget Office. A Potential Influenza Pandemic: An Update on Possible
Macroeconomic Effects and Policy Issues. May 22, 2006; revised July 27, 2006.
Antiviral Stockpiles for 50% of the
Population is Recommended
WHO recommends that national governments stockpile antiviral drugs
in advance of an influenza pandemic1
Stockpiles equivalent to 50% of the population, allowing post-exposure
prophylaxis in households could reduce clinical attack rates by 4050%2
The emergency stockpile of flu drugs will be doubled in Britain so that half
of the population is covered in the event of a pandemic”
Alan Johnson, the Health Secretary, November 22, 2007
1. WHO. WHO Rapid Advice Guidelines on pharmacological management of humans infected with avian
influenza A (H5N1) virus. Geneva: World Health Organization, 2006; 2. Ferguson NM et al. Nature 2006,
442:448-452.
WHO Recommendations (2007)
Antiviral treatment in patients with confirmed or strongly
suspected H5N1 infection
– Applies to adults (including pregnant women) and children
– Regimen for H5N1 is as recommended for seasonal influenza
Antiviral chemoprophylaxis in management of
avian (H5N1) influenza
– In high risk exposure groups oseltamivir or zanamivir
should be administered (strong recommendation)
– In moderate risk exposure groups oseltamivir /
zanamivir might be administered (weak
recommendation)
– Continuing for 7-10 days after the last known
exposure
Schünemann et al. WHO Rapid Advice Guidelines for pharmacological management of sporadic human infection with avian influenza A (H5N1) virus. Lancet
Infect Dis 2007; 7: 21-31.
WHO Recommends National Stockpiles of
Antivirals for Treatment and Prophylaxis
Purpose: Response to outbreaks within the country or the
treatment and prophylaxis of citizens during a pandemic
Timing: Pandemic phase III and later
Application: Stockpile under the control of a specific
nation and positioned within its borders.
Treatment of individuals with confirmed
or suspected avian or pandemic influenza
virus infection and high risk exposure
groups
Antiviral Stockpiles for 50% of the
Population is Recommended
Overall clinical attack rates during pandemics have
reached 30-35%1
Coverage required depends upon the virulence of the virus
once a pandemic starts
Stocks required for treatment and for prophylaxis
– Post exposure prophylaxis
– Prophylaxis for essential services workers
1. Glezen WP. Epidemiol Rev 1996; 18: 64-76.