The
Pharmaceutical Journal Vol 266 No 7130 p57-59The recent NICE guidance on zanamivir for treating influenza opened a door for pharmacists to become involved in the drug’s supply. It also stimulated a debate about the management of influenza. Clare Bellingham reports on the main issues
Every year, the influenza virus kills thousands of people and makes tens of
thousands of people ill in the United Kingdom. It is estimated that each year,
one in 10 adults and one in three children are affected by influenza and that,
in the UK, more than 150 million working days are lost because of ’flu-related
illness.
There are three forms of influenza virus. Influenza A is the type most commonly
associated with epidemics and is also responsible for pandemics. Influenza B
can cause epidemics, but less commonly than type A and influenza C is not associated
with epidemics. The reason for this pattern is that influenza A circulates in
human, animal and bird populations whereas types B and C are restricted to humans
only. Influenza C causes only a mild illness whereas types A and B cause the
symptoms of ’flu that we are familiar with - fever, chills, headache, body aches,
sore throat, dry cough, loss of appetite and fatigue.
The symptoms of influenza are similar to those of other viral diseases, but
unlike illnesses such as the common cold, the onset of ’flu is very sudden and
affects the whole body. Influenza symptoms are more severe than those present
in colds (see Figure 1).
The prevalence of influenza varies from year to year. The baseline rate for
influenza consultations with general practitioners (GPs) in winter is 50 cases
per 100,000 population a week. If this rises above 400/100,000, the outbreak
is classified as an epidemic. A pandemic is defined as when influenza affects
a high proportion of the global population. Pandemics occurred in 1918, 1957
and 1968 and virologists predict another will happen in the next few years.
The Public Health Laboratory Service posts regularly updated information about
this year’s influenza season on its website (www.phls.co.uk).
Information for the first week in January states that the level of reported
cases of influenza remains at baseline.
The management of influenza is based on vaccination, symptomatic relief and
antiviral drugs.
Vaccination is the most commonly used method of preventing influenza in the UK. Vaccines against influenza are currently offered to people who fall into “high-risk” groups. These are people:
The reported efficacy of vaccination varies considerably. In healthy adults,
vaccines are suggested to be effective in between 70 and 100 per cent of people
but very young children, the elderly and immunocompromised respond less well.
Efficacy in elderly populations has been reported to be between 30 and 60 per
cent. However, despite this low level of efficacy, there are substantial reductions
in hospitalisation for respiratory illness, influenza and pneumonia and deaths
from all causes are lower in people over 65 years of age who have been vaccinated
against influenza.
The World Health Organisation recommends which viral strains should be included
in the vaccination each year.
Zanamivir (Relenza) is a neuraminidase inhibitor licensed for the treatment
of influenza A and B when the virus is circulating in the community.
In its first appraisal of zanamivir in 1999, the National Institute for Clinical
Excellence (NICE) refused to recommend use of the drug. However, in November,
2000, following a second appraisal, the NICE issued guidance recommending the
use of zanamivir in “at risk” groups (see PJ, November 25, 2000, p777).
These are people:
Treatment with zanamivir has to be started within 36 hours of symptom onset.
It reduces the duration of symptoms by one to 1.5 days. However, the NICE says
that there are no reliable data about zanamivir’s impact on mortality or hospitalisation
rates.
At present, zanamivir is licensed in the UK for the treatment of influenza and
not for prophylaxis. Glaxosmithkline withdrew its application for a licence
for use of zanamivir as prophylaxis last year. The company says that this was
because it wanted to include data that could not be added to the original submission.
It is currently collating the new data.
Despite the NICE’s approval of zanamivir, doubts remain over its use. Aside
from the difficulties in implementing some aspects of the NICE guidance (see
later), a number of experts remain unconvinced of the drug’s benefits.
In December, 2000, Treatment Notes (a sister publication of the Drug
and Therapeutics Bulletin, both produced by the Consumers’ Association)
concluded: “Clinical trials have not yet shown whether zanamivir is useful for
people at high risk of getting ’flu complications. The benefits, risks and costs
of using the medicine across the NHS also are not clear. So, for the moment,
Treatment Notes does not recommend zanamivir.” It also noted that there
was no evidence to show whether zanamivir was useful for children under the
age of 12 and that the trials “do not show for certain” that zanamivir helps
people return to normal activity more quickly. Asked to comment on this, a spokeman
for Glaxosmithkline said that the company still believed that zanamivir provides
a potentially beneficial treatment option for “at risk” patients.
Concerns have also been raised over the safety of zanamivir in people with chronic
respiratory disease, including asthma (see PJ, January 22, 2000, p172).
In November, 2000, the US consumer group, Public Citizen, wrote to the NICE
to point out its concerns over the NICE recommending the use of zanamivir in
patients with asthma and chronic obstructive pulmonary disease. It said that,
in the US, the Food and Drug Administration did not generally recommend zanamivir
for these groups and urged the NICE to reverse its guidance for such patients.
However, data presented more recently at the annual meeting of the American
College of Allergy, Asthma and Immunology suggest that zanamivir is safe for
patients with asthma or chronic obstructive pulmonary disease.
The NICE recommended that zanamivir should be made available through patient
group directions (PGDs), creating an opportunity for community pharmacists to
become involved in its direct supply. At the time the guidance was issued, the
NICE and the Department of Health were keen for PGDs to be set up. The chief
executive of the NICE told a press conference launching the guidance that PGDs
were the most obvious and convenient way that patients could get zanamivir.
Despite pharmacists welcoming the opportunity for involvement, problems with
implementing PGDs quickly became apparent. The Department of Health said in
November, when the NICE guidance was released, that supply of zanamivir should
be planned as part of health authorities’ winter plan and that its supply should
be funded locally. In many cases, the winter plans had already been made and
funds allocated accordingly leaving little room to include zanamivir.
There were also problems with the supply of zanamivir itself. Pharmacists were
concerned over how “at risk” patients could be identified. There was a suggestion
that GPs could compile a list of “at risk” patients for use by pharmacists and
other health professionals implementing PGDs. However, some medical bodies advised
GPs against doing this because of the risk of assumed liability. There were
also concerns over the ethics of refusing to supply zanamivir, and over what
to do if a patient sent a relative to obtain zanamivir, a likely scenario considering
how debilitating influenza can be, particularly in the “at risk” groups.
Some health authorities have been able to resolve the problems and are implementing
PGDs for zanamivir. East Kent health authority, for example, has set up a specific
PGD where patients are referred to pharmacies following triage by NHS Direct
and surgeries. Each patient is given a referral number which is recorded by
the pharmacy. The patient (or his representative) is questioned by the pharmacist,
who makes the final decision on whether or not zanamivir is appropriate. Patients
cannot obtain zanamivir from pharmacies without going through the triage system.
Amantadine is an antiviral drug licensed for the treatment and prevention
of influenza A.
Amantadine was first licensed in 1970 for use against specific strains of influenza
A and, in 1977, was licensed for use against all influenza A strains. It is
also licensed for Parkinson’s disease (as Symmetrel). In January, 2000, amantadine
was launched as Lysovir, specifically for the treatment and prevention of influenza
A (see PJ, January 1, 2000, p39).
The summary of product characteristics (SPC) for Lysovir recommends that the
drug is used for prophylaxis for “at risk” individuals. The British National
Formulary states that amantadine may be used for prophylaxis in “at risk” individuals
only (see above under vaccines), including for use during the two weeks following
vaccination while the vaccine takes effect, and, additionally, for health care
workers and other key workers during an influenza epidemic. In terms of treatment,
the SPC for Lysovir suggests that the drug be given to “patients suffering from
clinical influenza in which complications might be expected to occur”.
Amantadine acts by inhibiting an early stage of viral replication. It is given
at a dose of one 100mg capsule daily for five days as treatment or, as prophylaxis,
as 100mg daily for as long as protection is needed. It is licensed for adults
and children over 10 years of age. A recent review published in the New England
Journal of Medicine (2000;343:1778) states that prophylaxis with amantadine
prevents about 50 per cent of infections and 70 to 90 per cent of illnesses.
In terms of treatment, clinical trials have reported that when amantadine is
started within 48 hours of onset of influenza symptoms, it reduces their severity
and the duration of fever by one to two days.
A trial of amantadine in health care workers in West Cumbria health care trust
was published in GHP (the journal of the Guild of Healthcare Pharmacists)
last month. It showed that during a 65-day outbreak of influenza, 74 treatment
packs of amantadine were issued. Treatment was successful in 80 per cent of
cases (success equated to two days absence or fewer) and in 78 per cent of successful
cases, no sickness absence was taken at all.
Despite the evidence to support its use, amantadine is not widely prescribed
in the UK. This is not the case in other countries, such as the United States.
Various reasons exist for the low uptake. Mr Tony Booley (sales and marketing
manager, Alliance [manufacturer of Lysovir]) believes that the most important
of these is a lack of awareness and knowledge of the properties of amantadine
for influenza. Behind this lies a dependence on vaccination as the key strategy
in influenza management and, consequently, antivirals have never been promoted
in the UK, he says. Another reason for the low uptake is that amantadine was
originally marketed for Parkinson’s disease. Packs of amantadine for treating
influenza were introduced last season which, the company hopes, will make it
easier for GPs to prescribe the drug.
There have also been concerns over the side effect profile of amantadine. Alliance
agreed that there had been some confusion over this issue because many of the
side effects that have been seen with the higher dose preparation of amantadine
used for treating Parkinson’s disease may not occur with the lower dose used
for influenza. The adverse effects of amantadine have been shown in clinical
trials to be dose-related and so are more common at higher doses but may still
occur at the dose used to treat influenza. The New England Journal of Medicine
review notes that amantadine stimulates the release of catecholamines which
accounts for its central nervous system side effects including anxiety, depression
and insomnia. Studies show that around 7 to 10 per cent of patients taking amantadine
experience side effects. Alliance says that it can be difficult to distinguish
between true side effects and symptoms of influenza itself.
In the US, rimantadine, an antiviral agent similar to amantadine, is also licensed
for prevention and treatment of influenza A. It does not have an effect on catecholamines
so may have fewer central nervous system effects.
The recent NICE guidance on zanamivir includes just one reference to these antivirals.
It reads: “Amantadine and rimantadine are two antiviral agents that have been
used in the prevention and treatment of influenza. Only amantadine is licensed
for use in the UK. The institute has not been asked to appraise either product.”
Amantadine should have been included in the NICE guidance, Mr Booley told The
Journal on January 4. The NICE had been set up to look at the cost-effectiveness
of interventions and it should compare new interventions with existing ones.
However, it failed to compare zanamivir with amantadine, he said. The NICE had
requested information from Alliance on amantadine. The company had submitted
information and was surprised to find that it was not included in the guidance.
Alliance is taking the matter up with the NICE and the Department of Health.
A spokesman for the Department of Health told The Journal on January
9 that it had been made clear throughout both the 1999 and 2000 appraisals of
zanamivir that the NICE was appraising an individual product. However, it was
possible that other products could be considered in any future appraisals, he
added.
In a press release issued in November, 2000, Alliance claimed that using amantadine
as an alternative to zanamivir could save the National Health Service £10m
a year. This is based on an estimate by the NICE that the annual cost of zanamivir
will be between £2.3m and £11m in England and Wales and that the
price of amantadine is approximately a tenth of the price of zanamivir.
The use of PGDs for the supply of zanamivir raises a question over why amantadine
is not being supplied in the same way.
Alliance says that it has discussed the matter with the Department of Health,
which agreed that there is no reason why PGDs could not be set up for amantadine.
The company has had a number of requests for information on amantadine from
primary care groups so it seems that the drug could soon be supplied in this
way. An outline PGD can be found on Alliance’s website (www.lysovir.com).
Comparing the two drugs, a case for amantadine certainly exists. Zanamivir is
licensed for the treatment of influenza A and B whereas amantadine is licensed
for the treatment and prevention of influenza A. Therefore, in cases of influenza
B only zanamivir could be used. But in cases of influenza A, there is a choice
between the drugs. The New England Journal of Medicine review suggested
that there is no clear advantage of neuraminidase inhibitors over amantadine
and rimantadine. Additionally, zanamivir is used as an inhalation whereas amantadine
is available in an oral dosage form. A large difference in cost separates the
drugs. A five-day course of zanamivir (Relenza) costs £24 and a five-day
supply of amantadine (Lysovir) costs £2.40.
Another drug for influenza is on the horizon, oseltamivir (Tamiflu). The drug,
a neuraminidase inhibitor like zanamivir, is currently licensed in the US but
not in the UK. Roche, its manufacturer, withdrew its licence application last
summer after a request from the regulatory authorities for further data (see
PJ, June 3, 2000, p837).
A spokeswoman for Roche told The Journal on January 4 that the company
hopes to resubmit a licence application as soon as possible. Oseltamivir offers
an advantage over zanamivir in that it is in an oral dosage form and so is less
likely to cause adverse effects in people with chronic respiratory disease.
However, it has been shown to cause gastrointestinal problems.
Influenza can be tackled in two ways. It can be prevented by vaccination or
by prophylactic use of amantadine and it can be treated using zanamivir or amantadine.
The Primary Care Virology group has published guidelines for the treatment of
influenza in the community (see Figure 2).
Until head-to-head trials are conducted, it is difficult to assess which approach
is the most effective for managing influenza. Part of the answer may be revealed
by researchers from Leicester Royal Infirmary who are conducting a systematic
review to examine the cost effectiveness of antivirals and vaccines for influenza.
In the meantime, we wait to see what the influenza virus will bring us this
year.
Mrs Bellingham is on the staff of The Pharmaceutical Journal