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| Journal of the New Zealand Medical Association,
26-August-2005, Vol 118 No 1221
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PHARMAC responds on salbutamol
We disagree with Dr John Gillies and colleagues’ views
(published in the 12 August 2005 issue of the
Journal; http://www.nzma.org.nz/journal/118-1220/1616/)
on the introduction of a new brand of salbutamol (Salamol) onto the New Zealand
Pharmaceutical Schedule. Salamol is efficacious, and blockages can occur with
any CFC-free inhalers (including Ventolin).
Patient perceptions are important—but some data
suggest that nearly half of patients will report subjective differences between
their own and study-supplied Ventolin inhalers.1 However, we acknowledge that
this issue did highlight the need to consider better education campaigns around
sole supply arrangements for asthma products. Patient education needs to include
regularly washing CFC-free inhalers—including Ventolin CFC-free
inhalers.
Efficacy, published research and use internationallySalamol was approved by Medsafe (the New Zealand Medicines
and Medical Devices Safety Authority, a business unit of the Ministry of Health)
in 2004, following a standard approval process, meaning that it meets the
standards of safety and efficacy required of medicines in New Zealand. The
approval process includes a rigorous review of the literature and proof of
bioequivalence with the innovator (in this case, Ventolin). The submission made
to Medsafe for approval of Salamol included clinical trial data. The approval of
a medicine by Medsafe is independent of PHARMAC.
International randomised double-blind studies have
demonstrated that respiratory function did not differ between generic and
branded salbutamol and that there was clinical equivalence between the generic
and the branded salbutamol1,2 (PubMed search using the keywords “generic
salbutamol”).
Salamol is, like Ventolin, a brand of salbutamol and is
bioequivalent. Salamol is also widely used internationally, having been approved
in the United States and the United Kingdom. In the United Kingdom (where it is
manufactured), Salamol has been registered and prescribed for over four years
and has a significant share of the salbutamol market there, with over 600,000
units being dispensed each month. There is nothing to compare this
product’s introduction with fenoterol’s safety concerns.
In response to the complaints PHARMAC had received from
patients and clinicians, Medsafe asked both Environmental Science Research (ESR)
and the Australian Therapeutic Goods Administration (TGA) to test Salamol and
investigate. PHARMAC and Medsafe are awaiting the final results and will advise
clinicians of Medsafe’s findings once these are available.
Patient perception and palatabilityWe do note that users of Salamol who have previously used
the Ventolin inhaler have reported that inhaler feels different when used.
Indeed the “force” and coldness of the spray feel different between
the two inhalers. This does not, however, affect the actual delivery of the
chemical. It is possible that this difference in delivery has led some patients
to conclude that the Salamol inhaler is less effective.
The Williamson study above,1 which compared open-label
Ventolin, blinded Ventolin and a generic salbutamol, indicates that generic
substitution of salbutamol is often affected by subjective negative perception
by both patients and doctors, which are not based on any clinical differences.
These may well resolve with time as people become accustomed to using the new
inhaler and realise that it is as effective as their old one.
In the same study, fifty-five per cent of patients said they
could detect a difference between the inhalers, when there were no significant
differences between treatments in any of the objective parameters measured. Of
particular interest however, 45% noted a difference between their usual Ventolin
and the open or blinded Ventolin. The authors concluded
inter alia that patients’ own
assessment of their relief inhaler seems to be influenced by factors other than
efficacy.1
Clinicians should also recognise that patients equate the
“coldness” and the impact of the propellant on the post pharyngeal
wall with efficacy. This does suggest that there should be more education around
proper inhaler technique to ensure that devices are being used properly.
Device issues including blockagesThe manufacturers of Salamol acknowledge that the device can
clog and advise that it should be washed regularly. All CFC-free salbutamol
inhalers can clog if not cared for by careful washing.3–5 Washing each
week with warm running water for at least 30 seconds prevents possible clogging.
The makers of Ventolin give the same advice on their packaging.
The PTAC submission included a study comparing the blockage
rates of Aeromir, Salamol and Ventolin. The study showed no significant
difference in blockage rates when the devices are cleaned in accordance with
manufacturers recommendations.
These factors highlight the importance nowadays, with the
advent of CFC-free inhalers, for clinicians to advise patients that, regardless
of the product, CFC-free inhalers can clog, and teach how and when to clean the
devices. Washing instructions are included in the patient information sheets
provided with each inhaler. Washing is important, as even if the device does not
completely obstruct, the doses delivered may still be reduced. This equally
applies to Ventolin.
The Salamol device’s size and shape is appears to be
identical to that of Serevent long-acting beta-agonist (LABA) metered dose
inhalers.
Alcohol contentAlcohol is a common solvent in many pharmaceuticals
especially liquid preparations. The amount of alcohol contained in each puff of
Salamol is in the thousandths of a millilitre—less than the amount of
naturally occurring alcohol found in a glass of freshly squeezed orange juice.6
The amount of alcohol used in MDIs is insufficient to have a
pharmacological effect7 or affect driving.8 Claims that inhaling micrograms of
alcohol will affect an adult’s driving ability have been refuted by the NZ
Police and in the United Kingdom (see footnote #1). Salamol is approved for use
in a number of predominantly Islamic countries, including the United Arab
Emirates and Kazakhstan.
Consultation with expert and patient groupsIn addition to our standard consultation
processes,9–11 the issues around generic salbutamol were discussed in
detail by the Pharmacology and Therapeutics Advisory Committee (PTAC12) and its
Respiratory subcommittee (both independent clinical advisory committees to
PHARMAC) and the Tender Medical subcommittee (which consists of clinicians and
pharmacists). The consultation document identifying which drugs are being
considered for tender was widely distributed to suppliers, professional bodies
and interested clinicians and other groups on 16 October 2002. This included the
Asthma and Respiratory Foundation of New Zealand (ARFNZ), the Thoracic Society
of Australia and New Zealand (TSANZ), the Paediatric Society of New Zealand, New
Zealand Medical Association, the Royal Australasian College of Physicians, and
the Royal New Zealand College of General Practitioners.
As outlined in the October 2002 letter, the Tender Medical
subcommittee considers all products proposed for tender before the final list is
approved by PHARMAC’s Board. It also considers all the products where bids
were received to give it the opportunity to review the products that are to be
proposed for sole subsidised supply. In the case of Salamol the subcommittee
considered there was no clinical reason not to award a tender, but did request
that the Respiratory subcommittee review the device before any decision was made
to accept the tender.
The Respiratory subcommittee in turn was satisfied with the
device, highlighting only that it may present an issue for Islamic patients who
may object to alcohol on religious grounds. This has since been discounted by
comment from Islamic spokespeople, and as the subcommittee noted, if a patient
did strongly object to taking a medicine containing alcohol they could use
terbutaline. The relevant part of the minutes of the subcommittee’s
September 2003 meeting is in footnote #2.
In May 2005 PTAC considered that Salamol should remain on
the Pharmaceutical Schedule and, subject to satisfactory TGAL results, saw no
clinical reason why PHARMAC should not proceed with a sole supply arrangement
for the product. However, it recommended that any continuation of subsidised
access to Salamol should be associated with an awareness campaign in which
PHARMAC emphasised the need to regularly wash all CFC free inhalers. The
relevant part of the minutes of PTAC’s May 2005 meeting is in footnote #3,
which further details various issues around Salamol.
Lesson learntWe acknowledge that there were a number of complaints about
Salamol with a great deal of media interest. Most complaints reported to CARM
were from pharmacists rather than doctors, with relatively few pharmacists at
that. Once we realised that public confidence in the product had been
unreasonably shaken, we reached agreement with Airflow to continue the listing
of both products. PHARMAC had no concerns over Salamol’s efficacy.
Ventolin now has the same access to subsidy as Salamol, and it remains up to the
supplier (GSK) as to whether it maintains a surcharge on Ventolin.
We understand from Medsafe that the UK experience showed
that any concerns were resolved simply by patient education. Medsafe also states
that in the UK that the Asthma Society and patient groups were all onside in a
background of CFC to non-CFC substitution.
This issue did highlight the need to consider education
campaigns around sole supply arrangements for asthma products. Both patients and
clinicians can be very “brand loyal” and any change to an
“iconic” product needs to be handled carefully. The Williamson study
concluded that careful encouragement is required when changing to a generic
product, and that this has particular implications for converting to CFC-free
products.1 Further, with hindsight we should have asked the supplier to give
more information to clinicians about the different taste and feel of Salamol.
CommentAdvice to patients must now include regularly washing all
CFC free inhalers—as has been needed since CFC-free Flixotide was
introduced in January 1998 and CFC-free Ventolin was introduced in June
2001.
PHARMAC considers sole supply arrangements in general to be
appropriate for the asthma market.
The authors’ arguments about role of the Asthma and
Respiratory Foundation (ARFNZ) might have been stronger had someone ensured that
any of the authors’ own conflicts of interest were declared. The
Journal’s policy on conflicts is clear,13 and such statements have
occurred in other Special Series articles.14,15 ARFNZ is but one of a number of
organisations with an advisory role that fund themselves in part through the
supply of pharmaceutical products.
There are larger issues for children with asthma, for
instance the lower rates of use of inhaled corticosteroids (ICSs) by some ethnic
groups when compared with their higher use of reliever inhalers and rates of
hospitalisation—as can be seen below in Figure 1 and Table 116 (details
can be supplied on request). These are issues we all need to look at
together.
Figure 1
 Table 1
 Conflict of
interest: Scott Metcalfe is externally contracted to work with PHARMAC
for public health advice. Peter Moodie, Andrew Davies, Wayne McNee, and Sean
Dougherty declare no conflicts.
Footnotes:
#1. Extract from
Airflow media statement 6 May 2005.
UK analysis by Lion
Laboratories, manufacturers of evidential breath machines, shows that if a
subject with no alcohol in his body used a similar inhaler to Salamol, sealed
his mouth closed and immediately blew into an intoximeter it would produce a
breath reading of 32 microgram per 100ml (three points below the UK upper limit
for driving). One minute later, not having used the inhaler again, the reading
was 1 microgram. Six minutes after using the inhaler there was no trace of
alcohol in a breath test. Provided a period of at least six minutes elapses
between the use of an inhaler and a breath test there is no effect on the
alcohol reading.
Lion Laboratories also
calculated that to raise the breath or blood, alcohol level from zero to the UK
legal limit for driving, a 70kg man would need to take over 5500 actuations of
the inhaler product in less than 30 minutes. This equates to around 27
containers.
#2. Relevant record
from PTAC’s Respiratory subcommittee meeting 11 September
2003
Salbutamol
metered dose inhaler
The subcommittee noted that
in response to the 2002/03 Invitation to Tender PHARMAC had received bids from
[deleted] suppliers for the salbutamol 100 mcg per dose aerosol inhaler, Airflow
Products’ being the best provisional bid. The subcommittee noted that this
product was not yet approved by Medsafe.
The subcommittee noted that
this product came from the UK based manufacturer Norton. The subcommittee noted
that the CFC-free inhaler contained small amounts of ethanol, which may be an
issue with some patients, such as Muslims. However, the subcommittee noted that
these patients could switch to terbutaline which was fully funded on the
Pharmaceutical Schedule.
The subcommittee considered
that there was no clinical reason not to award the tender for salbutamol metered
dose inhaler to Airflow, subject to Medsafe approval.
#3. Relevant record
from the Pharmacology and Therapeutics Advisory Committee meeting 19 May
2005
Salamol
(salbutamol)
The Committee noted that,
following consideration by the Tender Medical and Respiratory Sub-committees of
PTAC in 2003, the distributor of Salamol had been awarded a contract for sole
supply status, which was due to take effect on 1 July 2005. It noted that both
sub-committees had indicated that there was no clinical reason not to award sole
supply status to Salamol.
The Committee noted that
Salamol had been approved by Medsafe for distribution in New Zealand in December
2004 and that it had been available in the UK for almost 4 years and in the
United States for about 1 year.
The Committee noted that,
following listing on the Pharmaceutical Schedule in New Zealand, PHARMAC had
received 268 complaints about Salamol. The main areas of complaint were
categorised as follows:
The Committee
noted that similar problems with blocking had been reported in the UK. It noted
that the manufacturer (IVAX) had supplied studies, which showed that the
majority of complaints received in the UK related to clogging and dose delivery
failure. These problems were resolved when the inhalers were cleaned. The
Committee noted that the rate of complaints in the UK after 10 months of sales
in the UK was 110 per million inhalers sold, and this rate decreased over time
while sales increased.
The Committee noted that
Medsafe, using the technical expertise of ESR and the TGA laboratories (TGAL) in
Australia, had tested samples from two batches of Salamol as well as six
“faulty” inhalers. It noted that, while the results of the TGAL
testing were not yet available, Salamol had passed the tests conducted by ESR
which meant that the product met its quality specifications. The Committee
considered that the results of these tests to date showed no quality issues
associated with Salamol in regard to effectiveness and the number of
doses.
The Committee considered
some of the possible reasons for the other types of complaint. It noted that
Salamol does not have as strong an emission force compared to Ventolin and that
this may have contributed to perceptions of reduced effect. It also noted that
the product tastes different to Ventolin but did not regard the taste to be less
pleasant.
The Committee noted that
other inhalers also contain alcohol. It noted that, given the negligible levels
of alcohol contained in Salamol, the supplier had established that patients
would need to take 5,500 inhalations of Salamol in order to raise alcohol levels
significantly. The Committee also noted that a Muslim community spokesperson had
no objections to small amounts of alcohol in prescribed medications when used
under medical guidance. The Committee noted that it is sold in the Middle East
and registered in UAE. The Committee also noted that an Alcoholic’s
Anonymous (AA) worker had indicated no concern with the alcohol content.
The Committee noted that,
while Salamol may not fit all spacers, it fits a range including both subsidised
brands and the Volumatic spacer.
The Committee concluded that
the main complaint of significance was the issue of clogging. It noted that this
is a problem common to all CFC-free inhalers and that proper cleaning is
important. It noted that the datasheet for Salamol recommends storage at <
25°C compared with < 30°C for Ventolin but did not consider there
to be any evidence that this difference might impact on the rate of clogging.
The Committee noted that
clogging of the inhaler may result in patients becoming anxious. It acknowledged
that fear can have an adverse effect on a clinical situation, but considered
that this can generally be overcome by education.
The Committee considered
that Salamol should remain on the Pharmaceutical Schedule and, subject to
satisfactory TGAL results, saw no clinical reason why PHARMAC should not proceed
with a sole supply arrangement for the product. However, it recommended that any
continuation of subsidised access to Salamol should be associated with an
awareness campaign in which PHARMAC emphasised the need to regularly wash all
CFC free inhalers.
Scott Metcalfe
Public Health Physician Wellington Peter Moodie
Medical Director PHARMAC Wellington Andrew Davies
Hospital Pharmaceutical Contracts Manager PHARMAC Wellington Wayne McNee
Chief Executive PHARMAC Wellington Sean
Dougherty
Therapeutic Group Manager PHARMAC Wellington References:
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