Microsoft word - cough and cold assessment report.doc



Following concerns about the safety of over-the-counter (OTC) cough and cold
medicines in young children which were initially raised in the USA, the purpose of this
review is to evaluate all available evidence on risk:benefit relevant to UK use.
There are four main categories of pharmacologically active ingredients used in children’s
cough and cold medicines authorised in the UK for sale without prescription (OTC):
nasal decongestants (pseudoephedrine, ephedrine, phenylephrine, oxymetazoline and
xylometazoline), expectorants (guaifenesin and ipecacuanha), antitussives
(dextromethorphan and pholcodine); and antihistamines (diphenhydramine,
chlorphenamine, brompheniramine, promethazine, triprolidine and doxylamine).
Actives from the four categories are commonly used in combination with actives from
the other categories or other actives (many preparations also contain analgesics) to treat a
variety of symptoms of the common cold. Antihistamines are used almost entirely in
combination, most commonly with decongestants or antitussives and in some cases both.
Combination expectorant and decongestant preparations are also currently authorised in
the UK.

Data supplied by Marketing Authorisation Holders (MAHs) – following a request from
the MHRA to provide data - have been reviewed. Available data from the published
literature, UK spontaneous suspected adverse reaction reports, National Poisons Service
data and Hospital Event Statistics (HES) data have been reviewed. Assessments and
reviews from other regulatory authorities have been reviewed.
3.1 UK


Following an application from a MAH to remove the licensed indication, and dosages,
for children under two years of age, in February 2008 the Paediatric Medicines Expert
Advisory Group (PMEAG) and the Commission on Human Medicines (CHM) advised
that the risk to benefit balance associated with OTC cough and cold medicines for use in
the paediatric population under 2 years was no longer favourable. In addition, PMEAG
and CHM advised as an interim that products authorized for children aged 2-6 years
should be updated to include: information on maximum daily dose; a warning not to take
with any other cough and cold medicines; and instruction to seek the advice of a
pharmacist or other healthcare professional before using the medicine. Single-constituent
paracetamol and ibuprofen products were not affected.

Following a publication in April 2008 detailing adverse drug events from cough and cold
medications in children in the US, PMEAG were updated in June 2008. PMEAG
recommended that MAHs should be required to submit data to demonstrate a positive
risk:benefit of the authorised products. In addition, as a risk minimisation strategy
PMEAG considered that all OTC cough and cold medicines licensed for use in children
be supplied in child-resistant containers (CRCs) with appropriate dosing devices, as well
as guidance for parents and healthcare professionals on the appropriate management of
cough and cold symptoms.


International Regulatory Activity

3.2.1 USA

In the USA most OTC cough/cold medications are marketed under the authority of the
formal OTC "monograph" system rather than as individual marketing authorisations.
Amendment of a monograph involves writing a new regulation and may take some years
to implement. The FDA is in the process of developing a proposed rule to revise the
paediatric labelling contained in the Final monograph for cough, cold, allergy,
bronchodilator and antiasthmatic drug products for Over-the Counter human use
held a public meeting to obtain input regarding this process, including input on what
studies should be conducted to assess effectiveness and /or safety, if they should still be
available OTC and how should age be considered in making regulatory decisions. Public
consultation will be undertaken in 2009.
Although no regulatory action has been taken – the FDA review is still ongoing - most
manufacturers in the US have voluntarily amended product warnings to state ‘do not use
in children under 4 years of age’ and, for antihistamine products, added a warning that
they should not be used as a sedative has been included. In addition, manufacturers in the
US are conducting pharmacokinetic studies on 8 actives: phenylephrine,
diphenhydramine, pseudoephedrine, chlorphenamine, brompheniramine,
dextromethorphan, guaifenesin and doxylamine.

3.2.2 Canada

Further to its recommendation in 2007 that these products should not be used in children
under 2 years, Health Canada has announced that all oral cough and cold products should
state ‘not to be used for children under 6 years’ on the label. This recommendation takes
into account the following factors:
I. Recommendations from Canadian and international health professionals and experts that these medicines should not be used in children under 6; II. Body weight and its effect on how medicines work. Some children between the ages of 2 and 6 years may weigh the same as other children who are less than two years old, the most vulnerable group; III. Children under the age of 6 years generally have more colds compared to older children and therefore, are likely to be exposed more frequently to these medications; and IV. Younger children are less likely to be able to communicate a potential side-effect from a cough and cold medicine and to ask their parents/caregivers for help in the same way a child over the age of 6 can. For children aged 6 to 12 years Health Canada has introduced a number of restrictions
including strengthened warnings and requirements for child resistant packaging and
dosing devices.




Incidence of Cough and Cold in children

Children get more coughs and cold than adults. The frequency decreases with age as the
immune system develops. Estimates reported in the Lancet (Heikkinen & Jarvinen, 2003)
suggest that on average children under 1 year in the UK get about 6 colds a year, children
1-2 years get 5.7, 3-4 year olds get 4.5 and 5-9 year olds get 3.5 colds per year. Other
groups have estimated that children under 6 years get between 6-8 coughs a year with the
number diminishing around 6 years (Taylor, 1992).
Use of cough and cold products in children in UK

There is a high propensity for parents and carers to treat the symptoms of cough and cold
in children. A recent US publication reporting the results of the Slone survey (Vernacchio
et al, 2008) revealed that in a given week a cough and cold medication was used by
10.1% of US children. Exposure was highest to decongestants and first generation
antihistamines, followed by antitussives and expectorants. Multiple-ingredient products
accounted for 64.2% of all cough and cold medications.
From data provided by the Propriety Association of Great Britain (PAGB) it is estimated
that over 55 million packs of cough and cold medications with indications for children
under 12 years are sold in the UK each year and 12 million packs are sold with
indications authorised for children less that 6 years of age. This is in the context of an
estimated UK population of under 6 year olds of 3.6 million.
For products authorised for use in children aged under 6 years the most widely purchased
products are preparations containing expectorants (7.6 million), followed by
antihistamines (3.4 million), antitussives (2.3 million) and decongestants (1.9 million).
As most products are authorised for use in a range of age groups, including adults, these
figures do not necessarily reflect the relative usage of the different products in children.

Current NHS/Department of Health (DH) advice on treating colds and coughs in children
includes giving fluids and treating fever and pain with paracetamol or ibuprofen, and the
use of saline drops to loosen dried nasal secretions or help a stuffy nose in young children
and babies. Although steam inhalation is not suitable for children because of the risk of
scalding, a child may benefit from sitting in a hot, steamy bathroom. Simple cough
mixtures containing a demulcent, for example glycerin, and syrup can have a soothing
effect by coating the throat and relieving the irritation which causes the cough; a child
over the age of one may also be helped by a warm drink of lemon and honey. If a cough
as a result of a viral infection does not go after 2 weeks a doctor should be consulted.
With respect to the use of cough and cold medicines the DH publication Birth to Five
states that cough and cold medicines have not been shown to work and may produce side-
effects in young children and may cause poisoning if a child accidentally swallows more
than the recommended dose. However, despite this many parents and carers often feel the
need to treat a child with an OTC cough and cold medicine. It is therefore important these
medicines are used appropriately in order to minimise any risk.
It is important that parents have information on the appropriate preparations for the
child’s symptoms: cough suppressants should only be used to treat a dry cough;
antihistamine preparations should not be used if the child does not have a runny nose and
should not be used to sedate a child; and expectorants are appropriate only for a chesty or
productive cough. Specific warnings and precautions for the individual preparations
should be followed, including in relation to duration of use.
The label (and leaflet) should always be read and dosage advice appropriate for the
child’s age should be followed using the measuring device made for the medicine.

The reviews of the available safety and efficacy evidence for the ingredients in the four
drug categories are summarised below:


Safety and Efficacy
Previous (Cochrane) reviews have concluded: “There is insufficient data on the use of [nasal decongestants] in children and therefore they are not recommended for use in children younger than 12 …” “There is no good evidence for or against the effectiveness of OTC medicines in acute cough … it remains unclear whether these medications are helpful .” Very few trials have been conducted in children to current standards: a total of 38 clinical trials were considered for this review - these trials contain design faults which may have limited their ability to detect differences between treatment and control groups.
There are no robust data providing convincing evidence of efficacy for any of the active
ingredients – alone or in combination – in the treatment of cough and cold symptoms in
children. A summary of the evidence of efficacy and safety for each of the four mian
categories reviewed is set out below.

6.1.2 Sympathomimetic Nasal Decongestants

There are severe limitations to the efficacy studies given that many of the products were
first introduced decades ago. There has been no co-ordinated development program to
establish efficacy. What trials there are have not been carried out to current standards.
Many of the studies had populations of mixed ages (ie included adults and children).
Many studies evaluated the relief of nasal congestion in other conditions associated with
nasal stuffiness as well as the common cold. Standardised and validated objective
measures were not used and subjective symptoms of nasal stuffiness often do not
correlate with objective measures. Many of the studies were of multi-ingredient
products, seriously limiting the evaluation of the effect of single agents.
There is one inconclusive study of multiple-dose single-constituent pseudoephedrine in
the common cold in children/adolescents aged 2 to 16 years. Otherwise, there are no
adequately designed studies of the sympathomimetic nasal decongestants in this patient
population, so a favourable benefit to risk cannot be established.
From the 5 sympathomimetic nasal decongestants, there were 138 serious reactions in
children under the age of 12 years reported in the UK, with 3 of these classified as
overdose. For children of 6 years and under, there were 89 serious reactions with 3 of
these reported as overdose (ie all the overdoses were in the younger age group as were
2/3rds of the reactions).

6.1.3 Expectorants

No studies appeared to have investigated the effect of single-constituent guaifenesin in
acute cough in children, and 3 published studies in non-acute cough in children failed to
show any effect of guaifenesin. Sixteen published studies in adults (including 1 in adults
and children) were reviewed, which examined the effect of guaifenesin (alone or in
combination with other substances) on endpoints including acute cough, non-acute cough
and sputum viscosity or properties. These studies had mixed results but some provided
evidence of efficacy of guaifenesin in adults, in terms of easing of expectoration.
Unpublished data were also reviewed but did not provide any additional robust evidence
of efficacy of guaifenesin.
No studies appeared to have investigated the efficacy of ipecacuanha in acute cough in
any age group.

In the MHRA ADR database there are 78 serious reports associated with expectorants in
children aged under 12 years: 55 in children under 6 years and 23 in children aged 6-12
years. Two cases were associated with accidental overdose, both in children under 6
6.1.4 Antitussives

Overall, ten studies investigating antitussives in the treatment of acute cough in children
were identified. There were 8 studies reviewing the efficacy of dextromethorphan (DXM)
in the paediatric population. Only 3 of them reported a variable degree of positive effect
on the symptom scores; however, it is important to note that there were issues with the
design of the studies such as: definition and timing of treatment outcomes, adequacy of
dose, dosing frequency, and duration of therapy. Additionally in 2 of the studies a
combination drug was used and therefore it is unclear if the positive effect could be
attributed to DXM. The other much newer studies all failed to show any effect of DXM
in the treatment of acute cough, even when compared to honey.
Regarding pholcodine only 2 very old studies have been identified in the paediatric
population. In these studies no placebo groups were included and in one of them a
combination drug with paracetamol was used in patients aged 6 years and above. Both of
the studies report a general improvement of the overall cough and cold symptoms as
reported by parents without substantial details of the measured outcomes.
In the MHRA ADR database there are 14 unique reports of serious reports associated
with dextromethorphan in children aged 12 years and under with a total number of 18
suspected serious reactions. The most frequently reported reactions relate to neuro-
psychiatric disorders (7/18) and skin reactions (5/18). There has been no fatal case in
For pholcodine there are 21 unique reports of serious ADRs in children aged 12 years and
under. Overall there were 36 reported reactions equally distributed among the age groups
(0-2y, 2-6y, 6-12y). Across the age groups, the most frequently reported reactions relate
to neuro-psychiatric disorders (12/36) and skin reactions, including erythema, urticaria
and rash (10/36). There were also 2 cardiac reactions in the very young and in the older
age group and 6 respiratory reactions including asthma, bronchospasm and respiratory
depression, across all age groups. A fatal report associated with pholcodine was received
in January 2008. The original toxicology screen showed pholcodine at a level higher than
expected for therapy, however this has been ruled out as a cause of death which was
attributed to other causes.
6.1.5 Antihistamines

Five randomised–controlled trials investigating antihistamines in the treatment of cough
and cold in children were identified. Only one trial reported a positive effect (with
astemizole, a non-sedating antihistamine), however, the value of this study is limited as it
appeared to include children who did not have the common cold and may have had
symptoms of allergy instead. The other studies all failed to show any effect of
antihistamines in the treatment of the common cold but these studies did have limitations
which may have affected their ability to detect a difference between placebo and active
In the MHRA ADR database there are 127 serious reports associated with antihistamine
cough and cold preparations in children aged under 12 years: 92 in children under 6 years
and 35 in children aged 6-12 years. Only one case was associated with accidental
6.2.1 Suspected Adverse Drug Reactions - overview

The number of spontaneous suspected ADR reports for all groups is limited, but under-
reporting would be expected with OTC medicines. The value of spontaneous reports is
also limited as the frequency of adverse reactions cannot be established because of lack
of denominator data, particularly in different age groups. It is also difficult to attribute
causality as most of the reports are associated with multi-ingredient products and some
reactions may be as a result of the underlying disease rather than as a result of the
The main patterns of reports relate to CNS adverse effects with the antihistamines,
antitussives, and decongestants; and allergy/hypersensitivity reactions, particularly with
the expectorants.

There have been serious suspected ADR reports in children, over 360 in children under
12 were identified as part of the review, the majority in children aged under 6 years,
associated with cough and cold ingredients especially those containing pseudoephedrine,
diphenhydramine, chlorphenamine and dextromethorphan; also, a small number of
serious cases have been reported where guaifenesin was the only active substance. Some
of these reports are not associated with overdose. In addition, there are reports of abuse,
mainly from the US, Canada, and Scandinavia of dextromethorphan, alone or with other
drugs, mainly by adolescents.
6.2.2 Hospital

In England, data on hospital admissions and out-patient data are recorded by Hospital
Event Statistics (HES) - though the majority of attendances at A&E are not captured by
HES. In 2006/7 (the most recent data available) there were a total of 230 children in
England aged under 14 who were admitted to hospital following exposure to antitussives,
expectorants or common cold remedies (11 poisoning by antitussives, 39 poisoning by
expectorants, 182 poisoning by anti-common-cold remedies). Taking into account
population size the English data indicates a higher admission rate than in the US but this
may be because criteria for admission may differ, given the very different healthcare
systems, and the different age ranges (under 12 in US, under 14 in England).
6.2.3 National Poisons Information Service

Data have been provided by NPIS for the UK covering total calls annually from 2004 to
2007. The total number of calls for this 4-year period was 144,242. Data for the
antihistamines, antitussives and cough suppressants are shown below:
Under 5 years
Under 9 years

6.2.4 Published


In April 2008 a study by the Centers for Disease Control and Prevention (CDC) analysing
adverse drug events (ADEs) from cough and cold medication in children, based upon
emergency department visits in the US, was published (Schaefer et al, 2008). The data
suggest that annually approximately 7100 patients aged under 12 years were treated in
emergency departments in the USA for ADEs from cough and cold medicines.
In summary, most visits were reported for children aged between 2-5 years (64%), with
the majority of these being related to unsupervised ingestions (77%), however, a
substantial minority (18%) related to non-overdose adverse events such as allergy. In
contrast, for children aged less than 2 years almost half of the cases were due to excessive
dosing by caregivers.
Overall, from the data reviews a favourable risk/benefit for any of the drug categories in the treatment of cold and coughs in children cannot be established. As a favourable risk/benefit remains to be established in children it could be argued that cough and cold products should not be used in this age group. However, this could be seen as unnecessarily restricting availability of medicines in the absence of a significant safety concern in older children and adults; and it arguably fails to take into account the
extensive use, over many years, of these products.
Although there is some rationale for some combinations authorised in the UK the wide
use of such products means that children may be exposed to actives they do not need for
their particular symptoms; and the rationale for some combinations – such as those
containing an antihistamine (which dry up and thicken respiratory tract secretions) and an
expectorant (which is believed to make secretions easier to expel) - is illogical. More
importantly, some combinations of active ingredients may potentially increase the risk of
serious adverse reactions: for example, combinations containing both cough suppressants
and antihistamines which both act centrally may carry an increased risk of CNS side-
effects, such as hallucinations and convulsions.



The symptoms of cold are the body’s natural defence against the virus. In some
circumstances treatment of symptoms, even if effective, may not be desirable, since this
could reduce the body’s capacity to deal with the virus; this may be particularly pertinent
in the case of suppression of the cough reflex in young children.
Doses of these products, including fixed combination products, in children are based on
extrapolation from adult doses which assumes that disease progression and clinical
response in paediatric and adult populations are the same. Adjustments made on body
weight alone may not be sufficient as children may exhibit different drug absorption and
disposition compared with adults, particularly clearance which is a highly variable
parameter in the paediatric population, which are likely to impact on the drug response.
Few pharmacokinetic studies have yet been done on the drug categories in children and
therefore effective doses in children remain to be established.

The reviews of the drug categories highlight the paucity of data regarding both efficacy
and safety for cough and cold products in children; evidence of efficacy, in particular, is
largely based on extrapolation from adult data where available and there are no robust
data providing convincing evidence of efficacy for any of the active ingredients alone or
in combination for treatment of cough and cold in children.

Safety – adverse reactions
In terms of safety, under-reporting of suspected adverse reactions is a well-recognised
problem for all OTC medicines and particularly for long-established products. Serious
reactions have been reported in the UK and US with therapeutic doses in children over
the age of 2 years. Particular concern is raised about the number of serious reports
associated, especially from the US, with dextromethorphan at normal doses. The growing
problem of abuse of dextromethorphan is also a concern.
In addition, the pharmacology of some of the actives, particularly suppression of cough in
young children, raises concern. As many preparations contain combinations of actives
this potentially increases the risk of serious side-effects. For example, the risk of CNS
side-effects could be increased with two centrally acting actives such as with cough
suppressant/antihistamine combinations.
Available data show that young children are particularly sensitive to the effects of
overdose and this appears to account for the majority of adverse reactions reported in the
US. In addition, as illustrated in the CDC article, unsupervised ingestions peak around the
age of 3 years. Available UK data indicate that in the UK a significant number of
children are admitted to hospital following an overdose.

Risk from overdose and in normal use must both be considered in the context of
treatment of the symptoms of a self-limiting condition. It is important to note that
ineffectiveness of products could increase the likelihood of inappropriate use of these
medicines as parents and carers may be more inclined to overdose if the first dose given
has had no effect on the symptoms.


The Commission on Human Medicines (CHM) - the Government’s independent expert
advisors – concluded that:
• There is no robust evidence that cold and cough medicines containing the above ingredients work. Given that there have been some reports of harm with these ingredients, the risks of cough and cold medicines containing them outweigh the benefits; • For children aged over 6 years, the risk from these ingredients is reduced because: they suffer from cough and cold less frequently and consequently require medicines less often; with increased age and size, they tolerate the medicines better; and they can say if the medicine is working. For these reasons cold and cough medicines containing the above ingredients can continue to be available for these older children, but only through pharmacies; • Further research is required on how effective these products are in children over 6 years. • Cough and cold medicines containing the ingredients reviewed should not be used in children under 6. • Cough and cold medicines for 6 to 12 year olds containing the ingredients reviewed will continue to be available in pharmacies, with clearer advice on the packaging/labelling and from the pharmacist. • Products for children of 6 to 12 years containing the ingredients reviewed should be indicated for use “second line” to standard best care, and with duration of use restricted to no more than five days. • Cough and cold medicines for 6 to 12 year olds should have strengthened warnings on the packaging and labelling. • All liquid cough and cold medicines (including those for adults) should be supplied in a child resistant container. • Certain combinations (such as cough suppressants and expectorants) should be phased out. MHRA ACTION

On 28 February 2009 the MHRA announced the comprehensive package of measures set
out in the advice from the CHM. These are available on the MHRA website:
The MHRA is working with industry and healthcare professionals to encourage ‘best
practice’ and implement these measures. Industry has agreed to implement changes over
a period of time. They will make the necessary labelling changes to state that these
medicines should not be used in children under 6, introduce updated labelling, and
change the legal status of medicines authorised for children aged 6 – 12 years from
general sale (GSL) to pharmacy (P).
Newly labelled products will start to appear for the 2009 cough and cold season.
Medicines with the old labelling will not be cleared off shelves. This is because many of
these products are used in adults and children, and so cannot be withdrawn, creating a
shortage of these medicines. Withdrawing these medicines would not be proportionate
compared to the risk of side effects.
These changes should be completed by March 2010, except that the move towards
ensuring all liquid cough and cold medicines (including those for adults) are supplied in a
child resistant container will be implemented longer-term.


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