Safety Information

Revised: 28 June 2013

Minutes of the First Cough and Cold Review Group Meeting

23 July 2009

The first meeting of the Cough and Cold Review Group was held on 23 July 2009 in the Board Room, Medsafe, Wellington, New Zealand. The meeting commenced at 10.10am and closed at 1.15pm.

Cough and Cold Working Group Members present

A Shirtcliffe (Chair)
E Beatson
L Bryant
B Buckham
S Cole
E Galloway
H Kingston
D Reith
T Roper
R Savage
L Toop

Medsafe staff present as observers

A Cutfield
K Daly
J Hart
S Kenyon
J McNee
E Yousuf

1 Matters of Administration

1.1 Welcome and Apologies

The Chair welcomed the attendees to the meeting and briefed the Group on the reasons for the meeting.

Members were reminded that the role of the Working Group was to advise Medsafe on the use of cough and cold medicines in children. The purpose of the current meeting was to comment on the available safety and efficacy data and to assess the risk-benefit profile of cough and cold medicines for use in children under the age of twelve years in light of the available data.

The Chair requested that members approach the presentation and discussion of the available data from a healthcare professional perspective and provide representative opinions at the end of the meeting.

The Chair introduced the members of the Group and the Medsafe staff observing. Apologies were received from M Dalton.

1.2 Potential Conflicts of Interest

The Chair reported on the conflicts of interest.

The Group noted that there were some non-personal and non-specific conflicts of interest and considered that these potential conflicts would not adversely influence the discussions or decisions of the Working Group.

2 References

2.1 Efficacy

The Group considered the following data supplied by Medsafe and pharmaceutical companies in their review of the efficacy of cough and cold medicines in children.

2.2 Safety

The Group considered the following data supplied by Medsafe and pharmaceutical companies in their review of the safety of cough and cold medicines in children.

3 Consideration of efficacy data

3.1 Summary of pharmacokinetic data

D Reith provided a presentation on the pharmacokinetics of cough and cold medicines in children.

The Group noted that the pharmacodynamics of a particular pharmaceutical is dependent on the concentration of the pharmaceutical in plasma, which is dependent on the pharmacokinetics of the pharmaceutical. The group therefore recognised that the effect of a cough and cold medicine in a child is dependent on the absorption, distribution, metabolism and elimination of the medicine by the child.

3.1.1 Absorption

The Group noted that absorption of a pharmaceutical can be affected by gastric pH, gut motility, food and the formulation of the pharmaceutical.

3.1.2 Distribution

The Group noted that protein binding and water composition are two major factors which affect the distribution of a pharmaceutical. Neonates have decreased concentration of plasma proteins and higher water composition relative to older children and adults, which results in higher volume of distribution. However after the neonatal period there are few differences related to age.

3.1.3 Metabolism

The Group noted that there are major changes in the expression of drug metabolising enzymes at different ages, particularly between birth and two years of age. Substances that are not metabolised due to limited enzyme expression result in greater effect and increased risk of overdose and adverse effects due to accumulation.

3.1.4 Elimination

The Group noted that renal function matures dramatically from birth. It reaches optimal function by 24 months of age and then follows a steady decline throughout adulthood. Hence there could be a relative decrease in the clearance of substances eliminated via the kidneys in very young children with immature renal function which could result in greater effect and increased risk of overdose and adverse effects due to accumulation. In children around two years of age with optimal renal function there could be a relative increase in the clearance of substances eliminated via the kidneys which could result in decreased effect.

The Group noted there are very few physiological-based developmental changes beyond two years of age. Changes in pharmacokinetics from two years of age into adulthood relate primarily to size and are scaled on the basis of weight or weight0.75 (allometric scaling).

3.1.5 Calculations of dosing for children

The Group noted that dosing for children traditionally has been calculated on the bases of weight, age, weight and age (in neonates) and surface area. Novel methods of calculating dosing for children include allometric scaling and physiologically-based modelling. The Group noted that some cough and cold medicines have dosing recommendations based on age categories, but children's weights can be highly variable within an age category. The Group noted that industry is currently investigating opportunities for conducting further pharmacokinetic studies.

3.1.6 Additional discussion

The Group discussed the value of allometric scaling, the effect of genetic polymorphisms on the metabolism of cough and cold medicines, the effect of health at birth on pharmacokinetics and the proposed pharmacokinetic studies.

3.1.7 Conclusions

The Group concluded that the pharmacokinetics (absorption, distribution, metabolism and excretion) and therefore pharmacodynamics of pharmaceutical substances in children change rapidly between 0 and 24 months of age and that it is possible that some changes may also occur beyond this age.

3.2 Summary of efficacy data

L Bryant provided a presentation on the evidence of efficacy of cough and cold medicines in children.

The Group noted that the common cough/cold is a self-limiting condition and that symptoms often improve without treatment. Therefore the best comparator when assessing the efficacy of cough and cold medicines is placebo.

The Group considered data supplied by Medsafe and the pharmaceutical companies. Some data provided by the sponsors was unpublished and was reviewed with caution as it had not been peer-reviewed.

The Group noted the limitations of the available studies. There were systematic reviews of cough and cold medicines available, but none with an associated meta-analysis. Many of the randomised controlled trials involving cough and cold medicines were limited by bias - lack of blinding, lack of power (number of participants), lack of objective diagnosis, objective outcomes and source. Most of the studies reviewed were carried out before the adoption of Good Clinical Research Practice Guidelines in 1996.

The review of efficacy of cough and cold medicines explored the outcome of symptom relief (and time period) in children aged less than six years and in children aged between six and twelve years. Efficacy data in adults were not considered in this review.

In the absence of provision of data for ipecacuanha (expectorant), pholcodine (antitussive), xylometazoline (decongestant), promethazine and triprolidine (antihistamines) the Working Group had to assume there was no evidence of efficacy as the onus was on the sponsor to provide such data.

3.2.1 Expectorants/mucolytics

The Group noted there was currently inadequate data from high quality randomised trials to show evidence of benefit of expectorants/mucolytics in the treatment of the symptoms of the common cough/cold in children less than twelve years old. The Group agreed that it would be appropriate to further investigate the efficacy of bromhexine at the next meeting.

3.2.2 Antihistamines

The Group noted there was currently inadequate data from high quality randomised trials to show evidence of benefit of antihistamines in the treatment of the symptoms of the common cough/cold in children less than twelve years old.

3.2.3 Decongestants

The Group noted there was currently inadequate data from high quality randomised trials to show evidence of benefit of oral decongestants in the treatment of the symptoms of the common cough/cold in children less than twelve years old. The Group agreed that it would be appropriate to further investigate the efficacy of topical decongestants at the next meeting.

3.2.4 Antitussives (cough suppressants)

The Group noted there was currently inadequate data from high quality randomised trials to show evidence of benefit of antitussives in the treatment of the symptoms of the common cough/cold in children less than twelve years old.

3.2.5 Alternative treatments

The Group reviewed the available data regarding the efficacy of topical nasal anticholinergics, nasal saline, honey and lozenges as alternative therapies to treat the common cough/cold. The reviews concluded that there is currently no evidence to support the use of topical nasal anticholinergics for symptomatic control of non-specific cough in children, the use of topical nasal saline could be included as a treatment adjunct for the symptoms of chronic rhinosinusitis and further research into the area of treating children with chronic non-specific coughs with honey and/or lozenges is needed.

3.2.6 Additional discussion

The Group discussed the pathophysiology of the disease process of the common cough/cold in children relative to adults and the difference between no evidence of efficacy versus evidence of non-efficacy.

The Group was informed that further studies are being undertaken by industry, and are expected to be complete in 2011. While the group perceived there may be ethical difficulties for these studies in New Zealand, there are studies currently underway in the United States where the FDA in collaboration with the sponsors have initiated a program to study medicines in children.

The Group also discussed the development of new chemical entities for the treatment of the common cough/cold.

3.2.7 Conclusions

The Group noted there was currently inadequate data from high quality randomised trials to show evidence of benefit of expectorants, antihistamines, oral decongestants and antitussives in the treatment of the symptoms of the common cough/cold in children less than twelve years old.

The Group noted that further studies involving cough and cold medicines are underway in the United States with completion expected in 2011. The majority of members of the Group wished to make a recommendation based on the evidence currently available and did not wish to delay their recommendation pending completion of these studies.

The Group considered that extrapolation of efficacy data from adults would not be appropriate since there are differences in the disease process between adults and children.

The Group agreed that it would be appropriate to further investigate the efficacy of mucolytics (bromhexine) and topical decongestants at the next meeting.

The Group considered it would be appropriate to consider the efficacy and safety of alternatives such as complementary alternative medicines that may be used in the place of cough and cold medicines in children at the next meeting.

4 Consideration of Safety data

4.1 Summary of safety data

R Savage provided a presentation on the safety of cough and cold medicines in children, with a focus on New Zealand poisons and adverse reaction data.

The presentation considered the severity (rather than seriousness) of the adverse effects and the likelihood of harm.

The Group noted that adverse effects with cough and cold medicines can occur as a result of adverse reactions and interactions at therapeutic doses, accidental ingestion by a child resulting in overdose, medication/dosing errors by parents and prescribers resulting in unintentional overdose or deliberate overdose.

Information sources used in the review of safety data included non-randomised trials, observational studies, meta-analyses and major reviews, published case series, data from national and international spontaneous adverse reactions centres, data from national and international poisons centres and individual case safety reports from pharmaceutical companies. Placebo-controlled randomised trials were obtained for this review, however none of the studies retrieved had safety end points.

4.1.1 Expectorants/mucolytics

The Group noted that the known adverse effects to guaifenesin include GI discomfort, nausea, vomiting and urolithiasis (with abuse). The known adverse effects to ipecacuanha include GI discomfort, vomiting, haemorrhagic erosions, cardiotoxicity and abuse. The known adverse effects to bromhexine include hypersensitivity reactions, rash, anaphylaxis, headache, dizziness, sweating, GI effects and hepatic effects including transient increases in serum transaminases.

4.1.2 Antihistamines

The Group noted there are six chemical groupings of antihistamines; alkylamines, monoethanolamines, ethylenediamines, phenothiazines, piperazines and piperidines. The Group noted that older generation antihistamines have a broad spectrum of adverse reactions.

The Group noted that the common adverse effects to sedating antihistamines include CNS depression, drowsiness to deep sleep, incoordination, paradoxical stimulation, headache, psychomotor impairment, antimuscarinic effects, and GI effects such as nausea, vomiting, diarrhoea and epigastric pain. Rare adverse effects to sedating antihistamines include palpitations and arrhythmias, rashes, hypersensitivity reactions, photosensitivity, convulsions and blood disorders including agranulocytosis and haemolytic anaemia. The Group noted that the known effects of antihistamine overdose in children include CNS stimulation, ataxia, excitement, psychoses, hallucinations, convulsions, hyperpyrexia and tachycardia.

4.1.3 Decongestants

The Group noted that the known adverse effects to decongestants include cardiovascular effects such as hypertension, palpitations, tachycardia and arrhythmias; CNS stimulation effects such as insomnia, tremor and hallucinations; and hypersensitivity reactions. The Group noted that the known effects of decongestant overdose include excitement, nervousness, GI effects, nausea, ataxia, hallucinations, convulsions and tachycardia.

4.1.4 Antitussives

The Group noted that the known adverse effects to dextromethorphan and pholcodine include anaphylaxis, rash, constipation and CNS effects such as drowsiness, fatigue, dizziness, dystonia, psychosis, hallucinations, serotonin syndrome, drug abuse and respiratory depression. The Group noted that the known effects of antitussive overdose in children include excitation, confusion, extrapyramidal effects and respiratory depression.

4.1.5 Non-substance-specific safety data

The Group noted there is no reliable denominator data for poisons centre data and individual case safety reports (ICSRs - adverse reaction reports). In addition, data obtained from poisons centres and ICSRs are limited by incomplete reporting.

4.1.5.1 Poisons data

United States

Data from the American Association of Poisons Control Centres showed that over a seven and a half year period, the number of 'contacts, exposures or cases' for OTC cough and cold medicines in children under twelve years of age was 774,960. The reports included decongestants (48%), antihistamines (42%), antitussives (32%) and expectorants (9%). The Group noted that only a small proportion of subjects experienced serious reactions.

The Group noted that reasons for exposure to cough and cold medicines in children less than twelve years of age included inadequate measures to keep medicines out of the reach of children (including inappropriate storage and temporary opening) and therapeutic/medication errors (including incorrect dose, confused units of measure, more than one medicine containing the same ingredient, healthcare professional iatrogenic, ten-fold dosing error and incorrect form or concentration given and dispensed).

The Group noted that reasons for fatal exposure to cough and cold medicines in children less than twelve years of age included adverse reactions, intentional misuse, malicious intent, therapeutic error, unintentional general and unknown reason.

The Group noted that dispensing errors need to be addressed in the discussions of the Working Group.

United Kingdom

The Group noted that there were 100,000 calls received for OTC cough and cold medicines by the UK National Poisons Information Centre over a four year period. The Group also noted that 230 children were admitted to hospital in the UK over a one year period, following consumption of cough and cold medicines.

New Zealand

The Group noted the data provided by the New Zealand National Poisons Centre of cases requiring medical referral. The Committee noted that the greatest proportion of childhood reports (0-16 years of age) was in the two to six year age group. The Group noted that medicines implicated were mostly single ingredient antihistamine preparations primarily indicated for allergy, including Phenergan® (81), Histafen® (50), Polaramine® and Polaramine® Reptabs (37), Sudomyl® (15) and isolated cases of exposure to other medicines.

4.1.5.2 ADR reports to regulatory authorities / pharmacovigilance centres

The Group noted that most of the fatalities with cough and cold medicines in the US, Canada and Australia involved children under two years of age, with serious reactions at therapeutic doses occurring in children over the age of two years.

United Kingdom

The Group noted that serious reports involving cough and cold medicines in children under twelve years of age included a total of 397 reports for nasal decongestants, antihistamines, expectorants and antitussives. The Group noted that the main suspected adverse reactions were CNS related, with the exception of reports involving expectorants, where hypersensitivity was the main suspected adverse reaction.

Canada

The Group noted that 76% of Canadian reports of OTC cough and cold medicines involved children under six years of age (111 out of 145), with fatalities reported only in children under two years of age.

United States

The Group noted that the US AERS database at the time of the report contained 9 fatal reports with decongestants in children between two and six years of age and 28 fatal reports with antihistamines in children between two and six years of age.

The Group noted that deaths and serious CNS, cardiac and respiratory events have occurred with therapeutic doses and overdose.

The Group noted that convulsions were more common in children over the age of two years and more common after therapeutic doses than overdose, while serious cardiac and respiratory events occurred more often after overdose.

New Zealand

The Group noted that there are 44 reports in the Centre for Adverse Reactions Monitoring database associated with cough and cold medicines in children aged 18 years and below. The Group noted that the majority of the reports were allergic or CNS adverse effects. The Group noted that 8/44 reports involved serious reactions (two reports involved children two years of age and older). The Group noted that less than 25% of the reports in children involved overdose, however this may be underestimated as CARM does not usually receive data regarding overdose in ADR reports. The Group noted that seven cases in children involved hospitalisation, including one life-threatening reaction (pulmonary oedema in a six year old male who overdosed with phenylephrine). The Group noted that no childhood deaths involving cough and cold medicines have been reported in New Zealand.

4.1.5.3 Company ICSRs

The Group considered safety data submitted by sponsors, including individual case safety reports.

4.1.6 Additional discussion

The Group discussed the safety concerns of other over-the-counter medicines in children relative to concerns with cough and cold medicines, the safety profiles of various generations of antihistamines and whether suspected adverse effects could be a result of the disease itself or cough and cold medicines.

4.1.7 Conclusions

The Group noted that fatal reports of ADRs or overdose involving cough and cold medicines are very rare in children over two years of age.

The Group noted that serious ADR reports involving cough and cold medicines are rare in children over two years of age and there is widespread use of these medicines.

The Group noted that anaphylaxis is common to all the substances, while cardiovascular and CNS reactions are less likely with bromhexine and possibly guaifenesin. The inclusion of several substances with similar potential adverse effects in one medicine may increase the risk of these side effects in some children.

The Group noted that causes of overdose are of concern, but accidental childhood ingestion may often involve preparations purchased for adults, especially in New Zealand.

The Group was asked to consider whether contraindicating cough and cold medicines in children under six years of age would lead to more dosing errors if parents continue to give these medicines to their children.

The Group requested that a review of the number of reports with ibuprofen compared with cough and cold medicines be considered for the next meeting.

5 Benefit-Risk Balance

5.1 Factors to be considered

D Reith provided a presentation on the factors to be considered before assessing the benefit-risk balance of the use of cough and cold medicines in children.

5.1.1 Efficacy

The Group was asked to consider whether efficacy has been demonstrated in the target population in comparison with placebo and/or an active comparator, whether there are suitable alternative treatments and the severity of the condition being treated and its natural disease process.

5.1.2 Safety

The Group was advised to consider the adverse event profile in the target population, the serious adverse events (as well as non-serious events) and tolerability.

5.1.3 Benefit-Risk Profile

The Group was asked to focus on the following when assessing the benefit-risk profile

6 Consensus on Overall Position

The Chair summarised the data presented, suggesting that there is inadequate evidence of efficacy of expectorant/mucolytic-, antihistamine-, decongestant- and antitussive-containing cough and cold medicines in children under the age of twelve years. The Chair also noted that there are a small number of cases of potentially serious adverse reactions involving these medicines in children over the age of two, particularly antihistamines but there may be an exception for bromhexine and topical nasal decongestants.

The Group considered that cough and cold medicines have been used for many years and noted that there may be a public perception of safety and efficacy of these medicines. The Group noted that the reporting rate for serious adverse reactions involving cough and cold medicines in children in New Zealand was very low however this is not surprising as many of the adverse reactions are similar to symptoms of the common cough and cold and the reporting rate for all over-the-counter medicines is very low. The Group also considered whether any risk is acceptable in the patient population involved.

The Chair requested that each member of the Group consider the information that had been provided during the meeting and the opinions of the professional bodies they represent and individually comment on the use of cough and cold medicines in children, particularly in the two to under six years age group and the six to twelve year age group. Each member was provided with the opportunity to comment on the use of cough and cold medicines in children.

6.1 Group Consensus

6.1.1 Age Group: 2 to under 6 years

A consensus was not reached among members.

The majority of members considered a contraindication of cough and cold medicines containing expectorants/mucolytics, antihistamines, decongestants and antitussives in children under six years of age to be appropriate. However some members considered that no changes were required based on the available data and data expected following completion of further studies which are underway.

6.1.2 Age Group: 6 to 12 years

A consensus was not reached among members.

The majority of members considered the reclassification of cough and cold medicines containing experctorants/mucolytics, antihistamines, decongestants and antitussives to remove them from General Sale to be appropriate. The issue of reclassification should be directed to the Medicines Classification Committee which involves public consultation.

Some members considered that no changes were required based on the available data and data expected following completion of further studies which are underway.

6.1.3 Request for further data and consideration

The Group requested that more efficacy and safety data relating to bromhexine and topical decongestants be brought to the next meeting for further consideration.

The Group requested that comparator safety data of over-the-counter ibuprofen in children be brought to the next meeting for discussion.

7 Closing remarks

7.1 Recommendations to Medsafe

No actions have been recommended to Medsafe at this time. Any recommendations from the first meeting will be confirmed at the second meeting and made official in the minutes of the second meeting of the Cough and Cold Review Group.

7.2 Date of next meeting

The date for the second meeting of the Cough and Cold Review Group was confirmed as being 18 August 2009.

7.3 Agenda for next meeting

The Chair noted that one item on the agenda for the first meeting of the Cough and Cold Review Group was not addressed due to time constraints. This item will be discussed at the second meeting.

Matters to be discussed at the second meeting of the Cough and Cold Review Group include:

The Chair recommended that experts be invited to the next meeting to advise the Group on how best to communicate the issue and any changes to healthcare professionals and the general public.

The Chair thanked the members and the Medsafe observers for their attendance and closed the meeting at 1.15pm.