Download Department for Transport - Over-the

Department for Transport - Over-the-counter medicines and the potential for unwanted sleepiness (No.24)
Over-the-counter medicines and the potential for
unwanted sleepiness (No.24)
Table of contents
Executive Summary
Chapter 1:
Introduction
Chapter 2:
Sedating, Classical H 1 -receptor Antihistamines
Brompheniramine
Chlorpheniramine
Clemastine
Cyproheptadine
Diphenhydramine
Diphenylpyraline
Doxylamine
Pheniramine
Promethazine
Triprolidine
Cinnarizine
Cyclizine
Meclozine
Piperazine
Buclizine
Conclusions
Chapter 3:
Non-sedating, H 1 -Receptor Antihistamines
Acrivastine
Cetirizine
Levocabastine
Loratadine
Conclusions
Chapter 4:
-1-
Department for Transport - Over-the-counter medicines and the potential for unwanted sleepiness (No.24)
H 2 -Receptor Antihistamines
Cimetidine
Famotidine
Ranitidine
Conclusions
Chapter 5:
Opioid Analgesics and Antimotility Drugs
Codeine
Dihydrocodeine
Loperamide
Morphine
Conclusions
Chapter 6:
Muscarinic Antagonists
Hyoscine
Chapter 7:
Possible Drug Interactions
Antihistamines
Opioid Analgesics
Antimuscarinics
Chapter 8:
Cautionary and Advisory Labels
BNF Recommendations on Labelling and Road Safety
Chapter 9:
Conclusion
Chapter 10:
Summary of Key Points
Appendix 1
Appendix 2
Bibliography
Executive Summary
This report identifies those medicines available over the counter (OTC) that have the potential to cause
drowsiness, and therefore the potential to be hazardous to drivers and other road users. We identified a
total of 102 medicines for the treatment of coughs and colds, allergies, pain, nausea and gastrointestinal
upsets, all with the potential to cause sedation.
These medicines fall into three main groups, antihistamines (of which there are three sub-groups), opioids
and muscarinic antagonists. From the literature it is clear that the antihistamines cause the most sedation.
One sub-group, the classical H 1 -receptor antihistamines are particularly sedating, and are even used for
the relief of temporary sleep disturbance in some instances. The impairment caused by the recommended
doses of at least two of these drugs is greater than that caused by the legal blood alcohol concentration
-2-
Department for Transport - Over-the-counter medicines and the potential for unwanted sleepiness (No.24)
limit for driving in this country.
Each class of drug was reviewed individually. We looked at its structure and function, pharmacokinetics,
sedating properties and its effect on performance. Although some of the drugs reviewed do not usually
cause sedation at the recommended dose, if taken above the recommended dose then sedation is possible.
The elderly are particularly vulnerable to the sedative effects of these drugs. In old age, renal dysfunction
develops. The excretion rate of these drugs decreases and drug accumulation occurs within the body.
Recommended doses of drugs that normally do not cause impairment, will begin to cause drowsiness and
affect performance in these people. Many of the medicines we examined do not carry specific warnings
for the elderly.
The interactions between drugs were also considered. The majority of the reviewed substances enhanced
the sedating effect of ethanol. A person impaired in this way, but still legally allowed to drive, is a
potential hazard to themselves and other road users. It is highly likely that people will combine several
OTC drugs for the treatment of an ailment. It is often the belief that as medicines contain different
compounds they will not have an additive sedating effect; this is not the case.
Representative OTC preparations were purchased for each class of drug. We investigated the labelling on
these medicines, warning the consumer of potentially sedative effects. This labelling was not consistent.
Several medicines that were recommended by the British National Formulary (BNF) to have such
labelling, had none on the packaging. Even within classes of medicine there appears to be no labelling
consistency. Several mentioned drowsiness as a side effect on the package insert, but no mention of this
was made on the exterior packaging. The labelling of OTC medicines liable to cause drowsiness, needs to
be more closely monitored.
Chapter 1:
Introduction
In the area of road safety there has been ample investigation into alcohol and driving. Through
government campaigns, public awareness has risen and drink driving has become socially unacceptable.
There is increasing knowledge and public awareness of the effect of sleepiness and fatigue on driving.
However, the role of non-prescription, over-the-counter (OTC) medicines that contain sedating substances
has not been thoroughly investigated. Public awareness of their potentially hazardous effects is low.
Medications containing sedative substances include systemic cough and decongestant preparations,
anti-allergy medications including treatment for hayfever and urticaria, analgesics, anti-nausea
preparations, worm treatments, and preparations used for the treatment of gastrointestinal disturbances. A
summary of all the medications available is given in the appendix.
OTC medications often contain several agents. In this report we have concentrated on the ingredients
which have the potential to cause sedation. The active ingredients in the majority of these medications fall
into a group of drugs called the antihistamines. Antihistamines block the action of histamine, a substance
present in the body that amongst other things is involved in the inflammatory response associated with
allergies. There are three types of histamine receptor present in the body, namely H 1 , H 2 and H 3 .
Consequently, there are different types of antihistamine which act on these receptors. For the purpose of
this report we will class them as classical H 1 -receptor antihistamines, newer second-generation
-3-
Department for Transport - Over-the-counter medicines and the potential for unwanted sleepiness (No.24)
H 1 -receptor antihistamines, and H 2 -receptor antihistamines. The H 3 -receptors are not associated with
any OTC medicine that causes sedation.
As histamine is involved with the human sleep-wake mechanism in the brain, any antihistamine that
penetrates the blood brain barrier, into the CNS, has the potential to alter a person’s state of alertness.
There are two other groups of substances that have been found to cause sedation and are available OTC.
These are the opioids, that are used as analgesics and also as an anti-motility treatment, and a muscarinic
antagonist, used against nausea. For the purpose of this report we have broken down the available
medications into their generic drug groups, with each chapter based on one of the above classes of
substances. We have presented each generic drug individually, reviewing the literature available on its
structure and function, pharmacokinetics, its sedative effects and impairment of performance.
As well as reviewing the literature available on these potentially sedating substances, we have also looked
at their possible interactions with other medications. We purchased representative medications from each
of the generic drug groups. This allowed us to look closely at the packaging of these medicines, and to
review the information provided to the consumer about their sedative properties.
It is very difficult to monitor the amount of OTC medication being taken by the general public. Some
medications are available for night-time use only, due to their sedative effects, including those specifically
for the relief of temporary sleep disturbance. However, there are other medicines containing a similar
amount of the same generic drug which are available for daytime use. As well as their sedative properties,
the effect on individual performance tasks (e.g. vigilance) and ’real-life’ multi-tasks (e.g. driving) must be
taken into consideration. These two effects are not necessarily manifestations of the same
pharmacological effect, and therefore may occur in the absence of each other, or at different drug
concentrations.
This report provides a review of the current knowledge available on OTC medications and their sedative
and performance impairing properties in relation to driving. There are very few studies which look at
actual driving performance; therefore, laboratory testing on tasks relevant to driving have also been
reviewed. The report identifies possible areas of research.
Chapter 2:
Sedating, Classical H 1 -receptor Antihistamines
The older generation, classical histamine H 1 -receptor antagonists are well known to have sedating
properties, with some worse than others. Fifteen of these sedating antihistamines are present in OTC
medicines; we have identified 59 medicines in this category. There are 32 cough and decongestant
preparations, nine anti-allergy treatments, four anti-nausea treatments, seven analgesics, two worming
treatments and five treatments for the relief of temporary sleep disturbance. The latter group of
preparations is included briefly in this report to provide a comparison. This enables us to compare a
quantity of generic medicine known to cause sedation (used as a sleep inducer), with the quantity of the
same medicine in other OTC preparations.
The H 1 histamine receptors are located throughout the CNS and periphery. The classical antihistamines,
whilst acting on the peripheral histamine receptors, also penetrate the blood brain barrier and act on the
CNS receptors, causing varying levels of sedation as an unwanted side effect, except in those preparations
-4-
Department for Transport - Over-the-counter medicines and the potential for unwanted sleepiness (No.24)
used for the relief of temporary sleep disturbance.
Table 2.1 summarises the preparations available OTC that contain these classical sedating antihistamines.
The dosage and labelling information of the medicines we obtained is included in this table.
Table 2.1 is available as an MS Word download from the foot of this page.
Brompheniramine
There are two brands of OTC medicine that contain brompheniramine: Dimotane and Dimotapp. Both are
available in several forms; Dimotane as Dimotane tablets/elixir/LA/ Expectorant/Co/Plus and Dimotapp
as Dimotapp, or Dimotapp LA (long acting). The recommended dose of brompheniramine is 4-8mg, three
to four times daily. There is no mention in the BNF for altering the dose in the elderly. Dimotapp LA is
administered 12mg at night and 12mg in the morning, slightly different from the recommended dose. The
BNF designated label ’number two’, i.e. ’Warning. May cause drowsiness. If affected do not drive or
operate machinery. Avoid alcoholic drink.’
Structure and Function
OTC medicines containing brompheniramine can be cough and decongestant preparations. It is a long
acting antihistamine, and in studies looking at its ability to suppress wheal and flare, suppression of wheal
was still present nine hours post dose, and suppression of flare was still significant up to 48 hours post
dose (Simons et al., 1982).
Pharmacokinetics
Brompheniramine reaches a peak plasma concentration in around 3.1 ± 1.1 hours (Simons et al., 1982).
It has an elimination half-life of around 24.9 ± 9.3 hours and a clearance rate of 6.0 ± 2.3 ml/min/kg.
The long half-life of brompheniramine suggests that it could be administered to adults once daily (Paton
& Webster, 1985), however the recommended dosing is three to four times daily.
Sedation and effect on Performance
Brompheniramine causes drowsiness, however there is little literature to support this. One study
investigated its effect on visuo-motor coordination. Performance was impaired for up to three hours post
administration of 4mg brompheniramine, and administration of a sustained release form (12mg) impaired
performance for one and a half hours (Nicholson, 1979).
Chlorpheniramine
The following drugs are available OTC and contain chlorpheniramine: Contac 400, Dristan tablets,
Expulin, Galpseud Plus, Haymine, Piriton Allergy tablets/syrup, Boots Allergy Relief and Antihistamine
Tablets, Calimal and Lemsip Flu Strength Nightime. The recommended dose is 4mg every four to six
hours; maximum daily dose 24mg. This dosage is used in Piriton Allergy. However, some medicines
containing chlorpheniramine are long acting, for example Contac 400, which should be taken once in the
morning and once at bedtime (one Tab, 4mg). It is a slow release product with action over 24 hours. There
is no different dose stated for the elderly. Again the BNF recommends label number two: ’Warning. May
-5-
Department for Transport - Over-the-counter medicines and the potential for unwanted sleepiness (No.24)
cause drowsiness. If affected do not drive or operate machinery. Avoid alcoholic drink.’
Structure and Function
Chlorpheniramine is not a specific histamine H 1 -receptor antagonist; it has been shown to modulate
monoamine transmitters, and inhibit the uptake of serotonin, noradrenaline and dopamine. It has a much
lower affinity for peripheral -adrenoceptors and muscarinic receptors than for H 1 -receptors. Centrally,
chlorpheniramine has a higher affinity for H 1 -receptors compared with muscarinic sites (Nicholson et al.,
1991).
Pharmacokinetics
Chlorpheniramine is a long acting antihistamine. It is absorbed slowly and reaches a peak concentration in
around 2.8 hours. An 8mg dose of chlorpheniramine was found (Huang et al., 1982) to have a mean peak
plasma concentration of 17.9ng/ml. In the same study a mean elimination half-life of 28 hours was stated.
The pharmacokinetics of this drug, i.e. long half life and prolonged oral absorption, suggest that there is
no need to administer the drug chronically every four to six hours, and that accumulation may occur.
Excretion of chlorpheniramine was mainly through urine, with an average of 67% excreted this way
(Huang et al., 1982).
Sedation and effects on Performance
Chlorpheniramine has been shown to induce sedation and impair performance. One study in which dosage
mirrors that of everyday treatment (4mg four times daily for four weeks), found that 86% of participants
subjectively reported drowsiness after chlorpheniramine compared to 34% after placebo. This is a
significant increase in drowsiness, although those fewer participants reporting drowsiness after placebo
reported a greater level of sedation than those reporting drowsiness after chlorpheniramine (Weiler et al.,
1988). Another study that investigated the sedating properties of enantiomers (same elements, slightly
different structures in space, classed as + or -) of chlorpheniramine found that whilst 10mg (-)
chlorpheniramine showed no difference from placebo in sleep latency or subjective sleepiness, 10mg (+)
chlorpheniramine produced a reduction in sleep latency (time taken to fall asleep) one-and-a-half hours
post dose, and an increase in subjective sleepiness one-and-a-half and three hours post dose (Nicholson et
al., 1991). (+) Chlorpheniramine was also found to impair performance on digit symbol substitution tasks
at these times.
As stated above, there are no recommended alterations to the normal adult dose for administration to the
elderly. A recent study comparing the effects of old and new antihistamines on healthy elderly volunteers,
found that 8mg chlorpheniramine impaired cognitive processing and caused subjective sleepiness (Simons
et al., 1999). The authors found that there was less difference between the sedating effects of old and new
antihistamines in the elderly compared with younger adults.
Clemastine
Clemastine was a prescription only medication until 1992 (Schran et al., 1996). However, there are now
two brands of OTC medicine that contain clemastine: Tavergil and Aller-eze. Tavergil comes in both
tablet and elixir form, and Aller-eze is available as Aller-eze and Aller-eze Plus (clemastine combined
with phenylpropanolamine, a decongestant). The recommended dose of clemastine is 1mg twice daily,
-6-
Department for Transport - Over-the-counter medicines and the potential for unwanted sleepiness (No.24)
increased up to 6mg daily if required. Aller-eze follows this dosage recommendation, with each tablet
containing 1mg clemastine. Aller-eze Plus tablets, however, only contain 0.5mg but are taken every six
hours up to four times daily. Therefore, levels in the plasma are unlikely to be as high as those after each
dose of Aller-eze, so there may be less chance of sedation with the lower more frequent dosing. Again,
there is no difference in dosage for the elderly compared with other adults, and the BNF recommends
label number two: ’Warning. May cause drowsiness. If affected do not drive or operate machinery. Avoid
alcoholic drink.’
Strucure and Function
Clemastine is a benzhydryl ether with a marked antihistaminic activity, but has minimal effect on
acetylcholine receptors and is said to have minimal depressant side effects (Schran et al., 1996). It is often
given in combination with phenylpropanolamine, which is a nasal decongestant and acts via -adrenergic
receptors to cause vasoconstriction.
Pharmacokinetics
Clemastine has a fast onset and long duration of action (up to 12 hours). It has a moderate absorption rate,
and is almost totally absorbed into the gastrointestinal tract. The study by Schran et al., (1996) found a
mean peak plasma concentration of 0.58 ± 0.25 ng/ml/mg approximately 4.8 ± 1.3 hours (range 2-6
hours) after administration of 2mg clemastine, with a mean elimination half-life of 21.3 ± 11.6 hours.
Administration of clemastine with food did not increase the variability or otherwise affect plasma
concentration. Around 60-70% of clemastine is eliminated via urine (5% of which is unchanged
clemastine), the other 30-40% is eliminated via bile as metabolites. Neither food ingestion nor
administration with phenylpropanolamine alters the clearance rate of clemastine (Schran et al., 1996).
Sedation and the effects on Performance
Early studies do not suggest that clemastine produces any severe deterioration in performance
(Hindmarch, 1976; Hindmarch & Parrott, 1978). The reason for this lack of effect may be explained by a
study in 1975 which found that clemastine produced maximal impairment and drowsiness five hours post
dose (Peck et al., 1975); effects which may have been missed in the above studies. Administration of 1mg
clemastine produced impairment of visuo-motor coordination three hours (P<0.05) and five hours
(P<0.01) post dose, due to its slow absorption (Clarke & Nicholson, 1978). More recent reports have
indeed shown that clemastine induces drowsiness and impairs performance (Gaillard et al., 1988; Hopes et
al., 1992). Gaillard et al’s study evaluated performance at a reaction time task and a tracking task. The
latter was carried out twice - initially performed alone, and then simultaneously with a continuous
memory task. Administration of clemastine led to a decay in performance on the tracking task whether
performed alone or in conjunction with the continuous memory task. However, there was no significant
loss in performance at the memory task itself. This suggests that central processing and memory are not
affected by clemastine. There was no significant effect of clemastine on reaction time. It appears that
clemastine affects the processes involved in fast and continuous perceptual-motor co-ordination (Gaillard
et al., 1988). This study also asked subjects to fill out several visual-analogue-scales, which determined
mood and mental state. Subjects felt drowsier after taking clemastine and could correctly determine that
they had been given an active drug.
-7-
Department for Transport - Over-the-counter medicines and the potential for unwanted sleepiness (No.24)
In addition to investigating performance, Hopes et al. (1992) looked at EEG as an objective measure of
drowsiness. They found a decrease in vigilance after consumption of 2mg of clemastine, compared with
ebastine (a second generation antihistamine), along with impairment of psychomotor performance,
drowsiness and impairment of some cognitive processes. A study of the pharmacokinetics of clemastine
(Schran et al., 1996), found that around 20% of the participants reported feelings of drowsiness after
taking the drug.
Cyproheptadine
There is only one drug available OTC which contains cyproheptadine. It is the anti-allergy drug Periactin,
also used to treat migraine. The recommended dose for symptomatic relief of an allergy is usually 4mg
three to four times daily, with daily doses ranging from 4-20mg per day. The maximum daily dose is
32mg. For treatment of migraine, 4mg are given with a further 4mg after 30 minutes if necessary.
Maintenance is with 4mg given every four to six hours. There is no dose variation stated for the elderly,
although Merck Sharp & Dohme Ltd (not the BNF) do not recommend the use of Periactin by elderly
debilitated patients (Merck Sharp & Dohme Limited, 2000). Again, the BNF recommends label number
two: ’Warning. May cause drowsiness. If affected do not drive or operate machinery. Avoid alcoholic
drink.’
Structure and Function
Cyproheptadine as well as being an antihistamine is a serotonin antagonist. The literature on the structure
and function of cyproheptadine is plentiful; however, the majority of it is based on animal studies and
there is no literature available specifically on cyproheptadine and its function in humans.
Pharmacokinetics
Again, as with structure and function, the literature available does not contain information on the
pharmacokinetics of cyproheptadine in humans.
Sedation and the effects on Performance
Cyproheptadine is known to cause sedation, and it is a very common side effect of treatment, although, as
with other classical antihistamines after continuous treatment for around three or more days, drowsiness
may disappear, due to tolerance to the drug.
Diphenhydramine
Diphenhydramine is the most common sedating antihistamine available in OTC form. There are 14
different brands available to the public. Nine of these are systemic cough and decongestant preparations.
These include: Benylin (six types: chesty cough, with codeine, cough and congestion, dry cough, four flu
and day and night cold and flu relief), Bronalin expectorant, Covonia night-time formula, Guanor
Expectorant, Histalix, Nirolex for night-time coughs, Uniflu with gregovite C, Boots night-cold comfort
and Flurex bedtime. There are four brands that are available OTC sold for relief of temporary sleep
disturbance: Dreemon, Medinex, Nytol and Panadol Night. The remaining brand is Propain, which also
contains codeine and is an analgesic. The BNF does not state a recommended dose for diphenhydramine,
however the following doses have been recommended:
-8-
Department for Transport - Over-the-counter medicines and the potential for unwanted sleepiness (No.24)
Benylin Four Flu - 20ml (25mg), four times daily (100mg max in 24 hours).
Covonia Night Time Formula - 15ml (30mg) to be taken at bedtime, repeated six hours later if necessary
(therefore maximum dose 60mg).
Propain - One or two tablets (5-10mg) taken with water every four hours. Do not exceed ten tablets in 24
hours (50mg). Each tablet also contains 10mg codeine and 50mg caffeine.
Nytol - two tablets (50mg) twenty minutes before bedtime.
The recommended daily dose of Nytol (a treatment for the relief of temporary sleep disturbance), is less
than the recommended maximum daily dose of some of the other medications containing
diphenhydramine. In particular, the maximum daily dose of Benylin Four Flu, a medication ’suitable for
daytime use’ is 100mg, in 25mg doses. The BNF recommends warning label two: ’Warning. May cause
drowsiness. If affected do not drive or operate machinery. Avoid alcoholic drink.’
Structure and Function
Diphenhydramine is an ethanolamine-derivative antihistamine. It has marked anticholinergic and sedative
effects.
Pharmacokinetics
A recent study compared the effects of diphenhydramine in the young and elderly of both sexes (Scavone
et al., 1998). The mean ages of the test groups were: young men, 30.4y ± 5.8; elderly men, 64.3y ±
1.8; young women, 29.4y ± 2.4; elderly women, 70.1y ± 1.2. No significant effects of age or gender
were observed for any of the pharmacokinetic variables. Below, we shall give those stated for the young
men, as the majority of other studies are performed on this age group and gender. A maximum plasma
concentration of 35.3 ± 4.2 ng/ml was reached 2.1 ± 0.4 hours post administration of 25mg
diphenhydramine. The elimination half-life was calculated as approximately 4.1 ± 0.3 hours. Another
study, which also looked at the effect of low-dose oestrogen oral contraceptives in women, found that they
caused no significant changes on the pharmacokinetics of 50mg diphenhydramine (Luna et al., 1989).
There have been differences found in the pharmacokinetics of diphenhydramine between Caucasian and
Oriental people (Spector et al., 1980). Orientals, after administration of a 50mg dose, had plasma levels
approximately half that of Caucasians, although the half-life was similar. Because of this, Orientals appear
to be less affected by sedation or performance impairment.
Sedation and the effects on Performance
Diphenhydramine is well known to induce sedation and drowsiness. It has been found to increase tension
and anxiety and decrease vigour and activity. An increase in fatigue and symptoms of sleepiness,
drowsiness, mental and physical sedation and lowered ability to concentrate post-diphenhydramine
ingestion have been reported (Rice & Snyder, 1993). In the same study, self-reports of sleepiness were
higher after diphenhydramine ingestion than placebo, and enhancement of the post-prandial dip was
evident. Subjective reports of sleepiness were still present three hours after 50mg diphenhydramine
ingestion, and fatigue was still present after seven hours. An earlier study reported similar findings with
50mg diphenhydramine, producing significant feelings of drowsiness for up to six hours post-ingestion
-9-
Department for Transport - Over-the-counter medicines and the potential for unwanted sleepiness (No.24)
(Gengo et al., 1989). Mental impairment and drowsiness in this study produced parallel changes with
diphenhydramine concentrations, although drowsiness occurred at a lower threshold (nearly half the
concentration) than mental performance impairment. This suggests different manifestations of the same
pharmacological effect (Gengo et al., 1989).
As well as causing drowsiness and sedation, diphenhydramine (50mg) impairs performance of a number
of tasks. Psychomotor tests such as choice reaction time, tracking, hand steadiness and divided attention
have been found to cause impairment in comparison with placebo, peaking at three hours post ingestion
(Witek et al., 1992). The impairment and sedation caused by diphenhydramine becomes less apparent
upon chronic administration of the drug. One study administered 50mg diphenhydramine three times daily
for three days (Schweitzer et al., 1994). By the third day subjects had clearly developed a tolerance to the
drug, shown by a decrease in sleepiness and performance impairment.
There have been a few studies investigating the effect of diphenhydramine on driving performance. One
study compared the effect in laboratory studies of task performance with ’off road’ driving on a closed
circuit, after consumption of 25, 50 and 100mg diphenhydramine (Cohen et al., 1984). The authors found
that the ’off road’ driving was insensitive to the effects of any dose of diphenhydramine, whereas the
laboratory tasks were impaired at all doses. The study concluded that assessing the effect of drugs with
’off road’ driving could create negative results, which could lead to a potentially dangerous drug being
marketed without adequate warnings. A more recent paper compared the effects of diphenhydramine
(50mg) and alcohol (approx. 0.1% blood alcohol concentration, legal limit in UK is 0.08%) on
performance in a driving simulator for one hour (Weiler et al., 2000). Participants’ driving performance
was poorer after diphenhydramine, and was greater than that produced by a blood alcohol level well
above the legal limit. The authors also found that subjective feelings of drowsiness were a poor indicator
of performance impairment, which suggests that after consumption of antihistamines a patient should not
use drowsiness as an indicator as to whether they are fit to drive. The results of this last study have strong
implications for the availability of diphenhydramine OTC and the labelling on the packaging of such
medicines. The variability of the central effects produced in the above studies, emphasises the importance
of strictly controlled laboratory testing.
Diphenylpyraline
Eskornade is the only OTC medicine that contains diphenylpyraline. It is a systemic cough and
decongestant preparation. However, it is a fairly old product and not stocked by many pharmacists. The
BNF recommends warning label number two: ’Warning. May cause drowsiness. If affected do not drive
or operate machinery. Avoid alcoholic drink.’ There is very little literature available on diphenylpyraline
regarding both its pharmacokinetics and effects on sedation and performance.
Structure and Function
No literature is available on the structure and function of diphenylpyraline.
- 10 -
Department for Transport - Over-the-counter medicines and the potential for unwanted sleepiness (No.24)
Pharmacokinetics
No literature is available on the pharmacokinetics of diphenylpyraline.
Sedation and the effects on Performance
No literature is available on the effect of diphenylpyraline on sedation and performance.
Doxylamine
Three OTC medicines contain doxylamine: Vicks Medinite (a cold and flu treatment), and two medicines
that are analgesics: Boots Tension Headache Relief and Syndol. The BNF does not recommend specific
doses of doxylamine; however, the stated doses of two of these medicines are listed below:
Vicks Medinite - 30ml (7.5mg) at bedtime.
Syndol - One or two tablets (5-10mg) every four to six hours as needed for relief. Do not exceed eight
tablets (40mg) per day. Syndol tablets should not be taken continuously over prolonged periods using the
maximum dose. (Each tablet also contains 10mg codeine and 30mg caffeine.)
There is no recommended warning label stated by the BNF.
Structure and Function
Doxylamine is an antihistamine with hypnotic, anticholinergic and local anaesthetic effects. There is very
little literature available on this antihistamine, especially relating to its sedative effects and performance
impairment.
Pharmacokinetics
Doxylamine has been shown to reach a peak plasma concentration of approx. 99 ± 6 ng/ml, 2.4 ± 0.2
hours post ingestion of 25mg (Friedman & Greenblatt, 1985). In the same study an elimination half-life of
10.1 ± 0.4 hours and plasma clearance of 217ml/min was calculated. There was still some doxylamine
present (21ng/ml) 24 hours post dose. Around 60% of doxylamine is excreted unchanged in urine. As with
diphenhydramine, in women, the clearance rate is not affected by low-dose oestrogen oral contraceptives
(Luna et al., 1989). In women there is no difference in the pharmacokinetics for the young and the elderly.
However, in men the elderly have reduced plasma clearance and a prolonged drug half-life. Therefore, the
doses should be reviewed for this group (Friedman et al., 1989).
Sedation and the effects on Performance
There appears to be very little literature on the effect of doxylamine on performance and the levels of
sedation caused by its administration.
- 11 -
Department for Transport - Over-the-counter medicines and the potential for unwanted sleepiness (No.24)
Pheniramine
There is only one OTC product available containing pheniramine. This is the cough and decongestant
preparation, Triominic. However, we have been unable to obtain this product and there are no
recommended doses or labelling stated in the BNF.
Structure and Function
Pheniramine is in the alkylamine group of antihistamines, which are noted for producing less sedative
effects than other older antihistamines (Buckley et al., 1994). Since the introduction of newer, second
generation antihistamines the advantage of using pheniramine over the older antihistamines has become
negligible. Pheniramine is one of the most widely overdosed antihistamines available OTC, and has been
stated to be a drug of abuse (Buckley et al., 1994).
Pharmacokinetics
Oral administration of 30.5mg pheniramine produces a peak plasma concentration of between
173-274ng/ml 1-2.5 hours post dose (Witte et al., 1985). In the same study the elimination half-life of
pheniramine ranged from 16-19 hours. Between 33.4% and 43.3% of pheniramine is excreted unchanged
in urine, and a further 24.3-43.6% is excreted as a metabolite, N-desmethyl pheniramine.
Sedation and the effects on Performance
There is no literature available relating to pheniramine and its effect on sedation and performance
impairment.
Promethazine
Promethazine has been marketed as an OTC drug in the UK since 1985 (Adam & Oswald, 1986). There
are five OTC brands that contain promethazine. Two are cold and flu treatments: Medised and Night
Nurse. One is an allergy treatment, Phenergan, which is available in tablet and elixir form, and also as
Phenergan Nightime. Another, Sominex, is for the relief of temporary sleep disturbance. The remaining
product, Avomine, is an anti-nausea and vertigo preparation. The BNF’s recommended dose of
promethazine is 25mg at night, increased to 25mg twice daily if necessary, or 10-20mg two to three times
daily. All the drugs, with the exception of Avomine, are given at a dose at or below these
recommendations. Avomine packaging states up to four 25mg tablets in a day. The recommended dose of
Sominex is 20mg (promethazine) before going to bed. Sominex is marketed specifically as a sleep
inducer, unlike the other OTC medicines containing promethazine. The recommended dosage of
promethazine in Sominex is lower than in the majority of the other OTC medicines, indicating that
although not marketed as sleep inducers they may cause greater sedation than Sominex. Again, the BNF
recommends label number two: ’Warning. May cause drowsiness. If affected do not drive or operate
machinery. Avoid alcoholic drink.’
- 12 -
Department for Transport - Over-the-counter medicines and the potential for unwanted sleepiness (No.24)
Strucure and Function
Promethazine is a member of the phenothiazine group of drugs. It is potent and long acting, with a
duration of action of up to 12 hours. In addition to its antihistamine effects it is also an anti-emetic,
centrally sedative and anticholinergic. Promethazine is a relatively low dependence drug and there are
very few reports of abuse. It is classed as a hypnotic, and the majority of the medicines (above) work by
sedating the patient, and are only supposed to be used prior to bedtime, not during the day.
Pharmacokinetics
Absorption of promethazine from the gastrointestinal tract exceeds 80% in the majority of patients
(Taylor et al., 1983). After administration of 25mg promethazine orally, peak plasma concentrations of
2.4-18.0ng/ml were achieved between 1.5 and 3 hours post-administration. This study gave an elimination
half-life of 12.2 ± 2.19 hours, and a clearance rate of 1.14 ± 0.41 l/min; less than 1% of the
promethazine was eliminated unchanged in urine (Taylor et al., 1983).
Sedation and the effects on Performance
Promethazine (25mg) when taken at bedtime causes subjectively faster sleep onset, and an improvement
with the quality of sleep (Hindmarch & Parrott, 1978). It has highly sedative effects, and in a recent study,
30mg promethazine decreased activity levels (monitored by actimetry) significantly during the daytime,
with an increase in ’sleep-like’ activity (Hindmarch et al., 1999). In the same study, a significant
reduction in critical flicker fusion threshold was seen, which was still evident 12 hours
post-administration.
Administration of 10mg promethazine impaired performance on visuo-motor coordination tasks up to five
hours post ingestion (P<0.001; Clarke & Nicholson, 1978). Other studies investigating promethazine’s
effect on psychological performance found after administration of 12.5mg or 25mg, significant
impairments in psychomotor performance, information processing and feelings of alertness. This
impairment was maximal three to four hours post-dose, with performance returning to near normal eight
to nine hours post-dose (Parrott & Wesnes, 1987). It is also clear that there is a linear relationship between
the degree of impairment on pursuit performance and reaction time tasks, with promethazine
concentration (Kotzan et al., 1986). One study looked at the impact of promethazine on human
performance and compared it with that of alcohol. Unfortunately, administration of 25mg promethazine
was by intra-muscular injection and not orally, and was likely to have a slightly greater effect. It produced
performance decrements equivalent to a blood alcohol concentration of 0.085% (legal limit 0.08%). A
50mg promethazine injection was equivalent to a blood alcohol concentration of 0.137% (Cowings et al.,
2000).
Administration of the recommended dose of promethazine (25mg twice daily), seriously impairs
performance. After several days’ consumption patients may well become tolerant to its sedative and
performance impairment effects. Nevertheless, careful monitoring of initial promethazine administration
is recommended as, with a long duration of action, the chronic administration of promethazine at these
recommended doses could lead to increased plasma levels and a performance impairment similar to that
of alcohol intoxication.
- 13 -
Department for Transport - Over-the-counter medicines and the potential for unwanted sleepiness (No.24)
Triprolidine
There are two OTC brands that contain triprolidine: Actifed (available as expectorant or compound
linctus) and Sudafed Plus. The recommended dose of triprolidine is 2.5mg three to four times daily (every
four to six hours) with a maximum dose of 10mg in 24 hours. Again the BNF recommend label two:
’Warning. May cause drowsiness. If affected do not drive or operate machinery. Avoid alcoholic drink.’
Structure and Function
There was no literature on the structure and function of triprolidine.
Pharmacokinetics
Administration of 5mg triprolidine (twice the individual dose) produces a peak plasma concentration of 13
± 11ng/ml 1.91 ± 0.77 hours post administration. The elimination half-lives range between 1-14 hours
with a mean of 4.6 ± 4.3 hours (Cohen et al., 1985a). A more recent study (Miles et al., 1990) looked at
the pharmacokinetics of 2.5mg triprolidine, and found a peak plasma concentration of 5.6 ± 2.9ng/ml,
2.0 ± 1.2 hours post-dose. However there was no recorded data for half-life, although it should be
similar to that of 50mg triprolidine.
Sedation and effects on Performace
Triprolidine produces drowsiness and impairs performance. Both objective (continuous EEG recording
over two days) and subjective measures have shown that triprolidine produces more daytime sedation and
drowsiness than placebo (Stanley et al., 1996). Another study stated that 2.5mg and 5mg triprolidine
produced subjective sleepiness 1.5 hours post-dose, and 5mg was still producing an effect at three hours
post-dose (Cohen et al., 1985b). There have been several studies looking at the effect of triprolidine on
performance tasks. Cohen et al. also found impairment of adaptive tracking 1.5 hours post both doses, and
3.5 hours post the 5mg dose. Also, there was increased reaction time after 1.5 hours with both doses and
after three hours with 5mg (Cohen et al., 1985b). A study by Nicholson (1979) looking at visuo-motor
co-ordination reported that 2.5mg triprolidine had a near immediate effect on performance, lasting for up
to three hours. He also investigated a sustained release preparation containing 10mg triprolidine, which
produced performance impairment from 1.5 hours to 5 hours post-dose. Auditory vigilance impairment
has also been recorded one to two hours post-dose. With 5mg triprolidine this effect was still present six
to seven hours post-administration. Higher doses of triprolidine also impair digit symbol substitution
(Peck et al., 1975). Kerr et al. found impairment of critical flicker fusion and reaction time after 10mg
triprolidine; equivalent to that caused by a blood alcohol concentration of 0.05%. Although below the UK
legal limit, it is equivalent to the legal limit in many other countries (Kerr et al., 1994).
There have been two studies looking at the effect of triprolidine on actual driving performance. One study
(Brookhuis et al., 1993) monitored the effect of 10mg triprolidine on driving performance in actual traffic.
The authors found a significant increase in weaving and the subjects were slower at responding to
manoeuvres of a lead car. Betts et al. (1984) reported that driving performance impairment was found in a
group of experienced women drivers after triprolidine administration. Even though they knew their
performance was impaired, they were unable to correct their driving up to normal standards.
- 14 -
Department for Transport - Over-the-counter medicines and the potential for unwanted sleepiness (No.24)
Cinnarizine
There is one OTC medicine available that contains cinnarizine. It is called Stugeron and is used for the
control of vestibular disorders such as vertigo, tinnitus, nausea and vomiting, or can be used as a treatment
for motion sickness. The recommended dose of Stugeron for vestibular symptoms is 30mg (two tablets)
three times daily. For treatment of motion sickness the recommended dose is 30mg two hours before
travel, then 15mg every eight hours during the journey if necessary. Dosage for the elderly is the same as
for adults. Stugeron should preferably be taken after meals. The BNF recommends label number two
again: ’Warning. May cause drowsiness. If affected do not drive or operate machinery. Avoid alcoholic
drink.’
Structure and Function
Cinnarizine is a piperazine derivative, and as well as being an antihistamine it is able to inhibit
vasoconstrictor responses, due to its ability to block calcium entry into smooth muscle
(Castañeda-Hernández et al., 1993).
Pharmacokinetics
One study looked at the pharmacokinetics of both single and multiple dosing. However, each individual
dose was 75mg, and greater than any recommended dose. A single 75mg oral dose gave a maximum
plasma concentration of 275 ± 35.9 ng/ml, 3.0 ± 0.45 hours post-dose, and a elimination half-life of
23.6 ± 3.16 hours (Castañeda-Hernández et al., 1993). In the multiple dosing study 75mg of
cinnarizine was administered twice daily for 15 days. It was clear that the cinnarizine accumulated in the
body over this period. On day 15, an increased maximum plasma concentration of 739 ± 162.1 ng/ml
was produced after a similar time to that of single dosing (3.2 ± 0.49 hours).
Sedation and effects on Performance
There is relatively little literature on the sedating effect of cinnarizine and its effect on performance.
However, we did find one study which looked at the effect of 30mg cinnarizine on psychomotor
performance, information processing and feelings of alertness. Impairment in all these areas was maximal
five to six hours post-drug, and performance was still impaired eight to nine hours post-drug (Parrott &
Wesnes, 1987).
Cyclizine
There is one OTC drug available that contains cyclizine, called Valoid Tablets. They are used for the
treatment of nausea, vomiting, vertigo, motion sickness and labyrinthine disorders. The recommended
dose of cyclizine is 50mg up to three times daily. The BNF recommends label number two again:
’Warning. May cause drowsiness. If affected do not drive or operate machinery. Avoid alcoholic drink.’
- 15 -
Department for Transport - Over-the-counter medicines and the potential for unwanted sleepiness (No.24)
Structure and Function
There is little literature on cyclizine. As well as antihistaminic activity, it also has some anticholinergic
activity which may well play a part in its antiemetic effects. It is a derivative of piperazine.
Pharmacokinetics
We found no literature relating to the pharmacokinetics of cyclizine.
Sedation and effects on Performance
At the recommended dose of cyclizine (50mg), there are reportedly no significant effects on performance
or increases in subjective levels of sedation (Hamilton et al., 1982). However, this study did show that
twice the recommended dose (100mg) of cyclizine made subjects feel drowsier, and also impaired
performance, with increased reaction time.
Meclozine
Sea-legs is the only brand of meclozine on sale to the general public. It used for the treatment of motion
sickness. The recommended dose is two tablets (25mg) the night before, or one hour before travel. Only
25mg should be taken in 24 hours. The BNF recommends label two: ’Warning. May cause drowsiness. If
affected do not drive or operate machinery. Avoid alcoholic drink.’
Strucure and Function
The literature available on meclozine is fairly sparse. It is a H 1 histamine receptor antagonist and like
cyclizine, also has antimuscarinic activity.
Pharmacokinetics
No literature was available on the pharmacokinetics of meclozine.
Sedation and effects on Performance
Administration of 25mg of meclozine four times daily has been found to significantly increase subjective
levels of drowsiness compared with placebo. However this is four times the recommended daily dose.
Levels of drowsiness do reduce with chronic administration, but drowsiness is still significantly greater
seven days after starting the treatment (Schmitt & Shaw, 1986). Another study looking at the
administration of a single 50mg dose (twice the recommended dose) produced increased levels of
drowsiness, which were greatest seven hours post-dose (Manning et al., 1992). Impairment in
performance of choice reaction time and digit symbol substitution tasks was also found in this study, with
the greatest impairment occurring nine hours post-dose.
- 16 -
Department for Transport - Over-the-counter medicines and the potential for unwanted sleepiness (No.24)
Piperazine
Piperazine is used for the treatment of threadworm and roundworm infections. It is available in the form
of Pripsen, in both elixir and powder form. For the treatment of threadworms the recommended dose of
elixir is 15ml (2.25g) once daily for seven days, or the recommended dose of powder is one sachet (4g),
repeated after 14 days. For the treatment of roundworms the recommended dose of elixir is 30ml (4.5g) as
a single dose, with a repeat dose after two weeks; the recommended dose of powder is one sachet (4g)
repeated at monthly intervals for up to three months. The BNF does not recommend any labelling for this
compound.
Strucure and Function
No literature was found on the structure and function of piperazine.
Pharmacokinetics
No literature was found on the pharmacokinetics of piperazine.
Sedation and the effects on Performance
No literature was found on the effect of piperazine on sedation and performance; however, the BNF only
states drowsiness as a side effect in patients with neurological or renal abnormalities.
Buclizine
There is one OTC drug that contains buclizine, namely Migraleve. It also contains codeine. Migraleve is
an analgesic used for the treatment of migraine. Two types of tablet come in each packet: Migraleve Pink
containing 6.25mg buclizine and 8mg of codeine, and Migraleve yellow containing just 8mg codeine. The
recommended dose of Migraleve is two pink tablets (12.5mg buclizine, 16mg codeine) to be swallowed at
the first sign of a migraine attack. If the migraine persists then two yellow tablets (16mg codeine) should
be taken every four hours, after the pink dose. No more than eight tablets (two pink, six yellow) should be
taken in 24 hours. The BNF recommends label two: ’Warning. May cause drowsiness. If affected do not
drive or operate machinery. Avoid alcoholic drink.’
Strucuture and Function
No literature was found on the structure and function of buclizine.
Pharmacokinetics
No literature was found on the pharmacokinetics of buclizine.
- 17 -
Department for Transport - Over-the-counter medicines and the potential for unwanted sleepiness (No.24)
Sedation and the effects on Performace
The drowsiness warnings on the packet of Migraleve refer only to the pink tablets that contain buclizine.
However, we found no literature on the sedating and performance impairment effects of buclizine.
Conclusions
The classical H 1 -receptor antihistamines are the largest and best known group of OTC medicines that
produce sedation and performance impairment. All have recommended labelling warning against the
possibility of drowsiness, and the avoidance of driving or operating machinery if it does occur. It is clear
from the above review that all 15 of the classical antihistamines available OTC do indeed have sedative
effects. The level and duration of sedation or performance impairment varies between each antihistamine.
Some have fairly long half-lives. However, if their recommended dosage is repeated every few hours, this
may lead to an accumulation of the drug in the blood. Some medicines specifically for night-time use have
sleep-inducing properties; however, they also produce a serious hangover of impaired performance and
daytime sleepiness (Hindmarch, 2000). Some of the medications recommended for daytime use have more
active ingredient in them than those medications administered specifically for the relief of sleep
disturbance. With chronic use, the majority of these antihistamines lead to tolerance after three or four
days, producing a decrease in the level of sedation and performance impairment. This may in part be due
to the relief of symptoms by the antihistamines, improving the patient’s general wellbeing and
performance. It is advisable to inform patients that they may initially experience side effects, which will
possibly disappear with continued treatment. Many medicines include this information in their package
inserts.
Classical H 1 -receptor antihistamines are probably not as safe for widespread use as consumers and
healthcare professionals believe them to be, especially in the elderly. Although inexpensive and cost
effective, given the potential harm they may not be the medication of choice. The widespread use of
diphenhydramine, chlorpheniramine and other old H 1 antagonists in the elderly needs to be evaluated
(Simons et al., 1999). Renal dysfunction and neurological degeneration are prevalent in this population;
both of which lead to an increased likelihood of impairment and sedation.
There have been some studies comparing the more prevalent antihistamines with the effect of alcohol. At
the recommended doses, both diphenhydramine and promethazine impair performance to a greater extent
than the legal limit of alcohol for driving in this country, yet both are freely available OTC. There is a
high chance that a patient will consume above the recommended dosage, causing an even greater amount
of sedation and impairment.
Chapter 3:
Non-sedating, H 1 -Receptor Antihistamines
These second-generation antihistamines have appeared more recently than the classical antihistamines.
They were primarily developed to try to reduce the incidence of sedation present with classical
antihistamines when treating allergic conditions and urticaria. Four of the non-sedating antihistamines are
available to the general public; generically these are acrivastine, cetirizine, levocabastine and loratadine.
Between them there are six brands available (see Table 3.1), all of which are classed as prescription only
- 18 -
Department for Transport - Over-the-counter medicines and the potential for unwanted sleepiness (No.24)
medicines. However, the public can buy up to ten days supply without prescription (except levocabastine,
that has a restriction on volume). These drugs have been shown to provide a symptomatic relief equivalent
to that of the older classical antihistamines, but without their undesired side effects (Woodward, 1990).
The BNF places acrivastine, cetirizine and loratadine under the sub-heading of Nonsedating
Antihistamines. This statement is somewhat misleading as they are not totally free from sedative effects.
Under laboratory conditions the recommended doses of these antihistamines do not produce drowsiness;
however, there is other evidence to suggest that sedation may still occur at doses which may control a
patients allergic symptoms (Mattila & Paakkari, 1999).
Table 3.1 is available as an MS Word download from the foot of this page.
Acrivastine
The two available OTC brands of acrivastine are Semprex and Benadryl Allergy Relief, both of which are
anti-allergy treatments. Both are prescription only medication; however, the public can purchase up to ten
days supply without prescription. The BNF states that the incidence of sedation is low; however, it does
state that pharmacists should counsel/advise patients that drowsiness can occur and that it may affect
performance of skilled tasks (e.g. driving). Despite this, there is no recommended labelling stated for the
packaging and insert. The recommended dose of acrivastine is 8mg, three times daily. It should not be
given to the elderly as there have been no studies as yet with this age group, and they are likely to be more
susceptible to side effects.
Structure and Function
Acrivastine is a derivative of the sedating antihistamine triprolidine; it contains an acrylic acid side chain
ortho to the pyridine ring nitrogen atom. The acrylic acid group decreases the lipophicity of acrivastine
compared to triprolidine, and therefore reduces its penetration into the CNS, reducing sedation
(Balasubramanian et al., 1989). This reduction in sedation does not alter the antihistaminic activity
compared to that of triprolidine (Cohen et al., 1985b), as this is achieved by the antihistamine acting on
peripheral H 1 histamine receptors.
Pharmacokinetics
Acrivastine is a short acting antihistamine. It reaches a peak plasma concentration of approx. 150ng/ml
1.5 hours post administration of 8mg (Wellcome UK, 1999). It has a short plasma half-life of only 1.5
hours. Therefore, to maintain sufficient plasma levels for therapeutic efficacy it is administered three
times daily (Balasubramanian et al., 1989). The principal route of elimination of acrivastine is by renal
excretion.
Sedation and effects on Performance
One study comparing acrivastine to the classical antihistamine triprolidine, found that no dose of
acrivastine tested produced a significantly different result from placebo in behaviour or drowsiness,
although the maximum dose tested was 4mg, which is less than half the recommended dose (Cohen et al.,
1985b). Higher doses show that acrivastine has minimal CNS effects. Administration of 16mg, but not
8mg, was found to impair real driving performance. Therefore, the recommended dose of 8mg three times
- 19 -
Department for Transport - Over-the-counter medicines and the potential for unwanted sleepiness (No.24)
daily should not be sedating in healthy adults, due to acrivastines short duration of action (Mattila &
Paakkari, 1999).
Cetirizine
Zirtek is the only OTC medicine containing cetirizine. Like the two medicines containing acrivastine, it is
a prescription only medication that can be bought by the general public as long as only ten days supply is
purchased. As with acrivastine, pharmacists must advise patients on the risk of drowsiness and its possible
effect on performance (e.g. driving). Once again, there is no labelling recommended by the BNF for the
packaging. The BNF does state that the incidence of sedation is low. The recommended adult dose for
cetirizine is 10mg daily or 5mg twice daily. There is no research which suggests that it should not be
given to the elderly; however, in patients with renal dysfunction the dose should be reduced to half the
daily amount.
Structure and Function
Cetirizine is a carboxylated metabolite of hydroxyzine (a prescription-only sedating antihistamine). It is
present in Zirtek in the form of cetirizine hydrochloride. The recommended daily dose (10mg) produces
the same antihistaminic effect as 25mg (recommended dose) of hydroxyzine; however, it does not have its
sedative effects. This reduction in sedation is due to a combination of its polar property which reduces its
penetration of the blood brain barrier, and cetirizines high specificity for H 1 -histamine receptors
(hydroxyzine is not specific to histamine receptors; Mattila & Paakkari, 1999).
Pharmacokinetics
Cetirizine is absorbed rapidly and is poorly metabolised. Therefore, it has a rapid onset and prolonged
duration of action (Spencer et al., 1993). Its peak plasma concentration is reached within one hour of
administration. Peak plasma concentrations after the recommended dose of 10mg were found to be 257
± 148 ng/ml in a study looking at 12 young adult males (Gengo et al., 1987). When twice the
recommended dose was taken (20mg) a peak plasma concentration of 580.4 ± 203 ng/ml was reached.
Administration of cetirizine after food delays this rate but does not appear to affect the extent of
absorption (Baltes, 1988). The plasma half-life of cetirizine ranges from 6.5-10 hours (Spencer et al.,
1993), and varies slightly with the amount of drug given. Gengo et al.s study stated a duration of 6.6 hours
for 10mg and 7.7 hours for 20mg (Gengo et al., 1987). In the elderly, the half-life of cetirizine increases to
up to 25 hours (Woodward, 1990). This increase is probably dependent on renal impairment rather than
age per se (Spencer et al., 1993). Cetirizine is eliminated from the body mostly unchanged in urine (90%;
Mattila & Paakkari, 1999).
Sedation and effects on Performance
The literature on the effects of cetirizine on performance and its sedative effects is very inconsistent.
Some studies state that cetirizine does not produce any sedation or performance impairment at any
concentration tested (up to 20mg; Gengo et al., 1987). In one study administration of six times the
recommended dose (60mg) for seven days produced one volunteer (out of 25) who complained of fatigue
after the first cetirizine dose. This resolved itself and administration continued for the rest of the trial with
no repeat of the adverse effect (Sale et al., 1994). The direct measurement of daytime sleepiness following
5-20mg cetirizine, with EEG assessment, found these concentrations to be non-sedating. However, the
- 20 -
Department for Transport - Over-the-counter medicines and the potential for unwanted sleepiness (No.24)
study suggests that chronic partial sleep loss (imposed by many adults on themselves to meet social
pressures) could, when combined with a slightly sedating drug, cause an increase in sedation. The
combination of a sedative drug with illness-disrupted sleep (as is highly common with allergy sufferers)
could undoubtedly put some patients at high risk when driving (Seidel et al., 1990).
Other studies have found sedation after administering cetirizine. A review by Spencer et al. (1993)
reported on a study that investigated 2,193 cases of cetirizine treatment. With 5mg of cetirizine per day
sedation occurred in 11% of the cases. As the dose increased so did the incidence of sedation. 10mg
produced a 15% incidence and 20mg a 21% incidence. Another study carried out specifically to assess the
safety of cetirizine for use by air personnel found that all 5, 10 and 15mg doses of cetirizine increased
subjective sleepiness up to 7.5 hours post-ingestion compared with placebo. The increase in subjective
sleepiness, however, was not as great as that for promethazine (classical antihistamine). They also found
that sleep latency was affected by cetirizine most in the mid-afternoon (i.e. enhancement of the
mid-afternoon dip) although tracking performance was impaired most in the early morning, after drug
administration (Nicholson & Turner, 1998). From these findings the authors concluded that cetirizine was
not free of central nervous system effects, and they did not recommend its use for treatment in air
personnel.
Studies investigating driving performance after the administration of cetirizine also produce conflicting
results. No significant impairment of performance was found in two studies which investigated the effect
of 5,10 or 20mg of cetirizine and 10mg/day for one to four days, on simulated and actual driving
performance (Gengo et al., 1990; Volkerts et al., 1992). Contrary to this, one study found a significant
impairment in driving performance after a single 10mg dose of cetirizine (Ramaekers et al., 1992). This
same study also monitored EEG activity during driving and found that after cetirizine administration,
electrocortical deactivation occurred. The consumption of alcohol whilst taking cetirizine should be
avoided as cetirizine enhances alcohols depressive effect on the CNS (Spencer et al., 1993). When a
patient takes cetirizine, they may be putting themselves at risk if they drive after the consumption of
alcohol, even if they are below the legal limit.
Levocabastine
There is one product containing Levocabastine which is on sale to the general public. It is a nasal spray
for the treatment of seasonal allergic rhinitis and is called Livostin. It is classed as a prescription only
medication; however, it can be sold to the general public if supplied for the symptomatic relief of seasonal
allergic rhinitis in adults and children over 12 years, subject to a maximum strength of 0.05%
Levocabastine and a pack size of 10ml. The recommended dose is two sprays in each nostril twice a day,
extending to three to four times per day if necessary. The BNF does not recommend any labelling,
although it does state that fatigue and drowsiness have been reported as side effects of the drug.
Structure and Function
As well as being available as a nasal spray it is also used ocularly for the treatment of conjunctivitis.
Administration of the recommended dose (0.2mg) has been found to provide protection against allergens
up to 24 hours post-dose (Corren et al., 1999).
- 21 -
Department for Transport - Over-the-counter medicines and the potential for unwanted sleepiness (No.24)
Pharmacokinetics
Levocabastine has a fast onset and long duration of action. Administration of 0.2mg levocabastine
produces a peak plasma concentration of 1.4-2.2µg/l between one and two hours post-dose (Heykants et
al., 1995). It has an elimination half-life of 35-40 hours (Simons & Simons, 1999). Approximately 70% is
excreted unchanged in urine (Heykants et al., 1995).
Sedation and effects on Performance
We were unable to find much literature on the effects of levocabastine on sedation and performance. One
review paper stated that the incidence of adverse effects with levocabastine therapy is low and similar to
that observed with placebo (Dechant & Goa, 1991). Another study which investigated its effects on
psychomotor and cognitive function found that both the recommended dose, and four times the
recommended dose, produced the same results as placebo (Rombaut et al., 1991).
Loratadine
Claritin allergy (tablets/syrup) and Boots Hayfever relief are the two OTC medicines available that
contain loratadine. Like the other second-generation antihistamine medicines they are both prescription
only medication, but can be purchased by the public in packets of up to ten days supply without
prescription. Again, the BNF states that incidence of sedation is low; however, pharmacists must counsel
patients on its possible sedating effects and that it may effect their ability to drive safely. Again, as with
the other second generation antihistamines, the BNF makes no recommendation for labelling on the
packaging and insert. The recommended dose of loratadine for adults is 10mg daily, and no specific
difference in dose is stated for the elderly.
Structure and Function
Loratadine is structurally related to the sedating antihistamine azatadine. It has a high affinity for
peripheral H 1 histamine receptors and a low affinity for those in the CNS. It is very specific to histamine
receptors producing little activity at both acetylcholine (Ach) receptors and 1 adrenoceptors (Clissold et
al., 1989). It is a poor penetrator of the blood brain barrier, although it is fairly lipid soluble, therefore a
small amount does enter the CNS (Marttila & Paakkari, 1999).
Pharmacokinetics
Loratadine is a long acting antihistamine (18-24 hours; Clissold et al., 1989), rapidly absorbed after a
single oral dose. It reaches a peak plasma concentration 1-1.5 hours postadministration (Clissold et al.,
1989; Mattila & Paakkari, 1999), with peak plasma concentrations of 5µg/l (10mg capsule), 11µg/l
(20mg capsule), 26µg/l (40mg capsule). Therefore, the Pharmacokinetics are dose proportional (Clissold
et al., 1989). Loratadine has a plasma (elimination) half-life of 8-11 hours. It is metabolised to
descarboethoxyloratadine (DCL) which is pharmacologically active and has a much longer half-life of 1724 hours (Clissold et al., 1989). Consumption of a high fat meal prior to taking loratadine increased the
bioavailability of the compound, but still within levels observed after no food ingestion as shown in other
trials (Nomeir et al., 1996). A study of normal geriatric volunteers showed that the clearance of loratadine
tended to be slower and it had a greater half-life, however, inter-individual variation within each age
group was greater than the age effect (Hilbert et al., 1988), due to renal impairment.
- 22 -
Department for Transport - Over-the-counter medicines and the potential for unwanted sleepiness (No.24)
Sedation and effects on Performance
Loratadine does not appear to impair psychomotor performance tasks, including driving, even with doses
of up to 40mg (Mattila & Paakkari, 1999; Clissold et al., 1989). Although a slight impairment was seen at
40mg it was not significant. Sedation however, has been seen to occur at doses greater than the
recommended daily dose (20 or 40mg), and slight dose-related changes in EEG have been observed after
10, 20 and 40mg of loratadine; changes represent 1mg reduced alertness (Mattila & Paakkari, 1999).
Clissold et al. recorded sedation in 8% of 2,500 patients taking loratadine compared to 6% of the placebo
group. These authors stated that in most studies there was no significant difference in the incidence of
loratadine induced sedation compared to that of placebo (Clissold et al., 1989). No study has found any
enhancement of alcohols CNS depressant effect after loratadine consumption.
Conclusions
The second-generation antihistamines are certainly less sedating than the classical antihistamines;
however, research has shown that they are not entirely free from sedating effects. Cetirizine appears to
have the worst sedating effect of the four compounds. The literature on its sedative effect is far from
conclusive. Several studies have identified drowsiness and performance impairment as an adverse effect,
and therefore one must conclude that it is not free of sedative effects. As with cetirizine, the literature on
acrivastine and levocabastine also show evidence of some sedation, but not as great as the former.
Loratadine appears to be the least sedative of the four, although, again, it is not totally free from sedative
effects.
Administration of these four substances at the recommended doses is unlikely to affect driving
performance; however, patients can purchase up to ten days supply (or 10ml in the case of Livostin). If the
drug is not having its desired anti-allergy effect, it is highly possible that patients will consume more than
the recommended daily dose, thus increasing the risk of sedation and driving performance impairment,
especially in the case of cetirizine. This is particularly likely when treating chronic idiopathic urticaria,
where doses higher than those used for the treatment of seasonal allergic rhinitis are generally used
(Hindmarch, 2000). Individual differences must also be taken into account, as certain people, especially
the elderly and those with renal dysfunction, are more susceptible to sedation. The nonsedating
antihistamine sub-section of the BNF containing three of these four substances is misleading. These
medications can cause sedation, and therefore should not be classed as non-sedating, perhaps with the
exception of loratadine.
Chapter 4:
H 2 -Receptor Antihistamines
There are three generic drugs available OTC which are H 2 histamine receptor antihistamines; these are
cimetidine, famotidine and ranitidine. There are only four medicines available OTC that contain these
drugs. All are used for the treatment of gastro-intestinal disturbances, for example heartburn, indigestion,
hyperacidity and dyspepsia. Table 4.1 summarises the OTC medicines available containing H 2 -receptor
antihistamines, and includes the recommended dosage and labelling information for the medicines that we
purchased.
- 23 -
Department for Transport - Over-the-counter medicines and the potential for unwanted sleepiness (No.24)
Table 4.1 is available as an MS Word download from the foot of this page.
Cimetidine
There is only one brand of cimetidine available OTC. It is called Tagamet 100, and is used to treat and
prevent indigestion and heartburn. The recommended dose for the relief of these conditions is two tablets
(200mg) when symptoms appear. If symptoms persist for more than one hour then two more tablets can
be taken. A maximum of four tablets may be taken in any four-hour period, with not more than eight
tablets being administered in a 24-hour period. The recommended dose for the prevention of heartburn at
night is one tablet (100mg) before bedtime, and for the prevention of heartburn after meals, two tablets up
to 30 minutes before a meal. There is no warning label against drowsiness recommended by the BNF,
however tiredness is mentioned as a side effect of H 2 -receptor antagonists.
Structure and Function
Cimetidine was the first H 2 -receptor antagonist to be marketed, and has poor penetration across the blood
brain barrier into the CNS.
Pharmacokinetics
We found one paper on the Pharmacokinetics of oral cimetidine. Administration of 400mg cimetidine
reached a peak plasma concentration of 2.01 ± 0.49 g/ml, 2.9 ± 1.0 hours postdose. An elimination
half-life of 2.4 ± 0.7 hours was found in the same study (Pritchett et al., 1988). A paper which looked at
intravenous injection of cimetidine found that 65-75% of cimetidine was excreted in urine; however, there
is a strong inverse relationship between age and the clearance of cimetidine, which is probably due to
renal dysfunction rather than age alone (Ostro, 1987).
Sedation and effects on Performance
The literature on the sedating and performance effects of cimetidine is controversial. One study
comparing cimetidine with diphenhydramine (H 1 -receptor antihistamine) found that 300mg cimetidine
did cause some drowsiness, although not to the level of 50mg diphenhydramine (Moscati & Moore,
1990). There have been several studies, however, which have found that up to 400mg cimetidine does not
have any significant effect on alertness or the performance of several psychomotor and cognitive tasks
(Levin et al., 1984; Thofilopoulos et al., 1984). One study states that cimetidine (up to 400mg dose) is
unlikely to impair performance and may be used by individuals involved in skilled activity (i.e. driving;
Nicholson & Stone, 1984). A more recent study investigating the effect of cimetidine on the elderly (mean
age 71.25 years), administered three different dosages (maximum 1,600mg) of cimetidine and found no
observable decrements in cognitive performance in any of its 12 volunteers (Oslin et al., 1999).
Famotidine
There are two available brands of famotidine available OTC, Pepcid AC (including Pepcid AC Chewable)
and Boots Excess Acid Control. They are used for the relief of heartburn, dyspepsia and hyperacidity
when sold OTC. The recommended dose of Pepcid AC for symptom relief is one tablet (10mg). For the
prevention of symptoms it is one tablet 15 minutes before eating, or one tablet one hour prior to an
- 24 -
Department for Transport - Over-the-counter medicines and the potential for unwanted sleepiness (No.24)
evening meal if the symptoms are expected to interfere with sleep. The dose can be repeated if symptoms
return, with up to a maximum of two tablets (20mg) being taken in a 24-hour period. There is no
recommended labelling stated by the BNF for famotidine, however tiredness is mentioned as a side effect
of H 2 -antagonists.
Structure and Function
Famotidine is around 20 times more potent than cimetidine and seven and a half times more potent than
ranitidine in the treatment of excess acid (Echizen & Ishizaki, 1991). It is slightly longer acting than both
cimetidine and ranitidine, with 40mg (twice recommended daily OTC dose) having a duration of effect of
approximately 9.9 hours (Bisson et al., 1993).
Pharmacokinetics
After oral administration of famotidine, peak plasma concentrations are reached within two to four hours
(Echhizen & Ishizaki, 1991). In one study, oral administration of 40mg (twice recommended daily dose)
led to a peak plasma concentration of 104 ± 39 ng/ml, 2.3 ± 1 hour post-dose. In the same study, an
elimination half-life of 3.6 ± 1.1 hours was calculated (Kroemer & Klotz, 1987). Another study,
investigating the Pharmacokinetics of 20mg of famotidine given intravenously, found that in healthy
participants around 72.3 ± 10.9% was excreted in urine (Takabatake et al., 1985). The authors also
found that patients with mild renal failure showed very similar pharmacokinetic data to healthy
individuals. Those with moderate renal failure had an increased elimination half-life of 4.72 hours, and
those with severe renal failure, 12.07 hours. Smoking does not alter the Pharmacokinetics of famotidine
(Baak et al., 1992).
Effects on Sedation and Performance
We found very few studies on the effects of famotidine on sedation and performance. However, there has
been one recent study which compared the 20mg of famotidine (given intra-muscularly) with 50mg
diphenhydramine (Watson et al., 2000). The authors found that famotidine was comparable to
diphenhydramine when used to treat pruitis and urticaria, but this did not show any of the signs of
sedation that are associated with diphenhydramine.
Ranitidine
There is only one product available OTC which contains ranitidine, it is called Zantac 75 and is used for
the relief of indigestion and heartburn. The recommended dose is one tablet (75mg) on presentation of
symptoms, repeating the dose if symptoms return. A maximum of two tablets (150mg) is recommended in
any 24-hour period. The BNF do not recommend any warning labels for ranitidine packaging, although
tiredness is stated as a side effect of H 2 -receptor antagonists.
Structure and Function
Ranitidine is six to eight times more potent than cimetidine (Richards, 1983).
- 25 -
Department for Transport - Over-the-counter medicines and the potential for unwanted sleepiness (No.24)
Pharmacokinetics
Oral administration of 150mg ranitidine (twice individual recommended dose) produced a bimodal pattern
of plasma concentration. There were two peaks, the first at 1.1 ± 0.4 hours and the second at 3 ± 0
hours; the elimination half-life was 2.3 ± 0.4 hours (van Hecken et al., 1982). In the elderly, and those
aged over 50, a significant increase has been seen in the peak plasma concentration and elimination
half-life of 150mg ranitidine given twice daily (Greene et al., 1986). Fairly similar differences (although
more severe) were seen in patients with renal dysfunction (Garg et al., 1986) Another study found no sex
differences in the Pharmacokinetics of ranitidine (Abad-Santos et al., 1996).
Effects on Sedation and Performance
Ranitidine (150mg; twice individual dose) has been found not to cause any subjective sedation in healthy
subjects (Levin et al., 1984; Theofilopoulos et al., 1984). When administered in conjunction with
chlorpheniramine (sedating antihistamine) it reduced the levels of sedation induced by the latter substance
(Khosla et al., 1993). There have been several studies looking at the effect of ranitidine on performance.
Concentrations up to 300mg (four times the individual recommended dosage sold OTC) do not appear to
produce any impairment on a number of psychomotor and cognitive tasks (Nicholson & Stone, 1984;
Theofilopoulos et al., 1984; Khosla et al., 1993).
One effect of ranitidine is that with regular administration it increases blood alcohol levels in social
drinkers (DiPadova et al., 1992; Arora et al., 2000). This has implications for driving, as consumption of
alcohol at normally safe levels could lead to impairment of performance at a level above that of the legal
blood alcohol concentration, leading drivers to believe they are under the limit when in fact they are not.
Conclusions
The H 2 -receptor antagonists available OTC appear to be fairly safe where road safety is concerned. The
recommended dosage of those medicines available OTC is fairly low compared with prescription only
medicine dosages. Although tiredness is stated as a side effect of these medications in the BNF there are
few studies that have found this to be the case. Cimetidine is the only one of the three medicines that has
produced any significant subjective drowsiness effect in trials. Therefore, ranitidine is recommended in
preference to cimetidine for those involved in skilled activity. Administration of these substances to the
elderly should be done with some caution, as renal dysfunction does cause an alteration in the
Pharmacokinetics of these medicines and if side effects are to occur then it would be more likely in this
group. Another area of caution is the administration of ranitidine in regular social drinkers. It causes an
increase in blood alcohol levels. If patients are not aware of this fact then they may well break the law
unknowingly, and their performance will be impaired by alcohol to a greater extent than they would
expect.
Chapter 5:
Opioid Analgesics and Antimotility Drugs
There are four opioid compounds available OTC which are antimotility drugs, three of which are also
used as analgesics. They are codeine, dihydrocodeine, morphine (opioid analgesics) and loperamide.
There are twenty-eight medicines available containing these substances. Codeine and dihydrocodeine are
- 26 -
Department for Transport - Over-the-counter medicines and the potential for unwanted sleepiness (No.24)
morphine-like substances, and are classed as weak opioid agonists, as both their analgesic and unwanted
effects are much less than those of morphine. Loperamide is a pethidine congener and is only used for its
action in the gut. All of these drugs penetrate the blood brain barrier into the CNS and are all stated to
have drowsiness as a side effect. Table 5.1 summarises the medicines available OTC containing opioids.
The recommended dosage and labelling of medicines that we purchased are also summarised.
Table 5.1 is available as an MS Word download from the foot of this page.
Codeine
We have identified 14 medicines available OTC that contain codeine. These are Boots Migraine Relief,
Boots Tension Headache Relief (also contains doxylamine), Cocodamol, Codis 500, Feminax (also
contains hyoscine), Migraleve (also contains buclizine), Panadeine, Panadol Ultra, Paracodol, Propain,
Solpadeine, Solpadeine Max, Syndol and Veganin. They are all used for the treatment of mild to moderate
pain. The BNF recommended dose for codeine is 30-60mg every four hours when necessary, to a
maximum of 240mg daily. However, the three medicines we looked at had dosages below this
recommended dose:
Migraleve (also contains buclizine in the pink tablets) 16mg per dose, maximum daily dose of 64mg.
Solpadeine Max 25.6mg per dose, maximum daily dose of 102.4mg.
Veganin 13.6mg per dose, maximum daily dose of 54.4mg.
The BNF recommends warning label number two: Warning. May cause drowsiness. If affected do not
drive or operate machinery. Avoid alcoholic drink.
Structure and Function
In most OTC medicines codeine is in the form of codeine phosphate. It is a centrally acting analgesic that
is habit forming and has the potential for abuse. Codeine is readily absorbed from the gastrointestinal tract
and distributes around the body to various tissues. It crosses the blood brain barrier, easily penetrating the
CNS. Codeine is toxic at doses above 240mg.
Pharmacokinetics
The majority of studies investigating the Pharmacokinetics of codeine use doses higher than the
recommended doses for OTC medicines. One study investigated the Pharmacokinetics of continuous
codeine administration over a two and a half-day period. Initially 60mg of codeine was administered
every four hours for the first three doses, and 30mg was administered every four hours thereafter for
twelve doses. After the first 60mg dose a maximum plasma concentration of 138.8 ± 59.4 ng/ml was
reached after 1.1 ± 0.6 hours. An elimination half-life of 2.6 ± 0.9 hours was calculated (Band et al.,
1994). In the same study, steady-state pharmacokinetic data were calculated after the subjects had
completed the course of administration. A steady-state maximum plasma concentration of 222.9 ± 48.9
ng/ml was obtained 1.1 ± 0.3 hours (post-second dose). A slightly slower elimination half-life of 2.3 ±
0.7 hours was calculated. Elimination of codeine is primarily via the kidneys and around 90% of a single
dose is excreted within 24-hours.
- 27 -
Department for Transport - Over-the-counter medicines and the potential for unwanted sleepiness (No.24)
Sedation and effects on Performance
Although the BNF recommends warning labels for drowsiness on codeine packaging, very few studies
have found sedating effects with codeine. The study by Band et al. (1994) found that eight out of the 13
subjects experienced sleepiness at some point in the study; however, this may be due to the fact that they
were administered codeine at 11pm, 3am and 7am, so they had a disturbed nights sleep. Another study
found that administration of up to 60mg of codeine had no detectable sedative activity (Redpath &
Pleuvry, 1982).
Studies investigating the effect of codeine on performance all found that, generally, codeine did not
impair performance. However, each study did find that codeine affected specific tasks. In one study,
administration of 100mg codeine failed to affect performance in objective tests administered 90 minutes
post-dose. These tests included body sway, digit symbol substitution, flicker fusion and Maddox wing.
However, subjectively they did find that 100mg codeine did make participants mentally slow
(Saarialho-Kere et al., 1986). A more recent study also found that 60mg and 120mg of codeine did not
impair performance. Mild subjective effects on mood were found, but these appeared not to be dose
related (Walker & Zacny, 1998). One study did find slight impairment of visuo-motor coordination after
administration of both 60mg and 90mg of codeine. Dynamic visual acuity was also found to be impaired
but only after the 90mg dose (Bradley & Nicholson, 1986). The authors suggest that impairment of
neuromuscular function, and not sedation, is the likely cause of any performance impairment seen.
Dihydrocodeine
There are only two drugs available OTC that contain dihydrocodeine. These are Boots Dental Pain Relief
and Paramol. They are both used for the treatment of moderate to severe pain. The recommended dosage
stated by the BNF is 30mg every four to six hours when necessary. However, the recommended dose of
Paramol is one or two tablets (7.46- 14.92mg) every four to six hours, with a maximum of eight tablets
(59.68mg) in any 24-hour period. The BNF recommends warning label number two: Warning. May cause
drowsiness. If affected do not drive or operate machinery. Avoid alcoholic drink.
Structure and Function
Dihydrocodeine is pharmacologically very similar to codeine, and has no substantial advantages or
disadvantages (apart from cost) over codeine.
Pharmacokinetics
Rowell et al. (1983) reported that oral administration of 30mg dihydrocodeine produces a peak plasma
concentration of 71.8 ± 11.8 µg/l, 1.60 ± 0.12 hours post-dose. In the same study, administration of
60mg dihydrocodeine produced a peak plasma concentration of 146 ± 20.7 µg/l, 1.82 ± 0.11 hours
post-dose. Elimination half-lives ranged from 3.3-4.5 hours. Renal dysfunction alters the
Pharmacokinetics of dihydrocodeine by increasing the time to peak plasma concentration and reducing the
rate of clearance, thus increasing the overall duration of action of the drug (Barnes et al., 1985). Despite
these findings, age does not appear to alter the Pharmacokinetics of single oral doses of dihydrocodeine
(Davies et al., 1989). In the same study and after multiple dosing of dihydrocodeine, there was a
significant increase in maximum plasma concentration in the elderly.
- 28 -
Department for Transport - Over-the-counter medicines and the potential for unwanted sleepiness (No.24)
Sedation and effects on Performance
We found very little literature relating to the effect of dihydrocodeine on sedation and performance
impairment. One paper that assessed performance, looked at the effect of 20mg dihydrocodeine by
subcutaneous injection for the relief of tourniquet pain. The dihydrocodeine did not impair performance of
a symbol cancellation test, which measures attention (Szekely et al., 1986). Another more recent paper
looked at the effect of administering 90mg dihydrocodeine. There was no significant impairment to
several performance tasks, including digit symbol substitution, critical flicker fusion and choice reaction
time. The authors also found no significant increase in sedation compared to placebo after the
dihydrocodeine administration (Webb & Kamali, 1998).
Loperamide
There are seven medicines available OTC that contain loperamide. They are Arrett Capsules, Boots
Diareze, Diasorb, Diocalm Ultra, Imodium (including Imodium Liquid), Imodium Plus and Normaloe.
These are all treatments for the rehydration in acute and chronic diarrhoea in adults. The BNF
recommended dose for acute diarrhoea is 4mg initially followed by 2mg after every loose stool for up to
five days. The usual dose is 6-8mg daily, maximum dose of 16mg daily. For the treatment of chronic
diarrhoea the recommended dose is 4-8mg daily in divided doses, subsequently adjusted according to the
response. Maximum dose of 16mg daily. Drowsiness is stated as a side effect of loperamide; however,
there is no warning label recommend by the BNF.
Structure and Function
Loperamide has a relatively selective action on the gastrointestinal tract. Around 85% of administered
loperamide can be found in the gut. It was approved for non-prescription use in 1988 (Litovitz et al.,
1997).
Pharmacokinetics
We found one study that investigated the Pharmacokinetics of loperamide. Administration was a single
8mg dose in either capsule or syrup form. Peak plasma concentrations were reached 5.2 ± 0.3 hours and
2.4 ± 0.7 hours for the capsules and syrup respectively. Elimination half-lives of 11.2 ± 0.8 hours and
10.2 ± 0.6 hours respectively, were calculated. Approximately 1% of the dose was excreted as
unchanged loperamide in urine (Killinger et al., 1979).
Sedation and effects on Performance
There is little literature available on the effect of loperamide on sedation and performance. The BNF
states drowsiness as a side effect. The insert/packaging of Imodium Plus also states this; however, there
are no warning labels on the exterior packaging. We found one paper that analysed 216 poison centre
reports on the over-ingestion of loperamide. The most common symptom seen was drowsiness, with
15.7% of the cases reporting it as a side effect (Litovitz et al., 1997).
- 29 -
Department for Transport - Over-the-counter medicines and the potential for unwanted sleepiness (No.24)
Morphine
We have identified five OTC medicines containing morphine. They are Diocalm, Enterosan, J. Collis
Brownes Mixture, Kaolin and Morphine Mixture and Opazamines. The BNF does not state a
recommended dosage, however below are the recommended doses for three of the medicines:
Diocalm Two tablets (0.79mg) every two to four hours as required. Up to a maximum of 12 tablets
(4.74mg) in 24 hours.
J. Collis Brownes Mixture Two to three 5ml spoonfuls (10-15ml; 2-3mg). May be repeated once or twice
at four hourly intervals if required (difficult to interpret).
Kaolin and Morphine Mixture Two 5ml spoonfuls (10ml; 0.916mg). Repeat up to three times a day if
required.
The BNF recommends warning label number two: Warning. May cause drowsiness. If affected do not
drive or operate machinery. Avoid alcoholic drink.
Structure and Function
Morphine is effective in most kinds of acute and chronic pain; however, all the drugs sold OTC containing
morphine are antimotility medicines for the treatment of acute diarrhoea. It increases the tone and
rhythmic contractions of the intestine but diminishes propulsive activity and its overall effect is
constipating (Rang et al., 1995). Regular administration of morphine can lead to both tolerance and
dependence.
Pharmacokinetics
There were very few pharmacokinetic studies on administration of low doses of oral morphine, i.e. those
equivalent to OTC medications. One study looked at the administration of 20mg morphine in oral
slow-release form. A mean peak plasma concentration of 14.8ng/ml occurred two hours twenty two
minutes post-administration (Vater et al., 1984). Administration of oral solution morphine (non-slow
release) normally reaches a peak plasma concentration around 45 minutes post-dose (Hoskin et al., 1989).
The elimination half-life of morphine in healthy adults is between three and four hours (Rang et al.,
1995). The elderly often display reduced clearance rates and increased maximum plasma concentrations
(Baillie et al., 1989); again, this is probably due to renal dysfunction rather than ageing per se.
Sedation and effects on Performance
Morphine is a well-known sedative, it is used in higher concentrations to treat severe acute and chronic
pain and its sedative action aids its analgesic effect. Searching for literature on the subject of sedation and
performance was unproductive for the low doses of morphine available OTC. One paper that investigated
the actions of sustained release morphine on severe non-malignant pain found that performance on
perceptual and cognitive tasks was improved, although sedation levels increased. The authors concluded
that this performance improvement was probably due to the removal of pain as a mental stressor (Lorenz
et al., 1997).
- 30 -
Department for Transport - Over-the-counter medicines and the potential for unwanted sleepiness (No.24)
Conclusions
Morphine is well known as a sedating painkiller; however, from the literature we were unable to identify
the dose at which morphine begins to have these effects. The recommended dose of morphine on OTC
medicines is very low. However, morphine has the potential for dependence and abuse. The availability of
these medicines OTC leaves them more open to wrongful use and therefore administration above the
recommended dose.
Codeine and dihydrocodeine are derivatives of morphine. The literature stated that the chance of sedation
and performance impairment is very low. At the recommended doses of OTC medicines containing these
substances, there is little chance of people being affected in this way. However, as with morphine there is
a small potential for dependence; when this occurs, administration of these substances excessively above
the recommended dose may lead to impairment.
Although there was little literature on loperamide, from the one paper we did find, high doses could cause
sedation. If there is any possibility of sedation occurring then there is a need for labelling on packaging (at
present no warning is recommended). As with most medication, caution should be taken with the elderly
as enhanced effects of these drugs are likely to occur.
Chapter 6:
Muscarinic Antagonists
There is only one muscarinic antagonist available OTC that causes sedation, it is called hyoscine. Most
muscarinic antagonists produce excitatory effects on the CNS, unlike hyoscine. Table 6.1 summarises the
medicines available OTC that contain hyoscine. Recommended doses and labelling information are
included for the medicines that we purchased.
Table 6.1 is available as an MS Word download from the foot of this page.
Hyoscine
There are four OTC medicines available containing hyoscine. Two of these medicines, Kwells and
Joy-rides are used for the treatment and prevention of motion sickness. The other two medicines, Feminax
and Buscopan, are both pain killers for stomach cramps and period pain. Hyoscine is present in one of two
forms, either hyoscine hydrobromide or hyoscine-N-butylbromide. Kwells, Joy-rides and Feminax all
contain hyoscine hydrobromide. The recommended adult dose for motion sickness is 300µg 30 minutes
before the start of a journey followed by 300µg every six hours if required. A maximum of three doses
(900µg) is recommended in any 24-hour period. The recommended dosage of Kwells is the same as
described above. However, Feminax has a slightly different dosage recommendation of two tablets
(200µg) at the first onset of symptoms, then if necessary two tablets every four hours, with a maximum
dose of six tablets in 24 hours. Buscopan contains hyoscine-N-butylbromide, a drug that is marked in the
BNF as being less suitable for prescribing. It is a prescription only medicine; however, it can be sold to
the general public, provided that a single dose does not exceed 20mg, with daily doses not exceeding
80mg, and the pack does not contain a total of more than 240mg. The recommended dose of Buscopan is
two tablets (20mg) four times daily. The BNF recommends label number two, Warning. May cause
drowsiness. If affected do not drive or operate machinery. Avoid alcoholic drink.
- 31 -
Department for Transport - Over-the-counter medicines and the potential for unwanted sleepiness (No.24)
Structure and Function
Hyoscine is also known as scopolamine, and has different CNS actions to most muscarinic antagonists
such as atropine. Instead of causing excitation and restlessness at low doses, hyoscine produces sedation.
With higher doses it produces agitation and disorientation similar to that of atropine. Hyoscine also has a
significant anti-emetic effect, and that is why it is used for the treatment of motion sickness (Rang et al.,
1995).
Pharmacokinetics
Hyoscine is rapidly distributed throughout the body and has a fairly long duration of action. Oral
administration of 0.4mg hyoscine produced a mean peak plasma concentration of 528.6 ± 109.4 pg/ml.
In the same study, an elimination half-life of 4.5 ± 1.7 hours was calculated (Putcha et al., 1989).
Sedation and effects on Performance
Hyoscine is a sedative substance. Several studies have shown that administration of hyoscine produces
drowsiness. Parrott and Wesnes (1987) compared the effects of the recommended doses of two classical
antihistamines, promethazine and cinnarizine, with 0.6mg hyoscine using psychological performance tests
and a feeling state questionnaire. Although hyoscine did not produce as much performance impairment as
did the two antihistamines, it significantly reduced feelings of alertness and impaired performance at a
memory task. These effects were greatest between one to four hours post-drug. Another study looked at
four oral doses of hyoscine, ranging from 0.15mg to 1.2mg, and their effects on psychological
performance (Parrott, 1986). The author found a linear dose-related impairment on tasks which involved
continuous attention, continuous performance, memory and subjective feelings of alertness. One further
study actually looked at the effect of treating motion sickness with 0.3mg hyoscine, and found drowsiness
to be one of the most common side effects (Tokola et al., 1984).
Hyoscine also appears to affect many cognitive processes including impairment of verbal recall,
visuospatial recall, visual recognition memory, visuospatial praxis, visuoperceptual function and
psychomotor speed above doses of 0.22mg/70kg bodyweight (Flicker et al., 1990). Another study looked
at the effect of hyoscine on information processing and attention using event-related potentials (Brandeis
et al., 1992). The authors concluded that hyoscine caused significant impairment, to the extent that driving
could be affected.
The elderly are more susceptible to the side effects of hyoscine. When injected with 0.43mg/70kg
hyoscine elderly subjects demonstrated psychomotor slowing, being impaired by a greater extent on
recent memory and visuospatial praxis tasks (Flicker et al., 1992). One of the medicines containing
hyoscine (Feminax) also contains 100mg caffeine in each single dose. Caffeine has been shown to possess
cholinergic, cognition enhancing properties, which counteract the effect of hyoscine on performance tasks
(Riedel et al., 1995).
- 32 -
Department for Transport - Over-the-counter medicines and the potential for unwanted sleepiness (No.24)
Chapter 7:
Possible Drug Interactions
Combining medications can sometimes lead to adverse reactions, and in the case of a sedating OTC, a
possibility of enhanced sedation. Below is a list of possible interactions relevant to the OTC drugs in this
report. Patients may unknowingly combine two medications which (as they contain different substances)
they believe to be compatible. However, this may increase the levels of sedation and impair their driving
performance.
Antihistamines
Sedative interaction applies to a lesser extent to the non-sedating antihistamines, which do not appear to
potentiate the effects of alcohol. Interactions do not generally apply to antihistamines used for topical
action (including inhalation).
Alcohol: Enhanced sedative effect.
Antidepressants: MAOIs and tricyclics increase antimuscarinic and sedative effects.
Antimuscarinics: Increase antimuscarinic side effects.
Antivirals: Plasma concentration of non-sedating antihistamines possibly increased by ritonavir.
Anxiolytics and Hypnotics: Enhanced sedative effect.
Ulcer-healing drugs: Manufacturer advises possibility of increased plasma-loratadine concentration with
cimetidine.
Opioid Analgesics
Alcohol: Enhanced sedative and hypotensive effect.
Anti-arrhythmics: Delayed absorption of mexiletine; increased risk of ventricular arrhythmias with
levacetylmethadol and amiodarone, bretylium, disopyramide, flecainide, mexiletine, procainamide,
quinidine (avoid concomitant use).
Antidepressants: CNS excitation or depression (hypertension or hypotension) when pethidine and possibly
other opioid analgesics are given to patients receiving MAOIs (including moclobemide). Avoid
concomitant use and for two weeks after MAOI discontinued.
Antipsychotics: Enhanced sedative and hypotensive effect. Increased risk of ventricular arrhythmias with
levacetylmethadol and chlorpromazine, haloperidol, pimozide and thioridazine (avoid concomitant use).
Anxiolytics and Hypnotics: Enhanced sedative effect.
- 33 -
Department for Transport - Over-the-counter medicines and the potential for unwanted sleepiness (No.24)
Beta-blockers: Morphine possibly increases plasma concentration of esmolol.
Ulcer-healing Drugs: Cimetidine inhibits metabolism of opioid analgesics, notably pethidine (increased
plasma concentration).
Antimuscarinics
Many drugs have antimuscarinic effects. Concomitant use of two or more such drugs can increase side
effects, such as dry mouth, urine retention and constipation. Concomitant use can also lead to confusion in
the elderly. Interactions do not generally apply to antimuscarinics used by inhalation.
Alcohol: Sedative effect of hyoscine is enhanced.
Antihistamines: Increased antimuscarinic side effects.
Metoclopramide and Domperidone: Antimuscarinics antagonise gastro-intestinal effects.
Parasympathomimetics: Antagonism of effect.
This list was adapted from the BNF (September 2000).
Chapter 8:
Cautionary and Advisory Labels
BNF Recommendations on Labelling and Road Safety
The BNF provides a list of recommended wording for cautionary and advisory labels. Below is a list of
labels that are recommended for use when a sedating substance is being dispensed, and the advice that the
BNF gives to pharmacists on using them. However, pharmacists generally do not place labelling on the
packaging of OTC medicines, as this is done by the manufacturer:
Label number one: Warning. May cause drowsiness.
Chapter 9:
Conclusion
This report has summarised the available literature on substances available over-the-counter that have the
potential to cause sedation. It is clear that all the substances reviewed in this report have sedating effects,
even if it is only to a small degree. Primarily, the older-generation, H 1 -receptor antihistamines present the
most problems with regard to both sedation and performance impairment. The expression of such
manifestations is specific to the individual. A drug can induce sedation and performance impairment in
one person at the recommended dose, but have little or no effect upon another. In most people, and with
chronic administration, the body develops tolerance to the antihistamines, leading to a loss of sedative
effects three to four days after the initial administration. A review in 1997 stated that in a survey of
- 34 -
Department for Transport - Over-the-counter medicines and the potential for unwanted sleepiness (No.24)
hayfever sufferers over half (54%) treated themselves with OTC drugs, with around a third of them
experiencing drowsiness (Adelsberg, 1997). The newer second-generation antihistamines were developed
to try to reduce the incidence of sedation among those receiving allergy treatment. These drugs are an
improvement on the older classical antihistamines but are still not free from sedative effects. Despite this
fact, they are often referred to as nonsedating (in the BNF), and some medications containing them state
non-drowsy etc. on the packaging. They are also costly, being expensive to produce and purchase. When
the general public are selecting a medicine the price is something which is often taken into account if
there is a choice. Some people will still opt for the cheaper, sedating medicines.
The H 2 -receptor antihistamines appear to be the least likely amongst this group of OTC substances to
cause sedation, although it cannot be ruled out completely. These medications, along with the opioids if
taken at above the recommended dose, still have the potential to produce drowsiness. The opioids are also
habit forming, and have the potential for dependency. With this as an additional factor, they are more
likely to be abused than the other drugs cited in this report. Hyoscine, the only muscarinic antagonist that
has the potential to cause sedation, does so at the recommended doses.
The recommended doses of the majority of these medications do not provide for any alteration for the
elderly. However, the pharmacokinetics of substances are very often altered in this group of people due to
renal dysfunction. The increase in drug concentration in the blood, due to the slowing of excretion (and
therefore half-life), leads to an increased risk of sedation and performance impairment. Often, on
packaging and in guidelines to patients, there is no advisory information directed towards this group of
people. The risk of drowsiness, however small, should be stated on the packaging of medications. This is
not often the case.
Throughout the review we found several papers comparing the effects of some medications to alcohol. Of
concern to us is that the recommended doses of some classical antihistamines lead to greater performance
impairment and sedation than does the legal blood alcohol concentration limit for driving in the UK.
There are warnings about drowsiness on the packaging of these medications; some more clear than others.
Public awareness of the dangers of taking these medications and driving is fairly low. However, it is
highly likely that when taking these substances the majority of the population will continue on with their
driving, which may well be adversely affected. Thus the public needs to see taking these substances and
then driving as unacceptable, particularly as certain medications are more detrimental to performance than
alcohol.
Combining medication with alcohol can be particularly hazardous. There is an interaction between all the
classes of drugs reviewed in this report (with the exception of the newer antihistamines) and alcohol. The
sedative effects of alcohol are enhanced by administration of these OTC drugs. However, little research
has been undertaken into the effects of this combination in respect to driving. The lack of warning against
alcohol consumption on the packaging of a product containing ranitidine (one of the H 2 -receptor
antagonists) is also of concern. Ranitidine has been found to increase the blood alcohol concentration of
social drinkers. With no warning against the consumption of alcohol, social drinkers could find
themselves over the legal limit after consumption of a quantity of alcohol that would normally allow them
to drive within the law.
Some of these OTC preparations can also interact with other medications, causing increased sedation. It is
highly likely, for example, that a patient being treated with tricyclic antidepressants would not think twice
about treating a cough or cold with an antihistamine preparation. The doctor who prescribed the
- 35 -
Department for Transport - Over-the-counter medicines and the potential for unwanted sleepiness (No.24)
antidepressants may well have warned the patient about taking these substances; however, with long term
treatment such warnings may well be forgotten. There is a particular interaction between two types of
OTC medication which should be noted. The antihistamines can interact with the antimuscarinic hyoscine.
It is possible for someone to combine an anti-motion sickness drug with, for example, an anti-allergy
treatment or cough preparation, not realising that this will enhance the antimuscarinic side effects.
We found several discrepancies when examining the labelling of these medications. The labelling stated
by the BNF is only a recommendation, and is not followed to the letter by manufacturers. There are no
recommendations for how the warning labels should be displayed. From the range of medications we
looked at, the display of warnings varied immensely from no warning at all, to being the first thing one
would see when looking at a packet. With the packaging inserts of some OTC medications, drowsiness
could be stated as a possible side effect, but with no such warning given on the outside box or package.
We feel that there needs to be more rigour given to the labelling of OTC medications, with stricter
guidelines given to manufacturers about product labelling. The majority of medications we have described
in this report ought to have drowsiness labels on them, even when the chance of sedation is low; at present
this is not the case.
Whilst there is a desire for the medications in this report to be available OTC, some of them are probably
not as safe for widespread use as the public are led to believe. Even some healthcare professionals may
well be unaware of the extent to which drowsiness is caused by these medications. When considering
these medications and the issues of road safety, it should not be assumed that people will just take the
recommended dose. For example, the accumulation of compounds with long elimination half-lives, if
taken in above the recommended dose, will undoubtedly produce enhanced sedation and impaired
performance. This is a further reason for greater public awareness of the dangers associated with driving
and the consumption of potentially sedating OTC medications.
There have been few actual driving or car simulator studies carried out to investigate the actual effects of
OTC medicines on driving performance. Although one report stated that this type of study does not
provide a true picture of the performance effects of these substances, this simply points to the need for
more realistic simulation studies.
Chapter 10:
Summary of Key Points
All 15 of the classical, older-generation H1-receptor antihistamines have sedative effects.
With chronic administration of most of the classical antihistamines a tolerance develops after three to
four days, reducing their sedative effects.
Classical H1-receptor antihistamines are probably not as safe for widespread use as consumers and
healthcare professionals believe them to be, especially in the elderly.
Recommended doses of some of the H1-receptor antihistamines (diphenhydramine and
promethazine) impair performance to a greater extent than the legal blood alcohol concentration limit
for driving in this country.
The non-sedating, second-generation antihistamines are not entirely free from sedative effects.
H2-receptor antihistamines rarely cause drowsiness, with the exception of cimetidine, which is
slightly more likely to cause sedation than the other H2-receptor antihistamines.
Care should be taken with ranitidine when consuming with alcohol as it increases blood alcohol
- 36 -
Department for Transport - Over-the-counter medicines and the potential for unwanted sleepiness (No.24)
concentrations.
Recommended doses of opiates rarely cause sedation.
Administration of opiates above the recommended dose (highly likely as they are habit forming) may
cause sedation.
Hyoscine causes sedation at recommended doses.
Caution should be taken with all OTC medicines when treating the elderly. They are more
susceptible to sedation and performance impairment due to renal dysfunction in old age.
Most of the referenced OTCs have the potential to interact with alcohol, enhancing its sedative
effects.
Not all potentially sedating medicines have packaging labels warning of drowsiness, whether
recommended or not by the BNF.
Packaging labelling is sometimes misleading, as there can be no warning on the package even though
drowsiness is stated as a side effect on the package insert.
Appendix 1
Appendix 1 (Table of all available sedating OTC products and the substances they contain) is available as
an MS Excel download from the foot of this page.
Appendix 2
Appendix 2 (Table of the available sedating OTC products, their manufacturers, dosing and labelling
information) is available as an MS Word download from the foot of this page.
Bibliography
Abad-Santos, F., Carcas, A. J., Guerra, P., Govantes, C., Montuenga, C., Gomez, E., Fernandez, A. &
Frias, J. (1996). Evaluation of sex differences in the pharmacokinetics of ranitidine in humans. J. Clin.
Pharmacol., 36, 748-51.
Adam, K. & Oswald, J. (1986). The hypnotic effects of an antihistamine: promethazine. Br. J. Clin.
Pharmac., 22, 715-717.
Adelsberg, B. R. (1997). Sedation and performance issues in the treatment of allergic conditions. Arch.
Intern. Med., 157, 494-500.
Arora, S., Baraona, E. & Lieber, C. S. (2000). Alcohol levels are increased in social drinkers receiving
ranitidine. Am. J. Gastroenterol., 95, 208-213.
Baak, L. C., Ganesh, S., Jansen, J. B. & Lamers, C. B. (1992). Does smoking influence the
pharmacokinetics and pharmacodynamics of the H 2 -receptor antagonist famotidine? Br. J. Clin.
Pharmacol., 33, 193-196.
- 37 -
Department for Transport - Over-the-counter medicines and the potential for unwanted sleepiness (No.24)
Baillie, S. P., Bateman, D. N., Coates, P. E. & Woodhouse, K. W. (1989). Age and the pharmacokinetics
of morphine. Age ageing, 18, 258-62.
Balasubramanian, R., Klein, K. B., Pittman, A. W., Liao, S. H. T., Findlay, J. W. A. & Frosolono, M. F.
(1989). Pharmacokinetics of acrivastine after oral and colonic administration. J. Clin. Pharmacol., 29,
444-447.
Baltes, E. L. (1988). Pharmacokinetics of cetirizine. Allergy Forum. London. June 27, 1988, 7-9.
Band, C. J., Band, P. R., Deschamps, M., Besner, J-G. & Coldman, A. J. (1994). Human pharmacokinetic
study of immediate-release (codeine phosphate) and sustained-release (codeine contin) codeine. J. Clin.
Pharmacol., 34, 938-943.
Barnes, J. N., Williams, A. J., Tomson, M. J., Toseland, P. A. & Goodwin, F. J. (1985). Dihydrocodeine
in renal failure: further evidence for an important role of the kidney in the handling of opioid drugs. Br.
Med. J. (Clin. Res. Ed.), 290, 740-742.
Betts, T., Markman, D., Debenham, S., Mortiboy, D. & McKevitt, T. (1984). Effect of two antihistamine
drugs on actual driving performance. Br. Med. J. (Clin. Res. Ed.), 288, 281-282.
Bisson, C., St-Laurent, M., Michaud, J. T. & LeBel, M. (1993). Pharmacokinetics and pharmacodynamics
of ranitidine and famotidine in healthy elderly subjects: a double-blind, placebo-controlled comparison.
Pharmacotherapy, 13, 3-9.
Bradley, C. M. & Nicholson, A. N. (1986). Effects of a mu-opioid receptor agonist (codeine phosphate)
on visuo-motor coordination and dynamic visual acuity in man. Br. J. Clin. Pharmacol., 22, 507-512.
Brandeis, D., Naylor, H., Halliday, R., Callaway, E. & Yano, L. (1992). Scopolamine effects on visual
information processing, attention, and event-related potential map latencies. Psychophysiology, 29,
315-336.
British National Formulary (BNF) 40, September 2000. (2000). 40 th Ed., Derby, Great Britain, British
Medical Association and the Royal Pharmaceutical Society of Great Britain.
Brookhuis, K. A., De Vries, G. & De Waard, D. (1993). Acute and subchronic effects of the
H1-histaminereceptor antagonist ebastine in 10, 20 and 30mg doses, and triprolidine 10mg on car driving
performance. Br. J. Clin. Pharmacol., 36, 67-70.
Buckley, N. A., Whyte, I. M., Dawson, A. H. & Cruickshank, D. A. (1994). Pheniramine a much abused
drug. Med. J. Aust., 160, 188-192.
Castañeda-Hernández, G., Vargas-Alvarado, Y., Aguirre, F. & Flores-Murrieta, F. J. (1993).
Pharmacokinetics of cinnarizine after single and multiple dosing in healthy volunteers.
Arzneim.-Forsch./Drug Res., 43, 539-542.
Clarke, C. H. & Nicholson, A. N. (1978). Performance studies with antihistamines. Br. J. Clin.
Pharmacol., 6, 31-35.
- 38 -
Department for Transport - Over-the-counter medicines and the potential for unwanted sleepiness (No.24)
Clissold, S. P., Sorkin, E. M. & Goa, K. L. (1989). Loratadine. A preliminary review of its
pharmacodynamic properties and therapeutic efficacy. Drugs, 37, 42-57.
Cohen, A. F., Posner, J., Ashby, L., Smith, R. & Peck, A. W. (1984). A comparison of methods for
assessing the sedative effects of diphenhydramine on skills related to car driving. Eur. J. Clin. Pharmacol.,
27, 477-482.
Cohen, A. F., Hamilton, M. J., Liao, S. H. T., Findlay, J. W. A. & Peck, A. W. (1985a).
Pharmacodynamics and pharmacokinetics of BW 825C: a new antihistamine. Eur. J. Clin. Pharmacol., 28,
197-204.
Cohen, A. F., Hamilton, M., Philipson, R. & Peck, A. W. (1985b). The acute effects of acrivastine
(BW825C), a new antihistamine, compared with triprolidine on measures of central nervous system
performance and subjective effects. Clin. Pharmacol. Ther., 38, 381-386.
Corren, J., Rachelefsky, G., Spector, S., Schanker, H., Siegel, S., Holton, D., Karcher, K. & Travers, S.
(1999). Onset and duration of action of levocabastine nasal spray in atopic patients under nasal challenge
conditions. J. Allergy Clin. Immunol., 103, 575-580.
Cowings, P. S., Toscano, W. B., DeRoshia, C. & Miller, N. E. (2000). Promethazine as a motion sickness
treatment: impact on human performance and mood states. Aviat. Space Environ. Med., 71, 1013-1022.
Davies, K. N., Castleden, C. M., McBurney, A. & Jagger, C. (1989). The effect of ageing on the
pharmacokinetics of dihydrocodeine. Eur. J. Clin. Pharmacol., 37, 375-379.
Dechant, K. L. & Goa, K. L. (1991). Levocabastine. A review of its pharmacological properties and
therapeutic potential as a topical antihistamine in allergic rhinitis and conjunctivitis. Drugs, 41, 202-224.
DiPadova, C., Roine, R., Frezza, M., Gentry, R. T., Baraaona, E. & Lieber, C. S. (1992). Effects of
ranitidine on blood alcohol levels after ethanol ingestion. Comparison with other H 2 -receptor antagonists.
JAMA, 267, 83-86.
Echizen, H. & Ishizaki, T. (1991). Clinical pharmacokinetics of famotodine. Clin. Pharmacokinet., 21,
178-194.
Flicker, C., Serby, M. & Ferris, S. H. (1990). Scopolamine effects on memory, language, visuospatial
praxis and psychomotor speed. Psychopharmacology (Berl.), 100, 243-250.
Flicker, C., Ferris, S. H. & Serby, M. (1992). Hypersensitivity to scopolamine in the elderly.
Psychopharmacology (Berl.), 107, 437-441.
Friedman, H. & Greenblatt, D. J. (1985). The pharmacokinetics of doxylamine: use of automated gas
chromatography with nitrogen-phosphorus detection. J. Clin. Pharmacol., 25, 448-451.
Friedman, H., Greenblatt, D. J., Scavone, J. M., Burstein, E. S., Ochs, H.R., Harmatz, J. S. & Shader, R. I.
(1989). Clearance of the antihistamine doxylamine. Reduced in elderly men but not in elderly women.
Clin. Pharmacokinet., 16, 312-316.
- 39 -
Department for Transport - Over-the-counter medicines and the potential for unwanted sleepiness (No.24)
Gaillard, A. W. K., Gruisen, A. & de Jong, R. (1988). The influence of antihistamines on human
performance. Eur. J. Clin. Pharmacol., 35, 249-253.
Garg, D. C., Baltodano, N., Jallad, N. S., Perez, G., Oster, J. R., Eshelman, F. N. & Weidler, D. J. (1986).
Pharmacokinetics of ranitidine in patients with renal failure. J. Clin. Pharmacol., 26, 286-291.
Gengo, F. M., Ddabronzo, J., Yurchak, A., Love, S. & Miller, J. K. (1987). The relative antihistaminic and
psychomotor effects of hydroxyzine and cetirizine. Clin. Pharmacol. Ther., 42, 265-272.
Gengo, F., Gabos, C. & Miller, J. K. (1989). The pharmacodynamics of diphenhydramineinduced
drowsiness and changes in mental performance. Clin. Pharmacol. Ther., 45, 15-21.
Gengo, F. M., Gabos, C. & Mechtler, L. (1990). Quantitative effects of cetirizine and diphenhydramine on
mental performance measured using an automobile driving simulator. Ann. Allergy, 64, 520-526.
Greene, D. S., Szego, P. L., Anslow, J. A. & Hooper, J. W. (1986). The effect of age on ranitidine
pharmacokinetics. Clin. Pharmaciol. Ther., 39, 300-305.
Hamilton, M., Bush, M., Bye, C. & Peck, A. W. (1982). A comparison of triprolidine and cyclizine on
histamine (H1) antagonism, subjective effects and performance tests in man. Br. J. Clin. Pharmacol., 13,
441-444.
Heykants, J., Van Peer, A., Van de Velde, V., Snoeck, E., Meuldermans, W. & Woestenborghs, R. (1995).
The pharmacokinetic properties of topical levocabastine. A review. Clin. Pharmacokinet., 29, 221-230.
Hilbert, J., Moritzen, V., Parks, A., Radwanski, E., Perentesis, G., Symchowicz, S. & Zampaglione, N.
(1988). The pharmacokinetics of loratadine in normal geriatric volunteers. J. Int. Med. Res., 16, 50-60.
Hindmarch, I. (1976). The effects of the sub-chronic administration of an antihistamine, clemastine, on
tests of car driving ability and psychomotor performance. Curr. Med. Res. Opin., 4, 197-206.
Hindmarch, I. & Parrott, A. C. (1978). A repeated dose comparison of the side effects of five
antihistamines on objective assessments of psychomotor performance, central nervous system arousal and
subjective appraisals of sleep and early morning behaviour. Arzneimittelforschung, 28, 483-486.
Hindmarch, I., Shamsi, Z., Stanley, N. & Fairweather, D. B. (1999). A double-blind, placebo-controlled
investigation of the effects of fexofenadine, loratadine and promethazine on cognitive and psychomotor
function. Br. J. Clin. Pharmacol., 48, 200-206.
Hindmarch, I. (2000). Possible causes of daytime sleepiness with particular regard to patients with
Parkinsons disease. Eur. J. Neurol., 7, (Suppl. 4), 9-14.
Hopes, H., Meuret, G. H., Ungrthum, W., Leopold, G. & Wiemann, H. (1992). Placebo controlled
comparison of acute effects of ebastine and clemastine on performance and EEG. Eur. J. Clin. Pharmacol.,
42, 55-59.
Hoskin, P. J., Hanks, G. W., Aherne, G. W., Chapman, D., Littleton P. & Filshie, J. (1989). The
bioavailibility and pharmacokinetics of morphine after intravenous, oral and buccal administration in
healthy volunteers. Br. J. Clin. Pharmacol., 27, 499-505.
- 40 -
Department for Transport - Over-the-counter medicines and the potential for unwanted sleepiness (No.24)
Huang, S. M., Athanikar, N. K., Sridhar, K., Huang, Y. C. & Chiou, W. L. (1982). Pharmacokinetics of
chlorpheniramine after intravenous and oral administration in normal adults. Eur. J. Clin. Pharmacol., 22,
359-365.
Kerr, J. S., Dunmore, C. & Hindmarch, I. (1994). The psychomotor and cognitive effects of a new
antihistamine, mizolastine, compared to terfenadine, triprolidine and placebo in healthy volunteers. Eur. J.
Clin. Pharmacol., 47, 331-335.
Khosla, P. P., Saha, N., Koul, A., Chakraabarti, A., Sankaranarayanan, A. & Sharma, P. L. (1993). Effects
of ranitidine alone and in combination with chlorpheniramine on histamine-induced wheal and flare and
psychomotor performance. Indian J. Physiol. Pharmacol., 37, 132-134.
Killinger, J. M., Weintraub, H. S. & Fuller, B. L. (1979). Human pharmacokinetics and comparative
bioavailability of loperamide hydrochloride. J. Clin. Pharmacol., 19, 211-218.
Kotzan, J. A., Honigberg, I. L., Francisco, G. E., Zaman, R., Stewart, J. T. & Brown, W. J. (1986). Rotary
pursuit, a measure of human performance, and plasma concentrations of promethazine. Biopharm. Drug
Dispos., 7, 293-300.
Kroemer, H. & Klotz, U. (1987). Pharmacokinetics of famotidine in man. Int. J. Clin. Pharmacol. Ther.
Toxicol., 25, 458-463.
Levin, A., Barbat, J. R., Hedges, A. & Turner, P. (1984). The effects of cimetidine and ranitidine on
psychomotor function in healthy volunteers. Curr. Med. Res. Opin., 9, 301-303.
Litovitz, T., Clancy, C., Korberly, B., Temple, A. R. & Mann, K. V. (1997). Surveillance of loperamide
ingestions: an analysis of 216 poison centre reports. J. Toxicol. Clin. Toxicol. 35, 11-19.
Lorenz, J., Beck, H. & Bromm, B. (1997). Cognitive performance, mood and experimental pain before
and during morphine-induced analgesia in patients with chronic nonmalignant pain. Pain, 73, 369-375.
Luna, B. G., Scavone, J. M. & Greenblatt, D. J. (1989). Doxylamine and diphenhydramine
pharmacokinetics in women on low-dose estrogen oral contraceptives. J. Clin. Pharmacol., 29, 257-260.
Manning, C., Scandale, L., Manning, E. J. & Gengo, F. M. (1992). Central nervous system effects of
meclizine and dimenhydrinate: evidence of acute tolerance to antihistamines. J. Clin. Pharmacol., 32,
996-1002.
Mattila, M. J. & Paakkari, I. (1999). Variations among non-sedating antihistamines: are there real
differences? Eur. J. Clin. Pharmacol., 55, 85-93.
Merck Sharp & Dohme Limited. (2000). Periactin Electronic Medicines Compendium. 28 September
2000 12:21:00 GMT.
Miles, M. V., Balasubramanian, R., Pittman, A. W., Grossman, S. H., Pappa, K. A., Smith, M. F., Wargin,
W. A., Findlay, J. W. A., Poust, R. I. & Frosolono, M. F. (1990). Pharmacokinetics of oral and
transdermal triprolidine. J. Clin. Pharmacol., 30, 572-575.
- 41 -
Department for Transport - Over-the-counter medicines and the potential for unwanted sleepiness (No.24)
Moscati, R. M. & Moore, G. P. (1990). Comparisons of cimetidine and diphenhydramine in the treatment
of acute urticaria. Ann. Emerg. Med., 19, 12-15.
Nicholson, A. N. (1979). Effect of the antihistamines, brompheniramine maleate and triprolidine
hydrochloride, on performance in man. Br. J. Clin. Pharmacol., 8, 321-324.
Nicholson, A. N. & Stone, B. M. (1984). The H 2 -antagonists, cimetidine and ranitidine: studies on
performance. Eur. J. Clin. Pharmacol., 26, 579-582.
Nicholson, A. N. (1985). Central effects of H 1 and H 2 antihistamines. Aviat. Space Environ. Med., 56,
293-298.
Nicholson, A. N., Pascoe, P. A., Turner, C., Ganellin, C. R., Greengrass, P. M., Casy, A. F. & Mercer, A.
D. (1991). Sedation and histamine H 1 -receptor antagonism: studies in man with the enantiomers of
chlorpheniramine and dimethindene. Br. J. Pharmacol., 104, 270-276.
Nicholson, A. N. & Turner, C. (1998). Central effects of the H 1 -antihistamine, cetirizine. Aviat. Space
Environ. Med., 69, 166-171.
Nomeir, A. A., Mojaverian, P., Kosoglou, T., Affrime, M. B., Nezamis, J., Rodwanski, E., Lin, C. C. &
Cayen, M. N. (1996). Influence of food on the oral bioavailability of loratadine and pseudoephedrine from
extended-release tablets in healthy volunteers. J. Clin. Pharmacol., 36, 923-930.
Oslin, D. W., Katz, I. R., Sands, L. P., Bilker, W., DiFilippo, S. D. & DAngelo, K. (1999). Examination of
the cognitive effects of cimetidine in normal elderly volunteers. Am. J. Geriatr. Psychiatry, 7, 160-165.
Ostro, M. J. (1987). Pharmacodynamics and pharmacokinetics of parental histamine (H 2 )-receptor
antagonists. Am. J. Med., 83, 15-22.
Parrott, A. C. (1986). The effects of transdermal scopolamine and four dose levels of oral scopolamine
(0.15, 0.3, 0.6 and 1.2mg) upon psychological performance. Psychopharmacology (Berl.), 89, 347-354.
Parrott, A. C. & Wesnes, K. (1987). Promethazine, scopolamine and cinnarizine: comparative time course
of psychological performance effects. Psychopharmacology (Berl), 92, 513-519.
Paton, D. M. & Webster, D. R. (1985). Clinical pharmacokinetics of H 1 -receptor antagonists (the
antihistamines). Clin. Pharmacokinet., 10, 477-497.
Peck, A. W., Fowle, A. S. & Bye, C. (1975). A comparison of triprolidine and clemastine on histamine
antagonism and performance tests in man: implications for the mechanism of drug induced drowsiness.
Eur. J. Clin. Pharmacol., 8, 455-463.
Pritchett, E. L. C., Smith, W. M. & Kirsten, E. B. (1988). Pharmacokinetic and pharmacodynamic
interactions of propafenone and cimetidine. J. Clin. Pharmacol., 28, 619-624.
Putcha, L., Cintron, N. M., Tsui, J., Vanderploeg, J. M. & Kramer, W. G. (1989). Pharmacokinetics and
oral bioavailability of scopolamine in normal subjects. Pharm. Res., 6, 481-485.
- 42 -
Department for Transport - Over-the-counter medicines and the potential for unwanted sleepiness (No.24)
Raemaekers, J. G., Uiterwijk, M. M. C. & OHanlen, J. F. (1992). Effects of loratadine and cetirizine on
actual driving and psychometric test performance and EEG during driving. Eur. J. Clin. Pharmacol., 42,
363-369.
Rang, H. P., Dale, M. M. & Ritter, J. M. (1995). Analgesic Drugs. In: Pharmacology, 3 rd ed., ed.
Simmons, B. & Beasley, S., pp 609-633, USA, Churchill Livingstone.
Redpath, J. B. & Pleuvry, B. J. (1982). Double-blind comparison of the respiratory and sedative effects of
codeine phosphate and (+/)-glaucine phosphate in human volunteers. Br. J. Clin. Pharmacol., 14, 555-558.
Rice, V. J. & Snyder, H. L. (1993). The effects of Benadryl and Hismanal on mood, physiological
measures, antihistamine detection and subjective symptoms. Aviat. Space Environ. Med., 64, 717-725.
Richards, D. A. (1983). Comparative pharmacodynamics and pharmacokinetics of cimetidine and
ranitidine. J. Clin. Gastroenterol., 5 (Suppl. 1), 81-90.
Riedel, W., Hogervorst, E., Leboux, R., Verhey, F., van Praag, H. & Jolles, J. (1995). Caffeine attenuates
scopolamine-induced memory impairment in humans. Psychopharmacology (Berl.), 122, 158-168.
Rombaut, N., Bhatti, J. Z., Curran, S. & Hindmarch, I. (1991). Effects of topical administration of
levocabastine on psychomotor and cognitive function. Ann. Allergy, 67, 75-79.
Rowell, F. J., Seymour, R. A. & Rawlins, M. D. (1983). Pharmacokinetics of intravenous and oral
dihydrocodeine and its acid metabolites. Eur. J. Clin. Pharmacol., 225, 419-424.
Saarialho-Kere, U., Mattila, M. J. & Seppala, T. (1986). Pentazocine and codeine: effects on human
performance and mood and interactions with diazepam. Med. Biol., 64, 293-299.
Sale, M. E., Barbey, J. T., Woosley, R. L., Edwards, D., Yeh, J., Thakker, K. & Chung, M. (1994).
Pharmacodynamics and drug action. The electrocardiographic effects of cetirizine in normal subjects.
Clin. Pharmacol. Ther., 56, 295-301.
Scavone, J. M., Greenblatt, D. J., Harmatz, J. S., Engelhardt, N. & Shader, R. I. (1998). Pharmacokinetics
and pharmacodynamics of diphenhydramine 25mg in young and elderly volunteers. J. Clin. Pharmacol.,
38, 603-609.
Schmitt, L. G. & Shaw, J. E. (1986). Alleviation of induced vertigo. Therapy with transdermal
scopolamine and oral meclizine. Arch. Otolaryngol. Head Neck Surg., 112, 88-91.
Schran, H. F., Petryk, L., Chang, C.-T., OConnor, R. & Gelbert, M. B. (1996). The pharmacokinetics and
bioavailability of clemastine and phenylpropanolamine in singlecomponent and combination
formulations. J. Clin. Pharmacol., 36, 911-922.
Schweitzer, P. K., Muehlback, M. J. & Walsh, J. K. (1994). Sleepiness and performance during three-day
administration of cetirizine or diphenhydramine. J. Allergy Clin. Immunol., 94, 716-724.
Seidel, W. F., Cohen, S., Gourash Bliwise, N. & Dement, W. C. (1990). Direct measurement of daytime
sleepiness after administration of cetirizine and hydroxyzine with a standardized electroencephalographic
assessment. J. Allergy Clin. Immunol., 86, 1029-1033.
- 43 -
Department for Transport - Over-the-counter medicines and the potential for unwanted sleepiness (No.24)
Simons, F. E., Frith, E. M. & Simons, K. J. (1982). The pharmacokinetics and antihistaminic effects of
brompheniramine. J. Allergy Clin. Immunol., 70, 458-464.
Simons, F. E. & Simons, K. J. (1999). Clinical pharmacology of new histamine H 1 -receptor antagonists.
Clin. Pharmacokinet., 36, 329-352.
Simons, F. E., Fraser, T. G., Maher, J., Pillay, N. & Simons, K. J. (1999). Central nervous system effects
of H 1 -receptor antagonists in the elderly. Ann. Allergy Asthma Immunol., 82, 157-160.
Spector, R., Choudhury, A. K., Chiang, C.-K., Goldberg, M. J. & Ghoneim, M. M. (1980).
Diphenhydramine in Orientals and Caucasians. Clin. Pharmacol. Ther., 28, 229-234.
Spencer, C. M., Faulds, D. & Peters, D. H. (1993). Cetirizine. A reappraisal of its pharmacological
properties and therapeutic use in selected allergic disorders. Drugs, 46, 1055-1080.
Stanley, N., Alford, C. A., Rombaut, N. E. & Hindmarch, I. (1996). Comparison of the effects of
astemizole/pseudoephedrine and triprolidine/pseudoephedrine on CNS activity and psychomotor function.
Int. Clin. Psychopharmacol., 11, 31-36.
Szekely, J. I., Torok, K., Karczag, I., Tolna, J. & Till, M. (1986). Effects of D-Met2,
Pro5-enkephalinamide on pain tolerance and some cognitive functions in man. Psychopharmacology
(Berl.), 89, 409-413.
Takabatake, T., Ohta, H., Maekawa, M., Yamamoto, Y., Ishida, Y., Hara, H., Nakamura, S., Ushiogi, Y.,
Kawabata, M., Hashimoto, N. & Hattori, N. (1985). Pharmacokinetics of famotidine, a new H 2 -receptor
antagonist, in relation to renal function. Eur. J. Clin. Pharmacol., 28, 327-331.
Taylor, G., Houston, J. B., Shaffer, J. & Mawer, G. (1983). Pharmacokinetics of promethazine and its
sulphoxide metabolite after intravenous and oral administration to man. J. Clin. Pharmac., 15, 287-293.
Theofilopoulos, N., Szabadi, E. & Bradshaw, C. M. (1984). Comparison of the effects of ranitidine,
cimetidine and thioridazine on psychomotor functions in healthy volunteers. Br. J. Clin. Pharmacol., 18,
135-144.
Tokola, O., Laitinen, L. A., Aho, J., Gothoni, G. & Vapaatalo, H. (1984). Drug treatment of motion
sickness: scopolamine alone and combined with ephedrine in real and simulated situations.
Van Hecken, A. M., Tjandramaga, T. B., Mullie, A., Verbesselt, R. & de Schepper, P. J. (1982).
Ranitidine: single dose pharmacokinetics and absolute bioavailability in man. Br. J. Clin. Pharmacol., 14,
195-200.
Vater, M., Smith, G., Aherne, G. W. & Aitkenhead, A. R. (1984). Pharmacokinetics and analgesic effect
of slow-release oral morphine sulphate in volunteers. Br. J. Anaesth., 56, 821-827.
Volkerts, E. R., Van Willigenburg, A. P. P., Van Larr, M. W. & Maes, R. A. A. (1992). Does cetirizine
belong to the new generation of antihistamines? An investigation into its acute and subchronic effects in
highway driving, psychometric test performance and daytime sleepiness. Hum. Psychopharmacol. Clin.
Exp., 7, 227-238.
- 44 -
Department for Transport - Over-the-counter medicines and the potential for unwanted sleepiness (No.24)
Walker, D. J. & Zacny, J. P. (1998). Subjective, psychomotor and analgesic effects of oral codeine and
morphine in healthy volunteers. Psychopharmacology (Berl.), 140, 191-201.
Watson, N. T., Weiss, E. L. & Harter, P. M. (2000). Famotidine in the treatment of acute urticaria. Clin.
Exp. Dermatol., 25, 186-189.
Webb, J. & Kamali, F. (1998). Analgesic effects of lamotrigine and phenytoin on coldinduced pain: a
crossover placebo-controlled study in healthy volunteers. Pain, 76, 357-363.
Weiler, J. M., Donnelly, A., Campbell, B. H., Connell, J. T., Diamond, L., Hamilton, L. H., Rosenthal, R.
R., Hemsworth, G. R. & Perhach, Jr., J. L. (1988). Multicenter, double-blind, multiple-dose,
parallel-groups efficacy and safety trial of azelastine, chlorpheniramine, and placebo in the treatment of
spring allergic rhinitis. J. Allergy Clin. Immunol., 82, 801-811.
Weiler, J. M., Bloomfield, J. R., Woodworth, G. G., Grant, A. R., Layton, T. A., Brown, T. L., McKenzie,
D. R., Baker, T. W. & Watson, G. S. (2000). Effects of fexofenadine, diphenhydramine and alcohol on
driving performance. Ann. Intern. Med., 132, 354-363.
Wellcome UK. (1999). Semprex Capsules Electronic Medicines Compendium. 28 September 2000,
12:37:00 GMT.
Witek, Jr., T. J., Canestrari, D. A., Miller, R. D., Yang, J. Y. & Riker, D. K. (1992). The effects of
phenindamine tartrate on sleepiness and psychomotor performance. J. Allergy Clin. Immunol., 90,
953-961.
Witte, P. U., Irmisch, R., Hajdu, P. (1985). Pharmacokinetics of pheniramine (Avil) and metabolites in
healthy subjects after oral and intravenous administration. Int. J. Clin. Ther. Toxicol., 23, 59-62.
Woodward, J. K. (1990). Pharmacology of antihistamines. J. Allergy Clin. Immunol., 86, 606-612.
- 45 -