Current Medical Research & Opinion Vol. 26, No.

4, 2010, 889–899

0300-7995 Article 4949/465310

doi:10.1185/03007991003648015 All rights reserved: reproduction in whole or part not permitted

Review
Effects of intranasal xylometazoline, alone or
in combination with ipratropium, in patients
with common cold
Curr Med Res Opin Downloaded from informahealthcare.com by University of Connecticut on 10/23/12

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Abstract

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Ronald Eccles

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Common Cold Centre & Healthcare Clinical Trials,
Background:

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Cardiff University, Cardiff, UK

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Common cold is one of the most prevalent conditions that family doctors encounter. One of the first
Kaj Martensson

py us is
Novartis Consumer Health SA, Nyon, Switzerland
Shirley C. Chen
Novartis Consumer Health, Inc., New Jersey, USA
For personal use only.
symptoms to occur is nasal congestion, which can have a negative impact on daily life and prompts
m
many patients to seek treatment for relief. Xylometazoline nasal spray (Otrivin*) is a topical decongestant
that has been used successfully for many years and is generally recognized as an effective and safe therapy.
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However, most studies have investigated its clinical efficacy in healthy patients and few have included

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patients with common cold.

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Address for correspondence:

Scope:
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Prof Ronald Eccles, Director, Common Cold Centre &

1

Healthcare Clinical Trials, Cardiff School of To review the published clinical efficacy and safety of xylometazoline alone and in combination in the
20
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Biosciences, Cardiff University, Biomedical Sciences management of nasal congestion in patients with common cold. Literature searches of PubMed and the
Building, Museum Avenue, Cardiff CF10 3US, Cochrane Library were conducted to obtain published open or blinded, randomized, placebo- or active-
la d le ©

Wales, UK. controlled studies on the use of xylometazoline hydrochloride for the symptomatic relief of nasal congestion
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Tel.: þ44 (0)29 20874102; Fax: +44 (0)29

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in patients with common cold. Searches included papers published in English only, up to September 2009.
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20874093; eccles@cardiff.ac.uk
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Findings:
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Keywords: Despite the small number of studies identified in common cold (n ¼ 4), as per search criteria defined,
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Common cold – Decongestant – Intranasal – Nasal intranasal xylometazoline quickly and effectively relieved nasal congestion. When used alone,
congestion – Xylometazoline
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xylometazoline had a clinically relevant decongestant effect that was significantly superior for up to 10
au fo
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Accepted: 22 January 2010; published online: 12 February 2010 hours compared with placebo. The superior decongestant effect with xylometazoline led to high patient
Citation: Curr Med Res Opin 2010; 26:889–99 satisfaction with treatment. When used in combination with ipratropium bromide, nasal congestion and
Un t
th

rhinorrhoea were treated simultaneously, leading to significantly higher patient general impression scores
compared with either agent used alone. Xylometazoline was well tolerated, with generally mild to moderate
nasal-related side effects (e.g. epistaxis in 3.4% of patients, and blood-tinged mucus in 10–26% of patients)
that were easily resolved; the most frequently reported non-nasal AEs were headache (3.4%) and period
pain (10.3%); no cases of sedation were reported. As expected, no rhinitis medicamentosa or rebound
congestion was noted with short-term use (510 days). No clinically important differences in ciliary motility
and mucociliary clearance were observed. Xylometazoline does not result in sympathomimetic systemic side
effects seen with oral decongestants (e.g. pseudoephedrine, phenylephrine).

Conclusions:
The few studies available in common cold suggest that intranasal xylometazoline provides fast and effective
relief of nasal congestion and is well tolerated. When xylometazoline is used in combination with
ipratropium, patients with common cold experience the additive benefit of nasal congestion and
rhinorrhoea being treated simultaneously.

*OtrivinÕ is a registered trademark of Novartis AG, Basel, Switzerland.

! 2010 Informa UK Ltd www.cmrojournal.com Effects of intranasal xylometazoline in common cold Eccles et al. 889
 Current Medical Research & Opinion Volume 26, Number 4
Introduction
Nasal congestion is a normal component of the nasal cycle,
a physiologic process in which the nasal passages congest
and decongest rhythmically and asymmetrically over a
24-hour period1. However, irritation of the nasal mucous
membrane can cause inflammation and lead to swelling
and prolonged congestion of the nasal blood vessels in
both nasal passages. Nasal congestion can significantly
interfere with daily life as it may impede breathing, lead
to accumulation of thick nasal mucus (which can block the
nasal passageways and result in further breathing difficul-
ties), cause a frequent urge to blow the nose, and is an
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important factor in sleep disturbance, causing snoring
and apnea2,3. In short, nasal congestion can have a con-
siderable negative impact on daily life.
There are many common causes of nasal congestion,
including upper respiratory viral infections (common
cold or influenza), allergic rhinitis, sinus infections/
chronic sinusitis, vasomotor rhinitis and overuse of some
nasal sprays/drops. Of these, common cold is one of the
most prevalent and is the most common condition that
family doctors have to deal with4, affecting adults around
2–5 times per year and children 7–10 times per year5. The
For personal use only.
common cold can be triggered by more than 200 types of
viruses, but is most frequently caused by the rhino- and
coronaviruses6. Epidemiologic data suggest a peak inci-
dence in rhinoviral colds in early autumn and late
spring7. Despite the usually benign and self-limiting
nature of the illness, the common cold is a major and
recurrent cause of morbidity, accounting for 40% of all
time off work and 30% of all time off school4. This
places a large economic burden on society in terms of
visits to doctors and other healthcare providers, treatments
and a substantial loss in productivity.
Nasal congestion is normally one of the first symptoms
to be experienced in common cold8,9 (often concomitant
with rhinorrhoea, or ‘runny’ nose10,11), usually occurring
within 1–2 days and progressing to maximum severity at
2–3 days8,12. Overall, common cold symptoms (e.g. nasal
congestion, rhinorrhoea, sore throat, sinus pain, watery
eyes, cough, headache, chilliness, muscle aches and
pains5) typically last for 7–10 days13.
It is thought that the nasal congestion in common cold
results from host inflammatory immune responses triggered
by the viral infection, rather than direct cellular necrosis
or mucosal damage5,9,12,14,15. When a cold virus stimulates
the inflammatory cascade, vasodilator mediators of inflam-
mation such as bradykinins and prostaglandins are
released16,17. These produce dilation and increased vascu-
lar permeability of large veins in the nasal epithelium,
causing congestion in one or both nasal passages. (Thus
nasal congestion is not caused by too much mucus, as some
patients believe, but occurs when the nasal membranes
become swollen from inflamed blood vessels.) Prolonged
890 Effects of intranasal xylometazoline in common cold Eccles et al.
April 2010
congestion in this narrow nasal valve region causes
obstruction of the nasal airway, making it difficult for
patients to breathe properly5,18. The asymmetry of nasal
airflow associated with the nasal cycle is increased in a
common cold, which may result in one nasal passage
being patent while the other is completely obstructed5.
Nasal congestion (along with rhinorrhoea and sneez-
ing) causes irritation to patients and prompts most patients
to seek treatment for relief19,20. There is no marketed cure
for the common cold and symptomatic therapy is the only
treatment option for nasal congestion. To this end, numer-
ous oral and topical over-the-counter (OTC) deconge-
stant drugs have been marketed for both adults and
children21. A well known and commonly used deconge-
stant is xylometazoline hydrochloride nasal spray,
used alone (marketed as OtrivinÕ nasal spray) or in com-
bination with ipratropium bromide (used to reduce rhinor-
rhoea) (Otrivin Complete/Otrivin Comp/Otrivin Duo/
OtriDuoy). Xylometazoline is an imidazoline derivative,
an alpha-agonist sympathomimetic agent that mimics
the effects of sympathetic activation22,23. The drug helps
to relieve nasal congestion by locally constricting blood
vessels in the nasal mucosa (thus reducing swelling) and
reducing airway resistance (with a subjective sensation of
improved nasal airflow), and facilitates drainage of the
openings that connect the sinuses to the nasal cavity to
ensure they remain open8,24.
Xylometazoline hydrochloride has been used by several
million patients over several decades, suggesting it is an
effective and safe topical decongestant. However, most
studies have investigated its effects in healthy patients or
those with rhinitis and few have evaluated its clinical effi-
cacy in patients with common cold. Therefore, the aim of
this review was to evaluate the published efficacy and
safety of xylometazoline hydrochloride in patients with
nasal congestion associated with common cold and to con-
firm its role in the management of such patients.
Methods
Literature search
To review the efficacy and safety of xylometazoline hydro-
chloride, PubMed and the Cochrane Library were searched
to obtain published open or blinded, randomized, placebo-
or active-controlled studies on the use of xylometazoline
hydrochloride for the symptomatic relief of nasal conges-
tion in patients with common cold. Searches included
papers published in English only, up to September 2009.
The search terms used a combination of ‘common cold’
OR ‘rhinovirus’ OR ‘congestion’ AND ‘xylometazoline’,
yOtrivin Complete/Otrivin Comp/Otrivin Duo/OtriDuo are registered trade names
of Novartis Consumer Health SA. The list of trade names is not exhaustive and
some additional trade names exist and are registered in EU countries.
www.cmrojournal.com ! 2010 Informa UK Ltd

and the subsequent list of results was analyzed to identify
relevant studies. Further studies were disclosed by the
authors.
Data extraction
The data from each study identified was extracted by a
single reviewer and independently checked by a second
reviewer. Any discrepancies were resolved by discussion.
The characteristics of the studies (e.g. active and compara-
tor drug, population, trial duration, outcomes studied) and
key efficacy and safety findings of the studies were
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compiled.
Results
In total, four clinical studies were identified that evaluated
the efficacy and safety of intranasal xylometazoline hydro-
chloride in patients with common cold (Table 1), as per
the search and review criteria defined. Of these, three used
xylometazoline alone25–27 and one evaluated xylometazo-
line in combination with ipratropium (Otrivin Complete/
Otrivin Comp/Otrivin Duo/OtriDuo)28. Two of the stu-
For personal use only.
dies were double-blind, randomized, controlled trials25,28,
and two were open-label, non-comparative studies26,27.
In total, 998 patients were assessed (range 44–786). The
results of all studies are outlined in Table 2.
Efficacy
Xylometazoline hydrochloride alone
Clinical evidence indicates that intranasal xylometazoline
quickly and effectively reduces the nasal congestion asso-
ciated with common cold. In the most recent trial25, the
nasal conductance with xylometazoline (384.23 cm3/sec)
was 69.7% greater at 1 hour than with placebo
(226.42 cm3/sec) (p  0.0001) (Figure 1), demonstrating
the rapid relief provided by xylometazoline. The statistical
superiority of xylometazoline over placebo was maintained
for up to 10 hours (p ¼ 0.0009), with a non-statistical
trend in favour of xylometazoline for up to 12 hours.
These objective findings were supported by the peak sub-
jective effect (visual analogue scale, VAS), which was
34.3% lower with xylometazoline (20.7) compared with
placebo (31.5) (p ¼ 0.0298). In addition, the total
common cold symptoms score on day 1 of treatment
with xylometazoline (25.71) was 28.2% better than with
placebo (35.79) (p ¼ 0.0221), while superiority for xylo-
metazoline over placebo was also noted for some individual
common cold symptoms scores on day 1 (blocked nose,
sore throat, ear ache), day 2 (blocked nose), day 5
(runny nose), day 10 (runny nose) of treatment (p50.05).
The symptomatic relief of nasal congestion provided by
xylometazoline in this study confirms results seen in earlier
! 2010 Informa UK Ltd www.cmrojournal.com
Current Medical Research & Opinion Volume 26, Number 4 April 2010
studies. In open-label, non-comparative studies, a single
dose of xylometazoline reduced total nasal airway resis-
tance by 36.1% compared with baseline in patients with
common cold26, while nasal conductance remained signif-
icantly elevated for 6 hours compared with baseline
(p50.05)27. The improvement in nasal conductance was
reinforced by the subjective scores for nasal congestion,
which improved significantly over 6 hours27.
Xylometazoline hydrochloride plus ipratropium in
combination
Intranasal use of xylometazoline in combination with ipra-
tropium was shown to be effective at simultaneously reliev-
ing nasal congestion (and rhinorrhoea) associated with
common cold28. After 24 hours, as expected, all xylome-
tazoline treatment groups were significantly superior to
ipratropium alone and placebo with respect to nasal con-
gestion symptom scores (Figure 2). Superiority was main-
tained over 7 days (Figure 3). The combination treatment
containing the lower dose of xylometazoline (0.5 mg/ml)
was shown to be non-inferior to the higher dose xylome-
tazoline (1.0 mg/ml) combination with respect to nasal
congestion. At 24 hours, the general impression of treat-
ment scores for both ipratropium/xylometazoline combi-
nation groups were significantly higher than ipratropium
alone (p50.004), xylometazoline alone (p50.01) and
placebo, but only ipratropium/xylometazoline 1.0 mg/ml
maintained this superiority after 7 days (ipratropium/xylo-
metazoline 0.5 mg/ml was superior only to ipratropium at
this time point).
Safety
Adverse effects (AEs) (e.g. nasal effects such as blood-
tinged mucus and epistaxis, and systemic effects such as
headache, cough, etc.) were reported in patients with
common cold treated with nasal xylometazoline alone or
in combination with ipratropium; these were either
expected symptoms of the common cold or common
adverse reactions to xylometazoline (or ipratropium).
Table 3 lists the most common AEs (which occurred in
3% of patients) reported in those trials that gave a more
detailed description of the AEs experienced25,28.
Although AEs tended to occur more often in
drug-treated patients than in patients receiving placebo,
they were mostly mild to moderate and all studies that
reported AEs concluded that xylometazoline (alone or in
combination with ipratropium) was well tolerated. No
serious AEs or deaths were reported, and no clinically
important differences in nasal examinations were noted,
suggesting that the drug does not have an effect on nasal
mucosa. The most common AEs experienced were
nasal-related and included epistaxis (3.4% of patients)
and epistaxis/blood-tinged mucus (10–26% of patients).
However, these events were mild to moderate and easily
Effects of intranasal xylometazoline in common cold Eccles et al. 891
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For personal use only.

892
Table 1. Clinical studies included in the efficacy and safety review of the nasal administration of xylometazoline hydrochloride used alone or in combination in patients with common cold.

Reference Type of study Study treatment Comparator Population Trial Outcomes measured
First author, year Regimen, dose Regimen, dose Total N, mean age duration*
(SD), % male

Topical xylometazoline hydrochloride alone

Eccles, 200825 Double-blind, Xylometazoline 0.1% Placebo 61; xylometazoline 20 10 days Nasal conductance
parallel-group, 1 spray (0.14 g) per nostril, 1 spray per nostril, (1.6) yrs, 37.9%; Peak subjective effect (VAS)
Current Medical Research & Opinion Volume 26, Number 4

randomized, 3/day 3/day placebo 20.9 (5.2), Duration of relief of nasal

placebo-controlled 37.5% congestion
Total and individual cold

Effects of intranasal xylometazoline in common cold Eccles et al.

symptom scores
April 2010

General well-being
AEs
Williams, Open-label, Xylometazoline 0.1% None 47, 24 yrs 10 min Nasal airway resistance in
199226 non-comparative 2 sprays per nostril (single healthy patients and those
dose) with acute rhinitis due to
common cold
Hamilton, Open-label, Xylometazoline 0.1% None 44, 18–58 yrs, 47.7% 6 hours Subjective rating of symptoms
198127 non-comparative 2 sprays per nostril (single Nasal airway resistance (nasal
dose) conductance)
Topical xylometazoline hydrochloride plus ipratropium bromide in combination
Eccles, 200728 Multicenter, double-blind, Xylometazoline 1.0 mg/ml þ Placebo solution 786, 30 yrs, 46.6% 7 days Symptom scores for rhinor-
parallel-group, ipratropium 0.6 mg/ml 1 spray (140 ll) rhoea and nasal congestion
randomized, Xylometazoline 0.5 mg/ml þ per nostril, 3/day after first 24 hrs
placebo-controlled ipratropium 0.6 mg/ml Tissue use over first 24 hrs for
Xylometazoline 1.0 mg/ml rhinorrhoea
Ipratropium 0.6 mg/ml General impression of
1 spray (140 ll) per nostril, treatment after first
3/day 24 hrs and at end of
trial AEs

*Last follow up.

AEs ¼ adverse events; VAS ¼ visual analogue scale.

www.cmrojournal.com ! 2010 Informa UK Ltd

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For personal use only.

Table 2. Summary of key findings in clinical studies assessing intranasal xylometazoline hydrochloride used alone or in combination in patients with common cold.

Reference Efficacy findings* Safety findings (AEs)

First author, year

Intranasal xylometazoline hydrochloride alone

Eccles, 200825 With xylometazoline vs. placebo, respectively:
 Significantly greater decongestant effect: nasal conductance at 1 h 384.23 vs. 226.42 cm3/
sec (p  0.0001)
 Nasal conductance significantly superior for up to 10 hrs (p ¼ 0.0009), trend in favour of
xylometazoline for up to 12 hrs (not statistically significant)
 Significantly greater peak subjective effect: VAS 20.7 vs. 31.5 (p ¼ 0.0298)
 Significant improvement in:
– Total common cold symptoms score on day 1 of treatment (25.71 vs. 35.79) (p ¼ 0.0221)
 A total of 19 AEs reported, slightly higher in the placebo group (n ¼ 11; 1
severe, not drug related) compared with the xylometazoline group (n ¼ 8; all
mild–moderate, not considered drug related)
 The most frequently occurring AEs were headache (5 events) and
dysmenorrhoea (3 events)
 Nasal AEs (i.e. epistaxis) occurred in both groups, 1 event in each group

! 2010 Informa UK Ltd www.cmrojournal.com

– Some individual common cold symptoms scores on day 1 (blocked nose, sore throat, ear
ache), day 2 (blocked nose), day 5 (runny nose), day 10 (runny nose) of treatment
(p50.05)
 Significantly greater patient general evaluation and satisfaction with treatment (p50.05)
Williams, 199226 Compared with baseline, xylometazoline: Not measured
 Significantly decreased total nasal airway resistance by 36.1% in patients with common cold
(p ¼ 0.001)
– Asymmetry in nasal airway resistance was still present
 Abolished asymmetry in nasal airway resistance in healthy patients
Hamilton, 198127 Compared with baseline, xylometazoline: Not measured
 Rapidly and substantially improved nasal conductance, remained significantly elevated for 6
hour period, significantly greater than asymptomatic value from 10 min to 4 hours (p50.05)
 Subjective scores for nasal congestion improved significantly over 6 hours (p50.05)
 No differences in responses of cigarette smokers vs. non-smokers
Intranasal xylometazoline hydrochloride plus ipratropium bromide in combination
Eccles, 200728  With respect to symptom scores at 24 hrs:  420 AEs reported in 285 patients (rhinorrhoea, blood-tinged mucus,
– All ipratropium treatment groups superior to placebo for rhinorrhoea (p50.0001) epistaxis, nasal passage irritation, headache, nasal dryness, dry throat,
– All xylometazoline treatment groups superior to placebo for congestion (p ¼ 0.0001) sinusitis, pharyngitis, dry mouth, nausea, throat irritation)
– Both ipratropium/xylometazoline combinations superior to:  AEs distributed equally between treatments, apart from blood-tinged mucus,
g Xylometazoline alone with respect to rhinorrhoea (p50.0001) epistaxis, nasal passage irritation and nasal dryness, which had higher
g Ipratropium alone with respect to nasal congestion (p50.001) incidence in ipratropium groups
– Ipratropium/xylometazoline 0.5 mg/ml group non-inferior to ipratropium/xylometazoline  Nasal blood-tinged mucus/epistaxis reported in 15% (122/786) of all
1.0 mg/ml for nasal congestion patients; epistaxis reported in 41.8% (51/122) of these patients
 Over 7 days vs. placebo, clear and superior separation between symptoms scores for – Rate of blood-tinged mucus/epistaxis in ipratropium/xylometazoline (1.0
ipratropium groups for rhinorrhoea and xylometazoline groups for nasal congestion and 0.5 mg/ml) combination, ipratropium alone, xylometazoline alone
 Mean number of tissues used during first 24 hrs in all ipratropium treatment groups (39) and placebo groups, respectively: 26%, 21%, 14%, 10%, 6%
significantly lower than with xylometazoline alone or placebo (49) (p50.0001) – Most self-treated by applying pressure and tissue paper to the nose; no
 General impression scores for ipratropium/xylometazoline (1.0 and 0.5 mg/ml) patients visited their physician for treatment of epistaxis
combinations significantly superior to ipratropium alone (p50.004), xylometazoline  55 patients withdrew because of AEs
alone (p50.01) and placebo  No serious AEs reported
– Scores at 24 hrs, respectively: 2.8, 2.7, 2.3, 2.4, 2.1
– Scores after 7 days, respectively: 3.0, 2.8, 2.5, 2.6, 2.3
– After 7 days, ipratropium/xylometazoline 1.0 mg/ml superior to ipratropium (p50.001)
and xylometazoline (p ¼ 0.011), but ipratropium/xylometazoline 0.5 mg/ml superior only
to ipratropium (p ¼ 0.0002)
Current Medical Research & Opinion Volume 26, Number 4

*Where possible reported as intention-to-treat.

Effects of intranasal xylometazoline in common cold Eccles et al.

AEs ¼ adverse events.
April 2010

893
 Current Medical Research & Opinion Volume 26, Number 4 April 2010

600 Xylometazoline
550 Placebo
*
500 * * * * p < 0.0001

Mean nasal conductance (cm3/s)

*
450 * ** p = 0.0009
**
400
350
300
250
200
150
100
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50
0
Pre-dose 30 min 1h 6h 7h 8h 9h 10 h 11 h 12 h
Time

Figure 1. Extent and duration of relief from nasal congestion (nasal conductance) following intranasal administration of xylometazoline compared with
placebo (saline solution)25. The dotted line at a conductance of 250 cm3/s indicates a lower limit of conductance below which patients are generally
considered to be suffering from nasal congestion18. (Reproduced with permission from Eccles et al. (2008)25, ß OceanSide Publications, Inc.).

2.5 * p = 0.0001 vs. placebo

For personal use only.

2
Nasal congestion score

* * *

1.5

0.5

0
Ipra/Xylo 1.0 Ipra/Xylo 0.5 Ipratropium Xylometazoline Placebo
Day 1

Figure 2. Difference in nasal congestion symptom scores after 24 hours of treatment with intranasal xylometazoline used alone or in combination vs.
placebo28. (Reproduced with permission from Eccles et al. (2007)28, ß OceanSide Publications, Inc.).

resolved. The most frequently reported non-nasal AEs used alone, xylometazoline had a clinically relevant
were headache (3.4%) and period pain (10.3%). No decongestant effect that was significantly superior for up
cases of sedation were reported with xylometazoline. to 10 hours compared with placebo25. The superior decon-
gestant effect with xylometazoline leads to high patient
satisfaction with treatment25–27. When xylometazoline
was used in combination with ipratropium bromide,
Discussion nasal congestion and rhinorrhoea were treated simulta-
This review indicates that despite the small number of neously, which seemed to be of great benefit to
studies identified and the heterogeneity regarding the patients. The general impression scores given by patients
number of patients included and the methodology used, for the xylometazoline/ipratropium combinations were sig-
intranasal xylometazoline quickly and effectively relieves nificantly higher than those for xylometazoline and ipra-
nasal congestion in patients with common cold. When tropium used alone both at 24 hours and over 7 days28. The

894 Effects of intranasal xylometazoline in common cold Eccles et al. www.cmrojournal.com ! 2010 Informa UK Ltd

Table 3. Common (3%) adverse events reported in clinical trials of intranasal xylometazoline hydrochloride used alone or in combination in
patients with common cold.
Most common AEs (3%)
Nasal
Epistaxis
Epistaxis/blood tinged mucus
Systemic
Headache
Period pain
Cough
Cystitis
Toothache
a
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Concentration 0.1%.
b
Ipratropium/xylometazoline 0.5 mg/ml.
c
Ipratropium/xylometazoline 1.0 mg/ml.
AEs ¼ adverse events.
2.5
Nasal congestion scores
2 Xylometazoline
1.5
1 Intranasal xylometazoline hydrochloride has been used
For personal use only.
0.5
0 chronic sinusitis or in healthy subjects, using objective
0 2 4 6
Days
Figure 3. Symptom scores for nasal congestion over 7 days of treatment
with intranasal xylometazoline vs. placebo28. (Reproduced with permission
from Eccles et al. (2007)28, ß OceanSide Publications, Inc.).
study confirmed that when used in combination, xylome-
tazoline and ipratropium offered patients greater relief
from the nasal symptoms of common cold than either
drug used alone.
Xylometazoline was well tolerated when used alone or
in combination in common cold, although nasal-related
side effects did occur (e.g. epistaxis, blood-tinged mucus).
Nevertheless, such side effects were generally mild to mod-
erate in nature and did not cause any substantial problems
to patients. Excessive or long-term use of nasal sympatho-
mimetic agents may lead to rhinitis medicamentosa or
rebound congestion29. However, xylometazoline was not
used for longer than 7 days in the studies included, as the
common cold is a short, self-limiting disease. Therefore, as
expected, this effect was not observed in the studies
reviewed. In addition, intranasal administration of drugs
can have an adverse effect on nasal ciliary function30.
However, no clinically important differences in nasal
examination findings were noted in these common cold
studies. Intranasal administration of xylometazoline
ensures that little reaches the systemic circulation. Some
! 2010 Informa UK Ltd www.cmrojournal.com
Current Medical Research & Opinion Volume 26, Number 4 April 2010
Xylometazolinea Xylometazoline þ ipratropium Placebo/vehicle Study
% patients % patients % patients First author, year
3.4 – 3.1 Eccles, 200825
10 21b, 26c 6 Eccles, 200728
3.4 – 12.5 Eccles, 200825
10.3 – 0.0 Eccles, 200825
3.4 – 3.1 Eccles, 200825
3.4 – 0.0 Eccles, 200825
3.4 – 0.0 Eccles, 200825
drug may be inadvertently swallowed, but absorption from
the gastrointestinal tract is poor. Thus, xylometazoline use
does not result in sympathomimetic systemic side effects
Placebo such as tachycardia, anxiety, restlessness and insomnia,
which can be observed with systemic nasal decongestants
such as pseudoephedrine and phenylephrine.
successfully for many years for the symptomatic relief of
nasal congestion. Most of the studies to support its use
have been carried out in patients with allergic rhinitis,
8
(e.g. rhinomanometry) and subjective (e.g. symptom
scores, general impression scores) measurements
(Table 4)24,31–38. These studies indicate that xylometazo-
line effectively reduces nasal congestion within minutes
and has a superior decongestive effect compared with pla-
cebo. Few adverse effects were reported in those studies
that evaluated them, none of which were serious, and no
rhinitis medicamentosa or rebound congestion was
observed.
Other drugs than xylometazoline are used by patients
with common cold in an attempt to relieve nasal conges-
tion, but these appear to have varying degrees of efficacy.
Oxymetazoline – another imidazoline derivative – is used
worldwide to relieve nasal congestion and should have a
similar efficacy to xylometazoline. However, there are few
studies evaluating its efficacy in patients with nasal con-
gestion (e.g. as a result of acute rhinitis39–41), and only one
has been performed in patients with common cold (using
nasal drops)42. Therefore, it is difficult to confirm whether
oxymetazoline has a comparable efficacy to xylometazo-
line. Corticosteroids (potent anti-inflammatory agents)
would be expected to reduce nasal symptoms, yet the
results of clinical studies of intranasal or oral steroids
have shown no clinical benefit43–45. Although NSAIDs
can reduce fever, headache, earache and joint/muscle
pain, they don’t seem to have any beneficial effect on
nasal congestion46. The evidence that is available in
Effects of intranasal xylometazoline in common cold Eccles et al. 895
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896
Table 4. Clinical studies evaluating the nasal administration of xylometazoline hydrochloride in patients with nasal congestion not due to common cold.
Current Medical Research & Opinion Volume 26, Number 4

Reference First author, year Study characteristics Key results

Effects of intranasal xylometazoline in common cold Eccles et al.

Versus baseline
April 2010

Clarke, 199524 Open, non-controlled  Xylometazoline has a decongestant effect: median change from baseline in
Healthy subjects nasal resistance 0.2 kPal–1s and nasal sensation (VAS) 24 mm
Xylometazoline 0.1% (2 ml/nostril)  Significant relationship between nasal sensation and nasal resistance to
20 patients, median age 38 yrs, 40% male airflow (p50.05)
Single application
Active anterior rhinomanometry, subjective nasal patency (VAS)
Petruson, 198131 Open, non-controlled  With xylometazoline all patients could smell with 5 ml air, while 5 patients
Healthy subjects required 10–20 ml air before treatment
Xylometazoline 1 mg/ml (0.15 ml/nostril 3/day)  Nasal air flow increased significantly during the trial
20 patients, mean age 32 yrs, 20% male – Same dose of xylometazoline adequate during 6-week period
6 weeks follow-up – No tachyphylaxis observed
Posterior rhinomanometry, olfaction test, AEs – No reactive congestion observed after trial finished
 No reports of nasal irritation, 1 report of nasal dryness, 1 patient bled a few
drops, 6 patients experienced slightly stuffy nose during first 2 days
Versus placebo
Castellano, 200232 Double-blind, parallel-group, randomized  All formulations of xylometazoline had concentration-dependent
Healthy subjects decongestant effect, superior to placebo
Xylometazoline 0.1% vs. xylometazoline aqueous (0.025%, 0.05% or 0.1%, – No statistical significance between formulations
0.3 ml/nostril) or xylometazoline þ HA (0.025%, 0.05% or 0.1%) or placebo  Xylometazoline 0.1% significantly superior to placebo, with mean 45.2%
(both 0.3 ml/nostril) reduction in total inspiratory resistance and a similar reduction in expiratory
120 patients resistance
Single application  No AEs observed at any concentration
Active anterior rhinomanometry, AEs
Versus active control
Caenen, 200533 Open, controlled  Xylometazoline reduced nasal airway resistance by average 37.3% in all
Healthy subjects (n ¼ 10), chronic sinusitis patients (n ¼ 10) patients and healthy subjects over 8 hours
Xylometazoline 0.1% (2 sprays/nostril) vs. oral pseudoephedrine (120 mg)  Pseudoephedrine did not have clear and long lasting effect on turbinates
20 patients, 65% male  MRI clearly showed superior decongestant effect with xylometazoline over
8 hours follow-up pseudoephedrine
Active anterior rhinomanometry, nasal and sinus mucosal effects  No decongestant effect on sinus mucosa with either drug

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Stübner, 200134 Open, randomized, crossover  Decongestive effect with xylometazoline similar to cetirizine/pseudoephe-
Perennial allergic rhinitis drine, with no statistically significant differences
Xylometazoline 0.1% (1 spray/nostril, 2/day) vs. oral cetirizine (5 mg) plus  Rapid onset of decongestant activity with xylometazoline (530 min)
pseudoephedrine (120 mg) (1 capsule, 2/day)  Superior symptom scores for nasal congestion with xylometazoline, but all
36 patients, mean age 25.7  4.7 years, 50% male other symptom scores and global evaluation better with cetirizine/pseudoe-
4 days follow-up phedrine
Active anterior rhinomanometry, nasal cavity photographs, nasal secretions,  Lower nasal secretion with cetirizine/pseudoephedrine
symptoms scores, global evaluation, AEs  No clinically relevant AEs recorded
Tzachev, 200235 Double-blind, crossover, randomized  Both xylometazoline formulations had decongestant effect at initial mea-
Perennial allergic rhinitis surement (no significant differences between solutions), but 34.2% reduction
Xylometazoline 0.1% (RS) vs. xylometazoline 0.1% mucoadhesive (TS) (both in nasal airway resistance with TS and slight increase with RS on day 5
max. 6/day)  Nasal congestion was significantly reduced in both groups on day 5
20 patients, age 18–69 years, 35% men  Main AEs bitter taste and prickling, with slightly higher rate with RS

! 2010 Informa UK Ltd www.cmrojournal.com

5 days follow-up
Nasal airflow resistance (rhinomanometry), symptoms scores, AEs
Hochban, 199936 Single-blind  After 20 min, all drugs exhibited approx. 60% of their maximum decongestant
Healthy subjects effect
Xylometazoline 0.025%, 0.1% vs. oxymetazoline 0.01%, 0.05%, indanazoline  Max decongestant effect achieved after 40 min, with 20% increase in volume
0.118%, naphazoline 0.02%, tetryzoline 0.1%, tramazoline 0.1264% and  Xylometazoline 0.025% and 0.1% still had appreciable decongestant effect
placebo (0.3 ml/nostril, single application) after 4 hours (as did oxymetazoline 0.05% and 0.01% and tramazoline
108 patients, age 18–36 years, 55.6% male 0.1264%)
8 hours follow-up – Indanazoline 0.118%, naphazoline 0.02% and tetryzoline 0.1% had no
Acoustic rhinomanometry effect at all after 4 hours
 No differences between xylometazoline concentrations recommended for
adults and for infants in terms of efficacy
 No rebound effect with xylometazoline
Pickering, 199937 Open, randomized  Significant increase in PIF, PEF, MIF and MEF with xylometazoline
Healthy subjects – 30.2–44.0% change from nasal baseline (p50.001)
Stent alone followed by xylometazoline 0.05% (2 drops/nostril)
54 patients, mean age 9.5 years, 51.9% male
15 min follow-up
PIF and PEF, MIF and MEF, point where nasal flow–volume becomes super-
imposable on oral curve (%Sup)
Jessen, 198838 Open, controlled  Significant decongestant effect with pharmacologic decongestion vs.
‘Nasal congestion’ patients (n ¼ 100, mean age 29 years, 71% male) physical exercise (p50.05)
Xylometazoline 0.1% (0.09 ml, 0.14 ml or 0.42 ml) or oxymetazoline 0.05%  Compared with physical exercise, greatest decongestive effect with
(0.09 ml) vs. exercise xylometazoline 0.1% (2 sprays, 7–8 min apart)
15 min follow-up  Mean nasal airway resistance (expressed as v2) for all patients 33.7
Active anterior rhinomanometry after pharmacologic decongestion vs. 39.2 after exercise

VAS ¼ visual analogue scale; AEs ¼ adverse effects; HA ¼ hyaluronic acid; MRI ¼ magnetic resonance imaging; PIF and PEF ¼ peak inspiratory and expiratory flows; MIF and MEF ¼ mid inspiratory and expiratory flows.
Current Medical Research & Opinion Volume 26, Number 4

Effects of intranasal xylometazoline in common cold Eccles et al.

April 2010

897
 Current Medical Research & Opinion Volume 26, Number 4 April 2010
common cold appears to support the use of xylometazoline
nasal spray, either alone or in combination with ipratro-
pium, in relieving nasal congestion associated with
common cold.
This review is limited by the fact that only two search
engines (PubMed and Cochrane) were used and a limited
number of search terms included. Therefore, the search
technique may not have uncovered all relevant clinical
trials in common cold. What is clear is that few studies
of xylometazoline have been performed in patients with
common cold, despite the drug being a popular choice with
patients, and more are needed. In addition, these studies
vary considerably in the numbers of patients included and
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the methodology used, and two did not assess any safety
outcomes. More studies designed to specifically assess the
onset and duration of action and to fully evaluate the risk
of adverse events with xylometazoline would be beneficial,
as patients with a cold are likely to seek rapid and
long-lasting symptomatic relief from nasal congestion. In
addition, it is impossible to quantify whether xylometazo-
line is more effective than other types of drug available in
common cold as no head-to-head studies in this indication
have been carried out. Further, well conducted, rando-
mized, placebo- and active-controlled studies would be of
For personal use only.
great benefit in clarifying the role of intranasal xylometa-
zoline in common cold, to ensure that patients receive
optimal symptomatic relief of nasal congestion.
Conclusions
Four studies in common cold have demonstrated that
intranasal administration of xylometazoline hydrochloride
in patients with common cold quickly and effectively
relieves nasal congestion. Use of xylometazoline in com-
bination with ipratropium bromide provides greatest ben-
efits to patients by treating nasal congestion and
rhinorrhoea simultaneously. Xylometazoline is well toler-
ated when used alone or in combination with ipratropium.
Transparency
Declaration of funding
This study was sponsored by Novartis Consumer Health, Inc.,
which markets the reviewed drug (xylometazoline; Otrivin/Otrivin
Complete/Otrivin Comp/Otrivin Duo/OtriDuo) worldwide.
Declaration of financial/other relationships
K.M. and S.C. were both employees of Novartis Consumer
Health at the time of the manuscript preparation. R.E. has
worked in the past as a consultant with Novartis Consumer
Health, Inc. and had also received a grant for research, but has
received no financial remuneration for authorship of this review.
Peer reviewers may receive honoraria from CMRO for their
review work. Peer Reviewer 1 has disclosed that he/she is the
898 Effects of intranasal xylometazoline in common cold Eccles et al.
recipient of research grants from Dyax, Dynova and Meda; is a
consultant to Cornerstone, Dynova; and is on the speakers bureau
for AstraZeneca and ViroPharma. Peer Reviewer 2 has disclosed
that he/she has no relevant financial relationships.
Acknowledgements
The draft of this manuscript was prepared by a professional med-
ical writer (Deborah Nock, DPP-Cordell Ltd), with full review
and approval by all authors; this support was funded by Novartis
Consumer Health.
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