BENZYDAMINE

Oropharyngeal formulations

> Contents <

Contents

1. INTRODUCTION pag. 1 5. EFFICACY pag. 10 6. GLOBAL SAFETY ANALYSIS pag. 20

• Therapeutical rationale
2. CHEMICAL STRUCTURE pag. 2 5.1 PAINFUL INFLAMMATORY 7. POST MARKETING
CONDITIONS OF oropharynx EXPERIENCE pag. 21
3. CSAID Benzydamine TRACT 7.1 WORLDWIDE SALES AND
vs. NSAIDs pag. 3 5.2 ODONTO-STOMATOLOGIC CONSUMPTION
CONDITIONS 7.2 INCIDENCE OF ADVERSE EVENTS
4. PHARMACOLOGY pag. 4
5.3 USE IN PARTICULAR AND EVALUATION OF THE
4.1 PHARMACOKINETICS INFLAMMATORY CONDITIONS RISK/BENEFIT RATIO
4.2 PHARMACODYNAMICS OF THE ORAL CAVITY
4.2.1 Anti-inflammatory activity • Pharyngo-laryngeal pathology 8. REFERENCES pag. 22
following intubation
• Effects on cytokines
• Pharyngitis post-tonsillectomy
• Effects on chemotaxis
• Oral radiation Mucositis
• Effect on the production of prostaglandins
• Aphthous mouth ulcer
4.2.2 Local anaesthetic activity • Burning Mouth Syndrome
4.2.3 Antimicrobial activity 5.4 USE IN CHILDREN
BENZYDAMINE
Oropharyngeal formulations

1. INTRODUCTION
Benzydamine is an anti-inflammatory
agent with local anaesthetic and analge-
sic properties.1 It was synthesized in the
Laboratories of the Angelini Research In-
stitute in the 1960s, and marketed in Italy
in the 1970s. It was later released on the
market in more than 70 European, Ameri-
can and Asian Countries.
Pharmacodynamic investigations have
shown that benzydamine acts as a
suppressor of proinflammatory cyto-
kines, especially against Tumor Necrosis
Factor-α (TNF-α) and to a lesser ex-
tent, Interleukin-1β (IL-1β) and Che-
mokine ligand 2 (CCL2) monocyte che-
motactic protein-1 (MCP-1), 2-4 that are
well known to be potent mediators of
inflammation.5 However, it did not af-
fect other inflammatory cytokines like
Interleukin-6 (IL-6) and Interleukin-8
(IL-8) and, importantly, cytokines with
anti-inflammatory properties, such as
Interleukin-10 (IL-10) and interleukin-1
receptor antagonist (IL-1ra). 2-4
The mechanism of action of benzyda-
mine differs from that of the aspirin-like
drugs. The main difference is that benzy-
damine is - in comparison to aspirin like
drugs - a weak inhibitors of the synthesis
of prostaglandins, while it is a powerful
inhibitor of proinflammatory cytokines.
For that reason, it can be classified as a
Cytokine Suppressive Anti-inflammatory
Drug (CSAID).2,6
In addition to its anti-inflammatory
activity, benzydamine shows local an-
algesic/anesthetic effects7 that in the
topical route can be fully exploited and
turned into competitive advantages over
Non-Steroidal Anti-Inflammatory Drugs
(NSAIDs).
In fact, its elective therapeutic use is the
topical control of acute inflammation and
pain. Benzydamine formulated as 0.15%
mouthwash, 3 mg lozenges, 0.15% and
0.30% nebulizers, has its target indication
in the symptomatic treatment of pain and
irritative/inflammatory conditions of the
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oropharynx (gingivitis, stomatitis, phar-
yngitis), even when due to dental therapy,
although it has also been largely used in
various conditions ranging from post-
tonsillectomy pharyngitis or radiomucosi-
tis, to throat irritation and/or dysphagia
induced by intubation.
Benzydamine was widely used in clinical
practice and, therefore consistent clinical
experience together with a large amount
of literature demonstrating its efficacy
and tolerability, are available. The aim of
this document is to summarize the phar-
macological, pharmacokinetic and clinical
data available on benzydamine.
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2. CHEMICAL STRUCTURE

The chemical structure of benzydamine The molecular formula is C19H23N3O · HCl.

hydrochloride, or N,N-dimethyl-3-{[1- It has a molecular weight of 345.9 and a
(benzyl)-1H-indazol-3yl]oxy]-1-pro- melting point of 158.5 – 160.0 °C.
ponamine hydrochloride differs from that
of conventional NSAIDs. It is a white crys-
talline powder, very soluble in water, free-
ly soluble in ethanol (96%) and in chloro-
form, and practically insoluble in ether.

O N

N
N
HCI

Figure 1: structural formula of benzydamine hy-

drochloride.

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3. CSAID Benzydamine vs. NSAIDs

Although benzydamine is a non steroidal Following topical applications benzyda-

anti-inflammatory agent, it possesses a mine shows local anesthetic properties,7
different mechanism of action that dis- not common among other NSAIDs,8 which
tinguishes it from conventional NSAIDs. in topical use allows benzydamine to ex-
ert an immediate effect on pain.
The main feature that differentiates ben-
zydamine from aspirin-like drugs is its Figure 2 summarises the main features
mechanism of action. Unlike, NSAIDs, and advantages displayed by the CSAID
which derive their anti-inflammatory benzydamine compared to NSAIDs. Figure 2: features and advantages of CSAID ben-
zydamine respect to NSAIDs.
effects by inhibiting the synthesis of
prostaglandins,8 benzydamine inhibits the
production of proinflammatory cytokines,
NSAID CSAID-BENZYDAMINE
mainly TNF-α, and to a lesser extent IL-1β
and MCP-1.2-4 Thus, benzydamine, can be
fully considered a CSAID. 2,6
Anti- Cytockine Lack of some of the
inflammatory PGEs inhibition typical side-effects of the
inhibition
activity aspirin - like drugs
Since benzydamine lacks significant inhi-
bition against prostaglandins it does not
produce the characteristic side-effects VS
of aspirin-like drugs9 (Figure 2). Benzy-
damine, in fact, inhibits prostaglandins Local Structural features Structural features
synthesis in vitro only at concentrations anaestetic Non-similar to local similar to local Prompt relief of pain
activity anaesthetic drugs anaesthetic drugs
which are not reached in vivo (200-400
µg/ml) following both local and systemic
administrations.1

3
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4. PHARMACOLOGY

Benzydamine is a Cytokine Suppressive
Anti-inflammatory Drug, which is devoid
of activity on arachidonic acid metabo-
lism and has local anaesthetic and anal-
gesic properties.3
On the contrary to the systemic admin-
istration, the local application of benzy-
damine produces higher concentrations
in the inflamed area than in the blood, as
demonstrated in animals and humans.10,11
The capability of benzydamine to con-
centrate in the inflamed tissues, with
low systemic exposure, represents a clear
advantage by limiting potential systemic
or throat, even if detectable drug plasma two other treatments. The mean plasma
levels have been reported after topical ad- concentration time curves for each
ministrations, probably related to absorp- benzydamine treatment are shown in Fig-
tion through the oral mucosa.13 ure 3.
After a single administration of 0.15%
benzydamine solution by ingestion (25.5
mg benzydamine/70 kg), gargle (102 mg
benzydamine/70 kg), and spray (about 12 mg
benzydamine),14 detectable drug plasma
concentrations were observed in all sub- Figure 3: mean plasma concentration time curves
jects. After ingestion, the drug levels were of benzydamine following ingestion, gargle and
spray.14
clearly much higher than in either of the
200 Ingestion
Plasma benzydamine concentrations (ng/ml)

side effects.8 In addition, the benzydamine 180

Mouthwash-gargle
topical preparations show additional 160
Spray
pharmacological effects, such as a local 140
anaesthetic effect, that cannot be ob- 120

tained through systemic administration.12 100

80
60

4.1 PHARMACOKINETICS 40
20
Mouthwash, oral spray and lozenges are
0
oropharyngeal formulations intended to 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32
exert local effects in the oral cavity and/ Hours after administration

4

After repeated benzydamine doses by in-
gestion, gargle, and spray, no significant
accumulation of the drug was observed in
plasma. As reported after single adminis-
tration, the benzydamine level in plasma
differed between treatments, with the
spray and gargle benzydamine AUCs lower
than that observed after drug ingestion.14
Pharmacokinetic assessment of benzy-
damine 0.15% mouthwash obtained after
gargling with a 15 ml dose (6 gargles every
two hours), and after ingestion of a single
15 ml dose showed that the systemic ben-
zydamine bioavailability after multiple gar-
gling was approximately 16% in compari-
son to the single dose ingestion. 15
After the administration of a single 3 mg
benzydamine lozenge, peak plasma values
of 37.8 ng/ml with an AUC of 367 ng/ml*h
were observed approximately 2 hours
after administration.13 These levels are
not sufficient to produce systemic
pharmacological effects.16
Excretion occurs mainly through urine
and is mostly in the form of inactive me-
tabolites or conjugation products.17
4.2 PHARMACODYNAMICS
Benzydamine is a cytokine suppressive anti-
inflammatory drug2 with anti-inflammato-
ry, analgesic and local anaesthetic effects. It
is also reported to have a degree of antibac-
terial and antifungal activity in vitro.8
4.2.1 Anti-inflammatory activity
The main mechanism of action responsible
for the anti-inflammatory effect of benzy-
damine is its inhibitory activity on the pro-
duction of cytokines .2
However, benzydamine exerts other ac-
tivities that may contribute to its anti-
inflammatory effect, such as reducing the
perfusion flow and vascular permeability
produced by histamine, acetylcholine, se-
rotonin and epinephrine, the inhibition of
platelet aggregation, thrombus formation,
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degranulation of human polymorphonu-
clear leukocytes, and inhibition of the mi-
gration of human monocytes.10, 18, 19, 20
• Effects on cytokines
In pharmacodynamic investigations, per-
formed in vitro on mononuclear cells of
humans and mice exposed to different in-
ducers such as lipopolysaccharide (LPS) and
Candida albicans, benzydamine was shown
to inhibit TNF-α production and to a lesser
extent IL-1β and MCP-1, whereas it did not
affect IL-6 and IL-8 production.2,3
Data demonstrating this selective inhibitory
effect of benzydamine on cytokine produc-
tion in human mononuclear cells stimulated
by Candida albicans are reported in Table 1.3
Benzydamine (6.25-50 μM) produced a
dose-dependent reduction in TNF-α and
MCP-1. The release of IL-1β decreased with
benzydamine concentrations up to 25.0 μM,
while no clear effects on the release of IL-6
and IL-8 were observed.3
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Benzydamine Candida albicans-induced production of Figure 4: activity of benzydamine, ibuprofen and
naproxen on TNF-α and MCP-1 production by
TNF-α (ng/ml) IL-1β (pg/ml) IL-6 (U/ml) IL-8 (ng/ml) MCP-1 (ng/ml) Candida albicans-stimulated peripheral blood
Medium 7,6 ± 1,6 73,01 ± 6,46 419 ± 105 2,99 ± 0,22 1,56 ± 0,21 mononuclear cells (Adapted from Sironi et al.). 3

6.25 μM ND 51,82 ± 6,02 354 ± 73 2,48 ± 0,26 1,14 ± 0,24*

12.5 μM 6,4 ± 0,9 47,20 ± 3,24* 316 ± 91 2,78 ± 0,31 1,03 ± 0,22** 40 Ibuprofen

levels (ng/ml)
35 Naproxen
25.0 μM 4,9 ± 0,5** 39,52 ± 4,19** 656 ± 80** 2,57 ± 0,12 0,72 ± 0,06** Benzydamine
30
50.0 μM 1,9 ± 0,2** 66,20 ± 5,66 353 ± 307 2,77 ± 0,29 0,64 ± 0,05** 25
40 Ibuprofen

(ng/ml)
20

TNF-α levelsTNF-α
35 Naproxen
ND= Not Determined
15
30 Benzydamine
P<0.05 vs. medium, ** P<0.01 vs. medium by Dunnett’s test
a
) Results are from one representative normal subject of the five (TNF-α, IL-1β, IL-6 and IL-8) or six (MCP-1) examined 10
25
5
20
0
15
Table 1: effect of benzydamine on cytokine and chemokine production by peripheral blood mononuclear cellsa. 12,5 25 50
10 drug concentration (microM)
5
Importantly, in the same cells stimulated It is worth noting that unlike benzy- 0
12,5 25 50
with LPS and under conditions where TNF-α damine, NSAIDs such as ibuprofen and drug concentration (microM)
and IL-1β were decreased by benzydamine, naproxen were definitely powerless in
the drug did not modify the production of the suppression of inflammatory cy- 4

(ng/ml) levels (ng/ml)

3,5
cytokines with anti-inflammatory proper- tokine production from Candida acti-
3
ties, such as IL-10 and IL-1ra.4 vated mononuclear cells. 3 Figure 4 shows 4
2,5

MCP-1 levels MCP-1

the effects of different concentrations 3,5
2
These findings suggested that the anti- (12.5, 25 and 50 μM) of these two drugs 3
1,5
inflammatory activity of benzydamine on TNF-α and MCP-1 production in 2,5
1
stems from its ability to reduce the produc- comparison to the same concentrations 2
0,5
tion of proinflammatory cytokines, without of benzydamine. 1,5
0
12,5 25 50
1
affecting anti-inflammatory factors.4 drug concentration (microM)
0,5
6 0
12,5 25 50
drug concentration (microM)
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Benzydamine confirmed its suppressive
effect on these cytokines, while neither C5a C5a receptor PIP2
ibuprofen nor naproxen significantly re-
PLC β2
duced the amount of TNF-α and MCP-1
secreted from Candida-treated human
β PI3K
cells.3 β γ
α1 γ
G1 protein
• Effects on chemotaxis IP3 DAG Akt/PKB PIP3
Benzydamine exerts an inhibitor activity
on monocyte chemotaxis, a function
shared by immune cells and crucial in
inflammation.20 [Ca2*]i
p38 ERK
As shown in Figure 5, chemotactic acti-
vation is mediated by binding a chemot-
actic agonist to trans-membrane recep-
tors and results in the activation of
Chemotaxis
multiple signaling proteins and second
messengers. The activation of mitogen–
activated protein kinase (MAPKs), such Riboldi et al.20 showed that benzydamine in- Figure 5: proposed signal transduction model for
as extracellular-signal-regulated pro- hibited the migration of inflammatory leu- marcrophage chemotaxis. A chemotactic agonist
tein kinases 1/2 (ERK) and p38 MAPK kocytes, and this effect was associated with (C5a) by binding to transmembrane receptors dif-
seems to be one of the key components a strong inhibition of the MAPK pathway. ferentially stimulates ERK1/2and p38 MAPK phos-
phorylation to induce chemotactic migration.21
in signal transduction associated with In particular, benzydamine strongly inhib-
cell migration.21 ited chemoattractant-induced activation of
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both ERK1/2 and p38 MAPK pathways im-
plicated in cell migration.
These results suggested that the benzy-
damine inhibitory effect on monocyte
chemotaxis most likely contributes to its
anti-inflammatory activity. 20
• Effects on the production of
prostaglandins
It has been shown that prostaglandin
biosynthesis is stimulated by cytokines
such as IL-1 and TNF-α in various types
of cells, including gingival fibroblasts.
When the cells were treated simultane-
ously with benzydamine and IL-1β or
TNF-α, the drug significantly reduced the
stimulatory effect of these cytokines on
prostaglandin E2 (PGE2) production as well
as significantly reduced the production of
prostaglandin I2 (PGI2). 22
This capability of benzydamine to reduce
prostaglandin production induced by IL-
1β or TNF-α in gingival fibroblasts may
8
confirm the rationale for the use of the
drug in controlling inflammatory oropha-
ryngeal conditions.
4.2.2 Local anaesthetic activity
Following topical applications, benzyda-
mine shows local anaesthetic properties.7
In a clinical trial performed on 87 healthy
subjects benzydamine, when applied
topically to normal mucosa for 60 sec-
onds, was found to exert a remarkable
anaesthetic activity that was superior to
the control (cetylpyridinium hydrochlo-
ride 0.025%) and placebo mouthwashes,
showing also a long lasting effect (more
than 90 minutes).7 The local anaesthetic
activity of benzydamine has been shown
to be extremely useful in the treatment
of painful mouth and throat conditions,
mainly due to rapid pain relief.23
These local anaesthetic properties dem-
onstrated by benzydamine are most prob-
ably due to its structural features. In fact,
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the drug shares with local anaesthetics
an aromatic (hydrophobic) ring structure,
linked to a basic tertiary amine group (hy-
drophilic) by a short alkyl chain (Figure
6). Therefore, benzydamine similar to as
local anaesthetics, reversible block nerve
conduction when topically applied in
appropriate concentrations.24
4.2.3 Antimicrobial activity
Bactericidal activity of benzydamine (drug
concentrations ranged from 10 to 1280 µg/
ml) was determined against 110 bacterial
strains clinically isolated in Spain. For all
the bacteria studied, the MICs observed,
between 320 and 1280 µg/ml, were lower
than benzydamine concentration in the
marketed product (1500 µg/ml).25
The fungistatic and fungicidal activity of
benzydamine against Candida-albicans and
non-albicans strains (20 Candida strains:
18 clinical isolated and two American Type
Culture Collection strains) were also in-
vestigated. At lower concentrations ben-
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zydamine inhibited growth in all Candida Intermediate chain
strains studies (fungistatic activity), with (ester, ether or amide linkage)
MIC ranging between 6.25-50 μg/ml, while
at higher concentrations (0.2 mg/ml) it is
a fungicidal due to its direct damage to the
cytoplasmic membrane. The benzydamine Structural pattern of
concentration in oral solutions (0.15% N H+ local anaesthetic drugs
mouthwash and spray) is 30 times higher
than the MIC of the least susceptible Can-
dida strains.26 Hydrophobic Hydrophilic
aromatic ring quaternary amine

O N + H+

N
N
Benzydamine hydrochloride

Figure 6: structural features of benzydamine

shared with the known local anaesthetics.24

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5. EFFICACY
Therapeutic Rationale The amount of available clinical data on the
Benzydamine has been largely used in efficacy and safety of benzydamine is very
symptomatic treatment of pain, irritation extensive. Clinical trials hereinafter present-
and inflammation of the oropharynx, even ed are the most representative studies with
when due to dental therapy, although it the mouthwash, oropharyngeal spray and
has also been largely used for various con- lozenges formulations in adults and chil-
ditions ranging from post-tonsillectomy dren affected by various local mouth and
pharyngitis or radiomucositis, to throat throat inflammatory conditions.
irritation and/or dysphagia induced by in-
tubation.
The main characteristics that make topical 5.1 PAINFUL INFLAMMATORY
benzydamine (0.15% mouthwash, 0.15% and CONDITIONS OF OROPHARINX TRACT
0.30% oropharyngeal spray and lozenges) The effectiveness of benzydamine 0.15%
useful in the treatment of inflammatory and mouthwash in relieving throat pain and
painful disorders are hereinafter presented. dysphagia has been shown in different
FEATURES ADVANTAGES
Anti-inflammatory > Reversal of the typical signs and symptoms high
ACTIVITY of inflammation therapeutic
efficacy
TOPICAL ANAESTHETIC EFFECT > Prompt pain relief
> Penetration and accumulation in the site
of inflammation safe use
also
> Therapeutic actions where they are most required
SUITABLE DOSAGE FORMS in children
> Limitation of the systemic exposure
> Easy administration and good taste
high
compliance
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studies. In comparison to the placebo,
benzydamine displays a significantly better
reduction of pain with a more rapid decrease
of pain severity over a 2-day period.27
Patients with acute pharyngitis, rhinitis,
and tonsillitis instructed to gargle with
15 ml of mouthwash containing benzy-
damine (every 1.5-3 hours for 7 days) ex-
perienced a greater reduction of pain and
burning sensations starting from the 2nd
day of therapy, as compared to placebo-
treated patients. Dysphagia, otalgia, and
sensation of hypoacusia also appeared
to significantly improve in the group
treated with benzydamine. In addition, a
reduction in hyperemia and oedema of
the pharynx, as well as in hypertrophy
of the lymph nodes, was observed from
the 1st day of treatment in benzydamine-
treated patients.28
Schachtel et al. confirmed these findings
in two more placebo-controlled clinical
trials involving a total of 283 adults pa-
tients with acute sore throat.
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Patients were treated with benzydamine MEAN IMPROVEMENT
EFFICACY VARIABLES
0.15% mouthwash (15 ml dose every 2-4 Benzydamine (N=63) Placebo (N=61) p-value
hours up to 6 times daily for up 7 days) Difficulty swallowing scale
or placebo.29,30 25.9 mm 15.8 mm 0.018
(VAS 0 to 100mmm)
Change in pain scale
27.4 mm 18.6 mm 0.062
Results of efficacy parameters (difficulty (VAS 0 to 100mm)
swallowing scale, change in pain scale, Sore throat relief scale
1.9 units 1.3 units 0.023
and sore throat relief scale) assessed in (0=none to 6=complete)
the first study, are reported in Table 2.29
Table 2: overall mean improvement after benzydamine and placebo treatments in the intent-to-treat population.

Benzydamine was able to rapidly relieve

the characteristic symptoms of sore
throat, such as pain on swallowing and
pharyngeal inflammation by virtue of
its topical effects.29 Similar results were
obtained in the second trial with the ex-
ception of the difficulty in swallowing
scale.30
The effectiveness of benzydamine oro-
pharyngeal spray in the treatment of
acute or recurring chronic tonsillitis with-
out concurrent antibiotic therapy, was
compared with an association containing
the antiseptic hexamidine plus an anaes-
thetic local tetracaine.
Treatments showed a comparable effec- Efficacy parameters were evaluated ac-
tiveness, good tolerability and palatability, cording to a 4-point scale (0=no symp-
even if a quicker and intense improvement tomatology to 3=severe symptomatol-
was obtained with benzydamine.31 ogy). Results of these studies are shown
in Figures 7-8.
Benzydamine 0.15% mouthwash, thanks
to its proven effectiveness and extensive
use in the topical treatment of oral inflam-
matory and painful conditions, was chosen
as reference product in two clinical stud-
ies. These were performed with the aim of
demonstrating the therapeutic equivalence
of benzydamine 3 mg lozenges with the
mouthwash formulation, in the treatment
of oropharyngeal disease.32,33
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3 lozenges mouthwash
Mean score

0
Basal 3-4 6-7 9-10 Basal 3-4 6-7 9-10 Basal 3-4 6-7 9-10 Basal 3-4 6-7 9-10 Basal 3-4 6-7 9-10 Basal 3-4 6-7 9-10
time days days days time days days days time days days days time days days days time days days days time days days days

Edema Hyperemia Disphagia Burning sensation Swelling sensation Pain

Figure 7: mean score for the evaluated signs and

The efficacy of 3 mg benzydamine lozeng-
symptoms of the oropharyngeal disease record- es and its good tolerability were further
ed at basal and subsequent observation times confirmed in a controlled clinical study
(Adapted from De Vita).32 that included a large number of patients
(N=120) with acute or chronic disorders
of the respiratory tract characterized by
In both
3 studies, a clear improvement/re- cough and inflammatory symptoms of
Mean score
Benzydamine produced a progressive
clinical improvement in symptoms and
signs caused by the inflammatory pro-
cess. The cough symptom and the aver-
age number of cough, were significantly
reduced only in the groups treated with
thelozenges
associationmouthwash
and dextromethorphan.

duction of symptoms was observed with the oropharynx. Benzydamine 3 mg loz- Systemic and local tolerability of the
no statistically significant differences be- enges, dextromethorphan 7.5 mg loz- treatments was excellent.34
tween
2 the two benzydamine oropharyn- enges and their combination were ad-
geal dosage forms.32,33 ministered t.i.d for a period of 15 days.
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3
lozenges mouthwash
Mean score

0
Basal 3-4 6-7 9-10 Basal 3-4 6-7 9-10 Basal 3-4 6-7 9-10 Basal 3-4 6-7 9-10 Basal 3-4 6-7 9-10
time days days days time days days days time days days days time days days days time days days days

Edema Hyperemia Spontaneous pain Evoked pain Dentin Hypersensivity

Figure 8: mean score for the evaluated signs and

symptoms of the oropharyngeal disease record-
ed at basal and subsequent observation times
(Adapted from Di Maggio).33
The pharmaceutical form of tablets, to be
dissolved in the mouth, was very well ac-
cepted because of its simple administra-
tion, which improved patients’ compli-
ance. Lozenges also have an advantage
over sprays and gargles which is that of
being slow-releasing, thereby continu-
ously delivering the drug to the affected
areas of the throat.35
Thus, 3 mg benzydamine lozenges may rep-
resent a useful alternative to mouthwash,
especially in those cases in which a more
convenient pharmaceutical preparation
may facilitate the patients’ compliance, con-
tributing to a superior therapeutical result.
5.2 ODONTO-STOMATOLOGIC
CONDITIONS
The efficacy of benzydamine, in terms
of pain relief, has also been proven in
the treatment of patients suffering from
diseases of the periodontium and oral
mucosa.36-38
In periodontal disease, the main etio-
logic factor is dental plaque. Plaque can
be removed by brushing and flossing, but
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patient’s compliance with oral hygiene
regimens is often very low. Thus, a mouth-
wash capable of reducing plaque and in-
flammation would be a valuable aid in treat-
ing and preventing periodontal diseases.
The efficacy of a 7-day treatment with ben-
zydamine alone (3-4 times a day) in reduc-
ing plaque formation had been previously
demonstrated in two double-blind, placebo-
controlled clinical studies.12, 39 Significant
improvements were demonstrated with
benzydamine compared to placebo in all the
efficacy parameters tested: plaque index,
gingival index, healing, and pain reduction.
significant decrease in mean pain intensity
(Figure 9) Benzydamine, therefore, proved
its beneficial effects also on pain due to
conservative dental therapy.40
The therapeutic efficacy and local tolera-
bility of benzidamine 0.15% oropharyngeal
spray was demonstrated in comparison to
placebo in patients with various odonto-
stomatological conditions (such as gingi-
vitis, dental extractions, post-extraction
wounds, peri-coronal inflammations, exci-
sion of dental operculum and excision of
papillomas). Benzydamine 0.15% oropha-
ryngeal spray (4 nebulisations, 6 times dai-
<
demonstrated in patients undergoing ex-
traction of the third molars.42
Similarly, a very good clinical efficacy was
observed following treatment with benzy-
damine oropharyngeal spray and mouth-
wash in patients with oral erosive and
ulcerative lesions that appeared during
the course of various diseases. The symp-
tomatology improved evenly in 74% of
patients treated with oropharyngeal spray
and mouthwash after 3-4 days of adminis-
trations. It is important to note that in case
3,5

Mean pain level

ly for 4 days) was able to alleviate patients’ 3
3,047

Although the above results are very inter- discomfort with a significant improvement 2,5
esting, benzydamine 0.15% mouthwash is of symptoms and signs starting from the 1st 2
2,075

mainly used in the treatment of different
pathologies of the oral cavity, including ef-
fects due to dental therapy.
In patients (N=106) with chronic perio-
dontitis undergoing removal of dental
deposits, the treatment with benzydamine
0.15% mouthwash produced a statistically
treatment day. By the last day of treatment 1,5
all signs and symptoms disappeared with 1
a highly significant difference in favour of 0,5
the benzydamine group (p<0.001).41 0
Before
benzydamine application
After
benzydamine application
The usefulness of the post-operative treat-
ment with benzydamine 0.15% spray (6 Figure 9: comparison of the mean pain level be-
applications days for 5 days) was also fore and after benzydamine application.40

14

of single lesions benzydamine oropharyn-
geal spray formulation is the most simple
to use, since it allows a precise application
of the drug.37
5.3 USE IN PARTICULAR INFLAMMATORY
CONDITIONS OF THE ORAL CAVITY
Sore throat and/or dysphagia are often
reported by patients with nasal-gastric in-
tubation or undergoing tracheal intubation
during general anaesthesia. In fact, nasal-
gastric or tracheal intubation and direct
local surgical procedures involving mouth,
gums and throat often produce inflamma-
tory conditions of the oropharynx.
Benzydamine was also widely used in the
treatment of aphthous ulcers and oral mu-
cositis, a frequent complication of head
and neck radiotherapy.8
• Pharyngo-laryngeal pathology
following intubation
Twenty four to ninety percent of pa-
tients who receive general anaesthesia
and endotracheal intubation suffer from
postoperative sore throat.43 Benzydamine
mouthwash and oropharyngeal spray ap-
plied both before and after surgery have
been shown to be effective in reducing
the incidence and severity of the postop-
erative sore throat.
Pre-emptive treatment with benzydamine
mouthwash and oropharyngeal spray has
been reported to decrease the incidence
and severity of sore throat due to endo-
tracheal intubation.43,44
These findings were confirmed in a com-
parative clinical trial. In this study, gar-
gling with benzydamine (0.15% mouth-
wash, 15 ml dose made into 30 ml with
distilled water) reduced the incidence of
postoperative sore throat for up to 24
hours, while dispersible aspirin gargles
(350 mg tablet made into 30 ml with dis-
tilled water) only up to 2 hours.45
Two previous placebo-controlled studies
proved that benzydamine has a marked
therapeutic effect in the treatment of in-
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flammatory lesions due to nasal-gastric
and endotracheal intubation.
Patients with sore throat and/or dysphagia
due to the use of nasal gastric tube and
patients that underwent endotracheal
intubation received benzydamine 0.15%
mouthwash46 and 0.30% spray47, respec-
tively. The dosages scheduled consisted
of 15 ml dose of benzydamine every 2-3
hours for 1-2 days or of 10 nebulizations
of benzydamine spray every 3 hours for
3 days. Significant relief of pain and dys-
phagia was recorded in favour of benzy-
damine, with an improvement in signs and
symptoms clinically and statistically supe-
rior to that observed in the placebo group.
The improvement was evident starting
from Day 2, with the complete resolution
of symptomatology on Day 3.
• Pharyngitis post-tonsillectomy
Tonsillectomy, a surgical procedure com-
monly performed in children and young
adults, may often produce dysphagia, sore
15

throat and earache in the early post-oper-
ative period.48
Many studies performed on adult tonsil-
lectomized patients have shown the thera-
peutic efficacy of benzydamine, particu-
larly when topically administered as 0.15%
mouthwash (5 times daily for 7 days)49 or
as 0.15% oropharyngeal spray (2 nebulisa-
tions from 3 to maximum 8 times day for
3 days)48. Evidence of benzydamine’s anal-
gesic action was provided by its capability
in relieving throat pain and in difficulty in
swallowing, whereas evidence of benzyda-
mine’s anti-inflammatory action was given
by its high effectiveness in improving clini-
cal symptoms (hyperemia, edema and feel-
ings of “blocked ears”).49
The efficacy of benzydamine 0.15%
mouthwash (gargles every 3 hours) in the
post-operative management of tonsil-
lectomy was also assessed in comparison
with soluble aspirin (gargles every 3 hours
and then swallowed). Aspirin proved to be
slightly more effective in relieving pain and
16
discomfort of swallowing, while benzy-
damine oral rinse was superior in the relief
of earache, in promoting the healing of the
tonsil seat, with a shorter duration of the
treatment need.50
• Oral radiation mucositis
Patients who undergo radiation therapy to
the head and neck often develop mucositis
of the oropharynx that produces oral pain
and may limit food intake.51 In more than
half of patients with mucositis, the condi-
tion is so severe that it requires parenteral
analgesia, interruption of radiation thera-
py, and/or hospitalization and the need for
parenteral or tube feeding.52
The biology of ulcerative mucositis involves
the sequential interaction of cells, cytok-
ines and the oral microflora. The initial tis-
sue response to radiation appears to be the
release of a number of pro-inflammatory
cytokines including IL-1, IL-6 and TNF-α.52
Benzydamine inhibits the production of
such pro-inflammatory cytokines, particu-
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larly TNF-α, and IL-1β,2-4 therefore limit-
ing radiation mucositis through its ability
to suppress selected proinflammatory cy-
tokine production.52
Preliminary experiences to define the ther-
apeutic potency of benzydamine oral rinse
in this inflammation of the oral mucosa
were performed in the 80’s. In 1998 benzy-
damine was added to the US FDA Orphan
Drug List with the orphan designation for
the prophylactic treatment of oral muco-
sitis resulting from radiation therapy for
head and neck cancer.
Two earlier studies suggested that ben-
zydamine was effective in reducing the
severity of the pain associated with oral
mucositis.53,54 Subsequent single and multi-
center trials proved that topical benzy-
damine reduces the frequency and severity
of ulcerative oral lesions and decreases pain
in radiation-induced oral mucositis.51,52,54-57
The results of a large, multicenter, double-
blind, randomized trial published in 2001,

demonstrated that treatment with 0.15%
benzydamine mouthwash improved the ul-
cer-free rate and diminished the incidence
of ulceration and erythema. These findings
were observed in 172 patients (84 benzy-
damine, 88 placebo), treated for 2 minutes
4-8 times daily before and during radiation
therapy, and for 2 weeks after completion
of radiation therapy. The study also dem-
onstrated a delay in the need for rescue
medications (analgesics) in patients who
were treated with benzydamine compared
with patients treated with placebo.52
As reported in a review of publications on
the etiopathogenesis and prevention of
oral mucositis commonly sequel of radio-
therapy, chemotherapy, and radiochemo-
therapy, benzydamine, among the current
available products, was shown to have the
strongest scientific evidence of support for
prophylaxis of mucositis.58
In Clinical Practice Guidelines published in
2004 by the American Cancer Society, ben-
zydamine has been recommended in the
prevention of radiation-induced mucositis
in patients with head and neck cancer re-
ceiving moderate-dose radiotheraphy.59 This
recommendation for the use of benzydamine
in the prevention of radiation-induced mu-
cositis was confirmed in the updated clinical
practice guidelines published in the March
1, 2007 issue of Cancer.60
• Aphtous mouth ulcer
Recurrent aphthous ulcers affect up to
one fifth of the general population. Aph-
tous ulcers also called canker sores, aph-
thous stomata and aphthous stomatitis
are among the most common oral lesions
seen by dentist.8 This condition can be
painful for the patient, making it uncom-
fortable to speak, eat and/or drink. Their
aetiology, however, remains uncertain and
treatment is mainly symptomatic or with
anti-inflammatory agents.61
Studies performed to evaluate benzydamine
0.15% mouthwash in the treatment of aph-
thous ulcers suggest that it may be useful in
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reliving pain associated with these lesions.
In fact, in a placebo comparative study per-
formed on patients with aphtous ulcers,
61% of the subjects receiving benzydamine
experienced a reduction in pain severity of
at least 50%, as compared to 22% of the
patients on placebo.62 A preference for ben-
zydamine treatment was expressed by pa-
tients by virtue of its local anaesthetic effect
responsible for some pain relief.23
In a study examining the subjective effica-
cy of the 38 proprietary agents commonly
used for aphtous treatment, benzydamine
0.15% mouthwash appeared to provide
the best pain control and symptomatic
relief to patients with oral aphthae.61
• Burning mouth syndrome
Burning mouth syndrome is a source of oral
discomfort, mainly occurring in middle-
aged or elderly women, without an identifi-
able local pathology. In a pilot clinical trial,
patients with stomato-glossopyrosis rinsed
for 10 days with benzydamine mouthwash
17
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Children's sore throat pain thermometer scores

(mm)(mm)
over 60 minutes
60 Children's sore throat pain thermometer scores

baseline
over 60 minutes
60 Children's sore throat pain thermometer scores
50
or placebo, and assessed their pain, mouth In a placebo-controlled clinical trial per-

over(mm)
over baseline
over 60 minutes
40
50
dryness and burning sensation by means of formed in 146 children (4 to 17 years) with 60

over baseline
improvement
30
40
visual analog scale (VAS). Differences were sore throat, Schachtel et al.64 demonstrated 50

improvement
20
30
40
found between the two groups favouring the efficacy of benzydamine 0.15% mouth-
10
20

improvement
30
the benzydamine containing solution.63 wash. One single 15 ml dose of benzyda-

Mean
100
20
mine 0.15% mouthwash was significantly Placebo Benzydamine

MeanMean
100
better (p<0.05) than placebo in all efficacy Placebo Benzydamine
0
5.4 USE IN CHILDREN parameters (Figure 10), namely Children’s Placebo Benzydamine
Children's sore throat relief scores over 60 minutes
Children are less open to tolerate pain than Sore Throat Pain Thermometer (VAS 0 to 1,8

units)units)
Children's sore throat relief scores over 60 minutes
1,6
adults even if, from a pharmacological point 200 mm), Children’s Sore Throat Relief Scale 1,8

(score
1,4 Children's sore throat relief scores over 60 minutes
1,6
of view, it should be stated that children can- (Scale 0 to 4 units) and Nurse’s Change-in- 1,8
1,2

units)
(score
1,4

(scorerelief
1,6
not be merely considered as little adults. Top- Pain Scale (VAS 0 to 100 mm).64 Efficacy 1
1,2
1,4
0,8

relief
Men Men
ical treatments in part overcome this issue, evaluations were performed at 5-minute 1
1,2
0,6
0,8

Men relief
in view of the fact that everything should be intervals over a 1-hour evaluation period. 1
0,4
0,6
0,8
0,2
done to lessen discomfort in children. 0,4
0,6
0
0,2
In particular, oral topical treatments may When gargling with benzydamine mouth- 0,4
0
Placebo Benzydamine
0,2 Placebo Benzydamine
represent a clear advantage in young wash presents technical difficulties, such as 0
patients with painful conditions of the in the case of small children, benzydamine Placebo
Nurse's change-in-pain scores overBenzydamine
60 minutes
35
oropharynyx, especially when dysphagia can be successfully administered as oropha-

(mm) (mm)(mm)
Nurse's change-in-pain scores over 60 minutes
35
30
represents a limiting step in the ingestion ryngeal spray or lozenges.

improvement
Nurse's change-in-pain scores over 60 minutes
30
25
35
of any oral medication.

improvement
25
20
30

improvement
15
20

Mean
25
Topical benzydamine, in virtue of its well-
15
10

MeanMean
20
known anti-inflammatory properties and Figure 10: efficacy assessment after treatment
10
5
15
rapid pain control, is a valid therapeutic with a single 15 ml dose of benzydamine 0.15%
mouthwash or placebo.64 5
0
10
tool in the medication of children. 0
Placebo Benzydamine
5
Placebo Benzydamine
18 0
Placebo Benzydamine
 S
1,5
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1
3 Pharyngodinia Benzydamine

Symptom score
0,5
2,5 Placebo
0
2 Day 1 Day 2 Day 3 Day 4 Day 5 Day 6
1,5 Days of treatment

31 Pharyngodinia
The effectiveness of benzydamine 3 mg at swallowing, already 24 hours after sur- Benzydamine

Symptom score
0,5
2,5 Placebo
lozenges was proven in comparison with gery (Figure 11), was observed in young
20
benzydamine 0.15% mouthwash in a pa- patients (aged 3 to 17 years) treated with Day 1 Day 2 Day 3 Day 4 Day 5 Day 6
1,5
tient population (age range 4-67 years) benzydamine in comparison to placebo Days of treatment
1
that also involved children, affected by (4 nebulisations up to 8 times a day for 6 3 Dysphagia

Symptom score
Benzydamine
0,5
oropharyngeal disease. Benzydamine loz- days). The intensity of the symptoms pha- 2,5 Placebo

enges showed comparable therapeutic ef- ryngodynia, dysphagia, and if any otalgia 0
2
Day 1 Day 2 Day 3 Day 4 Day 5 Day 6
ficacy and tolerability with respect to the was graded with a 4-point score from 0 1,5
Days of treatment
mouthwash, with no statistically signifi- (no pain) to 3 (remarkable pain).66 1
3
cant differences between formulations.32 Dysphagia

Symptom score
0,5 Benzydamine
2,5 Placebo
Studies involving children suffering from 0
2 Day 1 Day 2 Day 3 Day 4 Day 5 Day 6
Benzydamine 0.15% oropharyngeal spray post-operative pain following tonsillecto-
1,5 Days of treatment
administered to children (age range 4-12 my showed that benzydamine was effective
1
years) with sore throat proved to be an effec- in the relief of typical discomfort, within 3 Dysphagia

Symptom score
Benzydamine
0,5
tive, acceptable and throuble-free treatment a few days. Benzydamine produced a sig- 2,5 Placebo
0
for sore-throat in younger patients which, in nificantly faster and greater improvement 2
Day 1 Day 2 Day 3 Day 4 Day 5 Day 6
most cases were eased from the pain.65 than placebo and was also significantly su- 1,5
Days of treatment
perior in the overall therapeutic effect.67-69 1
3 Benzydamine

Symptom score
Otalgia
According to the easy route of administra- 0,5
2,5 Placebo
tion, particularly in younger patients, ben- 0
2
Day 1 Day 2 Day 3 Day 4 Day 5 Day 6
zydamine 0.15% oropharyngeal spray has 1,5 Days of treatment
been effectively used in the post-operative 1
course of children and adolescents under- 3 Benzydamine

Symptom score
Otalgia
0,5
going adenotonsillectomy. Figure11: Symptom course during treatment (4 neb- 2,5
0
Placebo

A significant reduction in the intensity of ulisations in up to 8 times a day for 6 days) with ben- 2 Day 1 Day 2 Day 3 Day 4 Day 5 Day 6
zydamine and placebo (adapted from Fior et al.) 66
local pain (pharyngodynia) and/or of pain 1,5 Days of treatment

31
tom score Otalgia Benzydamine 19
0,5
2,5 Placebo
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6. GLOBAL SAFETY ANALYSIS

Benzydamine mouthwash, oropharyngeal RECORDED AEs No. OF CASES

No. AEs /TOTAL No. AEs / TOTAL
sprays and lozenges are medicinal prod- AEs (%) PATIENTS (%)

ucts for topical use, and since very modest Numbness, furry tongue, paraesthesia 134 39 1.7
systemic absorption occurs, systemic seri- Burning 85 25 1.1
ous adverse effects are not expected. Ben- Nausea, ratching, vomiting 44 13 0.6
zydamine shows a very good safety profile, Bad taste 32 9 0.4
as confirmed in clinical trials and by post- Dryness of the mouth / increased salivation 17 5 0.2
marketing pharmacovigilance information. Taste disturbances, loss of appetite 7 2 0.1
Dizziness 6 2 0.1
An open study involving 7,618 patients
Gastrointestinal disorders 6 2 0.1
with oropharyngeal diseases was per-
Allergic reaction 4 1 0.05
formed with the objective of monitoring
Sleep disturbance, tiredness 3 1 0.04
the frequency of side-effects following
benzydamine oral local treatment.70 Benzy- Others (headache, hot feeling) 2 1 0.03
damine resulted to be well tolerated locally. TOTAL 340 100 4.5
No serious adverse event was reported,
Table 3: rating of patients reporting AEs
while 340 out of 7,618 patients (4.5%) re-
ported not serious side effects.
activity of benzydamine is sometimes mis- ing, dry mouth sensation or increased sali-
The AEs recorded during the study and takenly interpreted as an adverse event. On vation were rarely observed with benzyda-
their incidences are reported in Table 3.70 the other hand, this is actually a very use- mine oral local treatment, as well as dryness
ful therapeutic characteristic of the drug, of the mouth or hypersensitivity reactions.
Numbness and burning were the most fre- which provokes a mild sensation of numb- Laryngospasm and angioema were very
quently reported side effects, most proba- ness in the mouth capable of immediately rarely and photosensitivity was uncommon
bly related to the local anaesthetic effect of relieving the local painful conditions. observed.
benzydamine. In fact, the local anaesthetic Other symptoms such as trouble swallow-
20
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7. POST MARKETING EXPERIENCE

The updated post marketing pharmacovig- Benzydamine treatment Estimated number of patients treated
ilance data refers to the period between Topical oromucosal pharmaceutical forms
January 2005 and August 2008. 71,72 (0.15% mouthwash + 0.15% oropharyngeal spray + 0.30% 43,056,669
oropharyngeal spray)
Lozenges 7,850,222
7.1 WORLDWIDE SALES AND
Table 4: estimated number of patients treated with benzydamine topical oromucosal pharmaceutical forms
CONSUMPTION (mouthwash, oral spray) and lozenges
In this period, the estimated number of pa-
tients treated with benzydamine mouth- Benzydamine treatment
wash, oropharyngeal spray and lozenges is Topical oromucosal pharmaceutical forms
reported in the following table. The avail- (0.15% mouthwash + 0.15% oropharyngeal spray + 0.30% 3 mg lozenges
able data for benzydamine 0.15% mouth- oropharyngeal spray)

wash, 0.15% and 0.30% oropharyngeal Type of events Expected Unexpected TOTAL Expected Unexpected TOTAL
spray are jointly treated as “topical oromu- Non serious 4 36 40 4 16 20
cosal pharmaceutical forms”.71,72
Serious 0 3 3 0 0 0
TOTAL 4 39 43 4 16 20
7.2 INCIDENCE OF ADVERSE EVENTS AND Table 5: adverse events reported to the Pharmacovigilance Service of ACRAF S.p.A. between January 2005
EVALUATION OF THE RISK/BENEFIT RATIO and August 2008
The adverse events reported to the Pharma-
covigilance Service of ACRAF S.p.A. in the Table 5.71,72 During the period considered, no stance and information reported in litera-
period between January 2005 and August adverse events occurring in patients treated ture confirmed the positive risk/benefit ratio
2008 for benzydamine topical oromucosal with benzydamine 0.15% mouthwash, 3 mg of benzydamine when topically used in the
pharmaceutical forms (mouthwash, 0.15% lozenges, 0.15% and 0.30% oropharyngeal treatment of painful and inflammatory con-
and 0.30% oropharyngeal spray) and ben- spray were published in literature. ditions of mouth and throat.71,72
zydamine lozenges are summarized in the Available safety data on the active sub-
21

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23

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24
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47. Mazzarella B, Macarone Palmieri A, Mastron-
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25

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69. Giacomelli F, Pastore F, Zangari M, Marchiori
C, Soranzo GP “Tonsillectomie: terapia e postop-
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