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eFFICACY
GLoBAL sAFetY AnALYsIs pag. 20
• Therapeutical rationale CHeMICAL stRUCtURe
5.1 PAINFUL INFLAMMATORY Post MARKetInG
CONDITIONS OF OROPHARYNx eXPeRIenCe
CsAID Benzydamine
7.1 WORLDWIDE SALES AND vs. nsAIDs
5.2 ODONTO-STOMATOLOGIC 7.2 INCIDENCE OF ADVERSE EVENTS 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 ReFeRenCes
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

Contents
Benzydamine is an anti-inflammatory The mechanism of action of benzyda- oropharynx (gingivitis, stomatitis, phar- agent with local anaesthetic and analge- mine differs from that of the aspirin-like yngitis), even when due to dental therapy, sic properties.1 It was synthesized in the drugs. The main difference is that benzy- although it has also been largely used in Laboratories of the Angelini Research In- damine is - in comparison to aspirin like various conditions ranging from post- stitute in the 1960s, and marketed in Italy drugs - a weak inhibitors of the synthesis tonsillectomy pharyngitis or radiomucosi- in the 1970s. It was later released on the of prostaglandins, while it is a powerful tis, to throat irritation and/or dysphagia market in more than 70 European, Ameri- inhibitor of proinflammatory cytokines. induced by intubation. can and Asian Countries.
For that reason, it can be classified as a Cytokine Suppressive Anti-inflammatory Benzydamine was widely used in clinical Pharmacodynamic investigations have Drug (CSAID).2,6 practice and, therefore consistent clinical shown that benzydamine acts as a experience together with a large amount suppressor of proinflammatory cyto- In addition to its anti-inflammatory of literature demonstrating its efficacy kines, especially against Tumor Necrosis activity, benzydamine shows local an- and tolerability, are available. The aim of Factor-α (TNF-α) and to a lesser ex- algesic/anesthetic effects7 that in the this document is to summarize the phar- tent, Interleukin-1β (IL-1β) and Che- topical route can be fully exploited and macological, pharmacokinetic and clinical mokine ligand 2 (CCL2) monocyte che- turned into competitive advantages over data available on benzydamine.
motactic protein-1 (MCP-1),2-4 that are Non-Steroidal Anti-Inflammatory Drugs well known to be potent mediators of inflammation.5 However, it did not af-fect other inflammatory cytokines like In fact, its elective therapeutic use is the Interleukin-6 (IL-6) and Interleukin-8 topical control of acute inflammation and (IL-8) and, importantly, cytokines with pain. Benzydamine formulated as 0.15% anti-inflammatory properties, such as mouthwash, 3 mg lozenges, 0.15% and Interleukin-10 (IL-10) and interleukin-1 0.30% nebulizers, has its target indication receptor antagonist (IL-1ra). 2-4 in the symptomatic treatment of pain and irritative/inflammatory conditions of the

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2. CHeMICAL stRUCtURe
The chemical structure of benzydamine The molecular formula is C H N O · HCl. hydrochloride, or N,N-dimethyl-3-{[1- It has a molecular weight of 345.9 and a 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.
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- effects by inhibiting the synthesis of zydamine respect to NSAIDs. prostaglandins,8 benzydamine inhibits the production of proinflammatory cytokines, 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 Cytockine
Lack of some of the
typical side-effects of the
Since benzydamine lacks significant inhi- aspirin - like drugs
bition against prostaglandins it does not produce the characteristic side-effects of aspirin-like drugs9 (Figure 2). Benzy-damine, in fact, inhibits prostaglandins synthesis in vitro only at concentrations Non-similar to local
similar to local
Prompt relief of pain
which are not reached in vivo (200-400 µg/ml) following both local and systemic administrations.1

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4. PHARMACoLoGY
Benzydamine is a Cytokine Suppressive or throat, even if detectable drug plasma two other treatments. The mean plasma Anti-inflammatory Drug, which is devoid levels have been reported after topical ad- concentration time curves for each of activity on arachidonic acid metabo- ministrations, probably related to absorp- benzydamine treatment are shown in Fig- lism and has local anaesthetic and anal- tion through the oral mucosa.13 ure 3.
gesic properties.3 After a single administration of 0.15% On the contrary to the systemic admin- benzydamine solution by ingestion (25.5 istration, the local application of benzy- mg benzydamine/70 kg), gargle (102 mg damine produces higher concentrations benzydamine/70 kg), and spray (about 12 mg in the inflamed area than in the blood, as benzydamine),14 detectable drug plasma demonstrated in animals and humans.10,11 concentrations were observed in all sub- Figure 3: mean plasma concentration time curves The capability of benzydamine to con- jects. After ingestion, the drug levels were of benzydamine following ingestion, gargle and centrate in the inflamed tissues, with clearly much higher than in either of the low systemic exposure, represents a clear advantage by limiting potential systemic side effects.8 In addition, the benzydamine topical preparations show additional pharmacological effects, such as a local anaesthetic effect, that cannot be ob- tained through systemic administration.12 Mouthwash, oral spray and lozenges are Plasma benzydamine concentrations (ng/ml) oropharyngeal formulations intended to exert local effects in the oral cavity and/ Hours after administration

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

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Candida albicans-induced production of Figure 4: activity of benzydamine, ibuprofen and naproxen on TNF-α and MCP-1 production by IL-6 (U/ml)
IL-8 (ng/ml)
Candida albicans-stimulated peripheral blood mononuclear cells (Adapted from Sironi et al.). 3 α levels (ng/ml) ND= Not Determined 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 α levels (ng/ml) 205 Table 1: effect of benzydamine on cytokine and chemokine production by peripheral blood mononuclear cel sa. drug concentration (microM) Importantly, in the same cells stimulated It is worth noting that unlike benzy- 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- cytokines with anti-inflammatory proper- tokine production from Candida acti- ties, such as IL-10 and IL-1ra.4 vated mononuclear cells.3 Figure 4 shows the effects of different concentrations These findings suggested that the anti- (12.5, 25 and 50 µM) of these two drugs MCP-1 levels (ng/ml inflammatory activity of benzydamine on TNF-α and MCP-1 production in stems from its ability to reduce the produc- comparison to the same concentrations MCP-1 levels (ng/ml 0,5 tion of proinflammatory cytokines, without of benzydamine.
affecting anti-inflammatory factors.4 drug concentration (microM) drug concentration (microM)

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Benzydamine confirmed its suppressive effect on these cytokines, while neither C5a C5a receptor
ibuprofen nor naproxen significantly re- duced the amount of TNF-α and MCP-1 secreted from Candida-treated human G1 protein
• Effects on chemotaxis
Benzydamine exerts an inhibitor activity on monocyte chemotaxis, a function shared by immune cells and crucial in inflammation.20 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 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- in signal transduction associated with In particular, benzydamine strongly inhib- phorylation to induce chemotactic migration.21 cell migration.21 ited chemoattractant-induced activation of Contents
both ERK1/2 and p38 MAPK pathways im- confirm the rationale for the use of the the drug shares with local anaesthetics plicated in cel migration.
drug in controlling inflammatory oropha- an aromatic (hydrophobic) ring structure, ryngeal conditions.
linked to a basic tertiary amine group (hy- These results suggested that the benzy- drophilic) by a short alkyl chain (Figure damine inhibitory effect on monocyte 6). Therefore, benzydamine similar to as chemotaxis most likely contributes to its 4.2.2 Local anaesthetic activity
local anaesthetics, reversible block nerve anti-inflammatory activity. 20 Following topical applications, benzyda- conduction when topically applied in mine shows local anaesthetic properties.7 • Effects on the production of
In a clinical trial performed on 87 healthy subjects benzydamine, when applied 4.2.3 Antimicrobial activity
It has been shown that prostaglandin topically to normal mucosa for 60 sec- Bactericidal activity of benzydamine (drug biosynthesis is stimulated by cytokines onds, was found to exert a remarkable concentrations ranged from 10 to 1280 µg/ such as IL-1 and TNF-α in various types anaesthetic activity that was superior to ml) was determined against 110 bacterial of cells, including gingival fibroblasts. the control (cetylpyridinium hydrochlo- strains clinically isolated in Spain. For all When the cells were treated simultane- ride 0.025%) and placebo mouthwashes, the bacteria studied, the MICs observed, ously with benzydamine and IL-1β or showing also a long lasting effect (more between 320 and 1280 µg/ml, were lower TNF-α, the drug significantly reduced the than 90 minutes).7 The local anaesthetic than benzydamine concentration in the stimulatory effect of these cytokines on activity of benzydamine has been shown marketed product (1500 µg/ml).25 prostaglandin E (PGE ) production as well to be extremely useful in the treatment as significantly reduced the production of of painful mouth and throat conditions, The fungistatic and fungicidal activity of prostaglandin I (PGI ). 22 mainly due to rapid pain relief.23 benzydamine against Candida-albicans and non-albicans strains (20 Candida strains: This capability of benzydamine to reduce These local anaesthetic properties dem- 18 clinical isolated and two American Type prostaglandin production induced by IL- onstrated by benzydamine are most prob- Culture Collection strains) were also in- 1β or TNF-α in gingival fibroblasts may ably due to its structural features. In fact, vestigated. At lower concentrations ben- Contents
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% local anaesthetic drugs mouthwash and spray) is 30 times higher than the MIC of the least susceptible Can-dida strains.26 Figure 6: structural features of benzydamine shared with the known local anaesthetics.24 Contents
5. eFFICACY
Therapeutic Rationale
The amount of available clinical data on the studies. In comparison to the placebo, Benzydamine has been largely used in efficacy and safety of benzydamine is very benzydamine displays a significantly better symptomatic treatment of pain, irritation extensive. Clinical trials hereinafter present- reduction of pain with a more rapid decrease and inflammation of the oropharynx, even ed are the most representative studies with of pain severity over a 2-day period.27 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- Patients with acute pharyngitis, rhinitis, ditions ranging from post-tonsillectomy dren affected by various local mouth and and tonsillitis instructed to gargle with pharyngitis or radiomucositis, to throat throat inflammatory conditions.
15 ml of mouthwash containing benzy- irritation and/or dysphagia induced by in- damine (every 1.5-3 hours for 7 days) ex- perienced a greater reduction of pain and The main characteristics that make topical 5.1 PAInFUL InFLAMMAtoRY
burning sensations starting from the 2nd benzydamine (0.15% mouthwash, 0.15% and ConDItIons oF oRoPHARInX tRACt
day of therapy, as compared to placebo- 0.30% oropharyngeal spray and lozenges) The effectiveness of benzydamine 0.15% treated patients. Dysphagia, otalgia, and useful in the treatment of inflammatory and mouthwash in relieving throat pain and sensation of hypoacusia also appeared painful disorders are hereinafter presented.
dysphagia has been shown in different to significantly improve in the group treated with benzydamine. In addition, a reduction in hyperemia and oedema of > Reversal of the typical signs and symptoms the pharynx, as well as in hypertrophy of inflammation therapeutic of the lymph nodes, was observed from toPICAL AnAestHetIC eFFeCt > Prompt pain relief
the 1st day of treatment in benzydamine- > Penetration and accumulation in the site treated patients.28 of inflammation safe use also > Therapeutic actions where they are most required in children Schachtel et al. confirmed these findings sUItABLe DosAGe FoRMs
> Limitation of the systemic exposure in two more placebo-controlled clinical trials involving a total of 283 adults pa- > Easy administration and good taste high compliance tients with acute sore throat. Contents
Patients were treated with benzydamine 0.15% mouthwash (15 ml dose every 2-4 Benzydamine (n=63)
hours up to 6 times daily for up 7 days) Difficulty swal owing scale (VAS 0 to 100mmm)Change in pain scale Results of efficacy parameters (difficulty swallowing scale, change in pain scale, Sore throat relief scale and sore throat relief scale) assessed in (0=none to 6=complete) the first study, are reported in Table 2.29 Table 2: overal mean improvement after benzydamine and placebo treatments in the intent-to-treat population. Benzydamine was able to rapidly relieve the characteristic symptoms of sore Treatments showed a comparable effec- Efficacy parameters were evaluated ac- throat, such as pain on swallowing and tiveness, good tolerability and palatability, cording to a 4-point scale (0=no symp- pharyngeal inflammation by virtue of even if a quicker and intense improvement tomatology to 3=severe symptomatol- its topical effects.29 Similar results were was obtained with benzydamine.31 ogy). Results of these studies are shown obtained in the second trial with the ex- in Figures 7-8.
ception of the difficulty in swallowing Benzydamine 0.15% mouthwash, thanks to its proven effectiveness and extensive use in the topical treatment of oral inflam- The effectiveness of benzydamine oro- matory and painful conditions, was chosen pharyngeal spray in the treatment of as reference product in two clinical stud- acute or recurring chronic tonsillitis with- ies. These were performed with the aim of out concurrent antibiotic therapy, was demonstrating the therapeutic equivalence compared with an association containing of benzydamine 3 mg lozenges with the the antiseptic hexamidine plus an anaes- mouthwash formulation, in the treatment thetic local tetracaine. of oropharyngeal disease.32,33 Contents
Burning sensation Swelling sensation The efficacy of 3 mg benzydamine lozeng- Benzydamine produced a progressive Figure 7: mean score for the evaluated signs and symptoms of the oropharyngeal disease record- es and its good tolerability were further clinical improvement in symptoms and ed at basal and subsequent observation times confirmed in a controlled clinical study signs caused by the inflammatory pro- (Adapted from De Vita).32 that included a large number of patients cess. The cough symptom and the aver- (N=120) with acute or chronic disorders age number of cough, were significantly of the respiratory tract characterized by reduced only in the groups treated with both studies, a clear improvement/re- cough and inflammatory symptoms of the association 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 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. Dentin Hypersensivity Burning sensation Swelling sensation Contents
Dentin Hypersensivity over sprays and gargles which is that of 5.2 oDonto-stoMAtoLoGIC
Figure 8: mean score for the evaluated signs and symptoms of the oropharyngeal disease record- being slow-releasing, thereby continu- ed at basal and subsequent observation times ously delivering the drug to the affected The efficacy of benzydamine, in terms (Adapted from Di Maggio).33 areas of the throat.35 of pain relief, has also been proven in the treatment of patients suffering from Thus, 3 mg benzydamine lozenges may rep- diseases of the periodontium and oral The pharmaceutical form of tablets, to be resent a useful alternative to mouthwash, dissolved in the mouth, was very well ac- especial y in those cases in which a more cepted because of its simple administra- convenient pharmaceutical preparation In periodontal disease, the main etio- tion, which improved patients' compli- may facilitate the patients' compliance, con- logic factor is dental plaque. Plaque can ance. Lozenges also have an advantage tributing to a superior therapeutical result.
be removed by brushing and flossing, but Contents
patient's compliance with oral hygiene significant decrease in mean pain intensity demonstrated in patients undergoing ex- regimens is often very low. Thus, a mouth- (Figure 9) Benzydamine, therefore, proved traction of the third molars.42 wash capable of reducing plaque and in- its beneficial effects also on pain due to flammation would be a valuable aid in treat- conservative dental therapy.40 Similarly, a very good clinical efficacy was ing and preventing periodontal diseases.
observed following treatment with benzy- The therapeutic efficacy and local tolera- damine oropharyngeal spray and mouth- The efficacy of a 7-day treatment with ben- bility of benzidamine 0.15% oropharyngeal wash in patients with oral erosive and zydamine alone (3-4 times a day) in reduc- spray was demonstrated in comparison to ulcerative lesions that appeared during ing plaque formation had been previously placebo in patients with various odonto- the course of various diseases. The symp- demonstrated in two double-blind, placebo- stomatological conditions (such as gingi- tomatology improved evenly in 74% of control ed clinical studies.12, 39 Significant vitis, dental extractions, post-extraction patients treated with oropharyngeal spray improvements were demonstrated with wounds, peri-coronal inflammations, exci- and mouthwash after 3-4 days of adminis- benzydamine compared to placebo in al the sion of dental operculum and excision of trations. It is important to note that in case efficacy parameters tested: plaque index, papillomas). Benzydamine 0.15% oropha- gingival index, healing, and pain reduction.
ryngeal spray (4 nebulisations, 6 times dai- ly for 4 days) was able to alleviate patients' Although the above results are very inter- discomfort with a significant improvement esting, benzydamine 0.15% mouthwash is of symptoms and signs starting from the 1st mainly used in the treatment of different treatment day. By the last day of treatment pathologies of the oral cavity, including ef- all signs and symptoms disappeared with fects due to dental therapy. a highly significant difference in favour of the benzydamine group (p<0.001).41 In patients (N=106) with chronic perio- benzydamine application benzydamine application dontitis undergoing removal of dental The usefulness of the post-operative treat- deposits, the treatment with benzydamine ment with benzydamine 0.15% spray (6 Figure 9: comparison of the mean pain level be- 0.15% mouthwash produced a statistically applications days for 5 days) was also fore and after benzydamine application.40 Contents
of single lesions benzydamine oropharyn- and endotracheal intubation suffer from flammatory lesions due to nasal-gastric geal spray formulation is the most simple postoperative sore throat.43 Benzydamine and endotracheal intubation.
to use, since it allows a precise application mouthwash and oropharyngeal spray ap- plied both before and after surgery have Patients with sore throat and/or dysphagia been shown to be effective in reducing due to the use of nasal gastric tube and the incidence and severity of the postop- patients that underwent endotracheal 5.3 Use In PARtICULAR InFLAMMAtoRY
erative sore throat. intubation received benzydamine 0.15% ConDItIons oF tHe oRAL CAVItY
mouthwash46 and 0.30% spray47, respec- Sore throat and/or dysphagia are often Pre-emptive treatment with benzydamine tively. The dosages scheduled consisted reported by patients with nasal-gastric in- mouthwash and oropharyngeal spray has of 15 ml dose of benzydamine every 2-3 tubation or undergoing tracheal intubation been reported to decrease the incidence hours for 1-2 days or of 10 nebulizations during general anaesthesia. In fact, nasal- and severity of sore throat due to endo- of benzydamine spray every 3 hours for gastric or tracheal intubation and direct 3 days. Significant relief of pain and dys- local surgical procedures involving mouth, These findings were confirmed in a com- phagia was recorded in favour of benzy- gums and throat often produce inflamma- parative clinical trial. In this study, gar- damine, with an improvement in signs and tory conditions of the oropharynx. gling with benzydamine (0.15% mouth- symptoms clinically and statistically supe- Benzydamine was also widely used in the wash, 15 ml dose made into 30 ml with rior to that observed in the placebo group. treatment of aphthous ulcers and oral mu- distilled water) reduced the incidence of The improvement was evident starting cositis, a frequent complication of head postoperative sore throat for up to 24 from Day 2, with the complete resolution and neck radiotherapy.8 hours, while dispersible aspirin gargles of symptomatology on Day 3.
(350 mg tablet made into 30 ml with dis-tilled water) only up to 2 hours.45 • Pharyngo-laryngeal pathology
• Pharyngitis post-tonsillectomy
Two previous placebo-controlled studies Tonsillectomy, a surgical procedure com- Twenty four to ninety percent of pa- proved that benzydamine has a marked monly performed in children and young tients who receive general anaesthesia therapeutic effect in the treatment of in- adults, may often produce dysphagia, sore Contents
throat and earache in the early post-oper- discomfort of swallowing, while benzy- larly TNF-α, and IL-1β,2-4 therefore limit- damine oral rinse was superior in the relief ing radiation mucositis through its ability of earache, in promoting the healing of the to suppress selected proinflammatory cy- Many studies performed on adult tonsil- tonsil seat, with a shorter duration of the tokine production.52 lectomized patients have shown the thera- treatment need.50 peutic efficacy of benzydamine, particu- Preliminary experiences to define the ther- larly when topically administered as 0.15% apeutic potency of benzydamine oral rinse mouthwash (5 times daily for 7 days)49 or • Oral radiation mucositis
in this inflammation of the oral mucosa as 0.15% oropharyngeal spray (2 nebulisa- Patients who undergo radiation therapy to were performed in the 80's. In 1998 benzy- tions from 3 to maximum 8 times day for the head and neck often develop mucositis damine was added to the US FDA Orphan 3 days)48. Evidence of benzydamine's anal- of the oropharynx that produces oral pain Drug List with the orphan designation for gesic action was provided by its capability and may limit food intake.51 In more than the prophylactic treatment of oral muco- in relieving throat pain and in difficulty in half of patients with mucositis, the condi- sitis resulting from radiation therapy for swallowing, whereas evidence of benzyda- tion is so severe that it requires parenteral head and neck cancer.
mine's anti-inflammatory action was given analgesia, interruption of radiation thera- by its high effectiveness in improving clini- py, and/or hospitalization and the need for Two earlier studies suggested that ben- cal symptoms (hyperemia, edema and feel- parenteral or tube feeding.52 zydamine was effective in reducing the ings of "blocked ears").49 severity of the pain associated with oral The biology of ulcerative mucositis involves mucositis.53,54 Subsequent single and multi- The efficacy of benzydamine 0.15% the sequential interaction of cells, cytok- center trials proved that topical benzy- mouthwash (gargles every 3 hours) in the ines and the oral microflora. The initial tis- damine reduces the frequency and severity post-operative management of tonsil- sue response to radiation appears to be the of ulcerative oral lesions and decreases pain lectomy was also assessed in comparison release of a number of pro-inflammatory in radiation-induced oral mucositis.51,52,54-57 with soluble aspirin (gargles every 3 hours cytokines including IL-1, IL-6 and TNF-α.52 and then swallowed). Aspirin proved to be Benzydamine inhibits the production of The results of a large, multicenter, double- slightly more effective in relieving pain and such pro-inflammatory cytokines, particu- blind, randomized trial published in 2001, Contents
demonstrated that treatment with 0.15% prevention of radiation-induced mucositis reliving pain associated with these lesions. benzydamine mouthwash improved the ul- in patients with head and neck cancer re- In fact, in a placebo comparative study per- cer-free rate and diminished the incidence ceiving moderate-dose radiotheraphy.59 This formed on patients with aphtous ulcers, of ulceration and erythema. These findings recommendation for the use of benzydamine 61% of the subjects receiving benzydamine were observed in 172 patients (84 benzy- in the prevention of radiation-induced mu- experienced a reduction in pain severity of damine, 88 placebo), treated for 2 minutes cositis was confirmed in the updated clinical at least 50%, as compared to 22% of the 4-8 times daily before and during radiation practice guidelines published in the March patients on placebo.62 A preference for ben- therapy, and for 2 weeks after completion 1, 2007 issue of Cancer.60 zydamine treatment was expressed by pa- of radiation therapy. The study also dem- tients by virtue of its local anaesthetic effect onstrated a delay in the need for rescue responsible for some pain relief.23 medications (analgesics) in patients who • Aphtous mouth ulcer
were treated with benzydamine compared Recurrent aphthous ulcers affect up to In a study examining the subjective effica- with patients treated with placebo.52 one fifth of the general population. Aph- cy of the 38 proprietary agents commonly tous ulcers also called canker sores, aph- used for aphtous treatment, benzydamine As reported in a review of publications on thous stomata and aphthous stomatitis 0.15% mouthwash appeared to provide the etiopathogenesis and prevention of are among the most common oral lesions the best pain control and symptomatic oral mucositis commonly sequel of radio- seen by dentist.8 This condition can be relief to patients with oral aphthae.61 therapy, chemotherapy, and radiochemo- painful for the patient, making it uncom- therapy, benzydamine, among the current fortable to speak, eat and/or drink. Their available products, was shown to have the aetiology, however, remains uncertain and • Burning mouth syndrome
strongest scientific evidence of support for treatment is mainly symptomatic or with Burning mouth syndrome is a source of oral prophylaxis of mucositis.58 discomfort, mainly occurring in middle-aged or elderly women, without an identifi- In Clinical Practice Guidelines published in Studies performed to evaluate benzydamine able local pathology. In a pilot clinical trial, 2004 by the American Cancer Society, ben- 0.15% mouthwash in the treatment of aph- patients with stomato-glossopyrosis rinsed zydamine has been recommended in the thous ulcers suggest that it may be useful in for 10 days with benzydamine mouthwash Contents
Children's sore throat pain thermometer scores over 60 minutes Children's sore throat pain thermometer scores 60 over 60 minutes or placebo, and assessed their pain, mouth In a placebo-control ed clinical trial per- 50 Children's sore throat pain thermometer scores dryness and burning sensation by means of formed in 146 children (4 to 17 years) with visual analog scale (VAS). Differences were sore throat, Schachtel et al.64 demonstrated found between the two groups favouring the efficacy of benzydamine 0.15% mouth- the benzydamine containing solution.
wash. One single 15 ml dose of benzyda- mine 0.15% mouthwash was significantly Mean improvement over baseline (mm) better (p<0.05) than placebo in al efficacy Mean improvement over baseline (mm) 5.4 Use In CHILDRen
parameters (Figure 10), namely Children's Mean improvement over baseline (mm) 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 Children's sore throat relief scores over 60 minutes adults even if, from a pharmacological point 200 mm), Children's Sore Throat Relief Scale 1,61,4 Children's sore throat relief scores over 60 minutes of view, it should be stated that children can- (Scale 0 to 4 units) and Nurse's Change-in- not be merely considered as little adults. Top- Pain Scale (VAS 0 to 100 mm).64 Efficacy ical treatments in part overcome this issue, evaluations were performed at 5-minute Men relief (score units) 1,2 in view of the fact that everything should be intervals over a 1-hour evaluation period. Men relief (score units) done to lessen discomfort in children. Men relief (score units) In particular, oral topical treatments may When gargling with benzydamine mouth- represent a clear advantage in young wash presents technical difficulties, such as patients with painful conditions of the in the case of smal children, benzydamine Nurse's change-in-pain scores over 60 minutes oropharynyx, especially when dysphagia can be successful y administered as oropha- 35 Nurse's change-in-pain scores over 60 minutes represents a limiting step in the ingestion ryngeal spray or lozenges.
30 Nurse's change-in-pain scores over 60 minutes of any oral medication.
Topical benzydamine, in virtue of its well- Mean improvement (mm) known anti-inflammatory properties and Figure 10: efficacy assessment after treatment Mean improvement (mm) rapid pain control, is a valid therapeutic with a single 15 ml dose of benzydamine 0.15% Mean improvement (mm) tool in the medication of children.
mouthwash or placebo.64 Contents
Symptom score 1,5 Days of treatment The effectiveness of benzydamine 3 mg at swallowing, already 24 hours after sur- lozenges was proven in comparison with gery (Figure 11), was observed in young benzydamine 0.15% mouthwash in a pa- patients (aged 3 to 17 years) treated with tient population (age range 4-67 years) benzydamine in comparison to placebo 1,5 Days of treatment that also involved children, affected by (4 nebulisations up to 8 times a day for 6 oropharyngeal disease. Benzydamine loz- days). The intensity of the symptoms pha- enges showed comparable therapeutic ef- ryngodynia, dysphagia, and if any otalgia ficacy and tolerability with respect to the was graded with a 4-point score from 0 Symptom score 1,5 Days of treatment mouthwash, with no statistically signifi- (no pain) to 3 (remarkable pain).66 cant differences between formulations.32 Studies involving children suffering from Benzydamine 0.15% oropharyngeal spray post-operative pain following tonsillecto- administered to children (age range 4-12 my showed that benzydamine was effective 1,5 Days of treatment years) with sore throat proved to be an effec- in the relief of typical discomfort, within tive, acceptable and throuble-free treatment a few days. Benzydamine produced a sig- for sore-throat in younger patients which, in nificantly faster and greater improvement most cases were eased from the pain.65 than placebo and was also significantly su- Symptom score 1,5 Days of treatment perior in the overall therapeutic effect.67-69 According to the easy route of administra- tion, particularly in younger patients, ben- zydamine 0.15% oropharyngeal spray has Symptom score 1,5 Days of treatment been effectively used in the post-operative course of children and adolescents under- Figure11: Symptom course during treatment (4 neb- A significant reduction in the intensity of ulisations in up to 8 times a day for 6 days) with ben- local pain (pharyngodynia) and/or of pain zydamine and placebo (adapted from Fior et al.) 66 Symptom score 1,5 Days of treatment 1,5 Days of treatment Days of treatment Contents
6. GLoBAL sAFetY AnALYsIs
Benzydamine mouthwash, oropharyngeal ReCoRDeD Aes
no. oF CAses
no. Aes /totAL no. Aes / totAL
sprays and lozenges are medicinal prod- PAtIents (%)
ucts for topical use, and since very modest Numbness, furry tongue, paraesthesia systemic absorption occurs, systemic seri- ous adverse effects are not expected. Ben- Nausea, ratching, vomiting zydamine shows a very good safety profile, as confirmed in clinical trials and by post- Dryness of the mouth / increased salivation marketing pharmacovigilance information.
Taste disturbances, loss of appetite An open study involving 7,618 patients with oropharyngeal diseases was per-formed with the objective of monitoring Al ergic reaction the frequency of side-effects following Sleep disturbance, tiredness benzydamine oral local treatment.70 Benzy- Others (headache, hot feeling) damine resulted to be well tolerated locally. No serious adverse event was reported, while 340 out of 7,618 patients (4.5%) re- Table 3: rating of patients reporting AEs 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 wel 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. benzydamine. In fact, the local anaesthetic Other symptoms such as trouble swal ow- Contents
7. Post MARKetInG eXPeRIenCe
The updated post marketing pharmacovig- 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% 7.1 WoRLDWIDe sALes AnD
Table 4: estimated number of patients treated with benzydamine topical oromucosal pharmaceutical forms (mouthwash, oral spray) and lozenges In this period, the estimated number of pa-tients treated with benzydamine mouth- 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 spray are jointly treated as "topical oromu- cosal pharmaceutical forms".71,72 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 topical y 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- Contents
8. ReFeRenCes
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64. Schachtel B, Ginsberg D, Shelanski M, Whel-
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Contents

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