Accession Number
Small Molecule

Benzydamine (also known as Tantum Verde and branded in some countries as Difflam), available as the hydrochloride salt, is a locally-acting nonsteroidal anti-inflammatory drug (NSAID) with local anaesthetic and analgesic properties for pain relief and anti-inflammatory treatment of typically topical inflammatory conditions associated with the mouth, throat, or muscoskeletal locations.

Although the indazole analogue benzydamine is a non-steroidal anti-inflammatory drug (NSAID), it has various physicochemical properties and pharmacologic activities that are different from those of traditional aspirin-like NSAIDs but facilitate benzydamine's mechanism of action as an effective locally-acting NSAID with local anaesthetic and analgesic properties. Moreover, unlike aspirin-like NSAIDs which are acids or metabolised to acids, benzydamine is in fact a weak base.

  • bencidamina
  • Benzydamine
Product Ingredients
IngredientUNIICASInChI Key
Benzydamine hydrochlorideK2GI407R4Q132-69-4HNNIWKQLJSNAEQ-UHFFFAOYSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
PharixiaMouthwash1.5 mgBuccalPendopharm Division Of De Pharmascience Inc1996-12-02Not applicableCanada
Sun-benz - Liq 0.15%Liquid.15 %Dental; OralSun Pharmaceutical Industries Limited1997-04-032011-07-29Canada
TantumSolution15 mgBuccalValeant Canada Lp Valeant Canada S.E.C.1993-12-31Not applicableCanada
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Apo-benzydamine Oral RinseLiquid0.15 %BuccalApotex Corporation1998-11-09Not applicableCanada
Novo-benzydamineMouthwash; Solution1.5 mgBuccal; OralNovopharm Limited2008-06-03Not applicableCanada
Novo-benzydamine - Oral RinseLiquid; Mouthwash1.5 mgBuccal; OralNovopharm Limited1997-02-062015-10-26Canada
Nu-benzydamine Oral RinseLiquid0.15 %BuccalNu Pharm IncNot applicableNot applicableCanada
Odan-benzydamineMouthwash1.5 mgBuccalOdan Laboratories Ltd2017-08-11Not applicableCanada
PMS-benzydamineMouthwash1.5 mgBuccalPharmascience Inc1999-04-30Not applicableCanada
Ratio-benzydamineSolution0.15 %OralRatiopharm Inc Division Of Teva Canada Limited1997-03-242010-05-21Canada
CAS number
Average: 309.413
Monoisotopic: 309.184112373
Chemical Formula
InChI Key



Available predominantly as a liquid mouthwash, oromucosal spray, or topical cream, benzydamine is most frequently employed as a locally acting analgesic and anti-inflammatory treatment for the relief of painful inflammatory conditions.

When formulated as a mouthwash or spray, benzydamine may be used to treat traumatic conditions like pharyngitis following tonsillectomy or the use of a naso-gastric tube, inflammatory conditions like pharyngitis, aphthous ulcers and oral ulceration due to radiation therapy, dentistry operations and procedures, or more general conditions like sore throat, sore tongue, sore gums, mouth ulcers, or discomfort caused by dentures. [6]

When used as a topical cream, benzydamine may be employed to relieve symptoms associated with painful inflammatory conditions of the muscolo-skeletal system including acute inflammatory disorders such as myalgia and bursitis or traumatic conditions like sprains, strains, bruises, sore muscles, stiff joints, or even the after-effects of fractures. [7]

Associated Conditions

Benzydamine is a non-steroidal anti-inflammatory drug (NSAID) designed to elicit local anesthetic and analgesic effects mainly for the mouth and throat. It specifically acts on the local mechanisms of inflammation such as pain, oedema, or granuloma. Typically applied topically, the drug demonstrates anti-inflammatory activity reducing oedema as well as exudate and granuloma formation. Moreover, benzydamine exhibits analgesic properties and local anaesthetic activity if pain is caused by an inflammatory condition. Benzydamine can be absorbed into the oral mucosa and intact skin. Once absorbed in the local area of pain or inflammation, benzydamine binds selectively to local inflamed tissues, usually allowing it to act with few adverse systemic effects. On average a period of 2 to 4 hours is necessary for the substance to reach peak plasma concentration. [5]

Benzydamine can be synthesized with the reaction of the N-benzyl derivative from methyl anthranilate with nitrous acid to give N-nitoso derivative. This is next reduced by sodium thiosulfate to give transient hydrazine. This hydrazine can then undergo spontaneous internal hydrazide formation. Treating this resultant enolate with 3-chloro-1-dimethylamkino propane ultimately yields benzydamine.

Mechanism of action

Despite being categorized as a non-steroidal anti-inflammatory drug (NSAID), benzydamine demonstrates various mechanisms of action that differ from those of traditional aspirin-like NSAIDs. In particular, benzydamine predominantly acts by inhibiting the synthesis of pro inflammatory cytokines like tumour necrosis factor-alpha (TNF-α) and interleukin-1β (IL-1β) without largely affecting other pro inflammatory cytokines (ie. such as IL-6 and IL-8) or anti-inflammatory cytokines (ie. like IL-10 or IL-1 receptor antagonist). [3, 5]

Moreover, benzydamine is largely a weak inhibitor of prostaglandin synthesis as it has been shown to effectively inhibit cyclooxygenase (COX) and lipoxygenase enzyme activity only at concentrations of 1mM or greater. Considering most contemporary usages of benzydamine are topical applications that are generally not well absorbed through the skin and/or non-specialized mucosae, benzydamine does not often achieve the kind of absorption or blood concentrations necessary to cause any extraneous distant systemic effects or COX inhibition, allowing it to localize its action. [3, 5]

Additionally, it is also hypothesized that benzydamine is capable of inhibiting the oxidative burst of neutrophils and membrane stabilization. These actions are exhibited by the substance’s ability to inhibit the release of granules from neutrophils and to stabilize lysosomes. [3, 5]

Furthermore, benzydamine is capable of a local anaesthetic effect that may be related to its capability for inhibiting the release of inflammatory mediators like substance P and calcitonin gene related peptide from sensory nerve endings. Since substance P is capable of causing the release of histamine from mast cells, benzydamine’s prevention of substance P release further contributes to an anti-inflammatory effect. [3, 5]

Benzydamine also demonstrates a non-specific antibacterial activity against various bacterial strains that are resistant to broad-spectrum antibiotics such as ampicillin, chloramphenicol, and tetracycline at concentrations of about 3 mmol/L. Combinatorial use of benzydamine and other antibiotics like tetracycline and chloramphenicol are also synergistic against antibiotic resistant strains of Staphylococcus aureus and Pseudomonas aeruginosa. [3]


Oral doses of benzydamine are well absorbed and plasma drug concentrations reach a peak fairly rapidly and then decline with a half-life of approximately 13 hours. When applied topically, although the local drug concentrations are relatively large, the systemic absorption of topically applied benzydamine is relatively low compared to oral doses. This low topical absorption contributes to a decreased potential for any systemic drug side-effects when benzydamine is administered in this way. [6]

Volume of distribution

The volume of distribution of benzydamine is 10 L [1, 3].

Protein binding

Benzydamine exhibits < 20% plasma protein binding after oral administration [6, 3].


Benzydamine is primarily metabolized by oxidation, dealkylation, and conjugation into hydroxy, dealkylated, and N-oxide metabolites [6, 3].

In general, however, when used at the recommended doses the levels at which benzydamine is absorbed or exposed into the body are usually not sufficient to produce systemic pharmacological effects [L

Route of elimination

The relatively high lipid solubility of the weak base benzydamine is thought to be associated with considerable passive resorption within the renal tubule, which suggests that only approximately 5% of benzydamine is excreted unchanged in the urine [1]. At the same time however, other studies have suggested that considerably larger amounts (50-65%) of the drug is excreted unchanged in urine [4].

While several inactive oxidized metabolites of benzydamine are excreted in urine, the benzydamine N-oxide metabolite can remain in plasma and demonstrate a half-life that is longer than the parent benzydamine compound [1].

Nevertheless, it is generally believed that excretion occurs mainly through urine and is mostly in the form of inactive metabolites or conjugation products [8].

Half life

Approximately 13 h after oral administration [6], with a terminal half life of about 7.7 h [3].


Benzydamine demonstrateas a systemic clearance of 170 ml/min [3].


A possible adverse reaction associated with the use of the mouthwash or oromucosal spray formulations of benzymadine is potential numbness and/or stinging in the mouth and/or throat [5, 6].

Some possible adverse reactions that tend to be associated more with topical cream formulations of benzymadine include increased sensitivity to sunlight, and localized itching, skin rash, redness, or swelling [7].

The prescribing information for all formulations of benzymadine however, warn against the possibility of severe allergic reaction (anaphylaxis) associated with swelling of the throat and mouth, difficulty in swallowing, speaking, and breathing, or wheezing [5, 6, 7].

As benzydamine is a non-steroidal anti-inflammatory drug (NSAID), it is necessary to determine if a patient is allergic to NSAIDs before considering its use [5, 6, 7].

Intoxication is expected as a consequence of accidental ingestion of large quantities of benzydamine (over 300 mg ingestion). Other symptoms associated with overdose of ingested benzydamine include gastrointestinal and central nervous system symptoms like nausea, vomiting, abdominal pain, oesophageal irritation, dizziness, hallucinations, agitation, anxiety, and irritability [6].

The official prescribing information for benzydamine generally suggest that benzydamine mouthwashes and sprays should not be used in pregnancy [6, 7] . Similarly, the official prescribing information for benzydamine also generally suggest that benzydamine mouthwashes and sprays should not be used during lactation unless considered essential by a physician [6, 7].

The prescribing information for topical cream formulations of benzydamine note that benzydamine cream should not be used in pregnancy or lactation unless considered necessary by the physician [5].

Overall, non-clinical data reveal no special hazards for humans based on conventional studies of safety pharmacology, repeated toxicity, genotoxicity, cardiogenic potential, and toxicity to reproduction [5]. Additionally, there is no evidence of teratogenic effects in animal studies [6].

Affected organisms
  • Humans and other mammals
Not Available
Pharmacogenomic Effects/ADRs
Not Available


Drug Interactions
(R)-warfarinThe risk or severity of bleeding and hemorrhage can be increased when Benzydamine is combined with (R)-warfarin.
(S)-WarfarinThe risk or severity of bleeding and hemorrhage can be increased when Benzydamine is combined with (S)-Warfarin.
1-(3-Mercapto-2-Methyl-Propionyl)-Pyrrolidine-2-Carboxylic AcidThe risk or severity of renal failure, hyperkalemia, and hypertension can be increased when Benzydamine is combined with 1-(3-Mercapto-2-Methyl-Propionyl)-Pyrrolidine-2-Carboxylic Acid.
1-benzylimidazoleThe risk or severity of hypertension can be increased when 1-benzylimidazole is combined with Benzydamine.
2,5-Dimethoxy-4-ethylamphetamineThe risk or severity of hypertension can be increased when 2,5-Dimethoxy-4-ethylamphetamine is combined with Benzydamine.
2,5-Dimethoxy-4-ethylthioamphetamineThe risk or severity of hypertension can be increased when Benzydamine is combined with 2,5-Dimethoxy-4-ethylthioamphetamine.
3,4-MethylenedioxyamphetamineThe risk or severity of hypertension can be increased when 3,4-Methylenedioxyamphetamine is combined with Benzydamine.
4-Bromo-2,5-dimethoxyamphetamineThe risk or severity of hypertension can be increased when 4-Bromo-2,5-dimethoxyamphetamine is combined with Benzydamine.
4-hydroxycoumarinThe risk or severity of bleeding and hemorrhage can be increased when Benzydamine is combined with 4-hydroxycoumarin.
4-MethoxyamphetamineThe risk or severity of hypertension can be increased when 4-Methoxyamphetamine is combined with Benzydamine.
Food Interactions
Not Available


General References
  1. Baldock GA, Brodie RR, Chasseaud LF, Taylor T, Walmsley LM, Catanese B: Pharmacokinetics of benzydamine after intravenous, oral, and topical doses to human subjects. Biopharm Drug Dispos. 1991 Oct;12(7):481-92. [PubMed:1932611]
  2. Silvestrini B, Barcellona PS, Garau A, Catanese B: Toxicology of benzydamine. Toxicol Appl Pharmacol. 1967 Jan;10(1):148-59. [PubMed:6031923]
  3. Quane PA, Graham GG, Ziegler JB: Pharmacology of benzydamine. Inflammopharmacology. 1998;6(2):95-107. doi: 10.1007/s10787-998-0026-0. [PubMed:17694367]
  4. Catanese B, Grasso A, Silverstrini B: Studies on the absorption and elimination of benzydamine in the mouse, rat, dog, and man. Arzneimittelforschung. 1966 Oct;16(10):1354-7. [PubMed:6014929]
  5. Electronic Medicines Compedium Difflam (Benzydamine Hydrochloride) Spray Monograph [Link]
  6. Electronic Medicines Compedium Benzydamine Hydrochloride 0.15% w/v Mouthwash Monograph [Link]
  7. Electronic Medicines Compedium Difflam (Benzydamine Hydrochloride) 3% Cream Monograph [Link]
  8. Benzydamine - Tantum Verde [Link]
External Links
PubChem Compound
PubChem Substance
ATC Codes
A01AD02 — BenzydamineM01AX07 — BenzydamineM02AA05 — BenzydamineG02CC03 — Benzydamine
AHFS Codes
  • 52:28.00 — Mouthwashes and Gargles
  • 52:08.20 — Nonsteroidal Anti-inflammatory Agents
Download (343 KB)

Clinical Trials

Clinical Trials
3CompletedSupportive CareHead and Neck Carcinoma / Mucositis1
3Unknown StatusPreventionFor Intervention1
4CompletedOtherIntubation Complications1
4CompletedSupportive CarePain NOS / Quality of Life1


Not Available
Not Available
Dosage forms
LiquidBuccal0.15 %
Mouthwash; solutionBuccal; Oral1.5 mg
Liquid; mouthwashBuccal; Oral1.5 mg
MouthwashBuccal1.5 mg
SolutionOral0.15 %
LiquidDental; Oral.15 %
SolutionBuccal15 mg
Not Available
Not Available


Experimental Properties
melting point (°C)320°FMSDS
water solubilityMiscibleMSDS
Predicted Properties
Water Solubility0.0491 mg/mLALOGPS
pKa (Strongest Basic)9.26ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area30.29 Å2ChemAxon
Rotatable Bond Count7ChemAxon
Refractivity105.56 m3·mol-1ChemAxon
Polarizability35.62 Å3ChemAxon
Number of Rings3ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
Not Available


Mass Spec (NIST)
Not Available
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available


This compound belongs to the class of organic compounds known as indazoles. These are compounds containing an indazole, which is structurally characterized by a pyrazole fused to a benzene.
Organic compounds
Super Class
Organoheterocyclic compounds
Sub Class
Direct Parent
Alternative Parents
Alkyl aryl ethers / Benzene and substituted derivatives / Pyrazoles / Heteroaromatic compounds / Trialkylamines / Azacyclic compounds / Organopnictogen compounds / Hydrocarbon derivatives
Benzopyrazole / Indazole / Alkyl aryl ether / Monocyclic benzene moiety / Benzenoid / Azole / Pyrazole / Heteroaromatic compound / Tertiary amine / Tertiary aliphatic amine
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available

Drug created on September 15, 2015 13:55 / Updated on February 21, 2019 20:13