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Taxonomy

Benzydamine

Identification

Name

Benzydamine

Accession Number

DB09084

Type

Small Molecule

Groups

Approved

Description

Benzydamine (also known as Tantum Verde or Difflam), available as the hydrochloride salt, is a locally-acting nonsteroidal anti-inflammatory drug (NSAID) with local anaesthetic and analgesic properties. It is used topically for pain relief and anti-inflammatory treatment of the mouth, throat, or muscoskeletal system.

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.

Structure

Similar Structures

Synonyms

Bencidamina
Benzydamine
Benzydaminum

Product Ingredients

Ingredient	UNII	CAS	InChI Key
Benzydamine hydrochloride	K2GI407R4Q	132-69-4	HNNIWKQLJSNAEQ-UHFFFAOYSA-N

Prescription Products

Name	Dosage	Route	Labeller	Marketing Start	Marketing End
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Pharixia	Mouthwash	Buccal	Pendopharm Division Of Pharmascience Inc	1996-12-02	Not applicable
Pharixia Alcohol Free	Mouthwash	Buccal	Pendopharm Division Of Pharmascience Inc	Not applicable	Not applicable
Sun-benz - Liq 0.15%	Liquid	Dental; Oral	Sun Pharmaceutical Industries Inc.	1997-04-03	2011-07-29
Tantum	Mouthwash	Buccal	Valeant Canada Lp Valeant Canada S.E.C.	1993-12-31	Not applicable

Additional Data Available

Application Number

A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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Product Code

A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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Generic Prescription Products

Name	Dosage	Route	Labeller	Marketing Start	Marketing End
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Apo-benzydamine Oral Rinse	Mouthwash	Buccal	Apotex Corporation	1998-11-09	Not applicable
Novo-benzydamine	Mouthwash; Solution	Buccal; Oral	Novopharm Limited	2008-06-03	2018-05-17
Novo-benzydamine - Oral Rinse	Liquid; Mouthwash	Buccal; Oral	Novopharm Limited	1997-02-06	2015-10-26
Nu-benzydamine Oral Rinse	Liquid	Buccal	Nu Pharm Inc	Not applicable	Not applicable
Odan-benzydamine	Mouthwash	Buccal	Odan Laboratories Ltd	2017-08-11	Not applicable
PMS-benzydamine	Mouthwash	Buccal	Pharmascience Inc	1999-04-30	Not applicable
Ratio-benzydamine	Solution	Oral	Ratiopharm Inc Division Of Teva Canada Limited	1997-03-24	2010-05-21

Additional Data Available

Application Number

A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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Product Code

A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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Categories

UNII

4O21U048EF

CAS number

642-72-8

Weight

Average: 309.413
Monoisotopic: 309.184112373

Chemical Formula

C₁₉H₂₃N₃O

InChI Key

CNBGNNVCVSKAQZ-UHFFFAOYSA-N

InChI

InChI=1S/C19H23N3O/c1-21(2)13-8-14-23-19-17-11-6-7-12-18(17)22(20-19)15-16-9-4-3-5-10-16/h3-7,9-12H,8,13-15H2,1-2H3

IUPAC Name

{3-[(1-benzyl-1H-indazol-3-yl)oxy]propyl}dimethylamine

SMILES

CN(C)CCCOC1=NN(CC2=CC=CC=C2)C2=CC=CC=C12

Pharmacology

Indication

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

Pharmacodynamics

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

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Adverse Effects

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Contraindications

Structured data covering drug contraindications. Each contraindication describes a scenario in which the drug is not to be used. Includes restrictions on co-administration, contraindicated populations, and more.

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Blackbox Warnings

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Absorption

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.

Metabolism

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.

Clearance

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

Toxicity

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

Pathways

Not Available

Pharmacogenomic Effects/ADRs

Not Available

Interactions

Drug Interactions

This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.

Drug	Interaction
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(R)-warfarin	The risk or severity of bleeding and hemorrhage can be increased when Benzydamine is combined with (R)-warfarin.
(S)-Warfarin	The 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 Acid	The risk or severity of hypertension can be increased when 1-(3-Mercapto-2-Methyl-Propionyl)-Pyrrolidine-2-Carboxylic Acid is combined with Benzydamine.
1-benzylimidazole	The risk or severity of hypertension can be increased when 1-benzylimidazole is combined with Benzydamine.
2,5-Dimethoxy-4-ethylamphetamine	The risk or severity of hypertension can be increased when 2,5-Dimethoxy-4-ethylamphetamine is combined with Benzydamine.
2,5-Dimethoxy-4-ethylthioamphetamine	The risk or severity of hypertension can be increased when Benzydamine is combined with 2,5-Dimethoxy-4-ethylthioamphetamine.
4-Bromo-2,5-dimethoxyamphetamine	The risk or severity of hypertension can be increased when 4-Bromo-2,5-dimethoxyamphetamine is combined with Benzydamine.
4-hydroxycoumarin	The risk or severity of bleeding and hemorrhage can be increased when Benzydamine is combined with 4-hydroxycoumarin.
4-Methoxyamphetamine	The risk or severity of hypertension can be increased when 4-Methoxyamphetamine is combined with Benzydamine.
5-methoxy-N,N-dimethyltryptamine	The risk or severity of hypertension can be increased when Benzydamine is combined with 5-methoxy-N,N-dimethyltryptamine.

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Severity

A severity rating for each drug interaction, from minor to major.

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Evidence Level

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Action

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Food Interactions

Not Available

References

General References

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]
Silvestrini B, Barcellona PS, Garau A, Catanese B: Toxicology of benzydamine. Toxicol Appl Pharmacol. 1967 Jan;10(1):148-59. [PubMed:6031923]
Quane PA, Graham GG, Ziegler JB: Pharmacology of benzydamine. Inflammopharmacology. 1998;6(2):95-107. doi: 10.1007/s10787-998-0026-0. [PubMed:17694367]
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]
Electronic Medicines Compedium Difflam (Benzydamine Hydrochloride) Spray Monograph [Link]
Electronic Medicines Compedium Benzydamine Hydrochloride 0.15% w/v Mouthwash Monograph [Link]
Electronic Medicines Compedium Difflam (Benzydamine Hydrochloride) 3% Cream Monograph [Link]
Benzydamine - Tantum Verde [Link]

External Links

PubChem Compound: 12555
PubChem Substance: 310265011
ChemSpider: 12036
BindingDB: 50095471
ChEBI: 94563
ChEMBL: CHEMBL12610
Wikipedia: Benzydamine

ATC Codes

A01AD02 — Benzydamine

M01AX07 — Benzydamine

M02AA05 — Benzydamine

G02CC03 — Benzydamine

R02AX03 — Benzydamine

AHFS Codes

52:28.00 — Mouthwashes and Gargles
52:08.20 — Nonsteroidal Anti-inflammatory Agents

MSDS

Download (343 KB)

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
1	Completed	Other	Healthy Volunteers	2
1	Completed	Other	Healthy Women	1
3	Completed	Supportive Care	Head and Neck Carcinoma / Mucositis	1
3	Completed	Treatment	Radiation Effects / Stomatitis	1
3	Unknown Status	Prevention	For Intervention	1
4	Completed	Other	Intubation Complications	1
4	Completed	Prevention	Post Operative Nausea and Vomiting (PONV) / Sore Throat	1
4	Completed	Supportive Care	Pain / Quality of Life	1
Not Available	Completed	Supportive Care	ERCP	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage forms

Form	Route	Strength
Mouthwash; solution	Buccal; Oral
Liquid; mouthwash	Buccal; Oral
Liquid	Buccal
Mouthwash	Buccal
Solution	Oral
Liquid	Dental; Oral

Prices

Not Available

Patents

Not Available

Properties

State

Solid

Experimental Properties

Property	Value	Source
melting point (°C)	320°F	MSDS
water solubility	Miscible	MSDS

Predicted Properties

Property	Value	Source
Water Solubility	0.0491 mg/mL	ALOGPS
logP	3.78	ALOGPS
logP	3.66	ChemAxon
logS	-3.8	ALOGPS
pKa (Strongest Basic)	9.26	ChemAxon
Physiological Charge	1	ChemAxon
Hydrogen Acceptor Count	3	ChemAxon
Hydrogen Donor Count	0	ChemAxon
Polar Surface Area	30.29 Å²	ChemAxon
Rotatable Bond Count	7	ChemAxon
Refractivity	105.56 m³·mol^-1	ChemAxon
Polarizability	35.62 Å³	ChemAxon
Number of Rings	3	ChemAxon
Bioavailability	1	ChemAxon
Rule of Five	Yes	ChemAxon
Ghose Filter	Yes	ChemAxon
Veber's Rule	Yes	ChemAxon
MDDR-like Rule	Yes	ChemAxon

Predicted ADMET features

Not Available

Spectra

Mass Spec (NIST)

Not Available

Spectra

Spectrum	Spectrum Type	Splash Key
Predicted GC-MS Spectrum - GC-MS	Predicted GC-MS	Not Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)	Predicted LC-MS/MS	Not Available

Taxonomy

Description: 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.
Kingdom: Organic compounds
Super Class: Organoheterocyclic compounds
Class: Benzopyrazoles
Sub Class: Indazoles
Direct Parent: Indazoles
Alternative Parents: Alkyl aryl ethers / Benzene and substituted derivatives / Pyrazoles / Heteroaromatic compounds / Trialkylamines / Azacyclic compounds / Organopnictogen compounds / Hydrocarbon derivatives
Substituents: 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 December 07, 2019 14:37

Benzydamine

Identification

Structure for Benzydamine (DB09084)

Pharmacology

Interactions

References

Clinical Trials

Pharmacoeconomics

Properties

Spectra

Taxonomy