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Name Metronidazole

Accession Number DB00916 (APRD00631)


Type small molecule
Groups

approved

Description
A nitroimidazole used to treat amebiasis; vaginitis; trichomonas infections;
giardiasis; anaerobic bacteria; and treponemal infections. It has also been proposed
as a radiation sensitizer for hypoxic cells. According to the Fourth Annual Report on
Carcinogens (NTP 85-002, 1985, p133), this substance may reasonably be
anticipated to be a carcinogen (Merck, 11th ed).
Structure
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms

Methronidazole

Metronidazol
Metronidazole Benzoate
Metronidazole Hcl
Metronidazole in Plastic Container
Metronidazolo
Synonyms

Methronidazole

Metronidazol
Metronidazole Benzoate
Metronidazole Hcl
Metronidazole in Plastic Container
Metronidazolo

Salts Not Available


Brand names
Acromona
Anagiardil
Apo-Metronidazole

Name Company

Arilin
Atrivyl
Bayer 5360
Bexon
Clont
Cont
Danizol

Brand mixtures

Brand Name Ingredients

Helidac

Metronidazole + Bismuth subsalicylate + tetracycline hydrochloride

Categories

Anti-Infective Agents

Anti-Infectives
Radiation-Sensitizing Agents
Antiprotozoals
Antiprotozoal Agents
CAS number 443-48-1
Weight

Average: 171.154

Monoisotopic: 171.064391169
Chemical Formula C6H9N3O3
InChI Key

InChIKey=VAOCPAMSLUNLGC-UHFFFAOYSA-N

InChI InChI=1S/C6H9N3O3/c1-5-7-4-6(9(11)12)8(5)2-3-10/h4,10H,2-3H2,1H3
Plain Text
IUPAC Name 2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethan-1-ol
SMILES

CC1=NC=C(N1CCO)[N+]([O-])=O

Plain Text
Mass Spec
Taxonomy

show (9.68 KB)

Kingdom

Organic

Classes

Nitroimidazoles

Substructures

Nitroimidazoles

Hydroxy Compounds
Oxoazaniums
Nitro compounds
Alcohols and Polyols
Imidazoles
Heterocyclic compounds
Aromatic compounds
Imines
Cyanamides
Pharmacology
Indication
For the treatment of anaerobic infections and mixed infections, surgical
prophylaxis requiring anaerobic coverage, Clostridium difficile-associated diarrhea
and colitis, Helicobacter pylori infection and duodenal ulcer disease, bacterial
vaginosis, Giardia lamblia gastro-enteritis, amebiasis caused by Entamoeba
histolytica, acne rosacea (topical treatment), and Trichomonas infections.
Pharmacodynamics
Metronidazole, a synthetic antibacterial and antiprotozoal
agent of the nitroimidazole class, is used against protozoa such as Trichomonas
vaginalis, amebiasis, and giardiasis. Metronidazole is extremely effective against
anaerobic bacterial infections and is also used to treat Crohn's disease, antibioticassociated diarrhea, and rosacea.
Mechanism of action
Metronidazole is a prodrug. Unionized metronidazole is
selective for anaerobic bacteria due to their ability to intracellularly reduce
metronidazole to its active form. This reduced metronidazole then covalently binds
to DNA, disrupt its helical structure, inhibiting bacterial nucleic acid synthesis and
resulting in bacterial cell death.
Absorption Well absorbed (at least 80%) with peak plasma concentrations
achieved in 1-3 hours following oral administration of therapeutic doses of
immediate release formulation.
Volume of distribution
Protein binding

Not Available

Less than 20% bound to plasma proteins.

Metabolism Hepatic metabolism by hydroxylation, oxidation, and glucuronidation.


Route of elimination

Not Available

Half life

6-8 hours

Clearance

Not Available

Toxicity
LD50=500 mg/kg/day (orally in rat). Adverse effects include reversible
peripheral neuropathy with prolonged therapy, CNS toxicity, disulfiram effect with
alcohol, dark red-brown urine, metallic taste, nausea, epigastric distress, dizziness,
vertigo and paresthesias associated with high doses, and neutropenia (reversible
and mild).
Affected organisms
Pathways

Bacteria and protozoa

Not Available

Pharmacoeconomics
Manufacturers

Gd searle llc

Able laboratories inc


Alembic ltd
Par pharmaceutical inc
Galderma laboratories lp
Altana inc
G and w laboratories inc
Sanofi aventis us llc
Taro pharmaceutical industries ltd
Tolmar inc
Graceway pharmaceuticals llc
Teva pharmaceuticals usa
Baxter healthcare corp
B braun medical inc
Abbott laboratories pharmaceutical products div
Abraxis pharmaceutical products
Elkins sinn div ah robins co inc
International medication systems ltd
Watson laboratories inc
Claris lifesciences ltd
Hospira inc

Laboratorios aplicaciones farmaceuticas sa de cv


Halsey drug co inc
Ivax pharmaceuticals inc sub teva pharmaceuticals usa
Lnk international inc
Mutual pharmaceutical co inc
Pliva inc
Sandoz inc
Superpharm corp
Teva pharmaceuticals usa inc
World gen llc
Ortho mcneil pharmaceutical inc
Savage laboratories inc div altana inc
Packagers

Actavis Group

Advanced Pharmaceutical Services Inc.


American Pharmaceutical Association
Ameri-Pac Inc.
Amerisource Health Services Corp.
Amneal Pharmaceuticals
Apace Packaging
Apotheca Inc.
A-S Medication Solutions LLC
Atlantic Biologicals Corporation
B. Braun Melsungen AG
Baxter International Inc.
Ben Venue Laboratories Inc.
Bryant Ranch Prepack
Cardinal Health
Carlisle Laboratories Inc.
Central Texas Community Health Centers

Claris Lifesciences Inc.


Community Action Inc. Community Health Services
Comprehensive Consultant Services Inc.
Contract Pharm
Darby Dental Supply Co. Inc.
Dept Health Central Pharmacy
Dermik Labs
DHHS Program Support Center Supply Service Center
Direct Dispensing Inc.
Dispensing Solutions
Diversified Healthcare Services Inc.
DPT Laboratories Ltd.
Dudley Corp.
E. Fougera and Co.
G & W Labs
Galderma Laboratories
GD Searle LLC
GlaxoSmithKline Inc.
Golden State Medical Supply Inc.
Graceway Pharmaceuticals
Group Health Cooperative
H and H Laboratories
H.J. Harkins Co. Inc.
Harris Pharmaceutical Inc.
Hawkins Inc.
Heartland Repack Services LLC
Hospira Inc.
Kaiser Foundation Hospital
Lake Erie Medical and Surgical Supply

Liberty Pharmaceuticals
Major Pharmaceuticals
Mckesson Corp.
Medisca Inc.
Medvantx Inc.
Mississippi State Dept Health
Murfreesboro Pharmaceutical Nursing Supply
Mutual Pharmaceutical Co.
Nord Ost Corp.
Nucare Pharmaceuticals Inc.
Nycomed Inc.
Obagi Medical Products Inc.
Palmetto Pharmaceuticals Inc.
Pangeo Pharma Quebec Inc.
Par Pharmaceuticals
Patheon Inc.
Patient First Corp.
PCA LLC
PD-Rx Pharmaceuticals Inc.
Pfizer Inc.
Pharmacia Inc.
Pharmedix
Pharmpak Inc.
Physicians Total Care Inc.
Pliva Inc.
Prasco Labs
Preferred Pharmaceuticals Inc.
Prepackage Specialists
Prepak Systems Inc.

Prescription Dispensing Service Inc.


Qualitest
Raz Co. Inc.
Rebel Distributors Corp.
Redpharm Drug
Remedy Repack
Rochester Pharmaceuticals
Sagent Pharmaceuticals
Sandhills Packaging Inc.
Sandoz
Sanofi-Aventis Inc.
SCS Pharmaceuticals
Southwood Pharmaceuticals
St Mary's Medical Park Pharmacy
Stat Rx Usa
Taro Pharmaceuticals USA
Teva Pharmaceutical Industries Ltd.
Tolmar Inc.
UDL Laboratories
Upsher Smith Laboratories
Vangard Labs Inc.
Veratex Corp.
Watson Pharmaceuticals
West-Ward Pharmaceuticals
Dosage forms
Capsule

Oral

Cream

Intravaginal

Cream

Topical

Gel

Intravaginal

Form Route Strength

Gel

Topical

Liquid Intravenous
Lotion Topical
Solution

Intravenous

Tablet Oral
Tablet, extended release Oral

Prices

Unit description

Cost

Unit

MetroLotion 0.75% Lotion 59ml Bottle 292.66 USD bottle


MetroCream 0.75% Cream 45 gm Tube
Metrogel 1% Gel 60 gm Tube
Metrogel 1% Kit Box
Metrogel 1% kit

281.09 USD tube

200.93 USD tube

200.93 USD box

193.2 USD

kit

Noritate 1% Cream 60 gm Tube 156.44 USD tube


MetroNIDAZOLE 0.75% Lotion 59ml Bottle

89.86 USD

bottle

MetroNIDAZOLE 0.75% Cream 45 gm Tube

80.87 USD

tube

MetroNIDAZOLE 0.75% Gel 45 gm Tube

74.0 USD

tube

MetroNIDAZOLE 0.75% Gel 70 gm Tube

68.53 USD

tube

DrugBank does not sell nor buy drugs. Pricing information is supplied for
informational purposes only.
Patents

Country

Patent Number

United States

6881726

2002-02-21 2022-02-21

United States

5536743

1993-07-16 2013-07-16

Canada

2470492

2010-02-23 2022-11-07

Canada

2161737

1998-10-20 2015-10-30

Properties
State solid

Approved

Expires (estimated)

Melting point

160 oC

Experimental Properties
water solubility

Property

<0.1g/100mL

logP

-0.1

logS

-1.26 [ADME Research, USCD]

Value Source

PhysProp

PhysProp

Predicted Properties
water solubility

PhysProp

Property

5.92e+00 g/l

logP

-0.15 ALOGPS

logP

-0.46 ChemAxon Molconvert

logS

-1.5

ALOGPS

pKa

ChemAxon Molconvert

Value Source

ALOGPS

hydrogen acceptor count 4

ChemAxon Molconvert

hydrogen donor count

ChemAxon Molconvert

polar surface area 83.87 ChemAxon Molconvert


rotatable bond count

ChemAxon Molconvert

refractivity 41.22 ChemAxon Molconvert


polarizability15.82 ChemAxon Molconvert

References
Synthesis Reference

Not Available

General Reference Shennan A, Crawshaw S, Briley A, Hawken J, Seed P, Jones G,


Poston L: A randomised controlled trial of metronidazole for the prevention of
preterm birth in women positive for cervicovaginal fetal fibronectin: the PREMET
Study. BJOG. 2006 Jan;113(1):65-74. Pubmed
Lamont RF: Can antibiotics prevent preterm birththe pro and con debate. BJOG.
2005 Mar;112 Suppl 1:67-73. Pubmed
Williams CS, Woodcock KR: Do ethanol and metronidazole interact to produce a
disulfiram-like reaction? Ann Pharmacother. 2000 Feb;34(2):255-7. Pubmed
Visapaa JP, Tillonen JS, Kaihovaara PS, Salaspuro MP: Lack of disulfiram-like reaction
with metronidazole and ethanol. Ann Pharmacother. 2002 Jun;36(6):971-4. Pubmed
External Links

Resource

Link

KEGG Drug D00409


PubChem Compound

4173

PubChem Substance

46508911

ChemSpider 4029
ChEBI 6909
ChEMBL

6909

Therapeutic Targets Database


Drug Product Database

DAP000534

649074

RxList http://www.rxlist.com/cgi/generic/metron.htm
Drugs.com

http://www.drugs.com/metronidazole.html

Wikipedia

http://en.wikipedia.org/wiki/Metronidazole

ATC Codes

A01AB17

D06BX01
G01AF01
J01XD01
P01AB01
AHFS Codes 84:04.92
84:04.04
08:30.92
PDB Entries Not Available
FDA label

show (115 KB)

MSDS show (73.9 KB)


Interactions
Drug Interactions
Acenocoumarol
acenocoumarol.

Drug Interaction
Metronidazole may increase the anticoagulant effect of

Amobarbital The barbiturate, amobarbital, decreases the effect of metronidazole.


Amprenavir Increased risk of side effects (oral solution)
Anisindione Metronidazole may increase the anticoagulant effect of anisindione.

Aprobarbital The barbiturate, aprobarbital, decreases the effect of metronidazole.


Busulfan

Metronidazole increases the effect/toxicity of busulfan

Butabarbital The barbiturate, butabarbital, decreases the effect of metronidazole.


Butalbital

The barbiturate, butalbital, decreases the effect of metronidazole.

Butethal

The barbiturate, butethal, decreases the effect of metronidazole.

Carbamazepine
Dicumarol

Metronidazole increases the effect of carbamazepine

Metronidazole may increase the anticoagulant effect of dicumarol.

Dihydroquinidine barbiturate
The barbiturate, dihydroquinidine barbiturate,
decreases the effect of metronidazole.
Disulfiram

Possible acute psychosis and confusion

Fluorouracil Risk of 5-FU toxicity when associated with metronidazole


Heptabarbital
metronidazole.

The barbiturate, heptabarbital, decreases the effect of

HexobarbitalThe barbiturate, hexobarbital, decreases the effect of metronidazole.


Lithium

Metronidazole increases the effect and toxicity of lithium

Methohexital
metronidazole.

The barbiturate, methohexital, decreases the effect of

Methylphenobarbital
The barbiturate, methylphenobarbital, decreases the
effect of metronidazole.
Pentobarbital
metronidazole.

The barbiturate, pentobarbital, decreases the effect of

Phenobarbital
metronidazole.

The barbiturate, phenobarbital, decreases the effect of

Primidone

The barbiturate, primidone, decreases the effect of metronidazole.

Quinidine barbiturate
The barbiturate, quinidine barbiturate, decreases the
effect of metronidazole.
Secobarbital The barbiturate, secobarbital, decreases the effect of metronidazole.
Tacrolimus

Metronidazole increases the levels/toxicity of tacrolimus

Talbutal

The barbiturate, talbutal, decreases the effect of metronidazole.

Tamsulosin Metronidazole, a CYP3A4 inhibitor, may decrease the metabolism and


clearance of Tamsulosin, a CYP3A4 substrate. Monitor for changes in
therapeutic/adverse effects of Tamsulosin if Metronidazole is initiated, discontinued,
or dose changed.

Tolterodine Metronidazole may decrease the metabolism and clearance of


Tolterodine. Adjust Tolterodine dose and monitor for efficacy and toxicity.
Tramadol
Metronidazole may increase Tramadol toxicity by decreasing Tramadol
metabolism and clearance.
Trazodone The CYP3A4 inhibitor, Metronidazole, may increase Trazodone
efficacy/toxicity by decreasing Trazodone metabolism and clearance. Monitor for
changes in Trazodone efficacy/toxicity if Metronidazole is initiated, discontinued or
dose changed.
Warfarin
Metronidazole may increase the serum concentration of warfarin by
decreasing its metabolism. Consider alternate therapy or a dose reduction in
warfarin. Monitor for changes in prothrombin time and therapeutic and adverse
effects of warfarin if metronidazole is initiated, discontinued or dose changed.

Food Interactions

Avoid alcohol.

Take with food to reduce irritation.


Targets

1. DNA
Pharmacological action: yes
Actions: binder

DNA is the molecule of heredity, as it is responsible for the genetic propagation of


most inherited traits. It is a polynucleic acid that carries genetic information on cell
growth, division, and function. DNA consists of two long strands of nucleotides
twisted into a double helix and held together by hydrogen bonds. The sequence of
nucleotides determines hereditary characteristics. Each strand serves as the
template for subsequent DNA replication and as a template for mRNA production,
leading to protein synthesis via ribosomes.
Gene Sequence: FASTA

References:
Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev
Drug Discov. 2006 Dec;5(12):993-6. Pubmed
Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of
drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. Pubmed

Salles JM, Salles MJ, Moraes LA, Silva MC: Invasive amebiasis: an update on
diagnosis and management. Expert Rev Anti Infect Ther. 2007 Oct;5(5):893-901.
Pubmed
Li AQ, Dai N, Yan J, Zhu YL: [Screening for metronidazole-resistance associated gene
fragments of Helicobacter pylori by suppression subtractive hybridization.] Zhejiang
Da Xue Xue Bao Yi Xue Ban. 2007 Sep;36(5):465-9. Pubmed
Edwards DI: Nitroimidazole drugsaction and resistance mechanisms. I.
Mechanisms of action. J Antimicrob Chemother. 1993 Jan;31(1):9-20. Pubmed

2. Oxygen-insensitive NADPH nitroreductase


Pharmacological action: yes
Actions: potentiator
Organism class: bacterial
UniProt ID: O25608
Gene: rdxA
SNPs: SNPJam Report

References:
Sisson G, Jeong JY, Goodwin A, Bryden L, Rossler N, Lim-Morrison S, Raudonikiene A,
Berg DE, Hoffman PS: Metronidazole activation is mutagenic and causes DNA
fragmentation in Helicobacter pylori and in Escherichia coli containing a cloned H.
pylori RdxA(+) (Nitroreductase) gene. J Bacteriol. 2000 Sep;182(18):5091-6.
Pubmed
Chisholm SA, Owen RJ: Mutations in Helicobacter pylori rdxA gene sequences may
not contribute to metronidazole resistance. J Antimicrob Chemother. 2003
Apr;51(4):995-9. Epub 2003 Mar 13. Pubmed
Debets-Ossenkopp YJ, Pot RG, van Westerloo DJ, Goodwin A, Vandenbroucke-Grauls
CM, Berg DE, Hoffman PS, Kusters JG: Insertion of mini-IS605 and deletion of
adjacent sequences in the nitroreductase (rdxA) gene cause metronidazole
resistance in Helicobacter pylori NCTC11637. Antimicrob Agents Chemother. 1999
Nov;43(11):2657-62. Pubmed
Pisharath H, Parsons MJ: Nitroreductase-mediated cell ablation in transgenic
zebrafish embryos. Methods Mol Biol. 2009;546:133-43. Pubmed
Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN,
Bourne PE: The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42.
Pubmed

3. Periplasmic [Fe] hydrogenase 1


Pharmacological action: unknown
Actions: inhibitor
Organism class: bacterial
UniProt ID: P29166
Protein Sequence: FASTA
Gene Sequence: FASTA

References:
Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev
Drug Discov. 2006 Dec;5(12):993-6. Pubmed
Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of
drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. Pubmed
Kutty R, Bennett GN: Studies on inhibition of transformation of 2,4,6-trinitrotoluene
catalyzed by Fe-only hydrogenase from Clostridium acetobutylicum. J Ind Microbiol
Biotechnol. 2006 May;33(5):368-76. Epub 2006 Jan 28. Pubmed

Enzymes

1. Cytochrome P450 2C9


Actions: substrate, inhibitor

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver


microsomes, this enzyme is involved in an NADPH-dependent electron transport
pathway. It oxidizes a variety of structurally unrelated compounds, including
steroids, fatty acids, and xenobiotics. This enzyme contributes to the wide
pharmacokinetics variability of the metabolism of drugs such as S- warfarin,
diclofenac, phenytoin, tolbutamide and losartan
UniProt ID: P11712
Gene: CYP2C9
Protein Sequence: FASTA

Gene Sequence: FASTA


SNPs: SNPJam Report

References:
Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S,
Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on
Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions.
Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24.
Pubmed

2. Cytochrome P450 3A4


Actions: substrate, inhibitor

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver


microsomes, this enzyme is involved in an NADPH-dependent electron transport
pathway. It performs a variety of oxidation reactions (e.g. caffeine 8-oxidation,
omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4hydroxylation) of structurally unrelated compounds, including steroids, fatty acids,
and xenobiotics. The enzyme also hydroxylates etoposide
UniProt ID: P08684
Gene: CYP3A4
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report

References:
Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S,
Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on
Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions.
Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24.
Pubmed

3. Cytochrome P450 2C8

Actions: inhibitor

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver


microsomes, this enzyme is involved in an NADPH-dependent electron transport
pathway. It oxidizes a variety of structurally unrelated compounds, including
steroids, fatty acids, and xenobiotics. In the epoxidation of arachidonic acid it
generates only 14,15- and 11,12-cis-epoxyeicosatrienoic acids. It is the principal
enzyme responsible for the metabolism the anti- cancer drug paclitaxel (taxol)
UniProt ID: P10632
Gene: CYP2C8
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report

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Metronidazol este un antiinfecios cu spectru larg de aciune.7 Compozitie:


Comprimate orale continand metronidazol 250 mg. Actiune farmacoterapeutica:
Chimioterapic activ fata de Trichomonas vaginalis, Lamblia intestinalis, Entamoeba
hystolitica si bacterii anaerobe. Folosit deasemenea, conform studiilor mai recente,
si in tratamentul demodicidozei, produsa de acarianul demodex folliculorum - (vezi
the online journal of dermatology) [1]).

Indicatii: Tricomoniaza vaginala si uretrala, lambliaza, dizenterie hepatica si abcese


hepatice amebiene, infectii cu anaerobi. Mod de administrare si posologie: In
trichomoniaza, la adulti, oral (dupa mese), cate 1 comprimat de 3 ori pe zi, timp de
7-10 zile; tratamentul partenerului este obligatoriu pentru a evita reinfectarea; in
caz de esec se poate repeta cura dupa 4-6 saptamani. In lambliaza, la adulti, cate 1
comprimat de 3 ori pe zi, 7-10 zile; la copiii de 2-5 ani, cate 1/2 comprimat de 3 ori
pe zi; la cei de 5-10 ani, cate 1 comprimat de 3 ori pe zi, 7-10 zile. In amebiaza, la
adulti, 2-3 comprimate de 3 ori pe zi, 5-10 zile; la copii 35-50 mg /kg corp pe zi,
fractionat in 3 doze, timp de 10 zile. In infectiile cu anaerobi, la adulti, cate 2-3
comprimate la fiecare 8 ore, 7-10 zile.

Reactii adverse: Greata, gust metalic, limba incarcata, cefalee (relativ frecvent),
diaree, uscaciunea gurii, neplacere epigastrica, varsaturi, arsuri vaginale, eruptii
cutanate, ameteli, somnolenta, leucopenie trecatoare (rareori); febra, congestie
nazala, disurie, scaderea libidoului, polinevrita, vertij, ataxie, convulsii (foarte rar).
Contraindicatii si precautii: Metronidazolul este contraindicat la bolnavii cu discrazii
sanguine (tratamentul se face sub controlul hemoleucogramei), psihoze si boli
neurologice active, alergie la medicamente; se evita in primele 3 luni de sarcina si
prudenta in continuare; nu se administreaza la lauze si in perioada de alaptare.

Interactiuni medicamentoase: Asocierea bauturilor alcoolice este contraindicata,


deoarece pot aparea reactii de tip disulfiram (greturi, varsaturi, congestia fetei,
stare de rau); prudenta in asociere cu anticoagulante orale (risc crescut de
accidente hemoragice).

Forma de prezentare: Flacon cu 20 de comprimate. Valabilitate: 2 ani de la data


fabricatiei.

Conditii de pastrare: La adapost de lumina si umiditate, la temperatura de -15 - +25


grade Celsius.

Human Health Effects:

Evidence for Carcinogenicity:


Metronidazole: reasonably anticipated to be a human carcinogen.
[DHHS/National Toxicology Program; Eleventh Report on Carcinogens: Metronidazole
(443-48-1) (January 2005). Available from, as of July 31, 2009:
http://ntp.niehs.nih.gov/ntp/roc/eleventh/profiles/s112metr.pdf **QC REVIEWED**

Human Toxicity Excerpts:


/SIGNS AND SYMPTOMS/ Some patients receiving metronidazole experience ... incr
in blood pressure caused by release of sympathomimetic amines.
[American Medical Association, AMA Department of Drugs, AMA Drug Evaluations.
3rd ed. Littleton, Massachusetts: PSG Publishing Co., Inc., 1977., p. 1066] **PEER
REVIEWED**

/SIGNS AND SYMPTOMS/ Neurotoxic effects, including seizures and peripheral


neuropathy, have occurred in individuals who received 6-10.4 g of metronidazole
orally every other day for 5-7 days for the treatment of malignant tumors. Nausea,
vomiting, and ataxia without serious resultant toxicity have been reported in
individuals who ingested up to 19.5 g of metronidazole in a single dose.
[McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information.
American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 891]
**PEER REVIEWED**

/SIGNS AND SYMPTOMS/ Metronidazole (Flagyl), a commonly prescribed


antimicrobial agent, can produce a reaction similar to that of disulfiram (Antabuse)
when administered to patients drinking ethanol. This drug/chemical interaction
results in accumulation of acetaldehyde in the blood. Acetaldehyde is hepatotoxic,
cardiotoxic, and arrythmogenic; no lethal serum acetaldehyde level has been
established. Sudden death has been reported in patients taking disulfiram while
using ethanol; ... fatalities have been reported due to ethanol/ metronidazole
interactions.

[Cina SJ et al; : Am J Forensic Med Pathol 17 (4): 343-6 (1996)] **PEER REVIEWED**
PubMed Abstract

/CASE REPORTS/ Neuropathy in 20 year old girl in which complete subjective


recovery has not apparently resulted 2 years after discontinuing drug is reported.
Patient was treated with 800 mg orally twice daily for 7 wks before developing
numbness of hands and feet.
[Hishon S, Pilling J; Br Med J 2: 832 (1977)] **PEER REVIEWED**

/CASE REPORTS/ Peripheral neuropathy was reported in 33 year old male with
Crohn's disease. Patient had been taking metronidazole in dosage of 400 mg 3
times daily for 6 months.
[Bradley WG et al; Br Med J 2: 610 (1977)] **PEER REVIEWED** PubMed Abstract

/CASE REPORTS/ Described is a case of a 31-year-old woman who died moments


after an assault by a male companion, during which he inflicted minor physical
trauma to her upper arm. Toxicologic analysis yielded elevated concentrations of
serum ethanol (162 mg/d), acetaldehyde (4.6 mg/d), and metronidazole (0.42
mg/L). The cause of death was reported to be cardiac dysrhythmia due to
acetaldehyde toxicity due to an ethanol/ metronidazole interaction. Autonomic
stress associated with the assault is likely to have contributed to this woman's
death.
[Cina SJ et al; : Am J Forensic Med Pathol 17 (4): 343-6 (1996)] **PEER REVIEWED**
PubMed Abstract

Drug Warnings:
Metronidazole crosses the placenta and enters the fetal circulation rapidly.
Adequate and well-controlled studies in humans have not been done. ... However,
the use of metronidazole in the treatment of trichomoniasis is not recommended
during the first trimester. If metronidazole is used during the second and the third
trimesters for trichomoniasis it is recommended that its use be limited to those
patients whose symptoms are not controlled by local palliative treatment. Also, the
1 day course of therapy should not be used since this results in higher maternal and
fetal serum concentrations.
[Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1,
Greenwood Village, CO. 2006., p. 2070] **PEER REVIEWED**

No information is available on the relationship of age to the effects of


metronidazole in geriatric patients. However, elderly patients are more likely to
have an age-related decrease in hepatic function, which may require an adjustment
in dosage in patients receiving metronidazole.
[Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1,
Greenwood Village, CO. 2006., p. 2070] **PEER REVIEWED**

Peripheral neuropathy, characterized by numbness, tingling, or paresthesia of an


extremity, and convulsive seizures have been reported rarely with oral or IV
metronidazole. Peripheral neuropathy is usually reversible if metronidazole is
discontinued but may persist in patients who receive prolonged therapy or higher
than recommended dosage of the drug. Dizziness, vertigo, incoordination, ataxia,
confusion, irritability, depression, weakness, insomnia, headache, syncope, tinnitus,
and hearing loss have also occurred with metronidazole. Headache occurred in 18%
of nonpregnant women receiving oral metronidazole (administered as extendedrelease tablets) for bacterial vaginosis, and among those reporting headache, 10%
described it as severe.
[McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information.
American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 889]
**PEER REVIEWED**

Urethral burning or discomfort, dysuria, cystitis, polyuria, incontinence, a sense of


pelvic pressure, dryness of the vagina or vulva, dyspareunia, and decreased libido
have been reported with oral metronidazole. Urine may be dark or reddish-brown in
color following oral or IV administration of metronidazole due to the presence of
water-soluble pigments which result from metabolism of the drug. Vulvovaginal
candidiasis (or yeast vaginitis) was reported in 15% of nonpregnant women
receiving oral metronidazole (administered as extended-release tablets) and in 12%
of those receiving clindamycin phosphate (2% clindamycin) vaginal cream in a
comparative study for the treatment of bacterial vaginosis. Although a definite
causal relationship to the drug has not been established, genital pruritus,
dysmenorrhea, and urinary tract infection have been reported in 5, 3, and 2%,
respectively, of nonpregnant women receiving oral metronidazole (administered as
extended-release tablets) for the treatment of bacterial vaginosis.
[McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information.
American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 890]
**PEER REVIEWED**

Hypersensitivity reactions including urticaria, pruritus, erythematous rash, flushing,


nasal congestion, fever, and fleeting joint pains sometimes resembling serum
sickness have been reported in patients receiving oral metronidazole. Erythematous
rash and pruritus have been reported in patients receiving IV metronidazole. Aseptic
meningitis, that appeared to be a hypersensitivity reaction, has occurred in at least

one patient after administration of oral metronidazole. The reaction consisted of


severe headache, fever, arthralgia, myalgia, stiff neck, nausea, and vomiting.
[McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information.
American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 890]
**PEER REVIEWED**

Furry tongue, glossitis, and stomatitis have been reported with oral metronidazole
and may be due to overgrowth of Candida which may occur during metronidazole
therapy. Candidiasis was reported in 3% of nonpregnant women receiving oral
metronidazole (administered as extended-release tablets) for the treatment of
bacterial vaginosis.
[McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information.
American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 890]
**PEER REVIEWED**

Mild, transient leukopenia and thrombocytopenia have been reported rarely in


patients receiving metronidazole, and bone marrow aplasia has been reported in at
least 1 patient.
[McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information.
American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 890]
**PEER REVIEWED**

The most frequent adverse reaction to oral metronidazole is nausea, which is


sometimes accompanied by headache, anorexia, dry mouth, and a sharp,
unpleasant metallic taste. Other occasional adverse GI effects of oral metronidazole
include vomiting, diarrhea, epigastric distress, abdominal discomfort, and
constipation. Nausea, vomiting, abdominal discomfort, a metallic taste, and
diarrhea have also been reported with IV metronidazole. Antibiotic-associated
pseudomembranous colitis, presumably caused by toxin-producing clostridia (e.g.,
C. difficile) resistant to metronidazole, has been reported rarely following oral
administration of the drug and has also been reported in at least one patient
following intravaginal administration of metronidazole. Pancreatitis, which has
improved following discontinuance of the drug but recurred upon subsequent
rechallenge, has been reported rarely during oral metronidazole therapy.
[McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information.
American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 889]
**PEER REVIEWED**

Photosensitivity reaction or rash was reported in less than 1% of patients receiving


combined therapy with tetracycline hydrochloride, metronidazole, and bismuth

subsalicylate (generally in conjunction with acid-suppression therapy) in clinical


trials.
[McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information.
American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 890]
**PEER REVIEWED**

Upper respiratory tract infection, rhinitis, sinusitis, and pharyngitis were each
reported in less than 5% of nonpregnant women receiving oral metronidazole
(administered as extended-release tablets) for the treatment of bacterial vaginosis.
[McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information.
American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 890]
**PEER REVIEWED**

Flattening of the T-wave has been reported rarely in ECG tracings of patients
receiving oral metronidazole.
[McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information.
American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 890]
**PEER REVIEWED**

Although a definite causal relationship to the drug has not been established,
bacterial infection and flu-like symptoms have been reported in 7 and 6%,
respectively, of nonpregnant women receiving oral metronidazole (administered as
extended-release tablets) for the treatment of bacterial vaginosis. Myopia in a
woman receiving metronidazole for trichomoniasis also has been associated with,
but not causally related to, the drug.
[McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information.
American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 890]
**PEER REVIEWED**

... Metronidazole should be used with caution in patients with evidence or a history
of blood dyscrasias, and total and differential leukocyte counts should be performed
before and after treatment with the drug, especially when repeated courses of
therapy are necessary.
[McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information.
American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 890]
**PEER REVIEWED**

Metronidazole should be used with caution and in reduced dosage in patients with
severe hepatic impairment. The manufacturers recommend that plasma

metronidazole concentrations be monitored in patients with severe hepatic


impairment. The manufacturers state that commercially available metronidazole
injection should be used with caution in patients receiving corticosteroids and in
patients predisposed to edema because the injection contains 28 mEq of sodium
per gram of metronidazole.
[McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information.
American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 890]
**PEER REVIEWED**

Metronidazole is contraindicated in individuals with a history of hypersensitivity to


the drug or other nitroimidazole derivatives. However, cautious desensitization has
been employed in some hypersensitive patients in whom metronidazole therapy
was considered necessary.
[McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information.
American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 890]
**PEER REVIEWED**

... Safe use of IV metronidazole in children for any indication and safe use of oral
metronidazole in children for any indication except amebiasis have not been
established; however, oral metronidazole has been used in children for indications
other than amebiasis (e.g., trichomoniasis, giardiasis) without unusual adverse
effects. The AAP and other clinicians recommend that children with trichomoniasis
be treated with oral metronidazole.
[McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information.
American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 890]
**PEER REVIEWED**

... The CDC, and other experts state that use of the drug during the first trimester
of pregnancy is contraindicated. Although evidence from case-controlled studies,
pooled analysis of cohort and case-controlled studies, and other information,
including some experience during first-trimester exposure, suggests that
metronidazole is not associated with a clinically important teratogenic or fetotoxic
risk, conflicting evidence potentially implicating an association between the drug
and certain fetal effects (e.g., cleft palate) also has been reported.
[McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information.
American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 890]
**PEER REVIEWED**

FDA Pregnancy Risk Category: B /NO EVIDENCE OF RISK IN HUMANS. Adequate, well
controlled studies in pregnant women have not shown increased risk of fetal
abnormalities despite adverse findings in animals, or, in the absence of adequate

human studies, animal studies show no fetal risk. The chance of fetal harm is
remote but remains a possibility./
**PEER REVIEWED**

Medical Surveillance:
PRECAUTIONS FOR "CARCINOGENS": Whenever medical surveillance is indicated, in
particular when exposure to a carcinogen has occurred, ad hoc decisions should be
taken concerning ... /cytogenetic and/or other/ tests that might become useful or
mandatory. /Chemical Carcinogens/
[Montesano, R., H. Bartsch, E.Boyland, G. Della Porta, L. Fishbein, R. A. Griesemer,
A.B. Swan, L. Tomatis, and W. Davis (eds.). Handling Chemical Carcinogens in the
Laboratory: Problems of Safety. IARC Scientific Publications No. 33. Lyon, France:
International Agency for Research on Cancer, 1979., p. 23] **PEER REVIEWED**

Populations at Special Risk:


Metronidazole (Flagyl), a commonly prescribed antimicrobial agent, can produce a
reaction similar to that of disulfiram (Antabuse) when administered to patients
drinking ethanol. This drug/chemical interaction results in accumulation of
acetaldehyde in the blood. Acetaldehyde is hepatotoxic, cardiotoxic, and
arrythmogenic; no lethal serum acetaldehyde level has been established. Sudden
death has been reported in patients taking disulfiram while using ethanol; ...
fatalities have been reported due to ethanol/ metronidazole interactions.
[Cina SJ et al; : Am J Forensic Med Pathol 17 (4): 343-6 (1996)] **PEER REVIEWED**
PubMed Abstract

Metronidazole crosses the placenta and enters the fetal circulation rapidly.
Adequate and well-controlled studies in humans have not been done. ... However,
the use of metronidazole in the treatment of trichomoniasis is not recommended
during the first trimester. If metronidazole is used during the second and the third
trimesters for trichomoniasis it is recommended that its use be limited to those
patients whose symptoms are not controlled by local palliative treatment. Also, the
1 day course of therapy should not be used since this results in higher maternal and
fetal serum concentrations.
[Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1,
Greenwood Village, CO. 2006., p. 2070] **PEER REVIEWED**

Probable Routes of Human Exposure:


Occupational exposure to metronidazole may occur through dermal contact where
metrondizole is produced. Exposure to metronidazole among the general population
may be limited to those administered the drug. (SRC)
**PEER REVIEWED**

Evidence for Carcinogenicity:


Metronidazole: reasonably anticipated to be a human carcinogen.
[DHHS/National Toxicology Program; Eleventh Report on Carcinogens: Metronidazole
(443-48-1) (January 2005). Available from, as of July 31, 2009:
http://ntp.niehs.nih.gov/ntp/roc/eleventh/profiles/s112metr.pdf **QC REVIEWED**

Human Toxicity Excerpts:

/SIGNS AND SYMPTOMS/ Some patients receiving metronidazole experience ... incr
in blood pressure caused by release of sympathomimetic amines.
[American Medical Association, AMA Department of Drugs, AMA Drug Evaluations.
3rd ed. Littleton, Massachusetts: PSG Publishing Co., Inc., 1977., p. 1066] **PEER
REVIEWED**

/SIGNS AND SYMPTOMS/ Neurotoxic effects, including seizures and peripheral


neuropathy, have occurred in individuals who received 6-10.4 g of metronidazole
orally every other day for 5-7 days for the treatment of malignant tumors. Nausea,
vomiting, and ataxia without serious resultant toxicity have been reported in
individuals who ingested up to 19.5 g of metronidazole in a single dose.
[McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information.
American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 891]
**PEER REVIEWED**

/SIGNS AND SYMPTOMS/ Metronidazole (Flagyl), a commonly prescribed


antimicrobial agent, can produce a reaction similar to that of disulfiram (Antabuse)
when administered to patients drinking ethanol. This drug/chemical interaction
results in accumulation of acetaldehyde in the blood. Acetaldehyde is hepatotoxic,
cardiotoxic, and arrythmogenic; no lethal serum acetaldehyde level has been
established. Sudden death has been reported in patients taking disulfiram while
using ethanol; ... fatalities have been reported due to ethanol/ metronidazole
interactions.
[Cina SJ et al; : Am J Forensic Med Pathol 17 (4): 343-6 (1996)] **PEER REVIEWED**
PubMed Abstract

/CASE REPORTS/ Neuropathy in 20 year old girl in which complete subjective


recovery has not apparently resulted 2 years after discontinuing drug is reported.
Patient was treated with 800 mg orally twice daily for 7 wks before developing
numbness of hands and feet.
[Hishon S, Pilling J; Br Med J 2: 832 (1977)] **PEER REVIEWED**

/CASE REPORTS/ Peripheral neuropathy was reported in 33 year old male with
Crohn's disease. Patient had been taking metronidazole in dosage of 400 mg 3
times daily for 6 months.
[Bradley WG et al; Br Med J 2: 610 (1977)] **PEER REVIEWED** PubMed Abstract

/CASE REPORTS/ Described is a case of a 31-year-old woman who died moments


after an assault by a male companion, during which he inflicted minor physical

trauma to her upper arm. Toxicologic analysis yielded elevated concentrations of


serum ethanol (162 mg/d), acetaldehyde (4.6 mg/d), and metronidazole (0.42
mg/L). The cause of death was reported to be cardiac dysrhythmia due to
acetaldehyde toxicity due to an ethanol/ metronidazole interaction. Autonomic
stress associated with the assault is likely to have contributed to this woman's
death.
[Cina SJ et al; : Am J Forensic Med Pathol 17 (4): 343-6 (1996)] **PEER REVIEWED**
PubMed Abstract

Drug Warnings:
Metronidazole crosses the placenta and enters the fetal circulation rapidly.
Adequate and well-controlled studies in humans have not been done. ... However,
the use of metronidazole in the treatment of trichomoniasis is not recommended
during the first trimester. If metronidazole is used during the second and the third
trimesters for trichomoniasis it is recommended that its use be limited to those
patients whose symptoms are not controlled by local palliative treatment. Also, the
1 day course of therapy should not be used since this results in higher maternal and
fetal serum concentrations.
[Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1,
Greenwood Village, CO. 2006., p. 2070] **PEER REVIEWED**

No information is available on the relationship of age to the effects of


metronidazole in geriatric patients. However, elderly patients are more likely to
have an age-related decrease in hepatic function, which may require an adjustment
in dosage in patients receiving metronidazole.
[Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1,
Greenwood Village, CO. 2006., p. 2070] **PEER REVIEWED**

Peripheral neuropathy, characterized by numbness, tingling, or paresthesia of an


extremity, and convulsive seizures have been reported rarely with oral or IV
metronidazole. Peripheral neuropathy is usually reversible if metronidazole is
discontinued but may persist in patients who receive prolonged therapy or higher
than recommended dosage of the drug. Dizziness, vertigo, incoordination, ataxia,
confusion, irritability, depression, weakness, insomnia, headache, syncope, tinnitus,
and hearing loss have also occurred with metronidazole. Headache occurred in 18%
of nonpregnant women receiving oral metronidazole (administered as extendedrelease tablets) for bacterial vaginosis, and among those reporting headache, 10%
described it as severe.

[McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information.
American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 889]
**PEER REVIEWED**

Urethral burning or discomfort, dysuria, cystitis, polyuria, incontinence, a sense of


pelvic pressure, dryness of the vagina or vulva, dyspareunia, and decreased libido
have been reported with oral metronidazole. Urine may be dark or reddish-brown in
color following oral or IV administration of metronidazole due to the presence of
water-soluble pigments which result from metabolism of the drug. Vulvovaginal
candidiasis (or yeast vaginitis) was reported in 15% of nonpregnant women
receiving oral metronidazole (administered as extended-release tablets) and in 12%
of those receiving clindamycin phosphate (2% clindamycin) vaginal cream in a
comparative study for the treatment of bacterial vaginosis. Although a definite
causal relationship to the drug has not been established, genital pruritus,
dysmenorrhea, and urinary tract infection have been reported in 5, 3, and 2%,
respectively, of nonpregnant women receiving oral metronidazole (administered as
extended-release tablets) for the treatment of bacterial vaginosis.
[McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information.
American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 890]
**PEER REVIEWED**

Hypersensitivity reactions including urticaria, pruritus, erythematous rash, flushing,


nasal congestion, fever, and fleeting joint pains sometimes resembling serum
sickness have been reported in patients receiving oral metronidazole. Erythematous
rash and pruritus have been reported in patients receiving IV metronidazole. Aseptic
meningitis, that appeared to be a hypersensitivity reaction, has occurred in at least
one patient after administration of oral metronidazole. The reaction consisted of
severe headache, fever, arthralgia, myalgia, stiff neck, nausea, and vomiting.
[McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information.
American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 890]
**PEER REVIEWED**

Furry tongue, glossitis, and stomatitis have been reported with oral metronidazole
and may be due to overgrowth of Candida which may occur during metronidazole
therapy. Candidiasis was reported in 3% of nonpregnant women receiving oral
metronidazole (administered as extended-release tablets) for the treatment of
bacterial vaginosis.
[McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information.
American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 890]
**PEER REVIEWED**

Mild, transient leukopenia and thrombocytopenia have been reported rarely in


patients receiving metronidazole, and bone marrow aplasia has been reported in at
least 1 patient.
[McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information.
American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 890]
**PEER REVIEWED**

The most frequent adverse reaction to oral metronidazole is nausea, which is


sometimes accompanied by headache, anorexia, dry mouth, and a sharp,
unpleasant metallic taste. Other occasional adverse GI effects of oral metronidazole
include vomiting, diarrhea, epigastric distress, abdominal discomfort, and
constipation. Nausea, vomiting, abdominal discomfort, a metallic taste, and
diarrhea have also been reported with IV metronidazole. Antibiotic-associated
pseudomembranous colitis, presumably caused by toxin-producing clostridia (e.g.,
C. difficile) resistant to metronidazole, has been reported rarely following oral
administration of the drug and has also been reported in at least one patient
following intravaginal administration of metronidazole. Pancreatitis, which has
improved following discontinuance of the drug but recurred upon subsequent
rechallenge, has been reported rarely during oral metronidazole therapy.
[McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information.
American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 889]
**PEER REVIEWED**

Photosensitivity reaction or rash was reported in less than 1% of patients receiving


combined therapy with tetracycline hydrochloride, metronidazole, and bismuth
subsalicylate (generally in conjunction with acid-suppression therapy) in clinical
trials.
[McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information.
American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 890]
**PEER REVIEWED**

Upper respiratory tract infection, rhinitis, sinusitis, and pharyngitis were each
reported in less than 5% of nonpregnant women receiving oral metronidazole
(administered as extended-release tablets) for the treatment of bacterial vaginosis.
[McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information.
American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 890]
**PEER REVIEWED**

Flattening of the T-wave has been reported rarely in ECG tracings of patients
receiving oral metronidazole.

[McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information.
American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 890]
**PEER REVIEWED**

Although a definite causal relationship to the drug has not been established,
bacterial infection and flu-like symptoms have been reported in 7 and 6%,
respectively, of nonpregnant women receiving oral metronidazole (administered as
extended-release tablets) for the treatment of bacterial vaginosis. Myopia in a
woman receiving metronidazole for trichomoniasis also has been associated with,
but not causally related to, the drug.
[McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information.
American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 890]
**PEER REVIEWED**

... Metronidazole should be used with caution in patients with evidence or a history
of blood dyscrasias, and total and differential leukocyte counts should be performed
before and after treatment with the drug, especially when repeated courses of
therapy are necessary.
[McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information.
American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 890]
**PEER REVIEWED**

Metronidazole should be used with caution and in reduced dosage in patients with
severe hepatic impairment. The manufacturers recommend that plasma
metronidazole concentrations be monitored in patients with severe hepatic
impairment. The manufacturers state that commercially available metronidazole
injection should be used with caution in patients receiving corticosteroids and in
patients predisposed to edema because the injection contains 28 mEq of sodium
per gram of metronidazole.
[McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information.
American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 890]
**PEER REVIEWED**

Metronidazole is contraindicated in individuals with a history of hypersensitivity to


the drug or other nitroimidazole derivatives. However, cautious desensitization has
been employed in some hypersensitive patients in whom metronidazole therapy
was considered necessary.
[McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information.
American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 890]
**PEER REVIEWED**

... Safe use of IV metronidazole in children for any indication and safe use of oral
metronidazole in children for any indication except amebiasis have not been
established; however, oral metronidazole has been used in children for indications
other than amebiasis (e.g., trichomoniasis, giardiasis) without unusual adverse
effects. The AAP and other clinicians recommend that children with trichomoniasis
be treated with oral metronidazole.
[McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information.
American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 890]
**PEER REVIEWED**

... The CDC, and other experts state that use of the drug during the first trimester
of pregnancy is contraindicated. Although evidence from case-controlled studies,
pooled analysis of cohort and case-controlled studies, and other information,
including some experience during first-trimester exposure, suggests that
metronidazole is not associated with a clinically important teratogenic or fetotoxic
risk, conflicting evidence potentially implicating an association between the drug
and certain fetal effects (e.g., cleft palate) also has been reported.
[McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information.
American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 890]
**PEER REVIEWED**

FDA Pregnancy Risk Category: B /NO EVIDENCE OF RISK IN HUMANS. Adequate, well
controlled studies in pregnant women have not shown increased risk of fetal
abnormalities despite adverse findings in animals, or, in the absence of adequate
human studies, animal studies show no fetal risk. The chance of fetal harm is
remote but remains a possibility./
**PEER REVIEWED**

Medical Surveillance:
PRECAUTIONS FOR "CARCINOGENS": Whenever medical surveillance is indicated, in
particular when exposure to a carcinogen has occurred, ad hoc decisions should be
taken concerning ... /cytogenetic and/or other/ tests that might become useful or
mandatory. /Chemical Carcinogens/
[Montesano, R., H. Bartsch, E.Boyland, G. Della Porta, L. Fishbein, R. A. Griesemer,
A.B. Swan, L. Tomatis, and W. Davis (eds.). Handling Chemical Carcinogens in the
Laboratory: Problems of Safety. IARC Scientific Publications No. 33. Lyon, France:
International Agency for Research on Cancer, 1979., p. 23] **PEER REVIEWED**

Populations at Special Risk:


Metronidazole (Flagyl), a commonly prescribed antimicrobial agent, can produce a
reaction similar to that of disulfiram (Antabuse) when administered to patients
drinking ethanol. This drug/chemical interaction results in accumulation of
acetaldehyde in the blood. Acetaldehyde is hepatotoxic, cardiotoxic, and
arrythmogenic; no lethal serum acetaldehyde level has been established. Sudden
death has been reported in patients taking disulfiram while using ethanol; ...
fatalities have been reported due to ethanol/ metronidazole interactions.
[Cina SJ et al; : Am J Forensic Med Pathol 17 (4): 343-6 (1996)] **PEER REVIEWED**
PubMed Abstract

Metronidazole crosses the placenta and enters the fetal circulation rapidly.
Adequate and well-controlled studies in humans have not been done. ... However,
the use of metronidazole in the treatment of trichomoniasis is not recommended
during the first trimester. If metronidazole is used during the second and the third
trimesters for trichomoniasis it is recommended that its use be limited to those
patients whose symptoms are not controlled by local palliative treatment. Also, the
1 day course of therapy should not be used since this results in higher maternal and
fetal serum concentrations.
[Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1,
Greenwood Village, CO. 2006., p. 2070] **PEER REVIEWED**

Probable Routes of Human Exposure:


Occupational exposure to metronidazole may occur through dermal contact where
metrondizole is produced. Exposure to metronidazole among the general population
may be limited to those administered the drug. (SRC)
**PEER REVIEWED**

Emergency Medical Treatment:

Emergency Medical Treatment: EMT Copyright Disclaimer:


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for general reference. THE COMPLETE POISINDEX(R) DATABASE OR MEDITEXT(R)

DATABASE SHOULD BE CONSULTED FOR ASSISTANCE IN THE DIAGNOSIS OR


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PURPOSE OR USE ARE HEREBY EXCLUDED. Micromedex does not assume any
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The following Overview, *** METRONIDAZOLE AND RELATED AGENTS ***, is relevant
for this HSDB record chemical.
Life Support:
o This overview assumes that basic life support measures
have been instituted.
Clinical Effects:
0.2.1 SUMMARY OF EXPOSURE
A) USES: Metronidazole is a synthetic 5-nitroimidazole
compound. Secnidazole and tinidazole are related
compounds and are long-acting 5-nitroimidazole
derivatives. These drugs have antiprotozoal and
antibacterial activity and are used in the treatment of
protozoal and anaerobic bacterial infections.
Metronidazole and tinidazole are used for the treatment
of trichomoniasis, amebic liver abscesses, intestinal
amebiasis, pelvic inflammatory disease, bacterial
vaginosis, giardiasis, and Clostridium
difficile-associated diarrhea as well as for
perioperative prophylaxis. Secnidazole is used to treat
giardiasis, intestinal amebiasis, bacterial vaginosis,
and vaginal trichomoniasis, but secnidazole is not

currently available in the United States.


B) PHARMACOLOGY: These chemicals are reduced in a process
unique to anaerobic metabolism; the short-lived
metabolite disrupts DNA and inhibits nucleic acid
synthesis.
C) TOXICOLOGY: Mechanism is not known.
D) EPIDEMIOLOGY: Metronidazole is commonly prescribed.
Acute toxicity is rare.
E) WITH THERAPEUTIC USE
1) METRONIDAZOLE: Characteristic adverse effects include
nausea, vomiting, anorexia, headache, and vertigo.
Peripheral neuropathy has been reported in children
receiving chronic therapy. Leukopenia has been reported
in approximately 1% of patients receiving therapeutic
dosing. In 2 patients, sensorineural hearing loss
occurred within 48 hours of use. An expected reaction
in a patient who takes metronidazole and drinks ethanol
is a disulfiram-like reaction; patients taking these
agents should avoid ingestion of ethanol during
treatment and for 3 days after cessation of treatment.
Nausea, vomiting, abdominal cramps, flushing, anxiety,
confusion, vertigo, and headache may occur. In severe
reactions, patients may become hypotensive.
2) TINIDAZOLE: Overall the adverse effects reported with
tinidazole are similar to those of metronidazole. In
clinical studies, adverse effects were mild and
self-limited with therapy.
F) WITH POISONING/EXPOSURE
1) MILD TO MODERATE TOXICITY: METRONIDAZOLE: Most patients

remain asymptomatic. Dark (green/black) urine and


increased liver enzymes have been reported. TINIDAZOLE:
At the time of this review, there are no reports of
human overdose with tinidazole.
2) SEVERE TOXICITY: CNS depression and seizures have been
reported rarely. Dizziness, diplopia, disorientation,
ataxia, and sensory neuropathy have been reported with
chronic overdose.
0.2.5 CARDIOVASCULAR
A) A healthy individual developed an acute reaction with
low blood pressure following therapeutic use of
tinidazole.
0.2.7 NEUROLOGIC
A) WITH THERAPEUTIC USE
1) Insomnia, vertigo, CNS depression, and rarely, seizures
may be noted. Peripheral neuropathy has been noted in
children receiving chronic therapy.
0.2.8 GASTROINTESTINAL
A) WITH THERAPEUTIC USE
1) Nausea, vomiting, metallic taste, anorexia, and dry
mouth may be noted. A disulfiram-like reaction may be
noted following concurrent metronidazole therapy and
ethanol ingestion.
0.2.9 HEPATIC
A) WITH POISONING/EXPOSURE
1) A transient increase in hepatic enzymes was reported in
one patient following overdose of metronidazole.
0.2.10 GENITOURINARY
A) WITH THERAPEUTIC USE

1) Darkening of the urine may be noted rarely during


therapeutic use.
B) WITH POISONING/EXPOSURE
1) Darkened urine has also been reported in one case of
overdose.
0.2.13 HEMATOLOGIC
A) WITH THERAPEUTIC USE
1) Leukopenia has been reported in about 1% of patients
receiving therapeutic doses.
0.2.14 DERMATOLOGIC
A) WITH THERAPEUTIC USE
1) Skin rash may be noted.
0.2.20 REPRODUCTIVE
A) Metronidazole is classified as FDA pregnancy category B.
However, as metronidazole crosses the placental barrier
and enters fetal circulation rapidly, use of
metronidazole is contraindicated during the first
trimester of pregnancy.
Laboratory:
A) Monitor vital signs and mental status.
B) Metronidazole plasma concentrations are not clinically
useful or readily available.
C) A CBC should be obtained if leukopenia is suspected
clinically.
D) Monitor serum electrolytes and glucose, and liver enzymes
in symptomatic patients.
E) No specific lab work is needed in most patients but may
be helpful in ruling out other causes of altered mental
status or seizures if they occur. Consider head CT and

lumbar puncture to rule out intracranial mass, bleeding


or infection for patients with CNS manifestations.
Treatment Overview:
0.4.2 ORAL/PARENTERAL EXPOSURE
A) MILD TO MODERATE TOXICITY
1) Patients may only need observation.
B) SEVERE TOXICITY
1) Treatment is symptomatic and supportive. Orotracheal
intubation for airway protection should be performed
early in cases of CNS depression or repeated seizure
activity.
2) DISULFIRAM-LIKE REACTION: Manage hypotension with IV
fluids. If hypotension persists, use direct-acting
vasopressors such as epinephrine or norepinephrine.
Benzodiazepines may be used for associated agitation or
anxiety. Fomepizole inhibits alcohol dehydrogenase,
preventing the formation of acetaldehyde, and could
theoretically be useful in treating severe
disulfiram-like reactions, although there is limited
experience with this therapy.
C) DECONTAMINATION
1) PREHOSPITAL: Most patients remain asymptomatic;
prehospital decontamination is not routinely
recommended.
2) HOSPITAL: Consider decontamination if a patient
presents promptly after a large oral overdose, is not
vomiting, and does not have CNS depression or seizures.
D) AIRWAY MANAGEMENT
1) Perform early in patients with CNS depression or

seizures.
E) ANTIDOTE
1) None.
F) NAUSEA
1) Antiemetics may be used to control nausea.
G) TACHYCARDIA
1) If the patient cannot tolerate fluids, IV fluids can be
given. If anxiety from a disulfiram-like reaction is
present, a benzodiazepine can be given.
H) HYPOTENSION
1) If patient is hypotensive, it is either from a
disulfiram-like reaction or a co-ingestant. Secure
intravenous access and put patient in supine position.
Initiate treatment with IV fluids. Initiate pressors if
necessary and titrate to a mean arterial pressure of at
least 60 mmHg. If a pressor is needed to increase blood
pressure, a direct-acting agent such as norepinephrine
or epinephrine is best. Insert foley bladder catheter
and monitor urine output.
I) HEADACHE
1) Oral analgesics can be given if tolerated. If the
patient is nauseated, IV analgesics can be given.
J) SEIZURES
1) Seizures are rare and often self-limited but may be a
result of CNS stimulation. Treatment includes IV
benzodiazepines. If seizures persist, use propofol or
barbiturates.
K) ENHANCED ELIMINATION
1) Hemodialysis and hemoperfusion are UNLIKELY to be of

value for metronidazole.


L) PATIENT DISPOSITION
1) HOME CRITERIA: Asymptomatic patients with unintentional
ingestions can be monitored at home.
2) OBSERVATION CRITERIA: Patients with deliberate
ingestions should be sent to a healthcare facility for
observation for at least 4 hours. Any patient with
symptoms should be sent to a healthcare facility and
observed until symptoms improve or resolve.
3) ADMISSION CRITERIA: Patients with significant seizure
activity, marked disulfiram-like reaction and/or
persistent abnormal vital signs should be admitted.
Patients with seizures, severe hypotension or any other
life-threatening result of toxicity should be admitted
to an intensive care setting.
4) CONSULT CRITERIA: Consult a poison center or medical
toxicologist for assistance in managing patients with
severe toxicity or in whom the diagnosis is not clear.
M) PITFALLS
1) Falsely attributing patient's symptoms to metronidazole
when the true underlying cause is due to another
etiology. Patients should avoid ethanol for 3 days
after exposure.
N) PHARMACOKINETICS
1) Metronidazole is metabolized in the liver and is a
CYP450 2C9 inhibitor. Sixty to 80% is excreted renally
with 20% unchanged in the urine. Six to 18% is excreted
in the feces. Half-life is approximately 8 hours.
O) DIFFERENTIAL DIAGNOSIS

1) CNS infection, intracranial hemorrhage, isoniazid


overdose, sympathomimetic toxidrome,
ethanol/barbiturate/other sedative withdrawal if
seizing.
Range of Toxicity:
A) TOXICITY: METRONIDAZOLE: ADULTS: Single doses up to 15 g
have been tolerated well. Seizures and peripheral
neuropathy have occurred after 5 to 7 days of doses of 6
to 10.4 g every other day. CHILDREN: Not well
established. However, peripheral neuropathy has been
reported in children taking a mean dose of 19 mg/kg/day
of metronidazole for 4 to 11 months.
B) THERAPEUTIC DOSES: METRONIDAZOLE: ADULTS: Varies
according to indication. Typical doses range from 250 to
2000 mg once to three times daily. CHILDREN: Varies
according to indication. Typical doses range from 7.5 to
30 mg/kg/day divided every 8 hours. TINIDAZOLE: ADULTS: A
single 2 g oral dose. CHILDREN (3 YEARS OF OLDER): 50
mg/kg/day up to 3 days.

[Rumack BH POISINDEX(R) Information System Micromedex, Inc., Englewood, CO,


2013; CCIS Volume 155, edition expires Feb, 2013. Hall AH & Rumack BH (Eds):
TOMES(R) Information System Micromedex, Inc., Englewood, CO, 2013; CCIS Volume
155, edition expires Feb, 2013.] **PEER REVIEWED**

Antidote and Emergency Treatment:


Maintain an open airway and assist ventilation if necessary. Treat coma, seizures,
hypotension, anaphylaxis, and hemolysis if they occur. Replace fluid losses resulting
from gastroenteritis with intravenous crystalloids. ... Administer activated charcoal.
Gastric emptying is not necessary if activated charcoal can be given promptly. Most

antibiotics are excreted unchanged in the urine, so maintenance of adequate urine


flow is important. The role of forced diuresis is unclear. Hemodialysis is not usually
indicated, except perhaps in patients with renal dysfunction and a high level of toxic
agent. /Antibacterial Agents/
[Olson, K.R. (Ed.); Poisoning & Drug Overdose. 4th ed. Lange Medical
Books/McGraw-Hill. New York, N.Y. 2004., p. 81] **PEER REVIEWED**

/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or


nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of
respiratory insufficiency and assist ventilations if needed. Administer oxygen by
nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if
necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and
treat if necessary ... . For eye contamination, flush eyes immediately with water.
Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use
emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for
dilution if the patient can swallow, has a strong gag reflex, and does not drool ... .
Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and
B/
[Currance, P.L. Clements, B., Bronstein, A.C. (Eds).; Emergency Care For Hazardous
Materials Exposure. 3Rd edition, Elsevier Mosby, St. Louis, MO 2005, p. 160] **PEER
REVIEWED**

/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for


airway control in the patient who is unconscious, has severe pulmonary edema, or is
in severe respiratory distress. Positive-pressure ventilation techniques with a bag
valve mask device may be beneficial. Consider drug therapy for pulmonary
edema ... . Consider administering a beta agonist such as albuterol for severe
bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... .
Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9%
saline (NS) or lactated Ringers if signs of hypovolemia are present. For
hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs
of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use
proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/
[Currance, P.L. Clements, B., Bronstein, A.C. (Eds).; Emergency Care For Hazardous
Materials Exposure. 3Rd edition, Elsevier Mosby, St. Louis, MO 2005, p. 160-1]
**PEER REVIEWED**

Animal Toxicity Studies:

Evidence for Carcinogenicity:


Metronidazole: reasonably anticipated to be a human carcinogen.
[DHHS/National Toxicology Program; Eleventh Report on Carcinogens: Metronidazole
(443-48-1) (January 2005). Available from, as of July 31, 2009:
http://ntp.niehs.nih.gov/ntp/roc/eleventh/profiles/s112metr.pdf **QC REVIEWED**

Non-Human Toxicity Excerpts:


/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ Metronidazole was
administered for lifetime in the diet of groups of six- to eight-week old Swiss mice at
levels of 0.06% (effective numbers: nine males and 10 females), 0.15% (19 males
and 20 females), 0.3% (18 males and 20 females) and 0.5% (35 males and 36
females); 70 male and 70 female mice were used as untreated controls. Survival
was similar in all groups. The incidence of lung tumours rose from 19% in untreated
males to 33, 58, 67 and 77% in treated males and from 20% in untreated females to
40, 50, 70 and 44% in treated females. Female mice also exhibited a significantly
increased incidence of lymphomas at the two highest dose levels, whereas no
significant increase was observed in the two other groups of treated females and in
none of the groups of treated males.
[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man.
Geneva: World Health Organization, International Agency for Research on Cancer,
1972-PRESENT. (Multivolume work). Available at:
http://monographs.iarc.fr/index.php p. V13 116 (1977)] **PEER REVIEWED**

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ Metronidazole has


been shown to be carcinogenic in a number of studies in mice. Pulmonary
tumorigenesis has been reported in six studies in mice, including one study in which
the animals were dosed on an intermittent schedule (every four weeks). Malignant
hepatic tumors have also been reported in male mice given very high doses
(approximately 500 mg/kg/day). Malignant lymphomas have been reported in one
lifetime feeding study in mice.
[Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1,
Greenwood Village, CO. 2006., p. 2070] **PEER REVIEWED**

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ Metronidazole has


also been shown to be carcinogenic in rats. Several long-term, oral-dosing studies in
rats have shown that metronidazole causes a statistically significant increase in the
incidence of various neoplasms, especially mammary and hepatic tumors, in female
rats.

[Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1,


Greenwood Village, CO. 2006., p. 2070] **PEER REVIEWED**

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ Metronidazole was


administered at a concentration of 0.135% in the diet to weanling female SpragueDawley rats for 66 weeks, followed by a 10-week observation period; 36 rats
survived for more than 10 weeks. Twelve rats developed benign mammary
fibroadenomas and three mammary adenocarcinomas. In an untreated control
group, 12 rats developed fibroadenomas and six adenocarcinomas among 71 rats
surviving for more than 10 weeks. Whereas untreated rats developed no more than
one mammary tumour, those developing, mammary tumours after metronidazole
treatment had an average of 2.8 tumours per tumour-bearing rat.
[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man.
Geneva: World Health Organization, International Agency for Research on Cancer,
1972-PRESENT. (Multivolume work). Available at:
http://monographs.iarc.fr/index.php p. V13 117 (1977)] **PEER REVIEWED**

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Metronidazole,


along with several other nitroheterocyclic compounds, was tested for
embryotoxicity in cultured rat embryos, and the effects were compared with those
of other 5-membered heterocycles. Sprague-Dawley rat embryos were explanted on
day 10 of gestation and grown in culture medium to which the test compounds were
added. After 26 hr in culture, the embryos were removed and examined for
malformations. Metronidazole, a nitroheterocycle with a low single-electron redox
potential, failed to elicit axial asymmetry and did not cause embryotoxicity, even at
2.0 mM concentration. Only one abnormality in 11 fetuses was observed at that
concentration and this was characterized as an abnormal rotation of flexure. All the
tested nitroheterocycles with high redox potential elicited axial asymmetry in the
embryos.
[Greenaway JC et al; Toxicol Appl Pharmacol 82:307-315 (1986)] **PEER
REVIEWED** PubMed Abstract

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Studies in rats


given doses of up to 5 times the usual human dose have not shown that
metronidazole causes impaired fertility or birth defects in the fetus. Metronidazole,
administered intraperitoneally to pregnant mice at approximately the human dose,
has been shown to cause fetotoxicity. When metronidazole was administered orally,
no fetotoxicity was seen in pregnant mice.
[Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1,
Greenwood Village, CO. 2006., p. 2070] **PEER REVIEWED**

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Metronidazole in


dosages up to 400 mg/kg daily for 28 days failed to produce any adverse effects on
fertility and testicular function in male rats. Reproduction studies in mice using
metronidazole doses up to 6 times the human dose on a mg/sq m basis have not
revealed evidence of impaired fertility.
[McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information.
American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 891]
**PEER REVIEWED**

/GENOTOXICITY/ In human patients receiving 750 mg/day, mutagenic activity was


found in the urine, using Salmonella typhimurium as a genetic indicator. A 2-4-fold
increase in the occurrence of chromosome abnormalities was observed in cultured
peripheral leucocytes from patients with Crohn's disease being treated with 2001,200 mg/day metronidazole for 1-24 months.
[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man.
Geneva: World Health Organization, International Agency for Research on Cancer,
1972-PRESENT. (Multivolume work). Available at:
http://monographs.iarc.fr/index.php p. V13 118 (1977)] **PEER REVIEWED**

/GENOTOXICITY/ No mutagenic activity was found in urine of mice treated for 4


days with daily doses ... to 400 mg/kg metronidazole, and marginal activity was
reported in host-mediated assay when mice were treated with 400 mg/kg for 5
days. S. typhimurium was used as genetic indicator in both tests.
[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man.
Geneva: World Health Organization, International Agency for Research on Cancer,
1972-PRESENT. (Multivolume work). Available at:
http://monographs.iarc.fr/index.php p. V13 118 (1977)] **PEER REVIEWED**

/GENOTOXICITY/ Metronidazole caused point mutations in Salmonella typhimurium


TA 100 without addition of liver homogenate. It is mutagenic only under anaerobic
conditions in mutant of TA 100 that is deficient in aerobic nitroreductase activity. ...
In fluctuation test, metronidazole induced streptomycin-resistant mutants in
Klebsiella pneumoniae.
[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man.
Geneva: World Health Organization, International Agency for Research on Cancer,
1972-PRESENT. (Multivolume work). Available at:
http://monographs.iarc.fr/index.php p. V13 117 (1977)] **PEER REVIEWED**

/GENOTOXICITY/ Significant incr in chromosome aberration frequency noted in 15


patients with Crohn's disease under treatment with metronidazole 200-1200 mg/day

compared to 7 patients with Crohn's disease not treated with metronidazole and 10
healthy controls.
[Mitelman F et al; Lancet 2: 802 (1976)] **PEER REVIEWED** PubMed Abstract

Non-Human Toxicity Values:


LD50 Albino Rat oral > 5 g/kg
[McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information.
American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 891]
**PEER REVIEWED**

Ecotoxicity Values:
LD50 Anas platyrhynchos (Mallard duck, 19 weeks old) oral >5000 mg/kg
[USEPA, Office of Pesticide Programs; Pesticide Ecotoxicity Database (2000) on 2Methyl-5-nitro-1H-imidazole-1-ethanol (443-48-1). Available from, as of May 10,
2006: http://cfpub.epa.gov/ecotox/quick_query.htm **PEER REVIEWED**

LC50 Anas platyrhynchos (Mallard duck, 17 days old) diet >5000 ppm/8 days
[USEPA, Office of Pesticide Programs; Pesticide Ecotoxicity Database (2000) on 2Methyl-5-nitro-1H-imidazole-1-ethanol (443-48-1). Available from, as of May 10,
2006: http://cfpub.epa.gov/ecotox/quick_query.htm **PEER REVIEWED**

LC50 Colinus virginianus (Bobwhite quail, 12 days old) diet >5000 ppm/8 days
[USEPA, Office of Pesticide Programs; Pesticide Ecotoxicity Database (2000) on 2Methyl-5-nitro-1H-imidazole-1-ethanol (443-48-1). Available from, as of May 10,
2006: http://cfpub.epa.gov/ecotox/quick_query.htm **PEER REVIEWED**

LC50 Americamysis bahia (Opossum shrimp, age 2 days) 182 ppm/96 hr (95%
confidence limit: 140-230 ppm); static /98% AI formulated product/
[USEPA, Office of Pesticide Programs; Pesticide Ecotoxicity Database (2000) on 2Methyl-5-nitro-1H-imidazole-1-ethanol (443-48-1). Available from, as of May 10,
2006: http://cfpub.epa.gov/ecotox/quick_query.htm **PEER REVIEWED**

EC50 Crassostrea virginica (Eastern oyster, embryo; intoxication, immobilization)


1012 ppm/48 hr; static /98% AI formulated product/
[USEPA, Office of Pesticide Programs; Pesticide Ecotoxicity Database (2000) on 2Methyl-5-nitro-1H-imidazole-1-ethanol (443-48-1). Available from, as of May 10,
2006: http://cfpub.epa.gov/ecotox/quick_query.htm **PEER REVIEWED**

LC50 Cyprinodon variegatus (Sheepshead minnow, weight 0.46 g) 1060 ppm/96 hr;
static /98% AI formulated product/
[USEPA, Office of Pesticide Programs; Pesticide Ecotoxicity Database (2000) on 2Methyl-5-nitro-1H-imidazole-1-ethanol (443-48-1). Available from, as of May 10,
2006: http://cfpub.epa.gov/ecotox/quick_query.htm **PEER REVIEWED**

EC50 Daphnia magna (Water flea, age <24 hr; intoxication, immobilization) >1000
ppm/48 hr; static /99% AI formulated product/
[USEPA, Office of Pesticide Programs; Pesticide Ecotoxicity Database (2000) on 2Methyl-5-nitro-1H-imidazole-1-ethanol (443-48-1). Available from, as of May 10,
2006: http://cfpub.epa.gov/ecotox/quick_query.htm **PEER REVIEWED**

LC50 Lepomis macrochirus (Bluegill sunfish, weight 0.1g) >100 ppm/96 hr; static /
99.4% AI formulated product/
[USEPA, Office of Pesticide Programs; Pesticide Ecotoxicity Database (2000) on 2Methyl-5-nitro-1H-imidazole-1-ethanol (443-48-1). Available from, as of May 10,
2006: http://cfpub.epa.gov/ecotox/quick_query.htm **PEER REVIEWED**

LC50 Oncorhynchus mykiss (Rainbow trout, weight 0.3 g) >100 ppm/96 hr; static /
99.4% AI formulated product/
[USEPA, Office of Pesticide Programs; Pesticide Ecotoxicity Database (2000) on 2Methyl-5-nitro-1H-imidazole-1-ethanol (443-48-1). Available from, as of May 10,
2006: http://cfpub.epa.gov/ecotox/quick_query.htm **PEER REVIEWED**

EC50 Pseudokirchneriella subcapitata (Green algae; decreased population growth)


40.4 mg/L/72 hr (95% confidence limit: 2.17-750 mg/L); static
[Lanzky PF, Halling-Sorensen B; Chemosphere 35 (11): 2553-61 (1997 ) Available
from, as of May 10, 2006: http://cfpub.epa.gov/ecotox/quick_query.htm **PEER
REVIEWED**

Metabolism/Pharmacokinetics:

Metabolism/Metabolites:
Approximately 30-60% of an oral or IV dose of metronidazole is metabolized in the
liver by hydroxylation, side-chain oxidation, and glucuronide conjugation. The major
metabolite, 2-hydroxy metronidazole, has some antibacterial and antiprotozoal
activity.

[McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information.
American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 892]
**PEER REVIEWED**

... Four other nitro-group-containing metabolites have been identified, each derived
from side-chain oxidation of ethyl and/or methyl group. They include 1-acetic acid-2methyl-5-nitroimidazole and 1-(2-hydroxyethyl)-2-carboxylic acid-5-nitroimidazole
salt.
[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man.
Geneva: World Health Organization, International Agency for Research on Cancer,
1972-PRESENT. (Multivolume work). Available at:
http://monographs.iarc.fr/index.php p. V13 118 (1977)] **PEER REVIEWED**

The liver is the main site of metabolism, and this accounts for over 50% of the
systemic clearance of metronidazole. The 2 principal metabolites result from
oxidation of side chains, a hydroxy derivative and an acid. The hydroxy metabolite
has a longer half-life (about 12 hr) and nearly 50% of the antitrichomonal activity of
metronidazole. Formation of glucuronides also is observed. Small quantities of
reduced metabolites, including ring-cleavage products, are formed by the gut flora.
The urine of some patients may be reddish-brown owing to the presence of
unidentified pigments derived from the drug.
[Hardman, J.G., L.E. Limbird, P.B., A.G. Gilman. Goodman and Gilman's The
Pharmacological Basis of Therapeutics. 10th ed. New York, NY: McGraw-Hill, 2001.,
p. 1106] **PEER REVIEWED**

Absorption, Distribution & Excretion:


Well absorbed orally; bioavailability at least 80%.

[Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1,


Greenwood Village, CO. 2006., p. 2069] **PEER REVIEWED**

Distributed to saliva, bile, seminal fluid, breast milk, bone, liver and liver abscesses,
lungs, and vaginal secretions; crosses the placenta and blood-brain barrier, also.
[Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1,
Greenwood Village, CO. 2006., p. 2069] **PEER REVIEWED**

At least 80% of an oral dose of metronidazole is absorbed from the GI tract.


Following oral administration of a single 250-mg, 500-mg, or 2-g dose of
metronidazole as immediate-release (conventional) preparations in healthy, fasting
adults, peak plasma concentrations of unchanged drug and active metabolites are
attained within 1-3 hours and average 4.6-6.5 ug/mL, 11.5-13 ug/mL, and 30-45
ug/mL, respectively. When a single 750-mg dose of metronidazole is administered
as two 375-mg capsules or three 250-mg conventional tablets in healthy, fasting
adult women, average peak plasma concentrations of unchanged drug and active
metabolites of 20.4-21.4 ug/mL are attained in an average of 1.4-1.6 hours;
metronidazole capsules and conventional tablets are bioequivalent at a single dose
of 750 mg. The rate of absorption and peak plasma concentrations of metronidazole
are decreased when conventional tablets or capsules of the drug are administered
with food; however, the total amount of drug absorbed is not affected.
[McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information.
American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 892]
**PEER REVIEWED**

Following oral administration of metronidazole 750 mg once daily as the extendedrelease tablet for 7 consecutive days in healthy, adult women, steady-state peak
plasma concentrations average 12.5 mcg/mL and are attained an average of 6.8
hours after the dose when the drug is given under fasting conditions; when the drug
is given at the same dosage under nonfasting conditions, steady-state peak plasma
concentrations average 19.4 mcg/mL and are attained an average of 4.6 hours after
the dose. Administration of metronidazole extended-release tablets with food
increases the rate of absorption and peak plasma concentrations of the drug.
According to the manufacturer, metronidazole extended-release and conventional
tablets are bioequivalent at a dose of 750 mg given under fasting conditions.
[McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information.
American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 892]
**PEER REVIEWED**

After IV infusion over 1 hour of a loading dose of 15 mg/kg of metronidazole as the


hydrochloride followed by IV infusion over 1 hour of 7.5-mg/kg doses every 6 hours
in healthy adults, peak steady-state plasma concentrations of unchanged

metronidazole average 26 mcg/mL and trough steady-state plasma concentrations


of the drug average 18 mcg/mL. In one crossover study in adults, areas under the
concentration-time curves (AUCs) were not significantly different following a single
500-mg oral dose of metronidazole as tablets or a single 500-mg IV dose of the drug
as metronidazole hydrochloride given over 20 minutes. Small amounts of
metronidazole are absorbed systemically when the drug is administered
intravaginally.
[McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information.
American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 892]
**PEER REVIEWED**

Metronidazole is widely distributed into most body tissues and fluids including
bone, bile, saliva, pleural fluid, peritoneal fluid, vaginal secretions, seminal fluid,
CSF, and cerebral and hepatic abscesses. Distribution is similar whether the drug is
administered orally or by IV infusion. Concentrations of metronidazole in CSF are
reported to be 43% of concurrent plasma concentrations in patients with uninflamed
meninges and equal to or greater than concurrent plasma concentrations of the
drug in patients with inflamed meninges. The drug also distributes into
erythrocytes. Limited data suggest that the volume of distribution of metronidazole
may be reduced in geriatric individuals as compared with younger individuals,
perhaps as a result of decreased erythrocyte uptake of the drug in such patients.
Metronidazole is less than 20% bound to plasma proteins.
[McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information.
American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 892]
**PEER REVIEWED**

Metronidazole readily crosses the placenta. Metronidazole is distributed into milk in


concentrations equal to concurrent plasma concentrations of the drug.
[McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information.
American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 892]
**PEER REVIEWED**

In a group of healthy adults, 19% of a single oral dose of 750-mg of radiolabeled


metronidazole was excreted in urine and 3% in feces as unchanged drug and
metabolites within 24 hours; 77% of the dose was excreted in urine and 14% in
feces as unchanged drug and metabolites within 5 days. Limited data suggest that
urinary excretion of unchanged drug and metabolites is decreased in geriatric
individuals as compared with younger individuals. Urine may be dark or reddishbrown in color following oral or IV administration of metronidazole or metronidazole
hydrochloride due to the presence of water-soluble pigments which result from
metabolism of the drug.

[McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information.
American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 892]
**PEER REVIEWED**

Metronidazole and primary metabolites rapidly removed from the blood by


hemodialysis (half-life is shortened to approximately 2.6 hours). Metronidazole is not
significantly removed by peritoneal dialysis.
[Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1,
Greenwood Village, CO. 2006., p. 2070] **PEER REVIEWED**

In 4 healthy male subjects given 750 mg (14)C-labelled metronidazole, 14% of


activity was excreted in feces and 77% in urine within 5 days. ... In women given
250 mg ... orally during pregnancy or lactation, drug was found in low concn (0.25
mg/kg) in embryonic tissue and in milk.
[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man.
Geneva: World Health Organization, International Agency for Research on Cancer,
1972-PRESENT. (Multivolume work). Available at:
http://monographs.iarc.fr/index.php p. V13 118 (1977)] **PEER REVIEWED**

Following IV admin of 1,2-(14)C-metronidazole to mice, activity was found in liver


and kidney, and in heart, brain, salivary gland, GI tract, spleen, and skeletal muscle
and was shown to cross placenta to fetus. In rats ... /it/ was conjugated in liver and
excreted in bile and urine.
[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man.
Geneva: World Health Organization, International Agency for Research on Cancer,
1972-PRESENT. (Multivolume work). Available at:
http://monographs.iarc.fr/index.php p. V13 117 (1977)] **PEER REVIEWED**

Whole-body arg /Autoradiography/ showed that IV or oral dose of ... (14)Cmetronidazole crossed blood-brain and placental barriers in pregnant mice. Uptake
from blood was rapid. Level of (14)C in maternal brain and fetus were similar to
those in maternal blood.
[The Chemical Society. Foreign Compound Metabolism in Mammals. Volume 2: A
Review of the Literature Published Between 1970 and 1971. London: The Chemical
Society, 1972., p. 110] **PEER REVIEWED**

Biological Half-Life:

The plasma half-life of metronidazole is reported to be 6-8 hours in adults with


normal renal and hepatic function. In one study using radiolabeled metronidazole
hydrochloride, the half-life of unchanged metronidazole averaged 7.7 hours and the
half-life of total radioactivity averaged 11.9 hours. The plasma half-life of
metronidazole is not affected by changes in renal function; however, the half-life
may be prolonged in patients with impaired hepatic function. In one study in adults
with alcoholic liver disease and impaired hepatic function, half-life of metronidazole
averaged 18.3 hours (range: 10.3-29.5 hours).
[McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information.
American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 892]
**PEER REVIEWED**

Half-life: Neonates 25-75 hours; Others: 6-8 hours, increases with hepatic
impairment.
[Lelkin, J.B., Paloucek, F.P., Poisoning & Toxicology Compendium. LEXI-COMP Inc. &
American Pharmaceutical Association, Hudson, OH 1998., p. 390] **PEER
REVIEWED**

The elimination half-life in dogs is 4.5hr, and in horses 1.5-3.3hr


[Kahn, C.M. (Ed.); The Merck Veterinary Manual 9th ed. Merck & Co. Whitehouse
Station, NJ. 2005, p. 2098] **PEER REVIEWED**

Mechanism of Action:
Microbicidal; active against most obligate anaerobic bacteria and protozoa by
undergoing intracellular chemical reduction via mechanisms unique to anaerobic
metabolism. Reduced metronidazole, which is cytotoxic but short-lived, interacts
with DNA to cause loss of helical structure, strand breakage, and resultant inhibition
of nucleic acid synthesis and cell death.
[Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1,
Greenwood Village, CO. 2006., p. 2069] **PEER REVIEWED**

Metronidazole is bactericidal, amebicidal, and trichomonacidal in action. The exact


mechanism of action of the drug has not been fully elucidated. Metronidazole is unionized at physiologic pH and is readily taken up by anaerobic organisms or cells. In
susceptible organisms or cells, metronidazole is reduced by low-redox-potential
electron transport proteins (e.g., nitroreductases such as ferredoxin) to unidentified
polar product(s) which lack the nitro group. The reduction product(s) appears to be
responsible for the cytotoxic and antimicrobial effects of the drug which include

disruption of DNA and inhibition of nucleic acid synthesis. Metronidazole is equally


effective against dividing and nondividing cells.
[McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information.
American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 891]
**PEER REVIEWED**

In in vivo studies in rats given metronidazole in dosages of 2-4 mg/100 g of body


weight, the drug reportedly inhibited the development of formalin-induced edema in
the rat paw. In vitro in neutrophils, metronidazole has a dose-dependent inhibitory
effect on generation of hydrogen peroxide and hydroxyl radicals, oxidants that may
cause tissue injury at the site of inflammation. This antioxidant effect appears to be
caused by a direct effect on neutrophil function and may contribute to the drug's
anti-inflammatory effect in vivo.
[McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information.
American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 891]
**PEER REVIEWED**

Results of in vitro studies using leukocytes obtained from patients with Crohns
disease indicate that exposing the cells to metronidazole concentrations of 10 or 50
mcg/mL improved both spontaneous and induced leukocyte migration in cells that
previously exhibited reduced migration; the drug had no effect on leukocytes
obtained from healthy adults or patients with Crohns disease when the cells
exhibited normal migration prior to exposure to the drug. This effect on leukocyte
migration also was observed in vivo in adults with Crohn's disease who received a
single 400-mg dose of metronidazole. It has been suggested that metronidazole
may increase leukocyte migration by a direct effect on the leukocytes, possibly by
causing the release of surface-bound immune complexes from the cell surface.
[McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information.
American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 891]
**PEER REVIEWED**

Interactions:
It is recommended that metronidazole not be used concurrently with, or for at least
1 day following, ingestion of alcohol; accumulation of acetaldehyde by interference
with the oxidation of alcohol may occur, resulting in disulfiram-like effects such as
abdominal cramps, nausea, vomiting, headache, or flushing; in addition,
modifications in the taste of alcoholic beverages have been reported during
concurrent use.
[Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1,
Greenwood Village, CO. 2006., p. 2070] **PEER REVIEWED**

Effects may be potentiated when /coumarin- or indandione-derivative


anticoagulants/ are used concurrently with metronidazole, because of inhibition of
enzymatic metabolism of anticoagulants; periodic prothrombin time determinations
may be required during therapy to determine if dosage adjustments of
anticoagulants are necessary.
[Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1,
Greenwood Village, CO. 2006., p. 2070] **PEER REVIEWED**

Hepatic metabolism of metronidazole may be decreased when metronidazole and


cimetidine are used concurrently, possibly resulting in delayed elimination and
increased serum metronidazole concentrations; monitoring of serum concentrations
as a guide to dosage is recommended since dosage adjustments of metronidazole
may be necessary during and after cimetidine therapy.
[Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1,
Greenwood Village, CO. 2006., p. 2070] **PEER REVIEWED**

It is recommended that metronidazole not be used concurrently with, or for 2


weeks following, disulfiram in alcoholic patients; such use may result in confusion
and psychotic reactions because of combined toxicity.
[Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1,
Greenwood Village, CO. 2006., p. 2070] **PEER REVIEWED**

Lithium concentrations may increase when metronidazole therapy is introduced;


serum lithium and serum creatinine levels should be monitored several days after
beginning metronidazole in order to detect impending lithium intoxication.
[Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1,
Greenwood Village, CO. 2006., p. 2070] **PEER REVIEWED**

Concurrent use of metronidazole with other neurotoxic medications may increase


the potential for neurotoxicity.
[Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1,
Greenwood Village, CO. 2006., p. 2070] **PEER REVIEWED**

Phenobarbital may induce microsomal liver enzymes, increasing metronidazole's


metabolism and resulting in a decrease in half-life and plasma concentrations.
[Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1,
Greenwood Village, CO. 2006., p. 2070] **PEER REVIEWED**

Metronidazole may impair the clearance of phenytoin, increasing phenytoin's


plasma concentration.
[Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1,
Greenwood Village, CO. 2006., p. 2070] **PEER REVIEWED**

Dizziness or paresthesia was reported in 1.5% of patients receiving combined


therapy with tetracycline hydrochloride, metronidazole, and bismuth subsalicylate
(generally in conjunction with acid-suppression therapy) in clinical trials; asthenia or
insomnia was reported in 1% of such patients. Nervousness, malaise, or syncope
was reported in less than 1% of patients receiving tetracycline hydrochloridemetronidazole-bismuth subsalicylate therapy in clinical trials.
[McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information.
American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 890]
**PEER REVIEWED**

Metronidazole may interact with astemizole (no longer commercially available in


the US) and terfenadine (no longer commercially available in the US), resulting in
potentially serious adverse cardiovascular effects. Prolongation of the QT interval
and QT interval corrected for rate (QTc) and, rarely, serious cardiovascular effects,
including arrhythmias (eg, ventricular tachycardia, atypical ventricular tachycardia
[torsades de pointes], ventricular fibrillation), cardiac arrest, palpitations,
hypotension, dizziness, syncope, and death, have been reported in patients
receiving the structurally similar antifungal ketoconazole concomitantly with usual
dosages of terfenadine or astemizole. Ketoconazole can markedly inhibit the
metabolism of astemizole or terfenadine, probably via inhibition of the cytochrome
P-450 enzyme system, resulting in increased plasma concentrations of unchanged
drug (to measurable levels) and reduced clearance of the active desmethyl or
carboxylic acid metabolite, respectively.
[McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information.
American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 891]
**PEER REVIEWED**

Metronidazole (Flagyl), a commonly prescribed antimicrobial agent, can produce a


reaction similar to that of disulfiram (Antabuse) when administered to patients
drinking ethanol. This drug/chemical interaction results in accumulation of
acetaldehyde in the blood. Acetaldehyde is hepatotoxic, cardiotoxic, and
arrythmogenic; no lethal serum acetaldehyde level has been established. Sudden
death has been reported in patients taking disulfiram while using ethanol; ...
fatalities have been reported due to ethanol/ metronidazole interactions.
[Cina SJ et al; : Am J Forensic Med Pathol 17 (4): 343-6 (1996)] **PEER REVIEWED**
PubMed Abstract

The manufacturers state that commercially available metronidazole injection


should be used with caution in patients receiving corticosteroids and in patients
predisposed to edema because the injection contains 28 mEq of sodium per gram of
metronidazole.
[McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information.
American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 890]
**PEER REVIEWED**

Pharmacology:

Therapeutic Uses:
Mesh Heading: Anti-infective agents, antiprotozoal agents, radiation-sensitizing
agents
[National Library of Medicine, SIS; ChemIDplus Record for <<insert chemical name
here; for example: Osmium>> <<(CAS#) i.e.(7440-04-2).>> Available from the
search page at http://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp as of <<date
info was found; i.e. March 18, 2005>>.] **PEER REVIEWED**

MEDICATION (VET): Antiprotozoal (Trichomonas); antiamebic; antibacterial


[O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and
Biologicals. 13th Edition, Whitehouse Station, NJ: Merck and Co., Inc., 2001., p.
1097] **PEER REVIEWED**

MEDICATION (VET): The success of metronidazole in treating human infections of


giardiasis, vaginal and oral trichomoniasis, and hepatic and intestinal amoebiasis
has lead to investigation of its potential use against certain protozoan diseases of
domestic animals. These are principally bovine urogenital trichomoniasis and
canine, feline, or primate intestinal giardiasis, trichomoniasis, amoebiasis, or
Balantidium infection. ...
[Booth, N.H., L.E. McDonald (eds.). Veterinary Pharmacology and Therapeutics. 5th
ed. Ames, Iowa: Iowa State University Press, 1982., p. 885] **PEER REVIEWED**

Oral metronidazole (extended release formulation) is used in the treatment of


bacterial vaginosis caused by Gardnerella vaginalis, Mobiluncus spp, mycoplasma

hominis and anaerobes (peptostreptococcus spp and Bacteroides spp). /Included in


US or Canadian product labeling/
[Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1,
Greenwood Village, CO. 2006., p. 2069] **PEER REVIEWED**

Metronidazole is used in the treatment of periodontal infections caused by


Bacteroides species. /NOT included in US product labeling/
[Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1,
Greenwood Village, CO. 2006., p. 2069] **PEER REVIEWED**

Oral metronidazole is used in the treatment of giardiasis caused by Giardia lamblia.


/NOT included in US product labeling/
[Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1,
Greenwood Village, CO. 2006., p. 2069] **PEER REVIEWED**

Some studies indicate that metronidazole may be effective, in combination with


bismuth subsalicylate or colloidal bismuth subcitrate, and other oral antibiotic
therapy, such as ampicillin or amoxicillin, in the treatment of Helicobacter pyloriassociated gastritis and duodenal ulcer. However, metronidazole resistance may
occur, especially in patients who have been previously exposed to metronidazole.
/NOT included in US product labeling/
[Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1,
Greenwood Village, CO. 2006., p. 2069] **PEER REVIEWED**

Metronidazole is used in the treatment of dracunculiasis (guinea worm infection)


caused by Dracunculus medinensis. It decreases the inflammation around the ulcer,
increasing the ease of removing the worm. /NOT included in US product labeling/
[Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1,
Greenwood Village, CO. 2006., p. 2069] **PEER REVIEWED**

Metronidazole is used in the treatment of antibiotic-associated diarrhea and colitis


caused by Clostridium difficile. /NOT included in US product labeling/
[Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1,
Greenwood Village, CO. 2006., p. 2069] **PEER REVIEWED**

Metronidazole is used in the treatment of inflammatory bowel disease. /NOT


included in US product labeling/

[Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1,


Greenwood Village, CO. 2006., p. 2069] **PEER REVIEWED**

Metronidazole is used in the treatment of Balantidium coli infection. /NOT included


in US product labeling/
[Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1,
Greenwood Village, CO. 2006., p. 2069] **PEER REVIEWED**

Oral metronidazole is indicated in the treatment of symptomatic and asymptomatic


trichomoniasis, in males and females, caused by Trichomonas vaginalis. /Included in
US product labeling/
[Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1,
Greenwood Village, CO. 2006., p. 2069] **PEER REVIEWED**

Metronidazole is indicated in the treatment of skin and soft tissue infections caused
by Bacteroides species, including the Bacteroides fragilis group. Clostridium species,
Fusobacterium species, Peptococcus species, and Peptostreptococcus species.
/Included in US product labeling/
[Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1,
Greenwood Village, CO. 2006., p. 2069] **PEER REVIEWED**

Metronidazole is indicated in the treatment of bacterial septicemia caused by


Bacteroides species, including the Bacteroides fragilis group, and Clostridium
species. /Included in US product labeling/
[Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1,
Greenwood Village, CO. 2006., p. 2069] **PEER REVIEWED**

Metronidazole is indicated in the treatment of lower respiratory tract infections,


including pneumonia, emphysema, and lung abscess, caused by Bacteroides
species, including the Bacteroides fragilis group. /Included in US product labeling/
[Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1,
Greenwood Village, CO. 2006., p. 2069] **PEER REVIEWED**

Intravenous metronidazole is indicated for the prophylaxis of perioperative


infections during colorectal surgery. /Included in US product labeling/
[Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1,
Greenwood Village, CO. 2006., p. 2069] **PEER REVIEWED**

Metronidazole is indicated in the treatment of female pelvic infections, including


endometritis, endomyometritis, tubo-ovarian abscess, and postsurgical vaginal cuff
infections, caused by Bacteroides species, including the Bacteroides fragilis group,
Clostridium species, Peptoccus species, and Peptostreptococcus species. /Included
in US product labeling/
[Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1,
Greenwood Village, CO. 2006., p. 2069] **PEER REVIEWED**

Metronidazole is indicated in the treatment of intra-abdominal infections, including


peritonitis, intra-abdominal abscess, and liver abscess, caused by Bacteroides
species, including the Bacteroides fragilis group, Clostridium species, Eubacterium
species, Peptococcus species, and Peptostreptococcus species. /Included in US
product labeling/
[Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1,
Greenwood Village, CO. 2006., p. 2069] **PEER REVIEWED**

Metronidazole is indicated in the treatment of endocarditis caused by Bacteroides


species, including the Bacteroides fragilis group. /Included in US product labeling/
[Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1,
Greenwood Village, CO. 2006., p. 2069] **PEER REVIEWED**

Metronidazole is indicated in the treatment of CNS infections, including meningitis,


caused by Bacteroides species, including the Bacteroides fragilis group. /Included in
US product labeling/
[Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1,
Greenwood Village, CO. 2006., p. 2069] **PEER REVIEWED**

Metronidazole is indicated in the treatment of brain abscess caused by Bacteroides


species, including the Bacteroides fragilis group. /Included in US product labeling/
[Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1,
Greenwood Village, CO. 2006., p. 2069] **PEER REVIEWED**

Metronidazole is indicated in the treatment of bone and joint infections caused by


Bacteroides species, including the Bacteroides fragilis group (Bacteroides fragilis,
Bacteroides distasonis, Bacteroides ovatus, Bacteroides thetaiotaomicron,
Bacteroides vulgatus). /Included in US product labeling/

[Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1,


Greenwood Village, CO. 2006., p. 2069] **PEER REVIEWED**

Oral metronidazole is indicated in the treatment of acute intestinal amebiasis


caused by Entamoeba histolytica. Metronidazole may not eradicate intestinal
amebic infections, requiring treatment with a luminal amebicide. /Included in US
product labeling/
[Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1,
Greenwood Village, CO. 2006., p. 2069] **PEER REVIEWED**

Metronidazole is indicated in the treatment of extraintestinal amebiases, including


amebic liver abscess, caused by Entamoeba histolytica. When used in the treatment
of invasive amebiasis, metronidazole should be administered concurrently or
sequentially with a luminal amebicide (eg, iodoquinol, paromomycin, tetracycline,
diloxanide furoate). When used in the treatment of amebic liver abscesses,
metronidazole therapy does not obviate the need for aspiration of the abscess.
/Included in US product labeling/
[Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1,
Greenwood Village, CO. 2006., p. 2069] **PEER REVIEWED**

Metronidazole is not effective against facultative anaerobes, obligate aerobes,


Propionibacterium acnes, Actinomyces species, or Candida albicans.
[Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1,
Greenwood Village, CO. 2006., p. 2069] **PEER REVIEWED**

Drug Warnings:
Metronidazole crosses the placenta and enters the fetal circulation rapidly.
Adequate and well-controlled studies in humans have not been done. ... However,
the use of metronidazole in the treatment of trichomoniasis is not recommended
during the first trimester. If metronidazole is used during the second and the third
trimesters for trichomoniasis it is recommended that its use be limited to those
patients whose symptoms are not controlled by local palliative treatment. Also, the
1 day course of therapy should not be used since this results in higher maternal and
fetal serum concentrations.
[Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1,
Greenwood Village, CO. 2006., p. 2070] **PEER REVIEWED**

No information is available on the relationship of age to the effects of


metronidazole in geriatric patients. However, elderly patients are more likely to
have an age-related decrease in hepatic function, which may require an adjustment
in dosage in patients receiving metronidazole.
[Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1,
Greenwood Village, CO. 2006., p. 2070] **PEER REVIEWED**

Peripheral neuropathy, characterized by numbness, tingling, or paresthesia of an


extremity, and convulsive seizures have been reported rarely with oral or IV
metronidazole. Peripheral neuropathy is usually reversible if metronidazole is
discontinued but may persist in patients who receive prolonged therapy or higher
than recommended dosage of the drug. Dizziness, vertigo, incoordination, ataxia,
confusion, irritability, depression, weakness, insomnia, headache, syncope, tinnitus,
and hearing loss have also occurred with metronidazole. Headache occurred in 18%
of nonpregnant women receiving oral metronidazole (administered as extendedrelease tablets) for bacterial vaginosis, and among those reporting headache, 10%
described it as severe.
[McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information.
American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 889]
**PEER REVIEWED**

Urethral burning or discomfort, dysuria, cystitis, polyuria, incontinence, a sense of


pelvic pressure, dryness of the vagina or vulva, dyspareunia, and decreased libido
have been reported with oral metronidazole. Urine may be dark or reddish-brown in
color following oral or IV administration of metronidazole due to the presence of
water-soluble pigments which result from metabolism of the drug. Vulvovaginal
candidiasis (or yeast vaginitis) was reported in 15% of nonpregnant women
receiving oral metronidazole (administered as extended-release tablets) and in 12%
of those receiving clindamycin phosphate (2% clindamycin) vaginal cream in a
comparative study for the treatment of bacterial vaginosis. Although a definite
causal relationship to the drug has not been established, genital pruritus,
dysmenorrhea, and urinary tract infection have been reported in 5, 3, and 2%,
respectively, of nonpregnant women receiving oral metronidazole (administered as
extended-release tablets) for the treatment of bacterial vaginosis.
[McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information.
American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 890]
**PEER REVIEWED**

Hypersensitivity reactions including urticaria, pruritus, erythematous rash, flushing,


nasal congestion, fever, and fleeting joint pains sometimes resembling serum
sickness have been reported in patients receiving oral metronidazole. Erythematous
rash and pruritus have been reported in patients receiving IV metronidazole. Aseptic
meningitis, that appeared to be a hypersensitivity reaction, has occurred in at least

one patient after administration of oral metronidazole. The reaction consisted of


severe headache, fever, arthralgia, myalgia, stiff neck, nausea, and vomiting.
[McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information.
American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 890]
**PEER REVIEWED**

Furry tongue, glossitis, and stomatitis have been reported with oral metronidazole
and may be due to overgrowth of Candida which may occur during metronidazole
therapy. Candidiasis was reported in 3% of nonpregnant women receiving oral
metronidazole (administered as extended-release tablets) for the treatment of
bacterial vaginosis.
[McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information.
American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 890]
**PEER REVIEWED**

Mild, transient leukopenia and thrombocytopenia have been reported rarely in


patients receiving metronidazole, and bone marrow aplasia has been reported in at
least 1 patient.
[McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information.
American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 890]
**PEER REVIEWED**

The most frequent adverse reaction to oral metronidazole is nausea, which is


sometimes accompanied by headache, anorexia, dry mouth, and a sharp,
unpleasant metallic taste. Other occasional adverse GI effects of oral metronidazole
include vomiting, diarrhea, epigastric distress, abdominal discomfort, and
constipation. Nausea, vomiting, abdominal discomfort, a metallic taste, and
diarrhea have also been reported with IV metronidazole. Antibiotic-associated
pseudomembranous colitis, presumably caused by toxin-producing clostridia (e.g.,
C. difficile) resistant to metronidazole, has been reported rarely following oral
administration of the drug and has also been reported in at least one patient
following intravaginal administration of metronidazole. Pancreatitis, which has
improved following discontinuance of the drug but recurred upon subsequent
rechallenge, has been reported rarely during oral metronidazole therapy.
[McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information.
American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 889]
**PEER REVIEWED**

Photosensitivity reaction or rash was reported in less than 1% of patients receiving


combined therapy with tetracycline hydrochloride, metronidazole, and bismuth

subsalicylate (generally in conjunction with acid-suppression therapy) in clinical


trials.
[McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information.
American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 890]
**PEER REVIEWED**

Upper respiratory tract infection, rhinitis, sinusitis, and pharyngitis were each
reported in less than 5% of nonpregnant women receiving oral metronidazole
(administered as extended-release tablets) for the treatment of bacterial vaginosis.
[McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information.
American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 890]
**PEER REVIEWED**

Flattening of the T-wave has been reported rarely in ECG tracings of patients
receiving oral metronidazole.
[McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information.
American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 890]
**PEER REVIEWED**

Although a definite causal relationship to the drug has not been established,
bacterial infection and flu-like symptoms have been reported in 7 and 6%,
respectively, of nonpregnant women receiving oral metronidazole (administered as
extended-release tablets) for the treatment of bacterial vaginosis. Myopia in a
woman receiving metronidazole for trichomoniasis also has been associated with,
but not causally related to, the drug.
[McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information.
American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 890]
**PEER REVIEWED**

... Metronidazole should be used with caution in patients with evidence or a history
of blood dyscrasias, and total and differential leukocyte counts should be performed
before and after treatment with the drug, especially when repeated courses of
therapy are necessary.
[McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information.
American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 890]
**PEER REVIEWED**

Metronidazole should be used with caution and in reduced dosage in patients with
severe hepatic impairment. The manufacturers recommend that plasma

metronidazole concentrations be monitored in patients with severe hepatic


impairment. The manufacturers state that commercially available metronidazole
injection should be used with caution in patients receiving corticosteroids and in
patients predisposed to edema because the injection contains 28 mEq of sodium
per gram of metronidazole.
[McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information.
American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 890]
**PEER REVIEWED**

Metronidazole is contraindicated in individuals with a history of hypersensitivity to


the drug or other nitroimidazole derivatives. However, cautious desensitization has
been employed in some hypersensitive patients in whom metronidazole therapy
was considered necessary.
[McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information.
American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 890]
**PEER REVIEWED**

... Safe use of IV metronidazole in children for any indication and safe use of oral
metronidazole in children for any indication except amebiasis have not been
established; however, oral metronidazole has been used in children for indications
other than amebiasis (e.g., trichomoniasis, giardiasis) without unusual adverse
effects. The AAP and other clinicians recommend that children with trichomoniasis
be treated with oral metronidazole.
[McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information.
American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 890]
**PEER REVIEWED**

... The CDC, and other experts state that use of the drug during the first trimester
of pregnancy is contraindicated. Although evidence from case-controlled studies,
pooled analysis of cohort and case-controlled studies, and other information,
including some experience during first-trimester exposure, suggests that
metronidazole is not associated with a clinically important teratogenic or fetotoxic
risk, conflicting evidence potentially implicating an association between the drug
and certain fetal effects (e.g., cleft palate) also has been reported.
[McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information.
American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 890]
**PEER REVIEWED**

FDA Pregnancy Risk Category: B /NO EVIDENCE OF RISK IN HUMANS. Adequate, well
controlled studies in pregnant women have not shown increased risk of fetal
abnormalities despite adverse findings in animals, or, in the absence of adequate

human studies, animal studies show no fetal risk. The chance of fetal harm is
remote but remains a possibility./
**PEER REVIEWED**

Interactions:
It is recommended that metronidazole not be used concurrently with, or for at least
1 day following, ingestion of alcohol; accumulation of acetaldehyde by interference
with the oxidation of alcohol may occur, resulting in disulfiram-like effects such as
abdominal cramps, nausea, vomiting, headache, or flushing; in addition,
modifications in the taste of alcoholic beverages have been reported during
concurrent use.
[Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1,
Greenwood Village, CO. 2006., p. 2070] **PEER REVIEWED**

Effects may be potentiated when /coumarin- or indandione-derivative


anticoagulants/ are used concurrently with metronidazole, because of inhibition of
enzymatic metabolism of anticoagulants; periodic prothrombin time determinations
may be required during therapy to determine if dosage adjustments of
anticoagulants are necessary.
[Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1,
Greenwood Village, CO. 2006., p. 2070] **PEER REVIEWED**

Hepatic metabolism of metronidazole may be decreased when metronidazole and


cimetidine are used concurrently, possibly resulting in delayed elimination and
increased serum metronidazole concentrations; monitoring of serum concentrations
as a guide to dosage is recommended since dosage adjustments of metronidazole
may be necessary during and after cimetidine therapy.
[Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1,
Greenwood Village, CO. 2006., p. 2070] **PEER REVIEWED**

It is recommended that metronidazole not be used concurrently with, or for 2


weeks following, disulfiram in alcoholic patients; such use may result in confusion
and psychotic reactions because of combined toxicity.
[Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1,
Greenwood Village, CO. 2006., p. 2070] **PEER REVIEWED**

Lithium concentrations may increase when metronidazole therapy is introduced;


serum lithium and serum creatinine levels should be monitored several days after
beginning metronidazole in order to detect impending lithium intoxication.
[Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1,
Greenwood Village, CO. 2006., p. 2070] **PEER REVIEWED**

Concurrent use of metronidazole with other neurotoxic medications may increase


the potential for neurotoxicity.
[Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1,
Greenwood Village, CO. 2006., p. 2070] **PEER REVIEWED**

Phenobarbital may induce microsomal liver enzymes, increasing metronidazole's


metabolism and resulting in a decrease in half-life and plasma concentrations.
[Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1,
Greenwood Village, CO. 2006., p. 2070] **PEER REVIEWED**

Metronidazole may impair the clearance of phenytoin, increasing phenytoin's


plasma concentration.
[Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1,
Greenwood Village, CO. 2006., p. 2070] **PEER REVIEWED**

Dizziness or paresthesia was reported in 1.5% of patients receiving combined


therapy with tetracycline hydrochloride, metronidazole, and bismuth subsalicylate
(generally in conjunction with acid-suppression therapy) in clinical trials; asthenia or
insomnia was reported in 1% of such patients. Nervousness, malaise, or syncope
was reported in less than 1% of patients receiving tetracycline hydrochloridemetronidazole-bismuth subsalicylate therapy in clinical trials.
[McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information.
American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 890]
**PEER REVIEWED**

Metronidazole may interact with astemizole (no longer commercially available in


the US) and terfenadine (no longer commercially available in the US), resulting in
potentially serious adverse cardiovascular effects. Prolongation of the QT interval
and QT interval corrected for rate (QTc) and, rarely, serious cardiovascular effects,
including arrhythmias (eg, ventricular tachycardia, atypical ventricular tachycardia
[torsades de pointes], ventricular fibrillation), cardiac arrest, palpitations,
hypotension, dizziness, syncope, and death, have been reported in patients
receiving the structurally similar antifungal ketoconazole concomitantly with usual

dosages of terfenadine or astemizole. Ketoconazole can markedly inhibit the


metabolism of astemizole or terfenadine, probably via inhibition of the cytochrome
P-450 enzyme system, resulting in increased plasma concentrations of unchanged
drug (to measurable levels) and reduced clearance of the active desmethyl or
carboxylic acid metabolite, respectively.
[McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information.
American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 891]
**PEER REVIEWED**

Metronidazole (Flagyl), a commonly prescribed antimicrobial agent, can produce a


reaction similar to that of disulfiram (Antabuse) when administered to patients
drinking ethanol. This drug/chemical interaction results in accumulation of
acetaldehyde in the blood. Acetaldehyde is hepatotoxic, cardiotoxic, and
arrythmogenic; no lethal serum acetaldehyde level has been established. Sudden
death has been reported in patients taking disulfiram while using ethanol; ...
fatalities have been reported due to ethanol/ metronidazole interactions.
[Cina SJ et al; : Am J Forensic Med Pathol 17 (4): 343-6 (1996)] **PEER REVIEWED**
PubMed Abstract

The manufacturers state that commercially available metronidazole injection


should be used with caution in patients receiving corticosteroids and in patients
predisposed to edema because the injection contains 28 mEq of sodium per gram of
metronidazole.
[McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information.
American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 890]
**PEER REVIEWED**

Drug Tolerance:
Natural and acquired resistances to metronidazole have been reported occasionally
in some strains of Trichomonas vaginalis. Although the clinical importance is
unclear, in vitro studies indicate that while some T. vaginalis isolates with reduced
susceptibility to metronidazole also have reduced susceptibility to tinidazole, the
minimum lethal concentration (MLC) of tinidazole for these strains may be lower
than the MLC of metronidazole. Rarely, resistance to the drug also has been
reported in Bacteroides fragilis and other anaerobic bacteria following long-term
therapy. There has been at least one report of a strain of metronidazole-resistant B.
fragilis that was cross-resistant in vitro to amoxicillin and clavulanate potassium,
imipenem, and tetracycline; the strain was susceptible to chloramphenicol and
clindamycin in vitro. Resistance to metronidazole may be due to poor cell
penetration and/or decreased nitroreductase activity.

[McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information.
American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 892]
**PEER REVIEWED**

Environmental Fate & Exposure:

Environmental Fate/Exposure Summary:


Metronidazole's production and use as an anti-infective agent, antiprotozoal agent
and radiation-sensitizing agent may result in its release to the environment through
various waste streams. It may be released to treatment systems as a result of
excretion and disposal of unused or expired medications. Metronidazole can also be
released from veterinary use. Metronidazole's former use as a pesticide may have
resulted in its direct release to the environment. If released to air, an estimated
vapor pressure of 3.1X10-7 mm Hg at 25 deg C indicates metronidazole will exist in
both the vapor and particulate phases in the atmosphere. Vapor-phase
metronidazole will be degraded in the atmosphere by reaction with
photochemically-produced hydroxyl radicals; the half-life for this reaction in air is
estimated to be 41 hrs. Particulate-phase metronidazole will be removed from the
atmosphere by wet or dry deposition. Metronidazole does not contain chromophores
that absorb at wavelengths >290 nm and therefore is not expected to be
susceptible to direct photolysis by sunlight. If released to soil, metronidazole is
expected to have very high mobility based upon an estimated Koc of 23. Reported
biodegradation half-lives of 9.7 to 26.9 days suggest biodegradation may be an
important environmental fate process in soil. Volatilization from moist soil surfaces
is not expected to be an important fate process based upon an estimated Henry's
Law constant of 1.7X10-11 atm-cu m/mole. If released into water, metronidazole is
not expected to adsorb to suspended solids and sediment based upon the
estimated Koc. No biodegradation was observed using closed bottle tests,
suggesting that biodegradation is a slow environmental fate process in water.
Volatilization from water surfaces is not expected to be an important fate process
based upon this compound's estimated Henry's Law constant. An estimated BCF of
3 suggests the potential for bioconcentration in aquatic organisms is low. Hydrolysis
is not expected to be an important environmental fate process since this compound
lacks functional groups that hydrolyze under environmental conditions.
Occupational exposure to metronidazole may occur through dermal contact where
metrondizole is produced. Exposure to metronidazole among the general population
may be limited to those administered the drug. (SRC)
**PEER REVIEWED**

Probable Routes of Human Exposure:


Occupational exposure to metronidazole may occur through dermal contact where
metrondizole is produced. Exposure to metronidazole among the general population
may be limited to those administered the drug. (SRC)
**PEER REVIEWED**

Natural Pollution Sources:


Although metronidazole is closely related to natural antitrichomonal agent,
azomycin, it is not known to occur in nature(1).
[(1) IARC; Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to
Man Geneva, Switzerland: World Health Organization, International Agency For
Research on Cancer, 1972-Present 13: 116 (1977)] **PEER REVIEWED**

Artificial Pollution Sources:


Metronidazole's production and use as an anti-infective agent, antiprotozoal agent
and radiation-sensitizing agent(1) may result in its release to the environment
through various waste streams(SRC). It may be released to treatment systems as a
result of excretion and disposal of unused or expired medications(2).
Metronidazole's former use as a pesticide may have resulted in its direct release to
the environment(3). An estimated 20 to 40% of outdated and unused medications
are disposed down household drains in Germany(4).
[Metronidazole's production and use as an anti-infective agent, antiprotozoal agent
and radiation-sensitizing agent(1) may result in its release to the environment
through various waste streams(SRC). It may be released to treatment systems as a
result of excretion and disposal of unused or expired medications(2).
Metronidazole's former use as a pesticide may have resulted in its direct release to
the environment(3). An estimated 20 to 40% of outdated and unused medications
are disposed down household drains in Germany(4).] **PEER REVIEWED**

Environmental Fate:
TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of
23(SRC), determined from a log Kow of -0.02(2) and a regression-derived
equation(3), indicates that metronidazole is expected to have very high mobility in
soil(SRC). Volatilization of metronidazole from moist soil surfaces is not expected to
be an important fate process(SRC) given an estimated Henry's Law constant of

1.7X10-11 atm-cu m/mole(SRC), using a fragment constant estimation method(4).


Metronidazole is not expected to volatilize from dry soil surfaces(SRC) based upon
an estimated vapor pressure of 3X10-7 mm Hg(SRC), determined from a fragment
constant method(5). Biodegradation half-lives in sandy soil-manure slurry of 9.7 to
14.7 days and in clay soil-manure slurry of 13.1 to 26.9 days(5), suggesting
biodegradation may be an important environmental fate process in soil(SRC).
[(1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Hansch C et al; Exploring QSAR.
Hydrophobic, Electronic, and Steric Constants. ACS Prof Ref Book. Heller SR, consult.
ed., Washington, DC: Amer Chem Soc p. 22 (1995)(3) Lyman WJ et al; Handbook of
Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9
(1990) (4) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (5)
Lyman WJ; p. 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau
GE, eds, Boca Raton, FL: CRC Press (1985) (6) Ingerslev F, Halling-Sorensen B;
Ecotox Environ Safety 48: 311-20 (2001)] **PEER REVIEWED**

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of


23(SRC), determined from a log Kow of -0.02(2) and a regression-derived
equation(3), indicates that metronidazole is not expected to adsorb to suspended
solids and sediment(SRC). Volatilization from water surfaces is not expected(3)
based upon an estimated Henry's Law constant of 1.7X10- 11 atm-cu m/mole(SRC),
developed using a fragment constant estimation method(4). According to a
classification scheme(5), an estimated BCF of 3(SRC), from its log Kow(2) and a
regression-derived equation(6), suggests the potential for bioconcentration in
aquatic organisms is low(SRC). No biodegradation was observed using closed bottle
tests(7), suggesting that biodegradation is a slow environmental fate process in
water(SRC).
[(1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Hansch C et al; Exploring QSAR.
Hydrophobic, Electronic, and Steric Constants. ACS Prof Ref Book. Heller SR, consult.
ed., Washington, DC: Amer Chem Soc p. 22 (1995) (3) Lyman WJ et al; Handbook of
Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9,
15-1 to 15-29 (1990) (4) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93
(1991) (5) Franke C et al; Chemosphere 29: 1501-14 (1994) (6) Meylan WM et al;
Environ Toxicol Chem 18: 664-72 (1999) (7) Alexy R et al; Chemosphere 57: 505-12
(2004)] **PEER REVIEWED**

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of


semivolatile organic compounds in the atmosphere(1), metronidazole, which has an
estimated vapor pressure of 3.1X10-7 mm Hg at 25 deg C(SRC), determined from a
fragment constant method(2), will exist in both the vapor and particulate phases in
the ambient atmosphere. Vapor-phase metronidazole is degraded in the atmosphere
by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for
this reaction in air is estimated to be 41 hrs(SRC), calculated from its rate constant
of 9.3X10-12 cu cm/molecule-sec at 25 deg C(SRC) that was derived using a
structure estimation method(3). Particulate-phase metronidazole may be removed
from the air by wet or dry deposition(SRC). Metronidazole does not contain

chromophores that absorb at wavelengths >290 nm and therefore is not expected


to be susceptible to direct photolysis by sunlight(SRC).
[(1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988) (2) Lyman WJ; p. 31 in
Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE, eds, Boca Raton,
FL: CRC Press (1985) (3) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993)]
**PEER REVIEWED**

Environmental Biodegradation:
AEROBIC: The biodegradation half-lives in sandy soil-manure slurry were 9.7 to 14.7
days and in clay soil-manure slurry were 13.1 to 26.9 days(1). Metronidazole was
found to be non-degradable in sewage treatment conditions(2). Metronidazole did
not degrade in closed bottle tests at concentrations of 5.95 ug/L and 5.95 mg/L(3).
[(1) Ingerslev F, Halling-Sorensen B; Ecotox Environ Safety 48: 311-20 (2001) (2)
Richardson ML, Bowron JM; J Pharm Pharmacol 37: 1-12 (1985) (3) Alexy R et al;
Chemosphere 57: 505-12 (2004)] **PEER REVIEWED**

ANAEROBIC: The anaerobic half-life of metrondizole was reported to be 74.5 days in


a sediment slurry sample(1).
[(1) Thiele-Bruhn S; J Plant Nutr Soil Sci 166: 145-67 (2003)] **PEER REVIEWED**

Environmental Abiotic Degradation:


The rate constant for the vapor-phase reaction of metronidazole with
photochemically-produced hydroxyl radicals has been estimated as 9.3X10-12 cu
cm/molecule-sec at 25 deg C(SRC) using a structure estimation method(1). This
corresponds to an atmospheric half-life of about 41 hours at an atmospheric
concentration of 5X10+5 hydroxyl radicals per cu cm(1). Metronidazole is not
expected to undergo hydrolysis in the environment due to the lack of functional
groups that hydrolyze under environmental conditions(2). Metronidazole does not
contain chromophores that absorb at wavelengths >290 nm and therefore is not
expected to be susceptible to direct photolysis by sunlight(SRC).
[(1) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) (2) Lyman WJ et al;
Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem
Soc pp. 7-4, 7-5 (1990)] **PEER REVIEWED**

Environmental Bioconcentration:

An estimated BCF of 3 was calculated for metronidazole(SRC), using a log Kow of


-0.02(1) and a regression-derived equation(2). According to a classification
scheme(3), this BCF suggests the potential for bioconcentration in aquatic
organisms is low(SRC).

[(1) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants.
ACS Prof Ref Book. Heller SR, consult. ed., Washington, DC: Amer Chem Soc p. 22
(1995) (2) Meylan WM et al; Environ Toxicol Chem 18: 664-72 (1999) (3) Franke C et
al; Chemosphere 29: 1501-14 (1994)] **PEER REVIEWED**

Soil Adsorption/Mobility:
The Koc of metronidazole is estimated as 23(SRC), using a log Kow of -0.02(1) and a
regression-derived equation(2). According to a classification scheme(3), this
estimated Koc value suggests that metronidazole is expected to have very high
mobility in soil.
[(1) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants.
ACS Prof Ref Book. Heller SR, consult. ed., Washington, DC: Amer Chem Soc p. 22
(1995) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods.
Washington, DC: Amer Chem Soc pp. 4-9 (1990) (3) Swann RL et al; Res Rev 85: 1728 (1983)] **PEER REVIEWED**

Volatilization from Water/Soil:


The Henry's Law constant for metronidazole is estimated as 1.7X10-11 atm-cu
m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law
constant indicates that metronidazole is expected to be essentially nonvolatile from
water surfaces(2). Metronidazole is not expected to volatilize from dry soil
surfaces(SRC) based upon an estimated vapor pressure of 3X10-7 mm Hg(SRC),
determined from a fragment constant method(3).
[(1) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (2) Lyman WJ
et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer
Chem Soc pp. 15-1 to 15-29 (1990) (3) Neely WB, Blau GE, eds, Boca Raton, FL: CRC
Press (1985)] **PEER REVIEWED**

Effluent Concentrations:

Metronidazole may be released to treatment systems as a result of excretion and


disposal of unused or expired medications(1). An estimated 20 to 40% of outdated
and unused medications are disposed down household drains in Germany(2). A
theoretical mean effluent concentration of metronidazole was calculated to be 6.2
ug/L from 1992 to 1994 in one hospital(3).
[(1) Richardson ML, Bowron JM; J Pharm Pharmacol 37: 1-12 (1985) (2) Kummerer K
et al; Chemosphere 40: 701-10 (2000) (3) Hartmann A et al; Environ Toxicol Chem
17: 377-82 (1998)] **PEER REVIEWED**

Environmental Standards & Regulations:

FIFRA Requirements:
As the federal pesticide law FIFRA directs, EPA is conducting a comprehensive
review of older pesticides to consider their health and environmental effects and
make decisions about their future use. Under this pesticide reregistration program,
EPA examines health and safety data for pesticide active ingredients initially
registered before November 1, 1984, and determines whether they are eligible for
reregistration. In addition, all pesticides must meet the new safety standard of the
Food Quality Protection Act of 1996. Pesticides for which EPA had not issued
Registration Standards prior to the effective date of FIFRA, as amended in 1988,
were divided into three lists based upon their potential for human exposure and
other factors, with List B containing pesticides of greater concern and List D
pesticides of less concern. Metronidazole is found on List C. Case No: 3096;
Pesticide type: antimicrobial; Case Status: No products containing the pesticide are
actively registered ... The case /is characterized/ as "cancelled." Under FIFRA,
pesticide producers may voluntarily cancel their registered products. EPA also may
cancel pesticide registrations if registrants fail to pay required fees or make/meet
certain reregistration commitments, or if EPA reaches findings of unreasonable
adverse effects.; Active ingredient (AI): metronidazole; Data Call-in (DCI) Date(s):
09/23/93; AI Status: The active ingredient is no longer contained in any registered
pesticide products ... "cancelled."
[United States Environmental Protection Agency/ Prevention, Pesticides and Toxic
Substances; Status of Pesticides in Registration, Reregistration, and Special Review.
(1998) EPA 738-R-98-002, p. 265] **PEER REVIEWED**

FDA Requirements:

The Approved Drug Products with Therapeutic Equivalence Evaluations List


identifies currently marketed prescription drug products, incl metronidazole,
approved on the basis of safety and effectiveness by FDA under sections 505 of the
Federal Food, Drug, and Cosmetic Act.
[DHHS/FDA; Electronic Orange Book-Approved Drug Products with Therapeutic
Equivalence Evaluations. Available from, as of July 25, 2006:
http://www.fda.gov/cder/ob/ **PEER REVIEWED**

Chemical/Physical Properties:

Molecular Formula:
C6-H9-N3-O3
**PEER REVIEWED**

Molecular Weight:
171.15
[O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and
Biologicals. 13th Edition, Whitehouse Station, NJ: Merck and Co., Inc., 2001., p.
1095] **PEER REVIEWED**

Color/Form:
Cream-colored crystals
[O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and
Biologicals. 13th Edition, Whitehouse Station, NJ: Merck and Co., Inc., 2001., p.
1095] **PEER REVIEWED**

WHITE TO PALE YELLOW CRYSTALS OR CRYSTALLINE POWDER


[Osol, A. and J.E. Hoover, et al. (eds.). Remington's Pharmaceutical Sciences. 15th
ed. Easton, Pennsylvania: Mack Publishing Co., 1975., p. 1161] **PEER REVIEWED**

Odor:
ODORLESS
[Osol, A. and J.E. Hoover, et al. (eds.). Remington's Pharmaceutical Sciences. 15th
ed. Easton, Pennsylvania: Mack Publishing Co., 1975., p. 1161] **PEER REVIEWED**

Melting Point:
158-160 deg C
[O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and
Biologicals. 13th Edition, Whitehouse Station, NJ: Merck and Co., Inc., 2001., p.
1095] **PEER REVIEWED**

Dissociation Constants:
pKa = 2.38
[Tolls J; Environ Sci Technol 35: 3397-406 (2001)] **PEER REVIEWED** PubMed
Abstract

Octanol/Water Partition Coefficient:


log Kow = -0.02
[Hansch, C., Leo, A., D. Hoekman. Exploring QSAR - Hydrophobic, Electronic, and
Steric Constants. Washington, DC: American Chemical Society., 1995.] **PEER
REVIEWED**

pH:
pH of saturated aq soln is 5.8
[O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and
Biologicals. 13th Edition, Whitehouse Station, NJ: Merck and Co., Inc., 2001., p.
1095] **PEER REVIEWED**

Solubilities:
g/100 ml at 20 deg C: 1.0 in water, 0.5 in ethanol, less than 0.05 in ether,
chloroform; sol in dilute acids; sparingly sol in dimethylformamide
[O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and
Biologicals. 13th Edition, Whitehouse Station, NJ: Merck and Co., Inc., 2001., p.
1096] **PEER REVIEWED**

In water, 11,000 mg/L at 25 deg C


[Yalkowsky, S.H., He, Yan., Handbook of Aqueous Solubility Data: An Extensive
Compilation of Aqueous Solubility Data for Organic Compounds Extracted from the
AQUASOL dATAbASE. CRC Press LLC, Boca Raton, FL. 2003., p. 282] **PEER
REVIEWED**

Spectral Properties:
IR: 14987 (Sadtler Research Laboratories IR Grating Collection)
[Lide, D.R., G.W.A. Milne (eds.). Handbook of Data on Organic Compounds. Volume I.
3rd ed. CRC Press, Inc. Boca Raton ,FL. 1994., p. V4: 3207] **PEER REVIEWED**

UV: 2561 (Absorption Spectra in the UV and visible Regions, Academic Press, New
York)
[Lide, D.R., G.W.A. Milne (eds.). Handbook of Data on Organic Compounds. Volume I.
3rd ed. CRC Press, Inc. Boca Raton ,FL. 1994., p. V4: 3207] **PEER REVIEWED**

NMR: 5648 (Sadtler Research Laboratories Spectral Collection)


[Lide, D.R., G.W.A. Milne (eds.). Handbook of Data on Organic Compounds. Volume I.
3rd ed. CRC Press, Inc. Boca Raton ,FL. 1994., p. V4: 3207] **PEER REVIEWED**

MASS: 76026 (NIST/EPA/MSDC Mass Spectral Database, 1990 version)


[Lide, D.R., G.W.A. Milne (eds.). Handbook of Data on Organic Compounds. Volume I.
3rd ed. CRC Press, Inc. Boca Raton ,FL. 1994., p. V4: 3207] **PEER REVIEWED**

Intense mass spectral peaks: 54 m/z, 81 m/z, 124 m/z, 171 m/z

[Pfleger, K., H. Maurer and A. Weber. Mass Spectral and GC Data of Drugs, Poisons
and their Metabolites. Parts I and II. Mass Spectra Indexes. Weinheim, Federal
Republic of Germany. 1985., p. 244] **PEER REVIEWED**

Vapor Pressure:
3.1X10-7 mm Hg at 25 deg C (est)
[US EPA; Estimation Program Interface (EPI) Suite. Ver.3.12. Nov 30, 2004. Available
from, as of Dec 21, 2005: http://www.epa.gov/oppt/exposure/pubs/episuitedl.htm
**PEER REVIEWED**

Other Chemical/Physical Properties:


Henry's Law constant = 1.7X10-11 atm-cu m/mol at 25 deg C (est)
[US EPA; Estimation Program Interface (EPI) Suite. Ver.3.12. Nov 30, 2004. Available
from, as of Dec 21, 2005: http://www.epa.gov/oppt/exposure/pubs/episuitedl.htm
**PEER REVIEWED**

Hydroxyl radical reaction rate constant = 9.3X10-12 cu cm/molecule-sec at 25 deg


C (est)
[US EPA; Estimation Program Interface (EPI) Suite. Ver.3.12. Nov 30, 2004. Available
from, as of Dec 21, 2005: http://www.epa.gov/oppt/exposure/pubs/episuitedl.htm
**PEER REVIEWED**

Chemical Safety & Handling:

Hazardous Reactivities & Incompatibilities:


Because reconstituted metronidazole hydrochloride solution has a low pH, the
solution may interact with aluminum resulting in a reddish-brown discoloration of
the solution. Therefore, aluminum hub needles should not be used to reconstitute
the drug or to transfer the reconstituted solution to the diluting fluid. Metronidazole
hydrochloride that has been reconstituted, diluted, and neutralized and
metronidazole injection do not interact with aluminum when administered over the
time period specified by the manufacturers; however, some discoloration of these

solutions may occur when they are in contact with aluminum for periods of 6 hours
or longer.
[McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information.
American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 893]
**PEER REVIEWED**

Protective Equipment & Clothing:


PRECAUTIONS FOR "CARCINOGENS": ... Dispensers of liq detergent /should be
available./ ... Safety pipettes should be used for all pipetting. ... In animal
laboratory, personnel should ... wear protective suits (preferably disposable, onepiece & close-fitting at ankles & wrists), gloves, hair covering & overshoes. ... In
chemical laboratory, gloves & gowns should always be worn ... however, gloves
should not be assumed to provide full protection. Carefully fitted masks or
respirators may be necessary when working with particulates or gases, & disposable
plastic aprons might provide addnl protection. ... Gowns ... /should be/ of distinctive
color, this is a reminder that they are not to be worn outside the laboratory.
/Chemical Carcinogens/
[Montesano, R., H. Bartsch, E.Boyland, G. Della Porta, L. Fishbein, R. A. Griesemer,
A.B. Swan, L. Tomatis, and W. Davis (eds.). Handling Chemical Carcinogens in the
Laboratory: Problems of Safety. IARC Scientific Publications No. 33. Lyon, France:
International Agency for Research on Cancer, 1979., p. 8] **PEER REVIEWED**

Preventive Measures:
PRECAUTIONS FOR "CARCINOGENS": Smoking, drinking, eating, storage of food or
of food & beverage containers or utensils, & the application of cosmetics should be
prohibited in any laboratory. All personnel should remove gloves, if worn, after
completion of procedures in which carcinogens have been used. They should ...
wash ... hands, preferably using dispensers of liq detergent, & rinse ... thoroughly.
Consideration should be given to appropriate methods for cleaning the skin,
depending on nature of the contaminant. No standard procedure can be
recommended, but the use of organic solvents should be avoided. Safety pipettes
should be used for all pipetting. /Chemical Carcinogens/
[Montesano, R., H. Bartsch, E.Boyland, G. Della Porta, L. Fishbein, R. A. Griesemer,
A.B. Swan, L. Tomatis, and W. Davis (eds.). Handling Chemical Carcinogens in the
Laboratory: Problems of Safety. IARC Scientific Publications No. 33. Lyon, France:
International Agency for Research on Cancer, 1979., p. 8] **PEER REVIEWED**

PRECAUTIONS FOR "CARCINOGENS": In animal laboratory, personnel should remove


their outdoor clothes & wear protective suits (preferably disposable, one-piece &
close-fitting at ankles & wrists), gloves, hair covering & overshoes. ... Clothing
should be changed daily but ... discarded immediately if obvious contamination
occurs ... /also,/ workers should shower immediately. In chemical laboratory, gloves
& gowns should always be worn ... however, gloves should not be assumed to
provide full protection. Carefully fitted masks or respirators may be necessary when
working with particulates or gases, & disposable plastic aprons might provide addnl
protection. If gowns are of distinctive color, this is a reminder that they should not
be worn outside of lab. /Chemical Carcinogens/
[Montesano, R., H. Bartsch, E.Boyland, G. Della Porta, L. Fishbein, R. A. Griesemer,
A.B. Swan, L. Tomatis, and W. Davis (eds.). Handling Chemical Carcinogens in the
Laboratory: Problems of Safety. IARC Scientific Publications No. 33. Lyon, France:
International Agency for Research on Cancer, 1979., p. 8] **PEER REVIEWED**

PRECAUTIONS FOR "CARCINOGENS": ... Operations connected with synth &


purification ... should be carried out under well-ventilated hood. Analytical
procedures ... should be carried out with care & vapors evolved during ...
procedures should be removed. ... Expert advice should be obtained before existing
fume cupboards are used ... & when new fume cupboards are installed. It is
desirable that there be means for decreasing the rate of air extraction, so that
carcinogenic powders can be handled without ... powder being blown around the
hood. Glove boxes should be kept under negative air pressure. Air changes should
be adequate, so that concn of vapors of volatile carcinogens will not occur.
/Chemical Carcinogens/
[Montesano, R., H. Bartsch, E.Boyland, G. Della Porta, L. Fishbein, R. A. Griesemer,
A.B. Swan, L. Tomatis, and W. Davis (eds.). Handling Chemical Carcinogens in the
Laboratory: Problems of Safety. IARC Scientific Publications No. 33. Lyon, France:
International Agency for Research on Cancer, 1979., p. 8] **PEER REVIEWED**

PRECAUTIONS FOR "CARCINOGENS": Vertical laminar-flow biological safety cabinets


may be used for containment of in vitro procedures ... provided that the exhaust air
flow is sufficient to provide an inward air flow at the face opening of the cabinet, &
contaminated air plenums that are under positive pressure are leak-tight. Horizontal
laminar-flow hoods or safety cabinets, where filtered air is blown across the working
area towards the operator, should never be used ... Each cabinet or fume cupboard
to be used ... should be tested before work is begun (eg, with fume bomb) & label
fixed to it, giving date of test & avg air-flow measured. This test should be repeated
periodically & after any structural changes. /Chemical Carcinogens/
[Montesano, R., H. Bartsch, E.Boyland, G. Della Porta, L. Fishbein, R. A. Griesemer,
A.B. Swan, L. Tomatis, and W. Davis (eds.). Handling Chemical Carcinogens in the
Laboratory: Problems of Safety. IARC Scientific Publications No. 33. Lyon, France:
International Agency for Research on Cancer, 1979., p. 9] **PEER REVIEWED**

PRECAUTIONS FOR "CARCINOGENS": Principles that apply to chem or biochem lab


also apply to microbiological & cell-culture labs ... Special consideration should be
given to route of admin. ... Safest method of administering volatile carcinogen is by
injection of a soln. Admin by topical application, gavage, or intratracheal instillation
should be performed under hood. If chem will be exhaled, animals should be kept
under hood during this period. Inhalation exposure requires special equipment. ...
Unless specifically required, routes of admin other than in the diet should be used.
Mixing of carcinogen in diet should be carried out in sealed mixers under fume
hood, from which the exhaust is fitted with an efficient particulate filter. Techniques
for cleaning mixer & hood should be devised before expt begun. When mixing diets,
special protective clothing &, possibly, respirators may be required. /Chemical
Carcinogens/
[Montesano, R., H. Bartsch, E.Boyland, G. Della Porta, L. Fishbein, R. A. Griesemer,
A.B. Swan, L. Tomatis, and W. Davis (eds.). Handling Chemical Carcinogens in the
Laboratory: Problems of Safety. IARC Scientific Publications No. 33. Lyon, France:
International Agency for Research on Cancer, 1979., p. 9] **PEER REVIEWED**

PRECAUTIONS FOR "CARCINOGENS": When ... admin in diet or applied to skin,


animals should be kept in cages with solid bottoms & sides & fitted with a filter top.
When volatile carcinogens are given, filter tops should not be used. Cages which
have been used to house animals that received carcinogens should be
decontaminated. Cage-cleaning facilities should be installed in area in which
carcinogens are being used, to avoid moving of ... contaminated /cages/. It is
difficult to ensure that cages are decontaminated, & monitoring methods are
necessary. Situations may exist in which the use of disposable cages should be
recommended, depending on type & amt of carcinogen & efficiency with which it
can be removed. /Chemical Carcinogens/
[Montesano, R., H. Bartsch, E.Boyland, G. Della Porta, L. Fishbein, R. A. Griesemer,
A.B. Swan, L. Tomatis, and W. Davis (eds.). Handling Chemical Carcinogens in the
Laboratory: Problems of Safety. IARC Scientific Publications No. 33. Lyon, France:
International Agency for Research on Cancer, 1979., p. 10] **PEER REVIEWED**

PRECAUTIONS FOR "CARCINOGENS": To eliminate risk that ... contamination in lab


could build up during conduct of expt, periodic checks should be carried out on lab
atmospheres, surfaces, such as walls, floors & benches, & ... interior of fume hoods
& airducts. As well as regular monitoring, check must be carried out after cleaningup of spillage. Sensitive methods are required when testing lab atmospheres. ...
Methods ... should ... where possible, be simple & sensitive. /Chemical Carcinogens/
[Montesano, R., H. Bartsch, E.Boyland, G. Della Porta, L. Fishbein, R. A. Griesemer,
A.B. Swan, L. Tomatis, and W. Davis (eds.). Handling Chemical Carcinogens in the
Laboratory: Problems of Safety. IARC Scientific Publications No. 33. Lyon, France:
International Agency for Research on Cancer, 1979., p. 10] **PEER REVIEWED**

PRECAUTIONS FOR "CARCINOGENS": Rooms in which obvious contamination has


occurred, such as spillage, should be decontaminated by lab personnel engaged in
expt. Design of expt should ... avoid contamination of permanent equipment. ...
Procedures should ensure that maintenance workers are not exposed to
carcinogens. ... Particular care should be taken to avoid contamination of drains or
ventilation ducts. In cleaning labs, procedures should be used which do not produce
aerosols or dispersal of dust, ie, wet mop or vacuum cleaner equipped with highefficiency particulate filter on exhaust, which are avail commercially, should be
used. Sweeping, brushing & use of dry dusters or mops should be prohibited.
Grossly contaminated cleaning materials should not be re-used ... If gowns or towels
are contaminated, they should not be sent to laundry, but ... decontaminated or
burnt, to avoid any hazard to laundry personnel. /Chemical Carcinogens/
[Montesano, R., H. Bartsch, E.Boyland, G. Della Porta, L. Fishbein, R. A. Griesemer,
A.B. Swan, L. Tomatis, and W. Davis (eds.). Handling Chemical Carcinogens in the
Laboratory: Problems of Safety. IARC Scientific Publications No. 33. Lyon, France:
International Agency for Research on Cancer, 1979., p. 10] **PEER REVIEWED**

PRECAUTIONS FOR "CARCINOGENS": Doors leading into areas where carcinogens


are used ... should be marked distinctively with appropriate labels. Access ... limited
to persons involved in expt. ... A prominently displayed notice should give the name
of the Scientific Investigator or other person who can advise in an emergency & who
can inform others (such as firemen) on the handling of carcinogenic substances.
/Chemical Carcinogens/
[Montesano, R., H. Bartsch, E.Boyland, G. Della Porta, L. Fishbein, R. A. Griesemer,
A.B. Swan, L. Tomatis, and W. Davis (eds.). Handling Chemical Carcinogens in the
Laboratory: Problems of Safety. IARC Scientific Publications No. 33. Lyon, France:
International Agency for Research on Cancer, 1979., p. 11] **PEER REVIEWED**

Stability/Shelf Life:
Stable in air but darkens on exposure to light.
[Osol, A. and J.E. Hoover, et al. (eds.). Remington's Pharmaceutical Sciences. 15th
ed. Easton, Pennsylvania: Mack Publishing Co., 1975., p. 1161] **PEER REVIEWED**

Metronidazole conventional tablets should be stored in well-closed, light-resistant


containers at less than 25 deg C. Metronidazole capsules should be stored in tight
containers at 15-25 deg C. Metronidazole extended-release tablets should be stored
in well-closed containers at approximately 25 deg C; temporary exposure to
temperatures of 15-30 deg C is acceptable.

[McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information.
American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 893]
**PEER REVIEWED**

Metronidazole hydrochloride powder for injection should be protected from light


and stored at less than 30 deg C. Metronidazole injection should be protected from
light and freezing and stored at 15-30 deg C. The manufacturer (Baxter) of
commercially available metronidazole injection ... states that this injection has an
expiration date of 24 months following the date of manufacture.
[McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information.
American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 893]
**PEER REVIEWED**

Shipment Methods and Regulations:


PRECAUTIONS FOR "CARCINOGENS": Procurement ... of unduly large amt ... should
be avoided. To avoid spilling, carcinogens should be transported in securely sealed
glass bottles or ampoules, which should themselves be placed inside strong screwcap or snap-top container that will not open when dropped & will resist attack from
the carcinogen. Both bottle & the outside container should be appropriately
labelled. ... National post offices, railway companies, road haulage companies &
airlines have regulations governing transport of hazardous materials. These
authorities should be consulted before ... material is shipped. /Chemical
Carcinogens/
[Montesano, R., H. Bartsch, E.Boyland, G. Della Porta, L. Fishbein, R. A. Griesemer,
A.B. Swan, L. Tomatis, and W. Davis (eds.). Handling Chemical Carcinogens in the
Laboratory: Problems of Safety. IARC Scientific Publications No. 33. Lyon, France:
International Agency for Research on Cancer, 1979., p. 13] **PEER REVIEWED**

PRECAUTIONS FOR "CARCINOGENS": When no regulations exist, the following


procedure must be adopted. The carcinogen should be enclosed in a securely
sealed, watertight container (primary container), which should be enclosed in a
second, unbreakable, leakproof container that will withstand chem attack from the
carcinogen (secondary container). The space between primary & secondary
container should be filled with absorbent material, which would withstand chem
attack from the carcinogen & is sufficient to absorb the entire contents of the
primary container in the event of breakage or leakage. Each secondary container
should then be enclosed in a strong outer box. The space between the secondary
container & the outer box should be filled with an appropriate quantity of shockabsorbent material. Sender should use fastest & most secure form of transport &
notify recipient of its departure. If parcel is not received when expected, carrier
should be informed so that immediate effort can be made to find it. Traffic

schedules should be consulted to avoid ... arrival on weekend or holiday ...


/Chemical Carcinogens/
[Montesano, R., H. Bartsch, E.Boyland, G. Della Porta, L. Fishbein, R. A. Griesemer,
A.B. Swan, L. Tomatis, and W. Davis (eds.). Handling Chemical Carcinogens in the
Laboratory: Problems of Safety. IARC Scientific Publications No. 33. Lyon, France:
International Agency for Research on Cancer, 1979., p. 13] **PEER REVIEWED**

Storage Conditions:
PRECAUTIONS FOR "CARCINOGENS": Storage site should be as close as practical to
lab in which carcinogens are to be used, so that only small quantities required for ...
expt need to be carried. Carcinogens should be kept in only one section of
cupboard, an explosion-proof refrigerator or freezer (depending on chemicophysical
properties ...) that bears appropriate label. An inventory ... should be kept, showing
quantity of carcinogen & date it was acquired ... Facilities for dispensing ... should
be contiguous to storage area. /Chemical Carcinogens/
[Montesano, R., H. Bartsch, E.Boyland, G. Della Porta, L. Fishbein, R. A. Griesemer,
A.B. Swan, L. Tomatis, and W. Davis (eds.). Handling Chemical Carcinogens in the
Laboratory: Problems of Safety. IARC Scientific Publications No. 33. Lyon, France:
International Agency for Research on Cancer, 1979., p. 13] **PEER REVIEWED**

Cleanup Methods:
PRECAUTIONS FOR "CARCINOGENS": A high-efficiency particulate arrestor (HEPA) or
charcoal filters can be used to minimize amt of carcinogen in exhausted air
ventilated safety cabinets, lab hoods, glove boxes or animal rooms ... Filter housing
that is designed so that used filters can be transferred into plastic bag without
contaminating maintenance staff is avail commercially. Filters should be placed in
plastic bags immediately after removal ... The plastic bag should be sealed
immediately ... The sealed bag should be labelled properly ... Waste liquids ...
should be placed or collected in proper containers for disposal. The lid should be
secured & the bottles properly labelled. Once filled, bottles should be placed in
plastic bag, so that outer surface ... is not contaminated ... The plastic bag should
also be sealed & labelled. ... Broken glassware ... should be decontaminated by
solvent extraction, by chemical destruction, or in specially designed incinerators.
/Chemical Carcinogens/
[Montesano, R., H. Bartsch, E.Boyland, G. Della Porta, L. Fishbein, R. A. Griesemer,
A.B. Swan, L. Tomatis, and W. Davis (eds.). Handling Chemical Carcinogens in the
Laboratory: Problems of Safety. IARC Scientific Publications No. 33. Lyon, France:
International Agency for Research on Cancer, 1979., p. 15] **PEER REVIEWED**

Disposal Methods:
SRP: At the time of review, criteria for land treatment or burial (sanitary landfill)
disposal practices are subject to significant revision. Prior to implementing land
disposal of waste residue (including waste sludge), consult with environmental
regulatory agencies for guidance on acceptable disposal practices.
**PEER REVIEWED**

PRECAUTIONS FOR "CARCINOGENS": There is no universal method of disposal that


has been proved satisfactory for all carcinogenic compounds & specific methods of
chem destruction ... published have not been tested on all kinds of carcinogencontaining waste. ... summary of avail methods & recommendations ... /given/ must
be treated as guide only. /Chemical Carcinogens/
[Montesano, R., H. Bartsch, E.Boyland, G. Della Porta, L. Fishbein, R. A. Griesemer,
A.B. Swan, L. Tomatis, and W. Davis (eds.). Handling Chemical Carcinogens in the
Laboratory: Problems of Safety. IARC Scientific Publications No. 33. Lyon, France:
International Agency for Research on Cancer, 1979., p. 14] **PEER REVIEWED**

PRECAUTIONS FOR "CARCINOGENS": ... Incineration may be only feasible method


for disposal of contaminated laboratory waste from biological expt. However, not all
incinerators are suitable for this purpose. The most efficient type ... is probably the
gas-fired type, in which a first-stage combustion with a less than stoichiometric
air:fuel ratio is followed by a second stage with excess air. Some ... are designed to
accept ... aqueous & organic-solvent solutions, otherwise it is necessary ... to absorb
soln onto suitable combustible material, such as sawdust. Alternatively, chem
destruction may be used, esp when small quantities ... are to be destroyed in
laboratory. /Chemical Carcinogens/
[Montesano, R., H. Bartsch, E.Boyland, G. Della Porta, L. Fishbein, R. A. Griesemer,
A.B. Swan, L. Tomatis, and W. Davis (eds.). Handling Chemical Carcinogens in the
Laboratory: Problems of Safety. IARC Scientific Publications No. 33. Lyon, France:
International Agency for Research on Cancer, 1979., p. 15] **PEER REVIEWED**

PRECAUTIONS FOR "CARCINOGENS": HEPA (high-efficiency particulate arrestor)


filters ... can be disposed of by incineration. For spent charcoal filters, the adsorbed
material can be stripped off at high temp & carcinogenic wastes generated by this
treatment conducted to & burned in an incinerator. ... LIQUID WASTE: ... Disposal
should be carried out by incineration at temp that ... ensure complete combustion.
SOLID WASTE: Carcasses of lab animals, cage litter & misc solid wastes ... should be
disposed of by incineration at temp high enough to ensure destruction of chem
carcinogens or their metabolites. /Chemical Carcinogens/

[Montesano, R., H. Bartsch, E.Boyland, G. Della Porta, L. Fishbein, R. A. Griesemer,


A.B. Swan, L. Tomatis, and W. Davis (eds.). Handling Chemical Carcinogens in the
Laboratory: Problems of Safety. IARC Scientific Publications No. 33. Lyon, France:
International Agency for Research on Cancer, 1979., p. 15] **PEER REVIEWED**

PRECAUTIONS FOR "CARCINOGENS": ... Small quantities of ... some carcinogens can
be destroyed using chem reactions ... but no general rules can be given. ... As a
general technique ... treatment with sodium dichromate in strong sulfuric acid can
be used. The time necessary for destruction ... is seldom known ... but 1-2 days is
generally considered sufficient when freshly prepd reagent is used. ... Carcinogens
that are easily oxidizable can be destroyed with milder oxidative agents, such as
saturated soln of potassium permanganate in acetone, which appears to be a
suitable agent for destruction of hydrazines or of compounds containing isolated
carbon-carbon double bonds. Concn or 50% aqueous sodium hypochlorite can also
be used as an oxidizing agent. /Chemical Carcinogens/
[Montesano, R., H. Bartsch, E.Boyland, G. Della Porta, L. Fishbein, R. A. Griesemer,
A.B. Swan, L. Tomatis, and W. Davis (eds.). Handling Chemical Carcinogens in the
Laboratory: Problems of Safety. IARC Scientific Publications No. 33. Lyon, France:
International Agency for Research on Cancer, 1979., p. 16] **PEER REVIEWED**

PRECAUTIONS FOR "CARCINOGENS": Carcinogens that are alkylating, arylating or


acylating agents per se can be destroyed by reaction with appropriate nucleophiles,
such as water, hydroxyl ions, ammonia, thiols & thiosulfate. The reactivity of various
alkylating agents varies greatly ... & is also influenced by sol of agent in the reaction
medium. To facilitate the complete reaction, it is suggested that the agents be
dissolved in ethanol or similar solvents. ... No method should be applied ... until it
has been thoroughly tested for its effectiveness & safety on material to be
inactivated. For example, in case of destruction of alkylating agents, it is possible to
detect residual compounds by reaction with 4(4-nitrobenzyl)-pyridine. /Chemical
Carcinogens/
[Montesano, R., H. Bartsch, E.Boyland, G. Della Porta, L. Fishbein, R. A. Griesemer,
A.B. Swan, L. Tomatis, and W. Davis (eds.). Handling Chemical Carcinogens in the
Laboratory: Problems of Safety. IARC Scientific Publications No. 33. Lyon, France:
International Agency for Research on Cancer, 1979., p. 17] **PEER REVIEWED**

Occupational Exposure Standards:

Manufacturing/Use Information:

Major Uses:
For Metronidazole (USEPA/OPP Pesticide Code: 120401) there are 0 labels match.
/SRP: Not registered for current use in the U.S., but approved pesticide uses may
change periodically and so federal, state and local authorities must be consulted for
currently approved uses./
[National Pesticide Informaton Retrieval System's USEPA/OPP Chemical Ingredients
Database on Metronidazole (443-48-1). Available from, as of April 20, 2006:
http://ppis.ceris.purdue.edu/htbin/epachem.com **PEER REVIEWED**

The active ingredient is no longer contained in any registered pesticide products ...
"cancelled."
[United States Environmental Protection Agency/ Prevention, Pesticides and Toxic
Substances; Status of Pesticides in Registration, Reregistration, and Special Review.
(1998) EPA 738-R-98-002, p. 265] **PEER REVIEWED**

Mesh Heading: Anti-infective agents, antiprotozoal agents, radiation-sensitizing


agents
[National Library of Medicine, SIS; ChemIDplus Record for Metronidazole (443-48-1).
Available from, as of Sep 27, 2006:
http://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp **PEER REVIEWED**

Topical treatment of inflammatory lesions of rosacea


[Physicians Desk Reference 60th ed, Thomson PDR, Montvale, NJ 2006., p. 1212]
**PEER REVIEWED**

Used in treatment of guinea worm


[Kirk-Othmer Encyclopedia of Chemical Technology. 4th ed. Volumes 1: New York, NY.
John Wiley and Sons, 1991-Present., p. V3: 469 (1992)] **PEER REVIEWED**

Inhibit growth of pathogenic protozoa Trichonomas vaginalus and Eistomoeta


histolyticum ... effective against infections resulting from anaerobic bacteria and
facultative anaerobes
[Kirk-Othmer Encyclopedia of Chemical Technology. 4th ed. Volumes 1: New York, NY.
John Wiley and Sons, 1991-Present., p. V8: 268 (1993)] **PEER REVIEWED**

MEDICATION (See also: Therapeutic Uses)


[O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and
Biologicals. 13th Edition, Whitehouse Station, NJ: Merck and Co., Inc., 2001., p.
1097] **PEER REVIEWED**

MEDICATION (VET) (See also: Therapeutic Uses)


[O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and
Biologicals. 13th Edition, Whitehouse Station, NJ: Merck and Co., Inc., 2001., p.
1097] **PEER REVIEWED**

Manufacturers:
3M Pharmaceuticals, 3M Center, Bldg. 275-6W-13, P.O. Box 33275, St. Paul, MN
55144, (880)447-4537
[SRI Consulting. 2005 Directory of Chemical Producers - United States, Menlo Park,
CA. 2005, p. 1822] **PEER REVIEWED**

Dermik Laboratories, 1050 Westlakes Dr., Berwyn, PA 19312, (800) 207-8049


[SRI Consulting. 2005 Directory of Chemical Producers - United States, Menlo Park,
CA. 2005, p. 1051] **PEER REVIEWED**

Galderma Laboratories, L.P., 14501 North Freeway, Ft. Worth, TX 76177 (800) 5828225
[SRI Consulting. 2005 Directory of Chemical Producers - United States, Menlo Park,
CA. 2005, p. 1212] **PEER REVIEWED**

Watson Laboratories, Inc., 311 Bonnie Circle, Corona, CA 92880, (800) 760-9224
[SRI Consulting. 2005 Directory of Chemical Producers - United States, Menlo Park,
CA. 2005, p. 3376] **PEER REVIEWED**

Methods of Manufacturing:
Jacob et al., US patent 2,944,061 (1960 to Rhone-Poulenc)

[O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and
Biologicals. 13th Edition, Whitehouse Station, NJ: Merck and Co., Inc., 2001., p.
1097] **PEER REVIEWED**

Metronidizole is prepared by heating 2-methyl-5-nitroimidizole with excess 2chloroethanol to obtain the crude product which is purified by extraction with
chloroform and recrystallization from ethyl acetate.
[Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New
York, NY: John Wiley and Sons, 1978-1984., p. V5 525] **PEER REVIEWED**

General Manufacturing Information:


Although metronidazole is closely related to natural antitrichomonal agent,
Azomycin, it is not known to occur in nature.
[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man.
Geneva: World Health Organization, International Agency for Research on Cancer,
1972-PRESENT. (Multivolume work). Available at:
http://monographs.iarc.fr/index.php p. V13 116] **PEER REVIEWED**

NMR spectroscopy & polarography were used to detect in vitro interactions


between metronidazole & biologically important metals. Only cupric ion showed
detectable interaction.
[Chien YW et al; J Pharm Sci 64: 957 (1975)] **PEER REVIEWED** PubMed Abstract

Reasonably anticipated to be a human carcingen


[O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and
Biologicals. 13th Edition, Whitehouse Station, NJ: Merck and Co., Inc., 2001., p.
1096] **PEER REVIEWED**

Formulations/Preparations:
Metronidazole, USP (flagyl), is avail as 250-mg tablets. Uncoated vaginal inserts,
each containing 500 mg, are also available.
[Goodman, L.S., and A. Gilman. (eds.) The Pharmacological Basis of Therapeutics.
5th ed. New York: Macmillan Publishing Co., Inc., 1975., p. 1087] **PEER
REVIEWED**

Capsule 375 mg; Gel, topical 0.75% [7.5 mg/mL] (30 g); Gel, vaginal 0.75% (5 g
applicator delivering 37.5 mg in 70 g tube); Injection, ready to use 5 mg/mL (100
mL); Powder for injection, as hydrochloride 500 mg; Tablet 250mg, 500 mg
[Lelkin, J.B., Paloucek, F.P., Poisoning & Toxicology Compendium. LEXI-COMP Inc. &
American Pharmaceutical Association, Hudson, OH 1998., p. 391] **PEER
REVIEWED**

Capsules 375 mg, Tablets 250 mg, 500 mg Flagyl 375, Pfizer; Tablets, extendedrelease, film-coated 750 mg Flagyl ER, Pfizer; Tablets, film-coated 250 mg, 500 mg
Flagyl, Pfizer; Parenteral Injection, for IV infusion only 5 mg/mL Flagyl I.V. RTU
(Viaflex [Baxter]), SCS Pharmaceuticals.
[McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information.
American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 893]
**PEER REVIEWED**

Laboratory Methods:

Clinical Laboratory Methods:


BIOASSAY PROCEDURES USING AGAR DIFFUSION TECHNIQUES HAVE BEEN
REPORTED: LEVISON ME, ANTIMICROB AGENTS CHEMOTHER (5) 446-468, 1974 &
RALPH ED ET AL, J INFECT DIS (132) 587-591, 1975. PLASMA; GAS
CHROMATOGRAPHY: MIDHA KK ET AL, J CHROMAT (87) 491-497, 1973 & WOOD NF, J
PHARM SCI (64) 1048-1049, 1975.
[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man.
Geneva: World Health Organization, International Agency for Research on Cancer,
1972-PRESENT. (Multivolume work). Available at:
http://monographs.iarc.fr/index.php p. V13 116] **PEER REVIEWED**

SENSITIVE ASSAY WAS DEVELOPED FOR DETERMINATION OF METRONIDAZOLE IN


PLASMA. LIMIT OF DETECTION FOR 2 ML SAMPLE IS 0.1 MCG/ML. ASSAY MAY BE
EMPLOYED FOR ANALYSIS OF URINE.
[BROOKS MA ET AL; DETERMINATION OF NITROIMIDAZOLES IN BIOLOGICAL FLUIDS
BY DIFFERENTIAL PULSE POLAROGRAPHY; J PHARM SCI 65: 112 (1976)] **PEER
REVIEWED**

GLC ANALYSIS OF METRONIDAZOLE IN HUMAN PLASMA.


[WOOD NF; GLC ANALYSIS OF METRONIDAZOLE IN HUMAN PLASMA; J PHARM SCI 64:
1048 (1975)] **PEER REVIEWED**

Analyte: metronidazole; matrix: blood, biological fluid; procedure: highperformance liquid chromatography with ultraviolet detection at 250 nm
[Koves EM; J Chromatogr A 692: 103-119 (1995). As cited in: Lunn G; HPLC Methods
for Pharmaceutical Analysis. Volumes 2-4. New York, NY: John Wiley & Sons, 2000.,
p.1360] **PEER REVIEWED**

Analyte: metronidazole; matrix: blood (serum); procedure: high-performance liquid


chromatography with ultraviolet detection at 210 nm
[Inagaki K et al; Ther Drug Monit 14: 306-311 (1992). As cited in: Lunn G, Schmuff
N; HPLC Methods for Pharmaceutical Analysis. New York, NY: John Wiley & Sons,
1997., p.615] **PEER REVIEWED**

Analyte: metronidazole; matrix: blood (serum); procedure: high-performance liquid


chromatography with ultraviolet detection at 318 nm; limit of detection: 30 ng/mL
[Rona K, Gachalyi B; J Chromatogr 420: 228-230 (1987). As cited in: Lunn G; HPLC
Methods for Pharmaceutical Analysis. Volumes 2-4. New York, NY: John Wiley & Sons,
2000., p.1354] **PEER REVIEWED**

Analyte: metronidazole; matrix: blood (serum), egg, tissue (liver, muscle);


procedure: high-performance liquid chromatography with ultraviolet detection at
350 nm; limit of quantitation: 5 ng/mL (serum), 2 ng/g (tissue, egg)
[Semeniuk S et al; Biomed Chromatogr 9: 238-242 (1995). As cited in: Lunn G; HPLC
Methods for Pharmaceutical Analysis. Volumes 2-4. New York, NY: John Wiley & Sons,
2000., p.1355] **PEER REVIEWED**

Analyte: metronidazole; matrix: blood (plasma), gastric juice, saliva; procedure:


high-performance liquid chromatography with ultraviolet detection at 317 nm; limit
of quantitation: 250 ng/mL (plasma, gastric juice), 100 ng/mL (saliva)
[Jessa MJ et al; J Chromatogr B 677: 374-379 (1996). As cited in: Lunn G; HPLC
Methods for Pharmaceutical Analysis. Volumes 2-4. New York, NY: John Wiley & Sons,
2000., p.1355] **PEER REVIEWED**

Analyte: metronidazole; matrix: blood (plasma), urine; procedure: highperformance liquid chromatography with ultraviolet detection at 338 nm; limit of
quantitation: <10 ng/mL
[Okonkwo PO, Eta EI; Life Sci 42: 539-545 (1988). As cited in: Lunn G; HPLC Methods
for Pharmaceutical Analysis. Volumes 2-4. New York, NY: John Wiley & Sons, 2000.,
p.1356] **PEER REVIEWED**

Analyte: metronidazole; matrix: blood (whole), urine; procedure: high-performance


liquid chromatography with ultraviolet detection at 320 nm
[Gaillard Y, Pepin G; J Chromatogr A 763: 149-163 (1997). As cited in: Lunn G; HPLC
Methods for Pharmaceutical Analysis. Volumes 2-4. New York, NY: John Wiley & Sons,
2000., p.1356] **PEER REVIEWED**

Analyte: metronidazole; matrix: tissue (vaginal); procedure: high-performance


liquid chromatography with ultraviolet detection at 313 nm; limit of detection: 100
ng/g
[Venkateshwaran TG, Stewart JT; J Chromatogr B 672: 300-304 (1995). As cited in:
Lunn G; HPLC Methods for Pharmaceutical Analysis. Volumes 2-4. New York, NY: John
Wiley & Sons, 2000., p.1361] **PEER REVIEWED**

Analyte: metronidazole; matrix: urine; procedure: high-performance liquid


chromatography with ultraviolet detection at 312 nm; limit of detection: 2 ng/mL
[Thomsen UG et al; J Chromatogr A 697: 175-184 (1995). As cited in: Lunn G; HPLC
Methods for Pharmaceutical Analysis. Volumes 2-4. New York, NY: John Wiley & Sons,
2000., p.1362] **PEER REVIEWED**

Analytic Laboratory Methods:


TWO SIMPLE COLORIMETRIC METHODS FOR EST OF METRONIDAZOLE IN MARKETED
TABLETS & SYRUPS ARE DESCRIBED.
[SANGHAVI NM, CHANDRAMOHAN HS; METHODS OF ESTIMATION OF
METRONIDAZOLE; INDIAN J PHARM 36: 151 (1974)] **PEER REVIEWED**

METHODS OF ASSAY OF METRONIDAZOLE TO MEET REGULATORY REQUIREMENTS


FOR PHARMACEUTICAL PRODUCTS COMMONLY EMPLOY NON-AQ TITRATION. THIS
HAS BEEN COMPARED TO POTENTIOMETRIC METHODS FOR DETERMINATION
/OF/...PHARMACEUTICAL PRODUCTS. TUCKERMAN MM & BICAN-FISTER T, ANALYSIS
OF METRONIDAZOLE, J PHARM SCI (58) 1401-1403, 1969.

[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man.


Geneva: World Health Organization, International Agency for Research on Cancer,
1972-PRESENT. (Multivolume work). Available at:
http://monographs.iarc.fr/index.php p. V13 116] **PEER REVIEWED**

PHARMACEUTICAL PRODUCTS; UV SPECTROPHOTOMETRY: KOMPANTSEVA EV ET AL,


FARMATSIYA (MOSCOW) 22, 45-48, 1973; & COLORIMETRIC METHODS: POPULAIRE P
ET AL, ANN PHARM FRANC (26) 549-556, 1968 & SANGHAVI NM ET AL, IND J PHARM
(36) 151-152, 1974; & COMPLEXOMETRIC DETERMINATIONS: GAJEWSKA M, ACTA
POL PHARM (29) 399-404, 1972.
[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man.
Geneva: World Health Organization, International Agency for Research on Cancer,
1972-PRESENT. (Multivolume work). Available at:
http://monographs.iarc.fr/index.php p. V13 116] **PEER REVIEWED**

Analyte: metronidazole; matrix: chemical identification; procedure: infrared


absorption spectrophotometry with comparison to standards
[U.S. Pharmacopeia. The United States Pharmacopeia, USP 29/The National
Formulary, NF 24; Rockville, MD: U.S. Pharmacopeial Convention, Inc., p1425
(2006)] **PEER REVIEWED**

Analyte: metronidazole; matrix: chemical identification; procedure: ultraviolet


absorption spectrophotometry with comparison to standards
[U.S. Pharmacopeia. The United States Pharmacopeia, USP 29/The National
Formulary, NF 24; Rockville, MD: U.S. Pharmacopeial Convention, Inc., p1425
(2006)] **PEER REVIEWED**

Analyte: metronidazole; matrix: chemical purity; procedure: dissolution in acetic


anhydride; addition of malachite green indicator; titration with perchloric acid to a
yellow-green endpoint
[U.S. Pharmacopeia. The United States Pharmacopeia, USP 29/The National
Formulary, NF 24; Rockville, MD: U.S. Pharmacopeial Convention, Inc., p1425
(2006)] **PEER REVIEWED**

Analyte: metronidazole; matrix: pharmaceutical preparation (gel; injection solution;


tablet); procedure: thin-layer chromatography with comparison to standards
(chemical identification)

[U.S. Pharmacopeia. The United States Pharmacopeia, USP 29/The National


Formulary, NF 24; Rockville, MD: U.S. Pharmacopeial Convention, Inc., p1426
(2006)] **PEER REVIEWED**

Analyte: metronidazole; matrix: pharmaceutical preparation (gel; injection


solution); procedure: retention time of liquid chromatogram with comparison to
standards (chemical identification)
[U.S. Pharmacopeia. The United States Pharmacopeia, USP 29/The National
Formulary, NF 24; Rockville, MD: U.S. Pharmacopeial Convention, Inc., p1426
(2006)] **PEER REVIEWED**

Analyte: metronidazole; matrix: pharmaceutical preparation (gel; tablet);


procedure: liquid chromatography with detection at 254 nm and comparison to
standards (chemical purity)
[U.S. Pharmacopeia. The United States Pharmacopeia, USP 29/The National
Formulary, NF 24; Rockville, MD: U.S. Pharmacopeial Convention, Inc., p1426
(2006)] **PEER REVIEWED**

Analyte: metronidazole; matrix: pharmaceutical preparation (injection solution);


procedure: liquid chromatography with detection at 320 nm and comparison to
standards (chemical purity)
[U.S. Pharmacopeia. The United States Pharmacopeia, USP 29/The National
Formulary, NF 24; Rockville, MD: U.S. Pharmacopeial Convention, Inc., p1426
(2006)] **PEER REVIEWED**

Analyte: metronidazole; matrix: pharmaceutical preparation (tablet); procedure:


ultraviolet absorption spectrophotometry with comparison to standards (chemical
identification)
[U.S. Pharmacopeia. The United States Pharmacopeia, USP 29/The National
Formulary, NF 24; Rockville, MD: U.S. Pharmacopeial Convention, Inc., p1427
(2006)] **PEER REVIEWED**

Analyte: metronidazole; matrix: pharmaceutical preparation (injection solution);


procedure: high-performance liquid chromatography with ultraviolet detection at
254 nm
[Belliveau PP et al; Am J Health-Syst Pharm 52: 1561-1563 (1995). As cited in: Lunn
G, Schmuff N; HPLC Methods for Pharmaceutical Analysis. New York, NY: John Wiley
& Sons, 1997., p.285] **PEER REVIEWED**

Analyte: metronidazole; matrix: pharmaceutical preparation (injection solution);


procedure: high-performance liquid chromatography with ultraviolet detection at
270 nm
[Rivers TE et al; Am J Hosp Pharm 48: 2638-2640 (1991). As cited in: Lunn G,
Schmuff N; HPLC Methods for Pharmaceutical Analysis. New York, NY: John Wiley &
Sons, 1997., p.285] **PEER REVIEWED**

Analyte: metronidazole; matrix: pharmaceutical preparation (injection solution);


procedure: high-performance liquid chromatography with ultraviolet detection at
270 nm
[Rivers TE, Webster, AA; Am J Health-Syst Pharm 52: 2568-2570 (1995). As cited in:
Lunn G, Schmuff N; HPLC Methods for Pharmaceutical Analysis. New York, NY: John
Wiley & Sons, 1997., p.285] **PEER REVIEWED**

Analyte: metronidazole; matrix: pharmaceutical preparation (tablet); procedure:


high-performance liquid chromatography with ultraviolet detection at 254 nm
[Das Gupta V; J Pharm Sci 73: 1331-1333 (1984). As cited in: Lunn G; HPLC Methods
for Pharmaceutical Analysis. Volumes 2-4. New York, NY: John Wiley & Sons, 2000.,
p.1357] **PEER REVIEWED**

Analyte: metronidazole; matrix: pharmaceutical preparation (suspension);


procedure: reversed-phase high-performance liquid chromatography with ultraviolet
detection at 270 nm; limit of detection: 1000 ng/mL /metronidazole benzoate/
[Sa'sa' SL et al; J Liq Chromatogr 9: 3617-3631 (1986). As cited in: Lunn G; HPLC
Methods for Pharmaceutical Analysis. Volumes 2-4. New York, NY: John Wiley & Sons,
2000., p.1357] **PEER REVIEWED**

Analyte: metronidazole; matrix: pharmaceutical preparation (suspension);


procedure: reversed-phase high-performance liquid chromatography with ultraviolet
detection at 254 nm /metronidazole benzoate/
[Pashankov PR, Kostova LL; J Chromatogr 394: 382-387 (1987). As cited in: Lunn G;
HPLC Methods for Pharmaceutical Analysis. Volumes 2-4. New York, NY: John Wiley &
Sons, 2000., p.1358] **PEER REVIEWED**

Analyte: metronidazole; matrix: pharmaceutical preparation (reaction mixture);


procedure: high-performance liquid chromatography with ultraviolet detection at
325 nm; limit of detection: 50 ng/mL

[Lunn G et al; J Pharm Sci 83: 1289-1293 (1994). As cited in: Lunn G; HPLC Methods
for Pharmaceutical Analysis. Volumes 2-4. New York, NY: John Wiley & Sons, 2000.,
p.1360] **PEER REVIEWED**

Analyte: metronidazole; matrix: solution; procedure: high-performance liquid


chromatography with ultraviolet detection at 250 nm
[Faouzi MEA et al; J Pharm Biomed Anal 13: 1363-1372 (1995). As cited in: Lunn G;
HPLC Methods for Pharmaceutical Analysis. Volumes 2-4. New York, NY: John Wiley &
Sons, 2000., p.1360] **PEER REVIEWED**

Metronidazole, a drug effective against certain protozoal and anaerobic infections,


was given female patients with Trichomoniasis urogenitalis. Group I received twice
daily 250 mg of metronidazole (supplied as 250 mg tablets Vagimid). Group II
received in a single dose 1.0 g (4 tablets); and group III, 2.0 g (8 tablets). Serum
and urine metronidazole levels were measured polarographically. Kinetic
parameters were determined from the measured values of the concentration time
curve by a computing program. An exact control of the therapeutic result was
carried out. In all patients peak serum levels occurred within 1-3 hr and averaged
5.1 +/- 1.7 microgram/ml after 250 mg doses, 19.6 +/- 3.8 microgram/ml after 1.0 g
doses and 40.6 +/- 9.3 microgram/ml after 2.0 g doses. About 35% of the
administered dose was recovered in the urine in 12 hr and about 50% in 24 hr.
Metronidazole shows protein binding of 10-20% equally in vivo and in vitro.
Minimum trichomonacidic concentrations of nearly 1 microgram/ml were still
present 12 hr after oral application of 250 mg metronidazole, and 24 hr to 36 hr,
respectively after 1.0 g and 2.0 g daily doses. The cure rate was 100%. No serious
side effects ocurred in any of the patients.

The clinical pharmacokinetics of metronidazole following oral, intravenous, rectal,


and intravaginal doses are described. Peak serum concentrations are quite similar
after oral or intravenous administration and average approximately 10 [mu]g/ml
after a single 500mg dose. After an oral dose the peak serum concentration is
reached approximately 1 hour after administration. Food does not significantly
affect absorption, and the bioavailability of the dose approaches 100%. For both
intravenous and oral administration, a linear doseconcentration curve pertained for
usual therapeutic doses between 200 and 2000mg.

Multiple oral or intravenous doses given every 6 to 8 hours result in some drug
accumulation with higher serum concentrations as compared with single doses. On
an intravenous dose regimen of 500mg every 8 hours, maximum metronidazole
serum concentrations average 25 [mu]g/ml and minimum concentrations 15
[mu]g/ml. Rectal administration of metronidazole by suppository resulted in peak
serum concentrations approximately one-half those following equivalent oral doses
and occurred at 4 hours after administration; the bioavailability of the rectal
suppository was approximately 80%. From the limited data available, the systemic
absorption of intravaginal metronidazole is very slow with peak serum
concentrations of approximately 2 [mu]g/ml being attained 8 to 24 hours after
administration of a 500mg dose.

Metronidazole is excreted in the urine as unchanged drug and primarily oxidative


metabolites, the major compounds being the hydroxy and acid metabolites. The
degree of urinary excretion is dependent upon the assay used. By bioassay, 15 to
20% of the administered dose is excreted as bioactive drug. By high pressure liquid
chromatography, in which unchanged metronidazole and the hydroxy and acid
metabolites are measured separately, total excretion of these compounds after 48
hours is approximately 30%, with the hydroxy metabolite being the primary
excretory product.

Detailed pharmacokinetic analysis of metronidazole has been performed using 1compartment and 2-compartment open models. The serum half-life of unchanged
metronidazole averaged 8.2 hours, as determined by specific chemical methods,
whereas using bioassay methods the half-life was somewhat longer. A 2compartment open model analysis described the serum concentration-time curve
with a rapid [alpha] (distribution) phase (half-life 1.24 hours) and a slower [beta]
(elimination) phase (half-life 9.76 hours). Metronidazole has a large apparent
volume of distribution and serum protein binding of 20% or less. In multiple-dose
regimens the hydroxy metabolite of metronidazole may be present in
concentrations up to 30% of those of the parent drug with a half-life of 9.7 hours.
The acid metabolite is rarely detected in serum. Metronidazole is widely distributed
throughout the body with tissue levels, in most cases, approximating serum levels.
This is especially important in the central nervous system where the drug readily
crosses both the blood-brain and blood-cerebrospinal fluid barriers.

The pharmacokinetics of metronidazole do not appear to differ significantly in


neonates, patients seriously ill with anaerobic infections, or during pregnancy.
However, dose modification is necessary in neonates because of the slower
elimination of the drug. In patients with renal failure, although the serum half-life of
metronidazole does not change, the half-life of the hydroxy metabolite increases 4fold and accumulates in the serum. Haemodialysis effectively removes
metronidazole and, to a lesser extent, the hydroxy metabolite, reducing the half-life
of the former to 2.6 hours and the latter to 7.8 hours. and diarrhoea, a reversible
leucocytopenia, and various neurological toxicities (the latter generally associated

with large doses over a prolonged period). Potentially serious toxicities including
tumourigenicity, dysmorphogenicity, and mutagenicity inferred from certain animal
models and bacterial test systems have not been confirmed in humans.

The pharmacokinetic properties of metronidazole complement its excellent


microbiological activity against anaerobic organisms, making it a very effective drug
in the treatment of anaerobic infections.

NAME

1.1 Substance

Metronidazole

(INN)

(WHO, 1992)

1.2 Group

ATC classification index

Antibacterials for systemic use(J01)/

Other antibacterials (J01X)/


Imidazole derivatives (J01XD).

(WHO, 1992)

1.3 Synonyms

Metronidazolo
Bayer-5630
NSC-50364
RP-8823
SC-10295

(Reynolds, 1993; Budavari, 1989)

1.4 Identification numbers

1.4.1 CAS number

443-48-1

1.4.2 Other numbers

RTECS

NI5600000

1.5 Brand names, Trade names

Monocomponent products

Worldwide

Flagyl

Other names

Argentina
Australia
Canada
Denmark

Debretol, Nalox, Tranoxa, Tricofin


Trichozole
Neo-Tric, Novonidazol, Trikacide
Elyzol, Trichomal

Germany

Clont, Fossyol, Krencosan, Rathimed N,


Sanatrichom, Trichos Cordes, TrichoGynaedron oral

Hungary

Klion

Italy

Deflamon, Geneflavir, Tricocet, Trivazol,


Vagilen

Norway

Elyzol

Poland

Entizol

Spain

Tricowas B

Sweden

Elyzol

Switzerland

Metrolag

Combination products

Entamizole D.S.
Dependal

(Reynolds, 1982)

(To be completed by each Centre using local data)

1.6 Manufacturers, Importers

May & Baker, Searle, Specia, Rhone-Poulenc, Boots


SK & F.

(To be completed by each Centre using local data)

1.7 Presentation, Formulation

Tablets, suspension and intravenous infusions


(previously vaginal pessaries, suppositories, intramuscular
injection)

Metronidazole tablets 200, 250, 400, 500 mg


Metronidazole injection 5 mg/mL, 100 and 300 mL
Metronidazole suppositories 0.5 and 1 g
Metronidazole vaginal ovule 500 mg.
Metronidazole suspension 200 mg/5 mL

(To be completed by each Centre using local data)

2. SUMMARY

2.1 Main risks and target organs

Gastrointestinal tract and nervous system are main


organs of toxicity (Roe, 1983).

2.2 Summary of clinical effects

Acute toxicity causes gastrointestinal tract symptoms.

Chronic toxicity causes neurological damage.

After oral or intravenous infusion the following effects can


occur:

Metallic taste in mouth, nausea, vomiting and anorexia.

Headache, dizziness, vertigo, syncope and even convulsive


seizure, and peripheral neuropathy.

2.3 Diagnosis

Clinical diagnosis is difficult to determine because of


the lack of history of toxic ingestions.

Laboratory analysis by HPLC should be considered for


information.

2.4 First aid measures and management principles

There is no specific antidote. Only symptomatic and


general supportive therapy is necessary.

Gastric lavage (preferably within 1 to 2 hours of the


ingestion)and activated charcoal after ingestion. At the
same time basic life support (airway, breathing and
circulation) must be maintained.

If convulsions occur give diazepam intravenously at 5 to 10


mg (0.04 mg/kg for children).

3. PHYSICO-CHEMICAL PROPERTIES

3.1 Origin of the substance

Discovery of aomycin (nitro imidazole) in 1955 by


Nakumura and demonstration of its anti-protozoal properties
by Horie in 1956 led to chemical synthesis of nitro
imidazoles.

3.2 Chemical structure

Structural formula

Molecular formula

C6H9O3N3

Molecular weight

171.16

Chemical names

2-(2-Methyl-5-nitroimidazol-1-yl)ethanol

2-methyl-5-nitroimidazole-1-ethanol

1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole

1-( beta-ethylol)-2-methyl-5-nitro-3-azapyrrole

(Reynolds, 1993; Budavari, 1989)

3.3 Physical properties

3.3.1 Properties of the substance

3.3.1.1 Colour

Pale yellow; darkens on exposure


to light.

3.3.1.2 State/Form

Crystalline powder

3.3.1.3 Description

Slightly soluble in water, in


alcohol, in acetone or in methylene
chloride; very slightly soluble in
ether.

pH of a saturated aqueous solution at 20C


is about 6.5.

Melting point 160C

(Reynolds, 1993; Budavari, 1989)

3.3.1 Properties of the locally available formulation(s)

To be completed by each Centre using local


data.

3.4 Other characteristics

3.4.1 Shelf-life of the substance

Injection

3 years.

Tablets

5 years

Suspension

2 years

Intravenous pre-mixed2 years


infusions

3.4.2 Shelf-life of locally available formulation(s)

To be completed by each Centre using local


data.

3.4.3 Storage conditions

Protect from direct sunlight, infusions to be


kept between 15 to 30C.

3.4.4 Bioavailability

Bioavailability of oral tablets is 93% to 95%.


Not affected by food or drink. (Ralph, 1983)

3.4.5 Specific properties and composition

Metronidazole benzoate is used for the


suspension form of metronidazole.

Metronidazole hydrochloride is used for the


intravenous form of metronidazole.

(Reynolds, 1993)

4. USES

4.1 Indications

4.1.1 Indications

Protozoal infections

Balantidium coli; Blastocystis hominis; Entamoeba


histolytica; Giardia intestinalis (Giardia lamblia);
and Trichomonas vaginalis.

Obligate anaerobic bacteria infections

Bacteroides spp and Clostridium spp (including C.


difficile, the causative organisms in
pseudomembranous colitis).

Infections

Campylobacter spp; Gardnerella vaginalis (which


causes bacterial vaginitis); Oral bacteria (Vincent's
gingivitis).

Amoebiasis

Intestinal and extra-intestinal, including amoebic


liver abscess

Other

Fascialiasism, Guinea-worm infection, Leishmaniasia,


Mononucleosis, Tropica eosinophilia, Vaginitis
(Gardnerella vaginalis), Vincent's infection.

Trichomonas vaginalis, both symptomatic and


carriers.

Anaerobic gram negative bacilli = Bacteroides


fragilis group, Fusobacterium species.

Anaerobic gram positive bacilli = Clostridium spp


susceptible strains of Eubacterium.

Anaerobic gram positive cocci = Peptococcus spp.


Peptostreptococcus spp.

4.1.2 Description

Not relevant.

4.2 Therapeutic dosage

4.2.1 Adults

Oral

Amoebiasis (Acute amoebic dysentery)

400 to 800 mg 3 times daily for 5 to 10 days.

Amoebiasis (Amoebic liver abscess)

400 to 800 mg 3 times daily for 5 to 10 days.

Trichomoniasis

2 g in single dose; or

250 mg 3 times daily for 5 to 7 days; or

400 mg twice a day; or

800 mg in the morning and 1200 mg at night, for 2


days.

Anaerobic infections

800 mg initial dose, followed by 400 mg every 8


hours, for about 7 days.

Giardiasis

2 g daily as a single dose for 3 days.

Parenteral

Anaerobic infections

500 mg as intravenous infusion every 8 hours.

Rectal

Anaerobic infections

1 g suppository every 8 hours for 3 days, then every


12 hours.

(Reynolds, 1993)

4.2.2 Children

Oral

Amoebiasis (Acute amoebic dysentery)

35 to 50 mg/kg daily in divided doses is


recommended.

Amoebiasis (Amoebic liver abscess)

35 to 50 mg/kg daily in divided doses has been


recommended.

Trichomoniasis

15 mg/kg daily in divided doses for 7 days has been


recommended.

Anaerobic infections

7.5 mg/kg every 8 hours.

Giardiasis

15 mg/kg daily in divided doses has been recommended


for 3 days.

Parenteral

Anaerobic infections

7.5 mg/kg as intravenous infusion every 8 hours.

Rectal

Anaerobic infections

7.5 mg/kg every 8 hours for 3 days, then every 12


hours.

(Reynolds, 1993)

4.3 Contraindications

Not for use in persons with prior history of


hypersensitivity to nitroimidazole derivatives or
metronidazole preparation.

It is contraindicated in trichonosomiasis in the first


trimester of pregnancy. Avoid use during breast-feeding
because metronidazole is excreted in breast milk. Nursing
should be discontinued during therapy and for two days
following metronidazole therapy.

It should be used with caution in cases with CNS diseases and


should be discontinued immediately if abnormal neurological
signs develop during treatment.

5. ROUTES OF ENTRY

5.1 Oral

It is the most frequent route of intoxication.

5.2 Inhalation

Not relevant.

5.3 Dermal

Not relevant.

5.4 Eye

Not relevant.

5.5 Parenteral

Intoxication after parenteral route is rare.

5.6 Other

No cases reported arising from rectal or vaginal


administration.

6. KINETICS

6.1 Absorption by route of exposure

Oral

Metronidazole is readily and almost completely absorbed from


the gastrointestinal tract (Reynolds, 1989). Bioavailability
is nearly 100%. Maximum concentrations occur in the serum
after about one hour and traces are detected after 24 hours
(Bergan et al., 1984; McGilveray, et al., 1978; Ralph,
1983).

It is well absorbed after oral administration. Following


ingestion of a 250 mg, 500 mg or 2000 mg dose of
metronidazole in healthy fasting adults peak plasma levels
are reached within one to three hours and average 4.6 to 6.5
micrograms/mL, 11.5 to 13 micrograms/mL and 30 to 45
micrograms/mL, respectively (McEvoy, 1995).

Rectal

Metronidazole is readily and almost completely absorbed from


the rectal mucosa (Reynolds, 1989).It is absorbed more slowly
after rectal administration than after oral dosing, with a
peak concentration at about four hours. Bioavailability by
this route is about 70%.

6.2 Distribution by route of exposure

The apparent volume of distribution is 0.6 to 0.8 L/kg;


after 400 mg intravenously, it is 1.05 l/kg (Jensen & Gugler,
1983; Gupte, 1983).

Protein binding is low, between 8 and 11% (Schwartz & Jeunet,


1976).

It also penetrates well in body tissue and fluids including


vaginal secretions, seminal fluid, saliva and breast milk,
and therapeutic concentration has been achieved in
cerebrospinal fluid (Schwartz & Jeunet, 1976).

As compared to serum concentration, the following tissue


concentrations are observed:

Middle ear mucosa


Gall bladder bile

180%
135%

CSF

120%

Abdominal muscles

110%

Fallopian tube
Uterus

100%
95%

Human milk

90%

Ileum

85%

Bone

80%

Colon

70%

Peritoneal cavity, appendix and choledochus bile 55% but


omentum has only 20% and subcutaneous tissue 10%.

(Houghton et al.,1979)

When given an oral suspension of benzoyl metronidazole, the


system availability is 80% of metronidazole.

When given as suppository, the bioavailability is between 44


to 80% and a mean 67% of oral dose (Bergan et al.,
1984).

6.3 Biological half-life by route of exposure

Elimination half-life after an intravenous infusion of


1.5 g is between 6.6 to 10.3 hours, with a mean of 8.4 hours.
The half-life of hydroxy metabolites is between 13.3 and 19.1
hours (Bergan et al., 1984). Repeated doses every 6 to 8
hours may result in some accumulation.

In cases of impaired liver function, elimination is slower.


In renal failure half-life of metronidazole is unchanged but
that of metabolites is increased.

6.4 Metabolism

Metronidazole is almost completely metabolized in liver.


Principal metabolites result from oxidation of side chain and
formation of glucuronides. A small amount of reduced
metabolites, including ring cleavage products, is formed by
gut flora (Koch et al., 1981).

Major metabolites are 1-(2 hydroxy-ethyl)-2-hydroxy methyl-5nitroimidazole which is active and which gives advantage in
terms of length of action, and the inactive 1-acetic acid-2methyl-5-nitroimadozole.

6.5 Elimination by route of exposure

Main route of elimination is by kidney but it is also


secreted in bile and breast milk. 77% is recovered from
urine and 14% from stool (Gray et al., 1961).

Urine of some patients may become reddish-brown due to some


unidentified pigment derived from this drug.

7. PHARMACOLOGY AND TOXICOLOGY

7.1 Mode of action

7.1.1 Toxicodynamics

It is basically a safe drug and has no direct


effects on mammalian cells which have aerobic
metabolism. In a few patients given very high
intravenous doses of metronidazole as an adjunct to
radiotherapy (Mahad & Wilson, 1981) epileptiform
seizures have been reported due to its direct effects
on CNS.

7.1.2 Pharmacodynamics

Metronidazole is an anti-pathogen with


selective toxicity to micro-aerophilic, anaerobic and
hypoxic/anoxic cells. Therefore its pharmacodynamic
actions are not relevant to toxicity in man.

7.2 Toxicity

7.2.1 Human data

7.2.1.1 Adults

Metronidazole has a very high


margin of safety. No lethal dose has been
described in humans as yet.

7.2.1.2 Children

Metronidazole has a very high


margin of safety. No lethal dose has been
described in humans as yet.

7.2.2 Relevant animal data

LD50 oral (rats)

1 to 5 g/kg.

LD50 oral (mice)

1 to 5 g/kg.

No serious toxicity has been reported in rats dosed


at 150 mg/kg/day, dogs at 50 to 75 mg/kg/day or
monkeys at 225 mg/kg/day (Roe, 1983).

Promotion of pulmonary tumour at a very high level in


the mouse (500 mg/kg/day), produced a statistically
significant increase in live tumours. Two lifetime
studies in hamsters were negative.

In higher doses, testicular dystrophy and


prostatiatrophy have been reported in rats and dogs
which showed ataxia, muscular atrophy and
tremors.

In long-term toxicity studies involving rats for 2


years (normal life span) high doses have been given
and the results have been conflicting. Cohen (1973)
reported no increase in tumour incidence, while
Rustia & Shubik (1972) found increased incidence of
tumours in male mice, female mice showed increased
incidence of lung tumour, but absolute incidence was
actually less than male mice controls. Female mice
also had lymphomas more often when given two higher
doses.

7.2.3 Relevant in vitro data

No data available.

7.3 Carcinogenicity

No data is available in humans. Studies in mice and


rats reported. Carcinogenic in rodents after high oral dose
(Voogel, 1981).

7.4 Teratogenicity

It crosses the placental barrier and enters fetal


circulation. Studies in rats in doses up to 5 times human
doses have not reported any harm to foetuses.

Although metronidazole has been given in all the stages of


pregnancy orally no adverse report has been received.
However, it is not recommended for use in first trimester of
pregnancy.

In nursing mothers and neonates there have not been any well
controlled studies, but because it appears in breast milk in
concentration similar to serum, it should not be used except
for amoebiasis.

7.5 Mutagenicity

Metronidazole is mutagenic in rodents in high doses for


prolonged periods. It is also mutagenic in bacteria (Voogde,
1981).

Mutagenic activity associated with metronidazole has been


reported in the urine of patients receiving therapeutic
doses.

7.6 Interactions

Metronidazole has disulfiram-like action and patients


reported abdominal distress, nausea, vomiting, flushing,
headache and abdominal distress if they drank alcohol during
treatment. Confusional and psychotic states have developed
when disulfiram and metronidazole are used together.

Intravenous "flagyl" infusion is incompatible with


cefamandole naftate, cefoxitin sodium, penicilllin potassium
(Olsen & Hebjorn, 1982), dextrose 10%, Hartmann solution,
hydrocortisone/sodium succinate.

Use of liver microsomal enzyme inducers like phenobarbitone


and phenytoin has resulted in reducing the half-life and
increasing the metabolism of metronidazole. While drugs like

cimetidine which decrease liver microsomal enzyme activity


result in prolongation of half-life and decrease plasma
clearance of metronidazole. Metronidazole is also reported to
potentiate the anticoagulant action of coumarin
anticoagulants leading to prolonged prothrombin time.

Laboratory test interactions

Metronidazole may interfere with certain types of


determination of serum chemistry values such as aspartate
aminotransferase. Alanine aminotransferase, lactic
dehydrogenase, triglycerides and hexokinase glucose. All
these involve enzymatic coupling of the assay to oxidationreduction of nicotine adenine dinucleotide (NAD+ -> - NADH).
It is due to similarity in absorbance peaks of NADH (340 nm)
and metronidazole (322 nm) at pH 7.

7.7 Main adverse effects

The two serious side effects of metronidazole are


convulsive seizure and peripheral neuropathy, characterized
by numbness and paraesthesia of the extremities.

Dizziness, vertigo, incoordination, ataxia, irritability,


depression, weakness and insomnia.

Gastrointestinal disturbances include nausea, vomiting,

anorexia, diarrhoea, epigastric distress and abdominal


cramping. Constipation has also been reported.

In the mouth a sharp metallic unpleasant taste, furry tongue,


glossitis and stomatitis have been reported with a sudden
overgrowth of candida.

Metronidazole and related chemicals have caused blood


dyscrasias, and temporary neutropenia has been reported after
metronidazole, which reverses after therapy. Rarely
thrombocytopenia.

Cardiovascular-flattening of the T waves may be seen in ECG


tracing.

Hypersensitivity - urticaria, erythematous rash, flushing,


nasal congestion, dryness of mouth, vulva and vagina and
fever.

Renal - dysuria, cystitis, polyuria, incontinence and a sense


of pelvic pressure. Instances of darkened urine are due to
unknown metabolites of metronidazole which have no clinical
significance. Other - proliferation of candida in vagina,
dyspareunia, decrease of libido, proctitis and fleeting joint
pains.

8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS

This Section (appears/will appear in future) at the end of


this PIM in the form of an appendix (Appendix 1).

9. CLINICAL EFFECTS

9.1 Acute poisoning

9.1.1 Ingestion

Single oral doses of metronidazole, up to 15


g, have been reported in suicide attempts and
accidental overdoses. Symptoms included nausea,
vomiting and ataxia.

Oral metronidazole has been studied as a radiation


sensitizer in the treatment of malignant tumours.
Neurotoxic effects including seizures and peripheral
neuropathy, have been reported after 5 to 7 days of
doses of 6 to 19.4 g every other day.

Nausea and vomiting (Siegel & Weisz, 1984; Lewis &


Kenna, 1967).

9.1.2 Inhalation

Not relevant.

9.1.3 Skin exposure

No data available (vaginal).

9.1.4 Eye contact

Not relevant.

9.1.5 Parenteral exposure

No data available.

9.1.6 Other

No data available.

9.2 Chronic poisoning

9.2.1 Ingestion

Nausea, headache, dry mouth, gastrointestinal


disturbances, rash.

Peripheral neuropathy: distal glove-stocking


hypoalgesia, hyperalgesia, paraesthesias of toes,
feet and calves (Bradley et al. 1977; Coxon & Pallis,
1976; Ramsay, 1968).

Central nervous system disturbances: disorientation,


ataxia, dysarthria, paraesthesias, grand mal seizures
(Halloran, 1982; Kusumi et al. 1980; Frytak, et al.
1978).

9.2.2 Inhalation

Not relevant.

9.2.3 Skin exposure

Not relevant.

9.2.4 Eye contact

Not relevant.

9.2.5 Parenteral exposure

No data available.

9.2.6 Other

No data available.

9.3 Course, prognosis, cause of death

Metronidazole overdoses are rarely fatal and usually do


not lead to prolonged periods of morbidity.

9.4 Systematic description of clinical effects

9.4.1 Cardiovascular

No data available.

9.4.2 Respiratory

No data available.

9.4.3 Neurological

9.4.3.1 Central nervous system (CNS)

Neurotoxic effects including


seizures have been reported after 5 to 7
days of doses of 6 to 19.4 g every other
day.

9.4.3.2 Peripheral nervous system

Neurotoxic effects including


peripheral neuropathy, have been reported
after 5 to 7 days of doses of 6 to 19.4 g
every other day.

9.4.3.3 Autonomic nervous system

No data available.

9.4.3.4 Skeletal and smooth muscle

No data available.

9.4.4 Gastrointestinal

Pseudomembranous colitis has been requently


observed (Saginur et al. 1980; Teasley et al.,
1983).

9.4.5 Hepatic

No data available.

9.4.6 Urinary

9.4.6.1 Renal

No data available.

9.4.6.2 Other

No data available.

9.4.7 Endocrine and reproductive systems

Gynaecomastia has been observed after 2 weeks


of therapy.

(Fagan et al., 1985).

9.4.8 Dermatological

No data available.

9.4.9 Eye, ear, nose, throat: local effects

No data available.

9.4.10 Haematological

Leucopenia has been reported.

9.4.11 Immunological

No data available.

9.4.12 Metabolic

9.4.12.1 Acid-base disturbances

No data available.

9.4.12.2 Fluid and electrolyte disturbances

No data available.

9.4.12.3 Others

No data available.

9.4.13 Allergic reactions

No data available.

9.4.14 Other clinical effects

No data available.

9.4.15 Special risks

No data available.

9.5 Other

No data available.

9.6 Summary

No data available.

10. MANAGEMENT

10.1 General principles

There is no specific antidote for metronidazole


poisoning. Therefore management of the patient should consist
of symptomatic and supportive therapy.

10.2 Relevant laboratory analyses

10.2.1 Sample collection

No data available.

10.2.2 Biomedical analysis

Blood counts to monitor leucopenia. Hepatic


function tests are important because in hepatic
disease the metabolism of metronidazole is delayed.
It should, however, be taken into account that
metronidazole may interfere with transaminase
determination, leading to falsely decreased serum
values.
(Rissing et al., 1978)

10.2.3 Toxicological analysis

10.2.4 Other investigations

10.3 Life supportive procedures and symptomatic/specific


treatment

Assess airway, breathing and circulation. Provide


symptomatic treatment. Diazepam is indicated for
seizures.

10.4 Decontamination

In the fully conscious patient, consider emesis or


gastric lavage if patient seen within 1 or 2 hours after
ingestion. Activated charcoal should be given afterwards. The
use of a cathartic is no longer recommended.

10.5 Elimination

Haemodialysis may theoretically have some value because


of the moderate volume of distribution and low protein
binding. However, no data is available.

10.6 Antidote treatment

10.6.1 Adults

There is no specific antidote for


metronidazole overdose. Therefore management of the
patient should consist of symptomatic and supportive
therapy.

10.6.2 Children

There is no specific antidote for


metronidazole overdose. Therefore management of the
patient should consist of symptomatic and supportive
therapy.

10.7 Management discussion

Not required.

11. ILLUSTRATIVE CASES

11.1 Case reports from literature

No data available.

11.2 Internally extracted data on cases

No data available.

11.3 Internal cases

No data available.

12. ADDITIONAL INFORMATION

12.1 Availability of antidotes

No data available.

12.2 Specific preventive measures

No data available.

12.3 Other

No data available.