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Metronidazole

1. NAME
   1.1 Substance
   1.2 Group
   1.3 Synonyms
   1.4 Identification numbers
      1.4.1 CAS number
      1.4.2 Other numbers
   1.5 Brand names, Trade names
   1.6 Manufacturers, Importers
   1.7 Presentation, Formulation
2. SUMMARY
   2.1 Main risks and target organs
   2.2 Summary of clinical effects
   2.3 Diagnosis
   2.4 First aid measures and management principles
3. PHYSICO-CHEMICAL PROPERTIES
   3.1 Origin of the substance
   3.2 Chemical structure
   3.3 Physical properties
      3.3.1 Properties of the substance
         3.3.1.1 Colour
         3.3.1.2 State/Form
         3.3.1.3 Description
      3.3.1 Properties of the locally available formulation(s)
   3.4 Other characteristics
      3.4.1 Shelf-life of the substance
      3.4.2 Shelf-life of locally available formulation(s)
      3.4.3 Storage conditions
      3.4.4 Bioavailability
      3.4.5 Specific properties and composition
4. USES
   4.1 Indications
      4.1.1 Indications
      4.1.2 Description
   4.2 Therapeutic dosage
      4.2.1 Adults
      4.2.2 Children
   4.3 Contraindications
5. ROUTES OF ENTRY
   5.1 Oral
   5.2 Inhalation
   5.3 Dermal
   5.4 Eye
   5.5 Parenteral
   5.6 Other
6. KINETICS
   6.1 Absorption by route of exposure
   6.2 Distribution by route of exposure
   6.3 Biological half-life by route of exposure
   6.4 Metabolism
   6.5 Elimination by route of exposure
7. PHARMACOLOGY AND TOXICOLOGY
   7.1 Mode of action
      7.1.1 Toxicodynamics
      7.1.2 Pharmacodynamics
   7.2 Toxicity
      7.2.1 Human data
         7.2.1.1 Adults
         7.2.1.2 Children
      7.2.2 Relevant animal data
      7.2.3 Relevant in vitro data
   7.3 Carcinogenicity
   7.4 Teratogenicity
   7.5 Mutagenicity
   7.6 Interactions
   7.7 Main adverse effects
8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS
9. CLINICAL EFFECTS
   9.1 Acute poisoning
      9.1.1 Ingestion
      9.1.2 Inhalation
      9.1.3 Skin exposure
      9.1.4 Eye contact
      9.1.5 Parenteral exposure
      9.1.6 Other
   9.2 Chronic poisoning
      9.2.1 Ingestion
      9.2.2 Inhalation
      9.2.3 Skin exposure
      9.2.4 Eye contact
      9.2.5 Parenteral exposure
      9.2.6 Other
   9.3 Course, prognosis, cause of death
   9.4 Systematic description of clinical effects
      9.4.1 Cardiovascular
      9.4.2 Respiratory
      9.4.3 Neurological
         9.4.3.1 Central nervous system (CNS)
         9.4.3.2 Peripheral nervous system
         9.4.3.3 Autonomic nervous system
         9.4.3.4 Skeletal and smooth muscle
      9.4.4 Gastrointestinal
      9.4.5 Hepatic
      9.4.6 Urinary
         9.4.6.1 Renal
         9.4.6.2 Other
      9.4.7 Endocrine and reproductive systems
      9.4.8 Dermatological
      9.4.9 Eye, ear, nose, throat: local effects
      9.4.10 Haematological
      9.4.11 Immunological
      9.4.12 Metabolic
         9.4.12.1 Acid-base disturbances
         9.4.12.2 Fluid and electrolyte disturbances
         9.4.12.3 Others
      9.4.13 Allergic reactions
      9.4.14 Other clinical effects
      9.4.15 Special risks
   9.5 Other
   9.6 Summary
10. MANAGEMENT
   10.1 General principles
   10.2 Relevant laboratory analyses
      10.2.1 Sample collection
      10.2.2 Biomedical analysis
      10.2.3 Toxicological analysis
      10.2.4 Other investigations
   10.3 Life supportive procedures and symptomatic/specific treatment
   10.4 Decontamination
   10.5 Elimination
   10.6 Antidote treatment
      10.6.1 Adults
      10.6.2 Children
   10.7 Management discussion
11. ILLUSTRATIVE CASES
   11.1 Case reports from literature
   11.2 Internally extracted data on cases
   11.3 Internal cases
12. ADDITIONAL INFORMATION
   12.1 Availability of antidotes
   12.2 Specific preventive measures
   12.3 Other
13. REFERENCES
14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES)







    1.  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         Debretol, Nalox, Tranoxa, Tricofin

             Australia         Trichozole

             Canada            Neo-Tric, Novonidazol, Trikacide

             Denmark           Elyzol, Trichomal

 

 

 

             Germany           Clont, Fossyol, Krencosan, Rathimed N, 

                               Sanatrichom, Trichos Cordes, Tricho- 

                               Gynaedron 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            180%

             Gall bladder bile            135%

             CSF                          120%

             Abdominal muscles            110%

             Fallopian tube               100%

             Uterus                       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-5- 

             nitroimidazole which is active and which gives advantage in 

             terms of length of action, and the inactive 1-acetic acid-2- 

             methyl-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 oxidation- 

             reduction 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.

 

 

 

    13. REFERENCES

 

        Adam et al. (1980) J Natl Cancer Int, 64: 555-560.

        

        Bergan T & Fotland MH (1984) In vitro interactions between 

        metronidazole or tinidazole and ampicillin, doxycycline and co- 

        trimoxazole on the effect against anaerobic bacteria. Scand J 

        Gastreoenterol, 91: 95-101.

        

        Bergan T, Leinebo O, Blom-Hagen T, & Salvesen B (1984) 

        Pharmacokinetics of metronidazole and its major metabolite after a 

        high intravenous dose. Scand J Gastroenterol, 91: 45-60.

        

        Bisaillan S & Sarazin R (1983) J Parenter Sci Techn 37(4): 12.

        

        Bradley WG, Karlsson IJ & Rassol CG (1977) Metronidazple 

        neuropathy. Br Med J 2(6087): 610-611.

        

        Budavari S ed. (1989) The Merck index, an encyclopedia of 

        chemicals, drugs, and biologicals, 11th ed. Rahway, New Jersey, 

        Merck and Co., Inc.  p 968.

        

        Cohen SM, Erturk E, Von Esch AM, Crovetti AJ, & Bryan GT (1973) 

        Carcinogenicity of 5-nitrofurans, 5-nitroimidazoles, 4- 

        nitrobenzenes, and related compounds. J Natl Cancer Inst. 

         51(2): 403-417.

        

        Coxon & Pallis (1976) Metronidazole neuropathy. J Neurol Neurosurg 

        Psychiatry, 39(4): 403-405.

        

        Edwards (1980) Br J Venr Dis 46: 285-290.

        

        Edwards et al. (1982) Int J Radiat Oncol Birt Phys, 

        8: 791-793.

        

        Fagan TC, Johnson DG, & Grosso DS (1985) Metronidazole-induced 

        gynecomastia. Jama, 254(22):3217.

        

        Frytak S, Moertel CG, & Childs DS (1978) Neurologic toxicity 

        associated with high dose metronidazole therapy. Ann Intern Med, 

        88(3): 361-362.

        

        Gray MS et al. (1961) Brit J Ven Dis, 37: 278.

        

        Gulaid A, Houghton GW, Lewellen OR, Smith J, & Thorne PS  (1978) 

        Determination of metronidazole and its major metabolites in body 

        fluid by HPLC. Br J Clin Pharmacol, 6(5): 430-432.

        

        Gupte S (1983) Phenobarbital and metabolism of metronidazole. N 

        Engl J Med, 308: 529.

        

 

 

 

        Halloran TJ (1982) Convulsions associated with high cumulative 

        doses of metronidazole. Drug Intell Clin Pharmacol, 16: 409.

        

        Houghton GW, Thorene PS, Smith J, Templeton R, Collier J, 

        MosegaardT & Lykkegaard-Nielsen M (1979) Metronidazole, Royal 

        Society of Med Inter Congress & Symposium series No. 16, Academic 

        Press and the Royal Society of Medicine, p-35.

        

        Jensen JC & Gugler R (1983) Single- and multiple-dose 

        metronidazole kinetics. Clin Pharmacol Ther 34(4): 481-487.

        

        Kay CM, Sankey MG, & Thomas LA (1980) A rapid and sensitive 

        specific semi-micro method involving high-pressure liquid 

        chromatography for the assay of metronidazole in plasma, saliva, 

        serum, urine and whole blood. Br J Clin Pharmacol 9: 528-529.

        

        Koch et al. (1981) Science, 211: 398-400.

        

        Kusumi RK, Plowffe JF, & Wyatt RH (1980) Central nervous system 

        toxicity associated with metronidazole Teheran. Ann Int Med, 

        93: 59-60.

        

        Lewis BV & Kenna AP (1967) Attempted suicide with flagyl. J Obstet 

        Gynec Br Commun, 72: 806-807.

        

        Loft S, Dossing M, Paulsen HE, Sonne J, Olesen KJ, Simonsen K, & 

        Andreasen PB (1986) Influence of dose and route of administration 

        on distribution of metronidazole and its major metabolites.  Eur J 

        Clin Pharmacol, 30: 469-473.

        

        Mahad JS & Wilson RL (1981) Toxicology Letters, 8: 359.

        

        McEvoy GK ed. (1995) American hospital formulary service, drug 

        information. Bethesda, American Society of Hospital Pharmacists, 

        pp 569-571.

        

        McGilveray IJ, Midha KK, Loo JC & Cooper JK (1978) The 

        bioavailability of commercial metronidazole formulations. Int J 

        Clin Pharmacol Biopharm, 16(3): 110-115.

        

        Olsen PR & Hebjorn M (1982) Arch Pharm Chem Sci, Ed. 10-69.

        

        PSM-II.  Professed reference dilut proc for ant sus testing of 

        Anaert bectria. National Committee for Clinical Lab stated 

        USA.

        

        Ralph ED & Kirby WM (1975) Bioassay of metronidazole with either 

        anaerobic or aerobic. J Infect Dis 132(5): 587-591.

        

        Ralph ED (1983) Clinical pharmacokinetics of metronidazole. Clin 

        Pharmacokinet, 8(1): 43-62.

        

 

 

 

        Ramsay ID (1968) Endocrine ophthalmopathy. Br Med J, 2: 706.

        

        Reynolds JEF ed. (1982) Martindale, the extra pharmacopoeia, 28th 

        ed. London, The Pharmaceutical Press, pp 968-973.

        

        Reynolds JEF ed. (1993) Martindale, the extra pharmacopoeia, 30th 

        ed. London, The Pharmaceutical Press, pp 516-521.

        

        Rissing JP, Newman C, & Moore WL (1978) Artificial depression of 

        serum glutamic oxaloacetic transaminase by metronidazole. 

        Antimicrob Agents Chemother, 14: 636-638.

        

        Roe F (1983) Toxicologic evaluation of metronidazole with 

        particular reference to carcinogenic, mutagenic and teratogenic 

        potential.  Surgery, 93: 158-164.

        

        La Russo et al. (1977) Mol Pharmacology, 13: 872-882.

        

        Rustia M & Shubik P (1972) Induction of lung tumors and malignant 

        lymphomas in mice by metronidazole. J Natl Cancer Inst, 48(3): 

        721-729.

        

        Saginur R, Hawley CR, & Bartlett JG (1980) Colitis associated with 

        metronidazole therapy. J Infect Dis, 141: 772-774.

        

        Satter et al. (Oct 1979) Collaboration evaluation of a proposed 

        reff. dilution method of susceptibility testing of Anae. bectria. 

        Ant Agents Chemothe, 16: 495-502.

        

        Schwartz OE & Jeunet F (1976) Comparative pharmacokinetic studies 

        of ornidazole and metronidazole in man. Chemotherapy, 

        22(1): 19.

        

        Shinn DLS (1962) Lancet, 1: 1191.

        

        Siegel JA & Weisz S (1984) The analysis of metronidazole in human 

        serum. An unusual overdose case. J Forensic Sci, 29: 639-643.

        

        Tally FP, Jacobus NV, & Gorbach SL (1978)  In vitro activity of 

        thienamycin. Antimicrob Agents Chemother, 14(3): 436-438.

        

        Teasley DG, Olson MM, & Gebhard RL et al. (1983) Prospective 

        randomised trial of metronidazole versus vancomycin for 

        clostridium difficile associated diarrhoea and colitis. Lancet, 

        2: 1043-1046.

        

        USP XXI (1985) The United States Pharmacopeia Ed. 28, Reckville, 

        United States Pharmacopeial Convention, Inc.

        

        Voogde CE (1981) On the mutagenicity of nitroimidazole. Mutat Res, 

        86: 243-277.

        

 

 

 

        WHO (1992) International nonproprietary names (INN) for 

        pharmaceutical substances. Geneva, World Health Organisation, 

        p 338.

        

        WHO (1992) Anatomical Therapeutic Chemical (ATC) classification 

        index. Oslo, WHO Collaborating Centre for Drug Statistics 

        Methodology, p 88.

 

    14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE 

        ADDRESS(ES)

 

        Authors      A. van Dyk

                     Hospital Pharmacist

                     Utrecht

                     Netherlands

        

                     Dr A.N.P. van Heijst

                     Bosch en Duin

                     Netherlands

        

                     Tel: 31-30-287178

        

        Date         16 February 1990

        

        Peer Review  Cardiff, United Kingdom, February 1994 (Group 

                     members: Dr R. Fernando, Dr K. Hartigan-Go, Dr G. 

                     Heinemeyer, Dr N. Maramba, Dr E. Wickstrom)

    









See Also:

        Metronidazole (IARC Summary & Evaluation, Supplement 7, 1987)

        Metronidazole (IARC Summary & Evaluation, Volume 13, 1977)

METRONIDAZOLE

(Group 2B)

For definition of Groups, see Preamble Evaluation.

Supplement 7: (1987) (p. 250)

CAS No.: 443-48-1

Chem. Abstr. Name: 2-Methyl-5-nitro-1H-imidazole-1-ethanol

A. Evidence for carcinogenicity to humans (inadequate)

Two epidemiological studies [ref: 1,2] of women treated with metronidazole showed some excesses of cancers of the uterine cervix, a neoplasm that has risk factors in common with vaginal trichomoniasis, the main indication in women for treatment with this drug. In one study [ref: 1], a greater excess of cervical cancer was observed in women with trichomoniasis who were not exposed to metronidazole than in those who were (relative risk, 2.1 versus 1.7). An excess of lung cancer (4 observed, 0.6 expected) seen in one of these studies [ref: 1] was not found in the other (2 observed, 2.6 expected) [ref: 3]. In the former, the excess was mainly of adenocarcinoma (3/4 cases) and was concentrated after at least ten years from first use of metronidazole (3 observed, 0.3 expected) [ref: 4]. Further follow-up and analysis of these data have suggested that the excess could be explained entirely by confounding with smoking [ref: 5]. Another study in which 12 280 users of metronidazole were followed up for two and one-half years gave a relative risk of 0.89 (95% confidence interval, 0.45-1.9) for all cancers [ref: 6].

B. Evidence for carcinogenicity to animals (sufficient)

Metronidazole has been tested for carcinogenicity by oral administration in mice and rats. It significantly increased the incidences of lung tumours in mice of each sex, of lymphomas in female mice [ref: 7,8] and of mammary, pituitary, testicular and liver tumours in rats [ref: 7,9,10]. It increased the incidence of colonic tumours induced in rats by subcutaneous administration of 1,2-dimethylhydrazine [ref: 11,12].

C. Other relevant data

Studies on bone-marrow cells and lymphocytes from a series of patients treated with metronidazole showed no increase in the incidence of chromosomal damage. Metronidazole was active in body fluid assays using sweat, faeces and urine from humans exposed in vivo and urine from rodents exposed in vivo [ref: 13].

Metronidazole did not induce micronuclei in bone-marrow cells of mice or rats, sister chromatid exchanges in bone-marrow cells of Chinese hamsters or unscheduled DNA synthesis in germ cells of male rabbits treated in vivo. Human cells exposed to metronidazole in vitro did not show increased incidences of chromosomal aberrations, whereas results with respect to sister chromatid exchanges were inconclusive. Metronidazole did not induce sister chromatid exchanges in cultured hamster cells; conflicting results were reported for the induction of mutation and DNA damage in rodent cells in vitro. It did not induce sex-linked recessive lethal mutations in Drosophila or recombination in yeast. It induced mutation in fungi and bacteria and induced prophage in bacteria [ref: 13].

Overall evaluation

Metronidazole is possibly carcinogenic to humans (Group 2B).

For definition of the italicized terms, see Preamble Evaluation.

Also see previous evaluation: Vol. 13 (1977)

References

  1. Beard, C.M., Noller, K.L., O'Fallon, W.M., Kurland, L.T. & Dockerty, M.B. (1979) Lack of evidence for cancer due to use of metronidazole. New Engl. J. Med., 301, 519-522
  1. Friedman, G.D. & Ury, H.K. (1980) Initial screening for carcinogenicity of commonly used drugs. J. natl Cancer Inst., 65, 723-733
  1. Friedman, G.D. (1980) Cancer after metronidazole. New Engl. J. Med., 302, 519
  1. Beard, C.M. (1980) Cancer after metronidazole. New Engl. J. Med., 302, 520
  1. Beard, C., Noller, K. & O'Fallon, W.M. (1985) Metronidazole and subsequent malignant neoplasms (Abstract). Am. J. Epidemiol., 122, 529
  1. Danielson, D.A., Hannan, M.T. & Jick, H. (1982) Metronidazole and cancer. J. Am. med. Assoc., 247, 2498-2499
  1. IARC Monographs, 13, 113-122, 1977
  1. Cavaliere, A., Bacci, M., Amorosi, A., Del Gaudio, M. & Vitali, R. (1983) Induction of lung tumors and lymphomas in BALB/c mice by metronidazole. Tumori, 69, 379-382
  1. Rustia, M. & Shubik, P. (1979) Experimental induction of hepatomas, mammary tumors, and other tumors with metronidazole in noninbred Sas:MRC(WI)BR rats. J. natl Cancer Inst., 63, 863-868
  1. Cavaliere, A., Bacci, M. & Vitali, R. (1984) Induction of mammary tumors with metronidazole in female Sprague-Dawley rats. Tumori, 70, 307-311
  1. Sloan, D.A., Fleiszer, D.M., Richards, G.K., Murray, D. & Brown, R.A. (1983) Increased incidence of experimental colon cancer associated with long-term metronidazole therapy. Am. J. Surg., 145, 66-70
  1. A-Kareem, A.M., Fleiszer, D.M., Richards, G.K., Senterman, M.K. & Brown, R.A. (1984) Effect of long-term metronidazole (MTZ) therapy on experimental colon cancer in rats. J. surg. Res., 36, 547-552
  1. IARC Monographs, Suppl. 6, 399-402, 1987

Synonyms

    Acromona

    Anagiardil

    Atrivyl

    Bayer 5360

    Bexon

    Clont

    Cont

    Danizol

    Deflamon-wirkstoff

    Efloran

    Elyzol

    Entizol

    1-(b-Ethylol)-2-methyl-5-nitro-3-azapyrrole

    Eumin

    Flagemona

    Flagesol

    Flagil

    Flagyl

    Flegyl

    Giatricol

    Gineflavir

    1-Hydroxyethyl-2-methyl-5-nitroimidazole

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

    1-(b-Hydroxyethyl)-2-methyl-5-nitroimidazole

    Klion

    Maxibol silanes

    Meronidal

    2-Methyl-5-nitro-1-imidazoleethanol

    2-Methyl-5-nitroimidazole-1-ethanol

    Metronidaz

    Metronidazol

    Monagyl

    Nalox

    Neo-Tric

    Nida

    Novonidazol

    Orvagil

    RP 8823

    Sanatrichom

    SC 10295

    Takimetol

    Trichazol

    Trichex

    Trichocide

    Trichomol

    Trichomonacid pharmachim

    Trichopal

    Trichopol

    Tricocet

    Tricom

    Tricowas B

    Trikacide

    Trikamon

    Trikojol

    Trikozol

    Trimeks

    Trivazol

    Vagilen

    Vagimid

    Vertisal 

Last updated: 3 March 1998

See Also:

        Metronidazole (IARC Summary & Evaluation, Volume 13, 1977)

        Metronidazole (PIM 347)




METRONIDAZOLE

VOL.: 13 (1977) (p. 113)

  1. Summary of Data Reported and Evaluation

5.1 Animal data

Metronidazole is carcinogenic in mice after its oral administration: it significantly increased the incidence of lung tumours in both sexes and the incidence of lymphomas in females. Its oral administration to rats increased the incidence and multiplicity of mammary fibroadenomas.

5.2 Human data

No case reports or epidemiological studies were available to the Working Group.

Subsequent evaluation: Suppl. 7 (1987)

Last updated: 25 March 1998

See Also:

        Metronidazole (IARC Summary & Evaluation, Supplement 7, 1987)

        Metronidazole (PIM 347)