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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.
 
 
 
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    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:
       Toxicological Abbreviations
       METRONIDAZOLE (JECFA Evaluation)
       Metronidazole  (IARC Summary & Evaluation, Supplement7, 1987)
       Metronidazole  (IARC Summary & Evaluation, Volume 13, 1977)