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Miconazole

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
      3.3.2 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 the 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 dosages
      4.2.1 Adult
      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
         7.1.2.2 Children
      7.2.2 Relevant animal date
      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 AND BIOMEDICAL INVESTIGATIONS
   8.1 Sample
      8.1.1 Collection
      8.1.2 Storage
      8.1.3 Transport
   8.2 Toxicological/toxicological analytical methods
      8.2.1 Test for active ingredient
      8.2.2 Test for biological sample
   8.3 Other laboratory analyses
      8.3.1 Haematological investigations
      8.3.2 Biochemical investigations
         8.3.2.1 Blood
         8.3.2.2 Urine
      8.3.3 Arterial blood gas analysis
      8.3.4 Other relevant biomedical analyses
   8.4 Interpretation
   8.5 References
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 Others
      9.4.7 Endocrine and reproductive systems
      9.4.8 Dermatological
      9.4.9 Eye, ears, 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

           Miconazole (INN)

           (WHO, 1992)

       1.2 Group

           ATC classification index 

           Antimycotics for systemic use (J02)/Imidazole derivatives 
           (J02AB). 

           (WHO, 1992)

       1.3 Synonyms

           R-18134

       1.4 Identification numbers

           1.4.1 CAS number

                 Miconazole  22916-47-8
                
                 Miconazole  22832-87-7
                 nitrate

           1.4.2 Other numbers

                 RTECS

                 N14770000

       1.5 Brand names, Trade names

           Daktarin (Arg, Austral, Belg, Fr, Ital, Neth, S.Afr, Spain, 
           Switz, U.K.); Dakcort (U.K.) Albistat (Belg, Neth), Andergin 
           (Ital); Brentan (Denm.); Daktar (Ger, Norw, Swed.); Deralbine 
           (Arg.); Dermonistat (U.K.), Epi-Monistat (Ger); Funginazol 
           (Spain); Fungisidin (Spain); Gyno-Daktar (Ger.); Gyno-
           Daktarin (Arg., Austral., Belg., Fr., Neth., S.Afri., U.K.); 
           Gyno-Monistat (Ger.); Micatin (Canad., USA); Micoderm, 
           (Ital.); Miconal, Micotef (Ital.); Monistat (Austral., 
           Canad., Switz., U.K., USA); Monistat-Derm (USA, Austral.). 

           (To be completed by each Centre using local data) 

       1.6 Manufacturers, Importers 

           Janssen (Daktacort, Daktarin, Brentan, Daktar, Gyno-Daktar, 
           Gyno-Daktarin, Monistat); ISOW (Andergin); Esteve (for 
           Daktarin in Spain); Ortho-Cilag (Dermonistat); Cilag (Epi-

           Monistat, Gyno-Monistat, Monistat, Monistat-Derm); Alcon 
           (Funginazol); Isdin (Fungisidin); McNeil (Micatin); Logifarm 
           (Micoderm); Ecobi (Miconal); LPB (Micotef); Ortho-
           Pharmaceutical (Micatin in USA, Monistat in USA); Johnson & 
           Johnson (Gyno-Daktar in S.Afr.); Ortho-Dermatological 
           (Monistat-Derm in USA). 

           (To be completed by each Centre using local data) 

       1.7 Presentation, Formulation 

           Daktacort (Janssen, UK): cream with miconazole nitrate 2%, 
           hydrocortisone 1%. 
           
           Daktarin (Janssen, UK) tablets containing miconazole 250 mg; 
           oral gel containing miconazole 125 mg/mL; concentrate for 
           intravenous infusion, miconazole 10 mg/mL, in a vehicle 
           containing Cremophor EL 10%, in ampoules of 20 mL; cream, 
           miconazole nitrate 2%; dusting-powder, miconazole nitrate 2%; 
           twin pack, combination pack, miconazole nitrate 2% cream and 
           miconazole nitrate 2% topical powder; topical powder spray, 
           aerosol, miconazole nitrate 2%. 
     
           Dermonistat (Ortho-Cilag, UK) ovules, vaginal capsules, 
           miconazole nitrate 1,2 g; pessaries, miconazole nitrate 100 
           mg; marginal cream, miconazole nitrate 2%; combipack, 
           miconazole nitrate 100 mg pessaries and miconazole nitrate 
           2%, cream; tampons, coated with miconazole nitrate 100 mg. 

           Monistat (Ortho-Cilag, UK) pessaries, miconazole nitrate 100 
           mg; vaginal cream, miconazole nitrate 2%. 

           (To be completed by each Centre using local data) 
         
    2. SUMMARY 

       2.1 Main risks and target organs 

           Acute poisonings with miconazole have not been reported. The 
           following adverse reactions have been described: 

           Cardiac arrhythmias (intravenous administration).
           Haematological alterations
           Gastrointestinal disturbances
           Local irritation and sensitivity reactions.

       2.2 Summary of clinical effects

           Cardiac 

           Tachycardia and arrhythmias after intravenous doses.  

           Haematological

           Aggregation of erythrocytes, anaemia, thrombocytopenia,
           thrombocytosis.

           Gastrointestinal

           Anorexia, nausea, vomiting, diarrhoea.

           Local reactions

           Irritation 

           Sensitivity (allergic) reactions

           Vulvovaginal burning, itching or irritation pelvic cramps, 
           rash, cutaneous pruritus, flushes. 

           Other

           Hyperlipidaemia, drowsiness, febrile reactions, 
           hyponatraemia, acute psychosis, arthralgia, anaphylaxis, 
           irritation of the meninges (by intrathecal injection). 

       2.3 Diagnosis

           Clinical diagnosis is difficult because of the wide range of 
           signs and symptoms of toxicity. 

       2.4 First aid measures and management principles 

           In case of oral overdosage the common measures to limit the 
           absorption of the drug from gastrointestinal tract, such as 
           emesis, gastric lavage or administration of activated 
           charcoal, should be performed, if patient seen early after 
           ingestion. 

           Symptomatic and supportive care is the basis for management. 

    3. PHYSICO-CHEMICAL PROPERTIES 

       3.1 Origin of the substance 

           Miconazole is a synthetic antifungal agent belonging to the 
           imidazole group. 

       3.2 Chemical structure 

           Structural formula 
           
           Molecular formula

           Miconazole        C18H14Cl4N20 

           Miconazole        C18H14Cl4N2C.HNO3 
           nitrate

           Molecular weight

           Miconazole        416.12
                    
           Miconazole        479.15  
           nitrate
           
           Structural Chemical names

           1-[2,4-Dichloro-beta-(2,4-
           dichlorobenzyloxy)phenylethyl]imidazole. 

           1-[2-(2,4-Dichlorophenyl)-2-[(2,4-
           dichlorophenyl)methoxy]ethyl]-1H-imidazole. 

           1-[2,4-Dichloro-beta-[(2,4-dichlorobenzyl) 
           oxy]phenylethyl]imidazole. 

           (Reynolds, 1993; Budavari, 1989)
           
       3.3 Physical properties

           3.3.1 Properties of the substance

                 3.3.1.1 Colour

                         White to pale cream

                 3.3.1.2 State/Form

                         Crystalline or microcrystalline powder.

                 3.3.1.3 Description

                         Odourless or almost odourless.

                         Practically insoluble in water; freely soluble 
                         in acetone. Solubilities are as follows: 

                         1 in 9.5 of alcohol, 1 in 2 of chloroform, 1 in 
                         15 of ether, 1 in 4 of isopropyl alcohol, 1 in 
                         5.3 of methyl alcohol, and 1 in 9 of propylene 
                         glycol. 

                         Melting point 170.5 °C

                         (Reynolds, 1993; Budavari, 1989) 

           3.3.2 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 

                 At least five years. 

           3.4.2 Shelf-life of the locally available formulation(s) 

                 To be completed by each Centre using local data. 

           3.4.3 Storage conditions 

                 Protect from light.  Store in well-closed containers. 

           3.4.4 Bioavailability 

                 To be completed by each Centre using local data. 

           3.4.5 Specific properties and composition 

                 To be completed by each Centre using local data. 

    4. USES 

       4.1 Indications 

           4.1.1 Indications 

                 Miconazole is an antifungal agent with similar 
                 antimicrobial activity to ketoconazole.  It is 
                 administered by intravenous infusion in the treatment 
                 of severe systemic fungal infections including 
                 candidiasis, coccidioidomycosis, cryptococcosis, 
                 paracoccidioidomycosis, and infections due to 
                 Pseudeliescheria boydii.  

                 Miconozole may be given by mouth for the treatment of 
                 oral and intestinal candidiasis.  

                 It has been given prophylactically to patients at high 
                 risk of opportunistic fungal infections.  

                 In fungal meningitis, intravenous treatment may be 
                 supplemented with intrathecal infections of miconazole.  
                 Miconazole nitrate is used locally. 

                 (Reynolds, 1989; Physician's Desk Reference, 1989) 

           4.1.2 Description 

                 Not relevant. 

       4.2 Therapeutic dosages 

           4.2.1 Adult 

                 Oral 

                 Oral and intestinal candidiasis 

                 125 to 250 mg as tablets or gel four times daily.

                 Parenteral

                  Systemic fungal infections

                 Intravenous doses of miconazole range from 0.2 to 1.2 g 
                 three times daily.  Each dose must be diluted in at 
                 least 200 mL of sodium chloride 0.9% or glucose 5% and 
                 infused slowly over 30 to 60 minutes. 
     
                 In fungal meningitis, intravenous treatment may be 
                 supplemented by a single daily dose of 20 mg given by 
                 intrathecal injection every 3 to 7 days. 

                 Skin
                 
                 Applied once or twice a day as a 2% cream, lotion or 
                 powder. 

                 Vaginal

                 5 to 10 g of a 2% cream once daily for 7 to 14 days or 
                 tampons containing 100 mg twice a day for 5 days. 

                 (Reynolds, 1993)

           4.2.2 Children

                 Oral

                 Oral and intestinal candidiasis

                 Over 6 years   125 mg four times daily
                 2 to 6 years   125 mg twice daily
                 Under 2 years  62.5 mg twice daily. 

                 Parenteral

                  Systemic fungal infections

                 20 to 40 mg/kg body-weight daily (intravenously) but 
                 not more than 15 mg/kg of miconazole should be given at 
                 each infusion.  
                
                 (Reynolds, 1993) 

       4.3 Contraindications

           Miconazole should not be used in patients known to be 
           hypersensitive to this drug.  

           Since imidazoles are absorbed in small amounts from the human 
           vagina, miconazole should not be used in the first trimester 
           of pregnancy unless the physician considers it essential to 
           the welfare of the patient. 

    5. ROUTES OF ENTRY

       5.1 Oral

           For the treatment of oral and intestinal candidiasis.

       5.2 Inhalation

           Not relevant

       5.3 Dermal

           For treatment of fungal infections of the skin and nails.

       5.4 Eye 

           Solutions of miconazole have been used for topical 
           application into the eye. 

       5.5 Parenteral

           Miconazole is administered by intravenous infusion in the 
           treatment of severe systemic fungal infections. 

       5.6 Other

           Miconazole nitrate is available in different formulations for 
           the treatment of vaginal candidiasis (intra-vaginal route). 
           An intravenous solution has been used for instillation in the 
           bladder, trachea and wounds. 

           (Reynolds, 1989; Dictionnaire Vidal, 1987; Physician's Desk 
           Reference, 1989). 

    6. KINETICS
            
       6.1 Absorption by route of exposure

           Oral

           After oral administration, miconozole is incompletely 
           absorbed from the gastrointestinal tract; peak plasma 
           concentrations of about 1 mcg/mL have been achieved 4 hours 
           after a dose of 1 g (Reynolds, 1989).  

           Parenteral

           By intravenous infusion, doses above 9 mg/kg body-weight 
           usually produce plasma concentrations above l mcg per mL 
           (Reynolds, 1989, Physician's Desk Reference). 

           Topical

           There is little absorption through skin or mucous membranes 
           when miconazole nitrate is applied topically (Reynolds, 
           1989). 

           Following intravaginal administration of miconazole nitrate, 
           small amounts are absorbed (Briggs et al., 1986).  

           Administration of a single dose of miconazole nitrate 
           suppositories (100 mg) to healthy subjects resulted in a 
           total recovery from the urine and faeces of 0.85% (+0.43%) of 
           the administered dose (Physician's Desk Reference, 1989). 

       6.2 Distribution by route of exposure 

           Data available indicates that over 90% of miconazole is bound 
           to plasma proteins.  Penetration into the cerebrospinal fluid 
           and sputum is poor but miconazole diffuses well into infected 
           joints (Reynolds, 1993).  Animal studies indicate that the 
           drug crossed the placenta (Physician's Desk Reference) but it 
           is unknown whether miconazole nitrate is excreted in breast 
           milk. 

       6.3 Biological half-life by route of exposure 

           Oral 

           The information available indicates that miconazole orally 
           administered has a half-life of about 24 hours. 

           Parenteral 

           The decrease of plasma concentrations after an intravenous 
           perfusion is biphasic, with half-life of 30 minutes (t 1/2a) 
           and 24 hours (t 1/2b). 

       6.4 Metabolism

           Miconazole is metabolised in the liver to inactive 
           metabolites.  Miconazole has an important first pass effect. 
           Hepatic metabolism of miconazole is by O-dealkylation and 
           oxidative N-dealkylation. 

       6.5 Elimination by route of exposure

           Oral

           Approximately 50% of an oral dose may be excreted mainly 

           unchanged in the faeces. 

           From 10 to 20% of an oral dose is excreted in the urine, 
           mainly as metabolites, within 6 days. 

           (Reynolds, 1989). 

           Parenteral 

           From 10 to 20% of an intravenous dose is excreted in the 
           urine, mainly as metabolites, within 6 days; 

           After an intravenous dose of miconozole, 40% of the 
           radioactivity is found in faeces and 18% in urine. 

           About 14 to 22% of the dose is excreted via the kidneys, 
           mainly as inactive metabolites (Physician's Desk Reference, 
           1989). 

    7. PHARMACOLOGY AND TOXICOLOGY 

       7.1 Mode of action

           7.1.1 Toxicodynamics

                 Since composition of fungal and mammalian cells 
                 membrane is different, miconazole does not affect the 
                 human cells. Many adverse effects have been associated 
                 with the injection vehicle which contains Cremophor EL 
                 (Reynolds, 1989). 

           7.1.2 Pharmacodynamics

                 The pharmacological mode of action of miconazole is 
                 unknown. (Physician's Desk Reference, 1989). In-vitro 
                 studies suggest that imidazoles impair the synthesis of 
                 ergosterol, which is a vital component of the fungi 
                 cell membranes.  In-vitro miconazole inhibited the 
                 ability of neutrophils to reach the site of infection 
                 promptly (chemotaxis) and it demonstrates marked 
                 immunosuppressive properties.   The clinical 
                 significance of these data is unknown.  
                
       7.2 Toxicity

           7.2.1 Human data

                 7.2.1.1 Adults

                         Information about toxic doses not available for 
                         humans.  Some symptoms of toxicity after a 
                         therapeutic doses with miconazole  are 
                         described in Section 9. 

                 7.1.2.2 Children

                         No data available.

           7.2.2 Relevant animal date

                 LD50 oral (mice)         578.1 mg/kg

                 LD50 oral (rats)         >640 mg/kg

                 LD50 oral (guinea pigs)  275.9 mg/kg

                 LD50 oral (dogs)         >160 mg/kg

                 (Physician's Desk Reference, 1989)

           7.2.3 Relevant in vitro data

                 No data available.

       7.3 Carcinogenicity

           Chronic/carcinogenicity studies in test animals have not been 
           performed (Physician's Desk Reference, 1989). 

       7.4 Teratogenicity

           In animals miconazole has not shown teratogenic effects but 
           is embryotoxic following high oral doses (80 mg/kg)(Walker, 
           1994, Physicians Desk Reference, 1989). In the rat studies 
           dystocia was reported at and above 80 mg/kg (Physician's Desk 
           Reference, 1989). These various effects were not seen in rats 
           tested with intravaginal products (Physician's Desk 
           Reference, 1989). 

           There has been no increase in congenital malformations in 
           pregnant patients using vaginal preparations (Briggs et al., 
           1986) 

           Reproduction studies showed that in rats and rabbits at 
           intravenous doses of 40 and 20 mg/kg respectively there was 
           no indication of embryotoxicity or teratogenicity 
           (Physician's Desk Reference, 1989). 

       7.5 Mutagenicity 

           No data available. 

       7.6 Interactions 

           Miconazole given systemically may enhance the activity of 
           anticoagulant or suphonylurea hypoglycaemic drugs. 

           The combination of amphotericin and miconazole appeared to be 
           less effective when either drug used alone. 

           Miconazole enhanced the activity of clomipramine, 
           carbamazepine and phenytoin. 

           The base contained in certain suppository formulations may 
           interact with some latex products, such as that used in 
           vaginal contraceptive diaphragms. 

           Since concomitant administration of rifampin and ketoconazole 
           (an imidazole), reduces the blood levels of the latter, the 
           concurrent administration of miconazole intravenously and 
           rifampicin should be avoided. 

           Ketoconazole increases the blood level of cyclosporin A, 
           therefore, there is the possibility of a drug interaction 
           involving cyclosporin A and intravenous miconazole; blood 
           levels of cyclosporin A should be monitored if the two drugs 
           are given concomitantly. 

           (Reynolds, 1989; Physician's Desk Reference, 1989; Dukes, 
           1984) 

       7.7 Main adverse effects 

           Cardiac 

           Tachycardia and arrhythmias after intravenous doses  

           Haematological 

           Aggregation of erythrocytes, anaemia, thrombocytosis. 

           Gastrointestinal 

           Anorexia, nausea, vomiting, diarrhoea. 

           Local reactions 

           Irritation, 

           Sensitivity (allergic) reactions 

           Vulvovaginal burning, itching or irritation pelvic cramps, 
           rash, cutaneous pruritus, flushes. 

           Other 

           Hyperlipidaemia, drowsiness, febrile reactions, 
           hyponatraemia, acute psychosis, arthralgia, anaphylaxis, 
           irritation of the meninges (by intrathecal injection). 

           (Reynolds, 1989, Physician's Desk Reference, 1989). 

    8. TOXICOLOGICAL AND BIOMEDICAL INVESTIGATIONS 
    
       8.1 Sample

           8.1.1 Collection

           8.1.2 Storage

           8.1.3 Transport

       8.2 Toxicological/toxicological analytical methods

           Data are not available

           8.2.1 Test for active ingredient

           8.2.2 Test for biological sample

       8.3 Other laboratory analyses

           8.3.1 Haematological investigations

                 It is recommended to perform haematological tests, 
                 including hemoglobin, hematocrit and platelet count, 
                 for the patients under treatment with miconazole. 

           8.3.2 Biochemical investigations

                 8.3.2.1 Blood

                         It is also recommended that clinical laboratory 
                         monitoring including electrolytes and lipids be 
                         performed. 

                 8.3.2.2 Urine

                         Not necessary

           8.3.3 Arterial blood gas analysis

                 Not necessary
                    
           8.3.4 Other relevant biomedical analyses

                 Not necessary

       8.4 Interpretation

           Miconazole may produce transient decreases in hematocrit, 
           aggregation of arrythrocytes, thromcytopenis, hyperlipidaemia 
           and hyponatraemia when is administered systemically. 

       8.5 References 

           (1,2.4).
    
    9. CLINICAL EFFECTS

       9.1 Acute poisoning 

           9.1.1 Ingestion

                 Has not been reported.  It is possible that 
                 gastrointestinal disturbances and other side-effects 
                 occur in case of acute overdosage. 

           9.1.2 Inhalation

                 Not relevant

           9.1.3 Skin exposure

                 No data available.

           9.1.4 Eye contact

                 No data available.

           9.1.5 Parenteral exposure

                 After intravenous administration of miconazole, 
                 phlebitis, nausea, vomiting, diarrhoea, allergic and 
                 febrile reactions, flushes and drowsiness have been 
                 reported. Tachycardia, tachypnea, cardiac arrhythmias 
                 and even cardiac arrest have followed the rapid 
                 intravenous injection of miconazole.  Rare adverse 
                 effects include acute psychosis, arthralgia and 
                 anaphylaxis (Reynolds, 1989). 

           9.1.6 Other 

                 After intrathecal injection miconazole may cause 
                 irritation of the meninges.  

                 Vulvovaginitis, burning, itching or irritation were 
                 reported with the use of miconazole nitrate by 
                 intravaginal route. 

                 (Reynolds, 1989). 

       9.2 Chronic poisoning 

           No available data 

           9.2.1 Ingestion 

                 No available data. 
                
           9.2.2 Inhalation 

                 No available data. 

           9.2.3 Skin exposure 

                 No available data. 

           9.2.4 Eye contact 

                 No available data. 

           9.2.5 Parenteral exposure 

                 No available data. 

           9.2.6 Other 

                 No available data. 

       9.3 Course, prognosis, cause of death 

           No deaths have been reported. 

       9.4 Systematic description of clinical effects 

           9.4.1 Cardiovascular 

                  Acute effect on the heart 

                 Rapid injection of undiluted miconazole by intravenous 
                 route may produce collapse, transient tachycardia, 
                 arrhythmia (ventricular tachycardia) and even (in one 
                 instance) cardiac arrest (Dukes, 1988). 

                  Vessels 

                 Phlebitis has been observed with intravenous 
                 administration (Dukes, 1988). 

           9.4.2 Respiratory

                 Tachypnea has been reported after rapid intravenous 
                 administration (Dukes, 1988). 

           9.4.3 Neurological

                 9.4.3.1 Central nervous system (CNS)

                         Drowsiness and headache has been described as 
                         side-effects.  Arachnoiditis has been described 
                         after intrathecal administration.  
                         Hyperaesthesia, euphoria and light-headedness 
                         have been mentioned. Acute toxic psychosis has 
                         been described as a rare effect (Dukes, 1988). 

                 9.4.3.2 Peripheral nervous system 

                         No data available. 

                 9.4.3.3 Autonomic nervous system 

                         Transient tachycardia has been reported after 
                         rapid intravenous administration (Reynolds, 
                         1989). 

                 9.4.3.4 Skeletal and smooth muscle 

                         Arthralgia has been reported when miconazole is 
                         given intravenously (Reynolds, 1989). 

           9.4.4 Gastrointestinal 

                 Gastrointestinal disturbances have been described both 
                 after intravenous administration or oral use of 
                 miconazole (nausea, vomiting, anorexia, diarrhoea) 
                 (Dukes, 1988; Reynolds, 1989). 

           9.4.5 Hepatic 

                 No serious hepatic toxicity has been reported.  Enzyme 
                 reduction was reported, similar to that caused by 
                 clotrimazole (Dukes, 1988). 

           9.4.6 Urinary 

                 9.4.6.1 Renal 

                         There are reports of haematuria and renal 
                         failure associated with the administration of 
                         miconazole intravenously (Reynolds, 1989). 

                 9.4.6.2 Others 

                         No relevant data available. 

           9.4.7 Endocrine and reproductive systems 

                 No data available 

           9.4.8 Dermatological 

                 Local reaction consist in irritation and sensitivity 
                 reactions; contact dermatitis has been reported.  
                 Pruritus and skin rashes may occur after oral, 
                 intravenous or intravaginal administration of 
                 miconazole (Reynolds, 1989). 

           9.4.9 Eye, ears, nose, throat: local effects

                 Local effects: local irritation and sensitivity 
                 reactions might occur when miconazole is topically 
                 applied into the eye. 

           9.4.10 Haematological 

                  Transient decreases in haematocrit, aggregation of 
                  erythrocytes and thrombocytopenia are reported when 
                  miconazole was given systemically. Thrombocytosis was 
                  reported in isolated cases (Physician's Desk 
                  Reference, 1989). 

           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 

                           Transient decreases in serum sodium levels 
                           has been reported following infusion of 
                           miconazole intravenously (Physician's Desk 
                           Reference, 1989). 

                  9.4.12.3 Others 

                           Hyperlipidaemia has occurred in some patients 
                           but reported to be due to the vehicle of the 
                           solution for intravenous infusion (Dukes, 
                           1988). 

           9.4.13 Allergic reactions 

                  Local sensitivity reactions have been reported; 
                  anaphylaxis is a rare adverse effect observed with the 
                  intravenous use of miconazole. 

           9.4.14 Other clinical effects 

                  Febrile reactions; acute psychosis; irritation of the 
                  meninges after intrathecal injection miconazole. 

           9.4.15 Special risks 
     
                   Pregnancy 

                  Clinical studies during which miconazole nitrate 
                  vaginal cream and suppositories were used for up to 14 
                  days in pregnant patients reveal no adverse effects or 
                  complications attributable to miconazole in infants 
                  born to these women.  However, miconazole should not 
                  be used in the first trimester of pregnancy unless the 
                  physician considers it essential to the welfare of the 
                  patient (Physician's Desk Reference, 1989). 

                   Breast-feeding 

                  It is not known whether miconazole is excreted in 
                  breast milk; caution should be exercised when this 
                  drug is administered to a nursing woman (Physician's 
                  Desk Reference, 1989). 

       9.5 Other

           No available data

       9.6 Summary

           Not relevant

    10. MANAGEMENT

        10.1 General principles

             Acute poisoning has not been reported.  In case of 
             overdosage by intravenous route or rapid injection cardiac 
             abnormalities may occur.  In such cases, it is recommended 
             to monitor cardiac function or to perform 
             electrocardiograms. 

        10.2 Relevant laboratory analyses 

             10.2.1 Sample collection 

                    As per Section 8. 

             10.2.2 Biomedical analysis 

                    It is recommended that clinical laboratory 
                    monitoring (including haemoglobin, haematocrit 
                    platelet count, electrolytes and lipids) be 
                    performed in systemic treatment. 

             10.2.3 Toxicological analysis 

                    Not relevant 

             10.2.4 Other investigations 

                    Not relevant 

        10.3 Life supportive procedures and symptomatic/specific 
             treatment 

             Symptomatic and supportive care is the basis for treatment. 
             Nausea or vomiting induced by miconazole infusion can be 
             mitigated with antihistaminic or antiemetic drugs, or by 
             reducing the dose, or slowing the rate of intravenous 
             infusion. 

        10.4 Decontamination 

             In case of oral overdosage the common measures to limit the 
             absorption of the drug from gastrointestinal tract, such as 
             emesis, gastric lavage or administration of activated 
             charcoal, should be considered, if patient seen early after 
             ingestion. 

        10.5 Elimination 

             Since over 90% of miconazole is bound in plasma proteins, 
             forced diuresis or dialysis is of no value in case of 
             miconazole overdosage. 

             Very little miconazole is removed by haemodialysis 
             (Reynolds, 1989). 

        10.6 Antidote treatment 

             10.6.1 Adults 

                    No antidote available. 

             10.6.2 Children 

                    No antidote available 

        10.7 Management discussion 

             Not relevant 

    11. ILLUSTRATIVE CASES 

        11.1 Case reports from literature 

             Case 1 

             A report of a generalised tonic-clonic convulsion in an 
             infant occurring 10 to 15 minutes after infusion of 
             miconazole.  A dose of 500 mg rather than the prescribed 
             dose of 50 mg had inadvertently been administered 
             (Coulthard et al., 1987) 

             Case 2 

             Mention of haematuria after 22 infusions of miconazole in a 
             6-year-old boy (Haapasaari et al., 1982). 

             Case 3 

             Renal failure was associated with miconazole 2.4 g daily 
             given intravenously to a renal transplant patient.  Renal 
             function improved on reducing the dose. (Lai et al., 1981).  

             Case 4 
            
             Generalized urticaria with tachycardia and facial oedema 
             were described during intravenous administration of 
             miconazole to a 3-year-old boy with systemic aspergillosis 
             (Dukes, 1988). 

        11.2 Internally extracted data on cases 

             No data available. 

        11.3 Internal cases 

             To be completed by each Centre using local data. 

    12. ADDITIONAL INFORMATION 

        12.1 Availability of antidotes 

             Antidotes are not available. 

        12.2 Specific preventive measures 

             Keep out of the reach of children 

        12.3 Other 

             Not relevant 
             
    13. REFERENCES 

        Briggs GG, Freeman RK & Yaffe SF (1986)  A reference guide to 
        fetal and neonatal risk drugs in pregnancy and lactation, 2nd 
        ed. Baltimore, Williams and Wilkins, p 294. 

        Budavari S ed. (1989) The Merck index, an encyclopedia of 
        chemicals, drugs, and biologicals, 11th ed. Rahway, New Jersey, 
        Merck and Co. Inc.,  p 972. 

        Coulthard K, Martin K, & Matthews N (1987) Convulsions after 
        miconazole overdose [letter]. Med J Aust 146(1): 57-58 

        Dictionnaire Vidal (1987) Vidal 1987. Paris, Editions du Vidal. 

        Dukes MNG ed. (1988) Meyler's Side Effects of Drugs, 11th ed. 
        Amsterdam, Elsevier, pp 575, 596. 

        Dukes MNG ed. (1984) Side Effects of Drugs. Annual 8. Amsterdam, 
        Elsevier, p 270. 

        Haapsaari J, Essen RV, Kahanpaa A, Kostiala AA, Holmberg K, & 
        Ahlqvist J (1982) Fungal arthritis simulating juvenile 
        rheumatoid arthritis. Br Med J Clin Res Ed, 285(6346):923-4. 

        Lai KN, Newton m, Seymour A, Pugsley D & Jones T (1981) 
        Miconazole treatment after renal transplant [letter]. Lancet, 
        2(8236): 48-49. 

        Physician's Desk Reference (1989) 43rd ed.,Ordell NJ, Medical 
        Economics, p 1498. 

        Reynolds JEF ed. (1989) Martindale, the extra pharmacopoeia, 
        29th ed. London, The Pharmaceutical Press, p 430. 

        Reynolds JEF ed. (1993) Martindale, the extra pharmacopoeia, 
        30th ed. London, The Pharmaceutical Press, pp 328-329. 

        Walker G ed.(1994) ABPI data sheet compendium. London, Datapharm 
        Publications Limited, p 677. 

        WHO (1992) International nonproprietary names (INN) for 
        pharmaceutical substances. Geneva, World Health Organisation,  
        p 339. 

        WHO (1992) Anatomical Therapeutic Chemical (ATC) classification 
        index. Oslo, WHO Collaborating Centre for Drug Statistics 
        Methodology, p 60. 

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

        Author         Dr Roberta Juan Gabach 
                       Toxicology Section 
                       Department of Internal Medicine 
                       Hospital de Clinicas 
                       "José de San Martin"

        Co-author      Dr Julia Higa ce Landoni
                       Professor and Chief
                       Toxicology Section
                       Department of Internal Medicine
                       Hospital de Clinicas "José de San Martin"

        Address        Av Córdoba 2351
                       1120 Buenos Aires
                       Argentina

        Peer Review    Drs Besbelli, Higa de Landoni, Wickstrom, & Ten 
                       Ham; Strasbourg, 1990.