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.