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MICONAZOLE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Miconazole is a synthetic 1-phenethyl-imidazole antifungal agent. It is available with or without a prescription in the United States.

Specific Substances

    1) Miconazolum
    2) R-18134
    3) 1-[2,4-Dichloro-beta-(2,4-dichlorobenzyloxy) phenethyl]imidazol
    4) CAS 22916-47-8
    1.2.1) MOLECULAR FORMULA
    1) C18H14Cl4N2O (Prod Info ORAVIG buccal tablets, 2010)

Available Forms Sources

    A) FORMS
    1) Miconazole is available in the United States as 50 mg buccal tablets (Prod Info ORAVIG buccal tablets, 2011). It is also available as topical aerosol, cream, liquid, lotion, powder, and vaginal cream and suppository.
    B) USES
    1) Buccal miconazole tablet is indicated in adult patients for the local treatment of oropharyngeal candidiasis (Prod Info ORAVIG buccal tablets, 2011).
    2) Intravaginal miconazole is recommended as an agent of choice for the treatment of vulvovaginal candidiasis (Pappas et al, 2009; Centers for Disease Control and Prevention, 2010).
    3) Miconazole 0.25%, zinc oxide 15%, and white petrolatum combination ointment is indicated for the treatment of diaper dermatitis complicated by documented candidiasis (microscopic evaluation reveals pseudohypae and/or budding yeast) (Prod Info VUSION(TM) topical ointment, 2006).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Buccal miconazole tablet is indicated in patients for the local treatment of oropharyngeal candidiasis. Intravaginal miconazole is recommended as an agent of choice for the treatment of vulvovaginal candidiasis. Miconazole 0.25%, zinc oxide 15%, and white petrolatum combination ointment is indicated for the treatment of diaper dermatitis complicated by documented candidiasis.
    B) PHARMACOLOGY: Miconazole is an imidazole antifungal agent that inhibits ergosterol synthesis by inhibiting the enzyme CYP450 14-alpha-demethylase. Additionally, miconazole affects triglyceride and fatty acid synthesis and increases the amount of reactive oxygen species within the cell.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) In general, miconazole is not highly toxic. Nausea, vomiting, abdominal pain, diarrhea, headache, dysgeusia, pruritus, contact dermatitis, and anaphylactic reactions have been reported following therapeutic use of miconazole. Buccal tablets have also caused oral discomfort, oral burning, oral pain, gingival pain, swelling, or pruritus, tongue ulceration, mouth ulceration, glossodynia, dry mouth, toothache, loss of taste, and altered taste.
    2) INTRAVENOUS: Intravenous miconazole has caused tremors, hallucinations, confusion, dizziness, hyponatremia, seizures, transient tachycardia and dysrhythmias, thrombophlebitis, thrombocytosis, microcytic normochromic anemia, phlebitis, and anemia. Intravenous formulation is no longer available in the United States.
    E) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Overdose effects are anticipated to be an extension of adverse effects observed following therapeutic doses.
    2) SEVERE TOXICITY: Severe toxicity is not expected after overdose of buccal or topical miconazole. INTRAVENOUS: Seizures have been reported following IV miconazole overdose. Cardiac and respiratory arrest have been observed after high-dose or rapid IV use. IV formulation is not available in the US.
    0.2.20) REPRODUCTIVE
    A) Oral miconazole is classified by the manufacturer as FDA pregnancy category C. There are no adequate and well-controlled studies of oral miconazole nitrate use during human pregnancy. In animal studies, oral miconazole nitrate use during pregnancy resulted in increased resorptions, embryo- and fetotoxicity, prolonged gestation, and dystocia. Due to the lack of human safety information, oral miconazole nitrate should be used in pregnant women only if the potential benefit outweighs the potential risk to the fetus. Clinical studies demonstrated that topical miconazole cream and suppositories used in pregnant women resulted in no teratogenic effects.
    0.2.21) CARCINOGENICITY
    A) At the time of this review, no data were available to assess the carcinogenic potential of this agent.

Laboratory Monitoring

    A) Routine laboratory studies are not likely to be necessary.
    B) Monitor serum electrolytes in patients with severe vomiting and/or diarrhea.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Correct any significant fluid and/or electrolyte abnormalities in patients with vomiting or diarrhea.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Severe toxicity is not expected after overdose of miconazole. In patients with acute allergic reaction, oxygen therapy, bronchodilators, diphenhydramine, corticosteroids, vasopressors, and epinephrine may be required.
    C) DECONTAMINATION
    1) PREHOSPITAL: Prehospital gastrointestinal decontamination is generally not necessary.
    2) HOSPITAL: Gastrointestinal decontamination is generally not necessary.
    D) AIRWAY MANAGEMENTS
    1) Endotracheal intubation and mechanical ventilation may be required in patients with severe allergic reaction.
    E) ANTIDOTE
    1) None.
    F) ACUTE ALLERGIC REACTION
    1) MILD to MODERATE effects: Monitor airway. Administer antihistamines with or without inhaled beta agonists, corticosteroids, or epinephrine. SEVERE Effects: Administer oxygen; aggressive airway management may be necessary. Administer antihistamines, epinephrine, corticosteroids as needed. Treatment includes IV fluids and ECG monitoring.
    G) ENHANCED ELIMINATION PROCEDURE
    1) Hemodialysis is UNLIKELY to be of value because of the high degree of protein binding and low toxicity of miconazole.
    H) PATIENT DISPOSITION
    1) HOME CRITERIA: A patient with an inadvertent ingestion, that remains asymptomatic can be managed at home.
    2) OBSERVATION CRITERIA: All patients with deliberate self-harm ingestions should be evaluated in a healthcare facility and monitored until symptoms resolve. Children with unintentional ingestions should be observed in a healthcare facility.
    3) ADMISSION CRITERIA: Hospital admission is rarely necessary. Patients should be admitted for severe vomiting, profuse diarrhea, severe abdominal pain, dehydration, and electrolyte abnormalities.
    4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    I) PITFALLS
    1) If significant toxicity develops, the diagnosis should be reconsidered. When managing a suspected miconazole overdose, the possibility of multidrug involvement should be considered.
    J) PHARMACOKINETICS
    1) Tmax: 7 hr (range, 2 to 24.1 hr) after a single 50 mg buccal dose. Absorption: oral: 25% to 30%; vaginal: approximately 1% to 1.4%. Protein binding: 90% to 93%. Renal excretion: less than 1% excreted in the urine unchanged. Feces: about 50%. Terminal half-life: 24 hr.
    0.4.3) INHALATION EXPOSURE
    A) INHALATION: Move patient to fresh air. Monitor for respiratory distress. If cough or difficulty breathing develops, evaluate for respiratory tract irritation, bronchitis, or pneumonitis. Administer oxygen and assist ventilation as required. Treat bronchospasm with an inhaled beta2-adrenergic agonist. Consider systemic corticosteroids in patients with significant bronchospasm.
    0.4.4) EYE EXPOSURE
    A) DECONTAMINATION: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, the patient should be seen in a healthcare facility.
    0.4.5) DERMAL EXPOSURE
    A) OVERVIEW
    1) DECONTAMINATION: Remove contaminated clothing and jewelry and place them in plastic bags. Wash exposed areas with soap and water for 10 to 15 minutes with gentle sponging to avoid skin breakdown. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

Range Of Toxicity

    A) TOXICITY: A toxic dose has not been established. THERAPEUTIC DOSE: BUCCAL: ADULTS: 50 mg buccally once daily for 14 days. CHILDREN: Safety and effectiveness not established in pediatric patients less than 16 yr of age. SUPPOSITORY/INTRAVAGINAL: ADULTS AND CHILDREN 12 YEARS AND OLDER: 200 mg intravaginally at bedtime for 3 days OR 100 mg intravaginally at bedtime for 7 days OR 1200 mg intravaginally once.
    B) INTRAVENOUS ROUTE: Bradycardia, ectopic atrial rhythm, and delayed intraventricular conduction were reported in a premature neonate who received intravenously administered miconazole 50 mg/kg every 8 hours for 3 days.

Clinical Effects

Summary Of Exposure

    A) USES: Buccal miconazole tablet is indicated in patients for the local treatment of oropharyngeal candidiasis. Intravaginal miconazole is recommended as an agent of choice for the treatment of vulvovaginal candidiasis. Miconazole 0.25%, zinc oxide 15%, and white petrolatum combination ointment is indicated for the treatment of diaper dermatitis complicated by documented candidiasis.
    B) PHARMACOLOGY: Miconazole is an imidazole antifungal agent that inhibits ergosterol synthesis by inhibiting the enzyme CYP450 14-alpha-demethylase. Additionally, miconazole affects triglyceride and fatty acid synthesis and increases the amount of reactive oxygen species within the cell.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) In general, miconazole is not highly toxic. Nausea, vomiting, abdominal pain, diarrhea, headache, dysgeusia, pruritus, contact dermatitis, and anaphylactic reactions have been reported following therapeutic use of miconazole. Buccal tablets have also caused oral discomfort, oral burning, oral pain, gingival pain, swelling, or pruritus, tongue ulceration, mouth ulceration, glossodynia, dry mouth, toothache, loss of taste, and altered taste.
    2) INTRAVENOUS: Intravenous miconazole has caused tremors, hallucinations, confusion, dizziness, hyponatremia, seizures, transient tachycardia and dysrhythmias, thrombophlebitis, thrombocytosis, microcytic normochromic anemia, phlebitis, and anemia. Intravenous formulation is no longer available in the United States.
    E) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Overdose effects are anticipated to be an extension of adverse effects observed following therapeutic doses.
    2) SEVERE TOXICITY: Severe toxicity is not expected after overdose of buccal or topical miconazole. INTRAVENOUS: Seizures have been reported following IV miconazole overdose. Cardiac and respiratory arrest have been observed after high-dose or rapid IV use. IV formulation is not available in the US.

Vital Signs

    3.3.2) RESPIRATIONS
    A) WITH THERAPEUTIC USE
    1) DYSPNEA has occasionally occurred with therapeutic intravenous administration.
    3.3.5) PULSE
    A) WITH THERAPEUTIC USE
    1) TACHYCARDIA may be seen with intravenous administration.

Heent

    3.4.3) EYES
    A) ANIMAL STUDIES
    1) TOPICALLY: A 1% solution was applied to rabbit eyes. Miconazole did not retard the closure of an epithelial defect or produce significant pathological changes (Foster et al, 1981).
    2) INTRAVITREOUS INJECTION: Retinal and lens toxicity was noted in rabbits and monkeys given 100 micrograms or greater intravitreously. Both miconazole and its vehicle produced toxicity. At doses of 10 to 80 micrograms, mild to moderate retinal necrosis was seen in some rabbit eyes, but no damage was seen in the monkeys tested (Tolentino et al, 1982).
    B) WITH THERAPEUTIC USE
    1) CASE REPORT: Corneal toxicity was reported in a 19-year-old woman with a history of penetrating keratoplasty for Acanthamoeba keratitis and treated with miconazole drops postoperatively (Zaidman, 1991). Approximately 2 months after the start of therapy, pinpoint vesicular epithelial elevations were noted during exam. All signs resolved and the graft remained stable after gradual discontinuation of miconazole therapy.

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) CONDUCTION DISORDER OF THE HEART
    1) WITH THERAPEUTIC USE
    a) SUMMARY: Transient tachycardia and dysrhythmias were noted after too rapid administration of undiluted intravenous miconazole (S Sweetman , 2000; Heel, 1980; Sung & Grendahl, 1977) . Fatal cardiac dysrhythmia, however, was reported in one patient despite a slow infusion (Coley & Crain, 1997).
    b) CASE REPORT: A 54-year-old man with a history of orthotopic heart transplantation secondary to cardiomyopathy, complicated by rejection, renal insufficiency, and right heart failure secondary to tricuspid regurgitation developed a widespread subcutaneous Scopulariopsis infection and was started on intravenous miconazole due to resistance to itraconazole. During his first miconazole infusion (800 mg in 800 mL 0.9% saline at 100 mL/hr) he developed junctional bradycardia (40 to 50 bpm), which resolved after the miconazole was discontinued. Despite a slow infusion (25 mL/hour), the patient developed bradycardia (rate 40 to 50 bpm) during his second dose. Idioventricular rhythm and widening QRS complexes occurred 30 to 60 minutes after the infusion was stopped. The rhythm progressed to ventricular fibrillation and the patient died despite aggressive cardiopulmonary resuscitation. The authors speculated that the bradycardia was most likely due to the vehicle (Cremophor EL) rather than the miconazole (Coley & Crain, 1997).
    c) CASE REPORT: Bradycardia, ectopic atrial rhythm, and delayed intraventricular conduction were reported in a premature neonate who received miconazole 50 mg/kg IV every 8 hours for 3 days (Kanarek & Williams, 1986).
    B) CARDIAC ARREST
    1) WITH POISONING/EXPOSURE
    a) Cardiac arrest has been noted after too rapid intravenous injection (Kanarek & Williams, 1986; Huygens, 1975) . Several cases of cardiorespiratory reactions and anaphylaxis have been reported. These included both cardiac and respiratory arrest. In several of these patients, the concentration of the miconazole administered was greater than manufacturer's recommendations (Fainstein & Bodey, 1980).
    1) The vehicle used in the intravenous solution (Cremaphor El) has been associated with cases of cardiorespiratory arrest (Coulthard et al, 1987).
    C) THROMBOPHLEBITIS
    1) WITH THERAPEUTIC USE
    a) Thrombophlebitis occurs in about 29% to 38% of patients given IV miconazole (Stranz, 1980).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) BRONCHOSPASM
    1) WITH THERAPEUTIC USE
    a) Wheezing and dyspnea have been associated with anaphylactic symptoms which have occurred with therapeutic administration of intravenous miconazole (S Sweetman , 2000; Prod Info Monistat IV(R), miconazole, 1990) .
    B) APNEA
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Respiratory arrest was seen in a patient given 1 gram of miconazole in 150 mL of isotonic solution every 8 hours (Fainstein & Bodey, 1980).
    1) The vehicle used in the intravenous solution (Cremaphor El) has been associated with cases of cardiorespiratory arrest (Coulthard et al, 1987).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) SEIZURE
    1) WITH POISONING/EXPOSURE
    a) Seizures have been associated with intravenous miconazole overdose (Coulthard et al, 1987). In one case, the grand mal seizures were preceded by several days of fine tremors (Jordan et al, 1979).
    B) CENTRAL NERVOUS SYSTEM FINDING
    1) WITH THERAPEUTIC USE
    a) In one study, about 16% of patients had neurologic side effects such as fine tremor, dizziness, confusion, and hallucinations (Jordan et al, 1979).
    C) HEADACHE
    1) WITH THERAPEUTIC USE
    a) In a randomized, double-blind trial in immunocompromised HIV-infected patients with oropharyngeal candidiasis, headache was reported in 7.6% of patients who received a miconazole 50 mg buccal tablet once daily for 14 days (n=290) compared with 6.6% of patients who received clotrimazole 10 mg troches 5 times daily for 14 days (n=287) (Prod Info ORAVIG buccal tablets, 2011).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA
    1) WITH THERAPEUTIC USE
    a) Nausea has been reported with the therapeutic use of miconazole (Prod Info ORAVIG buccal tablets, 2011).
    b) In a randomized, double-blind trial in immunocompromised HIV-infected patients with oropharyngeal candidiasis, nausea was reported in 6.6% of patients who received a miconazole 50 mg buccal tablet once daily for 14 days (n=290) compared with 7.7% of patients who received clotrimazole 10 mg troches 5 times daily for 14 days (n=287) (Prod Info ORAVIG buccal tablets, 2011).
    B) VOMITING
    1) WITH THERAPEUTIC USE
    a) Vomiting has been reported with the therapeutic use of miconazole (Prod Info ORAVIG buccal tablets, 2011).
    b) In a randomized, double-blind trial in immunocompromised HIV-infected patients with oropharyngeal candidiasis, vomiting was reported in 3.8% of patients who received a miconazole 50 mg buccal tablet once daily for 14 days (n=290) compared with 3.1% of patients who received clotrimazole 10 mg troches 5 times daily for 14 days (n=287) (Prod Info ORAVIG buccal tablets, 2011).
    C) LOSS OF APPETITE
    1) WITH THERAPEUTIC USE
    a) Anorexia has been reported after therapeutic intravenous doses (S Sweetman , 2000; Prod Info Monistat IV(R), miconazole, 1990) .
    D) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) Diarrhea has been reported with the therapeutic use of miconazole (Prod Info ORAVIG buccal tablets, 2011).
    b) In a randomized, double-blind trial in immunocompromised HIV-infected patients with oropharyngeal candidiasis, diarrhea was reported in 9% of patients who received a miconazole 50 mg buccal tablet once daily for 14 days (n=290) compared with 8% of patients who received clotrimazole 10 mg troches 5 times daily for 14 days (n=287) (Prod Info ORAVIG buccal tablets, 2011).
    E) ABDOMINAL PAIN
    1) WITH THERAPEUTIC USE
    a) Abdominal pain has been reported with the therapeutic use of miconazole (Prod Info ORAVIG buccal tablets, 2011).
    F) PAINFUL MOUTH
    1) WITH THERAPEUTIC USE
    a) In a randomized, double-blind trial in immunocompromised HIV-infected patients with oropharyngeal candidiasis, the following effects were reported in 12.1% of patients who received a miconazole 50 mg buccal tablet once daily for 14 days (n=290) compared with 9.4% of patients who received clotrimazole 10 mg troches 5 times daily for 14 days (n=287): oral discomfort, oral burning, oral pain, gingival pain, swelling, or pruritus, tongue ulceration, mouth ulceration, glossodynia, dry mouth, toothache, loss of taste, and altered taste (Prod Info ORAVIG buccal tablets, 2011).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) THROMBOCYTOSIS
    1) WITH THERAPEUTIC USE
    a) Thrombocytosis occurs in about 25% to 30% of patients given therapeutic intravenous doses. It is associated with a drop in hematocrit which is benign and resolves after the drug is discontinued (Stranz, 1980).
    B) ERYTHROCYTE AGGLUTINATION
    1) WITH THERAPEUTIC USE
    a) ERYTHROCYTE AGGREGATION: A few authors have observed erythrocyte aggregation after therapeutic doses. No additional adverse effects have developed due to this condition, and it disappears when the drug is discontinued (Sung & Grendahl, 1977; Stevens, 1976).
    C) ANEMIA
    1) WITH THERAPEUTIC USE
    a) Microcytic normochromic anemia has occurred with therapeutic intravenous doses; the prevalence may be about 5.5%. This may increase to 40% to 69% with higher doses (Stevens, 1983; Stranz, 1980) .
    D) WHITE BLOOD CELL ABNORMALITY
    1) WITH THERAPEUTIC USE
    a) GRANULOCYTE FUNCTION: Miconazole's vehicle in concentrations of 0.33% and above has interfered with granulocyte function (Lee & Maderazo, 1978). Miconazole suppressed granulocyte progenitor cells growth in culture (Meeker et al, 1983).
    E) THROMBOPHLEBITIS
    1) WITH THERAPEUTIC USE
    a) Thrombophlebitis occurs in about 29% to 38% of patients given IV miconazole (Stranz, 1980).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) CONTACT DERMATITIS
    1) WITH THERAPEUTIC USE
    a) Contact dermatitis has been reported with therapeutic use (Frenzel & Gutekunst, 1983; Foged & Hammershoy, 1982; Wade, 1979; Degreef & Verhoeve, 1975) . Some of the reactions may have been due to components of the vehicle.
    b) CASE REPORT: One study reported generalized symptoms of systemic contact dermatitis (generalized, itchy, maculopapular eruption) after 7 days of using an oral miconazole solution for oral candidiasis in an adult. Symptoms resolved with a 3-week course of corticosteroids. Patch testing was positive (Fernandez et al, 1996).
    1) Similar symptoms were described in an adult female following the use of a miconazole vaginal cream; patch testing was positive (Baes, 1991).
    c) One study found cutaneous allergy to butylated hydroxyanisole (Degreef & Verhoeve, 1975); another found similar effects to triethanolamine (Samsoen & Jelen, 1977).
    B) ITCHING OF SKIN
    1) WITH THERAPEUTIC USE
    a) Pruritus associated with skin rashes has occurred after intravenous administration of therapeutic doses (Stevens, 1983). Itching is seen in 20% to 25% of the cases, while 9% of cases develop rash (Stranz, 1980).
    C) ERUPTION
    1) WITH THERAPEUTIC USE
    a) Seven days after starting treatment with miconazole oral solution (Daktarin(R)) to treat candidiasis, a patient developed a generalized, pruritic, maculopapular eruption. The condition responded to 3-week treatment with oral corticosteroids. Patch tests were positive for systemic contact dermatitis, but cross-sensitization to other imidazoles was not determined (Fernandez et al, 1996a).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) ANAPHYLACTOID REACTION
    1) WITH THERAPEUTIC USE
    a) Anaphylactic reactions were reported in patients after their first dose of miconazole (Fainstein & Bodey, 1980). Symptoms included acute shortness of breath, choking, hypotension, cyanosis, and laryngeal edema. It is a rare effect of therapy (S Sweetman , 2000).
    B) ACUTE ALLERGIC REACTION
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Hypersensitivity as determined by a patch test (type 4 reaction according to Coombs and Gell) was noted in a 60-year-old man on several imidazole derivatives (Mucke, 1980).

Reproductive

    3.20.1) SUMMARY
    A) Oral miconazole is classified by the manufacturer as FDA pregnancy category C. There are no adequate and well-controlled studies of oral miconazole nitrate use during human pregnancy. In animal studies, oral miconazole nitrate use during pregnancy resulted in increased resorptions, embryo- and fetotoxicity, prolonged gestation, and dystocia. Due to the lack of human safety information, oral miconazole nitrate should be used in pregnant women only if the potential benefit outweighs the potential risk to the fetus. Clinical studies demonstrated that topical miconazole cream and suppositories used in pregnant women resulted in no teratogenic effects.
    3.20.2) TERATOGENICITY
    A) LACK OF INFORMATION
    1) There are no adequate and well-controlled studies of oral miconazole nitrate use during human pregnancy (Prod Info ORAVIG buccal tablets, 2010). However, clinical studies demonstrated that topical miconazole cream and suppositories used in pregnant women resulted in no teratogenic effects (Wallenburg & Wladimiroff, 1976; Culbertson, 1974).
    B) ANIMAL STUDIES
    1) Embryo- and fetotoxicity, increased fetal resorptions, prolonged gestation, and dystocia (rats only) were observed in pregnant rats and rabbits who were administered oral miconazole nitrate at doses of 80 mg/kg/day or higher. Intravenous miconazole at doses of 40 mg/kg/day in rats and 20 mg/kg/day in rabbits showed no embryofetotoxicity. Teratogenicity has not been observed in any animal study with miconazole (Prod Info ORAVIG buccal tablets, 2010).
    3.20.3) EFFECTS IN PREGNANCY
    A) LACK OF INFORMATION
    1) In a retrospective survey of vaginal or oral use of miconazole, clotrimazole, nystatin, aminacrine compounds, candicidin, or metronidazole, no statistically significant association was observed between these agents and the overall frequency of birth defects or for the specific defects investigated (cardiovascular, oral clefts, spina bifida) (Rosa et al, 1987).
    2) Clinical studies demonstrated that topical miconazole cream and suppositories used in pregnant women resulted in no teratogenic effects (Wallenburg & Wladimiroff, 1976; Culbertson, 1974).
    B) PREGNANCY CATEGORY
    1) Oral miconazole is classified by the manufacturer as FDA pregnancy category C (Prod Info ORAVIG buccal tablets, 2010).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREASTFEEDING
    1) The World Health Organization considers topical miconazole compatible with breastfeeding (Anon, 2002). However, it is not known whether oral miconazole is excreted in human breast milk. Until more data are available, use caution when considering the use of oral miconazole in lactating women (Prod Info ORAVIG buccal tablets, 2010).

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) At the time of this review, no data were available to assess the carcinogenic potential of this agent.
    3.21.3) HUMAN STUDIES
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the mutagenic or genotoxic potential of this agent.

Genotoxicity

    A) At the time of this review, no data were available to assess the mutagenic or genotoxic potential of this agent.
    B) Miconazole was tested for mutagenicity in the fluctuation test with Klebsiella pneumoniae and Escherichia coli K12 as test organisms. No evidence of mutagenicity was found (Voogd & van der Stel, 1983).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Routine laboratory studies are not likely to be necessary.
    B) Monitor serum electrolytes in patients with severe vomiting and/or diarrhea.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Hospital admission is rarely necessary. Patients should be admitted for severe vomiting, profuse diarrhea, severe abdominal pain, dehydration, and electrolyte abnormalities.
    6.3.1.2) HOME CRITERIA/ORAL
    A) A patient with an inadvertent ingestion, that remains asymptomatic can be managed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) All patients with deliberate self-harm ingestions should be evaluated in a healthcare facility and monitored until symptoms resolve. Children with unintentional ingestions should be observed in a healthcare facility.

Monitoring

    A) Routine laboratory studies are not likely to be necessary.
    B) Monitor serum electrolytes in patients with severe vomiting and/or diarrhea.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) PREHOSPITAL: Severe toxicity is not expected after overdose of miconazole. Prehospital gastrointestinal decontamination is generally not necessary.
    6.5.2) PREVENTION OF ABSORPTION
    A) SUMMARY: Gastrointestinal decontamination is generally not necessary.
    6.5.3) TREATMENT
    A) MONITORING OF PATIENT
    1) Routine laboratory studies are not likely to be necessary.
    2) Monitor serum electrolytes in patients with severe vomiting and/or diarrhea.
    B) ACUTE ALLERGIC REACTION
    1) SUMMARY
    a) Mild to moderate allergic reactions may be treated with antihistamines with or without inhaled beta adrenergic agonists, corticosteroids or epinephrine. Treatment of severe anaphylaxis also includes oxygen supplementation, aggressive airway management, epinephrine, ECG monitoring, and IV fluids.
    2) BRONCHOSPASM
    a) ALBUTEROL
    1) ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007). CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 mg/kg (up to 10 mg) every 1 to 4 hours as needed, or 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).
    3) CORTICOSTEROIDS
    a) Consider systemic corticosteroids in patients with significant bronchospasm.
    b) PREDNISONE: ADULT: 40 to 80 milligrams/day. CHILD: 1 to 2 milligrams/kilogram/day (maximum 60 mg) in 1 to 2 divided doses divided twice daily (National Heart,Lung,and Blood Institute, 2007).
    4) MILD CASES
    a) DIPHENHYDRAMINE
    1) SUMMARY: Oral diphenhydramine, as well as other H1 antihistamines can be used as indicated (Lieberman et al, 2010).
    2) ADULT: 50 milligrams orally, or 10 to 50 mg intravenously at a rate not to exceed 25 mg/min or may be given by deep intramuscular injection. A total of 100 mg may be administered if needed. Maximum daily dosage is 400 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).
    3) CHILD: 5 mg/kg/24 hours or 150 mg/m(2)/24 hours. Divided into 4 doses, administered intravenously at a rate not exceeding 25 mg/min or by deep intramuscular injection. Maximum daily dosage is 300 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).
    5) MODERATE CASES
    a) EPINEPHRINE: INJECTABLE SOLUTION: It should be administered early in patients by IM injection. Using a 1:1000 (1 mg/mL) solution of epinephrine. Initial Dose: 0.01 mg/kg intramuscularly with a maximum dose of 0.5 mg in adults and 0.3 mg in children. The dose may be repeated every 5 to 15 minutes, if no clinical improvement. Most patients respond to 1 or 2 doses (Nowak & Macias, 2014).
    6) SEVERE CASES
    a) EPINEPHRINE
    1) INTRAVENOUS BOLUS: ADULT: 1 mg intravenously as a 1:10,000 (0.1 mg/mL) solution; CHILD: 0.01 mL/kg intravenously to a maximum single dose of 1 mg given as a 1:10,000 (0.1 mg/mL) solution. It can be repeated every 3 to 5 minutes as needed. The dose can also be given by the intraosseous route if IV access cannot be established (Lieberman et al, 2015). ALTERNATIVE ROUTE: ENDOTRACHEAL ADMINISTRATION: If IV/IO access is unavailable. DOSE: ADULT: Administer 2 to 2.5 mg of 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube. CHILD: DOSE: 0.1 mg/kg to a maximum of 2.5 mg administered as a 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube (Lieberman et al, 2015).
    2) INTRAVENOUS INFUSION: Intravenous administration may be considered in patients poorly responsive to IM or SubQ epinephrine. An epinephrine infusion may be prepared by adding 1 mg (1 mL of 1:1000 (1 mg/mL) solution) to 250 mL D5W, yielding a concentration of 4 mcg/mL, and infuse this solution IV at a rate of 1 mcg/min to 10 mcg/min (maximum rate). CHILD: A dosage of 0.01 mg/kg (0.1 mL/kg of a 1:10,000 (0.1 mg/mL) solution up to 10 mcg/min (maximum dose 0.3 mg) is recommended for children (Lieberman et al, 2010). Careful titration of a continuous infusion of IV epinephrine, based on the severity of the reaction, along with a crystalloid infusion can be considered in the treatment of anaphylactic shock. It appears to be a reasonable alternative to IV boluses, if the patient is not in cardiac arrest (Vanden Hoek,TL,et al).
    7) AIRWAY MANAGEMENT
    a) OXYGEN: 5 to 10 liters/minute via high flow mask.
    b) INTUBATION: Perform early if any stridor or signs of airway obstruction.
    c) CRICOTHYROTOMY: Use if unable to intubate with complete airway obstruction (Vanden Hoek,TL,et al).
    d) BRONCHODILATORS are recommended for mild to severe bronchospasm.
    e) ALBUTEROL: ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007).
    f) ALBUTEROL: CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 milligram/kilogram (maximum 10 milligrams) every 1 to 4 hours as needed OR administer 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).
    8) MONITORING
    a) CARDIAC MONITOR: All complicated cases.
    b) IV ACCESS: Routine in all complicated cases.
    9) HYPOTENSION
    a) If hypotensive give 500 to 2000 milliliters crystalloid initially (20 milliliters/kilogram in children) and titrate to desired effect (stabilization of vital signs, mentation, urine output); adults may require up to 6 to 10 L/24 hours. Central venous or pulmonary artery pressure monitoring is recommended in patients with persistent hypotension.
    1) VASOPRESSORS: Should be used in refractory cases unresponsive to repeated doses of epinephrine and after vigorous intravenous crystalloid rehydration (Lieberman et al, 2010).
    2) DOPAMINE: Initial Dose: 2 to 20 micrograms/kilogram/minute intravenously; titrate to maintain systolic blood pressure greater than 90 mm Hg (Lieberman et al, 2010).
    10) H1 and H2 ANTIHISTAMINES
    a) SUMMARY: Antihistamines are second-line therapy and are used as supportive therapy and should not be used in place of epinephrine (Lieberman et al, 2010).
    1) DIPHENHYDRAMINE: ADULT: 25 to 50 milligrams via a slow intravenous infusion or IM. PEDIATRIC: 1 milligram/kilogram via slow intravenous infusion or IM up to 50 mg in children (Lieberman et al, 2010).
    b) RANITIDINE: ADULT: 1 mg/kg parenterally; CHILD: 12.5 to 50 mg parenterally. If the intravenous route is used, ranitidine should be infused over 10 to 15 minutes or diluted in 5% dextrose to a volume of 20 mL and injected over 5 minutes (Lieberman et al, 2010).
    c) Oral diphenhydramine, as well as other H1 antihistamines, can also be used as indicated (Lieberman et al, 2010).
    11) DYSRHYTHMIAS
    a) Dysrhythmias and cardiac dysfunction may occur primarily or iatrogenically as a result of pharmacologic treatment (epinephrine) (Vanden Hoek,TL,et al). Monitor and correct serum electrolytes, oxygenation and tissue perfusion. Treat with antiarrhythmic agents as indicated.
    12) OTHER THERAPIES
    a) There have been a few reports of patients with anaphylaxis, with or without cardiac arrest, that have responded to vasopressin therapy that did not respond to standard therapy. Although there are no randomized controlled trials, other alternative vasoactive therapies (ie, vasopressin, norepinephrine, methoxamine, and metaraminol) may be considered in patients in cardiac arrest secondary to anaphylaxis that do not respond to epinephrine (Vanden Hoek,TL,et al).

Inhalation Exposure

    6.7.1) DECONTAMINATION
    A) Move patient from the toxic environment to fresh air. Monitor for respiratory distress. If cough or difficulty in breathing develops, evaluate for hypoxia, respiratory tract irritation, bronchitis, or pneumonitis.
    B) OBSERVATION: Carefully observe patients with inhalation exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
    C) INITIAL TREATMENT: Administer 100% humidified supplemental oxygen, perform endotracheal intubation and provide assisted ventilation as required. Administer inhaled beta-2 adrenergic agonists, if bronchospasm develops. Consider systemic corticosteroids in patients with significant bronchospasm (National Heart,Lung,and Blood Institute, 2007). Exposed skin and eyes should be flushed with copious amounts of water.

Eye Exposure

    6.8.1) DECONTAMINATION
    A) EYE IRRIGATION, ROUTINE: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, an ophthalmologic examination should be performed (Peate, 2007; Naradzay & Barish, 2006).

Dermal Exposure

    6.9.1) DECONTAMINATION
    A) DERMAL DECONTAMINATION
    1) DECONTAMINATION: Remove contaminated clothing and wash exposed area thoroughly with soap and water for 10 to 15 minutes. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

Enhanced Elimination

    A) HEMODIALYSIS
    1) Hemodialysis is UNLIKELY to be of value because of the high degree of protein binding of miconazole.
    2) Miconazole does not appear to be removed significantly by hemodialysis nor is its half-life significantly shortened during hemodialysis (Lewi, 1976; Bennett, 1980).

Range Of Toxicity

Summary

    A) TOXICITY: A toxic dose has not been established. THERAPEUTIC DOSE: BUCCAL: ADULTS: 50 mg buccally once daily for 14 days. CHILDREN: Safety and effectiveness not established in pediatric patients less than 16 yr of age. SUPPOSITORY/INTRAVAGINAL: ADULTS AND CHILDREN 12 YEARS AND OLDER: 200 mg intravaginally at bedtime for 3 days OR 100 mg intravaginally at bedtime for 7 days OR 1200 mg intravaginally once.
    B) INTRAVENOUS ROUTE: Bradycardia, ectopic atrial rhythm, and delayed intraventricular conduction were reported in a premature neonate who received intravenously administered miconazole 50 mg/kg every 8 hours for 3 days.

Therapeutic Dose

    7.2.1) ADULT
    A) BUCCAL: 50 mg once daily for 14 days (Prod Info ORAVIG(R) buccal tablets, 2013).
    B) TOPICAL: Twice daily for 2 weeks (jock itch), or twice daily for 4 weeks (athlete's foot or ring worm), or 2 to 3 times daily for 3 to 7 days (vaginal yeast infection) (OTC Product Information, as posted to the DailyMed site 12/2013; OTC Product Information, as posted to the DailyMed site 12/2012; OTC Product Information, as posted to the DailyMed site 02/2013; OTC Product Information, as posted to the DailyMed site 09/2013; OTC Product Information, as posted to the DailyMed site 05/2014; OTC Product Information, as posted to the DailyMed site 05/2014a; OTC Product Information, as posted to the DailyMed site 09/2012)
    C) SUPPOSITORY/INTRAVAGINAL: 200 mg for 3 nights, or 100 mg for 7 nights, or 1200 mg for one night (OTC Product Information, as posted to the DailyMed site 05/2014a; OTC Product Information, as posted to the DailyMed site 06/2014; Prod Info Monistat(R) 3 Combination Pack, 2001; Pappas et al, 2009)
    7.2.2) PEDIATRIC
    A) BUCCAL
    1) CHILDREN 15 YEARS AND UNDER: Safety and effectiveness in the pediatric and adolescent population have not been established (Prod Info ORAVIG(R) buccal tablets, 2013).
    B) TOPICAL
    1) CHILDREN 3 TO 18 YEARS: Twice daily for 2 weeks (jock itch) or twice daily for 4 weeks (athlete's foot or ring worm) (OTC Product Information, as posted to the DailyMed site 12/2013; OTC Product Information, as posted to the DailyMed site 12/2012; OTC Product Information, as posted to the DailyMed site 02/2013; OTC Product Information, as posted to the DailyMed site 09/2013; OTC Product Information, as posted to the DailyMed site 05/2014)
    2) CHILDREN 13 TO 18 YEARS: 2 to 3 times daily for 3 to 7 days (vaginal yeast infection) (OTC Product Information, as posted to the DailyMed site 09/2012; OTC Product Information, as posted to the DailyMed site 05/2014a)
    C) SUPPOSITORY/INTRAVAGINAL
    1) CHILDREN 12 YEARS AND OLDER: 200 mg for 3 nights, or 100 mg for 7 nights, or 1200 mg for one night (OTC Product Information, as posted to the DailyMed site 05/2014a; OTC Product Information, as posted to the DailyMed site 06/2014; Prod Info Monistat(R) 3 Combination Pack, 2001; Pappas et al, 2009)

Maximum Tolerated Exposure

    A) Bradycardia, ectopic atrial rhythm, and delayed intraventricular conduction were reported in a premature neonate who received intravenously administered miconazole 50 mg/kg every 8 hours for 3 days (Kanarek & Williams, 1986).

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) The mean Cmax in the saliva of healthy adults (n=18) was 15.1 +/- 16.2 mcg/mL (range, 0.5 to 64.8 mcg/mL) after administration of a single miconazole 50 mg buccal dose (Prod Info ORAVIG buccal tablets, 2011).
    2) Tmax: The median Tmax in the saliva of healthy subjects (n=18) was 7 hr (range, 2 to 24.1 hr) after administration of a single miconazole 50 mg buccal dose (Prod Info ORAVIG buccal tablets, 2011).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Miconazole is an imidazole antifungal agent that interrupts ergosterol synthesis (an essential component of the fungal cell membrane) by inhibiting the enzyme CYP450 14-alpha-demethylase. Additionally, miconazole affects triglyceride and fatty acid synthesis and increases the amount of reactive oxygen species within the cell by inhibiting oxidative and peroxidative enzymes (Prod Info ORAVIG buccal tablets, 2011).
    B) Miconazole alters the permeability of the mycotic cell resulting in the leakage of essential constituents and the inhibition of glucose utilization of the cell (Sreedhara Swamy, 1974).

Physicochemical

Physical Characteristics

    A) Miconazole is an almost white to white powder (Prod Info ORAVIG buccal tablets, 2010).

Molecular Weight

    A) 416.13(Prod Info ORAVIG buccal tablets, 2010)

References

General Bibliography

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