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  • CLASSES

    Azole Antifungals
    Gynecological Antifungals
    Topical Dermatological Antifungals

    DEA CLASS

    OTC, Rx

    DESCRIPTION

    Imidazole antifungal; used topically, as a bioadhesive buccal tablet, and intravaginally for various fungal infections.

    COMMON BRAND NAMES

    Aloe Vesta, Antifungal, AZOLEN TINCTURE, Baza, Cruex, Desenex, Desenex Jock Itch, Fungoid, Lotrimin AF, Lotrimin AF Antifungal Liquid, Lotrimin AF Deodorant, Lotrimin AF Powder, Lotrimin AF Spray, Micaderm, Micatin, Micro-Guard, Mitrazol, Monistat 1 Day or Night Combination Pack, Monistat 1 Triple Action, Monistat 3, Monistat 3 Triple Action System Combination Pack, Monistat 3 Vaginal Cream (Prefilled), Monistat 3 Vaginal Cream Combination Pack, Monistat 3 Vaginal Cream Combination Pack (Prefilled), Monistat 3 Vaginal Ovule Combination Pack, Monistat 3 Vaginal Suppositories Combination Pack, Monistat 7, Monistat 7 Vaginal Cream Combination Pack, Monistat-Derm, Neosporin AF, Novana Anti-Fungal, Oravig, Remedy, Soothe & Cool INZO, Ting Antifungal, Triple Paste AF, Vagistat-3, Zeasorb, Zeasorb AF

    HOW SUPPLIED

    Aloe Vesta/Antifungal/Baza/Micaderm/Micatin/Miconazole/Miconazole Nitrate/Monistat 3 Vaginal Suppositories Combination Pack/Monistat 7/Monistat 7 Vaginal Cream Combination Pack/Monistat-Derm/Neosporin AF/Novana Anti-Fungal/Remedy/Soothe & Cool INZO Topical Cream: 2%, 2g, 2-200mg
    Cruex/Lotrimin AF/Lotrimin AF Antifungal Liquid/Lotrimin AF Deodorant/Lotrimin AF Powder/Lotrimin AF Spray/Ting Antifungal Topical Spray: 2%
    Desenex/Lotrimin AF Powder/Miconazole/Miconazole Nitrate/Micro-Guard/Mitrazol/Remedy/Zeasorb/Zeasorb AF Topical Pwd: 2%
    Fungoid Topical Sol: 2%
    Miconazole/Miconazole Nitrate/Monistat 1 Day or Night Combination Pack/Monistat 3 Triple Action System Combination Pack/Monistat 3 Vaginal Cream (Prefilled)/Monistat 3 Vaginal Ovule Combination Pack/Monistat 3 Vaginal Suppositories Combination Pack/Monistat 7/Monistat 7 Vaginal Cream Combination Pack/Vagistat-3 Vaginal Cream: 2%, 4%, 2-1200mg, 2-200mg
    Miconazole/Miconazole Nitrate/Monistat 1 Day or Night Combination Pack/Monistat 3 Triple Action System Combination Pack/Monistat 3 Vaginal Ovule Combination Pack/Monistat 3 Vaginal Suppositories Combination Pack/Vagistat-3 Vaginal Supp: 100mg, 200mg, 2-1200mg, 2-200mg
    Oravig Buccal Tablet, SL: 50mg
    Triple Paste AF Topical Ointment: 2%

    DOSAGE & INDICATIONS

    For the topical treatment of tinea pedis and tinea corporis.
    Topical application
    Adults, Adolescents, and Children >= 2 years

    Apply 2% preparation to the cleansed, dry, infected area twice daily for 4 weeks.

    For the treatment of tinea cruris.
    Topical application
    Adults, Adolescents, and Children >= 2 years

    Apply 2% preparation to the cleansed, dry, infected area twice daily for 2 weeks.

    For the treatment of tinea versicolor.
    Topical application (skin cream only)
    Adults, Adolescents, and Children >= 2 years

    Apply 2% preparation to the cleansed, dry, infected area twice daily. An improvement is generally noted within 2 weeks of treatment.

    For the treatment of cutaneous candidiasis (including diaper dermatitis† complicated by candidiasis) or mucocutaneous candidiasis (i.e., oropharyngeal candidiasis (thrush), vulvovaginal candidiasis).
    For the treatment of diaper dermatitis† complicated by candidiasis.
    Topical application (0.25% skin ointment only)
    Infants and Children younger than 3 years

    In a double-blind, parallel-group trial, male and female infants (n=202) were randomized to receive either 0.25% miconazole ointment or placebo ointment vehicle. Caregivers applied the medication at each diaper change and after the infant's bath for 7 days; no other topical products were used. Improvement in rash was seen in both treatment groups at days 3, 5, and 7; however, miconazole-treated infants had significantly fewer rash sites. Also, among miconazole-treated infants, improvement was most marked in patients whose baseline rashes were positive for C. albicans. Treatment with the active ointment was as safe as the ointment vehicle alone. It was concluded that miconazole nitrate 0.25% ointment was safe and effective for treating diaper dermatitis.

    For the treatment of uncomplicated vulvovaginal candidiasis (VVC).
    NOTE: Vaginal miconazole products are often packaged with additional miconazole cream for Candida-associated external vulvar symptoms (e.g., itching, irritation); the vulvar cream may be used topically to the affected area twice daily for up to 7 days, regardless of the intravaginal regimen utilized.
    NOTE: Pregnant women are not recommended to self-diagnose vaginal candidiasis or use OTC forms of miconazole unless specifically recommended to do so by their health care prescriber.
    Intravaginal dosage (1-day regimen, vaginal suppository)
    Female Adults, Adolescents, and Children at least 12 years

    For uncomplicated VCC in non-pregnant patients, one 1200 mg suppository inserted vaginally for one single dose. The dose may be administered anytime during the day, however, bedtime dosing may be preferable for some patients.

    Intravaginal application (3-day regimen, vaginal suppository or cream)
    Female Adults, Adolescents, and Children at least 12 years

    For uncomplicated VCC in non-pregnant patients, one 200 mg suppository inserted intravaginally once daily at bedtime for 3 consecutive days or one applicatorful (5 g) of the 4% cream intravaginally once daily at bedtime for 3 consecutive days.

    Intravaginal dosage (7-day regimens, suppository or vaginal cream)
    Female Adults, Adolescents, and Children at least 12 years

    For uncomplicated VCC in pregnant or non-pregnant patients, one 100 mg suppository inserted intravaginally once daily at bedtime for 7 consecutive days or one applicatorful (5 g) of the 2% cream intravaginally once daily at bedtime for 7 consecutive days. The CDC suggests treatment up to 14 days in immunocompromised patients.  

    For the treatment of recurrent or severe vulvovaginal candidiasis (VVC).
    Intravaginal dosage
    Adult and Adolescent females

    The CDC recommends one 100 mg suppository inserted intravaginally once daily at bedtime for 7 to 14 consecutive days or one applicatorful (5 g) of the 2% cream intravaginally once daily at bedtime for 7 to 14 consecutive days; subsequent intermittent topical treatment, as an alternative to oral fluconazole, for maintenance of recurrent VVC may be considered. For HIV-infected patients, treat for at least 7 days.

    For the treatment of cutaneous candidiasis.
    Topical application (skin cream only)
    Adults, Adolescents, and Children at least 2 years

    Apply 2% preparation to the cleansed, dry, infected area twice daily. An improvement is generally noted within 2 weeks of treatment.

    For the local treatment of oropharyngeal candidiasis (thrush).
    Transmucosal dosage (adhesive buccal tablet)
    Adults and Adolescents at least 16 years

    Apply one 50 mg buccal tablet to the upper gum region, just above the incisor tooth (canine fossa) once daily for 14 days.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    Maximum dosage information is product specific.

    Elderly

    Maximum dosage information is product specific.

    Adolescents

    Maximum dosage information is product specific.

    Children

    Maximum dosage information is product specific.

    Infants

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    No dosage adjustment needed for topical or vaginal products. While miconazole systemic exposure is minimal with buccal application and no specific dosage adjustments are recommended, adhesive buccal tablets should be administered with caution in patients with hepatic impairment.

    Renal Impairment

    No dosage adjustment needed for topical, adhesive buccal tablets, or vaginal products.

    ADMINISTRATION

     
    NOTE: Dosage and duration of therapy vary depending on the infecting organism and the product utilized.

    Oral Administration
    Other Oral Formulations

    Transmucosal Administration (adhesive buccal tablet)
    Apply tablet in the morning after brushing the teeth.
    Apply with dry hands.
    Place the rounded surface of the tablet against the upper gum just above the incisor tooth (canine fossa) and hold in place with a slight pressure over the upper lip for 30 seconds to assure adhesion.
    Although the tablet is rounded on one side for comfort, the flat side may also be applied to the gum.
    The tablet will gradually dissolve.
    Administration of subsequent tablets should be made to alternate sides of the mouth.
    Before applying the next tablet, clear away any remaining tablet material.
    Do not crush, chew or swallow.
    Food and drink can be taken normally.
    Avoid chewing gum.
    If tablet does not adhere or falls off within the first 6 hours, the same tablet should be repositioned immediately. If the tablet still does not adhere, a new tablet should be placed.
    If the tablet falls off or is swallowed after it was in place for 6 hours or more, a new tablet should not be applied until the next regularly scheduled dose.

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

    Intravenous Administration

    Infusion:
    Dilute appropriate dose of solution in at least 200 ml of NS. Do not exceed a concentration of 6 mg/ml.
    Infuse over 30—60 minutes.

    Intrathecal Administration

    To be administered by a qualified health care professional experienced in drug administration into the CNS.
    Use the parenteral miconazole injection, it is preservative-free.
    No dilution necessary.

    Other Injectable Administration

    Intraventricular Administration
    To be administered by a qualified health care professional experienced in drug administration into the CNS.
    Use the parenteral miconazole injection, it is preservative-free.
    No dilution necessary.
     
    Intravesical Administration
    Dilute 200 mg of miconazole injection in at least 200 ml of NS.
    Instill intermittently or as a continuous irrigation into the bladder.

    Topical Administration

    Wash hands before and after use. Use universal precautions (i.e., gloves) for application if needed.
    Cleanse the affected area and dry thoroughly prior to application.
    In the treatment of cutaneous Candida infections, occlusive dressings should be avoided since these dressings provide favorable conditions for yeast growth.

    Cream/Ointment/Lotion Formulations

    Cream: Apply a thin layer to the affected area. Gently rub into the skin. Do not use creams labeled for dermatologic use intravaginally.

    Other Topical Formulations

    Shake powder: Sprinkle powder in a thin layer over the affected area.
    Spray powder or liquid: Shake aerosol can well before use. Hold spray 4—6 inches from the affected area. Spray product in a thin layer over the affected area. Do not inhale the spray or accidentally spray eyes or mucous membranes.

    Intravaginal Administration

    Apply intravaginally only those miconazole products labeled for intravaginal use. Other products may cause irritation to sensitive vaginal tissues.
    Wash hands before and after use. Use universal precautions (i.e., gloves) for application if needed.
    Some products supply both intravaginal suppositories and vulvar cream in a combination package; the cream may be applied to the externally to the affected area (vulva) to relieve itching and discomfort.
    Use special applicator supplied by the manufacturer.
    Instruct patient on proper administration and treatment course (see Patient Information).
    Instruct patient not to use tampons, douches, or spermicides during the treatment course; the patient should also be instructed to abstain from sexual activity during treatment. Vaginal miconazole products may damage condoms, diaphragms, and cervical caps and cause them to fail.

    STORAGE

    Generic:
    - Store at room temperature (between 59 to 86 degrees F)
    - Store below 86 degrees F
    Aloe Vesta:
    - Store between 68 to 77 degrees F
    Antifungal:
    - Store between 68 to 77 degrees F
    AZOLEN TINCTURE:
    - Protect from freezing
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    Baza:
    - Store at room temperature (between 59 to 86 degrees F)
    Cruex:
    - Do Not Store at Temperatures Above 120 degrees F (49 degrees C)
    - Store between 68 to 77 degrees F
    Desenex:
    - Do Not Store at Temperatures Above 120 degrees F (49 degrees C)
    - Store between 68 to 77 degrees F
    Desenex Jock Itch:
    - Do Not Store at Temperatures Above 120 degrees F (49 degrees C)
    - Store between 68 to 77 degrees F
    Fungoid:
    - Protect from freezing
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    Lotrimin AF:
    - Do Not Store at Temperatures Above 120 degrees F (49 degrees C)
    - Store between 68 to 77 degrees F
    Lotrimin AF Antifungal Liquid:
    - Store between 68 to 77 degrees F
    Lotrimin AF Deodorant:
    - Do Not Store at Temperatures Above 120 degrees F (49 degrees C)
    - Store between 68 to 77 degrees F
    Lotrimin AF Powder:
    - Do Not Store at Temperatures Above 120 degrees F (49 degrees C)
    - Store between 68 to 77 degrees F
    Lotrimin AF Spray:
    - Do Not Store at Temperatures Above 120 degrees F (49 degrees C)
    - Flammable, keep away from heat and flame
    - Store between 68 to 86 degrees F
    Micaderm :
    - Store between 68 to 77 degrees F
    Micatin:
    - Do Not Store at Temperatures Above 120 degrees F (49 degrees C)
    - Store between 68 to 77 degrees F
    Micro-Guard :
    - Store at room temperature (between 59 to 86 degrees F)
    Mitrazol:
    - Store at room temperature (between 59 to 86 degrees F)
    Monistat 1 Day or Night Combination Pack:
    - Store between 68 to 77 degrees F
    Monistat 1 Triple Action:
    - Store between 68 to 77 degrees F
    Monistat 1 Vaginal Ovule Combination Pack:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Monistat 1 Vaginal Ovule Combination Pack (Prefilled):
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Monistat 3:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Monistat 3 Triple Action System Combination Pack:
    - Avoid exposure to heat
    - Store at room temperature (between 59 to 86 degrees F)
    Monistat 3 Vaginal Cream (Prefilled):
    - Store between 68 to 77 degrees F
    Monistat 3 Vaginal Cream Combination Pack:
    - Store between 68 to 77 degrees F
    Monistat 3 Vaginal Cream Combination Pack (Prefilled):
    - Store between 68 to 77 degrees F
    Monistat 3 Vaginal Ovule Combination Pack:
    - Avoid exposure to heat
    - Store at room temperature (between 59 to 86 degrees F)
    Monistat 3 Vaginal Suppositories Combination Pack:
    - Avoid exposure to heat
    - Store at room temperature (between 59 to 86 degrees F)
    Monistat 7:
    - Store at room temperature (between 59 to 86 degrees F)
    - Store at room temperature not exceeding 86 degrees F
    Monistat 7 Vaginal Cream Combination Pack:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Monistat-Derm:
    - Store between 68 to 77 degrees F
    Neosporin AF:
    - Do Not Store at Temperatures Above 120 degrees F (49 degrees C)
    - Store between 68 to 77 degrees F
    Novana Anti-Fungal:
    - Store between 68 to 77 degrees F
    Oravig:
    - Protect from moisture
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Remedy:
    - Store between 68 to 77 degrees F
    Soothe & Cool INZO:
    - Store between 68 to 77 degrees F
    Ting Antifungal:
    - Do Not Store at Temperatures Above 120 degrees F (49 degrees C)
    - Store between 68 to 77 degrees F
    Triple Paste AF :
    - Storage information not listed
    Vagistat-3:
    - Avoid exposure to heat
    - Store at room temperature (between 59 to 86 degrees F)
    Zeasorb:
    - Store at room temperature (between 59 to 86 degrees F)
    Zeasorb AF:
    - Store at room temperature (between 59 to 86 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    Onychomycosis

    As with many other topical antifungal drugs, topical miconazole is not effective for onychomycosis. This condition usually requires treatment with an oral (systemic) antifungal drug.

    Pregnancy

    Miconazole vaginal, buccal, and topical preparations are classified in FDA pregnancy risk category C. There is minor systemic absorption of vaginally applied imidazole agents. Some clinicians state that intravaginal miconazole should be used with caution in the first trimester, however, clinical trials of pregnant women, some of whom have been in the first trimester of gestation, have not shown adverse effects on the mother or fetus. Candida vulvovaginitis may be more difficult to treat during pregnancy and may require longer durations (e.g., 7—14 days) of therapy versus treatment in non-pregnant women. Self-medication during pregnancy is contraindicated; pregnant women who suspect they have vaginal candidiasis should be evaluated by a qualified health care professional prior to miconazole treatment. There are no adequate, well-controlled trials of the adhesive buccal tablet in pregnant women; therefore, the manufacturer recommends that this product should not be used during pregnancy unless the potential benefit to the mother outweighs the potential risk to the fetus. Intravenous miconazole is no longer available in the US; systemic formulations were classified in FDA pregnancy risk category C.

    Breast-feeding

    There are limited data describing miconazole use during breast-feeding and it is unknown if it is excreted into breast milk. Topical and vaginal application is not expected to result in significant maternal absorption, and therefore should not be of great risk to a breast-feeding infant. Instruct mothers not to apply miconazole topically to the breast during times of breast-feeding. Although systemic absorption is undetectable, adhesive buccal tablets should be used with caution when administered to breast-feeding women. Systemic formulations should be used with caution. Fluconazole, clotrimazole, and nystatin may be potential alternatives to consider during breast-feeding. However, site of infection, local susceptibility patterns, and specific microbial susceptibility should be assessed before choosing an alternative agent. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Contraceptive devices, menstruation

    Patients who are using intravaginal miconazole preparations are recommended to abstain from sexual intercourse during the treatment course. Contraceptive devices, including condoms, diaphragms, spermicides, and cervical caps can be damaged while using these products, and may lead to contraceptive failures. Although miconazole may be used during menstruation, instruct patients not to use tampons.

    Abdominal pain, bone marrow suppression, diabetes mellitus, females, fever, human immunodeficiency virus (HIV) infection, immunosuppression, vaginal discharge

    Self-administration of intravaginal miconazole for longer than 7 days is contraindicated. If there is no improvement in the condition after 3 days, or if the condition persists after 7 days, the patient should discontinue therapy and consult a physician. Self-administration for athlete's foot and ringworm should not exceed 4 weeks, and self administration for 'jock-itch' should not exceed 2 weeks. If there is no improvement noted, the patient should consult his/her health care prescriber. Some patients should not use non-prescription miconazole products without the supervision of a health care professional, including patients with immunosuppression, bone marrow suppression due to chemotherapy, diabetes mellitus, or human immunodeficiency virus (HIV) infection. Females should not self-treat with intravaginal miconazole products if the following signs and symptoms are present: abdominal pain, fever > 100 degrees F, or foul-smelling vaginal discharge. Such symptoms may be an indication of another vaginal infection or pelvic inflammatory disease. Approximately 20% of all vaginal candidal infections co-exist with another infection.

    Children, infants, neonates

    Topical application of miconazole is contraindicated in neonates, infants, and children under the age of 2 years, unless recommended by a qualified health care prescriber. Miconazole topical products should only be used on children under the direct supervision of an adult. Intravaginal miconazole products should only be utilized in neonates, infants, and children under the age of 12 years old if prescribed by a qualified health care professional. The safety and efficacy of miconazole adhesive buccal tablets has not been established in neonates, infants, children, and adolescents less than 16 years old. The ability of pediatric patients younger than 16 years to comply with the buccal tablet application instructions has not been established; use in younger children is not recommended due to the potential risk of choking.

    Azole antifungals hypersensitivity, milk protein hypersensitivity

    Miconazole is contraindicated in patients who are hypersensitive to the drug.  Miconazole buccal tablets are also contraindicated in patients with milk protein hypersensitivity. Hypersensitivity reactions may be due to the various vehicles present in the different miconazole formulations. Some of these vehicles have been associated with anaphylactoid reactions. Miconazole should be also be used with caution in patients with azole antifungals hypersensitivity. Miconazole may have a cross sensitivity with other azole derivatives. Monitor patients with a history of hypersensitivity to azoles.

    Hepatic disease

    Parenteral miconazole should be given with caution to patients with hepatic disease because it is metabolized in the liver. While miconazole systemic exposure is minimal with buccal application and no specific dosage adjustments are recommended, adhesive buccal tablets should be administered with caution in patients with hepatic impairment.

    Tobacco smoking

    Some miconazole products (e.g., aerosol sprays) are flammable and should not be used near heat or flame of any kind, including tobacco smoking.

    Accidental exposure, ocular exposure, ophthalmic administration

    Avoid accidental exposure, such as inhalation or ocular exposure, with use of miconazole. Ocular exposure during topical application should be treated by immediate flushing with cool, clean water; do not administer via ophthalmic administration. Contact an ophthalmologist if eye irritation persists.

    ADVERSE REACTIONS

    Severe

    anaphylactoid reactions / Rapid / Incidence not known

    Moderate

    anemia / Delayed / 2.8-2.8
    lymphopenia / Delayed / 1.7-1.7
    elevated hepatic enzymes / Delayed / 1.0-1.0
    neutropenia / Delayed / Incidence not known
    oral ulceration / Delayed / Incidence not known

    Mild

    infection / Delayed / 11.9-15.9
    diarrhea / Early / 6.0-9.0
    headache / Early / 5.0-7.6
    nausea / Early / 0.7-6.6
    dysgeusia / Early / 2.9-4.1
    vomiting / Early / 0.7-3.8
    xerostomia / Early / 2.8-2.8
    cough / Delayed / 2.8-2.8
    fatigue / Early / 2.8-2.8
    pruritus / Rapid / 2.0-2.0
    rash (unspecified) / Early / Incidence not known
    vaginal discharge / Delayed / Incidence not known
    skin irritation / Early / Incidence not known
    abdominal pain / Early / Incidence not known
    fever / Early / Incidence not known

    DRUG INTERACTIONS

    Acetohexamide: (Moderate) Hypoglycemia, sometimes severe, has been reported when systemic azole antifungals are coadministered with sulfonylureas. No formal drug interaction studies have been performed with buccal miconazole. Miconazole is a known inhibitor of CYP2C9. Although the systemic absorption of miconazole following buccal administration is minimal and plasma concentrations are substantially lower than when miconazole is given intravenously, the potential for interaction with drugs metabolized through CYP2C9 (such as the sulfonylureas) cannot be ruled out.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Moderate) No formal drug interaction studies have been performed with buccal miconazole. Miconazole is a known inhibitor of CYP3A4. Although the systemic absorption of miconazole following buccal miconazole administration is minimal and plasma concentrations of miconazole are substantially lower than when given intravenously, the potential for interaction with drugs metabolized through CYP3A4 (such as the ergot alkaloids) cannot be ruled out. Be alert for symptoms of a potential interaction, such as ischemia, cyanosis, and numbness of the extremities or other serious ergot-related effects.
    Caffeine; Ergotamine: (Moderate) No formal drug interaction studies have been performed with buccal miconazole. Miconazole is a known inhibitor of CYP3A4. Although the systemic absorption of miconazole following buccal miconazole administration is minimal and plasma concentrations of miconazole are substantially lower than when given intravenously, the potential for interaction with drugs metabolized through CYP3A4 (such as the ergot alkaloids) cannot be ruled out. Be alert for symptoms of a potential interaction, such as ischemia, cyanosis, and numbness of the extremities or other serious ergot-related effects.
    Chlorpropamide: (Moderate) Hypoglycemia, sometimes severe, has been reported when systemic azole antifungals are coadministered with sulfonylureas. No formal drug interaction studies have been performed with buccal miconazole. Miconazole is a known inhibitor of CYP2C9. Although the systemic absorption of miconazole following buccal administration is minimal and plasma concentrations are substantially lower than when miconazole is given intravenously, the potential for interaction with drugs metabolized through CYP2C9 (such as the sulfonylureas) cannot be ruled out.
    Dihydroergotamine: (Moderate) No formal drug interaction studies have been performed with buccal miconazole. Miconazole is a known inhibitor of CYP3A4. Although the systemic absorption of miconazole following buccal miconazole administration is minimal and plasma concentrations of miconazole are substantially lower than when given intravenously, the potential for interaction with drugs metabolized through CYP3A4 (such as the ergot alkaloids) cannot be ruled out. Be alert for symptoms of a potential interaction, such as ischemia, cyanosis, and numbness of the extremities or other serious ergot-related effects.
    Ergoloid Mesylates: (Moderate) No formal drug interaction studies have been performed with buccal miconazole. Miconazole is a known inhibitor of CYP3A4. Although the systemic absorption of miconazole following buccal miconazole administration is minimal and plasma concentrations of miconazole are substantially lower than when given intravenously, the potential for interaction with drugs metabolized through CYP3A4 (such as the ergot alkaloids) cannot be ruled out. Be alert for symptoms of a potential interaction, such as ischemia, cyanosis, and numbness of the extremities or other serious ergot-related effects.
    Ergonovine: (Moderate) No formal drug interaction studies have been performed with buccal miconazole. Miconazole is a known inhibitor of CYP3A4. Although the systemic absorption of miconazole following buccal miconazole administration is minimal and plasma concentrations of miconazole are substantially lower than when given intravenously, the potential for interaction with drugs metabolized through CYP3A4 (such as the ergot alkaloids) cannot be ruled out. Be alert for symptoms of a potential interaction, such as ischemia, cyanosis, and numbness of the extremities or other serious ergot-related effects.
    Ergot alkaloids: (Moderate) No formal drug interaction studies have been performed with buccal miconazole. Miconazole is a known inhibitor of CYP3A4. Although the systemic absorption of miconazole following buccal miconazole administration is minimal and plasma concentrations of miconazole are substantially lower than when given intravenously, the potential for interaction with drugs metabolized through CYP3A4 (such as the ergot alkaloids) cannot be ruled out. Be alert for symptoms of a potential interaction, such as ischemia, cyanosis, and numbness of the extremities or other serious ergot-related effects.
    Ergotamine: (Moderate) No formal drug interaction studies have been performed with buccal miconazole. Miconazole is a known inhibitor of CYP3A4. Although the systemic absorption of miconazole following buccal miconazole administration is minimal and plasma concentrations of miconazole are substantially lower than when given intravenously, the potential for interaction with drugs metabolized through CYP3A4 (such as the ergot alkaloids) cannot be ruled out. Be alert for symptoms of a potential interaction, such as ischemia, cyanosis, and numbness of the extremities or other serious ergot-related effects.
    Fosphenytoin: (Moderate) No formal drug interaction studies have been performed with buccal miconazole. Miconazole is a known inhibitor of CYP2C9. Although the systemic absorption of miconazole following buccal miconazole administration is minimal and plasma concentrations of miconazole are substantially lower than when given intravenously, the potential for interaction with drugs metabolized through CYP2C9 (such as phenytoin or fosphenytoin) cannot be ruled out.
    Glimepiride: (Moderate) Hypoglycemia, sometimes severe, has been reported when systemic azole antifungals are coadministered with sulfonylureas. No formal drug interaction studies have been performed with buccal miconazole. Miconazole is a known inhibitor of CYP2C9. Although the systemic absorption of miconazole following buccal administration is minimal and plasma concentrations are substantially lower than when miconazole is given intravenously, the potential for interaction with drugs metabolized through CYP2C9 (such as the sulfonylureas) cannot be ruled out.
    Glimepiride; Pioglitazone: (Moderate) Hypoglycemia, sometimes severe, has been reported when systemic azole antifungals are coadministered with sulfonylureas. No formal drug interaction studies have been performed with buccal miconazole. Miconazole is a known inhibitor of CYP2C9. Although the systemic absorption of miconazole following buccal administration is minimal and plasma concentrations are substantially lower than when miconazole is given intravenously, the potential for interaction with drugs metabolized through CYP2C9 (such as the sulfonylureas) cannot be ruled out.
    Glimepiride; Rosiglitazone: (Moderate) Hypoglycemia, sometimes severe, has been reported when systemic azole antifungals are coadministered with sulfonylureas. No formal drug interaction studies have been performed with buccal miconazole. Miconazole is a known inhibitor of CYP2C9. Although the systemic absorption of miconazole following buccal administration is minimal and plasma concentrations are substantially lower than when miconazole is given intravenously, the potential for interaction with drugs metabolized through CYP2C9 (such as the sulfonylureas) cannot be ruled out.
    Glipizide: (Moderate) Hypoglycemia, sometimes severe, has been reported when systemic azole antifungals are coadministered with sulfonylureas. No formal drug interaction studies have been performed with buccal miconazole. Miconazole is a known inhibitor of CYP2C9. Although the systemic absorption of miconazole following buccal administration is minimal and plasma concentrations are substantially lower than when miconazole is given intravenously, the potential for interaction with drugs metabolized through CYP2C9 (such as the sulfonylureas) cannot be ruled out.
    Glipizide; Metformin: (Moderate) Hypoglycemia, sometimes severe, has been reported when systemic azole antifungals are coadministered with sulfonylureas. No formal drug interaction studies have been performed with buccal miconazole. Miconazole is a known inhibitor of CYP2C9. Although the systemic absorption of miconazole following buccal administration is minimal and plasma concentrations are substantially lower than when miconazole is given intravenously, the potential for interaction with drugs metabolized through CYP2C9 (such as the sulfonylureas) cannot be ruled out.
    Glyburide: (Moderate) Hypoglycemia, sometimes severe, has been reported when systemic azole antifungals are coadministered with sulfonylureas. No formal drug interaction studies have been performed with buccal miconazole. Miconazole is a known inhibitor of CYP2C9. Although the systemic absorption of miconazole following buccal administration is minimal and plasma concentrations are substantially lower than when miconazole is given intravenously, the potential for interaction with drugs metabolized through CYP2C9 (such as the sulfonylureas) cannot be ruled out.
    Glyburide; Metformin: (Moderate) Hypoglycemia, sometimes severe, has been reported when systemic azole antifungals are coadministered with sulfonylureas. No formal drug interaction studies have been performed with buccal miconazole. Miconazole is a known inhibitor of CYP2C9. Although the systemic absorption of miconazole following buccal administration is minimal and plasma concentrations are substantially lower than when miconazole is given intravenously, the potential for interaction with drugs metabolized through CYP2C9 (such as the sulfonylureas) cannot be ruled out.
    Methylergonovine: (Moderate) No formal drug interaction studies have been performed with buccal miconazole. Miconazole is a known inhibitor of CYP3A4. Although the systemic absorption of miconazole following buccal miconazole administration is minimal and plasma concentrations of miconazole are substantially lower than when given intravenously, the potential for interaction with drugs metabolized through CYP3A4 (such as the ergot alkaloids) cannot be ruled out. Be alert for symptoms of a potential interaction, such as ischemia, cyanosis, and numbness of the extremities or other serious ergot-related effects.
    Methysergide: (Moderate) No formal drug interaction studies have been performed with buccal miconazole. Miconazole is a known inhibitor of CYP3A4. Although the systemic absorption of miconazole following buccal miconazole administration is minimal and plasma concentrations of miconazole are substantially lower than when given intravenously, the potential for interaction with drugs metabolized through CYP3A4 (such as the ergot alkaloids) cannot be ruled out. Be alert for symptoms of a potential interaction, such as ischemia, cyanosis, and numbness of the extremities or other serious ergot-related effects.
    Nystatin: (Moderate) The combination of miconazole and nystatin represents duplication of therapy whenever the drugs are used by similar routes and are usually avoided.
    Pergolide: (Moderate) No formal drug interaction studies have been performed with buccal miconazole. Miconazole is a known inhibitor of CYP3A4. Although the systemic absorption of miconazole following buccal miconazole administration is minimal and plasma concentrations of miconazole are substantially lower than when given intravenously, the potential for interaction with drugs metabolized through CYP3A4 (such as the ergot alkaloids) cannot be ruled out. Be alert for symptoms of a potential interaction, such as ischemia, cyanosis, and numbness of the extremities or other serious ergot-related effects.
    Phenytoin: (Moderate) No formal drug interaction studies have been performed with buccal miconazole. Miconazole is a known inhibitor of CYP2C9. Although the systemic absorption of miconazole following buccal miconazole administration is minimal and plasma concentrations of miconazole are substantially lower than when given intravenously, the potential for interaction with drugs metabolized through CYP2C9 (such as phenytoin or fosphenytoin) cannot be ruled out.
    Progesterone: (Moderate) Vaginal preparations of progesterone (e.g., Crinone, Endometrin, and Prochieve) should not be used with other intravaginal products (e.g., vaginal antifungals, such as clotrimazole, miconazole nitrate, terconazole, or tioconazole vaginal) as concurrent use may alter progesterone release and absorption from the vagina. Separate the times of administration to avoid the interaction. The manufacturers of Crinone and Prochieve indicate that other intravaginal products can be used as long as 6 hours has lapsed either before or after vaginal administration of progesterone. Endometrin is generally not recommended for use with other vaginal products (e.g., antifungal products) as this may alter progesterone release and absorption from the vaginal insert and the potential for interaction has not been formally assessed; use other vaginal products if medically necessary, but be aware that the response to Endometrin may be altered.
    Sulfonylureas: (Moderate) Hypoglycemia, sometimes severe, has been reported when systemic azole antifungals are coadministered with sulfonylureas. No formal drug interaction studies have been performed with buccal miconazole. Miconazole is a known inhibitor of CYP2C9. Although the systemic absorption of miconazole following buccal administration is minimal and plasma concentrations are substantially lower than when miconazole is given intravenously, the potential for interaction with drugs metabolized through CYP2C9 (such as the sulfonylureas) cannot be ruled out.
    Tolazamide: (Moderate) Hypoglycemia, sometimes severe, has been reported when systemic azole antifungals are coadministered with sulfonylureas. No formal drug interaction studies have been performed with buccal miconazole. Miconazole is a known inhibitor of CYP2C9. Although the systemic absorption of miconazole following buccal administration is minimal and plasma concentrations are substantially lower than when miconazole is given intravenously, the potential for interaction with drugs metabolized through CYP2C9 (such as the sulfonylureas) cannot be ruled out.
    Tolbutamide: (Moderate) Hypoglycemia, sometimes severe, has been reported when systemic azole antifungals are coadministered with sulfonylureas. No formal drug interaction studies have been performed with buccal miconazole. Miconazole is a known inhibitor of CYP2C9. Although the systemic absorption of miconazole following buccal administration is minimal and plasma concentrations are substantially lower than when miconazole is given intravenously, the potential for interaction with drugs metabolized through CYP2C9 (such as the sulfonylureas) cannot be ruled out.
    Torsemide: (Minor) No formal drug interaction studies have been performed with buccal miconazole. Systemic absorption of miconazole following buccal administration is minimal. Vaginal and topical preparations are not likely to interact. However, the diuretic effect and blood pressure response may be affected if torsemide is administered with a CYP2C9 inhibitor. Torsemide is a substrate of CYP2C9; miconazole inhibits CYP2C9. Concomitant use of torsemide and miconazole can theoretically decrease torsemide clearance and increase torsemide plasma concentrations.
    Warfarin: (Moderate) Concomitant administration of miconazole and warfarin has resulted in enhancement of anticoagulant effect. Closely monitor prothrombin time, International Normalized Ratio (INR), or other suitable anticoagulation tests if miconazole is administered concomitantly with warfarin. Also monitor for evidence of bleeding. Miconazole is a known inhibitor of CYP2C9 and CYP3A4. The systemic absorption of buccal miconazole is minimal and plasma concentrations of miconazole are substantially lower than when given intravenously. However, there have been reported cases of bleeding and bruising with orally administered miconazole. (Moderate) Concomitant administration of miconazole and warfarin has resulted in enhancement of anticoagulant effect. Closely monitor prothrombin time, International Normalized Ratio (INR), or other suitable anticoagulation tests if topical or vaginal miconazole is administered concomitantly with warfarin. Also monitor for evidence of bleeding. Miconazole is a known inhibitor of CYP2C9 and CYP3A4. The systemic absorption of miconazole following vaginal or topical administration is minimal and plasma concentrations of miconazole are substantially lower than when given intravenously. However, there have been reported cases of bleeding and bruising following the concomitant use of warfarin and topical or intravaginal miconazole.

    PREGNANCY AND LACTATION

    Pregnancy

    Miconazole vaginal, buccal, and topical preparations are classified in FDA pregnancy risk category C. There is minor systemic absorption of vaginally applied imidazole agents. Some clinicians state that intravaginal miconazole should be used with caution in the first trimester, however, clinical trials of pregnant women, some of whom have been in the first trimester of gestation, have not shown adverse effects on the mother or fetus. Candida vulvovaginitis may be more difficult to treat during pregnancy and may require longer durations (e.g., 7—14 days) of therapy versus treatment in non-pregnant women. Self-medication during pregnancy is contraindicated; pregnant women who suspect they have vaginal candidiasis should be evaluated by a qualified health care professional prior to miconazole treatment. There are no adequate, well-controlled trials of the adhesive buccal tablet in pregnant women; therefore, the manufacturer recommends that this product should not be used during pregnancy unless the potential benefit to the mother outweighs the potential risk to the fetus. Intravenous miconazole is no longer available in the US; systemic formulations were classified in FDA pregnancy risk category C.

    There are limited data describing miconazole use during breast-feeding and it is unknown if it is excreted into breast milk. Topical and vaginal application is not expected to result in significant maternal absorption, and therefore should not be of great risk to a breast-feeding infant. Instruct mothers not to apply miconazole topically to the breast during times of breast-feeding. Although systemic absorption is undetectable, adhesive buccal tablets should be used with caution when administered to breast-feeding women. Systemic formulations should be used with caution. Fluconazole, clotrimazole, and nystatin may be potential alternatives to consider during breast-feeding. However, site of infection, local susceptibility patterns, and specific microbial susceptibility should be assessed before choosing an alternative agent. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Like other azole antifungals, miconazole exerts its effect by altering the fungal cell membrane. Miconazole inhibits ergosterol synthesis by interacting with 14-alpha demethylase, a cytochrome P-450 enzyme that is necessary for the conversion of lanosterol to ergosterol, an essential component of the membrane. Miconazole also affects the synthesis of triglycerides and fatty acids and inhibits oxidative and peroxidative enzymes, increasing the amount of reactive oxygen species within the cell. Azole antifungals are considered fungistatic. In contrast, amphotericin B binds to ergosterol after it is synthesized. Inhibition of ergosterol synthesis results in increased cellular permeability, causing leakage of cellular contents. Miconazole does not appear to have the same effect on human cholesterol synthesis. Other antifungal effects of azole compounds have been proposed and include: inhibition of endogenous respiration; interaction with membrane phospholipids; inhibition of yeast transformation to mycelial forms; and accumulation of ergosterol precursors and toxic peroxides resulting in cytolysis of the cell. Other mechanisms may involve inhibition of purine uptake and impairment of triglyceride and/or phospholipid biosynthesis.

    PHARMACOKINETICS

    Miconazole has been administered by the intravenous, intraventricular, intravesicular, topical, adhesive buccal tablet, and intravaginal routes. Parenteral formulations are no longer marketed in the US and, thus, it is primarily administered intravaginally, via adhesive buccal tablet, or topically.
     
    Most of the absorbed miconazole is metabolized by the liver, with less than 1% of the administered dose found in the urine. There are no active metabolites. Terminal half-life in healthy volunteers is 24 hours after systemic administration.
     
    Affected Cytochrome P450 (CYP450) isoenzymes and drug transporters: CYP2C9, CYP2C19, CYP3A4
    Miconazole is a potent inhibitor of the CYP2C9 isoenzyme. In vitro, it is a potent inhibitor of the CYP2C19 isoenzyme and a moderate inhibitor of the CYP3A4 isoenzyme.

    Oral Route

    Transmucosal Route
    The miconazole adhesive buccal tablet is used for local treatment. A single, 50 mg buccal tablet provided mean maximum salivary concentrations of 15.1 mcg/ml at 7 hours after application in 18 healthy volunteers. The average saliva exposure, estimated as an AUC, was 55.23 mcg x h/ml. The median Tmax was 7 hours. In healthy volunteers, the average duration of buccal adhesion was 15 hours after a single application. Plasma concentrations evaluated after 7 days of treatment in 40 HIV-positive patients were all below the limit of quantification. A  formal food effect study has not been conducted; however, patients were allowed to eat and drink normally during clinical trials.

    Intravenous Route

    When administered over 1 hour, IV infusions of 9 mg/kg or 350 mg/m2 or above are needed to achieve plasma miconazole concentrations of at least 1 mcg/ml. (The usual MIC for most susceptible fungi is 0.5-2 mcg/ml.) Miconazole is widely distributed into most bodily tissues and fluids including inflamed joints, the vitreous humor of the eye, and the peritoneal cavity. Poor penetration is achieved in the sputum and saliva. Protein binding is over 90%. The elimination of miconazole occurs in a triphasic manner, with biological half-lives of each phase being 0.4, 2.1, and 24.1 hours, respectively. Metabolism of miconazole is mainly in the liver. Roughly 14—22% of a dose of IV miconazole is excreted in the urine as inactive metabolites.

    Topical Route

    There have been no reports indicating that miconazole nitrate is absorbed following application to intact skin. Average peak serum concentrations of 4.2 ng/ml have been reported after six daily applications of the 14-day regimen for vulvovaginal candidiasis. About 1% of this dose was recovered in urine and feces. Distribution, metabolism, and elimination of topical miconazole are the same as after intravenous administration.

    Other Route(s)

    Intravaginal Route
    Only small amounts of intravaginal miconazole are absorbed systemically. Average peak serum concentrations of 4.2 ng/ml have been reported after six daily applications of the 14-day regimen for vulvovaginal candidiasis. About 1% of this dose was recovered in urine and feces. Distribution, metabolism, and elimination of topical miconazole are the same as after intravenous administration.
     
    Intrathecal and Intraventricular Route
    Because IV miconazole does not distribute well into the CSF, the drug must be administered intraventricularly or intrathecally to achieve fungistatic CSF concentrations. Intrathecal administration of 20 mg miconazole has produced CSF concentrations of 1.1—2.4 mcg/ml at 24 hours, which decline to less than 0.24 mcg/ml at 72 hours.