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  • CLASSES

    Gynecological Antifungals

    DEA CLASS

    OTC

    DESCRIPTION

    Imidazole antifungal
    Fungicidal against Candida sp.
    Single intravaginal dose is effective

    COMMON BRAND NAMES

    Monistat 1 Simple Therapy, Vagistat-1

    HOW SUPPLIED

    Monistat 1 Simple Therapy/Vagistat-1 Vaginal Ointment: 6.5%

    DOSAGE & INDICATIONS

    For the treatment of vulvovaginal candidiasis (VVC).
    Intravaginal dosage (6.5% vaginal ointment)
    Female Adults

    For uncomplicated VVC, insert 1 applicatorful (about 4.6 g) intravaginally before bedtime as a single dose. The CDC recommends intermittent topical treatments as an alternative to fluconazole for maintenance of recurrent VVC. HIV opportunistic infection guidelines recommend topical treatment for 3 to 7 days for an uncomplicated infection, and 7 or more days if infection is severe or recurrent. Although this is a single-dose treatment, most women experience relief of symptoms within 7 days. If symptoms do not improve in three days or remain after seven days, a physician should be consulted.

    Female Children at least 12 years and Adolescents

    For uncomplicated VVC, insert 1 applicatorful (about 4.6 g) intravaginally before bedtime as a single dose. Although this is a single-dose treatment, most experience relief of symptoms within 7 days. If symptoms do not improve in three days or remain after seven days, a physician should be consulted.

    MAXIMUM DOSAGE

    Adults

    Maximum intravaginal dose is not available.

    Elderly

    Maximum intravaginal dose is not available.

    Adolescents

    Maximum intravaginal dose is not available.

    Children

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    No dosage adjustment needed.

    Renal Impairment

    No dosage adjustment needed.

    ADMINISTRATION

    Intravaginal Administration

    Tioconazole is usually administered intravaginally at bedtime as a single-dose treatment.
    Wash hands before and after administration.
    Read package directions carefully. The applicator should be opened just before use in order to prevent contamination. To use tioconazole vaginal ointment, gently insert the applicator tip high in the vagina and push the plunger to release the ointment into the vagina; gently remove the applicator.

    STORAGE

    1-Day:
    - Store at room temperature (between 59 to 86 degrees F)
    Monistat 1 Simple Therapy:
    - Store between 68 to 77 degrees F
    Vagistat-1:
    - Store at controlled room temperature (between 68 and 77 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    Infection

    Tioconazole is contraindicated in patients who have never had a vaginal yeast infection diagnosed by a physician.

    Pregnancy

    Tioconazole is classified as FDA pregnancy risk category C. There are limited data in pregnant women. Tioconazole did not adversely affect fetal viability or growth when administered orally to pregnant rats at doses up to 165 mg/kg/day during the period of organogenesis. However, tioconazole can cause dystocia in rats when treatment is extended through parturition; effects include prolongation of pregnancy, in utero deaths, and impaired pup survival. These effects are only observed with oral doses exceeding 20 mg/kg/day and intravaginal doses greater than 9 mg/kg/day. It is not known if tioconazole crosses the human placenta; however, there is negligible systemic absorption following intravaginal administration. Clinically significant exposure to the fetus is unlikely. According to CDC guidelines, many experts recommend 7 days of therapy with a topical azole preparation for the treatment of vulvovaginal candidiasis that occurs during pregnancy. Because tioconazole is administered as a single-dose treatment and the data regarding use in pregnant women is limited, an alternative antifungal (e.g., clotrimazole, miconazole or nystatin) should be considered. Pregnant women are advised to consult a health care professional prior to use.

    Breast-feeding

    There are no data regarding use of tioconazole during breast-feeding; excretion into breast milk is unknown. Systemic absorption following intravaginal administration is negligible. Although it's unlikely to produce detectable concentrations in breast-milk, nursing mothers are advised to consult a health care professional prior to use. Clotrimazole and miconazole 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, health care providers are encouraged to report the adverse effect to the FDA.

    Contraceptive devices, menstruation

    Patients should be advised not to use tampons, douches, spermicides, or other vaginal products while using tioconazole. Patients should avoid vaginal intercourse during treatment. The base used in tioconazole products may interact with contraceptive devices containing rubber or latex such as condoms, diaphragms, and cervical caps; these devices can be damaged while using tioconazole, and may lead to contraceptive failures or lack of protection from sexually transmitted diseases (STDs). Patients should avoid using condoms or vaginal contraceptive diaphragms for 3 days after treatment with tioconazole. Although tioconazole may be used during menstruation, instruct patients not to use tampons.

    Abdominal pain, fever, human immunodeficiency virus (HIV) infection, immunosuppression, pain, vomiting

    If symptoms do not improve within 3 days or remain after 7 days from day of treatment with tioconazole, a physician should be consulted and treatment discontinued. A physician should also be consulted if initial treatment is effective but symptoms recur within 2 months. Recurring yeast infections may be a sign of pregnancy or a serious condition such as AIDS or diabetes. Some patients should not use non-prescription tioconazole products without the supervision of a health care professional; patients with immunosuppression, undergoing chemotherapy, diabetes mellitus, or human immunodeficiency virus (HIV) infection should discuss use of these products with their health care professional prior to self-treatment. Females should not self-treat with intravaginal tioconazole products if the following signs and symptoms are present: back or shoulder pain, lower abdominal pain, chills, fever > 100 degrees F, nausea or vomiting, 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. If these symptoms occur during treatment, tioconazole should be discontinued and a physician consulted.

    Azole antifungals hypersensitivity

    Tioconazole should not be used in patients with a history of azole antifungals hypersensitivity. Hypersensitivity reactions may be due to the various vehicles present in tioconazole formulations.

    Children, infants, neonates

    Safe and effective use of tioconazole has not been established in neonates, infants and children less than 12 years of age.

    Ocular exposure

    Avoid ocular exposure to tioconazole. If ocular exposure occurs, treat by immediate flushing the affected eye with cool, clean water. Contact an ophthalmologist if eye irritation persists.

    ADVERSE REACTIONS

    Moderate

    contact dermatitis / Delayed / 1.0-10.0
    vaginal pain / Early / 0-1.0
    dyspareunia / Delayed / 0-1.0
    dysuria / Early / 0-1.0

    Mild

    pruritus / Rapid / 1.9-6.0
    vaginal irritation / Early / 1.9-6.0
    nocturia / Early / 0-1.0

    DRUG INTERACTIONS

    Acetaminophen; Butalbital; Caffeine; Codeine: (Moderate) The activity of codeine is due to its conversion to morphine via the cytochrome P450 (CYP) 2D6 hepatic isoenzyme. The CYP3A4 pathway is an important metabolic clearance route for codeine, and inhibition of this metabolic pathway by CYP3A4 inhibitors, such as azole antifungals, may lead to elevated codeine concentrations that are available for conversion to morphine by CYP2D6. Monitor patients for increased opiate-related side effects and adjust the dose of codeine as necessary.
    Acetaminophen; Codeine: (Moderate) The activity of codeine is due to its conversion to morphine via the cytochrome P450 (CYP) 2D6 hepatic isoenzyme. The CYP3A4 pathway is an important metabolic clearance route for codeine, and inhibition of this metabolic pathway by CYP3A4 inhibitors, such as azole antifungals, may lead to elevated codeine concentrations that are available for conversion to morphine by CYP2D6. Monitor patients for increased opiate-related side effects and adjust the dose of codeine as necessary.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) The activity of codeine is due to its conversion to morphine via the cytochrome P450 (CYP) 2D6 hepatic isoenzyme. The CYP3A4 pathway is an important metabolic clearance route for codeine, and inhibition of this metabolic pathway by CYP3A4 inhibitors, such as azole antifungals, may lead to elevated codeine concentrations that are available for conversion to morphine by CYP2D6. Monitor patients for increased opiate-related side effects and adjust the dose of codeine as necessary.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) The activity of codeine is due to its conversion to morphine via the cytochrome P450 (CYP) 2D6 hepatic isoenzyme. The CYP3A4 pathway is an important metabolic clearance route for codeine, and inhibition of this metabolic pathway by CYP3A4 inhibitors, such as azole antifungals, may lead to elevated codeine concentrations that are available for conversion to morphine by CYP2D6. Monitor patients for increased opiate-related side effects and adjust the dose of codeine as necessary.
    Chlorpheniramine; Codeine: (Moderate) The activity of codeine is due to its conversion to morphine via the cytochrome P450 (CYP) 2D6 hepatic isoenzyme. The CYP3A4 pathway is an important metabolic clearance route for codeine, and inhibition of this metabolic pathway by CYP3A4 inhibitors, such as azole antifungals, may lead to elevated codeine concentrations that are available for conversion to morphine by CYP2D6. Monitor patients for increased opiate-related side effects and adjust the dose of codeine as necessary.
    Clopidogrel: (Major) Administer clopidogrel and systemic azole antifungals together with caution. Clopidogrel requires hepatic biotransformation via 2 cytochrome dependent oxidative steps. The CYP3A4 isoenzyme is involved in one of the metabolic steps, and the CYP2C19 isoenzyme is involved in both steps. Systemic azole antifungals are inhibitors of CYP3A4 and some also inhibit CYP2C19 (e.g., fluconazole, ketoconazole, miconazole, voriconazole) and may decrease the hepatic metabolism of clopidogrel to its active metabolite. In a randomized crossover study, healthy subjects received a clopidogrel loading dose of 300 mg followed by 5 daily doses of 75 mg with or without the ketoconazole (400 mg/day). Ketoconazole decreased the active metabolite of clopidogrel by 48% after the 300 mg dose and 61% after the last maintenance dose was given. Ketoconazole also decreased the area under the concentration-time curve of clopidogrel's active metabolite by 22% after the loading dose and 29% after the last maintenance dose. If coadministration is unavoidable, the therapeutic effectiveness of clopidogrel should be closely monitored.
    Codeine: (Moderate) The activity of codeine is due to its conversion to morphine via the cytochrome P450 (CYP) 2D6 hepatic isoenzyme. The CYP3A4 pathway is an important metabolic clearance route for codeine, and inhibition of this metabolic pathway by CYP3A4 inhibitors, such as azole antifungals, may lead to elevated codeine concentrations that are available for conversion to morphine by CYP2D6. Monitor patients for increased opiate-related side effects and adjust the dose of codeine as necessary.
    Codeine; Guaifenesin: (Moderate) The activity of codeine is due to its conversion to morphine via the cytochrome P450 (CYP) 2D6 hepatic isoenzyme. The CYP3A4 pathway is an important metabolic clearance route for codeine, and inhibition of this metabolic pathway by CYP3A4 inhibitors, such as azole antifungals, may lead to elevated codeine concentrations that are available for conversion to morphine by CYP2D6. Monitor patients for increased opiate-related side effects and adjust the dose of codeine as necessary.
    Codeine; Phenylephrine; Promethazine: (Moderate) The activity of codeine is due to its conversion to morphine via the cytochrome P450 (CYP) 2D6 hepatic isoenzyme. The CYP3A4 pathway is an important metabolic clearance route for codeine, and inhibition of this metabolic pathway by CYP3A4 inhibitors, such as azole antifungals, may lead to elevated codeine concentrations that are available for conversion to morphine by CYP2D6. Monitor patients for increased opiate-related side effects and adjust the dose of codeine as necessary.
    Codeine; Promethazine: (Moderate) The activity of codeine is due to its conversion to morphine via the cytochrome P450 (CYP) 2D6 hepatic isoenzyme. The CYP3A4 pathway is an important metabolic clearance route for codeine, and inhibition of this metabolic pathway by CYP3A4 inhibitors, such as azole antifungals, may lead to elevated codeine concentrations that are available for conversion to morphine by CYP2D6. Monitor patients for increased opiate-related side effects and adjust the dose of codeine as necessary.

    PREGNANCY AND LACTATION

    Pregnancy

    Tioconazole is classified as FDA pregnancy risk category C. There are limited data in pregnant women. Tioconazole did not adversely affect fetal viability or growth when administered orally to pregnant rats at doses up to 165 mg/kg/day during the period of organogenesis. However, tioconazole can cause dystocia in rats when treatment is extended through parturition; effects include prolongation of pregnancy, in utero deaths, and impaired pup survival. These effects are only observed with oral doses exceeding 20 mg/kg/day and intravaginal doses greater than 9 mg/kg/day. It is not known if tioconazole crosses the human placenta; however, there is negligible systemic absorption following intravaginal administration. Clinically significant exposure to the fetus is unlikely. According to CDC guidelines, many experts recommend 7 days of therapy with a topical azole preparation for the treatment of vulvovaginal candidiasis that occurs during pregnancy. Because tioconazole is administered as a single-dose treatment and the data regarding use in pregnant women is limited, an alternative antifungal (e.g., clotrimazole, miconazole or nystatin) should be considered. Pregnant women are advised to consult a health care professional prior to use.

    There are no data regarding use of tioconazole during breast-feeding; excretion into breast milk is unknown. Systemic absorption following intravaginal administration is negligible. Although it's unlikely to produce detectable concentrations in breast-milk, nursing mothers are advised to consult a health care professional prior to use. Clotrimazole and miconazole 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, health care providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Tioconazole exerts its effect by disrupting normal fungal cell membrane permeability. Ergosterol is an essential component of the fungal cell membrane. Tioconazole inhibits ergosterol synthesis by interacting with 14-alpha demethylase, a cytochrome P-450 enzyme necessary for converting lanosterol to ergosterol. Inhibition of ergosterol synthesis results in increased cellular permeability, causing leakage of cellular contents such as phosphorous-containing compounds and potassium.

    PHARMACOKINETICS

    Tioconazole is administered intravaginally. Systemic absorption after a single intravaginal application in nonpregnant women is negligible.

    Other Route(s)

    Intravaginal Route
    One dose (applicatorful) of tioconazole 6.5% provides 3 days of in vitro antifungal activity, with vaginal concentrations maintained above the MIC. Systemic absorption after a single intravaginal application in nonpregnant women is negligible.