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  • CLASSES

    Antiinfectives and Antiseptics for Local Oral Treatment
    Gynecological Antifungals
    Topical Dermatological Antifungals

    DEA CLASS

    OTC, Rx

    DESCRIPTION

    Imidazole antifungal agent marketed in a variety of preparations including vaginal suppositories and cream, topical lotion and cream, topical solution, and lozenges. Used for infections due to pathogenic dermatophytes, yeasts, and Malassezia furfur including ringworm (dermatophytosis), vaginal and oral candidiasis, and tinea infections. Not indicated for subcutaneous mycoses.

    COMMON BRAND NAMES

    Alevazol, Anti-Fungal, Antifungal, Cruex, Desenex, Fungoid, Gyne-Lotrimin, Lotrimin, Lotrimin AF, Lotrimin AF Ringworm, Mycelex, Mycelex Troche

    HOW SUPPLIED

    Alevazol Topical Ointment: 1%
    Antifungal/Anti-Fungal/Clotrimazole/Cruex/Desenex/Lotrimin/Lotrimin AF/Lotrimin AF Ringworm Topical Cream: 1%
    Clotrimazole/Fungoid/Lotrimin/Lotrimin AF Topical Sol: 1%
    Clotrimazole/Gyne-Lotrimin/Mycelex Vaginal Cream: 1%, 2%
    Clotrimazole/Mycelex Troche Oropharyngeal Troche: 10mg

    DOSAGE & INDICATIONS

    For the treatment of candidiasis, specifically mucocutaneous candidiasis (i.e., oropharyngeal candidiasis (thrush), vulvovaginal candidiasis).
    For the treatment of oropharyngeal candidiasis (thrush).
    Transmucosal (troche) dosage
    Adults, Adolescents, and Children 3 years and older

    Dissolve a 10 mg troche slowly and completely in the mouth 5 times daily for 14 days. Prolonged use may be necessary in immunosuppressed patients. The Infectious Diseases Society of America (IDSA) recommends 7 to 14 days of therapy after clinical improvement in adult patients. The opportunistic infection guidelines recommend 10 mg PO 5 times daily for 7 to 14 days as an alternative initial treatment in HIV-infected patients.

    For the treatment of vulvovaginal candidiasis (VVC).
    Vaginal dosage (vaginal cream)
    Adult females

    For uncomplicated VVC, apply 1 applicatorful of 1% cream (50 mg) vaginally once daily at bedtime for 7 days or apply 1 applicatorful of 2% cream (100 mg) vaginally once daily at bedtime for 3 days. The manufacturer suggests that external application of the cream may also be used if there are extra-vaginal symptoms. The CDC recommends the same daily dose, with treatment durations of 7 to 14 days for the 1% cream, 3 days for the 2% cream, 7 days for pregnant patients, and 7 to 14 days for immunocompromised patients. For severe or recurrent VVC, the CDC recommends treating for 7 to 14 days; subsequent intermittent topical treatments may be considered. For HIV-infected patients, treat for 3 to 7 days for uncomplicated VVC and for at least 7 days for severe or recurrent VVC.

    Adolescent females

    For uncomplicated VVC, apply 1 applicatorful of 1% cream (50 mg) vaginally once daily at bedtime for 7 days or apply 1 applicatorful of 2% cream (100 mg) vaginally once daily at bedtime for 3 days. The American Academy of Pediatrics (AAP) suggests that the 1% cream may be administered up to 14 days and that 7 days of topical therapy is recommended for pregnant patients. The manufacturer suggests that external application of the cream may also be used if there are extra-vaginal symptoms. For HIV-infected patients, treat for 3 to 7 days for uncomplicated VVC and for at least 7 days for severe or recurrent VVC.

    Vaginal dosage (tablets)
    Adults and Adolescents

    One 100-mg vaginal tablet intravaginally once daily at bedtime for 7 days or two 100-mg tablets intravaginally once daily at bedtime for 3 days.

    For candidiasis prophylaxis to reduce the incidence of oropharyngeal candidiasis in immunocompromised patients undergoing chemotherapy or radiotherapy in the treatment of leukemia or solid tumors, or in allograft transplant patients who are receiving corticosteroid therapy.
    Transmucosal dosage
    Adults

    Dissolve a 10 mg troche slowly and completely in the mouth 3 times daily for the duration of chemotherapy or until steroids are reduced to maintenance levels.

    For the treatment of tinea corporis, tinea cruris, and tinea pedis.
    Topical dosage
    Adults

    Apply to affected skin and surrounding areas twice daily, morning and evening.

    Children and Adolescents 2 to 17 years

    Apply to affected skin and surrounding areas twice daily, morning and evening.

    For the treatment of fungal otitis externa†.
    Topical dosage (1% topical solution)
    Adults

    A typical dosage is 3 to 4 drops into affected ear 4 times daily for 7 days.

    Children and Adolescents 2 to 17 years

    A typical dosage is 3 to 4 drops into affected ear 4 times daily for 7 days.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    Maximum dosage information is not available.

    Elderly

    Maximum dosage information is not available.

    Adolescents

    Maximum dosage information is not available.

    Children

    Maximum dosage information is not available.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

    For storage information, see specific product information within the How Supplied section.

    Oral Administration
    Other Oral Formulations

    Transmucosal Administration
    Troches should be dissolved slowly in the mouth, do not chew.

    Topical Administration
    Cream/Ointment/Lotion Formulations

    Topical preparations should not be applied to the eye; do not use intravaginally.
    Rub cream or solution gently into cleansed affected skin.

    Intravaginal Administration

    Apply intravaginally only those clotrimazole products labeled for intravaginal use.
    Some products supply both intravaginal tablets and vaginal cream in a combination package; the intravaginal 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.
    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 clotrimazole products may damage condoms, diaphragms, and cervical caps and cause them to fail.

    STORAGE

    Alevazol :
    - Store at room temperature (between 59 to 86 degrees F)
    Antifungal:
    - Store between 68 to 77 degrees F
    Anti-Fungal:
    - Store between 68 to 77 degrees F
    Cruex:
    - Store between 68 to 77 degrees F
    Desenex:
    - Store between 68 to 77 degrees F
    Fungoid:
    - Store at room temperature (between 59 to 86 degrees F)
    Gyne-Lotrimin:
    - Store between 36 to 86 degrees F
    Lotrimin:
    - Store at room temperature (between 59 to 86 degrees F)
    Lotrimin AF:
    - Store at room temperature (between 59 to 86 degrees F)
    Lotrimin AF Ringworm:
    - Store between 68 to 77 degrees F
    Mycelex:
    - Store between 36 to 86 degrees F
    Mycelex Troche:
    - Protect from freezing
    - Store below 86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Onychomycosis

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

    Pregnancy

    Clotrimazole vaginal and topical preparations are classified in FDA pregnancy risk category B.Vaginal use during the second and third trimesters in humans has not resulted in any adverse effects; use in the first trimester has not been adequately studied and is not recommended. In animal studies, no fetal harm occurred following administration of intravaginal doses up to 100 mg/kg in pregnant rats. Self-medication during pregnancy is contraindicated. Clotrimazole oral lozenges for local therapy are classified as FDA pregnancy risk category C. Adequate and well-controlled studies have not been performed in humans. No teratogenic effects have been demonstrated in animal studies at doses up to 200 times the recommended human dose (RHD); however, doses of 100 time RHD was found to be embryotoxic in rats and mice. The manufacturer states to administer during pregnancy only if the potential benefits justify the potential risk to the fetus.

    Breast-feeding

    The use of clotrimazole during breast-feeding has not been studied. Topical application is not expected to result in significant maternal absorption, and should not be of significant risk to a breast-feeding infant. Instruct mothers not to apply clotrimazole topically to the breast during times of breast-feeding. The oral troches may be absorbed systemically, but significant infant exposure is unknown and expected to be low; observe the infant for any possible adverse effects. Fluconazole, miconazole, and nystatin may be potential alternatives to consider, though 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 ingested or administered drug, health care providers are encouraged to report the adverse effect to the FDA.

    Contraceptive devices, menstruation

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

    Azole antifungals hypersensitivity

    Clotrimazole should be used with caution in patients with azole antifungals hypersensitivity. Hypersensitivity reactions may be due to the various vehicles present in the different clotrimazole formulations. Clotrimazole may have a cross sensitivity with other azole derivatives.

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

    Self-administration of clotrimazole 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 clotrimazole therapy and consult a physician. Some patients should not use non-prescription clotrimazole 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 clotrimazole 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

    When used as indicated and in the recommended dosages, safety and effectiveness of the topical application of clotrimazole have been established in children. Intravaginal products should not be used in neonates, infants, or children under the age of 12 years unless it is under the direct supervision of a qualified health care professional. Use of oral lozenges is not recommended in neonates, infants, and children under the age of 3 years. Safe use of clotrimazole troches is limited by the child's ability to retain the lozenge properly in the mouth.

    Ocular exposure, ophthalmic administration

    Avoid ocular exposure to clotrimazole; do not give by ophthalmic administration. If ocular exposure occurs, treat by immediate flushing the affected eye with cool, clean water. Contact an ophthalmologist if eye irritation persists.

    Geriatric

    Clinical studies of clotrimazole did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the geriatric and younger patients.

    ADVERSE REACTIONS

    Moderate

    elevated hepatic enzymes / Delayed / 15.0-15.0
    vaginal pain / Early / 1.0-10.0
    erythema / Early / Incidence not known
    edema / Delayed / Incidence not known

    Mild

    skin irritation / Early / 1.0-10.0
    vaginal irritation / Early / 1.0-10.0
    abdominal pain / Early / 7.0-7.0
    nausea / Early / 5.0-5.0
    pruritus / Rapid / Incidence not known
    urticaria / Rapid / Incidence not known
    diarrhea / Early / Incidence not known
    vomiting / Early / Incidence not known

    DRUG INTERACTIONS

    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.

    PREGNANCY AND LACTATION

    Pregnancy

    Clotrimazole vaginal and topical preparations are classified in FDA pregnancy risk category B.Vaginal use during the second and third trimesters in humans has not resulted in any adverse effects; use in the first trimester has not been adequately studied and is not recommended. In animal studies, no fetal harm occurred following administration of intravaginal doses up to 100 mg/kg in pregnant rats. Self-medication during pregnancy is contraindicated. Clotrimazole oral lozenges for local therapy are classified as FDA pregnancy risk category C. Adequate and well-controlled studies have not been performed in humans. No teratogenic effects have been demonstrated in animal studies at doses up to 200 times the recommended human dose (RHD); however, doses of 100 time RHD was found to be embryotoxic in rats and mice. The manufacturer states to administer during pregnancy only if the potential benefits justify the potential risk to the fetus.

    The use of clotrimazole during breast-feeding has not been studied. Topical application is not expected to result in significant maternal absorption, and should not be of significant risk to a breast-feeding infant. Instruct mothers not to apply clotrimazole topically to the breast during times of breast-feeding. The oral troches may be absorbed systemically, but significant infant exposure is unknown and expected to be low; observe the infant for any possible adverse effects. Fluconazole, miconazole, and nystatin may be potential alternatives to consider, though 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 ingested or administered drug, health care providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Like other azole antifungals, clotrimazole exerts its effect by altering the fungal cell membrane. Clotrimazole inhibits ergosterol synthesis by interacting with 14-alpha demethylase, a cytochrome P-450 enzyme that is necessary for converting lanosterol to ergosterol, an essential component of the membrane. 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 such as phosphorous-containing compounds and potassium. Clotrimazole does not appear to have the same activity upon human cholesterol synthesis. Other antifungal effects of azole compounds have been proposed and include: inhibition of endogenous respiration, interaction with membrane phospholipids, and inhibition of transformation of yeasts to mycelial forms. Additional mechanisms may involve inhibition of purine uptake and impairment of triglyceride and/or phospholipid biosynthesis.  As a treatment for infectious diarrhea, clotrimazole is thought to interfere with chloride and resulting fluid accumulation in epithelial cells lining the intestine.
     
    Clotrimazole inhibits the movement of calcium and potassium ions across the cell membrane. This action may be responsible for in vitro and animal data demonstrating an antitumor effect of clotrimazole. This action may also explain why clotrimazole prevents the dehydration of the red blood cell in patients with sickle cell disease. Clotrimazole inhibits the loss of intracellular potassium by blocking the ion transport pathway known as the Gardos channel.

    PHARMACOKINETICS

    Clotrimazole is not administered systemically; it is administered via oral/transmucosal lozenges (troches), topically, or intravaginally. Small amounts absorbed are metabolized in the liver and excreted in the bile.

    Oral Route

    Transmucosal Route
    Clotrimazole oral lozenges are used for local treatment and are not significantly bioavailable. Concentrations persisting in saliva are believed to be due to clotrimazole binding to oral mucosa.

    Topical Route

    There is little systemic absorption following clotrimazole topical application.

    Other Route(s)

    Intravaginal Route
    Roughly 5—10% of clotrimazole is absorbed after vaginal use. Fungicidal concentrations persist in the vagina for up to 3 days after application.