Clotrimazole is an imidazole antifungal agent. It is used for the treatment of infections caused by various species of pathogenic dermatophytes, yeasts, and Malassezia furfur. These include ringworm (dermatophytosis), vaginal and oral candidiasis, and tinea infections. The ability of formulations to reach subcutaneous tissues is poor, so clotrimazole is not indicated in the treatment of subcutaneous mycoses. Clotrimazole is marketed in a variety of preparations including vaginal suppositories and cream, topical lotion and cream, topical solution, and lozenges. Clotrimazole was approved by the FDA in 1975. Oral forms of clotrimazole continue to be investigated for the treatment of infectious diarrhea and as a unique treatment to block sickling of erythrocytes in sickle cell disease.
General Administration Information
For storage information, see specific product information within the How Supplied section.
Route-Specific Administration
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.
Dermatologic adverse events, including blistering, burning, edema, erythema, generalized skin irritation, peeling, pruritus, stinging, and urticaria, have been reported following topical application of clotrimazole. Cases of pruritus have also developed in patients receiving oral clotrimazole troches.
Administration of clotrimazole oral troches has been associated with the development of abnormal liver function tests (LFTs). During clinical trials, elevated hepatic enzymes were observed in approximately 15% of patients receiving treatment with clotrimazole oral troches. In the majority of cases, the hepatic enzyme increases were minimal and difficult to distinguish from other therapies and underlying conditions. Health care providers are advised to periodically monitor LFTs in clotrimazole oral troches recipients.
Reports of nausea, vomiting, and unpleasant mouth sensations have been noted following use of clotrimazole oral troches. In one clinical trial of HIV-infected adults, the most common gastrointestinal adverse events were abdominal pain (7%) and nausea (5%); occasionally mild diarrhea was reported.
Use of clotrimazole vaginal products has been associated with mild increases in vaginal pain (burning), vaginal itching, and vaginal irritation. Instruct patients to seek medical attention if these symptoms become severe. Additionally, educate patients to contact their health care provider if symptoms of abdominal pain, fever, foul-smelling vaginal discharge, hives, or skin rash (unspecified) develop as these may be a sign of a more severe illness.
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.
There are no adequate and well-controlled studies of oral clotrimazole in pregnant women. No teratogenic effects have been demonstrated in animal studies at doses up to 200-times the human dose; however, doses of 100-times the adult human dose were embryotoxic in rats and mice. Use oral clotrimazole lozenges during pregnancy only if the potential benefit justifies the potential risk to the fetus. Clotrimazole is very poorly absorbed after dermal or intravaginal administration. In clinical trials, vaginal use during the second and third trimesters in humans has not resulted in any adverse effects; there are no adequate and well-controlled studies of pregnant women during the first trimester. In animal studies, no fetal harm occurred after intravaginal doses up to 100 mg/kg in pregnant rats. Use topical or vaginal clotrimazole during the first trimester of pregnancy only if clearly indicated; however, CDC guidelines recommend 7 days of therapy with a topical azole preparation (including clotrimazole) for the treatment of vulvovaginal candidiasis that occurs during pregnancy.
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.
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.
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.
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.
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.
Per the manufacturer, this drug has been shown to be active against most strains of the following microorganisms either in vitro and/or in clinical infections: Candida albicans, Candida krusei, Candida pseudotropicalis, Candida sp., Epidermophyton floccosum, Malassezia furfur, Microsporum canis, Trichophyton mentagrophytes, Trichophyton rubrum
NOTE: The safety and effectiveness in treating clinical infections due to organisms with in vitro data only have not been established in adequate and well-controlled clinical trials.
For the treatment of cutaneous candidiasis:
Topical dosage (cream):
Adults: Apply to affected and surrounding area(s) twice daily.
Children and Adolescents: Apply to affected and surrounding area(s) twice daily.
For the treatment of oropharyngeal candidiasis (thrush):
Transmucosal dosage:
Adults: 10 mg PO 5 times daily for 7 to 14 days.
Children and Adolescents 3 to 17 years: 10 mg PO 5 times daily for 7 to 14 days.
For oropharyngeal candidiasis prophylaxis in patients immunocompromised by chemotherapy, radiotherapy, or corticosteroid therapy in the treatment of leukemia, solid tumors, or renal transplant:
Transmucosal dosage:
Adults: 10 mg PO 3 times daily for the duration of chemotherapy or until steroids are reduced to maintenance levels.
For the treatment of vulvovaginal candidiasis (VVC):
-for the treatment of uncomplicated VVC:
Intravaginal dosage (1% vaginal cream):
Adults: 1 applicatorful (50 mg clotrimazole/5 g cream) intravaginally at bedtime for 7 to 14 days in pregnant and non-pregnant patients. External application of the cream may also be used if there are extra-vaginal symptoms.
Children and Adolescents 12 to 17 years: 1 applicatorful (50 mg clotrimazole/5 g cream) intravaginally at bedtime for 7 to 14 days in pregnant and non-pregnant patients. External application of the cream may also be used if there are extra-vaginal symptoms.
Intravaginal dosage (2% vaginal cream):
Adults: 1 applicatorful (100 mg clotrimazole/5 g cream) intravaginally at bedtime for 3 days in non-pregnant patients. External application of the cream may also be used if there are extra-vaginal symptoms.
Children and Adolescents 12 to 17 years: 1 applicatorful (100 mg) intravaginally at bedtime for 3 days in non-pregnant patients. External application of the cream may also be used if there are extra-vaginal symptoms.
-for the treatment of severe or recurrent VVC*:
Intravaginal dosage (1% vaginal cream):
Adults: 1 applicatorful (50 mg clotrimazole/5 g cream) intravaginally at bedtime for 7 to 14 days. Subsequent intermittent topical treatment may be considered for maintenance of recurrent VVC as an alternative to fluconazole.
Adolescents: 1 applicatorful (50 mg clotrimazole/5 g cream) intravaginally at bedtime for 7 to 14 days. Subsequent intermittent topical treatment may be considered for maintenance of recurrent VVC as an alternative to fluconazole.
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 tinea versicolor:
Topical dosage:
Adults: Apply to affected skin and surrounding areas twice daily, morning and evening.
Children and Adolescents: Apply to affected skin and surrounding areas twice daily, morning and evening.
Maximum Dosage Limits:
-Adults
50 mg/day PO; 1 applicatorful (50 or 100 mg clotrimazole/5 g cream) intravaginally/day. Maximum dosage not available for topical products.
-Geriatric
50 mg/day PO; 1 applicatorful (50 or 100 mg clotrimazole/5 g cream) intravaginally/day. Maximum dosage not available for topical products.
-Adolescents
50 mg/day PO; 1 applicatorful (50 or 100 mg clotrimazole/5 g cream) intravaginally/day. Maximum dosage not available for topical products.
-Children
12 years: 50 mg/day PO; 1 applicatorful (50 or 100 mg clotrimazole/5 g cream) intravaginally/day. Maximum dosage not available for topical products.
3 to 11 years: 50 mg/day PO. Maximum dosage not available for topical products. Safety and efficacy of other formulations have not been established.
1 to 2 years: Maximum dosage not available for topical products. Safety and efficacy of other formulations have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
*non-FDA-approved indication
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.
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.
-Route-Specific Pharmacokinetics
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.