Clotrimazole

Article Author:
Neil Khatter
Article Editor:
Moien AB Khan
Updated:
7/10/2020 2:49:37 PM
PubMed Link:
Clotrimazole

Indications

Clotrimazole is a synthetic imidazole with a broad spectrum of antimycotic activity.[1] Clotrimazole is an FDA approved drug to treat oral candidiasis, vaginal candidiasis, and dermatomycoses. Clotrimazole is effective in the treatment of skin infections such as athlete's foot, jock itch, ringworm, pityriasis versicolor, intertrigo, and erythrasma.[2][3]

In addition, clotrimazole has some activity against certain Gram-positive bacteria, and at very high concentrations has activity against Trichomonas spp.[4] In adults and children older than 12 years, the FDA has approved the use of clotrimazole in combination with betamethasone propionate (corticosteroid) for the topical treatment of inflammatory tinea due to Epidermophyton floccosum and Trichophyton. However, caution should be exercised, as the use of such combinations can aggravate fungal infections.[5]

Mechanism of Action

Clotrimazole exerts its action primarily by damaging the permeability barrier in the fungal cytoplasmic membrane.[6] Clotrimazole thereby inhibits the biosynthesis of ergosterol in a concentration-dependent manner through the inhibition of demethylation of 14 alpha lanosterol.[7] When ergosterol synthesis becomes inhibited, the cell is no longer able to construct an intact and functional cell membrane.[8] Ergosterol also directly promotes the growth of fungal cells in a hormone-like fashion; therefore, the rapid onset of the above events leads to a dose-dependent inhibition of fungal growth.

Though clotrimazole exerts its anti-fungal action by decreasing the biosynthesis of ergosterol, clotrimazole exerts other different pharmacological actions. These include the inhibition of sarcoplasmic reticulum Ca2+ ATPase, depletion of intracellular calcium, and blocking of calcium-dependent potassium channels and voltage-dependent calcium channels.[9][10] Such action of clotrimazole on different cell targets accounts for other effects of this drug that are separate from its antimycotic activities.[1]

Administration

Clotrimazole is available as topical lotions, powders, oral lozenges, and vaginal inserts/tablets under a variety of tradenames approved by the FDA.

Oral Administration Other Oral Formulations

  • Transmucosal administration
  • Patients should slowly dissolve troches in the mouth, do not chew.

Topical Administration Cream/Ointment/Lotion Formulations

  • Rub cream or solution gently into the cleansed affected skin.
  • Topical preparations should not be used in the eye; or used intravaginally.

Intravaginal Administration

Intravaginal application is only for those clotrimazole products labeled for intravaginal use. Some commercially available preparations contain both intravaginal tablets and vaginal cream in a combination package.  The intravaginal cream may be applied externally to the affected area (vulva) to relieve itching and discomfort.

Use special applicator supplied by the manufacturer.

Instruct patients on proper administration and treatment courses.

Patients should not use tampons, douches, or spermicides during treatment. The patient should also receive instruction to abstain from sexual activity during treatment. Vaginal clotrimazole products may cause damage to condoms, diaphragms, and cervical caps and cause them to fail.

Vaginal dosage (vaginal cream) adult females

  • One applicatorful of 1% cream (50 mg) vaginally for seven days or one applicatorful of 2% cream (100 mg) vaginally for three days, applied at bedtime.
  • External application of the cream may also is an option if there are extra-vaginal symptoms. Guidelines recommend treatment for seven days for pregnant patients and 7 to 14 days for immunocompromised patients.[11][12]

Adolescent females 12 to 17 years

  • Apply one applicatorful of 1% cream (50 mg) vaginally for seven days or one applicatorful of 2% cream (100 mg) vaginally at bedtime for three days. External application of the cream may also are an option if there are extra-vaginal symptoms. Guidelines recommend treatment for seven days for pregnant patients and 7 to 14 days for immunocompromised patients.

For the treatment of oropharyngeal candidiasis (thrush). Transmucosal dosage adults

  • 10 mg PO 5 times daily for 7 to 14 days[13]

Children and Adolescents 3 to 17 years

  • 10 mg PO 5 times daily for 7 to 14 days

For the treatment of tinea versicolor. Topical dosage adults

Adults

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

Children and Adolescents

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

Adverse Effects

The adverse effects of oral formulation include itching, nausea, and vomiting. >10% of patients using the oral formulation may have abnormal liver function tests. For this reason, liver function tests should have periodic monitoring when taking oral clotrimazole (troche). When using clotrimazole to treat vulvovaginal candidiasis, <10% of patients have a vulvar or vaginal burning sensation. Other side effects include rash, hives, blisters, burning, itching, peeling, redness, swelling, pain, or other signs of skin irritation.[14] For topical formulations, it should be used externally and should be discontinued if irritation or sensitivity develops at the site of administration.

Contraindications

Onychomycosis

Topical clotrimazole is not effective for onychomycosis. Fungal nail infections usually require treatment with an oral (systemic) antifungal drug.

Pregnancy

Clotrimazole demonstrates poor absorption after dermal or intravaginal administration. Only topical preparations are recommended in pregnancy.[15] There are inadequate well-controlled human studies with the use of topical or intravaginal clotrimazole during the first trimester of pregnancy clotrimazole should only be used if indicated.[16] However, clinical trials showed intravaginal clotrimazole to be safe in clinical trials during the second and the third trimester of pregnancy and are recommended for use.[17][12] 

Clotrimazole is not known to cross the placenta.[11] FDA classifies clotrimazole as a class C drug in pregnancy risk classification. There are no adequate, well-controlled studies for oral clotrimazole in pregnant women. There have been no teratogenic effects demonstrated after clotrimazole therapy in pregnancy.[17] In animal studies with dosing up to 200 times the human dose, doses of 100 times the adult human dose have been embryotoxic in rats and mice. There are well-controlled studies in humans; hence the use of oral clotrimazole lozenges during pregnancy should only be an option if the potential benefit justifies the potential risk to the fetus.

Breast-feeding

The use of clotrimazole during breast-feeding has not been studied. No data is available about the excretion of clotrimazole in breast milk. Topical clotrimazole poses little risk to nursing infants as topical clotrimazole is not expected to result in significant maternal absorption.[18] Instruct mothers not to apply clotrimazole topically to the breast during times of breast-feeding. The oral troches should be used only when needed, as this may be systemically absorbed. Report to the FDA.if a breast-feeding infant experiences any adverse effects.

Contraceptive devices, menstruation

Patients should abstain from sexual intercourse during the treatment course. With intravaginal clotrimazole preparations, contraceptive failures can occur during the treatment due to the damage of contraceptive devices such as diaphragms, condoms, and cervical caps. Tampon use is not advisable while using clotrimazole during menstruation

Azole antifungals hypersensitivity

Patients with azole antifungals hypersensitivity should avoid using clotrimazole. Hypersensitivity reactions commonly occur due to the components in the formulation present in different clotrimazole preparations.

Ocular exposure, ophthalmic administration

If eye contact with clotrimazole occurs, treat immediately by flushing the affected eye with cool, clean water. Contact an ophthalmologist if eye irritation persists

Drug-Drug Interactions

Clotrimazole therapy may result in a significant rise in tacrolimus levels, leading to tacrolimus-associated toxicities. Hence caution should be exercised.[19]

Monitoring

Clotrimazole is not for systemic administration; it is administered via oral/transmucosal lozenges (troches), either topically or intravaginally. Small quantities 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 appear to be due to clotrimazole binding to the oral mucosa.

Topical Route

There is minimal systemic absorption following topical application of clotrimazole.

Other Route(s)

Intravaginal Route - roughly 5 to 10% of clotrimazole undergoes absorption following vaginal use. Fungicidal concentrations can persist in the vagina for up to 3 days after application

Toxicity

When clotrimazole is applied locally and topically, the toxic effects such as pelvic cramps, hives, skin rash, occasional headache, itching, and irritation of vulva and vagina may be observed. Stop the medication if there are any adverse effects.

Enhancing Healthcare Team Outcomes

With any atypical symptoms, careful evaluation and reassessment should take place before prescribing or dispensing clotrimazole. Vaginal candidal infections can co-exist with other sexually transmitted infections. Hence symptoms such as foul-smelling vaginal discharge, abdominal pain, or fever higher than 100 degrees F may be indicative of another vaginal infection or pelvic inflammatory disease. 

The physician or the nurse practitioner should also counsel the patient on the importance of reading labels to understand the possible side effects and also to avoid drug-related toxicities due to overdosing. Pharmacists should also check for any associated drug interactions and inform the prescriber and the patient of any concerns.


References

[1] Crowley PD,Gallagher HC, Clotrimazole as a pharmaceutical: past, present and future. Journal of applied microbiology. 2014 Sep;     [PubMed PMID: 24863842]
[2] Woo TE,Somayaji R,Haber RM,Parsons L, Diagnosis and Management of Cutaneous Tinea Infections. Advances in skin     [PubMed PMID: 31335433]
[3] Kalra MG,Higgins KE,Kinney BS, Intertrigo and secondary skin infections. American family physician. 2014 Apr 1;     [PubMed PMID: 24695603]
[4] Sawyer PR,Brogden RN,Pinder RM,Speight TM,Avery, Clotrimazole: a review of its antifungal activity and therapeutic efficacy. Drugs. 1975;     [PubMed PMID: 1097234]
[5] Ely JW,Rosenfeld S,Seabury Stone M, Diagnosis and management of tinea infections. American family physician. 2014 Nov 15;     [PubMed PMID: 25403034]
[6] Haller I, Mode of action of clotrimazole: implications for therapy. American journal of obstetrics and gynecology. 1985 Aug 1;     [PubMed PMID: 3895959]
[7] Hitchcock CA,Dickinson K,Brown SB,Evans EG,Adams DJ, Interaction of azole antifungal antibiotics with cytochrome P-450-dependent 14 alpha-sterol demethylase purified from Candida albicans. The Biochemical journal. 1990 Mar 1;     [PubMed PMID: 2180400]
[8] Ghannoum MA,Rice LB, Antifungal agents: mode of action, mechanisms of resistance, and correlation of these mechanisms with bacterial resistance. Clinical microbiology reviews. 1999 Oct;     [PubMed PMID: 10515900]
[9] Bartolommei G,Tadini-Buoninsegni F,Hua S,Moncelli MR,Inesi G,Guidelli R, Clotrimazole inhibits the Ca2 -ATPase (SERCA) by interfering with Ca2 binding and favoring the E2 conformation. The Journal of biological chemistry. 2006 Apr 7;     [PubMed PMID: 16452481]
[10] Jan CR,Tseng CJ,Chou KJ,Chiang HT, Novel effects of clotrimazole on Ca2 signaling in Madin Darby canine kidney cells. Life sciences. 2000;     [PubMed PMID: 10855950]
[11] Sobel JD, Use of antifungal drugs in pregnancy: a focus on safety. Drug safety. 2000 Jul;     [PubMed PMID: 10915033]
[12] Sexually Transmitted Diseases: Summary of 2015 CDC Treatment Guidelines. Journal of the Mississippi State Medical Association. 2015 Dec;     [PubMed PMID: 26975162]
[13] Pappas PG,Kauffman CA,Andes DR,Clancy CJ,Marr KA,Ostrosky-Zeichner L,Reboli AC,Schuster MG,Vazquez JA,Walsh TJ,Zaoutis TE,Sobel JD, Clinical Practice Guideline for the Management of Candidiasis: 2016 Update by the Infectious Diseases Society of America. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2016 Feb 15;     [PubMed PMID: 26679628]
[14] Jelen G,Tennstedt D, Contact dermatitis from topical imidazole antifungals: 15 new cases. Contact dermatitis. 1989 Jul;     [PubMed PMID: 2530045]
[15] van Schalkwyk J,Yudin MH, Vulvovaginitis: screening for and management of trichomoniasis, vulvovaginal candidiasis, and bacterial vaginosis. Journal of obstetrics and gynaecology Canada : JOGC = Journal d'obstetrique et gynecologie du Canada : JOGC. 2015 Mar;     [PubMed PMID: 26001874]
[16] Black RA,Hill DA, Over-the-counter medications in pregnancy. American family physician. 2003 Jun 15;     [PubMed PMID: 12825840]
[17] Czeizel AE,Tóth M,Rockenbauer M, No teratogenic effect after clotrimazole therapy during pregnancy. Epidemiology (Cambridge, Mass.). 1999 Jul;     [PubMed PMID: 10401880]
[18] Spencer JP,Gonzalez LS 3rd,Barnhart DJ, Medications in the breast-feeding mother. American family physician. 2001 Jul 1;     [PubMed PMID: 11456429]
[19] Vasquez E,Pollak R,Benedetti E, Clotrimazole increases tacrolimus blood levels: a drug interaction in kidney transplant patients. Clinical transplantation. 2001 Apr;     [PubMed PMID: 11264634]