Clotrimazole

BRAND NAMES

• Lotrimin: A well-known brand, especially recognized for its topical creams and solutions. Lotrimin AF is a popular formulation commonly used to treat athlete’s foot and jock itch.

• Canesten: A widely available brand, particularly in the UK and Australia, offering a range of clotrimazole-based antifungal products for various fungal infections.

• Mycelex: This brand name refers to clotrimazole troches (lozenge-like tablets) used to treat oral thrush, as well as topical forms for skin infections.

• Lotrisone: A combination medication that contains clotrimazole, an antifungal agent, and betamethasone dipropionate, a corticosteroid, designed to treat fungal infections accompanied by inflammation or itching.

MECHANISM OF ACTION

Clotrimazole works by disrupting the fungal cell membrane’s permeability through the inhibition of ergosterol biosynthesis, a key component required for maintaining membrane integrity and function. By blocking the enzyme lanosterol 14-demethylase (CYP51), clotrimazole reduces ergosterol levels, impairing cell membrane formation and leading to dose-dependent inhibition of fungal growth. In addition to its antifungal action, clotrimazole also affects other cellular processes by inhibiting sarcoplasmic reticulum Ca²⁺-ATPase, depleting intracellular calcium, and blocking calcium-dependent potassium and voltage-dependent calcium channels, resulting in pharmacological effects beyond its antimycotic activity.

PHARMACOKINETICS:

Absorption

Clotrimazole has minimal systemic absorption, with its action mainly confined to the site of application. When administered vaginally, only about 3–10% of the dose enters the bloodstream, where it is quickly metabolized in the liver into inactive forms and eliminated mainly through the feces. 

Distribution

Clotrimazole is mainly intended for localized use, with its distribution largely confined to the site of application and very little systemic absorption. Any small amount that does enter the bloodstream is quickly metabolized by the liver and subsequently excreted.

Metabolism

Clotrimazole is metabolized in the liver via the cytochrome P450 system, particularly CYP3A4, with any systemically absorbed portion converted into inactive metabolites

Excretion

Clotrimazole is mainly excreted through the feces, with only a small portion eliminated via urine. Following systemic absorption, it is metabolized in the liver and excreted in the bile, which accounts for most of its elimination. The drug has a half-life of approximately 3.5 to 5 hours.

PHARMACODYNAMICS

Clotrimazole is a broad-spectrum antifungal that inhibits the growth of pathogenic yeasts by altering the permeability of their cell membranes. At concentrations up to 20 mcg/mL, it acts primarily as a fungistatic agent, though at higher concentrations it can be fungicidal in vitro against Candida albicans and other Candida species. While clotrimazole is generally regarded as fungistatic rather than fungicidal, its ability to kill fungi at elevated concentrations demonstrates that this distinction is not absolute. Resistance to clotrimazole, once uncommon, has become increasingly prevalent in certain patient populations.

ADMINISTRATION

Clotrimazole can be applied topically as a cream, solution, or lotion, used intravaginally in the form of creams or tablets/pessaries, or taken as a lozenge (troche) for oral infections. The choice of administration method depends on the type and location of the fungal infection being treated.

DOSAGE AND STRENGTH

Clotrimazole is available in several formulations for different types of fungal infections. Topically, it is offered as creams, lotions, or solutions at strengths of 1% or 2%, typically applied to the affected area once or twice daily for 2–4 weeks. For vaginal infections, clotrimazole comes as creams (1% or 2%) or tablets/pessaries (100 mg, 200 mg, or 500 mg) and is usually administered once daily for 3–7 days, depending on the product and infection severity. For oral thrush, clotrimazole lozenges or troches are available at 10 mg, with one lozenge slowly dissolved in the mouth five times daily for 14 days. The choice of formulation and dosage depends on the location and type of fungal infection being treated.

DRUG INTERACTIONS

Clotrimazole can interact with other medications, primarily due to its effect on liver enzymes, especially CYP3A4. Key points regarding drug interactions include:

1. CYP3A4 Inhibition: Clotrimazole can inhibit CYP3A4, which may increase the blood levels of drugs metabolized by this enzyme, potentially leading to toxicity.

2. Oral Anticoagulants: Co-administration with warfarin or other anticoagulants can increase the risk of bleeding.

3. Statins: Levels of certain statins (e.g., simvastatin, atorvastatin) may rise, increasing the risk of muscle-related side effects.

4. Benzodiazepines and Immunosuppressants: Drugs like midazolam, triazolam, cyclosporine, or tacrolimus may have enhanced effects or toxicity when taken with clotrimazole.

5. Topical vs. Oral Use: Significant systemic interactions are rare with topical or vaginal use due to minimal absorption, but caution is needed with oral or high-dose therapy.

FOOD INTERACTIONS

Clotrimazole does not have any known interactions with food in its topical, vaginal, or oral lozenge forms. Patients can typically eat and drink normally while using the medication, unless otherwise directed by their healthcare provider.

CONTRAINDICATIONS

Clotrimazole is contraindicated primarily in individuals with a known hypersensitivity (allergy) to clotrimazole or any other ingredients in the specific formulation, or to other azole antifungal agents. 

Beyond this, there are specific warnings and contraindications based on the form of the medication (topical, vaginal, or oral lozenge): 

General Contraindications and Warnings

• Systemic Use: Clotrimazole is for topical (skin), intravaginal, or oral transmucosal (lozenge) use only. It is not indicated for systemic (taken internally as a pill) or ophthalmic (eye) administration.

• Serious Allergic Reaction: Do not use if you experience symptoms of a serious allergic reaction, such as swelling of the face, lips, mouth, or throat, difficulty breathing, or hives and a widespread rash.

SIDE EFFECTS

Topical (cream, solution, spray, vaginal preparations):

• Burning or stinging sensation

• Itching or redness

• Skin irritation not present before use

• Peeling or blistering of the skin

• Pimple-like bumps

• Swelling at the application site

Oral (lozenges/troches):

• Nausea and vomiting

• Stomach pain or abdominal cramps

• Itching

• Unpleasant sensations in the mouth

OVER DOSE

Overdose of clotrimazole is generally uncommon, particularly with topical or vaginal use, due to its minimal systemic absorption. Excessive application may increase the risk of local side effects such as irritation, redness, burning, or itching at the site of application. For oral lozenges or troches, taking more than the recommended dose can result in gastrointestinal symptoms, including nausea, vomiting, abdominal pain, or diarrhea. There is no specific antidote for clotrimazole overdose, and management is typically supportive, focusing on relieving symptoms. Patients should discontinue use and seek medical advice if significant adverse effects occur.

TOXICITY

Clotrimazole exhibits low systemic toxicity in humans when applied topically or used as directed in oral lozenges, as only a small amount is absorbed into the bloodstream. Any adverse effects are generally limited to the site of application, with mild reactions such as skin irritation, burning, or itching being the most common.